Perinatal outcomes associated with pre-exposure prophylaxis for HIV prevention during pregnancy: a systematic review and meta-analysis

Background The World Health Organization (WHO) recommends tenofovir disoproxil fumarate (TDF)-based oral pre-exposure prophylaxis (PrEP), the dapivirine vaginal ring, and long-acting intramuscular injectable cabotegravir (CAB-LA) for HIV prevention in populations at substantial risk of HIV infection. Pregnancy is a period of elevated risk of maternal HIV infection and transmission to the infant. This systematic review and meta-analysis assessed the risk of adverse perinatal outcomes among HIV-negative pregnant women with exposure to any PrEP modality. Methods We conducted a systematic review by searching Medline, EMBASE, CINAHL, Global Health, the Cochrane Library, WHO ICTR, ISRCTN, PACTR, and ClinicalTrials.gov for studies published between 1 January 2000 and 29 August 2023. We included studies reporting on the association of antenatal exposure to any PrEP modality with 13 perinatal outcomes: preterm birth (PTB), very PTB, spontaneous PTB, spontaneous very PTB, low birthweight (LBW), very LBW, term LBW, preterm LBW, small for gestational age (SGA), very SGA, miscarriage, stillbirth, or neonatal death (NND). Quality assessments of included studies were performed. Fixed-effect meta-analyses were conducted to calculate odds ratios (ORs) and 95% confidence fi dence intervals (95% CIs). The protocol is registered with PROSPERO, CRD42022339825. Findings Of 18,598 citations identified, fi ed, 13 studies (eight randomised controlled trials (RCTs) and fi ve cohort studies), assessing 8712 pregnant women in Africa, were included. Oral PrEP, compared to no PrEP, was not associated with PTB in meta-analyses of six RCTs (OR 0.73, 95% CI 0.43-1.26; - 1.26; I2 2 = 0.0%) or fi ve unadjusted cohort studies (OR 0.84, 95% CI 0.69-1.03; - 1.03; I2 2 = 0.0%), but was associated with a reduced risk of PTB in three adjusted cohort studies (aOR 0.67; 95% CI 0.52-0.88, - 0.88, I2 2 = 0.0%). There was no association of oral PrEP with LBW, vLBW, SGA, or NND, compared to no PrEP. There was no association with PTB when oral TDF/emtricitabine (FTC) PrEP, oral TDF PrEP, and tenofovir vaginal gel were compared to each other. There was no association of the dapivirine vaginal ring with PTB or NND, compared to placebo or oral TDF/FTC PrEP. We found no data on CAB-LA. Interpretation We found no evidence of adverse perinatal outcomes associated with PrEP exposure during pregnancy. Our fi ndings support the WHO recommendation to provide oral PrEP to women of reproductive age and pregnant women. More data is needed to assess the safety of all PrEP modalities in pregnancy.