Lead author: Geoffrey A. Weinberg, MD, with the Medical Care Criteria Committee; May 2021
Potentially increased NTDs and DTG: NTDs are birth defects, including meningomyelocele and spina bifida, thought to occur early after conception during development of the embryonic neural tube. The neural tube closes by approximately 8 weeks gestational age, which is 8 weeks after the last menstrual period or approximately 6 weeks post-conception. Ingestion of folic acid or folate by a pregnant individual significantly lowers the rate of NTDs; all individuals in the United States who are pregnant or trying to conceive and engaged in prenatal care are routinely administered 400 µg of folic acid daily. The background rate of NTDs in the general population in the United States and other countries that routinely fortify food with folate or folic acid is low: approximately 0.07% of all births (7/10,000 births) [Reefhuis, et al. 2020].
In 2018, an unplanned interim analysis of a large observational clinical trial conducted in Botswana, a country where food is not routinely fortified with folate or folic acid, was performed. The researchers found NTDs in 0.94% of 426 infants exposed at conception to maternal DTG-based antiretroviral therapy (ART) compared with 0.12% of 11,300 infants exposed to non–DTG-based ART. Importantly, however, as more data were collected, the rates of infant NTDs markedly declined [Antiretroviral Pregnancy Registry Steering Committee 2022; DHHS 2022; Zash 2020; Zash, et al. 2019; Zash, et al. 2018]. The latest available data, through April 2020, now show that the rate of infant NTDs with maternal DTG-based ART use at conception is not any greater than it is in infants exposed to non–DTG-based ART at conception: 0.19% [Antiretroviral Pregnancy Registry Steering Committee 2022; DHHS 2022; Zash 2020]. No increases have been found in the registry data or through pharmacovigilance database studies from Europe and the United States [van De Ven, et al. 2020; Vannappagari and Thorne 2019]. Nor have any differences been found in the rates of NTDs among infants in a randomized controlled open-label phase 3 trial of DTG-based versus EFV-based ART in pregnant individuals, though the median gestational age at enrollment in this trial was 22 weeks, and all enrollees were at 14 weeks or more gestational age at enrollment [Lockman, et al. 2021].
Benefits of DTG: There are many known benefits of DTG as a component of ART for all adults, pregnant or not, and many children. DTG is potent, rapidly reduces viral load, has a high barrier to HIV genetic resistance, and is generally well-tolerated. Moreover, folate deficiency is uncommon in countries such as the United States. Thus, both the U.S. Department of Health and Human Services and the World Health Organization consider DTG a preferred ARV drug for individuals with HIV in all trimesters of pregnancy, and those with HIV who are trying to conceive. If an alternative ART regimen that does not include DTG is the best choice, alternatives to DTG during pregnancy include raltegravir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir (see the NYSDOH AI guideline Selecting an Initial ART Regimen > Specific Factors to Consider and Discuss With Patients). No data currently exist to support the use of bictegravir during pregnancy or the period surrounding conception. Further, cobicistat-boosted regimens containing elvitegravir, darunavir, or atazanavir are not recommended due to reduced levels of the integrase inhibitors given with cobicistat during pregnancy.
Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry Interim Report for 1 January 1989 – 31 July 2022. 2022 Dec 19. http://apregistry.com/forms/exec-summary.pdf [accessed 2021 Apr 19]
DHHS. Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States. 2022 Mar 17. https://clinicalinfo.hiv.gov/en/guidelines/perinatal/whats-new-guidelines [accessed 2021 Apr 19]
Lockman S, Brummel SS, Ziemba L, et al. Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet 2021;397(10281):1276-1292. [PMID: 33812487]
Reefhuis J, FitzHarris LF, Gray KM, et al. Neural tube defects in pregnancies among women with diagnosed HIV infection – 15 jurisdictions, 2013-2017. MMWR Morb Mortal Wkly Rep 2020;69(1):1-5. [PMID: 31917782]
van De Ven NS, Pozniak AL, Levi JA, et al. Analysis of pharmacovigilance databases for dolutegravir safety in pregnancy. Clin Infect Dis 2020;70(12):2599-2606. [PMID: 31595301]
Vannappagari V, Thorne C. Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir. J Acquir Immune Defic Syndr 2019;81(4):371-378. [PMID: 30939532]
Zash R. Update on neural tube defects with antiretroviral exposure in the Tsepamo study, Botswana. IAC; 2020 Jul 6-10; Virtual. https://www.natap.org/2020/IAC/IAC_112.htm
Zash R, Holmes L, Diseko M, et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. N Engl J Med 2019;381(9):827-840. [PMID: 31329379]
Zash R, Makhema J, Shapiro RL. Neural-tube defects with dolutegravir treatment from the time of conception. N Engl J Med 2018;379(10):979-981. [PMID: 30037297]