Diethylstilbestrol and risk of psychiatric disorders: a critical review and new insights.

Objectives: We explored whether in utero DES exposure has produced consistent findings with regard to an increased risk of psychiatric disorders.

Methods: We reviewed systematically the epidemiological studies investigating a possible association between prenatal DES exposure and risk of psychiatric disorders.

Results: We identified 10 relevant studies reporting the psychiatric outcome of offspring with a history of in utero DES exposure compared to a control group. We classified them into four categories: (1) a mail survey in a sample from a randomized double-blind controlled trial of prophylactic DES for first pregnancy in the early 1950s reported that depression and anxiety were twice as frequent in the exposed group compared to the placebo group; (2) five small clinical samples with inconclusive results; (3) two large cohorts of DES-exposed participants: the first study reported a higher lifetime history of weight loss related to anorexia nervosa whereas the second did not found any significant difference; (4) two subsamples from general population cohorts: the first study did not found any significant difference whereas the second reported that exposed women showed a higher rate of incident depression than non-exposed women.

Conclusions: The role of prenatal exposure to DES as an environmental risk factor for psychiatric disorders requires more evidence before any conclusions can be drawn. If confirmed, several explanations could be proposed: gene × environment interaction and epigenetic mechanisms, although phenocopy and gene-environment aggregation are plausible.