Antiviral
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
The limited human data do not allow a prediction as to the risk of delavirdine during pregnancy. The animal data indicate that the drug may represent a risk to the developing human fetus. If indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Delavirdine is a synthetic nonnucleoside reverse transcriptase inhibitor (nnRTI) that is used in the treatment of HIV type 1 (HIV-1). Because resistant viruses emerge rapidly with delavirdine monotherapy, the drug should always be used in combination with other antiretroviral agents (1). Other drugs in this class are efavirenz and nevirapine.
Reproductive studies with delavirdine have been conducted in rats and rabbits. Ventricular septal defects were produced when pregnant rats were administered the agent during organogenesis at doses producing systemic levels equal to or lower than the expected human exposure at the recommended dose (EHE) (1). Reduced pup survival on the day of birth was also noted at this dose. At doses producing 5 times the EHE, marked maternal toxicity, embryo toxicity, fetal developmental delay, and reduced pup survival were observed. Delavirdine administered during organogenesis to rabbits caused maternal toxicity, embryo toxicity, and abortions (1). The lowest dose producing these effects was about six times the EHE. No malformations were observed in the surviving rabbit offspring, but only a few were available for examination (1).
It is not known if delavirdine crosses the human placenta. The molecular weight of the free base (about 457) is low enough that passage to the fetus should be expected.
During premarketing clinical studies, seven unplanned pregnancies occurred, resulting in three ectopic pregnancies, three healthy live births, and one premature infant with a birth defect (1). The infant, exposed early in gestation to about 6 weeks of delavirdine and zidovudine, had a small muscular ventricular septal defect.
The Antiretroviral Pregnancy Registry reported, for January 1989 through July 2009, prospective data (reported before the outcomes were known) involving 4702 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (2). Congenital defects were noted in 134, a prevalence of 2.8% (95% confidence interval [CI] 2.4–3.4). In the 6100 live births with earliest exposure in the 2nd/3rd trimesters, there were 153 infants with defects (2.5%, 95% CI 2.1–2.9). The prevalence rates for the two periods did not differ significantly. There were 288 infants with birth defects among 10,803 live births with exposure anytime during pregnancy (2.7%, 95% CI 2.4–3.0). The prevalence rate did not differ significantly from the rate expected in a nonexposed population. There were 14 outcomes exposed to delavirdine (11 in the 1st trimester and 3 in the 2nd/3rd trimesters) in combination with other antiretroviral agents. There were no birth defects. In reviewing the birth defects of prospective and retrospective (pregnancies reported after the outcomes were known) registered cases, the Registry concluded that, except for isolated cases of neural tube defects with efavirenz exposure in retrospective reports, there was no other pattern of anomalies (isolated or syndromic) (2). (See Lamivudine for required statement.)
Two reviews, one in 1996 and the other in 1997, concluded that all women currently receiving antiretroviral therapy should continue to receive therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate therapy (3,4). The same conclusion was reached in a 2003 review with the added admonishment that therapy must be continuous to prevent emergence of resistant viral strains (5). In 2009, the updated U.S. Department of Health and Human Services guidelines for the use of antiretroviral agents in HIV-1-infected patients continued the recommendation that therapy, with the exception of efavirenz, should be continued during pregnancy (6). If indicated, delavirdine should not be withheld in pregnancy because the expected benefit to the HIV-positive mother outweighs the unknown risk to the fetus. Updated guidelines for the use of antiretroviral drugs to reduce perinatal HIV-1 transmission also were released in 2006 (7). Women receiving antiretroviral therapy during pregnancy should continue the therapy but, regardless of the regimen, zidovudine administration is recommended during the intrapartum period to prevent vertical transmission of HIV to the newborn (7).
BREASTFEEDING SUMMARY
No reports describing the use of delavirdine during lactation have been located. The molecular weight of the free base (about 457) is low enough that excretion into breast milk should be expected. The effect on a nursing infant is unknown.
Reports on the use of delavirdine during human lactation are unlikely, however, because the antiviral agent is used in the treatment of HIV infections. HIV-1 is transmitted in milk, and in developed countries, breastfeeding is not recommended (3,4,6,8–10). In developing countries, breastfeeding is undertaken, despite the risk, because there are no affordable milk substitutes available. Until 1999, no studies had been published that examined the effect of any antiretroviral therapy on HIV-1 transmission in milk. In that year, a study involving zidovudine was published that measured a 38% reduction in vertical transmission of HIV-1 infection despite breastfeeding when compared with controls (see Zidovudine).
References
1.Product information. Rescriptor. Pfizer, 2006.
2.Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 July 2009. Wilmington, NC: Registry Coordinating Center, 2009. Available at www.apregistry.com. Accessed May 29, 2010.
3.Carpenter CCJ, Fischi MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1996. JAMA 1996;276;146–54.
4.Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
5.Minkoff H. Human immunodeficiency virus infection in pregnancy. Obstet Gynecol 2003;101:797–810.
6.Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. December 1, 2009:1–161. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed September 17, 2010:60, 96–8.
7.Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. May 24, 2010:1–117. Available at http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf. Accessed September 17, 2010:30 (Table 5).
8.Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
9.De Martino M, Tovo P-A, Pezzotti P, Galli L, Massironi E, Ruga E, Floreea F, Plebani A, Gabiano C, Zuccotti GV. HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS 1992;6:991–7.
10.Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.