Contraceptive and reproductive risk factors for cervical intraepithelial neoplasia in American Indian women

Melissa Schiffa, Jill Millera, Mary Masuka, Linda van Asselt Kinga, Kathleen K Altobellia, Cosette M Wheelera and Thomas M Beckerb

a University of New Mexico School of Medicine, 2211 Lomas, NE Albuquerque, NM 87131, USA.
b Oregon Health Sciences University, Department of Public Health and Preventive Medicine, 3181 SW Sam Jackson Park Road-CB669, Portland, OR 97201–3098, USA.

Reprint requests: Melissa Schiff, MD, Fred Hutchinson Cancer Research Center, Weiss-Daling Studies, 1124 Columbia St, Seattle, WA 98104, USA. E-mail: mschiff{at}u.washington.edu


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objectives To evaluate contraceptive and reproductive risk factors for cervical intraepithelial neoplasia (CIN) in southwestern American Indian women.

Methods We conducted a clinic-based case-control study. Cases were American Indian women with biopsy-proven CIN I, CIN II or CIN III. Controls were from the same clinics and had normal cervical epithelium. All subjects underwent structured interviews focused on contraceptive and reproductive factors. Laboratory assays included polymerase chain reaction (PCR)-based tests for cervical human papillomavirus (HPV) infection.

Results We enrolled 628 women in the study. The strongest risk factors for CIN II/III included HPV infection (adjusted odds ratio [OR] = 7.9, 95% CI : 4.7–13.2), and low income (OR = 3.1, 95% CI : 1.7–5.7). The use of an intrauterine device (IUD) ever (OR = 3.0, 95% CI : 1.4–6.1) and currently (OR = 4.1, 95% CI : 1.1–14.6), and >=3 vaginal deliveries (OR = 5.2, 95% CI : 2.4–11.1) were associated with CIN II/III. History of infertility was also associated with CIN II/III (OR = 2.1, 95% CI : 1.0–4.2).

Conclusions The data suggest that history of infertility, IUD use and vaginal deliveries were associated with CIN among American Indian women.

Keywords Indians North American, cross cultural comparison, cervix dysplasia

Accepted 30 May 2000


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Cervical intraepithelial neoplasia (CIN) is a well-recognized precursor for cervical carcinoma. While human papillomavirus (HPV) infection is reported to be the strongest risk factor for CIN,1–3 contraceptive and reproductive risk factors have also been found to play a role in this disease.4,5 Use of hormonal contraception has been associated with an increased risk for the development of cervical neoplasia, possibly through hormonal mechanisms regulating the replication of HPV.6,7 Use of other types of contraception—including intrauterine device use and barrier methods—have been less clearly associated with cervical neoplasia.8,9

Reproductive risk factors for pre-invasive cervical neoplastic lesions and for invasive cervical cancer have also been evaluated in many studies. The risk for CIN and cancer has been shown to increase with gravidity and parity.4,10–12 High parity has been associated with cervical neoplasia even after adjustment for sexual activity and other risk factors.4,10,12 Possible mechanisms that have been hypothesized include hormonal effects on cervical epithelium,6,7 prolonged immunosuppression during multiple pregnancies,13,14 and cervical trauma from vaginal deliveries.4,12 Caesarean delivery, miscarriage, and abortion have not been found to be associated with cervical neoplasia.4,10,12

Although many prior studies have evaluated contraceptive and reproductive risk factors for cervical neoplasia, few have controlled for the presence of cervical HPV infection, and few published data have evaluated cervical neoplasia risks in American Indian women. American Indian women in New Mexico have high rates of cervical carcinoma15 and different patterns of exposure to HPV infection16 and reproductive and contraceptive17 risk factors. Controlling for multiple confounders in the analysis, we utilized a case-control study design to evaluate contraceptive and reproductive risk factors for CIN in a southwestern American Indian population.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Subjects
Subjects were enrolled in this study through three Indian Health Service (IHS) facilities in New Mexico. The IHS provides free medical care to all American Indians in the state, as well as to those in surrounding states and reservations.

The case women were enrolled through the Colposcopy Clinics at three IHS facilities before clinical evaluation for cervical squamous intraepithelial lesions (CIN I, II or III; slight, moderate, severe dysplasia/carcinoma in situ) detected through routine Papanicolaou (Pap) tests. Colposcopy clinic visits were scheduled within a month of the diagnosis of cervical dysplasia on the routine screening Pap test. Most patients (75%) had colposcopy performed within 6 months of their initial diagnosis (range 0–62 months, median 3.8 months). All case women were American Indian (by self report and validated through medical record reviews, which include tribal enrolment information), aged 18–45 years, and not pregnant. Subjects were contacted on presentation to the colposcopy clinic and invited to participate in the interviews as an additional part of their clinic visit. Informed consent was obtained for subjects to participate in interviews and to undergo cervical sampling.

Control women with normal cervical epithelium were selected from the same clinics through which case women were referred for their colposcopic examinations. Controls were also American Indian women aged 18–45 years, and not pregnant. We selected control subjects from women who presented to the IHS facilities who required a pelvic examination for any reason, including family planning-related visits, annual examinations, and other reasons listed in Table 1Go. Besides the age restriction, no matching criteria were employed. Medical records were reviewed to ensure that potential study controls had documented normal Pap tests in addition to meeting the other study enrolment criteria.


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Table 1 Demographic characteristics of American Indian study participants, American Indian Dysplasia study, 1994–1997
 
We enrolled subjects during a 3-year period, beginning November 1994 and extending through October 1997. Study participation among eligible study subjects was high, with a total of 48 refusals (6.2% of the total eligible subjects invited into the study). Of the 48 refusals, 23 (48%) were case women. The reasons for refusal were related primarily to lack of available time to undergo the interviews.

Although case women with cervical neoplasia were invited into the study based on Pap tests showing squamous epithelial lesions, the presence of CIN on histological examination of cervical tissue taken on the day of study entry was necessary for subjects to remain in the analysis. Of the case women enrolled on the basis of Pap test results, 57 did not have histological confirmation of dysplasia on biopsy and were dropped from the final analysis. Of those subjects, 56 had normal or non-diagnostic biopsy results and one subject did not have a biopsy performed. No study subject had invasive cervical carcinoma on biopsy. Most (94.6%) of the cervical smears from the clinic sites were interpreted by the same reference pathology laboratory under contract to the IHS facilities in New Mexico. The remaining 5.4% of all study Pap smears were processed by a separate laboratory that was also under a contract to the IHS facility in Albuquerque.

For control women, biopsy specimens were not obtained and we required that the Pap test on the day of study entry be negative for subjects to remain in the analysis. Women who were selected as controls but who had atypia or dysplasia on the Pap test on the day of study entry were excluded from the analysis (n = 37 [5.1%]).

We also excluded seven women who reported no sexual activity with a male partner, as these subjects were not likely to have been exposed to the reproductive and sexually transmitted disease risk factors of interest in this study.

All study subjects were paid US$20 for their time for participation in this investigation.

Interviews
All study subjects were interviewed by trained interviewers who focused on relevant risk factors for the development of CIN suggested by previous research. After informed consent was obtained, the interviewers asked participants about reproductive and sexual histories, sexually transmitted diseases (STD), hygienic practices, and cigarette use. Demographic data were also collected. All interviews were carried out in English and lasted from 60 to 90 minutes. The colposcopy clinics were scheduled to meet on specific days of the week; thus, due to logistical problems associated with the clinics' schedules, the interviewers were not blinded to case or control status of the study subjects. Medical records were examined to validate responses about episodes of STD, Pap test screening, and contraceptive use.

Pelvic examination and specimen collection
Pelvic examinations and cervical specimen collection preceded colposcopic examination of the cervix for case women. Control women had cervical specimens taken at the time of pelvic examination. Specimens were collected for all women in the following order: Pap tests, fixed and air dried; dacron cervical swab of the endocervix and ectocervix, placed in standard transport media (Digene Diagnostics, Silver Spring, MD) for later identification of HPV genome; endocervical swab for identification of Chlamydia trachomatis and Neisseria gonorrhoeae using Genprobe assays (San Diego, CA); vaginal pool swab for wet mount identification of trichomonads, yeast, and clue cells under light microscopy; and vaginal pool swab placed on glass slide and air-dried for later microscopic identification of organisms that are associated with bacterial vaginosis.18

Following cervical specimen collection, case subjects underwent colposcopic examination of the cervix using application of 5% acetic acid with cotton swabs. All case women underwent cervical biopsy and endocervical curettage. Treatment for any abnormal conditions was provided by gynaecologists and staff at the IHS.

Identification of HPV
The HPV genotype was identified from cervical specimens using a newly developed reverse blot method that employs a biotin-labelled PCR product hybridized to an array of immobilized oligonucleotide probes. Using the reverse blot ‘strip’ test, genotype discrimination of multiple HPV types can be accomplished in a single hybridization and wash cycle.19 The genotypes discriminated on this strip included types 6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 66, 68 (ME180), MM4 (W13B), MM7 (P291), MM8 (P155), and MM9 (PAP 238A). Two concentrations of B-globin probes allowed for assessment of individual specimen adequacy following amplification. This method of HPV detection has shown high accuracy compared to other dot blot methods.20 The HPV types were classified as high risk versus low risk based on reported cancer associations as described previously.19,21 High-risk types included HPV 16,18, 26, 31, 33, 35, 39, 45, 51, 52, 55, 56, 58, 59, 68, MM4, MM7, and MM9. Low-risk types included HPV 6, 11, 40, 42, 53, 54, 57, 66, and MM8.

Statistical analysis
We used logistic regression to model case-control status and to estimate odd ratios (OR). We separated case groups according to level of severity of the histological findings into CIN I and CIN II/III. The OR were adjusted for age, age at first intercourse, lifetime number of sex partners, and HPV infection. We adjusted for these variables because prior studies of risk factors for CIN have adjusted for these confounders and we designed this analysis to be comparable to prior analyses, even though most adjusted OR were not significantly different from unadjusted measures. We calculated 95% CI about the point estimates of effect for each of the variables we present. Although crude OR with 95% CI are reported in the Tables, we report only adjusted OR and 95% CI in the text (adjusted for age, age at first intercourse, lifetime number of sex partners, and HPV infection). Most of the predictor variables were obtained as categorical variables; other variables were recoded into categories for ease of interpretation or to diminish the effects of outliers. For our final logistic regression model, we included variables that were biologically plausible and variables that were statistically significant in our initial analyses after adjustment for age, age at first intercourse, lifetime number of sex partners, and HPV infection. We used standard SAS software for all of these analyses (SAS, version 6.12, 1996 North Carolina).

This protocol was approved by the University of New Mexico Human Health Sciences Center Research Review Board, the National IHS Human Research Review Board as well as by the local IHS hospital review boards.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Demographic data are presented in Table 1Go. Most of the American Indian women enrolled in this study were from southwestern tribes and were of full Indian blood quantum. The majority were married or living with a partner and had completed some education beyond high school. The mean age for controls was 28.6 years, while the mean age for cases was 28.5 years for CIN I cases and 27.6 years for CIN II/III cases.

Table 2Go highlights risk factors for CIN I and CIN II/III related to demographic characteristics and sexual behaviour. Women with the lowest levels of education (high school graduate or less) and annual family income (<US$10 000) had significantly increased risk of dysplasia (CIN I and CIN II/III) compared to those with the highest levels of education and income. Human papillomavirus infection was the strongest risk factor for CIN I and CIN II/III. Age at first intercourse, lifetime number of sex partners, and cigarette smoking were not associated with CIN (data not shown).


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Table 2 Risks for cervical intraepithelial neoplasia (CIN) by selected risk factors, American Indian Dysplasia study, 1994–1997
 
Risks for CIN associated with various contraceptive methods are illustrated in Table 3Go. Compared to controls, women with CIN I who ever or currently used oral contraception and women who had used oral contraception for >=5 years had a decreased risk for dysplasia. Ever use and past use of an intrauterine device (IUD) was associated with an increased risk of both CIN I and CIN II/III. Current use of an IUD was also associated with an increased risk of CIN II/III. Past use and ever use of depot-medroxyprogesterone were associated with an increased risk of CIN I. Use of barrier methods of contraception (diaphragm, condoms) was not associated with a reduced risk of either CIN I or CIN II/III, although diaphragm use was limited by small cell sizes.


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Table 3 Risks for cervical intraepithelial neoplasia (CIN) associated with contraception methods, American Indian Dysplasia study, 1994–1997
 
In addition to contraception methods, we also evaluated reproductive factors as risks for CIN. After adjustment for age, sexual behaviour, and HPV infection, we found that a short interval between menarche and first intercourse was associated with CIN II/III (P < 0.002 for each year, OR = 0.81, 95% CI : 0.73–0.93). Women with higher gravidity (>=3 pregnancies) and higher numbers of vaginal deliveries (>=3 vaginal deliveries) were at significantly increased risk for CIN I and CIN II/III (Table 4Go). One or more miscarriages were associated with a nearly twofold increase in the risk for CIN I. Caesarean deliveries and abortions were not associated with CIN. History of infertility was significantly associated with an increased risk for CIN II/III.


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Table 4 Risks for cervical intraepithelial neoplasia (CIN) associated with reproductive factors, American Indian Dysplasia study, 1994–1997
 
We also evaluated douching and types of douching products as risk factors for CIN. The practice of douching ever, frequency of douching and type of douching product were not associated with CIN (data not shown).

We used logistic regression to simultaneously evaluate the effects of multiple risk factors potentially associated with CIN II/III. We included age and other variables that we found to be significantly associated with CIN in partially-adjusted models. We found the strongest risk factor was HPV infection (Table 5Go). Other risk factors that were also significantly associated with CIN II/III included annual family income <US$10 000, history of an STD, vaginal deliveries, and history of infertility. The model that included multiple risk factors showed less of an effect of IUD use (ever) on the risk of CIN II/III, compared to data shown in Table 3Go; other risk factors in the model did not change significantly.


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Table 5 Logistic regression model of risk factors for cervical intraepithelial neoplasia (CIN II/III), American Indian Dysplasia study, 1994–1997
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Comparable to other recent studies on cervical neoplasia, we found HPV to be the strongest risk factor for CIN. Several contraceptive and reproductive risk factors were also associated with CIN I and CIN II/III. Oral contraceptive use greater than 5 years was negatively associated with CIN I but no association was found for oral contraceptive use or duration of use with CIN II/III. Current, past, and ever use of an IUD was a moderate risk factor for CIN II/III, while ever and past use of depot-medroxyprogesterone was a risk factor for CIN I. Consistent with many other published studies,4,10–12 our data showed that three or more pregnancies or vaginal deliveries were associated with moderate risk for all grades of CIN.

Most previous studies5,22–24 have reported an increased risk of CIN with long-term oral contraceptive use. In laboratory investigations, oestrogen and progesterone have been found to promote viral replication through transcription regulatory regions on the HPV genome.7,25–27 Several studies have reported a negative association for CIN and oral contraceptive use, but these relationships were not statistically significant after adjustment for confounders.11,28–30 We found a negative association between ever and current oral contraceptive use and CIN in this study. In our earlier, comparably designed study of risk factors for CIN in Hispanic and non-Hispanic white women in New Mexico, our data also showed a negative association between oral contraceptive use and dysplasia.31 We suspected that selection bias may have strongly affected those results, however, as many control women were enrolled at clinic visits that were related to contraception. Our data in the current study also suggested an increased risk of CIN I among ever and past depot-medroxyprogesterone users. Thomas et al.32 reported an increased risk of cervical carcinoma in situ with increased duration of depot-medroxyprogesterone use. It is difficult to explain why we found an effect with progesterone (only) contraception but not with the combination of oestrogen and progesterone.

Few studies have evaluated the effect of IUD use on risk for CIN. We found an increased risk for CIN II/III among current and past IUD users, after adjustment for multiple confounders. In our final regression model, however, IUD use (ever) was not significantly associated with CIN II/III. Lassise et al. reported a non-significant reduced risk of cervical cancer associated with copper IUD use and no effect from inert IUD use.8 Other researchers found no increased risk of development of CIN comparing women using oral contraceptives, IUD, or depot-medroxyprogesterone for contraception.33 Peters et al., in a case-control study of risk factors for cervical cancer among Los Angeles area Hispanic women, also found no association between IUD use and cervical cancer.11 In our earlier study among Hispanics and non-Hispanic whites,31 we found a (non-significant) association of IUD use with dysplasia (OR = 1.6, 95% CI : 0.8–3.2). We have no data from animal or laboratory studies that would help explain the finding that suggests an association between IUD use and dysplasia.

In addition to risks associated with specific types of contraception, we found several reproductive factors to be associated with CIN. In this study, American Indian women had a fivefold increased risk of CIN II/III with >=3 vaginal deliveries. Many studies report increased risk of cervical neoplasia with increased number of pregnancies, and with vaginal deliveries in particular, even after adjustment for sexual behaviour and HPV infection.1,4,10,31,34,35 In our previous study, Hispanic and non-Hispanic white women in New Mexico had a 3.9-fold increase in risk of CIN II/III associated with >=3 vaginal deliveries.31 Possible explanations for this association with vaginal delivery include exposure to elevated oestrogen and progesterone levels affecting HPV replication,6,36 prolonged or repeated episodes of immunosuppression associated with pregnancy,13,14 and mechanical damage to the cervical epithelium from trauma during vaginal delivery.4,12

In addition to vaginal delivery, we also evaluated other pregnancy outcomes including miscarriage, abortion, and caesarean delivery. While we found that women with one or more miscarriages were at increased risk of CIN I, we found no association with abortion and CIN I or CIN II/III. Most published reports have found no association with miscarriage or abortion and cervical neoplasia.4,10,35 Finally, similar to a study by Brinton et al.,4 our study showed no association between caesarean delivery and CIN. This finding is difficult to explain because all pregnant women who were delivered by caesarean section were exposed to high levels of oestrogen and progesterone, immunosuppression, and some mechanical damage to the cervix (except for those who did not experience labour) prior to surgical delivery. We do not have data to explain this finding. History of infertility was associated with increased risk for CIN II/III. Infertility may be mediated by prior infection with an STD (other than HPV infection) and this may explain the association.

We hypothesized that study subjects who reported initiation of sexual activity before or near menarche would be at increased risk of CIN. If sexually transmitted HPV infection is the primary cause of CIN, and if highly metaplastic cells found among peri-menarchal young women are more likely to become infected with HPV and progress toward dysplasia, our data would be expected to show a relation of these events with CIN. After adjustment for age, sexual behaviour, and HPV infection, we found that a short interval between menarche and first intercourse was associated with CIN II/III (OR = 0.82, 95% CI : 0.71–0.94). This possible association warrants further evaluation in cohort or other studies.

Finally, we performed a multiple logistic regression analysis of all contraceptive and reproductive variables to examine their effects on CIN II/III (Table 5Go). We found that HPV infection and >=3 vaginal deliveries were strong risk factors for dysplasia and income <US$10 000 per year, history of any STD and one or two vaginal deliveries, and history of infertility were moderate risk factors for CIN II/III. A shorter interval between age at menarche and age at first intercourse was associated with an increased risk for dysplasia.

Our study has potential limitations that must be considered in interpretation of our results. Some of these limitations include lack of blinding of interviewers to case or control status of the subjects, and lack of validation of interview data. In addition, recall bias is always a potential problem in case-control research. To address some of these potential problems, we used a structured interview and standard protocol for cases and controls. We also validated a sample of nurse practitioners' study interviews through re-interviews of study subjects, and examined medical records for possible differences in reported information compared to charted information. For the few inconsistencies we found between interview and medical record data, we used charted information in the analysis. We reminded study subjects at several points in the interview about the confidential nature of all data collected to increase the likelihood of accurate responses about sexual behaviour. We would have preferred random sampling of controls from tribal rosters or other IHS rosters, instead of selecting controls from the clinic patients who presented for routine care and other reasons (Table 1Go). The opportunity for bias in our results based on the use of a clinic-based comparison group is possible, but the magnitude of effect of this source of bias is not easily estimated. A larger proportion of the control women presented for annual exams (and these visits include prescriptions for contraceptives) compared to the case women and this selection bias could have effected the OR associating various types of contraceptives with CIN. Another limitation was the long time period between initial abnormal Pap and colposcopy for the case women. Some potential cases became ineligible because their dysplasia was not confirmed at the time of biopsy. Our HPV data are limited by a single specimen collected at study entry; additional sampling would likely result in a higher proportion of control women with HPV infection. We did not collect information on sexual behaviour of male partners of the study subjects. Thus, we cannot evaluate the possible effects of male behaviour as a risk for dysplasia among females. We included American Indian women from tribes outside of the Southwest (approximately 10% of all study subjects). Although this feature of the study is not likely to introduce bias, the study is not strictly focused on risk factors for dysplasia among southwestern American Indian women. The proportion of non-southwestern tribal subjects is not large enough to allow broad generalizability of our findings to all American Indian groups. Last, we had limited statistical power related to numbers of cases of CIN II/III in our study. However, since CIN I and CIN II/III may represent different disease processes,3 we determined that the appropriate strategy was to analyse and present the study findings as stratified by these two groups, even though study power would be increased by combining the two groups.

In conclusion, we found that HPV infection was the strongest risk factor for CIN. We also found that low income, history of any STD, and an increasing number of vaginal deliveries were associated with CIN, while caesarean delivery, abortion, and most indicators of oral contraceptive use were not associated with dysplasia. While IUD use was also associated with dysplasia in crude and partially adjusted analyses, these risk factors did not remain as significant variables in our final regression model. Future studies should evaluate the effects of contraception while controlling for HPV infection, and evaluate the reasons vaginal delivery but not caesarean delivery is a risk factor for development of cervical neoplasia. Additional focus on the possible association between short interval from menarche to first intercourse also warrants further study.


    Acknowledgments
 
The investigators would like to thank all of the Indian Health Service personnel who helped to facilitate this study in the clinic sites. In particular, Drs Eve Espey, Tony Ogburn, Alan Waxman, and Ms Rose Rowan were particularly valuable to the study's success. Drs Gary Escudera, William Freeman, and Tim Fleming assisted the study team with protocol approvals. Dr Jennie Joe and Dr Linda Burhanisstipanov provided expertise in the design of the questionnaire. Dee Comiskey and Tresia Denetclaw assisted with data entry. Dawn Hamilton and Barbara Evans assisted with programming of data entry screens. George Montoya, Pat Stauber, and Dr Phil Garry provided valuable assistance and advice for the clinical nutrition specimens. Darren Schaffer, Helena Frank and Evelyn Hood were very valuable as laboratory assistants. Gary Oty, Kerry Hatch, Linda Nims, Dr David Mills, and support staff of the New Mexico State Laboratory Division provided laboratory expertise for analyses of study specimens. The laboratory of Drs Francis Lee and Andre Nahmias performed serum antibody assays for herpes viruses. The investigators would also like to recognize the valuable contributions of Fred Ettcity and Ray Rodgers of the Indian Health Service. The guidance provided by the IHS Service Unit Health Boards was also very helpful to the project. This research was supported by a National Cancer Institute grant to Dr Schiff, R01-CA-55348. Dr Becker was supported by a Faculty Research Award from the American Cancer Society.

Disclaimer

The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the IHS.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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