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].
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.
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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.
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