There has been a steep rise in neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD) over the years, and it now appears that the increases may be the result of exposure to a drug that hasn't been around since the 1950s. New findings provide the first evidence that ADHD in children may be linked to the use of the pregnancy drug DES in not their mothers, but their grandmothers.

Exposure to endocrine-disrupting chemicals (EDCs), which, as their name implies, interfere with hormone function, has long been seen as linked to an increase in neurodevelopmental disorders. Animal studies have suggested that EDC exposure may change the expression of certain genes in fetal egg cells during pregnancy. The studies also suggest these epigenetic changes may be passed along to the future children of female offspring exposed to EDCs in the womb.

Grandmothers' use of DES during the first trimester of pregnancy was associated with a 36 percent increased risk of ADHD among their F2 grandchildren.

Now researchers from Columbia and Harvard report that the grandchildren of women who took the drug diethylstilbestrol (DES), a synthetic form of the female hormone estrogen and a known endocrine-disrupting compound, during pregnancy had an increased risk of ADHD compared to the grandchildren of women who did not take DES. Doctors prescribed DES from about 1938 until 1971 to help pregnant women who had had miscarriages or premature deliveries. The researchers say their study is the first to suggest this potential neurodevelopmental consequence of DES so many years later.

“Our aim was to explore the potential impact of DES use across generations, and specifically on third-generation neurodevelopment,” Marianthi-Anna Kioumourtzogiou, an assistant professor of environmental health sciences at the Columbia University Mailman School of Public Health and lead author on the study, said in a statement.

The researchers looked at data from over 47,500 women enrolled in the ongoing Nurses Health Study II. The three generations analyzed in this study were participants (F1), their mothers (F0), and the F1 generation’s live-born children (F2).

Slightly less than two percent of the F0 mothers had used DES when pregnant with the F1 participants; and 98.2 percent had not used the drug. Grandmothers' use of DES during the first trimester of pregnancy was associated with a 36 percent increased risk of ADHD among their F2 grandchildren. The F2 grandchild’s gender had no effect on the increase in ADHD risk.

The use of DES for pregnancy complications was phased out after a 1953 study found it had no treatment value, and it was banned in 1971 after another study found it was linked to vaginal cancer in the offspring, called DES daughters, of the women who took it. The drug was also later linked to other reproductive problems in DES daughters.

DES may have been banned, but pregnant women continue to be exposed to many environmental EDCs, “Although current exposures are at a lower level and potency than seen with DES, cumulative exposure to these chemicals is a cause for concern, and is deserving of future study,” said Marc Weisskopf, senior author on the study and a professor of environmental and occupational epidemiology at the Harvard T. H. Chan School of Public Health.

The study and a related editorial are published in JAMA Pediatrics.