Congenital Anomalies and In Utero Antiretroviral Exposure in Human Immunodeficiency Virus–Exposed Uninfected Infants

Abstract

Importance Most studies examining the association of prenatal antiretroviral exposures with congenital anomalies (CAs) in children born to HIV-infected women have been reassuring, but some suggest increased risk with specific antiretrovirals. Objectives To evaluate associations of in utero antiretroviral exposures with CAs in HIV-exposed uninfected children. Design prospective cohort study, the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicities (SMARTT) study. Setting 22 US medical centers Participants 2580 HIV-exposed, uninfected children enrolled in SMARTT between 2007–2012. Exposures First trimester exposure to any antiretroviral and to specific antiretroviral medications. Main Outcome The primary endpoint was a CA, based on clinician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate associations of CAs with first trimester antiretroviral exposures, adjusting for demographic and maternal characteristics. Results CAs occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI: 5.85–7.82%); there were 242 confirmed major CAs (72 musculoskeletal, 55 cardiovascular). The prevalence of CAs increased significantly in successive birth cohorts (3.8% for children born <2002 up to 8.3% for 2008–2010). In adjusted models, there was no association of first trimester exposures to any antiretroviral, to combination antiretroviral regimens, or to any drug class with CAs. No individual antiretroviral in the reverse transcriptase inhibitor drug classes was associated with increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir (adjusted odds ratio (aOR)=1.93, 95% confidence interval (CI):1.23,3.03) and for ritonavir used as a booster (aOR=1.52, 95%CI: 1.08,2.14). With first trimester atazanavir, risks were highest for skin and musculoskeletal CAs (aORs=5.24 and 2.55, respectively). Conclusions and Relevance Few individual antiretrovirals and no drug classes were associated with increased risk of CAs after adjustment for calendar year and maternal characteristics. While the overall risk remained low, there was a relative increase in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV use during pregnancy still outweigh such risks, although further studies are warranted.

Birth Outcomes for Pregnant Women with HIV Using Tenofovir–Emtricitabine

“…Several studies have shown relationships between ATV and delayed language development 28–30 and social– emotional development. 30 First-trimester ATV use has also been linked to an increased risk of skin and musculoskeletal malformations, 16 and in utero TDF exposure may be linked to reduced bone mineral content in infants. 14 …”

Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design

“…21,35,36 A comprehensive safety assessment must consider a wide range of possible adverse outcomes. However, we evaluated multiple domains of interest which could reflect mitochondrial dysfunction, epigenetic effects, or other mechanisms of toxicity related to intrauterine exposures.…”

Disclosing in utero HIV/ARV exposure to the HIV‐exposed uninfected adolescent: is it necessary?

“…Despite earlier reports in humans revealing neural tube defects in infants exposed to efavirenz (EFV) early in gestation [99,109], a more recent meta-analysis of 2026 infants countered these results and found no risk (RR=0.78, 95% CI: 0.56–1.08) [93]. In addition, the French EPF [80] and a recent US study [101] found overall low rates of congenital anomalies associated with EFV.…”