Safety and dosing of antiretroviral medications in pregnancy

INTRODUCTION — Decisions regarding antiretroviral therapy (ART) in the pregnant person with human immunodeficiency virus (HIV) are complex. In addition to the typical considerations of virologic potency, side effects, and formulation, clinicians need to also take into consideration other factors, such as possible changes in pharmacokinetics due to physiologic changes occurring during the course of pregnancy, potential toxicities that may be magnified during pregnancy, and potential toxicity to the fetus and child.

This topic will address the clinical data on the safety and pharmacology of the more commonly used antiretroviral medications during pregnancy. Antiretrovirals that are not commonly used or used only in limited situations are not discussed in this topic.

Guidelines for ART of pregnant persons with HIV in the United States are developed by the Panel on Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States; these guidelines include detailed information on the safety and pharmacokinetics of antiretroviral drugs in pregnancy [1]. Guidelines for ART of pregnant women residing in resource-limited settings, where antiretroviral drug access may be more limited and preferred drug choices may differ, are developed by the World Health Organization (WHO) and may differ from recommendations in the United States; WHO guideline updates can be found on its website.

Antiretroviral selection and other management issues for the pregnant woman with HIV are discussed in detail elsewhere. (See "Prenatal evaluation of women with HIV in resource-rich settings" and "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings" and "Intrapartum and postpartum management of pregnant women with HIV and infant prophylaxis in resource-rich settings" and "Prevention of vertical HIV transmission in resource-limited settings".)

GENERAL PRINCIPLES — Antiretroviral therapy (ART) is recommended for all individuals with HIV, including pregnant persons, regardless of immune, clinical, or viral status [1]. ART reduces HIV-related morbidity and mortality, even in individuals with high CD4 cell counts [2,3] and has greatly decreased vertical HIV transmission over the years [4]

In pregnant persons, antiretroviral regimen selection should take into account the resistance profile of the virus, the safety and efficacy of the drugs in the mother and fetus, the convenience and adherence potential of the regimen, the potential for drug interactions with other medications, and pharmacokinetic data in pregnancy. Generally, pregnant persons can receive the same regimens recommended for treatment of nonpregnant adults when data are sufficient to determine whether drug exposure during pregnancy is adequate. On the other hand, some newer drug regimens recommended as preferred agents for nonpregnant adults have only limited data or have not yet been studied in pregnancy and are not generally recommended for pregnant people first initiating ART during pregnancy. However, many pregnant persons are already receiving ART when they become pregnant. Regimens with limited pregnancy data may generally be continued in treatment-experienced pregnant persons who have virologic suppression; more frequent viral load testing (eg, every one to two months during pregnancy) is recommended to confirm continued virologic suppression. Preferred antiretroviral agents in pregnancy and regimen selection for pregnant persons are discussed in detail elsewhere. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings" and "Prevention of vertical HIV transmission in resource-limited settings".)

The benefits of ART outweigh the risk of adverse effects to the pregnant person and their infant. The short-term and long-term data are reassuring and support the treatment of HIV throughout pregnancy. While no long-term effects of in utero exposure have been attributed to a specific antiretroviral drug, clinicians should remain vigilant, particularly as new agents are introduced. It is possible that in utero exposure to antiretroviral agents could have delayed effects, as were ultimately identified with diethylstilbestrol. Information on in utero antiretroviral exposure should be maintained in a child's medical record in case problems that could be long-term complications are identified in the future.

Clinicians are encouraged to contact the Antiretroviral Pregnancy Registry to prospectively report antiretroviral exposures in pregnancy to assist in monitoring pregnancy outcomes of pregnant persons exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com). The registry is a collaborative project of pharmaceutical manufacturers with an advisory committee of obstetric and pediatric practitioners. The registry is anonymous. Information is compiled from case reports and updated every six months for public review.

PREGNANCY OUTCOMES WITH COMBINATION ART EXPOSURE — Overall, the known benefits of combination antiretroviral therapy (ART) for pregnant persons far outweigh the known and potential risks (see "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings", section on 'Rationale for maternal ART'). However, clinicians should be aware of and discuss with patients the potential risk for adverse pregnancy outcomes with HIV infection and ART. Some, but not all, studies have suggested a small increase in the risk for preterm birth, pregnancy loss, and impaired fetal growth. Of note, untreated maternal HIV infection itself has been associated with adverse pregnancy outcomes [5,6]. Studies on teratogenicity of specific antiretroviral agents have been overall reassuring but cannot rule out small increased risk in rare defects. For all these outcomes, further longitudinal data are warranted to clarify the risk, particularly as new antiretroviral agents are approved for treatment.

Fetal growth — It is difficult to determine the effect of ART on fetal growth since most of the available data evaluated older ART regimens that are rarely used now in clinical practice. Studies evaluating the risk of combination antiretroviral agents during pregnancy on poor fetal growth and low birth weight have demonstrated conflicting results [7-15]. Similarly, studies evaluating maternal estradiol and progesterone levels, which can impact fetal growth and birth weight, and their association with antiretroviral agents have been conflicting. Two studies have reported an increase in estradiol in pregnant persons receiving protease inhibitor-based therapy [16,17]. One of these studies reported a differential impact of drug class, with an increase of estradiol with lopinavir-ritonavir and a decrease with efavirenz-based therapy, and no effect on progesterone [16]. Other studies have reported decreased progesterone levels in females receiving protease inhibitor-based therapy [18,19]. Nevertheless, whether poor growth is due more to underlying maternal characteristics or to the medications themselves, regular monitoring of fetal growth is important in pregnant persons with HIV. While some experts would rely on appropriate growth of uterine fundal height, others recommend ultrasound assessment in the third trimester to ensure adequate fetal growth. (See "Prenatal evaluation of women with HIV in resource-rich settings", section on 'Prenatal fetal monitoring' and "Fetal growth restriction: Screening and diagnosis".)

Studies of fetal growth effects associated with specific agents are discussed below.

Preterm birth — There may be an increased risk of preterm delivery prior to 37 weeks gestation with combination antiretroviral regimens, particularly with those that contain protease inhibitors. Data from prospective cohort studies are conflicting, while a large randomized trial conducted in resource-limited settings did find an increased risk [5,20-32]. Even in those studies that demonstrate an increased risk with protease inhibitors, the increases are modest, and the effects on infant morbidity and mortality are unknown. Thus, given the clear benefits to maternal health and a reduction in perinatal transmission of HIV, certain protease inhibitors remain preferred antiretroviral agents for pregnant persons with HIV in resource-rich settings. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings", section on 'Approach by patient population'.)

In a trial comparing a protease inhibitor-containing combination ART regimen with a triple-nucleoside regimen, preterm (<37 weeks) births were more frequent among those in the protease inhibitor group (24 versus 11 percent) [22]. However, there were no differences in infant hospitalizations or mortality rates through six months of age. In another randomized trial (PROMISE trial) conducted in resource-limited settings that compared two protease inhibitor-containing combination ART regimens (lopinavir-ritonavir plus either zidovudine-lamivudine [zidovudine-ART arm] or tenofovir-emtricitabine [tenofovir-ART] arm) with zidovudine plus single-dose nevirapine (zidovudine-alone arm) among nearly 3500 pregnant women with HIV and CD4 cell counts >350 cells/microL [29], rates of preterm birth <37 weeks of gestation were higher with the two protease inhibitor-containing combination ART regimens compared with zidovudine-alone group. However, the rates of very preterm birth at <34 weeks and neonatal deaths, most of which occurred in very preterm infants, were not statistically higher with each of the combination ART regimens compared with zidovudine alone. Meta-analyses of observational studies have shown similar results [20,33].

Lower rates of preterm births have been observed with the dolutegravir-tenofovir alafenamide (TAF) drug combination compared with efavirenz-based ART. In the VESTED/IMPACT 2010 study that randomized 643 ART-naïve pregnant persons to three different ART arms (dolutegravir-tenofovir disoproxil fumarate [TDF]-emtricitabine; dolutegravir-TAF-emtricitabine; or efavirenz-TDF-emtricitabine), preterm birth rates were lower in the dolutegravir-TAF arm compared with the efavirenz arm (6 versus 12 percent, -6.3 percent difference; 95% CI -11.8 to -0.9) [34]. Observational studies showed similar findings [32].

Studies of preterm birth associated with specific agents are discussed below.

Pregnancy loss — The impact of combination ART on the risk of pregnancy loss is uncertain and more difficult to study, as pregnancy losses may not be reported as reliably as premature birth. Some studies suggest a possible increased risk with ART exposure at conception, but certain limitations reduce confidence in the findings.

In an observational study from Botswana, the rate of still birth among persons with HIV infection who had started various ART regimens prior to conception was 1.4-fold higher than among those without HIV infection (3.4 versus 2.1 percent) [15].

In a post-hoc analysis of a trial of females with CD4 cell counts >400 cells/microL, rates of spontaneous abortion and stillbirth were higher (23.6 versus 11.9 percent, relative risk 2.0, 95% CI 1.1-3.5) among those who had been randomly assigned to continue ART following an earlier pregnancy (and thus were more likely to have been on ART at the time of conception of the index pregnancy) than among those assigned to discontinue ART following an earlier pregnancy (and thus were more likely not to have been on ART at the time of conception) [35]. However, approximately 10 percent of participants in the continue ART arm were not taking ART at conception, and 13 percent in the discontinue ART arm were taking ART at conception, and in the as-treated analysis, the association between ART at conception and pregnancy loss was of a lower magnitude and no longer statistically significant.

In contrast, in the United States Women's Interagency HIV study, among females living with HIV, lower rates of miscarriage (spontaneous loss of pregnancy at <29 weeks gestation) were associated with low viral load (which likely reflects ART use; adjusted odds ratio [OR] 0.45, 95% CI 0.24-0.84) and use of protease inhibitor therapy compared with non-use of combination ART (adjusted OR 0.40, 95% CI 0.21-0.79) [36]. Although the proportion of females living with HIV who experienced a miscarriage (37 percent) was higher than the general population (10 to 20 percent of United States females), the rate of miscarriage was similar compared with females without HIV with similar socioeconomic status (39 percent).

Teratogenicity — As of the end of July 2023, the prevalence of congenital anomalies reported to the Antiretroviral Pregnancy Registry among infants born to individuals with exposure to any antiretroviral agent during pregnancy was 643 congenital anomalies out of 22,017 live births, or 2.9 percent [37]. The prevalence was not different between persons with first trimester exposure and those with initial antiretroviral exposure after the first trimester. These congenital anomalies rates are comparable to the prevalence of congenital anomalies reported in the United States (2.72 percent, according to surveillance by the Centers for Disease Control and Prevention [CDC]). Other studies have suggested that overall, first-trimester antiretroviral exposure is not associated with an increased risk of congenital anomalies [38,39]. Data on specific antiretroviral exposures are discussed in the sections dedicated to specific agents below, although data are limited for many of the newer antiretroviral drugs.

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Class effects

Mitochondrial toxicity — Mitochondrial toxicity is an adverse effect of nucleoside reverse transcriptase inhibitor (NRTI) treatment and can lead to myopathy, peripheral neuropathy, and hepatic steatosis with lactic acidosis, the last of which may have a female preponderance and can be life-threatening [40,41]. Mitochondrial toxicity is a consequence of NRTI binding to mitochondrial deoxyribonucleic acid (DNA) polymerase gamma, which leads to mitochondrial DNA depletion and dysfunction. The various NRTI agents inhibit mitochondrial DNA polymerase gamma to varying degrees in vitro.

The greatest inhibition of mitochondrial DNA polymerase gamma among commonly used NRTIs is with zidovudine. Tenofovir (either disoproxil fumarate or alafenamide), emtricitabine, lamivudine, and abacavir inhibit the mitochondrial enzyme to a much lesser extent. Although clinicians should be vigilant for symptoms of mitochondrial toxicity in pregnant persons taking NRTIs, mitochondrial toxicity is much less of a concern with the newer ART regimens. Mitochondrial toxicity symptoms overlap with commonly associated symptoms of pregnancy (eg, nausea, vomiting, abdominal bloating, fatigue). The hepatic lactic acidosis syndrome has similarities to the rare, but life-threatening, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), which occurs in association with fatty liver during the third trimester. (See "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)

There is also the risk of mitochondrial toxicity among infants whose mothers used NRTIs during pregnancy. Hematologic abnormalities consistent with mitochondrial depletion (eg, anemia and neutropenia) have been reported in studies of infants with in utero NRTI exposure from both the United States and Europe [42-44]. Additionally, mitochondrial dysfunction should be considered as a potential etiology of neurologic abnormalities in children with past ART exposure, although the association is still not well defined [45-53].

Malignancy risk — Research to date has been reassuring regarding the risk of malignancy among HIV-exposed uninfected children with perinatal antiretroviral drug exposure, although the lack of a formal tracking registry for long-term complications, including malignancy, makes detection of true risk difficult.

Studies from the United States and United Kingdom, with median follow-up ranging between 14.5 months to 4.2 years, reported no cases of malignancy among children with antiretroviral exposure (mostly exposure to zidovudine) [54-56]. Additionally, in studies of French children exposed to nucleoside reverse transcriptase inhibitors in utero, the overall incidence of cancer did not differ significantly from that of the general population (21 cases observed among over 15,000 children) [57,58].

In another study of 3087 HIV-exposed but uninfected children followed in New Jersey for a median of 9.8 years, there were four diagnoses of cancer; cancer incidence among HIV-exposed children without perinatal antiretroviral exposure did not differ significantly from that among HIV-exposed children with perinatal exposure (22.5 versus 14.3 per 100,000 person-years) [59]. Additionally, the number of cases in children with perinatal antiretroviral exposure did not significantly differ from the number of cases expected based on state and national reference rates for children aged <19 years.

Abacavir — Abacavir is a preferred NRTI for use in pregnancy in the United States [1].

●Fetal safety – Short-term data on the use of abacavir in pregnancy do not suggest major concerns about fetal safety [31,37]. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to abacavir are available to exclude a 1.5-fold increase in risk of overall congenital anomalies and a twofold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary systems; the prevalence of congenital anomalies reported to the registry was 3.2 percent [37].

In a separate analysis of data from the Antiretroviral Pregnancy Registry, there was no excess risk of spontaneous abortions, stillbirths, preterm births, and low birth weight with in utero exposure to an abacavir-containing antiretroviral regimen compared with other regimens [60].

●Maternal safety – Serious hypersensitivity reactions have been associated with abacavir therapy in nonpregnant adults and have rarely been fatal; symptoms include fever, skin rash, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain. Abacavir should only be used in individuals, pregnant or otherwise, with a negative HLA-B*5701 test and without a history of a possible abacavir hypersensitivity reaction. (See "Abacavir hypersensitivity reaction".)

●Dosing – No dose adjustments are warranted for abacavir during pregnancy [61,62]. In a pharmacokinetic study of 25 females with HIV, pregnancy did not affect abacavir exposure during the third trimester or at 6 to 12 weeks postpartum [61].

Emtricitabine — Emtricitabine is a preferred NRTI for use in pregnancy in the United States as well as in other resource-rich and resource-limited settings [1,63].

●Fetal safety – Short-term data on the use of emtricitabine in pregnancy do not suggest major concerns about fetal safety. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to emtricitabine are available to exclude a 1.5-fold or more increase in overall congenital anomalies and a twofold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary systems; the prevalence of congenital anomalies reported to the registry was 2.9 percent [37]. Data from animal studies have also shown no evidence of teratogenicity.

●Dosing – No dose adjustments are warranted for emtricitabine during pregnancy. In a study of 31 patients who received emtricitabine, the pharmacokinetic exposure to emtricitabine was approximately 25 percent lower during the third trimester of pregnancy compared with the post-partum period [64]. However, this was not associated with virologic failure or perinatal transmission of HIV.

Lamivudine — Lamivudine is a preferred NRTI for use in pregnancy in the United States as well as in other resource-rich and resource-limited settings [1,63].

●Fetal safety – Short-term data on the use of lamivudine in pregnancy do not suggest major concerns about fetal safety. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to lamivudine are available to exclude a 1.5-fold or more increase in overall congenital anomalies and a twofold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary systems; the prevalence of congenital anomalies in the registry was 3.1 percent [37].

●Dosing – No dose adjustments are warranted for lamivudine during pregnancy. In a pharmacokinetic study of 114 pregnant and 47 nonpregnant females on long-term antiretroviral therapy that included lamivudine, rate of clearance of lamivudine was 22 percent higher during pregnancy [65]. Accordingly, plasma lamivudine levels were lower in pregnant persons but comparable to levels historically observed in other nonpregnant adults.

Tenofovir

Tenofovir disoproxil fumarate — Tenofovir disoproxil fumarate (TDF) is a preferred NRTI for use in pregnancy in the United States, as well as in other resource-rich and resource-limited settings [1,63].

Very preterm birth/neonatal mortality — Although a previous trial has raised concern of a possible increased risk of very preterm birth and neonatal death with TDF exposure during pregnancy, more recent studies have demonstrated reassuring findings on birth outcomes. In the PROMISE study, there was an unexpectedly higher rate of very preterm delivery (<34 weeks) and neonatal death in the tenofovir-based ART group compared with the zidovudine-based ART group among women enrolled during the second part of the study. However, other explanations for these findings include the possibility of an unusually low neonatal mortality rate in the zidovudine-based ART group or that the adverse effects are specific to the combination therapy of TDF with lopinavir-ritonavir. More recent observational studies [15,66-68] and randomized trials [34] have not demonstrated the same associations as seen in the PROMISE trial. As an example, in a trial of 643 ART-naïve pregnant females randomized to three different ART regimen arms (dolutegravir-TDF-emtricitabine, dolutegravir-tenofovir alafenamide [TAF]-emtricitabine, or efavirenz-TDF-emtricitabine), although the rate of neonatal mortality was higher in the dolutegravir-TDF-emtricitabine group compared with the dolutegravir-TAF-emtricitabine group (2 versus 1 percent), the outcome barely met the cutoff for statistical significance. In an observational study of data from United States pregnancy cohorts, in utero exposure to TDF plus emtricitabine and lopinavir-ritonavir was associated with a similar rate of very preterm birth compared with zidovudine plus lamivudine and lopinavir-ritonavir (risk ratio 0.85, 95% CI 0.34-2.13), although the number of events was small [68].

Fetal growth and development — Short-term data on the effect of TDF during pregnancy on fetal growth and development are generally reassuring. Some but not all studies have suggested adverse effects on certain growth parameters and bone mineral density in early infancy, although the clinical and long-term significance of these findings are uncertain.

In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to TDF are available to exclude a 1.5-fold or more increase in overall congenital anomalies and a twofold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary systems; the prevalence of congenital anomalies reported was 2.5 percent [37]. TDF has not demonstrated teratogenicity in rodents, monkeys, or rhesus macaques [69].

Studies evaluating the fetal effects of intrauterine TDF exposure have also been overall reassuring [70-72]. In a systematic review of studies evaluating outcomes among pregnant or lactating persons with HIV (26 studies) and without HIV (7 studies) who received TDF, the drug appeared safe in pregnancy [70]. No statistically significant differences in most pregnancy, maternal, and infant adverse outcomes between TDF- and non-TDF-containing regimens were identified; these outcomes included pregnancy incidence, stillbirth or pregnancy loss, preterm delivery <37 week, low birth weight <2500 or <1500 grams, small for gestational age, congenital anomalies, and infant (>14 days) or maternal mortality. The impact of TDF-containing ART on very preterm delivery (<34 weeks) and neonatal mortality are discussed elsewhere. (See 'Very preterm birth/neonatal mortality' above.)

Most studies in the systematic review reported normal infant linear growth with TDF exposure. One reported slightly lower [73] and one reported higher [74] length-for-age z-scores at one year of age in TDF-exposed infants. Results from a large randomized trial also suggested no difference in longitudinal growth (height, weight, and head circumference) at 24 weeks of age between infants exposed to maternal TDF-based ART (with a protease inhibitor) during breastfeeding and those without TDF exposure (who had instead received infant nevirapine prophylaxis) [75]. In four studies, no differences in laboratory or bone marker abnormalities were reported [70]. However, in one study of infants born to mothers with HIV, those exposed to TDF in utero (n = 74) had lower bone mineral content, as measured by dual-energy X-ray absorptiometry (DXA) scan, compared to those with no TDF exposure (n = 69) [76], potentially consistent with a rhesus macaque study that found decreased fetal bone porosity with very high-dose TDF use [77]. However, in a subsequent randomized trial, non-TDF-containing ART regimens resulted in similarly lower bone mineral content, suggesting that ART in general, rather than TDF specifically, may be associated with a decrement in neonatal bone mineral content [78]. In a randomized trial of TDF to prevent mother-to-child hepatitis B virus (HBV) transmission, there was no significant effect of maternal TDF use compared with placebo on maternal or infant bone mineral density one year after delivery/birth [72]. Several longer-term studies of TDF-exposed infants of females with HIV followed through age 18 months in Vietnam and Malawi found that TDF use during pregnancy was not associated with bone radiologic of biomarker abnormalities, growth impairment, or renal dysfunction [79,80]. Similarly, long-term follow-up of children of mothers with HBV who did or did not receive TDF during late pregnancy found comparable long-term growth, renal function, and bone development up to six to seven years after delivery [81].

Maternal safety — The potential adverse effects of TDF have been well described in nonpregnant individuals with HIV and mainly include renal toxicity and modest bone density loss (see "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir disoproxil fumarate'). Similar results have been shown in pregnant persons, although the absolute difference in kidney function appears to be minimal. As an example, an analysis from the IMPAACT PROMISE study found that the mean maternal calculated creatinine clearance at delivery in the TDF-ART arm was lower than the zidovudine-ART arm but that the difference was not thought to be clinically significant [82]. There were no safety concerns with TDF-containing ART regimen for maternal or infant renal function. Similarly, in an African trial of breastfeeding females with HIV and CD4 counts >350 cells/microL, declines in spine and hip bone mineral density from 14 days to 74 weeks postpartum were greater among those who were randomly assigned to receive TDF-based ART (with a protease inhibitor) postpartum compared with those assigned to receive no ART (their infants received nevirapine instead) for postpartum prevention of transmission [83]. Whether this decline reverses after the cessation of breastfeeding merits further study.

Dosing — No dose adjustments are routinely recommended for TDF during pregnancy. However, because of moderate decreases in drug levels during the third trimester, special attention to virologic monitoring to ensure suppression should be conducted for females on a TDF-containing regimen. Several pharmacokinetic studies have demonstrated lower levels of TDF (area under the curve concentrations and/or trough levels) during the third trimester of pregnancy compared with postpartum or nonpregnant females [64,84,85]. However, decreases in TDF levels were not associated with virologic failure or perinatal transmission of HIV [64,85]. In one study, increased weight (>90 kg) was associated with TDF levels below target during pregnancy.

Tenofovir alafenamide — TAF is a preferred NRTI for use in pregnancy in the United States [1].

Data on the use of TAF during pregnancy are limited but accumulating. In a randomized trial that included 643 females with HIV who were initiating an antiretroviral regimen during pregnancy, those who received a TAF-containing dolutegravir-based regimen had a lower rate of preterm delivery (6 versus 9 percent), lower neonatal mortality (1 versus 2 percent), and fewer composite adverse pregnancy outcomes that included preterm delivery, small gestational age, stillbirth, and spontaneous abortion (24 versus 33 percent) compared with those who received an equivalent TDF-containing dolutegravir-based regimen [34]. Maternal weight gain was greater with TAF than TDF combined with dolutegravir (0.38 versus 0.32 kg per week), although weight gain with both was less than that recommended for the second/third trimester (0.42 kg per week). There was no detected difference in maternal or neonatal grade 3 or higher adverse events with TAF versus TDF combined with dolutegravir.

In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to TAF are available to exclude a twofold or more increase in overall congenital anomalies; the prevalence of congenital anomalies reported was 3.9 percent [37].

No dose adjustments are routinely recommended for TAF during pregnancy. In one study of 43 pregnant females given TAF with or without cobicistat, TAF levels were lower during the second and third trimesters compared with postpartum, but were comparable to levels in nonpregnant adults [86]. In another study of 20 pregnant European females, TAF plasma concentrations were reduced by about half during third trimester but remained above the threshold for adequate virologic activity [87].

Zidovudine — Zidovudine is an alternative NRTI for use in pregnancy in the United States [1]. It is still used in resource-limited settings, as part of second- and third-line regimens [63].

Fetal safety — Short-term data on the safety of zidovudine during pregnancy are generally reassuring.

There has been no evidence of an increased incidence of congenital abnormalities in infants born to females with antepartum zidovudine exposure over the general population [37,48,88,89]. The prevalence of congenital anomalies among infants with first trimester exposure to zidovudine in the Antiretroviral Pregnancy Registry was 3.2 percent , with sufficient data to rule out at least a 1.5-fold increase in risk of overall congenital anomalies and a twofold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary systems [37]. Other cohort studies in the United States and Europe have also not identified an association between first trimester zidovudine exposure and congenital anomalies [90,91].

However, data from the French Perinatal Cohort have suggested an association between first trimester in utero zidovudine exposure and congenital heart disease (predominantly ventricular septal defects [VSD]) [92,93]. Among 3262 infants with first trimester zidovudine exposure, the rate of congenital heart disease was 1.5 percent compared with 0.7 percent among 9626 infants without zidovudine exposure (adjusted OR 2.2, 95% CI 1.5-3.2) [92]. Most of the anomalies observed were minor. This was in contrast to the Antiretroviral Pregnancy Registry data, which included 67 reported cases of VSD among over 22,000 live births with any antiretroviral exposure, without an excess of cases associated with zidovudine exposure [37,94].

Studies evaluating other outcomes have also been reassuring [48,95,96]. After nearly six years of follow-up of infants of trial participants, immunologic, neurologic, and growth parameters were similar between children who had in utero zidovudine exposure and those who were exposed to placebo [48,95].

No evidence of teratogenicity or toxicity has been observed in animal models. However, in vitro and animal study evidence has suggested carcinogenic potential. The relevance of these data to humans is unknown. No tumors have been observed in 727 children with in utero zidovudine exposure followed for over 1100 person-years [54]. While these data are reassuring, follow-up is still limited and needs to be continued into adulthood before it can be concluded that there is no carcinogenic risk.

Dosing — No dose adjustments are warranted for zidovudine during pregnancy. The pharmacokinetics of zidovudine do not appear to be changed during pregnancy [97].

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Efavirenz — Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is an alternative agent for use in pregnancy in the United States as well as in other resource-rich and resource-poor settings [1,63].

Fetal safety — In early studies, rare reports of congenital anomalies in human case reports that were potentially consistent with malformations identified in animal studies had raised initial concerns about the potential for teratogenicity, but increasing data from clinical studies and reports of efavirenz use in pregnancy have been overall reassuring.

In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to efavirenz are available to exclude a 1.5-fold or more increase in congenital anomalies and a twofold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary systems; the prevalence of congenital anomalies reported was 2.3 percent [37]. Additionally, a meta-analysis of 21 studies evaluating outcomes of 2026 births with first trimester in utero efavirenz exposure, including the Antiretroviral Pregnancy Registry, did not find an increased relative risk of overall congenital anomalies comparing infants born to females receiving efavirenz-based versus non-efavirenz-based regimens (relative risk 0.78, 95% CI 0.56-1.08) [98]. Subsequent studies have also not suggested an increased risk of congenital anomalies with efavirenz exposure [38,93,99]. Although studies from two large pediatric acquired immunodeficiency syndrome (AIDS) cohorts (PACTG 219 and P1025) had reported an increased risk of congenital anomalies with first trimester efavirenz exposure compared with exposure to other antiretroviral drugs, no specific pattern congenital anomalies was observed, and there was overlap in reported anomalies between the two papers [100,101].

Data also demonstrate that periconception efavirenz exposure is not associated with neural tube defects. In primate studies, significant central nervous system (CNS) malformations (anencephaly and unilateral anophthalmia in one and microphthalmia in another) and a cleft palate were observed in 3 of 20 infant cynomolgus monkeys born to mothers who received efavirenz from gestational day 20 to 150 in doses comparable to systemic human therapeutic exposure [102]. The Antiretroviral Pregnancy Registry includes one neural tube defect (meningomyelocele) and one report of anophthalmia with severe facial clefts and amniotic banding out of 1196 first trimester exposures (giving a neural tube defect prevalence of 0.09 percent, compared with an overall prevalence of 0.06 percent in the United States) [103,104]. In a large observational study in Botswana, the prevalence of neural tube defects was 0.04 percent among 7959 infants with efavirenz exposure, similar to that among 90,000 females without HIV (0.08 percent) [105].

Two cohort studies have suggested that in utero efavirenz exposure may be associated with a higher incidence of microcephaly and lower scores on neurodevelopmental assessments among HIV-exposed children, although other studies have not reported this association [106-108]. The risk of preterm birth with efavirenz is discussed below. (See 'Maternal safety' below.)

Expert recommendations from the World Health Organization (WHO), United States, and United Kingdom do not restrict the use of efavirenz during pregnancy [1,63,109]. In many resource-limited settings, efavirenz is an alternative first-line regimen.

Selection of ART during pregnancy is discussed elsewhere. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings", section on 'ART selection and management'.)

Maternal safety — Important potential side effects with efavirenz include CNS toxicity, rash, hyperlipidemia, and elevated hepatic transaminases. However, data from randomized clinical trials suggest that the rate of adverse events with efavirenz-containing ART is similar to that with integrase inhibitor-based regimens.

As an example, in the IMPAACT 2010 VESTED trial of pregnant females starting ART at >14 weeks gestation, there was no difference in maternal or infant grade 3 or higher adverse events between efavirenz- and dolutegravir-based regimens (with either TDF or TAF) [34]. Preterm delivery was more common with efavirenz than dolutegravir-based regimens (12 percent versus 6 to 9 percent) in that trial. However, in the DolPHIN-2 trial of pregnant females starting ART at >28 weeks gestation, efavirenz was associated fewer reported serious adverse effects than dolutegravir (11 versus 22 percent), and the rate of preterm delivery was not statistically different between the two groups [110]. Finally, in a randomized clinical trial comparing initial therapy with efavirenz and raltegravir-based regimens in pregnant females starting ART at >20 weeks gestation, the rates of adverse events and preterm delivery were similar with the two regimens [111]. (See "Overview of antiretroviral agents used to treat HIV", section on 'Efavirenz'.)

Dosing — No dose adjustments are warranted for efavirenz during pregnancy. The pharmacokinetics of efavirenz during pregnancy do not appear to be significantly different from that in nonpregnant adults. In 25 pregnant females taking efavirenz as part of combination antiretroviral therapy (ART), the clearance of efavirenz was higher and the concentration at 24 hours was lower during the third trimester than several weeks postpartum [112]. However, the area under the curve remained similar at both time points and was comparable to that reported in nonpregnant adults.

Rilpivirine — Oral rilpivirine is an alternative NNRTI for use in pregnancy in the United States [1]. It is reserved for those with a viral load <100,000 copies/mL and a CD4 count ≥200 cells/microL.

Data on the use of oral rilpivirine during pregnancy are relatively limited. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to oral rilpivirine are available to exclude a twofold or more increase in congenital anomalies; the prevalence of congenital anomalies reported to the registry was 2.0 percent [37]. Studies in rats and rabbits have revealed no evidence of fetal harm at systemic exposures substantially higher than that achieved with the standard dose.

No dose adjustments are indicated for oral rilpivirine during pregnancy. In pharmacokinetic studies, oral rilpivirine levels were approximately 30 to 40 percent lower during pregnancy [113,114]. Nevertheless, exposure levels exceeded the target during pregnancy in most participants, and there was no loss of virologic suppression.

There are limited data on the pharmacokinetics and safety of injectable rilpivirine during pregnancy. Injectable rilpivirine is not recommended for initial therapy in antiretroviral-naïve pregnant persons although may be continued in those who are virally suppressed and become pregnant while on injectable rilpivirine therapy [1].

Nevirapine — Nevirapine is not recommended for ART in pregnant persons because of potential for maternal skin and liver toxicity [1,63]. A pregnant person who enters care on a nevirapine-containing regimen should be switched to a safer ART regimen, regardless of CD4 cell count.

Short-term data on the use of nevirapine in pregnancy do not suggest major concerns about fetal safety. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to nevirapine are available to exclude a 1.5-fold or more increase in congenital anomalies and a twofold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary systems; the prevalence of congenital anomalies reported to the registry was 3.1 percent [37]. Teratogenic effects have not been observed in reproductive studies with rats and rabbits.

The main toxicity concerns with nevirapine in general are a hypersensitivity reaction with severe skin rash and hepatotoxicity; the risk of these is higher with higher CD4 cell counts. Severe nevirapine-associated skin rash, hepatotoxicity, and liver failure have also been reported in pregnant persons [115-118], although pregnancy is not clearly associated with a higher risk for these reactions [119].

No dose adjustments are warranted for nevirapine during pregnancy. Pharmacokinetic data on chronic antenatal nevirapine dosing in pregnant persons during the third trimester have demonstrated that pharmacokinetic parameters in the pregnant person are similar to those in a nonpregnant adult [120]. Serum nevirapine elimination in the infants was accelerated compared to newborns whose mothers received only a single intrapartum dose.

Doravirine — Data on doravirine in pregnancy are extremely limited. Given the lack of data on pharmacokinetics and safety during pregnancy, this drug is not recommended for initial therapy, although may be continued in those who are virally suppressed and become pregnant while on doravirine therapy [1].

PROTEASE INHIBITORS

Class effects — There are several side effects that appear to be protease inhibitor class effects, whereas others are agent specific. Some of the class side effects are insulin resistance, hyperglycemia, diabetes, hyperlipidemia, lipodystrophy, hepatotoxicity, and side effects caused by interactions with other hepatically metabolized drugs.

Gestational diabetes — Although protease inhibitors are associated with insulin resistance and impaired glucose tolerance in general [121-123], most studies in pregnant persons do not indicate an increased rate of gestational diabetes with their use [124-127]. Pregnant persons with HIV who are on combination antiretroviral therapy should undergo glucose screening consistent with standard pregnancy recommendations. However, some experts consider protease inhibitor exposure a risk factor for glucose intolerance and, therefore, perform earlier testing for those maintained on protease inhibitor-containing regimens. (See "Gestational diabetes mellitus: Screening, diagnosis, and prevention", section on 'Procedures and laboratory issues'.)

Preterm birth — Although conflicting, several studies that have suggested a small increased risk of preterm birth with combination ART have implicated protease inhibitors. This is discussed elsewhere. (See 'Preterm birth' above.)

Darunavir — Ritonavir-boosted darunavir is a preferred protease inhibitor for use in treatment-naïve pregnant individuals who have had exposure to cabotegravir-based pre-exposure prophylaxis; for all other pregnant individuals, it is an alternative agent [1]. Darunavir boosted with cobicistat is not recommended for initial therapy in pregnancy.

Fetal safety — Limited data on the use of darunavir in pregnancy do not suggest major concerns about fetal safety. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to darunavir are available to exclude a twofold or more increase in overall congenital anomalies; the prevalence of congenital anomalies reported was 3.6 percent [37]. Infants in case reports of maternal darunavir use have described no congenital or major metabolic anomalies [128-130].

No embryotoxicity or teratogenicity has been seen in mice or rats at drug levels approximately 50 percent of that achieved in humans, nor in rabbits at drug levels 5 percent of that achieved in humans at the recommended therapeutic dose.

Dosing — Because of low trough levels with once-daily dosing in pregnancy, 600 mg/100 mg twice-daily dosing of darunavir, to be taken with food, is recommended during pregnancy [1]. In studies of darunavir-ritonavir administered as 600 mg/100 mg twice daily or 800 mg/100 mg once daily during pregnancy, darunavir levels were substantially reduced during the third trimester compared with postpartum, particularly with once-daily dosing [131-133]. However, one study noted that there was no clinically relevant decrease in levels of the active form of darunavir during pregnancy, and several case reports have described successful maternal viral suppression and prevention of transmission with typical twice-daily dosing [128-130].

Cobicistat-boosted darunavir is not recommended for initial therapy during pregnancy. (See 'Cobicistat' below.)

Atazanavir — Ritonavir-boosted atazanavir is an alternative protease inhibitor for use in pregnancy in the United States [1].

Fetal safety — Short-term data on the use of atazanavir in pregnancy do not suggest major concerns about fetal safety. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to atazanavir are available to exclude a 1.5-fold or more increase in overall congenital anomalies and a twofold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary systems; the prevalence of congenital anomalies reported to the registry was 2.5 percent [37]. One study of 2580 children born to mothers with HIV suggested an increased risk of congenital anomalies, predominantly musculoskeletal and skin anomalies, with first-trimester atazanavir exposure [38], but this finding has not been replicated. Atazanavir did not produce teratogenic effects in rabbits or rats at systemic drug exposure achieved in humans at the recommended therapeutic dose.

Elevation in indirect (unconjugated) bilirubin occurs frequently with atazanavir use in pregnant and nonpregnant adults and children. This is attributable to atazanavir-related inhibition of hepatic UDP glucuronyl transferase enzyme. There are few data as to whether atazanavir therapy would exacerbate physiologic hyperbilirubinemia in the neonate [134].

Dosing — Dosing increases of atazanavir to 400 mg daily, boosted with low-dose 100 mg ritonavir, may be warranted for some during pregnancy, particularly antiretroviral-experienced individuals. Although some experts recommend this increased atazanavir dosing in all persons during the second and third trimesters, use of the standard dose (300 mg atazanavir plus 100 mg ritonavir daily) with careful virologic monitoring during the second and third trimester can also be considered. The package insert recommends increased atazanavir dosing only for antiretroviral-experienced pregnant persons in the second and third trimesters also receiving either TDF or an H₂-receptor antagonist. Atazanavir should not be used in patients receiving both TDF and H₂ receptor antagonists.

Several studies have observed that the area under the plasma concentration-time curves (AUC) for atazanavir are lower in pregnant than nonpregnant females during use of atazanavir-ritonavir 300 mg/100 mg once daily, and in some studies, are lower than in the same female postpartum [134-137]. Nevertheless, most pregnant females in these studies can achieve an undetectable viral load by the time of delivery. Co-administration with TDF further lowers the AUC for atazanavir by 25 percent compared with postpartum levels in the same patient and by 50 percent compared with postpartum levels in those who did not receive TDF [136]. Use of an increased dose of atazanavir-ritonavir 400 mg/100 mg during pregnancy results in an AUC for atazanavir equivalent to historic nonpregnant females with HIV receiving standard-dose atazanavir [135,136]. Similarly, pregnant patients receiving the increased atazanavir dose with TDF had an AUC equivalent to that seen in nonpregnant patients with HIV receiving standard-dose atazanavir and TDF [138].

Lopinavir-ritonavir — Lopinavir-ritonavir is not recommended for use in pregnancy except in special circumstances [1,63].

Fetal safety — Short-term data on the use of lopinavir-ritonavir in pregnancy do not suggest major concerns about fetal safety. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to lopinavir-ritonavir are available to exclude a 1.5-fold or more increase in overall congenital anomalies and a twofold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary systems; the prevalence of congenital anomalies reported was 2.1 percent [37]. There is no evidence of teratogenicity with administration of lopinavir-ritonavir to pregnant rats or rabbits.

Dosing — Many experts increase lopinavir-ritonavir dosing to 600 mg/150 mg twice daily during the second and third trimesters to maintain adequate serum drug levels, particularly in protease-inhibitor-experienced patients, and then return to standard dosing (400 mg/100 mg twice daily) immediately postpartum [1]. If the standard doses are used during pregnancy, virologic response and, if available, lopinavir drug concentrations should be carefully monitored. Once-daily dosing, as studied in adults, is not recommended during pregnancy. Pharmacokinetic data demonstrate a reduction in lopinavir levels during the second half of pregnancy with administration of standard doses of lopinavir-ritonavir. We also avoid initiating lopinavir-ritonavir with tenofovir disoproxil fumarate (TDF) during pregnancy because of concerns for a potential increase in TDF levels with concomitant lopinavir-ritonavir. (See 'Very preterm birth/neonatal mortality' above.)

Several studies have suggested that lopinavir concentrations are decreased late in pregnancy compared with postpartum or levels in nonpregnant individuals [139,140]. Reports of clinical experience suggest that most, if not all, pregnant persons receiving standard lopinavir-ritonavir tablet dosing during pregnancy will have trough lopinavir levels that exceed 1.0 mcg/mL, which is the usual trough concentration recommended for monitoring antiretroviral-naïve subjects, but not the higher trough concentrations recommended for protease inhibitor-experienced patients [141,142]. A prospective study of 33 pregnant females with HIV evaluated the pharmacokinetics with the following dosing strategy: two lopinavir-ritonavir tablets (400 mg/100 mg) twice daily during the second trimester, three tablets (600 mg/150 mg) twice daily during the third trimester, and two tablets (400 mg/100 mg) twice daily post-delivery through two weeks postpartum [143]. Drug serum levels were stable throughout and comparable to those levels seen in nonpregnant adults taking standard dosing of lopinavir-ritonavir (eg, two tablets twice daily).

INTEGRASE INHIBITORS

Dolutegravir — Dolutegravir is a preferred integrase inhibitor for use in pregnancy in the United States [1] as well as in other resource-rich and resource-limited settings [1,63].

Fetal safety — Dolutegravir use at the time of conception is not associated with risk of neural tube defects compared with non-dolutegravir-based antiretroviral therapy (ART) [144,145]. Use of dolutegravir in nonpregnant women of childbearing potential is discussed elsewhere. (See "HIV and women", section on 'Individuals of childbearing potential'.)

In a report of an ongoing birth-outcomes surveillance study in Botswana (where folate supplementation is not routinely done) that included data through March 2022, neural tube defects were documented in 10 of 9460 infants (0.11 percent) born to mothers taking dolutegravir at conception compared with 25 of 23,664 infants (0.11 percent) born to mothers taking non-dolutegravir ART at conception; this difference was not statistically significant [144]. There were four neural tube defects among 6551 infants (0.06 percent) born to mothers who started dolutegravir during pregnancy and 108 among 170,723 infants (0.07 percent) born to mothers without HIV infection. The initial report from this study had previously suggested a higher risk of neural tube defects with dolutegravir use at the time of conception (observed in 4 of 426 infants, or 0.94 percent); the estimated magnitude of the risk markedly decreased after analysis of more exposures [146-148]. Another observational study from a different region of Botswana had documented one neural tube defect among 152 infants born to mothers taking dolutegravir at conception compared with none among 381 infants born to mothers taking non-dolutegravir ART at conception, but these numbers are too small to make an accurate risk assessment [149]. In a birth-outcomes surveillance study in Eswatini, the prevalence of neural tube defects among 4902 pregnant persons receiving dolutegravir at conception was the same as in 17,285 pregnant persons without HIV (0.08 percent in both groups) [145].

Other observational studies had suggested that rates of stillbirth, neonatal death, small for gestational age, and preterm birth with dolutegravir-based regimens (started before or during pregnancy) are comparable with other antiretroviral regimens in females with HIV [105,150-152]. As an example, in an observational study of over 1000 pregnant females on ART during pregnancy, there was no difference in adverse birth outcomes (preterm birth, low birth weight, small gestational age) between patients who received dolutegravir during pregnancy compared with those who received other antiretrovirals [152].

In the Antiretroviral Pregnancy Registry prospective reports of pregnancy outcomes, the calculated rate of overall congenital anomalies after first-trimester dolutegravir exposure was 3.3 percent; one neural tube defect has been reported in 957 preconception dolutegravir exposures as of July 2023 in the Antiretroviral Pregnancy Registry [37].

Dosing — No dose adjustments are indicated for dolutegravir during pregnancy [153,154]. Third trimester and postpartum dolutegravir pharmacokinetics were evaluated in the context of a randomized trial comparing dolutegravir versus efavirenz-based ART among 60 Ugandan and South African ART-naïve females with HIV [153]. Dolutegravir exposures were lower in the third trimester and postpartum period than those previously reported in nonpregnant individuals; however, only one had dolutegravir levels below the protein-adjusted IC90.

Dolutegravir should not be administered within two hours of iron- or calcium-containing preparations, including prenatal vitamins.

Raltegravir — Raltegravir is an alternative integrase inhibitor for use in pregnancy in the United States [1].

Maternal safety — In a randomized clinical trial (NICHD P1081) comparing raltegravir and efavirenz-based regimens in pregnant persons starting ART at >20 weeks gestation, raltegravir was associated with a more rapid decline in viral load than efavirenz; rates of grade 3 or higher maternal adverse events, preterm delivery, and other adverse pregnancy outcomes were similar with the two regimens [111].

Fetal safety — Short-term data on the use of raltegravir in pregnancy do not suggest major concerns about fetal safety. In a randomized trial of pregnant persons starting ART at >20 weeks gestation (NICHD P1081), the rates of grade 3 or higher adverse events among infants born to mothers receiving raltegravir versus efavirenz were similar; the frequency of congenital anomalies was low and similar with the two regimens, and no neural tube defects were observed [111]. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to raltegravir are available to exclude a twofold or more increase in overall congenital anomalies; the prevalence of congenital anomalies reported was 3.8 percent [37]. Extranumerary ribs were found in rats at dose exposure threefold higher than human.

In an industry-sponsored review of individuals in resource-rich settings who used raltegravir during pregnancy, there were no neural tube defects documented among the 1991 prospectively reported pregnancies (including 456 with raltegravir use at the time of conception) [155]. While reassuring, the number of periconception exposures is insufficient to determine a lack of association with neural tube defects. Among the 435 pregnancies that were retrospectively reported, there were three neural tube defects, one of which occurred with raltegravir exposure at the time of conception.

Dosing — Raltegravir should only be dosed twice daily in pregnancy; otherwise, no dose adjustments are warranted. In studies of pregnant females who received the standard dose of 400 mg twice daily as part of their antiretroviral regimen, there was great interindividual variability in serum levels but no clinically significant reductions in third trimester concentrations compared with postpartum [156,157]. Raltegravir should not be administered within two hours of iron or calcium containing preparations, including prenatal vitamins.

Elvitegravir — Elvitegravir (combined with cobicistat) is not recommended for initiation in pregnancy until more data are available [1]. In a pharmacokinetic study of 30 females taking an elvitegravir-cobicistat-containing regimen during pregnancy, the elvitegravir area under the curve was reduced by 24 and 44 percent in the second and third trimesters, respectively, compared with postpartum levels, and trough levels were 81 and 89 percent lower in the second and third trimesters; viral suppression at delivery was observed in 76 percent [158]. These data raise concern that subtherapeutic drug levels may occur among some persons receiving elvitegravir during pregnancy, with viral rebound leading to potential increased risk of perinatal transmission. A subsequent retrospective study of 134 pregnant females on an elvitegravir-cobicistat-containing regimen reported rates of viral suppression of 81 percent at delivery overall and 88 percent of those who began elvitegravir prior to conception, with perinatal transmission observed in one of 134 infants (0.8 percent) [159]. Additional data are needed to confirm the efficacy of elvitegravir-cobicistat during pregnancy before recommending its use.

In the retrospective study mentioned above, there were no cases of neural tube defects among the 82 females who were taking elvitegravir at the time of conception; however, the number of periconception exposures is insufficient to determine a lack of association with neural tube defects [159]. In the Antiretroviral Pregnancy Registry, sufficient data on first-trimester exposures to elvitegravir are available to exclude a twofold or more increase in overall congenital anomalies; the prevalence of congenital anomalies reported was 2.9 percent [37]. Studies in animals that have received elvitegravir have not demonstrated evidence of teratogenicity.

Bictegravir — Data on bictegravir in pregnancy are limited. The drug is an alternative for initial therapy in antiretroviral-naïve pregnant persons and can be continued in those who are virally suppressed and become pregnant while on bictegravir therapy [160]. No safety concerns have been observed. As of July 2023, there were 423 first-trimester exposures to bictegravir in the Antiretroviral Pregnancy Registry, which can exclude a twofold or more increase in overall congenital anomalies; the prevalence of congenital anomalies reported was 4.3 percent [37].

The pharmacokinetics of bictegravir during pregnancy do not appear to be significantly different from that in nonpregnant adults. In an open-label, single-arm study of 32 pregnant women with HIV who switched to bictegravir plus TAF/FTC during pregnancy, mean trough concentrations of bictegravir remained higher than the 95 percent effective concentration [161]. None of the women developed virologic failure and there were no perinatal transmissions.

Cabotegravir — Data on cabotegravir in pregnancy are extremely limited. In an analysis of 25 pregnant women who were taking long-acting cabotegravir and rilpivirine by injection at conception, there were six miscarriages, eight elective abortions, one ectopic pregnancy, and ten live births. One of the infants born had congenital ptosis [162]. Given the lack of data on pharmacokinetics and safety during pregnancy, this drug is not recommended for initial therapy although may be continued in those who are virally suppressed and become pregnant while on therapy [1].

PHARMACOLOGIC BOOSTERS

Ritonavir — Short-term data on the use of ritonavir in pregnancy do not suggest major concerns about fetal safety. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to ritonavir are available to exclude a 1.5-fold or more increase in congenital anomalies and a twofold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary systems; the prevalence of congenital anomalies reported was 2.5 percent [37].

Cobicistat — Cobicistat is not recommended for initiation in pregnancy until more data are available [1]. Emerging data have suggested that second- and third-trimester levels of elvitegravir-cobicistat are reduced by approximately 50 percent and are associated with loss of virologic suppression at the time of delivery [158]. Similar decreases in second- and third-trimester drug levels and associated virologic failure were observed with darunavir-cobicistat [163].

Studies in animals that have received cobicistat have not demonstrated evidence of teratogenicity. In the Antiretroviral Pregnancy Registry, sufficient data on first trimester exposures to cobicistat are available to exclude a twofold or more increase in congenital anomalies; the prevalence of congenital anomalies reported was 3.4 percent [37].

OTHER AGENTS — Antiretrovirals that are not commonly used or used only in limited situations are not discussed in this topic. Detailed information on the safety and pharmacokinetics of these antiretrovirals can be found in the United States Department of Health and Human Services guidelines on reducing perinatal HIV transmission [1].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV treatment in pregnant patients".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here is the patient education article that is relevant to this topic. We encourage you to print or e-mail this topic to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: HIV and pregnancy (Beyond the Basics)")

SUMMARY

●General principles − Antiretroviral therapy (ART) is recommended for all people with HIV, including those who are pregnant. An additional goal is to decrease the risk of perinatal transmission of HIV infection. Overall, the known benefits of combination ART for pregnant persons far outweigh the known and potential risks. Nevertheless, decisions regarding the optimal ART regimen for pregnant persons need to take into consideration changes in pharmacokinetics during pregnancy and potential toxicities to the mother and fetus. (See 'Introduction' above and 'General principles' above.)

●Pregnancy outcomes with combination ART exposure − Long-term data on the safety of in utero drug exposure in humans are not available for any antiretroviral drug; however, with rare exceptions, the short-term data are reassuring. Health professionals are encouraged to contact the Antiretroviral Pregnancy Registry to prospectively report antiretroviral exposures in pregnancy to assist in monitoring pregnancy outcomes of pregnant persons exposed to antiretroviral medications. Information on in utero antiretroviral exposure should be maintained in a child's medical record in case problems that could be long-term complications are identified in the future. (See 'General principles' above and 'Pregnancy outcomes with combination ART exposure' above.)

●Nucleoside reverse transcriptase inhibitors − Short-term data on the safety of commonly used nucleoside reverse transcriptase inhibitors (NRTIs) during pregnancy do not suggest major concerns. Asymptomatic anemia and neutropenia have been reported in infants with in utero NRTI exposure. Some studies have suggested adverse effects on certain growth parameters and bone mineral density in early infancy with in utero exposure to tenofovir disoproxil fumarate, but the long-term significance of these is unclear. Data on an association between in utero zidovudine exposure and congenital heart defects are inconsistent and also of unclear long-term significance. (See 'Nucleoside reverse transcriptase inhibitors' above.)

●Protease inhibitors − Short-term data on the safety of commonly used protease inhibitors in pregnancy do not suggest major concerns. Although protease inhibitors are associated with insulin resistance and impaired glucose tolerance in general, most studies in pregnant persons do not indicate an increased rate of gestational diabetes with their use. Several studies that have suggested a small increased risk of preterm birth with combination ART have implicated protease inhibitors, but data are conflicting. Plasma levels of many protease inhibitors are reduced during pregnancy and dosing adjustments may be warranted in certain situations. (See 'Protease inhibitors' above.)

●Integrase inhibitors and cobicistat − There is no difference in risk of neural tube defects with dolutegravir exposure at the time of conception compared with non-dolutegravir ART exposure at the time of conception. There are only limited data on periconception exposures to other integrase inhibitors. Lower levels of cobicistat-boosted agents during pregnancy have been associated with loss of virologic suppression at delivery; hence, initiation of cobicistat-containing regimens during pregnancy is not recommended. (See 'Integrase inhibitors' above and 'Cobicistat' above.)

●More information − More detailed information on the safety and pharmacokinetics of these and other antiretrovirals can be found in the United States Department of Health and Human Services guidelines on reducing perinatal HIV transmission. The selection of antiretroviral regimens for use during pregnancy in resource-rich and resource-limited settings is discussed in detail elsewhere. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings", section on 'ART selection and management' and "Prevention of vertical HIV transmission in resource-limited settings", section on 'Maternal antiretroviral therapy'.)