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Agonistas dopaminérgicos para la prevención del síndrome de hiperestimulación ovárica

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References

References to studies included in this review

Alhalabi 2011 {published and unpublished data}

Alhalabi M, Samawi S, Kafri N, Sharif J, Saker A, Othman A. Role of quinagolide (Norprolac) in preventing ovarian hyperstimulation syndrome (OHSS) in high risk intracytoplasmic sperm injection (ICSI) patients. Fertility and Sterility 2010;98(3 Suppl 1):S103. CENTRAL
Alhalabi M, Samawi S, Taha A, Kafri N, Modi S, Khatib A. Quinagolide reduces OHSS in high risk ICSI patients. Human Reproduction 2011;26(Suppl 1):P‐508. CENTRAL

Alvarez 2007a {published data only}

Alvarez C, Bosch E, Melo MAB, Fernandez‐Sanches M, Munoz E A, Remohi J, et al. The dopamine agonist cabergoline prevents moderate‐severe early ovarian hyperstimulation syndrome (OHSS) in high‐risk ART patients. Human Reproduction 2006;21:i96. CENTRAL
Alvarez C, Martí‐Bonmatí L, Novella‐Maestre E, Sanz R, Gómez R, Fernández‐Sánchez M, et al. Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction. Journal of Clinical Endocrinology and Metabolism 2007;92:2931‐7. CENTRAL

Amir 2015 {published and unpublished data}

Amir H, Yaniv D, Hasson J, Amit A, Gordon D, Azem F. Cabergoline for reducing ovarian hyperstimulation syndrome in assisted reproductive technology treatment cycles. A prospective randomized controlled trial. Journal of Reproductive Medicine 2015;60(1‐2):48‐54. CENTRAL
Amir H, Yaniv Kovalski D, Amit A, Azem F. Can dopamine agonist cabergoline reduce ovarian hyperstimulation syndrome in ART treatment cycles? A prospective randomized study. Fertility and Sterility 2011;95(4):S84. CENTRAL

Beltrame 2013 {published and unpublished data}

Beltrame AL, Serafini P, Motta ELA, Soares JM, Baracat. The effects of bromocriptine on VEGF, kidney function and ovarian hyperstimulation syndrome in in vitro fertilization patients: a pilot study. Gynecological Endocrinology 2013;29(3):201‐4. CENTRAL

Busso 2010 {published data only}

Busso C, Fernandez‐Sanchez M, Garcia‐Velasco JA, Landeras J, Ballesteros A, Munoz E, et al. The non‐ergot derived dopamine agonist quinagolide in prevention of early ovarian hyperstimulation syndrome in IVF patients: a randomized, double‐blind, placebo‐controlled trial. Human Reproduction 2010;25(4):995‐1004. CENTRAL

Carizza 2008 {published data only}

Carizza C, Abdelmassih V, Abdelmassih S, Ravizzini P, Salgueiro L, Salgueiro PT, et al. Cabergoline reduces the early onset of ovarian hyperstimulation syndrome: a prospective randomized study. Reproductive Biomedicine Online 2008;17:751‐5. CENTRAL
Carizza C, Abdelmassih V, Ravizzini PC, Salgueiro LL. Ongoing clinical pregnancy is not affected by cabergoline use in women undergoing ICSI with estradiol levels beyond 4000 pg/ml on the day of the hCG. Human Reproduction 2008;23(suppl 1):i141. CENTRAL

Dalal 2014 {published and unpublished data}

Dalal R, Mishra A. Comparison of coasting with cabergoline administration for prevention of early severe OHSS. BJOG 2014;121:78. CENTRAL

Fetisova 2014 {published and unpublished data}

Fetisova S, Korneeva I, Saroyan T, Krechetova L. Ivanets T. Effects of cabergoline administration for the prevention of OHSS upon the levels of VEGF, VEGFR‐1 and VEGFR‐2 in high risk IVF/ICSI patients. Human Reproduction 2014;29(Suppl 1):P‐482. CENTRAL

Ghahiri 2015 {published data only}

Ghahiri A, Mogharehabed N, Hosseini N. Evaluation of intravenous hydroxyethyl starch, intravenous albumin 20% and oral cabergoline for prevention of ovarian hyperstimulation syndrome in patients undergoing ovulation induction. Journal of Research in Medical Sciences 2015;20(7):693‐6. CENTRAL
Ghahiri A, Mogharehabed N, Hosseini N. Evaluation of three different strategies (intravenous hydroxyl ethyl starch, intravenous albumin 20%, and oral cabergoline) for prevention of ovarian hyperstimulation syndrome in patients undergoing ovulation induction. Iranian Journal of Reproductive Medicine 2014;12(6):4. CENTRAL

Jellad 2016 {published data only}

Jellad S, Haj Hassine A, Basly M, Mrabet A, Chibani M, Rachdi R. Vascular endothelial growth factor antagonist reduces the early onset and the severity of ovarian hyperstimulation syndrome. Journal de Gynécologie, Obstétrique et Biologie de la Reproduction 2016 May 27 [Epub ahead of print]. CENTRAL

Matorras 2013 {published and unpublished data}

Matorras R, Andres M, Mendoza R, Prieto B, Pijoan JI, Exposito A. Prevention of ovarian hyperstimulation syndrome in GnRH agonist IVF cycles in moderate risk patients: randomized study comparing hydroxyethyl starch versus cabergoline and hydroxyethyl starch. European Journal of Obstetrics and Gynecology and Reproductive Biology 2013;170(2):439‐43. CENTRAL

Salah 2012 {published data only}

Salah AMR, EI‐Helew Y. Can cabergoline prevent ovarian hyperstimulation syndrome in polycystic ovarian patients undergoing gonadotropin stimulation?. Evidence Based Women's Health Journal 2012;2(2):56‐9. CENTRAL
Salah Edeen AMR, Alhelou YM. Can cabergoline prevent ovarian hyperstimulation syndrome in PCO patients undergoing gonadotropin stimulation? Comparative study with prednisolone. Human Reproduction 2009;24(1):i60. CENTRAL

Shaltout 2012 {published data only}

Shaltout A, Shohayeb A, Eid M. Role of cabergoline in preventing ovarian hyperstimulation syndrome in high risk intracytoplasmic sperm injection (ICSI) patients and effect on outcome. Human Reproduction 2009;24(Suppl 1):O‐154. CENTRAL
Shaltout A, Shohayeb A, Youssef MA. Can dopamine agonist at a low dose reduce ovarian hyperstimulation syndrome in women at risk undergoing ICSI treatment cycles? A randomized controlled study. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2012;165(2):254‐8. CENTRAL

Sohrabvand 2009 {published data only}

Sohrabvand F, Ansaripour S, Bagheri M, Shariat M, Jafarabadi M. Cabergoline versus coasting in the prevention of ovarian hyperstimulation syndrome and assisted reproductive technologies outcome in high risk patients. International Journal of Fertility and Sterility 2009;3(1):35‐40. CENTRAL

Tehraninejad 2012 {published data only}

Tehraninejad ES, Hafezi M, Arabipoor A, Aziminekoo E, Chehrazi M, Bahmanabadi A. Comparison of cabergoline and intravenous albumin in the prevention of ovarian hyperstimulation syndrome: a randomized clinical trial. Journal of Assisted Reproduction and Genetics 2012;29(3):259‐64. CENTRAL

Torabizadeh 2013 {published and unpublished data}

Torabizadeh A, Vahidroodsari F, Ghorbanpour Z. Comparison of albumin and cabergoline in the prevention of ovarian hyperstimulation syndrome: a clinical trial study. Iranian Journal of Reproductive Medicine 2013;11(10):837‐42. CENTRAL

References to studies excluded from this review

Aflatoonian 2008 {published and unpublished data}

Aflatoonian A, Ghandi S, Tabibnejad N. Comparison of coasting with cabergoline administration for prevention of early severe OHSS in ART cycles. Iranian Journal of Reproductive Medicine 2008;6(2):51‐5. CENTRAL

Agha Hosseini 2010 {published and unpublished data}

Agha Hosseini M, Aleyasin A, MAhdavi A, Nezami R, Safdarian L, Fallahi P. Cabergoline for prevention of ovarian hyperstimulation syndrome in high risk patients. Iranian Journal of reproductive Medicine 2010;8:70. CENTRAL

Alvarez 2007b {published data only}

Alvarez C, Alonso‐Muriel I, Garcia G, Crespo J, Bellver J, Simon C, et al. Implantation is apparently unaffected by the dopamine agonist cabergoline when administered to prevent ovarian hyperstimulation syndrome in women undergoing assisted reproduction treatment: a pilot study. Journal of Clinical Endocrinology and Metabolism 2007;22:3210‐4. CENTRAL

Ata 2009 {published data only}

Ata B, Seyhan A, Orhaner S, Urman B. High dose cabergoline in management of ovarian hyperstimulation syndrome. Fertility and Sterility 2009;92(3):1168.e1‐4. CENTRAL

Fouda 2016 {published and unpublished data}

Fouda UM, Sayed AM, Elshaer HS, Hammad BEM, Shaban MM, Elsetohy KA, et al. GnRH antagonist rescue protocol combined with cabergoline versus cabergoline alone in the prevention of ovarian hyperstimulation syndrome: a randomized controlled trial. Journal of Ovarian Research 2016;9(1):29. CENTRAL

Ghaebi 2016 {published data only}

Ghaebi NK, Amirian M, Zarmehri B, Zabihi H. Comparison of the effect of letrozole versus cabergoline for prevention of ovarian hyperstimulation syndrome (OHSS) in patients under ovulation induction treatments and IVF cycles. Iranian Journal of Obstetrics, Gynecology and Infertility 2016;18(184):1‐8. CENTRAL

Gualtieri 2011 {published data only}

Gualtieri M, Hoffman D, Barrionuevo M, Christie D, Mouhayar Y, Ory SJ. The effects of cabergoline on ovarian hyperstimulation syndrome (OHSS) and pregnancy outcomes on in vitro fertilization (IVF) patients. Fertility and Sterility 2011;95(4):S259‐60. CENTRAL

Guvendag 2010 {published data only}

Guvendag GES, Dilbaz S, Cinar O, Ozdegirmenci O, Aydin S. The effect of cabergoline on follicular microenvironment profile in patients with high risk of OHSS. Fertility and Sterility 2010;94(4):S180‐1. CENTRAL

Hatton 2012 {published data only}

Hatton A, Parry S, Hughes G, Wallbutton S, Binnersley S, Lavender A, et al. Cabergoline does not appear to affect pregnancy rates in patients undergoing assisted reproduction. Human Fertility 2012;15(s1):16. CENTRAL

Hosseini 2011 {published data only}

Hosseini MA, Aleyasin A, Mahdavi A, Nezami R, Safdarian L, Fallahi P. The effectiveness of cabergoline for the prevention of ovarian hyperstimulation syndrome. Iranian Journal of Medical Science 2011;36(3):207‐12. CENTRAL

Khan 2010 {published data only}

Khan Z, Rollene N, Amols M, Gada R, Coddington C. Cabergoline and ganirelix therapy for early moderate to severe ovarian hyperstimulation syndrome (OHSS) results in faster recovery than in early untreated OHSS. Fertility and Sterility 2010;93(5):S14. CENTRAL

Naredi 2013 {published and unpublished data}

Naredi N, Karunakaran S. Calcium gluconate infusion is as effective as the vascular endothelial growth factor antagonist cabergoline for the prevention of ovarian hyperstimulation syndrome. Journal of Human Reproductive Sciences 2013;6(4):248‐52. CENTRAL

Rollene 2009a {published data only}

Rollene NL, Amols MH, Hudson SBA, Coddington CC. Treatment of ovarian hyperstimulation syndrome using a dopamine agonist and gonadotropin releasing hormone antagonist: a case series. Fertility and Sterility 2009;92(3):1169.e15‐7. CENTRAL

Rollene 2009b {published data only}

Rollene NL, Amols MH, Hudson SBA, Jensen JR, Morbeck DE, Coddington CC. Cabergoline and ganirelix treatment of ovarian hyperstimulation syndrome (OHSS) results in rapid clinical improvement. Fertility and Sterility 2009;92(3):S240‐1. CENTRAL

Saad 2016 {published data only}

Saad AS, Mohamed KA, Saad SAA. Calcium dobesilate versus cabergoline for prevention of ovarian hyperstimulation syndrome. Human Reproduction 2016;31(Supp1):P‐580. CENTRAL

Seow 2013 {published and unpublished data}

Seow KM, Lin YH, Bai CH, Chen HJ, Hsieh BC, Huang LW, et al. Clinical outcome according to timing of cabergoline initiation for prevention of OHSS: a randomized controlled trial. Reproductive Biomedicine Online 2013;26(6):562‐8. CENTRAL

Sherwal 2010 {published data only}

Sherwal V, Malik S, Bhatia V. Effect of bromocriptine on the severity of ovarian hyperstimulation syndrome and outcome in high responders undergoing assisted reproduction. Journal of Human Reproductive Sciences 2010;3(2):85‐90. CENTRAL

Soliman 2011 {published data only}

Soliman BS. Cabergoline vs intravenous albumin or combination of both for prevention of the early onset ovarian hyperstimulation syndrome. Middle East Fertility Society Journal 2011;16(1):56‐60. CENTRAL

Spitzer 2011 {published data only}

Spitzer D, Wogatzky J, Murtinger M, Zech MH, Haidbauer R, Zech NH. Dopamine agonist bromocriptine for the prevention of ovarian hyperstimulation syndrome. Fertility and Sterility 2011;95(8):2742‐4.e1. CENTRAL

Zargar 2011 {published data only}

Zargar M, Nikbakht R, Pourmatroud E, Ghasemi K, Hemadi M. Comparison of the clinical efficacy of two different cabergoline regimens on prevention of ovarian hyperstimulation syndrome (OHSS). Research Journal of Obstetrics and Gynecology 2011;4(2):51‐8. CENTRAL

References to studies awaiting assessment

Ahmadi 2010 {published data only}

Ahmadi S, Rahmani E, Oskouian H. Cabergoline versus human albumin in prophylaxis of ovarian hyperstimulation syndrome. Reproductive Biomedicine Online 2010;20:S41. CENTRAL
Ahmadi SH, Rahmani E, Oskouian H. Cabergoline versus human albumin in prophylaxis of ovarian hyperstimulation syndrome. Iranian Journal of Reproductive Medicine 2011;9(Suppl 1):6 Abstract O‐13. CENTRAL

Bassiouny 2015 {published and unpublished data}

Cabergoline and Coasting to Prevent OHSS; Combining Cabergoline and Coasting in Gonadotropin Releasing Hormone(GnRH)Agonist Protocol in Intracytoplasmic Sperm Injection (ICSI) to Prevent Ovarian Hyperstimulation Syndrome (OHSS): a Randomized Clinical Trial. Ongoing study Starting date of trial not provided. Contact author for more information.

El Khattan 2015 {published and unpublished data}

Comparative Study Between Cabergoline and Intravenous Calcium in the Prevention of Ovarian Hyperstimulation in Women with Polycystic Ovarian Disease Undergoing Intracytoplasmic Sperm Injection (ICSI). Ongoing studyJuly 2013.

Hendricks 2015 {published and unpublished data}

Study of Cabergoline for Prevention of Ovarian Hyperstimulation Syndrome (OHSS) in In Vito Fertilization Cycles and Derivation of OHSS Biomarkers. Ongoing study 15 February 2012.

Kamel 2015 {published and unpublished data}

Effect of Cabergoline on Endometrial Vascularity During Intracytoplasmic Sperm Injection. Ongoing studyDecember 2014.

Khaled 2014 {unpublished data only}

Diosmin versus Cabergoline for Prevention of Ovarian Hyperstimulation Syndrome (Infertility). Ongoing studyMay 2014.

NCT01530490 {unpublished data only}

NCT01530490. Cabergoline and hydroxyethyl starch in ovarian hyperstimulation syndrome prevention. clinicaltrials.gov/ct2/show/NCT01530490 Date first received: 26 January 2012. CENTRAL

Aboulghar 2002

Aboulghar M, Evers JLH, Al‐Inany HG. Intravenous albumin for preventing severe ovarian hyperstimulation syndrome. Cochrane Database of Systematic Reviews 2002, Issue 2. [DOI: 10.1002/14651858.CD001302]

Aboulghar 2003

Aboulghar MA, Mansour RT. Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures. Human Reproduction Update 2003;9(3):275‐89.

Aboulghar 2009

Aboulghar M. Symposium: update on prediction and management of OHSS ‐ prevention of OHSS. Reproductive Biomedicine Online 2009;19(1):33‐42.

Al‐Inany 2011

Al‐Inany H, Youssef M, Aboulghar M, Broekmans F, Sterrenburg M, Smit J, et al. Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2011, Issue 5. [DOI: 10.1002/14651858.CD001750.pub3]

Baumgarten 2013

Baumgarten M, Polanski L, Campbell B, Raine‐Fenning N. Do dopamine agonists prevent or reduce the severity of ovarian hyperstimulation syndrome in women undergoing assisted reproduction? A systematic review and meta‐analysis. Human Fertility (Cambridge, England) 2013;16(3):168‐74.

Busso 2009

Busso CE, Garcia‐Velasco J, Gomez R, Alvarez C, Simon C, Pellicer A. Symposium: update on prediction and management of OHSS: prevention of OHSS ‐ dopamine agonists. Reproductive Biomedicine Online 2009;19(1):43‐51.

Casper 2015

Casper RF. Reducing the risk of OHSS by GnRH agonist triggering. Journal of Clinical Endocrinology and Metabolism 2015;100(12):4396‐8.

Castelo‐Branco 2009

Castelo‐Branco C, Del Pino M, Valladares E. Ovarian hyperstimulation, hyperprolactinaemia and LH gonadotroph adenoma. Reproductive Biomedicine Online 2009;19(2):153‐5.

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D'Angelo A, Amso NN. Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database of Systematic Reviews 2002, Issue 3. [DOI: 10.1002/14651858.CD002811]

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D'Angelo A, Amso NN. Embryo freezing for preventing ovarian hyperstimulation syndrome. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD002806.pub2]

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Delvigne A, Rozenberg S. A qualitative systematic review of coasting, a procedure to avoid ovarian hyperstimulation syndrome in IVF patients. Human Reproduction Update 2002;18(3):291‐6.

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Edwards RG. IVF, IVM, natural cycle IVF, minimal stimulation IVF ‐ time for a rethink. Reproductive Biomedicine Online 2007;15(1):106‐19.

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Alhalabi 2011

Methods

Randomised controlled prospective study

No details on randomisation

Cabergoline vs no drugs

Setting: Syria

Participants

272 high‐risk women undergoing ICSI with long protocol using GnRHa, E2 level on day of hCG ≥ 4000 pg/mL, ≥ 20 follicles ≥ 10 mm in diameter

Quinagolide group: 136 women

Control group: 136 women

June 2007 to January 2010

Interventions

Quinagolide group: quinagolide (Norprolac) 150 mg/day from the day of hCG administration for 15 days (6/136 (4.41%) women developed OHSS)

Control group: no drugs (126/136 (9.12%) women developed OHSS)

Outcomes

OHSS symptoms assessed according to Gola's classification system, 4, 8 and 12 days after hCG administration

Incidence of OHSS (quinagolide group vs control group): 6/136 vs 26/136

Live birth rate: not stated

Miscarriage rate: not stated

Clinical pregnancy rate: not stated, numbers reported as "similar rates"

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment: not stated

Notes

2 different abstracts: in the Human Reproduction abstract: control group = 98 women, in the Fertility and Sterility abstract: control group = 136 women. This difference made it at risk for improper randomisation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patients were randomly divided into two groups"

Allocation concealment (selection bias)

Unclear risk

Lack of sufficient information to permit judgement; only abstract available

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Lack of sufficient information to permit judgement; only abstract available

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Lack of sufficient information to permit judgement; only abstract available

Selective reporting (reporting bias)

Unclear risk

Lack of sufficient information to permit judgement; only abstract available. No reporting on adverse effects or tolerability

Other bias

Unclear risk

Lack of sufficient information to permit judgement; only abstract available. 2 different abstracts with different control group size, suggesting improper randomisation

Alvarez 2007a

Methods

Parallel design, single‐centre randomised controlled trial

Computer‐based randomisation

Cabergoline vs placebo

Setting: Spain

Participants

82 oocytes donors, high‐risk women with development of 20 to 30 follicles > 12 mm in diameter and retrieval of > 20 oocytes

Exclusion criterion: coasting

Cabergoline group: 41 women, only 35 women remained, because 6 women were discarded for < 20 oocytes retrieved

Control group: 41 women, only 32 women remained, because 7 women were discarded for < 20 oocytes retrieved and 2 donors decided to withdraw

No differences between groups in age or BMI; did not report the duration of infertility and causes of infertility

Interventions

Cabergoline group: cabergoline tablet 0.5 mg/day for 8 days from the day of hCG injection

Control group: placebo tablet daily for 8 days

Outcomes

Moderate and severe OHSS identified by the modified classification of Golan and colleagues (Golan 1989)

  • Severe OHSS (cabergoline group vs control group): 4/41 vs 6/41

  • Moderate OHSS (cabergoline group vs control group): 7/41 vs 14/41

Live birth rate: not stated

Miscarriage rate: not stated

Clinical pregnancy rate (cabergoline group vs control group): 16/41 vs 16/41

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment (cabergoline group vs control group): 8/41 vs 4/41 (adverse effects)

Notes

Supported by Grant SAF2004‐06028 from Spanish Government

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The patients were allocated into two groups based on a computer randomization"

Allocation concealment (selection bias)

Unclear risk

Lack of sufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes

Low risk

Assessor and participants blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "thirteen patients discarded for not meeting the inclusion criteria and two donors decided to withdraw"

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

Unclear risk

Lack of sufficient information to permit judgement

Amir 2015

Methods

Parallel design, single‐centre, randomised controlled trial

Computer‐based randomisation

Cabergoline vs no intervention

Setting: Israel

Participants

40 high‐risk women undergoing IVF/ET or IVF‐PGD, aged 18 to 40 years, serum E2 > 4000 pg/mL or the development of > 20 follicles > 12 mm in diameter

Exclusion criteria: systemic disease and participating in other research studies

Cabergoline group: 20 women

Control group: 20 women

Interventions

Cabergoline group: cabergoline tablet 0.5 mg/day for 8 days from the day of hCG injection

Control group: no cabergoline

Outcomes

Moderate and severe OHSS identified by the modified classification of Golan and colleagues (Golan 1989) assessed at day of ET, ET+7, ET+12

  • Severe OHSS (cabergoline group vs control group): 0/20 vs 2/20

  • Moderate OHSS (cabergoline group vs control group): 3/20 vs 10/20

Live birth rate: not reported

Miscarriage rate (cabergoline group vs control group): 0/20 vs 1/20

Clinical pregnancy rate (live heart beat) (cabergoline group vs control group): 2/20 vs 5/20

Multiple pregnancy rate (cabergoline group vs control group): 0/20 vs 1/20

Any other adverse effects of the treatment: not stated

Notes

Did apply coasting to both groups in about 50% of women if serum E2 level > 5000 pg/mL

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random numbers

Allocation concealment (selection bias)

Unclear risk

Lack of sufficient data to permit judgement

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Neither participants nor physicians blinded, only ultrasound experts were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing data

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

Unclear risk

Lack of sufficient data to permit judgement

Beltrame 2013

Methods

Multicentre, prospective, randomised, double‐blind, placebo‐controlled study

3 clinics

Bromocriptine vs folic acid

Setting: Brazil

Participants

47 women aged < 38 years undergoing IVF with ≥ 20 follicles as assessed by transvaginal ultrasound and E2 > 3000 pg/mL on the day prior to hCG administration

Exclusion criteria: hyperprolactinaemia; use of dopaminergic agents or other medications for the treatment of hyperprolactinaemia or pituitary tumours; systemic diseases, such as arterial hypertension, hypotension, orthostatic hypotension, cardiovascular disease and diabetes mellitus; polycystic ovaries

Bromocriptine group: 23 women, 12/23 dropped out

Folic acid group: 24 women, 7/24 dropped out

Interventions

Bromocriptine group: bromocriptine 2.5 mg/day continued for 14 days

Folic acid group (placebo): folic acid 2.0 mg/day continued for 14 days

Capsules same appearance and form

Outcomes

Incidence of OHSS (subgroups mild, moderate, severe), VEGF levels, urinary function

Moderate and severe OHSS according to its OHSS criteria

  • Severe OHSS (bromocriptine group vs control group): 1/23 vs 6/24

  • Moderate OHSS (bromocriptine group vs control group): 3/23 vs 4/24

  • Total OHSS (bromocriptine group vs control group): 4/23 vs 10/24

Live birth rate: not stated

Miscarriage rate: not stated

Clinical pregnancy rate: not stated

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment: not stated

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer generated using a random number generation algorithm

Allocation concealment (selection bias)

Unclear risk

Lack of information to permit a judgement

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double blind; medication and folic acid as a placebo in same appearance capsules

Incomplete outcome data (attrition bias)
All outcomes

High risk

High dropout numbers without dropout analysis

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

Unclear risk

Lack of information to permit a judgement

Busso 2010

Methods

Randomised, parallel, double‐blind randomised controlled trial

Quinagolide vs placebo

Setting: Spain

Participants

182 women undergoing IVF and ICSI treatment and at risk of developing OHSS with ≥ 20 follicles of ≥ 10 mm on the day of hCG administration

Exclusion criteria: > 30 follicles or serum E2 6000 pg/mL (or both) had cycle cancellation, previous coasting in this cycle, any clinically significant systemic disease, endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney), history of recurrent miscarriage, undiagnosed vaginal bleeding

Quinagolide 50 μg group: 51 women

Quinagolide 100 μg group: 52 women

Quinagolide 200 μg group: 26 women

Control group: 53 women

Interventions

4 tablets for every woman (combination of placebo/quinagolide 50 μg)

Quinagolide 50 μg group: quinagolide 50 μg + 3 placebo tablets once daily, continuing until the day before the serum hCG test which took place 17+2 days after oocyte retrieval

Quinagolide 100 μg group: quinagolide 100 μg + 2 placebo tablets once daily, continuing until the day before the serum hCG test which took place 17+2 days after oocyte retrieval

Quinagolide 200 μg group: quinagolide 200 μg + no placebo tablets once daily, continuing until the day before the serum hCG test which took place 17+2 days after oocyte retrieval

Control group: 4 placebo tablets once daily, continuing until the day before the serum hCG test which took place 17+2 days after oocyte retrieval

Outcomes

Moderate and severe OHSS identified by the modified classification of Golan and colleagues (Golan 1989)

  • Moderate/severe OHSS (quinagolide 50 μg group vs quinagolide 100 μg group vs quinagolide 200 μg group vs placebo group): 6/51 vs 7/52 vs 1/26 vs 12/53

Live birth rate (quinagolide 50 μg group vs quinagolide 100 μg group vs quinagolide 200 μg group vs placebo group): 23/51 vs 29/52 vs 14/26 vs 27/53

Miscarriage rate: not stated

Clinical pregnancy rate (quinagolide 50 μg group vs quinagolide 100 μg group vs quinagolide 200 μg group vs placebo group): 22/51 vs 26/52 vs 11/26 vs 27/53

Multiple pregnancy rate: not stated

Discontinued because of adverse events (quinagolide 50 μg group vs quinagolide 100 μg group vs quinagolide 200 μg group vs placebo group): 3/51 vs 7/52 vs 7/26 vs 0/53

Any other adverse effects of the treatment: nausea, dizziness, somnolence, diarrhoea, vomiting, lower abdominal pain, headache, abdominal distension, flatulence, upper abdominal pain, syncope

Notes

Sponsored by Ferring Pharmaceuticals

WHO registry reference: EUCTR2006‐000415‐15‐ES

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation list prepared for each centre by a statistician not involved in the trial, and based on this the clinics were provided with individual code envelopes that were sealed to conceal the treatment group allocation

Allocation concealment (selection bias)

Low risk

Computer‐generated randomisation list provided to the clinics with individual code envelopes that were sealed to conceal the treatment group allocation. Block size was not disclosed

Blinding (performance bias and detection bias)
All outcomes

Low risk

Double blind (participants, staff and trial sponsor). All participants received 4 tablets (medication or placebo, or both)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Systematic OHSS evaluation performed; high‐dose arm stopped after poor tolerability of high‐dose medication

Selective reporting (reporting bias)

Low risk

Most of outcomes were evaluated

Other bias

High risk

Poor tolerability of high dose could have revealed allocated group

Sponsored by Ferring Pharmaceuticals

Very high‐risk women (> 30 follicles or serum E2 6000 pg/mL, or both) excluded and underwent cycle cancellation

Carizza 2008

Methods

Parallel, single‐centre randomised controlled trial

Computer‐based randomisation

Cabergoline vs no intervention

Setting: Brazil

Participants

166 women undergoing IVF and ICSI treatment and at risk of developing OHSS, defined as serum E2 > 4000 pg/mL on the day of hCG administration

Exclusion criteria: not stated

Cabergoline group: 83 women

Control group: 83 women, 3 women were withdrawn for not completing the follow‐up tests

No differences between groups in age or BMI

Did not report the duration of infertility and causes of infertility

Interventions

All participants received routine preventive IV HA 20 g on the day of oocyte retrieval

Cabergoline group: cabergoline 0.5 mg/day for 3 weeks from the day after oocyte retrieval

Control group: no intervention

Outcomes

Moderate and severe OHSS identified by the modified classification of Golan and colleagues (Golan 1989)

  • Severe OHSS (cabergoline group vs control group): 2/83 vs 1/83

  • Moderate OHSS (cabergoline group vs control group): 7/83 vs 14/83

Live birth rate: not stated

Miscarriage rate (cabergoline group vs control group): 1/83 vs 3/83

Clinical pregnancy rate (cabergoline group vs control group): 33/83 vs 32/83

Multiple pregnancy rate (cabergoline group vs control group): multiple pregnancies were documented in all the severe cases of OHSS in both groups (2/83 vs 1/83)

Any other adverse effects of the treatment: not stated

Notes

Authors reported no financial or commercial conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐based randomisation

Allocation concealment (selection bias)

Unclear risk

Lack of sufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Lack of sufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3/200 women in control group could not complete their follow‐up

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

Unclear risk

Lack of sufficient information to permit judgement

Dalal 2014

Methods

Single‐centre randomised controlled trial

Computer‐based randomisation by independent research assistant

Cabergoline vs coasting

Setting: India

Participants

60 women undergoing IVF or ICSI cycles and at risk of developing OHSS, defined as the presence of preovulatory follicles ≥ 20 in both ovaries and the E2 level ≥ 2500 pg/mL

Exclusion criteria: not stated

Cabergoline group: 30 women

Coasting group: 30 women

Interventions

Cabergoline group: cabergoline 0.5 mg/day orally from the day of hCG for 8 days

Coasting group: gonadotropins were withheld (while GnRHa was maintained), until the serum level of E2 started to decline in each group. 1 woman needed ascites tapped, and the remaining 29 women received 6% HES infusion

Outcomes

Moderate and severe OHSS: classification not described but according to Golan (Golan 1989) criteria (from private correspondence with author)

  • Severe OHSS (cabergoline group vs coasting group): 5/30 vs 4/30

  • Moderate OHSS: not stated

  • Total OHSS: not stated

Live birth rate: not stated

Miscarriage rate (cabergoline group vs coasting group): 0/30 vs 2/30

Clinical pregnancy rate (defined as presence of gestational sac or cardiac activity 3 weeks after transfer) (cabergoline group vs coasting group): 8/30 vs 4/30

Multiple pregnancy rate (cabergoline group vs coasting group): 2/30 vs 0/30

Any other adverse effects of the treatment: cancelling of ET due to poor embryo quality (cabergoline group vs coasting group): 1/30 vs 1/30. Other adverse events not stated

Notes

Received draft of full‐text article in peer review currently per private email; additional information per private correspondence with first author.

58 women received fluid of 6% HES and the remaining included woman received an ascites tap instead of HES.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Use of randomisation software (www.randomizer.org/)

Allocation concealment (selection bias)

Unclear risk

Independent research assistant allocated; concealment unclear

Blinding (performance bias and detection bias)
All outcomes

High risk

No blinding involved. The participants and clinicians were aware in which arm of the study they were

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No dropouts/loss of follow‐up in the 2 groups

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

High risk

OHSS identified/classification not described. 29 participants in both groups also received HES infusion, 1 participant from each group had ascites tap, unclear which participant was involved

Fetisova 2014

Methods

Randomised trial based on blinded envelopes

Cabergoline vs no intervention

Setting: Russia

Participants

168 women included, but only 128 high‐risk women defined as transvaginal aspiration of ≥ 15 follicles

Cabergoline group: 65 women

Control group (no intervention): 63 women

No significant difference between groups in somatic and obstetric anamnesis

Interventions

Cabergoline group: cabergoline 0.5 mg/day from the day after oocyte retrieval for 5 days before ET day

Control group: no intervention

Outcomes

Moderate and severe OHSS, diagnosis OHSS not stated

  • Severe OHSS (cabergoline group vs control group): 3/65 vs 6/63

  • Moderate OHSS (cabergoline group vs control group): 4/65 vs 13/63

  • Total OHSS (cabergoline group vs control group): 7/65 vs 19/63

Live birth rate: not stated

Miscarriage rate (cabergoline group vs control group): 4/65 vs 6/63

Clinical pregnancy rate (cabergoline group vs control group): 21/65 vs 23/63

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment: not stated

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Lack of information to permit judgement

Allocation concealment (selection bias)

Low risk

Blinded envelopes method

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Lack of sufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No loss to follow‐up

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

Unclear risk

Lack of sufficient information to permit judgement

Ghahiri 2015

Methods

Randomised controlled trial based on random number table

Cabergoline vs albumin vs HES

Setting: Iran

Participants

91 high‐risk women with E2 > 3000 pg/mL or > 20 follicles on the day of hCG administration or previous history of OHSS, or a combination

Cabergoline group: 31 women

Albumin group: 30 women

HES group: 30 women

No significant difference between groups regarding gravidity, parity, death, ectopic pregnancy, abortion and mean age

Interventions

Cabergoline group: cabergoline 0.5 mg daily for 7 days after oocyte retrieval

Albumin group: 2 vials (2 × 50 mL) HAs IV 30 minutes after oocyte retrieval within 4 hours

HES group: 1000 mL of 6% HES IV 30 minutes after oocyte retrieval within 4 hours

Outcomes

Moderate and severe OHSS identified by the classification of Golan and colleagues (Golan 1989)

  • Severe OHSS (cabergoline group vs albumin group vs HES group): 1/31 vs 3/30 vs 0/30

  • Moderate OHSS (cabergoline group vs albumin group vs HES group): 4/31 vs 2/30 vs 2/30

  • Total OHSS (cabergoline group vs albumin group vs HES group): 5/31 vs 5/30 vs 2/30

Live birth rate: not stated

Miscarriage rate: not stated

Clinical pregnancy rate: not stated

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment: not stated

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number table

Allocation concealment (selection bias)

Unclear risk

Lack of sufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Lack of sufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No loss to follow‐up

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

Unclear risk

Lack of sufficient information to permit judgement

Jellad 2016

Methods

Single‐centre, prospective randomised study ("randomly divided in two groups")

Cabergoline vs no medication

Setting: Tunisia

Participants

146 women undergoing IVF or ICSI and receiving GnRHa. OHSS risk defined as a plasma E2 level > 3000 pg/mL on the day of hCG administration or the development of ≥ 18 follicles > 12 mm in diameter, or both

Exclusion criteria: coasting cases, aged > 40 years, history of uterine surgery, and submucosal and intramural fibromas > 5 cm

Cabergoline group: 78 women

Control group: 68 women

Interventions

Cabergoline group: cabergoline 0.5 mg/day for 8 days starting on the day of hCG injection

Control group (no intervention): no medication treatment

Outcomes

Moderate and severe OHSS identified according to the criteria of Golan and colleagues (Golan 1989)

  • Severe OHSS (cabergoline group vs control group): 2/78 vs 8/68

  • Moderate OHSS (cabergoline group vs control group): 8/78 vs 17/68

  • mild, moderate or severe OHSS (cabergoline group vs control group): 25/78 vs 25/68

Live birth rate: not stated

Miscarriage rate: only reported for women who developed OHSS (cabergoline group vs control group): 3/25 vs 6/25

Clinical pregnancy rate only reported for women who developed OHSS (cabergoline group vs control group): 20/25 vs 14/25

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment: not stated

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Lack of information to permit judgement

Allocation concealment (selection bias)

Unclear risk

Lack of information to permit judgement

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Lack of information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

High risk

No follow‐up data from the non‐OHSS women in both groups, no data on possible loss to follow‐up or dropout

Selective reporting (reporting bias)

High risk

Pregnancy data from the non‐OHSS women in both groups not reported

Other bias

High risk

Coasting cases (women at highest risk for severe OHSS) were excluded, unclear based on what criteria coasting was opted for

Matorras 2013

Methods

Blinded randomised controlled trial

Randomisation based on computer‐generated numbers in sequentially numbered sealed envelopes

Cabergoline + 6% HES vs 6% HES

Setting: Spain

Participants

182 women undergoing IVF using their own oocytes and receiving GnRHa treatment and considered at risk of OHSS (all aged < 40 years). OHSS risk defined as a plasma E2 level > 3000 pg/mL on the day of hCG administration or development of 20 follicles >12 mm, or both

Exclusion criteria: E2 levels > 5000 pg/mL where cycles were cancelled

Cabergoline group: 88 women

Control group: 94 women

Interventions

Cabergoline group: slow IV infusion of 500 mL of 6% HES during follicle aspiration plus cabergoline 0.5 mg orally for 8 days starting on day of hCG administration

Control group: slow IV infusion of 500 mL of 6% HES during follicle aspiration

Outcomes

Moderate and severe OHSS identified by the modified classification of Golan and colleagues (Golan 1989)

  • Severe OHSS (cabergoline + HES group vs control group): 2/88 vs 1/94

  • Moderate OHSS (cabergoline + HES group vs control group): 3/88 vs 2/94

  • Total OHSS (cabergoline + HES group vs control group): 5/88 vs 3/94

Live birth rate: not stated

Miscarriage rate (cabergoline + HES group vs control group): 5/88 vs 9/94

Clinical pregnancy rate (cabergoline + HES group vs control group): 43/88 vs 48/94

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment: not stated

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was performed using computer‐generated numbers

Allocation concealment (selection bias)

Low risk

Sequentially numbered sealed envelopes were used

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Both the embryologists and the gynaecologists performing oocyte aspiration, ET and post‐transfer follow‐up, were blinded to the co‐administration of cabergoline. Participants were not blinded; however, low risk of causing bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No loss to follow‐up

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

Unclear risk

High‐risk cycles were cancelled (E2 > 5000 pg/mL), which might have excluded severe OHSS cases

Salah 2012

Methods

Blinded randomised controlled trial

Cabergoline vs prednisolone vs no intervention

Setting: United Arab Emirates

Participants

200 women with polycystic ovarian syndrome undergoing IVF treatment and possibility of developing OHSS

Exclusion criteria: previous oophorectomy, immune diseases that affect the permeability of blood vessels, such as systemic lupus, disseminated sclerosis and rheumatoid arthritis

Cabergoline group: 75 women, 2 women lost to follow‐up

Prednisolone group: 75 women, 3 women lost to follow‐up

Control group (no intervention): 50 women, 2 women lost to follow‐up

Interventions

Cabergoline group: cabergoline 0.5 mg tablets, 1 tablet on 2 successive days, starting from the day of hCG injection, and repeated 1 week later

Prednisolone group: prednisolone 10 mg tablets twice a day to day of pregnancy test

Control group: no intervention

Outcomes

Moderate and severe OHSS identified by the modified classification of Golan and colleagues (Golan 1989)

  • Severe OHSS (cabergoline group vs control group): 0/75 vs 2/50

  • Moderate OHSS (cabergoline group vs control group): 2/75 vs 4/50

  • OHSS (cabergoline group vs prednisolone group vs control group): 2/75 vs 7/75 vs 6/50

Live birth rate: not stated

Miscarriage rate: not stated

Clinical pregnancy rate: not stated

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment: not stated

Notes

No high‐risk women identified (e.g. based on E2 or ultrasound) except that this population was young women with PCOS

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Lack of information to permit judgement

Allocation concealment (selection bias)

Low risk

Sealed envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blind to the participants

Incomplete outcome data (attrition bias)
All outcomes

Low risk

7/200 women after randomisation could not complete their follow‐up, no reasons stated

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

High risk

No high‐risk women identified (e.g. based on E2 or ultrasound) except this population was young women with PCOS

Shaltout 2012

Methods

Randomised controlled trial

Computer‐based randomisation

Cabergoline vs no intervention

Setting: Egypt

Participants

200 women undergoing ICSI treatment and at risk of developing OHSS, defined by E2 level on day of hCG > 3500 pg/mL with ≥ 20 follicles > 12 mm diameter

Cabergoline group: 100 women; 2 had empty follicles, 2 had failure of fertilisation and 1 discontinued

Control group: 100 women; 3 had empty follicles and 1 had failure of fertilisation

Exclusion criterion: E2 ≥ 5000 pg/mL

No differences between the groups in age, BMI and causes of infertility

Interventions

Cabergoline group: cabergoline tablet 0.25 mg/day for 8 days from the day of hCG injection

Control group: no intervention

Outcomes

Moderate and severe OHSS identified according to Golan and colleagues (Golan 1989)

  • Severe OHSS (cabergoline group vs control group): 1/100 vs 3/100

  • Moderate OHSS (cabergoline group vs control group): 4/100 vs 11/100

Live birth rate (cabergoline group vs control group): 37/100 vs 36/100

Miscarriage rate (cabergoline group vs control group): 5/100 vs 5/100

Clinical pregnancy rate (cabergoline group vs control group): 42/100 vs 41/100

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment: not stated

Notes

Number of women excluded for dropout (no ET because no oocytes found, no embryos yielded, etc., 1 adverse event)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐based randomisation method

Allocation concealment (selection bias)

Unclear risk

Lack of sufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Lack of sufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

9 women could not complete their follow‐up but exact reasons not stated

Selective reporting (reporting bias)

Low risk

Most outcomes were included

Other bias

Unclear risk

Lack of sufficient information to permit judgement

Sohrabvand 2009

Methods

Parallel design, randomised controlled trial

Block randomisation

Cabergoline vs coasting

Setting: Iran

Participants

60 women at risk of OHSS defined by ≥ 20 follicles in both ovaries, most being ≤ 14 mm in diameter and serum E2 level 3000 pg/mL

Cabergoline group: 30 women

Coasting group: 30 women

Exclusion criterion: contraindication to dopamine agonists

No significant differences between groups in age, BMI, menstrual cycle pattern, duration of infertility and causes of infertility

Interventions

Cabergoline group: cabergoline tablet 0.5 mg/day for 7 days after hCG administration

Coasting group: gonadotropin administration was ceased until serum E2 levels reached < 3000 pg/mL before hCG administration

Outcomes

Moderate and severe OHSS identified by the classification of Golan and colleagues (Golan 1989)

  • Severe OHSS (cabergoline group vs coasting group): 0/30 vs 0/30

  • Moderate OHSS (cabergoline group vs coasting group): 1/30 vs 7/30

  • Total OHSS (cabergoline group vs coasting group): 1/30 vs 7/30

Live birth rate: not stated

Miscarriage rate: not stated

Clinical pregnancy rate (cabergoline group vs coasting group): 14/30 vs 7/30

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment: not stated

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random number table blocks according to Biostatistics in Health Systems

Allocation concealment (selection bias)

Unclear risk

Lack of sufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Lack of sufficient information to permit judgement

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No loss to follow‐up

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

Unclear risk

Lack of sufficient information to permit judgement

Tehraninejad 2012

Methods

Parallel, single‐centre randomised controlled trial

Not blinded

Computer‐based randomisation

Cabergoline vs HA

Setting: Iran

Participants

140 women aged 15 to 37 years

Inclusion criteria: risk of developing OHSS, defined by the development of 20 to 30 follicles > 12 mm in diameter on the day of hCG administration and retrieval of > 20 oocytes, ovarian stimulation with long protocol

Exclusion criteria: coasting cases, aged > 37 years, previous uterine surgery, intramural or submucosal myoma sizes > 5 cm

Cabergoline group: 70 women, 1 woman lost to follow‐up

Albumin group: 70 women, 1 woman lost to follow‐up

No differences between groups in age, BMI, duration of infertility, type of infertility, basal FSH, LH levels and E2 levels on the day of hCG administration but there was a difference in cause of infertility.

Interventions

Cabergoline group: cabergoline tablet 0.5 mg/day 7 days beginning on day of oocyte retrieval

Control group: HA 20% IV infusion

Outcomes

Moderate and severe OHSS identified by the modified classification of Golan and colleagues (Golan 1989)

  • Severe OHSS (cabergoline group vs control group): 1/70 vs 16/70

  • Moderate OHSS (cabergoline group vs control group): 14/70 vs 33/70

Live birth rate: not stated

Miscarriage rate (cabergoline group vs control group): 1/70 vs 3/70

Clinical pregnancy rate (cabergoline group vs control group): 20/70 vs 26/70

Multiple pregnancy rate (cabergoline group vs control group): 3/70 vs 5/70

Any other adverse effects of the treatment: not stated

Notes

1 dropout in each group. Not reported when they dropped out or if they had even started. Excluded from analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐based randomisation method

Allocation concealment (selection bias)

Unclear risk

Lack of sufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Midwife open the sealed envelopes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

2/140 women lost to follow‐up

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

Unclear risk

Lack of sufficient information to permit judgement

Torabizadeh 2013

Methods

Single‐centre, randomised controlled trial

Blinded for sampling. No statement on blinding for allocation

Randomisation not described

Cabergoline vs HA

Setting: Iran

Participants

95 women, every other participant sampled. > 20 oocytes during oocyte retrieval, ovary size > 10 cm, serum E2 > 2500 pg/mL, considered eligible if high risk with > 20 follicles; randomisation when confirmed > 20 follicles retrieved in both ovaries at day of hCG injection

Exclusion criterion: < 20 oocytes retrieved

Cabergoline group: 47 women

Albumin group: 48 women

Interventions

Cabergoline group: cabergoline 0.5 mg/day oral from day of hCG injection to 8 days

Control group: 10 units IV HA at the start of oocyte retrieval

Outcomes

Moderate and severe OHSS; identified/classification not described other than "classified according to related criteria"

  • Severe OHSS (cabergoline group vs control group): 1/47 vs 5/48

  • Moderate OHSS (cabergoline group vs control group): 3/47 vs 5/48

Live birth rate: not stated

Miscarriage rate: not stated

Clinical pregnancy rate: not stated

Multiple pregnancy rate: not stated

Any other adverse effects of the treatment: not stated

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quote: "The method of sampling was randomized sampling as we selected every other person. Randomization was used to allocate the patients to two groups immediately after confirmation of retrieval of >20 oocytes. but intervention started already on day 2 before retrieval (hCG administration)"!

Allocation concealment (selection bias)

Unclear risk

Lack of sufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Quote: "physician who controlled the patients was blind"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No loss to follow‐up

Selective reporting (reporting bias)

Unclear risk

No exclusions (no live birth rated mentioned)

Other bias

Unclear risk

Lack of sufficient information to permit judgement

BMI: body mass index; E2: oestradiol; ET: embryo transfer; FSH: follicle‐stimulating hormone; GnRH: gonadotropin‐releasing hormone; GnRHa: gonadotropin‐releasing hormone agonist; HA: human albumin; hCG: human chorionic gonadotrophin; HES: hydroxyethyl starch; ICSI: intracytoplasmic sperm injection; IV: intravenous; IVF: in vitro fertilisation; LH: luteinising hormone; OHSS: ovarian hyperstimulation syndrome; PGD: preimplantation genetic diagnosis; VEGF: vascular endothelial growth factor; WHO: World Health Organization.

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Aflatoonian 2008

Not randomised, "divided into two groups according to patients convenience"

Agha Hosseini 2010

Not an RCT; historic control group

Alvarez 2007b

A pilot study, not an RCT

Ata 2009

Case report

Fouda 2016

Studied co‐intervention on top of cabergoline rather than cabergoline

Ghaebi 2016

Only women who were already developed signs of (mild) OHSS included

Gualtieri 2011

Retrospective analysis, not an RCT

Guvendag 2010

Case control study, not an RCT

Hatton 2012

A retrospective study, not an RCT

Hosseini 2011

Not an RCT

Khan 2010

Not an RCT

Naredi 2013

Quasi‐randomised, odd/even participants appointed to intervention groups

Rollene 2009a

Case series

Rollene 2009b

Retrospective cohort study

Saad 2016

Quasi‐randomised (odd and even numbers)

Seow 2013

2 differently timed cabergoline regimens, no control group

Sherwal 2010

Historical matched control group

Soliman 2011

Not an RCT

Spitzer 2011

Retrospective study

Zargar 2011

Evaluated 2 different cabergoline regimens on prevention of OHSS

OHSS: ovarian hyperstimulation syndrome; RCT: randomised controlled trial.

Characteristics of studies awaiting assessment [ordered by study ID]

Ahmadi 2010

Methods

Prospective randomised controlled trial

Cabergoline vs human albumin

Participants

112 high‐risk women undergoing ART

Cabergoline group: 56 women

Albumin group: 56 women

No statistically significant differences in age, BMI, number of follicles and oocyte retrieved, and serum E2 on the day of hCG injection

Interventions

Cabergoline group: cabergoline tablet 0.5 mg/day until 12 days from oocytes retrieval

Albumin group: 20 g IV human albumin on the day of oocyte retrieval

Outcomes

The OHSS frequency was significantly lower in the cabergoline group (P < 0.001). There were no significant differences in pregnancy rate, implantation and miscarriages between groups

Notes

Meeting abstract, no numbers mentioned, no response from authors yet

ART: assisted reproduction technology; BMI: body mass index; E2: oestradiol; hCG: human chorionic gonadotrophin; IV: intravenous; OHSS: ovarian hyperstimulation syndrome.

Characteristics of ongoing studies [ordered by study ID]

Bassiouny 2015

Trial name or title

Cabergoline and Coasting to Prevent OHSS; Combining Cabergoline and Coasting in Gonadotropin Releasing Hormone(GnRH)Agonist Protocol in Intracytoplasmic Sperm Injection (ICSI) to Prevent Ovarian Hyperstimulation Syndrome (OHSS): a Randomized Clinical Trial

Methods

RCT

To randomly compare 3 study groups involving high‐risk women to 1 of 3 arms of management, either coasting for 1 to 3 days or receiving cabergoline for 8 days or coasting for 1 day plus receiving cabergoline for 8 days in women undergoing ICSI following the long luteal GnRHa protocol

Participants

Women undergoing ICSI

Inclusion criteria:

  • aged ≤ 35, BMI ≤ 30

  • long protocol GnRHa cycles

  • E2 level on day of hCG ≥ 3500 pg/mL

  • Retrieving > 15 oocytes

Exclusion criteria:

  • Male factor

  • Uterine factor

Interventions

Group 1: active comparator: coasting. In their ICSI cycle, participants will continue their agonist treatment while stopping the hMG injections for 1 to 3 days until drop of E2 to a safe level to prevent OHSS. Early OHSS assessed at day of ET and 7 days after this date. Late OHSS assessed 14 days after ET

Group 2: active comparator: cabergoline. In their ICSI cycle, participants will take cabergoline 0.25 mg/day for 8 days from hCG triggering day to prevent OHSS. Early OHSS assessed at day of ET and 7 days after this date. Late OHSS assessed 14 days after ET

Group 3: active comparator: coasting + cabergoline. In their ICSI cycle, participants will continue their agonist treatment while stopping the hMG injections for 1 day plus receiving cabergoline 0.25 mg/day for 8 days from hCG triggering day to prevent OHSS. Early OHSS assessed at day of ET and 7 days after this date. Late OHSS assessed 14 days after ET

Outcomes

Primary outcomes:

  • rate and degree of OHSS (composite outcome) (time frame: 14 days) (designated as safety issue: no)

  • symptoms of nausea, vomiting, shortness of breath, abdominal pain, abdominal distension; ovarian size and fluid in Douglas pouch by ultrasound

  • haematocrit, total leucocytic count, creatinine and E2 level as biochemical markers

  • early OHSS first 9 days after ovum pickup and late is after 9 to 14 days (time of pregnancy test)

Secondary outcomes:

  • number of oocytes (time frame: 1 day) (designated as safety issue: no)

  • number of oocytes collected on the day of oocyte collection

Other outcomes:

  • number of metaphase II (MII) oocytes (time frame: 1 day) (designated as safety issue: no), number of MII oocytes collected on the day of oocyte collection

  • fertilisation rate (time frame: 2 days) (designated as safety issue: no), number of embryos that show signs of fertilisation in each participant

  • number of embryos (time frame: 3 to 5 days) (designated as safety issue: no), number of embryos assessed for ET in each participant

  • quality of embryos (time frame: 3 to 5 days) (designated as safety issue: no), quality of embryos transferred to each participant whether good or poor

  • implantation rate (time frame: 14 days) (designated as safety issue: no). The participants who have a positive quantitative β‐hCG) and do not continue their pregnancy with a drop in the result and start of menstruation

  • clinical pregnancy rate (time frame: 28 days) (designated as safety issue: no), participants who show an intrauterine gestational sac with positive fetal pulsations on ultrasound 14 days after their pregnancy test

  • early miscarriage rate (time frame: 12 weeks) (designated as safety issue: no), pregnancy loss in the first 12 weeks of gestation

  • ongoing pregnancy rate (time frame: 12 weeks) (designated as safety issue: no) pregnancies going beyond 12 weeks of gestation

  • live birth rate (time frame: 40 weeks) (designated as safety issue: no) live births occurring

Starting date

Contact information

[email protected]

Notes

El Khattan 2015

Trial name or title

Comparative Study Between Cabergoline and Intravenous Calcium in the Prevention of Ovarian Hyperstimulation in Women with Polycystic Ovarian Disease Undergoing Intracytoplasmic Sperm Injection (ICSI)

Methods

Participants

Interventions

Cabergoline group: cabergoline (Dostinex) 0.5 mg/day oral tablets for 8 days from the day of hCG injection. Once in the trial
Calcium gluconate group: intravenous infusion of 10% calcium gluconate 10 mL in 200 mL of physiological saline on the day of ovum pickup. Once in the treatment cycle and each participant will undergo 1 treatment cycle during the trial

To monitor the adherence to the medication, we ask the participant for the drug tablet return

Outcomes

Primary outcomes:

  • occurrence of OHSS which can be diagnosed clinically by participant's monitoring symptoms accompanied by ultrasonography and laboratory investigation

  • severity of OHSS which is detected by the need for ascitic drainage and the need for hospitalisation

Secondary outcomes:

  • chemical pregnancy rate: positive (serum β‐hCG) 14 days following ET

  • clinical pregnancy rate: positive pregnancy test and positive fetal heart beat by ultrasound after 6 weeks' gestational age

  • miscarriage rate: diagnosed by ultrasound/clinically

  • ectopic rate: diagnosed by ultrasound/clinically

Starting date

July 2013

Contact information

[email protected]

Notes

Hendricks 2015

Trial name or title

Study of Cabergoline for Prevention of Ovarian Hyperstimulation Syndrome (OHSS) in In Vito Fertilization Cycles and Derivation of OHSS Biomarkers

Methods

Randomised controlled trial

Endpoint classification: efficacy study

Intervention model: parallel assignment

Masking: double blind (participant, carer, investigator, outcomes assessor)

Primary purpose: prevention

Participants

Inclusion criterion:

  • participants with > 20 oocytes collected after COH in both GnRH agonist and antagonist cycles

Exclusion criteria:

  • allergy to dopamine agonists

  • undergoing in vitro maturation cycles

  • where GnRH analogues have been used to trigger oocyte maturation in antagonist cycles

Interventions

Cabergoline group: cabergoline 0.5 mg tablet, 1 tablet daily for 8 days

Control group: placebo 1 tablet daily for 8 days

Outcomes

Primary outcome:

  • development of moderate or severe OHSS necessitating admission for management of OHSS (time frame: within 2 weeks after hCG trigger) (designated as safety issue: no)

Secondary outcome:

  • need for abdominal or pleural tap (time frame: within 3 weeks after hCG trigger) (designated as safety issue: no)

  • other complications of OHSS (venous thromboembolism, cardiac failure, renal failure, acute respiratory failure, pulmonary oedema and coma) (time frame: within 3 weeks after hCG trigger) (designated as safety issue: no)

  • admission into intensive care unit (time frame: within 3 weeks after hCG trigger) (designated as safety issue: no)

  • examination of potential biomarkers for OHSS (time frame: 1 to 2 years) (designated as safety issue: no)

Starting date

15 February 2012

Contact information

[email protected]

Notes

NCT01535859

Kamel 2015

Trial name or title

Effect of Cabergoline on Endometrial Vascularity During Intracytoplasmic Sperm Injection

Methods

Allocation: non‐randomised

Endpoint classification: efficacy study

Intervention model: parallel assignment

Masking: open label

Primary purpose: diagnostic

Participants

Inclusion criteria:

  • aged 18 to 40 years

  • normal serum prolactin level

  • tubal factor of infertility

  • unexplained infertility

  • BMI ≥ 30 kg/m2

  • E2 > 3500 pg/mL on day of ovulation trigger

  • underwent coasting for OHSS prevention

  • > 20 follicles ≥ 11 mm on the day of final oocyte maturation

Exclusion criteria:

  • contraindication to pregnancy e.g. somatic and mental diseases that are contraindications for carrying of a pregnancy and childbirth, inborn malformations or acquired deformations of uterus cavity which make embryo implantation or carrying of a pregnancy impossible, ovarian tumours

  • severe male factor infertility.

  • women with hyperprolactinaemia

  • frozen ET cycles

  • uterine anomalies

  • uterine synechia

  • history of genital tuberculosis

  • repeated implantation failure in ICSI

  • taking medication that is known to alter prolactin levels, e.g. antipsychotics, atypical agents and risperidone

  • thyroid dysfunction

  • medical disorders affecting serum prolactin, e.g. acromegaly, chronic renal failure and hypothyroidism

Interventions

Cabergoline group: women AT RISK of OHSS receiving cabergoline 0.5 mg/day for 8 days from the day of oocyte pickup for prevention of hyperstimulation

Control group: women AT RISK of OHSS not receiving cabergoline

Control group 2: will serve as a control group and will include age‐ and BMI‐matched women NOT AT RISK of OHSS, and not receiving cabergoline

Outcomes

Primary outcome:

  • pregnancy rate (chemical, clinical) (time frame: 2 weeks after ET) (designated as safety issue: no). β‐hCG) > 10 IU on day 12 after ET

Secondary outcomes:

  • miscarriage rate (time frame: 3 weeks after positive β‐hCG) (designated as safety issue: no). First ultrasound at 7 weeks' gestation

  • OHSS rate (time frame: 4 weeks) (designated as safety issue: no). Early‐ and late‐onset OHSS

  • vascularisation index (time frame: 5 days) (designated as safety issue: no). 3D ultrasound and power Doppler examination done before ovum pickup and repeated before transfer

  • flow index (time frame: 5 days) (designated as safety issue: no). 3D ultrasound and power Doppler examination done before ovum pickup and repeated before transfer

  • vascularisation flow index (time frame: 5 days) (designated as safety issue: no). 3D ultrasound and power Doppler examination done before ovum pickup and repeated before transfer

  • pulsatility index (time frame: 5 days) (designated as safety issue: no). 3D ultrasound and power Doppler examination done before ovum pickup and repeated before transfer

  • resistance index (time frame: 5 days) (designated as safety issue: no). 3D ultrasound and power Doppler examination done before ovum pickup and repeated before transfer

  • peak systolic velocity (time frame: 5 days) (designated as safety issue: no). 3D ultrasound and power Doppler examination done before ovum pickup and repeated before transfer

  • end‐diastolic velocity (time frame: 5 days) (designated as safety issue: no). 3D ultrasound and power Doppler examination done before ovum pickup and repeated before transfer

Starting date

December 2014

Contact information

[email protected]

Notes

NCT02306564

Khaled 2014

Trial name or title

Diosmin versus Cabergoline for Prevention of Ovarian Hyperstimulation Syndrome (Infertility)

Methods

Allocation: randomised

Endpoint classification: safety/efficacy study

Intervention model: single group assignment

Masking: single blind (participant)

Primary purpose: prevention

Participants

200 women at risk of OHSS during ICSI cycles will be randomly scheduled into 2 equal groups

Inclusion criteria: infertile women undergoing ICSI or polycystic ovarian syndrome, aged 23 to 48 years with 1 of the following:

  • presence of > 20 follicles by ultrasound

  • E2 > 3000 pg/mL

  • retrieval of > 15 follicles

Exclusion criteria: none

Interventions

Diosmin group: diosmin 2 × 500 mg tablets every 8 hours will be given from day of hCG injection for 14 days

Cabergoline group: cabergoline 1 × 0.5 mg tablet/day will be given from day of hCG injection for 8 days

Outcomes

Primary outcome:

  • number of participants with OHSS (time frame: every 2 weeks for 8 weeks) (designated as safety issue: yes). Assessed by: abdominal bloating, mild abdominal pain, nausea and vomiting, oliguria, acute respiratory distress syndrome, ultrasound (ovarian size usually ˃ 8 cm), ultrasound evidence of ascites, laboratory haemoconcentration, haematocrit ˃ 45%, hypoproteinaemia

Secondary outcomes:

  • pregnancy rate (time frame: 14 days after ET) (designated as safety issue: yes)

  • β‐hCG (serum hCG test) will be checked 14 days after ET

Starting date

May 2014

Contact information

[email protected]

Notes

NCT02134249

NCT01530490

Trial name or title

Cabergoline and Hydroxyethyl Starch in Ovarian Hyperstimulation Syndrome Prevention

Methods

Randomised open, parallel trial

Participants

Women aged 18 to 40 years

Inclusion criterion:

  • women at risk of OHSS (> 20 follicles observed > 12 mm in diameter or E2 levels of 3000 pg/mL to 5000 pg/mL)

Exclusion criterion:

  • aged > 40 years

Interventions

Cabergoline group: slow infusion of 500 mL of 6% HES during follicular aspiration alone or combined with cabergoline 0.5 mg administration for 8 days, starting on the day of hCG administration

Control group: slow infusion of 500 mL of 6% HES during follicular aspiration

Outcomes

Primary outcome: risk of OHSS

Secondary outcome: pregnancy rate

Starting date

August 2007

Contact information

None

Notes

NCT01530490; this is the Matorras 2013 paper

3D: 3‐dimensional; β‐hCG: β‐human chorionic gonadotrophin; BMI: body mass index; COH: controlled ovarian hyperstimulation; E2: oestradiol; ET: embryo transfer; GnRH: gonadotropin‐releasing hormone; GnRHa: gonadotropin‐releasing hormone agonist; hCG: human chorionic gonadotrophin; HES: hydroxyethyl starch; hMG: human menopausal gonadotropin; ICSI: intracytoplasmic sperm injection; OHSS: ovarian hyperstimulation syndrome; RCT: randomised controlled trial.

Data and analyses

Open in table viewer
Comparison 1. Dopamine agonist versus placebo/no intervention

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Moderate or severe ovarian hyperstimulation syndrome (OHSS) Show forest plot

8

1022

Odds Ratio (M‐H, Fixed, 95% CI)

0.27 [0.19, 0.39]

Analysis 1.1

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).

1.1 Cabergoline vs placebo/no treatment

5

521

Odds Ratio (M‐H, Fixed, 95% CI)

0.26 [0.16, 0.42]

1.2 Quinagolide vs placebo

2

454

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.15, 0.51]

1.3 Bromocriptine vs placebo (folic acid)

1

47

Odds Ratio (M‐H, Fixed, 95% CI)

0.29 [0.08, 1.14]

2 Subgroup analysis by severity of OHSS Show forest plot

7

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.2

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 2 Subgroup analysis by severity of OHSS.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 2 Subgroup analysis by severity of OHSS.

2.1 Severe OHSS

7

750

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.14, 0.56]

2.2 Moderate OHSS

7

750

Odds Ratio (M‐H, Fixed, 95% CI)

0.37 [0.24, 0.57]

3 Live birth Show forest plot

1

182

Odds Ratio (M‐H, Fixed, 95% CI)

1.01 [0.53, 1.91]

Analysis 1.3

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 3 Live birth.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 3 Live birth.

3.1 Quinagolide vs placebo

1

182

Odds Ratio (M‐H, Fixed, 95% CI)

1.01 [0.53, 1.91]

4 Clinical pregnancy rate Show forest plot

4

432

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.54, 1.22]

Analysis 1.4

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 4 Clinical pregnancy rate.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 4 Clinical pregnancy rate.

4.1 Cabergoline vs no intervention

3

250

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.48, 1.38]

4.2 Quinagolide vs placebo

1

182

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.43, 1.54]

5 Multiple pregnancy Show forest plot

1

40

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 8.26]

Analysis 1.5

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 5 Multiple pregnancy.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 5 Multiple pregnancy.

5.1 Cabergoline vs placebo/no treatment

1

40

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 8.26]

6 Miscarriage Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.6

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 6 Miscarriage.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 6 Miscarriage.

6.1 Cabergoline vs placebo/no treatment

2

168

Odds Ratio (M‐H, Fixed, 95% CI)

0.66 [0.19, 2.28]

7 Adverse events Show forest plot

2

264

Odds Ratio (M‐H, Fixed, 95% CI)

4.54 [1.49, 13.84]

Analysis 1.7

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 7 Adverse events.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 7 Adverse events.

7.1 Cabergoline vs placebo/no treatment

1

82

Odds Ratio (M‐H, Fixed, 95% CI)

2.24 [0.62, 8.14]

7.2 Quinagolide vs placebo

1

182

Odds Ratio (M‐H, Fixed, 95% CI)

16.64 [0.98, 282.02]

Open in table viewer
Comparison 2. Dopamine agonist plus co‐intervention versus co‐intervention

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Moderate or severe ovarian hyperstimulation syndrome (OHSS) Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

0.57 [0.31, 1.03]

Analysis 2.1

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).

1.1 Cabergoline + albumin vs albumin

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

0.55 [0.23, 1.34]

1.2 Cabergoline + hydroxyethyl starch (HES) vs HES

2

382

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.26, 1.30]

2 Live birth Show forest plot

1

200

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.59, 1.86]

Analysis 2.2

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 2 Live birth.

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 2 Live birth.

2.1 Cabergoline + HES vs HES

1

200

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.59, 1.86]

3 Clinical pregnancy rate Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.71, 1.40]

Analysis 2.3

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 3 Clinical pregnancy rate.

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 3 Clinical pregnancy rate.

3.1 Cabergoline + albumin vs albumin

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.56, 1.96]

3.2 Cabergoline + HES vs HES

2

382

Odds Ratio (M‐H, Fixed, 95% CI)

0.98 [0.65, 1.47]

4 Multiple pregnancy Show forest plot

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

2.02 [0.18, 22.77]

Analysis 2.4

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 4 Multiple pregnancy.

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 4 Multiple pregnancy.

4.1 Cabergoline + albumin vs albumin

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

2.02 [0.18, 22.77]

5 Miscarriage Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

0.65 [0.30, 1.42]

Analysis 2.5

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 5 Miscarriage.

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 5 Miscarriage.

5.1 Cabergoline + albumin vs albumin

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

0.33 [0.03, 3.19]

5.2 Cabergoline + HES vs HES

2

382

Odds Ratio (M‐H, Fixed, 95% CI)

0.73 [0.31, 1.68]

6 Adverse events Show forest plot

2

366

Odds Ratio (M‐H, Fixed, 95% CI)

3.03 [0.12, 75.28]

Analysis 2.6

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 6 Adverse events.

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 6 Adverse events.

6.1 Cabergoline + albumin vs albumin

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.2 Cabergoline + HES vs HES

1

200

Odds Ratio (M‐H, Fixed, 95% CI)

3.03 [0.12, 75.28]

Open in table viewer
Comparison 3. Dopamine agonist versus active interventions

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Moderate or severe ovarian hyperstimulation syndrome (OHSS) Show forest plot

6

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 3.1

Comparison 3 Dopamine agonist versus active interventions, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).

Comparison 3 Dopamine agonist versus active interventions, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).

1.1 Cabergoline vs human albumin

3

296

Odds Ratio (M‐H, Fixed, 95% CI)

0.21 [0.12, 0.38]

1.2 Cabergoline vs prednisolone

1

150

Odds Ratio (M‐H, Fixed, 95% CI)

0.27 [0.05, 1.33]

1.3 Cabergoline vs hydroxyethyl starch (HES)

1

61

Odds Ratio (M‐H, Fixed, 95% CI)

2.69 [0.48, 15.10]

1.4 Cabergoline vs coasting

2

120

Odds Ratio (M‐H, Fixed, 95% CI)

0.50 [0.18, 1.45]

2 Clinical pregnancy rate Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 3.2

Comparison 3 Dopamine agonist versus active interventions, Outcome 2 Clinical pregnancy rate.

Comparison 3 Dopamine agonist versus active interventions, Outcome 2 Clinical pregnancy rate.

2.1 Cabergoline vs human albumin

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.68 [0.33, 1.38]

2.2 Cabergoline vs coasting

2

120

Odds Ratio (M‐H, Fixed, 95% CI)

2.65 [1.13, 6.21]

3 Multiple pregnancy Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 3.3

Comparison 3 Dopamine agonist versus active interventions, Outcome 3 Multiple pregnancy.

Comparison 3 Dopamine agonist versus active interventions, Outcome 3 Multiple pregnancy.

3.1 Cabergoline vs human albumin

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.13, 2.54]

3.2 Cabergoline vs coasting

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

5.35 [0.25, 116.31]

4 Miscarriage Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 3.4

Comparison 3 Dopamine agonist versus active interventions, Outcome 4 Miscarriage.

Comparison 3 Dopamine agonist versus active interventions, Outcome 4 Miscarriage.

4.1 Cabergoline vs human albumin

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.03, 3.19]

4.2 Cabergoline vs coasting

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

0.19 [0.01, 4.06]

Study flow diagram search August 2016.
Figures and Tables -
Figure 1

Study flow diagram search August 2016.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison 1: Dopamine agonist (without co‐intervention) versus placebo/no intervention, outcome: 1.1 moderate or severe ovarian hyperstimulation syndrome.
Figures and Tables -
Figure 4

Forest plot of comparison 1: Dopamine agonist (without co‐intervention) versus placebo/no intervention, outcome: 1.1 moderate or severe ovarian hyperstimulation syndrome.

Forest plot of comparison: 2 Dopamine agonist plus co‐intervention versus co‐intervention, outcome: 2.1 Moderate or severe ovarian hyperstimulation syndrome.
Figures and Tables -
Figure 5

Forest plot of comparison: 2 Dopamine agonist plus co‐intervention versus co‐intervention, outcome: 2.1 Moderate or severe ovarian hyperstimulation syndrome.

Forest plot of comparison 3: Cabergoline versus active interventions, outcome: 3.1 moderate or severe ovarian hyperstimulation syndrome.
Figures and Tables -
Figure 6

Forest plot of comparison 3: Cabergoline versus active interventions, outcome: 3.1 moderate or severe ovarian hyperstimulation syndrome.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).
Figures and Tables -
Analysis 1.1

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 2 Subgroup analysis by severity of OHSS.
Figures and Tables -
Analysis 1.2

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 2 Subgroup analysis by severity of OHSS.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 3 Live birth.
Figures and Tables -
Analysis 1.3

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 3 Live birth.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 4 Clinical pregnancy rate.
Figures and Tables -
Analysis 1.4

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 4 Clinical pregnancy rate.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 5 Multiple pregnancy.
Figures and Tables -
Analysis 1.5

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 5 Multiple pregnancy.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 6 Miscarriage.
Figures and Tables -
Analysis 1.6

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 6 Miscarriage.

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 7 Adverse events.
Figures and Tables -
Analysis 1.7

Comparison 1 Dopamine agonist versus placebo/no intervention, Outcome 7 Adverse events.

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).
Figures and Tables -
Analysis 2.1

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 2 Live birth.
Figures and Tables -
Analysis 2.2

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 2 Live birth.

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 3 Clinical pregnancy rate.
Figures and Tables -
Analysis 2.3

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 3 Clinical pregnancy rate.

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 4 Multiple pregnancy.
Figures and Tables -
Analysis 2.4

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 4 Multiple pregnancy.

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 5 Miscarriage.
Figures and Tables -
Analysis 2.5

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 5 Miscarriage.

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 6 Adverse events.
Figures and Tables -
Analysis 2.6

Comparison 2 Dopamine agonist plus co‐intervention versus co‐intervention, Outcome 6 Adverse events.

Comparison 3 Dopamine agonist versus active interventions, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).
Figures and Tables -
Analysis 3.1

Comparison 3 Dopamine agonist versus active interventions, Outcome 1 Moderate or severe ovarian hyperstimulation syndrome (OHSS).

Comparison 3 Dopamine agonist versus active interventions, Outcome 2 Clinical pregnancy rate.
Figures and Tables -
Analysis 3.2

Comparison 3 Dopamine agonist versus active interventions, Outcome 2 Clinical pregnancy rate.

Comparison 3 Dopamine agonist versus active interventions, Outcome 3 Multiple pregnancy.
Figures and Tables -
Analysis 3.3

Comparison 3 Dopamine agonist versus active interventions, Outcome 3 Multiple pregnancy.

Comparison 3 Dopamine agonist versus active interventions, Outcome 4 Miscarriage.
Figures and Tables -
Analysis 3.4

Comparison 3 Dopamine agonist versus active interventions, Outcome 4 Miscarriage.

Summary of findings for the main comparison. Dopamine agonist versus placebo/no intervention

Dopamine agonist vs placebo/no intervention

Patient or population: women of reproductive age undergoing any ART therapy

Settings: ART unit

Intervention: dopamine agonist

Comparison: placebo/no intervention

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo/no intervention

Risk with dopamine agonist

Incidence of moderate or severe OHSS

286 per 1000

97 per 1000

(71 to 135)

OR 0.27

(0.19 to 0.39)

1022

(8 studies)

⊕⊕⊕⊝
Moderate 1

Live birth rate

509 per 1000

512 per 1000

(355 to 665)

OR 1.01

(0.53 to 1.91)

182
(1 studies)

⊕⊕⊝⊝
Low 1,2

Clinical pregnancy rate

401 per 1000

352 per 1000

(266 to 450)

OR 0.81

(0.54 to 1.22)

432

(4 studies)

⊕⊕⊕⊝
Moderate 1

Multiple pregnancy

50 per 1000

17 per 1000

(1 to 303)

OR 0.32

(0.01 to 8.26)

40
(1 study)

⊕⊝⊝⊝
Very low 1,3

Miscarriage pregnancy rate

72 per 1000

49 per 1000

(15 to 151)

OR 0.66

(0.19 to 2.28)

168

(2 studies)

⊕⊕⊝⊝
Low 1,4

Adverse events

43 per 1000

168 per 1000

(62 to 381)

OR 4.54

(1.49 to 13.84)

264
(2 studies)

⊕⊝⊝⊝
Very low 1,5

*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).

ART: assisted reproductive technology; CI: confidence interval; OHSS: ovarian hyperstimulation syndrome; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded one level for serious risk of bias associated with poor reporting of study methods.

2 Downgraded one level for serious risk of imprecision: confidence interval compatible with benefit in either arm or with no difference between the groups.

3 Downgraded two levels for very serious risk of imprecision: only one event.

4 Downgraded one level for serious risk of imprecision: only 10 events.

5 Downgraded one level for serious risk of imprecision: only 29 events.

Figures and Tables -
Summary of findings for the main comparison. Dopamine agonist versus placebo/no intervention
Comparison 1. Dopamine agonist versus placebo/no intervention

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Moderate or severe ovarian hyperstimulation syndrome (OHSS) Show forest plot

8

1022

Odds Ratio (M‐H, Fixed, 95% CI)

0.27 [0.19, 0.39]

1.1 Cabergoline vs placebo/no treatment

5

521

Odds Ratio (M‐H, Fixed, 95% CI)

0.26 [0.16, 0.42]

1.2 Quinagolide vs placebo

2

454

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.15, 0.51]

1.3 Bromocriptine vs placebo (folic acid)

1

47

Odds Ratio (M‐H, Fixed, 95% CI)

0.29 [0.08, 1.14]

2 Subgroup analysis by severity of OHSS Show forest plot

7

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Severe OHSS

7

750

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.14, 0.56]

2.2 Moderate OHSS

7

750

Odds Ratio (M‐H, Fixed, 95% CI)

0.37 [0.24, 0.57]

3 Live birth Show forest plot

1

182

Odds Ratio (M‐H, Fixed, 95% CI)

1.01 [0.53, 1.91]

3.1 Quinagolide vs placebo

1

182

Odds Ratio (M‐H, Fixed, 95% CI)

1.01 [0.53, 1.91]

4 Clinical pregnancy rate Show forest plot

4

432

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.54, 1.22]

4.1 Cabergoline vs no intervention

3

250

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.48, 1.38]

4.2 Quinagolide vs placebo

1

182

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.43, 1.54]

5 Multiple pregnancy Show forest plot

1

40

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 8.26]

5.1 Cabergoline vs placebo/no treatment

1

40

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 8.26]

6 Miscarriage Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

6.1 Cabergoline vs placebo/no treatment

2

168

Odds Ratio (M‐H, Fixed, 95% CI)

0.66 [0.19, 2.28]

7 Adverse events Show forest plot

2

264

Odds Ratio (M‐H, Fixed, 95% CI)

4.54 [1.49, 13.84]

7.1 Cabergoline vs placebo/no treatment

1

82

Odds Ratio (M‐H, Fixed, 95% CI)

2.24 [0.62, 8.14]

7.2 Quinagolide vs placebo

1

182

Odds Ratio (M‐H, Fixed, 95% CI)

16.64 [0.98, 282.02]

Figures and Tables -
Comparison 1. Dopamine agonist versus placebo/no intervention
Comparison 2. Dopamine agonist plus co‐intervention versus co‐intervention

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Moderate or severe ovarian hyperstimulation syndrome (OHSS) Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

0.57 [0.31, 1.03]

1.1 Cabergoline + albumin vs albumin

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

0.55 [0.23, 1.34]

1.2 Cabergoline + hydroxyethyl starch (HES) vs HES

2

382

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.26, 1.30]

2 Live birth Show forest plot

1

200

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.59, 1.86]

2.1 Cabergoline + HES vs HES

1

200

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.59, 1.86]

3 Clinical pregnancy rate Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.71, 1.40]

3.1 Cabergoline + albumin vs albumin

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.56, 1.96]

3.2 Cabergoline + HES vs HES

2

382

Odds Ratio (M‐H, Fixed, 95% CI)

0.98 [0.65, 1.47]

4 Multiple pregnancy Show forest plot

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

2.02 [0.18, 22.77]

4.1 Cabergoline + albumin vs albumin

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

2.02 [0.18, 22.77]

5 Miscarriage Show forest plot

3

548

Odds Ratio (M‐H, Fixed, 95% CI)

0.65 [0.30, 1.42]

5.1 Cabergoline + albumin vs albumin

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

0.33 [0.03, 3.19]

5.2 Cabergoline + HES vs HES

2

382

Odds Ratio (M‐H, Fixed, 95% CI)

0.73 [0.31, 1.68]

6 Adverse events Show forest plot

2

366

Odds Ratio (M‐H, Fixed, 95% CI)

3.03 [0.12, 75.28]

6.1 Cabergoline + albumin vs albumin

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.2 Cabergoline + HES vs HES

1

200

Odds Ratio (M‐H, Fixed, 95% CI)

3.03 [0.12, 75.28]

Figures and Tables -
Comparison 2. Dopamine agonist plus co‐intervention versus co‐intervention
Comparison 3. Dopamine agonist versus active interventions

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Moderate or severe ovarian hyperstimulation syndrome (OHSS) Show forest plot

6

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Cabergoline vs human albumin

3

296

Odds Ratio (M‐H, Fixed, 95% CI)

0.21 [0.12, 0.38]

1.2 Cabergoline vs prednisolone

1

150

Odds Ratio (M‐H, Fixed, 95% CI)

0.27 [0.05, 1.33]

1.3 Cabergoline vs hydroxyethyl starch (HES)

1

61

Odds Ratio (M‐H, Fixed, 95% CI)

2.69 [0.48, 15.10]

1.4 Cabergoline vs coasting

2

120

Odds Ratio (M‐H, Fixed, 95% CI)

0.50 [0.18, 1.45]

2 Clinical pregnancy rate Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Cabergoline vs human albumin

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.68 [0.33, 1.38]

2.2 Cabergoline vs coasting

2

120

Odds Ratio (M‐H, Fixed, 95% CI)

2.65 [1.13, 6.21]

3 Multiple pregnancy Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Cabergoline vs human albumin

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.13, 2.54]

3.2 Cabergoline vs coasting

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

5.35 [0.25, 116.31]

4 Miscarriage Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Cabergoline vs human albumin

1

140

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.03, 3.19]

4.2 Cabergoline vs coasting

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

0.19 [0.01, 4.06]

Figures and Tables -
Comparison 3. Dopamine agonist versus active interventions