Animal studies have failed to reveal evidence of adverse developmental outcomes with the components of this drug. Animal studies with dolutegravir showed no adverse effects on embryofetal development at up to the highest dose tested in rats and rabbits; systemic exposures to this component were less than (rabbits) and about 38 times (rats) the exposure in humans at the recommended dose (50 mg/day). Animal studies with rilpivirine showed no evidence of significant embryofetal toxicity at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose (25 mg/day). There are no controlled data in human pregnancy with this combination drug.

Placental transfer to the fetus has been reported as high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with dolutegravir and moderate to high (cord blood/maternal delivery plasma drug ratio at least 0.3) with rilpivirine. In studies of pregnant women using rilpivirine, the cord blood-to-maternal plasma ratio ranged from 0.3 to 0.81.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral therapy, an Antiretroviral Pregnancy Registry (APR) has been established. Healthcare providers are encouraged to prospectively register patients. For additional information: apregistry.com

The APR has received prospective reports of over 725 exposures to dolutegravir-containing regimens (over 450 exposed in the first trimester; over 275 exposed in the second/third trimester) resulting in live births. There was 1 neural tube defect observed among 382 periconception dolutegravir exposures reported with pregnancy outcome. Enough first-trimester exposures have been monitored to detect at least a 2-fold increased risk of overall birth defects; no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to dolutegravir was 3.5% and 4.2%, respectively.

The APR has received prospective reports of over 650 exposures to rilpivirine-containing regimens (over 475 exposed in the first trimester; over 175 exposed in the second/third trimester) resulting in live births; there was no difference between rilpivirine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. Enough first-trimester exposures have been monitored to detect at least a 2-fold increased risk of overall birth defects; no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to rilpivirine was 1.4% and 1.5%, respectively.

Defects related to neural tube closure occur from conception through the first 6 weeks of gestation; embryos exposed to dolutegravir from time of conception through the first 6 weeks of gestation may be at risk. Encephalocele and iniencephaly (2 of the 5 birth defects reported with dolutegravir), although often called neural tube defects, may occur after neural tube closure, which may be past 6 weeks of gestation (but within the first trimester). Since understanding of the reported types of neural tube defects associated with dolutegravir is limited and conception date may not be ascertained with precision, an alternative to this drug should be considered at the time of conception through the first trimester. Initiation of this drug is not recommended in patients actively trying to become pregnant unless there is no suitable alternative.

In a birth outcome surveillance study in Botswana, 7 cases of neural tube defects were reported out of 3591 deliveries (0.19%) to women taking dolutegravir-containing regimens at time of conception; in comparison, neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) and 0.08% (70/89,372 deliveries) in the non-dolutegravir and HIV-uninfected arms, respectively. The 5 cases reported with dolutegravir (out of 1683 deliveries [0.3%]) included 1 case each of encephalocele, anencephaly, and iniencephaly, and 2 cases of myelomeningocele. In the same study, 1 infant out of 3840 (0.03%) deliveries to women who started dolutegravir during pregnancy had a neural tube defect, compared with 3 infants out of 5952 (0.05%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy.

Most neural tube defects occur within the first 4 weeks of embryonic development after conception (about 6 weeks after last menstrual period).

Data analyzed to date from other sources (including the APR, clinical trials, and postmarketing data) are insufficient to address the risk of neural tube defects with dolutegravir.

Data from the birth outcome surveillance study and postmarketing sources with more than 1000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes (e.g., fetotoxicity, neonatal toxicity).

According to the Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, dolutegravir is recommended as a preferred antiretroviral drug throughout pregnancy and as an alternative antiretroviral drug in patients who are trying to conceive. The risks and benefits of using dolutegravir should be discussed with the patient. Current guidelines should be consulted for additional information.

The Panel on Antiretroviral Guidelines for Adults and Adolescents provide the following recommendations for patients of childbearing potential:
-A pregnancy test should be performed before starting a dolutegravir-containing regimen.
-The benefits of using dolutegravir and the risk of neural tube defects should be discussed with patients to allow them to make informed decisions about care.
-Dolutegravir may be used as an alternative antiretroviral drug for patients who are trying to conceive and those who are sexually active and not using contraception.
-Dolutegravir may be used as a recommended option for patients who are using effective contraception.
Current guidelines should be consulted for additional information.

In a clinical trial, this drug (in combination with background regimen) was evaluated in 19 HIV-1-infected pregnant patients (who were using a rilpivirine-based regimen at time of enrollment) during the second and third trimesters and postpartum; 12 patients completed the trial through postpartum period (6 to 12 weeks after delivery) and 6 pregnancy outcomes were missing. Total rilpivirine exposure was about 30% to 40% lower during pregnancy compared with postpartum (6 to 12 weeks); protein binding was similar (greater than 99%) during the second and third trimester and postpartum. One patient discontinued the trial after fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Of the 12 patients who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was sustained in 10 patients (83.3%) through the third trimester visit and in 9 patients (75%) through the 6- to 12-week postpartum visit; virologic outcomes during the third trimester visit were missing for 2 patients who were withdrawn (1 was nonadherent to study drug; 1 withdrew consent). Of the 10 infants with HIV test results available (born to 10 HIV-1-infected pregnant patients), all had negative HIV-1 test results at time of delivery and up to 16 weeks postpartum; all 10 infants received antiretroviral prophylaxis with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum (no new safety findings compared with its known safety profile in HIV-1-infected adults).

AU TGA pregnancy category B1: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Use should be avoided at time of conception through the first trimester of pregnancy unless there is no alternative; this drug should be used during the second and third trimesters of pregnancy only if the benefit outweighs the risk to the fetus.
-According to some authorities: Use is not recommended.

AU TGA pregnancy category: B1
US FDA pregnancy category: Not assigned.

Risk summary: Insufficient data available on use of this drug in pregnant women to definitively inform a drug-related risk; data from a birth outcome surveillance study identified an increased risk of neural tube defects when dolutegravir is used at time of conception (compared to non-dolutegravir-containing regimens).

Comments:
-A pregnancy exposure registry is available.
-Lower exposures of both components have been observed during pregnancy.
-Pregnancy testing should be performed in patients of childbearing potential before starting this drug; patients of childbearing potential who are using this drug should be advised to consistently use effective contraception throughout therapy.
---According to some authorities: Patients of childbearing potential should be advised about the potential risk of neural tube defects with dolutegravir, including consideration of effective contraceptive measures.
-In patients of childbearing potential currently using this drug who are actively trying to become pregnant, or if pregnancy is confirmed in the first trimester, the risks and benefits of continuing this drug versus switching to another antiretroviral regimen should be assessed and switching to an alternative regimen should be considered.
---According to some authorities: If pregnancy is planned, the risks and benefits of continuing this drug should be discussed with the patient.
-Pregnant patients should be apprised of the potential harm to the embryo exposed to this drug from time of conception through the first trimester of pregnancy; a benefit-risk assessment should consider factors such as feasibility of switching, tolerability, ability to maintain viral suppression, and risk of transmission to the infant against the risk of neural tube defects.

See references

Breastfeeding is not recommended during use of this drug.

Excreted into human milk: Yes (dolutegravir); Unknown (rilpivirine)
Excreted into animal milk: Yes (rilpivirine)

Comments:
-The effects in the nursing infant are unknown; potential for HIV-infected infants developing viral resistance and breastfed infants developing side effects similar to those in adults
-The US CDC, American Academy of Pediatrics, and manufacturer advise HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected.
-Local guidelines should be consulted if replacement feeding is not an option.

DOLUTEGRAVIR:
Dolutegravir is detectable in maternal milk in low amounts. Elimination by neonates appears prolonged and the drug has been detected in infant plasma during breastfeeding. Dolutegravir has been used safely in HIV-infected mothers during breastfeeding.

An HIV-infected mother took a combination tablet (abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg) once a day. Her breast milk dolutegravir levels (measured periodically over 10 months) averaged about 100 mcg/L at 11 hours after dosing; authors estimated an infant dose of 15 mcg/kg/day. During the period of exclusive nursing (up to about 30 weeks postpartum), her infant had a plasma dolutegravir level of 100 mcg/L; as supplemental food was introduced, plasma levels declined to about 30 mcg/L at 35 weeks and to zero with no nursing after about 50 weeks postpartum. With exclusive nursing for about 30 weeks and partial nursing for about 20 weeks, the infant showed no obvious side effects.

After taking dolutegravir (dose not provided but presumed 50 mg/day) plus 2 unspecified nonnucleoside reverse transcriptase inhibitors, 2 HIV-infected women donated 2 milk samples each; both women breastfed their infants (extent not provided, but presumed exclusively). At 2 weeks postpartum, steady-state breast milk dolutegravir levels were 154.2 and 40.9 mcg/L at 4 and 24 hours after dosing, respectively, in 1 woman; the plasma levels in 1 infant were 67.8 and 75.5 mcg/L at 4 and 24 hours after maternal dosing, respectively. In the other woman, steady-state breast milk dolutegravir levels were 116.3 and 17.7 mcg/L at 3 and 24 hours after dosing, respectively; the plasma level in the other infant was 16.3 mcg/L at 24 hours after maternal dosing. At 2 and 9 days, respectively, after stopping the drug, breast milk levels were undetectable (less than 10 mcg/L); 2 days after the drug was stopped, 1 infant had a plasma level of 58.6 mcg/L when the maternal plasma level was 103.8 mcg/L.

Of 29 pregnant HIV-infected women randomized to receive an antiretroviral regimen containing dolutegravir (50 mg orally once a day), 17 women underwent extensive postpartum sampling of breast milk and maternal serum, and their breastfed infants had serum levels obtained, at a median of 10 days postpartum; median peak level of dolutegravir in milk was 84.6 mcg/L with a minimum of 22.3 mcg/L while the median peak serum drug level in the infants was 66.7 mcg/L with a minimum of 60.9 mcg/L. Only 1 woman had a milk drug level of 14 mcg/L at 48 hours; all other milk samples were negative for dolutegravir at 48, 72, and 96 hours after discontinuation. After drug discontinuation, levels were detectable in 100%, 80%, and 80% of breastfed infants at 48, 72, and 96 hours after the final maternal dose, respectively; the ratio of paired maternal and infant serum levels was 0.03 and 0.08 at the peak and trough, respectively. Data from this study were used to create a pharmacokinetic model of dolutegravir into milk. Using the model, the level of dolutegravir in breast milk over 24 hours averaged 0.05 mg/L (range: 0.029 to 0.1 mg/L), corresponding to an absolute infant dose of 2.2 mcg/kg/day; this corresponded to a weight-adjusted infant dose of 0.26% of the maternal dose.

In a study that randomized nursing mothers to anti-HIV regimens containing either dolutegravir (n = 29) or efavirenz (n = 31), the regimens were reportedly well tolerated by the infants and no difference in infant side effects were observed between the 2 regimens.

RILPIVIRINE:
No published data available regarding use during breastfeeding; an alternate agent may be preferred.

See references