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

Abstract

Background: Researches 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 Reviewer's 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 longterm BMI in offspring.

Effect of Metformin (MTF) Intervention During Pregnancy in Women With Polycystic Ovarian Syndrome (PCOS): A Systematic Review

“…These findings are significant considering that women with PCOS are at an increased risk of developing complications such as gestational diabetes mellitus (GDM), PIH, and preterm delivery [ 26 , 17 ]. The findings of this study are consistent with a number of high-quality studies supporting the benefits of MTF in reducing the risk of pregnancy complications [ 19 ].…”

“…It was found that MTF treatment during pregnancy reduced the risk of PIH, preeclampsia, macrosomia (abnormally large birth weight), and preterm delivery compared to placebo [ 19 , 14 , 20 ]. These findings are significant considering that women with PCOS are at an increased risk of developing complications such as gestational diabetes mellitus (GDM), PIH, and preterm delivery [ 26 , 17 ].…”

“…Regarding the impact on offspring, the review indicated that MTF treatment during pregnancy decreased the risk of macrosomia (large birth weight) but was associated with larger fetal head circumference [ 19 ]. There was no evidence of an association between MTF treatment and fetal birth weight or length.…”

Insulin resistance in polycystic ovary syndrome across various tissues: an updated review of pathogenesis, evaluation, and treatment

“…Metformin, the most widely used insulin sensitizer for PCOS, reduces hepatic glucose production, inhibits gluconeogenesis and adipogenesis, improves peripheral tissue sensitivity to insulin, and prevents excessive insulin activity in the ovary [153]. Numerous studies have shown that metformin not only reduces weight and metabolic disorders but also corrects menstrual patterns, restores ovulation, and even improves chances of pregnancy [154]. Evidence-based guidelines recommend the use of metformin in obese, insulin-resistant women with PCOS to manage weight and endocrine and metabolic disorders, in conjunction with lifestyle adjustments [155,156].…”

Metformin With or Without Clomiphene Citrate Versus Laparoscopic Ovarian Drilling With or Without Clomiphene Citrate to Treat Patients With Clomiphene Citrate-Resistant Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

“…Most medications prescribed for pregnant and lactating women are “off-label” because most of the clinically approved medications do not have appropriate drug labeling information ( Ren et al, 2021 ). The limited evidence indicates the long-term safety of the fetus exposed to metformin excluding mild adverse anthropometric profiles (sex hormone binding globulin levels and long-term body mass index in offspring) ( Roy and Sahoo, 2021 ; Zhu et al, 2022 ). Although the FDA has not completely ruled out the risk of metformin in pregnancy, “these studies cannot establish the lacking metformin-associated risk because of methodological limitations, including the small sample size and inconsistent comparator groups” ( https://packageinserts.bms.com/pi/pi_glucophage.pdf ), many of the reviewed studies concluded that metformin is a safe choice at the beginning of pregnancy without persuasive evidence of increased risk for miscarriages or congenital malformations ( Quadir, 2021 ).…”