Obesity May Increase Risk for Brain Abnormality in Newborns

Laird Harrison

February 15, 2013

SAN FRANCISCO, California — Genes in the amniotic fluid of pregnant women who are obese suggest that the brains of their growing babies are developing differently, according to a new study.

This is particularly concerning because about one third of American women are obese at the time of conception (defined as a body mass index [BMI] above 30 kg/m²).

"Our analysis of cell-free fetal RNA in the amniotic fluid of obese women demonstrates differences in gene expression as early as the second trimester," said lead researcher Andrea Edlow, MD, from Tufts University in Boston, Massachusetts, here at the Society for Maternal-Fetal Medicine 33rd Annual Meeting.

This small study builds on previous research that identified differences in the fetuses of lean and obese women. Epidemiologic studies have found an association between obesity in mothers and disorders such as autism and attention-deficit/hyperactivity disorder in their children, Dr. Edlow pointed out to Medscape Medical News.

Meta-analyses have shown the association to be quite strong, although not unequivocal.

Brain cells don't just multiply as a fetus matures; sometimes they die.

Brain cells don't just multiply as a fetus matures; sometimes they die, Dr. Edlow explained. She equated the process to pruning or sculpting. "It prevents the overgrowth of unnecessary precursor cells," she said.

Research in rodents has identified genetic and structural brain differences, including apoptosis, in the fetuses of obese and lean rats. "We know that apoptosis plays a critical role in normal brain development," said Dr. Edlow.

So far, no genetic differences in human fetuses of obese mothers have been identified.

This study looked for such changes in amniotic fluid, which "provides a crucial window into brain development," said Dr. Edlow.

Researchers analyzed amniotic fluid samples from 8 women with a BMI of at least 30 kg/m² and 8 with an BMI below 25 kg/m². The samples came from amniocentesis that the women underwent for reasons unrelated to this study.

Other than BMI, the 2 groups were similar, and there was no statistically significant difference in maternal or gestational age. Both groups had 4 male and 4 female fetuses.

Differences in Gene Regulation

The researchers performed a transcriptomic analysis of the cell-free RNA in the samples. They found statistically significant differences between the 2 groups in the regulation of 205 genes (< .05).

In the samples of obese women, 114 antiapoptotic genes were upregulated and 91 proapoptotic genes were downregulated. "The direction of the expression in these genes all favored decreased apoptosis," Dr. Edlow noted.

Differences in apoptosis regulation were particularly strong in genes involved in nervous system pathways, specifically those involving cerebral cortex cells, hippocampal cells, and sympathetic neurons.

Among the most upregulated genes in obese women were BCL2 and BCL3, both of which are involved in resistance to apoptosis. The most downregulated gene was the proapoptotic STK24.

The APOD gene was also upregulated in obese women. This gene is involved in lipid stabilization. In rat models, it protects brain cells after injuries; however, overexpression of the gene has been associated with psychosis and schizophrenia.

If borne out by future research, such findings might lead to the development of medications that could be used to prevent psychiatric disorders from developing, Dr. Edlow said.

Limitations of the Study

During the discussion period after the presentation, an audience member asked whether the researchers had excluded mothers with conditions such as diabetes and hypercholesterolemia.

"We were unable to evaluate the maternal conditions in this case, and they certainly could influence gene expression," Dr. Edlow acknowledged.

Another audience member wanted to know how much the cell-free RNA is associated with RNA in brain tissue.

"We did not observe decreased apoptosis in the brains of these fetuses," Dr. Edlow responded. "It was suggestive of decreased apoptosis...but we can't demonstrate that these RNA's are mapping to the brain."

It's too early to conclude that the brains of obese women's babies are abnormal, cautioned Mary D'Alton, MD, chair of obstetrics and gynecology at Columbia University in New York City, who was asked by Medscape Medical News to comment on the study.

"This is a very preliminary investigation," she said. "The last thing I would want to do is scare people."

Dr. D'Alton pointed out that physicians are already counseling obese mothers to slim down for other well-established reasons.

An important next step in the research will be to compare brain images of the fetuses of obese and lean women, added Richard Berkowitz, MD, professor of obstetrics and gynecology at Columbia.

The researchers, Dr. D'Alton, and Dr. Berkowitz have disclosed no relevant financial relationships.

Society for Maternal-Fetal Medicine (SMFM) 33rd Annual Meeting: Abstract 37. Presented February 15, 2013.