Safety of antiviral medication for the treatment of herpes during pregnancy

General properties and mechanism of action

Valacyclovir is well absorbed after oral administration; absorption of a single dose of 1000 mg is 54% higher than that achieved after single 200- or 800-mg doses of oral acyclovir.⁷ Valacyclovir is rapidly metabolized to acyclovir, the triphosphorylated form of which selectively inhibits human HSV DNA polymerase, reducing viral DNA replication. Similarly, famciclovir is the oral prodrug of its active form penciclovir; it is more stable than acyclovir triphosphate, as evidenced by longer half-lives intracellularly, which might account for the prolonged in vitro antiviral activity.⁸ Acyclovir 5% and penciclovir 1% creams are used to treat orolabial herpes (HSV-1). Penciclovir was not detected in the plasma or urine of healthy volunteers after single or repeated application of the 1% cream.⁹ Systemic absorption of acyclovir following topical application is minimal or undetectable in adults.¹⁰

Safety of antivirals during pregnancy

Although controlled studies evaluating the effectiveness of oral antivirals for recurrent HSV outbreaks in the mother and neonatal HSV infections at delivery do exist, they are limited by small sample sizes, the lack of fetal safety outcomes, and variation in timing of exposure.¹¹ However, data on the safety of antiviral drugs during pregnancy have been collected in pregnancy registries, usually established by the manufacturers. The oldest registry (ie, Acyclovir Pregnancy Registry) was open from 1984 to 1998, evaluating the use of oral or intravenous acyclovir in pregnant women. In total, 1234 pregnancies were noted with 1246 outcomes from 24 countries; 756 exposed pregnancies were studied in the first trimester. The risk of birth defects was 3.2% (95% confidence interval 2.0% to 5.0%), which is similar to the baseline risk of birth defects in the general population. No unusual defects or patterns of defects were seen, but the limitation of the results was the high loss to follow-up (27% of registrants).¹² During the years 1995 to 1999, the manufacturer of valacyclovir maintained its pregnancy registry, and 110 exposures were reported with 111 known outcomes. Within the first trimester, 1 birth defect was reported out of 28 exposures; 2 of 31 and 1 of 51 exposures resulted in defects in the second and third trimesters, respectively. Prenatal exposures were too limited to provide pregnancy outcomes. According to personal written correspondence from GlaxoSmithKline to Motherisk (January 2010), this registry was limited by the number of registrants and the length of monitoring.

A recent Danish population-based retrospective cohort study used data from its nationwide registry to examine live-born infants born between 1996 and 2008 who were exposed to antivirals during pregnancy and the rate of major birth defects within the first year of life. Of the 837 795 enrolled infants, 1804 pregnancies were exposed to acyclovir, valacyclovir, or famciclovir in the first trimester; prevalence odds ratios were considered no different between exposed and unexposed cohorts. Similar results were found when evaluating second and third trimester data. There was also no significant difference in the prevalence of malformations between exposed and unexposed groups when examining exposure during the first trimester to individual antivirals. The rate of malformations was 2.0% for acyclovir (32 of 1561 infants) and 3.1% for valacyclovir (7 of 229 infants). For famciclovir, exposure was uncommon with 1 infant of 26 exposed having a birth defect. As a supplementary analysis, the association between the use of dermatologic acyclovir and penciclovir creams and major birth defects was evaluated. The rate of malformations in those exposed to acyclovir cream and penciclovir cream in the first trimester (2.3%, 65 of 2850 infants, and 4.2%, 5 of 118 infants, respectively) was not different from the unexposed cohort; similar results were found in the second and third trimesters of pregnancy.¹³

Conclusion

The accumulated evidence for the safety of oral acyclovir and valacyclovir, established from the manufacturer’s pregnancy registries and as a result of the Danish cohort study, does not demonstrate an increase in the rate of major birth defects when compared with the general population or an unexposed group. Data on the safety of famciclovir’s use during pregnancy is quite limited, and although it might not be expected to increase the risk of major malformations, it should not be the first choice of medication for treatment of HSV during pregnancy. In addition, topical antiviral preparations of acyclovir and penciclovir resulted in no increased rate of major birth defects during pregnancy. Limitations of the safety data on antivirals include a high lost-to-follow-up rate in the registries and the lack of prospective controlled studies. However, these data are reassuring, allowing physicians to offer pregnant patients either acyclovir or valacyclovir for treatment of primary or recurrent HSV infection, which not only treats the mother’s condition, but also reduces the likelihood of transmission to the neonate, without unduly compromising fetal safety.