In 1994, the U.S. Public Health Service issued guidelines recommending the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus (HIV).1 In 1995, the U.S. Public Health Service issued recommendations for routine HIV counseling and voluntary testing for all pregnant women.2 The 1994 guidelines were updated, most recently in 2002, to include the use of combination antiretroviral chemoprophylaxis for HIV disease.3 In association with advances in the care and medical management of HIV-infected pregnant women, the number of perinatally acquired immunodeficiency syndrome (AIDS) cases have declined dramatically in the United States,4 and the use of zidovudine monotherapy during pregnancy reduces the risk of perinatal transmission from 25% to 8%.5 Highly active antiretroviral therapy (HAART), which became available in 1996, is currently the standard of care for all persons with HIV/AIDS.3
The purpose of this analysis was to describe trends in pregnancy rates for HIV-infected women, estimate factors associated with pregnancy in HIV-infected women, and determine whether pregnancy rates have changed since the publication of the U.S. Public Health Service recommendations for the use of zidovudine to prevent perinatal transmission of HIV and the advent of HAART. We postulated that clinical improvements in HIV disease, which are attributed to widespread use of HAART, may be associated with changes in women's reproductive decisions and sexual activity because of improved health and that pregnancy rates may have increased in response to these factors. Our analysis updates a study by Chu et al6 that examined pregnancy rates in HIV-infected women between January 1990 and August 1994, before HAART was approved. Their analysis found that 14% (n = 570) of HIV-infected women were pregnant at entry into medical care and that pregnancies were more likely to occur in black women than in white women and women aged less than 25 years than in women aged 35 years or older. The authors also found that pregnancy was less likely to occur in women with an AIDS-opportunistic illness than in women without an AIDS-opportunistic illness.
Our analysis updates information about pregnancy rates in HIV-infected women and examines trends, particularly in the era of HAART. Such information is critical for health care providers who care for HIV-infected women who may become pregnant at some point during the course of their HIV disease.
MATERIALS AND METHODS
Our analysis was restricted to HIV-infected women aged 15–44 years enrolled in the Adult/Adolescent Spectrum of HIV Disease Project with follow-up care from January 1992 through December 2001. This project is funded by the Centers for Disease Control and Prevention (CDC) in 10 areas: Atlanta, GA; Dallas, TX; Denver, CO; Detroit, MI; Houston, TX; Los Angeles, CA; New York, NY; New Orleans, LA; Seattle, WA; and Bayamon, Puerto Rico. The Adult/Adolescent Spectrum of Disease Project was reviewed and approved by both local and CDC Institutional Review Boards.
The methods of the Adult/Adolescent Spectrum of HIV Disease Project have been described previously.7 Briefly, all HIV-seropositive persons aged 13 years or older who receive medical care at any one of more than 100 participating facilities are eligible to be enrolled. At enrollment, information is collected on conditions occurring in the previous 12-month period. Patient medical records are subsequently abstracted at 6-month intervals for information regarding illnesses, medical conditions, prescriptions, CD4+ T-lymphocyte counts, viral load measurements and other laboratory tests, health care use, and vital status.
Only women with prospective follow-up who could become pregnant were included in the analysis. Pregnancy rates were calculated for follow-up time after enrollment and expressed per 100 person-years. The annual pregnancy rate was standardized to the overall study population according to age, race, HIV exposure mode, and Adult/Adolescent Spectrum of HIV Disease project city. This adjustment was performed to observe the pregnancy rate in a comparable population from year to year.
To study factors associated with pregnancy in a multivariable analysis, we used Poisson regression. To account for intrasubject correlations, we calculated robust variances (independence working correlation structure) using generalized estimating equations.8 The following covariates were included in the model: age group, race, HIV exposure mode, Adult/Adolescent Spectrum of HIV Disease project city, calendar year, antiretroviral therapy during the previous 6-month interval (including HAART, other antiretroviral therapy, and no antiretroviral therapy), and clinical status (no AIDS, history of AIDS-opportunistic illness, and history of CD4+ T-lymphocyte count of less than 200 cells/μL). In a separate multivariable model, a variable for calendar period compared pregnancy rates for 1997 through 2001 relative to 1992 through 1996. We defined prescribed use of HAART according to guidelines,3 which consisted of 2 nucleoside reverse transcriptase inhibitors and either a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor or 3 nucleoside reverse transcriptase inhibitors, including abacavir. Results from the Poisson regression are presented as adjusted rate ratios (RR) with 95% confidence intervals (CI). Analyses were performed by using the SAS/STAT 8.x for Windows (SAS Institute, Cary, NC).
The study population consisted of 8,857 women aged 15–44 years who received care at an Adult/Adolescent Spectrum of HIV Disease Project participating facility from January 1992 through December 2001. Of these, 5,509 (62%) were black and 1,759 (20%) were Hispanic (Table 1). At enrollment in the Adult/Adolescent Spectrum of HIV Disease Project, 1,419 (16%) were pregnant. Median age at initial follow-up was 32 years. The risk mode for HIV transmission was classified as injection drug use for 2,860 (32%) and heterosexual contact for 3,555 (40%). Among the 8,857 women in our study, 1,185 pregnancies occurred during 21,617 person-years of follow-up; the overall crude pregnancy rate was 5.5 per 100 person-years (95% CI 5.2, 5.8).
Pregnancy rates varied considerably by demographic and clinical characteristics of patients (Table 1). Pregnancies were significantly more likely to occur among women aged 15–24 years (adjusted RR 9.2; 95% CI 7.4, 11.3) and 25–34 years (adjusted RR 4.0; 95% CI 3.3, 4.9) than in women aged 35–44 years and less likely to occur in injection drug users (adjusted RR 0.8; 95% CI 0.7, 0.9) than in women whose risk mode of HIV transmission was heterosexual contact. Pregnancies were significantly less likely to occur in women with history of AIDS-opportunistic illness (adjusted RR 0.4; 95% CI 0.3, 0.5) and women with history of CD4+ T-lymphocyte count of less than 200 cells/μL but no AIDS-opportunistic illness (adjusted RR 0.6; 95% CI 0.5, 0.7) than in HIV-positive women without AIDS. Prescription of HAART during the previous 6-month interval was associated with a higher rate of pregnancy relative to prescription of other antiretroviral therapy (ART) regimens (adjusted RR 1.3; 95% CI 1.0, 1.6). Also, persons not prescribed any ART during the prior 6-month interval had higher pregnancy rates than those prescribed ART but not HAART (adjusted RR 1.7; 95% CI 1.5, 2.0).
Standardized pregnancy rates remained above 6% for the period 1998 through 2001 (Figure 1). Estimated from a multivariable Poisson regression, the pregnancy rate was significantly higher during the era of widespread use of HAART, from 1997 through 2001 (RR 1.2; 95% CI 1.1, 1.4), compared with the rate from 1992 through 1996. Prescribed use of HAART among women in this study population, regardless of stage of disease, increased from 8% in 1996 to 33% in 1997, and to 53% during 1998 through 2001.
Among 1,922 women who were either pregnant at enrollment or became pregnant during follow-up, 461 (24.0%) were pregnant more than once. Collectively, these women had 556 new pregnancies during 5,447 person-years follow-up (10.2 per 100 person-years). Factors associated with multiple pregnancies were similar to those for women in our analysis of one or more pregnancies during project follow-up. Higher rates of multiple pregnancies were observed for younger women, for women not receiving antiretroviral therapy, and during recent years of widespread use of HAART (1998–2001). Lower rates were observed for women with AIDS and injection drug users (data not shown).
The results of our analysis show that HIV-infected women in the United States were more likely to become pregnant in the era of HAART (1997–2001) than in previous years. During 1997–2001, HAART became increasingly available, more combinations became available, and there was a better understanding of when to initiate HAART and when to switch these regimens.3 The observed higher pregnancy rates among HIV-infected women during the era of HAART may be the result of a number of factors. Increased survival times for women with AIDS as well as delayed progression to AIDS may result in greater opportunities to become pregnant. Also, because we observed significantly higher pregnancy rates during the HAART era, more women may be choosing to become pregnant.
Although we were not able to measure how many women in the Adult/Adolescent Spectrum of HIV Disease Project chose to become pregnant, it is generally thought that reproductive decisions take into account a number of cultural, social, and societal factors.9,10 Despite studies before the Pediatric AIDS Clinical Trials Group Protocol 076 Study Group trial suggesting that knowledge of HIV infection is not associated with decisions to plan a pregnancy,11–13 we hypothesized that some HIV-infected women may choose to become pregnant, particularly with the success of the Pediatric AIDS Clinical Trials Group Protocol 076 Study Group trial and HAART regimens. The finding of no observed changes after the Pediatric AIDS Clinical Trials Group Protocol 076 Study Group trial (1994–1996) is consistent with the findings of another study conducted in Canada.14 Although the effects of HAART on fertility are largely unknown, improved immune function and lack of progression to AIDS may result in a greater likelihood of becoming pregnant. We found a modest increase in pregnancies in women receiving HAART compared with women receiving other antiretroviral therapy regimens. Further studies are needed to examine the relationship among HIV disease, use of HAART, and fertility.
Some studies have found differences in pregnancy rates by mode of exposure, with higher rates among women whose HIV exposure was injecting drug use15,16; others have not found differences in pregnancy rates by exposure mode.9,17 In this analysis, pregnancy was significantly less common among women for whom injecting drug use was the mode of HIV exposure. Although information was not available regarding sexual behavior, this is an interesting finding given that among HIV-infected women, another study has found that women who are injection drug users are more likely to be sexually active than other women.14
Our finding of higher pregnancy rates for younger women is consistent with findings of other studies,9,14 as is our finding of higher pregnancy rates for women with asymptomatic HIV compared with women with CD4+ immunosuppression.17 Declining levels of sexual activity have also been shown to be associated with CD4+ immunosuppression.14 Although we did not directly measure levels of sexual activity according to HIV disease stage, we did observe higher pregnancy rates for women with asymptomatic HIV than for women with an AIDS-opportunistic illness or CD4+ T-lymphocyte counts less than 200 cells/μL.
Retrospective studies have shown that HIV-infected women are less likely to become pregnant17,18 and give birth than are women who are not infected.14,15,19 Furthermore, births decline among HIV-infected women as AIDS develops.20
Because some of the Adult/Adolescent Spectrum of HIV Disease Project facilities include obstetric and gynecologic clinics, it is likely that some of the women were diagnosed with HIV at the time they sought prenatal care.6 Although the proportion of women who received their HIV diagnosis concurrent with prenatal care are unknown, it provides an opportunity for women to receive HAART both for maternal health and to reduce perinatal transmission; health care professionals can play a key role by providing referrals to comprehensive services that benefit both mother and child. Such services should include HIV prevention counseling; HIV testing for early diagnosis; coordinated HIV treatment and prenatal care for HIV-infected women21; and access to substance-abuse treatment programs, social services, and family planning.22 Increased efforts are also needed to increase access, availability, and use of prenatal care.21
Limitations to our analysis include lack of data on pregnancy outcome; these data are not routinely collected in the Adult/Adolescent Spectrum of HIV Disease Project, so it is not known what proportions of pregnancies resulted in live births. Because birth rates among women in this project are unknown, this precludes a comparison to those rates among the general population of women in the United States. Also, although information regarding prescribed therapies was available, compliance and adherence to these prescribed therapies is unknown. Although the Adult/Adolescent Spectrum of HIV Disease Project includes a large and diverse cohort of women, these women may not be representative of the entire population of HIV-infected women in the United States. As a comparison to the women in the Adult/Adolescent Spectrum of HIV Disease Project, we examined data for women aged 18–44 years who were enrolled in the Supplement to HIV/AIDS Surveillance project, a multisite interview project among persons with HIV and AIDS. Similar proportions of women in the Adult/Adolescent Spectrum of HIV Disease Project and the Supplement to HIV/AIDS Surveillance project (24.0% versus 20.7%, respectively) were pregnant more than once after HIV diagnosis (CDC, unpublished data).
This observed increase in pregnancy rates among HIV-infected women illustrates the need for continued efforts during the prenatal, perinatal, and neonatal periods to maintain the mother's health, make changes in ART during pregnancy if necessary, and monitor the newborn's HIV status postpartum. Health care providers and HIV prevention planners will also need up-to-date information to better understand the reproductive choices of HIV-infected women in the era of HAART and to ensure that the increasing number of women living with HIV have adequate services and access to care. The findings of this analysis should help health care providers in both obstetrics and gynecology and primary care be more aware of the reproductive potential of their patients and be prepared to help them make informed choices.
1. Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. MMWR Recomm Rep 1994;43(RR-11):1–20.
2. U.S. Public Health Service recommendations for human immunodeficiency virus counseling and voluntary testing for pregnant women. MMWR Morb Mortal Wkly Rep Recomm Rep
3. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Bethesda, MD: US Department of Health and Human Services; July 14, 2003. Available at: http://www.aidsinfo.nih.gov/guidelines/default_db2.asp?id=50
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22. Centers for Disease Control and Prevention. Revised recommendations for HIV screening of pregnant women. MMWR Morb Mortal Wkly Recomm Rep 2001;50(RR-19):59–86.
Adult/Adolescent Spectrum of HIV Disease Project Group: Melanie Thompson, MD, and Ericka Sinclair, MS, AIDS Research Consortium of Atlanta; David Cohn, MD, Arthur Davidson, MD, and Cornelius Rietmeijer, MD, Denver Department of Health and Hospitals; Jane Turner, MS, and Amy Wohl, PhD, Los Angeles County Department of Health Services; Anne Morse, BS, Stephanie Broyles, MS, and C. Lynn Besch, MD, Louisiana Department of Health; Linda Wotring, PhD, and Eve Mokotoff, MPH, Michigan Department of Community Health; Judy Sackoff, PhD, and Marie Antoinette Bernard, MD, New York City Department of Health; Alejandro Amill, Robert Hunter, MD, and Maria de los Angeles Gomez, PhD, University Central del Caribe, Bayamon; and Sandra Miranda, Puerto Rico Department of Health; Susan Buskin, PhD, and Sharon Hopkins, DVM, Seattle-King County Department of Public Health; Sylvia Odem, MPH, Texas Department of Health, Austin, Texas, and Philip Keiser, MD, Parkland Hospital, Dallas, Texas; Wes McNeely, MS, Department of Health and Human Services, Houston, Texas.