DES Raises ADHD Risk in Grandchildren

Ricki Lewis, PhD

May 21, 2018

The grandchildren of women who took the endocrine disrupter diethylstilbestrol (DES) during pregnancy face increased risk for attention-deficit/hyperactivity disorder (ADHD), according to results published online today in JAMA Pediatrics.

From 1938 through 1971, 5 to 10 million women in the United States were prescribed DES during pregnancy. Use began to wane in 1953, after a study found no benefit in preventing certain adverse pregnancy complications. Subsequently, in utero exposure has been linked to vaginal adenocarcinoma and adenosis in some of the "DES daughters," and to hypospadias in grandsons and delayed regular menstrual cycles and fewer live births in granddaughters.

Previous studies in mice have shown that endocrine disruptors affect neurodevelopment of the third generation through effects on germline cells, but evidence in humans has been lacking, largely because there are few large cohorts that follow more than two generations.

For the current study, Marianthi-Anna Kioumourtzoglou, ScD, from the Department of Environmental Health Sciences at Columbia University Mailman School of Public Health, New York City, and colleagues investigated possible effects of DES exposure in humans on neurodevelopment in the third generation, and specifically, ADHD, using data from one of the few cohorts, the Nurses Health Study II.

The researchers collected health information in questionnaires mailed in 2013 to participants in the ongoing Nurses' Health Study II about DES exposure during in utero development and attention-deficit/hyperactivity disorder (ADHD) diagnosis in their children. Using terminology borrowed from genetics, the women who took DES are referred to as the F0 generation, the study participants are their daughters (F1 generation), and the participants' children are referred to as the F2 generation. The participants provided information on both their mothers' DES exposure and physician-diagnosed childhood ADHD in their children.

Among 47,540 participants, 861 (1.8%) F0 mothers received DES while pregnant with the F1 participants. Of the 106,198 grandchildren, 5587 (5.3%) were diagnosed with ADHD, and the grandmothers of 137 (2.5%) of them took DES while pregnant.

The analysis showed an increased risk for ADHD among grandchildren of F0 DES users vs F0 nonusers, at 7.7% vs 5.2% (adjusted odds ratio [OR], 1.36; 95% confidence interval [CI], 1.10 - 1.67). The risk increased to an OR of 1.63 (95% CI, 1.18 - 2.25) if DES exposure occurred during the first trimester of pregnancy, suggesting a possible critical period, although the statistical power was low for the second and third trimester assessments. Sex of the grandchildren was not significant.

The researchers caution that "multigenerational neurodevelopmental deficits" associated with DES exposure in utero might add to other environmental exposure to endocrine disruptors, such as in pollution. "Because [endocrine-disrupting chemicals] are ubiquitous, the high prevalence of exposure and the possibility of cumulative consequences must be considered," they write.

Limitations of the study include recall bias from the participants about their mothers' exposures and maternal errors in reporting diagnoses of ADHD.

The multigenerational effects of DES exposure could arise in two ways: direct changes to the DNA sequence and epigenetic changes, which affect chromosome modifications and gene expression but not the DNA base sequence. The new study did not distinguish the two possible mechanisms.

In an accompanying editorial, Joel T. Nigg, PhD, from the Department of Psychiatry, Oregon Health & Science University, Portland, focuses on the possibility that the increased ADHD risk in the F2 generation could be a result of epigenetic changes caused by DES exposure. In addition, he notes, as the authors do, that there are a multitude of other endocrine disrupting pollutants in the environment that might also affect neurodevelopment.

"Kioumourtzoglou et al use an approach that is as important as it is underused: an examination of multigenerational transmission of environmental associations. That approach may be the most important from an epidemiological perspective," Nigg writes.

"When it comes to psychiatric illness, we are overdue for a 'decade of the environment' or perhaps a 'decade of epigenetics' in which truly integrative science takes center stage," he continues. "What has become clear is that environmental moderators or mediators of psychopathology and neurodevelopmental disorders should be high-priority."

The researchers and editorial writer have disclosed no relevant financial relationships.

JAMA Pediatr. Published online May 21, 2018.

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