Diethylstilbestrol Use in Pregnancy Linked to Multigenerational Neurodevelopmental Deficits

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Use of diethylstilbestrol by F0 mothers is associated with an increased risk of ADHD among the F2 generation.
Use of diethylstilbestrol by F0 mothers is associated with an increased risk of ADHD among the F2 generation.

Diethylstilbestrol exposure during pregnancy is associated with multigenerational neurodevelopmental deficits in childhood, including ADHD, according to a study published in JAMA Pediatrics.

Marianthi-Anna Kioumourtzoglou, ScD, from the Department of Environmental Health Sciences at the Columbia University Mailman School of Public Health in New York City, and colleagues, used data from the Nurses' Health Study II (NHSII) to examine the potential third-generation outcomes (ADHD) of diethylstilbestrol, a potent perinatal endocrine-disrupting chemical (EDC). In 1989, a total of 116,686 female registered nurses between the ages of 25 and 42 years enrolled in the NHSII prospective cohort by completing a mailed questionnaire. The NHSII has a retention rate of more than 90%. Follow-up questionnaires are mailed to participants every 2 years to gather updated information on lifestyle and risk factors, medication use, and major illness occurrence.

All NHSII participants (F1 generation) were born between 1946 and 1964, when diethylstilbestrol was still being prescribed. In 1993, the mailed questionnaire included questions about the use of diethylstilbestrol by the participant's mother (F0 generation) during her pregnancy with the F1 participant. We excluded from our analyses F1 participants who did not return the 1993, 2005, or 2013 questionnaires (the relevant surveys that collected outcome and exposure data) and who did not report any live-born children.

In 1993, a supplementary questionnaire was mailed to 2,742 F1 participants who reported that their F0 mothers had been exposed to diethylstilbestrol while pregnant with the F1 participants. Among the 2,317 participants (84.5%) who responded, 2,032 (87.7%) reported being certain or somewhat certain of their mothers' exposure, 123 (5.3%) were not certain, and 162 (7.0%) reported no such exposure.

The outcome of interest was an F1 participant's report of whether any of her children ever received a doctor's diagnosis of ADHD. This question was first asked in the 2005 questionnaire, although at that time the date of birth of the child or children with ADHD was not asked. This question was repeated in the 2013 questionnaire, further requesting information on the birth years of the children with an ADHD physician diagnosis.

For the main analysis, the researchers included information on F1 participants who provided concordant responses (92.6% concordance) in the 2005 and 2013 questionnaires to the question of whether any of their children had been diagnosed with ADHD by a physician, using the child-specific responses from the 2013 questionnaire to minimize any potential outcome misclassification. They also conducted analyses of all participants who responded to the 2013 questionnaire to include their children, who may have received a diagnosis after 2005. 

A total of 47,540 F0 mothers were included in the main analysis, 861 (1.8%) of whom were exposed to diethylstilbestrol while pregnant with the F1 participants and 46,679 (98.2%) who were not. The total number of children was 106,198, and 5,587 (5.3%) of them were diagnosed with ADHD. The median F2 year of birth was 1,983 (interquartile range, 1978-1988). The grandmothers of 137 F2 children with ADHD (2.5%) were exposed to diethylstilbestrol while pregnant with the F1 participants.

Use of diethylstilbestrol by F0 mothers was associated with an increased risk of ADHD among the F2 generation: 7.7% vs 5.2%, adjusted odds ratio (OR), 1.36 and an OR of 1.63 if diethylstilbestrol was taken during the first trimester of pregnancy. No effect modification was observed by the F2 children's sex.

“We found evidence in humans of increased ADHD risk in the third generation following diethylstilbestrol exposure during F0 pregnancy,” the authors concluded. “The levels of a high number of EDCs to which humans are daily exposed are lower than that of the prescribed diethylstilbestrol; thus, extending this work to lower levels of exposure is warranted. Because EDCs are ubiquitous, the high prevalence of exposure and the possibility of cumulative consequences must be considered.”

Reference

Kioumourtzoglou MA, Coull BA, O'Reilly EJ. Association of exposure to diethylstilbestrol during pregnancy with multigenerational neurodevelopmental deficits. JAMA Pediatr. Published online May 21, 2018. doi:10.1001/jamapediatrics.2018.0727

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