Extended antenatal use of triple antiretroviral therapy for prevention of mother-to-child transmission of HIV-1 correlates with favorable pregnancy outcomes
Marazzi, Maria C.a; Palombi, Leonardob; Nielsen-Saines, Karinc; Haswell, Jered; Zimba, Inese; Magid, Nurja A.e; Buonomo, Ersiliab; Scarcella, Paolab; Ceffa, Susannaf; Paturzo, Giovannae; Narciso, Pasqualeg; Liotta, Giuseppeb
bDepartment of Public Health, University of Tor Vergata, Rome, Italy
cDivision of Infectious Diseases, David Geffen UCLA School of Medicine, Los Angeles, California, USA
dBlantyre DREAM Medical Center, Blantyre, Malawi
eMaputo DREAM Medical Center, Maputo, Mozambique
fCommunity of Sant’Egidio, Rome, Italy
gNational Institute of Infectious Diseases, Rome, Italy.
Correspondence to Karin Nielsen-Saines, MD, MPH, Division of Infectious Diseases, David Geffen UCLA School of Medicine, MDCC 22-442 10833 LeConte Ave., Los Angeles, CA 90095, USA. Tel: +1 310 206 6640; fax: +1 310 825 9175; e-mail: firstname.lastname@example.org
Received 23 March, 2011
Revised 20 May, 2011
Accepted 27 May, 2011
Objective: To evaluate pregnancy outcomes in a cohort of HIV-infected women receiving triple antiretroviral therapy (ART) for prevention of mother-to-child-transmission.
Methods: A retrospective cohort study with review of records of 3273 HIV-positive women receiving prenatal care in Malawi and Mozambique from July 2005 to December 2009 was conducted in Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) centers. Patients were offered nevirapine-based triple ART initiated in pregnancy until 6 months postpartum. Main outcome measures were maternal mortality, abortion/stillbirth, prematurity, and low birth weight.
Results: Maternal mortality was 1.2% (42/3273): 7.4% in 68 women with no antenatal ART and 0.7% in 1370 with at least 90 days of antenatal ART [P < 0.001; odds ratio (OR) 0.29 (95% confidence interval [CI] 0.14–0.96]. Abortion/stillbirth was 5.2% (169/3273): 26.5% in 68 women with no ART and 5.0% in 1370 women with at least 90 days of antenatal ART [P < 0.001; OR 0.39 (95% CI 0.27–0.57)]. Prematurity was 19.1%: 70% in 10 women with no antenatal ART and 8.5% in 1330 women with at least 90 days of antenatal ART [P < 0.001; OR 0.15 (95% CI 0.14–0.19)]. Low birth weight was 11.5% (57/496) and not associated with ART duration. The protective effect of antenatal ART against mortality, fetal demise, and prematurity was independent of CD4 strata. Multivariate analysis for BMI, CD4 cell count, virus load, days in care, predelivery length of ART, and hemoglobin demonstrated an independent association between predelivery length of ART and CD4 with maternal mortality, abortion/stillbirth, and prematurity. ART toxicities were infrequent (5.2%).
Conclusion: Antenatal triple ART reduces adverse pregnancy outcomes in HIV-infected women.
There is significant variability in the approach to prevention of mother-to-child-transmission (PMTCT) of HIV-1 in resource-limited settings despite the well established prophylactic advantage of triple antiretroviral therapy (ART) for PMTCT purposes [1–6]. Reports on pregnancy outcomes following triple ART administration to pregnant women have been conflicting. Some studies have suggested triple ART may be associated with low birth weight or prematurity [7–9], whereas others have not found an association between adverse pregnancy outcomes and treatment, but with advanced maternal disease . HIV infection undoubtedly has been shown to be a relevant risk factor for maternal mortality in the African continent [11,12]. The Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) program uses triple ART for the purposes of HIV PMTCT at all 31 DREAM centers throughout 10 African countries since its inception in 2002. A dramatic decline in HIV MTCT has been observed, accompanied by a significant decline in maternal and infant mortality resulting in infant HIV-free survival exceeding 92% at 12 months of age [4,5,13]. In order to evaluate the impact of maternal triple ART on maternal mortality and pregnancy outcomes, a detailed review of all mother–infant pairs enrolled in a public health PMTCT program in Mozambique and Malawi was conducted. Pregnancy outcomes included rates of miscarriage, stillbirth, and prematurity and maternal outcomes included maternal mortality and antiretroviral toxicities.
Patients and methods
Retrospective observational cohort study.
The inclusion criteria for HIV-1-infected women followed at DREAM centers for prenatal care were as follows: prenatal care at DREAM centers; availability of pregnancy outcome data: miscarriage, stillbirth, or delivery of a live-born infant; intent to follow-up at DREAM centers postpartum; maternal informed consent to participate in the program; and intent to breast-feed. Data were analyzed in a blinded fashion with the removal of patient identifiers. The study was approved by institutional review boards and regulatory institutions in Italy, Mozambique, and Malawi.
Data were pooled from DREAM centers in Mozambique and Malawi. All files available for mother–infant pairs followed in PMTCT programs from July 2005 to June 2009 were reviewed. Data were collected on maternal demographics, obstetric and medical history, gestational age, BMI, laboratory parameters including HIV-1 virus load, T-cell subsets, hemoglobin and transaminases, antiretroviral history, duration, and mortality data. Clinical centers used electronic medical records linked to medical, nutritional, and laboratory data.
Pregnancy outcomes included spontaneous abortion or stillbirth, prematurity, and low birth weight. Abortion was defined as fetal death occurring at less than 32 weeks of gestation and stillbirth as greater than 32 weeks of gestation (determines fetal viability in resource-limited settings). Prematurity was defined as delivery of a live infant at less than 37 weeks gestation. Prematurity rates were determined only for women who accessed program centers before 37 weeks of gestation. Gestational age was estimated by clinical examination and date of last menstrual period. Birth weight data were obtained when infants presented to centers within a week of birth or had birth weights recorded on health cards. Low birth weight was defined as less than 2.5 kg. Maternal outcomes included maternal mortality rate (MMR), defined as death during pregnancy, at delivery, or within 42 days after delivery.
SPSS v. Windows 16.0.1 (SPSS Inc., Chicago, Illinois, USA) was used for data analysis. Data were censored at the time of death, or at the last patient visit before loss to follow-up, or on 30 June 2009. Ninety-five percent confidence intervals (CIs) for incidence of adverse pregnancy events were calculated and Pearson χ2-test was used for assessment of potential differences in pregnancy and maternal outcomes according to length of predelivery ART. To assess the impact of ART on pregnancy outcomes and mortality, data were dichotomized according to baseline CD4 cell counts and viral load in order to generate univariate odds ratio (OR) for each strata and adjusted Mantel–Haenszel OR for the entire sample and multivariate risk analysis. Duration of predelivery ART and gestational age at ART initiation were continuous variables in the model. Binary logistic regression forward stepwise model was performed for the main outcomes.
Medical records for 3273 pregnant women followed from July 2005 to June 2009 were reviewed. Ninety-four percent of pregnancies (n = 3071) resulted in 3148 live births. Infant 12-month HIV-free survival was 92.5%, with a corresponding infant mortality rate of 6.7% and a cumulative HIV-transmission rate of 2% at 12 months of age . Baseline characteristics of the population, details of antiretroviral administration, and pregnancy outcomes are outlined in Table 1. Maternal mortality was 1.2% (42/3273) with nine of 42 deaths (21%) occurring in the immediate postpartum period. The abortion/stillbirth rate was 5.2% (169/3273), with 3.1% stillbirths (101/3273) and 2.1% spontaneous abortions (68/3273). Premature deliveries occurred in 19.1% (564/2955) of pregnancies. The prevalence of low birth weight was 11.5% in a subset of patients (57/496), as this parameter was available for 19% (496/2584) of evaluable infants. Fifty percent of women had baseline CD4 cell counts lower than 350 cells/μl, whereas the median time of observation in prenatal care and antenatal treatment duration with triple ART was 3 months. Twelve percent of women received less than 1 month of triple ART before delivery and 3% less than 1 week.
Maternal mortality strongly correlated with the length of antenatal ART. It was 10-fold higher in women with no treatment before delivery as compared with women with 90 days or more of triple ART prior to birth (Table 2). MMR adjusted for observation time was 13-fold lower in women with more than 90 days of triple antenatal ART, as seen in Table 2. A CD4 stratified analysis demonstrated that the impact of ART on maternal mortality was also present in women with CD4 cell counts higher than 350 cells/μl (Table 3). The Mantel–Haenszel OR demonstrated a 70% reduction in the risk of maternal death in women receiving more than 30 days of triple ART before delivery. The multivariate logistic regression analysis demonstrated an independent association between baseline CD4 cell counts, hemoglobin, BMI, and predelivery length of maternal ART with maternal mortality (Table 4).
Abortion and stillbirth
The impact of antenatal ART on cumulative abortion/stillbirth rates was significant. As seen in Table 2, fetal demise rates fell from 26.5 to 5% when stratified by duration of maternal triple ART, P less than 0.001. When rates were adjusted for days of patient observation, the fetal demise rate declined from 3.3 for women with no treatment to 0.13 for women receiving 90 days of antenatal ART, which is a 25-fold decrease (P < 0.001). The incidence of abortion/stillbirth in women who conceived while on triple ART and maintained ART throughout pregnancy was 6.8% (22/323). The incidence of this outcome in women who received no ART throughout pregnancy was 26.5% (18/68), a relative risk of 4.24 (95% CI 1.79–10.07). Fetal demise was highly associated with duration of maternal ART (Table 3). Fetal demise occurred in 6.5% of women with lower CD4 cell counts and 3.7% of women with CD4 cell count greater than 350 cells/μl. This outcome doubled (from 5.8 to 11.6%) in women with lower CD4 cell count if ART duration was less than 1 month during pregnancy and tripled (from 2.9 to 8.7%) in women in the higher CD4 strata who received less than 1 month of ART. Figure 1 demonstrates the rate of fetal demise by baseline maternal CD4 cell counts and duration of ART in pregnancy. Women with the highest rate of immune suppression (CD4 cell count <200 cells/μl) had the highest rate of abortion/stillbirth events. Regardless of maternal CD4 cell strata, women with little to no ART treatment during pregnancy had a two-fold to four-fold increase in the rate of fetal demise. Table 4 demonstrates a multivariate analysis with an independent protective effect of longer triple ART duration and higher maternal CD4 cell counts on abortion/stillbirth risk.
There was a significant association between prematurity and duration of maternal triple ART. As seen in Table 2, both crude and adjusted prematurity rates per 100 observation days demonstrated a significant statistical association with duration of maternal ART (P < 0.001). An association between prematurity risk and reduced exposure to triple ART in pregnancy was present regardless of CD4 strata. Proportions were similar, 58 and 56% of women with lower or higher CD4 cell counts, respectively, had premature deliveries if triple ART were used in pregnancy for less than 1 month. The protective effect of triple ART was similar across CD4 categories with reduction in the risk of prematurity by 85% according to Mantel–Hanszel OR (Table 3). The association between triple ART and prematurity was confirmed in the multivariate analysis in which a protective effect of longer treatment courses was noted. A protective effect associated with higher CD4 cell counts was also noted.
Low birth weight
Birth weight measures were available for 496 infants. Infants born before 37 weeks gestation (n = 564) were excluded, as the attempt was to evaluate low birth weight independent of prematurity. Birth weight analyses exploring potential associations with maternal baseline and treatment parameters were not performed due to the small proportion of patients. Low birth weight (<2.5 kg) was present in 11.5% of infants, a finding not inferior to country-wide statistics for the general population of Malawi and Mozambique. Growth parameters to 18 months of age for children in this cohort were previously reported .
Anemia defined as hemoglobin lower than 8.0 g/100 ml up to 6 months postpartum from ART initiation (in patients with baseline pre-ART hemoglobin higher than 8.0 g/100 ml) was present in 226 of 2670 women (7.8%). The difference in anemia between patients receiving zidovudine-based triple ART and stavudine-based triple ART was 1% (3.99% in zidovudine arm vs. 3.0% in stavudine arm) in the first 6 weeks postpartum and 2.7% in the first 6 months postpartum (8.3% vs. 5.6% respectively; P = 0.03). Grade 3 or 4 liver toxicities were observed in 69 of 3273 women (2.1%). Grade 3 or 4 skin rashes were present in 80 of 3273 women (2.4%) and Steven–Johnsons Syndrome diagnosed in 39 (1.2%). A high number of adverse reactions (109/3273 women, 3.5%) were due to peripheral neuropathy, which developed late in the postpartum period. Cases of toxicity concurrent with antiretroviral use were low considering the high background morbidity. No toxicity-related deaths occurred. The number of women who required a change in alternate ART treatment due to toxicities was 367 (11.2%), 171 (5.2%) of whom had severe adverse reactions. Approximately one-third of patients who switched ART after several months of therapy did so due to the development of peripheral neuropathy. The remaining 258 women (7.9%) switched ART because of the development of liver toxicities, skin rash, Steven–Johnson Syndrome, or anemia.
HIV-1 infection has been shown to be associated with adverse pregnancy outcomes in prior studies conducted in sub-Saharan Africa [16–19]. Wherever cohorts of HIV-infected and uninfected pregnant women were compared in resource-limited settings, pregnant women with HIV infection fared worse. In addition to a significantly higher mortality risk, HIV-infected women have consistently higher rates of problems throughout gestation including prematurity, low birth weight, fetal demise, and perinatal mortality [6–19]. A South African study demonstrated that HIV was strongly associated with adverse pregnancy outcomes in a prospective cohort of 3465 women of whom 1449 were HIV-infected . Similar findings were reported in Tanzania where HIV-infected women had a much higher likelihood of small for gestational age infants, preterm births, and perinatal death . Among patients with HIV, the ones with most advanced disease are at higher risk of dying, regardless of pregnancy status . Pregnant patients with AIDS, anemia, and poor nutrition have worse fetal outcomes, as measured by the same parameters . Patients with advanced disease are most likely to receive triple ART. As a consequence, a number of studies have linked triple ART to worse pregnancy outcomes [21–23], although in many settings, receipt of ART is a marker for advanced disease, which in itself is linked to an adverse endpoint. In early large-scale studies , it was demonstrated that the pivotal variable for an adverse outcome is AIDS, whereas the use of triple ART can often represent a surrogate marker for this condition.
Maternal death is the worst possible pregnancy outcome. In our cohort, women who received antenatal triple ART for 90 days or longer were 13 times less likely to die than women with no treatment. This was a progressive trend that is directly proportional to duration of treatment and present at all CD4 cell count levels, not only in women with advanced disease. Although women with lower CD4 cell counts had a higher maternal mortality rate, duration of prenatal treatment showed a 70% protective effect in both groups of patients. The assumption that women with higher CD4 cell counts are not at risk of dying during or immediately following pregnancy in sub-Saharan Africa is inaccurate. Pregnant women with higher CD4 cell counts have been found to have a higher mortality risk especially in the immediate postpartum period [18,24]. Pregnancy-associated complications such as anemia and nutritional deficiencies (highly prevalent in resource-limited settings) contribute to worsening HIV disease  and can render a more vulnerable immunologic state. Coupled with the increased surrounding comorbidity of TB, malaria, anemia, and malnutrition of the resource-limited setting environment, the risk of death is magnified. In our cohort, anemia was independently associated with mortality. The excessive mortality of HIV-infected pregnant women in sub-Saharan Africa, particularly in face of high virus loads (not necessarily in women with lowest CD4 counts) is documented in large cohort studies . Our data underscore the beneficial impact of triple ART in reducing maternal mortality at all CD4 cell count levels. Nevertheless, in sub-Saharan Africa, women with higher CD4 cell counts are not typically offered triple ART during pregnancy, as it is generally assumed that treatment can be deferred and that the risk for HIV MTCT is considerably lower. Our data demonstrate otherwise as in this same cohort, 50% of perinatal transmissions occurred in women with higher CD4 cell counts .
The relative risk of abortion and stillbirth in women who received no ART was 4.24. Women who received less than 30 days of treatment were two-fold to three-fold more likely to develop fetal demise. This finding, although more prevalent in women with advanced disease, was consistently associated with duration of treatment. Low CD4 cell counts were also found to be significantly associated with adverse pregnancy outcomes, including abortion or stillbirth, mortality, and prematurity. Untreated maternal HIV infection has been found to be associated with fetal death . Studies of the pathogenesis of HIV transmission suggest that early fetal infection may lead to a higher miscarriage rate, with female fetuses being more susceptible to infection . A higher fragility of male fetuses following in-utero HIV infection has been postulated as the mechanism behind a sex predilection for female infants in a case series in Malawi . Regardless of the mechanism of fetal demise, extended antenatal triple ART clearly correlated with a lower abortion/stillbirth rate.
The correlation between prematurity and use of triple ART is often debated. An association between poor nutrition, low BMI, and prematurity is well established and has been documented in several nutritional studies of pregnant HIV-infected women in Tanzania and Zambia [14,19,28]. A strong association between maternal AIDS and prematurity has been demonstrated in a large series . Advanced maternal HIV disease has been clearly associated with an increased risk of prematurity, as high as 27% in a Swiss cohort of treated women . In African cohorts, prematurity rates are reported at 19% according to nutritional studies in Tanzania where patients had a median CD4 cell count of 500 cells/μl . In our cohort, prematurity was the parameter that most closely correlated with duration of triple ART, ranging from 70% in a small subset of women with no treatment to 8.5% in women with at least 3 months of antenatal ART. Prematurity rates were extremely high in women who had less than 30 days of ART (56–58%). Our analyses for prematurity were adjusted per 100 days of observation time in order to eliminate confounding by duration of observation. In addition, all patients who were late presenters at or beyond 37 weeks of gestation were excluded from this specific analysis in order to avoid selection bias. One limitation was the absence of ultrasound data to confirm gestational age, which was assessed on physical examination (measure of the uterine fundus), and history of last menstrual period. Nevertheless, reliance on physical examination for determination of gestational age is the norm in most African settings.
One limitation of our study was that adherence data were not collected in this cohort. However, our program focuses heavily on adherence through the community activist initiative, which has prompted adherence rates higher than 95% in patients who continue in the program . Another limitation was that we did not have data on incident HIV infections. Because most patients initiated medical care within the first trimester of pregnancy, we presume most infections anteceded pregnancy. MTCT rates were very low, which corroborates this assumption.
Maternal toxicities due to antiretroviral treatment were relatively uncommon and within the range of adverse reactions reported for women in similar cohorts such as women receiving triple ART in the BAN study, a randomized control study in a similar population in Malawi . In our cohort, anemia and peripheral neuropathy occurred most frequently, and despite the wide use of nevirapine, adverse reactions due to skin rashes and alterations in liver function tests were infrequent, an observation consistent with prior studies by our group [31–35].
In summary, extended triple ART was highly protective against adverse pregnancy outcomes including maternal mortality in a large cohort of pregnant women followed in a public health program in Malawi and Mozambique. The level of protection against mortality, fetal demise, and prematurity conferred by longer courses of antenatal triple ART surpassed CD4 cell count thresholds and benefited patients at all stages of HIV disease. Pregnant HIV-infected women in resource-limited settings, regardless of disease stage, are at higher risk for a series of significant complications including fetal and maternal death as compared with their uninfected counterparts. Early triple ART should be provided, whenever possible, to all HIV-infected pregnant women in resource-limited settings for reduction of maternal mortality and improved pregnancy outcomes.
Each individual author fully contributed to the preparation of this manuscript: J.H, I.Z., and N.A.M. obtained the original patient data set in Malawi and Mozambique. E.B. and P.S. obtained, plotted, and analyzed all maternal clinical parameters and participated in the data analysis. A.M.D.A, P.N., and S.M. coordinated all data collection efforts from DREAM health clinics in Mozambique and Malawi and performed preliminary data analysis. G.P. and S.C. were responsible for the performance of all laboratory studies and coordinated the laboratory data for the project. K.N.-S., G. L., and L.P. performed the final data analysis and wrote the manuscript in conjunction with M.C.M., who was also responsible for supervision of health center activities and database coordination. L.P. is the Principal Investigator and the Medical Director of the DREAM program who coordinated all research efforts for the present article.
This manuscript represents valid work and has not been previously published nor is being considered for publication elsewhere.
The authors would like to acknowledge the multiple members of the DREAM program who participated in the conduct of this study and all study participants.
Conflicts of interest
The Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) Program, of the Sant’Egidio Community, a faith-based NGO in Rome, Italy, is sponsored by multiple organizations including the World Bank Treatment Acceleration Program, several Italian private banks, several governmental cooperations including the German Agency for Technical Cooperation, the Agence Francaise de Développement, the Catalan Agency for Development Cooperation, the Belgium Development Cooperation, and the United States President Emergency Plan for AIDS Relief among others. DREAM Program–Project Malawi was funded in Malawi by Intesa Sanpaolo, Italy, and the CARIPLO Foundation, Italy. The present study was not funded by a specific award.
There are no conflicts of interest.
Preliminary findings of the study were presented at the 5th International AIDS Society Meeting on HIV Pathogenesis, Treatment and Prevention in Cape Town, South Africa as an oral presentation, 19–22 July 2009, abstract TUAC102.
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