IntroductionAntidiabetic drugs (OADs) are increasingly prescribed to treat hyperglycaemia during pregnancy in women with gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), even though long-term effects on offspring are unknown. This systematic review summarises the evidence of follow-up studies of randomised controlled trials (RCTs) reporting on long-term effects of prenatal exposure to OADs on offspring.MethodsThe MEDLINE, EMBASE and CENTRAL databases were searched from inception to April 2018 for the concepts antidiabetic agents and prenatal exposure (or pregnancy and offspring/child) in combination with an RCT search filter. RCTs evaluating post-neonatal health effects in offspring and comparing maternal treatment with an OAD with no treatment, placebo, an alternative OAD or insulin during pregnancy were eligible for inclusion. Two independent researchers selected, extracted and assessed the data. Meta-analyses were performed using a random effects model and the Cochrane Collaboration’s risk of bias tool was used for quality assessment.ResultsTen studies were included, with a maximal follow-up duration of 9 years, comprising 778 children of mothers with GDM or PCOS who were randomised to either metformin or insulin/placebo during pregnancy. Meta-analysis showed that children prenatally exposed to metformin were heavier compared to controls (standardised mean difference (SMD) 0.26 [95% CI 0.11–0.41]), but not taller (SMD 0.10 [95% CI −0.14–0.33]). Additionally, offspring body mass index (BMI) z scores did not differ according to metformin exposure (mean difference 0.30 [95% CI −0.01–0.61]). Individual small studies reported that prenatal exposure to metformin was associated with greater mid-upper arm, head and waist circumferences, biceps skinfolds, waist-to-height ratio, more arm fat, higher fasting glucose, ferritin and lower LDL cholesterol in offspring.ConclusionPrenatal exposure to metformin is associated with increased offspring weight, but not with height or BMI. Larger follow-up studies are needed to confirm and look into the implications of these findings.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0479-0) contains supplementary material, which is available to authorized users.

Recent studies implicate maternal gestational diabetes mellitus (GDM) in differential methylation of infant DNA. Folate and vitamin B12 play a role in DNA methylation, and these vitamins may also influence GDM risk. The aims of this study were to determine folate and vitamin B12 status in obese pregnant women and investigate associations between folate and vitamin B12 status, maternal dysglycaemia and neonatal DNA methylation at cytosine-phosphate-guanine sites previously observed to be associated with dysglycaemia. Obese pregnant women who participated in the UK Pregnancies Better Eating and Activity Trial were included. Serum folate and vitamin B12 were measured at the oral glucose tolerance test (OGTT) visit. Cord blood DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. Regression models with adjustment for confounders were used to examine associations. Of the 951 women included, 356 (37.4%) were vitamin B12 deficient, and 44 (4.6%) were folate deficient. Two-hundred and seventy-one women (28%) developed GDM. Folate and vitamin B12 concentrations were not associated with neonatal DNA methylation. Higher folate was positively associated with 1-h plasma glucose after OGTT (β = 0.031, 95% CI 0.001–0.061, p = 0.045). There was no relationship between vitamin B12 and glucose concentrations post OGTT or between folate or vitamin B12 and GDM. In summary, we found no evidence to link folate and vitamin B12 status with the differential methylation of neonatal DNA previously observed in association with dysglycaemia. We add to the evidence that folate status may be related to maternal glucose homoeostasis although replication in other maternal cohorts is required for validation.