Gestation is a sensitive period. Over the last 30 years, a growing body of epidemiological research has suggested that poor nutrition in pregnancy hurts the baby by setting metabolism to a “thrifty” state that leads, decades later, to Type 2 diabetes and heart disease.
This idea, known to scientists as the “Barker hypothesis” after its original proponent, British epidemiologist David Barker, MD, PhD, is perhaps best supported by research on Dutch adults born around the time of the Dutch famine of World War II. Individuals who were in utero during the famine had higher rates of heart disease, diabetes, obesity and other health problems than other study subjects. But, although similar findings have emerged from many observational studies, epidemiology can’t uncover cause-and-effect links connecting fetal growth restriction to later metabolic problems.
So a new study, published this week in Circulation: Genomic and Precision Medicine takes a different approach.
The research team, led by Stanford scientist Erik Ingelsson, MD, PhD, examined relationships between actual birth weight, genetic markers for predicted birth weight, metabolic disease status and cardiovascular disease in up to 500,000 British adults. With this very large cohort and a genetic technique called Mendelian randomization, the scientists could ask cause-and-effect questions about how several metabolic factors — including adult obesity, high blood pressure, blood cholesterol, blood sugar and insulin levels — contribute to diabetes and heart disease in adulthood.
Some of the prime suspects for the cause-and-effect link turned out not to be implicated, Ingelsson told me.
"We can confirm the Barker hypothesis, but it doesn’t seem to be mediated through body mass index or hypertension," Ingelsson said. "That was surprising and interesting."
The researchers had hypothesized that high blood pressure would be part of the link between low birth weight, cardiovascular disease and diabetes, but that isn't likely, the data showed.
The scientists saw that adult obesity was linked with high rather than low birth weight; contrary to the findings of some prior research, low birth weight and rapid weight gain in childhood did not seem to drive the connection between reduced fetal growth and adult metabolic disease.
The team did find cause-and-effect links between low birth weight and increased LDL cholesterol, less effective glucose metabolism, coronary heart disease and Type 2 diabetes.
"This is the first really robust evidence of causality for the Barker hypothesis," Ingelsson said. He hopes the work will help strengthen the rationale for preventing poor fetal growth. "In practice, I think this finding should be used for future population guidelines for maternal care. Malnutrition is still a big problem globally, and population-level interventions to improve nutrition during fetal life could translate into less disease later in life."
One big still-unanswered question is what might be done to intervene between infancy and adulthood for those born with low birth weight. I called Stanford's Thomas Robinson, MD, an expert in childhood obesity and metabolic disease, for his take on this issue.
"Looking at data from Barker hypothesis studies doesn’t tell you whether you can overcome adult disease by giving kids better care. We might be able to erase what occurs before birth, but we just don’t know," Robinson told me. "But we know that kids who are born with low birth weights are definitely at higher risk; they need even more attention. And we should be making sure everyone has not just a healthy pregnancy, but a healthy childhood as well."
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