title: Prenatal diethylstilbestrol exposure and high-grade squamous cell neoplasia of the lower genital tract.
abstract: 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.
  
  
  
  We explored whether neoplasia risk remains elevated among DES-exposed women as they age.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Electronic address: troisir@mail.nih.gov.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Troisi
authors.affiliation: Department of Epidemiology, Boston University School of Public Health, Boston, MA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Hatch
authors.affiliation: Slone Epidemiology Unit, Boston University, Boston, MA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Palmer
authors.affiliation: Departments of Community and Family Medicine and Pediatrics, Dartmouth Medical School, and the Norris Cotton Cancer Center and the Hood Center for Children and Families, Lebanon, NH.
authors.forename: Linda
authors.initials: L
authors.lastname: Titus
authors.affiliation: Departments of Pathology and Obstetrics and Gynecology, Duke University Medical Center, Durham, NC.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Robboy
authors.affiliation: Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA.
authors.forename: William C
authors.initials: WC
authors.lastname: Strohsnitter
authors.affiliation: Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Herbst
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX.
authors.forename: Ervin
authors.initials: E
authors.lastname: Adam
authors.affiliation: Information Management Services Inc, Rockville, MD.
authors.forename: Marianne
authors.initials: M
authors.lastname: Hyer
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Hoover
mesh_terms: D000328:Adult; D000367:Age Factors; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D002584:Cervix Uteri / Q000473:pathology*; D004054:Diethylstilbestrol / Q000009:adverse effects*; D005260:Female; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D065006:Papanicolaou Test; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D012306:Risk; D002578:Uterine Cervical Dysplasia / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D014626:Vaginal Smears
chemical_list: D004054:Diethylstilbestrol
keywords: Pap smear screening; cervical dysplasia; cervix; diethylstilbestrol; squamous neoplasia; vagina