In vitro maturation in subfertile women with polycystic ovarian syndrome who are undergoing assisted reproduction

Review question

Is in vitro maturation efficient compared to standard assisted reproduction techniques (ART) in subfertile women with polycystic ovarian syndrome (PCOS)?

Background

Women with PCOS undergoing conventional ART are at an increased risk of ovarian hyperstimulation syndrome, a medical condition that can occur in women who take fertility medications to stimulate oocytes growth. The condition is associated with enlargement of both ovaries, fluid in the body of the woman, around her lungs and/or her heart, serious illness, and in rare cases, death. When women with PCOS take medications to stimulate their ovaries, the oocytes produced are often immature, which is the main reason that these oocytes are poorly fertilised and lead to low pregnancy rates. In addition, as previously noted, stimulation of the ovaries of women with PCOS with drugs often leads to ovarian hyperstimulation. These women may thus benefit from earlier retrieval of oocytes followed by their maturation in the laboratory, a technique known as in vitro maturation (IVM), as this would reduce the aforementioned risks. However, while successful fertilisation, embryo development, and term pregnancies resulting from IVM oocytes have been reported, some concern has been expressed regarding the safety of the method in terms of the health of the children born and the rate of genetic anomalies they carry. We reviewed the evidence up to April 2018, for the third time.

Study characteristics

We performed a comprehensive literature search of the standard medical databases (from database inception to 17 April 2018) in consultation with the Cochrane Gynaecology and Fertility Group Information Specialist, for all randomised controlled trials (studies in which participants are assigned to a treatment group using a random method) investigating the efficiency of IVM compared to conventional ART in subfertile women with PCOS. We searched for and included studies irrespective of language and country of origin. Two review authors independently selected and evaluated studies, extracted data, and attempted to contact the authors of studies for which data were missing. We found two studies (71 women), published as abstracts in international conferences, and six ongoing trials that met our inclusion requirements.

Key results

Though promising data on the IVM technique have been published, unfortunately there is still no evidence concerning our primary outcomes of live-birth and miscarriage rates from properly conducted randomised controlled trials upon which to base any practice recommendations regarding IVM before ART for women with PCOS. Of the secondary outcomes specified in this review, very low-quality evidence showed that clinical pregnancy was higher when IVM was compared to conventional ART, whereas the incidence of ovarian hyperstimulation syndrome was zero in both studies in both groups. We are awaiting the results of six ongoing trials and eagerly anticipate further evidence from good-quality trials in the field.

Quality of the evidence

The quality of the evidence was very low for all outcomes.

Authors' conclusions: 

Though promising data on the in vitro maturation (IVM) technique have been published, unfortunately there is still no evidence from properly conducted randomised controlled trials upon which to base any practice recommendations regarding IVM before in vitro fertilisation (IVF) or intracytoplasmic sperm injection for women with polycystic ovarian syndrome. Regarding our secondary outcomes, very low-quality evidence showed that clinical pregnancy was higher with IVM when compared to IVF, whereas the incidence of ovarian hyperstimulation syndrome was zero in both studies in both groups. We are awaiting the results of six ongoing trials and eagerly anticipate further evidence from good-quality trials in the field.

Read the full abstract...
Background: 

Polycystic ovarian syndrome (PCOS) occurs in 4% to 7% of all women of reproductive age and 50% of women presenting with subfertility. Subfertility affects 15% to 20% of couples trying to conceive. A significant proportion of these women ultimately need assisted reproductive technology (ART). In vitro fertilisation (IVF) is one of the assisted reproduction techniques employed to raise the chances of achieving a pregnancy. For the standard IVF technique, stimulating follicle development and growth before oocyte retrieval is essential, for which a large number of different methods combining gonadotrophins with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist are used. 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 subfertility involves earlier retrieval of immature oocytes at the germinal-vesicle stage followed by in vitro maturation (IVM). So far, the only data available have derived from observational studies and non-randomised clinical trials.

Objectives: 

To assess the effectiveness and safety of IVM followed by IVF or ICSI versus conventional IVF or ICSI among women with PCOS undergoing assisted reproduction.

Search strategy: 

This is the second update of this review. We performed the search on 17 April 2018.

The search was designed with the help of the Cochrane Gynaecology and Fertility Group Information Specialist, for all published and unpublished randomised controlled trials (RCTs).

We searched the the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL via the Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, and the trial registers for ongoing and registered trials and the Open Grey database for grey literature from Europe. We made further searches in the National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, together with PubMed and Google for any recent trials that have not yet been indexed in the major databases.

Selection criteria: 

All RCTs on the intention to perform IVM before IVF or ICSI compared with conventional IVF or ICSI for subfertile women with PCOS, irrespective of language and country of origin.

Data collection and analysis: 

Two review authors independently selected studies, assessed risk of bias, extracted data from studies, and attempted to contact the authors of studies for which data were missing. Our primary outcomes were live birth per woman randomised and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods.

Main results: 

We found two RCTs suitable for inclusion in the review and six ongoing trials that have not yet reported results. Both included studies were published as abstracts in international conferences.

Both studies were at unclear or high risk of bias for most of the seven domains assessed. Common problems were unclear reporting of study methods and lack of blinding. The main limitations in the overall quality of the evidence were high risk of bias and serious imprecision.

There were no data on the primary outcomes of this review, namely live birth per woman randomised and miscarriage.

Both studies reported clinical pregnancy rate: there was evidence of an effect between IVM and IVF, favouring the former (odds ratio 3.10, 95% confidence interval 1.06 to 9.00; 71 participants; 2 studies; I2 = 0%; very low-quality evidence). The incidence of OHSS was zero in both studies in both groups.

There were no data for the other outcomes specified in this review.

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