ime ofconception compared with non-dolutegravir-containing antiretroviral regimens. As defectsrelated to closure of the neural tube occur from conception through the first 6 weeks of gestation,embryos exposed to dolutegravir from the time of conception through the first 6 weeks ofgestation are at potential risk. In addition, 2 of the 4 birth defects (encephalocele andiniencephaly) that have been observed with dolutegravir use, although often termed neural tubedefects, may occur post-neural tube closure, the time period of which may be later than 6 weeksof gestation, but within the first trimester. Due to the limited understanding of the types ofreported neural tube defects associated with dolutegravir use and because the date of conceptionmay not be determined with precision, avoid use of DOVATO at the time of conception throughthe first trimester of pregnancy. No neural tube defects have been reported in infants born tomothers who have started dolutegravir after the first trimester of pregnancy (see Data).
If there are plans to become pregnant or if pregnancy is confirmed while on DOVATO duringthe first trimester, if possible, switch to an alternative regimen. Advise pregnant individuals ofthe potential risk to the embryo exposed to DOVATO from the time of conception through thefirst trimester of pregnancy.
There are insufficient human data on the use of DOVATO during pregnancy to definitivelyassess a drug-associated risk for birth defects and miscarriage. The background risk for majorbirth defects for the indicated population is unknown. In the U.S. general population, theestimated background rate for major birth defects and miscarriage in clinically recognizedpregnancies is 2% to 4% and 15% to 20%, respectively.
In animal reproduction studies, no evidence of adverse developmental outcomes was observed withdolutegravir at systemic exposures (AUC) less than (rabbits) and 50 times (rats) the exposure inhumans at the recommended human dose (RHD) (see Data). Oral administration of lamivudine topregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC)similar to the RHD; however, no adverse developmental effects were observed with oraladministration of lamivudine to pregnant rats during organogenesis at plasma concentrations(Cmax) 35 times the RHD (see Data).
Data
Human Data: Dolutegravir: As of May 2018, in an ongoing birth outcome surveillance study inBotswana, there have been 4 cases of neural tube defects reported out of 426 births (0.94%) tomothers who were exposed to dolutegravir-containing regimens at the time of conception. Incomparison, the neural tube defect preva lence rates were 0.12% (14/11,300) in the nondolutegravirarm and 0.09% (61/66,057) in the HIV-uninfected arm. Four cases reported with
dolutegravir included one case each of encephalocele, anencephaly, myelomeningocele, and iniencephaly. No infant born to a woman who started dolutegravir during pregnancy had a neuraltube defect (n = 2,812).
Data analyzed to date from other sources including the APR, clinical trials, and postmarketingdata are insufficient to address the risk of neural tube defects with dolutegravir.
Lamivudine: Based on prospective reports to the APR of over 12,000 exposures tolamivudine during pregnancy resulting in live births (including over 5,000 exposed in the firsttrimester), there was no difference between the overall risk of birth defects for lamivudinecompared with the background birth defe |
