Protease Inhibitor–Based ART Associated With Babies Born Small or Very Small

A large systematic review on pregnant women living with HIV found that protease inhibitor–based antiretroviral therapy (ART) use was associated with increased risk of babies being born small or very small for their gestational age, but not with other adverse pregnancy outcomes.

Protease inhibitor (PI)–based antiretroviral therapy (ART) use among pregnant women living with HIV is associated with a significantly increased risk of their children being born small or very small for their gestational age, according to a systematic review published in EClinicalMedicine.

Around 1.3 million women with HIV become pregnant each year, and most of these women live in sub-Saharan Africa where there are high rates of maternal and child mortality. ART use is recommended for all pregnant women living with HIV, but a lack of evidence on whether ART—especially PI-ART—can increase the risk of adverse pregnancy outcomes prompted a systematic review including 57,546 pregnant women living with HIV from 34 studies.

Compared with non–PI-ART use, PI-ART was linked to a 24% increased risked risk of babies being born small for gestational age (SGA) and a 40% increased risked risk of being born very small for gestational age (VSGA). According to the authors, this is the first meta-analysis to demonstrate that PI-ART is significantly associated with both SGA and VSGA, compared with non-PI-ART.

However, the treatment was not associated with an increased risk of pre-term birth or any other adverse pregnancy outcomes, contradicting past study findings. The authors noted this is mainly due to the larger number of studies on pre-term birth included in this review.

“In addition, we included only ART (i.e. triple drug) regimens in our analyses, thereby excluding studies using monotherapy and dual therapy, which were included in previous analyses,” the authors said. “This highlights the importance of regularly updating meta-analyses as new data becomes available and inclusion of relevant regimens in analyses.”

Additionally, the authors found no significant differences in pregnancy outcomes between the 3 most commonly used PIs: lopinavir, atazanavir, and darunavir. Current US, UK, and European guidelines advise against lopinavir/ritonavir (LPV/r), citing an increased risk of pre-term birth with its use. This review suggests LPV/r was only associated with a higher risk of pre-term birth when compared with nelfinavir, another PI that is no longer recommended due to its inferior virological efficacy. According to the authors, this finding should inform international treatment guidelines.

While this is the largest systematic review on this topic to date, multiple limitations were also noted. One limitation was that all studies included in the review run the risk of bias, such as indication bias linked to PI-ART being a second-line treatment in many low- and middle-income countries, and therefore other first-line treatments may not have helped women in these areas.

Another major limitation was lack of data on certain important confounders. Because of this, evaluations could not be made between effects of confounders such as maternal viral load and CD4 cell count, which are associated with adverse outcomes.

The authors emphasized the need for further research on efficacy and safety of various ART use for pregnant women with HIV, and the need for more global efforts to improve perinatal outcomes for these women.

“In summary, the available mechanistic data are limited and complex, and highlight the need to firmly establish the epidemiological associations between HIV/ART and specific perinatal outcomes before embarking on mechanistic and intervention studies,” they wrote.


Cowdell I, Beck K, Portwood C, 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 7, 2022. doi:10.1016/j.eclinm.2022.101368

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