Many studies have demonstrated an association between a mother’s body mass index (BMI) during, or just before, early pregnancy and her child’s birth weight and later BMI. As well as factors, such as shared environment and learned behaviours, a causal intrauterine effect has been suggested. It was thought that mothers with higher BMI will have higher blood levels of glucose (sugars) and lipids (fats). The hypothesis being that as glucose crosses the placenta, a fetus generates more insulin to process it, resulting in faster growth and more body fat than for babies with mothers with lower BMI and glucose levels. It was also considered that this fetal response could then ‘programme’ how offspring grow and manage glucose and insulin thereafter, meaning children would be ‘fatter’ throughout life – a process known as ‘developmental programming’. If true, women begetting daughters would trigger an obesity epidemic cycling across generations. The ObesityDevelop project, supported by the European Research Council, wanted to investigate the hypothesised causal intrauterine effect. The project showed that higher than average maternal BMI did result in heavier offspring, likely driven by the mother’s higher blood glucose levels. But beyond infancy, there wasn’t strong evidence that a mother’s pregnancy BMI had a lasting effect on a child’s body mass or fat mass indices. “This is reassuring as it seems that intergenerational obesity cycling is unlikely,” says project coordinator Deborah Lawlor. “But a healthy maternal BMI remains important. Mothers with higher BMIs will have larger babies potentially causing birth and pregnancy difficulties such as gestational diabetes and hypertensive disorders such as pre-eclampsia.”
Beyond association to causation
Despite being the commonest measure of adiposity – or fatness – BMI has been criticised for being too general. ObesityDevelop used additional measures, including scans to measure fat mass index which separates fat from lean mass, while also looking at waist size which may indicate abdominal organ and liver fat. To correlate the risk factor in mothers (fatness during pregnancy) with an offspring outcome (birth weight and later life fatness), the team used data from large cohort studies in a collaboration called MR-PREG. These included the Avon Longitudinal Study of Parents and Children which has been running for 30 years and the Born in Bradford study, involving pregnant women between 2007 and 2010. “These studies have rich data on health, behaviours, social status and environmental exposures, alongside detailed biological blood markers measured repeatedly in family members across generations. They also commonly have genome-wide data for mothers, offspring and sometimes fathers,” explains Lawlor, from the University of Bristol, the project host. To investigate genes as obesity risk factors, genome-wide association studies were used. The team applied genetic analyses developed by the University of Bristol to the data sets, based on a method called mendelian randomisation. This was complemented by multivariable regression which looks for associations in the data, whilst controlling for confounding factors such as shared social mother/child environments. Using both approaches helped ensure the veracity of the findings as they controlled for different biases, genetic pleiotropy and confounding factors respectively.
Population-wide healthcare and targeted pregnancy support
One of the team’s conclusions was that anti-obesity strategies targeting only women of reproductive years are not appropriate. “Hopefully our work will help convince policymakers to target population-wide health and all family members,” concludes Lawlor. The MR-PREG consortium continues to investigate the causes of adverse pregnancy and perinatal outcomes looking particularly at the molecular mechanisms involved in those outcomes.
ObesityDevelop, intrauterine, pregnancy, obesity, fat, genome, behaviours, mothers, offspring, adiposity, BMI, glucose