Epidemiology and Social
Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth
Szyld, Edgardo Ga; Warley, Eduardo Ma; Freimanis, Lauraf; Gonin, Renéf; Cahn, Pedro Eb; Calvet, Guilherme Ac; Duarte, Geraldod; Melo, Victor He; Read, Jennifer Sg; for the NISDI Perinatal Study Group
From the aHosp Diego Paroissien, Brazil
bHospital Juan Fernandez, Buenos Aires, Argentina, Brazil
cHospital dos Servidores do Estado, Rio de Janeiro, Brazil
dSchool of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil
eSchool of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
fWestat, Rockville, USA
gPediatric, Adolescent, and Maternal AIDS Branch, NICHD, NIH, DHHS, Bethesda, Maryland, USA.
*See Appendix for listing of study group members.
Received 12 March, 2006
Accepted 16 June, 2006
Correspondence to Dr E. Szyld, Gavilan 1086 (1406), Buenos Aires, Argentina. E-mail: firstname.lastname@example.org
Note: Presented in part at the 12th Conference on Retroviruses and Opportunistic Infections. Boston, February 2005 [abstract 806].
Objective: To determine the relationship between maternal antiretroviral regimens during pregnancy and adverse infant outcomes [low birth weight (LBW) and preterm birth]. The a priori hypothesis was that protease inhibitor (PI)-containing regimens are associated with an increased risk of LBW and preterm birth.
Design: Prospective cohort study of HIV-1-infected women and their infants (NISDI Perinatal Study).
Methods: Data were analysed from 681 women receiving at least one antiretroviral drug [in order of increasing complexity: one or two nucleoside reverse transcriptase inhibitors (1–2 NRTI), two NRTI plus one non-nucleoside reverse transcriptase inhibitor (NNRTI) (HAART/NNRTI), or two NRTI plus one PI (HAART/PI)] for at least 28 days during pregnancy, and who delivered live born, singleton infants with known birth weight and gestational age by 1 March 2005. Multivariable logistic regression modeling was used to assess the relationship of maternal ART with LBW and with preterm birth, adjusting for covariates.
Results: The incidence of LBW and preterm birth, respectively, was 9.6% and 7.4% (1–2 NRTI), 7.4% and 5.8% (HAART/NNRTI), and 16.7% and 10.6% (HAART/PI). There was no statistically significant increased risk of LBW [adjusted odds ratio (AOR), 1.5; 95% confidence interval (95% CI), 0.7–3.2] or preterm birth (AOR, 1.1; 95% CI, 0.5–2.8) among women who received HAART/PI compared with women receiving 1–2 NRTI.
Conclusions: Among a population of HIV-1-infected women in Latin America and the Caribbean, maternal receipt of PI-containing ART regimens during pregnancy was not associated with a statistically significant increase in risk of LBW or preterm birth.
An increasing proportion of HIV-1-infected women are receiving combination antiretroviral therapy regimens (ART), including HAART, during pregnancy for their own health or for prevention of mother-to-child transmission of HIV-1. Receipt of combination ART regimens is associated with a decreased risk of mother-to-child transmission of HIV-1 [1–6].
Higher rates of preterm birth [7–9] and low birth weight (LBW) [8–12] have been described among HIV-1-infected pregnant women compared with the general population of pregnant women. Among HIV-1-infected women, an increased risk of preterm birth and LBW has been associated with more severe immunosuppression [8,13]. Other identified risk factors for LBW and preterm birth among HIV-1-infected women are race/ethnicity, age, substance abuse, parity, prior preterm birth, hypertension, diabetes mellitus, anemia, low maternal weight, substance abuse, poor prenatal care, and sexually transmitted infections [8,12–14]. Receipt of antiretroviral drugs during pregnancy has been associated with an increased risk of preterm birth and/or LBW in some [15–17], but not other [14,18,19], studies. Of note, receipt of combination ART regimens including protease inhibitors (PI) during pregnancy has been associated with very LBW (VLBW)  and with preterm birth [20,21]. It has been postulated that exposure to HAART, which often contains at least one PI, leads to insulin resistance and endothelial inflammation, with a concomitantly increased risk of pre-eclampsia in the mother [22–24]. Pre-eclampsia, in turn, is associated with LBW and preterm birth [25,26].
There are few published data regarding the relationship between maternal ART receipt during pregnancy and infant outcomes in Latin America and the Caribbean. Therefore, this study analyzed data from the National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI) Perinatal Study in order to test the hypothesis that receipt of PI-containing ART during pregnancy is associated with an increased risk of LBW and preterm birth among infants of HIV-1-infected women.
The NISDI Perinatal Protocol
The NISDI Perinatal Protocol is a prospective cohort study conducted in Latin American and Caribbean countries. The primary objectives include characterizing adverse events among HIV-1-infected women and their infants according to ART exposure. Enrollment began in September 2002 and is ongoing. Prior to enrollment, all women provide signed informed consent for enrollment of themselves and their infants. The protocol was approved by the ethical review board at each clinical site where subjects were enrolled, as well as by institutional review boards of both the sponsoring institution (NICHD) and of the data management and statistical center (Westat). Maternal subjects were recruited from preexisting outpatient clinics for HIV-1-infected pregnant women at participating clinical sites. Maternal study visits are conducted during pregnancy, at labor/delivery, and three subsequent times until 6 months postpartum. Infants born to HIV-1-infected women enrolled in the protocol are followed until 6 months of age. During study visits, a medical history is obtained, a physical examination is conducted, and laboratory samples are obtained. Study participants are seen by infectious disease specialists, obstetricians with expertise in the management of HIV-1-infected women during pregnancy and postpartum, or pediatricians with expertise in the management of HIV-1-exposed and HIV-infected children at participating clinical sites. Adherence to ART is not assessed as part of the NISDI Perinatal Protocol.
Study population, primary predictor and outcome variables
The study population was restricted to women enrolled in the NISDI Perinatal Protocol for the first time (second pregnancies on-study excluded) who received at least one ART regimen for at least 28 days during pregnancy and who delivered a live born, singleton infant with known birth weight and gestational age by 1 March 2005. The ART regimen consisted of one or two nucleoside/nucleotide analogue reverse transcriptase inhibitor (1–2 NRTI) only; two NRTI with one non-nucleoside reverse transcriptase inhibitor (HAART/NNRTI); or two NRTI with one PI (HAART/PI)], Antiretroviral regimens were determined by the study participant's clinician, independent of participation in the NISDI protocol. Regimens containing three drugs (HAART/PI or HAART/NNRTI) were considered of greater complexity than regimens containing only one or two NRTI. If a subject received both HAART/PI and HAART/NNRTI for ≥ 28 days each during pregnancy, a regimen containing HAART/PI was considered more complex than a regimen containing HAART/NNRTI. LBW was defined as a birth weight of < 2500 g. VLBW was defined as a birth weight of < 1500 g. Preterm infants were those with a gestational age at birth of < 37 completed weeks. Very preterm infants were those with a gestational age at birth of < 34 completed weeks. Infant gestational age at birth (in completed weeks) was determined either by obstetrical estimation (dates of last menstrual period with or without ultrasound ) or by pediatric newborn examination [28–30].
Clinical, immunological, and virological characteristics of the women were assessed at enrollment and at labor/delivery or hospital discharge following delivery. Maternal clinical disease staging was performed with the Centers for Disease Control (CDC) 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS among Adolescents and Adults . After venipuncture was performed at a study visit, blood was transported to laboratories identified by each clinical site for flow cytometry and for plasma viral load assays.
Receipt of ART during pregnancy was categorized as prophylaxis or treatment. Women were classified as having received prophylaxis if they were not receiving ART when they became pregnant but they initiated one or more antiretroviral drugs during pregnancy and discontinued these drugs at or before the postpartum visit at 6–12 weeks. Conversely, women were classified as receiving treatment if they were receiving ART when they became pregnant and/or continued ART after the 6–12 week postpartum visit.
Mode of delivery was categorized as vaginal or cesarean section delivery and, if cesarean section, as cesarean section before labor and before ruptured membranes (ECS) or as cesarean section after labor and/or after ruptured membranes (NECS). A maternal history of substance abuse during the index pregnancy was ascertained through maternal interview at enrollment. Maternal nutritional status at enrollment was characterized according to a body mass index (BMI) adjusted for length of gestation using an algorithm available from the Ministry of Health of Argentina .
Information collected at each study visit regarding maternal diagnoses experienced since the last visit was used to construct other covariates of interest. The presence of hypertension was defined on the basis of a diagnosis of eclampsia, pre-eclampsia, pregnancy-induced hypertension, or chronic hypertension. Women with sexually transmitted infections were those diagnosed with any of the following conditions at any time during the index pregnancy: acquired syphilis, gonorrhea, chancroid, lymphogranuloma, salpingitis/pelvic inflammatory disease, urethritis, chlamydial infection, or trichomoniasis. Women with renal disease were those diagnosed with any of the following conditions at any time during the index pregnancy: bacteriuria (asymptomatic or symptomatic), interstitial nephritis, nephropathy, proximal renal tubular acidosis, pyelonephritis, renal disorder not otherwise specified, renal failure, renal tubular acidosis, renal Fanconi syndrome, and urinary tract infection. Women with diabetes were those diagnosed with any of the following conditions prior to or during the index pregnancy: type I or type II diabetes, pregestational diabetes or gestational diabetes. Anemia was defined as grade 3 or worse hemoglobin values at any time during pregnancy (hemoglobin ≤ 84 g/l) . Women with bleeding during pregnancy were those with any of the following diagnoses during pregnancy until delivery of the infant: abruption, vaginal bleeding at < 28 weeks of gestation, or vaginal bleeding at ≥ 28 weeks of gestation.
Associations of categorical variables with the outcomes (LBW and preterm birth) were evaluated using Fisher–Freeman–Halton exact test . Variables at least marginally associated with outcome (at the 20% significance level) were considered candidates for the multivariable logistic regression modeling. For the logistic regression modeling, both stepwise selection and backward elimination strategies were applied to determine whether both selection procedures arrived at the same parsimonious model (using a 5% significance level). When necessary, the variable representing the most complex ART regimen received during pregnancy for ≥ 28 days, the primary risk factor of interest in this study, was forced into the LBW and preterm birth models.
Size of study population; primary predictor and outcome variables
At 1 March 2005, 803 women had enrolled in the NISDI Perinatal Study in Argentina, the Bahamas, Brazil, and Mexico for the first time (16 second pregnancies on study were excluded), of whom 48 were still pregnant, 15 had stillbirths, six had spontaneous abortions, and 734 had delivered live born infants. Of these 734 infants, 722 were singletons for whom birth weight and gestational age data were available. Of the 722 mothers of singleton infants, five did not receive any antiretroviral drugs during pregnancy and 29 received ART but for < 28 days. Of the remaining 688 mothers, the most complex ART regimen of ≥ 28 days received during pregnancy was 1–2 NRTI (94), HAART/PI (330), HAART/NNRTI (257), or other (7). Therefore, the study population consisted of 681 mother–infant pairs.
Of these 681 women, the median duration of receipt of ART was 118 days. Most women (73%) received only one ART regimen during pregnancy. Approximately 21% received two ART regimens during pregnancy, while only 7% received three or more regimens.
Of the 681 infants, 598 (87.8%) had a birth weight ≥ 2500 g, 78 (11.5%) had a birth weight of 1500–2499 g, and 5 (0.7%) had a birth weight < 1500 g. The distribution of gestational ages for these infants was ≥ 37 completed weeks for 624 (91.6%), 34–36 completed weeks for 49 (7.2%), and < 34 completed weeks for 8 (1.2%).
Univariate analyses of low birth weight
The variables associated most strongly with an increased risk of LBW were the most complex ART regimen received for ≥ 28 days during pregnancy, maternal HIV clinical disease stage at enrollment and at labor/delivery, maternal adjusted BMI, and maternal hypertension (Table 1). In terms of ART regimen, a regimen of HAART/PI was associated with the highest rate of LBW (16.7%); the rate was 7.4% with HAART/NNRTI and 9.6% with 1–2 NRTI. Comparing women by clinical disease stage, mothers who had progressed to AIDS had the highest proportion of infants of LBW (23.2%) compared with women with CDC class A or B. For maternal adjusted BMI, those mothers who were underweight had the highest proportion of LBW infants (23.9%) compared with women who were of normal weight or who were overweight or obese. Finally, for maternal hypertension, mothers who developed pre-eclampsia or eclampsia and mothers with chronic hypertension had the highest proportion of LBW infants (63.6% and 33.3%, respectively) compared with mothers with pregnancy-induced hypertension or mothers without hypertension.
Univariate analyses of preterm birth
Maternal characteristics most strongly associated with preterm birth were country of residence, maternal HIV clinical disease stage at enrollment and at labor/delivery, maternal plasma HIV-1 RNA concentration at enrollment, diabetes, mode of delivery, and hypertension (Table 1). With regard to maternal disease stage, mothers who had progressed to AIDS had the highest proportion of preterm infants (17.9%). When considering maternal plasma HIV-1 RNA concentration, mothers with < 1000 copies/ml at enrollment had the lowest proportion of infants with preterm birth (5.8%). Diabetic mothers had significantly higher rates of preterm births (25%) than those without diabetes (8.0%). When considering hypertension, mothers with pre-eclampsia/eclampsia or with chronic hypertension had the highest proportions of preterm infants (54.5% and 16.7%, respectively). Finally, those who delivered by cesarean section (either ECS or NECS) had higher rates of preterm birth (10.8% and 14.7%, respectively) than those who delivered vaginally (3.4%). Nonetheless, the mean gestational age for those infants who were born by cesarean section was 38.4 weeks, with a median of 38 weeks. Among women with ECS, the most frequent indication was prevention of mother-to-child transmission of HIV (47%), followed by repeat cesarean section (25%). The most common indication for NECS was prevention of mother-to-child transmission of HIV-1 (32%), followed by prolonged rupture of membranes (13%).
Variables included in multivariable modeling for LBW were country of residence, most complex ART regimen received for ≥ 28 days during pregnancy, HIV clinical classification at enrollment and at labor and delivery, plasma HIV-1 RNA concentration at enrolment, tobacco use during pregnancy, reason for receipt of ART during pregnancy, history of preterm birth, maternal diabetes, adjusted BMI, mode of delivery, and hypertension. Estimated odds ratios (OR) and confidence intervals (CI), both unadjusted and adjusted, for the variables included in the final model are shown in Table 2. After adjustment, mothers receiving HAART/PI did not have a statistically significant increased risk of having a LWB infant compared with mothers receiving 1–2 NRTI (adjusted OR, 1.5; 95% CI, 0.7–3.2). Independent risk factors for LBW were pre-eclampsia/eclampsia, NECS, maternal diabetes, and maternal underweight.
Variables included in multivariable modeling for preterm birth were country of residence; most complex ART regimen received for ≥ 28 days during pregnancy; HIV-1 clinical classification at enrollment and at labor and delivery; plasma HIV-1 RNA concentration at enrollment and hospital discharge; maternal diabetes; adjusted BMI; mode of delivery; and hypertension. Estimated OR and CI for the variables included in the final model are shown in Table 3. Although the most complex maternal ART regimen for ≥ 28 days during pregnancy did not enter the model in the stepwise selection or backwards elimination regression modeling, it was forced into the model (since the intended analysis was to evaluate the association of maternal ART regimens and preterm birth). After adjustment, HAART/PI was not associated with a statistically significant increased likelihood of preterm birth compared with receipt of 1–2 NRTI: adjusted OR, 1.1 (95% CI, 0.5–2.8). Independent risk factors for preterm birth were pre-eclampsia/eclampsia, cesarean delivery, maternal diabetes, and maternal underweight.
In our analysis of data regarding HIV-1-infected women and their infants at multiple clinical sites in Latin America and the Caribbean, the highest incidence of LBW and of preterm birth was noted among women whose most complex regimen during pregnancy contained a PI. There was an increased risk of preterm birth and LBW among women whose most complex regimen contained a PI compared with those receiving 1–2 NRTI. However, this increased risk was not statistically significant in either the unadjusted or the adjusted analyses. The wide CI values reflect the small number of outcome events observed.
Studies of HIV-1-infected women conducted before the introduction of ART prophylaxis or treatment during pregnancy suggested that HIV-1-infected women were at increased risk of adverse infant outcomes, including preterm birth [7–9] and LBW [8–12]. In addition, studies in which HIV-1-infected women either received or did not receive one or more antiretroviral drugs during pregnancy have continued to demonstrate a relationship between maternal HIV disease stage (e.g., as manifested by lower CD4 cell counts) and the risk of preterm birth and LBW [8,13,19].
A small study by Lorenzi and colleagues in 1998 , which suggested a relationship between maternal ART during pregnancy and preterm birth, prompted a number of studies evaluating maternal ART regimens during pregnancy and adverse infant outcomes, such as preterm birth and LBW. These studies have had conflicting results. Studies from Europe have provided support for an association between receipt of ART during pregnancy and an increased risk of preterm birth and LBW. For example, analyses of data regarding 3902 mother–child pairs in the European Collaborative Study and the Swiss Mother and Child HIV Cohort Study, which controlled for maternal CD4 cell count and illicit drug use, revealed increased risks of preterm birth among HIV-1-infected mothers who received combination ART regimens during pregnancy (OR 2.6 with a PI and OR 1.8 without a PI) . Subsequently, analysis of data from the European Collaborative Study regarding 2414 uninfected children born to HIV-1-infected women revealed an increased risk of preterm birth, but not LBW, with maternal receipt of ART during pregnancy. Women who received combination ART regimens with a PI were four times more likely (adjusted OR, 4.1; 95% CI, 2.3–7.2) to deliver a preterm infant than those receiving no ART. Women receiving combination ART regimens without a PI had a nearly three times greater likelihood (adjusted OR, 2.7; 95% CI, 1.5–4.7) of delivering preterm . In a more recent analysis by the same group of investigators , antenatal receipt of HAART (initiated before pregnancy) was strongly associated with preterm birth (adjusted OR, 2.05; 95% CI, 1.43–2.95), particularly very preterm birth. In contrast to the results of European studies, US studies have not consistently associated maternal receipt of ART during pregnancy with an increased risk of preterm birth or LBW. For example, in the overall analysis of 3266 HIV-1-infected women enrolled in seven clinical studies during the 1990s, receipt of combination ART regimens was not associated with increased rates of preterm birth or LBW (compared with no ART or monotherapy). However, in a subgroup analysis, there was an association between receipt of PI-containing regimens and VLBW . In a more recent analysis of data from 3443 HIV-1-infected women and their infants in PACTG 367 , maternal receipt of ART was associated with lower risks of preterm birth and of LBW (compared with no ART receipt during pregnancy). A report from the Women and Infants Transmission Study, describing 2543 HIV-1-infected women, did not document an increase in adverse infant outcomes associated with maternal combination ART regimen . Finally, the most recent study analysed data from HIV-1-infected women receiving care at one hospital in the United States from 1990 through 2002. In this cohort of over 1300 women, only receipt of a combination ART regimen including a PI was associated with an increased risk of preterm birth (compared with any other combination ART; OR, 1.8; 95% CI, 1.1–3.0) .
Our study of HIV-1-infected women and their infants in Latin America and the Caribbean did not demonstrate an increased risk of preterm birth and LBW with PI-containing regimens. However, it is important to note that, in contrast to previous studies, the reference group for our analyses was women who received 1–2 NRTI (and not women without any ART exposure during pregnancy, because of the small size of this group).
Independent risk factors for both preterm birth and LBW included eclampsia and pre-eclampsia. An association between HAART and an increased risk of pre-eclampsia has been observed [22–24], and the association of hypertension and pre-eclampsia with increased risks of preterm birth and LBW is well recognized [25,26].
The overall rates of preterm birth and LBW among the HIV-1-infected women in this cohort are much lower than the rates reported in other studies of HIV-1-infected women and their infants. These lower rates could be related to a lower frequency of cesarean section deliveries, but also to other factors, such as the lower rate of alcohol and illegal substance use during pregnancy compared with North American and European studies [18,19,21]. This lower rate of alcohol and substance use likely reflects the primary mode of HIV transmission in Latin America (heterosexual transmission) . The observed rate of preterm birth (8.4%) in our cohort of HIV-1-exposed infants is similar to that reported for the general population of infants in the Latin American countries represented in this study [36–41]. However, the observed rate of LBW (12.2%) in our cohort is higher than those reported for the general population of infants in Argentina (7%), Bahamas (7%), Brazil (10%), and Mexico (9%) .
Among the strengths of this study is the recruitment of a large number of study participants across several countries in Latin America and the Caribbean, and the prospective collection of data (minimizing the potential for recall bias), with a very low rate of loss to follow-up . However, this study has limitations. We did not have information regarding adherence to ART. Also, at the beginning of this study, we did not collect data on the duration of receipt of ART prior to pregnancy and, therefore, we could not assess the importance of this factor as it relates to adverse infant outcomes. Although we did have information regarding the duration of ART exposure during pregnancy and the number of regimens received during pregnancy, the relatively small number of events among women receiving different ART regimens precluded further analyses evaluating duration of receipt or number of regimens and the outcomes of interest (preterm birth and LBW). Because of the small number of infants at VLBW, analyses of this as an outcome variable were not conducted. In terms of the multivariable modeling, the number of outcome events was relatively small in some instances (e.g., maternal hypertension) given the total number of parameters being estimated, affecting the precision of models' estimates (leading to wide CI values). Consequently, the risk estimates associated with the independent risk factors, particularly hypertension and diabetes, should be interpreted with caution as they were included in the model primarily for adjustment purposes and not risk estimation.
We conclude that among HIV-1-infected women in Latin America and the Caribbean, receipt of a PI-containing regimen during pregnancy is not associated with an increased risk of LBW and preterm birth compared with regimens containing only 1–2 NRTI. However, it is important to continue to monitor HIV-1-infected women and their children, especially the uninfected children, for potential adverse events associated with maternal treatment of HIV-1 disease or with receipt of interventions to prevent mother-to-child transmission of HIV-1.
Sponsorship: This study was funded by NICHD Contract N01-HD-3-3345.
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Principal investigators, study coordinators, coordinating center representatives, and NICHD staff include: Argentina: Buenos Aires: Marcelo H. Losso, Adriana S. Durán, Silvina Ivalo, Alejandro Hakim (Hospital General de Agudos José María Ramos Mejía); Pedro Cahn, Maria Rolon (Hospital Juan Fernandez); Edgardo Szyld, Eduardo Warley (Hospital Diego Paroissien); Mariana Ceriotto, Susana Luciano, Maria Laura Collins (Hospital de Agudos Dra. Cecilia Grierson); Bahamas: Nassau: Perry Gomez, Percival McNeil, Marva Jervis, Chanelle Diggiss, Rosamae Bain (Princess Margaret Hospital); Brazil: Belo Horizonte: Jorge Pinto, Victor Melo, Fabiana Kakehasi (Universidade Federal de Minas Gerais); Caxias do Sul: Ricardo de Souza, Jose Mauro Madi (Universidade de Caxias do Sul/Hospital Geral de Caxias do Sul); Ricardo de Souza, Rosangela Boff, Ruti Pipi (Universidade de Caxias do Sul/Ambulatório Municipal de DST/AIDS); Porto Alegre: Ricardo de Souza, Breno Riegel Santos, Rita Lira (Universidade de Caxias do Sul/Hospital Conceicao); Ricardo de Souza, Rosana da Fonseca, Mario Peixoto, Rita Lira (Universidade de Caxias do Sul/Hospital Femina); Ribeirão Preto: Marisa M Mussi-Pinhata, Geraldo Duarte, Alessandra C. Marcolin (HCFMRP-USP); Rio de Janeiro: Marcos Machado D'Ippolito, Esau Custodio Joao, Jacqueline Menezes, Guilherme Amaral Calvet (Hospital dos Servidores do Estado); Sao Paulo: Regina Celia de Menezes Succi, Prescilla Chow Lindsey (Federal University of Sao Paulo); Mexico: Mexico City: Javier Ortiz Ibarra, Ricardo Figueroa-Damian, Guadalupe Noemi Plazola - Camacho (Instituto Nacional de Perinatología); Data Management and Statistical Center: René Gonin, James Korelitz, Susan Truitt, Roslyn Hennessey, Yolanda Bertucci, Laura Freimanis, D. Robert Harris, Julianne Byrne (Westat, Rockville, MD, USA); NICHD: Lynne Mofenson, Jack Moye, Jennifer S. Read, Leslie Serchuck, Heather Watts (National Institute of Child Health and Human Development, Bethesda, Maryland, USA). Supported by NICHD Contract #N01-HD-3-3345.
HIV-1; HAART; low birth weight; preterm; pregnancy
© 2006 Lippincott Williams & Wilkins, Inc.
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