Antioxidantes para la subfertilidad masculina
Referencias
Referencias de los estudios incluidos en esta revisión
Referencias de los estudios excluidos de esta revisión
Referencias de los estudios en espera de evaluación
Referencias de los estudios en curso
Referencias adicionales
Referencias de otras versiones publicadas de esta revisión
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Study characteristics | ||
| Methods | Triple‐blinded controlled clinical study Duration of study: from 2018 to 2019 | |
| Participants | Country: Iran Population: infertile men with varicocele, treated after microsurgical repair, N = 60 Mean age: 31.14 ± 5.54 years (alpha lipoic acid group) and 31.89 ± 5.06 years (placebo group) Inclusion criteria: men with uni/ bilateral grade II–III varicocele (confirmed by Doppler duplex ultrasonography if ambiguous on palpation). Exclusion criteria: azoospermia, occupational exposure to heat, radiation, and pesticides, a history of mumps, cryptorchidism, solitary testis, urogenital malignancies/infections, endocrinopathies, Sertoli cell only syndrome, leukocytospermia, scrotal trauma, high fever prior to sampling, recurrent varicocele, severe alcoholism and heavy smoking | |
| Interventions | Alpha lipoic acid 600 mg, oral daily (n = 30) versus Placebo (n = 30) Both treatments were given after microsurgical repair of varicocele. Duration of treatment: 80 days | |
| Outcomes | Semen analysis, protamine deficiency (CMA3 staining), sperm DNA fragmentation with SCSA and TUNEL test, sperm lipid peroxidation with BODIPY staining | |
| Notes | E‐mailed author [email protected] on 15‐03‐2021 requesting information on population. Reply on 23‐03‐2021 and 10‐04‐2021: Quote: “In the first study, the infertile couples, with primary infertility, referred to our center for infertility treatment. Following the consultation with clinical andrologist they were recognized to have varicocele (grade II‐III) and subsequently they were included in our study. Therefore, inclusion was based on infertile couples with varicocele.” | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "The permutation block randomization method was used, applying nine blocks containing eight units (individuals) for the sample size, and a random sequence was built using all the possible permutations." |
| Allocation concealment (selection bias) | Low risk | Quote: "Drug and placebo packaging was identical, and medications were given to the participants according to the randomization sequence, to which the clinician, healthcare providers, individuals in charge of data collection and analysis, and statistician were all blinded. The codes were revealed only after the final analysis of the data." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Drug and placebo packaging was identical, and medications were given to the participants according to the randomization sequence, to which the clinician, healthcare providers, individuals in charge of data collection and analysis, and statistician were all blinded. The codes were revealed only after the final analysis of the data." |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "All samples were provided by masturbation after 3–4 days of abstinence, subsequently liquefied at room temperature, fixed and analysed based on the World Health Organization (WHO) criteria by an instructed operator who was blinded to the type of the treatment given to each donor." |
| Incomplete outcome data (attrition bias) | High risk | Quote: "A total of 60 individuals met the inclusion criteria and were enrolled in the study. Of these, 41 – 22 men who had received placebo and 19 who had received ALA – attended the post‐medication sampling." |
| Selective reporting (reporting bias) | Low risk | All outcomes reported. Protocol available (IRCT20110804007223N10) |
| Study characteristics | ||
| Methods | Randomised single‐centre cross‐over trial Duration of study: 8 months | |
| Participants | Country: Japan Population: infertile men, N = 10 Mean age: 36 years (treatment group age range 24 to 49 years, control age range 30 to 37 years) Inclusion criteria: male infertility (ROS > 5 x 10,000 counts/10,000,000 viable spermatozoa) Exclusion criteria: azoospermia, pyospermia | |
| Interventions | Ethylcysteine 600 mg (n = 5) versus Vitamin E 600 mg (n = 5) Duration of treatment: 3 months, with a one month wash out, then cross‐over for another 3 months. Only data from the first phase were used in data analysis | |
| Outcomes | Sperm parameters, blood serum and seminal plasma levels of ethyl cysteine and vitamin E | |
| Notes | In Japanese. Data extraction translated by Ichiro, a colleague of Samantha Roberts, 29.01.2009 Author contacted 'no further information is available' | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "Patients were divided randomly" |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | No incomplete outcome data |
| Selective reporting (reporting bias) | Unclear risk | Sperm parameters reported. No protocol available. |
| Study characteristics | ||
| Methods | Prospective randomised clinical trial Duration of study: from June 2018 to November 2019, treatment 3 months | |
| Participants | Country: Iraq Population: patients with idiopathic OAT, N = 65 Mean age: 27.24±7.81 years Inclusion criteria: a history of infertility lasting for at least 12 months despite regular unprotected intercourse. OAT was diagnosed by semen analysis results showing abnormal sperm concentration (<15 million/mL), progressive motility (<32%), and total motility (<40%) as defined by the fifth edition of the WHO criteria for semen analysis and abnormal morphology (<30% normal morphology) as defined by the fourth edition of the WHO criteria. Exclusion criteria: azoospermia, varicocele, genital tract infection, cryptorchidism, testicular trauma or scrotal surgery, endocrine disorders, systemic illness including hepatic and renal diseases, smoking, recent intake of antioxidants, and the presence of female factor infertility. | |
| Interventions | Coenzyme Q10 200 mg oral single dose daily (n = 35) versus Coenzyme Q10 400 mg oral single dose daily (n = 30) Duration of treatment: 3 months | |
| Outcomes | Semen analysis, seminal total antioxidant capacity, seminal superoxide dismutase, seminal catalase activity | |
| Notes | Coenzyme Q10 200 mg group is the same as Alahmar 2020 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned. |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned. |
| Blinding of participants and personnel (performance bias) | High risk | Open label (clinicaltrials.gov) |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned. |
| Incomplete outcome data (attrition bias) | Low risk | Numbers in outcome tables match randomised numbers. No lost to follow up mentioned. |
| Selective reporting (reporting bias) | Unclear risk | All outcomes reported. Study protocol published after completion of the study (NCT03850561). |
| Study characteristics | ||
| Methods | Prospective randomised study Duration of study: inclusions from June 2018 to January 2019 | |
| Participants | Country: Iraq Population: men with idiopathic infertility and oligoasthenoteratospermia, N = 70 Mean age: 25.4 ± 7.71 years Inclusion criteria: a history of infertility of at least 12 months despite regular unprotected intercourse. Oligoasthenoteratospermia was diagnosed according to the WHO guidelines (5th edition) by semen analysis showing abnormal sperm concentration (< 15 million/mL), progressive motility (< 32%), and total motility (< 40%). Abnormal morphology (< 30% normal morphology) was assessed by the WHO guidelines (4th edition). Exclusion criteria: azoospermia, varicocele, genital tract infection, cryptorchidism, testicular trauma or scrotal surgery, endocrine disorders like hypothalamic, pituitary, thyroid, diabetes mellitus, adrenal gland and exogenous medications, systemic illness, recent antioxidants intake, smoking, alcohol, relevant medications, and the presence of female factors. | |
| Interventions | Coenzyme Q10 200 mg oral single dose daily (n = 35) versus Selenium 200 mcg oral single dose daily (n = 35) Duration of treatment: 3 months | |
| Outcomes | Sperm parameters, seminal total antioxidant capacity, seminal superoxide dismutase activity, seminal catalase activity | |
| Notes | Power calculation performed, not mentioned on which outcome parameter it is based Coenzyme Q10 (200 mg) group is the same as Alahmar 2019 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "The selected patients who fulfilled the selection criteria were randomly assigned (using simple randomization)". Not clear what is meant with "simple randomization". |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned. |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label (from clinicaltrials.gov) |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned. |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote: "In this prospective randomized study, seventy patients enrolled in the study (four patients did not complete the study)." Not clear to which group patients belonged. |
| Selective reporting (reporting bias) | Low risk | All outcomes reported. Protocol available (NCT03834831). |
| Study characteristics | ||
| Methods | Randomised controlled triple‐blind trial Duration of study: unclear. | |
| Participants | Country: Iran Population: infertile men under fertility treatment aged 20‐45 years old, N = 72 Mean age: 34.86 ± 4.65 (placebo group) and 34.37 ± 4.83 (intervention group) Inclusion criteria: physical and mental health (ascertained based on the records of the case); BMI of 18.5–30; no vitamin D3 supplement consumption during the past 3 months; no use of drugs affecting the levels of vitamin D3 for example glucocorticoids and anticonvulsants; no use of medications that affect spermatogenesis during the past 3 months for example cimetidine, spironolactone; absence of azoospermia in the spermogram, suffering from idiopathic disruptive spermograms, no genital infection or history of taking medication for STDs (sexually transmitted disease) within the past 3 months for example ciprofloxacin and ofloxacin; absence of anatomical abnormalities of the reproductive system such as varicocele; no contact with pesticides, heavy metals and high levels of heat based on their job; no smoking of either cigarette or hookahs during the past 3 months, no use of alcoholic drinks and illicit drugs; serum vitamin D3 levels ≤30 ng/L; Iranian nationality; and fertility of the spouse. Exclusion criteria: no more than one dose of vitamin D3 intake per day during the study, the incidence of complications diagnosed by a urologist and a nutritionist which prevented the continuation of vitamin D3 intake, and the use of other supplements or drugs during the study which were banned in the inclusion criteria. | |
| Interventions | Vitamin D3 50,000 IU tablets once a week for 8 weeks and a maintenance dose of vitamin D3 50,000 once a month in the remaining 4 weeks (n = 35) versus Placebo (oral paraffin) (n = 37) Duration of treatment: 12 weeks | |
| Outcomes | Spermogram, serum hormones, serum vitamin D3 level | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomization was done in form of drawings: the placebo and vitamin D3 containers were identical and coded with numbers from 1 to 72 by a person who was not aware of the randomization process. All containers were placed in an opaque bag. The participants then received the containers that were randomly taken out of the bag." |
| Allocation concealment (selection bias) | Low risk | Quote: "Randomization was done in form of drawings: the placebo and vitamin D3 containers were identical and coded with numbers from 1 to 72 by a person who was not aware of the randomization process. All containers were placed in an opaque bag. The participants then received the containers that were randomly taken out of the bag." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "The subjects, researchers, and statistics specialists were not informed of the contents of the containers (and consequently, were not aware which subjects belonged to which study group) until the end of the data analysis." |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "The subjects, researchers, and statistics specialists were not informed of the contents of the containers (and consequently, were not aware which subjects belonged to which study group) until the end of the data analysis." |
| Incomplete outcome data (attrition bias) | Low risk | Quote: “We randomly assigned 35 patients to the intervention and 37 patients to the control group; however, as described in Fig. 1, five patients in the intervention group and five patients in the control group were excluded.” From figure 1: 2/37 in placebo group and 1/35 in intervention group “did not receive allocated intervention due to failure to see the results of the tests by the doctor”; 3/37 in placebo group and 4/35 in intervention group were lost to follow‐up due to vitamin D3 above 30 ng/L and "Did not complete the tests at the end of the intervention". |
| Selective reporting (reporting bias) | Low risk | All outcomes reported. Protocol available (IRCT2016111830947n1, protocol does not mention vitamin D3 level and free androgen index (FAI) as outcomes). |
| Study characteristics | ||
| Methods | Randomised, single‐blind clinical trial Duration of study: from January 2015 to December 2017, follow‐up 6 months | |
| Participants | Country: Iran Population: infertile patients with VC who underwent sub‐inguinal VCT, N = 64 Mean age: : 30.27 ± 4.67 years (supplement group) and 30.47 ± 6.09 years (placebo group) Inclusion criteria: VC was proven by physical examination in a warm room after applying the Valsalva maneuver in the standing position. The abnormalities in sperm parameters including count, morphology and motility of sperm were evaluated in two separate semen analyses and patients with VC diagnosis and abnormal sperm parameters were planned for VCT. Exclusion criteria: were usage of supplements, vitamins or alcohol, tobacco smoking, addiction to opium or using opium during the follow‐up period, diabetes mellitus, peptic ulcer history, hormonal disorders (based on clinical history and medical examination), chronic or active genitourinary infection (according to the history, medical examination, urine and semen analysis) and previous reaction to folic acid, selenium or vitamin E. As well, patients with missed follow‐up, incorrect usage of drugs, presenting side effects, and delayed complications of VCT including recurrent VC, hydrocele or testicular atrophy were excluded from the study | |
| Interventions | Subinguinal VCT followed by: Folic acid 5 mg + selenium 200 mcg + Vitamin E 400 IU orally daily (n = 32) versus No treatment (n = 32) Duration of treatment: 6 months | |
| Outcomes | Semen analysis | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "In this study, permuted block randomization was used to allocate interventions in a completely random manner to the two treatment groups. Six blocks of 4 were defined. Structure of each block was four‐way combination of two methods of intervention in a perfectly balanced way. Random digits table was used for random assignment of blocks to each group. Additional matching did not take place." |
| Allocation concealment (selection bias) | High risk | Quote: "Accordingly, a list was prepared. Eligible participants were enrolled in the study according to the list, respectively." |
| Blinding of participants and personnel (performance bias) | High risk | Quote: "All subjects were aware of receiving VitE‐Se‐FA supplementation." |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Laboratory specialist and statistic consultant were blinded to treatment assignment." "All laboratory analyses were performed by specialists blinded to study protocol." |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "During the study, four patients (n=4) were excluded due to lost to follow‐up and thus, the data of 60 patients were evaluated." |
| Selective reporting (reporting bias) | Low risk | All outcomes reported. Protocol available (IRCT2015091223855N2). |
| Study characteristics | ||
| Methods | Randomised controlled open‐label trial Duration of the study: unclear | |
| Participants | Country: Egypt Population: men with isolated idiopathic athenozospermia, prior to intrauterine insemination (IUI), N = 60 Mean age: unknown, quote "both treatment groups were homogenous at the time of randomisation regarding the type and duration of infertility" Inclusion criteria: couples with idiopathic athenozospermia (progressive motility < 32%) with normal other seminal criteria and normal infertility workup for female partner Exclusion criteria: unclear | |
| Interventions | N‐acetylcysteine (NAC) 600 mg (n = 30) versus No treatment (n = 30) Duration of treatment: 12 weeks | |
| Outcomes | Sperm concentration, progressive sperm motility, clinical pregnancy rate | |
| Notes | Conference abstract, no full text. Attempted to contact authors 04.02.2014, unable to find e‐mail address. Letter posted 12.02.2014 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "Couples were randomised" Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Quote: "Open‐labelled" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Unclear risk | Unknown ‐ conference abstract |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: from May 2008 to November 2010 | |
| Participants | Country: Iran Population: infertile men with varicocele grade III, N = 160 (only 112 completed the study) Mean age: age range from 20 to 43 (mean ± SD: 29.07 ± 6.8) years Inclusion criteria: the presence of a grade III varicocele assessed by clinical parameters and was confirmed by Doppler ultrasound scanning Exclusion criteria: evidence of leukocytospermia, low testicular volume < 15 mL, congenital urogenital abnormalities and urogenital infections | |
| Interventions | Zinc 66 mg (n = 32) versus Folic acid 5 mg (n = 26) versus Zinc 66 mg + Folic acid 5 mg (n = 29) versus Placebo (n = 25) Duration of treatment: 6 months, after varicocelectomy | |
| Outcomes | Sperm parameters; number, morphology, halo formation rate, motility, forward progressive motility, chromomycin A3 positivity | |
| Notes | Trial registration: IRCT138802261910N1 E‐mailed the author 03.03.2014 ([email protected] / [email protected]). Author replied 06.03.2014 with information included in the ROB table. Author e‐mailed again to ask about pregnancy data and dropouts from which group. The author informed us that Azizollahi 2011 was part of this trial and gave pregnancy and dropout data (there were originally 40 in each group). Quote: "At that time we observed 2 pregnancies in zinc/folic acid group, 1 pregnancy in zinc group, and no pregnancy in placebo and folic acid group. These data were just 6 months after the start of the trial." | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "For randomisation we used a table with 200 numbers (1 to 200). Before the trial we gave each group a number between 1 and 4 and allocated each group into the table. By this method the first, fifth, ninth, 13th and ... patients were allocated into the group 1 and the same manner was applied to the other groups" |
| Allocation concealment (selection bias) | Low risk | Quote: "We used sealed containers with the randomisation number on them. Drugs or placebo were in opaque capsules" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Our study was double blind. Neither the urologist nor the patient or examiner in the lab were aware of the arrangement of the study" |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Our study was double blind. Neither the urologist nor the patient or examiner in the lab were aware of the arrangement of the study" |
| Incomplete outcome data (attrition bias) | Low risk | Information gained from communication with the author explained the dropout numbers |
| Selective reporting (reporting bias) | Low risk | Clinical pregnancy rate data gained from email correspondence with the author. Protocol available. |
| Study characteristics | ||
| Methods | Single‐blind randomised controlled clinical trial Duration of study: from June 2016 to September 2018 | |
| Participants | Country: Iran Population: idiopathic infertile patients, patients with oligo, astheno, terato or oligoasthenoteratospermia, N = 70 Mean age: 37.23 ± 7.09 years (intervention group) and 36.65 ± 6.41 years (placebo group) Inclusion criteria: willingness to participate in the study; not being able to get pregnant after at least one year of regular unprotected sex; abnormal seminal analysis results (confirmed after two semen analyses within 3‐4 week intervals done after the same sexual abstinence periods (3‐5 days)); absence of underlying causes screened according to pre‐testicular, testicular and post‐testicular factors. We started antioxidant treatment for cases with a history of VCT at least 3 months later. Also, VC recurrence was ruled out again. Exclusion criteria: participant’s unwillingness to continue, urogenital infection with antioxidant properties, symptom of an allergy to antioxidant therapy, diagnosis of pre‐testicular, testicular or post‐testicular factors. | |
| Interventions | Selenium 200 mcg + Folic acid 5 mg + Vitamin E 400 IU per day, oral (n = 35) versus Matching placebo (sodium glycolate 100%) 250 mg per day, oral (n = 35) Duration of treatment: 3 months | |
| Outcomes | Sperm parameters | |
| Notes | Patients were also trained to change their lifestyle during the study period | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Patients who met the inclusion criteria were grouped as either intervention (n=35) or placebo group (n=35), through permuted block randomization method." |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Quote: "The placebo group received matching placebo (250 mg per day, oral) for three months." However: "single‐blinded study", unclear if personnel was blinded. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Leaving the study intervention group: n = 5, leaving the study placebo group: n = 3. Reason not mentioned. |
| Selective reporting (reporting bias) | Low risk | All outcomes in methods section reported. Protocol available (IRCT2017012432153N1). Seminal white blood cell count in protocol not reported. Sperm motility index and functional sperm concentration not mentioned in protocol. |
| Study characteristics | ||
| Methods | Randomised double‐blind trial Duration of study: 9 months, follow‐up 3 months | |
| Participants | Country: Italy Population: infertile men with idiopathic asthenozoospermia, N = 60 Mean age: 30 (range 24 to 38) years Inclusion criteria: primary infertility > 2 years after regular intercourse with a fertile woman, 20 to 40 years of age, normal rheologic characteristics, sperm count > 20 x 106 /mL, sperm motility < 50%, normal sperm morphological features > 30%, seminal WBC < 1 x 106 /mL, negative sperm culture and chlamydia and mycoplasma urealyticum, normal serum gonadotropins, T, E2 and PRL, absence of infectious or genital disease, no anatomic abnormalities of the genital tract, absence of systemic diseases or treatment with other drugs within the 3 months before enrolment in the study, absence of smoking, alcohol or recreational drug use or of occupational chemical exposure | |
| Interventions | L‐carnitine 3g (n = 15) versus L‐acetyl carnitine 3g (n = 15) versus L‐carnitine 2g + L‐acetyl carnitine 1g (n = 14) versus Placebo (n = 15) Duration of treatment: 6 months | |
| Outcomes | Sperm parameters | |
| Notes | 2018: email sent on 07.03.2018 to author Balercia ([email protected]: error, found new email: [email protected]) to ask if pregnancy rate were clinical pregnancies, how they were conceived, methods of randomisation and blinding Reply from author on 12.03.2018: Quote: "Pregnancies were clinical pregnancies, spontaneously conceived. I had at this time no data about the weekly progression, but the outcome of all pregnancies was newborn babies." New information added to RoB table. Added data in meta‐analysis on clinical pregnancy, live birth and progressive motility ('Antioxidants vs placebo/no treatment' and 'head to head') | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote (from email): "The randomisation was made by blinded key" |
| Allocation concealment (selection bias) | Low risk | Quote (from email): "sealed opaque envelopes provided by the monitor" (reply email) |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Low risk | Quote (from email): "The randomisation was made by a blinded key, sealed opaque envelopes provided by the monitor, without any access for the researchers (except the hypothesis of adverse events). The key of randomization was available just at the end of the study." (reply email) |
| Incomplete outcome data (attrition bias) | Low risk | 1 withdrawal from the L carnitine 2 g/day + L acetyl carnitine 1 g/day group Quote (from email): "as far your last question, I can confirm the results concerning the drop‐out has not be considered in data analysis" (reply email) Conclusion: no ITT. |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: 10 months, follow‐up 3 months | |
| Participants | Country: Italy Population: infertile men with idiopathic asthenozoospermia, N = 60 Mean age: 32 (range 27 to 32) years Inclusion criteria: age 20 to 40 years, infertility > 2 years, regular sexual intercourse with a potentially fertile female, normal rheologic characteristics (appearance, consistency and liquefaction) of semen and volume and pH in normal range, sperm count > 20 x 106 /mL, sperm motility < 50% (WHO 1999), normal morphology > 30%, seminal WBC < 1 x 106 /mL and a negative sperm culture and chlamydia and Mycoplasma urealyticum (M.urealyticum) detection, normal levels of gonadotropins, absence of genital disease and anatomical abnormalities of the genital tract including variocoele and antibodies, absence of systemic disease or treatment with other drugs within 3 months of being enrolled in the study, absence of smoking, alcohol and drug addiction and exposure to occupational chemicals Exclusion criteria: transient decrease in semen quality during run in and those who had sudden improvement in semen parameters during run in | |
| Interventions | Coenzyme Q10 200 mg (n = 30) versus Placebo (n = 30) Duration of treatment: 6 months | |
| Outcomes | Primary: sperm parameters, variations of coenzyme Q10 and ubiquinol concentrations in seminal plasma and spermatozoa Secondary: pregnancy rate | |
| Notes | 2018: added data on progressive sperm motility Email sent to author ([email protected]) to ask if pregnancies were clinical and if he has live birth rates Reply of author Balercia on 29.03.2018: Quote: "Like the other study, I can confirm that pregnancies were clinical pregnancies, spontaneously conceived, but I had no data about the weekly progression (our outcome was another and we just reported the pregnancies as “collateral” data). All pregnancies gave newborn babies (patient/parent contacted us to share the joyful moment”)". Data added. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | At end of trial the paper mentions ‐ quote: "after opening randomisation list" page 1789 |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Quote: "Semen quality was assessed by the same biologist" Blinding not mentioned. |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "5 patients dropped out of the study", 2 from the treatment group and 3 from the placebo group; this was discovered after opening the randomisation list at the end of the study. ITT was carried out |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised clinical trial Duration of study: unclear, from 2011 to 2013 | |
| Participants | Country: Iran Population: subfertile men with varicocele grade 2‐3, N = 40 Mean age: 30.1 ± 4.4 (range: 22‐45) years Inclusion criteria: age < 45 years, primary infertility, left‐sided varicocele (grade 2‐3) diagnosed by palpation and Doppler duplex ultrasound. Female partner with age < 35 years, normal ovulatory cycles and patent tubes (confirmed by hysterosalpingography or laparoscopy). Exclusion criteria: varicocele grade I, azoospermia, recurrent varicocele, leukocytospermia, urogenital infections, testicular size discrepancy, abnormal hormonal profile, anatomical disorders, Klinefelter’s syndrome, cancer, fever in the 90 days prior to surgery, seminal sperm antibodies, excessive alcohol and drug consumption, previous history of scrotal trauma or surgery, occupational exposure. Female partner with endometriosis, cycle irregularity, or gross anatomical abnormalities | |
| Interventions | N‐acetylcysteine (NAC) 200 mg (n = 20) versus No treatment (n = 20) Duration of treatment: 3 months, directly after varicocelectomy | |
| Outcomes | Sperm parameters, DNA‐fragmentation (TUNEL), protamine deficiency, ROS levels | |
| Notes | Email sent to last author Nasr‐Esfahani (mh.nasr‐[email protected]) on 06.03.2018 to ask about the allocation concealment, sequence generation and definition of pregnancies and method of conceiving. Reply the same day from author (06.03.2018): Quote: "Clinical, spontaneous, pregnancies confirmed by heartbeat." Rest of information in RoB. Authors replied on 04.04.18 answering that data was presented with SEM | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote (from email):"Randomisation done by table. We used computer‐generated or random allocation software and with one block" |
| Allocation concealment (selection bias) | High risk | Quote (from email): "Dr would prescribe the NAC based on randomization table" |
| Blinding of participants and personnel (performance bias) | High risk | No blinding of participants or health care providers (control is no treatment) |
| Blinding of outcome assessment (detection bias) | Low risk | Quote (from email): “All parameters assessed in this study were carried out by a single trained individual unaware of treatment assignment.” "Lab collected the sample based on a table of allocation and handed the sample over to the researcher that carried out the semen analysis and sperm functional tests and was unaware to randomization. A third person called the patients and enquired about pregnancy and whether it was confirmed by heartbeat. Finally, the data gathered and analyzed independently of Dr or researchers" |
| Incomplete outcome data (attrition bias) | High risk | Quote: “In this study, five individuals were excluded from the treatment group due to lack of compliance with NAC use, according to the study protocol" Lack of compliance directly related to treatment, furthermore 25% dropout is high. No ITT. |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised trial Duration of study: unclear | |
| Participants | Country: Italy Population: men with severe idiopathic oligoasthenospermia (sperm concentration < 5000 /μl), N = 42 Mean age: group A and B 35 (range 30 to 40) years, Group C 31 (range 24 to 34) years Inclusion criteria: severe idiopathic oligoasthenospermia (sperm concentration < 5000 /μl) Exclusion criteria: genomic, hormonal or inflammatory diseases | |
| Interventions | Acetyl‐carnitine 1 g + L‐carnitine 2 g + Cinnoxicam (n = 14) versus Acetyl‐carnitine 1 g + L‐carnitine 2 g (n = 14) versus No treatment (n = 14) Duration of treatment: unclear | |
| Outcomes | Sperm parameters | |
| Notes | Conference abstract. No full text or data given. Contacted authors but no reply. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "randomised (1patient = 1 block) analysis of variance" Was this at the time of sequence generation or at data analysis? |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Control is no treatment. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned. |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Unclear risk | Unclear conference abstract |
| Study characteristics | ||
| Methods | Randomised single‐centre,triple‐blinded, clinical trial Duration of study: from January 2011 to August 2014, follow‐up 14 months | |
| Participants | Country: Denmark Population: men part of an infertile couple with impaired semen quality, N = 307 Mean age: 34.8 ± 6.6 years Inclusion criteria: impaired semen quality (determined by WHO criteria) and vitamin D insufficient (25 OHD level #50 nmol/L) Exclusion criteria: serious comorbidities | |
| Interventions | Vitamin D 1400 IU + calcium 500 mg (n = 151) plus vitamin D 300,000 IU oil once orally versus Placebo (n = 156) plus placebo oil once orally Duration of treatment: 150 days (5 months) | |
| Outcomes | Sperm parameters, reproductive hormones, live birth rate | |
| Notes | Power calculation performed. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Infertile men were randomly assigned 1:1 (in blocks of 10) to either placebo or.." "Included men were given a specific trial identity number determined by minimization using the computer program Minim (21). Minimization was done using four groups based on serum 25OHD, sperm concentration, body mass index (BMI) and serum inhibin B" |
| Allocation concealment (selection bias) | Low risk | Quote: "Randomization and manufacture of the high initial dose of vitamin D and placebo were performed by Glostrup Apotek." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "triple‐blinded", "To avoid unblinding, the principal investigator gave the necessary clinical information to the sponsor, who had a list of numbers headed by X or Y. This ensured that both the principal investigator and the sponsor were unaware whether the patient was allocated to the vitamin D plus calcium (active) group or the placebo group (i.e., double blinding)." |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "The trial remained blinded until all biochemical analyses, data handling, and statistical analyses by an independent statistician had been completed (i.e., triple blinding)." |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "Twenty men in the placebo group and 18 in the vitamin D plus calcium group were lost to follow‐up. In total, 269 of 307 men (87.6%) completed the study (Fig. 1). By counting returned tablets, it was evident that one man in the vitamin D group and three in the placebo group were noncompliant; however, all data from these four men were included in all the analyses." Quote: "Twenty‐nine of the 269 men completing the trial reported their partner was pregnant before start of the intervention, whereas five men lost their partner during the study period, leaving 235 with the possibility of effecting a pregnancy." ITT. No explanation given for lost to follow‐up? Therefore unclear risk |
| Selective reporting (reporting bias) | Low risk | All the outcomes from the protocol were reported |
| Study characteristics | ||
| Methods | Randomised double‐blind controlled trial Duration of study: from May 2013 to October 2014 | |
| Participants | Country: Thailand Population: men with abnormal semen analysis, N = 68 Mean age: treatment group (folate only) 26.08 ± 0.76 years, control group 24.7 ± 10.84 years Inclusion criteria: abnormal semen analysis of at least one parameter according to WHO Criteria 2010(13) (concentration < 15 million/ml, motility < 40%, or morphology < 4%), failure of the female partner to conceive after one year of regular unprotected sexual intercourse, no history of tamoxifen and folate allergy Exclusion criteria: use of tamoxifen and folate within three months before recruitment, use of other medicines or vitamin during study period | |
| Interventions | Placebo (n = 15) versus Tamoxifen citrate 20 mg (n = 15) versus Folate 5 mg (n = 15) versus Tamoxifen citrate 20 mg + Folate 5 mg (n = 15) Duration of treatment: 3 months | |
| Outcomes | Sperm parameters, hyaluronan binding assay, hypo‐osmotic swelling test and DNA damage (Comet assay, tail length) | |
| Notes | Only folate and placebo arm included. Email sent to author on 06.03.2018 to Boonyarangkul ([email protected]) to ask about the randomisation process, blinding of outcome assessment, drop‐out rate and funding of trial. Reminder email sent on 22.03.2018 to authors Boonyarangkul and Chiamchanya ([email protected]; [email protected]). No reply to date (19.04.2018) Data used in meta‐analysis, however a sensitivity analysis was performed due to great baseline imbalance between these two groups, especially sperm concentration | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | High risk | Baseline imbalance in concentration control versus folate group |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote: "Eight patients were excluded from the study (three patients declined to participate and five patients stop medication before completing the trial)" Unclear in which groups they participated. Data analysis by the authors was done without the 8 dropouts |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled study Duration of study: from December 2014 to June 2015, follow‐up unclear | |
| Participants | Country: Italy Population: infertile men with oligo‐ and/or astheno‐ and/or teratozoospermia, N = 104, divided in two clusters, 52 patients with varicocele grade I‐III and 52 patients without varicocele Mean age: 32.5 ± 6.7 years Inclusion criteria: age 18 – 50 years, oligo‐, astheno‐ and/or teratozoospermia, with or without varicocele, having a history of infertility for more than 12 months, varicocele patients were not surgically treated before and during the treatment, patients without varicocele were suffering from idiopathic male infertility, no other previous history of diseases affecting fertility. Fertile female partners were required with regular menstrual cycles, age <40 and couples not looking for fertility‐related procedures (IVF/ICSI/IUI) for the next 90 days Exclusion criteria: known hypersensitivity to any of the treatment compounds, history of undescended testes or cancer, endocrine disorders, history of post‐pubertal mumps, genitourinary surgery, obstructive azoospermia or obstructive pathology of the urogenital system, autoimmune disease, cystic fibrosis, history of taking any therapy affecting fertility within last 3 months, excessive consumption of alcohol or regular use of illicit or “recreational” drugs, positive serology for HIV, participants following any special diet, any condition which in the opinion of the investigator might put the participant at risk by participating in this study, participants involved in any other clinical trials | |
| Interventions | Proxeed Plus 2 sachets (n = 52) (l‐carnitine 1000 mg, fumarate 725 mg, acetyl‐l‐carnitine 500 mg, fructose 1000 mg, CoQ10 20 mg, vitamin C 90 mg, zinc 10 mg, folic acid 200 μg and vitamin B12 1.5 μg) versus Placebo 2 sachets (n = 52) Duration of treatment: 6 months | |
| Outcomes | Sperm parameters, pregnancy rate | |
| Notes | Power calculation performed. Email sent to author Busetto ([email protected]) on 07.03.2018 to ask about allocation concealment, blinding of outcome assessment and if the pregnancies were clinical and spontaneous conceived. Reply from author on 07.03.2018: Quote: "All natural pregnancies, spontaneously conceived, confirmed by ultrasound and we had just one abortion." See RoB. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "The block randomisation method was used to randomise subjects into groups resulting in equal sample sizes to ensure a balance across the groups over time." Quote (from email): "Randomisation schedule (nQuery Advisor nTerim 2.0 (2012) program)" |
| Allocation concealment (selection bias) | Low risk | Quote (from email): "The randomization was done by an external company (non‐pharmaceutical)" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote (from email): "We used a double blind system and so researched didn't know anything about the randomization". Placebo used. |
| Blinding of outcome assessment (detection bias) | Low risk | Quote (from email): "An external statistician evaluated everything external" |
| Incomplete outcome data (attrition bias) | Low risk | "Ten patients dropped out from the study leaving 45 patients with varicocele and 49 without varicocele." "As for the ANCOVA, the p‐values refer to the intention‐to‐treat population (ITT). The last observation carried forward (LOCF) method was used for replacing the missing data" Reasons for dropout not mentioned. |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: follow‐up 9 months | |
| Participants | Country: Italy Population: idiopathic men with variocoele or idiopathic oligo‐asthenospermia (OAT), N = 325 Mean age: 34 (range 27 to 40) years Inclusion criteria: men with OAT and with deficiencies in all sperm patterns whose chief complaint was primary couple infertility > 12 months with regular intercourse. Normal sperm appearance, consistency, liquefaction, volume, pH. Female partner without fertility problems. Varicoceles. Exclusion criteria: azoospermia, seminal WBC concentration more than 1000,000/mL, positive urethral chlamydia swab test, oligospermia < 5,000,000 /mL, hormonal alterations, age > 40 years, presence of anti‐sperm antibodies, drug, tobacco or alcohol abuse, ongoing medical treatments, presence of hydrocoele, diabetes,hypertension, x‐ray exposure in previous 8 months, peptic ulcer, unexplained gastric pain, previous hypersensitivity to NSAIDS or carnitines, carnitine metabolism deficiency, bilateral variocoele, prostate abnormalities, previous or current testicular pathology, testicle echographic abnormalities | |
| Interventions | Placebo starch tablets 2 times/day + glycerine suppository (1 every 4 days) (n = 118) versus L‐carnitine 1 x 2 g/day + acetyl‐L‐carnitine 500 x 2 mg/day + glycerine suppository (n = 101) versus L‐carnitine 1x 2 g/day + acetyl‐L‐carnitine 500 x 2 mg/day + glycerine suppository + cinnoxicam suppository 1 x 30 mg (every 4 days) (n = 106) Duration of treatment: 6 months | |
| Outcomes | Primary: sperm parameters Secondary: pregnancy, side effects | |
| Notes | Cinnoxicam is a NSAID, therefore the third arm was not included in meta‐analysis as per protocol Author contacted regarding uneven numbers and missing placebo and continuous data Author replied that raw data were not available due to computer crash Data used from "Idiopathic oligoasthenoteratospermic males" in Table 2, calculated mean+SD from median+IQR. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "casual random tables" |
| Allocation concealment (selection bias) | Low risk | Quote: "drug placebos identical in appearance", "anonymized carnitine and cinnoxicam and glycerine suppository containers; and filled and sealed anonymous color coded boxes", "the color code was disclosed to physicians by pharmacists and by IRB at the end of the research" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "All study personnel and participants were blinded to treatment assignment for the duration of the study" |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "All study personnel and participants were blinded to treatment assignment for the duration of the study" |
| Incomplete outcome data (attrition bias) | High risk | 325 randomised but only 185 accounted for; 55 dropouts from 185 (42%), 53 reasons given for the dropouts |
| Selective reporting (reporting bias) | Unclear risk | Sperm parameters as primary outcome. Intention to collect biochemical pregnancy data as secondary outcome recorded in the methods. No protocol available. |
| Study characteristics | ||
| Methods | Prospective, randomised, controlled study Duration of the study: from 12th of June 2013 to 2016 | |
| Participants | Country: China Population: infertile men with idiopathic OAT, N = 312 Mean age: 30.72 ± 5.2 years Inclusion criteria:
Exclusion criteria:
| |
| Interventions | L‐carnitine 10 ml, oral twice daily (n = 78) versus Coenzyme Q10 20 mg, oral three times daily (n = 78) versus L‐carnitine 10 ml twice daily + coenzyme Q10 20 mg three times daily (n = 78) versus Vitamin B1 (placebo group), dosage and frequency not mentioned (n = 78) Duration of treatment: 3 months | |
| Outcomes | Semen analysis, sperm DNA fragmentation with sperm chromatin dispersion test, sperm acrosome reaction, clinical pregnancy, pregnancy rate, abortion rate | |
| Notes | Article in Chinese, translated by Yue Wang, Yongchuan Gu, and Catherine Jia‐yun Tsai. E‐mailed authors [email protected] on 06‐05‐2021 requesting information on treatment in placebo group and additional outcome for all groups. No reply to date 03‐09‐2021. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Using the computer‐generated random number sequence" |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | High risk | 262/312 completed the study, more drop outs in the intervention groups (16, 15, 15) compared to the vitamin B1 placebo group (4) . Most due to “protocol violation”. More lost to follow up in pregnancy data, not accounted for. |
| Selective reporting (reporting bias) | Unclear risk | All outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised placebo‐controlled trial Duration of study: unclear | |
| Participants | Country: Canada Population: healthy asthenozoospermic men who were patients of an infertility clinic, N = 28 Mean age: placebo group 35.2 years, treatment group 400 mg 38.3 years and treatment group 800 mg 34.4 years Inclusion criteria: asthenozoospermic, sperm motility < 50% of total sperm Exclusion criteria: unclear | |
| Interventions | Docosahexaenoic acid (DHA) 400 mg (n = 9) versus Docosahexaenoic acid (DHA) 800 mg(n = 10) versus Placebo (n = 9) Duration of treatment: 3 months | |
| Outcomes | Sperm parameters | |
| Notes | Data with SEs converted to SDs. Placebo arms split | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "The 28 subjects were randomly assigned to ..." |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | All men randomised were in the analysis, no dropouts. |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: from February 2010 to May 2011 | |
| Participants | Country: Iran Population:infertile men with palpable varicocele grade 2‐3, N = 115 Mean age: 27.6 ± 5.3 years. Inclusion criteria: a palpable varicocele in physical examination and accompanying abnormalities in count, motility, or morphology of sperm in two separate semen analyses (according WHO criteria 1999), age range between 18 and 50, weight between 50 kg and 100 kg, being married Negative inclusion criteria:
Exclusion criteria: missed follow‐up, incorrect usage of the capsules, demonstrating side effects due to vitamin C, commencement of smoking or opium addiction during the follow‐up period, delayed complications of varicocelectomy such as: hydrocele, recurrence of varicocele, and testicular atrophy. | |
| Interventions | Vitamin C 500 mg (n = 46) versus Placebo (n = 69) Duration of treatment: 3 months, after varicocelectomy | |
| Outcomes | Primary: mean sperm count, motility (mean per cent of type A plus type B divided by all motility types) , morphology index (before and after surgery) Secondary: complications of surgery, varicocele grade, age and weight | |
| Notes | Trial registration: IRCT201103042134N2 Email sent to author on 06.03.2018 to dr Kabir ([email protected]) to ask about funding and if the new matched cases were randomised. Reply on 23.03.2018 with all questions answered (see RoB) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Simple randomization method using Excel 2010 software (Microsoft Corporation, Washington, USA) by RANDBETWEEN(0;1000000)”function." Quote: "Five patients from the intervention group and eight patients from controls did not show‐up for the follow‐up visits and were substituted with matched new cases" Reply from authors by email: new cases were randomised |
| Allocation concealment (selection bias) | Low risk | Quote: "The allocation sequence was produced by our statistician and was delivered to our pharmacist. Participants were enrolled by the two executive urologists who were unaware of the results of the allocation table. Then based on the number in the sequence being odd or even each new patient after varicocele surgery was assigned to intervention or placebo group by our pharmacist who supplied the drugs. The ratio of placebo to intervention group was 1.5" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double‐blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Analyzed in a reference laboratory (Sina Laboratory of Arak) by an experienced specialist in pathology and clinical laboratory medicine. Complications of surgery, varicocele grade, age and weight were determined" Reply from authors by email: outcome assessors were blinded |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "Five patients from the intervention group and eight patients from controls did not show‐up for the follow‐up visits and were substituted with matched new cases" Quote (from email): "We were able to have access to some of these drop‐out cases. None of them mentioned disease‐, medication‐, or study‐related causes for loss to follow up. Moving out from the city, changing their mind for participating in the study immediately after accepting to participate, personal secret causes and so on were among some of these reasons." |
| Selective reporting (reporting bias) | Low risk | Quote: "Our secondary complications were rare and they were excluded from the study and only those with clinically cured varicocele were selected for the final analysis. If there was any other unaccounted factor from Ivanissevich method that could affect the results, since both groups had the same type of operation, it would be balanced in the two groups" All the outcomes from the aim of the study and methods were reported. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: 4 weeks | |
| Participants | Country: USA Population: men with sperm agglutination, N = 30 Mean age: range 25 to 45 years Inclusion criteria: sperm agglutination over 25%, negative sperm antibodies, physically normal, no inflammatory disease Exclusion criteria: unclear | |
| Interventions | Ascorbic acid (vitamin C) 1000 mg (n = 10) versus Ascorbic acid (vitamin C) 200 mg (n = 10) versus Placebo (n = 10) Duration of treatment: 3 weeks | |
| Outcomes | Seminal parameters | |
| Notes | Placebo numbers split by 2. Data were given in SE converted to SD New comment 2018: progressive forward motility instead of total motility, data total sperm motility moved to outcome progressive sperm motility | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "By random selection, three groups of 10 subjects each.." |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Each subject was told he was receiving AA and expected improvement in sperm quality" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | No dropouts |
| Selective reporting (reporting bias) | Unclear risk | All specified outcomes were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: from January 2013 to February 2014 | |
| Participants | Country: China Population: men with idiopathic oligoasthenozoospermia (N = 86) Mean age: treatment group 31.5 ± 3.7 years, control group, 32.0 ± 4.1 years Inclusion criteria: 18 to 45‐year‐old male infertility patients, no contraception after marriage and infertility more than 12 months, normal sex life, no abnormal fertility of the women. According to WHO requirements 5 × 106/mL < sperm concentration < 20 × 106/mL, 10% < forward motility sperm percentage < 50%. Exclusion criteria: severe oligozoospermia; dead sperm disease due to erectile dysfunction (ED) or retrograde ejaculation or non‐ejaculation; drug, uncontrolled bacterial prostatitis, fever and other factors affecting fertility; taking drugs that may affect sperm function; congenital malformations, fine tract obstruction, testicular atrophy; tuberculosis, liver, kidney and haematopoietic system of severe primary disease, mental illness. | |
| Interventions | Vitamin D 200 IU + calcium 600 mg chewable tablet once daily (n = 43) versus Vitamin E 100 mg + vitamin C 100 mg three times a day (n = 43) Duration of treatment: 3 months | |
| Outcomes | Sperm parameters, adverse reactions, pregnancy rate | |
| Notes | Email sent on 23.07.2018 to Dr Deng ([email protected]) with questions regarding the randomisation, blinding, outcome data assessment. No reply to date | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "86 patients were randomly divided into treatment group and control group" |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Not blinded: treatment A once daily chewable tablets, treatment B tablets three times a day |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: unclear | |
| Participants | Country: Japan Population: infertile men with oligoasthenospermia, N = 96 Mean age: unclear Inclusion criteria: unclear Exclusion criteria: unclear | |
| Interventions | Vardenafil 10 mg (n = 23) versus Sildenafil 50 mg (n = 25) versus L‐carnitine 1000 mg (n = 26) versus No treatment (n = 22) Duration of treatment: 12 weeks | |
| Outcomes | Seminal parameters | |
| Notes | Excluded were vardenafil (n = 23) and sildenafil (n = 25) Tried multiple times to contact authors for randomisation details and methods. No response. Last contacted in Feburary 2014. E‐mail addresses tried: saitomo@kochi‐u.ac.jp, [email protected] | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Control no treatment. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | No dropouts or lost to follow‐up mentioned. |
| Selective reporting (reporting bias) | Unclear risk | All data points accounted for. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: unclear | |
| Participants | Country: Turkey Population: infertile men with a left‐sided clinical varicocele, N = 56 Mean age: 25.8 ± 4.6 years Inclusion criteria: males diagnosed with a left‐sided clinical varicocele in the urology polyclinic, and for whom subinguinal varicocelectomy was planned Exclusion criteria: the use of alcohol, tobacco or any drugs including vitamins | |
| Interventions | Vitamin E 600 mg (n = 22) versus No treatment (n = 23) Duration of treatment: 12 months, start after varicocelectomy | |
| Outcomes | Sperm parameters, pregnancy rate | |
| Notes | Power calculation performed Email sent to author on 06.03.2018 to dr Ener ([email protected]) to ask about funding, the randomisation process, blinding of outcome assessment and if the reported pregnancies were clinical pregnancies and how they were conceived. Reminder email sent to Ener and Ozayar ([email protected]) on 22.03.2018. No reply to date (19.04.2018), data on pregnancy not used, unknown if clinical | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Control group is no treatment |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote: "A total of 45 patients were included in the study." Quote: "Of note, our cohort was not without limitation. During the study set‐up, the sample size was calculated as 56. However, 11 patients who could not use vitamin E regularly, or did not come to visit in control periods, were excluded from the study." Not clear in which groups drop‐outs belonged |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled triple‐blinded trial Duration of study: 12 weeks | |
| Participants | Country: Iran Population: asthenozoospermic infertile men, N = 50 Mean age: unclear Inclusion criteria: patients interest in contribution aged 20‐45 who have passed at least one year from the date they have decided to have a baby, not to using pregnancy protection methods, affected by idiopathic asthenozoospermia based on WHO criteria, normal serum gonadotropin, testosterone and prolactin values Exclusion criteria: affected by genital system infection or taking drug for the infection during past three months, affected by anatomical anomalies in genital system such as varicocoele, surgical history on testicles and vas deferens | |
| Interventions | Docosahexaenoic acid (DHA) 465 mg + vitamin E 600 IU (n = 25) versus Placebo (n = 25) Duration of treatment: 12 weeks | |
| Outcomes | Sperm parameters, serum fatty acid concentration and sperm membrane fatty acid concentration | |
| Notes | In Arabic, translated. Tried multiple times to contact authors for further study details with no response. Last tried to contact Feburary 2014: [email protected] | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Stratified blocked randomisation |
| Allocation concealment (selection bias) | Low risk | Cans containing capsules marked as A1, A2, B1, B2 and patients, researchers and physician were unaware of the types of drugs |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Cans containing capsules marked as A1, A2, B1, B2 and patients, researchers and physician were unaware of the types of drugs" |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Triple‐blinded" "Cans containing capsules marked as A1, A2, B1, B2 and patients, researchers and physician were unaware of the types of drugs" |
| Incomplete outcome data (attrition bias) | Low risk | Withdrawals and exclusions: Intervention group (3 withdrawals): one man could not refer to the clinic in sixth week, the wife of the other one got pregnant, and another one was excluded because he have not taken more than 10% of the capsules Control group (6 withdrawals): two men could not refer to the clinic in sixth week, one man could not refer to the clinic in 12th week. One man used complementary Coenzyme Q10, and another one was excluded because he have not taken more than 10% of the capsules |
| Selective reporting (reporting bias) | Unclear risk | Sperm parameters reported. No protocol available. |
| Study characteristics | ||
| Methods | RandomiSed, double‐blind, placebo‐controlled trial Duration of study: from April 2013 to May 2015, follow‐up 12 weeks | |
| Participants | Country: Iran Population: idiopathic asthenozoospermic men, N = 180 Mean age: 32.67 ± 4.44 years (DHA + Vitamin E) 32.96 ± 4.17 years (DHA + placebo) 32.80 ± 4.13 years (Vitamin E + placebo) and 33.04 ± 4.08 years (placebo) Inclusion criteria: healthy, voluntary, idiopathic asthenozoospermic men, aged 20–45 years, unwanted childlessness for ≥1 year with the same female partner, normal endocrine function, and with the total number (or concentration) of spermatozoa, and percentage of morphologically normal spermatozoa, equal to or above the lower WHO reference limits Exclusion criteria:
| |
| Interventions | Docosahexaenoic acid (DHA) 465 mg + Vitamin E 600 IU daily, oral, frequency not mentioned (DE, n = 45) versus DHA 465 mg + Vitamin E resembling placebo (medium‐chain triglycerides) (DP, n = 45) versus Vitamin E 600 IU + DHA resembling placebo (medium‐chain triglycerides) (EP, n = 45) versus DHA resembling and Vitamin E resembling placebo (medium‐chain triglycerides) (PP, n = 45) Duration of treatment: 12 weeks | |
| Outcomes | Semen analysis, oxidative stress of seminal plasma (TAC, MDA, free 8 isoprostane), fatty acid analysis of blood serum and sperm membrane, serum vitamin E assay, | |
| Notes | Power calculation provided based on progressive sperm motility. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Computer‐generated randomization" |
| Allocation concealment (selection bias) | Low risk | Quote: "Sealed envelopes opened at enrolment" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Placebo capsules contained medium‐chain triglycerides, were shaped similarly to either DHA or vitamin E capsules" "Double blind" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "Out of 180 participants, 41men in theDE group (91%), 42 men in the DP group (93%), 41 men in the EP group (91%), and 40 men in the PP group (89%) completed the protocol of the study." Figure 2 shows reasons: "discontinued treatment" and "lost to follow‐up". Method of imputation provided. |
| Selective reporting (reporting bias) | Low risk | All outcome reported. Protocol available (NCT01846325). Only sperm motility and count mentioned in protocol. |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: quote: "from January 2010 to July 2014" (information from email) | |
| Participants | Country: Spain Population: men from infertile couples participating in an IVF/ICSI program, N = 113 according to final manuscript and authors, grouped into three categories: normozoospermic, oligozoospermic and asthenozoospermic. Mean age: 37.6 ± 3.8 years Inclusion criteria: duration of infertility of at least 12 months and female age less than 40, as this a mandatory criterion in all Spanish public hospitals Exclusion criteria: quote: "the patient does not sign the informed consent" (information from email) | |
| Interventions | Vitamin E (α‐tocopherol) 400 mg (n = 55, n = 50 completed treatment) versus Placebo (n = 59, n = 51 completed treatment) Duration of treatment: 3 months | |
| Outcomes | Sperm concentration, sperm count, progressive motility (A+B%), pregnancy rate | |
| Notes | Conference abstract. Trial registration: EudraCT 2007‐000960‐25 Email sent to author Exposito ([email protected];) and Matorras ([email protected]) on 20.02.2018 and 07.03.2018 to request full text or data regarding the outcomes in the OAT/azoospermic group Reply from author Matorras on 13.03.2018, received draft of manuscript.("we hope we are able to submit it for publication in two months") and asked some more questions about design/methods and data (means with SD) on the subgroup of men with male factor (so without the normospermic men). Reply on 24.03.2018: see RoB. Data not usable in meta‐analysis due to the fact that is data for all the 3 categories (normozoospermic, oligozoospermic and asthenozoospermic) together. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote (from email): "To maintain the blindness to the investigator and the subject, the investigator receives the information of the treatment allocation number from the computer system." Computer randomisation |
| Allocation concealment (selection bias) | Low risk | Quote (from email): "To maintain the blindness to the investigator and the subject, the investigator receives the information of the treatment allocation number from the computer system. The subject receives his study medication package from the study site of the institution." Investigator receives a number belonging to a study medication package |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double‐blind". Placebo used. Quote (from email): "All the active and placebo capsules are identical in appearance, shape, smell and taste" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Quote (from email): "At the end 101 couples completed the treatment (placebo group N=51 and vitamin E group N=50). Nine couples withdrew from this study before completing their 3 months of treatment due to IVF cycle cancelled or a lack of continuing interest(8%) (five of the placebo group and four of the vitamin E group)(N=104) .Three couples achieved spontaneous pregnancy at 50, 60 and 90 days of treatment;two of them belonged to placebo group and the other belonged to the vitamin E group (2.7%)" Quote (from email): "The data analysis was done with the people who completed the study (n=101)" No ITT. Reasons for drop‐out well explained and balanced. |
| Selective reporting (reporting bias) | Low risk | All the outcomes from the aim of the study and methods were reported |
| Study characteristics | ||
| Methods | Randomised controlled, intention‐to‐treat, single‐centre study. Duration of study: 12 months, from January 2003 to June 2005 | |
| Participants | Country: Italy Population: men with persistent oligospermia (5 to 20 m/ml), N = 42 Mean age: treatment group 32 (27.5 to 35.5) years, control 33 (23 to 36) years Inclusion criteria: having performed a retrograde embolization with concomitant oligospermia, persistent oligospermia and infertility > 12 months Exclusion criteria: smoking, alcohol consumption, taking any fertility drugs within 3 months prior to the study, serious medical or psychiatric condition, abnormal hormonal profile, sperm infection | |
| Interventions | N‐acetylcysteine (NAC) 600 mg + vitamins‐minerals (vitamin C, vitamin E, vitamin A, thiamine, riboflavin, pyridoxin, nicotinamide, pantothenate, biotin, cyanocobalamin, ergocalciferol, calcium, magnesium, phosphate, iron, manganese, copper, zinc) (n = 20) versus No treatment (n = 22) Duration of treatment: 90 days | |
| Outcomes | Primary: seminal parameters Secondary: pregnancy (undefined) and adverse effects | |
| Notes | Power calculation performed. Attempted to contact author regarding median data. No response yet (2014) 2018: motility reported as WHO Class A motile sperm instead of total motility, added to table 'data not usable for meta‐analysis' | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Subjects were randomly assigned to either antioxidant therapy or no medical therapy. Randomisation number was assigned by random allocation software using a block randomisation design" |
| Allocation concealment (selection bias) | Low risk | Quote: "All steps of randomisation process were performed blindly in the pharmacy of our hospital" |
| Blinding of participants and personnel (performance bias) | High risk | Control is no treatment |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "All ejaculate analysis was analyzed blindly with respect to the treatment groups" |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "intention to treat" |
| Selective reporting (reporting bias) | Unclear risk | No protocol available. |
| Study characteristics | ||
| Methods | 'Open perspective randomised' study Duration of study: unclear | |
| Participants | Country: Russia Population: men with varicocele, N = 114 Mean age: 34.1 ± 12.1 years Inclusion criteria: aged 25‐45 years, participants’ wives had not become pregnant in the last 12 months or more, despite regular unprotected sexual intercourse between the partners; oligo‐,asteno‐ and/or teratozoospermia, varicocele evident upon palpation confirmed by Doppler ultrasonography of scrotum blood vessels, normal constitutional development as determined by the physical exam Exclusion criteria: previously established genetic causes of infertility (Klinefelter syndrome, micro deletions AZF, CFTR), azoospermia, clinical and laboratory evidence for inflammatory changes to sex glands, pyospermia, follicle‐stimulating hormone (FSH) overproduction, immunologic infertility (MAR‐test IgG > 10%), pronounces somatic pathology, psychosexual or ejaculatory disfunction | |
| Interventions | SpermActin‐forte (acetyl‐L‐carnitine, L‐carnitine fumarate and alpha‐lipoic acid) (n = 38) versus SpermActin‐forte + Vitamin complex 'Man's formula' (n = 38) versus No treatment (n = 38) Duration of treatment: 3 months, after microsurgical varicocelectomy (MVE) | |
| Outcomes | Sperm parameters, DNA fragmentation, side effects | |
| Notes | Article in Russian, translated by Andrew Dubovyi. Ethical approval and obtaining informed consent not mentioned in text. Email sent to author Ovchinnikov ([email protected]) on 29.03.2018 to ask about the randomisation process, blinding of outcome assessors, drop‐outs and which side‐effects they aimed for ("No side effects related to the pharmacological treatment were observed."). Reply on 11.04.18, see RoB. Data on adverse events used. Data on sperm parameters (median+IQR) adjusted to mean+SD. Placebo arm split. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Using adaptive dynamic randomization with stratification patients were assigned to one of three groups of 38 subjects" Quote (from email): "It was computer randomized block design" |
| Allocation concealment (selection bias) | Unclear risk | Quote (from email): "Randomization was done by the researchers" |
| Blinding of participants and personnel (performance bias) | High risk | Control is no treatment, furthermore group A uses 1 tablet, group B uses 2 tablets Quote (from email):"The study was not blinded" |
| Blinding of outcome assessment (detection bias) | Low risk | Quote (from email): question was the person who assessed the outcomes blinded? "Yes" |
| Incomplete outcome data (attrition bias) | Low risk | Quote (from email):"There were no lost to follow‐up participants (the samples were small)" |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. Quote (from email) when asking about which adverse events were aimed for: "We have not registered any side effects, including gastro‐intestinal, urological, neurological complications, etc" |
| Study characteristics | ||
| Methods | Open‐label, prospective, randomised placebo‐controlled study Duration of study: unclear | |
| Participants | Country: Russia Population: infertile men aged 25‐45 years with an increased level of sperm DNA fragmentation and oxidative stress, N = 80 Mean age: 34.9 years Inclusion criteria:
Exclusion criteria: • the presence of active inflammatory processes; • laboratory signs of inflammatory changes in the accessory gonads; • established genetic causes of infertility (Klinefelter's syndrome, AZF microdeletion, CFTR); • cryptozoospermia; • azoospermia; • necrozoospermia; • pyospermia; • hypergonadotropic and hypogonadotropic hypogonadism; • varicocele; • the presence of an immune form of infertility (MAR‐test lgG > 50%); • severe somatic pathology; • psychosexual and ejaculatory dysfunction. | |
| Interventions | Spermactin Forte (dosage not described in report; l‐carnitine fumarate 2000 mg + acetyl‐L‐carnitine 1000 mg + alpha‐lipoic acid 100 mg + ascorbic acid 100 mg), oral once daily (n = 60) versus Placebo (n = 20) Duration of treatment: 180 days | |
| Outcomes | Spermiogram, ROS concentration, sperm DNA fragmentation with TUNEL assay, pregnancy rate, live birth rate | |
| Notes | Article in Russian, translated by Alyona Oryshchuk. E‐mailed author Dr. Ovchinnikov [email protected] to request information. Reply on 18‐05‐2021 concerning RoB: "Investigators and outcome assessors were blinded". "No patients were lost to follow up or withdrawn". Reply on 31‐05‐2021 with information on pregnancies: "Spontaneous pregnancies. It is correct that the one case in group A was a clinical pregnancy (7‐8 weeks) (with positive heartbeat on ultrasound). It is correct that the one case in group B was a clinical pregnancy (5‐6 weeks) (with positive heartbeat on ultrasound). It is correct that the one case in group B (anembryonic pregnancy) was a biochemical pregnancy (no discernible heartbeat seen)." Results of sperm parameters expressed as median+IQR, data adjusted to mean+SD for meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: “Adaptive dynamic randomisation”, from e‐mail: “computer randomised block design” |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: “double‐blind”, see e‐mail quote |
| Blinding of outcome assessment (detection bias) | Low risk | See e‐mail quote |
| Incomplete outcome data (attrition bias) | Low risk | See e‐mail quote |
| Selective reporting (reporting bias) | Unclear risk | All outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Prospective, randomised, double‐blind and placebo‐controlled intervention study Duration of study: unclear | |
| Participants | Country: Spain Population: men between 18 and 50 years with a previous history of infertility of at least one year, N = 60 Mean age: unclear Inclusion criteria: men aged between 18 and 50 years with a previous history of infertility of at least one year and whose semen analysis met the following criteria: (a) sperm count greater than 10 million per mL; (b) sperm progressive motility of less than 60%; and (c) normal sperm morphology of less than 2% Exclusion criteria: not mentioned | |
| Interventions | Docosahexaenoic acid (DHA) 0.5 g oral daily dose (n = 15) versus DHA 1 g oral daily dose (n = 15) versus DHA 2 g oral daily dose (n = 15) versus Placebo: 0.5 daily dose of primrose oil (n = 15) Duration of treatment: 3 months | |
| Outcomes | Semen analysis, ROS, mitochondrial membrane potential (MMP), lipid peroxidation, DNA fragmentation with TUNEL assay | |
| Notes | E‐mailed author ([email protected]) on 10‐03‐2021 and 04‐05‐2021 to request SD of different results. No reply to date (03‐09‐2021). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "The randomization list was generated using Randomization.com [http://www. randomization.com] with randomly permuted blocks of 60 subjects randomized into four blocks." |
| Allocation concealment (selection bias) | Low risk | Quote: "The list was kept in a locked drawer in the administration office, to which the clinical staff who enrolled the participants in the study had no access; group allocation was requested by telephone." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Physicians and patients were blinded to the assigned study intervention." |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "Fig 1. No patients were lost to follow‐up, and no patients discontinued the intervention. The outcome data for all patients who were randomized were included in the final data analysis." |
| Selective reporting (reporting bias) | Low risk | All outcomes reported. Protocol available (NCT02889341). |
| Study characteristics | ||
| Methods | Randomised placebo‐controlled double‐blind parallel three‐arm multicentre trial Duration of study: follow‐up 6 months | |
| Participants | Country: India Population: Idiopathic oligoasthenozoospermia men, N = 138 (N = 125 completed the study) Mean age: 30.74 (range 24‐45) years Inclusion criteria: age 21‐50 years, infertility >1 year, sperm count less than 15 million/mL, sperm total motility < 40%, no history of taking therapy for infertility, no history of OAT, regular sexual intercourse with a potentially normal fertile female, willing to sign informed consent and likely to be available for all visits during follow‐up period Exclusion criteria: primary testicular disease, any organic cause for infertility including varicocele, prostate‐vesiculo‐epididymitis,genital infectious disease,planning for any other ART during study period, serum follicle‐stimulating hormone FSH >15 mIU/mL, abnormal serum levels of LH, testosterone, estradiol and prolactin, presence of antispermatozoa antibodies, severe oligospermia (< 2 million sperm/mL), azoospermia, seminal WBCs more than 1 x 106 mL, major hepatic and renal disease, myopathy, history of allergy to any ingredient of the formulation, not likely to be available for follow‐up, have participated in another clinical trial in the past 3 months, female partners with anatomic or physiological alterations causing subfertility | |
| Interventions | Fixed doses combination (FDC) 2 tablets (coenzyme Q10 50 mg + L‐carnitine 500 mg + lycopene 2.5 mg + zinc 12.5 mg) (n = 46) versus Fixed doses combination (FDC) 1 tablet + 1 Placebo tablet (n = 43) versus Placebo 2 tablets (n = 36) Duration of treatment: 180 days | |
| Outcomes | Primary: improvement in sperm count, total sperm motility (90 and 180 days) Secondary: pregnancy rate, side effects | |
| Notes | Email sent on 06.03.2018 to dr Zaveri ([email protected]) to ask about the pregnancies (clinical? How conceived?), the randomisation process, blinding of outcome assessment and allocation of 13 dropouts. Reminder email sent on 27.03.2018. Reply on 30.03.2018 from author; see text in RoB. Pregnancy data not used, distribution in groups unknown, only reply from author quote: "No pregnancies were not followed up to stage 12 weeks. So no pregnancy was clinical. 9 pregnancies were conceived through ART 3 Conceived spontaneous" Numbers from text: 6 in FDC 2, 7 in FDC 1, 2 in Placebo. Pregnancy data used in table 1. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote (from email): "Procedures were computer" |
| Allocation concealment (selection bias) | Low risk | Quote: "Centrally randomised to one of three treatment arms (arm 1‐3) in a 1:1:1 ratio" Central randomisation |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double‐blinded". Placebo used |
| Blinding of outcome assessment (detection bias) | Low risk | Quote (from email): "Yes outcome assessment was blinded " |
| Incomplete outcome data (attrition bias) | Low risk | 13 lost to follow‐up (dropout), quote: "at different stage during the study" Asked by email in which groups or what reasons. Quote (reply email): "5 in paternia BID, 6 in placebo, 2 in paternia BID" Data‐analysis only on the 125 who completed the study. Low risk because dropouts accounted for. |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. |
| Study characteristics | ||
| Methods | Prospective observational study Duration of study: from March 2013 to April 2015 | |
| Participants | Country: India Population: men with idiopathic male infertility with high reactive oxygen species (ROS), N = 175 Inclusion criteria: unclear Exclusion criteria: unclear | |
| Interventions | Diet rich in antioxidants and lifestyle changes (n = 80) versus Combined oral antioxidant (n = 95) versus Placebo (n = 75) Duration of treatment: unclear | |
| Outcomes | Semen parameters, antioxidant concentrations (CoQ‐10, L‐carnitine, zinc), plasma total antioxidant capacity (TAC), total glutathione (GSH), sperm DNA fragmentation (TUNEL assay) | |
| Notes | Conference abstract only. Not clear if it is a randomised clinical trial. Email sent to authors Goswami and Chakravarty ([email protected]; [email protected]) on 20.02.2018 and 06.03.2018. Email sent to authors again on 30.06.2021, reply: "yes it was a randomised controlled trial among Infertile male without any reasonable or specific cause and were waiting for IUI or IVF treatment cycle." Requested clarification on randomisation of placebo group ("maintained in parallel") and information on study design, RoB and study results on 01.07.2021. No reply to date (03‐09‐2021). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | Quote: "A placebo‐controlled group was maintained in parallel", might even be non‐randomised. |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned. |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned. |
| Incomplete outcome data (attrition bias) | Unclear risk | Number of drop‐outs or lost to follow up not mentioned. |
| Selective reporting (reporting bias) | Unclear risk | Conference abstract. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled double‐blind trial Duration of study: unclear | |
| Participants | Country: France Population: infertile males, N = 64 Mean age: unclear Inclusion criteria: TUNEL assay showed a presence of fragmented DNA ≥ 15% of ejaculated spermatozoa Exclusion criteria: variocele, genitourinary inflammation, infection, smoking | |
| Interventions | Vitamin C 1000 mg + Vitamin E 1000 mg (n = 32) versus Placebo (n = 32) Duration of treatment: 2 months | |
| Outcomes | Sperm parameters | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "The study was double‐blinded with both the authors and the patients unaware of which of the patients was in the treatment or control arm of the study" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | No dropouts |
| Selective reporting (reporting bias) | Unclear risk | No protocol available. |
| Study characteristics | ||
| Methods | Randomised triple‐blind placebo‐controlled trial | |
| Participants | Country: Iran Population: men with idiopathic asthenozoospermia, N = 48 Mean age: 33.56 ± 5.07 years Inclusion criteria: unwilling childlessness at least 24 months in duration with a female partner, no medical condition that could account for infertility, normal fertile female partner according to investigations, all patients were needed to have stopped all medical therapy R12 weeks before study initiation Exclusion criteria: the history of epididymo‐orchitis, prostatitis, genital trauma, testicular torsion, inguinal or genital surgery, urinary tract infection, or previous hormonal therapy, another genital disease (cryptorchidism, current genital inflammation or varicocele), severe general or central nervous system disease and endocrinopathy, use of cytotoxic drugs, immunosuppressants, anticonvulsants, androgens, or antiandrogens, recent history of sexually transmitted infection, psychologic or physiologic abnormalities that would impair sexual performance or the ability to provide semen samples, drug or alcohol abuse, hepatobiliary disease, significant renal insufficiency, occupational and environmental subjections to possible reproductive toxins, BMI of >30 kg/m2, participation in another investigational study, unlikely availability for follow‐up | |
| Interventions | Alpha‐lipoic acid (ALA) 600 mg (n = 23) versus Placebo (n = 21) Duration of treatment: 12 weeks | |
| Outcomes | Sperm parameters, markers of oxidative stress (total antioxidant capacity (TAC) and malondialdehyde (MDA)), side effects | |
| Notes | Email sent to last author Haidari ([email protected]) on 06.03.2018 to ask what side effects they aimed for and reasons for lost to follow‐up. Reminder email sent on 22.03.2018 to Haidari and Dadfar ([email protected]). No reply to date (19.04.2018). E‐mail sent to both authors to ask about small SDs, reply on 18.07.2021 that this was "due to the accuracy in sampling and selecting of infertile subjects and also accurate matching when grouping patients". | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Each eligible patient received a randomization number which was determined by a computer‐generated schedule. Then a randomization table was generated by the method of random permuted blocks" |
| Allocation concealment (selection bias) | Low risk | Quote: "Persons who were operationally independent from the study investigator performed the study randomization" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "The investigator, clinician prescriber, and patients were blinded to the treatment condition" |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Patients'data collected during this trial were kept confidential and locked in a secure area. Randomization codes of the study were opened only after all participants had completed the study protocol" |
| Incomplete outcome data (attrition bias) | Low risk | N = 48, quote: "44 completed the study, rest lost to follow‐up: data analysis with 23 of 24 in ALA group, 21 of 24 in placebo group" Reasons lost to follow‐up not mentioned. |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: from January 2013 to June 2014 | |
| Participants | Country: Iraq Population: infertile men with idiopathic oligozoospermia (OA), N = 128 (in flow chart "182") Mean age: 37.54 ± 2.46 years Inclusion criteria: repeated exhibition of OA without detectable cause (idiopathic OA) Exclusion criteria: leukocytospermia, altered testicular volume of a minimum of 20 ml as depicted by ultrasonography, varicocele as detected by clinical examination and ultrasonography, abnormal FSH levels, couples with combined male and female factors | |
| Interventions | Tamoxifen 20 mg (n = 45) versus L‐carnitine 1000 mg (n = 20) versus Tamoxifen 20 mg + L‐carnitine 1000 mg (n = 34) versus Placebo (n = 29) Duration of treatment: 3 to 6 months followed by ICSI | |
| Outcomes | Sperm parameters, fertility and pregnancy outcome following ICSI | |
| Notes | Email sent to author Haje on 06.03.2018 ([email protected]) to ask about randomisation, dropouts, amount of pregnancies (instead of %) and if they were clinical, and to provide raw data specified for amount of months treatment used? Reminder email sent on 22.03.2018. No reply to date (19.04.2018). Data not usable: range of treatment 3 ‐ 6 months, not specified as separates, pregnancy in % instead of numbers, unknown if clinical or not. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Dropouts not mentioned. Furthermore baseline characteristics not mentioned |
| Selective reporting (reporting bias) | Unclear risk | Primary and secondary outcomes are mentioned and provided. No protocol available. |
| Study characteristics | ||
| Methods | Double‐blinded, randomised, controlled trial Duration of study: from March 2014 to September 2017, follow‐up 90 days | |
| Participants | Country: China Population: men suffering oligozoospermia, N = 769 Mean age: 31.6 ± 2.3 years Inclusion criteria: oligozoospermia was demonstrated in at least 3 semen analyses performed within a period of 6 months; infertility for at least 1 year; no medical treatment in the previous 6 months; no presence of varicocele; no smoking; no obesity; no infection of the accessory sex glands; no identifiable cytogenetic abnormalities. All of the wives received a complete infertility workup to rule out female factors. All partners ovulated regularly detected by transvaginal ultrasound scanning; no anatomic abnormalities detected by ultrasound scanning; no abnormal fallopian tube anatomy detected by hysterosalpingography. Exclusion criteria: not mentioned. | |
| Interventions | Folic acid 0.8 mg orally per day (n = unclear) versus Placebo (starch‐filled capsules), dose and frequency not mentioned (n = unclear) Duration of treatment: 3 months | |
| Outcomes | Evaluation of MTHFR polymorphism to divide patients in genotype subgroups, semen analysis, MDA, sperm DNA fragmentation with TUNEL assay, biochemical pregnancy, clinical pregnancy, spontaneous pregnancy or with use or ART treatment, abortions, live birth, gestational week at birth | |
| Notes | Outcomes reported for specific MTHFR polymorphism groups only. E‐mailed author 06‐04‐2021 and 04‐05‐2021 to request data for all groups. No reply to date (03‐09‐2021). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "according to simple randomization method using EXCEL 2010 software" |
| Allocation concealment (selection bias) | Low risk | Quote: "The statistician produced the allocation sequence and delivered it to the pharmacist. Specialist in this study was not known of the results of allocation table." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double‐blind" "Patients in folic acid treatment group received folic acid at the dose of 0.8 mg/day for 3 months, and the patients serving as the placebo group received starchfilled capsules for 3 months." |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | High risk | Semen volume, abortions and gestational age at birth are not reported. Not all polymorphism group are reported. Protocol not available. |
| Study characteristics | ||
| Methods | Open‐label randomised, controlled trial Duration of study: from February 2013 to October 2019 | |
| Participants | Country: India Population: couples who were scheduled for ART owing to male factor subfertility, N = 200 Mean age: 37.28 ± 3.9 years (intervention group) and 37.48 ± 4.9 (control group) Inclusion criteria: abnormal semen analysis was defined as follows: mild oligozoospermia with a sperm concentration of more than 5 million/mL and less than 15 million/mL, and/or asthenozoospermia with sperm motility more than 25% and less than 32%, and/or teratozoospermia with sperm morphology of less than 4%. Exclusion criteria: ‐ Couples in whom the female partner was over 37 years of age or those who were diagnosed with moderate or severe endometriosis. ‐ Couples with a male partner whose semen analysis was suggestive of severe male factor, defined as a sperm concentration <5 million/mL. ‐ Those who had taken oral antioxidants in the past 3 months. | |
| Interventions | Antioxidant consisting of vitamin C 500 mg + vitamin E 400 mg + zinc 140 mg once daily orally prior to ART treatment (ICSI) (n = 100) versus No treatment prior to ART treatment (ICSI) (n = 100) Duration of treatment: 3 months | |
| Outcomes | Clinical pregnancy rate, miscarriage rate, fertilisation rate, ongoing pregnancy rate, live birth rate per embryo transfer, semen parameters | |
| Notes | Data of semen parameters adjusted to mean+SD for meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomization was performed using computer‐generated random numbers at the time of ART booking." |
| Allocation concealment (selection bias) | Low risk | Quote: "Allocation concealment was achieved using opaque sealed envelopes which were sequentially numbered and contained the group code." |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label, no placebo control group |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | High risk | Quote: "A total of 65 couples (36 in antioxidant and 29 in the control arm) did not undergo ART, deviated from the protocol or had a cancellation of the treatment cycle before oocyte retrieval or embryo transfer." "The overall attrition rate was high (32.5%, 65/200)." |
| Selective reporting (reporting bias) | High risk | Certain secondary outcome parameters are only presented as per protocol analysis. Protocol available (CTRI/2013/02/003431) |
| Study characteristics | ||
| Methods | Randomised double‐blinded placebo cross‐over trial Duration of study: unclear | |
| Participants | Country: UK Population: men with high levels of reactive oxygen species (ROS) of a couple undergoing IVF, N = 30 Mean age: unclear, median age 32 years Inclusion criteria: attending fertility clinic, high levels of ROS in semen. Female partner has patent tubes and is ovulating | |
| Interventions | Vitamin E 600 mg (n = 15) versus Placebo (n = 15) Duration of treatment: 3 months, 1 month wash‐out, 3 more months after cross‐over | |
| Outcomes | Primary outcomes: sperm parameters Secondary outcomes: adverse effects, live birth | |
| Notes | Power calculation performed. Attempted to contact author regarding median difference data, no response as yet (2014). Only first phase data used in analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "The study was a randomised double blind placebo controlled trial". "The randomisation was performed by the manufacturer" |
| Allocation concealment (selection bias) | Unclear risk | Quote: "The randomisation was performed by the manufacturer" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "the code was blind for the researcher and patients. The code was broken at the end of the trial" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote: "30 patients completed the study over 2 years" Changed to unclear risk in 2018 (was low risk); not reported how many were randomised to start with, or how many drop‐outs |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported as stated in the methods section. No protocol available. |
| Study characteristics | ||
| Methods | Single‐centre randomised trial Duration of the study: from January 2016 to January 2018, follow‐up 6 months | |
| Participants | Country: Turkey Population: infertile patients with low sperm counts (oligo‐ and/or astheno‐ and/ or teratozoospermia) and grade I‐III varicocele, N = 93 Mean age: 32.86 ± 3.14 years (intervention group) and 32.18 ± 2.44 years (control group) Inclusion criteria: male patients older than 18 years and with infertility history ≥ 12 months; the participants’ spouses were younger than 35 years old; their hormone profiles and menstrual cycles were regular; they had no known diseases that might cause infertility. Exclusion criteria: patients who had previously undergone a genitourinary system and/or varicocele surgery; had idiopathic infertility; had a disease affecting fertility and received a medical treatment affecting fertility for the previous 3 months; had a history of undescended testis, testicular cancer, testicular trauma, post‐pubertal mumps and endocrine disorder, or an obstructive urogenital disease; who followed a fertility‐specific diet; who ingested excessive alcohol, cigarettes, drugs, opioids, or hallucinogens; whose HIV serology was positive; or who had an acute infection and another identified cause of infertility were not included in the study. | |
| Interventions | Oral antioxidant supplement containing 1 g of L‐carnitine fumarate, 0.5 g of Acetyl‐Lcarnitine, 1 g of fructose, 50 mg of citric acid, 90 mg of vitamin C, 10 mg of zinc, 200 mcg of folic acid, 50 mcg of selenium, 20 mg of coenzyme Q‐10, and 1.5 mcg of vitamin B12. Dosage was two sachets daily. (n = 64) versus No treatment (n = 29) Duration of treatment: 6 months | |
| Outcomes | Semen analysis, clinical pregnancy rate, peroxidase positive leukocytes, adverse events | |
| Notes | E‐mailed author on 10‐03‐2021 and 04‐05‐2021: how was clinical pregnancy assessed? Reply on 05‐05‐2021: “1‐ Clinical pregnancies were defined by an obstetrician by demonstrating fetal heart rate by USG. And on 01‐06‐2021: “4 pregnancies with assisted reproductive techniques were in the group that did not receive antioxidants.” | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "we used the simple random allocation method to allocate patients to antioxidant and non‐antioxidant groups using Excel 2010 software" |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | No placebo control group, participants had to pay for the treatment |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "During the study period, 2 patients left the study and 1 patient was lost in the follow‐up" 2 patients in antioxidant group and 1 patient in control group. |
| Selective reporting (reporting bias) | High risk | Quote: "As there were only seven patients with grade 1 varicocele in both groups, they were not evaluated." No protocol available. |
| Study characteristics | ||
| Methods | Randomised, double‐blind, placebo‐controlled, prospective, parallel arms study Duration of study: from September 2018 and August 2019, follow‐up 6 months | |
| Participants | Country: Ukraine Population: males aged 21‐50 years with idiopathic male infertility and at least 1 of 3 abnormal values, N = 83 Mean age: 32.5 ± 6.1 years (verum group) and 32.7 ± 5.2 years (placebo group) Inclusion criteria: were informed consent form signed, age 21‐50 years, idiopathic male infertility defined as absence of conception in a couple having a regular unprotected intercourse for 12 months with a woman without evident pathology that could cause infertility, oligo‐ (sperm concentration < 15 million/mL) and/or astheno‐ (<32% forms with progressive motility) and/or teratozoospermia (<4% of sperm cells with normal morphology), affirmed availability throughout the study period and a mobile phone. Exclusion criteria: allergy to any component of the TDS, known genetic, anatomical, endocrine, and inflammatory or traumatic testicular cause of male infertility; known or suspected genetic, anatomical, endocrine, and inflammatory cause of female infertility; inflammatory bowel disease; moderate‐to‐severe disease of any systems; sexually transmitted diseases; alcohol or drug addiction of any couple counterpart as suspected by investigator; difficulty understanding the study requirements as judged by an investigator; use of any investigational product within the previous 3 months before entering the study; and use of any drugs that stimulate or suppress spermatogenesis within previous 3 months. | |
| Interventions | Verum TDS, (1990 mg of l‐carnitine/ l‐acetyl‐carnitine, 250 mg of l‐arginine, 100 mg of glutathione, 40 mg of coenzyme Q10, 7.5 mg of zinc, 234 mg of vitamin B9, 2 mcg of vitamin B12, 50 mcg of selenium and excipients), one oral dose daily (n = 42) versus Placebo TDS, containing the excipients orange/beta‐carotene colourant, citric acid anhydride, sorbitol, silicium dioxide, magnesium stearate, and maltodextrin (n = 41) Duration of treatment: 6 months | |
| Outcomes | Spermiogram, pregnancy rate, time to conception, adverse events | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Random numbers were generated online with no restrictions to randomization by the statistician using the web site Randomization.com." |
| Allocation concealment (selection bias) | Low risk | Quote: "The investigators and patients were concealed, which type of the TDS, verum or placebo, was selected." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "The investigators and patients were concealed, which type of the TDS, verum or placebo, was selected." "Both placebo and verum boxes with sachets of the TDS looked the |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Numbers in outcome tables match randomised numbers. Quote from abstract: "All males finished the study". |
| Selective reporting (reporting bias) | High risk | Time to pregnancy is not reported. Protocol available (NCT03588949): "... couples will be screened for conception, pregnancy, and a newborn." Newborns not reported. |
| Study characteristics | ||
| Methods | Prospective randomised clinical trial Duration of study: from September 2015 to February 2017 | |
| Participants | Country: Russia Population: infertile couples with male factor (obstructive azoospermia), N = 46 Mean age: 42.6 ± 7.2 years (men) and 32.1 ± 5.5 years (women) Inclusion criteria: treatment with fresh TESA/ICSI Exclusion criteria: genetic anomaly (CBAVD: Congenital bilateral absence of the vas deferens) | |
| Interventions | Antioxidant supplement (vitamin E 400 mg, vitamin C 1000mg, selenium 50 mcg once daily and L‐carnitine 1000 mg) twice daily. (n = 24) versus No treatment (n = 22) Duration of treatment: 10 weeks | |
| Outcomes | Fertilisation rate, implantation rate, clinical pregnancy rate, live birth rate per TESA/ICSI cycle. Also reported: embryo quality, early pregnancy loss. | |
| Notes | Conference abstract, no published report available. E‐mailed author [email protected] on 16‐03‐2021 to ask for dosage, frequency and duration of treatment and method of assessing clinical pregnancy. Reply on 18‐03‐2021: "The treatment included: Vit C 1000 mg, vit E 400 mg, selenium 50 mkg — once a day, L‐carnitin 1000 mg x 2 p/d — during 10 weeks. Clinical pregnancy was defined as a pregnancy observed sonographically by the visualization of a fetal heart beat by 7 weeks of gestation." Contacted author for data on early pregnancy loss / miscarriage to add to data analysis. Received reply on 16/7 with data on miscarriage (antioxidants: 4, no treatment: 6). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned, conference abstract |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned, conference abstract |
| Blinding of participants and personnel (performance bias) | High risk | No placebo control group |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned, conference abstract |
| Incomplete outcome data (attrition bias) | Low risk | Numbers in outcome tables match randomized numbers. No lost to follow‐up reported, |
| Selective reporting (reporting bias) | Unclear risk | Conference abstract. No protocol available. |
| Study characteristics | ||
| Methods | Prospective randomised double‐blind placebo‐controlled trial Duration of study: from November 2014 to January 2019 | |
| Participants | Country: Slovenia Population: infertile men with OAT, N = 80 Mean age: 35.0 ± 5.2 years (intervention group) and 36.4 ± 5.5 years (placebo group) Inclusion criteria: patients were considered OAT after at least two previous semen analysis and andrological examination in the frame of their infertility treatment after their partner being unable to conceive for at least 12 months of unprotected sexual intercourse or after a failed assisted conception procedure. Semen quality was defined as OAT according to the WHO 2010 guidelines: oligospermia (O) − sperm concentration < 15 million/ml; asthenozoospermia (A) – progressive motility of spermatozoa < 32%; teratozoospermia (T) − < 4% spermatozoa with normal morphology. Exclusion criteria: smoking more than 20 cigarettes per day, genetic causes of infertility, endocrinopathies, genital tract infections, undescended testis, systemic diseases, history of testicular cancer and treatment with other drugs and food supplements, such as antioxidants, during the last three months before enrolling in this study. | |
| Interventions | Astaxanthin 16 mg and 40 mg vitamin E oral daily (n = 40) versus Placebo (n = 40) Duration of treatment: 3 months | |
| Outcomes | Semen analysis, DNA fragmentation with TUNEL assay, MMP, FSH, adverse events | |
| Notes | E‐mailed authors [email protected] on 16‐03‐2021 about daily dosage of vitamin E in astaxanthin capsules and availability of pregnancy related outcomes. Reply 17‐03‐2021: "One capsule contained 10 mg of vitamin E, the daily dosage of vitamin E was 40 mg. As a secondary aim we evaluated the outcome of the ART for 19 couples in the astaxanthin with vitamin E group and 17 couples in the placebo group who had the ICSI procedure within three months after the participants finished the intervention. The average age of participants female partner was 34.0 ± 3.6 years in the astaxanthin with vitamin E group and was not significantly different from those in the placebo group, 34.9 ± 5.0 years (p = 0.507). There was no significant difference between both groups in the pregnancy rates per cycle, spontaneous abortion rates per pregnancy and delivery rates per cycle after the transfer of fresh embryos." Data added to meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "A computerized randomization table was used for the purpose of randomization." |
| Allocation concealment (selection bias) | Low risk | Quote: "A random allocation sequence was generated and participants were enrolled and assigned to interventions by a third party, thus ensuring that both the enrolled participants and researchers were blinded." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "A random allocation sequence was generated and participants were enrolled and assigned to interventions by a third party, thus ensuring that both the enrolled participants and researchers were blinded." |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "Eight patients in both groups (10%) dropped out for personal reasons during the treatment, and thus, 72 patients completed the trial." "Five patients were not included in the statistical analyses on changes in sperm total number and concentration and 27 patients were not included in the statistical analyses on the motility of spermatozoa as in these patients only a few mobile or immobile spermatozoa in the semen sample were present." |
| Selective reporting (reporting bias) | High risk | All outcomes in methods section reported. Protocol available (NCT02310087): “In the ART procedure (ICSI) the fertilization rate, the quality of embryos, pregnancy rates and miscarriages rates in 1st trimester will be compared between the study and control group.” These pregnancy outcomes are not reported. |
| Study characteristics | ||
| Methods | Randomised double‐blind parallel trial Duration of study: from January 1985 to June 1986 | |
| Participants | Country: Japan, 25 centres Population: men with abnormal sperm count or motility, N = 375 Mean age: unclear, average 32.8 (SD 4.8) years | |
| Interventions | Mecobalamin (vitamin B12) 6.000 mcg (n = 125) versus Mecobalamin (vitamin B12) 1.500 mcg (n = 124) versus Placebo (n = 126) Duration of treatment: 12 weeks | |
| Outcomes | Sperm concentration, sperm motility | |
| Notes | Article in Japanese, translated by Dr Tomoko Kumaga and Tan Wantao. No contact details available for authors. No useable data available. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "The 396 patients were divided into 3 groups (6000ug/day, 1500ug/day, placebo) by randomisation. The implementation of randomisation and allocation concealment was carried out by two people (Doctor Yamamoto, Doctor Shimizu) |
| Allocation concealment (selection bias) | Unclear risk | See above |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | No ITT. 21 lost to follow‐up; 19 dropouts, 2 polypharmacy 2018 Change in RoB to unclear. Not sure in which groups dropouts belonged. |
| Selective reporting (reporting bias) | High risk | Subgroup analysis performed as an addition post‐treatment |
| Study characteristics | ||
| Methods | Randomised placebo‐controlled, double‐blind cross‐over trial Duration of study: 10 months | |
| Participants | Country: Italy Population: infertile men with oligoasthenoteratozoospermia (OAT), N = 100 Mean age: unclear, range: 20 to 40 years Inclusion criteria: age between 20 to 40 years with infertility lasting longer than 2 years, regular sexual intercourse with a gynaecologically normal female partner with no female infertility, absence of endocrine disease, genital infections, obstructive cryptorchism, antisperm antibodies, normal sperm parameters with no significant differences after 3 tests, mild oligospermia with perm concentration 10 to 20 x 106/mL and motility 10% to 30% Exclusion criteria: unclear | |
| Interventions | L‐carnitine 2 g (n = 43) versus Placebo (n = 43) Duration of treatment: 2 months of washout, 2 months of therapy/placebo, 2 more months of washout, 2 more months of placebo/therapy | |
| Outcomes | Sperm parameters, pregnancy rate | |
| Notes | Power calculation performed First phase data: attempted to contact author regarding standard deviations, how many were in each group for the first phase and how many of the 4 who went to assisted reproduction did so in the first phase and what do they mean by 172 cycles. No response yet (2014). Added to outcome data 'not usable for meta‐analysis' | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blinded", "seemingly identical placebo" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | 14 withdrew ‐ 4 went onto assisted reproduction, 6 did not return for second period and 4 due to pregnancy in first phase. Therefore should only be?4 at the most lost from first phase. No ITT All withdrawals accounted for whole trial however how many were lost in the first phase in first phase |
| Selective reporting (reporting bias) | Unclear risk | All outcomes are reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised placebo‐controlled, double‐blind trial Duration of study: 8 months | |
| Participants | Country: Italy Population: infertile men with OAT, N = 60 Mean age: unclear, range 20 to 40 years Inclusion criteria: oligoasthenoteratospermia, age between 20 to 40 years, infertility > 2 years with regular intercourse, no endocrine disease, cryptorchidism, genital infections or obstructions, variocoele or testicular hypertrophy, antisperm antibodies Exclusion criteria: none | |
| Interventions | L‐carnitine 2 g + L‐acetyl‐carnitine 1000 mg (n = 30) versus Placebo (n = 26) Duration of treatment: 6 months | |
| Outcomes | Sperm parameters, pregnancy rate | |
| Notes | Power calculation performed Attempted to contact author regarding 8‐month follow‐up data. No reply as yet (2014) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Mentions coding: quote: "When codes were broken at the end of the study" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | 4 men withdrew from the placebo group. 60 randomised 56 analysed. No ITT |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blinded parallel trial Duration of study: 3 months | |
| Participants | Country: Eastern China Population: infertile men with oligoasthenospermia, N = 150 Mean age: treatment group 30 ± 5.5 (23 to 45) years, control group 32 ± 3.5 (24 to 46) years Inclusion criteria: no smoking or alcohol use, any fertility medication needed to be stopped 2 weeks before Exclusion criteria: none | |
| Interventions | L‐carnitine 2 g + acetyl‐L‐carnitine 1 g (n = 85) (90 with ITT) versus Vitamin E 200 mg + vitamin C 200 mg (n = 53) (60 with ITT) Duration of treatment: 3 months | |
| Outcomes | Sperm parameters, pregnancy rate | |
| Notes | Article in Chinese, translated by Shaofu Li 10.11.2008. Contact author regarding methods of randomisation, concealment and whether SD or SEs used and query that this is the same trial as Li 2005a 2018: added data on progressive motility | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Quote: "Double‐blind" but unclear who is blinded as the control is another antioxidant i.e. not placebo |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Attrition explained. Withdrawal: 5 from treatment group and 7 from control |
| Selective reporting (reporting bias) | Unclear risk | No protocol available. |
| Study characteristics | ||
| Methods | Randomised trial Duration: unclear | |
| Participants | Country: Eastern China Population: infertile men with oligoasthenospermia, N = 80 Mean age: 29 ± 3.5 (23 to 40) years Inclusion criteria: no smoking or alcohol, any fertility medication needed to be stopped 2 weeks before Exclusion criteria: none | |
| Interventions | L‐carnitine 2 g (n = 40) versus Vitamin E 100 mg + Vitamin C 200 mg (n = 40) Duration of treatment: 3 months | |
| Outcomes | Seminal parameters, pregnancy rate | |
| Notes | Article in Chinese, translated by Shaofu Li 10.11.2008. Attempted to contact author re methods of randomisation, concealment and whether SD or SEs used and whether this is the same trial as Li 2005. Also asked whether there were any data on pregnancy rate. Translator replied 22.09.2009 no pregnancy data were available in the text of the trial | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Withdrawal: 8 from treatment (n = 32) and 9 from control (n = 31). 21% loss to follow‐up. No ITT |
| Selective reporting (reporting bias) | Unclear risk | No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled cross‐over trial Duration of study: 10 months | |
| Participants | Country: Italy Population: infertile men with oligoasthenospermia, N = 100 Mean age: unclear, range 20 to 40 years Inclusion criteria: age 20 to 40 years,infertility > 2 years, 3 baseline semen analysis demonstrating concentration 10 to 20 106/mL, 10% to 30% total motility, forward progression < 15%, abnormal morphological forms < 70%, curvilinear velocity 10 to 30 /second + linearity < 4 Exclusion criteria: unclear | |
| Interventions | L‐carnitine 2 g (n = ?) versus Placebo (n = ?) Duration of treatment: 2 months | |
| Outcomes | Sperm parameters | |
| Notes | Abstract only Attempted to contact author re first phase data, outcomes, randomisation, concealment and whether there was a full publication of the trial | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | 86 patients completed the trial out of 100. Need to see full trial for the reasons for withdrawals and ITT |
| Selective reporting (reporting bias) | Unclear risk | Abstract only |
| Study characteristics | ||
| Methods | Randomised, prospective, double‐blind, placebo‐controlled trial Duration of study: unclear | |
| Participants | Country: China Population: patients with a left‐sided clinical varicocele, who were mildly oligospermic(sperm count: 5–15 million) and could not have a child for at least 1 year, N = 54 Mean age: 32.76 years (intervention group) and 32.23 years (placebo group) Inclusion criteria: the diagnostic criteria for varicocele were the presence of two or more varicose veins in the relaxed state and retrograde flow for duration of more than 2 seconds during the Valsalva manoeuvre, patients for whom subinguinal VCT was planned. Exclusion criteria: the use of alcohol, tobacco or any drugs including vitamins | |
| Interventions | Melatonin 400 mg oral daily (n = 27) versus Placebo (starch‐filled capsules) (n = 27) Both treatments were given after subinguinal VCT. Duration of treatment: 3 months | |
| Outcomes | Semen analysis, serum hormones (FSH, testosterone, inhibin B) and TAC and MDA in seminal plasma | |
| Notes | Not clear if mean+SEM or mean+SD provided. Unclear if outcomes were assessed in all randomised patients. E‐mailed author Dr. Zhang on 11‐05‐2021 and 17‐05‐2021 with e‐mail addresses [email protected] and [email protected]. Both not functioning. E‐mail to Jun‐[email protected], [email protected] and [email protected] on 28‐05‐2021. No reply to date (03‐09‐2021). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Simple randomisation method using Excel 2010 software" |
| Allocation concealment (selection bias) | Low risk | Quote: "The allocation sequence was produced by our statistician and was delivered to our pharmacist. Participants were enrolled by the two executive urologists who were unaware of the results of allocation table." |
| Blinding of participants and personnel (performance bias) | Unclear risk | Double‐blind and placebo‐controlled mentioned in the title but blinding of participants and personnel not mentioned in the report. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Not clear from results in how many patients the outcomes were assessed. |
| Selective reporting (reporting bias) | Unclear risk | All outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind controlled trial Duration of study: from July 2009 to September 2010 | |
| Participants | Country: Mexico Population: men with idiopathic oligoasthenozoospermia, N = 54 Mean age: unclear Inclusion criteria: patients between the ages of 20 to 45 years with a diagnosis of idiopathic oligoasthenozoospermia. The diagnosis of oligoasthenozoospermia was reached by performing two semen analyses on different dates with an interval of three weeks between them. Exclusion criteria: infertile patients with normal findings on semen analysis, chronic smokers, antioxidants use in the last 6 months prior to the study, chronic degenerative diseases such as diabetes or high blood pressure Hormonal abnormalities | |
| Interventions | Resveratrol (3,5,4´‐trihydroxystilbene) 25 mg + 725 mg microcrystalline cellulose (n = 18) versus SG1002 (hydrogen sulphide) 750 mg (n = 18) versus Placebo 750 mg microcrystalline cellulose (n = 18) Duration of treatment: 75 days | |
| Outcomes | Sperm parameters (with A+B type sperm motility) | |
| Notes | SG1002 (hydrogen sulphide) excluded because it is a gaseous transmitter Email sent to second author Sordia‐Hernandez ([email protected]) on 22.03.2018 to ask details about the randomisation process and for him to provide more data (SDs). Inconsistence in sentence about adverse events: 3 side effects in SG1002 group, however in the sentence before only 2 in this group? Data not usable, no SD's. No reply to date (19.04.2018). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double‐blind". Quote: "Bottles and capsules for each treatment were identical and identified by a code unknown to the researchers or subject." Placebo used. |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Sperm analysis performed by lab technicians, blinded to the treatment group" |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "Of the seven subjects who did not complete the study (3 from the placebo group, 2 from the resveratrol treatment group and 2 from the SG1002 treatment group), none returned for follow‐up visits and therefore no data on sperm count, motility or abnormality was available and an intent to treat analysis could not be carried out. Four of these subjects were lost in follow‐up while the other three withdrew due to unpleasant smelling sweat (SG1002 treatment group), nausea and flatulence (SG1002 treatment group), and inconvenience (SG1002 treatment group)." Quote: "All study subjects who did not comply with medication given as prescribed, who discontinued the drug or were hypersensitive to it were eliminated" Reasons enough explained, all 3 in SG1002 due to side effects, however we did not include this arm |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind controlled trial Duration of study: 10 weeks | |
| Participants | Country: Spain Population: infertile men, N = 42 (abstract), N = 64 (from author) Mean age: treatment group 35.23 years, placebo 36.10 years, overall average age 35 years Inclusion criteria: men suffering from male factor infertility, according to the WHO guidelines (WHO 1999), and who were undergoing infertility evaluation during the period 2009 to 2011 Exclusion criteria: oncological patients, those suffering from metabolic disease, chromosomal or genetic alterations, and patients on anticoagulant treatment | |
| Interventions | Brudy Plus 1500 mg of DHA‐enriched oil (DHA 1000 mg + eicosapentaenoic acid (EPA) 135 mg) (n = 35) versus Placebo (n = 29) Duration of treatment: 10 weeks | |
| Outcomes | Sperm DNA fragmentation, seminal parameters, lipid composition, antioxidant capacity | |
| Notes | Conference abstract only. Contacted author multiple times by e‐mail ([email protected]) for further study details. Clarified that the abstract details were different from that in the final study, a copy of the unofficial manuscript was submitted to the review authors. Last contact was on 26.02.2014 2018: added data on progressive sperm motility | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Random list with a computer program |
| Allocation concealment (selection bias) | Low risk | Closed and numerated envelopes with allocation group |
| Blinding of participants and personnel (performance bias) | Low risk | Participants knew that they was included in group A or B but only Brudy technology knew the assignation to the control group or experimental group |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind, placebo‐controlled trial Duration of study: from May 2008 to August 2012 | |
| Participants | Country: Iran Population: infertile men with idiopathic OAT, N = 235 Mean age: treatment (L‐carnitine) group 30 ± 1.7 years, control group 30 ± 4.6 years Inclusion criteria: age 25 – 40 years, infertile men with OAT, healthy fertile wives Exclusion criteria: existence of genital abnormalities (undescended testes, varicocele, atrophy of testes), occupational chemical exposure history, systemic diseases, abnormal semen volume, pH, agglutination or viscosity, serum hormonal abnormalities (FSH, LH, testosterone, estradiol, prolactin), wives with known fertility risk factors confirmed by gynaecologist | |
| Interventions | Pentoxifylline 800 mg + L‐carnitine 1000 mg (n = 58) versus Pentoxifylline 800 mg + Placebo (n = 59) versus L‐carnitine 1000 mg + Placebo (n = 59) versus Placebo (n = 59) Duration of treatment: 3 months | |
| Outcomes | Sperm parameters (progressive sperm motility), selection of type of assisted reproductive techniques (ART) | |
| Notes | Only data from L‐carnitine and placebo arm used. Email sent to author ([email protected]) on 06.03.2018 to ask about the randomisation process and blinding of the outcome assessment Reminder email sent to Ketabchi on 22.03.2018. No reply to date (19.04.2018). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "Randomized by Bloch method to four groups" Bloch (block?) method, does this mean computerised? Insufficient explanation |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double‐blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote: "After intervention 23 patients excluded from study (3 patients for drug intolerance in group I, and 20 patients for uncooperative in group II and III)" Data‐analysis only with for those who completed the study (N = 212) According to figure 1: 5 patients (instead of 3 mentioned in text) dropped out due to drug intolerance in group I? Type error? Reasons and exact numbers for dropout not given for L‐carnitine arm specifically. |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: from December 2014 to January 2016, follow‐up 6 months | |
| Participants | Country: Serbia Population: men with idiopathic oligoasthenozoospermia, N = 175 Mean age: 31.5 years Inclusion criteria: men visiting the Andrology centre, (18‐50 years) and with difficulty in conceiving > 12 months; one semen analysis that demonstrated either total sperm number ≤15 million per mL; progressive motility < 32%; normal viscosity and normal leucocytes number (<1 × 106/mL); total ejaculate volume 1.0 mL; sperm vitality ≤58% live; normal sperm morphology <4% (according to WHO, 2010). The following female partners were included in the study: Exclusion criteria: motility < 5%; sperm concentration <1 × 106/mL; history of undescended testes; subjects with known hypersensitivity to ingredients in Proxeed Plus; endocrine disorders affecting the hypothalamic–pituitary axis; history of post‐pubertal mumps; presence of anti‐sperm antibodies; history of endocrine disease; autoimmune disease, cystic fibrosis, or testicular cancer; leucocytospermia, leucocyte count >1 × 106/mL; use of antioxidant agents or vitamins within the 8 weeks prior to inclusion in the study (for subjects using vitamin supplementation, an 8‐week wash‐out period was required prior to inclusion in the study); use of vitamin or natural treatment for infertility at any time; history of taking any therapy for infertility within the last 2 months including over‐the‐counter treatment and vitamin supplementation; history of excessive consumption of alcohol 90 days prior to the start of the trial; subjects involved in other clinical trials. | |
| Interventions | Proxeed Plus (L‐carnitine 1 g, acetyl‐L‐carinitine 0.5 g, fumarate 0.725 g, fructose 1 g, critic acid 50 mg, zinc 10 mg, coenzyme Q10 20 mg, selenium 50 mcg, vitamin C 90 mg, folic acid 1.5 mcg, vitamin B12 1.5 mcg), oral twice daily (n = 125) versus Placebo made with the exipients of the supplementation without the active substances, oral twice daily (n = 50) Duration of treatment: 6 months (and 2 months wash‐out) | |
| Outcomes | Semen analysis, DNA fragmentation with Halosperm assay, alfa glucosidase activity, seminal plasma L‐ carnitine | |
| Notes | Email sent to last author Agarwal ([email protected]) on 20.02.2018. Answer on 21.02.18 "this study is not published in a journal at this time" New email on 06.03.2018 to ask raw data (means with SD) and more information about randomisation/blinding outcome/dropout rates. Reply on 22.03.18 from Agarwal & Micic ([email protected]) with more information in a word document. Only medians with IQR. See RoB. Full report added in 2021. Data on semen parameters provided as median+IQR. Data adjusted to mean+SD for meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote (from email): "Random list was made using the nQuery Advisor nTerim 2.0 (2012) program" |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote (from email): "This is a double blind study. Neither the patient, providers, nor investigators responsible for collecting data or analyzing laboratory specimens have been knowledgeable regarding the assignment of active or placebo product. A file has been maintained at each of the sites under the responsibility of the primary investigator which will provide product identification for each subject. Upon entry into the study, subjects have been assigned a unique study identification number." |
| Blinding of outcome assessment (detection bias) | Low risk | Quote (from email): "Neither the patient, providers, nor investigators responsible for collecting data or analyzing laboratory specimens have been knowledgeable regarding the assignment of active or placebo product. " |
| Incomplete outcome data (attrition bias) | Low risk | Quote (from email): "From the treated group (total 125 ) drop out was 6 subjects; 2 of them got flu with high temperature, 2 went form Serbia (new job), 2 stopped without reason. And from the placebo group ( total 5o ) drop out was 4; 2 drop out without explanation, 1 underwent abdominal surgery, and 1 divorced" |
| Selective reporting (reporting bias) | High risk | Sperm concentration not reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: 3 months | |
| Participants | Country: Italy Population: infertile men with asthenospermia, N = 180 Mean age: range 25 and 49 years Inclusion criteria: age between 28 and 45, sperm concentration < 20 x 106 spermatozoa /mL, sperm progressive motility < 30%, normal morphology < 30%, leucocyte < 1 x 106 /mL, no infections Exclusion criteria: men younger than 28 and over 45, sperm concentration > 20 x 106 spermatozoa /mL, sperm progressive motility > 30%, normal morphology > 30%, leucocyte > 1 x 106 /mL, current infections, history of testicular pathology: cryptorchidism, varicocele, surgical operations, radiotherapy or chemotherapy, use of anabolic steroids, deficiency of hypothalamic‐pituitary‐gonadal axis, genital tract infections | |
| Interventions | L‐arginine 1660 mg + carnitine 150 mg + acetyl‐carnitine 50 mg + ginseng 200 mg in one vial (n = 90) versus No treatment (n = 90) Duration of treatment: 3 months | |
| Outcomes | Sperm parameters, sexual satisfaction | |
| Notes | Article in Italian, translated by Roberto D'Amico. Contacted author by email ([email protected]) to clarify study details, recruitment, randomisation, blinding, ethics approval, study population, withdrawals and to clarify progressive mortality. Last response was on 12.03.2014 Quote: "Total motility and progressive motility are similar terms for the same definition: all the spermatozoa that have progressive or not linear motility" 2018: motility data included as progressive motility | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Control is no treatment |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned. |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: 3 months | |
| Participants | Country: Iran Population: infertile men with OAT who have been trying for pregnancy for > 1 year unprotected intercourse, N = 60 (analysed N = 47) Mean age: 34 years Inclusion criteria: seminal WBC < 1,000,000 /mL, absence of anatomical abnormalities of the genital tract, absence of infectious genital diseases or systemic diseases, absence of treatment with other drugs and dietary supplement during the 3 months before enrolling in the study, at last absence of smoking, drug, and alcohol use or occupational chemical exposure Exclusion criteria: seminal WBC > 1,000,000 /mL, presence of anatomical abnormalities of the genital tract, presence of infectious genital diseases or systemic diseases, presence of treatment with other drugs and dietary supplement during the 3 months before enrolling in the study, currently smoking, using drug, or alcohol use or occupational chemical exposure | |
| Interventions | Coenzyme Q10 (CoQ10) 200 mg (n = 23) versus Placebo (n = 24) Duration of treatment: 3 months | |
| Outcomes | Sperm motility and concentration, progression, total antioxidant capacity (TAC) | |
| Notes | Power calculation performed Contacted regarding methods, randomisation, allocation concealment, recruitment, blinding and dropouts. Response from Azadeh Nadjarzadeh ([email protected])in October 2013 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote (from email):"Participants were randomised using block randomisation. It was done by Dr Motevallian who is epidemiologist and it has done before study" |
| Allocation concealment (selection bias) | Low risk | Quote (from email): "Before the trial a colleague, that had not role in the study, coded the bottles of Coenzyme Q10 and placebo (that were similar) in A and B and give them to one of the staff of Avicenna Research centre. Only that person has a list of randomisation and give A or B bottles to the participants according to their code" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote (from email): "Both participants and investigators blinded" |
| Blinding of outcome assessment (detection bias) | Low risk | Quote (from email): "The appearance and the bottles of capsules were similar and none of outcome assessors knew group, because everyone had a code after being allocated group A and B" |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "13 dropped out for personal reasons" ‐ 22%: 7 from treatment group and 6 from the control group |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised, double‐blind, clinical trial Duration of study: from January 2018 to October 2018 | |
| Participants | Country: Iran Population: men who had a history of primary and secondary infertility for at least 5 years, N = 44 Mean age: 32.89 ± 2.33 years (lycopene group) 32.15 ± 2.16 years (placebo group) Inclusion criteria: infertile men aged between 25 and 45 years, a sperm count of less than 20 million per millilitres, normal sperm of < 65% and spermia of <3.0 mL, and average motility of < 60% while receiving no treatments. Exclusion criteria: history of disorders (urinary tract infection, testicular atrophy, testicular torsion, azoospermia, asthenospermia, inguinal and genital surgery, genital trauma, and other genital diseases, such as current genital inflammation and cryptorchidism), anatomical disorders, endocrinopathy, previous hormonal therapy, use of androgens, antiandrogens, anticoagulants, cytotoxic drugs, or immunosuppressants, patients with physiological and psychiatric disorders that could affect sperm and sexual performance, alcohol and drug abuse, and body mass index of ≥ 30 kg/m2. | |
| Interventions | Lycopene 25 mg oral once daily (n = 22) versus Placebo (n = 22) Duration of treatment: 12 weeks | |
| Outcomes | Semen analysis, seminal TAC, MDA and glutathione peroxidase | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned, "convenience sampling"? |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "All patients and the clinician that prescribed the supplements were blind to the treatment. In order to guarantee the blindness, lycopene and placebo were prepared similar in appearance." |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | 5/22 in lycopene and 3/22 in placebo group lost to follow‐up. |
| Selective reporting (reporting bias) | Low risk | Outcomes mentioned in methods are all reported. Protocol available (IRCT20171105037249N1). Depression mentioned in protocol not reported. |
| Study characteristics | ||
| Methods | Randomised comparative study Duration of study: unclear | |
| Participants | Country: Tunisia Population: infertile males with OAT, N = unclear Mean age: unclear Inclusion criteria: males with OAT. Exclusion criteria: unclear | |
| Interventions | Vitamin E 400 mg + Selenium 200 μg (n = 12) versus Vitamin B2, B6 and B12 (n = 8) Duration of treatment: 3 months | |
| Outcomes | Seminal parameters | |
| Notes | Abstract only Attempted to contact authors regarding methods of randomisation and data. No reply as yet (2014). No extractable data from the abstract. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "In a prospective randomised comparative study" |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Control is no treatment |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled open trial Duration of study: follow‐up 12 months | |
| Participants | Country: Kuwait Population: men with asthenozoospermia attending infertility and andrology clinic, N = 100 Mean age: treatment group 37.8 ± 7.9 years, control group 38.1 ± 8.2 years Inclusion criteria: men with asthenozoospermia, spermatozoa motility impaired with > 4 0% non‐motile sperm, have been trying to conceive for at least one year plus no obvious female factor Exclusion criteria: none mentioned | |
| Interventions | Zinc 500 mg (n = 49) versus No treatment (n = 48) Duration of treatment: 3 months | |
| Outcomes | Sperm parameters | |
| Notes | Attempted to contact authors regarding methods randomisation and concealment questioned. No reply as yet (2014). Data on sperm count/motility not used; only percentage of increase/decrease given | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Control is no treatment |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | 100 men randomised, 97 analysed, dropouts are not accounted for |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled open trial Duration of study: unclear | |
| Participants | Country: Kuwait Population: men with asthenozoospermia attending infertility clinic in Kuwait, N = 45 Mean age: 35 ± 1 years Inclusion criteria: asthenozoospermia with normal sperm concentration (20 to 250 million/mL) but with 40% or more immotile sperm Exclusion criteria: asthenozoospermia but sperm concentration of < 20 million/mL | |
| Interventions | Zinc 400 mg (n = 11) versus Zinc 400 mg + Vitamin E 20 mg (n = 12) versus Zinc 400 mg + Vitamin E 20 mg + Vitamin C 10 mg (n = 14) versus No treatment (n = 8) Duration of intervention: 3 months | |
| Outcomes | Sperm parameters | |
| Notes | Attempted to contact author regarding methods of randomisation, it states that quote: "8 men served as non‐ therapy control". No reply as yet (2014). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Control is another antioxidant or no treatment |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | All outcomes are reported. No dropouts |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind cross‐over trial Duration of study: unclear, from 2005 to 2006 | |
| Participants | Country: Iran Population: infertile men, N = 30 Mean age: 29.5 (SD 5.48) years Inclusion criteria: at least two abnormal spermograms based on WHO criteria with a two‐week interval during four weeks, normal range of gonadotropins, testosterone an prolactin concentrations Exclusion criteria: variocoele, testicular atrophy, ejaculatory disorders, use of medications, azoospermia, endocrinological disorders, ICSI candidacy or other causes of infertility | |
| Interventions | L‐carnitine 2 g (n = 15) versus Placebo (n = 15) Duration of treatment: 8 weeks, washout period of 8 weeks, changed intervention and use for 8 more weeks | |
| Outcomes | Sperm parameters | |
| Notes | Abstract in English, full text in Arabic. Contacted the author and he is filling out the data extraction sheets. Author responded but data queries remain contacted again re SDs and pregnancies in first phase of cross‐over. Author responded saying that the data were given in SDs and there were 3 pregnancies in the first phase 2018: added data on progressive motility for first phase (2 months). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Low risk | Quote: "sealed opaque envelopes" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "outcome assessor was blinded" |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote: "loss to follow up was not accounted for" |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Comparative, randomised, prospective, controlled study Duration of study: unclear | |
| Participants | Country: Russia Population: men aged 25 to 45 years planning an ART program, N = 80 Mean age: 34 ± 3.2 years Inclusion criteria:
Exclusion criteria:
| |
| Interventions | Androdoz (4 capsules contain: l‐arginine 720 mg, l‐carnitine 240 mg, l‐carnosine 92 mg, coenzyme Q10 10 mg, glycyrrhizic acid 6 mg), oral, 2 capsules twice daily (n = 60) versus No treatment (n = 20) In both groups patients were also treated with ART. Duration of treatment: 3 months | |
| Outcomes | Spermiogram, sperm hyaluronan binding assay (HBA), clinical pregnancy, adverse events | |
| Notes | Article in Russian, translated by Alyona Oryshchuk. E‐mailed authors Dr. Ovchinnikov ([email protected]) to request additional information on RoB, definition of pregnancy outcome and results of all semen parameters. Reply on 18‐05‐2021: "It was computer randomized block design (the adaptive dynamic randomization with stratification)." From e‐mail: outcome assessors were blinded and allocation was concealed. Data on sperm parameters (total sperm motility, progressive motility, concentration) used for data analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote (from e‐mail): "It was computer randomized block design (the adaptive dynamic randomization with stratification)." |
| Allocation concealment (selection bias) | Low risk | From e‐mail, see notes |
| Blinding of participants and personnel (performance bias) | High risk | No placebo group |
| Blinding of outcome assessment (detection bias) | Low risk | From e‐mail, see notes |
| Incomplete outcome data (attrition bias) | Low risk | Quote (from e‐mail): “No one in this study was lost to follow‐up.” |
| Selective reporting (reporting bias) | High risk | Not all outcomes are reported, results on semen parameters are missing. |
| Study characteristics | ||
| Methods | Randomised trial with add‐on intervention Duration of study: unclear | |
| Participants | Country: Iran Population: men with male factor infertility and varicocele, N = 100 Mean age: treatment group 26.73 ± 6.25 years, control group 27.52 ± 5.23 years Inclusion criteria: left‐sided clinical or subclinical varicocele plus one of these factors: primary infertility, secondary infertility, or impaired semen analysis. Exclusion criteria: right‐ sided isolated varicocele, bilateral varicocele, and each side varicocele that did not decompress in lying position, or any medical or surgical history of male factor infertility ‐ Medical: opium or drug abuse, any prior medical treatment for infertility, recurrent urinary tract infection, sexually transmitted disease, prostatitis, mumps in childhood, epididymo‐orchitis, and so forth ‐ Surgical: cryptorchidism, orchiopexy, prior varicocelectomy repair, inguinal hernia repair, other inguinal surgeries, and so forth | |
| Interventions | L‐carnitine 750 mg (n = 50) versus No treatment (n = 50) Duration of treatment: 6 months, after varicocelectomy | |
| Outcomes | Sperm parameters, DNA damage (TUNEL, PDA test), adverse effects | |
| Notes | Email sent to last author Noori ([email protected]) on 06.03.2018: Asked about the SD's for sperm motility (A+B%), concentration and DNA fragmentation. Asked about allocation concealment and blinding of outcome assessment. Reminder email sent to Noori and Pourmand ([email protected]) on 22.03.2018. Only data on adverse events used. No reply to date (19.04.2018). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "Block randomization was performed for controlling less probable variation in varicocelectomy technique or surgeon within the time of study" Not specified how block randomisation was performed. |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Control group is no treatment after varicocelectomy |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | See appendix, none lost to follow‐up |
| Selective reporting (reporting bias) | Unclear risk | All the outcomes from the aim of the study and methods were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: from January 2012 to March 2013 | |
| Participants | Country: Panama Population: infertile healthy men, N = 60 (quote: "60 patients completed the study", how may were randomised?) Mean age: unclear Inclusion criteria: infertile healthy men without previous treatments, non smokers, no alcoholics or drug users Exclusion criteria: varicocele and leukocyte‐spermia were excluded | |
| Interventions | L‐carnitine 1 g/12 hours (n = ?) versus Spermotrend (Catalysis) 1 x /8 hours (n = ?) versus Maca extract 1 g/12 hours (n = ?) versus Placebo 1x/12 hours (n = ?) Duration of treatment: 13 weeks | |
| Outcomes | Sperm motility, sperm concentration, normal sperm morphology | |
| Notes | Conference abstract only. Letter written and posted regarding methods and data 12.02.2014 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind cross‐over trial Duration of study: unclear | |
| Participants | Country: UK (two centres) Population: men with severe oligozoospermia, N = 64 Mean age: unclear Inclusion criteria: sperm count of less than 10 million per ejaculate on each of 2 occasions immediately preceding the trial, no uncorrected varicoceles or testicular maldescent, testicular biopsy already performed (Johnsen 1970), no drugs taken in past 3 months which were known to affect spermatogenesis, no history of biliary disease owing to a suggestion that arginine might interfere with the metabolism of bile salts, the wives of all these men had been fully investigated with regard to fertility Exclusion criteria: men with varicocoele | |
| Interventions | Arginine 4 g (n = 35) versus Placebo (n = 29) Duration of treatment: 12 weeks, than cross‐over without intervening wash‐out period | |
| Outcomes | Total sperm motility, hormone levels | |
| Notes | No data available for sperm parameters. Unable to contact author | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | 10 participants withdrew reasons were given but unsure from which group, the paper stated that they used ITT but data not presented. The study did not report the outcomes for the different phases of the trial (i.e. not separated into phase 1 phase 2). Pregnancy data are separated into phase one data but probably biochemical and will be used in biochemical pregnancy table. |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. Pregnancy not stated in the methods section as an outcome of interest but reported in the results. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: unclear | |
| Participants | Country: Iran Population: men from infertile couples with proved male factor infertility, N = 83 Mean age: unclear Inclusion criteria: infertile men (OAT) with sperm concentrations of < 20 x 106 mL‐1, sperm motility < 50% (grades a, b, c) and sperm normal morphology < 30% Exclusion criteria: unclear | |
| Interventions | Folic acid 5 mg + Placebo (n = 20) versus Folic acid 5 mg + Zinc sulphate 220 mg (n = 21) versus Zinc sulphate 220 mg + Placebo (n = 24) versus Placebo + Placebo (n = 18) Duration of treatment: 16 weeks | |
| Outcomes | Sperm concentration, motility (grade A+B+C), morphology, sperm viability, sperm mitochondrial function, sperm chromatin status (DNA damage measured by staining methods), semen and blood folate/zinc/B12, total antioxidant capacity (TAC) and malondialdehyde (MDA) concentration | |
| Notes | Trial registration: IRCT138706091079N2 Email sent to last author Sadeghi ([email protected]) on 06.03.2018 to ask about the mean age, exclusion criteria, if there are means+SD instead of medians of the sperm concentration and sperm motility, randomisation process, dropouts/lost to follow‐ups Reminder email sent to Sadeghi on 22.03.2018. No reply to date (19.04.2018). Data on DNA fragmentation used (means+SD). Other sperm parameters are provided as median+IQR and were therefore converted to mean+SD. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "randomly allocated into four treatment groups with different supplementations." |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blinded". Placebo used. |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Semen analysis and sperm function assays were assessed individually and blindly by two laboratory experts" |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Low risk | Reported all the outcomes from the methods and protocol; trial registration (IRCT138706091079N2) |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: 8 weeks | |
| Participants | Country: Germany Population: men with infertility for over one year, N = 33 Mean age: treatment group 36.1 ± 5.0 years, control group 35.2 ± 4.8 years Inclusion criteria: asthenozoospermia (< 50% motile) diagnosed after 2 examinations, normal or reduced sperm concentration (> 20 x 106 per ejaculate) and without infection of access glands Exclusion criteria: unclear | |
| Interventions | Vitamin C 1000 mg + Vitamin E 800 mg (n = 15) versus Placebo (n = 16) Duration of treatment: 8 weeks | |
| Outcomes | Primary: sperm parameters Secondary: pregnancy rate and adverse effects | |
| Notes | Power calculation performed. Contacted author about the allocation concealment and pregnancy and adverse effects were outcomes in their protocol. Author Rolf replied saying that pregnancy and adverse effects were stated in the protocol 2018: progressive forward motility instead of total motility, data total sperm motility moved to outcome progressive sperm motility | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomisation was performed with random numbers without further stratification by the pharmacist and the code was withheld from researchers and patients" |
| Allocation concealment (selection bias) | Unclear risk | Pharmacist performing randomisation and code withheld from patients and researchers. However no mention of type of containers or envelopes |
| Blinding of participants and personnel (performance bias) | Low risk | Double‐blind ‐ patients and researchers |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | All data reported, 2 patients withdrew from the trial: quote: "results from two patients were rejected from analysis." 1 from the treatment group due to poor compliance and 1 from the placebo group due to genital tract infection. No ITT |
| Selective reporting (reporting bias) | Unclear risk | All semen outcomes reported and author states (e‐mail 22.09.09) that pregnancy and adverse effects were set a priori in the protocol. No protocol available. |
| Study characteristics | ||
| Methods | Randomized placebo‐controlled clinical trial Duration of study: from January 2016 to December 2018 | |
| Participants | Country: Iraq Population: infertile male participants, N = 151 Mean age: 32.2±10.2, 31.4±11.6 and 30.1±7.6 in the coenzyme Q10, glutathione and placebo group respectively Inclusion criteria: normal female factor with idiopathic OAT Exclusion criteria: with a chronic disease like mumps, hydrocele, neoplasm, trauma from prolonged riding, hypospadias, vas deferens obstruction, varicocele, and genital tract infection were excluded from this study, also those who received treatment recently. | |
| Interventions | Coenzyme Q10 200 mg orally, frequency not mentioned (n = 50) versus Glutathione 250 mg orally, frequency not mentioned (n = 51) versus Placebo (oral sugar sachets) (n = 50) Duration of treatment: 6 months | |
| Outcomes | Semen parameters | |
| Notes | Data on semen parameters provided as percentage improvement. Email sent to first author ([email protected]) several times. No reply to date (03‐09‐2021). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned if sachets look identical |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Number of patients randomised to placebo group not mentioned in methods section. |
| Selective reporting (reporting bias) | High risk | Baseline characteristics not mentioned in outcomes table (marriage time, job type, social habits). Only % of improvement reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: 56 weeks | |
| Participants | Country: Iran Population: men with idiopathic oligoasthenoteratospermia, asthenospermia or teratospermia of 2 years duration, N = 468 (548 recruited) Mean age: 31 (25 to 48) years Inclusion criteria: sperm count > 5 x 106 /mL, over 2 years of failed conception, no female fertility problems, no history of possible cause for male infertility Exclusion criteria: abnormal testes, history of cancer or chemotherapy, testosterone or antiandrogen use, use of selenium or N‐acetylcystine supplements, abnormal hormone levels, genital disease, genital inflammation or variocoele, history of genital surgery, major surgery, central nervous system injury, a known sperm defect or retrograde ejaculation. Y chromosome abnormalities, sexually transmitted disease, genitourinary infection, leukocytospermia, smoking, any environmental exposures to reproductive toxins. Medical, neurological or psychological problems. A history of drug or alcohol abuse, hepatobiliary disease or significant renal insufficiency. Any endocrine abnormality, a b BMI of 30 kg/m2 or over, participation in another investigational study and a likelihood of being unavailable for follow‐up | |
| Interventions | Selenium 200 µg (n = 116) versus N‐acetylcysteine (NAC) 600 mg (n = 118) versus Selenium 200 µg + N‐acetylcysteine (NAC) 600 mg (n = 116) versus Placebo (n = 118) Duration of treatment: 26 weeks or 6.5 weeks | |
| Outcomes | Primary outcome: sperm parameters Secondary outcomes: spontaneously reported adverse events | |
| Notes | Power calculation performed. Attempted to contact authors regarding side effect data that had not yet been added to the review due to the query of multiple comparisons. Also to ask whether data are in SD (as reported in the text) or SE, as requested by statistician 24.09.2010 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "randomisation table generated by the method of random permuted blocks. Patient randomisation numbers were allocated to each site in ascending sequence in blocks." |
| Allocation concealment (selection bias) | Low risk | Quote: "Assignment to treatment groups was performed using a sealed envelope technique." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Eligible patients were randomly assigned to double blind.." Quote: "Placebo pills were coated with titanium oxide to ensure an identical appearance and smell." |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Analysed: n = 105 in selenium group (loss 11), n = 106 in placebo group (loss 12), n = 105 in N‐acetylcysteine group (loss 13) and n = 104 in selenium + N‐acetylcysteine group (loss 12) All withdrawals were accounted for in each treatment group. Withdrawal was mainly due to withdrawal of consent followed by lost to follow‐up and lastly for reasons of missing data. No ITT |
| Selective reporting (reporting bias) | Unclear risk | The published report includes all expected outcomes. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind controlled trial Duration of study: from February 2005 until October 2006, follow‐up 14 months | |
| Participants | Country: Iran Population: infertile men with idiopathic oligoasthenoteratospermia, N = 212 (recruited 268) Mean age: treatment group 28 ± 9 years, placebo group 28 ± 10 years Inclusion criteria: minimum 2 years unprotected intercourse with 2 years unwilling childlessness. male infertility diagnosed if 1 or more standard semen parameters were below cutoff levels accepted by WHO. A fertile female partner. No known medical condition that could account for infertility, testicular volume 12 mL or greater. No medical therapy for at least 12 weeks before the study begins. Only patients seeking medical attention for infertility were included Exclusion criteria: azoospermia or severe oligospermia (sperm count less than 5 million/mL. An history of epypidymo‐orchitis, prostatitis, genital trauma, testicular torsion, inguinal or genital surgery. Any genital or central nervous system disease, endocrinopathy, cytotoxic drugs, immunosuppressants, anticonvulsives, androgens, antiandrogens, a recent history of Sexually transmitted disease. Psychological or physiological abnormalities that would impair sexual functioning or ability to produce sperm samples. Drug, alcohol or substance abuse. Liver disease, renal insufficiency or chromosome abnormalities. occupational and environmental exposures to reproductive toxins. A BMI of 30 kg/m2 or over, participation in another investigational study and a likelihood of being unavailable for follow‐up | |
| Interventions | Coenzyme Q10 (CoQ10) 300 mg (n = 106) versus Placebo (n = 106) Duration of treatment: 26 weeks or 6.5 months | |
| Outcomes | Primary outcomes: sperm parameters and testicular volume Secondary outcomes: adverse effects and hormone levels | |
| Notes | Power calculation performed. Attempted to contact authors to ask whether data is in SD (as reported in the text) or SE, as requested by statistician 24.09.2010 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Each eligible patient received a randomisation number, which was determined by a computer generated schedule. Therafter a randomisation table was generated by the method of random permuted blocks. Individuals who were geographically and operationally independent of the study investigator performed the study randomisation" |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "The clinician prescriber and the patients were blinded to the treatment condition. To maintain and guarantee blinding CoQ10 and placebo were identical in appearance." |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Participant data collected during this trial were kept confidential and locked in a secure office area. Randomisation codes were opened only after all patients had completed the whole study protocol." |
| Incomplete outcome data (attrition bias) | Low risk | All patients who dropped out of the trial were accounted for ‐ 8 from treatment group and 10 from placebo group for reasons such as withdrawal of consent, missing data and loss to follow‐up. |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Double‐blind randomised study Duration of study: January 2007 to June 2008 | |
| Participants | Country: Iran Population: men with primary infertility and idiopathic oligoasthenoteratospermia, N = 238 Mean age: treatment group 32 ± 9 years, placebo group 32 ± 10 years Inclusion criteria: unwanted childlessness of at least 24 months with same female partner; no known medical condition that could account for their infertility; and total testicular volume ≥ 12 ml. The female partner had to be diagnosed normal. Exclusion criteria: patients who were determined to have abnormal testes, cryptorchidism, varicocele and genital surgery via physical examination and clinical testing were excluded. Y chromosome deletions, abnormal karyotypes; patients with azoospermia or any hormonal abnormality; a history of use of cancer chemotherapy, testosterone, anti‐androgens or anti‐oxidants; tobacco use; concomitant medical problems known to be associated with diminished fertility; hepatobiliary disease; significant renal insufficiency; body mass index (BMI) ‡ 30 and occupational and environmental exposures to potential reproductive toxins. | |
| Interventions | Omega‐3 (DHA 1.12 g and EPA 0.72 g / day) (n = 119) versus Placebo (with 1% fish oil) (n = 119) Duration of treatment: 32 weeks (after a 5 week wash‐out period) | |
| Outcomes | Sperm parameters, fatty acid composition of red blood cells, spermatozoa and seminal plasma, seminal plasma antioxidant status, adverse events | |
| Notes | Power calculation performed. Adverse events not added to gastrointestinal upsets, risk to count doubles. Attempted to contact author for data. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomisation table was generated by the method of random permuted blocks [...]. The randomisation process was carried out by another member of staff independent of the study and blind to the assessment." |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned. |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "matching placebo", "The placebo was corn oil, selected as it minimally alters the fatty acid composition of the typical diet. To preserve the double‐blind status in the proposed study, a small amount of fish oil (1%) was added to the placebo." |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned. |
| Incomplete outcome data (attrition bias) | Low risk | 106/119 in omega‐3 group and 105/119 in placebo group completed 32 weeks study period, reasons for all dropouts are provided, ITT. |
| Selective reporting (reporting bias) | Unclear risk | All outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: from June 2010 to January 2011 | |
| Participants | Country: Iran Population: infertile men with primary infertility for at least 2 years, N = 228 Mean age: treatment group 31 years, control group 32 years Inclusion criteria: history of primary infertility of more than 2 years, abnormal sperm count and motility according to WHO criteria, wife age between 20 and 40 years, documentation of fertile female partner, no known medical or surgical condition which can result in infertility Exclusion criteria: history of cancer chemotherapy or radiotherapy, history of genital disease such as cryptorchidism and varicocoele, history of genital surgery, BMI 30 kg/m2 or greater, any endocrinopathy, Y chromosome microdeletion or karyotype abnormalities, leukocytospermia (more than 106 WBC per mL), drug, alcohol or substance abuse, tobacco use, use of anticonvulsants, androgens or antiandrogens, significant liver (serum bilirubin greater than 2.0 mg/dL) or renal function (serum creatinine greater than 2.0 mg/dL) impairment, occupational and environmental exposure to reproductive toxins, severe oligozoospermia (less than 5 x 106 /mL), azoospermia and testicular volume less than 12 mL | |
| Interventions | Coenzyme Q10 (Ubiquinol) 200 mg (n = 114) versus Placebo (n = 114) Duration of treatment: 26 weeks | |
| Outcomes | Sperm volume, sperm density, sperm motility, sperm morphology, seminal plasma antioxidant status | |
| Notes | Power calculation performed | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random number table |
| Allocation concealment (selection bias) | Low risk | The randomisation codes were centrally assigned by the co‐ordination centre after checking the main eligibility criteria |
| Blinding of participants and personnel (performance bias) | Low risk | All investigators and study staff were blinded to treatment allocation during the whole study period, All of the participants were naive for treatment |
| Blinding of outcome assessment (detection bias) | Low risk | All investigators and study staff were blinded to treatment allocation during the whole study period, All of the participants were naive for treatment |
| Incomplete outcome data (attrition bias) | Low risk | 228 were randomised of 264 eligible Ubiquinol group – 13 excluded at end of treatment (3 protocol violations, 4 withdrawal of consent and 6 lost to follow‐up). At 12 weeks follow‐up a further 5 were lost to follow‐up Placebo group – 12 excluded at end of treatment (4 protocol violations, 4 withdrawal of consent, 6 lost to follow‐up. At 12 weeks follow‐up a further 7 were lost to follow‐up |
| Selective reporting (reporting bias) | High risk | The authors do not pre‐specify which outcome measures will be reported. The primary outcome is a % change from baseline at the end of the treatment period |
| Study characteristics | ||
| Methods | Multicentre, double‐blind, block‐randomised, placebo‐controlled clinical trial | |
| Participants | Country: USA Population: male partner of couples planning infertility treatment, N = 2370 Mean age: 32.5 ± 5.7 years (intervention group) and 32.7 ± 6.0 years (placebo group) Inclusion criteria: men aged ≥18 years and women aged 18‐45 years, recruitment also included couples planning ovulation induction and IUI Exclusion criteria: couples were ineligible if they were planning use of donor sperm or a gestational surrogate, were pregnant at enrolment, or if the male had obstructive azoospermia or other known infertility causes unlikely to benefit from supplementation. Men were instructed to abstain from dietary supplements containing folic acid or zinc, as well as medications known to interact with folic acid or zinc. Men with poorly controlled chronic diseases (e.g. heart disease, diabetes, hypertension, cancer) were excluded. Men were excluded initially for anaemia (haemoglobin concentration <13 g/dL) using a point‐of‐care haemoglobin meter to avoid enrolling men with vitamin B12 deficiency. After October 30, 2015, men with haemoglobin concentrations less than 13 g/dL were enrolled, with a follow‐up serum vitamin B12 and methylmalonic acid measurement. | |
| Interventions | Folic acid 5 mg + zinc 30 mg oral daily (n = 1185) versus Placebo (n = 1185) Duration of treatment: 6 months, a minimum of 4.5 to 6 weeks before the ovulatory phase of the first infertility treatment cycle. | |
| Outcomes |
| |
| Notes | Power calculation provided. Only data used from supplementary eTable 3, with data of a subgroup “restricted to men with known male factor infertility or poor semen quality at baseline”. Male factor infertility diagnosis was self‐reported. E‐mailed author Dr. Schisterman ([email protected]) on 02‐06‐2021 to request data on pregnancies in the “male factor infertility” subgroup. No reply to date (03‐09‐2021). Some participants used multivitamins within 3 months of enrolment in the trial (40% in the intervention group, 38% in the placebo group) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Computerized randomization algorithm" |
| Allocation concealment (selection bias) | Low risk | Quote: "... permuted block design with block sizes of 2, 4, or 6 (in random order) within each infertility treatment stratum and study site and was implemented by blinded study coordinators." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Participants, trial staff, and investigators were blinded to treatment throughout the trial." |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Participants, trial staff, and investigators were blinded to treatment throughout the trial." |
| Incomplete outcome data (attrition bias) | Low risk | 315/1185 lost to follow‐up in intervention group, 282/1185 lost to follow‐up in placebo group, "missed six month visit". Sample not collected for semen analysis and DNA fragmentation in 76/870 in intervention group, 68/903 in placebo group. Additional exclusions for morphology, TMSC and DNA fragmentation assessment due to "Insufficient quantity or quality". All patients included in primary analysis of live birth rate. |
| Selective reporting (reporting bias) | High risk | Progressive motility, reproductive hormones and biomarkers not reported. Protocol available (NCT01857310). |
| Study characteristics | ||
| Methods | Randomised double‐blind trial Duration of study: 3 months and two weeks | |
| Participants | Country: UK Population: men attending subfertility clinic with low sperm motility, N = 64 (recruited N = 69) Mean age: 33.3 ± 0.64 years Inclusion criteria: low sperm motility Exclusion criteria: not mentioned | |
| Interventions | Selenium 100 µg (n = 16) versus Selenium 100 µg + Vitamin A 1 mg + Vitamin C 10 mg + Vitamin E 15 mg (n = 30) versus Placebo (n = 18) Duration of treatment: 3 months | |
| Outcomes | Primary outcome: sperm parameters Secondary outcome: pregnancy rates | |
| Notes | Uneven numbers, multivitamin numbers are double the other groups Asked author if they have separate numbers for pregnancy data. Currently have 5 pregnancies in the 2 treatment groups and none in placebo Furthermore; who was blinded, was the placebo identical when group 2 contained so many different vitamins. Was there any allocation concealment? Author has retired and is not able to be contacted. Data not added to table 'data for undefined or biochemical pregnancy' | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "As the patients entered the trial they were randomly allocated to one of three treatments, which had in turn been randomised within each block of four numbers and 'blinded' using a numeric code." Unclear as to why the uneven nature of the numbers in the groups i.e. 30 in multivitamin group and 16 in selenium, 18 in placebo |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Numbers of withdrawals and reasons (non compliance) were reported |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: from March 2015 to November 2015 | |
| Participants | Country: Iran Population: Idiopathic subfertile men, N = 114 Mean age: Inclusion criteria: Idiopathic subfertile male with sperm rates 5 ‐ 20 million cells/mL, and according to failure of female to conceive after one year regular and unprotected intercourse Exclusion criteria: chromatically fertility disorder (Y chromosome deletions), use of zinc three months before recruitment | |
| Interventions | Zinc sulphate 10 mL solution of 0.5% (n = 61) versus Placebo 10 mL (n = 53) Duration of treatment: 3 months | |
| Outcomes | Sperm parameters, side‐effects, serum and semen plasma levels of zinc | |
| Notes | Trial registration: IR.IUMS.REC.1394.26155 Email sent to second author Norouzi ([email protected]) on 06.03.2018 to ask if they can provide mean+SD instead of median, and if the motility is total motility or progressive motility. Reply on 11.03.2018: "yes we use SD for motility and total concentration, for both of them instead of a median. Motility means group A+ B (progressive motility)" New email on 12.03.2018 to ask if they can then provide mean + SD. Reply on 04.04.18 answering "In this study we used the SPSS software (SPSS, Inc., Chicago, IL, USA, version 20) for statistical analyses. After normality testing confirmed by Shapiro‐wilk test, quantitative data were reported as mean ± SD. Unfortunately there are some spelling and statistical errors in the final version of article. In the review process, some changes have been made in the manuscript and subtitle of the tables have been deleted. So all outcome are Mean ± SD." | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "In the current study males were divided into groups A and B by block randomized sampling." Quote: "sub fertile males were assigned according to a simple computer schedule into two groups to receive zinc sulfate or placebo." |
| Allocation concealment (selection bias) | Low risk | Quote: "Solutions were coded from 1 to 120 according to the randomization list by hospital pharmacy. Each code was given to one participant to receive one container of solution that according to their group called participates took zinc sulfate (0.5) or placebo." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double‐blind" Quote: "Containers of zinc solution and placebo were similar, and all of them had zinc syrup label. The secretary of infertility unit did not know about the box content and patients by showing their groups label could receive the medicine." |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "seven subjects in the zinc group withdrew because of adverse gastrointestinal side effects, and three subjects in the zinc group and four subjects in the placebo group withdrew because of lack of motivation" Dropouts accounted for and reasons mentioned. No ITT |
| Selective reporting (reporting bias) | Low risk | Reported all the outcomes from the methods section and according to the protocol: trial registration (IR.IUMS.REC.1394.26155) |
| Study characteristics | ||
| Methods | Randomised double‐blind trial Duration of study: 24 weeks, follow‐up unclear | |
| Participants | Country: USA Population: infertile men aged 18 to 65 years, N = 26 Mean age: 36.2 ± 5.8 years, 35.3 ± 7.5 years Inclusion criteria: males 18 to 65 years with infertility of at least six months duration, sperm concentration of at least 5 million sperm/mL, motility of 10% to 50%, absent pyospermia and normal FSH and testosterone levels Exclusion criteria: history of post‐pubertal mumps, cryptorchism, vasal or epididymal surgery, history of medication or chemotherapy. recent alcohol, chronic marijuana. Use of testosterone or steroids. Exposure to environmental toxins. Recent history of fever or diabetes, liver failure, renal failure, endocrine disorder, untreated variocoele, urogenital infection, or prior vasectomy reversal | |
| Interventions | L‐carnitine 2000 mg + L‐acetylcarnitine 1000 mg (n = 12) versus Placebo (n = 9) Duration of treatment: 4 months | |
| Outcomes | Primary outcome: sperm parameters Secondary outcomes: pregnancy rate | |
| Notes | Author replied 21.09.2009 saying: Quote "The published 2006 trial is the published version of the 2003 abstract (Pryor 2003)" and giving details of randomisation and concealment. Author says he will try and find out about the 5 patients that dropped out. Why did ‐ "5 additional patients entered the study but dropped out before completion" ‐ when did these patients enter and were they randomised? Quote: "One of these 5 dropped out because of pregnancy three months after starting carnitine" Pryor paper excluded as it is the same study as Sigman, author also gave details of randomisation and allocation concealment, author will try to find info on 5 patients who dropped out. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Patients were randomised to receive carnitine or placebo" Quote: "The randomisation was done by a third party a company that oversaw the trial. We sent the patient number of new recruited patients in to them, they assigned them a study number that was associated with a collection of medication/placebo." The author replied to randomisation query 23.09.09 saying that the protocol stated that ‐ "treatments will be assigned randomly to a subject number. The numbers will range from 1‐84 for study centre 1 and 85‐168 for study centre 2. Randomisation of treatments for each centre will be done independently. One half of subject numbers will be placebo, the other half, active ingredient." |
| Allocation concealment (selection bias) | Low risk | Quote: "The investigators and study sites had the study medication/placebo packets identified by number only. They were blinded to what was in the medication/placebo packets. We were sent the code at the conclusion of the trial." The author replied to a query on allocation concealment on 23.09.09 saying that the protocol stated that ‐ " Integrated Data Solutions, Inc. will keep the randomisation code in a separate sealed envelope for each site until the end of the study. The randomisation lists will be provided to the packaging company for packaging of the packets into patient medication boxes.” |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Both the investigators and the patient were blinded to the treatment arm assignment." |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "5 additional patients entered the study but dropped out before completion. One of these dropped out because of pregnancy three months after starting carnitine." Author replied to query re drop outs, quote: "I have data on one drop out at my site ‐ the drop out occurred after randomisation to carnitine. The drop out occurred before the first follow‐up study visit. The other four drop outs were from the other study site ‐ I am trying to get that data for you" (23.09.09) |
| Selective reporting (reporting bias) | Unclear risk | All outcomes of interest were reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled open‐label trial Duration of study: unclear, from 2008 to 2009 | |
| Participants | Country: Russia Population: men with chronic prostatitis and abnormal fertility for more than 6 months, N = 30 Mean age: unclear, range 18 to 40 years | |
| Interventions | Selznic (selenium + zinc + vitamins) (n = 15) versus Placebo (n = 15) Duration of treatment: 3 months | |
| Outcomes | Sperm motility, sperm concentration | |
| Notes | Article in Russian, translated by Vasya Vlassov. No SD available. Need to contact authors regarding methods, standard deviations, type of control and any pregnancy data. Author Vasya 17.02.14 saying that the control was placebo and SD's not given. Emailed the institution 18.02.2014 regarding methods and data, no reply as of 07.03.2013. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | No allocation concealment |
| Blinding of participants and personnel (performance bias) | Unclear risk | Quote: "Open labelled". However placebo used, might be a translation problem |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: unclear | |
| Participants | Country: Greece Population: oligoasthenospermic infertile (OAI) men, N = 39 Mean age: unclear Inclusion criteria: unclear Exclusion criteria: unclear | |
| Interventions | Avanafil 150 mg (n = 13) versus L‐carnitine 1.5 g (n = 14) versus No treatment (n = 12) Duration of treatment: 12 weeks | |
| Outcomes | Sperm parameters, length of sperm midpiece (LMP), outcome of hypoosmotic swelling test (%HPST), seminal plasma citrate concentration | |
| Notes | Abstract only. Email sent to Dimitriadis ([email protected]) on 21.02.2018 to ask for data/full text, reply the same day from the author: Quote: "This work has not been published as a full paper". New email sent on 26.02.2018 to ask if we could receive data (mean+SD) for the L‐carnitine and placebo group. Reminder email sent on 22.03.2018. No reply received to date (19.04.2018). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Control is no treatment group |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Unclear risk | Unclear, only abstract available |
| Study characteristics | ||
| Methods | Multicentre, randomised clinical trial Duration of study: from December 2015 to December 2018, follow‐up 6 months | |
| Participants | Country: USA Population: male partner with at least one abnormal semen parameter on a semen analysis, N = 171 Median (IQR) age: 34.0 years (30.0‐38.0) in intervention group and 34.0 years (30.0‐37.0) in placebo group Inclusion criteria: heterosexual couples with at least 12 months of infertility were eligible. Male partners were 18 years of age or older with at least one abnormal semen parameter on a semen analysis in the preceding 6 months: sperm concentration ≤ 15 million/mL (oligospermia), total motility ≤ 40% (asthenospermia), normal morphology ≤ 4% (teratospermia), or DNA fragmentation ≥ 25%. Female partners were between 18 and 40 years of age with regular menstrual cycles (defined as 25 to 35 days in duration), evidence of ovulation (by biphasic basal body temperature, ovulation predictor kits, or luteal serum progesterone level ≥ 3 ng/ mL), and a normal uterine cavity with at least one patent fallopian tube. Women over the age of 35 had a normal ovarian reserve, defined as an early follicular phase follicle stimulating hormone (FSH) level of ≤10 IU/L, an anti‐mullerian hormone (AMH) level of ≥ 1.0 ng/mL, or antral follicle count >10. Exclusion criteria: male partners were excluded if they had a sperm concentration <5 million/mL on the screening semen analysis or if they were taking fertility medication or testosterone. Men were required to refrain from taking any vitamins for 4 weeks before randomisation. | |
| Interventions | Antioxidant formulation (500 mg of vitamin C, 400 mg of vitamin E, 0.20 mg of selenium, 1000 mg of L‐carnitine, 20 mg of zinc, 1000 mg of folic acid, 10 mg of lycopene, and 2,000 IU of vitamin D) oral daily (n = 85) versus Placebo (n = 86) Antioxidant or placebo added to treatment with IUI with ovulation induction with Clomid. Duration of treatment: at least 3 months and up to 6 months | |
| Outcomes | Live births, pregnancy (defined as a positive home pregnancy test), semen parameters, DNA fragmentation with SCSA test, adverse events, pregnancy loss, still birth, plasma vitamin levels | |
| Notes | Power calculation provided. Only the change in semen parameters are reported. “Because we failed to reject the null hypothesis for the internal pilot, further enrolment in the trial was stopped based on the recommendation of the data and safety monitoring board; all enrolled couples completed the study protocol.” E‐mailed authors [email protected] and [email protected] to request outcome data expressed as mean+SD and data on clinical pregnancy rate. Reply on 18‐03‐2021 with requested data. Data from supplementary table 5 were used for “live births‐as treated”‐ analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "The randomization scheme was generated using a computer‐generated random number sequence in randomly varying blocks of four and six stratified by site and female age (<35 years andR35 years of age) with allocation 1:1 by the data‐coordinating center through a Web‐based, secured randomization service." |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "The study medications were assigned in a double‐blind fashion." |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | High risk | 18/85 in antioxidant group withdrawn (1 lost to follow up, 2 medication side effects, 6 no longer interested in participating, 4 unable to contact patient, 2 possible zika exposure, 1 moving out of the area, 1 not responding to Clomid, 1 other). 9/86 in placebo group withdrawn (1 100% globozoospermia, 2 no longer interested in participating, 2 patient non‐compliant to protocol, 1 patient and spouse separated, 1 unable to continue study due to personal constraints, 1 rest cycle needed due to right ovary cyst, 2 other). However in the results section there is additional missing data, reason are not mentioned. |
| Selective reporting (reporting bias) | High risk | Time to pregnancy not reported. Protocol available (NCT02421887). |
| Study characteristics | ||
| Methods | Double‐blind, randomised, placebo‐controlled study Duration of study: from June 2015 to August 2016 | |
| Participants | Country: Sweden Population: men who had been referred for infertility – defined as at least one year of unsuccessful attempt to achieve pregnancy, in whom previously performed semen analysis showed DFI ≥ 25%, N = 79 Mean age: 38.0 ± 5.2 years (antioxidant group) and 37.3 ± 4.9 years (placebo group) Inclusion criteria:
Exclusion criteria:
| |
| Interventions | Antioxidant supplement (vitamin C 30 mg, vitamin E 5 mg, vitamin B12 0.5 mcg, l‐carnitine 750 mg, coenzyme Q10 10 mg, folic acid 100 mcg, zinc 5 mg, selenium 25 mcg), oral twice daily (n = 37) versus Placebo (maltodextrin, calcium carbonate, citric acid, steviol glycoside, flavours, beta‐carotene and silicon dioxide), oral twice daily (n = 40) Duration of treatment: 6 months | |
| Outcomes | Pregnancy (defined as positive urine test), adverse events, semen analysis, DNA fragmentation with SCSA | |
| Notes | Power calculation is conducted prior to study. E‐mailed authors [email protected] on 23‐03‐2021. Reply on 24‐03‐2021 and 11‐05‐2021: Tables with means and SDs of sperm concentration, total motility, progressive motility and DFI at the different time points, are provided. "Pregnancy was not our primary outcome, so we do not have any data on ultrasound. We defined pregnancy as positive urine test." Pregnancy data not used due to biochemical pregnancy. Data on sperm parameters adjusted from median+IQR to mean+SD for meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "They were pre‐packed in identical boxes and numbered according to a randomization list, by the pharmaceutical company that supplied with the products." |
| Allocation concealment (selection bias) | Low risk | Quote: "The allocation sequence was concealed from patients, health care providers, data collectors and researchers." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "double‐blind, placebo‐controlled", "They were pre‐packed in identical |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "The allocation sequence was concealed from patients, health care providers, data collectors and researchers." |
| Incomplete outcome data (attrition bias) | Unclear risk | Quote: "Of the remaining 77 men, 37 were randomized to antioxidant treatment and 40 to placebo. Two men missed three months visit, and two other men missed six months visit. The reason in all four cases was that the subjects, due to lack of time, missed the 2 days time window for the visit." Not clear to which group the patients belong. |
| Selective reporting (reporting bias) | Low risk | All outcomes reported. Protocol available. Pregnancies not mentioned in protocol. |
| Study characteristics | ||
| Methods | Randomised double‐blind controlled trial Duration of study: 6 months, follow‐up unclear | |
| Participants | Country: Saudi Arabia Population: asthenozoospermic men attending a fertility centre, N = 110 Mean age: treatment group 34.8 (27 to 52) years, control group 33.2 (22 to 45) years Inclusion criteria: asthenospermic (≥ 20 x 106 /mL). sperm motility ≤ 40%, normal sperm count, leucocyte concentration < 5%, normal fructose concentration, normal female Exclusion criteria: unclear | |
| Interventions | Vitamin E 300 mg (n = 52) versus Placebo (n = 35) Duration of treatment: 6 months | |
| Outcomes | Primary outcome: motility and MDA concentration Secondary outcome: live birth, pregnancy, miscarriage | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "Either 100mg vitamin E or a placebo was prescribed in a random double blind fashion". Method of randomisation not stated |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | Quote:"Double blinded". Placebo used. Quote: "If the semen sample improved and the patient's spouse became pregnant, the treatment was stopped; otherwise it was continued for 6 months. The placebo was given for 6 months" This could suggest that the investigators or clinicians had knowledge of whether the patients were in the placebo or antioxidant group, therefore this trial was rated as high risk. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | High risk | The exact dropout figures for each group is unclear. Quote: "A total of 110 patients were enrolled in the study, but some of the patients dropped out and some left the region and failed to continue. When the experiment was terminated, 52 patients were found to have taken vitamin E and 35 patients to have taken the placebo." Assuming the groups were equal initially then the placebo group lost 20 men and the intervention lost 3. A dropout rate of >20% |
| Selective reporting (reporting bias) | Unclear risk | All outcomes stated in the methods were reported in results. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: from February 2017 to April 2018 | |
| Participants | Country: China Population: male infertility patients with low acrosin activity, N = 232 Mean age: 30.67 ± 0.39 years (L‐carnitine group) and 31.36 ± 0.78 years (control group) Inclusion criteria: all the patients had conceived for more than 1 year after marriage without contraception; sexual life is normal; did not take any medication for 3 months before treatment. Exclusion criteria: cryptorchidism, genitourinary tract infection, endocrine disease, testicular dysplasia, varicocele, failure to receive treatment or funding as prescribed, patients with other systemic diseases. | |
| Interventions | L‐carnitine 1 g, oral suspension three times daily (n = 173) versus Vitamin E (placebo) 100 mg, oral capsules 3 times daily (n = 59) Duration of treatment: 3 months | |
| Outcomes | Semen analysis: sperm concentration and progressive motility, sperm acrosome activity | |
| Notes | Article in Chinese, translated by Yue Wang, Yongchuan Gu, and Catherine Jia‐yun Tsai. Ethical approval and informed consent not mentioned in text. Abstract mentions 180 patients in L‐carnitine group, full report mentions 173. E‐mailed author [email protected] on 06‐05‐2021 for additional data for Risk of Bias assessment. No reply to date (03‐09‐2021). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned, unclear if L‐carnitine and placebo look identical. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | 9 lost to follow‐up, 11 did not take medication as indicated. Results for 156 patients in l‐carnitine group and 56 in placebo group are reported, that means 21 patients missing. Unclear to which group the withdrawals belonged. |
| Selective reporting (reporting bias) | Unclear risk | All outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind controlled trial Duration of study: 1.5 years, follow‐up 13 weeks | |
| Participants | Country: Australia Population: infertile men, couple undergoing IVF, N = 60 (recruited N = 82) Mean age: treatment group 37.1 ± 5.1 years, placebo group 35.5 ± 4.3 years Inclusion criteria: men with sperm samples showing oxidative stress and a significant level of DNA fragmentation (> 25% TUNEL positive) Exclusion criteria: female partner with diminished ovarian reserve or if the female partner is aged over 39 years | |
| Interventions | Menevit (folate 0.5 mg + garlic 1000 mg + lycopene 6 mg + vitamin E 400 IU + vitamin C 100 mg + zinc 25 mg + selenium 26 μg + palm oil) (n = 40) versus Placebo (containing palm oil) (n = 20) Duraton of treatment: 3 months, prior to IVF cycle | |
| Outcomes | Primary outcome: embryo quality Secondary outcomes: pregnancy, multiple pregnancy, fertilisation rate, side effects | |
| Notes | Power calculation performed Associate Professor Tremellen provided live birth data in December 2014 "Only one pregnancy failed in the Menevit arm after 13 weeks (late miscarriage 19 weeks of male infant). All other pregnancies, including the twin pregnancies went on to live birth and all babies appear to be doing well from the records". There were three sets of twins in the combined antioxidants group and nil in the placebo group. Each twin pregnancy and live birth was counted as one event in the data analyses due to the protocol specifications of the review | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote:"The randomisation schedule was computer generated in blocks of six by Bayer Consumer Care Australia". Using a 2:1 ratio Quote: "There were no significant differences between the active and the placebo group in terms of important baseline prognostic characteristics..." |
| Allocation concealment (selection bias) | Low risk | Quote: "the appropriately numbered bottles of capsules delivered to the clinical site without any participant knowing the treatment sequence. Patients were allocated the next numerical treatment package (one to sixty as they became eligible for enrolment" |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double‐blind". Placebo used. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | All withdrawals were accounted for, 2 from the intervention group, 4 from placebo all due to the couples not going through to embryo transfer |
| Selective reporting (reporting bias) | Unclear risk | All specified outcomes are reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: unclear | |
| Participants | Country: Greece Population: infertile men with idiopathic oligoasthenospermia with normal serum testosterone levels, N = 217 Mean age: unclear Inclusion criteria: unclear Exclusion criteria: unclear | |
| Interventions | Profertil (content not mentioned in report, from www.profertil.eu: for 2 capsules: l‐carnitine 440 mg, l‐arginine 250 mg, coenzyme Q10 15 mg, vitamin E 120 mg, zinc 40 mg, folic acid 800 mcg, glutathione 80 mg, selenium 60 mcg), oral twice daily (n = 45) versus L‐carnitine 1000 mg oral daily (n = 44) versus Profertil twice daily + avanafil 25 mg oral twice daily (n = 43) versus Avanafil 25 mg oral twice daily (n = 43) versus No treatment (n = 42) Duration of treatment: 90 days | |
| Outcomes | Serum hormones (FSH, LH, testosterone), semen analysis, sperm capacity to undergo hyperactivation, hypo‐osmotic swelling test, sperm DNA integrity with SCSA, zinc level in seminal plasma, clinical pregnancy | |
| Notes | Obtainment of informed consent not mentioned in report. Data presented as mean + SD: “as we previously described Dimitriadis et al., 2010”. Number of drop‐outs unclear. E‐mailed author Dr. Sofikitis [email protected] on 23‐03‐2021 and 04‐05‐2021. Sent e‐mail to co‐author Dr. Dimitriadis [email protected] on 28‐05‐2021. No reply to date (03‐09‐2021). Data on clinical pregnancies used except for the avanafil groups. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | High risk | No placebo control, different types of medication and frequency of intake. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Only mentioned for seminal zinc level: "blind fashion and duplicates". |
| Incomplete outcome data (attrition bias) | Unclear risk | Number of patients not mentioned in results tables. |
| Selective reporting (reporting bias) | Unclear risk | All outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised, multi‐centre, double‐blind, placebo‐controlled study Duration of study: unclear | |
| Participants | Country: Russia Population: infertile men, N = 109 Mean age: unclear Inclusion criteria: "diagnosis of infertility was made on the basis of absence of pregnancy during 1 year of regular sexual intercourse without contraception. All patients had one or more abnormal semen parameters" from e‐mail. Exclusion criteria:
| |
| Interventions | Brudy plus (docosahexaenoic acid 350 mg, omega‐3 fatty acids up to 500 mg, antioxidants (mixture of tocopherols) 0.45 mg), one oral tablet three times daily (n = 59) versus Vegetable oil, one oral tablet three times daily (n = 50) Duration of treatment: 90 days | |
| Outcomes | Semen analysis, DNA fragmentation (assay unclear), mixed antiglobulin reaction(MAR)‐test, cryotolerance test, electron microscopic analysis of spermatozoa | |
| Notes | Full report available in Russian, translation by Alyona Oryshchuk. Ethical approval not mentioned in report. E‐mailed author Dr. Zhivulko [email protected] on 03‐05‐2021 requesting information on population. Reply on 05‐05‐2021: "Diagnosis of infertility was made on the basis of absence of pregnancy during 1 year of regular sexual intercourse without contraception. All patients had one or more abnormal semen parameters" E‐mail 06‐05‐2021 requesting results of semen parameters (only data available on parameters after cryotolerance test). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "Randomization was performed using envelopes. On the day of randomization, the investigator selected the lowest numbered randomization envelope. The patient was given a dietary supplement with the number indicated inside the envelope." Not mentioned how sequence was generated. |
| Allocation concealment (selection bias) | Unclear risk | Generation of sequence not mentioned, so concealment is unclear. |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double‐blind, placebo controlled study" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Quote: "Due to the loss of follow‐up with the patients and failure to appear for control tests, 4 patients were excluded from the study". From figure: 1 withdrawal in placebo group, 3 withdrawals in Brudy plus group. |
| Selective reporting (reporting bias) | High risk | No results on semen analysis, only results after cryotolerance test reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: from August 2007 to August 2009 | |
| Participants | Country: China Population: infertile men with asthenozoospermia, N = 135 Mean age: unclear, range 23 to 26 years Inclusion criteria: male asthenozoospermia patients, aged 23 to 26 years old, with a history of infertility for about 1 to 10 years, and with no contraception measures after marriage at least 12 months, has normal sex life, the wife’s fertility is normal., semen analysis for at least twice based on WHO criteria (Forward mobile sperm (a + b level) < 50%, and fast forward movement sperm (a level) < 25%, sperm density > 20 x 106 /mL), tests for peripheral blood chromosome and reproductive hormones (FSH, LH, PRL, T) were normal, the tests for semen ureaplasma mycoplasma and chlamydia trachomatis were negative, semen WBC < 1 x 106 /mL Exclusion criteria:cryptorchidism, testicular dysplasia, varicoceles, reproductive tract infection | |
| Interventions | L‐carnitine 2 g + Vitamin E (n = 68) versus Vitamin E (n = 67) Duration of treatment: 3 months | |
| Outcomes | Pregnancy rates, adverse effects, % forward motile sperm, sperm density, % sperm normal morphology | |
| Notes | Article in Chinese, translated by Liu Qi. E‐mailed Qi (translator) regarding pregnancy and adverse event data, then may need to write to the authors. No reply to date. 2018: added data on progressive sperm motility | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "A total of 135 patients with asthenozoospermia were randomly divided into Groups". Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | 22 dropouts. Numbers from each group are given but no reasons are provided for the withdrawals. ITT not used in the trial analysis |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised double‐blind placebo‐controlled trial Duration of study: from July 1997 to August 1998 | |
| Participants | Country: the Netherlands Population: fertile and subfertile men, N = 103 (recruited subfertile N = 258) Mean age: 34.3 ± 3.9 years Inclusion criteria for subfertile group: failure of the woman to conceive after 1 year regular unprotected intercourse and sperm concentration of 5 to 20 million/mL Exclusion criteria for subfertile group: chromosomal disorders, cryptorchidism, vasectomy, use of folic acid or zinc supplements in the previous 3 months, vitamin B deficiency | |
| Interventions | Folic acid 5 mg (n = 22) versus Zinc sulphate 66 mg (n = 23) versus Zinc sulphate 66 mg + Folic acid 5 mg (n = 24) versus Placebo (n = 25) Duration of treatment: 26 weeks | |
| Outcomes | Sperm parameters | |
| Notes | Data in median and range. Use of fertile and subfertile men. Adjusted data to mean+SD for meta‐analysis. Placebo arm split. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "eligible fertile and subfertile men were randomly assigned according to a simple computer‐generated randomisation schedule in four blocks to receive folic acid and placebo, zinc sulphate and placebo, zinc sulphate and folic acid, or placebo and placebo, which resulted in eight subgroups." "At the end of the trial, the research fellow received the randomisation list that matched the codes from the hospital pharmacy." |
| Allocation concealment (selection bias) | Low risk | Quote: "capsules were coded by the hospital pharmacy according to the randomisation list." |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Double blind" Quote: "Neither the research fellow and the participants knew whether the participants received folic acid, zinc sulphate or placebo capsules" Quote: "Folic acid and placebo capsules were yellow and identical in appearance. Zinc sulphate and placebo capsules were white and identical in appearance" |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | 9 men withdrew from the subfertile arm of the trial, 1 due to side effects (gastrointestinal) and 8 due to lack of motivation. It is unclear which treatment groups these men were randomised to |
| Selective reporting (reporting bias) | Unclear risk | Outcomes reported. No protocol available. |
| Study characteristics | ||
| Methods | Randomised pilot study Duration of study: unclear | |
| Participants | Country: Belgium Population: men attending andrology clinic, N = 22 Mean age: unclear Inclusion criteria: unclear Exclusion criteria: unclear | |
| Interventions | Acetyl‐cysteine 600 mg (n = 5) versus Mixture of essential fatty acid (EFA) (DHA 1 g + y‐linolenic acid + arachidonic acid 100 mg) + α‐tocopherol (vitamin E) + β‐carotene (n = 12) versus Acetylcysteine + essential fatty acid (EFA) + antioxidants (n = 5) Duration of treatment: 4 to 6 months | |
| Outcomes | Sperm parameters, DNA damage (oh8dG) | |
| Notes | Abstract only. No extractable data. Attempted to contact authors re availability of data as means, if published?, methods of randomisation and allocation concealment | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Unclear risk | Not mentioned |
| Selective reporting (reporting bias) | Unclear risk | Abstract only |
| Study characteristics | ||
| Methods | Randomised, placebo‐controlled trial Duration of study: 3 months | |
| Participants | Country: Hungary Population: subfertile men, N = 20 (recruited N = 26) Mean age: treatment group 29.6 years, placebo group 28.3 years Inclusion criteria: unsuccessful attempt at pregnancy for over one year. A healthy female partner examined by a gynaecologist. Sperm volume < 2 mL and/or sperm concentration < 20 million/mL and/or morphology ratio < 30% and/or motility < 50%. No genital tract infection, no bacteria or fungi in urine or semen. Hormones are within physiological range. Intact renal function. No excessive magnesium intake Exclusion criteria: unclear | |
| Interventions | Magnesium 3000 mg (n = 10) versus Placebo (n = 10) Duration of treatment: 90 days | |
| Outcomes | Primary: sperm parameters Secondary: clinical pregnancy and side effects | |
| Notes | Attempted to contact authors regarding methods of randomisation and allocation concealment | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not mentioned |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Quote: "The members of Group P received the same number of placebo tablets which closely resembled the Magnerot tablets." Not mentioned |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | 20 were randomised and 14 were analysed. Quote: "To date 26 patients have participated in the study and 20 men (10 in both groups) have completed the program of treatment. Six patients (2 in group M and 4 in group P were excluded from the program, including five cases for poor compliance, since they did not attend the control meeting at the end of treatment. One patient from Group M experienced severe diarrhoea and so his treatment was halted." |
| Selective reporting (reporting bias) | Unclear risk | All sperm data for outcomes in the trial were given, however clinical pregnancy only reported in the results section and not mentioned in methods. No protocol available. |
| Study characteristics | ||
| Methods | Randomised controlled trial Duration of study: from January 2014 to February 2015 | |
| Participants | Country: China Population: patients with idiopathic asthenospermia, N = 120 Mean age: 32.5 years (treatment group) and 31.7 years in control group Inclusion criteria:
Exclusion criteria: unclear | |
| Interventions | Vitamin E 100 mg, oral twice daily (n = 50) versus Vitamin E 100 mg, oral twice daily + compound amino acid capsules 3 capsules twice daily Duration of treatment: 90 days | |
| Outcomes | Semen analysis: total sperm motility and progressive motility, pregnancy (definition of pregnancy unclear), adverse events | |
| Notes | Article in Chinese, translated by Yue Wang, Yongchuan Gu, and Catherine Jia‐yun Tsai. E‐mailed author [email protected] on 06‐05‐2021 to request information on “compound amino acids” and definition of pregnancy outcome. No reply to date (03‐09‐2021). Pregnancy data in Table 1 because of unclear definition. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | SAS software was used to generate random serial number |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not mentioned |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned |
| Incomplete outcome data (attrition bias) | Low risk | Numbers in results tables match randomised numbers. |
| Selective reporting (reporting bias) | Unclear risk | All outcomes reported. No study protocol available. |
AI: artificial insemination; ALA: alpha‐lipoic acid; ART: assisted reproductive technique;BMI: body mass index;DFI: DNA fragmentation index; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; FSH: follicle‐stimulating hormone; GSH: glutathione; HBA: hyaluronan binding assay;HCG:Human chorionic gonadotropin; ICSI: intracytoplasmic sperm injection; IgG: immunogobulin G;ITT: intention‐to‐treat; mg: milligram; IQR: interquartile range; IU: international unit; IUI: intrauterine insemination; IVF: in vitro fertilisation; LH: luteinizing hormone;mcg; microgram; MDA: malondialdehyde; mg: milligram; MMP: mitochondrial membrane potential; NSAID: non‐steroidal anti‐inflammatory; OAT:oligoasthenoteratozoospermia; PRL: prolactin;RoB: risk of bias; ROS: reactive oxygen species; SCSA: sperm chromatin structure analysis; SD: standard deviation; SE: standard error; SEM: standard error of the mean; STD: sexually transmitted disease; TAC: total antioxidant capacity; TESA: Testicular sperm aspiration; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick end labeling; VC: varicocele; VCT: varicocelectomy; WBC: white blood cell; WHO: World Health Organization.
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| Ineligible based on intervention: main intervention is oral Vitamin E. However there was also an in vitro Berberine wash added to the collected sperm in 10 random participants from both groups (treatment group with oral Vitamin E or untreated group) | |
| Ineligible based on study population: women | |
| Ineligible based on study design: "prospective randomised trial", however there was no control group, only comparison before and after treatment with antioxidants | |
| Ineligible based on intervention: Curcumin Nanomicelle is a herbal product | |
| Ineligible based on control: subfertile men with zinc treatment versus fertile men without treatment | |
| Ineligible based on study population: normozoospermic men and donors | |
| Ineligible based on study population: normozoospermic men and donors | |
| Ineligible based on outcome: seminal antioxidant levels and endocrine parameters. Furthermore, same study population/group as Azizollahi 2013 which was already included in the 2014 update | |
| Post hoc analysis of same study group as Busetto 2018, included in the 2018 update of the review. | |
| Ineligible based on study population: not subfertile men | |
| Ineligible based on population: idiopathic infertile men, not male factor | |
| Ineligible based on study design: not a randomized controlled trial | |
| Ineligible based on intervention: treatment with myo‐inositol plus herbal extracts (Tribulus Terrestris, Alga Ecklonia Bicyclis) | |
| Ineligible based on study design: not a randomised controlled trial | |
| Ineligible based on intervention: includes fertility drugs like tamoxifen. Group A tamoxifen + vitamin E, Group B tamoxifen | |
| Ineligible based on population: includes men with idiopathic infertility and normal sperm parameters | |
| Ineligible based on study design: used non‐randomised controls recruited from another unrelated trial | |
| Ineligible based on study population: inappropriate population, polymorphisms | |
| Ineligible based on study population: antioxidant given to the women | |
| Ineligible based on study design: review article | |
| Ineligible based on intervention: in vitro selenium, no oral intake | |
| Ineligible based on intervention: clomiphene + vitamin E versus placebo, fertility enhancing drug | |
| Ineligible based on study design: prospective cohort study, not a randomised controlled trial | |
| Ineligible based on control: healthy fertile patients with intervention or control group of healthy patients undergoing IVF for a female factor | |
| Ineligible based on intervention: plant extracts, herbal formulation | |
| Ineligible based on intervention: fertility enhancing drug, protocol exclusion criteria. Group A Tamofixfen citrate with antioxidant, group B tamoifen alone and group C placebo | |
| Ineligible based on study design: not randomised quote: "men were classified into groups". Numbers of men in the groups were uneven | |
| Ineligible based on study design: prospective study, not randomised | |
| Ineligible based on population: includes infertile men who are normospermic, oligospermic or azoospermic. No subpopulation with extraction data | |
| Ineligible based on study population: women | |
| Ineligible based on intervention: oral myo‐inositol supplement with treatment of the semen with myo‐inositol incubation. The control group did not receive any form of treatment (no oral, no incubation). Not able to differentiate between effect due to oral supplement or incubation | |
| Ineligible based on intervention: used a herbo‐mineral supplement | |
| Ineligible based on intervention: route of supplementation was intramuscular not oral | |
| Ineligible based on study population: women | |
| Ineligible based on study population: also included infertile men with normospermic parameters. No subgroup analysis | |
| Ineligible based on intervention: pentoxifylline no longer included, fertility enhancing drug | |
| Ineligible based on intervention: pentoxifylline no longer included, fertility enhancing drug | |
| Ineligible based on study design: not randomised, 105 men in the treatment group and 35 in control. Abstract only | |
| Ineligible based on (repetitive) study population: same study as Pourmand 2014, second author Movahedin | |
| Ineligible based on (repetitive) study population: exact same population, including the baseline characteristics and period of inclusion, as Nadjarzadeh 2011. Different outcome parameters (seminal plasma levels of antioxidant enzymes and oxidative stress) | |
| Ineligible based on study design: no RCT, full text received from first author by email, after translation of full text (in Russian) to English found out there was no control group | |
| Ineligible based on control: control group was treated with ferrous sulphate. This is not an antioxidant so not suitable for head‐to‐head comparison | |
| Ineligible based on no data to publish: study was terminated, not being able to recruit enough participants (contact with author) | |
| Ineligible based on no data to publish: recruiting participants not successful (contact with author) | |
| Ineligible based on intervention: treatment with probiotics | |
| Ineligible based on outcome: endocrine parameters and seminal antioxidant level. Furthermore, same study population as Azizollahi 2013 (included in update 2014) | |
| Ineligible based on study design: a commentary on Ghanem 2010 | |
| Ineligible based on study design: not randomised, allocation method is by alternation. Translated from Bulgarian by Ivan Sola. Quote; "50 of them were randomly invited to participate depending on their order of attendance to the clinic" | |
| Ineligible based on study population: women were treated with vaginal suppositories | |
| Same study as Gamidov 2017, included study in 2018 update of the review | |
| Ineligible based on study design: not a randomised controlled trial | |
| Ineligible based on study population: women | |
| Ineligible based on intervention: pentoxifylline no longer included, fertility enhancing drug | |
| Ineligible based on intervention: saffron, herbal not a supplement | |
| Ineligible based on study design: not randomised, based on conference abstract | |
| Ineligible based on study population: not subfertile men | |
| Ineligible based on study design: not randomised, the study uses alternate allocation, odd and even numbers. Appears to be a report of the study Nikolova 2007 | |
| Ineligible based on intervention: L‐arginine combined with herbal extract | |
| Ineligible based on intervention: tamoxifen, protocol exclusion criteria (tamoxifen + Q10 versus tamoxifen). Quote: “trials that included men taking other fertility enhancing drugs” | |
| Ineligible based on intervention: Spirulina platensis (4 g) and Resveratrol (500 mg) are plant extracts not antioxidant supplements | |
| Ineligible based on control: inappropriate control (anti‐inflammatory) group. Treatment is not compared to placebo or another antioxidant | |
| Ineligible based on control: Inappropriate comparison. The same antioxidant is compared at different times ‐ L‐carnitine + acetyl‐carnitine versus L‐carnitine + acetyl‐carnitine | |
| Ineligible based on control: inappropriate control (anti‐inflammatory). Treatment is not compared to placebo or another antioxidant | |
| Ineligible based on intervention: pentoxifylline no longer included, fertility enhancing drug | |
| Ineligible based on intervention: fertility enhancing drug, protocol exclusion criteria. Group A L‐carnitine + tamoxifen, Group B L‐carnitine, Group C tamoxifen. No placebo or no treatment control | |
| Ineligible based on study population: not subfertile men | |
| Ineligible based on study design: probably not randomised, no mention of randomisation in the abstract and uneven numbers between the groups, attempted to contact authors with no reply |
IVF: in vitro fertilisation; RCT: randomised controlled trial
Characteristics of studies awaiting classification [ordered by study ID]
| Methods | Interventional (clinical trial) Design Allocation: randomised controlled trial Masking: blinded (patient/participant, investigator/therapist) Control: placebo Assignment: parallel Study design purpose: treatment |
| Participants | Males with minimum age of 18 years Inclusion criteria
Exclusion criteria
|
| Interventions | Drug: Taking AM019016 (verum), dietary food, 3 capsules once a day Ingredients: vitamin D, E, C, B12, B6, B2, Folic Acid, L‐Carnithine, L‐Arginine, Coenzyme Q10, Zinc, Selenium, β‐carotene, Copper, Pigrafert (combination of pine bark, grape seed, green tea extract). Control: Taking AM019016 (placebo), 3 capsules once a day Ingredients placebo: maltodextrin, release agent magnesium salts of feed fatty acids and dye E171 and hydropropylmethylcellulose in the capsule shell. Free of gluten and lactose. Duration: 12 weeks |
| Outcomes | Primary Parameters for the assessment of the benefit by preparation and evaluation of spermograms according to the WHO criteria (2010, 5th edition)
Secondary Parameters for the assessment of tolerability:
|
| Notes | Secondary ID: S15(a)/2017 Email Baumgraβ 07.04.2021 to ask about current status. |
| Methods | Randomised controlled trial Duration of study: unclear |
| Participants | Country: Russia Population: "men with pathozoospermia", N = 60 Mean age: Unclear (age ranfge 25‐40 years) Inclusion criteria: unclear Exclusion criteria: unclear |
| Interventions | Speroton complex (L‐carnitine + vitamin E + folic acid + selenium + zinc) (n = 30) versus No treatment (n = 30) Duration of treatment: unclear |
| Outcomes | Semen analysis, level of fructose and zinc, pregnancy |
| Notes | Full text not available. Contacted author Dr Kuzmenko ([email protected] and [email protected]) to request full text for more information on study population: pathozoospermia? No reply to date. |
| Methods | Interventional (clinical trial) Design Allocation: randomised Masking: triple‐blind (participant, caregiver, investigator) Placebo control Parallel assignment |
| Participants | Males, 19 years to 60 years Inclusion criteria
Exclusion criteria
|
| Interventions | Drug: Spermotrend (vitamins plus other antioxidants) twice a day Control: placebo twice a day Duration: 12 weeks |
| Outcomes | Primary
Secondary
|
| Notes | Email sent 08.02.2018 to [email protected] Email sent 07.04.2021 to [email protected] |
| Methods | Interventional (clinical Trial). Phase 3 Design Allocation: randomised Intervention model: parallel assignment Masking: quadruple (participant, care provider, investigator, outcomes assessor) |
| Participants | Males, 18 years to 60 years Inclusion criteria
Exclusion criteria
|
| Interventions | Drug: folic acid 15 mg per day (tablets of 5 mg) Control: placebo of folic acid Duration: 3‐4 months |
| Outcomes | Primary
Secondary
|
| Notes | Email sent 08.02.18 to [email protected]. Received an answer 09.02.18 that the trial recruiting phase is completed. Submitting the results within a few weeks. Email sent 07.04.21 to [email protected]. Reply on 08.04.21 that the article is submitted. |
| Methods | Interventional (clinical trial), phase 2/3 Design Allocation: randomised |
| Participants | Male 25 years to 65 years Inclusion criteria
Exclusion criteria
|
| Interventions | Sham arm (normospermic): 4000 mg/die of myo‐inositol + 400 µg of folic acid (phase 2) Active arm (OAT): myo‐inositol 4000 mg/die associated to 400 µg of folic acid (phase 3) Placebo arm (normospermic): 400 µg of folic acid Duration: three months |
| Outcomes | Primary
|
| Notes | Email sent 07.02.18 to Gulino ([email protected]) to ask if this study correlates with the same study population of study NCT01560065 (Gulino 2016) Email sent 07.04.2021 to [email protected]. |
ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilisation; MTHFR: methylene tetrahydrofolate reductas;OAT: oligoasthenoteratozoospermia; WHO: World \health \Organization
Characteristics of ongoing studies [ordered by study ID]
| Study name | Assessment of seminal plasma myeloperoxidase level (ROS) and the effect of vitamin C therapy on semen quality in infertile men |
| Methods | Interventional (clinical trial) Design Allocation: randomised Intervention model: randomised, parallel group, placebo‐controlled trial Masking: quadruple (participant, investigator, outcome assessor and date‐entry operator) Target sample size: 258 |
| Participants | Male patients aged 20‐45 years with infertility. Inclusion criteria:
Exclusion criteria:
|
| Interventions | Drug: vitamin C 500 mg, oral once daily Control: calcium supplements Duration: 3 months |
| Outcomes | Primary:
Secondary:
|
| Starting date | 01‐04‐2019 |
| Contact information | Radha Vembu, Designation Associate Professor Affiliation Sri Ramachandra Institute of Higher Education and Research Address No 74, II floor, Venkatasai flats, Rajagopalan street,SDK Amman Nagar, Valsaravakkam, Chennai 87 Sri Ramachandra Nagar, Porur, Chennai TAMIL NADU 600116 India Phone 9841141310 Email [email protected] |
| Notes | Email sent 08‐03‐21 to Radha Vembu. Reply on 07‐04‐21: “We have certain issues in starting the trial. Hence, we don't have information to share.” |
| Study name | Effect of CO‐Q 10 supplementation versus placebo on spermogram parameters and sexual function in infertile men: a double‐blind randomized clinical trial |
| Methods | Interventional (clinical trial) Design Allocation: randomised Intervention model: double‐blind randomised clinical trial, phase II Masking: participant, care provider, investigator, outcome assessor Sample size: 70 |
| Participants | Men with primary infertility, aged 18‐40 years. Inclusion criteria: Abnormality in at least one of the sperm parameters (volume, concentration, number, motility, or morphology) and body mass index less than 30 Exclusion criteria: Chromosomal abnormalities, varicocele, cryptorchidism, chronic diseases such as diabetes, kidney disease, infectious diseases, genital tract infection, thyroid disorder, drug or alcohol use, taking spermatogenic drugs (methotrexate, nitrofurantoin, colchicine or chemotherapy), taking pituitary suppressive drugs (testosterone, GnRh analogs), taking anti‐androgens (cimetidine or spironolactone), taking alpha‐blockers, antidepressants, or phenothiazide, history of testis surgery |
| Interventions | Routine infertility treatment plus: Drug: coenzyme Q10 30 mg daily Control: placebo once daily Duration: 12 weeks |
| Outcomes | Primary: sperm volume, count, concentration, motility and morphology Secondary: None |
| Starting date | 21‐01‐2020 |
| Contact information | Taiebeh Gharakhani, Master Hamedan University of Medical Sciences Fatemieh Hospital, Pasdaran Ave., Hamadan, 6517838695 Phone: +98 81 3828 3939 Email: [email protected] Dr. Seyedeh Zahra Massomi, PhD, Fertility Health Specialist School of Nursing and Midwifery, Hamadan University of Medical Sciences, Shahid Fahmideh Ave. Hamadan, 6517838695 Phone: +98 81 3838 0572 Email: [email protected] Email: [email protected] |
| Notes |
| Study name | The effect of vitamin C supplementation on quality of spermogram in infertile men with asthenozoospermia with a balanced diet in Mother and Childhospital, Shiraz, 1392 |
| Methods | Interventional (clinical trial) Design Allocation: randomised Intervention model: randomised, double‐blinded, placebo‐controlled trial Masking: participant, care provider, investigator |
| Participants | Inclusion:
Exclusion:
|
| Interventions | Drug: vitamin C tablets once daily Control: placebo Duration: one month |
| Outcomes | Primary: sperm count, shade, movement and volume Secondary: none |
| Starting date | 21‐03‐2018 |
| Contact information | Shiraz University of Medical Sciences Sedighe Forouhari, Ph.D, Supervisor, Reproductive Health College Of Nursing Midwifery, Shiraz, Fars, 71345‐1978 Phone: +98 71 1647 4257 Email: [email protected] |
| Notes | According to www.irct.ir: recruitment complete. |
| Study name | The effect of alpha lipoic acid on sperm parameters, DNA integrity and oxidative stress in infertile men with increased level of sperm DNA damage |
| Methods | Interventional (clinical trial) Design Allocation: randomised Intervention model: triple‐blind randomised clinical trial Masking: participant, care provider, investigator, outcome assessor, date analyser, data and safety monitoring board Sample size: 80 |
| Participants | Inclusion criteria:
Exclusion criteria:
|
| Interventions | Drug: Alpha lipoic acid (ALA) 300 mg twice daily Control: placebo 300 mg twice daily Duration: 3 months |
| Outcomes | Primary: DNA damage, sperm motility, sperm morphology, count, vitality, lipid peroxidation (MDA level), mitochondrial membrane potential, total antioxidant capacity, superoxide dismutase. glutathione peroxidase, reactive oxygen species, chromatin evaluation Secondary: fertilisation rate |
| Starting date | 22‐06‐2018 |
| Contact information | Prof. Mohammad Hossein Nasr Esfahani, Embryologist Royan Institute No.371, Allikhani Aleey, Mehr St., Salman Farsi Ave., Isfahan, Iran, 8158968433 Phone: +98 31 9501 5682 Email: mh.nasr‐[email protected] |
| Notes | Email sent 08‐03‐2021. Reply from author on 23‐03‐2021 that the paper has been submitted to a journal but is not yet published. |
| Study name | Evaluating the therapeutic effect of theophylline and zinc sulphate vo‐administration in infertile men |
| Methods | Interventional (clinical trial) Design Allocation: simple randomisation Intervention model: clinical trial with placebo‐control group, parallel groups, double‐blind, randomised Masking: participants, investigator, outcome assessors and data analysers Sample size: 120 |
| Participants | Infertile men referred to the infertility treatment centre Inclusion criteria:
Exclusion criteria:
|
| Interventions | Drug: Group 2: theophylline 200 mg daily, Group 3: zinc sulphate 220 mg daily, Group 4: theophylline 200 mg daily + zinc sulphate 220 mg daily Control: placebo Duration: 3 months |
| Outcomes | Primary: spermiogram, hormone levels (LH, FSH, testosterone), malondialdehyde level, TNF‐alpha and interleukin 10, DNA fragmentation (SDFA), sperm viability, total antioxidant level of semen (TAC), expression of caspase 3, BAX, BCL2 genes and ‐proteins, inflammatory factors, sperm maturation, sperm capacitation Secondary: None |
| Starting date | 22‐12‐2019 |
| Contact information | Dr. Alireza Noushad Kamran Rastak Fertility Clinic, Sina Hospital, Next to Imam Khomeini Stadium, Hepko Ave., Arak Markazi, 3818853558 Phone: +98 86 3340 5343 Email: [email protected] Atena Sadat Azimi, PhD student Arak University, No. 6313, At the top of Azimi shop, Haqqani Street, Arak Markazi, 3815166315 Phone: +98 86 3277 7300 Email: a‐[email protected] |
| Notes | Email sent to Atena Azimi 08‐03‐2021. Reply on 09‐03‐2021 that recruitment has been completed, no published paper available. |
| Study name | Effect of vitamin E on quality and quantity of sperm in infertile men after varicocelectomy |
| Methods | Interventional (Clinical trial) Design Allocation: randomised Interventional model: randomised, superiority, parallel group trial, blinded Masking: participants, outcome assessors and data analysers |
| Participants | Inclusion criteria:
Exclusion criteria:
|
| Interventions | Drug: varicocelectomy and vitamin E 400 IU once daily Control: varicocelectomy and placebo Duration: 3 months |
| Outcomes | Primary: Variables in the spermiogram include semen volume, sperm count, and sperm motility Secondary: None |
| Starting date | 22‐09‐2021 |
| Contact information | Kasra Saeedian, medical student Mashhad University of Medical Sciences No. 34, Nazari Ave., Fajr Street., Motahari Street, Tehran, 1588746675 Phone: +98 21 8881 1033 Email: [email protected] |
| Notes |
| Study name | Neotililty trial: effect of coenzyme Q10 on semen parameters in men with idiopathic infertility |
| Methods | Interventional (clinical Trial) Design Intervention model: single‐group assignment Masking: none (open‐label) |
| Participants | Males, 20 years to 50 years Inclusion criteria
Exclusion criteria
|
| Interventions | Drug: coenzyme Q10 200 mg daily Control: placebo daily Duration: 26 weeks |
| Outcomes | Primary
Secondary
|
| Starting date | August 2017 |
| Contact information | Anum Siddiqui, PharmD / Masood Jawaid, MRCS,FCPS HillPark Hospital Karachi, Pakistan 9221‐34315195 NCT03104998,%20PE/PK/Neotility/SP/2017‐01,%20Neotililty%20Trial:%20Effect%20of%20Coenzyme%20Q10%20on%20Semen%20Parameters%20in%20Men%20With%20Idiopathic%20Infertility" type="EXTERNAL">[email protected] |
| Notes | Email sent 07.04.2021 to Siddiqui and Jawaid asking for current status. Clinicaltrials.gov: withdrawn. |
| Study name | The impact of a nutritional supplement (Impryl®) on male fertility (SUMMER) |
| Methods | Interventional (clinical Trial) Design Allocation: randomised Intervention model: multicentre, randomised double‐blind placebo‐controlled clinical trial/superiority study Masking: triple (participant, care provider, investigator) |
| Participants | Males, 18 years to 50 years Inclusion criteria
OR
OR
Furthermore
Exclusion criteria
|
| Interventions | Drug: Impryl, one tablet daily Ingredients: food supplement with betaine, cystine, zinc, niacin, folic acid (di5MTHF‐glucosamine), Vitamin B12 (cobalamin), Vitamin B6, Vitamin B2 (Riboflavin) Control: placebo, one tablet daily Duration: 6 months |
| Outcomes | Primary
Secondary
|
| Starting date | April 2018 |
| Contact information | Wiep de Ligny, MD Radboud University Nijmegen, the Netherlands, 6500HB +31 (0) 651751244 NCT03337360,%20NL61414.091.17,%20SUMMER‐study:%20the%20Impact%20of%20a%20Nutritional%20Supplement%20(Impryl%C2%AE)%20on%20Male%20Fertility">[email protected] |
| Notes | 02.06.2021: study is still recruiting, currently 470 patients included. |
| Study name | Omega‐3 PUFA for treatment of patients with idiopathic oligoasthenoteratospermia |
| Methods | Interventional (clinical trial) Design Allocation: randomised Intervention model: double‐blind, placebo‐controlled and randomised exploratory clinical trial Masking: quadruple (participants, care providers, investigators and data analysers) Sample size: 30 |
| Participants | Inclusion criteria:
Exclusion criteria:
|
| Interventions | Drug: omega 3 fatty acid 1 g per capsule (EPA 400 mg + DHA 320 mg) Control: placebo capsule, mainly composed of corn oil Duration: 40 days |
| Outcomes | Primary: sperm concentration Secondary: progressive sperm ratio, DNA fragmentation index, gut microbiota composition |
| Starting date | 08‐11‐2017 |
| Contact information | Bing Yao Center for Reproductive Medicine, Jinling Hospital Nanjing, Jiangsu, China, 210000 86‐25‐80860174 |
| Notes |
| Study name | Impact of a nutritional supplements' combination (FERTILIS) on male infertility: a monocentric double Bbind Rrndomized placebo controlled trial |
| Methods | Interventional (clinical trial) Design Allocation: randomised Intervention model: comparative, interventional, prospective, monocentric, double‐blind, randomised, placebo‐controlled trial Masking: quadruple (participants, care providers, investigators and outcome assessors) |
| Participants | Inclusion criteria:
Exclusion criteria: none |
| Interventions | Drug: Fertilis Homme twice daily Ingredients: l‐carnitine 220 mg, zinc 20 mg, selenium 0.03 mg, l‐arginine 125 mg, l‐glutathione 40 mg, folic acid 0.4 mg, coenzyme Q10 7.5 mg and vitamin E 60 mg Control: placebo (sugar pills) twice daily Duration: 3 months |
| Outcomes | Primary: sperm DNA fragmentation index Secondary: ejaculatory volume, sperm cell density, sperm quality (i.e. morphology, total motility and progressive motility), spontaneous pregnancy, pregnancy consecutive to assisted reproductive techniques, fertilization rate during IVF, embryo cleavage rate and embryo quality during ICSI, clinical pregnancy, live birth, adverse events |
| Starting date | 17‐02‐2020 |
| Contact information | Amina Radoui, MSc Tunisia Farhat Hached Hospital Sousse, Tunisia |
| Notes | Email sent to Amina Radoui 08‐03‐2021. Reply on 07‐04‐2021: “The study is continuing inclusions of patients (currently at 97 inclusion) after putting it on hold during the first COVID‐19 wave in Tunisia, March – June 2020. We haven’t produced any preliminary results as insufficient monitoring & follow‐up data is available.” |
| Study name | Administration of antioxidants to infertile men and spermqQuality |
| Methods | Interventional (clinical trial) Design Allocation: randomised Intervention model: randomised, quadruple‐blinded, placebo‐controlled clinical trial Masking: participant, care provider, investigator, outcome assessor |
| Participants | Inclusion criteria:
Exclusion criteria:
|
| Interventions | Drug: Spermotrend Ingredients: vitamin C 30 mg, vitamin B6 1 mg, folic acid 100 mcg, vitamin B12 0.5 mcg, vitamin E 5 mg, zinc 7.5 mg, selenium 13.2 mcg, l‐cysteine Control: placebo Duration: 3 months |
| Outcomes | Primary: sperm motility (A, B, C and D), sperm concentration, vitality, morphology Secondary: ROS (8OHdG), DNA fragmentation index |
| Starting date | 30‐03‐2020 |
| Contact information | Stratis Kolibianakis, Professor Pinelopi Ioannidou, MD Aristotle University Of Thessaloniki, Andrology lab Zeginiadou Armatura, Greece |
| Notes |
| Study name | The role of micro nutrient supplement in improvement of the sperm DNA fragmentation |
| Methods | Interventional (clinical trial) Design Allocation: randomised Intervention model: randomised controlled trial Masking: triple (participant, care provider, investigator) |
| Participants | Male from infertile couples treated at the Center of Reproductive Endocrinology and Infertility, Hue University Hospital, Vietnam, aged 18‐60 years. Inclusion criteria:
Exclusion criteria:
|
| Interventions | Drug: PROfortil twice daily + Vitamin E 400 IU once daily Ingredients: l‐carnitine 440 mg + l‐arginine 250 mg, coenzyme Q10 15 mg, vitamin E 120 mg, zinc 40 mg, folic acid 800 mcg, glutathione 80 mg, selenium 60 mcg Control: Vitamin E 400 IU once daily Duration: 3 months |
| Outcomes | Primary:
Secondary:
|
| Starting date | 18‐09‐219 |
| Contact information | Minh Tam Le, A.Prof 0084989228779 leminhtam@huemed‐univ.edu.vn Hue University Vietnam |
| Notes |
| Study name | Effects of different antioxidants on sperm parameters in infertile males |
| Methods | Interventional (clinical trial) Design Allocation: randomised Intervention model: randomised controlled trial Masking: outcome assessors Sample size: 105 |
| Participants | Inclusion criteria:
Exclusion criteria:
|
| Interventions | Drug: vitamin C 1000 mg and zinc 20 mg once daily Control: acetyl‐cysteine 200 mg and selenium 100 mg once daily, vitamin E 1000 mg and folic acid 400 mcg once daily Duration: 12 weeks |
| Outcomes | Primary: sperm motility, concentration and morphology Secondary: none |
| Starting date | 15‐02‐2016 |
| Contact information | Mohamed Elsamra, Professor of Obstetrics and Gynaecology Faculty of Medicine, University of Alexandria 175 Horyia Street, Ibrahimia, Alexandria, 21524, Egypt [email protected]; 002‐01111113015 Elsayedamr Basma, Patient Information Manager 30 Garden City Smouha, Alexandria, 21615, Egypt [email protected]; 00201223106023 Sherif Aggag, Consultant, Department of Clinical Pathology 4 Hamed ElKohly Street, San Stifano, Alexandria, 21532, Egypt [email protected]; 002‐01223271716 |
| Notes |
ART: assisted reproductive technique;BMI: body mass index;DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; FSH: follicle‐stimulating hormone; GnRH: gonadotropin releasing hormone; ICSI: intracytoplasmic sperm injection;DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; IUI: intrauterine insemination; IVF: in vitro fertilisation; LH: luteinizing hormone;MDA: malondialdehyde; OAT:oligoasthenoteratozoospermia; PUFA: polyunsaturated fatty acids; ROS: reactive oxygen species; SCSA: sperm chromatin structure analysis; TAC: total antioxidant capacity; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick end labeling; WHO: World Health Organization.
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | ||||||||||||||||||||||||
| 1.1 Live birth; type of antioxidant Show forest plot | 12 | 1283 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.43 [1.07, 1.91] | ||||||||||||||||||||||||
| Analysis 1.1  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 1: Live birth; type of antioxidant | ||||||||||||||||||||||||||||
| 1.1.1 Astaxanthin + Vitamin E | 1 | 36 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.63 [0.34, 7.69] | ||||||||||||||||||||||||
| 1.1.2 Carnitines | 1 | 60 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.00 [0.24, 4.25] | ||||||||||||||||||||||||
| 1.1.3 Coenzyme Q10 | 1 | 60 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.16 [0.53, 8.82] | ||||||||||||||||||||||||
| 1.1.4 Vitamin D + Calcium | 1 | 330 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.03 [0.59, 1.80] | ||||||||||||||||||||||||
| 1.1.5 Vitamin E | 2 | 140 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 8.51 [2.36, 30.70] | ||||||||||||||||||||||||
| 1.1.6 Zinc | 1 | 100 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 3.74 [1.02, 13.74] | ||||||||||||||||||||||||
| 1.1.7 Combined antioxidants | 5 | 557 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.28 [0.86, 1.91] | ||||||||||||||||||||||||
| 1.2 Live birth; IVF/ICSI Show forest plot | 5 | 372 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.63 [1.01, 2.61] | ||||||||||||||||||||||||
| Analysis 1.2  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 2: Live birth; IVF/ICSI | ||||||||||||||||||||||||||||
| 1.3 Clinical pregnancy; type of antioxidant Show forest plot | 20 | 1706 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.89 [1.45, 2.47] | ||||||||||||||||||||||||
| Analysis 1.3  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 3: Clinical pregnancy; type of antioxidant | ||||||||||||||||||||||||||||
| 1.3.1 Astaxanthin + Vitamin E | 1 | 36 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.32 [0.35, 4.96] | ||||||||||||||||||||||||
| 1.3.2 Carnitines | 2 | 125 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.17 [0.30, 4.59] | ||||||||||||||||||||||||
| 1.3.3 Coenzyme Q10 | 1 | 60 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.16 [0.53, 8.82] | ||||||||||||||||||||||||
| 1.3.4 Folic acid | 1 | 53 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Not estimable | ||||||||||||||||||||||||
| 1.3.5 Magnesium | 1 | 26 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 8.73 [0.17, 445.08] | ||||||||||||||||||||||||
| 1.3.6 N‐acetylcysteine (NAC) | 2 | 100 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.00 [0.71, 5.63] | ||||||||||||||||||||||||
| 1.3.7 Vitamin E | 2 | 117 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 6.71 [1.98, 22.69] | ||||||||||||||||||||||||
| 1.3.8 Zinc | 2 | 153 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 4.43 [1.39, 14.14] | ||||||||||||||||||||||||
| 1.3.9 Zinc + Folic acid | 1 | 53 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 3.86 [0.15, 99.84] | ||||||||||||||||||||||||
| 1.3.10 Combined antioxidants | 10 | 983 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.67 [1.22, 2.28] | ||||||||||||||||||||||||
| 1.4 Clinical pregnancy; IVF/ICSI Show forest plot | 6 | 452 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.73 [1.15, 2.61] | ||||||||||||||||||||||||
| Analysis 1.4  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 4: Clinical pregnancy; IVF/ICSI | ||||||||||||||||||||||||||||
| 1.5 Adverse events Show forest plot | 21 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.5  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 5: Adverse events | ||||||||||||||||||||||||||||
| 1.5.1 Miscarriage | 6 | 664 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.46 [0.75, 2.83] | ||||||||||||||||||||||||
| 1.5.2 Ectopic pregnancy | 2 | 260 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.59 [0.16, 16.01] | ||||||||||||||||||||||||
| 1.5.3 Stillbirth | 1 | 200 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.14 [0.00, 6.82] | ||||||||||||||||||||||||
| 1.5.4 Gastrointestinal | 16 | 1355 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.70 [1.46, 4.99] | ||||||||||||||||||||||||
| 1.5.5 Euphoria | 1 | 86 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.21 [0.16, 9.01] | ||||||||||||||||||||||||
| 1.5.6 Headache | 1 | 171 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.32 [0.95, 5.67] | ||||||||||||||||||||||||
| 1.5.7 Upper respiratory infection | 1 | 171 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.01 [0.25, 4.17] | ||||||||||||||||||||||||
| 1.5.8 Nasofaryngitis | 1 | 171 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.57 [0.17, 1.92] | ||||||||||||||||||||||||
| 1.6 Sperm DNA fragmentation at 3 months or less; type of antioxidant Show forest plot | 12 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.6  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 6: Sperm DNA fragmentation at 3 months or less; type of antioxidant | ||||||||||||||||||||||||||||
| 1.6.1 Astaxanthin + Vitamin E | 1 | 72 | Mean Difference (IV, Fixed, 95% CI) | 1.40 [‐6.64, 9.44] | ||||||||||||||||||||||||
| 1.6.2 Folic acid | 1 | 38 | Mean Difference (IV, Fixed, 95% CI) | ‐5.80 [‐13.40, 1.80] | ||||||||||||||||||||||||
| 1.6.3 Folic acid + Zinc | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | ‐1.20 [‐9.36, 6.96] | ||||||||||||||||||||||||
| 1.6.4 N‐acetylcysteine (NAC) | 1 | 35 | Mean Difference (IV, Fixed, 95% CI) | 3.90 [‐0.42, 8.22] | ||||||||||||||||||||||||
| 1.6.5 PUFAs | 3 | 137 | Mean Difference (IV, Fixed, 95% CI) | ‐1.16 [‐4.00, 1.68] | ||||||||||||||||||||||||
| 1.6.6 Vitamin C + Vitamin E | 1 | 64 | Mean Difference (IV, Fixed, 95% CI) | ‐13.80 [‐17.50, ‐10.10] | ||||||||||||||||||||||||
| 1.6.7 Zinc | 1 | 42 | Mean Difference (IV, Fixed, 95% CI) | 1.30 [‐8.62, 11.22] | ||||||||||||||||||||||||
| 1.6.8 Combined antioxidants | 5 | 569 | Mean Difference (IV, Fixed, 95% CI) | ‐0.52 [‐2.00, 0.96] | ||||||||||||||||||||||||
| 1.7 Sperm DNA fragmentation at 6 months; type of antioxidant Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.7  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 7: Sperm DNA fragmentation at 6 months; type of antioxidant | ||||||||||||||||||||||||||||
| 1.7.1 Combined antioxidants | 3 | 320 | Mean Difference (IV, Fixed, 95% CI) | ‐4.57 [‐6.49, ‐2.66] | ||||||||||||||||||||||||
| 1.7.2 Zinc + Folic acid | 1 | 853 | Mean Difference (IV, Fixed, 95% CI) | 3.00 [0.02, 5.98] | ||||||||||||||||||||||||
| 1.8 Sperm DNA fragmentation (data not suitable for meta‐analysis) Show forest plot | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| Analysis 1.8
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 8: Sperm DNA fragmentation (data not suitable for meta‐analysis) | ||||||||||||||||||||||||||||
| 1.8.1 Folic acid | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 1.9 Total sperm motility at 3 months or less; type of antioxidant Show forest plot | 25 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.9  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 9: Total sperm motility at 3 months or less; type of antioxidant | ||||||||||||||||||||||||||||
| 1.9.1 Astaxanthin + Vitamin E | 1 | 72 | Mean Difference (IV, Fixed, 95% CI) | ‐5.20 [‐11.56, 1.16] | ||||||||||||||||||||||||
| 1.9.2 Carnitines | 5 | 244 | Mean Difference (IV, Fixed, 95% CI) | 31.28 [31.19, 31.37] | ||||||||||||||||||||||||
| 1.9.3 Carotenoids | 1 | 36 | Mean Difference (IV, Fixed, 95% CI) | 3.50 [‐6.95, 13.95] | ||||||||||||||||||||||||
| 1.9.4 Coenzyme Q10 | 1 | 47 | Mean Difference (IV, Fixed, 95% CI) | 3.61 [‐6.13, 13.35] | ||||||||||||||||||||||||
| 1.9.5 Folic acid | 2 | 89 | Mean Difference (IV, Fixed, 95% CI) | 4.56 [‐5.63, 14.74] | ||||||||||||||||||||||||
| 1.9.6 Magnesium | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 14.50 [‐6.01, 35.01] | ||||||||||||||||||||||||
| 1.9.7 N‐acetylcysteine (NAC) | 1 | 35 | Mean Difference (IV, Fixed, 95% CI) | 14.60 [0.32, 28.88] | ||||||||||||||||||||||||
| 1.9.8 PUFAs | 3 | 105 | Mean Difference (IV, Fixed, 95% CI) | ‐2.40 [‐9.89, 5.09] | ||||||||||||||||||||||||
| 1.9.9 Selenium | 1 | 34 | Mean Difference (IV, Fixed, 95% CI) | 14.90 [1.14, 28.66] | ||||||||||||||||||||||||
| 1.9.10 Vitamin C + Vitamin E | 1 | 64 | Mean Difference (IV, Fixed, 95% CI) | 2.90 [‐7.76, 13.56] | ||||||||||||||||||||||||
| 1.9.11 Vitamin E | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 18.90 [4.90, 32.90] | ||||||||||||||||||||||||
| 1.9.12 Zinc | 3 | 118 | Mean Difference (IV, Fixed, 95% CI) | 12.85 [5.40, 20.29] | ||||||||||||||||||||||||
| 1.9.13 Zinc + Folic acid | 2 | 93 | Mean Difference (IV, Fixed, 95% CI) | 5.26 [‐3.64, 14.16] | ||||||||||||||||||||||||
| 1.9.14 Zinc + Vitamin E | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 26.00 [12.85, 39.15] | ||||||||||||||||||||||||
| 1.9.15 Zinc + Vitamin E + Vitamin C | 1 | 22 | Mean Difference (IV, Fixed, 95% CI) | 26.00 [12.62, 39.38] | ||||||||||||||||||||||||
| 1.9.16 Combined antioxidants | 7 | 684 | Mean Difference (IV, Fixed, 95% CI) | 12.71 [11.33, 14.08] | ||||||||||||||||||||||||
| 1.10 Total sperm motility at 3 months or less (data not suitable for meta analysis) Show forest plot | 2 | Other data | No numeric data | |||||||||||||||||||||||||
| Analysis 1.10
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 10: Total sperm motility at 3 months or less (data not suitable for meta analysis) | ||||||||||||||||||||||||||||
| 1.10.1 Vitamin E | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 1.10.2 Combined antioxidants | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 1.11 Total sperm motility at 6 months; type of antioxidant Show forest plot | 17 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.11  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 11: Total sperm motility at 6 months; type of antioxidant | ||||||||||||||||||||||||||||
| 1.11.1 Carnitines | 3 | 136 | Mean Difference (IV, Fixed, 95% CI) | 10.09 [5.99, 14.19] | ||||||||||||||||||||||||
| 1.11.2 Coenzyme Q10 | 3 | 479 | Mean Difference (IV, Fixed, 95% CI) | 7.28 [6.85, 7.72] | ||||||||||||||||||||||||
| 1.11.3 Folic acid | 2 | 98 | Mean Difference (IV, Fixed, 95% CI) | 0.16 [‐6.96, 7.29] | ||||||||||||||||||||||||
| 1.11.4 N‐acetylcysteine (NAC) | 1 | 211 | Mean Difference (IV, Fixed, 95% CI) | 1.90 [1.20, 2.60] | ||||||||||||||||||||||||
| 1.11.5 Selenium | 1 | 211 | Mean Difference (IV, Fixed, 95% CI) | 3.20 [2.50, 3.90] | ||||||||||||||||||||||||
| 1.11.6 Selenium + N‐acetylcysteine (NAC) | 1 | 210 | Mean Difference (IV, Fixed, 95% CI) | 6.30 [5.60, 7.00] | ||||||||||||||||||||||||
| 1.11.7 Vitamin D + Calcium | 1 | 260 | Mean Difference (IV, Fixed, 95% CI) | ‐4.00 [‐9.57, 1.57] | ||||||||||||||||||||||||
| 1.11.8 Vitamin E | 2 | 132 | Mean Difference (IV, Fixed, 95% CI) | 11.60 [6.18, 17.02] | ||||||||||||||||||||||||
| 1.11.9 Zinc | 2 | 105 | Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐6.95, 6.95] | ||||||||||||||||||||||||
| 1.11.10 Zinc + Folic acid | 3 | 956 | Mean Difference (IV, Fixed, 95% CI) | 0.24 [‐2.54, 3.02] | ||||||||||||||||||||||||
| 1.11.11 Combined antioxidants | 4 | 394 | Mean Difference (IV, Fixed, 95% CI) | 6.76 [4.77, 8.75] | ||||||||||||||||||||||||
| 1.12 Total sperm motility at 9 months or more; type of antioxidant Show forest plot | 5 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.12  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 12: Total sperm motility at 9 months or more; type of antioxidant | ||||||||||||||||||||||||||||
| 1.12.1 Carnitines | 1 | 59 | Mean Difference (IV, Fixed, 95% CI) | 8.54 [3.01, 14.07] | ||||||||||||||||||||||||
| 1.12.2 Coenzyme Q10 | 3 | 479 | Mean Difference (IV, Fixed, 95% CI) | 3.33 [2.91, 3.76] | ||||||||||||||||||||||||
| 1.12.3 Vitamin E | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 2.20 [‐8.48, 12.88] | ||||||||||||||||||||||||
| 1.13 Total sperm motility over time Show forest plot | 36 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.13  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 13: Total sperm motility over time | ||||||||||||||||||||||||||||
| 1.13.1 Total sperm motility at 3 months or less | 25 | 1638 | Mean Difference (IV, Fixed, 95% CI) | 31.17 [31.07, 31.26] | ||||||||||||||||||||||||
| 1.13.2 Total sperm motility at 6 months | 17 | 2880 | Mean Difference (IV, Fixed, 95% CI) | 5.77 [5.45, 6.10] | ||||||||||||||||||||||||
| 1.13.3 Total sperm motility at 9 months or more | 5 | 583 | Mean Difference (IV, Fixed, 95% CI) | 3.36 [2.94, 3.78] | ||||||||||||||||||||||||
| 1.14 Progressive sperm motility at 3 months or less; type of antioxidant Show forest plot | 28 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.14  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 14: Progressive sperm motility at 3 months or less; type of antioxidant | ||||||||||||||||||||||||||||
| 1.14.1 Astaxanthin + Vitamin E | 1 | 72 | Mean Difference (IV, Fixed, 95% CI) | ‐5.10 [‐11.46, 1.26] | ||||||||||||||||||||||||
| 1.14.2 Carnitines | 4 | 285 | Mean Difference (IV, Fixed, 95% CI) | 20.92 [20.52, 21.32] | ||||||||||||||||||||||||
| 1.14.3 Carotenoids | 1 | 36 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐7.27, 6.87] | ||||||||||||||||||||||||
| 1.14.4 Coenzyme Q10 | 1 | 47 | Mean Difference (IV, Fixed, 95% CI) | 4.60 [‐3.54, 12.74] | ||||||||||||||||||||||||
| 1.14.5 Folic acid | 2 | 81 | Mean Difference (IV, Fixed, 95% CI) | 5.08 [‐4.00, 14.16] | ||||||||||||||||||||||||
| 1.14.6 N‐acetylcysteine (NAC) | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 3.80 [‐1.03, 8.63] | ||||||||||||||||||||||||
| 1.14.7 PUFAs | 4 | 181 | Mean Difference (IV, Fixed, 95% CI) | 1.53 [0.32, 2.74] | ||||||||||||||||||||||||
| 1.14.8 Vitamin C | 2 | 145 | Mean Difference (IV, Fixed, 95% CI) | 10.95 [4.10, 17.80] | ||||||||||||||||||||||||
| 1.14.9 Vitamin C + Vitamin E | 1 | 31 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐9.77, 10.17] | ||||||||||||||||||||||||
| 1.14.10 Vitamin D | 1 | 62 | Mean Difference (IV, Fixed, 95% CI) | ‐0.84 [‐7.65, 5.97] | ||||||||||||||||||||||||
| 1.14.11 Zinc | 2 | 157 | Mean Difference (IV, Fixed, 95% CI) | 1.14 [‐3.37, 5.64] | ||||||||||||||||||||||||
| 1.14.12 Zinc + Folic acid | 1 | 54 | Mean Difference (IV, Fixed, 95% CI) | 3.80 [‐13.66, 21.26] | ||||||||||||||||||||||||
| 1.14.13 Combined antioxidants | 9 | 993 | Mean Difference (IV, Fixed, 95% CI) | 11.16 [9.91, 12.41] | ||||||||||||||||||||||||
| 1.15 Progressive sperm motility at 6 months; type of antioxidant Show forest plot | 12 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.15  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 15: Progressive sperm motility at 6 months; type of antioxidant | ||||||||||||||||||||||||||||
| 1.15.1 Carnitines | 2 | 145 | Mean Difference (IV, Fixed, 95% CI) | 11.66 [8.68, 14.64] | ||||||||||||||||||||||||
| 1.15.2 Coenzyme Q10 | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 5.00 [2.13, 7.87] | ||||||||||||||||||||||||
| 1.15.3 Folic acid | 2 | 81 | Mean Difference (IV, Fixed, 95% CI) | ‐1.77 [‐10.21, 6.67] | ||||||||||||||||||||||||
| 1.15.4 PUFAs | 1 | 227 | Mean Difference (IV, Fixed, 95% CI) | 8.80 [8.11, 9.49] | ||||||||||||||||||||||||
| 1.15.5 Vitamin D + Calcium | 1 | 260 | Mean Difference (IV, Fixed, 95% CI) | ‐4.00 [‐9.59, 1.59] | ||||||||||||||||||||||||
| 1.15.6 Zinc | 1 | 57 | Mean Difference (IV, Fixed, 95% CI) | 2.00 [‐13.56, 17.56] | ||||||||||||||||||||||||
| 1.15.7 Zinc + Folic acid | 1 | 54 | Mean Difference (IV, Fixed, 95% CI) | 2.70 [‐14.58, 19.98] | ||||||||||||||||||||||||
| 1.15.8 Combined antioxidants | 5 | 470 | Mean Difference (IV, Fixed, 95% CI) | 4.01 [2.05, 5.96] | ||||||||||||||||||||||||
| 1.16 Progressive sperm motility at 6 months (data not suitable for meta analysis) Show forest plot | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| Analysis 1.16
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 16: Progressive sperm motility at 6 months (data not suitable for meta analysis) | ||||||||||||||||||||||||||||
| 1.16.1 Coenzyme Q10 | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 1.16.2 Glutathione | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 1.17 Progressive sperm motility at 9 months or more; type of antioxidant Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.17  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 17: Progressive sperm motility at 9 months or more; type of antioxidant | ||||||||||||||||||||||||||||
| 1.17.1 Carnitines | 1 | 59 | Mean Difference (IV, Fixed, 95% CI) | 7.77 [2.68, 12.87] | ||||||||||||||||||||||||
| 1.17.2 Coenzyme Q10 | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐0.90 [‐2.68, 0.88] | ||||||||||||||||||||||||
| 1.18 Progressive sperm motility over time Show forest plot | 32 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.18  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 18: Progressive sperm motility over time | ||||||||||||||||||||||||||||
| 1.18.1 Progressive sperm motility at 3 months or less | 27 | 2054 | Mean Difference (IV, Fixed, 95% CI) | 17.98 [17.62, 18.34] | ||||||||||||||||||||||||
| 1.18.2 Progressive sperm motility at 6 months | 12 | 1304 | Mean Difference (IV, Fixed, 95% CI) | 8.05 [7.43, 8.66] | ||||||||||||||||||||||||
| 1.18.3 Progressive sperm motility at 9 months or more | 2 | 119 | Mean Difference (IV, Fixed, 95% CI) | 0.04 [‐1.64, 1.72] | ||||||||||||||||||||||||
| 1.19 Sperm concentration at 3 months or less; type of antioxidant Show forest plot | 36 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.19  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 19: Sperm concentration at 3 months or less; type of antioxidant | ||||||||||||||||||||||||||||
| 1.19.1 Astaxathin + Vitamin E | 1 | 72 | Mean Difference (IV, Fixed, 95% CI) | ‐1.00 [‐6.79, 4.79] | ||||||||||||||||||||||||
| 1.19.2 Carnitines | 5 | 333 | Mean Difference (IV, Fixed, 95% CI) | 8.71 [8.09, 9.34] | ||||||||||||||||||||||||
| 1.19.3 Carotenoids | 1 | 36 | Mean Difference (IV, Fixed, 95% CI) | 6.30 [0.62, 11.98] | ||||||||||||||||||||||||
| 1.19.4 Coenzyme Q10 | 1 | 47 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐12.37, 12.17] | ||||||||||||||||||||||||
| 1.19.5 Folic acid | 3 | 119 | Mean Difference (IV, Fixed, 95% CI) | 3.72 [‐4.01, 11.44] | ||||||||||||||||||||||||
| 1.19.6 Magnesium | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 5.20 [‐2.61, 13.01] | ||||||||||||||||||||||||
| 1.19.7 N‐acetylcysteine (NAC) | 2 | 95 | Mean Difference (IV, Fixed, 95% CI) | 4.59 [‐0.27, 9.46] | ||||||||||||||||||||||||
| 1.19.8 PUFAs | 5 | 209 | Mean Difference (IV, Fixed, 95% CI) | 3.42 [1.69, 5.15] | ||||||||||||||||||||||||
| 1.19.9 Selenium | 1 | 34 | Mean Difference (IV, Fixed, 95% CI) | 21.20 [‐4.90, 47.30] | ||||||||||||||||||||||||
| 1.19.10 Vitamin C | 1 | 115 | Mean Difference (IV, Fixed, 95% CI) | 9.70 [0.09, 19.31] | ||||||||||||||||||||||||
| 1.19.11 Vitamin C + Vitamin E | 2 | 95 | Mean Difference (IV, Fixed, 95% CI) | 1.31 [‐6.58, 9.20] | ||||||||||||||||||||||||
| 1.19.12 Vitamin D | 1 | 62 | Mean Difference (IV, Fixed, 95% CI) | ‐2.12 [‐8.85, 4.61] | ||||||||||||||||||||||||
| 1.19.13 Vitamin E | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 18.90 [3.92, 33.88] | ||||||||||||||||||||||||
| 1.19.14 Zinc | 3 | 199 | Mean Difference (IV, Fixed, 95% CI) | 6.74 [2.81, 10.68] | ||||||||||||||||||||||||
| 1.19.15 Zinc + Folic acid | 2 | 93 | Mean Difference (IV, Fixed, 95% CI) | 0.48 [‐6.79, 7.75] | ||||||||||||||||||||||||
| 1.19.16 Combined antioxidants | 11 | 1165 | Mean Difference (IV, Fixed, 95% CI) | 0.53 [‐0.33, 1.40] | ||||||||||||||||||||||||
| 1.20 Sperm concentration at 3 months or less (data not suitable for meta analysis) Show forest plot | 2 | Other data | No numeric data | |||||||||||||||||||||||||
| Analysis 1.20
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 20: Sperm concentration at 3 months or less (data not suitable for meta analysis) | ||||||||||||||||||||||||||||
| 1.20.1 Carnitines | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 1.20.2 Vitamin E | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 1.21 Sperm concentration at 6 months; type of antioxidant Show forest plot | 20 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.21  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 21: Sperm concentration at 6 months; type of antioxidant | ||||||||||||||||||||||||||||
| 1.21.1 Carnitines | 3 | 201 | Mean Difference (IV, Fixed, 95% CI) | 7.42 [4.97, 9.87] | ||||||||||||||||||||||||
| 1.21.2 Coenzyme Q10 | 3 | 479 | Mean Difference (IV, Fixed, 95% CI) | 8.80 [7.95, 9.64] | ||||||||||||||||||||||||
| 1.21.3 Folic acid | 3 | 128 | Mean Difference (IV, Fixed, 95% CI) | 17.39 [11.09, 23.69] | ||||||||||||||||||||||||
| 1.21.4 N‐acetylcysteine (NAC) | 1 | 211 | Mean Difference (IV, Fixed, 95% CI) | 3.30 [1.80, 4.80] | ||||||||||||||||||||||||
| 1.21.5 PUFAs | 1 | 227 | Mean Difference (IV, Fixed, 95% CI) | 12.50 [11.39, 13.61] | ||||||||||||||||||||||||
| 1.21.6 Selenium | 1 | 211 | Mean Difference (IV, Fixed, 95% CI) | 4.10 [2.45, 5.75] | ||||||||||||||||||||||||
| 1.21.7 Selenium + N‐acetylcysteine (NAC) | 1 | 210 | Mean Difference (IV, Fixed, 95% CI) | 8.60 [6.89, 10.31] | ||||||||||||||||||||||||
| 1.21.8 Vitamin D + Calcium | 1 | 269 | Mean Difference (IV, Fixed, 95% CI) | ‐2.50 [‐8.18, 3.18] | ||||||||||||||||||||||||
| 1.21.9 Vitamin E | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 5.90 [‐10.83, 22.63] | ||||||||||||||||||||||||
| 1.21.10 Zinc | 2 | 105 | Mean Difference (IV, Fixed, 95% CI) | 5.51 [‐4.00, 15.01] | ||||||||||||||||||||||||
| 1.21.11 Zinc + Folic acid | 3 | 956 | Mean Difference (IV, Fixed, 95% CI) | 1.44 [‐6.70, 9.58] | ||||||||||||||||||||||||
| 1.21.12 Combined antioxidants | 6 | 534 | Mean Difference (IV, Fixed, 95% CI) | 3.16 [2.28, 4.05] | ||||||||||||||||||||||||
| 1.22 Sperm concentration at 6 months (data not suitable for meta analysis) Show forest plot | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| Analysis 1.22
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 22: Sperm concentration at 6 months (data not suitable for meta analysis) | ||||||||||||||||||||||||||||
| 1.22.1 Glutathione | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 1.22.2 Coenzyme Q10 | 1 | Other data | No numeric data | |||||||||||||||||||||||||
| 1.23 Sperm concentration at 9 months or more; type of antioxidant Show forest plot | 5 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.23  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 23: Sperm concentration at 9 months or more; type of antioxidant | ||||||||||||||||||||||||||||
| 1.23.1 Carnitines | 1 | 59 | Mean Difference (IV, Fixed, 95% CI) | 4.17 [‐1.71, 10.06] | ||||||||||||||||||||||||
| 1.23.2 Coenzyme Q10 | 3 | 479 | Mean Difference (IV, Fixed, 95% CI) | 3.93 [3.19, 4.67] | ||||||||||||||||||||||||
| 1.23.3 Vitamin E | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 11.40 [‐2.56, 25.36] | ||||||||||||||||||||||||
| 1.24 Sperm concentration over time Show forest plot | 46 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||||||||||||||
| Analysis 1.24  Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 24: Sperm concentration over time | ||||||||||||||||||||||||||||
| 1.24.1 Sperm concentration at 3 months or less | 35 | 2535 | Mean Difference (IV, Fixed, 95% CI) | 5.49 [5.02, 5.96] | ||||||||||||||||||||||||
| 1.24.2 Sperm concentration 6 months | 19 | 2995 | Mean Difference (IV, Fixed, 95% CI) | 7.21 [6.73, 7.70] | ||||||||||||||||||||||||
| 1.24.3 Sperm concentration at 9 months or more | 5 | 583 | Mean Difference (IV, Fixed, 95% CI) | 3.95 [3.22, 4.69] | ||||||||||||||||||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | ||||||||||||
| 2.1 Live birth; type of antioxidant Show forest plot | 1 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.1  Comparison 2: Head‐to‐head antioxidant(s), Outcome 1: Live birth; type of antioxidant | ||||||||||||||||
| 2.1.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.00 [0.13, 7.92] | ||||||||||||
| 2.1.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.34 [0.06, 1.79] | ||||||||||||
| 2.1.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.34 [0.06, 1.79] | ||||||||||||
| 2.2 Clinical pregnancy; type of antioxidant Show forest plot | 4 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.2  Comparison 2: Head‐to‐head antioxidant(s), Outcome 2: Clinical pregnancy; type of antioxidant | ||||||||||||||||
| 2.2.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.00 [0.13, 7.92] | ||||||||||||
| 2.2.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.34 [0.06, 1.79] | ||||||||||||
| 2.2.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.34 [0.06, 1.79] | ||||||||||||
| 2.2.4 L‐carnitine vs Coenzyme Q10 | 1 | 156 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.48 [0.54, 4.05] | ||||||||||||
| 2.2.5 L‐carnitine vs L‐carnitine + Coenzyme Q10 | 1 | 156 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.62 [0.27, 1.46] | ||||||||||||
| 2.2.6 Coenzyme Q10 vs L‐carnitine + Coenzyme Q10 | 1 | 156 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.43 [0.18, 1.06] | ||||||||||||
| 2.2.7 Vitamin D + Calcium vs Vitamin E + Vitamin C | 1 | 86 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 5.13 [1.21, 21.79] | ||||||||||||
| 2.2.8 Combined antioxidants vs L‐carnitine | 1 | 89 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.93 [0.20, 19.08] | ||||||||||||
| 2.3 Sperm DNA fragmentation; type of antioxidant Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.3  Comparison 2: Head‐to‐head antioxidant(s), Outcome 3: Sperm DNA fragmentation; type of antioxidant | ||||||||||||||||
| 2.3.1 L‐carnitine vs Coenzyme Q10 | 1 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐0.80 [‐2.22, 0.62] | ||||||||||||
| 2.3.2 L‐carnitine vs L‐carnitine + Coenzyme Q10 | 1 | 125 | Mean Difference (IV, Fixed, 95% CI) | 0.40 [‐1.14, 1.94] | ||||||||||||
| 2.3.3 Coenzyme Q10 vs L‐carnitine + Coenzyme Q10 | 1 | 126 | Mean Difference (IV, Fixed, 95% CI) | 1.20 [‐0.25, 2.65] | ||||||||||||
| 2.3.4 L‐carnitine vs Vitamin B1 | 1 | 136 | Mean Difference (IV, Fixed, 95% CI) | ‐1.50 [‐3.22, 0.22] | ||||||||||||
| 2.3.5 Coenzyme Q10 vs Vitamin B1 | 1 | 137 | Mean Difference (IV, Fixed, 95% CI) | ‐0.70 [‐2.34, 0.94] | ||||||||||||
| 2.3.6 Vitamin B1 vs L‐carnitine + Coenzyme Q10 | 1 | 137 | Mean Difference (IV, Fixed, 95% CI) | 1.90 [0.16, 3.64] | ||||||||||||
| 2.4 Total sperm motility at 3 months or less; type of antioxidant Show forest plot | 12 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.4  Comparison 2: Head‐to‐head antioxidant(s), Outcome 4: Total sperm motility at 3 months or less; type of antioxidant | ||||||||||||||||
| 2.4.1 Coenzyme Q10 200 mg vs Coenzyme Q10 400 mg | 1 | 65 | Mean Difference (IV, Fixed, 95% CI) | ‐4.86 [‐10.60, 0.88] | ||||||||||||
| 2.4.2 Docosahexaenoic acid (DHA) 400 mg vs Docosahexaenoic acid 800 mg | 1 | 19 | Mean Difference (IV, Fixed, 95% CI) | 7.40 [‐11.35, 26.15] | ||||||||||||
| 2.4.3 DHA vs DHA + Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐3.77 [‐5.42, ‐2.12] | ||||||||||||
| 2.4.4 DHA versus Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐1.60 [‐3.30, 0.10] | ||||||||||||
| 2.4.5 DHA + Vitamin E vs Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | 2.17 [0.54, 3.80] | ||||||||||||
| 2.4.6 Ethylcysteine vs Vitamin E | 1 | 10 | Mean Difference (IV, Fixed, 95% CI) | ‐1.90 [‐41.97, 38.17] | ||||||||||||
| 2.4.7 L‐acetyl carnitine + L‐carnitine vs Vitamin E + Vitamin C | 1 | 138 | Mean Difference (IV, Fixed, 95% CI) | 23.10 [20.14, 26.06] | ||||||||||||
| 2.4.8 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 3.40 [‐3.73, 10.53] | ||||||||||||
| 2.4.9 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 4.80 [‐1.76, 11.36] | ||||||||||||
| 2.4.10 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 1.40 [‐6.42, 9.22] | ||||||||||||
| 2.4.11 Selenium vs combined antioxidants | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | 3.20 [‐10.13, 16.53] | ||||||||||||
| 2.4.12 Vitamin C 200mg vs Vitamin C 1000mg | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐43.00 [‐67.10, ‐18.90] | ||||||||||||
| 2.4.13 Vitamin E + 'Compound amino acids' vs Vitamin E | 1 | 120 | Mean Difference (IV, Fixed, 95% CI) | 11.90 [8.71, 15.09] | ||||||||||||
| 2.4.14 Zinc vs Folic acid | 2 | 124 | Mean Difference (IV, Fixed, 95% CI) | ‐3.01 [‐11.38, 5.35] | ||||||||||||
| 2.4.15 Zinc vs Zinc + Folic acid | 2 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐2.91 [‐10.92, 5.10] | ||||||||||||
| 2.4.16 Zinc + Folic acid vs Folic acid | 2 | 121 | Mean Difference (IV, Fixed, 95% CI) | 0.24 [‐6.17, 6.66] | ||||||||||||
| 2.4.17 Zinc vs Zinc + Vitamin E | 1 | 18 | Mean Difference (IV, Fixed, 95% CI) | ‐1.00 [‐15.00, 13.00] | ||||||||||||
| 2.4.18 Zinc vs Zinc + Vitamin E + Vitamin C | 1 | 12 | Mean Difference (IV, Fixed, 95% CI) | ‐1.00 [‐19.66, 17.66] | ||||||||||||
| 2.4.19 Zinc + Vitamin E vs Zinc + Vitamin E + Vitamin C | 1 | 18 | Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐18.97, 18.97] | ||||||||||||
| 2.5 Total sperm motility at 6 months; type of antioxidant Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.5  Comparison 2: Head‐to‐head antioxidant(s), Outcome 5: Total sperm motility at 6 months; type of antioxidant | ||||||||||||||||
| 2.5.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 4.10 [‐2.70, 10.90] | ||||||||||||
| 2.5.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 3.40 [‐2.87, 9.67] | ||||||||||||
| 2.5.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.70 [‐7.73, 6.33] | ||||||||||||
| 2.5.4 N‐acetylcysteine (NAC) vs Selenium + N‐acetylcysteine (NAC) | 1 | 234 | Mean Difference (IV, Fixed, 95% CI) | ‐4.40 [‐5.14, ‐3.66] | ||||||||||||
| 2.5.5 Selenium vs N‐acetylcysteine (NAC) | 1 | 234 | Mean Difference (IV, Fixed, 95% CI) | 1.30 [0.56, 2.04] | ||||||||||||
| 2.5.6 Selenium vs Selenium + N‐acetylcysteine (NAC) | 1 | 232 | Mean Difference (IV, Fixed, 95% CI) | ‐3.10 [‐3.85, ‐2.35] | ||||||||||||
| 2.5.7 Zinc vs Folic acid | 2 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐1.03 [‐5.18, 3.13] | ||||||||||||
| 2.5.8 Zinc vs Zinc + Folic acid | 2 | 127 | Mean Difference (IV, Fixed, 95% CI) | ‐1.69 [‐6.95, 3.58] | ||||||||||||
| 2.5.9 Zinc + Folic acid vs Folic acid | 2 | 126 | Mean Difference (IV, Fixed, 95% CI) | 1.03 [‐4.23, 6.29] | ||||||||||||
| 2.6 Total sperm motility at 9 months or more; type of antioxidant Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.6  Comparison 2: Head‐to‐head antioxidant(s), Outcome 6: Total sperm motility at 9 months or more; type of antioxidant | ||||||||||||||||
| 2.6.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 3.70 [‐1.69, 9.09] | ||||||||||||
| 2.6.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 5.30 [‐0.73, 11.33] | ||||||||||||
| 2.6.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 1.60 [‐3.29, 6.49] | ||||||||||||
| 2.7 Progessive sperm motility at 3 months or less; type of antioxidant Show forest plot | 10 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.7  Comparison 2: Head‐to‐head antioxidant(s), Outcome 7: Progessive sperm motility at 3 months or less; type of antioxidant | ||||||||||||||||
| 2.7.1 Coenzyme Q10 200 mg vs Coenzyme Q10 400 mg | 1 | 65 | Mean Difference (IV, Fixed, 95% CI) | ‐3.52 [‐9.71, 2.67] | ||||||||||||
| 2.7.2 Docosahexaenoic acid (DHA) vs DHA + Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐2.22 [‐3.50, ‐0.94] | ||||||||||||
| 2.7.3 DHA vs Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐0.39 [‐1.67, 0.89] | ||||||||||||
| 2.7.4 DHA + Vitamin E vs Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | 1.83 [0.68, 2.98] | ||||||||||||
| 2.7.5 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 4.00 [‐1.88, 9.88] | ||||||||||||
| 2.7.6 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 5.00 [‐0.68, 10.68] | ||||||||||||
| 2.7.7 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 1.00 [‐5.41, 7.41] | ||||||||||||
| 2.7.8 L‐carnitine vs Vitamin B1 | 1 | 136 | Mean Difference (IV, Fixed, 95% CI) | 1.70 [‐1.54, 4.94] | ||||||||||||
| 2.7.9 L‐carnitine vs Coenzyme Q10 | 1 | 125 | Mean Difference (IV, Fixed, 95% CI) | 1.30 [‐1.70, 4.30] | ||||||||||||
| 2.7.10 L‐carnitine vs L‐carnitine + Coenzyme Q10 | 1 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐8.20 [‐12.31, ‐4.09] | ||||||||||||
| 2.7.11 Coenzyme Q10 vs L‐carnitine + Coenzyme Q10 | 1 | 126 | Mean Difference (IV, Fixed, 95% CI) | ‐9.50 [‐13.54, ‐5.46] | ||||||||||||
| 2.7.12 Coenzyme Q10 vs Vitamin B1 | 1 | 137 | Mean Difference (IV, Fixed, 95% CI) | 0.40 [‐2.75, 3.55] | ||||||||||||
| 2.7.13 Vitamin B1 vs L‐carnitine + Coenzyme Q10 | 1 | 137 | Mean Difference (IV, Fixed, 95% CI) | ‐9.90 [‐14.12, ‐5.68] | ||||||||||||
| 2.7.14 L‐acetyl carnitine + L‐carnitine vs Vitamin E + Vitamin C | 1 | 138 | Mean Difference (IV, Fixed, 95% CI) | 13.30 [11.21, 15.39] | ||||||||||||
| 2.7.15 L‐carnitine vs Vitamin E + Vitamin C | 1 | 63 | Mean Difference (IV, Fixed, 95% CI) | 30.50 [27.70, 33.30] | ||||||||||||
| 2.7.16 L‐carnitine vs Vitamin E | 1 | 212 | Mean Difference (IV, Fixed, 95% CI) | 1.90 [1.31, 2.49] | ||||||||||||
| 2.7.17 L‐carnitine + Vitamin E vs Vitamin E | 1 | 113 | Mean Difference (IV, Fixed, 95% CI) | 14.10 [10.11, 18.09] | ||||||||||||
| 2.7.18 Vitamin D + Calcium vs Vitamin E + Vitamin C | 1 | 86 | Mean Difference (IV, Fixed, 95% CI) | 6.90 [5.38, 8.42] | ||||||||||||
| 2.7.19 Vitamin E + 'Compound amino acids' vs Vitamin E | 1 | 120 | Mean Difference (IV, Fixed, 95% CI) | 6.10 [3.87, 8.33] | ||||||||||||
| 2.8 Progressive sperm motility at 6 months; type of antioxidant Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.8  Comparison 2: Head‐to‐head antioxidant(s), Outcome 8: Progressive sperm motility at 6 months; type of antioxidant | ||||||||||||||||
| 2.8.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 6.30 [0.42, 12.18] | ||||||||||||
| 2.8.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 5.70 [0.10, 11.30] | ||||||||||||
| 2.8.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | ‐0.60 [‐6.93, 5.73] | ||||||||||||
| 2.9 Progressive motility at 6 months (data not suitable for meta‐analysis) Show forest plot | 1 | Other data | No numeric data | |||||||||||||
| Analysis 2.9
Comparison 2: Head‐to‐head antioxidant(s), Outcome 9: Progressive motility at 6 months (data not suitable for meta‐analysis) | ||||||||||||||||
| 2.10 Progressive sperm motility at 9 months; type of antioxidant Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.10  Comparison 2: Head‐to‐head antioxidant(s), Outcome 10: Progressive sperm motility at 9 months; type of antioxidant | ||||||||||||||||
| 2.10.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 3.80 [‐1.50, 9.10] | ||||||||||||
| 2.10.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 5.50 [‐0.11, 11.11] | ||||||||||||
| 2.10.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 1.70 [‐4.17, 7.57] | ||||||||||||
| 2.11 Sperm concentration at 3 months or less; type of antioxidant Show forest plot | 11 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.11  Comparison 2: Head‐to‐head antioxidant(s), Outcome 11: Sperm concentration at 3 months or less; type of antioxidant | ||||||||||||||||
| 2.11.1 Coenzyme Q10 200 mg vs Coenzyme Q10 400 mg | 1 | 65 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐3.26, 3.66] | ||||||||||||
| 2.11.2 Docosahexaenoic acid (DHA) 400 mg vs Docosahexaenoic acid (DHA) 800 mg | 1 | 19 | Mean Difference (IV, Fixed, 95% CI) | ‐6.80 [‐41.87, 28.27] | ||||||||||||
| 2.11.3 DHA vs DHA + Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐1.45 [‐2.47, ‐0.43] | ||||||||||||
| 2.11.4 DHA vs Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐0.24 [‐1.26, 0.78] | ||||||||||||
| 2.11.5 DHA + Vitamin E vs Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | 1.21 [0.28, 2.14] | ||||||||||||
| 2.11.6 Ethylcysteine vs Vitamin E | 1 | 10 | Mean Difference (IV, Fixed, 95% CI) | 2.20 [‐16.65, 21.05] | ||||||||||||
| 2.11.7 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 1.70 [‐10.97, 14.37] | ||||||||||||
| 2.11.8 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 4.10 [‐9.17, 17.37] | ||||||||||||
| 2.11.9 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 2.40 [‐11.14, 15.94] | ||||||||||||
| 2.11.10 L‐carnitine vs Vitamin E + Vitamin C | 1 | 63 | Mean Difference (IV, Fixed, 95% CI) | 15.50 [12.49, 18.51] | ||||||||||||
| 2.11.11 L‐carnitine vs Vitamin E | 1 | 212 | Mean Difference (IV, Fixed, 95% CI) | 0.70 [‐0.34, 1.74] | ||||||||||||
| 2.11.12 L‐carnitine + Vitamin E vs Vitamin E | 1 | 113 | Mean Difference (IV, Fixed, 95% CI) | 1.90 [‐10.52, 14.32] | ||||||||||||
| 2.11.13 Selenium vs Combined antioxidants | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | 14.70 [‐6.51, 35.91] | ||||||||||||
| 2.11.14 Zinc vs Folic acid | 2 | 124 | Mean Difference (IV, Fixed, 95% CI) | ‐1.30 [‐8.65, 6.06] | ||||||||||||
| 2.11.15 Zinc vs Zinc + Folic acid | 2 | 125 | Mean Difference (IV, Fixed, 95% CI) | 2.93 [‐3.67, 9.54] | ||||||||||||
| 2.11.16 Zinc + Folic acid vs Folic acid | 2 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐4.11 [‐9.79, 1.57] | ||||||||||||
| 2.12 Sperm concentration at 6 months; type of antioxidant Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.12  Comparison 2: Head‐to‐head antioxidant(s), Outcome 12: Sperm concentration at 6 months; type of antioxidant | ||||||||||||||||
| 2.12.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 5.90 [‐8.92, 20.72] | ||||||||||||
| 2.12.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 8.10 [‐5.54, 21.74] | ||||||||||||
| 2.12.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 2.20 [‐10.89, 15.29] | ||||||||||||
| 2.12.4 N‐acetylcysteine (NAC) vs Selenium + N‐acetylcysteine (NAC) | 1 | 234 | Mean Difference (IV, Fixed, 95% CI) | ‐5.30 [‐6.86, ‐3.74] | ||||||||||||
| 2.12.5 Selenium vs N‐acetylcysteine (NAC) | 1 | 234 | Mean Difference (IV, Fixed, 95% CI) | 0.80 [‐0.71, 2.31] | ||||||||||||
| 2.12.6 Selenium vs Selenium + N‐acetylcysteine (NAC) | 1 | 232 | Mean Difference (IV, Fixed, 95% CI) | ‐4.50 [‐6.20, ‐2.80] | ||||||||||||
| 2.12.7 Zinc vs Folic acid | 2 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐10.10 [‐19.12, ‐1.08] | ||||||||||||
| 2.12.8 Zinc vs Zinc + Folic acid | 2 | 127 | Mean Difference (IV, Fixed, 95% CI) | ‐13.58 [‐25.99, ‐1.17] | ||||||||||||
| 2.12.9 Zinc + Folic acid vs Folic acid | 2 | 126 | Mean Difference (IV, Fixed, 95% CI) | 1.78 [‐9.93, 13.49] | ||||||||||||
| 2.13 Sperm concentration at 6 months (data not suitable for meta‐analysis) Show forest plot | 1 | Other data | No numeric data | |||||||||||||
| Analysis 2.13
Comparison 2: Head‐to‐head antioxidant(s), Outcome 13: Sperm concentration at 6 months (data not suitable for meta‐analysis) | ||||||||||||||||
| 2.14 Sperm concentration at 9 months or more; type of antioxidant Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |||||||||||||
| Analysis 2.14  Comparison 2: Head‐to‐head antioxidant(s), Outcome 14: Sperm concentration at 9 months or more; type of antioxidant | ||||||||||||||||
| 2.14.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Random, 95% CI) | 8.20 [‐0.07, 16.47] | ||||||||||||
| 2.14.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Random, 95% CI) | 6.10 [‐3.74, 15.94] | ||||||||||||
| 2.14.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Random, 95% CI) | ‐2.10 [‐10.24, 6.04] | ||||||||||||
Methodological risk of bias summary: review authors' judgements about each methodological bias item for each included study.
Methodological risk of bias graph: review authors' judgements about each methodological bias item presented as percentages across all included studies.
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.1 Live birth; type of antioxidant.
Funnel plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.1 Live birth; type of antioxidant.
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.3 Clinical pregnancy; type of antioxidant.
Funnel plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.5 Clinical pregnancy; type of antioxidant.
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.5 Adverse events.
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.6 Sperm DNA fragmentation; type of antioxidant.
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.9 Total sperm motility at 3 months or less; type of antioxidant.
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.14 Progressive sperm motility at 3 months or less; type of antioxidant.
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment, outcome: 1.19 Sperm concentration at 3 months or less; type of antioxidant.
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 1: Live birth; type of antioxidant
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 2: Live birth; IVF/ICSI
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 3: Clinical pregnancy; type of antioxidant
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 4: Clinical pregnancy; IVF/ICSI
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 5: Adverse events
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 6: Sperm DNA fragmentation at 3 months or less; type of antioxidant
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 7: Sperm DNA fragmentation at 6 months; type of antioxidant
| Sperm DNA fragmentation (data not suitable for meta‐analysis) | |||
| Study | Intervention | Control | P‐value |
|---|---|---|---|
| Folic acid | |||
| Boonyarangkul 2015 | Folic acid DNA tail length, COMET assay 3 month: Mean = 4.04 (n = 15) SE = 0.94 6 month: Mean = 6.01 SE = 1.49 | Placebo DNA tail length, COMET assay 3 month: Mean = 10.08 (n = 15) SE = 3.39 6 month: Mean = 8.69 SE = 4.28 | Not provided |
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 8: Sperm DNA fragmentation (data not suitable for meta‐analysis)
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 9: Total sperm motility at 3 months or less; type of antioxidant
| Total sperm motility at 3 months or less (data not suitable for meta analysis) | |||
| Study | Intervention | Control | P value |
|---|---|---|---|
| Vitamin E | |||
| Kessopoulou 1995 | Vitamin E Median difference = 7 (n = 15) Min/max difference = ‐27 ‐ 34 | Placebo Median difference = 7 (n = 15) Min/max difference = ‐33 ‐ 36 | Not provided |
| Combined antioxidants | |||
| Galatioto 2008 | N‐acetylcysteine (NAC) 600 mg + vitamins‐minerals % of motile sperm (Class A WHO) = 58% (n = 20) | No treatment % of motile sperm (Class A WHO) = 51% (n = 22) | P = 0.847 |
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 10: Total sperm motility at 3 months or less (data not suitable for meta analysis)
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 11: Total sperm motility at 6 months; type of antioxidant
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 12: Total sperm motility at 9 months or more; type of antioxidant
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 13: Total sperm motility over time
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 14: Progressive sperm motility at 3 months or less; type of antioxidant
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 15: Progressive sperm motility at 6 months; type of antioxidant
| Progressive sperm motility at 6 months (data not suitable for meta analysis) | |||
| Study | Intervention | Control | P value |
|---|---|---|---|
| Coenzyme Q10 | |||
| Saeed Alkumait 2020 | Coenzyme Q10 200 mg % improvement = 36 (n = 50) | Placebo % improvement = 4 (n = 50) | 0.01 |
| Glutathione | |||
| Saeed Alkumait 2020 | Glutathione 250 mg % improvement = 38 (n = 51) | Placebo % improvement = 4 (n = 50) | 0.01 |
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 16: Progressive sperm motility at 6 months (data not suitable for meta analysis)
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 17: Progressive sperm motility at 9 months or more; type of antioxidant
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 18: Progressive sperm motility over time
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 19: Sperm concentration at 3 months or less; type of antioxidant
| Sperm concentration at 3 months or less (data not suitable for meta analysis) | |||
| Study | Intervention | Control | P value |
|---|---|---|---|
| Carnitines | |||
| Lenzi 2003 | L‐carnitine Mean = 9 (1st phase data) (n = 43) No SD given | Placebo Mean = 5.3 (n = 43) No SD given | P = 0.03 |
| Vitamin E | |||
| Kessopoulou 1995 | Vitamin E Median difference = ‐15 (n = 15) Min/max difference = ‐58 ‐ 59 | Placebo Median difference = 0 (n = 15) Min/max difference = ‐37 ‐ 160 | Not provided |
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 20: Sperm concentration at 3 months or less (data not suitable for meta analysis)
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 21: Sperm concentration at 6 months; type of antioxidant
| Sperm concentration at 6 months (data not suitable for meta analysis) | |||
| Study | Intervention | Control | P value |
|---|---|---|---|
| Glutathione | |||
| Saeed Alkumait 2020 | Glutathione 250 mg % improvement = 26 (n = 51) | Placebo % improvement = 2 (n = 50) | 0.01 |
| Coenzyme Q10 | |||
| Saeed Alkumait 2020 | Coenzyme Q10 200 mg % improvement = 24 (n = 50) | Placebo % improvement = 2 (n = 50) | 0.01 |
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 22: Sperm concentration at 6 months (data not suitable for meta analysis)
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 23: Sperm concentration at 9 months or more; type of antioxidant
Comparison 1: Antioxidant(s) versus placebo or no treatment, Outcome 24: Sperm concentration over time
Comparison 2: Head‐to‐head antioxidant(s), Outcome 1: Live birth; type of antioxidant
Comparison 2: Head‐to‐head antioxidant(s), Outcome 2: Clinical pregnancy; type of antioxidant
Comparison 2: Head‐to‐head antioxidant(s), Outcome 3: Sperm DNA fragmentation; type of antioxidant
Comparison 2: Head‐to‐head antioxidant(s), Outcome 4: Total sperm motility at 3 months or less; type of antioxidant
Comparison 2: Head‐to‐head antioxidant(s), Outcome 5: Total sperm motility at 6 months; type of antioxidant
Comparison 2: Head‐to‐head antioxidant(s), Outcome 6: Total sperm motility at 9 months or more; type of antioxidant
Comparison 2: Head‐to‐head antioxidant(s), Outcome 7: Progessive sperm motility at 3 months or less; type of antioxidant
Comparison 2: Head‐to‐head antioxidant(s), Outcome 8: Progressive sperm motility at 6 months; type of antioxidant
| Progressive motility at 6 months (data not suitable for meta‐analysis) | |||
| Study | Coenzyme Q10 (n=50 | Glutathione (n=51) | P value |
|---|---|---|---|
| Saeed Alkumait 2020 | % improvement = 36 | % improvement = 38 | Not provided |
Comparison 2: Head‐to‐head antioxidant(s), Outcome 9: Progressive motility at 6 months (data not suitable for meta‐analysis)
Comparison 2: Head‐to‐head antioxidant(s), Outcome 10: Progressive sperm motility at 9 months; type of antioxidant
Comparison 2: Head‐to‐head antioxidant(s), Outcome 11: Sperm concentration at 3 months or less; type of antioxidant
Comparison 2: Head‐to‐head antioxidant(s), Outcome 12: Sperm concentration at 6 months; type of antioxidant
| Sperm concentration at 6 months (data not suitable for meta‐analysis) | |||
| Study | Coenzyme Q10 (n=50) | Glutathione (n=51) | P value |
|---|---|---|---|
| Saeed Alkumait 2020 | % improvement = 24 | % improvement = 26 | Not provided |
Comparison 2: Head‐to‐head antioxidant(s), Outcome 13: Sperm concentration at 6 months (data not suitable for meta‐analysis)
Comparison 2: Head‐to‐head antioxidant(s), Outcome 14: Sperm concentration at 9 months or more; type of antioxidant
| Antioxidants compared to placebo or no treatment for patients with male subfertility | ||||||
| Patient or population: patients with male subfertility | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo or no treatment | Risk with antioxidants | |||||
| Live birth rate per couple randomised | 162 per 1000 | 216 per 1000 (171 to 269) | OR 1.43 (1.07 to 1.91) | 1283 (12 RCTs) | ⊕⊝⊝⊝ | |
| Clinical pregnancy rate per couple randomised | 146 per 1000 | 245 per 1000 (199 to 297) | OR 1.89 (1.45 to 2.47) | 1706 (20 RCTs) | ⊕⊕⊝⊝ | |
| Adverse events ‐ Miscarriage | 48 per 1000 | 68 per 1000 (36 to 125) | OR 1.46 (0.75 to 2.83) | 664 (6 RCTs) | ⊕⊝⊝⊝ | |
| Adverse events ‐ Gastrointestinal | 15 per 1000 | 39 per 1000 (22 to 71) | OR 2.70 (1.46 to 4.99) | 1355 (16 RCTs) | ⊕⊕⊝⊝ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level for serious risk of bias: lack of blinding and incomplete accounting of patients and outcome events 2 Downgraded one level for suspected publication bias based on the funnel plot 3 Downgraded one level for serious imprecision: less than 400 events 4 Downgraded one level for serious imprecision: crossing the line of no effect | ||||||
| Undefined or biochemical pregnancy | Antioxidant | Control | Peto OR [CI] | ||
| Antioxidant(s) versus placebo or no treatment | |||||
| Combined antioxidants | Events | Total | Events | Total | |
| 35 | 234 | 32 | 194 | ||
| 1 | 20 | 0 | 22 | 8.17 [0.16 to 413.39] | |
| 13 | 92 | 2 | 46 | 2.72 [0.88 to 8.46] | |
| 18 | 85 | 26 | 86 | 0.62 [0.32 to 1.24] | |
| 3 | 37 | 4 | 40 | 0.80 [0.17 to 3.74] | |
| Arginine | |||||
| 2 | 35 | 2 | 29 | 0.82 [0.11 to 6.16] | |
| Carnitines | 25 | 154 | 3 | 145 | |
| 1 | 12 | 1 | 9 | 0.74 [0.04 to 13.02] | |
| 3 | 15 | 0 | 15 | 8.57 [0.82 to 89.45] | |
| 6 | 43 | 0 | 43 | 8.37 [1.61 to 43.58] | |
| 4 | 30 | 0 | 26 | 7.20 [0.95 to 54.34] | |
| 9 | 39 | 1 | 47 | 7.50 [2.01 to 27.98] | |
| Coenzyme Q10 | 6 | 136 | 3 | 136 | |
| 0 | 106 | 0 | 106 | Not estimable | |
| 0 | 23 | 0 | 24 | Not estimable | |
| Vitamin C + Vitamin E | |||||
| 0 | 15 | 0 | 16 | Not estimable | |
| Vitamin E | |||||
| 5 | 28 | 5 | 28 | 1.00 [0.26 to 3.88] | |
| Head‐to‐head antioxidant(s) | Events | Total | Events | Total | |
| L‐acetyl carnitine + L‐carnitine vs Vitamin E + Vitamin C | |||||
| 10 | 85 | 2 | 53 | 2.72 [0.81 to 9.14] | |
| L‐carnitine + Vitamin E vs Vitamin E | |||||
| 21 | 68 | 3 | 67 | 6.01 [2.49 to 14.47] | |
| Vitamin E + amino acids vs Vitamin E | |||||
| 4 | 70 | 1 | 50 | 2.52 [0.41 to 15.35] | |
| Study ID | Design, population | Outcomes described in methods section | Outcomes reported on in results | In meta‐analysis Y or N | Results | Conclusions + = positive effect ‐ = negative or no effect |
| Parallel, placebo Men post‐varicocelectomy N = 60 | Sperm parameters, DNA fragmentation | Sperm parameters, DNA fragmentation | Y ‐ sperm parameters Y ‐ DNA fragmentation | ALA improved sperm motility compared to baseline. No significant difference in sperm parameters between ALA and placebo. | ‐ ALA does not improve semen quality compared to placebo after varicocelectomy | |
| Cross‐over, head‐to‐head Infertile men, high ROS levels N = 10 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Ethylcystein did not improve sperm density and motility but "sperm function" increased and ROS levels decreased, compared to vitamin E | + Ethylcysteine shown to be effective for improvement of sperm parameters when compared to vitamin E | |
| Parallel, head‐to‐head Idiopathic OAT N = 65 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | CoQ10 200 and 400 mg improved sperm concentration and motility, greater improvement with 400 mg | + CoQ10 improves sperm parameters, greater improvement with a 400 mg dose compared to 200 mg | |
| Parallel, head‐to‐head Idiopathic OAT N = 70 | Sperm parameters | Sperm parameters | N ‐ number of drop‐outs unclear | CoQ10 and selenium each improved sperm concentration and motility, greater improvement with CoQ10 | + CoQ10 and selenium improve sperm parameters, greater improvement with CoQ10 | |
| Parallel, placebo Infertile men N = 72 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Vitamin D did not improve sperm parameters | ‐ Vitamin D does not improve sperm parameters | |
| Parallel, no treatment Men post‐varicocelectomy N = 64 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Co‐administration of folic acid, selenium and vitamin E improved sperm concentration and motility | + A combination of folic acid + selenium + vitamin E improves sperm parameters after varicocelectomy | |
| Parallel, no treatment Idiopathic asthenozospermia, IUI N = 30 Conference abstract | Sperm parameters, chemical and clinical pregnancy | Sperm parameters, chemical and clinical pregnancy | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical | NAC increased sperm concentration and motility. Clinical pregnancy was not significantly different between the groups | + NAC improves semen quality and improves pregnancy rates prior to IUI, no improvement of pregnancy rate | |
| Multiple arm trial Men post‐varicocelectomy N = 160 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical | Mild improvement in sperm parameters with the use of antioxidants zinc, folic acid or both | + Co‐administration of zinc and folic acid improved sperm parameters and increased varicocelectomy outcomes, only zinc an improvement in pregnancy rate | |
| Parallel, placebo Idiopathic OAT N = 70 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | No improvement of sperm parameters with the use of selenium, folic acid and vitamin E | ‐ Co‐administration of selenium, folic acid and vitamin E were not effective to improve sperm parameters | |
| Multiple arm, placebo Infertile men N = 60 | Sperm parameters | Sperm parameters, pregnancy rate | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical Y ‐ live birth | Improvement in motility in LAC group. | + Long‐term carnitine is effective in increasing sperm motility. No evidence of increased live birth or clinical pregnancy. | |
| Parallel, placebo Infertile and unexplained N = 60 | Sperm parameters | Sperm parameters, pregnancy rate | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical | Co enzyme Q10 increased sperm motility. | + Q10 is effective in improving sperm kinetic features in asthenospermia. No evidence of increased live birth or clinical pregnancy. | |
| Parallel, no treatment Subfertile men with varicocele N = 40 | Sperm parameters, DNA fragmentation | Sperm parameters, DNA fragmentation, clinical spontaneous pregnancies | Y ‐ sperm parameters Y ‐ DNA fragmentation Y ‐ pregnancy rate, clinical (SEs converted to SDs) | Sperm parameters significantly improved after surgery compared to before surgery in both the NAC and control groups. NAC might have an additional value by improving sperm motility post‐varicocelectomy | + The results of this study revealed that NAC improved chromatin integrity and pregnancy rate when administered as adjunct therapy post‐varicocelectomy | |
| Multiple arm, no treatment Severe idiopathic oligoasthenospermia N = 42 Conference abstract | Sperm parameters | Sperm parameters | N ‐ no data available | A significant improvement in morphology concentration, motility in the carnitine group No side effects | + Quality of semen is positively associated with fertilisation and implantation rates in assisted reproduction | |
| Parallel, placebo Infertile men with impaired semen quality N = 307 | Sperm parameters, reproductive hormones, live birth rate | Sperm parameters, reproductive hormones, live birth rate | Y ‐ sperm parameters, concentration provided as median + IQR and converted to mean + SD Y ‐ live birth rate | Vitamin D was not associated with changes in semen parameters, although spontaneous pregnancies tended to be higher in couples in which the man was in the treatment group | ± Vitamin D did not improve semen quality. The positive impact of vitamin D supplementation on live birth rate and serum inhibin B in oligozoospermic and vitamin D–deficient men may be of clinical importance and warrant verification by others. | |
| Multiple arm, placebo, tamoxifen excluded Men with abnormal semen analysis N = 68 | Sperm parameters, DNA damage (Comet assay) | Sperm parameters, DNA tail length | Y ‐ sperm parameters | Folate alone significantly decreased DNA tail length at 3‐months. Sperm motility was significantly increased after 3‐months Folate alone. | + Our study indicated that folate in combination with Tamoxifen citrate could improve sperm quality including semen parameters and sperm DNA integrity | |
| Parallel, placebo Infertile men with OAT, 50% included with varicocele N = 104 | Sperm parameters, pregnancy rate | Sperm parameters, pregnancy rate | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical | Sperm concentration, total sperm count, progressive and total motility were significantly increased in supplemented (Proxeed Plus) patients. Increased pregnancy rate | + Supplementation with metabolic and antioxidant compounds could be efficacious when included in strategies to improve fertility | |
| Multiple arm, placebo Idiopathic OAT men with varicocele N = 325 | Sperm parameters, pregnancy rate, adverse events | Sperm parameters, pregnancy rate, adverse events | Y ‐ sperm parameters (median +IQR converted to mean + SD) N ‐ pregnancy rate, unclear if clinical Table 1 Y ‐ adverse events | Significant increase in sperm parameters for carnitines when compared to placebo. Carnitine groups had a significantly higher pregnancy rate than placebo group | + The antioxidant plus anti‐inflammatory group was more effective in improving sperm parameters and pregnancy than those of carnitines alone or placebo however carnitines alone were more effective than placebo | |
| Multiple arm, head‐to‐head Idiopathic OAT N = 312 | Sperm parameters, DNA fragmentation, pregnancy rate | Sperm parameters, DNA fragmentation, pregnancy rate | Y/N ‐ sperm parameters, results not available for all groups and parameters Y ‐ DNA fragmentation Y ‐ pregnancy rate, clinical | Significant improvement of sperm parameters and DNA fragmentation in the L‐carnitine plus CoQ10 group compared to placebo. Combination and L‐carnitine groups had remarkably higher pregnancy rate than placebo group | + Combination of LC and CoQ10 improve semen parameters and outcome of clinical pregnancy | |
| Multiple arm, placebo Asthenozoospermic men N = 28 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters (SEs converted to SDs) | DHA showed no effect on sperm motility or concentration | ± DHA supplementation increased DHA levels in the sperm but not motility or concentration | |
| Parallel, placebo Infertile men with varicocele N = 115 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Vitamin C was not effective on sperm count but improved sperm motility and morphology significantly | + Ascorbic acid can play a role as adjuvant treatment after varicocelectomy in infertile men | |
| Multiple arm, placebo Men with sperm agglutination N = 30 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters (SEs converted to SDs) | The group receiving 1000 mg of AA showed more improvement in parameters than the 200mg group and the placebo | + Vitamin C can improve sperm parameters, especially dosage of 1000 mg. | |
| Head‐to‐head Men with idiopathic oligoasthenozoospermia N = 86 | Sperm parameters, adverse reactions, pregnancy rate | Sperm parameters, adverse reactions, pregnancy rate | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical | Vitamin D is a safe option for the treatment of idiopathic oligoasthenozoospermia and can effectively improve the semen quality especially the progressive sperm motility | + Vitamin D can improve forward movement sperm number and percentage, improve the woman's clinical pregnancy rate, and is well tolerated | |
| Multiple arm, no treatment, vardenafil/sildenafil arms excluded Men with oligoasthenospermia N = 75 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | An improvement in sperm concentration with carnitine versus no treatment | + Enhancement of Leydig cell secretory function may increase sperm concentration and motility | |
| Parallel, no treatment Infertile men with varicocele N = 56 | Sperm parameters, pregnancy rate | Sperm parameters, pregnancy rate | Y ‐ sperm parameters N ‐ pregnancy rate, unknown if clinical Table 1 | The administration of vitamin E increased all of the parameters; however not statistically significant | ‐ Vitamin E supplementation does not improve the sperm parameters after varicocelectomy | |
| Parallel, placebo Asthenoszoospermic men N = 50 | Sperm parameters | Sperm parameters, sperm membrane and serum fatty acids | N ‐ sperm parameters, data not usable, no continuous data but categories from 'significantly improvement' to 'worsened' | Sperm parameters improved with DHA + vitamin E supplementation | + Sperm parameters improve with DHA + vitamin E supplementation | |
| Multiple arm, placebo Asthenozoospermic men N = 180 | Sperm parameters | Sperm parameters | N ‐ sperm parameters, only imputed data provided | Significant increase of sperm concentration in the DHA + vitamin E group compared to groups treated with DHA+placebo, vitamin E+placebo and placebo. | + Combined DHA and vitamin E improve sperm parameters | |
| Parallel, placebo Normozoospermic, oligozoospermic and asthenozoospermic men N = 113 | Sperm parameters, pregnancy rate | Sperm parameters, pregnancy rate | N ‐ sperm parameters N ‐ pregnancy rate Both not included because data included normospermic men | 50% of oligozoospermic men improved sperm concentration and sperm count to normozoospermic levels. This trend was also observed in asthenozoospermic men, but nog significantly | + Vitamin E treatment by oral administration improves semen parameters | |
| Parallel, no treatment Men with persistent oligospermia after embolisation of varicocele N = 42 | Sperm parameters, pregnancy rate, adverse events | Sperm parameters, pregnancy rate, adverse events | N ‐ sperm parameters, only medians given N ‐ pregnancy, unclear if clinical Table 1 N ‐ adverse events | Significant difference in sperm count in combined antioxidant group but not in motility. One pregnancy in the NAC group No significant adverse effects | ± NAC does not improve pregnancy rate, no significant adverse events, but do significantly increase sperm count | |
| Multiple arm, no treatment Men with varicocele N = 114 | Sperm parameters, DNA fragmentation, adverse events | Sperm parameters, DNA fragmentation, adverse events | Y ‐ sperm parameters (median+IQR converted to mean+SD) Y ‐ DNA fragmentation (median+IQR converted to mean+ SD) Y ‐ adverse events | SpermActine (SA) resulted in a 22.3% decrease in the level of sperm DNA fragmentation at 3 months. SA + vitamin complex resulted in a 27% increase in the sperm concentration at 3 months. There were no side effects of pharmacotherapy. | + Antioxidant therapy leads to an improvement in the basic sperm parameters (sperm concentration and motility) and a decrease in the level of sperm DNA fragmentation in the short term. There were no side effects | |
| Parallel, placebo Infertile men with high oxidative stress and DNA fragmentation N = 80 | Sperm parameters, DNA fragmentation, pregnancy rate, live birth | Sperm parameters, DNA fragmentation, pregnancy rate, live birth, adverse events | Y ‐ sperm parameters Y ‐ DNA fragmentation Y ‐ pregnancy rate, clinical Y ‐ live births Y ‐ adverse events | Spermactin Forte significantly improvement sperm motility and decreased oxidative stress. There were more pregnancies in the intervention group (13 versus 1) | + The use of the SpermActin Forte antioxidant improves sperm analysis in most patients. SpermActin Forte is an effective and safe method of treating male infertility | |
| Multiple arm, placebo Infertile men N = 60 | Sperm parameters, DNA fragmentation | Sperm parameters, DNA fragmentation | N ‐ sperm parameters, outcomes provided as change + SD Analysis 1.15; Analysis 1.20 N ‐ DNA fragmentation, outcomes provided as change + SD Analysis 1.8 | Significant increase of progressive sperm motility in the DHA 1g and 2g groups after 1 month and in the DHA 0.5 group after 3 months. Greater effect in asthenozoospermic men | + DHA (0.5, 1 and 2g) had beneficial effects on sperm function without producing any adverse effects, obtaining more immediate results with higher doses | |
| Multiple arm, placebo Idiopathic OAT men N = 138 | Sperm parameters, pregnancy rate, adverse events | Sperm parameters, pregnancy rate, adverse events | Y ‐ sperm parameters N ‐ pregnancy rate, not clinical Table 1 Y ‐ adverse events | Combined antioxidant significantly improved sperm count and total motility in both treatment arms (1 vs 2 tablets). Mild adverse events were reported, no severe. | + Exogenous administration of fixed dose combination of antioxidants is safe and effective therapy in improving the male subfertility regarding sperm parameters. Only mild adverse events when using combined antioxidants | |
| Multiple arm, placebo Arm treated with diet enriched in antioxidants not used Men with idiopathic infertility and high ROS N = 175 Conference abstract | Sperm parameters, DNA fragmentation | DNA fragmentation | N ‐ sperm parameters, not reported in results N ‐ DNA fragmentation, no results reported besides p‐value | No difference in DNA fragmentation between the study groups | +/‐ No conclusions on antioxidants versus placebo. A diet rich in antioxidants and lifestyle modifications can bring almost the same effect as antioxidant supplements | |
| Parallel, placebo Infertile males with high DNA fragmentation N = 64 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | No significant difference in concentration or motility however DNA fragmentation was significantly reduced in the vitamin C + E when compared to placebo | + A short oral treatment of Vitamin C + E can reduce DNA fragmentation | |
| Parallel, placebo Men with idiopathic asthenozoospermia N = 48 | Sperm parameters, adverse events | Sperm parameters, adverse events | Y ‐ sperm parameters N ‐ adverse events, reported "none", however not clear which side effects they aimed for | Sperm parameters were significantly higher in ALA group. No side effects due to the oral administration of ALA were observed in any participants. | + Medical therapy of asthenoteratospermia with ALA supplement could improve quality of semen parameters | |
| Multiple arm, placebo, tamoxifen arms excluded Infertile men with idiopathic OAT N = 128 | Sperm parameters, pregnancy rate | Sperm parameters, pregnancy rate | N ‐ sperm parameters, range of treatment 3 ‐ 6 months and not divided N ‐ pregnancy rate, unclear if pregnancy and no numbers but percentage | L‐carnitine did not improve sperm count or motility. Only tamoxifen or tamoxifen + L‐carnitine improved pregnancy rate, not significantly. | ± Administration of tamoxifen or L‐carnitine can improve sperm parameters and ICSI outcomes. Combining those result in maximum therapeutic effect | |
| Parallel, placebo Oligozoospermic men N = 769 | Sperm parameters, evaluation of MTHFR polymorphism, DNA fragmentation, pregnancy rate, live birth | Sperm parameters, evaluation of MTHFR polymorphism, DNA fragmentation, pregnancy rate, live birth | N ‐ sperm parameters N ‐ DNA fragmentation N ‐ pregnancy, clinical N ‐ live births All outcomes reported for MTHFR polymorphism groups only | Folic acid significantly increased sperm parameters, decreased oxidative stress and DNA fragmentation and lead to a higher pregnancy and live birth rate in the MTHFR 677 TT group. Effect not seen in other MTHFR groups. | + Folic acid has a beneficial effect on oligozoospermia with MTHFR 677 TT genotype in terms of sperm parameters, DNA fragmentation and pregnancy outcomes | |
| Parallel, no treatment Infertile men scheduled for ART N = 200 | Sperm parameters, pregnancy rate, live birth, adverse events | Sperm parameters, pregnancy rate, live birth, adverse events | Y ‐ sperm parameters (median+IQR converted to mean+SD) Y ‐ pregnancy rate, clinical Y ‐ live births Y ‐ adverse events | No significant difference in clinical pregnancies or live births when combined vitamin C + vitamin E + zinc were compared to no treatment. No improvement of sperm parameters | ‐ No difference in clinical pregnancy and live births. No improvement of sperm parameters | |
| Cross‐over, placebo Male infertility N = 30 | Sperm parameters, adverse events, live birth | Sperm parameters, adverse effects, live birth | N ‐ sperm parameters, only medians given Analysis 1.10; Analysis 1.20 Y ‐ pregnancy rate, clinical Y ‐ live births Y ‐ adverse events | No differences in sperm outcomes were seen between the groups. 1 pregnancy in the vitamin E group and nil in the placebo (first phase data) | + No difference in semen parameters. There is evidence of increased live birth and clinical pregnancy rate | |
| Parallel, no treatment Varicocele patients with oligozoospermia N = 93 | Sperm parameters, clinical pregnancy, adverse events | Sperm parameters, clinical pregnancy, adverse events | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical Y ‐ adverse events | Significant improvement of sperm parameters and higher clinical pregnancy rate in combined antioxidant group compared to no treatment | + Antioxidant treatment provides an important contribution | |
| Parallel, placebo Idiopathic infertility N = 83 | Sperm parameters, clinical pregnancy, adverse events | Sperm parameters, clinical pregnancy, adverse events | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical Y ‐ adverse events | The percentage of normal spermiograms was significantly higher in the combined antioxidant group. Higher spontaneous pregnancy rate in antioxidant group | + Combined l‐carnitine/l‐acetyl‐carnitine, l‐arginine, | |
| Parallel, no treatment Obstructive azoospermia, TESA/ICSI candidates N = 46 Conference abstract | Clinical pregnancy, live births | Clinical pregnancy, live birth, embryo quality, early pregnancy loss | Y ‐ pregnancy rate, clinical Y ‐ live births N ‐ adverse events, miscarriage. No data provided by authors. | Clinical pregnancy and live birth rate were 62,5% vs 59,1% and 54,1% vs 40,9% in the antioxidant and no treatment group, respectively. Higher early pregnancy loss rate in control group | + Antioxidant therapy may have a positive effect for patients with obstructive azoospermia. It might improve ART outcome and decrease pregnancy loss | |
| Parallel, placebo Infertile men with OAT N = 80 | Sperm parameters, DNA fragmentation, adverse events | Sperm parameters, DNA fragmentation, adverse events, after contact with author: clinical pregnancy rate and live births after ICSI | Y ‐ sperm parameters Y ‐ DNA fragmentation Y ‐ adverse events Y ‐ pregnancy rate, clinical Y ‐ live births | No statistical differences in sperm parameters between astaxanthin + vitamin E group and placebo | ‐ The oral intake of astaxanthin did not affect any semen parameters in patients with OAT | |
| Multiple arm, placebo Men with abnormal sperm count or motility N = 396 | Sperm parameters | Sperm parameters | N ‐ sperm parameters, only scales given | No statistical difference in sperm outcomes in vitamin B 12 groups or placebo | ‐ No improvement in sperm parameters after use of vitamin B12 | |
| Cross‐over, placebo Infertile men with OAT N = 100 | Sperm parameters, pregnancy rate | Sperm parameters, pregnancy rate | Y ‐ sperm parameters N ‐ pregnancy rate, no definition of pregnancy given see Table 1 | The patient groups showed no differences in sperm outcomes between therapy (carnitine) and placebo groups. Six pregnancies in the carnitine group and nil in the placebo (first phase) | + The pregnancies obtained during the carnitine therapy period could suggest that carnitines may also lead to improvement in sperm function and fertilisation | |
| Parallel, placebo Infertile men with OAT N = 60 | Sperm parameters, pregnancy rate, adverse events | Sperm parameters, pregnancy rate, adverse events | Y ‐ sperm parameters N ‐ pregnancy rate, no definition of pregnancy given Table 1 N ‐ adverse events | Four participants taking carnitine induced a pregnancy in their partner and nil in the placebo | + No evidence of improved sperm parameters | |
| Head‐to‐head Infertile men with OAT N = 150 | Sperm parameters, pregnancy rate | Sperm parameters, pregnancy rate | Y ‐ sperm parameters N ‐ pregnancy rate, no definition given Table 1 | L‐carnitine and acetyl carnitine more effective than vitamin E + vitamin C for pregnancy, sperm parameters and no evidence of adverse events | + L‐carnitine and acetyl carnitine more effective than vitamin E + vitamin C for pregnancy, sperm parameters and no evidence of adverse events | |
| Head‐to‐head Infertile men with OAT N = 80 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Statistical significance for carnitines over vitamin E + C | + Improvement of sperm parameters for carnitines compared to vitamin E + C | |
| Cross‐over Infertile men with OAT N = 100 Conference abstract | Sperm parameters | Sperm parameters | N ‐ sperm parameters, no data available | Sperm parameters (concentration, motility) carnitines versus placebo | + Improvement of sperm parameters | |
| Multiple arm, placebo, SG1002 arm excluded Men with idiopathic OAT N = 54 | Sperm parameters | Sperm parameters | N ‐ sperm parameters, no SDs given | Resveratrol treatment did not significantly affect any of the parameters. | ‐ Resveratrol treatment did not significantly affect any of the parameters. SG1002 may reverse oligoasthenozoospermia. It seems to be more potent antioxidant than resveratrol | |
| Parallel, placebo Infertile men N = 50 Conference abstract + manuscript from author | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | No differences were found in traditional sperm parameters or lipid composition of the sperm membrane after DHA treatment, only reduction in the percentage of spermatozoa with DNA damage | + Positive effect only on DNA fragmentation | |
| Multiple arm, placebo, pentoxifylline arms excluded Infertile men with OAT N = 235 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | L‐carnitine only improved sperm motility, combined with pentoxifylline it improves all sperm parameters. | + Positive effect only on sperm motility | |
| Parallel, placebo Men with OAT N = 175 | Sperm parameters, DNA fragmentation | Sperm parameters, DNA fragmentation | Y ‐ sperm parameters Y ‐ DNA fragmentation (median+IQR converted to mean + SD) | Proxeed Plus significantly improved sperm volume, motility and DNA fragmentation compared to baseline. | + Beneficial effects of carnitine | |
| Parallel, no treatment Infertile men with idiopathic asthenospermia N = 180 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Significant improvement in sperm motility. | + Improvement of sexual satisfaction Significant improvement in sperm motility | |
| Parallel, placebo Men with Idiopathic OAT N = 60 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Non‐significant changes in semen parameters of CoQ10 group. | ‐ CoQ10 further evidence suggesting that supplementation is associated with alleviating oxidative stress, although it does not show any significant effects on sperm concentration, motility and morphology | |
| Parallel, placebo Men with history of infertility N = 44 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Significant improvement of sperm concentration with lycopene compared to placebo. Increase of total motility in lycopene group compared to baseline. | + Lycopene improves sperm parameters and oxidative stress biomarkers in infertile men | |
| Head‐to‐head Men with OAT N = unclear, 20? | Sperm parameters | Sperm parameters | N ‐ sperm parameters, no data available | Vitamin E + selenium significantly improves sperm motility | + Vitamin E + selenium associated with improved sperm motility when compared with vitamin B | |
| Parallel, no treatment Men with asthenozoopermia N = 100 | Sperm parameters | Sperm parameters, pregnancy, live birth | N ‐ sperm parameters, only % increase or decrease, not usable Y ‐ pregnancy rate, clinical Y ‐ live birth | Significant improvement in sperm quality by zinc therapy | + Zinc has a role in improving sperm parameters. Significant increase in pregnancy, not live birth | |
| Multiple arm, no treatment Men with asthenozoospermia N = 100 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Zinc therapy alone, in combination with vitamin E or with vitamin E+C were associated with comparably improved sperm parameters and less sperm DNA fragmentation | + Zinc therapy reduces asthenozoospermia | |
| Cross‐over, placebo Infertile men N = 30 | Sperm parameters | Sperm parameters, pregnancy rate | Y ‐ sperm parameters N ‐ pregnancy rate, not defined as clinical Table 1 | Significant improvements in mean sperm concentration and progressive sperm motility upon two months of L‐carnitine intake but no significant changes were found in sperm volume or morphology. | + Sperm outcomes and biochemical pregnancies. L‐carnitine intake effectively improved the mean sperm count and progressive sperm motility | |
| Parallel, no treatment Men planning ART treatment N = 80 | Sperm parameters, clinical pregnancy, adverse events | Sperm parameters, clinical pregnancy, adverse events | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical Y ‐ adverse events | No significant change in sperm motility. A pregnancy rate in the combined antioxidants (Androdoz) group was 45% compared to 25% in the control group. | +/‐ Androdoz contributes to an increase in positive outcomes of ART program. "Androdoz improves the main criteria of sperm analysis and functional tests (HBA‐test)". This is based on the improvement of morphology | |
| Parallel, no treatment Men with male factor infertility and varicocele N = 100 | Sperm parameters, DNA fragmentation, adverse events | Sperm parameters, DNA fragmentation, adverse events | N ‐ sperm parameters, no SD given Y ‐ adverse events | No statistical difference between the two groups (varicocelectomy with L‐carnitine or with no adjuvant therapy). | ‐ Addition of 750 mg of L‐carnitine orally daily to standard inguinal varicocelectomy does not add any extra benefit in terms of improvement in semen analysis parameters or | |
| Multiple arm, placebo Infertile men N = 60 Conference abstract | Sperm parameters | Sperm parameters | N ‐ sperm parameters, data not available | L‐carnitine significantly improves sperm concentration, Spermotrend and Maca improve sperm motility. | + Sperm concentration with L‐carnitine and motility with combined antioxidant Spermotrend | |
| Cross‐over, placebo Men with severe oligozoospermia N = 64 | Sperm parameters, pregnancy rate | Sperm parameters, pregnancy rate | N ‐ sperm parameters, bar graph of % patients showing an increase in motility and density N ‐ pregnancy rate, not clear if clinical. Included in biochemical analysis Table 1 | Arginine was no more effective than placebo for sperm parameters and biochemical pregnancy rates | ‐ There was no difference in the conception rates of the wives or changes in the quality of the semen during each period of treatment | |
| Multiple arm, placebo Men with proven male factor infertility N = 83 | Sperm parameters, DNA fragmentation | Sperm parameters, DNA fragmentation | Y ‐ sperm parameters ( median+IQR converted to mean+ SD) Y ‐ DNA fragmentation | Sperm concentration, DNA fragmentation not significantly improved in either group | ‐ Zinc sulphate and folic acid supplementation did not ameliorate sperm quality in infertile men with severely compromised sperm parameters, OAT | |
| Asthenospermia N = 33 | Sperm parameters, pregnancy rates, adverse events | Sperm parameters, pregnancy rate, adverse events | Y ‐ sperm parameters N ‐ pregnancy rate, not stated as clinical pregnancy N ‐ adverse events, not clear which side effects aimed for | No adverse events or pregnancies in either group | ‐ Overall no difference vitamin E + C versus placebo | |
| Multiple arm, placebo Infertile men N = 151 | Sperm parameters | Sperm parameters | N ‐ sperm parameters, data provided as percentage improvement, Analysis 1.16; Analysis 1.22 | Significantly higher percentage improvement of progressive sperm motility and concentration with glutathione or CoQ10 compared to placebo | + Both glutathione and CoQ10 are effective treatment options for improving sperm motility, morphology and concentration | |
| Multiple arm, placebo Men with idiopathic OAT N = 468 | Sperm parameters, adverse events | Sperm parameters, adverse events | Y ‐ sperm parameters N ‐ adverse events, not specified which adverse events aimed for | All semen parameters significantly improved with selenium and N‐acetyl‐cysteine treatment. Administering selenium plus N‐acetyl‐cysteine resulted in additive beneficial effects. Zero adverse events | + Supplemental selenium and N‐acetyl‐cysteine improve semen quality. Zero adverse events | |
| Parallel, placebo Men with idiopathic OAT N = 212 | Sperm parameters, adverse events | Sperm parameters, adverse events | Y ‐ sperm parameters N ‐ adverse events, not specified which adverse events aimed for | Significant improvement in sperm density and motility after coenzyme Q10 therapy. Zero adverse events | + Coenzyme Q10 supplementation resulted in a statistically significant improvement in certain sperm parameters. Zero adverse events | |
| Parallel, placebo Men with idiopathic OAT N = 238 | Sperm parameters, adverse events | Sperm parameters, adverse events | Y ‐ sperm parameters N ‐ adverse events, not clear how many patients had gastrointestinal upsets in total | Significant improvement of sperm concentration and progressive motility after omega‐3 fatty acids therapy. Significantly more adverse events (gastrointestinal and pruritus) in the omega‐3 group | + These findings suggest a protective effect of omega‐3 fatty acid intake in idiopathic infertile men. More adverse events in omega‐3 group | |
| Parallel, placebo Infertile men N = 228 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Sperm parameters improved significantly after coenzyme Q10 | + Coenzyme Q10 was significantly effective in men with unexplained oligoasthenoteratozoospermia for improving sperm density, sperm motility and sperm morphology | |
| Parallel, placebo Male partner of couples planning infertility treatment. Data from subfertile men used. N = 2370 | Sperm parameters, DNA fragmentation, clinical pregnancy, live births, adverse events | Sperm parameters, DNA fragmentation, clinical pregnancy, live births, adverse events | Y ‐ sperm parameters Y ‐ DNA fragmentation N ‐ pregnancy, clinical; N ‐ live births N ‐ adverse events Data not provided for male factor infertility subgroup | No significant difference in sperm parameters between folic acid + zinc and placebo. No results on clinical outcomes in male factor subgroup | ‐ Folic acid and zinc did not significantly improve semen quality. The findings also were similar when restricted to men with known male factor infertility or poor semen quality at baseline | |
| Multiple arm, placebo Men with subfertility and low sperm motility N = 69 | Sperm parameters, pregnancy rate | Sperm parameters, pregnancy rate | Y ‐ sperm parameters N ‐ pregnancy rate, not usable due to pooling of data in the two intervention groups Table 1 | Sperm motility increased in both selenium‐treated groups, only significant if both treatment groups were combined. Sperm density unaffected | ± Selenium supplementation in subfertile men with low selenium status can improve sperm motility and the chance of successful conception. However, not all patients responded; 56% showed a positive response to treatment | |
| Parallel, placebo Idiopathic subfertile men N = 114 | Sperm parameters, adverse events | Sperm parameters, adverse events | Y‐ sperm parameters Y ‐ adverse events | Significant increase in concentration in zinc group | + Normal sperm percentage and total sperm concentration increased after zinc sulphate treatment | |
| Parallel, placebo Infertile men with low sperm motility N = 26 | Sperm parameters, pregnancy rate | Sperm parameters, pregnancy rate | Y ‐ sperm parameters N ‐ pregnancy rate, biochemical Table 1 | No statistically significant or clinically significant increase in motility or total motile sperm counts between baseline, 12 weeks, or 24 weeks in the carnitine or placebo arms. | ‐ Carnitine supplementation demonstrated no clinically or statistically significant effect on sperm motility or total motile sperm counts. No difference in pregnancy rate | |
| Parallel, placebo Men with chronic prostatitis and infertility N = 30 | Sperm parameters | Sperm parameters | N ‐ sperm parameters, no SD given Analysis 1.10 | One‐month course of therapy produced no side effects, had a positive effect on low fertility of ejaculate. | + Selenium + zinc improve | |
| Multiple arm, no treatment, Avanafil excluded Oligoasthenospermic infertile men N = 39 Abstract only | Sperm parameters | Sperm parameters | N ‐ sperm parameters, no data available | No significant difference in L‐carnitine group regarding sperm parameters | ‐ No direct conclusion made about L‐carnitine. From result section concluded: no impact on sperm parameters after use of L‐carnitine | |
| Parallel, placebo Men with one abnormal semen parameter N = 171 | Sperm parameters, DNA fragmentation, clinical pregnancy, live birth | Sperm parameters, DNA fragmentation, clinical pregnancy, live birth | Y ‐ sperm parameters Y ‐ DNA fragmentation (data shared by authors after requested via e‐mail) Y ‐ pregnancy, clinical Y ‐ live birth | No difference in sperm motility, DNA fragmentation, pregnancy rate and live birth rate between combined antioxidants and placebo | ‐ No improvement in semen parameters in infertile males. This study suggests that combination antioxidants does not improve pregnancy or live birth rates | |
| Parallel, placebo Infertile men with DNA fragmentation ≥ 25% N = 79 | Sperm parameters, DNA fragmentation, pregnancy rate, adverse events | Sperm parameters, DNA fragmentation, pregnancy rate, adverse events | Y ‐ sperm parameters Y ‐ DNA fragmentation N ‐ pregnancy rate, biochemical Table 1 Y ‐ adverse events | No statistically significant difference between the antioxidant and placebo group was seen for semen parameters including DNA fragmentation | ‐ Six months treatment with combined antioxidants had no effect on sperm parameters including DNA fragmentation | |
| Parallel, placebo Asthenospermic men N = 110 | Sperm parameters | Sperm parameters, pregnancy rate, live birth, miscarriage | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical Y ‐ live birth Y ‐ adverse events: miscarriage | Vitamin E significantly decreased the MDA concentration in spermatozoa and improved sperm motility. Significant increase pregnancy/live birth rate | + Vitamin E increases sperm motility, pregnancy rate and live birth rate compared to placebo | |
| Parallel, head‐to‐head Infertile men with low acrosin activity N = 232 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters | Significant increase of progressive sperm otility in men treated with L‐carnitine compared to vitamin E | + L‐carnitine can effectively elevate sperm acrosin activity in male infertility patients, particularly in those with asthenozoospermia | |
| Parallel, placebo Male factor infertility N = 60 | Pregnancy rate, adverse events | Pregnancy rate, adverse events, live birth provided by author | Y ‐ pregnancy rate, clinical Y ‐ live birth Y ‐ adverse events | Antioxidant group recorded a statistically significant improvement in viable pregnancy rate. Side‐effects on the Menevit antioxidant were rare (8%) and mild in nature. | + Menevit antioxidant appears to be a useful ancillary treatment that significantly improves pregnancy rates in couples undergoing IVF‐ICSI treatment. Side‐effects on the Menevit antioxidant were rare (8%) and mild in nature. | |
| Multiple arm, head‐to‐head Profertil + avanafil and avafanil only groups not used Idiopathic OAT N = 217 | Sperm parameters, DNA fragmentation, pregnancy rate | Sperm parameters, DNA fragmentation, pregnancy rate | N ‐ sperm parameters N ‐ DNA fragmentation Not reported in how many patients sperm outcomes were assessed Y ‐ pregnancy rate, clinical | Significantly higher total and progressive sperm motility in Profertil group compared to L‐carnitine and no treatment. No difference in pregnancy rate | + Profertil or Profertil combined with avanafil or or avanafil alone improves sperm membrane permeability with an improvement in sperm motility | |
| Parallel, placebo Infertile men with at least one abnormal sperm parameter N = 109 | Sperm parameters, DNA fragmentation | Sperm parameters, DNA fragmentation | N ‐ sperm parameters N ‐ DNA fragmenation Only results after cryotolerance test provided | No statistical differences between results after Brudy plus (combined antioxidant) and placebo | +/‐ No conclusions on outcomes of interest. Brudy Plus increases cryotolerance, promotes the normal formation of the genetic material and reduces the frequency of ultrastructural sperm disorders. | |
| Head‐to‐head Infertile men with asthenozoospermia N = 135 | Sperm parameters, pregnancy rate, adverse events | Sperm parameters, pregnancy rate, adverse events | Y ‐ sperm parameters N ‐ pregnancy rate, not clear if clinical Table 1 N ‐ adverse events, zero found, however not clear which they aimed for | Significant increase in L‐carnitine + vitamin E group for sperm motility, no difference for sperm density and morphology. Pregnancy rate significantly higher in L‐carnitine + vitamin E group | + L‐carnitine (+vitamin E) significantly improves sperm motility and pregnancy rate | |
| Multiple arm, placebo Fertile and subfertile men N = 103 | Sperm parameters | Sperm parameters | Y ‐ sperm parameters (median+IQR converted to mean+ SD) | Subfertile men demonstrated a significant 74% increase in total normal sperm count and a minor increase of 4% abnormal spermatozoa | + Total normal sperm count increases after combined zinc sulphate and folic acid treatment in both subfertile and fertile men | |
| Head‐to‐head, pilot Men attending andrology clinic N = 22 Conference abstract | Sperm parameters | Sperm parameters | N ‐ sperm parameters, only before and after median data given | No significant difference in sperm parameters after treatment (acetyl‐cysteine or DHA). DNA damage measured by 8‐OHdG (fmol/ug) was significantly decreased after supplementation | ‐ No improvement of sperm parameters | |
| Parallel, placebo Men with idiopathic infertility N = 20 | Sperm parameters, clinical pregnancy, adverse events | Sperm parameters, clinical pregnancy, adverse events | Y ‐ sperm parameters Y ‐ pregnancy rate, clinical Y ‐ adverse events | No significant changes in sperm characteristics were detected | ‐ Magnesium neither leads to a significant improvement of sperm variables nor does it increase the pregnancy rates | |
| Parallel, head‐to‐head Idiopathic asthenozoospermia N = 120 | Sperm parameters, pregnancy rate | Sperm parameters, pregnancy rate | Y ‐ sperm parameters N ‐ pregnancy rate, definition unclear Table 1 Y ‐ adverse events | Significant increase of total and progressive sperm motility in vitamin E and vitamin E + compound amino acids group. Greater increase in compound amino acids group. 5.7% pregnancy in combined group, 2% in vitamin E group. No adverse events | + Compound amino acid combined with vitamin E can safely and effectively improve sperm motility in idiopathic asthenospermia patients. | |
| DHA: docosahexaenoic acid; IUI: intrauterine insemination; NAC: N‐acetylcysteine; OAT:oligoasthenoteratozoospermia; ROS: reactive oxygen species | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Live birth; type of antioxidant Show forest plot | 12 | 1283 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.43 [1.07, 1.91] |
| 1.1.1 Astaxanthin + Vitamin E | 1 | 36 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.63 [0.34, 7.69] |
| 1.1.2 Carnitines | 1 | 60 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.00 [0.24, 4.25] |
| 1.1.3 Coenzyme Q10 | 1 | 60 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.16 [0.53, 8.82] |
| 1.1.4 Vitamin D + Calcium | 1 | 330 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.03 [0.59, 1.80] |
| 1.1.5 Vitamin E | 2 | 140 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 8.51 [2.36, 30.70] |
| 1.1.6 Zinc | 1 | 100 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 3.74 [1.02, 13.74] |
| 1.1.7 Combined antioxidants | 5 | 557 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.28 [0.86, 1.91] |
| 1.2 Live birth; IVF/ICSI Show forest plot | 5 | 372 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.63 [1.01, 2.61] |
| 1.3 Clinical pregnancy; type of antioxidant Show forest plot | 20 | 1706 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.89 [1.45, 2.47] |
| 1.3.1 Astaxanthin + Vitamin E | 1 | 36 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.32 [0.35, 4.96] |
| 1.3.2 Carnitines | 2 | 125 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.17 [0.30, 4.59] |
| 1.3.3 Coenzyme Q10 | 1 | 60 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.16 [0.53, 8.82] |
| 1.3.4 Folic acid | 1 | 53 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Not estimable |
| 1.3.5 Magnesium | 1 | 26 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 8.73 [0.17, 445.08] |
| 1.3.6 N‐acetylcysteine (NAC) | 2 | 100 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.00 [0.71, 5.63] |
| 1.3.7 Vitamin E | 2 | 117 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 6.71 [1.98, 22.69] |
| 1.3.8 Zinc | 2 | 153 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 4.43 [1.39, 14.14] |
| 1.3.9 Zinc + Folic acid | 1 | 53 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 3.86 [0.15, 99.84] |
| 1.3.10 Combined antioxidants | 10 | 983 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.67 [1.22, 2.28] |
| 1.4 Clinical pregnancy; IVF/ICSI Show forest plot | 6 | 452 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.73 [1.15, 2.61] |
| 1.5 Adverse events Show forest plot | 21 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.5.1 Miscarriage | 6 | 664 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.46 [0.75, 2.83] |
| 1.5.2 Ectopic pregnancy | 2 | 260 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.59 [0.16, 16.01] |
| 1.5.3 Stillbirth | 1 | 200 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.14 [0.00, 6.82] |
| 1.5.4 Gastrointestinal | 16 | 1355 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.70 [1.46, 4.99] |
| 1.5.5 Euphoria | 1 | 86 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.21 [0.16, 9.01] |
| 1.5.6 Headache | 1 | 171 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.32 [0.95, 5.67] |
| 1.5.7 Upper respiratory infection | 1 | 171 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.01 [0.25, 4.17] |
| 1.5.8 Nasofaryngitis | 1 | 171 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.57 [0.17, 1.92] |
| 1.6 Sperm DNA fragmentation at 3 months or less; type of antioxidant Show forest plot | 12 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.6.1 Astaxanthin + Vitamin E | 1 | 72 | Mean Difference (IV, Fixed, 95% CI) | 1.40 [‐6.64, 9.44] |
| 1.6.2 Folic acid | 1 | 38 | Mean Difference (IV, Fixed, 95% CI) | ‐5.80 [‐13.40, 1.80] |
| 1.6.3 Folic acid + Zinc | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | ‐1.20 [‐9.36, 6.96] |
| 1.6.4 N‐acetylcysteine (NAC) | 1 | 35 | Mean Difference (IV, Fixed, 95% CI) | 3.90 [‐0.42, 8.22] |
| 1.6.5 PUFAs | 3 | 137 | Mean Difference (IV, Fixed, 95% CI) | ‐1.16 [‐4.00, 1.68] |
| 1.6.6 Vitamin C + Vitamin E | 1 | 64 | Mean Difference (IV, Fixed, 95% CI) | ‐13.80 [‐17.50, ‐10.10] |
| 1.6.7 Zinc | 1 | 42 | Mean Difference (IV, Fixed, 95% CI) | 1.30 [‐8.62, 11.22] |
| 1.6.8 Combined antioxidants | 5 | 569 | Mean Difference (IV, Fixed, 95% CI) | ‐0.52 [‐2.00, 0.96] |
| 1.7 Sperm DNA fragmentation at 6 months; type of antioxidant Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.7.1 Combined antioxidants | 3 | 320 | Mean Difference (IV, Fixed, 95% CI) | ‐4.57 [‐6.49, ‐2.66] |
| 1.7.2 Zinc + Folic acid | 1 | 853 | Mean Difference (IV, Fixed, 95% CI) | 3.00 [0.02, 5.98] |
| 1.8 Sperm DNA fragmentation (data not suitable for meta‐analysis) Show forest plot | 1 | Other data | No numeric data | |
| 1.8.1 Folic acid | 1 | Other data | No numeric data | |
| 1.9 Total sperm motility at 3 months or less; type of antioxidant Show forest plot | 25 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.9.1 Astaxanthin + Vitamin E | 1 | 72 | Mean Difference (IV, Fixed, 95% CI) | ‐5.20 [‐11.56, 1.16] |
| 1.9.2 Carnitines | 5 | 244 | Mean Difference (IV, Fixed, 95% CI) | 31.28 [31.19, 31.37] |
| 1.9.3 Carotenoids | 1 | 36 | Mean Difference (IV, Fixed, 95% CI) | 3.50 [‐6.95, 13.95] |
| 1.9.4 Coenzyme Q10 | 1 | 47 | Mean Difference (IV, Fixed, 95% CI) | 3.61 [‐6.13, 13.35] |
| 1.9.5 Folic acid | 2 | 89 | Mean Difference (IV, Fixed, 95% CI) | 4.56 [‐5.63, 14.74] |
| 1.9.6 Magnesium | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 14.50 [‐6.01, 35.01] |
| 1.9.7 N‐acetylcysteine (NAC) | 1 | 35 | Mean Difference (IV, Fixed, 95% CI) | 14.60 [0.32, 28.88] |
| 1.9.8 PUFAs | 3 | 105 | Mean Difference (IV, Fixed, 95% CI) | ‐2.40 [‐9.89, 5.09] |
| 1.9.9 Selenium | 1 | 34 | Mean Difference (IV, Fixed, 95% CI) | 14.90 [1.14, 28.66] |
| 1.9.10 Vitamin C + Vitamin E | 1 | 64 | Mean Difference (IV, Fixed, 95% CI) | 2.90 [‐7.76, 13.56] |
| 1.9.11 Vitamin E | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 18.90 [4.90, 32.90] |
| 1.9.12 Zinc | 3 | 118 | Mean Difference (IV, Fixed, 95% CI) | 12.85 [5.40, 20.29] |
| 1.9.13 Zinc + Folic acid | 2 | 93 | Mean Difference (IV, Fixed, 95% CI) | 5.26 [‐3.64, 14.16] |
| 1.9.14 Zinc + Vitamin E | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 26.00 [12.85, 39.15] |
| 1.9.15 Zinc + Vitamin E + Vitamin C | 1 | 22 | Mean Difference (IV, Fixed, 95% CI) | 26.00 [12.62, 39.38] |
| 1.9.16 Combined antioxidants | 7 | 684 | Mean Difference (IV, Fixed, 95% CI) | 12.71 [11.33, 14.08] |
| 1.10 Total sperm motility at 3 months or less (data not suitable for meta analysis) Show forest plot | 2 | Other data | No numeric data | |
| 1.10.1 Vitamin E | 1 | Other data | No numeric data | |
| 1.10.2 Combined antioxidants | 1 | Other data | No numeric data | |
| 1.11 Total sperm motility at 6 months; type of antioxidant Show forest plot | 17 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.11.1 Carnitines | 3 | 136 | Mean Difference (IV, Fixed, 95% CI) | 10.09 [5.99, 14.19] |
| 1.11.2 Coenzyme Q10 | 3 | 479 | Mean Difference (IV, Fixed, 95% CI) | 7.28 [6.85, 7.72] |
| 1.11.3 Folic acid | 2 | 98 | Mean Difference (IV, Fixed, 95% CI) | 0.16 [‐6.96, 7.29] |
| 1.11.4 N‐acetylcysteine (NAC) | 1 | 211 | Mean Difference (IV, Fixed, 95% CI) | 1.90 [1.20, 2.60] |
| 1.11.5 Selenium | 1 | 211 | Mean Difference (IV, Fixed, 95% CI) | 3.20 [2.50, 3.90] |
| 1.11.6 Selenium + N‐acetylcysteine (NAC) | 1 | 210 | Mean Difference (IV, Fixed, 95% CI) | 6.30 [5.60, 7.00] |
| 1.11.7 Vitamin D + Calcium | 1 | 260 | Mean Difference (IV, Fixed, 95% CI) | ‐4.00 [‐9.57, 1.57] |
| 1.11.8 Vitamin E | 2 | 132 | Mean Difference (IV, Fixed, 95% CI) | 11.60 [6.18, 17.02] |
| 1.11.9 Zinc | 2 | 105 | Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐6.95, 6.95] |
| 1.11.10 Zinc + Folic acid | 3 | 956 | Mean Difference (IV, Fixed, 95% CI) | 0.24 [‐2.54, 3.02] |
| 1.11.11 Combined antioxidants | 4 | 394 | Mean Difference (IV, Fixed, 95% CI) | 6.76 [4.77, 8.75] |
| 1.12 Total sperm motility at 9 months or more; type of antioxidant Show forest plot | 5 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.12.1 Carnitines | 1 | 59 | Mean Difference (IV, Fixed, 95% CI) | 8.54 [3.01, 14.07] |
| 1.12.2 Coenzyme Q10 | 3 | 479 | Mean Difference (IV, Fixed, 95% CI) | 3.33 [2.91, 3.76] |
| 1.12.3 Vitamin E | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 2.20 [‐8.48, 12.88] |
| 1.13 Total sperm motility over time Show forest plot | 36 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.13.1 Total sperm motility at 3 months or less | 25 | 1638 | Mean Difference (IV, Fixed, 95% CI) | 31.17 [31.07, 31.26] |
| 1.13.2 Total sperm motility at 6 months | 17 | 2880 | Mean Difference (IV, Fixed, 95% CI) | 5.77 [5.45, 6.10] |
| 1.13.3 Total sperm motility at 9 months or more | 5 | 583 | Mean Difference (IV, Fixed, 95% CI) | 3.36 [2.94, 3.78] |
| 1.14 Progressive sperm motility at 3 months or less; type of antioxidant Show forest plot | 28 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.14.1 Astaxanthin + Vitamin E | 1 | 72 | Mean Difference (IV, Fixed, 95% CI) | ‐5.10 [‐11.46, 1.26] |
| 1.14.2 Carnitines | 4 | 285 | Mean Difference (IV, Fixed, 95% CI) | 20.92 [20.52, 21.32] |
| 1.14.3 Carotenoids | 1 | 36 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐7.27, 6.87] |
| 1.14.4 Coenzyme Q10 | 1 | 47 | Mean Difference (IV, Fixed, 95% CI) | 4.60 [‐3.54, 12.74] |
| 1.14.5 Folic acid | 2 | 81 | Mean Difference (IV, Fixed, 95% CI) | 5.08 [‐4.00, 14.16] |
| 1.14.6 N‐acetylcysteine (NAC) | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 3.80 [‐1.03, 8.63] |
| 1.14.7 PUFAs | 4 | 181 | Mean Difference (IV, Fixed, 95% CI) | 1.53 [0.32, 2.74] |
| 1.14.8 Vitamin C | 2 | 145 | Mean Difference (IV, Fixed, 95% CI) | 10.95 [4.10, 17.80] |
| 1.14.9 Vitamin C + Vitamin E | 1 | 31 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐9.77, 10.17] |
| 1.14.10 Vitamin D | 1 | 62 | Mean Difference (IV, Fixed, 95% CI) | ‐0.84 [‐7.65, 5.97] |
| 1.14.11 Zinc | 2 | 157 | Mean Difference (IV, Fixed, 95% CI) | 1.14 [‐3.37, 5.64] |
| 1.14.12 Zinc + Folic acid | 1 | 54 | Mean Difference (IV, Fixed, 95% CI) | 3.80 [‐13.66, 21.26] |
| 1.14.13 Combined antioxidants | 9 | 993 | Mean Difference (IV, Fixed, 95% CI) | 11.16 [9.91, 12.41] |
| 1.15 Progressive sperm motility at 6 months; type of antioxidant Show forest plot | 12 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.15.1 Carnitines | 2 | 145 | Mean Difference (IV, Fixed, 95% CI) | 11.66 [8.68, 14.64] |
| 1.15.2 Coenzyme Q10 | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 5.00 [2.13, 7.87] |
| 1.15.3 Folic acid | 2 | 81 | Mean Difference (IV, Fixed, 95% CI) | ‐1.77 [‐10.21, 6.67] |
| 1.15.4 PUFAs | 1 | 227 | Mean Difference (IV, Fixed, 95% CI) | 8.80 [8.11, 9.49] |
| 1.15.5 Vitamin D + Calcium | 1 | 260 | Mean Difference (IV, Fixed, 95% CI) | ‐4.00 [‐9.59, 1.59] |
| 1.15.6 Zinc | 1 | 57 | Mean Difference (IV, Fixed, 95% CI) | 2.00 [‐13.56, 17.56] |
| 1.15.7 Zinc + Folic acid | 1 | 54 | Mean Difference (IV, Fixed, 95% CI) | 2.70 [‐14.58, 19.98] |
| 1.15.8 Combined antioxidants | 5 | 470 | Mean Difference (IV, Fixed, 95% CI) | 4.01 [2.05, 5.96] |
| 1.16 Progressive sperm motility at 6 months (data not suitable for meta analysis) Show forest plot | 1 | Other data | No numeric data | |
| 1.16.1 Coenzyme Q10 | 1 | Other data | No numeric data | |
| 1.16.2 Glutathione | 1 | Other data | No numeric data | |
| 1.17 Progressive sperm motility at 9 months or more; type of antioxidant Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.17.1 Carnitines | 1 | 59 | Mean Difference (IV, Fixed, 95% CI) | 7.77 [2.68, 12.87] |
| 1.17.2 Coenzyme Q10 | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐0.90 [‐2.68, 0.88] |
| 1.18 Progressive sperm motility over time Show forest plot | 32 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.18.1 Progressive sperm motility at 3 months or less | 27 | 2054 | Mean Difference (IV, Fixed, 95% CI) | 17.98 [17.62, 18.34] |
| 1.18.2 Progressive sperm motility at 6 months | 12 | 1304 | Mean Difference (IV, Fixed, 95% CI) | 8.05 [7.43, 8.66] |
| 1.18.3 Progressive sperm motility at 9 months or more | 2 | 119 | Mean Difference (IV, Fixed, 95% CI) | 0.04 [‐1.64, 1.72] |
| 1.19 Sperm concentration at 3 months or less; type of antioxidant Show forest plot | 36 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.19.1 Astaxathin + Vitamin E | 1 | 72 | Mean Difference (IV, Fixed, 95% CI) | ‐1.00 [‐6.79, 4.79] |
| 1.19.2 Carnitines | 5 | 333 | Mean Difference (IV, Fixed, 95% CI) | 8.71 [8.09, 9.34] |
| 1.19.3 Carotenoids | 1 | 36 | Mean Difference (IV, Fixed, 95% CI) | 6.30 [0.62, 11.98] |
| 1.19.4 Coenzyme Q10 | 1 | 47 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐12.37, 12.17] |
| 1.19.5 Folic acid | 3 | 119 | Mean Difference (IV, Fixed, 95% CI) | 3.72 [‐4.01, 11.44] |
| 1.19.6 Magnesium | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 5.20 [‐2.61, 13.01] |
| 1.19.7 N‐acetylcysteine (NAC) | 2 | 95 | Mean Difference (IV, Fixed, 95% CI) | 4.59 [‐0.27, 9.46] |
| 1.19.8 PUFAs | 5 | 209 | Mean Difference (IV, Fixed, 95% CI) | 3.42 [1.69, 5.15] |
| 1.19.9 Selenium | 1 | 34 | Mean Difference (IV, Fixed, 95% CI) | 21.20 [‐4.90, 47.30] |
| 1.19.10 Vitamin C | 1 | 115 | Mean Difference (IV, Fixed, 95% CI) | 9.70 [0.09, 19.31] |
| 1.19.11 Vitamin C + Vitamin E | 2 | 95 | Mean Difference (IV, Fixed, 95% CI) | 1.31 [‐6.58, 9.20] |
| 1.19.12 Vitamin D | 1 | 62 | Mean Difference (IV, Fixed, 95% CI) | ‐2.12 [‐8.85, 4.61] |
| 1.19.13 Vitamin E | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 18.90 [3.92, 33.88] |
| 1.19.14 Zinc | 3 | 199 | Mean Difference (IV, Fixed, 95% CI) | 6.74 [2.81, 10.68] |
| 1.19.15 Zinc + Folic acid | 2 | 93 | Mean Difference (IV, Fixed, 95% CI) | 0.48 [‐6.79, 7.75] |
| 1.19.16 Combined antioxidants | 11 | 1165 | Mean Difference (IV, Fixed, 95% CI) | 0.53 [‐0.33, 1.40] |
| 1.20 Sperm concentration at 3 months or less (data not suitable for meta analysis) Show forest plot | 2 | Other data | No numeric data | |
| 1.20.1 Carnitines | 1 | Other data | No numeric data | |
| 1.20.2 Vitamin E | 1 | Other data | No numeric data | |
| 1.21 Sperm concentration at 6 months; type of antioxidant Show forest plot | 20 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.21.1 Carnitines | 3 | 201 | Mean Difference (IV, Fixed, 95% CI) | 7.42 [4.97, 9.87] |
| 1.21.2 Coenzyme Q10 | 3 | 479 | Mean Difference (IV, Fixed, 95% CI) | 8.80 [7.95, 9.64] |
| 1.21.3 Folic acid | 3 | 128 | Mean Difference (IV, Fixed, 95% CI) | 17.39 [11.09, 23.69] |
| 1.21.4 N‐acetylcysteine (NAC) | 1 | 211 | Mean Difference (IV, Fixed, 95% CI) | 3.30 [1.80, 4.80] |
| 1.21.5 PUFAs | 1 | 227 | Mean Difference (IV, Fixed, 95% CI) | 12.50 [11.39, 13.61] |
| 1.21.6 Selenium | 1 | 211 | Mean Difference (IV, Fixed, 95% CI) | 4.10 [2.45, 5.75] |
| 1.21.7 Selenium + N‐acetylcysteine (NAC) | 1 | 210 | Mean Difference (IV, Fixed, 95% CI) | 8.60 [6.89, 10.31] |
| 1.21.8 Vitamin D + Calcium | 1 | 269 | Mean Difference (IV, Fixed, 95% CI) | ‐2.50 [‐8.18, 3.18] |
| 1.21.9 Vitamin E | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 5.90 [‐10.83, 22.63] |
| 1.21.10 Zinc | 2 | 105 | Mean Difference (IV, Fixed, 95% CI) | 5.51 [‐4.00, 15.01] |
| 1.21.11 Zinc + Folic acid | 3 | 956 | Mean Difference (IV, Fixed, 95% CI) | 1.44 [‐6.70, 9.58] |
| 1.21.12 Combined antioxidants | 6 | 534 | Mean Difference (IV, Fixed, 95% CI) | 3.16 [2.28, 4.05] |
| 1.22 Sperm concentration at 6 months (data not suitable for meta analysis) Show forest plot | 1 | Other data | No numeric data | |
| 1.22.1 Glutathione | 1 | Other data | No numeric data | |
| 1.22.2 Coenzyme Q10 | 1 | Other data | No numeric data | |
| 1.23 Sperm concentration at 9 months or more; type of antioxidant Show forest plot | 5 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.23.1 Carnitines | 1 | 59 | Mean Difference (IV, Fixed, 95% CI) | 4.17 [‐1.71, 10.06] |
| 1.23.2 Coenzyme Q10 | 3 | 479 | Mean Difference (IV, Fixed, 95% CI) | 3.93 [3.19, 4.67] |
| 1.23.3 Vitamin E | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 11.40 [‐2.56, 25.36] |
| 1.24 Sperm concentration over time Show forest plot | 46 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.24.1 Sperm concentration at 3 months or less | 35 | 2535 | Mean Difference (IV, Fixed, 95% CI) | 5.49 [5.02, 5.96] |
| 1.24.2 Sperm concentration 6 months | 19 | 2995 | Mean Difference (IV, Fixed, 95% CI) | 7.21 [6.73, 7.70] |
| 1.24.3 Sperm concentration at 9 months or more | 5 | 583 | Mean Difference (IV, Fixed, 95% CI) | 3.95 [3.22, 4.69] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Live birth; type of antioxidant Show forest plot | 1 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 2.1.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.00 [0.13, 7.92] |
| 2.1.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.34 [0.06, 1.79] |
| 2.1.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.34 [0.06, 1.79] |
| 2.2 Clinical pregnancy; type of antioxidant Show forest plot | 4 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 2.2.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.00 [0.13, 7.92] |
| 2.2.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.34 [0.06, 1.79] |
| 2.2.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.34 [0.06, 1.79] |
| 2.2.4 L‐carnitine vs Coenzyme Q10 | 1 | 156 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.48 [0.54, 4.05] |
| 2.2.5 L‐carnitine vs L‐carnitine + Coenzyme Q10 | 1 | 156 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.62 [0.27, 1.46] |
| 2.2.6 Coenzyme Q10 vs L‐carnitine + Coenzyme Q10 | 1 | 156 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.43 [0.18, 1.06] |
| 2.2.7 Vitamin D + Calcium vs Vitamin E + Vitamin C | 1 | 86 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 5.13 [1.21, 21.79] |
| 2.2.8 Combined antioxidants vs L‐carnitine | 1 | 89 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.93 [0.20, 19.08] |
| 2.3 Sperm DNA fragmentation; type of antioxidant Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.3.1 L‐carnitine vs Coenzyme Q10 | 1 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐0.80 [‐2.22, 0.62] |
| 2.3.2 L‐carnitine vs L‐carnitine + Coenzyme Q10 | 1 | 125 | Mean Difference (IV, Fixed, 95% CI) | 0.40 [‐1.14, 1.94] |
| 2.3.3 Coenzyme Q10 vs L‐carnitine + Coenzyme Q10 | 1 | 126 | Mean Difference (IV, Fixed, 95% CI) | 1.20 [‐0.25, 2.65] |
| 2.3.4 L‐carnitine vs Vitamin B1 | 1 | 136 | Mean Difference (IV, Fixed, 95% CI) | ‐1.50 [‐3.22, 0.22] |
| 2.3.5 Coenzyme Q10 vs Vitamin B1 | 1 | 137 | Mean Difference (IV, Fixed, 95% CI) | ‐0.70 [‐2.34, 0.94] |
| 2.3.6 Vitamin B1 vs L‐carnitine + Coenzyme Q10 | 1 | 137 | Mean Difference (IV, Fixed, 95% CI) | 1.90 [0.16, 3.64] |
| 2.4 Total sperm motility at 3 months or less; type of antioxidant Show forest plot | 12 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.4.1 Coenzyme Q10 200 mg vs Coenzyme Q10 400 mg | 1 | 65 | Mean Difference (IV, Fixed, 95% CI) | ‐4.86 [‐10.60, 0.88] |
| 2.4.2 Docosahexaenoic acid (DHA) 400 mg vs Docosahexaenoic acid 800 mg | 1 | 19 | Mean Difference (IV, Fixed, 95% CI) | 7.40 [‐11.35, 26.15] |
| 2.4.3 DHA vs DHA + Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐3.77 [‐5.42, ‐2.12] |
| 2.4.4 DHA versus Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐1.60 [‐3.30, 0.10] |
| 2.4.5 DHA + Vitamin E vs Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | 2.17 [0.54, 3.80] |
| 2.4.6 Ethylcysteine vs Vitamin E | 1 | 10 | Mean Difference (IV, Fixed, 95% CI) | ‐1.90 [‐41.97, 38.17] |
| 2.4.7 L‐acetyl carnitine + L‐carnitine vs Vitamin E + Vitamin C | 1 | 138 | Mean Difference (IV, Fixed, 95% CI) | 23.10 [20.14, 26.06] |
| 2.4.8 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 3.40 [‐3.73, 10.53] |
| 2.4.9 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 4.80 [‐1.76, 11.36] |
| 2.4.10 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 1.40 [‐6.42, 9.22] |
| 2.4.11 Selenium vs combined antioxidants | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | 3.20 [‐10.13, 16.53] |
| 2.4.12 Vitamin C 200mg vs Vitamin C 1000mg | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐43.00 [‐67.10, ‐18.90] |
| 2.4.13 Vitamin E + 'Compound amino acids' vs Vitamin E | 1 | 120 | Mean Difference (IV, Fixed, 95% CI) | 11.90 [8.71, 15.09] |
| 2.4.14 Zinc vs Folic acid | 2 | 124 | Mean Difference (IV, Fixed, 95% CI) | ‐3.01 [‐11.38, 5.35] |
| 2.4.15 Zinc vs Zinc + Folic acid | 2 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐2.91 [‐10.92, 5.10] |
| 2.4.16 Zinc + Folic acid vs Folic acid | 2 | 121 | Mean Difference (IV, Fixed, 95% CI) | 0.24 [‐6.17, 6.66] |
| 2.4.17 Zinc vs Zinc + Vitamin E | 1 | 18 | Mean Difference (IV, Fixed, 95% CI) | ‐1.00 [‐15.00, 13.00] |
| 2.4.18 Zinc vs Zinc + Vitamin E + Vitamin C | 1 | 12 | Mean Difference (IV, Fixed, 95% CI) | ‐1.00 [‐19.66, 17.66] |
| 2.4.19 Zinc + Vitamin E vs Zinc + Vitamin E + Vitamin C | 1 | 18 | Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐18.97, 18.97] |
| 2.5 Total sperm motility at 6 months; type of antioxidant Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.5.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 4.10 [‐2.70, 10.90] |
| 2.5.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 3.40 [‐2.87, 9.67] |
| 2.5.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.70 [‐7.73, 6.33] |
| 2.5.4 N‐acetylcysteine (NAC) vs Selenium + N‐acetylcysteine (NAC) | 1 | 234 | Mean Difference (IV, Fixed, 95% CI) | ‐4.40 [‐5.14, ‐3.66] |
| 2.5.5 Selenium vs N‐acetylcysteine (NAC) | 1 | 234 | Mean Difference (IV, Fixed, 95% CI) | 1.30 [0.56, 2.04] |
| 2.5.6 Selenium vs Selenium + N‐acetylcysteine (NAC) | 1 | 232 | Mean Difference (IV, Fixed, 95% CI) | ‐3.10 [‐3.85, ‐2.35] |
| 2.5.7 Zinc vs Folic acid | 2 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐1.03 [‐5.18, 3.13] |
| 2.5.8 Zinc vs Zinc + Folic acid | 2 | 127 | Mean Difference (IV, Fixed, 95% CI) | ‐1.69 [‐6.95, 3.58] |
| 2.5.9 Zinc + Folic acid vs Folic acid | 2 | 126 | Mean Difference (IV, Fixed, 95% CI) | 1.03 [‐4.23, 6.29] |
| 2.6 Total sperm motility at 9 months or more; type of antioxidant Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.6.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 3.70 [‐1.69, 9.09] |
| 2.6.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 5.30 [‐0.73, 11.33] |
| 2.6.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 1.60 [‐3.29, 6.49] |
| 2.7 Progessive sperm motility at 3 months or less; type of antioxidant Show forest plot | 10 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.7.1 Coenzyme Q10 200 mg vs Coenzyme Q10 400 mg | 1 | 65 | Mean Difference (IV, Fixed, 95% CI) | ‐3.52 [‐9.71, 2.67] |
| 2.7.2 Docosahexaenoic acid (DHA) vs DHA + Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐2.22 [‐3.50, ‐0.94] |
| 2.7.3 DHA vs Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐0.39 [‐1.67, 0.89] |
| 2.7.4 DHA + Vitamin E vs Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | 1.83 [0.68, 2.98] |
| 2.7.5 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 4.00 [‐1.88, 9.88] |
| 2.7.6 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 5.00 [‐0.68, 10.68] |
| 2.7.7 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 1.00 [‐5.41, 7.41] |
| 2.7.8 L‐carnitine vs Vitamin B1 | 1 | 136 | Mean Difference (IV, Fixed, 95% CI) | 1.70 [‐1.54, 4.94] |
| 2.7.9 L‐carnitine vs Coenzyme Q10 | 1 | 125 | Mean Difference (IV, Fixed, 95% CI) | 1.30 [‐1.70, 4.30] |
| 2.7.10 L‐carnitine vs L‐carnitine + Coenzyme Q10 | 1 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐8.20 [‐12.31, ‐4.09] |
| 2.7.11 Coenzyme Q10 vs L‐carnitine + Coenzyme Q10 | 1 | 126 | Mean Difference (IV, Fixed, 95% CI) | ‐9.50 [‐13.54, ‐5.46] |
| 2.7.12 Coenzyme Q10 vs Vitamin B1 | 1 | 137 | Mean Difference (IV, Fixed, 95% CI) | 0.40 [‐2.75, 3.55] |
| 2.7.13 Vitamin B1 vs L‐carnitine + Coenzyme Q10 | 1 | 137 | Mean Difference (IV, Fixed, 95% CI) | ‐9.90 [‐14.12, ‐5.68] |
| 2.7.14 L‐acetyl carnitine + L‐carnitine vs Vitamin E + Vitamin C | 1 | 138 | Mean Difference (IV, Fixed, 95% CI) | 13.30 [11.21, 15.39] |
| 2.7.15 L‐carnitine vs Vitamin E + Vitamin C | 1 | 63 | Mean Difference (IV, Fixed, 95% CI) | 30.50 [27.70, 33.30] |
| 2.7.16 L‐carnitine vs Vitamin E | 1 | 212 | Mean Difference (IV, Fixed, 95% CI) | 1.90 [1.31, 2.49] |
| 2.7.17 L‐carnitine + Vitamin E vs Vitamin E | 1 | 113 | Mean Difference (IV, Fixed, 95% CI) | 14.10 [10.11, 18.09] |
| 2.7.18 Vitamin D + Calcium vs Vitamin E + Vitamin C | 1 | 86 | Mean Difference (IV, Fixed, 95% CI) | 6.90 [5.38, 8.42] |
| 2.7.19 Vitamin E + 'Compound amino acids' vs Vitamin E | 1 | 120 | Mean Difference (IV, Fixed, 95% CI) | 6.10 [3.87, 8.33] |
| 2.8 Progressive sperm motility at 6 months; type of antioxidant Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.8.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 6.30 [0.42, 12.18] |
| 2.8.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 5.70 [0.10, 11.30] |
| 2.8.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | ‐0.60 [‐6.93, 5.73] |
| 2.9 Progressive motility at 6 months (data not suitable for meta‐analysis) Show forest plot | 1 | Other data | No numeric data | |
| 2.10 Progressive sperm motility at 9 months; type of antioxidant Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.10.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 3.80 [‐1.50, 9.10] |
| 2.10.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 5.50 [‐0.11, 11.11] |
| 2.10.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 1.70 [‐4.17, 7.57] |
| 2.11 Sperm concentration at 3 months or less; type of antioxidant Show forest plot | 11 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.11.1 Coenzyme Q10 200 mg vs Coenzyme Q10 400 mg | 1 | 65 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐3.26, 3.66] |
| 2.11.2 Docosahexaenoic acid (DHA) 400 mg vs Docosahexaenoic acid (DHA) 800 mg | 1 | 19 | Mean Difference (IV, Fixed, 95% CI) | ‐6.80 [‐41.87, 28.27] |
| 2.11.3 DHA vs DHA + Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐1.45 [‐2.47, ‐0.43] |
| 2.11.4 DHA vs Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐0.24 [‐1.26, 0.78] |
| 2.11.5 DHA + Vitamin E vs Vitamin E | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | 1.21 [0.28, 2.14] |
| 2.11.6 Ethylcysteine vs Vitamin E | 1 | 10 | Mean Difference (IV, Fixed, 95% CI) | 2.20 [‐16.65, 21.05] |
| 2.11.7 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 1.70 [‐10.97, 14.37] |
| 2.11.8 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 4.10 [‐9.17, 17.37] |
| 2.11.9 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 2.40 [‐11.14, 15.94] |
| 2.11.10 L‐carnitine vs Vitamin E + Vitamin C | 1 | 63 | Mean Difference (IV, Fixed, 95% CI) | 15.50 [12.49, 18.51] |
| 2.11.11 L‐carnitine vs Vitamin E | 1 | 212 | Mean Difference (IV, Fixed, 95% CI) | 0.70 [‐0.34, 1.74] |
| 2.11.12 L‐carnitine + Vitamin E vs Vitamin E | 1 | 113 | Mean Difference (IV, Fixed, 95% CI) | 1.90 [‐10.52, 14.32] |
| 2.11.13 Selenium vs Combined antioxidants | 1 | 46 | Mean Difference (IV, Fixed, 95% CI) | 14.70 [‐6.51, 35.91] |
| 2.11.14 Zinc vs Folic acid | 2 | 124 | Mean Difference (IV, Fixed, 95% CI) | ‐1.30 [‐8.65, 6.06] |
| 2.11.15 Zinc vs Zinc + Folic acid | 2 | 125 | Mean Difference (IV, Fixed, 95% CI) | 2.93 [‐3.67, 9.54] |
| 2.11.16 Zinc + Folic acid vs Folic acid | 2 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐4.11 [‐9.79, 1.57] |
| 2.12 Sperm concentration at 6 months; type of antioxidant Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.12.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 5.90 [‐8.92, 20.72] |
| 2.12.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 8.10 [‐5.54, 21.74] |
| 2.12.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 2.20 [‐10.89, 15.29] |
| 2.12.4 N‐acetylcysteine (NAC) vs Selenium + N‐acetylcysteine (NAC) | 1 | 234 | Mean Difference (IV, Fixed, 95% CI) | ‐5.30 [‐6.86, ‐3.74] |
| 2.12.5 Selenium vs N‐acetylcysteine (NAC) | 1 | 234 | Mean Difference (IV, Fixed, 95% CI) | 0.80 [‐0.71, 2.31] |
| 2.12.6 Selenium vs Selenium + N‐acetylcysteine (NAC) | 1 | 232 | Mean Difference (IV, Fixed, 95% CI) | ‐4.50 [‐6.20, ‐2.80] |
| 2.12.7 Zinc vs Folic acid | 2 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐10.10 [‐19.12, ‐1.08] |
| 2.12.8 Zinc vs Zinc + Folic acid | 2 | 127 | Mean Difference (IV, Fixed, 95% CI) | ‐13.58 [‐25.99, ‐1.17] |
| 2.12.9 Zinc + Folic acid vs Folic acid | 2 | 126 | Mean Difference (IV, Fixed, 95% CI) | 1.78 [‐9.93, 13.49] |
| 2.13 Sperm concentration at 6 months (data not suitable for meta‐analysis) Show forest plot | 1 | Other data | No numeric data | |
| 2.14 Sperm concentration at 9 months or more; type of antioxidant Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 2.14.1 L‐carnitine vs L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Random, 95% CI) | 8.20 [‐0.07, 16.47] |
| 2.14.2 L‐carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Random, 95% CI) | 6.10 [‐3.74, 15.94] |
| 2.14.3 L‐acetyl carnitine vs L‐carnitine + L‐acetyl carnitine | 1 | 30 | Mean Difference (IV, Random, 95% CI) | ‐2.10 [‐10.24, 6.04] |
