Age at Menarche and Pregnancy and Perinatal Outcomes: triangulating evidence from multivariable regression and Mendelian randomization analyses

Observational studies have suggested that younger age at menarche is associated with increased risk of adverse pregnancy outcomes. However, it is unclear to what extent these associations may be explained by maternal adiposity.

We explored the relationship between age at menarche and 13 pregnancy and perinatal outcomes, with and without adjustment for BMI. Evidence was triangulated across two approaches. Multivariable regression was conducted in the Avon Longitudinal Study of Parents and Children, a UK birth cohort, using adult BMI to proxy childhood BMI. Univariate and multivariable Mendelian Randomization (MR) utilised pregnancy data from the MR-PREG collaboration, accounting for genetically-instrumented childhood BMI.

Both analytical approaches suggested a decreased risk of gestational hypertension, preeclampsia, and hypertensive disorders of pregnancy with older age at menarche; these estimates all attenuated when BMI was accounted for. For example, associations with hypertensive disorders of pregnancy were attenuated in multivariable regression (OR=0.91, 95%CI: 0.87-0.94 adjusting for highest educational attainment, non-white ethnicity, age, parity, offspring sex; to OR=0.97, 95%CI: 0.93-1.01 after BMI adjustment), and in univariate MR (OR=0.90, 95%CI: 0.84-0.97) to multivariable MR accounting for childhood BMI (OR=1.01, 95%CI: 0.94-1.09).

Findings across both approaches did not support effects of age at menarche on perinatal depression, low birthweight, very pre-term birth, post-term birth, small-for-gestational-age, or large-for-gestational-age. Multivariable regression adjusting for BMI did not support an association of age at menarche with gestational diabetes. Univariate MR suggested a protective effect of older age at menarche on gestational diabetes, which attenuated in multivariable MR adjusting for childhood BMI.

Multivariable regression and univariate MR did not identify associations between age at menarche with neither continuous birthweight, high birthweight (>4500g) nor preterm birth. However, multivariable MR suggested that after accounting for childhood BMI, an older age at menarche may be causally related to higher birthweight, increased risk of high birthweight, and decreased risk of preterm birth.

Our findings suggested that reported associations between an earlier age at menarche and hypertensive disorders of pregnancy are driven by confounding by childhood adiposity.
Future work is needed to understand mechanisms underlying the protective effect of older age at menarche on offspring birthweight and preterm delivery.