Elsevier

The Lancet HIV

Volume 3, Issue 1, January 2016, Pages e33-e48
The Lancet HIV

Articles
Perinatal outcomes associated with maternal HIV infection: a systematic review and meta-analysis

https://doi.org/10.1016/S2352-3018(15)00207-6Get rights and content

Summary

Background

The HIV pandemic affects 36·9 million people worldwide, of whom 1·5 million are pregnant women. 91% of HIV-positive pregnant women reside in sub-Saharan Africa, a region that also has very poor perinatal outcomes. We aimed to establish whether untreated maternal HIV infection is associated with specific perinatal outcomes.

Methods

We did a systematic review and meta-analysis of the scientific literature by searching PubMed, CINAHL (Ebscohost), Global Health (Ovid), EMBASE (Ovid), and the Cochrane Central Register of Controlled Trials and four clinical trial databases (WHO International Clinical Trials Registry Platform, the Pan African Clinical Trials Registry, the ClinicalTrials.gov database, and the ISRCTN Registry) for studies published from Jan 1, 1980, to Dec 7, 2014. Two authors independently reviewed the studies retrieved by the scientific literature search, identified relevant studies, and extracted the data. We investigated the associations between maternal HIV infection in women naive to antiretroviral therapy and 11 perinatal outcomes: preterm birth, very preterm birth, low birthweight, very low birthweight, term low birthweight, preterm low birthweight, small for gestational age, very small for gestational age, miscarriage, stillbirth, and neonatal death. We included prospective and retrospective cohort studies and case-control studies reporting perinatal outcomes in HIV-positive women naive to antiretroviral therapy and HIV-negative controls. We used a random-effects model for the meta-analyses of specific perinatal outcomes. We did subgroup and sensitivity analyses and assessed the effect of adjustment for confounders. This systematic review and meta-analysis is registered with PROSPERO, number CRD42013005638.

Findings

Of 60 750 studies identified, we obtained data from 35 studies (20 prospective cohort studies, 12 retrospective cohort studies, and three case-control studies) including 53 623 women. Our meta-analyses of prospective cohort studies show that maternal HIV infection is associated with an increased risk of preterm birth (relative risk 1·50, 95% CI 1·24–1·82), low birthweight (1·62, 1·41–1·86), small for gestational age (1·31, 1·14–1·51), and stillbirth (1·67, 1·05–2·66). Retrospective cohort studies also suggest an increased risk of term low birthweight (2·62, 1·15–5·93) and preterm low birthweight (3·25, 2·12–4·99). The strongest and most consistent evidence for these associations is identified in sub-Saharan Africa. No association was identified between maternal HIV infection and very preterm birth, very small for gestational age, very low birthweight, miscarriage, or neonatal death, although few data were available for these outcomes. Correction for confounders did not affect the significance of these findings.

Interpretation

Maternal HIV infection in women who have not received antiretroviral therapy is associated with preterm birth, low birthweight, small for gestational age, and stillbirth, especially in sub-Saharan Africa. Research is needed to assess how antiretroviral therapy regimens affect these perinatal outcomes.

Funding

None.

Introduction

Maternal HIV infection, with its associated maternal morbidity and mortality and risk of mother-to-child transmission of HIV, affected the outcomes of three millennium development goals (MDGs): the reduction of child mortality (MDG 4), the improvement of maternal health (MDG 5), and the combating of HIV/AIDS and other diseases (MDG 6).1 The disease burden caused by HIV infection is reduced by antiretroviral therapy, but coverage is incomplete.2 In part because of incomplete antiretroviral therapy coverage, MDG targets were not met, and high rates of maternal and child mortality and morbidity persist, particularly in sub-Saharan Africa where 91% of HIV-positive pregnant women live.1, 2, 3

Whether maternal HIV infection affects perinatal outcomes, which are major contributors to poor health worldwide, is unknown. An estimated 2·6 million stillbirths,4 2·8 million neonatal deaths,5 14·9 million preterm births,6 32·4 million small-for-gestational-age births,7 and 18 million low birthweight babies7 occur every year. These outcomes are inter-related, with preterm birth being the leading cause of neonatal and child mortality,5, 8 fetal growth restriction being associated with stillbirths,9 and 41% of low birthweight infants being preterm.7 Sub-Saharan Africa has the highest rates of stillbirths and neonatal deaths worldwide,4, 10 and nine of the 11 countries with the highest preterm birth rates are also in sub-Saharan Africa,6 which has the second highest small for gestational age and low birthweight rates after south Asia.7 Therefore, sub-Saharan Africa carries very high rates of adverse perinatal outcomes and the highest burden of maternal HIV infection. Because an increasing number of pregnant women worldwide are receiving antiretroviral therapy, the likelihood of new data emerging on the associations between treatment naive HIV and perinatal outcomes is low.

Research in context

Evidence before this study

A systematic review and meta-analysis on perinatal outcomes associated with maternal HIV infection was published in 1998. Only publications up to 1996 were included, many of which were abstracts. The perinatal outcomes were poorly or not defined, gestational age estimation methods were not assessed, and a fixed-effects model was used to pool the data despite substantial between-study heterogeneity.

Added value of this study

We have done a systematic review and meta-analysis including studies published up to 2014, at a stage in the epidemic when an increasing number of pregnant women worldwide are receiving antiretroviral therapy, making the likelihood of new evidence emerging in the future low. Perinatal outcomes were clearly defined a priori, inclusion and exclusion criteria were strictly applied to reduce bias, and a random-effects model was used to pool the data. Our study shows that antiretroviral therapy-naive maternal HIV infection is strongly associated with increased risks of preterm birth, low birthweight, small for gestational age, and stillbirth, and weakly associated with term low birthweight and preterm low birthweight. The evidence did not support an effect on very preterm birth, very low birthweight, very small for gestational age, miscarriage, or neonatal death.

Implications of all the available evidence

The evidence for an association of maternal HIV infection with adverse perinatal outcomes is strongest and most consistent in sub-Saharan Africa, the region with the highest burden of maternal HIV infection. Antiretroviral therapy reduces maternal morbidity and mortality and greatly reduces mother-to-child transmission of HIV, but the effect of different antiretroviral therapy regimens on perinatal outcomes is unknown. WHO recommends triple-drug antiretroviral therapy regimens during pregnancy for all HIV-positive women and lifelong treatment thereafter. With continued expansion of treatment programmes, especially in sub-Saharan Africa, an urgent need exists to assess the effect of antenatal antiretroviral therapy regimens on perinatal outcomes.

We did a systematic review and meta-analysis with the aim of establishing whether antiretroviral therapy-naive maternal HIV infection is associated with 11 specific perinatal outcomes.

Section snippets

Search strategy and selection criteria

We did this systematic review and meta-analysis according to a protocol developed with the Cochrane guidelines.11 We searched five electronic scientific literature databases (PubMed, CINAHL (Ebscohost), Global Health (Ovid), EMBASE (Ovid), and the Cochrane Central Register of Controlled Trials) and four trial databases (WHO International Clinical Trials Registry Platform, the Pan African Clinical Trials Registry, ClinicalTrials.gov database, and the ISRCTN Registry) to identify studies

Results

Our search yielded 60 750 citations, 35 of which were included in this meta-analysis (figure 1). These studies included data for 53 623 women in 18 countries in 20 prospective and 12 retrospective cohort studies, and three case-control studies.13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 53, 54 No randomised controlled trials were identified. The study and population characteristics, methods used to correct

Discussion

HIV infection is strongly associated with increased risks of preterm birth, low birthweight, small for gestational age, and stillbirth, and weakly associated with term and preterm low birthweight. The evidence did not support an effect of maternal HIV infections on very preterm birth, very low birthweight, very small for gestational age, miscarriage, or neonatal death. Overall, the evidence is strongest and most consistent in sub-Saharan Africa, the region with the highest burden of maternal

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