Metformin administration during pregnancy tends to reduce the risk of gestational diabetes mellitus and improve pregnancy outcomes in previously infertile women with polycystic ovary syndrome who become pregnant.

Metformin reduces incidences of miscarriage and preterm delivery in polycystic ovary syndrome (PCOS) women, but its impact on gestational diabetes mellitus (GDM) is conflicting. Hence, this study set up selection criteria to include previously infertile women with PCOS but without pre-existing DM who became pregnant, aiming to minimize confounders and investigate the influence of metformin on GDM, miscarriage, and preterm delivery. This study included 195 previously infertile women with PCOS who became pregnant. They were divided into metformin (receiving metformin during pregnancy) and control (not receiving metformin) groups without intervention. Metformin group tended to have a lower incidence of GDM versus control group (13.3% versus 23.3%, P = 0.070). A logistic regression model adjusted for all baseline characteristics (demographics, infertile duration, and diabetes mellitus-related features) showed that metformin was associated with a decreased probability of GDM (odds ratio (OR): 0.426, P = 0.037). Metformin group showed a similar incidence of miscarriage (6.7% versus 11.1%, P = 0.273), but decreased incidences of preterm delivery (not statistically significant) (6.7% versus 13.3%, P = 0.091) and miscarriage or preterm delivery (13.3% versus 24.4%, P = 0.046) versus control group. A logistic regression model adjusted for all the aforementioned features revealed that metformin was related to a lower risk of miscarriage or preterm delivery (OR: 0.417, P = 0.040). Fetal outcomes, including birth weight (P = 0.245) and the incidence of 5 min-Apgar score ≤ 7 (P = 0.702), were similar between groups. Metformin administration during pregnancy may reduce GDM, miscarriage, and preterm delivery risks without adverse effects on fetal outcomes in previously infertile women with PCOS.

Liu H ，Liu Y ，Wei C ，Zhang S ，Xu Y ... -  《-》

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

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

Siristatidis CS ，Papapanou M ，Maheshwari A ，Vaidakis D ... -  《Cochrane Database of Systematic Reviews》

Gonadotropins for ovulation induction in women with polycystic ovary syndrome.

Ovulation induction with follicle-stimulating hormone (FSH) is a second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate or letrozole, though induction protocols and types of gonadotropins used vary greatly. To compare the effectiveness and safety of gonadotropins as a second-line treatment for ovulation induction in women with PCOS who do not ovulate or conceive after clomiphene citrate or letrozole. In March 2024, we searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase and PsycINFO. We checked references of all relevant studies. We had no language or date restrictions. All randomised controlled trials (RCTs) reporting data on clinical outcomes in women with PCOS who did not ovulate or conceive on clomiphene citrate or letrozole, and were undergoing ovulation induction with urinary-derived gonadotropins, including urofollitropin in purified FSH (uFSH) or highly purified FSH (HP-FSH) form, human menopausal gonadotropin (HMG) and highly purified human menopausal gonadotropin (HP-HMG), or recombinant FSH (rFSH) were eligible. We included trials reporting on ovulation induction followed by intercourse or intrauterine insemination. We excluded studies that described co-treatment with clomiphene citrate, metformin, luteinising hormone, or letrozole. We implemented the core outcome set for infertility. Our critical outcomes were live birth rate and multiple pregnancy rate per woman. Important outcomes were clinical pregnancy, pregnancy loss, incidence of ovarian hyperstimulation syndrome (OHSS) per woman, total gonadotropin dose, total duration of stimulation per woman, gestational age at birth, birthweight, neonatal mortality, and major congenital anomaly. We used the Cochrane RoB 1 tool to assess bias in the included studies. Where meta-analysis was possible, we combined data using a fixed-effect model to calculate the risk ratio (RR) or mean difference. We summarised the overall certainty of evidence for the main outcomes using GRADE criteria. We included 15 studies with 2348 women. Ten trials compared rFSH with urinary-derived gonadotropins (one compared rFSH with human menopausal gonadotropin (HMG), and nine compared rFSH with urinary FSH). Three trials compared HMG with purified FSH (uFSH). One trial compared HP-FSH with purified FSH (uFSH) and one trial compared gonadotropins with continued clomiphene citrate. Recombinant FSH (rFSH) versus urinary-derived gonadotropins There may be little or no difference in the birth rate between rFSH and urinary-derived gonadotropins (RR 1.21, 95% confidence interval (CI) 0.83 to 1.78; 5 RCTs, 505 participants; low-certainty evidence). This suggests that if the observed average live birth per woman who used urinary-derived gonadotropins is 16%, the chance of live birth with rFSH is between 13% and 28%. There may be little or no difference between groups in multiple pregnancy (RR 0.86, 95% CI 0.46 to 1.61; 8 RCTs, 1368 participants; low-certainty evidence), clinical pregnancy rate (RR 1.05, 95% CI 0.88 to 1.27; 8 RCTs, 1330 participants; low-certainty evidence), or miscarriage rate (RR 1.20, 95% CI 0.71 to 2.04; 7 RCTs, 970 participants; low-certainty evidence). We are uncertain whether rFSH reduces ectopic pregnancy (RR 2.81, 95% CI 0.12 to 67.90; 1 RCT, 151 participants; very-low certainty evidence) or the incidence of OHSS (RR 1.48, 95% CI 0.82 to 2.65; 10 RCTs, 1565 participants; very low-certainty evidence) when compared to urinary-derived gonadotropins. Human menopausal gonadotropin (HMG) versus purified urinary FSH (uFSH) When compared to uFSH, we are uncertain whether HMG improves live birth rate (RR 1.44, 95% CI 0.55 to 3.76; 2 RCTs, 79 participants), or reduces multiple pregnancy (RR 6.56, 95% CI 0.28 to 152.45; 3 RCTs, 102 participants). We are also uncertain whether HMG improves clinical pregnancy rate (RR 1.31, 95% CI 0.66 to 2.59; 3 RCTs, 102 participants), reduces miscarriage rate (RR 0.33, 95% CI 0.06 to 1.97; 2 RCTs, 98 participants), or reduces the incidence of OHSS (RR 7.07, 95% CI 0.42 to 117.81; 2 RCTs, 53 participants) when compared to uFSH. No trials reported on ectopic pregnancy. The certainty of the evidence was very low for all outcomes. Gonadotropins versus continued clomiphene citrate Gonadotropins (FSH) probably result in more live births than continued clomiphene citrate (RR 1.24, 95% CI 1.05 to 1.46; 1 RCT, 661 participants; moderate-certainty evidence). This suggests that for a woman with a live birth rate of 41% with continued clomiphene citrate, the live birth rate with gonadotropins was between 43% and 60%. There may be little or no difference in multiple pregnancy between treatments (RR 0.89, 95% CI 0.33 to 2.44; 1 RCT, 661 participants; low-certainty evidence). Gonadotropins probably result in more clinical pregnancies than continued clomiphene citrate (RR 1.31, 95% CI 1.13 to 1.52; 1 RCT, 661 participants; moderate-certainty evidence), and may result in more miscarriages (RR 2.23, 95% CI 1.11 to 4.47; 1 RCT, 661 participants; low-certainty evidence). We are uncertain if there is a difference in ectopic pregnancy between the groups (RR 0.51, 95% CI 0.09 to 2.77; 1 RCT, 661 participants; very low-certainty evidence). None of the women developed OHSS. The main limitations were imprecision, inconsistency, and indirectness. There may be little or no difference in live birth, multiple pregnancy, clinical pregnancy, or miscarriage rates between rFSH and uFSH in women with PCOS. For HMG versus uFSH, we are uncertain whether one or the other improves or lowers rates of live birth, multiple pregnancy, clinical pregnancy, or miscarriage. We are uncertain whether any of the interventions reduce ectopic pregnancy or the incidence of OHSS. In women with clomiphene citrate failure, gonadotropins (FSH) probably result in more live births and clinical pregnancies than continued clomiphene citrate without increasing multiple pregnancies. Gonadotropins may increase the miscarriage rate per woman. We are uncertain if gonadotropins reduce ectopic pregnancy. None of the women developed OHSS. This Cochrane review had no dedicated funding. Protocol (2012) https://doi.org/10.1002/14651858.CD010290 Review (2015) https://doi.org/10.1002/14651858.CD010290.pub2/full Update (2019) https://doi.org/10.1002/14651858.CD010290.pub3.

Weiss NS ，Kostova EB ，Mol BWJ ，van Wely M ... -  《-》

Polycystic ovary syndrome and gestational diabetes mellitus association to pregnancy outcomes: A national register-based cohort study.

It is well known that both women with polycystic ovary syndrome (PCOS) and women with gestational diabetes mellitus (GDM) have increased risks of adverse pregnancy outcomes, but little is known whether the combination of these two conditions exacerbates the risks. We explored risk estimates for adverse pregnancy outcomes in women with either PCOS or GDM and the combination of both PCOS and GDM. Nationwide register-based historical cohort study in Sweden including women who gave birth to singleton infants during 1997-2015 (N = 281 806). The risks of adverse pregnancy outcomes were estimated for women exposed for PCOS-only (n = 40 272), GDM-only (n = 2236), both PCOS and GDM (n = 1036) using multivariable logistic regression analyses. Risks were expressed as odds ratios with 95% confidence intervals (CIs) and adjusted for maternal characteristics, including maternal BMI. Women with neither PCOS nor GDM served as control group. Maternal outcomes were gestational hypertension, preeclampsia, postpartum hemorrhage, and obstetric anal sphincter injury. Neonatal outcomes were preterm birth, stillbirth, shoulder dystocia, born small or large for gestational age, macrosomia, low Apgar score, infant birth trauma, cerebral impact of the infant, neonatal hypoglycemia, meconium aspiration syndrome and respiratory distress. Based on non-significant PCOS by GDM interaction analyses, we found no evidence that having PCOS adds any extra risk beyond that of having GDM for maternal and neonatal outcomes. For example, the adjusted odds ratio for preeclampsia in women with PCOS-only were 1.18 (95% CI 1.11-1.26), for GDM-only 1.77 (95% CI 1.45-2.15), and for women with PCOS and GDM 1.86 (95% CI 1.46-2.36). Corresponding adjusted odds ratio for preterm birth in women with PCOS-only were 1.34 (95% CI 1.28-1.41), GDM-only 1.64 (95% CI 1.39-1.93), and for women with PCOS and GDM 2.08 (95% CI 1.67-2.58). Women with PCOS had an increased risk of stillbirth compared with the control group (aOR 1.52, 95% CI 1.29-1.80), whereas no increased risk was noted in women with GDM (aOR 0.58, 95% CI 0.24-1.39). The combination of PCOS and GDM adds no extra risk beyond that of having GDM alone, for a number of maternal and neonatal outcomes. Nevertheless, PCOS is still an unrecognized risk factor in pregnancy, exemplified by the increased risk of stillbirth.

Valdimarsdottir R ，Vanky E ，Elenis E ，Ahlsson F ，Lindström L ，Junus K ，Wikström AK ，Poromaa IS ... -  《-》

Vitamin D supplementation for women during pregnancy.

Vitamin D supplementation during pregnancy may help improve maternal and neonatal health outcomes (such as fewer preterm birth and low birthweight babies) and reduce the risk of adverse pregnancy outcomes (such as severe postpartum haemorrhage). To examine whether vitamin D supplementation alone or in combination with calcium or other vitamins and minerals given to women during pregnancy can safely improve certain maternal and neonatal outcomes. We searched the Cochrane Pregnancy and Childbirth Trials Register (which includes results of comprehensive searches of CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, and relevant conference proceedings) (3 December 2022). We also searched the reference lists of retrieved studies. Randomised and quasi-randomised trials evaluating the effect of supplementation with vitamin D alone or in combination with other micronutrients for women during pregnancy in comparison to placebo or no intervention. Two review authors independently i) assessed the eligibility of studies against the inclusion criteria, ii) assessed trustworthiness based on pre-defined criteria of scientific integrity, iii) extracted data from included studies, and iv) assessed the risk of bias of the included studies. We assessed the certainty of the evidence using the GRADE approach. The previous version of this review included 30 studies; in this update, we have removed 20 of these studies to 'awaiting classification' following assessments of trustworthiness, one study has been excluded, and one new study included. This current review has a total of 10 included studies, 117 excluded studies, 34 studies in awaiting assessment, and seven ongoing studies. We used the GRADE approach to assess the certainty of the evidence. This removal of the studies resulted in evidence that was downgraded to low-certainty or very low-certainty due to study design limitations, inconsistency between studies, and imprecision. Supplementation with vitamin D compared to no intervention or a placebo A total of eight studies involving 2313 pregnant women were included in this comparison. We assessed four studies as having a low risk of bias for most domains and four studies as having high risk or unclear risk of bias for most domains. The evidence is very uncertain about the effect of supplementation with vitamin D during pregnancy compared to placebo or no intervention on pre-eclampsia (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.21 to 1.33; 1 study, 165 women), gestational diabetes (RR 0.53, 95% CI 0.03 to 8.28; 1 study, 165 women), preterm birth (< 37 weeks) (RR 0.76, 95% CI 0.25 to 2.33; 3 studies, 1368 women), nephritic syndrome (RR 0.17, 95% CI 0.01 to 4.06; 1 study, 135 women), or hypercalcaemia (1 study; no cases reported). Supplementation with vitamin D during pregnancy may reduce the risk of severe postpartum haemorrhage; however, only one study reported this outcome (RR 0.68, 95% CI 0.51 to 0.91; 1 study, 1134 women; low-certainty evidence) and may reduce the risk of low birthweight; however, the upper CI suggests that an increase in risk cannot be ruled out (RR 0.69, 95% CI 0.44 to 1.08; 3 studies, 371 infants; low-certainty evidence). Supplementation with vitamin D + calcium compared to no intervention or a placebo One study involving 84 pregnant women was included in this comparison. Overall, this study was at moderate to high risk of bias. Pre-eclampsia, gestational diabetes, and maternal adverse events were not reported. The evidence is very uncertain about the effect of supplementation with vitamin D and calcium on preterm birth (RR not estimable; very low-certainty evidence) or for low birthweight (RR 1.45, 95% CI 0.14 to 14.94; very low-certainty evidence) compared to women who received placebo or no intervention. Supplementation with vitamin D + calcium + other vitamins and minerals versus calcium + other vitamins and minerals (but no vitamin D) One study involving 1298 pregnant women was included in this comparison. We assessed this study as having a low risk of bias in all domains. Pre-eclampsia was not reported. The evidence is very uncertain about the effect of supplementation with vitamin D, calcium, and other vitamins and minerals during pregnancy compared to no vitamin D on gestational diabetes (RR 0.42, 95% CI 0.10 to 1.73; very low-certainty evidence), maternal adverse events (hypercalcaemia no events and hypercalciuria RR 0.25, 95% CI 0.02 to 3.97; very low-certainty evidence), preterm birth (RR 1.04, 95% CI 0.68 to 1.59; low-certainty evidence), or low birthweight (RR 1.12, 95% CI 0.82 to 1.51; low-certainty evidence). This updated review using the trustworthy assessment tool removed 21 studies from the previous update and added one new study for a total of 10 included studies. In this setting, supplementation with vitamin D alone compared to no intervention or a placebo resulted in very uncertain evidence on pre-eclampsia, gestational diabetes, preterm birth, or nephritic syndrome. It may reduce the risk of severe postpartum haemorrhage; however, only one study reported this outcome. It may also reduce the risk of low birthweight; however, the upper CI suggests that an increase in risk cannot be ruled out. Supplementation with vitamin D and calcium versus placebo or no intervention resulted in very uncertain evidence on preterm birth and low birthweight. Pre-eclampsia, gestational diabetes, and maternal adverse events were not reported in the only study included in this comparison. Supplementation with vitamin D + calcium + other vitamins and minerals versus calcium + other vitamins and minerals (but no vitamin D) resulted in very uncertain evidence on gestational diabetes and maternal adverse events (hypercalciuria) and uncertain evidence on preterm birth and low birthweight. Pre-eclampsia was not reported in the only study included in this comparison. All findings warrant further research. Additional rigorous, high-quality, and larger randomised trials are required to evaluate the effects of vitamin D supplementation in pregnancy, particularly in relation to the risk of maternal adverse events.

Palacios C ，Kostiuk LL ，Cuthbert A ，Weeks J ... -  《Cochrane Database of Systematic Reviews》