What is the best therapy for women who produce too many eggs when having fertility treatment?

Key messages

– We do not know if in vitro maturation (growing immature eggs outside the body until they are mature enough for fertilisation) is better than in vitro fertilisation (treatment where eggs are fertilised with sperm in a laboratory) in increasing live births and pregnancies in women with polycystic ovarian syndrome (where the ovaries do not produce eggs properly) who undergo fertility treatment.

– In vitro maturation increases miscarriage and reduces ovarian hyperstimulation syndrome (painful condition where the ovaries produce too many eggs) in women with polycystic ovarian syndrome compared to in vitro fertilisation.

– There is little to no difference in premature births (before the due date) and the baby's development while in the womb, but more studies are needed.

What is the problem?

Women who have difficulty getting pregnant (reduced fertility) may need treatment to increase their chances of conceiving. This is where women take medication to stimulate egg growth, the eggs are removed and fertilised with sperm in a laboratory, and the fertilised egg is returned to the woman's womb. This is called in vitro fertilisation. Some women with reduced fertility have ovaries that do not produce eggs properly (called polycystic ovarian syndrome). If these women take medication to stimulate egg growth, they may produce too many eggs (called ovarian hyperstimulation syndrome). This causes the ovaries to swell and become painful and may cause serious illness or (rarely) death. When women with polycystic ovarian syndrome take medications to stimulate their ovaries, the eggs produced are often too immature to be fertilised by sperm, leading to low pregnancy rates.

Women with polycystic ovarian syndrome may benefit from the earlier retrieval of eggs if the eggs are matured in the laboratory before they are fertilised (called in vitro maturation). While successful pregnancies have been reported, there is concern about the health of the babies born.

What did we want to find out?

We wanted to know if in vitro maturation is beneficial or harmful compared to in vitro fertilisation techniques in women with reduced fertility and polycystic ovarian syndrome.

What did we do?

We searched for studies investigating in vitro maturation and in vitro fertilisation techniques in women with reduced fertility and polycystic ovarian syndrome. We compared and summarised the results of these studies and rated our confidence in the evidence based on factors such as study method and size. We were interested in live births (delivery of a live baby after 20 weeks of pregnancy), miscarriage (loss of pregnancy during the first 20 weeks of pregnancy), clinical pregnancy (a fetal heartbeat on ultrasound scan at seven weeks of pregnancy), ovarian hyperstimulation, premature births, and the baby's development while in the womb.

What did we find?

We found four studies. Two provided insufficient data, but the other two published their results in full. These two studies involved 810 women.

Main results

Live birth rate was similar between in vitro maturation and in vitro fertilisation, but our confidence in the evidence is very low (2 studies, 739 women). If 45 women out of 100 have a live birth following in vitro fertilisation, the chance with in vitro maturation would be between 13 and 53 women out of 100.

In vitro maturation increases miscarriage compared to in vitro fertilisation (2 studies, 378 women). If 20 women out of 100 have a miscarriage following in vitro fertilisation, the chance with in vitro maturation would be between 20 and 40 women out of 100.

In vitro maturation results in a large reduction in ovarian hyperstimulation syndrome (2 studies, 739 women). If 4 women out of 100 have ovarian hyperstimulation syndrome with in vitro fertilisation, the chance with in vitro maturation would be between 0 and 2 women out of 100.

There may be little to no difference in clinical pregnancy, but our confidence in the evidence is very low (2 studies, 739 women). In vitro maturation probably results in little to no difference in premature birth (2 studies, 739 women) and our confidence in the evidence is very low about the baby's health, development, or genetics while in the womb (1 study, 351 women).

What are the limitations of the evidence?

There is still uncertainty about the effect of in vitro maturation on live births and clinical pregnancies compared to in vitro fertilisation because the study methods differed and did not include enough women to provide meaningful results. We are confident that in vitro maturation increases the chance of miscarriage, and reduces the possibility of ovarian hyperstimulation syndrome.

We are moderately confident in the evidence for premature birth due to the small number of women enrolled and have little confidence in the evidence for the baby's health, development, or genetics while in the womb due to the small number of women enrolled in only one study. These findings should be interpreted with caution.

How up to date is the evidence?

We reviewed the evidence up to February 2023. This is the third update of this review.

Authors' conclusions: 

There is continuous scientific interest in IVM, and promising data have been published. Concerning live birth and clinical pregnancy, we are very uncertain about the effect of the technique when compared to IVF after using a GnRH antagonist protocol. In contrast, high-certainty evidence shows that IVM increases miscarriage per clinical pregnancy and reduces the incidence of moderate or severe OHSS in women with PCOS compared to IVF after a GnRH antagonist protocol.

Regarding the rest of the outcomes, low- to moderate-certainty evidence showed little to no difference in preterm birth and risk of congenital anomalies between the two modalities. We eagerly anticipate further evidence from high-quality trials in the field (we found five ongoing trials).

Read the full abstract...
Background: 

Polycystic ovarian syndrome (PCOS) occurs in 8% to 13% of all women of reproductive age and 50% of women presenting with infertility (i.e. inability to reach a pregnancy after 12 months or more of regular unprotected sexual intercourse). A proportion of these women ultimately need assisted reproductive technology. In vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) are assisted reproduction techniques used to raise the chances of a pregnancy. In women with PCOS, the supra-physiological doses of gonadotrophins used for controlled ovarian hyperstimulation (COH) often result in an exaggerated ovarian response characterised by the development of a large cohort of follicles of uneven quality, retrieval of immature oocytes, and increased risk of ovarian hyperstimulation syndrome (OHSS). A potentially effective intervention for women with PCOS-related infertility involves earlier retrieval of immature oocytes at the germinal-vesicle stage followed by in vitro maturation (IVM). This is the third update of this Cochrane review on the subject (after the last update on 27 June 2018).

Objectives: 

To assess the benefits and harms of IVM followed by IVF or ICSI versus conventional IVF or ICSI among women with PCOS.

Search strategy: 

On 27 February 2023, we searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, and the Open Grey database. We further searched the National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We also searched reference lists of relevant papers and Google Scholar for any additional trials.

Selection criteria: 

We included randomised controlled trials (RCTs) comparing IVM before IVF or ICSI with conventional IVF or ICSI for infertile women with PCOS, irrespective of language and country of origin.

Data collection and analysis: 

Two review authors independently selected studies, assessed the risk of bias, extracted data from studies, and, where needed, attempted to contact the authors for missing data. Our primary outcomes were live birth per woman randomised and miscarriage. We performed statistical analysis using Review Manager. We assessed the certainty of the evidence using GRADE and the risk of bias using the Cochrane RoB 2 tool.

Main results: 

We found four published trials suitable for inclusion in this update. The studies involved 810 subfertile women undergoing assisted reproductive technology. Two of four were already included in the previous version of the review, were published as abstracts in international conferences, and were at high risk of bias. The two new studies were at low risk of bias in all domains and in terms of all outcomes. We implemented the random-effects model for the quantitative analyses and restricted the primary analysis to studies at low risk of bias in all domains.

We are very uncertain about the effect of IVM or capacitation IVM (a new biphasic IVM system improving the developmental competence of oocytes) on live birth when compared to IVF when a GnRH antagonist protocol was applied (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.17 to 1.32; I2 = 91%; 2 studies, 739 participants; very low-certainty evidence). This suggests that if the chance of live birth following standard IVF is assumed to be 45.7%, then the chance of IVM would be 12.5% to 52.6%. In contrast, IVM or capacitation IVM increases miscarriage per clinical pregnancy (where clinical pregnancy was defined as evidence of a fetal heart beat on ultrasound at seven gestational weeks) in women with PCOS when compared to IVF (OR 1.66, 95% CI 1.02 to 2.70; I2 = 0%; 2 studies, 378 clinical pregnancies; high-certainty evidence). This suggests that if the chance of miscarriage following standard IVF is assumed to be 20.1%, then the chance using IVM would be 20.4% to 40.4%. Results remained similar when using the risk ratio (RR) as the measure of effect.

We are uncertain about the effect of IVM or capacitation IVM on clinical pregnancy when compared to IVF when a GnRH antagonist protocol was applied (OR 0.49, 95% CI 0.14 to 1.70; I2 = 94%; 2 studies, 739 participants; very low-certainty evidence). The results were similar after pooling the RRs.

IVM or capacitation IVM results in a large reduction in the incidence of moderate or severe OHSS as compared to IVF when a GnRH antagonist protocol was applied (OR 0.08, 95% CI 0.01 to 0.67; I2 = 0%; 2 studies, 739 participants; high-certainty evidence). This suggests that if the incidence of OHSS following IVF is assumed to be 3.5%, then the incidence with IVM would be 0% to 2.4%. Also, there is probably little to no difference in preterm birth between IVM or capacitation IVM and IVF after the application of a GnRH antagonist protocol (OR 0.69, 95% CI 0.31 to 1.52; I² = 45%; 2 studies, 739 participants; moderate-certainty evidence). As for congenital anomalies, one study reported no events, while another showed an uncertain effect of IVM (OR 0.33, 95% CI 0.01 to 8.24; 1 study, 351 participants; low-certainty evidence). Results remained similar when using the RR as the measure of effect.

There were no data from any of the studies for cycle cancellation, oocyte fertilisation, or subgroup analyses.