The association of smoking and risk of condyloma acuminatum in women

The Association of Smoking and Risk of Condyloma Acuminatum in Women JOSEPH G. FELDMAN, DrPH, KEITH CHIRGWIN, MD, JACK A. DEHOVITZ, MD, AND HOWARD MINKOFF, MD Objective: To determine the relation b e t w e e n cigarette s m o k i n g and the incidence of genital warts in a cohort of h u m a n i m m u n o d e f i c i e n c y virus (HIV)-infected w o m e n (without AIDS-defining conditions) (n = 148) and in HIVnegative w o m e n (n = 428). Methods: W o m e n were recruited between March 1990 and December 1993 from an urban, inner-city medical center and nearby c o m m u n i t y health centers. W o m a n initially free of genital warts (n = 576) were f o l l o w e d prospectively for up to 37 months, with an average of 14 months. Results: The observed incidence of genital warts per 100 person-years was almost three times higher in smokers than in non-smokers, both in HIV-positive (13.3 versus 5.0, respectively) and HIV-negative w o m e n (1.5 versus 0.5, respectively), In a Poisson regression m o d e l adjusting for variables significantly related to genital warts, including sexual activity, current smokers were 5.2 times (95% confidence interval 1.02, 26.0) more likely to develop genital warts. The prevalence of h u m a n papillomavirus (HPV) by polymerase chain reaction at baseline examination and the incidence of other sexually transmitted diseases were similar in smokers and non-smokers. Conclusions: Our findings are compatible with the hypothesis that the rate of progression of symptomatic exophytic HPV disease is increased in smokers. (Obstet Gynecol 1997; 89:346-50. Copyright © 1997 by The American College of Obstetricians and Gynecologists.)

The hypothesis that tobacco use increases the risk of cervical cancer was introduced in 1977.1 Recent research suggests that cigarettes m a y promote the occurrence of cervical neoplasia by mitigating the effect of host mucosal immunity on h u m a n papillomavirus (HPV) by reducing the number of Langerhans cells, a Fewer data exist in regard to any association between tobacco use From the Departments of Preventive Medicine, Medicine, and Obstetrics and Gynecology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York. This study was supported by NIAID grant RO1-AZ-31834, contract NO1-AI-95014, and CONRAD Program, subproject agreement CS4-94134.

346 0029-7844/97/$17.00 PII s0029-7844(97)00011-2

and exophytic warts, which are also caused by HPV, albeit different types. We have previously described the relation of genital warts to h u m a n immunodeficiency virus (HIV) serostatus in cohorts of HIV-infected and HIV-negative women. 3 In the present study, we used the same cohorts to compare the annual incidence of genital warts in smokers and non-smokers and to determine whether smoking has a greater association with venereal warts in HIV-seropositive women.

Materials and Methods Between March 1990 and December 1993, 253 HIVinfected and 681 HIV-negative study participants were recruited from patient care programs at the State University of N e w York Health Science Center at Brooklyn, Kings County Hospital Center, and nearby community health centers that serve an urban, minority population in central Brooklyn, N e w York. Inclusion criteria for the HIV-infected w o m e n were a positive HIV antibody test and the absence of AIDS-defining conditions per the 1987 Centers for Disease Control AIDS case definition. W o m e n with HIV infection were recruited from HIV care programs. A m o n g the 325 HIV-infected w o m e n eligible, 90% agreed to participate. Inclusion criteria for the HIV-negative w o m e n were a negative HIV antibody test at entry, no history of intravenous drug use, and at least one male sexual partner within the previous year. The HIV-negative w o m e n were recruited from primary care sites, including family planning and drug treatment clinics and community-based sites. A m o n g 1085 w o m e n eligible, 63% agreed to participate. Informed consent was obtained from all participants. The cohorts are described in more detail elsewhere. 3"4 In this report, we focus on the 148 HIV-positive w o m e n and the 428 seronegative w o m e n without genital warts at enrollment who were eligible and returned for at least one follow-up visit. Study visits occurred at entry and every 6 months.

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Demographic data and history of drug use, alcohol use, and sexual behavior were obtained by questionnaires administered by trained interviewers in English, Spanish, or Creole, as appropriate. Study clinicians obtained medical histories and performed standardized clinical examinations, including complete pelvic and anorectal examinations with thorough inspection of the external genitalia. At each visit, the patients were categorized as to whether venereal warts were present on examination. The examiner was not aware of the women's smoking status at the time of the examination because these data were gathered by the interviewer before the examination. Cervical specimens were obtained for culture of Neisseria gonorrhoeae and Chlamydia trachomatis, and vaginal specimens were used for culture of Trichomonas vaginalis. Cultures for each were performed as described previously. 3"4 All genital lesions underwent viral culture for herpes simplex virus, direct fluorescent antibody for Treponema pallidum, and Gram stain and culture on Mueller-Hinton chocolate agar for Haemophilus ducreyi, as described previously. 3'4 Cervicovaginal cells collected by lavage were tested for HPV DNA and typed by both polymerase chain reaction (PCR) and Southern blot hybridization techniques in the HIVnegative cohort, and by PCR only in the HIV-positive cohort, as described previously. 3"6 Serum samples were screened for antibody to HIV-1 using an enzyme immunoassay, and positive samples underwent confirmatory testing by the Western blot assay. Syphilis serologic status was determined using the rapid plasma reagin test and, for confirmation, the T pallidum hemagglutination assay. Information on smoking was obtained as part of the medical history using a standardized questionnaire. Women were asked if they ever smoked, whether they were currently smoking, the number of years smoked, and the amount smoked daily; the women were grouped into none, zero to ten cigarettes, 11-20, 21-40, and 41 or more. The outcome measure was the diagnosis of a new case of warts in a woman who was free of venereal warts at study onset. Women with genital warts at baseline were excluded from the analysis to minimize the possibility of misclassifying new and old lesions. The risk of warts associated with smoking was determined using multiple Poisson regression analysis. The Poisson distribution is often used to model rare events, and in the present study, the occurrence of warts in non-smoking HIV-negative women was less than one per 100 person-years. 7 Variables forced into the model included smoking, age, place of birth (United States or foreign), and HIV status. In addition, the number of lifetime sexual partners and acquisition of any sexually transmitted diseases (STDs) (N gonorrhoeae, C trachoma-

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Table 1. Characteristics of Women Followed and Lost to Follow-Up in the Human Irnmunodeficiency Virus-Negative Cohort Characteristic

Followed

Lost to follow-up

P

Age (y) Years of education Foreign birth Smoker Cocaine use in past year Lifetime partners <3 4-5 6-9 10-19

30.5 z 82 11.5 + 2.3 61.2 30.8 16.6

29.7 ÷ 7.9 11.5 -+ 2.4 37.9 39.9 28.5

.19 .91 .01 .02 .01

25.6 29.0 16.3 18.9

24.1 23.3 16.2 15.0

10.2

21.3

5.6 92.8 1.6 8.9 24.1 8.4 0.9

7.1 89.3 3.2 4.3 23.7 7.9 1.2

>20

Ethnicity Hispanic Black Other Chlamydia Trichomonas Syphilis Gonorrhea

.03

.28 .03 .99 .89 .71

Data are presented as mean + standard deviation or percent.

tis, T vaginalis, and syphilis) during follow-up (summarized as yes or no) were added separately to the model. Actual computations were performed on SPSS (Statistical Package for the Social Sciences; SPSS Inc., Chicago, IL) using the module on general loglinear analysis.

Results Women were followed for an average of 1.1 years, with a range of 3-37 months. One-third of the HIV-negative women and 10% of the HIV-positive women were lost to follow-up. Table 1 shows characteristics of the women followed and lost to follow-up in the HIVnegative cohort. Women lost to follow-up included higher proportions who were born in the United States, who smoked cigarettes, who were recent cocaine users, and who had more than 20 lifetime sexual partners. Age, education, and ethnicity did not differ between smokers and non-smokers in either cohort (Table 2). Smokers were more likely to have been born in the United States, to have used cocaine in the past year, and to have had more than 20 lifetime sexual partners (P < .001). Almost one-quarter of HIV-negative smokers reported 20 or more lifetime sexual partners, compared with less than 5% of HIV-negative non-smokers. Among HIV-positive women, almost 40% of smokers had 20 or more lifetime partners, compared with less than 18% of non-smokers. The unadjusted annual incidence rate of genital warts among both HIV-positive and HIV-negative smokers

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Wartsand Smoking 347

Table 2. Demographic Characteristics of Smokers and Non-Smokers in I Iuman hnmunodeficiency VirusPositive and - N e g a t i v e Cohorts HIV-Negative

HW-Positive

Smoker Non-smoker Characteristic (n = 132) (n = 296) P

Smoker Non-smoker (n = 74) (n = 74)

Age 31.0 -+ 8.7 29.5 ± 6.8 .09 31.0 ± 8.7 29.5 +_6.8 Years of 11.5 ± 2.4 11.5 +- 1.9 .89 11.0 ± 2.5 11.0 + 1.8 education Etl-micity Hispanic 6.8 5.1 21.6 29.7 Black 91.7 93.2 .90 68.9 67.6 Other 1.6 1.7 9.5 2.7 Place of birth United States 75.8 22.3 .001 86.5 62.2 Foreign 24.2 77.7 13.5 37.8 Cocaine use in past year .001 25.7 5.4 Yes 62.1 8.1 No 37.9 91.9 74.3 94.6

.09 .88

.16

.001

.001

was almost three times higher than among non-smokers (Table 3). A f t e r a d j u s t m e n t in the P o i s s o n r e g r e s s i o n m o d e l for f o r e i g n v e r s u s U n i t e d States b i r t h a n d for H I V status, t h e r e l a t i v e risk (RR) of d e v e l o p i n g w a r t s in c u r r e n t s m o k e r s v e r s u s n o n - s m o k e r s i n c r e a s e d to 5.2:1 (P -< .04, 95% c o n f i d e n c e i n t e r v a l [CI] 1.02, 26.0). T h e m o d e l fit the d a t a w e l l ( l i k e l i h o o d r a t i o 2(2 = 5.1, 5 dr, P = .40). A s n o t e d earlier, s m o k e r s in e a c h c o h o r t reported significantly more lifetime sexual partners (P < .001). B o t h p r e v a l e n c e at b a s e l i n e a n d h i s t o r y of v e n e r e a l w a r t s w e r e a s s o c i a t e d w i t h t h e n u m b e r of l i f e t i m e s e x u a l p a r t n e r s (P = .002) (Table 4). H o w e v e r , t h e i n c i d e n c e of v e n e r e a l w a r t s w a s n o t r e l a t e d to the n u m b e r of l i f e t i m e s e x u a l p a r t n e r s (Table 5). This m a y r e s u l t f r o m t h e s i m i l a r i t y in the n u m b e r of s e x u a l

Table 3. Observed Annual Incidence of Venereal Warts in H u m a n Immunodeficiency Virus-Positive and -Negative Women

Positive Current smoker Non-smoker Negative Current smoker Non-smoker

New Rate cases per 100 95% of Person- person- Relative Exact confidence warts years years risk mid-P* interval 8 3

60 60

3 2

207 408

Total

13.3 5.0 1.45 0.5

2.7

.15

0.7, 12.4

Feldman et al

History of warts

Prevalent warts at enrolhnent

Neither

-<3 4-9 10-19 >20

14 (36.9%) 13 (34.2%) 11 (29.0%)

8 (25.0%) 6 (18.8%) 8 (25.0%) 10 (31.3%)

211 (24.0%) 373 (42.3%) 146 (16.6%) 152 (17.2%)

38

32

882

2.9

.26

0.4, 24.9

2.8

.05

1.0, 8.9

Warts and Smoking

P exact*

.002

* Fisher exact test.

p a r t n e r s since t h e last f o l l o w - u p ( m e d i a n = 1) in w o m e n w h o s m o k e d a n d t h o s e w h o d i d not, as w e l l as in w o m e n w h o d e v e l o p e d w a r t s a n d t h o s e w h o d i d not. N o n e t h e l e s s , to a d j u s t for t h e p o s s i b i l i t y that the n u m b e r of l i f e t i m e s e x u a l p a r t n e r s is l i n k e d to c u r r e n t s e x u a l risk b e h a v i o r a n d m i g h t b e c o n f o u n d e d w i t h s m o k i n g , w e e x a m i n e d t h e r e l a t i o n of s m o k i n g to i n d i c a t o r s of c u r r e n t risk b e h a v i o r , s u c h as STD a n d H P V a c q u i s i tion. C u r r e n t s m o k i n g w a s n o t r e l a t e d to the a c q u i s i t i o n of an STD (Table 6) or to the p r e v a l e n c e of H P V at b a s e l i n e . In H I V - n e g a t i v e w o m e n , u s i n g t h e S o u t h e r n b l o t test, t h e p r e v a l e n c e of H P V w a s 21% in s m o k e r s a n d 19% in n o n - s m o k e r s at t h e t i m e of the b a s e l i n e e x a m i n a t i o n . U s i n g PCR, w h i c h w a s a v a i l a b l e for b o t h cohorts, the rates of H P V in t h e s e r o n e g a t i v e c o h o r t w e r e 49% for s m o k e r s a n d 41% for n o n - s m o k e r s (P = .27). I n the s e r o p o s i t i v e cohort, the rates w e r e 76% a n d 72% in s m o k e r s a n d n o n - s m o k e r s , r e s p e c t i v e l y (P = .82). T h e l e v e l of e x c e s s risk of w a r t s in s m o k e r s w a s n o t s i g n i f i c a n t l y a l t e r e d w h e n l i f e t i m e s e x u a l p a r t n e r s (or its l o g a r i t h m i c t r a n s f o r m a t i o n ) , c u r r e n t age (or its loga r i t h m i c t r a n s f o r m a t i o n ) , or t h e a c q u i s i t i o n of N gonorrhoeae, C trachomatis, T vaginalis, or s y p h i l i s w e r e a d d e d s e p a r a t e l y as c o v a r i a t e s , n o r d i d t h e fit of t h e m o d e l c h a n g e significantly. T h e e x c e s s risk of d e v e l o p i n g w a r t s a m o n g s m o k e r s w a s c o n s i s t e n t in H I V - p o s i t i v e a n d H I V - n e g a t i v e w o m e n , as the i n t e r a c t i o n b e t w e e n s m o k i n g a n d H I V status w a s n o t s i g n i f i c a n t (P = .66). There were no significant interactions between HIV

Table 5. Incidence of Genital Warts by Lifetime Sexual Partners Lifetime sexual partners

HIV = human immunodeficiency virus. * The mid-P is a P value with a continuity correction for highly discrete data.

348

Lifetime sexual partners

Total

HIV = human immunodeficiency virus. Data are presented as mean -+ standard deviation or percent.

HIV status

Table 4. History and Prevalence of Genital Warts by Lifetime Sexual Partners

<3 4-9 10-19 ->20

New cases*

Personyears

Rate per 100 person-years

P exact 1

4 5 4 2

168 326 148 106

2.4 1.5 2.7 1.9

Referent .52 .86 .83

* One case did not report lifetime partners. : Compared with 0-3 lifetime partners.

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Table 6. Incidence of Sexually Transmitted Diseases* in Current Smokers and Non-Smokers

HIV status Positive Current smoker Non-smoker Negative Current smoker Non-smoker

New Rate cases per 100 95% of Person- person- Relative confidence P STDs years years risk interval exact 3 5

64 60

4.7 8.3

0.6

0.1, 2.4

.45

16 22

207 408

7.9 5.4

1.4

0.7, 2.7

.28

HIV = human immunodeficiencyvirus; STD = sexually transmitted disease. *Includes syphilis, Neisseria ,gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis.

status and the number of sexual partners in predicting the incidence of warts. Ever-smokers (which combines current and former smokers) had 3.7 times greater risk (95% CI 0.7, 19.7) of developing warts. Risk increased with the number of cigarettes smoked (RR 1.38; 95% CI 0.02, 27.9) and the number of years of smoking (RR 1.09; 95% CI 0.90, 1.32), but the power to detect doseresponse relations was low, as evidenced by the wide CIs and the absence of statistical significance for either of these relations. To ascertain whether smokers were more likely than non-smokers to have had warts, we compared the histories of venereal warts in each group at baseline. A m o n g non-smokers, 3.2% reported a history of venereal warts, compared with 8.1% in smokers (RR 2.5; 95% CI 1.6, 4.0), a difference similar to that observed for the incidence data. The association of smoking and history of warts was consistent in each cohort.

Discussion We have shown in a prospective study of smoking and genital warts that tobacco use is associated with an increased incidence of genital warts, which is of similar magnitude in both HIV-positive and HIV-negative women. Although this is the first prospective study focused on warts, a previous case-control study of 49 women with a history of condyloma acuminatum and 196 age-mat,~ned controls found that women who ever smoked haa a 3.7 times greater risk of reporting such a history than women who never smoked, s However, that approach cannot fully explore the possible confounding of smoking and increased frequency of sexual risk-taking. Many reports exist regarding the association of smoking and cervical cancer. That association may be confounded, as there is a strong link between cigarette smoking and sexual activity. It is widely accepted that a

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sexually transmitted pathogen plays a causal role in cervical cancer. Several measures of sexual activity are associated with the risk of cervical cancer, such as age at first coitus, number of sexual partners, prostitution, and failure to use condoms. 9 One study simulating the degree of misclassification of the true pathogen and its association with tobacco concluded that the effect of tobacco on cervical cancer may well be due to residual confounding. 1° Most studies that adjust for measures of sexual activity find a reduced association between smoking and cervical cancer. 1~ ~3 Our finding of a consistent fivefold excess in the risk of genital warts in current smokers based on prospective data from two cohorts suggests a synergy between cigarette smoking and another manifestation of HPV, ie, warts. Sexual activity possibly confounds this association, as smokers had many more lifetime sexual partners than non-smokers, and HPV is sexually transmitted. In fact, there was a correlation between lifetime partners and lifetime history of warts. Therefore, it might also be expected that the prevalence of HPV infection would be higher in smokers. However, in both cohorts, the prevalence of HPV was similar in smokers and non-smokers. This could be due to a similarity in recent sexual activity between smokers and nonsmokers. Tlle incidence of STDs in both cohorts was similar in smokers and non-smokers, as was the number of recent sex partners, suggesting that sexual risk behavior during follow-up was similar in the groups. The similarity in sexual behavior may relate to the relatively short follow-up period. Nonetheless, these findings (eg, similar HPV prevalence, STD incidence, and number of recent partners) suggest that disease acquisition plays less of a role in explaining our observations than does the possibility that smoking promotes the manifestation of growth of HPV. A reactivation of a prevalent latent HPV infection would also account for the absence of association between the number of lifetime sexual partners and the incidence of clinical warts. The role of smoking may be through its impact on Langerhans cells, which are dendritic cells derived from the bone marrow that play an important role in immune responses of the squamous epithelium. 14 Their depletion in the cervix has been shown to correlate with the presence of HPV infection. 15 Langerhans cells are reduced in cutaneous warts, and smoking also has been associated with a reduction in Langerhans cells. There are certain limitations in our study. The relatively high loss to follow-up rate in the HIV-negative cohort could have biased the sample. In fact, there were differences in place of birth, drug use, and number of sexual partners between those who returned and those lost to follow-up. However, this pattern in the group lost to follow-up would diminish the association of

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Warts and Smoking

349

warts w i t h smoking, as those w h o s m o k e d a n d w h o h a d 20 or more sexual partners were less likely to return. These are the very g r o u p s that one w o u l d expect to be at the highest risk of d e v e l o p i n g warts. Smokers were m o r e likely to report a history of warts, a n d it is possible that w o m e n w i t h a prior history of venereal warts were more familiar with the lesions, l e a d i n g to increased visits a n d clinical scrutiny a n d c o n s e q u e n t l y a n association b e t w e e n the incidence of warts a n d smoking. However, in o n l y two of the 16 i n c i d e n t cases of warts did the w o m e n report a history at baseline, a n d in a n y event, w o m e n w i t h a n d w i t h o u t a history of warts h a d a similar n u m b e r of follow-up visits. Antiretroviral or other t h e r a p y m a y have affected the expression of warts. However, half of both smokers a n d n o n - s m o k e r s were taking a z i d o t h y m i d i n e d u r i n g follow-up. In addition, the association of warts a n d smoking in the HIV-negative cohort, in w h i c h no one was on such medication, was similar, lessening the possibility that HIV medications biased the association. Subjects were e x a m i n e d at 6 - m o n t h intervals; warts m a y have occurred a n d d i s a p p e a r e d in this interval, a n d thus w o u l d not have b e e n detected on clinical examination. H o w e v e r , w h e t h e r this w o u l d be related to s m o k i n g status is unclear. Finally, there was a m u c h higher follow-up rate in n o n - s m o k e r s in the HIV-negative cohort (83% versus 57%). Smokers with warts m a y have b e e n more likely to r e t u r n for follow-up t h a n smokers w i t h o u t warts, p r o d u c i n g a bias in the HIV-negative cohort. However, in the HIV-positive cohort, loss to follow-up was only 10% a n d smokers a n d n o n - s m o k e r s were e q u a l l y compliant, yet smokers were still m o r e likely to develop warts. Thus, each cohort reinforces the other in r e d u c i n g the likelihood of v a r i o u s types of bias. I n s u m m a r y , w e f o u n d a fivefold excess risk of i n c i d e n t genital warts associated with s m o k i n g in both HIV-positive a n d HIV-negative w o m e n , which did not a p p e a r to be related solely to sexual activity.

References 1. WinkelsteinW. Smokingand cancer of the uterine cervix:Hypothesis. Am J Epidemiol 1977;106:25~9. 2. McArdle JP, Muller K. Quantitative assessment of Langerhans' cells in human cervical intra epithelial neoplasia and wart virus infection. Am J Obstet Gynecol 1986;154:509-15.

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3. Chirgwin K, Feldman J, Augenbraun M, Landesman S, MinkoffH. Incidence of venereal warts in HIV-infected and uninfected women. J Infect Dis 1995;172:235-8. 4. DeHovitz J, Kelly P, Feldman J, Sierra M, Clarke L, BrombergJ, et al. Sexuallytransmitted diseases, sexual behavior, and cocaine use in inner-city women. Am J Epidemiol 1994;140:1125-34. 5. BurkRD, KellyP, FeIdmanJG, BrombergJ, Vermund SH, Dehovitz JA, et al. Decliningprevalence of cervicovaginalhuman papilloma virus infection with age is independent of other risk factors. Sex Transm Dis 1996;23:333-41. 6. Ho GF, Burk RD, Klein S, Kadish AS, Chang CJ, Palan P, et al. Persistent genital human papilloma virus infection as a risk factor for persistent cervical dysplasia. J Natl Cancer Inst 1995;87:1365 71. 7. Kleinbaum DG, Kupper LL, Muller Keith F. Applied regression analysis and other multivariate methods. Boston: PWS-KentPublishing Company, 1988:497-512. 8. Daling JR, Shermenk J, Weiss NS. Risk factors for condyloma acuminatum in women. Sex Transm Dis 1986;13:16-8. 9. Cramer D. Uterine cervix. In: Schottenfeld D, Fraumeni JC, eds. Cancer epidemiology and prevention. Philadelphia: WB Saunders, 1982;881-900. 10. Phillips AN, Davey-Smith G. Cigarette smoking as a potential cause of cervical cancer: Has confounding been controlled? Int J Epidemiol 1994;23:42-9. 11. Brinton LA. Editorial commentary:Smoking and cervicalcancer-current status. Am J Epidemiol 1990;131:958-60. 12. Layde PM. Smoking and cervical cancer: Cause or coincidence. JAMA 1989;261:1631-3. 13. Phillips AN, Davey-SmithG. Smoking and human papillomavirus infection. Causal link not proved. BMJ 1993;306:1268. 14. Tay SK, Jenkins D, Madelox O, Campion M, Singer A. Subpopulations of Langerhans cells in cervical neoplasia. Br J Obstet Gynaecol 1987;94:10-5. 15. Hawthorn RAS, Murdoch JB, Maclean AB, Mackie RM. Langerhans' cells and subtypes of human papilloma virus in cervical intraepithelial neoplasia. BMJ 1988;297:643-6.

Address reprint requests to: Joseph G. Feldman, DrPH SUNY--Health Science Center at Brooklyn Department of Preventive Medicine 450 Clarkson Avenue, Box 43 Brooklyn, N Y 11203-2098

Received September 16, 1996. Received in revisedform December 2, 1996. Accepted December 4, 1996. Copyright © 1997 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.

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