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RESEARCH AND PRACTICE |
Susan B. Brogly is with the Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Mass. D. Heather Watts is with the Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, Bethesda, Md. Nathalie Ylitalo and George R. Seage III are with the Department of Epidemiology, Harvard School of Public Health, Boston. Eduardo L. Franco is with the Departments of Epidemiology and Biostatistics and of Oncology, McGill University, Montreal, Quebec. James Oleske is with the Department of Pediatrics, University of Medicine and Dentistry of New Jersey, Newark. Michelle Eagle is with the Division of Pediatric Infectious Disease and Immunology, University of Florida, Gainesville. Russell Van Dyke is with the Department of Pediatrics, Tulane University Health Science Center, New Orleans, La.
Correspondence: Requests for reprints should be sent to Susan B. Brogly, PhD, Center for Biostatistics in AIDS Research, Harvard School of Public Health, 651 Huntington Ave, Boston, MA 02115–6017 (e-mail: sbrogly{at}sdac.harvard.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONReferences |
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Objectives. We sought to describe the reproductive health of adolescent girls perinatally infected with HIV.
Methods. We estimated the incidence of first pregnancy, genital infections, and abnormal cervical cytology for 638 girls aged 13 years and older in the Pediatric AIDS Clinical Trials Group protocol 219C.
Results. Thirty-eight girls became pregnant, for a first pregnancy rate of 18.8/ 1000 person-years; 7 of these girls had additional pregnancies (95% confidence interval [CI]=13.3, 25.7). Thirty-two pregnancies resulted in live births. All girls received antiretroviral therapy during pregnancy. One infant was HIV infected, 29 were uninfected, and 2 had unknown infection status, for a rate of mother-to-child transmission of HIV in infants with known infection status of 3.3% (95% CI=0.1, 18.6). Condylomata and trichomoniasis were the most frequent genital infections. Forty-eight (47.5%) of 101 girls with Papanicolaou test examinations had abnormal cervical cytology, including atypical cells of undetermined significance (n=18), low-grade squamous intraepithelial lesions (SIL; n=27), and high-grade SIL (n=3). Many abnormalities persisted despite intervention.
Conclusions. Pregnancy rates were lower and cervical abnormalities were higher than among non–HIV-infected adolescents. These findings underscore the importance of Papanicolaou tests and promotion of safer sexual practices in this population.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONReferences |
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Although reproductive health outcomes for adolescent girls with behaviorally acquired HIV infection have been studied extensively, little data exist on the reproductive health of girls with perinatal HIV infection. A high risk of genital human papillomavirus infection and its sequelae, cervical squamous intraepithelial lesions (SIL),4–6 as well as other genital infections,7 has been documented in women and adolescents infected with HIV through sexual activity and drug use. Adolescents perinatally infected with HIV are often cared for in pediatric infectious disease clinics, where reproductive health issues may not be routinely addressed.
In this study, we estimated rates of pregnancy and pregnancy outcomes, genital infections, and cervical cytological abnormalities in a cohort of perinatally HIV-infected adolescents in the United States.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONReferences |
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Protocol 219C was a revised version of PACTG protocol 219, which began in 1993; the primary change was to remove the restriction by which protocol 219 enrolled only children who were currently or previously enrolled in an ACTG clinical trial or whose mother was enrolled in an ACTG clinical trial during pregnancy. HIV-infected children enrolled in 219C if they were aged 21 years or younger, able to adhere to protocol visits, and receive medical care at a PACTG clinical site. Children were followed until loss of contact, protocol withdrawal, death, or their 25th birthday. The clinical centers involved in protocol 219C obtained approval from their respective review boards for human research, and the child or the child’s parent or guardian provided written informed consent.
The study population for our investigation was restricted to perinatally HIV-infected girls aged 13 years or older who participated in protocol 219C. A girl was considered to have perinatally acquired HIV infection if her mother was HIV infected during pregnancy, labor, or delivery according to clinical records; according to HIV DNA polymerase chain reaction or RNA assays, most girls were shown to be HIV positive during infancy or early childhood. Because of the paucity of data on rates of pregnancy and pregnancy outcomes, including mother-to-child transmission of HIV, we sought to include all pregnancies that occurred in the cohort and so used the minimum age of occurrence of pregnancy—13 years—in defining the study base.
Data Collection
A wide range of demographic, clinical, immunologic, and virologic data were obtained at participants’ enrollment in PACTG protocol 219C and at follow-up visits, which took place every 3 months; these data included information on living conditions, diagnostic test results and histories of clinical diagnoses, pregnancies and pregnancy outcomes, ART use, Centers for Disease Control and Prevention (CDC) disease classification,8 CD4-positive T lymphocyte number CD4+ and percentage and plasma HIV viral load copy number (obtained through blood samples), and pelvic tests and cervical Papanicolaou (Pap) tests.
The 219C protocol initially requested pelvic examinations—which included a visual inspection of the cervix and vagina and a bi-manual examination—every 3 years beginning at age 15 years or the onset of sexual activity, whichever came first. Cervical Pap tests initially were requested of sexually active girls every 3 years. Beginning in 2002, pelvic and Pap tests were administered annually. Pap tests were fixed with a spray preservative and sent to the local PACTG site’s laboratory for reading. Because the protocol 219C participants received their primary care from clinicians at the PACTG site, clinically indicated test results were recorded in addition to those specified in the 219C protocol.
Identification of Reproductive Outcomes
All pregnancies and pregnancy outcomes recorded in the 219C database were identified and confirmed by the clinical site. Live-born infants were classified by the primary care provider as HIV infected or uninfected on the basis of HIV DNA polymerase chain reaction or RNA assays. Diagnoses of atypical squamous cells of undetermined significance (ASCUS), low-grade SIL, or high-grade SIL were made according to the Bethesda system for cervical cytological diagnosis.9 Although screening for genital infections was not performed routinely as part of protocol 219C, the physician attending the pelvic examination frequently diagnosed symptomatic cases. The diagnostic procedures for genital condylomata, trichomoniasis, chlamydial infection, gonorrhea, and syphilis were based on the PACTG site’s standard diagnostic procedures and were conducted at the institution’s local laboratory, all of which were accredited by the Colleges of American Pathology. Girls were identified as sexually active through disclosure or occurrence of pregnancy or genital infection.
Statistical Methods
We estimated the cumulative incidence of first pregnancy and the incidence rate per 1000 person-years from the girl’s 13th birthday to the date of the conception of the first pregnancy or the last cohort visit, whichever occurred first. The date of conception was determined by subtracting the gestational age of the fetus or infant from the date of the pregnancy outcome. In estimating the rate of mother-to-child transmission of HIV, pregnancies that yielded multiple births were assessed as a single transmission if any infants were HIV infected and as a single nontransmission if none were infected. The cumulative incidence of first genital condylomata, trichomoniasis, chlamydial infection, gonorrhea, and syphilis also were estimated; girls with a diagnosis of the genital infection before age 13 years were excluded from analyses for that particular outcome. Incidence rates of pregnancy and cumulative incidence of genital infections were estimated for all girls and for girls known to be sexually active.
Analysis of abnormal cervical cytology was restricted to 101 girls for whom Pap tests were given. The cumulative incidence of low- or high-grade SIL was estimated for 40 girls whose first Pap test was indicative of normal cervical cytology and who then received at least 1 subsequent Pap test (with normal or abnormal result). The treatment and persistence of cervical abnormalities were described.
Differences in CDC disease classification, CD4+ percentage, HIV RNA copy number, in utero ART exposure, and ART use according to sexual activity, pregnancy, and cervical cytology were assessed using the Kruskal–Wallis, 
2, and Fisher exact tests as appropriate.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONReferences |
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). Sexually active girls were less likely to be on ART than non–sexually active girls; however, among girls on ART, there was no significant difference in the proportions on the 3 highly active antiretroviral therapies described in Table 1.
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). Girls who became pregnant were significantly older than those who did not, and in general, the differences in characteristics between the 2 groups paralleled the differences between sexually active and non–sexually active girls shown in Table 1
. In addition, among girls known to be sexually active, those who became pregnant were more likely to have abnormal cervical cytology during follow-up than those who did not become pregnant.
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Genital Infections
The estimated cumulative incidence of genital condylomata, chlamydial infection, trichomoniasis, gonorrhea, and syphilis from age 13 to 19 years for all girls and for sexually active girls is shown in Table 2. Incidence was highest for genital condylomata and trichomoniasis. In addition to cases of condylomata in girls aged 13 years and older, 23 girls had condylomata diagnosed before the age of 13 years. The mean age at diagnosis of these 23 girls was 6.3 years (range = 2.7–11.0); 18 girls had documentation of HIV infection prior to the diagnosis of condylomata.
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Thirty of 101 girls with Pap tests had abnormal cervical cytology at the first examination for a prevalence of 29.7% (95% CI=20.0, 42.4), and 18 girls had abnormal cervical cytology during follow-up. The first abnormal cytological diagnosis was ASCUS for 18 girls, low-grade SIL for 27 girls, and high-grade SIL for 3 girls. The 12-month cumulative incidence of low- or high-grade SIL in 40 girls with a first normal Pap test and at least 1 subsequent Pap test was 17.5% (95% CI=4.7, 30.2; Figure 2). There were no significant differences in demographic characteristics, ART use, or HIV clinical, immunologic, or virologic status between girls with normal cervical cytology and those with abnormal cervical cytology; however, girls with abnormal cervical cytology were significantly more likely to have a genital infection during follow-up than girls with normal cervical cytology.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONReferences |
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The pregnancy incidence rate of 33.5 per 1000 person-years among girls aged 15 to 19 years in our study was lower than that documented for predominantly non–HIV-infected girls of similar age in the United States in 1999 (86.7 per 1000),10 which is consistent with the findings of lower pregnancy rates in HIV-infected versus non–HIV-infected women.11 Because of the small numbers, the 219C pregnancy incidence rates were not standardized according to racial distributions in the United States; race/ethnicity has been associated with pregnancy and pregnancy outcomes.10 Very few non–HIV-infected children participated in protocol 219C until adolescence, which precluded use of reference rates in this population for the present study. In addition, some spontaneously or therapeutically aborted pregnancies may not have been documented, which could have underestimated the pregnancy rate in this population.
All adolescents who delivered a live birth were on ART—mainly a combination of 3 or more drugs, 1 of which was a protease inhibitor or NNRTI—at some point during pregnancy, and only 1 infant was HIV infected. The estimated rate of mother-to-child transmission of HIV of 3.3% (95% CI = 0.1, 18.6) is similar to rates observed in the Women and Infants Transmission Study for women receiving dual ART in which, in most cases, both drugs were NRTIs (3.8% [95% CI = 1.1, 6.5]), and for women receiving combination ART of 3 or more drugs, which included a protease inhibitor, NNRTI, or both (1.2% [95% CI = 0.0, 2.5]).12 However, there were a small number of live births in our study, and the CI is wide and also includes higher rates. In a case study of 8 perinatally HIV-infected adolescents and young adults in Puerto Rico, 5 first pregnancies resulted in live births, 4 of the 5 mothers were on ART, and none of the infants were HIV infected.1 Similarly, no mother-to-child transmission of HIV occurred among 26 infants born to perinatally HIV-infected adolescents in India.3 Further study is needed to ascertain the effectiveness of ART in preventing second-generation perinatal HIV transmission given the potential for transmission of a virus resistant to 1 or more classes of ART. Of note, none of the pregnant girls in our study were themselves exposed to ART in utero.
Rates of genital infections—including trichomoniasis, chlamydial infection, and gonorrhea—documented in our study population were lower than those found in the Reaching for Excellence in Adolescent Care and Health (REACH) cohort,13 which was expected because the REACH cohort comprised girls infected with HIV during adolescence, presumably through sexual transmission. Although screening for genital infections was not performed routinely as part of the 219C protocol, girls frequently were assessed at the time of the pelvic examination, and symptomatic cases were independently diagnosed through primary care. Thus, the reported rates represent the minimum rate of genital infections. Nevertheless, the observation that 23 of 638 girls had genital condylomata at a young age is troubling. We were unable to determine whether these young condylomata cases were related to recent exposure through sexual abuse, voluntary sexual activity, or acquisition of human papilloma virus (HPV) during delivery. However, the localization of the condylomata suggests that sexual abuse or activity was more likely to have been the source of infection.
The prevalence of abnormal cervical cytology was 29.7%, which is higher than the prevalence of 11.5% documented among 375 women aged 18 to 24 years attending a university health clinic in Montreal14 and lower than the 56.4% among 133 girls infected with HIV in adolescence in the REACH cohort.6 Further, although based on small numbers, the 36-month cumulative incidence of SIL among girls in protocol 219C (32.8%; 95% CI = 15.5, 50.0) was higher than that observed in high-risk non–HIV-infected adolescents in San Francisco (15.0%; 95% CI = 13.0, 17.0).15 The high proportion of abnormal cervical cytology in our population compared with university students also could be because of increased susceptibility to and persistence of HPV and other genital infections in these girls, as has been demonstrated in HIV-infected women.16 Although we had no virologic information on HPV infection, many cervical abnormalities persisted in affected girls, even with intervention. No associations between clinical, immunologic, or virologic profiles and cervical cytology were identified, but the analysis had limited power. In addition, the estimated cumulative incidence of SIL was based on a small number of participants, only half of whom participated in protocol 219C past age 19 years.
It is unsettling that only 58% of 174 girls known to be sexually active had documented Pap tests. The PACTG site provided the girls’ primary medical care, and testing and diagnoses from routine clinical care supplemented the data collected through the 219C protocol. The estimated rates of cervical cytological abnormalities could be misleading if girls for whom Pap tests were given had different profiles of abnormal cervical cytology than those who did not. Likewise, we may have overestimated the incidence of pregnancy and genital infection because sexual activity was identified through disclosure or the occurrence of the outcome of pregnancy or a genital infection. Nonetheless, this study provides preliminary data on a unique cohort of girls infected early in the HIV epidemic and who survived to reproductive age.
A considerable proportion of adolescents in our cohort engaged in unprotected sexual intercourse despite close and frequent contact with HIV clinics. Sexual activity in perinatally HIV-infected adolescent girls is probably more common than many pediatricians assume. Indeed, 45 pregnancies occurred, and almost 48% of the girls who had a Pap test had cytological abnormalities detected. In addition, few diagnosed cervical abnormalities cleared, even with intervention. These findings underscore the importance of obtaining sexual histories, providing counseling to prevent unintended pregnancies, screening for genital infections, administering routine Pap tests, and closely managing cervical lesions. Education on safer sexual practices is needed in this population.
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Acknowledgments |
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We thank the adolescents and families for their participation in PACTG protocol 219C and the individuals and institutions involved in the conduct of 219C.
Human Participant Protection
The clinical centers involved in PACTG protocol 219C obtained approval from their institutional review boards for human research, and the child or the child’s guardian provided written informed consent.
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Footnotes |
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Note. The National Institute of Child Health and Human Development was involved in the design, data collection, and conduct of protocol 219C but was not involved in the present analysis, the interpretation of the data, the writing of the manuscript, or the decision to submit for publication.
Contributors
S. B. Brogly conducted the statistical analysis and drafted the article. D.H. Watts assisted with the writing of the article. S. B. Brogly, D. H. Watts, N. Ylitalo, E. L. Franco, and G. R. Seage designed the present study. G. R. Seage, J. Oleske, and R. Van Dyke developed the PACTG 219C protocol and obtained funding. J. Oleske, M. Eagle, and R. Van Dyke recruited patients and provided data. All authors helped to form ideas, interpret findings, and provide critical input to the article.
Accepted for publication July 12, 2006.
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References |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONReferences |
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4. Maiman M, Fruchter R, Serur E, Remy J, Feuer G, Boyce J. Human immunodeficiency virus infection and cervical neoplasia. Gynecol Oncol. 1990;38:377–382.[CrossRef][Web of Science][Medline]
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7. Belongia E, Danila R, Angamuthu V, et al. A population-based study of sexually transmitted disease incidence and risk factors in human immunodeficiency virus-infected people. Sex Transm Dis. 1997;24: 251–256.[Web of Science][Medline]
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9. Kurman R, Solomon D. The Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses. New York, NY: Springer-Verlag; 1994.
10. Ventura S, Abma J, Mosher W, Henshaw S. Revised pregnancy rates, 1990–97, and new rates for 1998–99: United States. Natl Vital Stat Rep. October 31, 2003;52(7).
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14. Richardson H, Franco E, Pintos J, Bergeron J, Arella M, Tellier P. Determinants of low-risk and high-risk cervical human papillomavirus infections in Montreal university students. Sex Transm Dis. 2000;27: 79–86.[Web of Science][Medline]
15. Moscicki A-B, Hills N, Shiboski S, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. JAMA. 2001;285:2995–3002.
16. Massad L, Riester K, Anastos K, et al. Prevalence and predictors of squamous cell abnormalities in Pa-panicolaou smears from women infected with HIV-1. J Acquir Immune Defic Syndr. 1999;21:33–41.[Web of Science][Medline]
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