The following section is included in detail to highlight the changing safety status of newly introduced antiretroviral drugs and how ART guidelines will reflect the currently available data as more women and infants are exposed in pregnancy.

Dolutegravir

Botswana embarked upon a birth outcome surveillance programme in 2014. In 2018, the Tsepamo Study in Botswana reported a potential safety issue with 4 neural tube defects (NTDs) being detected out of 426 pregnancies with dolutegravir exposure at the time of conception (incidence of 0.9% with a background rate of 0.1%). When dolutegravir was commenced during pregnancy, no NTD were detected in 2,824 pregnancies.

The US guidelines were quick to respond, initially recommending that dolutegravir not be used in pregnant women during the first trimester and in non-pregnant women trying to conceive due to concerns about a possible increased risk of NTDs (AIII). Previously it was recommended that pregnant women currently prescribed dolutegravir who present for care during the first trimester, be provided counselling regarding the risks and benefits of continuing dolutegravir or switching to another regimen.

Subsequent reports in 2018 from the APR relating to 246 live births and from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) registry relating to 81 live births showed no CNS defects in either registry. The APR has reported one NTD being observed among the 834 integrase inhibitor periconception exposures through to 31 January 2019, including 1 bictegravir, 289 dolutegravir, 243 elvitegravir, and 310 raltegravir periconception exposures. In Brazil, the world’s second largest surveillance cohort, 1,468 women were identified over the period Jan 2015-Mar 2018: 382 were exposed to dolutegravir, 78 to raltegravir and 1086 to efavirenz. No NTD were detected.

Combined with the Tsepamo data, there are now >14,000 births among women on dolutegravir at conception with 14 NTDs identified, giving a weighted NTD prevalence of 0.098%, which is not significantly different than nondolutegravir regimens at conception or women without HIV infection in either country. These data do not support an association of NTD and dolutegravir. There is a background risk of NTDs (0.05% to 0.1% for women not HIV-infected) regardless of ART regimen.

Dolutegravir is now a recommended integrase inhibitor in the guidelines. However, note that recent research has suggested that dolutegravir interferes with the binding of folate to its receptor. The availability of adequate folic acid supplements and folic acid fortified foods in pregnancy is essential.

Efavirenz

Efavirenz has long been classified as a Category D drug in pregnancy (for definitions of Australian categorisation system for prescribing medicines in pregnancy, see https://www.tga.gov.au/australian-categorisation-system-prescribing-medicines-pregnancy) following the initial reports of teratogenicity in the preclinical primate data and retrospective reports of an increased risk of neural tube defects in humans. However, a recent meta-analysis of 1437 women in 19 studies with first trimester efavirenz exposure found no increased risk of birth defects and only one neural tube defect (incidence: 0.07%).^[38]

Current British HIV Association guidelines and DHHS guidelines recommend that effective efavirenz-based ART be continued in a pregnant woman presenting in the first trimester. Pregnancy recognition often occurs after the critical time of organogenesis and the development and closure of the neural tube is usually complete by 28 days post-conception. Therefore, in theory, changes to efavirenz-based regimens after 4 weeks post-conception will not significantly reduce the risk of neural tube defects and after 8 weeks will have minimal effect on the risk for other structural defects.

Atazanavir

Atazanavir is associated with an increase in serum levels of bilirubin in the mother, which in theory might increase the risk of hyperbilirubinaemia-related disease in the neonate.

However, a number of studies have shown no pathologic clinical maternal or foetal effects to date. ^[39]

Tenofovir

There have been some concerns in the past regarding bone and growth abnormalities in infants exposed to tenofovir in utero.  However, the duration of treatment and clinical significance of any study findings thus far do not preclude the use of tenofovir in pregnancy.

Cabotegravir + Rilpivirine (Cabenuva)

Data are not currently available about the efficacy and safety of injectable cabotegravir (CAB) and rilpivirine (RPV) during pregnancy. Not recommended due to concerns regarding potential inferior virologic efficacy and low drug levels with risk of viral rebound. For those who are considering switching regimens prior to conception to prevent foetal exposure, it is recommended that the injections must be stopped at least one year before conception to ensure that these long-acting drugs are fully eliminated.

For women on long-acting injectable antiretroviral therapy who have a history of poor adherence to oral medications, switching from long-acting injectable CAB and RPV to oral ART to prepare for conception may be associated with increased risk of viral rebound and NNRTI resistance. Shared decision-making should be used when making decisions about changing to an oral regimen.