Adverse Perinatal Outcomes Associated With HAART and Monotherapy

Clara Portwood; Claudia Murray; Harriet Sexton; Mary Kumarendran; Zoe Brandon; Bradley Johnson; Shona Kirtley; Joris Hemelaar


AIDS. 2022;36(10):1409-1427. 

In This Article

Abstract and Introduction


Objectives: Assess adverse perinatal outcomes in pregnant women living with HIV (WLHIV) receiving HAART or zidovudine (ZDV) monotherapy, compared with antiretroviral therapy (ART)-naive WLHIV and HIV-negative women.

Design: Systematic review and meta-analysis.

Methods: We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between 1 January 1980 and 20 April 2020. We included studies reporting on the association of pregnant WLHIV receiving HAART or ZDV monotherapy with 11 perinatal outcomes: preterm birth (PTB), very PTB, spontaneous PTB (sPTB), low birth weight (LBW), very LBW, term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Random-effects meta-analyses were conducted.

Results: Sixty-one cohort studies assessing 409 781 pregnant women were included. WLHIV receiving ZDV monotherapy were associated with a decreased risk of PTB [relative risk 0.70, 95% confidence interval (CI) 0.62–0.79] and LBW (0.77, 0.67–0.88), and comparable risk of SGA, compared with ART-naive WLHIV. WLHIV receiving ZDV monotherapy had a comparable risk of PTB and LBW, and an increased risk of SGA (1.16, 1.04–1.30) compared with HIV-negative women. In contrast, WLHIV receiving HAART were associated with a comparable risk of PTB and LBW, and increased risk of SGA (1.38, 1.09–1.75), compared with ART-naive WLHIV. WLHIV receiving HAART were associated with an increased risk of PTB (1.55, 1.38–1.74), sPTB (2.09, 1.48–2.96), LBW (1.79, 1.51–2.13), term LBW (1.88, 1.23–2.85), SGA (1.80,1.34–2.40), and VSGA (1.22, 1.10–1.34) compared with HIV-negative women.

Conclusion: Pregnant WLHIV receiving HAART have an increased risk of a wide range of perinatal outcomes compared with HIV-negative women.


In 2020, 37.7 million people worldwide were living with HIV, including 19.3 million women of childbearing age.[1] Each year, an estimated 1.3 million women living with HIV (WLHIV) are pregnant, of whom the vast majority reside in sub-Saharan Africa.[1] Antiretroviral therapy (ART)-naive maternal HIV infection is associated with an increased risk of preterm birth (PTB), low birthweight (LBW), small for gestational age (SGA), and stillbirth compared with HIV-negative women.[2] Adverse perinatal outcomes are major contributors to neonatal and child mortality and morbidity, with the highest rates found in sub-Saharan Africa.[3–5] The United Nations' Sustainable Development Goal 3 (SDG3) target 3.2 aims to reduce neonatal and under-5 mortality to 12 and 25 per 1000 live births, respectively, by 2030.[6]

In 1994, a randomized controlled trial (RCT) demonstrated that antenatal zidovudine (ZDV) monotherapy reduced the risk of mother-to-child HIV transmission.[7] In the past, WHO guidelines recommended ZDV monotherapy in pregnant WLHIV to prevent vertical HIV transmission (option A), or HAART for pregnant WLHIV requiring treatment for their own health as well as prevention of vertical HIV transmission (option B).[8] From 2013, WHO recommended that all pregnant WLHIV should receive HAART during pregnancy.[9] In 2015, this recommendation was updated so that all people living with HIV should initiate HAART as soon as possible after diagnosis, including pregnant WLHIV.[10] Consequently, the proportion of pregnant WLHIV receiving ZDV monotherapy decreased from 31 to 0% in the period 2011–2020, whereas the proportion of pregnant WLHIV receiving HAART increased from 27 to 83% during the same period.[1] These trends were accompanied by a 41% reduction in vertical HIV transmission globally during 2010–2018.[11] However, the impact of these changes in antenatal ART regimens on other important perinatal outcomes is unknown.

Several studies suggest adverse perinatal outcomes are associated with ART exposure during pregnancy but evidence is conflicting regarding different regimens.[12–15] A recent network meta-analysis of seven randomized controlled trials (RCTs), which compared ART regimens initiated during pregnancy, showed that a number of HAART regimens were associated with an increased risk of LBW, very LBW and PTB, compared with ZDV monotherapy.[16] Some cohort studies report that HAART exposure is associated with increased risk of PTB and LBW in pregnant WLHIV, whereas ZDV monotherapy is not.[17,18] However, others report no significant association.[19]

As the number of pregnancies exposed to HAART increases and ZDV monotherapy has been phased out, it is important to understand the effects of HAART and ZDV monotherapy on perinatal outcomes in WLHIV, and whether either therapy restores the risk of perinatal outcomes to levels seen in HIV-negative women. We conducted a systematic review and meta-analysis of cohort studies examining the risk of 11 specific perinatal outcomes in WLHIV receiving HAART or ZDV monotherapy, compared with ART-naive WLHIV and HIV-negative women.