Adverse perinatal outcomes associated with antiretroviral therapy in women living with HIV: A systematic review and meta-analysis

Abstract

Background: Maternal HIV infection is associated with an increased risk of adverse perinatal outcomes. The World Health Organization (WHO) recommends immediate initiation of lifelong antiretroviral therapy (ART) for all people living with HIV, including pregnant women living with HIV (WLHIV). We aimed to assess the risk of adverse perinatal outcomes in WLHIV receiving ART compared to ART-naïve WLHIV and HIV-negative women.

Materials and methods: We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between Jan 1, 1980, and April 20, 2020. Two investigators independently selected relevant studies and extracted data from studies reporting on the association of pregnant WLHIV receiving ART with adverse perinatal outcomes. Perinatal outcomes examined were preterm birth (PTB), very PTB, spontaneous PTB (sPTB), low birth weight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Random-effects meta-analyses examined the risk of adverse perinatal outcomes in WLHIV receiving ART compared to ART-naïve WLHIV and HIV-negative women. Subgroup and sensitivity analyses were performed based on country income status and study quality, and adjustment for confounding factors assessed.

Results: Of 94,594 studies identified, 73 cohort studies, including 424,277 pregnant women, met the inclusion criteria. We found that WLHIV receiving ART are associated with a significantly decreased risk of PTB (relative risk 0.79, 95% CI 0.67-0.93), sPTB (0.46, 0.32-0.66), LBW (0.86, 0.79-0.93), and VLBW (0.62, 0.39-0.97) compared to ART-naïve WLHIV. However, WLHIV receiving ART are associated with a significantly increased risk of PTB (1.42, 1.28-1.57), sPTB (2.20, 1.32-3.67), LBW (1.58, 1.36-1.84), term LBW (1.88, 1.23-2.85), SGA (1.69, 1.32-2.17), and VSGA (1.22, 1.10-1.34) compared to HIV-negative women.

Conclusion: ART reduces the risk of adverse perinatal outcomes in pregnant WLHIV, but the risk remains higher than in HIV-negative women. Our findings support the WHO recommendation of immediate initiation of lifelong ART for all people living with HIV, including pregnant WLHIV.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021248987.

Keywords: HIV; antiretroviral; perinatal; pregnancy; preterm (birth).

FIGURE 1

Study selection. *For example, women living with HIV were not pregnant. †For example, paper did not provide relevant outcome data. ‡For example, Assisted Reproductive Technology. ART, antiretroviral therapy; HIV, human immunodeficiency virus; LBW, low birthweight; NND, neonatal death; PTB, preterm birth; SGA, small for gestational age; sPTB, spontaneous preterm birth; VLBW, very low birthweight; VPTB, very preterm birth; VSGA, very small for gestational age; WLHIV, women living with HIV. See Materials and methods for definitions of perinatal outcomes.

FIGURE 2

Perinatal outcomes of women living with HIV receiving ART compared to women living with HIV without ART and HIV-negative women. Random-effects meta-analysis results for perinatal outcomes associated with women living with HIV receiving ART compared to women living with HIV without ART (A) and HIV-negative women (B). Statistically significant effects are presented with red dots and non-significant effects with black dots. ART, antiretroviral therapy; HIV, human immunodeficiency virus; LBW, low birthweight; NND, neonatal death; PTB, preterm birth; RR, relative risk; SGA, small for gestational age; sPTB, spontaneous preterm birth; VLBW, very low birthweight; VPTB, very preterm birth; VSGA, very small for gestational age; WLHIV, women living with HIV; 95% CI, 95% confidence interval.

FIGURE 3

Subgroup and sensitivity analyses based on country income status and study quality. Random-effects meta-analysis results for perinatal outcomes associated with women living with HIV receiving ART compared to women living with HIV without ART (A–D) and HIV-negative women (E–I). Subgroups consisted of studies done in high income countries (A,E) or low- and middle-income countries (B,F). Sensitivity analysis was done for studies of good (G), average (C,H) or poor (D,I) quality. Statistically significant effects are presented with red dots and non-significant effects with black dots. ART, antiretroviral therapy; HIV, human immunodeficiency virus; LBW, low birthweight; NND, neonatal death; PTB, preterm birth; RR, relative risk; SGA, small for gestational age; sPTB, spontaneous preterm birth; VLBW, very low birthweight; VPTB, very preterm birth; VSGA, very small for gestational age; WLHIV, women living with HIV; 95% CI, 95% confidence interval.