Dolutegravir (DTG) is an integrase strand transfer inhibitor (InSTI) with once-daily dosing, good viral efficacy, high barrier to resistance, and good tolerability. Preliminary data from the NIH-supported Botswana birth defects surveillance project (Tsepamo study) reported a potential increased risk of neural tube defects (NTD) in infants born to HIV-positive women receiving DTG-based antiretroviral therapy (ART) prior to conception, compared to non-DTG ART or to uninfected women (0.9%, 0.1% , and 0.09%, respectively). Using data from the Antiretroviral Pregnancy Registry (APR), a voluntary, international, prospective exposure-registration cohort study with independent Advisory Committee oversight, we describe central nervous system (CNS) defects and NTD in infants born to women receiving InSTIs.
Data on prospectively enrolled pregnancies through 31Jan2018 with birth outcome are summarized. Birth defects are reviewed by a dysmorphologist, coded according to modified Metropolitan Atlanta Congenital Defects Program criteria, classified by organ system and assigned timing of exposure to each InSTI (DTG, elvitegravir [EVG], raltegravir [RAL]). Birth defects within the CNS organ system include both NTDs and encephalocele, which is reported separately from NTD.
A total of 19,688 pregnancies resulted in 20,026 fetal outcomes including 18,685 live births. APR reports come from North America (75%), Europe (8%), Africa (7%), South America (6%) and Asia (4%). There were 1,021 live births with an InSTI exposure at any time during pregnancy, of which 507 had ongoing exposure at conception, including 121 DTG, 155 EVG, and 231 RAL live birth outcomes. There were no NTD or other CNS birth defects among prospective cases for any InSTI drug (Table).
No occurrences of CNS defects or NTDs were observed among 1,021 prospective live birth outcomes with InSTI exposure at any time. This frequency is consistent with the observed low prevalence of NTD in developed countries (~0.1%), as most APR reports (83%) come from North America and Europe where food is supplemented with folate, which reduces NTD prevalence. However, InSTIs are a newer class of ARVs and the number of pregnancies with InSTI exposure in the APR to date is insufficient to draw definitive conclusions about a potential association between DTG and NTD, or to look at specific geographic regions. Healthcare providers are encouraged to continue to report pregnancies with prospective antiretroviral exposures to the APR.