Neonates born to overweight/obese women are larger and at higher
risk of birth complications. Many maternal obesity-related traits are
observationally associated with birth weight, but the causal nature of these
associations is uncertain.
To test for genetic evidence of causal associations of maternal body
mass index (BMI) and related traits with birth weight.
Design, Setting and Participants
We used Mendelian randomization to test whether maternal BMI and
obesity-related traits are causally related to offspring birth weight.
Mendelian randomization makes use of the fact that genotypes are randomly
determined at conception and are thus not confounded by non-genetic factors.
Data were analysed on 30,487 women from 18 studies. Participants were of
European ancestry from population- or community-based studies located in
Europe, North America or Australia and participating in the Early Growth
Genetics (EGG) Consortium. Live, term, singleton offspring born between 1929
and 2013 were included. We tested associations between a genetic score of 30
BMI-associated single nucleotide polymorphisms (SNPs) and (i) maternal BMI
and (ii) birth weight, to estimate the causal relationship between BMI and
birth weight. Analyses were repeated for other obesity-related traits.
Genetic scores for BMI, fasting glucose level, type 2 diabetes,
systolic blood pressure (SBP), triglyceride level, HDL-cholesterol level,
vitamin D status and adiponectin level.
Main Outcome(s) and Measure(s)
Offspring birth weight measured by trained study personnel (n=2
studies), from medical records (n= 10 studies) or from maternal report (n=6
Among the 30,487 newborns the mean birth weight in the various
cohorts ranged from 3325 g to 3679 g. The genetic score for BMI was
associated with a 2g (95%CI: 0, 3g) higher offspring birth weight per
maternal BMI-raising allele (P=0.008). The maternal genetic
scores for fasting glucose and SBP were also associated with birth weight
with effect sizes of 8g (95%CI: 6, 10g) per glucose-raising allele
(P=7×10−14) and −4g
(95%CI: −6, −2g) per SBP-raising allele
(P=1×10−5), respectively. A 1
standard deviation (1 SD ≈ 4kg/m2) genetically higher
maternal BMI was associated with a 55g (95% CI: 17, 93g) higher birth
weight. A 1-SD genetically higher maternal fasting glucose (≈
0.4mmol/L) or SBP (10mmHg) were associated with a 114g (95%CI: 80, 147g)
higher or −208g (95% CI: −394, −21g) lower birth
weight, respectively. For BMI and fasting glucose these genetic associations
were consistent with the observational associations, but for SBP, the
genetic and observational associations were in opposite directions.
Conclusions and Relevance
In this Mendelian randomization study of more than 30,000 women with
singleton offspring from 18 studies, genetically elevated maternal BMI and
blood glucose levels were potentially causally associated with higher
offspring birth weight, whereas genetically elevated maternal systolic blood
pressure was shown to be potentially causally related to lower birth weight.
If replicated, these findings may have implications for counseling and
managing pregnancies to avoid adverse weight-related birth outcomes.