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Fertility in adolescent women previously treated for genitourinary chlamydial infection
Adolesc Pediatr Gynecol (1994) 7:147-152
Adolescent and Pediatric Gynecology
1994
© Springer-Verlag New York Inc.
Fertility in Adolescent Women Previously Treated for Genitourinary Chlamydial Infection B.P. Katz, Ph.D.,1,4 S. Thorn, B.A.,1 M.J. Blythe, M.D.,3 J.N. Amo, M.D.,1,6 V.M. Caine, M.D.,1.5 R.B. Jones, M.D., Ph.D. 1,2 Departments of IMedicine, 2Microbiology and Immunology, and 3Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana; 4Regenstrief Institute for Health Care, 5Marion County Health Department, Indianapolis, Indiana; 6Richard L. Roudebush Veterans Medical Center, and Department of Health Policy and Administration, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and 7School of Public Health, Indianapolis, Indiana
Abstract. Study Objective: To obtain follow-up pregnancy data on adolescent women in order to examine the effectiveness of anti-chlamydial therapy in the prevention of early infertility. Design: A longitudinal follow-up of adolescent women originally enrolled in a study of prevalence and recurrence of genital chlamydial infection. Setting: Public health adolescent clinics in Marion County (Indianapolis), Indiana. Participants: Sexually active female patients between 11 and 20 years old receiving gynecological care between October 1985 and February 1990. Interventions: None. Main Outcome Measures: Pregnancy during the follow-up period was ascertained using self-report during a telephone survey and/or the computerized record system of the county hospital. Rates were compared among the women separated into three groups: more than one documented chlamydial infection, a single infection, and no documented infection. Results: Using both data sources, the lowest proportion of women who became pregnant during the follow-up period was observed in the single infection group (34.9%, p = 0.029), but the other two groups were similar (multiple infections 54.2%, no documented infection 51.0%). Among women who were contacted by phone, the overall proportion was higher (68.3%) and did not differ by group even after adjustment for sexual activity and condom use. Conclusions: These data do not show an association between a history of treated genitourinary chlamydial infection and infertility. The frequent monitoring and treatAddress reprint requests to: Barry P. Katz, Ph.D., Indiana University School of Medicine Department of Medicine, Division of Biostatistics, Riley Research Wing, RR 135, 702 Barnhill Drive, Indianapolis, IN 46202-5200, USA
ment featured in the original study may have affected this.
Key Words. Chlamydial infection-InfertilityPregnancy
Introduction Genital infections with Chlamydia trachomatis have been associated with infertility. The presence of antibodies to C. trachoma tis is associated with both tubal fertility problems l - 3 and a sixfold increase in the risk of ectopic pregnancy.4 Pelvic inflammatory disease (PID), an important sequela of chlamydial infection, has been directly linked to the development of infertility. An increasing number of episodes of PID and/or the severity of a single episode make infertility more probable. 5 Clinically inapparent chlamydial infections have also been found in the endometrium and fallopian tubes of infertile women, some of whom had received appropriate antibiotic therapy. 6,7 Chlamydial DNA has been detected in a high proportion of women with distally occluded tubes undergoing reconstructive surgery, thus further suggesting persistence in these tissues. 8 One recent study found that early treatment of mice with chlamydial salpingitis preserved fertility, whereas a delay in treatment led to reduced fertility. 9 A recent review of the literature summarizes the association of genital chlamydial infections with fertility problems in women. 10
148
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Fertility After GU Chlamydial Infection
Recurrent chlamydial infection appears to be common even after antichlamydial therapy, and it remains unclear if subsequent infection reflects relapse or reinfection. II In either case, a single chronic infection or multiple infections may increase the chance of tubal scarring and infertility with or without clinical evidence of PID. Previous studies of women attending adolescent clinics in Indianapolis have shown both a high prevalence of infection with C. trachomatis 12 and a 39% incidence of recurrence after apparently successful treatment. 13 The purpose of the present study was to obtain follow-up pregnancy data on these adolescent women 1Y2-4 years after enrollment in the study in order to examine the effectiveness of antichlamydial therapy in the prevention of early infertility. Specifically, we addressed the null hypothesis that those who had been successfully treated for single or multiple chlamydial infections are as fertile as those never infected. To test the fertility of the infected and uninfected adolescents, we examined the number of pregnancies and live births during the follow-up period.
Methods
Between October 1985 and February 1990, all sexually active adolescent female patients between 11 and 20 years old receiving gynecological care at any of four Marion County Public Health Adolescent Clinics were asked to participate in a longitudinal study of chlamydial infection. Informed consent was obtained from all patients according to the guidelines of the Indiana University-Purdue University at Indianapolis Institutional Review Board. For the present study, women had to have been enrolled in the longitudinal study before January 1, 1989 to allow sufficient follow-up time and have either two negative or at least one positive chlamydial culture. As previously described, 12,14 tissue culture was performed in cycloheximide-treated McCoy cells with a single blind passage and immunofluorescent staining of inclusions. Four hundred ninetysix women were identified and separated into three groups for analysis: 1) more than one documented chlamydial infection (68 women); 2) a single infection and at least one follow-up negative genital culture (109 women); and 3) at least two visits to one of the clinics with cultures obtained and no positive culture (319 women). All women with infection(s) during the original study were given antichlamydial therapy consisting of a 7-day course of tetracycline, erythromycin, or doxycycline. 12
We examined the charts of all 496 women to obtain a phone number and/or a valid ID number from the city-county hospital in Marion County (Indianapolis). The phone numbers were used to perform a telephone survey from June through August 1990. The survey used a standardized form containing questions about sexual activity, contraception, interim sexually transmitted diseases (STD), pregnancy, and live births. The majority of patients attending the adolescent clinics receive their medical care primarily at the city-county hospital and its associated clinics. Most of those subjects who did not already have a hospital ID number were assigned one when PAP smears were performed in the adolescent clinics during the longitudinal study, and the specimens were sent to the hospital laboratory for evaluation. The hospital and its associated outpatient clinics are served by the Regenstrief Automated Medical Records System (RAMRS)15 which stores data on all inpatient and outpatient encounters. RAMRS was used to identify all discharge and emergency room diagnoses that were associated with pregnancy or STD. In addition, the RAMRS was used to examine the results of all pregnancy tests that were performed from January 1, 1988 through July 31, 1990 for women whose ID numbers could be obtained from their charts. Of the 68 women with more than one chlamydial infection, 41 had both phone and ID numbers, 5 just ID numbers, 2 just phone numbers and 20 neither. For the 109 women with a single infection, 63 had both, 20 just ID numbers, and 26 neither. For the 319 women who had never been infected, 174 had both, 1 had just a phone number, 23 just ID numbers, and 121 neither. All subjects who had an ID or phone number, or both, were included in the study. This yielded a total of 329 women available for the follow-up study. For analysis purposes, women were considered to have been pregnant if they reported a pregnancy in the phone survey, had a record of a positive pregnancy test (urine or blood), or had a discharge or emergency room diagnosis of abortion (missed or threatened) ectopic pregnancy, fetal demise, pregnancy, pregnancy complications, premature labor, single liveborn, spontaneous vaginal delivery, or twins liveborn. They were considered to have had a live birth if they reported one in the phone surveyor had a discharge diagnosis of single liveborn, spontaneous vaginal delivery, or twins liveborn. Chi square tests were used to compare dichotomous characteristics and outcomes such as race (black or white), contraceptive use, and pregnancy and live birth rates among the three groups. Comparisons of pregnancy and live birth rates obtained
Katz et al:
Fertility After GU Chlamydial Infection
149
Table 1. Demographic Characteristics by Infection Status
Race (% white) Age (years) Age at first intercourse Age at menarche
Multiple Infections
Single Infection
No Documented Infection
p-value
20.8 19.6 (3.0)a
33.7 20.0 (1.8)
42.8 19.6 (2.1)
0.014 0.47
13.9 (2.1) 12.2 (1.7)
14.3 (2.0) 12.1 (1.5)
14.0 (1.9) 12.1 (1.5)
0.42 0.84
aMean (standard deviation).
in the telephone survey were adjusted for sexual activity and contraceptive use using a MantelHaenszel procedure. Mean age, age at first intercourse, age at menarche, and number of sexual partners were compared using one-way analysis of variance.
Results The demographic characteristics of the study subjects by infection status are presented in Table 1. The three groups did not differ with respect to age, age at first intercourse, or age at menarche. The racial composition of the three groups did differ significantly (p = 0.014), with a lesser proportion of white women in the group with multiple infections (20.8%) than in the single infection (33.7%) or no documented infection (42.8%) groups. Of the 281 women with phone numbers listed on their charts, 104 (37.0%) responded to our phone survey. The response rate did not differ significantly among the three groups (p = 0.51). Of the 177 women who could not be contacted, 137 had an incorrect or disconnected phone number or had moved. The remaining 40 had correct phone numbers, but could not be contacted within the time frame of the phone survey. The mean age, age at first intercourse, and age at menarche of the respondents did not differ from those not in the phone survey. However, there were a greater proportion of blacks among those who answered (respondents 69.9%, nonrespondents 59.5%), although the difference was not statistically significant (p = 0.084). Pregnancy and Live Births Combining data from RAMRS and the telephone survey, the proportion of women who had been pregnant at least once during the follow-up period differed among the three groups (p = 0.029). The lowest proportion was found in the group with a single infection, but the other two groups were very similar (Table 2). The overall proportion of women with a documented pregnancy was 47.4%. Documented live births occurred in 31.6% of the women
Table 2. Fertility Measures for All Women by Infection Statusa
Variable n = 329 % Pregnant % With live
birth
Multiple Infections
Single Infection
No Documented Infection
p-vaIue b
48 54.2
83 34.9
198 51.0
0.029
35.4
27.7
32.3
0.62
aData obtained using RAMRS and phone survey. bp-value for chi square test comparing the three groups.
included in the study. This proportion did not differ significantly among the three groups. If we limit the analysis to only those for whom we have data concerning contraception and sexual activity (respondents to the phone survey), the overall proportions of women who were pregnant and those who had live births are much higher than the whole group, 68.3% and 52.9%, respectively (Table 3). These proportions, however, do not differ among the three groups, even after adjustment for oral contraceptive use, condom use, and sexual activity. Sexual Activity and Contraceptive Use Data concerning sexual activity and contraceptive use were collected for the 104 respondents using a telephone survey (Table 4). In the 6 months prior to the survey, about 70% of the women in all three groups had a frequency of sexual intercourse of once per week or greater. In the year prior to that, the single infection group had a lower frequency of sexual intercourse than the other two groups (p = 0.049). All three groups had an average of about two partners during the 2 years prior to the survey. Frequent condom use (at least 75% of the time) was reported by 15 to 20% of the women in all three groups in the 6 months prior to the survey. For the year before that, reported rates were 5-10% lower. The proportion of young women regularly using oral contraceptives was highest in the single infection group in the past 6 months, but this difference was not statistically significant. Overall, more than half of the women used birth control pills. During the year prior to that, less of the group without a
Katz et al:
150
Fertility After GU Chlamydial Infection
Table 3. Fertility Measures for Phone Survey Respondents By Infection Statusa
Variable
n = 104 % Pregnant % With live birth
Multiple Infections
Single Infection
No Documented Infection
p-value b
19 63.2
21 66.7
64 70.3
0.83
52.6
61.9
50.0
0.58
aData obtained using RAMRS and phone survey. bp-value for chi square test comparing the three groups.
positive culture used contraceptives than the other two groups (p = 0.02; no positive culture 51.6%, single infection 71.4%, multiple infections 84.2%). Of the subgroup who frequently used condoms, over half also used oral contraceptives. Only 16.4% of the women reported being unable to become pregnant after trying, with the largest proportion in the group with no documented infection. This difference was not statistically significant. Pregnancy was not associated with frequency of intercourse, number of partners, or condom use (Table 5). Those who did not become pregnant were more likely to use oral contraceptives 7-18 months before the survey (75.8%) than those who were pregnant during the follow-up period (54.9%, p = 0.042). For the 6 months after that, no association was detected, but the oral contraceptive rate remained higher in those without a pregnancy (60.6% vs.46.5%). PID and Ectopic Pregnancy
Based on the data available in the RAMRS, five of the women appeared at the emergency room with PID, three from the uninfected group and two from the single infection group. Of these five, two subsequently had live births (both no positive culture group). In addition, two other women had emergency room diagnoses of ectopic pregnancy (both single infection group).
Discussion
About half of the women in the study had at least one documented pregnancy during the follow-up period. The proportion of women who had live births did not differ among the three groups either in the total study population (about one-third) or in the subset who participated in the telephone survey. Although those who had a single chlamydial infection during the previous study were less likely to become pregnant, those with recurrent infection and those who had never had a documented infec-
tion had similar pregnancy rates. These results are not consistant with the hypothesis that sustained or repeated infections lead to infertility. U nfortunately, data regarding contraceptive use and sexual activity that might help explain these results were only available for the subset of women who participated in the telephone survey. The pregnancy rate among this subset, although higher, did not differ by group, with or without adjustment for these factors. Other STD, such as gonorrhea, are unlikely to have influenced these results as they were rarely observed in the original study.12,13 Although two methods offollow-up were used, ascertainment was still incomplete, and an unmeasurable reporting bias among the groups could account for the lower pregnancy rate among those with a single infection. These findings suggest that antichlamydial therapy may have had a role in preventing early infertility among these young women. The proportion of the 329 women who definitely had a pregnancy was 47.4%. This proportion is based primarily on the RAMRS data and is likely to be an underestimate as some of the women may have received care at another hospital. Among those in the phone survey, 32.7% (34/104) said they received medical care from other hospitals, or from clinics that would normally refer patients to hospitals other than the city-county hospital. If the proportion receiving care elsewhere is similar among the 225 who were not in the telephone survey, then about one-third of the women may have had pregnancies and live births that would have gone unrecorded in this study. Complete information was available only among those who participated in the telephone survey. The proportion who had been pregnant among survey respondents was 68.3%. However, in light of the low response rate, the number of patients without phone numbers, and the racial difference between respondents and nonrespondents, this may also be a biased estimate of the overall pregnancy rate. In any case, it is clear that at least half of these young women became pregnant during the follow-up period, even though well over half of them reported use of oral contraceptives and/or condoms at some time during the 18 months prior to the phone survey. There were five cases of PID and two ectopic pregnancies recorded during the follow-up period. None of these women had a documented recurrent infection during the initial study period. In addition, three of the five women with PID did not have any documented infection during the initial study. Thus, there appeared to be a low incidence of serious sequelae among these women. This may be due, in part, to the use of oral contraceptives which have been associated with decreased risk of chlamydial
Katz et al:
Fertility After GU Chlamydial Infection
151
Table 4. Sexual Activity and Contraceptive Use Among Survey Respondents By Infection Status Single Infection
Multiple Infections
Variable n Frequency of intercourse> lIwk Past 6 months 7-18 mos. ago Frequent condom use Past 6 mos. 7-18 mos. ago Frequent oral contraceptive use Past 6 mos. 7-18 mos. ago Tried but unable to become pregnant Mean # partners Past 2 years (SD)
No Documented Infection
p-value
19
21
64
68.4% 79.0%
71.4% 42.9%
70.3% 67.2%
0.98 0.049
15.8% 10.5%
19.1% 14.3%
17.2% 6.3%
0.96 0.50
52.6% 84.2% 5.3% 1.7 (0.9)
71.4% 71.4% 14.3% 2.4 (2.4)
43.8% 51.6% 20.3% 2.0 (1.7)
0.10 0.020 0.29 0.43
Q
Q
QRegular use is
~75%
of the time.
Table 5. Sexual Activity and Contraceptive Use By Pregnancy Status Never Pregnant
Variable
n
33
Frequency of intercourse >lIwk Past 6 months 7-18 mos. ago Frequent condom Past 6 mos. 7-18 mos. ago Frequent oral Q contraceptive use Past 6 mos. 7-18 mos. ago Mean # partners Past 2 years (SD) QRegular use is
~75%
Pregnant
p-value
infection and the ability to become pregnant, or the incidence of live births. These young women, regardless of previous infection, exhibited a high rate of pregnancy during the study period.
71
69.7% 60.6%
70.4% 66.2%
0.94 0.58
15.2% 12.1%
18.3% 7.0%
0.69 0.46
Acknowledgment. This work was supported in part by a grant from the NIAID Number U01-AI-31494 Sexually Transmitted Diseases Research Center.
References 1. Jones RB, Ardery BR, Hui SL, Cleary RE: Correla-
60.6% 75.8% 1.9 0.6)
46.5% 54.9% 2.0 (1.8)
0.18 0.042 0.75
2.
of the time.
PID 16 and to the treatment of chlamydial infection in the initial study. There was also no compelling evidence of infertility among women with a previous single or recurrent chlamydial infection. Although diagnosis of genitourinary chlamydial infection does not indicate PID, those cases with infection were at risk for PID and subsequent infertility, yet had seemingly good outcomes. Although data are not complete, except for those in the phone survey, birth rates were not too dissimilar regardless of other factors. The frequent monitoring and treatment of infection that was a feature of the initial study may have been responsible for this. The women followed in this study are still young and some could still have fertility problems in the future. In summary, there was no association in this population between a history of treated chlamydial
3. 4. 5.
6.
7.
8.
tion between serum antichlamydial antibodies and tubal factor as a cause of infertility. Fertil Steril 1982; 38:553 Moore DE, Foy HM, Daling JR, et al: Increased frequency of serum antibodies to chlamydia trachomatis in infertility due to distal tubal disease. Lancet 1982: 574 Brunham RC, Maclean IW, Binns B, Peeling RW: Chlamydia trachomatis: its role in tubal infertility. J Infect Dis 1985; 152: 1275 Walters MD, Eddy CA, Gibbs RS, et al: Antibodies to Chlamydia trachomatis and risk for tubal pregnancy. Am J Obstet GynecoI1988;159:942 Westrom L: Incidence, prevalence, and trends of acute pelvic inflammatory disease and its consequences in industrialized countries. Am J Obstet Gynecol 1980;138:880 Cleary RE, Jones RB: Recovery of Chlamydia trachoma tis from the endometrium in infertile women with serum antichlamydial antibodies. Fertil Steril 1985;44:233 Shepard MK, Jones RB: Recovery of Chlamydia trachomatis from endometrial and fallopian tube biopsies in women with infertility of tubal origin. Fertil Steril 1989;52:232 Campbell LA, Patton DL, Moore DE et al: Detec-
152
9.
10. 11.
12.
Katz et al:
Fertility After GU Chlamydial Infection
tion of chlamydia trachomatis deoxyribonucleic acid in women with tubal infertility. Fertil Steril 1993 ;59: 4550 Zan a J, Muffat-Joly M, Thomas D, et al: Roxithromycin treatment of mouse chlamydial salpingitis and protective effect on fertility. Antimicrob Agents Chemother 1991 ;35:430 Cates Jr W, Wasserheit IN: Genital chlamydial infections: epidemiology and reproductive sequelae. Am J Obstet GynecoI1991 ;164:1771 Katz BP, Caine VA , Batteiger BE, Jones RB : A randomized trial to compare 7- and 21-day tetracycline regimens in the prevention of recurrence of infection with Chlamydia trachoma tis . Sex Transm Dis 1991 ; 18:36 Blythe MJ, Katz BP, Orr DP, Caine VA, Jones RB: Historical and clinical factors associated with Chla-
13. 14.
15 .
16.
mydia trachomatis genitourinary infection in female adolescents. J Pediatr 1988;112: 1000 Blythe MJ, Katz BP, Batteiger BE, Ganser JA , Jones RB: Recurrent genitourinary chlamydial infections in sexually active females. J Pediatr 1992;121:487 Jones RB, Katz BP, Van Der Pol B, et al: Effect of blind passage and multiple sampling on recovery of Chlamydia trachomitis from urogenital specimens. J Clin Microbiol 1986;24: 1029 McDonald CJ, Hui SL, Smith DM, et al: Reminders to physicians from an introspective computer medical record. A two-year randomized trial. Ann Intern Med 1984;100: 130 Wolner-Hanssen P, Eschenbach DA, Paavonen J , et al: Decreased risk of symptomatic chlamydial pelvic inflammatory disease associated with oral contraceptive use. JAMA 263;54
Adolescent and Pediatric Gynecology
1994
© Springer-Verlag New York Inc.
Fertility in Adolescent Women Previously Treated for Genitourinary Chlamydial Infection B.P. Katz, Ph.D.,1,4 S. Thorn, B.A.,1 M.J. Blythe, M.D.,3 J.N. Amo, M.D.,1,6 V.M. Caine, M.D.,1.5 R.B. Jones, M.D., Ph.D. 1,2 Departments of IMedicine, 2Microbiology and Immunology, and 3Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana; 4Regenstrief Institute for Health Care, 5Marion County Health Department, Indianapolis, Indiana; 6Richard L. Roudebush Veterans Medical Center, and Department of Health Policy and Administration, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and 7School of Public Health, Indianapolis, Indiana
Abstract. Study Objective: To obtain follow-up pregnancy data on adolescent women in order to examine the effectiveness of anti-chlamydial therapy in the prevention of early infertility. Design: A longitudinal follow-up of adolescent women originally enrolled in a study of prevalence and recurrence of genital chlamydial infection. Setting: Public health adolescent clinics in Marion County (Indianapolis), Indiana. Participants: Sexually active female patients between 11 and 20 years old receiving gynecological care between October 1985 and February 1990. Interventions: None. Main Outcome Measures: Pregnancy during the follow-up period was ascertained using self-report during a telephone survey and/or the computerized record system of the county hospital. Rates were compared among the women separated into three groups: more than one documented chlamydial infection, a single infection, and no documented infection. Results: Using both data sources, the lowest proportion of women who became pregnant during the follow-up period was observed in the single infection group (34.9%, p = 0.029), but the other two groups were similar (multiple infections 54.2%, no documented infection 51.0%). Among women who were contacted by phone, the overall proportion was higher (68.3%) and did not differ by group even after adjustment for sexual activity and condom use. Conclusions: These data do not show an association between a history of treated genitourinary chlamydial infection and infertility. The frequent monitoring and treatAddress reprint requests to: Barry P. Katz, Ph.D., Indiana University School of Medicine Department of Medicine, Division of Biostatistics, Riley Research Wing, RR 135, 702 Barnhill Drive, Indianapolis, IN 46202-5200, USA
ment featured in the original study may have affected this.
Key Words. Chlamydial infection-InfertilityPregnancy
Introduction Genital infections with Chlamydia trachomatis have been associated with infertility. The presence of antibodies to C. trachoma tis is associated with both tubal fertility problems l - 3 and a sixfold increase in the risk of ectopic pregnancy.4 Pelvic inflammatory disease (PID), an important sequela of chlamydial infection, has been directly linked to the development of infertility. An increasing number of episodes of PID and/or the severity of a single episode make infertility more probable. 5 Clinically inapparent chlamydial infections have also been found in the endometrium and fallopian tubes of infertile women, some of whom had received appropriate antibiotic therapy. 6,7 Chlamydial DNA has been detected in a high proportion of women with distally occluded tubes undergoing reconstructive surgery, thus further suggesting persistence in these tissues. 8 One recent study found that early treatment of mice with chlamydial salpingitis preserved fertility, whereas a delay in treatment led to reduced fertility. 9 A recent review of the literature summarizes the association of genital chlamydial infections with fertility problems in women. 10
148
Katz et al:
Fertility After GU Chlamydial Infection
Recurrent chlamydial infection appears to be common even after antichlamydial therapy, and it remains unclear if subsequent infection reflects relapse or reinfection. II In either case, a single chronic infection or multiple infections may increase the chance of tubal scarring and infertility with or without clinical evidence of PID. Previous studies of women attending adolescent clinics in Indianapolis have shown both a high prevalence of infection with C. trachomatis 12 and a 39% incidence of recurrence after apparently successful treatment. 13 The purpose of the present study was to obtain follow-up pregnancy data on these adolescent women 1Y2-4 years after enrollment in the study in order to examine the effectiveness of antichlamydial therapy in the prevention of early infertility. Specifically, we addressed the null hypothesis that those who had been successfully treated for single or multiple chlamydial infections are as fertile as those never infected. To test the fertility of the infected and uninfected adolescents, we examined the number of pregnancies and live births during the follow-up period.
Methods
Between October 1985 and February 1990, all sexually active adolescent female patients between 11 and 20 years old receiving gynecological care at any of four Marion County Public Health Adolescent Clinics were asked to participate in a longitudinal study of chlamydial infection. Informed consent was obtained from all patients according to the guidelines of the Indiana University-Purdue University at Indianapolis Institutional Review Board. For the present study, women had to have been enrolled in the longitudinal study before January 1, 1989 to allow sufficient follow-up time and have either two negative or at least one positive chlamydial culture. As previously described, 12,14 tissue culture was performed in cycloheximide-treated McCoy cells with a single blind passage and immunofluorescent staining of inclusions. Four hundred ninetysix women were identified and separated into three groups for analysis: 1) more than one documented chlamydial infection (68 women); 2) a single infection and at least one follow-up negative genital culture (109 women); and 3) at least two visits to one of the clinics with cultures obtained and no positive culture (319 women). All women with infection(s) during the original study were given antichlamydial therapy consisting of a 7-day course of tetracycline, erythromycin, or doxycycline. 12
We examined the charts of all 496 women to obtain a phone number and/or a valid ID number from the city-county hospital in Marion County (Indianapolis). The phone numbers were used to perform a telephone survey from June through August 1990. The survey used a standardized form containing questions about sexual activity, contraception, interim sexually transmitted diseases (STD), pregnancy, and live births. The majority of patients attending the adolescent clinics receive their medical care primarily at the city-county hospital and its associated clinics. Most of those subjects who did not already have a hospital ID number were assigned one when PAP smears were performed in the adolescent clinics during the longitudinal study, and the specimens were sent to the hospital laboratory for evaluation. The hospital and its associated outpatient clinics are served by the Regenstrief Automated Medical Records System (RAMRS)15 which stores data on all inpatient and outpatient encounters. RAMRS was used to identify all discharge and emergency room diagnoses that were associated with pregnancy or STD. In addition, the RAMRS was used to examine the results of all pregnancy tests that were performed from January 1, 1988 through July 31, 1990 for women whose ID numbers could be obtained from their charts. Of the 68 women with more than one chlamydial infection, 41 had both phone and ID numbers, 5 just ID numbers, 2 just phone numbers and 20 neither. For the 109 women with a single infection, 63 had both, 20 just ID numbers, and 26 neither. For the 319 women who had never been infected, 174 had both, 1 had just a phone number, 23 just ID numbers, and 121 neither. All subjects who had an ID or phone number, or both, were included in the study. This yielded a total of 329 women available for the follow-up study. For analysis purposes, women were considered to have been pregnant if they reported a pregnancy in the phone survey, had a record of a positive pregnancy test (urine or blood), or had a discharge or emergency room diagnosis of abortion (missed or threatened) ectopic pregnancy, fetal demise, pregnancy, pregnancy complications, premature labor, single liveborn, spontaneous vaginal delivery, or twins liveborn. They were considered to have had a live birth if they reported one in the phone surveyor had a discharge diagnosis of single liveborn, spontaneous vaginal delivery, or twins liveborn. Chi square tests were used to compare dichotomous characteristics and outcomes such as race (black or white), contraceptive use, and pregnancy and live birth rates among the three groups. Comparisons of pregnancy and live birth rates obtained
Katz et al:
Fertility After GU Chlamydial Infection
149
Table 1. Demographic Characteristics by Infection Status
Race (% white) Age (years) Age at first intercourse Age at menarche
Multiple Infections
Single Infection
No Documented Infection
p-value
20.8 19.6 (3.0)a
33.7 20.0 (1.8)
42.8 19.6 (2.1)
0.014 0.47
13.9 (2.1) 12.2 (1.7)
14.3 (2.0) 12.1 (1.5)
14.0 (1.9) 12.1 (1.5)
0.42 0.84
aMean (standard deviation).
in the telephone survey were adjusted for sexual activity and contraceptive use using a MantelHaenszel procedure. Mean age, age at first intercourse, age at menarche, and number of sexual partners were compared using one-way analysis of variance.
Results The demographic characteristics of the study subjects by infection status are presented in Table 1. The three groups did not differ with respect to age, age at first intercourse, or age at menarche. The racial composition of the three groups did differ significantly (p = 0.014), with a lesser proportion of white women in the group with multiple infections (20.8%) than in the single infection (33.7%) or no documented infection (42.8%) groups. Of the 281 women with phone numbers listed on their charts, 104 (37.0%) responded to our phone survey. The response rate did not differ significantly among the three groups (p = 0.51). Of the 177 women who could not be contacted, 137 had an incorrect or disconnected phone number or had moved. The remaining 40 had correct phone numbers, but could not be contacted within the time frame of the phone survey. The mean age, age at first intercourse, and age at menarche of the respondents did not differ from those not in the phone survey. However, there were a greater proportion of blacks among those who answered (respondents 69.9%, nonrespondents 59.5%), although the difference was not statistically significant (p = 0.084). Pregnancy and Live Births Combining data from RAMRS and the telephone survey, the proportion of women who had been pregnant at least once during the follow-up period differed among the three groups (p = 0.029). The lowest proportion was found in the group with a single infection, but the other two groups were very similar (Table 2). The overall proportion of women with a documented pregnancy was 47.4%. Documented live births occurred in 31.6% of the women
Table 2. Fertility Measures for All Women by Infection Statusa
Variable n = 329 % Pregnant % With live
birth
Multiple Infections
Single Infection
No Documented Infection
p-vaIue b
48 54.2
83 34.9
198 51.0
0.029
35.4
27.7
32.3
0.62
aData obtained using RAMRS and phone survey. bp-value for chi square test comparing the three groups.
included in the study. This proportion did not differ significantly among the three groups. If we limit the analysis to only those for whom we have data concerning contraception and sexual activity (respondents to the phone survey), the overall proportions of women who were pregnant and those who had live births are much higher than the whole group, 68.3% and 52.9%, respectively (Table 3). These proportions, however, do not differ among the three groups, even after adjustment for oral contraceptive use, condom use, and sexual activity. Sexual Activity and Contraceptive Use Data concerning sexual activity and contraceptive use were collected for the 104 respondents using a telephone survey (Table 4). In the 6 months prior to the survey, about 70% of the women in all three groups had a frequency of sexual intercourse of once per week or greater. In the year prior to that, the single infection group had a lower frequency of sexual intercourse than the other two groups (p = 0.049). All three groups had an average of about two partners during the 2 years prior to the survey. Frequent condom use (at least 75% of the time) was reported by 15 to 20% of the women in all three groups in the 6 months prior to the survey. For the year before that, reported rates were 5-10% lower. The proportion of young women regularly using oral contraceptives was highest in the single infection group in the past 6 months, but this difference was not statistically significant. Overall, more than half of the women used birth control pills. During the year prior to that, less of the group without a
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Fertility After GU Chlamydial Infection
Table 3. Fertility Measures for Phone Survey Respondents By Infection Statusa
Variable
n = 104 % Pregnant % With live birth
Multiple Infections
Single Infection
No Documented Infection
p-value b
19 63.2
21 66.7
64 70.3
0.83
52.6
61.9
50.0
0.58
aData obtained using RAMRS and phone survey. bp-value for chi square test comparing the three groups.
positive culture used contraceptives than the other two groups (p = 0.02; no positive culture 51.6%, single infection 71.4%, multiple infections 84.2%). Of the subgroup who frequently used condoms, over half also used oral contraceptives. Only 16.4% of the women reported being unable to become pregnant after trying, with the largest proportion in the group with no documented infection. This difference was not statistically significant. Pregnancy was not associated with frequency of intercourse, number of partners, or condom use (Table 5). Those who did not become pregnant were more likely to use oral contraceptives 7-18 months before the survey (75.8%) than those who were pregnant during the follow-up period (54.9%, p = 0.042). For the 6 months after that, no association was detected, but the oral contraceptive rate remained higher in those without a pregnancy (60.6% vs.46.5%). PID and Ectopic Pregnancy
Based on the data available in the RAMRS, five of the women appeared at the emergency room with PID, three from the uninfected group and two from the single infection group. Of these five, two subsequently had live births (both no positive culture group). In addition, two other women had emergency room diagnoses of ectopic pregnancy (both single infection group).
Discussion
About half of the women in the study had at least one documented pregnancy during the follow-up period. The proportion of women who had live births did not differ among the three groups either in the total study population (about one-third) or in the subset who participated in the telephone survey. Although those who had a single chlamydial infection during the previous study were less likely to become pregnant, those with recurrent infection and those who had never had a documented infec-
tion had similar pregnancy rates. These results are not consistant with the hypothesis that sustained or repeated infections lead to infertility. U nfortunately, data regarding contraceptive use and sexual activity that might help explain these results were only available for the subset of women who participated in the telephone survey. The pregnancy rate among this subset, although higher, did not differ by group, with or without adjustment for these factors. Other STD, such as gonorrhea, are unlikely to have influenced these results as they were rarely observed in the original study.12,13 Although two methods offollow-up were used, ascertainment was still incomplete, and an unmeasurable reporting bias among the groups could account for the lower pregnancy rate among those with a single infection. These findings suggest that antichlamydial therapy may have had a role in preventing early infertility among these young women. The proportion of the 329 women who definitely had a pregnancy was 47.4%. This proportion is based primarily on the RAMRS data and is likely to be an underestimate as some of the women may have received care at another hospital. Among those in the phone survey, 32.7% (34/104) said they received medical care from other hospitals, or from clinics that would normally refer patients to hospitals other than the city-county hospital. If the proportion receiving care elsewhere is similar among the 225 who were not in the telephone survey, then about one-third of the women may have had pregnancies and live births that would have gone unrecorded in this study. Complete information was available only among those who participated in the telephone survey. The proportion who had been pregnant among survey respondents was 68.3%. However, in light of the low response rate, the number of patients without phone numbers, and the racial difference between respondents and nonrespondents, this may also be a biased estimate of the overall pregnancy rate. In any case, it is clear that at least half of these young women became pregnant during the follow-up period, even though well over half of them reported use of oral contraceptives and/or condoms at some time during the 18 months prior to the phone survey. There were five cases of PID and two ectopic pregnancies recorded during the follow-up period. None of these women had a documented recurrent infection during the initial study period. In addition, three of the five women with PID did not have any documented infection during the initial study. Thus, there appeared to be a low incidence of serious sequelae among these women. This may be due, in part, to the use of oral contraceptives which have been associated with decreased risk of chlamydial
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Fertility After GU Chlamydial Infection
151
Table 4. Sexual Activity and Contraceptive Use Among Survey Respondents By Infection Status Single Infection
Multiple Infections
Variable n Frequency of intercourse> lIwk Past 6 months 7-18 mos. ago Frequent condom use Past 6 mos. 7-18 mos. ago Frequent oral contraceptive use Past 6 mos. 7-18 mos. ago Tried but unable to become pregnant Mean # partners Past 2 years (SD)
No Documented Infection
p-value
19
21
64
68.4% 79.0%
71.4% 42.9%
70.3% 67.2%
0.98 0.049
15.8% 10.5%
19.1% 14.3%
17.2% 6.3%
0.96 0.50
52.6% 84.2% 5.3% 1.7 (0.9)
71.4% 71.4% 14.3% 2.4 (2.4)
43.8% 51.6% 20.3% 2.0 (1.7)
0.10 0.020 0.29 0.43
Q
Q
QRegular use is
~75%
of the time.
Table 5. Sexual Activity and Contraceptive Use By Pregnancy Status Never Pregnant
Variable
n
33
Frequency of intercourse >lIwk Past 6 months 7-18 mos. ago Frequent condom Past 6 mos. 7-18 mos. ago Frequent oral Q contraceptive use Past 6 mos. 7-18 mos. ago Mean # partners Past 2 years (SD) QRegular use is
~75%
Pregnant
p-value
infection and the ability to become pregnant, or the incidence of live births. These young women, regardless of previous infection, exhibited a high rate of pregnancy during the study period.
71
69.7% 60.6%
70.4% 66.2%
0.94 0.58
15.2% 12.1%
18.3% 7.0%
0.69 0.46
Acknowledgment. This work was supported in part by a grant from the NIAID Number U01-AI-31494 Sexually Transmitted Diseases Research Center.
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60.6% 75.8% 1.9 0.6)
46.5% 54.9% 2.0 (1.8)
0.18 0.042 0.75
2.
of the time.
PID 16 and to the treatment of chlamydial infection in the initial study. There was also no compelling evidence of infertility among women with a previous single or recurrent chlamydial infection. Although diagnosis of genitourinary chlamydial infection does not indicate PID, those cases with infection were at risk for PID and subsequent infertility, yet had seemingly good outcomes. Although data are not complete, except for those in the phone survey, birth rates were not too dissimilar regardless of other factors. The frequent monitoring and treatment of infection that was a feature of the initial study may have been responsible for this. The women followed in this study are still young and some could still have fertility problems in the future. In summary, there was no association in this population between a history of treated chlamydial
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Fertility After GU Chlamydial Infection
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