Genital infections with herpes simplex virus (both HSV-1 and HSV-2) are among the most common sexually transmitted diseases. Although the true incidence of the infection in women is unknown, data from one large national study suggested that it is greater than 26% (Obstet. Gynecol. 2007;109:1489-98).
Treatment with antiviral drugs is indicated in pregnancy because both herpes types can infect the fetus (rarely) and newborn (commonly), resulting in significant morbidity and mortality. Primary infections have a higher risk of perinatal transmission than does recurrent infection.
Gerald G. Briggs, B.Pharm, FCCP
Primary infection close to delivery has the highest risk for fetal and neonatal complications. Intrauterine infection, although rare, can result in abortions or stillbirths, skin scars, ophthalmic complications (chorioretinitis, microphthalmia), and brain damage. In addition to death, neonatal infection may involve the skin, eyes, mouth, and central nervous system, and if disseminated, the liver, lung, brain, skin, and adrenals (Reprod. Toxicol. 2006;21:436-45).
Treatment of herpes in pregnancy usually involves either acyclovir or valacyclovir. A third agent, famciclovir, also is used but to a much lesser extent. For primary infection, a 7- to 10-day course (or longer if healing is incomplete) of acyclovir or valacyclovir is recommended, whereas a symptomatic recurrent episode should be treated for 5 days with either drug. Daily doses of either agent starting from 36 weeks' gestation are recommended for suppression (Obstet. Gynecol. 2007;109:1489-98). An advantage of valacyclovir is the twice-daily dosing, compared with the three times daily dosing for acyclovir.
There is a substantial amount of pregnancy data for acyclovir, most of which came from the Acyclovir in Pregnancy Registry. The prevalence of birth defects among registry cases was similar to the expected background risk, and there was no pattern among the defects suggesting a common cause. A 2009 review concluded that acyclovir was safe in pregnancy (Indian J. Dermatol. Venereol. Leprol. 2009;75:566-74).
There are far less pregnancy data for valacyclovir and famciclovir, raising questions about the risk of these antivirals. However, because valacyclovir is a prodrug that is converted in vivo to acyclovir, many believe it should be classified the same as acyclovir.
In a population-based historical cohort study of all live-born infants in Denmark between 1996 and 2008, national registries were used to determine individual exposure to antiviral drugs, classification of birth defects observed within the first year of life, and potential confounders (JAMA 2010;304;859-66). Infants with chromosomal abnormalities, genetic syndromes, birth defect syndromes with known causes, or congenital viral infections were excluded from the analysis. Among 1,816 infants exposed during the first trimester to acyclovir, valacyclovir, or famciclovir, 40 (2.2%) had a major birth defect, compared with 19,920 (2.4%) among those not exposed, an insignificant difference.
For specific drugs, the number of birth defects and infants exposed in the first trimester was 32/1,561 for acyclovir (2.0%), 7/229 for valacyclovir (3.1%), and 1/26 for famciclovir (3.8%). The data for acyclovir and valacyclovir were nonsignificant, and the data for famciclovir were too small to analyze. The observed birth defects were classified into 13 subgroups: nervous system, eye, ear-face-neck, heart, respiratory, orofacial clefts, digestive system, abdominal wall, urinary, genital, limb, musculoskeletal, and miscellaneous.
Famciclovir is a prodrug that is converted in vivo to penciclovir, the active antiviral agent. The animal data suggest low risk, but the human pregnancy experience is too limited to accurately assess the potential for embryo-fetal risk. In addition to the 26 cases described above, first-trimester exposure to famciclovir in six pregnancies was reported in a 1998 observational cohort study (Br. J. Obstet. Gynaecol. 1998;105:882-9). The outcomes included two spontaneous abortions and four normal, full-term infants. Although a risk assessment cannot be made with confidence based on human experience, if famciclovir is indicated it should not be withheld because of pregnancy.
Both acyclovir and valacyclovir appear to be compatible with breastfeeding. However, there are no human data for famciclovir and, until such data are available, the drug is best avoided during breastfeeding.
Mr. Briggs is a pharmacist clinical specialist, Outpatient Clinics, Memorial Care Center for Women at Miller Children's Hospital, Long Beach, Calif.; a clinical professor of pharmacy at the University of California, San Francisco; and an adjunct professor of pharmacy at the University of Southern California, Los Angeles. He had no disclosures related to the topic.