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

Abstract

IntroductionWe previously reported an increased risk of being small for gestational age (SGA) and a decreased risk of being large for gestational age (LGA) after in utero exposure to metformin compared with insulin exposure. This follow-up study investigated if these observations remain when metformin exposure (henceforth, metformin cohort) is compared with non-pharmacological antidiabetic treatment of gestational diabetes mellitus (GDM; naïve cohort), instead of insulin.Research design and methods This was a Finnish population register-based cohort study from singleton children born during 2004–2016. Birth outcomes from metformin cohort (n=3964) and the naïve cohort (n=82 675) were used in the main analyses. Additional analyses were conducted in a subcohort, restricting the metformin cohort to children of mothers with GDM only (n=2361). Results were reported as inverse probability of treatment weighted OR (wOR), with the naïve cohort as reference.Results No difference was found for the outcome of SGA between the cohorts in the main analyses (wOR 0.97, 95% CI 0.73 to 1.27) or in the additional analyses (wOR 1.01, 95% CI 0.75 to 1.37). No difference between the cohorts was found for the risk of LGA (wOR 0.91, 95% CI 0.75 to 1.11) in the main analyses but a decreased risk was observed in the additional analyses (wOR 0.72, 95% CI 0.56 to 0.92).Conclusions This follow-up study found no increase in the risk of SGA or LGA after in utero exposure to metformin, compared with drug-naïve GDM. The decreased risk of LGA in mothers with GDM may suggest residual confounding. The lack of increased SGA risk aligns with findings from studies using metformin in non-diabetic pregnancies. In contrast, lower birth weight and increased SGA birth risk were observed in GDM pregnancies for metformin versus insulin. Metformin should be avoided with emerging growth restriction in utero. The interplay of intrauterine hyperglycemia and pharmacological treatments needs further assessment.

Neonatal outcome following metformin‐treated gestational diabetes mellitus: A population‐based cohort study

“…Indeed, mean birthweight was significantly lower, and macrosomia significantly less prevalent in infants exposed to metformin as single adjunctive treatment compared with nutrition therapy alone. However, the difference in mean birthweight disappeared when infant sex and gestational age at birth was taken into consideration, and in line with results reported by Brand et al 2,11 . we found no association between SGA and metformin treatment.…”

“…However, the difference in mean birthweight disappeared when infant sex and gestational age at birth was taken into consideration, and in line with results reported by Brand et al. 2 , 11 we found no association between SGA and metformin treatment. Our results further support a similar risk of LGA as previously reported by some authors, 13 , 15 and contradicts results favoring metformin treatment over nutrition therapy.…”

“…Our results further support a similar risk of LGA as previously reported by some authors, 13 , 15 and contradicts results favoring metformin treatment over nutrition therapy. 11 , 12 , 14 Different definitions of SGA and LGA are used in the literature, and different reference populations yield different proportions of inappropriate growth when using a fixed definition on the same data. 34 This likely explains contradictory findings between studies.…”

“… 9 Randomized controlled trials have confirmed that short‐term neonatal outcome following metformin treatment is noninferior to insulin treatment, 8 but long‐term safety data are still limited. 2 , 10 , 11 However, only a few studies have investigated neonatal outcome following metformin treatment in comparison with nutrition therapy, 11 , 12 , 13 , 14 , 15 , 16 and most studies evaluating neonatal outcome following GDM have not distinguished metformin alone from combined metformin‐insulin treatment, which makes it difficult to draw conclusions regarding metformin treatment per se.…”