Age at menarche and adverse pregnancy and perinatal outcomes: triangulating evidence from multivariable and Mendelian...

Observational studies have suggested that a younger age at menarche is associated with increased risks of adverse pregnancy and perinatal outcomes. However, it is unclear whether these relationships are causal.

We estimated the associations between age at menarche and 13 pre-specified pregnancy outcomes by using two approaches. We estimated observational associations in the Avon Longitudinal Study of Parents and Children (N = 9441) using multivariable regression accounting for educational attainment, ethnicity, maternal age, parity, offspring sex, and adiposity. We conducted two-sample Mendelian randomization (MR) using data from the Mendelian Randomization in Pregnancy (MR-PREG) collaboration (77 683-707 797 pregnancies) and multivariable MR (MVMR) accounting for genetically-proxied adiposity.

Older age at menarche was associated with lower risks of hypertensive disorders of pregnancy, gestational hypertension, and preeclampsia, but accounting for adiposity attenuated these effects across approaches. For example, per 1-year older age at menarche, the odds ratio (OR) for hypertensive disorders of pregnancy was 0.88 (95% confidence interval (CI) : 0.84, 0.93) in inverse variance weighted MR and 0.95 (95% CI: 0.90, 1.01) in MVMR, while the observational association attenuated from OR = 0.91 (95% CI: 0.87, 0.94) to OR = 0.97 (95% CI: 0.93, 1.01). No clear evidence was found for the effects of age at menarche on small-for-gestational-age, low birthweight, post-term birth, or perinatal depression from either approach. For other outcomes evidence was limited by imprecision (very preterm birth, gestational diabetes) or inconsistent effects in sensitivity analyses (offspring birthweight, large-for-gestational-age, high birthweight, preterm birth).

We find little robust evidence for causal effects of age at menarche on pregnancy outcomes. Effects of younger menarche on increased risks of hypertensive disorders of pregnancy may be driven by adiposity.