Higher birthweight may be associated with greater height in mid-childhood, while links between birthweight and childhood body mass index appear to be largely explained by shared genetic factors rather than direct intrauterine effects, according to a recent study.
In the study, investigators analyzed data from 26,301 genotyped mother-offspring pairs from three prospective birth cohorts: the Avon Longitudinal Study of Parents and Children; Born in Bradford cohort; and the Norwegian Mother, Father and Child Cohort Study. Replication analyses included 3,885 mother-offspring pairs from the UK Biobank. Using a two-sample Mendelian randomization framework, the investigators separated maternal intrauterine genetic effects from inherited offspring genetic effects to evaluate the associations between pregnancy-related conditions, birth phenotypes, and growth outcomes measured at approximately age 8 to 10 years.
The primary outcomes were mid-childhood body mass index (BMI) and height. Exposures included gestational diabetes, gestational hypertension, preeclampsia, birthweight, gestational duration, and placental weight. The investigators reported that a 1-unit increase in birthweight was associated with a 0.45-unit increase in mid-childhood height, corresponding to an estimated increase of approximately 2.3 cm at 8 years. Similar findings were observed across multiple sensitivity analyses.
The relationship between birthweight and mid-childhood BMI differed from the findings on mid-childhood height. Associations were observed when analyses used offspring genetic variants associated with birthweight, but not when the analyses isolated maternal intrauterine genetic effects. According to the investigators, this pattern suggested that “the relationship between birthweight and mid-childhood BMI [...] was predominantly driven by genetic pleiotropy.”
The investigators found no strong evidence that gestational hypertension or preeclampsia affected mid-childhood BMI or height. Gestational diabetes showed a small causal association with greater mid-childhood height in one inverse variance weighted analysis, but the finding was attenuated in sensitivity analyses and was not consistently replicated in the UK Biobank cohort.
Additional analyses examined maternal intrauterine influences acting through birthweight, gestational duration, and placental weight. Maternal genetic effects linked to gestational duration and placental weight were not associated with mid-childhood BMI or height. Maternal genetic effects associated with higher birthweight were linked to greater mid-childhood height, although the association weakened after removing height-associated genetic variants, suggesting maternal height and skeletal growth pathways may partly explain the findings.
The investigators noted several limitations. Genetic instruments explained only a modest proportion of exposure variability, which may have reduced the power to detect small effects. Outcomes were limited to anthropometric measurements obtained during mid-childhood, and the findings may not apply to earlier childhood or adolescence. All of the patients included in the analysis were of European ancestry, potentially limiting generalizability to other populations. The investigators also acknowledged that Mendelian randomization captured only pathways reflected in currently available genetic instruments.
“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,” wrote lead study author Kym-Mai Nguyen, of the Institute for Molecular Bioscience at The University of Queensland in Australia, and colleagues.
The study authors reported no competing interests. Funding sources included the Australian National Health and Medical Research Council, Wellcome Trust, the UK Medical Research Council, the British Heart Foundation, and other institutional and governmental research funders.
Source: BMC Medicine
