Duration of Human Immunodeficiency Virus Infection ...

American Journal of Epidemiology Copyright © 2000 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved

Vol. 151, No. 10 Printed In U.S.A.

Duration of Human Immunodeficiency Virus Infection and Likelihood of Giving Birth in a Medicaid Population in Maryland

Lisa M. Lee,1-2 Pascals M. Wortley,2 Patricia L. Fleming,2 Lois J. Eldred,3 and Ronald H. Gray1

acquired immunodeficiency syndrome; birth rate; fertility; HIV; pregnancy; women

Women constitute the fastest-growing group of persons affected by acquired immunodeficiency syndrome (AIDS) in the United States (1, 2). Women of reproductive age are especially at risk; as of December 1998, women aged 13-49 years accounted for 87 percent of all AIDS cases in women (1). Although the biologic, social, and cultural influences on reproduction are probably altered by the presence of human immunodeficiency virus (HTV) infection, few US studies have examined the association between HTV and fertility.

Several studies have documented a dramatic reduction in fertility after clinical AIDS diagnosis (3, 4); however, evidence of reduction for asymptomatic HTVinfected women is less clear. Recent data from Africa (3, 5-8), Europe (9), and Australia (10) suggest that fertility may be reduced among HIV-infected women as compared with uninfected women. The extent to which this reduction is real has implications in several areas. Of primary interest to disease surveillance are levels of, and trends in, HIV incidence and prevalence rates. Seroprevalence among women, children, and entire populations has been estimated from results of sentinel surveys of newborns and women seeking antenatal care. Population seroprevalence is estimated under the assumption that women with HTV have fertility patterns similar to those of uninfected women (11). If women with HTV are less likely to become pregnant or to give birth, seropositivity rates among women of childbearing age could be underestimated (12). Incidence estimates from serial seroprevalence studies can be misinterpreted if the assumption of equal fertility is invalid (13). Projections of the need for maternal antiretroviral therapy and of pediatric HIV infection could also be misleading. Secondly, demographic projections of the effect of HIV on population dynamics must incorporate assumptions

Received for publication February 11, 1999, and accepted for publication July 7, 1999. Abbreviations: AFDC, Aid to Families with Dependent Children; AIDS, acquired Immunodeficiency syndrome; Cl, confidence interval; HIV, human immunodeficiency virus; HIVIS, Human Immunodeficiency Virus Information System; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification. 1 Department of Population and Family Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD. 2 Division of HIV/AIDS Prevention—Surveillance and Epidemiology, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA. 3 AIDS Administration, Maryland Department of Health and Mental Hygiene, Baltimore, MD. Reprint requests to Dr. Lisa M. Lee, Division of HIV/AIDS Prevention—Surveillance and Epidemiology, Centers for Disease Control and Prevention, Mail Stop E-47, 1600 Clifton Road NE, Atlanta, GA 30333 (e-mail: LGL5©cdc.gov).

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The objective of this study was to examine the effect of duration of human immunodeficiency virus (HIV) infection on a woman's likelihood of giving birth. Using longitudinal data from the Maryland state Human Immunodeficiency Virus Information System and a retrospective cohort design, the authors compared 1,642 women with acquired immunodeficiency syndrome (AIDS) to 8,443 uninfected women enrolled in the Medicaid program between 1985 and 1995. The decade before AIDS diagnosis was divided into four 2.5-year periods. Proximity to AIDS diagnosis served as a proxy for duration of infection. An extension of the Cox model was used to estimate the relative risk for giving birth, with adjustment for covariates and repeated outcomes. The average number of births per 100 person-years was 6.0 for HIV-infected women and 11.1 for uninfected women (adjusted relative risk = 0.63; 95% confidence interval (Cl): 0.57, 0.68). Accounting for duration of infection, the adjusted relative risks for birth among HIV-infected women, as compared with uninfected women, were 0.85 (95% Cl: 0.71, 1.03), 0.74 (95% Cl: 0.63, 0.86), 0.55 (95% Cl: 0.47, 0.64), and 0.45 (95% Cl: 0.38, 0.55) for successive 2.5-year periods before AIDS diagnosis. Demographic characteristics, contraception, abortion, fetal loss, or drug use could not fully explain the reductions. These results suggest that HIV-infected women experience a progressive reduction in births years before the onset of AIDS. This may compromise estimation of HIV prevalence and interpretation of time trends from serosurveillance of pregnant women. Am J Epidemiol 2000; 151:1020-8.

Duration of HIV Infection and Likelihood of Birth

about fertility among infected women, usually assuming that birth rates for infected women are similar to those for uninfected women of similar racial and age groups (14). Differential fertility between HIVpositive and HTV-negative women could lead to biased estimates of the effect of HTV on population growth and age structure. The goal of this research was to examine the effect of duration of HTV infection, measured by time prior to AIDS diagnosis, on the likelihood of giving birth. MATERIALS AND METHODS Data

Study design and sample

We compared two groups of women to determine the effect of HTV and duration of infection on the likelihood of giving birth. The study population included women of reproductive age (15-44 years) who resided in Maryland and were covered by Medicaid for at least one 6-month period between 1985 and 1995. Two major categories of enrollees qualify for Medicaid in Maryland. The "categorically needy" are persons receiving Supplemental Security Income or Temporary Am J Epidemiol

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Assistance to Needy Families (formerly Aid to Families with Dependent Children (AFDC)). The "medically needy" are persons whose necessary medical care costs exceed their financial resources. Most women enrolled in the Maryland Medicaid program are eligible due to receipt of Temporary Assistance to Needy Families. This population, which is largely minority, poor, and urban, is similar to the population of women at highest risk for HTV and AIDS in the United States (16, 17). The HTV-infected cohort was selected at the time of AIDS diagnosis. By November 1995, 2,472 Maryland women of reproductive age had a diagnosis of AIDS and had been reported to the HTV/AIDS Reporting System. Of these, 1,838 (74.4 percent) had ever had Medicaid coverage, and 1,642 (66.4 percent) had had coverage before they were diagnosed with AIDS. The infected group consisted of these 1,642 women who had had Medicaid coverage before their AIDS diagnosis. A retrospective record of health care services sought before AIDS diagnosis was created for these women. The HTV-negative cohort was selected from the remaining pool of Medicaid enrollees who were covered at any point during 1990-1995. These years were chosen because more than 80 percent of women in the infected group had received their diagnosis and had been covered by Medicaid during this period. We randomly selected 8,500 women with no evidence of HTV-related billing codes. Of these 8,500 presumednegative women, 56 were excluded because of incomplete eligibility information, and one was excluded because of implausible outcome events. This left in the comparison group 8,443 uninfected women, for whom we created a retrospective record of health care services sought from enrollment through the last date of service or the end of 1995. The above process yielded two cohorts of women— one infected, one uninfected—which were compared with respect to the incidence of birth. Variable definitions

Data on outcome, predictor, potentially confounding, and person-time variables were obtained or derived from HTVIS. Demographic information was obtained from Medicaid eligibility files. Information on all outcomes and on several potentially confounding variables was created from adjudicated Medicaid claims data. Data on AIDS-related variables for infected women were obtained from the HTV/ATDS Reporting System. Coding nets developed to identify specific variables consisted of diagnostic or procedure codes from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) (18),


We used the Maryland state Human Immunodeficiency Virus Information System (HTVIS), which was developed to examine epidemiologic, clinical, economic, and health care utilization issues pertaining to the AIDS epidemic in Maryland (15). Briefly, HTVIS is a relational database that combines several administrative databases available to the Maryland Department of Health and Mental Hygiene. It comprises information from the HTV/AIDS Reporting System, vital records, Medicaid claims and eligibility records, hospital discharge data, subacute and chronic care facilities, psychiatric and drug treatment centers, and a variety of community-based programs. HTVIS allowed us to create a longitudinal, person-based record of epidemiologic and medical service data for persons with AIDS who were enrolled in the Medicaid program. Under statutory authority, HTVIS was established at, and is maintained by, the Center for Epidemiology and Health Services Research (formerly the Center for AIDS Services Planning and Development) in the Maryland Department of Health and Mental Hygiene (Baltimore, Maryland). Each contributing agency has signed a memorandum of agreement that outlines confidentiality and security responsibilities. This research was approved by the Johns Hopkins University School of Hygiene and Public Health Committee on Human Research.

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multivariate models, age served as the timeline and thus was modeled as a continuous variable. Socioeconomic status was controlled for by restricting the cohort to the Medicaid population, which, by definition, is near or below federal and state poverty levels. Eligibility criterion at Medicaid enrollment was divided into two categories: AFDC/fertility-related criteria and all others. Race was categorized as Black versus Nonblack (most of the Nonblacks were White). Residence was dichotomized as Baltimore City versus all other areas. Alcohol and illicit drug use were identified from health care provider contact records. This method probably captured severe dependency but may have missed less severe abuse and newer users. Contraceptive information was limited to the use of prescription-based methods (i.e., oral contraceptives, implants and injectable contraceptives, intrauterine devices, and the diaphragm or cervical cap). Tubal ligation and sterilizing procedures (e.g., hysterectomy) were considered censoring events in the multivariate analysis, and women were removed at the time of occurrence of either event. Because pelvic inflammatory disease and its sequela, salpingitis, can severely impair fertility (24), we identified episodes of pelvic inflammatory disease with a coding net consisting of procedure and diagnostic codes indicating the disease. We identified diabetes mellitus, associated in some studies with fetal loss (25), by ICD9-CM diagnostic codes. Information on parity, or the number of live infants a woman had borne before Medicaid enrollment, was not in the HTVIS or Medicaid databases. A proxy measure was constructed for each birth identified in Medicaid claims data and is referred to as "births during observation." Because length of follow-up varied over the study period, outcome event rates were calculated using person-years. The beginning of observation was defined as the date of the first Medicaid claim, and the end of observation was defined as the date of the last Medicaid claim or a censoring event (e.g., tubal ligation). Finally, because we were interested in pre-ATDS person-time, exposed women were censored at the date of AIDS diagnosis. Statistical methods

Covariates were compared by HTV infection status. The %2 and Student's t tests were used to test the statistical significance of differences in proportions and means. Because of the strong potential for confounding by age and illness, we conducted stratified analyses to examine the effect of HTV infection on the likelihood of giving birth independent of socioeconomic status, age, and time before AIDS diagnosis. Agespecific event rates were compared at each time interval before AIDS diagnosis. Am J Epidemiol Vol. 151, No. 10, 2000


Physicians' Current Procedural Terminology codes (19), or codes generated by the state Medicaid administration. We used the National Drug Codes (20) to identify pharmacy claims for prescription medications of interest. Outcome variables defined by coding nets included birth, induced abortion, and fetal loss. Potentially confounding variables included alcohol use, illicit drug use, contraceptive use, tubal ligation, other types of sterilization, pelvic inflammatory disease, and diabetes mellitus. Birth was the main outcome of interest. A coding net consisting of ICD-9-CM diagnostic codes for live delivery, normal or complicated delivery, and complications of the puerperium was used to identify births. The coding net also included procedure codes indicating vaginal or cesarean section delivery. Intermediate outcomes included induced abortion and fetal loss. Diagnostic, procedure, and state-specific codes indicating induced and elective abortions were used to identify induced abortions, which are covered by Medicaid through private providers and clinic services. Diagnostic and procedure codes indicating spontaneous abortion, stillbirth, and delivery of a nonviable fetus were used to identify fetal losses. Because Medicaid data are claim-based, not personbased, multiple claims for one event were identified by date of service. Event dates were used to examine births and other reproductive events (i.e., fetal loss, induced abortion, and ectopic pregnancy) that were coded as having occurred during the same episode of care. One comparison woman was removed from the sample because of incompatible events that could not be reconciled. Using person-years as the denominator, we computed total fertility rates based on age-specific birth rates. Intermediate outcomes included fetal loss and induced abortion at any gestational age. Adjusted fetal loss ratios measured the number of fetal losses per 100 births plus half of the induced abortions (21). Induced abortion ratios measured the number of induced abortions per 100 births. Differences in these outcomes were examined by HTV infection status. Duration of HTV infection, the predictor variable of interest, was constructed for infected women by subtracting the date of the outcome event from the date of AIDS diagnosis. We calculated 10 years of exposure on the basis of incubation time from HTV infection to clinical diagnosis of AIDS (22, 23). These 10 years preceding AIDS diagnosis were categorized into four 2.5-year intervals: 10-7.5 years, 7.49-5.0 years, 4.9-2.5 years, and 2.49-0 years before AIDS. Potentially confounding variables were defined as follows. In stratified analyses, age was divided into 5year categories (15-19 years through 40-44 years). In

Duration of HIV Infection and Likelihood of Birth

RESULTS

Of the 10,085 Medicaid-enrolled women studied, 1,642 were HTV-infected and 8,443 had no history of HTV-related billing claims and thus were considered HTV-negative. The mean number of years between the first and last Medicaid visits was 7.0 (standard deviation 3.5) for HIV-positive women and 6.6 (standard deviation 3.8) for HTV-negative women. Fifty-nine percent of HIV-positive women had a first positive HTV test date recorded. For these women, the median time between knowledge of infection and AIDS diagnosis was 1.3 years (range, 0-11.5 years). The crude birth rate (births per 100 person-years) during the 10year period was 6.0 (690/11,526) among HIV-positive women and 11.1 (6,266/56,215) among HIV-negative women (p < 0.001). Infected women were significantly older than women who were uninfected (table 1). Most women in both groups were enrolled in the Medicaid program under AFDC/fertility-related criteria, but HIV-negative women were significantly more likely to be so. Significantly more of the infected women were Black, Baltimore City residents, and drug users and had had pelvic inflammatory disease. Significantly fewer of the HIV-positive women had used prescription-based contraceptives, had had a tubal ligation or other sterilization procedure, or had diabetes. In all subgroups, except sterilization, the relative risk for giving birth was significantly reduced among HIV-positive women. Am J Epidemiol

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Age-specific birth rates among HTV-infected women progressively declined with proximity to AIDS diagnosis, particularly among younger women aged 15—24 years (figure 1). Lower age-specific birth rates in some age groups were evident 10 years before AIDS diagnosis. The age-adjusted total fertility rates in the HIVnegative and HIV-positive groups were 3.33 (95 percent confidence interval (CI): 3.25,3.41) and 2.36 (95 percent CI: 2.14,2.51), respectively. Total .fertility rates for HIVinfected women in the four 2.5-year study periods were 2.48 (95 percent CI: 2.03, 2.93) for 10-7.5 years before diagnosis, 2.02 (95 percent CI: 1.69, 2.34) for years 7.49-5.0, 1.43 (95 percent CI: 1.15, 1.72) for years 4.9-2.5, and 1.10 (95 percent CI: 0.79, 1.40) for years 2.49-0. Thus, the reduction in fertility became more pronounced with longer presumed duration of HIV infection (measured by time before AIDS diagnosis). Induced abortion ratios were consistently higher for HrV-infected women throughout all exposure periods. The ratio of induced abortions per 100 births was 20.4 among uninfected women; among infected women, induced abortion ratios and age-adjusted rate ratios for the four 2.5-year periods before AIDS diagnosis were 40.6 (rate ratio = 1.7; 95 percent CI: 1.4, 2.2), 37.2 (rate ratio = 1.6; 95 percent CI: 1.3, 2.0), 47.9 (rate ratio = 1.9; 95 percent CI: 1.5, 2.3), and 42.5 (rate ratio = 1.7; 95 percent CI: 1.3, 2.1), respectively. No differences were observed in age-adjusted fetal loss ratios of infected versus uninfected women (rate ratio = 1.05; 95 percent Q : 0.88, 1.26). The multivariate Cox models are shown in tables 2 and 3. Confidence intervals were derived from robust variance estimates, accounting for the potential lack of independence of repeated outcome events per woman. Model 1 included an exposure variable that categorized women as HIV-infected or uninfected, regardless of proximity to AIDS diagnosis for infected women (table 2). The adjusted relative risk of birth among the HIVinfected women compared with uninfected women was 0.63 (95 percent CI: 0.57, 0.68). Model 2 was an examination of the effect of estimated duration of HIV infection, modeled in 2.5-year periods prior to AIDS diagnosis, on the likelihood of giving birth (table 3). The most distant period (10.0-7.5 years before ADDS diagnosis) did not significantly influence the likelihood of giving birth (relative risk = 0.85; 95 percent CI: 0.71, 1.03). However, significant and progressive reductions in the relative hazard of giving birth were observed in the three more proximate periods (table 3). Statistically significant covariates in model 1 remained significant in model 2. DISCUSSION

Our main finding in this study was a progressive reduction in the likelihood of giving birth among HIV-


Multivariate time-to-event analysis was used to accommodate variations in follow-up time and censored observations. An extension of the Cox model was used to accommodate the potential for multiple outcome events per subject, time-dependent covariates, and periods during which a woman was not at risk for a birth (26). It was conservatively assumed that women who had given birth were not at risk of a subsequent birth for 8.5 months postpartum (27). Exact age between 15 and 44 years was used as the time-to-event, because of the strong effect of age on the probability of giving birth (28). A woman who gave birth at age x was compared with all other women aged x in the risk set. Time-dependent covariates included induced abortion and contraceptive use in the age interval, births during observation, and time before AIDS diagnosis for infected women. Variables selected for consideration in the time-toevent analysis were those that demonstrated, in the preliminary analysis, strong associations with HTV infection and with births. We used stepwise selection to develop the multivariate models and the - 2 log L statistic to compare models. All statistical analyses were performed with SAS software (29).

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Leeetal. TABLE 1. Data on covariates and unadjusted relative risks for giving birth, by human Immunodeficiency virus (HIV) Infection status, Maryland, 1985-1995 HIVinfected women (n= 1,642)

HIVuninfected women (n = 8,443)

P value

Mean age (years) At entry into Medlcaid program In 1990

28.2 32.2

23.3 27.9