Clinical Question: 

While on the labor and delivery unit, I encountered a pregnant patient with PCOS who was on Metformin for the duration of her pregnancy. I wanted to explore the utility of Metformin on maternal outcomes in this patient population, as PCOS is a syndrome that I come across very frequently. 

 

PICO Question:

In pregnant patients with PCOS, does the use of Metformin compared to placebo or no intervention improve maternal outcomes, such as metabolic and androgenic parameters? 

P	I	C	O
Pregnant patients	Metformin	Placebo	Fasting glucose
Patients with PCOS		No intervention	Metabolic parameters
Polycystic ovarian syndrome			Androgenic parameters

 

Database Search:

Pubmed

Search Criteria: metformin use in pregnant patients with PCOS

Filters: free full text, last 10 years, clinical trial, meta-analysis, RCT, systematic review

Results: 48

 

Science Direct

Search Criteria: use of metformin in pregnant PCOS patients 

Filters: 2014-2024, review articles, English

Results: 220

 

Cochrane

Search Criteria: metformin use in pregnancy with PCOS 

Filters: 2014-2024, review articles

Results: 1

 

Search Strategy: I noticed that this search criteria did not yield as many results on PubMed as my usual PICO searches. I read through the titles and a few of the abstracts on the first three pages of each search engine (except for Cochrane which only yielded one result). I focused on trying to find articles with high levels of evidence, such as systematic reviews or meta-analyses and more recent findings. I used articles that directly addressed the effect of metformin on various maternal outcomes in pregnant patients with PCOS. 

 

Articles Chosen

 

Article 1: 

Kanda S, Chatha U, Odoma VA, et al. Effect of Metformin (MTF) Intervention During Pregnancy in Women With Polycystic Ovarian Syndrome (PCOS): A Systematic Review. Cureus. 2023;15(8):e44166. Published 2023 Aug 26. doi:10.7759/cureus.44166

 

Why I chose this article: This article addresses maternal outcomes like live birth rates, clinical pregnancy rates, miscarriage rates, and pregnancy complications (gestational diabetes, preeclampsia), and includes relevant comparisons between MTF, placebo, and no treatment. The article includes various sources and evidence quality, it synthesizes the current findings comprehensively.

 

Abstract

Metformin (MTF) is a commonly prescribed medication for women with polycystic ovarian syndrome (PCOS), but its impact on pregnancy outcomes in women with PCOS remains controversial. This systematic review aims to evaluate the effects of MTF intervention on pregnancy outcomes in women with PCOS and the impact of MTF on offspring. A comprehensive search is conducted in PubMed, Google Scholar, and ScienceDirect databases from 2019 up to May 16, 2023. Only review articles and meta-analyses are included, focusing on women with PCOS who received MTF during pregnancy or as part of infertility treatment. The primary outcomes of interest are clinical pregnancy rate (CPR), miscarriage rate, preterm birth rate, and live birth rate. Secondary outcomes are the safety profile of MTF. Data extraction and quality assessment are performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the assessment using the multiple systematic reviews (AMSTAR) 2 tool, respectively. The initial search produced 1877 studies. Thirteen studies were included in the review. While the use of MTF during pregnancy in women with PCOS may have some benefits in reducing certain pregnancy complications such as pregnancy-induced hypertension (PIH), gestational diabetes mellitus (GDM), preeclampsia, preterm delivery, reducing the risk of ovarian hyperstimulation syndrome (OHSS) in women with PCOS undergoing in vitro fertilization (IVF); however, there is no significant difference in clinical pregnancy and live birth rates overall, but subgroup analysis suggests potential benefits for women with a higher body mass index (BMI). MTF is associated with a larger fetal head circumference and potential long- term effects on offspring’s BMI and obesity. Further research is needed to better understand the optimal dosing of MTF, long-term effects, and effects in specific subgroups. The heterogeneity of the included studies limited the ability to analyze the data effectively, leading to challenges in drawing definitive conclusions.

 

—-

Article 2:

Zhu D, Chen Y, Huang J, et al. Effects of metformin on pregnancy outcome, metabolic profile, and sex hormone levels in women with polycystic ovary syndrome and their offspring: a systematic review and meta-analysis. Ann Transl Med. 2022;10(7):418. doi:10.21037/atm-22-909

 

Why I chose this article: This article is a strong fit to answer this PICO question because it examines the effects of metformin compared to placebo or no intervention on maternal outcomes. It provides comprehensive evidence through a systematic review and meta-analysis, highlighting key outcomes such as reduced pregnancy complications (PIH, preterm delivery) and improved metabolic profiles. 

 

Abstract

Background: Research of the efficacy and safety of metformin on long-term pregnancy outcomes remains conflicted. We performed an updated systematic review and meta-analysis to systematically investigate the effect of metformin treatment on pregnancy outcome, metabolic profile, and sex hormone characteristics in women with polycystic ovary syndrome (PCOS) and their offspring.

Methods: The PubMed, Embase, and Cochrane Library databases were searched from inception to July 10, 2021 with the keywords “metformin”, “PCOS”, and “pregnancy”. Randomized controlled studies reported pregnant related outcomes after metformin intervention among PCOS women were included, while abstracts and reviews were excluded. Two authors independently identified trials, extracted data and assessed risk of bias with Cochrane Reviewers Handbook 5.0. Random effects models were used to evaluate the pooled risk ratios (RR) and 95% confidence intervals (95% CI) of pregnancy outcome, metabolic profile, and sex hormone levels.

Results: Eighteen studies were included. The majority of trials were in medium methodological quality. In terms of pregnancy complications among women with PCOS, metformin treatment was associated with a significantly reduced risk of preterm delivery (RR =0.37, 95% CI: 0.23–0.61), pregnancy-induced hypertension (PIH) and preeclampsia (RR =0.45, 95% CI: 0.24–0.83) and macrosomia (RR =0.26, 95% CI: 0.11–0.64). In terms of offspring, metformin significantly associated with larger head circumference (MD =0.29, 95% CI: 0.13–0.45) and higher long-term body mass index (BMI) measures (MD =0.37, 95% CI: 0.17–0.56). In terms of metabolic profile and sex hormone characteristics, a significant decrease in homeostatic model assessment for insulin resistance (HOMA2-IR) scores was found in mothers (MD =−0.32, 95% CI: −0.63 to −0.02), whereas a significant increase of sex hormone binding globulin (SHBG) levels was detected in offspring (MD =0.33, 95% CI: 0.01–0.65).

Discussion: Although the relative low quality of randomized controlled trials (RCTs) and limited results made it difficult to draw a definite conclusion, our study showed that metformin treatment during pregnancy can reduce the risk of pregnancy complications but may have impacts on increasing SHBG levels and long- term BMI in offspring.

 

—

Article 3:

Andra F, Abbott D, Stridsklev S, et al. Sustained Maternal Hyperandrogenism During PCOS Pregnancy Reduced by Metformin in Non-obese Women Carrying a Male Fetus. J Clin Endocrinol Metab. 2020;105(12):3762-3770. doi:10.1210/clinem/dgaa605

 

Why I chose this article: The study is a placebo-controlled randomized trial design, which is considered the gold standard for evaluating treatment effects and minimizes bias. It includes a substantial number of PCOS participants, enhancing the statistical power and reliability of the findings. The article specifically investigates the impact of Metformin on androgen levels, a critical factor in managing PCOS and its associated complications during pregnancy.

 

Abstract

Context

Large, longitudinal studies on androgen levels in pregnant women with polycystic ovary syndrome (PCOS) are lacking. While metformin has a mild androgen-lowering effect in non-pregnant women with PCOS, its effects on maternal androgen levels in pregnancy are less well understood.

Objective

To describe androgen patterns in pregnant women with PCOS and in healthy control women, and to explore the potential effects of metformin on maternal androgen levels in PCOS.

Design and Setting

A post hoc analysis from a randomized, placebo-controlled, multicenter study carried out at 11 secondary care centers and a longitudinal single-center study on healthy pregnant women in Norway.

Participants

A total of 262 women with PCOS and 119 controls.

Intervention

The participants with PCOS were randomly assigned to metformin (2 g daily) or placebo, from first trimester to delivery.

Main Outcome Measures

Androstenedione (A4), testosterone (T), sex-hormone binding globulin (SHBG), and free testosterone in‐ dex (FTI) at 4 time points in pregnancy.

Results

Women with PCOS versus healthy controls had higher A4, T, and FTI, and lower SHBG at all measured time points in pregnancy. In the overall cohort of women with PCOS, metformin had no effect on A4, T, SHBG, and FTI. In subgroup analyses, metformin reduced A4 (P = 0.019) in nonobese women. Metformin also reduced A4 (P = 0.036), T (P = 0.023), and SHBG (P = 0.010) levels through pregnancy in mothers with a male fetus.

Conclusion

Metformin had no effect on maternal androgens in PCOS pregnancies. In subgroup analyses, a modest androgen-lowering effect was observed in nonobese women with PCOS. In PCOS women carrying a male fetus, metformin exhibited an androgen-lowering effect.

—

Article 4:

Tarry-Adkins JL, Ozanne SE, Aiken CE. Impact of metformin treatment during pregnancy on maternal outcomes: a systematic review/meta-analysis. Sci Rep. 2021;11(1):9240. Published 2021 Apr 29. doi:10.1038/s41598-021-88650-5

 

Why I chose this article: This article provides comprehensive data on various maternal outcomes, including gestational weight gain, risk of pre-eclampsia, cesarean section rates, and gastrointestinal side effects. It specifically addresses the subgroup of women with PCOS, reporting on the effects of metformin compared to placebo and other interventions. Additionally, the article has a high level of evidence as it is a meta-analysis.

 

Abstract

We systematically assessed the impact of metformin treatment on maternal pregnancy outcomes. PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov and Cochrane databases were systematically searched (inception‐1st February 2021). Randomized controlled trials reporting pregnancy outcomes in women randomized to metformin versus any other treatment for any indication were included. Outcomes included gestational weight gain (GWG), pre‐eclampsia, gestational hypertension, preterm birth, gestational age at delivery, cesarean section, gestational diabetes, glycaemic control, and gastrointestinal side‐effects. Two independent reviewers conducted screening, with a third available to evaluate disagreements. Risk‐of‐bias and GRADE assessments were conducted using Cochrane Risk‐of‐Bias and GRADE‐pro software. Thirty‐five studies (n = 8033 pregnancies) met eligibility criteria. GWG was lower in pregnancies randomized to metformin versus other treatments (1.57 kg ± 0.60 kg; I2 = 86%, p < 0.0001), as was likelihood of pre‐eclampsia (OR 0.69, 95% CI 0.50–0.95; I2 = 55%, p = 0.02). The risk of gastrointestinal side‐effects was greater in metformin‐ exposed versus other treatment groups (OR 2.43, 95% CI 1.53–3.84; I2 = 76%, p = 0.0002). The risk of other maternal outcomes assessed was not significantly different between metformin‐exposed versus other treatment groups. Metformin for any indication during pregnancy is associated with lower GWG and a modest reduced risk of pre‐eclampsia, but increased gastrointestinal side‐effects compared to other treatments.

—

Article 5:

Melin J, Forslund M, Alesi S, et al. The impact of metformin with or without lifestyle modification versus placebo on polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Eur J Endocrinol. 2023;189(2):S37-S63. doi:10.1093/ejendo/lvad098

 

Why I chose this article: This is a systematic review and meta-analysis of 32 randomized controlled trials. It uses high-quality evidence on metformin’s impact on various outcomes, such as BMI, insulin resistance, lipid profiles, and menstrual cycle regularity, specifically in the PCOS population. Additionally, it addresses potential side effects, making it a well-rounded source for understanding both the benefits and limitations of metformin in clinical practice. 

 

Abstract

Objective: Available evidence has shown that metformin improves insulin sensitivity and weight management in polycystic ovary syndrome (PCOS). Nevertheless, key knowledge gaps remain regarding its efficacy and the specific outcomes in this population. This review evaluates the effectiveness of metformin and lifestyle modification compared with placebo in the management of PCOS and will inform the forthcoming, 2023 evidence-based PCOS guidelines.

Design: Systematic review and meta-analysis of the literature.

Methods: A search was performed in MEDLINE, EMBASE, PsycINFO, AllEBM, and CINAHL. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and included randomized controlled trials published in English through July 2022.

Results: Moderate certainty of evidence showed a larger reduction of body mass index (BMI) (mean difference [MD] −0.53, 95% confidence interval [CI] −0.95 to −0.12 kg/m2), homeostatic model assessment for insulin resistance (MD −0.50, 95% CI −0.91 to −0.09) (critical outcomes), and fasting glucose (MD −0.13, 95% CI −0.19 to −0.07 mmol/L) with metformin compared to placebo with increased mild gastrointestinal adverse effects (odds ratio [OR] 7.67, 95% CI 2.74–21.46). Low certainty of evidence showed a larger reduction of waist–hip ratio (MD −0.02, 95% CI −0.03 to −0.00), total cholesterol (MD −0.24, 95% CI −0.43 to −0.05 mmol/L), low- density lipoprotein (MD −0.16, 95% CI −0.30 to −0.01 mmol/L), and triglycerides (MD −0.11, 95% CI −0.20 to −0.02 mmol/L) with metformin than placebo.

Conclusions: Metformin should be considered an efficacious adjunct to lifestyle interventions in adults with PCOS, especially for those with a higher BMI, to improve weight loss, insulin resistance, and lipids.

 

—

Article 6:

Kim CH, Chon SJ, Lee SH. Effects of lifestyle modification in polycystic ovary syndrome compared to metformin only or metformin addition: A systematic review and meta-analysis. Sci Rep. 2020;10(1):7802. Published 2020 May 8. doi:10.1038/s41598-020-64776-w

 

Why I chose this article: This article has a high level of evidence as it is a systematic review and meta-analysis. It analyzes the effects of lifestyle management combined with Metformin against LSM alone, which is relevant since lifestyle changes are often recommended alongside pharmacological interventions in managing PCOS during pregnancy.

 

Abstract

Polycystic ovary syndrome (PCOS) is a common disease that has an effect on approximately 10% of women of childbearing age. Although there is evidence regarding the role of lifestyle factors in the development of PCOS, the exact etiology remains unclear. Additionally, metformin is used in the treatment of PCOS but its role remains unclear. We compared the effects of lifestyle modification (LSM) + metformin and metformin alone on PCOS. We performed a systematic review by searching electronic databases for publications until December 2019. The primary endpoints were clinical outcomes, such as menstrual cycles and pregnancy rates, and the secondary endpoints were anthropometric, metabolic, and androgenic parameters. The meta-analysis revealed that there was no significant difference in the improvements in the menstrual cycles between LSM and metformin alone (weighted mean difference [MD] = 1.62) and between LSM + metformin and LSM (MD = 1.20). The pregnancy rates and body mass indices were not significantly different between LSM and metformin alone (MD = 1.44 and −0.11, respectively). LSM reduced insulin resistance (MD = −0.52) and increased serum levels of sex hormone-binding globulins (MD = 8.27) compared with metformin. Therefore, we suggest recommending lifestyle modifications actively to women with PCOS if they do not have indications for metformin.

 

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc)	Outcome(s) studied	Key Findings	Limitations and Biases
Srishti Kanda, Uzair Chatha, Victor A. Odoma , Aakanksha Pitliya , Esraa M. AlEdani, Japneet K. Bhangu, Khalid Javed, Prabhleen Kaur Manshahia, Shamsun Nahar, Pousette Hamid	Systematic review	– Articles from PubMed, Google Scholar, and ScienceDirect that addressed the impact of MTF intervention in pregnancy in women with PCOS between 2019 and May 16, 2023. – A total of 1,877 articles were selected, and 35 articles were evaluated for eligibility and quality. Finally, 13 articles were included in the study.	– Live birth rate – Clinical Pregnancy Rate and Miscarriage Rate – Ovarian Hyperstimulation Syndrome – Impact of MTF on Pregnancy Complications – Impact of offspring	– There is uncertainty about metformin’s effect on live birth rates, with low-quality evidence showing it may reduce pregnancy and live birth rates compared to clomiphene citrate alone. – MTF may improve clinical pregnancy rates and reduce miscarriage rates, especially when combined with CC, but results vary based on BMI. – MTF reduces pregnancy complications, such as gestational diabetes and preeclampsia, and may affect offspring growth, increasing the risk of obesity.	– Inclusion of only review articles and meta-analyses from specific databases (PubMed, Google Scholar, and ScienceDirect), published in the last five years in English leads to a possibility of missing relevant research studies that may provide different perspectives on the topic.  – While the review briefly mentioned long-term effects on offspring, such as increased BMI and obesity risk, the extent and significance of these effects were not extensively explored.
Daiyu Zhu, Yan Chen, Jianfeng Huang, Hongxia Deng, Xiaoyang Shen, Danhua Lu, Liangzhi Xu	Systematic review and meta analysis	– The study population were women who were pregnant and diagnosed with PCOS according to the Rotterdam 2003 criteria or offspring whose mother had been diagnosed with PCOS – Metformin was used as an intervention on participants during pregnancy – Study included a placebo control group who were not treated with metformin during pregnancy	–  The study assessed pregnancy complications, including PIH and preeclampsia, GDM, and preterm birth, or offspring outcomes, including birth weight, birth length, head circumference at birth, and body mass index.	– Continual use of metformin during pregnancy significantly reduces the risks of pregnancy-induced hypertension,  preeclampsia, preterm delivery, and macrosomia.  – Metformin does not significantly improve live birth rates or reduce the risks of gestational diabetes or miscarriage compared to placebo.  – For offspring, metformin exposure is associated with larger head circumference at birth and higher long-term BMI, but it does not affect birth weight, birth length, or cognitive function in later childhood.  – Metformin significantly decreases insulin resistance in mothers but has no significant effect on fasting glucose or glycated hemoglobin. – Metformin showed no significant differences in sex hormone levels in mothers or offspring, except for slightly higher SHBG levels in the offspring.	– There are a limited number of studies addressing the relevant outcomes, especially regarding long-term metabolic profile and sex hormone levels, and so our results should be interpreted cautiously.  – The qualities of eligible studies were not high.  – Although there were no no significant differences in maternal sex hormone levels between groups, the impact of maternal sex hormones on the sex hormones of offspring should be further studied.
Frida Andra, David Abbott, Solhild Stridsklev, Anne Vibeke Schmedes,  Ingrid Hov Odsater, Eszter Vanky, and Oyvind Salvesen	Randomized, placebo controlled, multicenter study	– A total of 262 women with PCOS and 119 controls. – The participants with PCOS were randomly assigned to metformin (2 g daily) or placebo, from first trimester to delivery.	– Androstenedione (A4), testosterone (T), sex-hormone binding globulin (SHBG), and free testosterone in‐ dex (FTI) at 4 time points in pregnancy.	– Pregnant women with PCOS exhibited higher levels of androstenedione (A4), testosterone (T), and free testosterone index (FTI) compared to healthy controls during the first half of pregnancy. – While A4 and T levels remained relatively stable throughout pregnancy in women with PCOS, FTI levels decreased over time. – Overall, metformin did not show significant androgen-lowering effects in the total PCOS study population. However, subgroup analyses revealed that it did lower A4 levels in nonobese women with PCOS and in those carrying male fetuses. – The study noted similar androgen levels across pregnancies regardless of fetal sex, but metformin specifically reduced A4 and T levels in mothers carrying male fetuses.	– Limitations include limited assessments of maternal steroid hormones and lacking measurements of additional androgens throughout pregnancy.  – The control group did not have third-trimester serum samples, and serum sampling times varied between groups, potentially affecting comparability.  – Additionally, while the population was representative, biases in participant selection and adherence could influence the findings’ generalizability.
Jane L. Tarry‐Adkins, Susan E. Ozanne1 & Catherine E. Aiken	Systematic review and meta analysis	– 35 studies (8033 participants) for this meta-analysis.  – The majority of these studies (27 studies; 5319 participants) investigated metformin treatment for diabetes in pregnancy. – Eligible studies were identified comparing metformin to insulin, glyburide, and placebo	– Investigated gestational weight gain, pre-eclampsia, gestational hypertension, preterm birth, gestational age at delivery, c-section, and side effects of metformin vs placebo.	– Metformin treatment during pregnancy is associated with reduced gestational weight gain in women with maternal obesity and PCOS. – Although there were no significant differences in the risk of pre-eclampsia or gestational HTN when comparing metformin to other treatments, a trend toward reduced preeclampsia was noted in metformin-treated women overall.  – Randomization to metformin was linked to a lower likelihood of cesarean section, particularly in women with maternal obesity, but did not significantly impact gestational age at delivery or the risk of preterm birth across different indications.	– The study has a moderate-to-low risk of bias overall, but the presence of six studies with a high risk of bias may still influence the results, despite their exclusion not materially altering the outcomes.  – While most included studies reported similar maternal baseline characteristics, the potential for unmeasured confounding factors remains a limitation.
Johanna Melin, Maria Forslund,  Simon Alesi,  Terhi Piltonen,  Daniela Romualdi,  Poli Mara Spritzer, Chau Thien Tay, Alexia Pena, Selma Feldman Witchel, Aya Mousa, Helena Teede	Systematic Review and meta analysis	– A literature search was performed from induction until 2017 using the databases Ovid Medline, Embase, PsycINFO, All EBM, and CINAHL. – 32 RCTs were included in this systematic review, with a total of 1660 studies screened. – Metformin dosages were between 850 to 2000 mg daily. – Performed subgroup analyses by BMI, categorized as those with BMI < 25 and those with BMI ≥ 25.	– BMI, fasting glucose levels, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profiles, total testosterone and free androgen index, menstrual cycle regularity, and gastrointestinal adverse effects.	– Metformin significantly reduced BMI, HOMA-IR, and fasting glucose compared to placebo, but had mixed results for hirsutism and menstrual regularity.  – When comparing metformin combined with lifestyle changes to placebo plus lifestyle, metformin users had a lower BMI and experienced more gastrointestinal side effects, though no significant differences in hirsutism were noted. – Only a few studies compared metformin directly to lifestyle interventions, finding no significant difference in BMI but some advantages in testosterone levels	– There is an absence of larger studies specifically focusing on women with a BMI <25 kg/m² and adolescents with PCOS, which could impact the generalizability of the findings.  – Additionally, the risk of language bias is noted, as studies published in languages other than English were excluded.
Chan Hee Kim, Seung Joo Chon, Seon Heui Lee	Systematic review and meta analysis	– 13 studies were selected in total, 11 which are RCTs. – Six studies compared LSM with metformin alone, eight studies compared LSM + metformin with LSM, and one study was included in both.	– Main outcomes were menstrual cycle frequency, pregnancy rate, weight loss, metabolic parameters such as fasting glucose, insulin, HOMA-IR, and androgenic parameters such as total testosterone, free androgen index, and sex hormone-binding globulin.	– The comparison of menstrual cycles showed no significant difference in frequency improvement between lifestyle management and metformin alone; however, LSM combined with metformin led to a significantly greater number of menstrual cycles over six months compared to LSM alone. – No significant differences in pregnancy rates were observed between LSM and metformin groups, whether used alone or in combination. – Both LSM and metformin resulted in significant weight loss, but no significant difference in weight loss or BMI was found between the combined LSM + metformin and LSM groups. – Fasting glucose and insulin levels did not show significant differences between the groups, though LSM + metformin significantly reduced fasting insulin compared to LSM alone. – Metformin alone significantly reduced total testosterone levels compared to LSM, but no significant differences were observed between LSM + metformin and LSM regarding testosterone levels or sex hormone- binding globulin levels.	– Six studies had a high risk of selection bias, and four studies reported a high risk in the blinding of participants, personnel, and outcome assessments.  – Five studies had a high risk of attrition bias associated with high drop rates.

Conclusion(s):

Article 1: Metformin may provide benefits for pregnant women with PCOS, such as reducing the risk of pregnancy complications like ovarian hyperstimulation syndrome, pregnancy-induced hypertension, gestational diabetes, macrosomia, and preterm birth. It shows potential in improving clinical pregnancy rates, especially in women with higher BMI. However, there are concerns about MTF’s association with increased fetal head circumference and long-term effects on offspring, such as higher BMI and increased risk of obesity. 

 

Article 2: Metformin treatment during pregnancy in women with PCOS significantly reduces the risk of pregnancy complications such as pregnancy-induced hypertension, preeclampsia, preterm delivery, and macrosomia. However, metformin may lead to an increase in fetal head circumference at birth and higher BMI in offspring in the long term. While metformin improves insulin resistance in mothers with PCOS, its effects on offspring’s metabolic health remain uncertain, though SHBG levels were increased in offspring. 

 

Article 3: Pregnant women with PCOS have higher circulating maternal androgen levels compared to healthy controls. While Metformin did not have a significant effect on maternal androgen levels overall, it showed a modest androgen-lowering effect in specific subgroups: nonobese women with PCOS and those carrying male fetuses. 

 

Article 4: While metformin use during pregnancy is associated with reduced gestational weight gain and a decreased likelihood of cesarean section in women with obesity, its benefits for preventing pre-eclampsia and gestational hypertension are less clear, with no significant differences noted across treatment indications. Additionally, metformin does not appear to reduce the incidence of gestational diabetes and is associated with increased gastrointestinal side effects. 

 

Article 5: Metformin demonstrates evidence in reducing BMI and improving metabolic outcomes in adults with polycystic ovary syndrome who have a BMI of 25 kg/m² or higher. While metformin shows benefits in lowering weight, insulin resistance, and certain lipid levels, its effects on hirsutism and menstrual regularity are less certain. The findings indicate that metformin can be a valuable option for managing weight and metabolic disorders in this population, but its effectiveness in non-obese women and adolescents with PCOS is less clear.

 

Article 6: Lifestyle management generally offers more benefits than metformin alone for improving clinical outcomes in women with PCOS, particularly in menstrual frequency and pregnancy outcomes. While the combination of LSM and metformin shows some advantages in reducing fasting serum insulin levels and improving menstrual cycles, it does not significantly lower BMI compared to LSM alone. Therefore, LSM should be prioritized as the primary treatment, with metformin considered only if necessary due to its side effects. 

 

Overarching Conclusion: 

The overarching conclusion from these six articles is that while metformin can offer certain benefits for pregnant women with PCOS, such as reducing the risk of pregnancy complications and improving metabolic outcomes, its effectiveness varies across different populations and conditions. There are concerns regarding potential negative effects on fetal health, such as increased fetal head circumference and long-term obesity risk in offspring. Moreover, lifestyle management is generally more effective than metformin alone for improving clinical outcomes in women with PCOS, particularly concerning menstrual frequency and pregnancy outcomes. The combination of LSM and metformin shows some advantages, particularly in insulin sensitivity, but does not significantly impact BMI. Overall, LSM should be prioritized, with metformin considered only when necessary, highlighting the need for careful treatment selection and further research on these interventions.

 

Clinical Bottom Line

Weight of the Evidence:

This paper analyzes six articles, and weighs them in the following order: Article 2, Article 1, Article 4, Article 3, Article 5, Article 6.

Article 2 is a comprehensive systematic review with a meta-analysis that included a placebo control group. It has strong findings on significant reductions in pregnancy complications (PIH, preeclampsia, preterm delivery, and macrosomia). It also has a detailed analysis of offspring outcomes related to metformin exposure. However, it did not show significant improvement in live birth rates or reduction in gestational diabetes compared to placebo. It also had a limited number of studies on long-term metabolic outcomes, suggesting the need for cautious interpretation. Article 1 is a systematic review of a considerable number of studies, examining multiple maternal and offspring outcomes. It highlights the impact of Metformin on reducing pregnancy complications and miscarriage rates when combined with clomiphene citrate. However, there is some uncertainty regarding live birth rates with low-quality evidence. There is also limited exploration of long-term effects on offspring, such as increased obesity risk. Article 4 is a large meta-analysis (35 studies, 8033 participants) with a focus on a variety of maternal outcomes. It has observations of reduced gestational weight gain and potential trends towards lower preeclampsia risk in metformin-treated women. However, there is a moderate-to-low risk of bias, with some included studies having a high risk of bias. It also lacked significant impact on several other critical outcomes, such as gestational age at delivery or preterm birth. Article 3 is a randomized, placebo-controlled design with a decent sample size. It provides specific insights into hormonal changes during pregnancy and subgroup analyses based on obesity and fetal sex. However, it did not show significant overall androgen-lowering effects in the total PCOS population. It also had limited hormone assessments and potential biases in participant selection and adherence. Article 5 is a systematic review covering a variety of outcomes related to PCOS and Metformin treatment. It highlights significant reductions in BMI and insulin resistance. However, it had mixed results for hirsutism and menstrual regularity, limiting applicability. There is also a risk of language bias and absence of larger studies focusing on certain populations. Article 6 focuses on the comparison of lifestyle management and Metformin, addressing multiple outcomes. However, there were no significant differences in pregnancy rates or improvement in menstrual cycles.

 

Magnitude of Any Effects: 

The articles were largely unanimous in their conclusions that metformin offers benefits while still raising concerns about gastrointestinal side effects. Metformin significantly reduces the risk of complications like gestational diabetes and preeclampsia, though the exact percentage decrease varies by study. Some articles noted a reduction in pregnancy-induced hypertension and macrosomia but highlighted concerns about fetal head circumference. Lifestyle management generally outperformed metformin alone in improving menstrual frequency and pregnancy outcomes, suggesting a greater effect size for LSM, although exact numbers were not consistently reported.

 

Clinical Significance:

The findings from these articles highlight several important points for managing women with PCOS, especially during pregnancy. Metformin can help reduce pregnancy complications like gestational diabetes and preeclampsia, improving outcomes for mothers and babies. However, it appears to be more effective for certain subgroups, such as non-obese women, suggesting that treatment should be tailored to individual needs. Lifestyle management is shown to be more beneficial than metformin alone for improving menstrual cycles and pregnancy outcomes, emphasizing the importance of incorporating lifestyle changes into treatment plans. Additionally, there are concerns about the long-term effects of metformin on children, which means healthcare providers should carefully consider its use during pregnancy. Overall, these findings suggest that while metformin can be helpful, it should complement lifestyle changes rather than replace them, and more research is needed to optimize treatment strategies for women with PCOS.