Disentangling the relationship between intrauterine exposures and offspring growth in mid-childhood

Conventional epidemiological studies have suggested that lower birthweight and adverse pregnancy events are associated with later life obesity and cardiometabolic disorders, suggesting that intrauterine factors may play an important role in the offspring’s later life health. Nevertheless, it remains unclear whether the link between intrauterine factors and childhood anthropometry is causal or driven by confounding or genetic factors. We performed two-sample Mendelian randomization (MR) to assess whether adverse pregnancy-related conditions (gestational diabetes, gestational hypertension and pre-eclampsia) and birth outcomes (birthweight, gestational duration and placental weight) have a causal effect on mid-childhood (age 8–10) body mass index (BMI) and height. We selected independent genetic variants from the largest publicly available genome-wide association studies that were associated (P < 5 × 10− 8) with each of the exposures. We partitioned the genetic effect on mid-childhood BMI and height into maternal- and offspring-specific components using 26,301 genotyped mother-offspring pairs from three birth cohorts to account for the correlation between maternal and offspring genotype. The analyses were replicated in 3,885 mother-offspring pairs from the UK Biobank. We found evidence for a causal effect of birthweight on mid-childhood height (βbirthweight−height = 0.45 standard deviation (SD) per SD change in birthweight, 95% CI = 0.33–0.57), which can partially be explained by birth length and maternal height, rather than strong mediation through intrauterine factors. Meanwhile, the relationship between birthweight and mid-childhood BMI (βbirthweight−BMI = 0.30 SD per SD change in birthweight, 95% CI = 0.21–0.40) was predominantly driven by genetic pleiotropy. Neither pregnancy-related conditions nor maternal intrauterine effect through gestational duration and placental weight showed no strong evidence of having a causal effect on offspring BMI or height in mid-childhood. Our study suggests that intrauterine exposures acting through gestational diabetes, gestational hypertension, preeclampsia, birthweight, gestational duration and placental weight are unlikely to be key drivers of offspring mid-childhood BMI or height. The causal relationship identified between birthweight and mid-childhood height but not with mid-childhood BMI suggests that the intrauterine environmental and genetic factors impacting birthweight may be predominantly related to skeletal growth.