New Research Suggests Higher ADHD Risk in DES Grandchildren

young man daydreaming ADHD

A new study found that 7.7% of DES grandchildren in the study population have attention deficit hyperactivity disorder, compared to 5.2% of children without any links to DES exposure. After accounting for several other factors, the study suggests that DES grandchildren have a higher risk for ADHD than the general population. For more about ADHD, see Need to Know: ADHD.

DES (diethylstilbestrol) was the first synthetic estrogen to be created. It was prescribed to millions of pregnant women in the mistaken belief that it could prevent miscarriage. It did not work, but instead DES harmed the mothers, the children born of those pregnancies and now, possibly the grandchildren. For more about DES, see our sister site: DES Action USA.

The study was published in JAMA Pediatrics. The research was observational, using data that had already been collected for different purposes unrelated to DES. It therefore cannot show that DES exposure caused ADHD in the third generation. There is a chance that other factors might account for the increased risk, including statistical oddities.

Nevertheless, the study’s finding of a positive link between ADHD and DES exposure in the third generation emphasizes the need for further research into ways the DES third generation might differ from the general population. As more studies identify these differences, if they are replicated in additional studies, it will become easier to determine what effects may directly result from DES exposure in the third generation’s parents.

How the Study Was Conducted

Researchers used surveys from the Nurses’ Health Study II to look for any associations between neuro-developmental conditions and prenatal exposure to DES. Among the 47,540 women enrolled in the Nurses’ Health Study, 1.8% (856) of their mothers had taken DES while pregnant with them.

Then the scientists examined rates of ADHD, as diagnosed by a physician, among the participants’ children. The researchers found that 7.7% of DES Daughters’ children had ADHD, compared to 5.2% of children whose mothers were not exposed to DES.
The difference between these percentages is small, but it was statistically significant, which means it’s likely the difference is not due to chance.

In relative terms, the children whose grandmothers took DES at any time during pregnancy had about 36% higher likelihood of having ADHD than other children, and a 63% higher likelihood if the DES was taken during the first trimester.
“Although additional studies are warranted, these findings could suggest that the first trimester is a critical exposure window,” the researchers wrote.

Those percentages, though they look high, only represent the increased risk over the regular population risk, however. (For example, if 10% of the population has a condition, a group with 63% increased risk means that 16% of those group members would actually have that condition.)

The researchers did not see any difference in risk according to the grandchildren’s sex.

Over email, DES Action USA executive director Su Robotti asked the researchers why they chose to look specifically at ADHD. Lead author Marianthi-Anna Kioumourtzoglou, ScD, a professor of environmental health at Columbia University Mailman School of Public Health in New York, said they had planned to look at neurodevelopmental outcomes in general.

“In our study population, we did not have many outcomes. We only had information on autism spectrum disorder (ASD) and ADHD,” Dr. Kioumourtzoglou wrote. “Due to the rare exposure (only 1.8% of the mothers used DES during pregnancy), we decided to start our analyses looking at ADHD because we had more identified cases than for ASD.” She added that they hope to look at other outcomes in the future, but they are still determining how to proceed.

What Past Research Has Found

Previous research in animals has revealed differences in the neurology and development of third or fourth generation offspring when their parents or grandparents had been been exposed to endocrine disruptors. Those findings cannot be directly applied to humans, however, because rodent brains, for example, may be too different from human brains to compare.

It’s also difficult to determine what doses of DES are most appropriate to use in rodent research to represent an exposure similar to what humans would have. Many toxicology studies use very high dosages that do not accurately reflect dosages in humans.
That said, previous research has already identified other conditions in humans that are more common among those whose parents were prenatally exposed to DES.

For example, DES Granddaughters are more likely to have delayed menstruation, irregular periods and fewer live births than their peers. DES Grandsons have a slightly higher risk of hypospadias—an abnormal placement of the urethra on the penis. And birth defects appear slightly more likely to occur in DES Grandchildren than in those without a family history of DES exposure.

These Studies Cannot Show Causation

The human findings above, however, are from studies with several limitations. The most important of these limitations is that the studies are observational and therefore cannot show causation. It will require multiple additional studies to learn more about whether these conditions definitely represent third generation effects from DES exposure.

Observational studies also carry the risk that other factors the researchers don’t know about—and therefore cannot account for—may explain differences seen in DES Grandchildren. Researchers try to adjust their calculations to consider other factors, such as socioeconomic status and smoking during pregnancy.

But it’s impossible to know all the possible ways that children born to DES Daughters and Sons may be different from other children, regardless of the DES connection.

In this most recent study, the strongest finding suggesting possible causation is the increased risk among those whose mothers’ DES exposure was in the first trimester.

The study was funded by the National Institutes of Health and the Escher Fund for Autism. Find it at doi 10.1001/jamapediatrics.2018.0727.