Grandmaternal DES and ADHD in Children

Dr Kioumourtzoglou‘s reply to comments in ref to “Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits“, 2018

We appreciate the interest that Drs Ryan and Smith and Dr Costas have expressed in our article.

Drs Ryan and Smith raise the issue of exposure misclassification and the potential problem of overreporting of grandmaternal diethylstilbestrol (DES) exposure by mothers whose children have attention-deficit/hyperactivity disorder (ADHD).

First, we were not clear in the article, but the κ of 0.74 for nurse and grandmother reporting was specific for DES.

We also found that the DES-specific κ value did not vary by ADHD status.

Concern for biased recall does need to be considered, and our results should indeed be interpreted cautiously, while hopefully spurring more work in this area.

That said, some aspects of our study differ from the military study Drs Ryan and Smith reference.

When the nurses reported their mothers’ DES exposure (1993), there had been no human studies of any third-generation effects and possibly only 1 mouse study of tumors. Thus, the level of attention to potential anthrax effects on those directly exposed was not there for third-generation DES effects in 1993.

In addition, the nurses were not queried about ADHD in their children until, at earliest, 12 years after the question about their mothers’ DES exposure (2005). So the possibility of priming the nurse to think about a possible DES-ADHD association by asking about exposure and outcome at the same time was avoided.

Additionally, the specificity of elevated effects in the first trimester would argue against recall bias. In our models, we simultaneously included terms for unknown trimester DES exposure and exposure in other trimesters as a check for confounding, which also works as a check for recall bias in this case.

Indeed, one might expect that nurses falsely recalling grandmaternal DES exposure would be more likely to report that they did not know the trimester of exposure, yet that group did not exhibit increased odds of ADHD.

In addition to these points, in responding to this letter we conducted the same analysis restricted to the 18 792 F0 women (42 097 F2 children) who provided information themselves about DES use during pregnancy with F1, instead of F1 reporting. In these analyses, we found virtually the same result, although with wider 95% CI as expected with the smaller numbers: adjusted odds ratio, 1.31 (95% CI, 1.00-1.71).



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