Results of the previous search

Our searches on 14 November 2016 revealed 2401 reports, of which 785 were duplicates, leaving 1622 reports. After screening the title and abstract, we found 12 reports to be potentially eligible, and retrieved these reports in full text.

In the first version of our review (Wong 2017), we included four studies (Chen 2016; Ferraretti 1999; Shapiro 2011a; Shapiro 2011b). We excluded four studies: (Absalan 2013; Aflatoonian 2010; Boostanfar 2016; Yang 2015)). We classified one study as awaiting assessment because it did not clearly report the methods it used (Chandel 2016). 

For the previous version of the review, we contacted the authors of three included studies reporting on the primary outcomes Ferraretti 1999; Shapiro 2011a; Shapiro 2011b and one excluded study, Absalan 2013, for missing data. We asked the study authors about these missing data and about bias (e.g. randomisation and blinding). One author did not reply to our request for information (Absalan 2013). The remaining authors very kindly responded to our request for additional information, and we were able to include these data in our analysis.

Results of the current search

Our searches on 23 September 2020 revealed 2395 reports, of which 1127 were duplicates, leaving 1268 reports. After screening the title and abstract, we found 13 reports to be potentially eligible, and retrieved these reports in full text.

We excluded three studies: one we considered not properly randomised (Magdi 2017); one randomised women to a different intervention that was not clear from the abstract (Simon 2020); and one was not the correct study design, which was not clear from the abstract screening (Beyer 2016).

Six studies were ongoing and awaiting data (ACTRN12612000422820; ACTRN12616000643471; ISRCTN61225414; NCT02133950; NCT02570386; NCT03349905).

We contacted the authors of five studies (Aflatoonian 2018; Aghahosseini 2017; Coates 2017; Shi 2018; Stormlund 2020), included in the additional analysis regarding live birth rate after first embryo transfer for cumulative live birth rate. None of the study authors responded to our request for this additional information.

We included 11 new randomised controlled trials (RCTs) in the update.

We reassessed Chandel 2016, which was awaiting assessment from the previous version of the review (Wong 2017). We have excluded this study because we did not consider it to be properly randomised.

The current review includes 15 studies in total: four studies from the first version of the review (Chen 2016; Ferraretti 1999; Shapiro 2011a; Shapiro 2011b), and 11 new studies (Aflatoonian 2018; Aghahosseini 2017; Coates 2017; Santos‐Ribeiro 2020; Shapiro 2016; Shi 2018; Stormlund 2020; Vuong 2018; Wei 2019; Wong 2021; Zhang 2018). We included eight studies in the meta‐analyses, which are the eight primary reports of the RCTs (Chen 2016; Ferraretti 1999; Santos‐Ribeiro 2020; Shapiro 2011a; Shapiro 2011b; Vuong 2018; Wei 2019; Wong 2021).

See the study flow diagram (Figure 1) and study tables (Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies).

Study design and setting

Of the 15 studies included in the systematic review, eight were the primary reports of the RCTs and had data on primary and secondary outcomes and therefore included in the meta‐analysis. Six of these eight were single‐centre studies, conducted in reproductive medical centres in Belgium, Italy, the Netherlands, USA and Vietnam (Ferraretti 1999; Santos‐Ribeiro 2020; Shapiro 2011a; Shapiro 2011b; Vuong 2018; Wong 2021), and two were multicentre studies conducted in reproductive medical centres throughout China (Chen 2016; Wei 2019).

We included two studies for secondary outcomes (Shapiro 2016; Zhang 2018). Both studies are follow‐up studies of included RCTs. Shapiro 2016 reports on the follow‐up data of Shapiro 2011a and Shapiro 2011b. Zhang 2018 reports on the follow‐up data of Chen 2016.

Thirteen studies supplied data for the additional analysis – live birth after a first embryo transplant (Aflatoonian 2018; Aghahosseini 2017; Chen 2016; Coates 2017; Ferraretti 1999; Santos‐Ribeiro 2020; Shapiro 2011a; Shapiro 2011b; Shi 2018; Stormlund 2020; Vuong 2018; Wei 2019; Wong 2021).

Participants

The eight studies reporting on the primary outcome enrolled a total of 4712 women, with 2342 women undergoing the 'freeze all' strategy and 2370 women undergoing the conventional IVF/ICSI strategy with fresh embryo transfer.

Ferraretti 1999 and Santos‐Ribeiro 2020 evaluated the 'freeze all' strategy in the context of prevention of OHSS. Shapiro 2011a; Shapiro 2011b; Vuong 2018; Wei 2019 and Wong 2021 evaluated the 'freeze all' strategy in the context of an offered approach to improve susceptibility of the endometrium. Chen 2016 evaluated the 'freeze all' strategy in the context of both an offered approach to improve susceptibility of the endometrium and prevention of OHSS.

The inclusion criteria of the two Shapiro studies were based on the number of antral follicles observed at baseline ultrasound examination: Shapiro 2011a included normal responders (8 to 15 antral follicles), and Shapiro 2011b included high responders (> 15 antral follicles). Ferraretti 1999 included women at risk of developing OHSS, based on level of estradiol (E2) and number of retrieved eggs (≥ 15 oocytes). Santos‐Ribeiro 2020 included women with an excessive response to ovarian stimulation (≥ 18 follicles measuring ≥ 11 mm on the day of the GnRH triggering). Chen 2016 included women with polycystic ovary syndrome. Vuong 2018 and Wei 2019 included women without polycystic ovary syndrome. Wong 2021 included women with any IVF indication, independent of the number of follicles or available embryos.

In all studies, the baseline characteristics were comparable between the two strategies.

The ages of the women included by Shapiro 2011a and Shapiro 2011b ranged from 18 to 41 years. The mean age for the women included in Ferraretti 1999 ranged from 31.4 to 31.6 years. Women in Chen 2016 were between the ages of 20 and 34 years. The mean age of women in Vuong 2018 was 32 years. In Wei 2019 the mean age of the participants was 28.8 years. The mean age for the women included in Santos‐Ribeiro 2020 ranged from 30.4 to 31.2 years. The mean age for the women included in Wong 2021 ranged from 35.1 to 35.2 years. 

For details about the extra studies used for additional analysis (Aflatoonian 2018; Aghahosseini 2017; Coates 2017; Shi 2018; Stormlund 2020), see Characteristics of included studies.

Interventions

In Chen 2016, women received recombinant FSH at a daily dose of 112.5 IU for those weighing less than 60 kg and 150 IU for those weighing over 60 kg starting on day 2 or 3 of the menstrual cycle. This was adjusted following ovarian response. hCG could be added when considered appropriate. On the day of oocyte retrieval, women had to have more than 3 and fewer than 30 oocytes with a low risk of OHSS to be randomised. Intramuscular progesterone at a daily dose of 80 mg was administered for luteal‐phase support in the fresh‐transfer group. Embryos were cryopreserved at day 3 of development. Oral oestradiol valerate was used for endometrial preparation on day 2 or 3 of the second menstrual cycle after oocyte retrieval. Intramuscular progesterone (80 mg/day) was added when endometrial thickness reached 8 mm or more or at the physician’s discretion. On day 4 of progesterone administration, two day‐3 frozen embryos were thawed and transferred. Luteal‐phase support with oestradiol valerate and intramuscular progesterone for endometrium preparation continued until 10 weeks after conception.

Women in Ferraretti 1999 received a down‐regulation protocol with gonadotropin‐releasing hormone (GnRH) analogue (0.3 mg subcutaneous buserelin acetate (Suprefact) twice a day) and ovarian stimulation with urinary gonadotropin (4 ampoules of follicle‐stimulating hormone (FSH) on the first and second days of treatment, and 2 ampoules of FSH plus 2 ampoules of human menopausal gonadotropins on the third and fourth treatment days). This was followed by an adjusted dosage of gonadotropins according to the individual response measured by plasma concentration of E2 and follicular growth assessed by ultrasound (Ferraretti 1996). Human chorionic gonadotropin (hCG) was administered 34 to 36 hours before follicle aspiration followed by 20 g of intravenous albumin. Embryos were frozen at the pronuclear stage. All embryos were transferred at the early cleavage stage (day 3) in artificial cycles. The artificial cycle treatment included oral administration of oestradiol valerate, 2 mg daily for the first 5 days of the cycle; 4 mg/day from day 6 to day 10; 6 mg/day from day 11 to day 13; then 4 mg/day from day 14 onward. On day 15 of the cycle, 50 mg of progesterone in oil was administered daily, and on day 17 the dose was increased to 100 mg/day.

In women in Santos‐Ribeiro 2020, ovarian stimulation commenced after confirmation that the woman was not pregnant and that she had basal serum levels of estradiol (< 80 pg/mL) and progesterone (< 1.5 ng/mL). Treating physicians decided which exogenous gonadotropins should be used according to the woman’s profile and preference, including either recombinant FSH (Gonal‐FVR or Puregon) or highly purified urinary human menopausal gonadotropins (MenopurVR). All women included underwent exogenous ovarian stimulation using GnRH antagonist suppression from day 6 of stimulation onwards with daily injections of either ganirelix or cetrorelix. Final oocyte maturation was triggered with 0.2 mg triptorelin as soon as at least three follicles of larger than 17 mm were observed. A GnRH agonist was the preferred triggering agent for both groups in order to avoid the elevated risk of OHSS associated with hCG triggering in high responders. Oocyte retrieval was performed approximately 36 hours after the GnRH agonist administration. In the fresh transfer arm, following oocyte retrieval, intensified luteal phase support was provided with a single administration of 1500 IU of exogenous hCG approximately one hour after oocyte retrieval followed by 200 mg of vaginal micronized progesterone (UtrogestanVR) three times a day plus 2 mg of oral estradiol valerate (ProgynovaVR) twice daily. The embryo transfer was performed on day 3 or 5 of development with preference to the latter whenever at least four good‐quality embryos were available on day 3. The choice to transfer one or two embryos was decided by the clinician at consultation prior to commencing the ART treatment, mainly depending on the woman’s age and the number of embryos replaced in the previous treatment cycles, according to Belgian law. All remaining good‐quality embryos were vitrified. In the 'freeze all' arm, no fresh luteal phase support was provided following oocyte retrieval. Instead, all viable embryos were vitrified, preferably at blastocyst stage (day 5 or 6), according to the same, before‐mentioned threshold of good‐quality embryos available on day 3. Women started with exogenous hormone therapy for endometrial preparation in the next cycle. This therapy was initiated only after confirmation that the woman had basal serum levels of estradiol/progesterone and consisted of 2 mg of oral estradiol valerate (ProgynovaVR ) twice daily for seven days followed by three times a day for another six days. Endometrial development was assessed using ultrasound and if the endometrium was 7 mm or more, 200 mg of vaginal Utrogestan three times a day was added to the treatment scheme. The frozen embryo transfer was scheduled according to the developmental stage of the embryo.

In Shapiro 2011a and Shapiro 2011b, women received down‐regulation with a GnRH antagonist and a combination of recombinant FSH and highly purified urinary FSH. hCG was administered 34 to 36 hours prior to follicle aspiration. In those women with greater ovarian response, 4 mg leuprolide acetate was added concomitant to the hCG. Embryos were vitrified at the pronuclear stage. All embryos were transferred as blastocysts in artificial cycles. Women with fresh embryo transfers received 6.0 mg daily E2 and daily progesterone injections (100 mg), with progesterone supplementation beginning one to two days after follicle aspiration and E2 initiated as needed. Women with cryopreserved embryo transfers were down‐regulated with leuprolide acetate in a subsequent cycle and received oral 6.0 mg daily E2 and E2 patches as needed starting 10 to 14 days before thawing to achieve a target endometrial thickness of at least 8 mm. Daily progesterone injections (typically 100 mg) were started the day before thawing. In both groups, E2 and progesterone supplements were adjusted as needed to sustain serum levels of at least 200 pg/mL and 15 ng/mL, respectively, until increasing serum levels indicated placental production, at 9 to 10 weeks’ gestation.

Women in Vuong 2018 underwent ovarian hyperstimulation according to the protocol for the use of FSH and GnRH antagonists. The dose of recombinant FSH ranged from 150 to 300 IU per day, depending on the woman’s age, anti‐Müllerian hormone levels, and response to FSH in any prior IVF cycle. When the mean diameter of at least two leading follicles was 17 mm, 250 μg of recombinant hCG was administered, and oocyte retrieval was performed 36 hours later. Embryos were cryopreserved at day 3 of development. In the following cycle, the endometrium was prepared with the use of oral estradiol valerate at a dose of 8 mg per day, starting on the second or third day of the menstrual cycle. Endometrial thickness was monitored from day 6 onward, and vaginal progesterone at a dose of 800 mg per day was started when the endometrial thickness reached 8 mm or more. A maximum of two embryos of grade 1 or 2 were thawed on the day of embryo transfer, three days after the start of progesterone. Luteal‐phase support with oestradiol valerate and vaginal progesterone for endometrium preparation continued until seven weeks after conception.

In Wei 2019 women were given GnRH antagonist (ganirelix) regimen for ovarian stimulation. Recombinant FSH (Puregon) was started on day 1 to 3 of the menstrual cycle. When at least two follicles were 18 mm or greater in mean diameter, hCG at a dose of 4000 IU to 10000 IU was administered to induce the final maturation of oocytes. Oocyte retrieval was done 34 hours to 36 hours after hCG injection. Luteal phase support was started from the day of oocyte retrieval with vaginal progesterone gel (Crinone) 90 mg per day and oral dydrogesterone (Duphaston) 10 mg twice daily. On day 3 of embryo culture, embryos were graded by morphological criteria. Women who had four or more high‐grade embryos were randomly assigned to the fresh or frozen blastocyst transfer group. In the 'freeze all' group, luteal phase support was stopped after randomisation. On day 3, embryos were removed from cleavage media and replaced in blastocyst media. All blastocysts were vitrified on day 5 or day 6 according to embryo development. At least 4 weeks later, the endometrium was prepared either with a natural cycle regimen or artificial cycle regimen, at the discretion of local investigators. For the natural ovulatory cycle regimen, ovulation was determined by ultrasound monitoring. Oral dydrogesterone (Duphaston) 10 mg three times daily was administered for luteal phase support after ovulation. A single cryopreserved blastocyst was transferred on the fifth day after ovulation. If pregnancy was achieved, luteal phase support was continued until 10 weeks’ gestation. For the artificial cycle regimen, oral oestradiol valerate (Progynova) at a dose of 4 mg to 8 mg daily was started on day 1 to 3 of the menstrual cycle. Vaginal progesterone gel (Crinone) 90 mg per day and oral dydrogesterone 10 mg twice daily were added when the endometrial thickness reached 7 mm or more. A single frozen‐thawed blastocyst was transferred on the fifth day after progesterone initiation. If pregnancy was achieved, oral oestradiol valerate was continued until eight weeks’ gestation, and vaginal progesterone gel and oral dydrogesterone were continued until 10 weeks’ gestation.

Women in Wong 2021 underwent pituitary downregulation with a long GnRH agonist protocol with or without oral contraceptive pill pre‐treatment. Ovarian stimulation was conducted with human menopausal gonadotrophin (Menopur) or recombinant FSH (Puregon or Gonal‐F) in women with polycystic ovary syndrome starting from the seventh day without oral contraceptive pill pre‐treatment. The starting dose depended on the antral follicle count. Ovarian stimulation was continued until three or more follicles with a diameter of 18 mm had developed. Ovulation was triggered with 5000 or 10,000 IU hCG (Pregnyl). A single embryo transfer was performed for women below 38 years of age and a double embryo transfer policy for women of 38 years of age and above, if two or more embryos were available. Embryos were cryopreserved on day 6 of culture. Women started with oral oestrogen supplementation of 6 mg daily on the first day of their first menstruation after the follicular aspiration. If the endometrium had reached 8 mm, women started vaginal progesterone of 600 mg daily and continued the oral oestrogen. At the seventh day of vaginal progesterone administration, the cryopreserved embryo transfer was performed. If pregnancy occurred, oestrogen and progesterone supplementation was continued until the eleventh week of gestation.

Outcomes

Data were extracted from study reports or provided by authors for the following outcomes.

Awaiting classification

Currently there are no studies awaiting classification.

Ongoing studies

We identified six ongoing studies from trials registers that may have results for inclusion in future versions of this review (ACTRN12612000422820; ACTRN12616000643471; ISRCTN61225414; NCT02133950; NCT02570386; NCT03349905). Note that studies that we did not include studies that were registered in the trials registers but that were not started or that were withdrawn or stopped.

Sequence generation

Ferraretti 1999 did not describe the method of randomisation in the published article, but replied in a personal communication that the method of randomisation was performed with random sealed envelopes; we judged this study to be at unclear risk of this bias. Shapiro 2011a and Shapiro 2011b did not report on the method for random sequence generation; we judged these two studies at unclear risk of bias.

Sequence generation in Chen 2016 was well described; an online central randomisation system was used. We considered risk of selection bias related to sequence generation to be low. Vuong 2018 performed sequence generation randomly by an independent study co‐ordinator by means of block randomisation using a computer‐generated random list and therefore we considered risk of selection bias related to sequence generation to be low. Risk of selection bias related to sequence generation in Wei 2019 was also considered low based on the use of block randomisation using a computer‐generated random list. Santos‐Ribeiro 2020 randomised women by means of a computer‐generated randomisation list. Wong 2021 randomised women with an online randomisation program using block randomisation with a maximum block size of 6, stratified for age (18 years through 35 and 35 through 43 years) and study centre. Couples were allocated in a 1:1 ratio to the 'freeze all' strategy or the conventional strategy. We judged these two studies at low risk of bias.

Allocation concealment

Shapiro 2011a and Shapiro 2011b performed allocation concealment by drawing randomly among identical, opaque, unmarked, sealed envelopes, and we therefore judged both studies to be at low risk of selection bias related to allocation concealment. Chen 2016 used an online central randomisation system (www.medresman.org) to generate the assignment sequence automatically, which was unknown to the clinical investigators. Santos‐Ribeiro 2020 sealed each entry of the list in a sequentially numbered opaque envelope and allocated participants in that order. Participating physicians did not have access to the randomisation list. Wei 2019 used a sequence that was entered into their central online database, secured by username and password log‐in. Wong 2021 used a randomisation program to generate a unique study number with allocation code after entry of the participant’s date of birth and randomisation date. We also judged these four studies to be at low risk of bias.

The first author of the Ferraretti 1999 study provided additional information on allocation concealment. This study performed participant allocation by sealed envelopes, and we therefore judged it to be unclear risk of bias for this domain. Vuong 2018 randomised patients by means of block randomisation by an independent study co‐ordinator using a computer‐generated random list, there was no further explanation about allocation concealment. We also judged this study to be at unclear risk of bias.

Performance bias

Blinding of doctors and participants was not possible due to the nature of the intervention. Therefore the risk of performance bias was low in all eight studies.

Detection bias

As described in the Methods section, blinding of the participant or the clinician is technically not possible due to the nature of the intervention in this study design. We felt that lack of blinding was not likely to influence findings for the primary outcomes live birth or OHSS. The risk of performance bias was low in all eight studies.

1.1 Effectiveness: cumulative live birth rate per woman

All studies included in the meta‐analysis collected data on cumulative live birth rates (Chen 2016; Ferraretti 1999; Santos‐Ribeiro 2020; Shapiro 2011a; Shapiro 2011b; Vuong 2018; Wei 2019; Wong 2021).

There is probably little or no difference between the 'freeze all' strategy and the conventional IVF/ICSI strategy in cumulative live birth rate (OR 1.08, 95% CI 0.95 to 1.22; I² = 0%; 8 RCTs, 4712 women; moderate‐quality evidence). The evidence suggests that for a cumulative live birth rate of 58% following the conventional strategy, the cumulative live birth rate following the 'freeze all' strategy would be between 57% and 63%. 

As there was no indication of statistical heterogeneity an identical estimate for the OR was found when using the random‐effects model. The corresponding RR was 1.03 (95% CI 0.99 to 1.08; Table 2). A sensitivity analysis including only studies without risk of selection bias (Chen 2016; Santos‐Ribeiro 2020; Vuong 2018; Wei 2019; Wong 2021), found a comparable result (OR 1.09, 95% CI 0.95 to 1.23; I² = 0%; 4 RCTs, 4328 women). A sensitivity analysis adopting a random‐effects model or using risk ratio did not lead to a change in result.

There is also probably no difference between the two strategies in cumulative live birth rate when the studies are analysed per cleavage stage (OR 1.09, 95% CI 0.93 to 1.29; I² = 0%; 3 RCTs, 2415 women; moderate‐quality evidence) or blastocyst transfer stage (OR 1.06, 95% CI 0.88 to 1.27; I² =14%; 5 RCTs, 2297 women; moderate‐quality evidence; Analysis 1.1; Figure 4).

Figure 4

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Forest plot of comparison 1. Freeze‐all versus conventional IVF, outcomes per woman, outcome 1.1 live birth rate

1.2 Safety: ovarian hyperstimulation syndrome (OHSS) per woman

Two studies reported on OHSS per woman if hospitalisation was required (Ferraretti 1999; Wong 2021). Two studies did not report on OHSS (Shapiro 2011a; Shapiro 2011b), but we were able to obtain these data by personal communication with the authors. However, we did not include the data from these two studies in the analysis, as women with high risk of OHSS were excluded and received the 'freeze all' strategy as standard. Chen 2016; Santos‐Ribeiro 2020; Vuong 2018 and Wei 2019 reported these data. The risk for developing OHSS may be lower after the 'freeze all' strategy compared to the conventional IVF/ICSI strategy (Peto OR 0.26, 95% CI 0.17 to 0.39; I² = 0%; 6 RCTs, 4478 women; low‐quality evidence; Analysis 1.2; Figure 5). As there was no indication of statistical heterogeneity, we found an identical estimate for the OR when using the random‐effects model. The corresponding RR was 0.25 (95% CI 0.14 to 0.44; Table 2). A sensitivity analysis including only studies without risk of selection bias (Chen 2016; Santos‐Ribeiro 2020; Vuong 2018; Wei 2019; Wong 2021), found a comparable result (OR 0.27, 95% CI 0.18 to 0.40; I² = 12%; 5 RCTs, 4354 women). A sensitivity analysis adopting a random‐effects model or using risk ratio did not lead to a change in result.

Figure 5

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Forest plot of comparison 1. Freeze‐all versus conventional IVF, outcomes per woman, outcome 1.2 ovarian hyperstimulation syndrome (OHSS)

1.3 Ongoing pregnancy rate per woman

Four studies reported on the cumulative ongoing pregnancy rates (Shapiro 2011a; Shapiro 2011b; Vuong 2018; Wong 2021). There was probably little or no difference between the two strategies in the cumulative ongoing pregnancy rate (OR 0.95, 95% CI 0.75 to 1.19; I² = 31%; 4 RCTs, 1245 women; moderate‐quality evidence; Analysis 1.3). 

1.4 Clinical pregnancy rate per woman

Four studies reported on cumulative clinical pregnancy rate (Ferraretti 1999; Santos‐Ribeiro 2020; Vuong 2018; Wong 2021). There may be no difference between the two strategies in clinical pregnancy rate though the confidence interval of the estimate (OR 0.92, 95% CI 0.72 to 1.16; I² = 35%; 4 RCTs; 1320 women; low‐quality evidence; Analysis 1.4).

1.5 Ectopic pregnancy rate

Two studies reported on the cumulative ectopic pregnancy rate (Vuong 2018; Wong 2021). We are uncertain whether there is a difference between the two strategies in cumulative ectopic pregnancy rate (Peto OR 0.61, 95% CI 0.31 to 1.22; I² = 0%; 2 RCTs. 986 women; low‐quality evidence; Analysis 1.5).

Five studies reported on ectopic pregnancy rate after the first embryo transfer (Chen 2016; Ferraretti 1999; Vuong 2018; Wei 2019; Santos‐Ribeiro 2020). We are uncertain whether there is a difference between the two strategies in ectopic rate after the first embryo transfer (Peto OR 0.64, 95% CI 0.39 to 1.06; I² = 0%; 5 RCTs, 4274 women; low‐quality evidence; Analysis 1.5).

1.6 Miscarriage rate

Two studies reported on the cumulative miscarriage rate (Vuong 2018; Wong 2021). We are uncertain whether the two strategies differ in cumulative miscarriage rate (Peto OR 1.06, 95% CI 0.72 to 1.55; I² = 55%; 2 RCTs, 986 women; very low‐quality evidence; Analysis 1.6).

All eight studies reported on miscarriage rate after the first embryo transfer (Chen 2016; Ferraretti 1999; Santos‐Ribeiro 2020; Shapiro 2011a; Shapiro 2011b; Vuong 2018; Wei 2019; Wong 2021). We are uncertain about the existence of a difference between the two strategies in miscarriage rate after the first embryo transfer (Peto OR 0.90, 95% CI 0.76 to 1.07; I² = 64%; 8 RCTs, 4569 women; very low‐quality evidence; Analysis 1.6).

1.7 Multiple pregnancy rate

Two studies reported on the cumulative multiple‐pregnancy rate (Vuong 2018; Wong 2021). We are uncertain whether the two strategies differ in cumulative multiple‐pregnancy rate (Peto OR 0.88, 95% CI 0.61 to 1.25; I² = 63%; 2 RCTs. 986 women; very low‐quality evidence; Analysis 1.7).

Five studies reported on multiple‐pregnancy rate after the first embryo transfer (Chen 2016; Shapiro 2011b; Vuong 2018; Wei 2019; Wong 2021). We are uncertain whether the two strategies differ in multiple‐pregnancy rate after the first embryo transfer (Peto OR 1.18, 95% CI 0.96 to 1.45; I² = 45%; 5 RCTs, 4266 women; very low‐quality evidence; Analysis 1.7).

1.8 Gestational diabetes

One study reported the cumulative rates of gestational diabetes (Vuong 2018), therefore pooling was not possible. We are uncertain whether the two strategies differ in cumulative rates of gestational diabetes (Peto OR 0.83, 95% CI 0.36 to 1.94; 1 RCT, 782 women; low‐quality evidence; Analysis 1.8).

Three studies reported on the rate of gestational diabetes after the first embryo transfer (Vuong 2018; Wei 2019; Zhang 2018). We are uncertain whether the two strategies differ in gestational diabetes after the first embryo transfer (Peto OR 1.34, 95% CI 0.96 to 1.86; I² = 20%; 3 RCTs, 3940 women; low‐quality evidence; Analysis 1.8).

1.9 Hypertensive disorders of pregnancy

One study reported the cumulative rates of hypertensive disorders of pregnancy (Vuong 2018), therefore pooling was not possible. We are uncertain whether the two strategies differ in cumulative rates of hypertensive disorders of pregnancy (Peto OR 0.70, 95% CI 0.27 to 1.82; 1 RCT, 782 women; low‐quality evidence; Analysis 1.9; Figure 6).

Figure 6

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Forest plot of comparison: 1 Freeze‐all versus conventional IVF, outcomes per woman, outcome 1.9 hypertensive disorders of pregnancy

Three studies reported on the rate of hypertensive disorders of pregnancy after the first embryo transfer (Chen 2016; Vuong 2018; Wei 2019). The risk of hypertensive disorders might be increased following the 'freeze all' strategy (Peto OR 2.15, 95% CI 1.42 to 3.25; I² = 29%; 3 RCTs, 3940 women; low‐quality evidence; Analysis 1.9; Figure 6).

1.10 Preterm delivery (less than 37 weeks of gestational age)

Two studies reported the cumulative rates of preterm delivery (Vuong 2018; Wong 2021). We are uncertain whether the two strategies differ in cumulative rates of preterm delivery (Peto OR 0.62, 95% CI 0.39 to 0.99; I² = 0%; 2 RCTs, 986 women; low‐quality evidence; Analysis 1.10).

Three studies reported on the rate of preterm delivery after the first embryo transfer (Chen 2016; Vuong 2018; Wei 2019). We are uncertain whether the two strategies differ in preterm delivery after the first embryo transfer (Peto OR 1.15, 95% CI 0.89 to 1.50; I² = 0%; 3 RCTs, 3940 women; low‐quality evidence; Analysis 1.10).

1.11 Perinatal and neonatal death

One study reported the cumulative rates of perinatal and neonatal death (Vuong 2018), therefore pooling was not possible. Based on results from this solitary study (not meta‐analysis) we are uncertain whether the two strategies differ in cumulative rates of perinatal and neonatal death (Peto OR 0.13, 95% CI 0.01 to 1.30; 1 RCT, 782 women; very low‐quality evidence; Analysis 1.11).

Two studies reported on the rate of perinatal and neonatal death after the first embryo transfer (Chen 2016; Vuong 2018). We are uncertain whether the two strategies differ in perinatal and neonatal death after the first embryo transfer (Peto OR 2.27, 95% CI 0.65 to 7.84; I² = 88%; 2 RCTs, 2290 women; very low‐quality evidence; Analysis 1.11).

1.12 Neonatal hospitalisation (for more than three days or NICU admission)

One study reported the cumulative rates of neonatal hospitalisation (Vuong 2018), therefore pooling was not possible. We are uncertain whether the two strategies differ in cumulative rates of neonatal hospitalisation (Peto OR 1.00, 95% CI 0.29 to 3.48; 1 RCT, 782 women; very low‐quality evidence; Analysis 1.12).

Three studies reported on the rate of neonatal hospitalisation after the first embryo transfer (Vuong 2018; Wei 2019; Zhang 2018). We are uncertain whether the two strategies differ in neonatal hospitalisation after the first embryo transfer (Peto OR 1.37, 95% CI 1.07 to 1.75; I² = 0%; 3 RCTs, 3940 women; low‐quality evidence; Analysis 1.12).

1.13 Large for gestational age (birth weight above 90th percentile)

One study reported the cumulative rates of large‐for‐gestational‐age babies (Vuong 2018). Based on the results from this solitary study we are uncertain whether the two strategies differ in cumulative rates of having a large‐for‐gestational‐age baby (Peto OR 1.97, 95% CI 0.63 to 6.15; 1 RCT, 782 women; low‐quality evidence; Analysis 1.13; Figure 7).

Figure 7

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Forest plot of comparison 1. Freeze‐all versus conventional IVF, outcomes per woman, outcome 1.13 large for gestational age (birth weight above 90th percentile)

Three studies reported on the rate of large for gestational age after the first embryo transfer (Vuong 2018; Wei 2019; Zhang 2018). Based on these studies the risk of having a large‐for‐gestational‐age baby might be increased following the 'freeze all' strategy (Peto OR 1.96, 95% CI 1.51 to 2.55; I² = 0%; 3 RCTs, 3940 women; low‐quality evidence; Analysis 1.13; Figure 7).

1.14 Small for gestational age (birth weight below 10th percentile)

One study reported the cumulative rates of small for gestational age babies (Vuong 2018), therefore pooling was not possible. The results of this solitary study suggest that the cumulative risk of having a small‐for‐gestational‐age baby might be lower following the 'freeze all' strategy (Peto OR 0.36, 95% CI 0.16 to 0.80; 1 RCT, 782; low‐quality evidence; Analysis 1.14; Figure 8).

Figure 8

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Forest plot of comparison 1. Freeze‐all versus conventional IVF, outcomes per woman, outcome 1.14 small for gestational age (birth weight below 10th percentile)

Three studies reported on the rate of small for gestational age after the first embryo transfer (Vuong 2018; Wei 2019; Zhang 2018). We are uncertain whether the two strategies differ in the risk of having a small‐for‐gestational‐age baby after the first embryo transfer (Peto OR 0.82, 95% CI 0.65 to 1.05; I² = 64%; 3 RCTs, 3940 women; very low‐quality evidence; Analysis 1.14; Figure 8).

1.15 Congenital abnormalities

Three studies reported on congenital abnormalities (Chen 2016; Wei 2019; Wong 2021). We are uncertain whether the two strategies differ in rates of congenital abnormalities per live‐born children plus number of foetuses therapeutically terminated (OR 1.08, 95% CI 0.65 to 1.78; I² = 0%; 3 RCTs, 1789 live‐born children plus number of foetuses therapeutically terminated; low‐quality evidence; Analysis 1.15).

1.16 Birth weight

Five studies reported on birth weight (Chen 2016; Shapiro 2016; Vuong 2018; Wei 2019; Wong 2021). The risk for having a higher birth weight of singleton babies born is probably increased following the 'freeze all' strategy (MD 127 g, 95% CI 77.1 to 177.8; I² = 0%; 5 RCTs, 1607 singletons; moderate‐quality evidence).

We are uncertain whether birth weight of multiples is higher in the 'freeze all' strategy compared to the conventional IVF/ICSI strategy (MD 49.5, 95% CI −21.2 to 120.1; I² = 17%; 4 RCTs, 804 children born from multiples; low‐quality evidence; Analysis 1.16; Figure 9).

Figure 9

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Forest plot of comparison 1. Freeze‐all versus conventional IVF, outcomes per woman, outcome 1.16 birth weight of babies born

Wong 2021 had three twin live‐born in the conventional IVF strategy and none in the 'freeze all' strategy and could therefore not be pooled in the analysis.