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• This meta-analysis provided stronger evidence that women with PCOS undergoing IVF are at increased risk of adverse clinical outcomes.
• Sufficient studies make it possible to explore the heterogeneity sources using subgroup analyses
• Larger number of included studies enhanced the statistical power for rare adverse outcomes
Abstract
This meta-analysis aimed to study whether pregnancy-related outcomes and complications differed between patients with polycystic ovary syndrome (PCOS) and those with other causes of infertility who had undergone IVF. A systematic search of PubMed, Embase, the Cochrane Library and Chinese databases was carried out to identify relevant studies published before July 2018. Outcomes were expressed as odds ratios (OR) and 95% confidence intervals (CI). Subgroup analyses and sensitivity analyses were also conducted. Twenty-nine studies were identified for inclusion. Women with PCOS had higher risks of miscarriage (OR 1.41, 95% CI 1.04–1.91), ovarian hyperstimulation syndrome (OR 4.96, 95% CI 3.73–6.60), gestational diabetes mellitus (OR 2.67, 95% CI 1.43–4.98), pregnancy-induced hypertension (OR 2.06, 95% CI 1.45–2.91), preterm birth (OR 1.60, 95% CI 1.25–2.04) and large-for-gestational-age babies (OR 2.10, 95% CI 1.01–4.37). Women with PCOS showed similar rates of clinical pregnancy, multiple pregnancy, ectopic pregnancy, small for gestational age and congenital malformations, and a higher live birth rate, compared with women without PCOS. This study provides an update on and comprehensive evidence to support the observation that despite the fact that PCOS patients achieve a better live birth rate, physicians should continue to consider them to be at high risk of adverse pregnancy-related outcomes.
Polycystic ovary syndrome (PCOS) is one of the most common and complex hormonal disorders seen in women and is considered to be a significant public health issue (
Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).
Human reproduction (Oxford., England).2004; 19: 41-47
). PCOS has a negative effect on women's health across the lifespan, leading to, for example, anxiety, depression, insulin resistance, abdominal obesity, hypertension and dyslipidaemia (
Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan.
). Depending on the particular criteria used for diagnosis and the population studied, the prevalence of PCOS has been reported to range from 8% to 13% in women of childbearing age women worldwide (
Androgen Excess Society Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline.
Journal of Clinical Endocrinology & Metabolism.2006; 91: 4237-4245
). It is reported that over 90% of women suffering from anovulation as a cause of infertility present with ultrasound or endocrine features associated with PCOS (
Recommendations from the international evidence-based guideline for the management of PCOS stated that letrozole is the first-line pharmacological therapy for infertility, with clomiphene and metformin also having a role both alone and in combination. Gonadotrophins are commonly used as a second-line intervention for women with PCOS and anovulatory infertility (
International PCOS Network Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.
Human reproduction (Oxford., England).2018; 33: 1602-1618
). With the rapid refinement of infertility treatments, IVF has resulted in improved pregnancy outcomes and has become a viable alternative third-line choice for women with PCOS if ovulation induction treatment has failed or there are coexisting tubal or male infertility factors. However, pregnancies conceived via IVF are associated with increased risks of obstetric and neonatal complications compared with spontaneous pregnancies (
). Accumulating evidence demonstrates that women with polycystic ovaries who require IVF are at particular risk of ovarian hyperstimulation syndrome (OHSS) (
). However, only a few studies have been published on this topic, involving only a small number of participants and lacking the power to demonstrate statistically significant differences in some pregnancy outcomes when there are low background risks of complications. Whether PCOS has an independent role in increasing pregnancy complications in IVF pregnancies remains controversial and conflicting.
A number of systematic reviews and meta-analyses (
) have reported obstetric and neonatal complications in women with PCOS, but there has been only one meta-analysis on the obstetric and neonatal outcomes of the women with PCOS who have undergone IVF (
). That meta-analysis of nine observational studies showed that, compared with patients with pure tubal infertility, PCOS patients had an increased risk of OHSS. However, the relatively small number of studies in the meta-analysis decreased its statistical power and limited the possibility of performing further subgroup analyses, especially for the rare pregnancy outcomes. Additionally, the review focused primarily on the conventional outcomes of IVF in women with PCOS, including oocyte retrieval, number of oocytes fertilized, clinical pregnancy rate, miscarriage rate and rate of OHSS, and did not consider other perinatal outcomes or pregnancy complications.
It has been 12 years since the last meta-analysis was published, and many subsequent studies related to this topic, yielding mixed results, have since been reported. Reviewing the newly published studies in a new meta-analysis would improve statistical power and help to find a meaningful difference for clinical outcomes, especially rare ones. The primary aim of the present study was therefore to undertake an update and comprehensive meta-analysis based on the available evidence, and to address the question of whether pregnancy-related outcomes and complications differ between women with PCOS and other causes of infertility who have undergone IVF.
Materials and methods
Data sources and search strategies
The following databases were employed to identify the relevant literature: PubMed, Embase, the Cochrane Library and Chinese databases including the China National Knowledge Infrastructure and Wanfang databases. In addition, references from the studies retrieved as well as meta-analyses were also searched by hand to identify additional studies. The search strategy was based on the following combined search terms: (‘Polycystic Ovary Syndrome’ (MeSH) OR Hyperandrogenism OR anovulation OR oligomenorrhea OR amenorrhea OR hirsutism) AND (‘Fertilization in Vitro’ (MeSH) OR ‘In Vitro Fertilization’ OR ‘Sperm Injections, Intracytoplasmic’ (MeSH) OR ‘Intracytoplasmic Sperm Injection’ OR (‘Assisted Reproductive Technique’)) AND (‘pregnancy outcomes’ OR ‘pregnancy complications’ OR ‘perinatal outcomes’ OR ‘obstetrics outcomes’ OR ‘obstetrics complications’ OR ‘adverse outcomes’).
The literature was searched up to July 2018 and was limited to English- and Chinese-language articles. There were no limits on year of publication. The grey literature and conference abstracts were excluded. No additional information was extracted by contacting the authors of the studies retrieved. A Preferred Reporting Items for Systematic Reviews and Meta-analyses statement was used to report the results of this meta-analysis.
Selection criteria
The Population, Intervention, Comparison, and Outcome framework was used to assess the studies included or excluded from this systematic meta-analysis. Studies were considered to meet the eligibility criteria if: (i) they were randomized controlled trials, cohort studies or case-control studies; (ii) they involved women with PCOS who underwent IVF; (iii) they had matched controls who were women without PCOS who had undergone IVF, and the factors causing infertility in the control group were not restricted except for male infertility factors; and (iv) they reported at least one of the outcomes of interest and the data could be extracted for a 2 × 2 table. Poor-quality studies, review articles, government reports and conference abstracts were excluded.
The diagnosis of the PCOS was based on the 2003 Rotterdam criteria, which required at least two out of three criteria: oligomenorrhea and/or anovulation; clinical and/or biochemical signs of hyperandrogenism; and polycystic ovaries on ultrasound scanning (
Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).
Human reproduction (Oxford., England).2004; 19: 41-47
The pregnancy outcomes for this meta-analysis were clinical pregnancy rate, live birth rate, miscarriage rate, multiple pregnancy rate, ectopic pregnancy rate and rate of OHSS. Clinical pregnancy rate was defined as the presence of a gestational sac on transvaginal ultrasonography and expressed per started cycle or per embryo transfer. The live birth rate per cycle was calculated as the proportion of cycles resulting in live births compared with all cycles started. The miscarriage rate was calculated as the ratio of spontaneous abortions to clinical pregnancies and expressed per clinical pregnancy. The pregnancy-related complications were gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), preterm birth, small for gestational age (SGA), large for gestational age (LGA) and congenital malformations.
Data extraction and quality appraisal of the evidence
Applying the selection criteria, two independent reviewers conducted the first literature screening by scanning the titles and abstracts. Full articles were retrieved for further assessment if they met the inclusion criteria. Where there was any doubt about inclusion, the study was discussed with a third reviewer. Data extracted from the selected studies by two reviewers using a special data extraction form were authors, year of publication, study period, study setting, study design, sample source, number of participants (PCOS and non-PCOS), definition of PCOS, previous treatment, causes of infertility in control group, treatment protocol and primary and secondary outcomes.
Risk of bias
The risk of bias of the included studies was assessed by two reviewers using the Newcastle–Ottawa Scale, which is widely used for evaluating the quality of observational studies in a systematic review. This score has eight items with a full score of nine stars and assesses three aspects of the research. Any disagreements or discrepancies were resolved after discussion by a third reviewer, to reach a consensus.
Statistics analysis
The original data extracted from the included studies were collated into 2 × 2 tables. Heterogeneity of the studies was tested using the Q statistic as well as the I2 statistic. Values of I2 <5 0% and Q at the P < 0.10 level of significance were considered as showing low heterogeneity. Categorical outcomes included in this meta-analysis were pooled using the fixed effects model or random effects model in the generic inverse method. When I2 > 50%, studies were considered to be heterogeneous, and the outcome data were pooled, with a random effects model. The statistical analyses were conducted using R software Version 3.5.1 (The R Foundation, Austria). The significance level was set at P < 0.05. The pooled outcomes were expressed using odds ratios (OR) and 95% confidence intervals (CI).
In the presence of heterogeneity, subgroup analyses were undertaken to assess the potential effects on the outcomes of confounding factors, for example the factors causing infertility in control participants, the methods of embryo transfer (fresh or frozen embryo transfer), whether the study controlled for single-embryo transfer, and the treatment protocol of gonadotrophin-releasing hormone (GnRH). Sensitivity analyses were performed to evaluate the robustness of the results. The publication bias of the included studies was investigated based on a funnel plot and Egger linear regression.
Results
Literature search
A total of 2109 records were initially identified, and nine further studies were identified after a hand-search of the cross-references. Of these, 409 studies were excluded as they showed duplication, and 1596 records were excluded on the basis of the first scanning of the titles and abstracts; this left 113 studies for a further full assessment review. Based on the inclusion criteria, 83 studies were removed: 60 studies were irrelevant to the current research or had irrelevant outcomes, seven studies were conference abstracts, seven did not use IVF, two had no control groups, two had no data for PCOS patients, two were cross-sectional studies, one was a review, for two 2 it was not possible to extract the data into 2 × 2 tables, and one used male infertility controls. Finally, 28 cohort studies (
Is the fertile window extended in women with polycystic ovary syndrome? Utilizing the Society for Assisted Reproductive Technology registry to assess the impact of reproductive aging on live-birth rate.
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet.2015; 28: 475-478
) met the selection criteria; these included 24 studies published in English (82.8%) and five in Chinese (17.2%). The study extraction process is shown in Figure 1.
Figure 1Flow diagram showing the detailed selection of studies included in the meta-analysis.
Characteristics and quality of the included studies
The characteristics of the 29 studies are summarised in Table 1. The sample size varied across the studies (9–631 patients and 19–16,416 cycles). Out of 29 reviewed studies, 17 (
Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet.2015; 28: 475-478
Is the fertile window extended in women with polycystic ovary syndrome? Utilizing the Society for Assisted Reproductive Technology registry to assess the impact of reproductive aging on live-birth rate.
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
) in Africa (3.4%). All the studies reported a diagnosis of PCOS, using the definition given by the 2003 Rotterdam criteria or being consistent with this criteria.
Table 1Characteristics of the included studies
Article
Control group
Treatment protocol
Number of PCOS/control patients (cycles) or pregnancies
Outcomes
Type of embryos transferred
Control for single embryo transfer or singleton pregnancy
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
Is the fertile window extended in women with polycystic ovary syndrome? Utilizing the Society for Assisted Reproductive Technology registry to assess the impact of reproductive aging on live-birth rate.
Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet.2015; 28: 475-478
Is the fertile window extended in women with polycystic ovary syndrome? Utilizing the Society for Assisted Reproductive Technology registry to assess the impact of reproductive aging on live-birth rate.
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet.2015; 28: 475-478
Is the fertile window extended in women with polycystic ovary syndrome? Utilizing the Society for Assisted Reproductive Technology registry to assess the impact of reproductive aging on live-birth rate.
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet.2015; 28: 475-478
Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet.2015; 28: 475-478
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
Is the fertile window extended in women with polycystic ovary syndrome? Utilizing the Society for Assisted Reproductive Technology registry to assess the impact of reproductive aging on live-birth rate.
Analysis of the data available from 24 studies showed that PCOS patients had no difference in clinical pregnancy rate per started cycle when compared with the non-PCOS patients in the random effects model (OR 1.03, 95% CI 0.90–1.18, I2 = 64.3%, PQ < 0.01).
Considering the significant heterogeneity among the studies, subgroup analyses were applied to assess the potential effects of the confounding factors on the clinical pregnancy rate, including the factors causing infertility in control patients, the methods of embryo transfer (fresh or frozen embryo transfer) and whether studies included adjustment for confounding factors. After subgroup analyses, we found that only adjustment for confounding factors accounted for some of the heterogeneity between studies. In the adjusted studies (
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
), women with PCOS showed an increased clinical pregnancy rate per started cycle in comparison to non-PCOS patients (OR 1.18, 95% CI 1.04–1.35, I2 = 0; Figure 2a) and no significant difference was found in clinical pregnancy rate between women and without PCOS in the non-adjusted studies (
Is the fertile window extended in women with polycystic ovary syndrome? Utilizing the Society for Assisted Reproductive Technology registry to assess the impact of reproductive aging on live-birth rate.
) reported data on the rate of clinical pregnancy per embryo transfer. There was no significant heterogeneity between studies. The estimated OR (1.07) between women with and without PCOS was pooled through the fixed effects model, with a 95% CI of 0.80–1.45 (Figure 2b).
Is the fertile window extended in women with polycystic ovary syndrome? Utilizing the Society for Assisted Reproductive Technology registry to assess the impact of reproductive aging on live-birth rate.
) provided the outcome of live birth rate per cycle. A low heterogeneity was identified between studies (I2 = 37.7%). Women with PCOS had a higher live birth rate than participants with other factors causing infertility (OR 1.29, 95% CI 1.24–1.34; Supplemental Figure 1). Subgroup analysis showed that for studies with a control group of tubal infertility alone (
Is the fertile window extended in women with polycystic ovary syndrome? Utilizing the Society for Assisted Reproductive Technology registry to assess the impact of reproductive aging on live-birth rate.
), patients with PCOS showed a higher live birth rate (OR 1.30 95% CI 1.24-1.35, I2 = 0, Supplemental Figure 1) than those without, while no significant difference was found in live birth rate among women with or without PCOS in the subgroup of studies using controls with non-PCOS infertility (
) were involved in the meta-analysis here, including 636 PCOS and 5299 non-PCOS patients. No significant heterogeneity was identified among the studies (I2 = 0). There was no significant difference in multiple pregnancy rate between the two groups (OR 1.06, 95% CI 0.87–1.30; Supplemental Figure 2).
Is the fertile window extended in women with polycystic ovary syndrome? Utilizing the Society for Assisted Reproductive Technology registry to assess the impact of reproductive aging on live-birth rate.
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
) reported the outcome of miscarriage. A higher miscarriage rate was observed in PCOS patients compared with non-PCOS patients (OR 1.41, 95% CI 1.04–1.91, I2 = 64.7%, PQ<0.01; Supplemental Figure 3). In the subgroup analysis, a significantly higher miscarriage rate was observed in women with PCOS in control groups involving all infertility factors (
) (OR 1.52, 95% CI 1.04–2.22, I2 = 21.4%), whereas there was no significant difference between PCOS and non-PCOS patients for the control group with pure tubal infertility factors.
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
) reported data on ectopic pregnancy rate, including 570 women with PCOS and 9238 controls. No significant difference in ectopic pregnancy rate was shown between women with and without PCOS (OR 1.52, 95% CI 0.96–2.41, I2 = 34.8%; Supplemental Figure 4).
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
) referred to the outcome of OHSS, contributing 158 events in the PCOS group and 108 events in the control group. Seven studies described data on the rate of severe OHSS, two studies described the rate of OHSS, and two studies reported both the severe OHSS rate and the mild-to-moderate OHSS rate. The OHSS rate was significantly higher in PCOS than non-PCOS patients (OR 4.96, 95% CI 3.73–6.60, I2 = 0; Supplemental Figure 5). Although no heterogeneity was shown between the studies reporting OHSS, a subgroup analysis according to treatment protocol was performed as this may have influenced OHSS rates. The analysis showed that PCOS patients who were treated on a GnRH long agonist protocol (
The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins.
Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet.2015; 28: 475-478
) referring to GDM were included in the meta-analysis, contributing 66 events in the PCOS group and 118 events in the non-PCOS group. Compared with the control group, PCOS patients had an increased risk of GDM (OR 2.67, 95% CI 1.43–4.98, I2 = 61%, PQ = 0.03; Figure 3a).
Figure 3Odds ratios (OR) for adverse pregnancy-related outcomes and complications comparing polycystic ovary syndrome (PCOS) and matched controls undergoing IVF. CI, confidence interval.
Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet.2015; 28: 475-478
) reported information on pregnancy-induced hypertension, involving 768 PCOS patients and 2067 controls. Low heterogeneity was identified across studies (I2 = 28.3%). The risk of PIH was higher in PCOS than non-PCOS patients in the fixed effects model (OR 2.06, 95% CI 1.45–2.91; Figure 3b).
Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet.2015; 28: 475-478
). The OR and 95% CI of having a preterm birth were 1.60 and 1.25–2.04, respectively, in PCOS patients compared with non-PCOS patients. There was no significant heterogeneity among the studies (I2 = 0.6%; Figure 3c).
) reported data on SGA. There were no differences in the prevalence of SGA comparing the PCOS and non-PCOS groups (OR 1.50, 95% CI 0.98–2.30, I2 = 22.5%; Figure 3d).
) reported data on LGA, including 780 PCOS patients and 2600 control patients. A significantly increased risk of LGA was shown in women with PCOS in comparison to women without (OR 2.10, 95% CI 1.01–4.37, I2 = 65.7%, P = 0.02; Figure 3e).
Obstetric outcomes in women with polycystic ovary syndrome and isolated polycystic ovaries undergoing in vitro fertilization: a retrospective cohort analysis.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet.2015; 28: 475-478
) included in the meta-analysis reported data on congenital malformations. The analysis showed no significant differences between PCOS patients and matched patients (OR 1.17, 95% CI 0.51–2.65, I2 = 0; Figure 3f).
Sensitivity analysis
Sensitivity analyses were performed to examine the influence of variation between the studies on the estimate of overall risk. Exclusion of any one study at a time yielded consistent results, with only a slight variation. The results of the sensitivity analysis are summarised in Table 2.
Table 2Association between women with PCOS and pregnancy-related complications and perinatal outcomes of IVF pregnancies
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