Cohorts

The NCI Combined DES Cohorts Follow-Up Study consists of the following: (1) women who participated in the DESAD cohort ; (2) women whose mothers participated in a clinical trial of DES in 1951 through 1952 (Dieckmann cohort); (3) women whose mothers were treated in a large private infertility practice in Massachusetts (Horne Cohort); and (4) women from Massachusetts, New Hampshire, Maine, and the Mayo Clinic whose mothers participated in the Women’s Health Study (WHS) cohort, a study of the subsequent health effects of DES in women who were administered DES during their pregnancy.

Mailed questionnaires and physical examinations

The follow-up of the 4 combined cohorts by NCI began in 1994 with a mailed questionnaire, with subsequent questionnaires mailed in 1997, 2001, 2006, and 2011. Prior to the combined follow-up questionnaire study (1984 through 1989), DESAD cohort members were mailed annual questionnaires, and medical records and pathology reports were collected for cancers and gynecologic neoplasia. In 1982 through 1983, many members of the DESAD cohort still participated in annual screening examinations as part of the study protocol. The last routine follow-up of the Dieckmann cohort consisted of a mailed questionnaire in 1990. The Horne cohort was reassembled for follow-up along with unexposed siblings in the mid-1970s, and mailed annual questionnaires through the 1980s. Daughters from the WHS cohort had not been followed up before the combined follow-up in 1994.

The Dieckmann and DESAD studies incorporated a comprehensive gynecologic examination around the time of recruitment in the mid-1970s into their original cohorts that systematically identified vaginal epithelial change (VEC) by means of colposcopy or iodine staining. Identical screening protocols were used for the exposed and unexposed women. VEC is glycogen-poor squamous epithelium found in the vagina or exocervix that presumably reflects glandular epithelium undergoing transformation over time to glycogenated, normal adult-type squamous epithelium. These changes were more frequent in women prenatally exposed to DES early in pregnancy who also had large cumulative doses of DES by the end of pregnancy. No attempt was made to systematically physically examine members of the Horne or WHS cohorts.

Institutional review board approvals were obtained at the field centers and the NCI. Participants indicated their informed consent by completion of a questionnaire or telephone interview, and/or with written consent for pathology and slide reports.

DES exposure and covariate ascertainment

For all combined cohort participants, prenatal exposure to DES, or the lack thereof, was documented by the medical record or a physician’s note. Gestational week of first DES use was available for 75% of all exposed women, and for 80.2% of the DESAD and Dieckmann exposed groups. Because data for total cumulative DES dose were available for only 38% of the women, we classified the individual cohorts as high- or low-dose based on differences in prescribing practices by US region (unknown for a subgroup of the WHS ). Agreement between the dose categories and individual doses was excellent among those with complete data. Information on highest level of education, smoking status, and frequency of routine medical examinations, including Pap smears, in the last 5 years was collected on the 1994 questionnaire. Smoking status was updated on the 2006 questionnaire, and menopausal status and frequency of Pap smears were ascertained on all 5 questionnaires and treated as time-dependent.

Cervical intraepithelial neoplasia grade ≥2 confirmation

Reports of cervical intraepithelial neoplasia (CIN) grade ≥2 (CIN2+) were available from 2 sources: records from the original cohorts (1982 through 1988) and the NCI combined cohort study questionnaires (1989 through 2011); the methods for confirmation of cases were similar. The combined cohort study questionnaires ascertained new diagnoses of neoplasia, and biopsies of the cervix, vagina, or vulva that indicated a precancerous condition (dysplasia or carcinoma in situ, but not abnormal Pap smears only). Pathology records were obtained for reported biopsy-confirmed, genital-tract neoplasia of any grade (including HPV infection). Slides also were requested for pathology-confirmed diagnoses of CIN2+, and were reviewed by 1 pathologist (S.J.R.), blinded to DES-exposure status.

Among participants included in the analysis, 5237 (89% of exposed and 88% of unexposed) completed a questionnaire during the 1994 follow-up or after, and 1247 women (23.8%) reported having had a biopsy of the lower genital tract. Pathology reports were obtained for 986 (79%) of those reporting a biopsy, and of these, 206 (21%) indicated CIN2+. Pathology reports for the remaining self-reports indicated CIN1 (n = 280) or other benign diagnoses (n = 500, eg, squamous metaplasia, inflammation, HPV only). Representative slides were reviewed for 169 (82%) CIN2+ cases confirmed by pathology reports, and 30 cases were downgraded to CIN<2. Eight of the CIN2 cases were glandular cell type, and not included in the main analysis. All 8 glandular lesions were cervical; 7 were DES-exposed (2 were invasive, 1 was adenocarcinoma in situ, 3 were CIN3, and 1 was CIN2), and 1 was unexposed (CIN3). An additional 10 cases were not reported as biopsies, but identified from pathology reports obtained for other reasons. Of the 178 pathology-confirmed diagnoses of squamous CIN2+ included in the analysis, 163 were cervix (including n = 11 cases of invasive carcinoma of the cervix), 9 were vagina, and 6 were vulva (n = 2 were invasive). The National Death Index was routinely searched and 1 additional invasive case was identified, resulting in a total of 3 deaths in the exposed group from invasive lower genital tract cancer among CIN2+ cases.

Exclusions and follow-up information

Information from patient history and medical record review was used to ascertain history of diagnoses and treatments. Table 1 shows exclusions and follow-up information. Of 7232 women in the study, 460 who were lost to follow-up or died before 1982 were excluded. To limit the analysis to incident disease, 200 cases were excluded due to pathology-confirmed high-grade neoplasia diagnosed before the start of follow-up and an additional 107 were excluded who reported cervical dysplasia before the start of follow-up. Because prior treatment of the cervix may lower the subsequent incidence of CIN2+, 416 women who received treatment before 1982 were excluded at baseline from the main analyses. In addition, 150 women (0 cases) who had a hysterectomy prior to 1982 were excluded. Of 5899 women in the analysis, 5237 (89% of exposed and 89% of unexposed) responded to any of the NCI follow-up questionnaires.

Statistical analysis

The analyses focused on the first occurrence of pathology-confirmed CIN2+. Person-years at risk for each woman were computed from Jan. 1, 1982 (except for the WHS, for which follow-up started in 1994 through 1995) until the date of first documented diagnosis of CIN2+, date of last known follow-up, or date of last questionnaire response. The start of follow-up was chosen to correspond to the end of follow-up in the original cohort study of incident dysplasia among the DESAD cohort, which comprises 70% of the current study population. Women were censored at the reported date of hysterectomy, except when CIN2+ was diagnosed at surgery. Participants who reported dysplasia on the questionnaire but for whom we were not able to obtain pathology records were censored at their reported diagnosis year. Among the exposed, follow-up ranged from <1-32.0 years with a median of 25.4 (25th percentile, 13.6; 75% percentile, 30.0) and among the unexposed it was <1-32.0 years with a median of 18.2 years (25th percentile, 11.9; 75th percentile, 29.9).

The association of DES and CIN2+ was estimated with hazard ratios (HR) and 95% confidence interval (CI) from Cox regression models, using statistical software (SAS, Version 9.2; SAS Institute Inc, Cary, NC). The models included original study cohort (except for models evaluating dose because the Dieckmann cohort had a uniform dose) and birth year, and used age as the time metric. Additional covariates included education, age at first intercourse, number of sexual partners, smoking status, and menopausal status. Pap smear screening represented the number of Pap smears in the 5 years before the most recent questionnaire. Categories for each of the covariates are listed in Table 2 . Missing values were categorized separately and included in the models; a complete case approach yielded the same results for DES and CIN2+ (not shown). Associations were evaluated by DES dose and timing, and in the Dieckmann and DESAD cohorts, by presence or absence of VEC.

Table 2

Distribution of high-grade squamous neoplasia (cervical intraepithelial neoplasia grade ≥2) for selected characteristics by diethylstilbestrol exposure status

Characteristics	DES exposed			DES unexposed
	Person-years, n	%	Cases, n	Person-years, n	%	Cases, n
All	88,098		145	35,934		33
Cohort
DESAD	72,915	82.8	98	19,251	53.6	17
Dieckmann	6408	7.3	16	5695	15.9	8
Horne	5731	6.5	26	4326	12.0	3
WHS	3044	3.5	5	6663	18.5	5
Age, y (time-dependent)
<30	14,548	16.5	41	4418	12.3	6
30–34	15,110	17.2	41	5152	14.3	9
35–39	15,710	17.8	26	5728	15.9	4
40–44	14,083	16.0	21	5725	15.9	3
45–49	12,146	13.8	6	5537	15.4	5
≥50	16,505	18.7	10	9377	26.1	6
Birth year
<1953	34,732	39.4	48	18,095	50.4	15
≥1953	53,366	60.6	97	17,839	49.6	18
Calendar year (time-dependent)
<1995	44,544	50.6	98	15,373	42.8	17
≥1995	43,558	49.4	47	20,565	57.2	16
Education (1994)
<4-y College	27,170	30.8	48	13,696	38.1	20
4-y College	30,541	34.7	56	11,487	32.0	5
Graduate school	23,440	26.6	35	8849	24.6	7
Missing	6948	7.9	6	1902	5.3	1
Smoking status (at exit or 2006)
Never	45,916	52.1	71	17,087	47.5	6
Ever	38,094	43.2	69	17,589	49.0	25
Missing	4088	4.7	5	1261	3.5	2
Menopausal status (time-dependent)
Premenopausal	73,103	83.0	138	28,383	79.0	29
Postmenopausal	14,503	16.5	6	7342	20.4	4
Missing	492	0.56	1	209	0.58	0
Age at first intercourse
≤18 y	36,511	41.4	72	15,642	43.5	16
≥19 y	45,167	51.3	67	17,502	48.7	14
Missing	6420	7.3	6	2790	7.8	3
No. of male partners (1994)
<5	42,742	48.5	35	16,779	46.7	8
5–9	17,168	19.5	46	7948	22.1	9
≥10	26,102	29.6	59	9330	26.0	13
Missing	2086	2.4	5	1876	5.2	3
No. of Pap smears a
<3	18,903	21.5	14	8286	23.1	6
≥3	59,436	67.5	101	23,266	64.8	21
Missing	9760	11.1	30	4382	12.2	6

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Neuraxial analgesia to increase the success rate of external cephalic version: a systematic review and meta-analysis of randomized controlled trials
2. Effect of race/ethnicity on clinical presentation and risk of gestational trophoblastic neoplasia in patients with complete and partial molar pregnancy at a tertiary care referral center
3. High-fructose diet in pregnancy leads to fetal programming of hypertension, insulin resistance, and obesity in adult offspring
4. Consistently inconsistent: interest in sexual function

Stay updated, free articles. Join our Telegram channel

Join