Animal studies have failed to reveal evidence of adverse developmental outcomes at up to the highest dose tested in rats and rabbits; systemic exposures to this drug were less than (rabbits) and about 27 times (rats) the exposure in humans at the maximum recommended human dose. There are no controlled data in human pregnancy.

Placental transfer to the fetus has been reported as high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with this drug.

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

The APR has received prospective reports of over 925 exposures to dolutegravir-containing regimens (over 550 exposed in the first trimester; over 375 exposed in the second/third trimester) resulting in live births. There was 1 neural tube defect observed among 539 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/live births with first trimester and second/third trimester exposures was 3.3% and 5.3%, respectively; the background birth defect rate was 2.7% in the US reference population.

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 0.07% (87/119,630 deliveries) in the non-dolutegravir and HIV-uninfected arms, respectively. The 7 cases reported with this drug included 2 cases of encephalocele, 1 case of anencephaly, 1 case of iniencephaly, and 3 cases of myelomeningocele. In the same study, no increased risk of neural tube defects was detected in women who started this drug during pregnancy; 2 infants out of 4448 (0.04%) deliveries to women who started this drug during pregnancy had a neural tube defect, compared with 5 infants out of 6748 (0.07%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana; it is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate.

Most neural tube defects occur within the first 4 weeks of embryonic development after conception (about 6 weeks after last menstrual period). If pregnancy is confirmed in the first trimester while using this drug, the benefits and risks of continuing therapy versus switching to another antiretroviral regimen should be discussed with the patient; gestational age and the critical period of neural tube defect development should be considered.

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

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, this drug is considered a preferred antiretroviral drug for use throughout pregnancy and for women who are trying to conceive. The risks and benefits of using this drug should be discussed with the patient. Current guidelines should be consulted for additional information.

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.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.

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 an ongoing birth outcome surveillance study identified an increased risk of neural tube defects when used at time of conception.

Comments:
-A pregnancy exposure registry is available.
-Defects related to neural tube closure occur from conception through the first 6 weeks of gestation; embryos exposed to this drug from time of conception through the first 6 weeks of gestation may be at risk.
-Pregnancy testing is recommended in patients of childbearing potential before starting this drug.
-Patients of childbearing potential who are using this drug should be counseled on the consistent use of effective contraception.
-Patients of childbearing potential (including those actively trying to become pregnant) should be apprised of the potential risk of neural tube defects with use of this drug; the risks and benefits of this drug should be assessed and should be discussed with the patient to decide if an alternative regimen should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester.
---A benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero exposure to this drug during critical periods of fetal development.
-According to some authorities: Patients of childbearing potential should be advised about the potential risk of neural tube defects with this drug, including consideration of effective contraceptive measures; if pregnancy is planned, the risks and benefits of continuing this drug should be discussed with the patient.

See references

Breastfeeding is not recommended during use of this drug.

Excreted into human milk: Yes

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.

This drug is detectable in maternal milk in low amounts. Elimination by neonates appears prolonged and the drug has been detected in infant plasma during breastfeeding. This drug 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 this drug (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 drug 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 drug 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 28 pregnant HIV-infected women randomized to receive an antiretroviral regimen containing this drug (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 this drug 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 this drug 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 this drug into milk. Using the model, the level of this drug 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 0.27% of the maternal dose. In 21 of the breastfed infants, 65 serum levels were measured postpartum. In the first 24 hours and over the 96 hours after the last maternal dose, infant serum levels were 4.9% and 11% of maternal plasma level, respectively; the increase indicates slower drug elimination in infants compared to their mothers.

See references