Pregnancy, perinatal and childhood outcomes in women with and without polycystic ovary syndrome and metformin during pregnancy: a nationwide population-based study

Abstract

Background Polycystic Ovary Syndrome (PCOS) is an endocrine disorder that affects women in reproductive age and represents an unfavourable risk factor for several pregnancy and perinatal outcomes. Despite, no guidelines or pharmaceutical strategies for treating PCOS during pregnancy are available. The aim of this study is to determine the association between polycystic ovary syndrome with or without metformin and the pregnancy, perinatal outcomes as well as the risk of obesity in children born to these mothers. Methods In this nationwide population-based cohort study based in Swedish population, all singleton births (n = 1,016,805) from 686,847 women since 2006 up to 2016 were included. Multivariable logistic and Cox regression modelling with odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals were used to study the association between the exposure of maternal PCOS, metformin during pregnancy (or the combination of both) and: 1) Pregnancy outcomes: preeclampsia, gestational diabetes, caesarean section, and acute caesarean section, 2) Perinatal outcomes: preterm birth, stillbirth, low birth weight, macrosomia, Apgar < 7 at 5 min, small for gestational age and large for gestational age, and 3) Childhood Obesity. Results PCOS in women without metformin use during pregnancy was associated with higher risks of preeclampsia (OR = 1.09, 1.02–1.17), gestational diabetes (OR = 1.71, 1.53–1.91) and caesarean section (OR = 1.08, 1.04–1.12), preterm birth (OR = 1.30, 1.23–1.38), low birth weight (OR = 1.29, 1.20–1.38), low Apgar scores (OR = 1.17, 1.05–1.31) and large for gestational age (OR = 1.11, 1.03–1.20). Metformin use during pregnancy (in women without PCOS) was associated with a 29% lower risks of preeclampsia (OR = 0.71, 0.51–0.97), macrosomia and large for gestational age. Obesity was more common among children born to mothers with PCOS without metformin (HR = 1.61, 1.44–1.81); and those with metformin without PCOS (HR = 1.67, 1.05–2.65). PCOS with metformin was not associated with any adverse outcome. Conclusion PCOS was associated with increased risks of adverse pregnancy and perinatal outcomes and childhood obesity. Metformin appears to reduce these risks in mothers with polycystic ovary syndrome and their children; but may increase the risk of childhood-obesity in children form women without PCOS.

Metformin in pregnancy and risk of abnormal growth outcomes at birth: a register-based cohort study

“…In prospective clinical trials in obese non-diabetic women, metformin use versus placebo did not alter the risk of LGA birth, 19 20 whereas in a recent cohort study on pregnant women without diabetes and PCOS exposed or non-exposed to metformin, a reduced LGA risk for metformin exposure was found. 21 Prepregnancy BMI and gestational hyperglycemia are considered drivers of LGA risk in the offspring. 22 In summary, current evidence suggests that metformin may reduce hyperglycemia-related LGA.…”

Gestational diabetes and other adverse pregnancy outcomes in polycystic ovary syndrome

“…Fornes et al [41 ▪ ] also found an increased risk of obesity in offspring of individuals with PCOS not treated with metformin, as well as in individuals without PCOS treated with metformin compared with those without PCOS or metformin treatment. Individuals with PCOS on metformin during pregnancy had no increased risk of childhood obesity [41 ▪ ]. There was no increased risk of adverse outcomes in pregnant individuals with PCOS on metformin compared with those without PCOS or metformin treatment [41 ▪ ].…”

“…Individuals with PCOS on metformin during pregnancy had no increased risk of childhood obesity [41 ▪ ]. There was no increased risk of adverse outcomes in pregnant individuals with PCOS on metformin compared with those without PCOS or metformin treatment [41 ▪ ]. Further research is warranted into the effect of PCOS and metformin during pregnancy on offspring.…”

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

“…Indeed, metformin administration in STZ-diabetic rats resulted in improved testosterone, LH and FSH hormones levels (Nasrolahi et al 2013 ). Various studies have shown that treatment with metformin is effective in reproductive system diseases, including female and male reproduction in endocrine pathologies (Lee et al 2019 ; Shpakov 2021 , ul haq Shah, Shrivastava et al 2022 ), endometriosis (Zhao et al 2018 , Mu et al 2020 , Stochino-Loi et al 2021 , Kimber-Trojnar et al 2022 ), polycystic ovary syndrome (Chen et al 2019 ; Fornes et al 2022 , Xu et al 2022 ) and prostate (Sun et al 2018 , Chen, Wang et al 2021a , b , c , Aydın et al 2022 , Morale et al 2022 ).…”