Prenatal diethylstilbestrol exposure and high-grade squamous cell neoplasia of the lower genital tract

• Published in: American journal of obstetrics and gynecology Vol. 215; no. 3; pp. 322.e1 - 322.e8
• Main Authors: Troisi, Rebecca, ScD, Hatch, Elizabeth E., PhD, Palmer, Julie R., ScD, Titus, Linda, PhD, Robboy, Stanley J., MD, Strohsnitter, William C., DSc, Herbst, Arthur L., MD, Adam, Ervin, MD, Hyer, Marianne, MS, Hoover, Robert N., MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2016
• Subjects: Adult; Age Factors; Carcinoma, Squamous Cell - chemically induced; Carcinoma, Squamous Cell - epidemiology; Carcinoma, Squamous Cell - pathology; cervical dysplasia; cervix; Cervix Uteri - pathology; diethylstilbestrol; Diethylstilbestrol - adverse effects; Female; Humans; Incidence; Middle Aged; Obstetrics and Gynecology; Pap smear screening; Papanicolaou Test; Pregnancy; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - epidemiology; Prenatal Exposure Delayed Effects - pathology; Risk; squamous neoplasia; Uterine Cervical Dysplasia - chemically induced; Uterine Cervical Dysplasia - epidemiology; Uterine Cervical Dysplasia - pathology; Uterine Cervical Neoplasms - chemically induced; Uterine Cervical Neoplasms - epidemiology; Uterine Cervical Neoplasms - pathology; vagina; Vaginal Smears; cervical dysplasia; cervix; squamous neoplasia; vagina; Pap smear screening; diethylstilbestrol
• ISSN: 0002-9378; 1097-6868
• DOI: 10.1016/j.ajog.2016.03.007

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.