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. 2016 Sep;215(3):322.e1-8.
doi: 10.1016/j.ajog.2016.03.007. Epub 2016 Mar 12.

Prenatal Diethylstilbestrol Exposure and High-Grade Squamous Cell Neoplasia of the Lower Genital Tract

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Prenatal Diethylstilbestrol Exposure and High-Grade Squamous Cell Neoplasia of the Lower Genital Tract

Rebecca Troisi et al. Am J Obstet Gynecol. .
Free PMC article


Background: Prenatal diethylstilbestrol (DES) exposure is associated with an excess risk of clear-cell adenocarcinoma of the vagina and cervix, and of high-grade squamous neoplasia.

Objective: We explored whether neoplasia risk remains elevated among DES-exposed women as they age.

Study design: In all, 4062 DES-exposed and 1837 unexposed daughters were followed for approximately 30 years (1982 through 2013) for pathology-confirmed diagnoses of cervical intraepithelial neoplasia grade ≥2 (CIN2+) of the lower genital tract (n = 178). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated adjusting for birth year and individual study cohort.

Results: The cumulative incidence of CIN2+ in the DES-exposed group was 5.3% (95% CI, 4.1-6.5%) and in the unexposed group was 2.6% (95% CI, 1.5-3.7%). The HR for DES and CIN2+ was 1.98 (95% CI, 1.33-2.94), and was similar with further adjustment for frequency of cervical cancer screening (HR, 1.97; 95% CI, 1.33-2.93). The HR was 2.10 (95% CI, 1.41-3.13) with additional adjustment for other potential confounders. The HR for DES exposure was elevated through age 44 years (age <45 years HR, 2.47; 95% CI, 1.55-3.94), but not in women age ≥45 years (HR, 0.91; 95% CI, 0.39-2.10). In exposed women, HRs for DES were 1.74 (95% CI, 1.09-2.79) among those who had earlier evidence of vaginal epithelial changes (VEC), presumably reflecting glandular epithelium undergoing transformation to normal, adult-type squamous epithelium, and 1.24 (95% CI, 0.75-2.06) among those without VEC, compared with unexposed women. The HRs for DES and CIN2+ were higher among women with earlier intrauterine exposure (HR, 2.64; 95% CI, 1.64-4.25 for <8 weeks' gestation and HR, 1.41; 0.88-2.25 for ≥8 weeks' gestation), and lowest when exposure began >15th week (HR, 1.14; 95% CI, 0.59-2.20).

Conclusion: CIN2+ incidence was higher among the DES exposed, particularly those with early gestational exposure and VEC. The HR for DES and CIN2+ remained positive and significant until the mid-40s, confirming that the recommendation of annual cytological screening among these women is appropriate. Whether those ≥45 years of age continue to require increased screening is unclear, and would require a careful weighing of possible risks and benefits.

Keywords: Pap smear screening; cervical dysplasia; cervix; diethylstilbestrol; squamous neoplasia; vagina.

Conflict of interest statement

The authors report no conflicts of interest.


Figure 1
Figure 1. Cumulative incidence of cervical intraepithelial neoplasia 2+ by diethylstilbestrola exposure status and age, adjusted for birth year and cohort
aDES=diethylstilbestrol. The cumulative incidence of CIN2+ rose more steeply with age among the DES-exposed through approximately age 45, when it appeared to level off.

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