Treatment with protease inhibitor (PI)-based antiretroviral therapy (ART) among women with HIV infection who were pregnant was associated with an increased risk for poor perinatal outcomes, including small for gestational age (SGA) and very SGA. However, PI-based ART was not associated with an increased risk for preterm birth (PTB), and perinatal outcomes were similar between the different ART regimens assessed. These findings were published in eClinicalMedicine.

Investigators conducted a systematic review of prospective and retrospective cohort studies published between January 1980 and April 2020 that assessed adverse perinatal outcomes among women with HIV infection on PI-based ART. Outcomes of interest included PTB, very PTB, spontaneous PTB, low birth weight (LBW), very LBW, term LBW, preterm LBW, SGA, very SGA, stillbirth, and neonatal death. Using pairwise random-effects meta-analyses, the investigators compared the risk for each outcome between both nonPI-based ART and different PI-based ART regimens.

There were 34 studies comprising 57,546 patients from 22 countries included in the final analysis. Quality assessments categorized 20 studies as average quality and 14 as poor quality; 24 studies were conducted in high-income countries.

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In a random-effects meta-analysis that compared PI-based ART with nonPI-based ART, PI-based ART was not significantly associated with PTB. Results also showed that PI-based ART was not significantly associated with very PTB, spontaneous PTB, LBW, very LBW, or term LBW. However, significant associations were observed in regard to an increased risk for both SGA (relative risk [RR], 1.24; 95% CI, 1.08-1.43) and very SGA (RR, 1.40; 95% CI, 1.09-1.81). Of note, only 1 of the included studies examined the effect of PI-based ART on stillbirth and neonatal death, but no significant associations were found.

In regard to the use of different PI-based ART regimens, lopinavir/ritanovir (LPV/r)-based ART was significantly associated with an increased risk for PTB (RR, 1.33; 95% CI, 1.03-1.72). No other significant associations were found between the use of different PI-based ART regimens and the assessed outcomes.

Compared with nonboosted PI-based ART, boosted PI-based ART was significantly associated with an increased risk for both PTB (RR, 1.36; 95% CI, 1.12-1.65) and very PTB (RR, 1.85; 95% CI, 1.02-3.37).

This study may have been limited by indication bias and chronologic bias due to its observational design, and the investigators were not able to assess potential confounders such as maternal HIV viral load and CD4 cell count.

According to the investigators, “more evidence is needed regarding the comparative safety and efficacy of different ART regimens in pregnancy and further effort should be made to improve perinatal outcomes among [women with HIV infection] worldwide…”


Cowdell, I, Beck K, Portwood C, Sexton H, Kumarendran M, Brandon Z, et al. Adverse perinatal outcomes associated with protease inhibitor-based antiretroviral therapy in pregnant women living with HIV: A systematic review and meta-analysis. EClinicalMedicine. Published online April 6, 2022. doi:10.1016/j.eclinm.2022.101368