Antiviral
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
For the management of herpes in pregnancy, either valacyclovir or acyclovir are recommended for primary or first-episode infection (for 7–10 days), symptomatic recurrent episode (for 5 days), and daily suppression (from 36 weeks’ gestation until delivery), but only acyclovir is recommended for severe or disseminated disease (1). Although the experience with valacyclovir in early pregnancy is limited, many studies have reported the use of acyclovir during all stages of pregnancy (see also Acyclovir). Based on the combined data, there is no evidence of a major risk to the human fetus from valacyclovir or acyclovir. Long-term follow-up of children exposed in utero to these agents is warranted.
FETAL RISK SUMMARY
Valacyclovir is biotransformed to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. The drug is active against herpes simplex virus (HSV) types 1 and 2 and varicella-zoster virus. It is used in the treatment of herpes zoster (shingles) and recurrent genital herpes simplex.
Reproduction studies were conducted in rats and rabbits during organogenesis with doses producing concentrations 10 and 7 times human plasma levels, respectively (2). No teratogenic effects were observed with these doses.
The active metabolite, acyclovir, readily crosses the human placenta (see Acyclovir). An abstract and study, both published in 1998, compared the pharmacokinetics of valacyclovir and acyclovir in late pregnancy (3,4). Acyclovir accumulated in the amniotic fluid but not in the fetus. The mean maternal/umbilical vein plasma ratio at delivery was 1.7.
The Valacyclovir Pregnancy Registry listed 157 prospective reports of women exposed to the oral antiviral drug during gestation covering the period from January 1, 1995, through April 30, 1999 (5). Of the total, 47 (30%) pregnancies were lost to follow-up. Among the 111 (1 set of twins) known outcomes, 29 had earliest exposure in the 1st trimester and their outcomes were 5 spontaneous abortions, 2 induced abortions, 1 infant with a birth defect (talipes), and 21 infants (including the twins) without birth defects. When the earliest exposure was in the 2nd trimester, 31 pregnancies were enrolled and their outcomes were 2 stillbirths, 2 infants with birth defects (fingers and toes fused—extensive webbing; small cleft in front gum), and 27 without birth defects. In the remaining 51, the earliest exposure occurred in the 3rd trimester, with 1 infant with a dermal sinus tract and 50 without birth defects (5).
A total of 34 retrospective reports of valacyclovir exposure during pregnancy were submitted to the Registry (5). Two of the exposures occurred during an unspecified gestational time and both resulted in live births without defects. In 14 pregnancies, the earliest exposure occurred during the 1st trimester. The outcomes of these pregnancies were three spontaneous losses, eight induced abortions, and three infants without birth defects. For the pregnancies whose earliest exposure was in the 2nd trimester (N = 4) or 3rd trimester (N = 14), there was 1 birth defect (2nd trimester exposure) and 17 infants without defects (5).
A 1999 case report described a woman at 20 weeks’ gestation who had a generalized HSV infection that was treated with IV acyclovir for about 2 weeks followed by valacyclovir for the remainder of the pregnancy (6). She delivered a full-term, healthy female infant who was treated prophylactically with oral acyclovir for 1 month. No abnormalities were detected during a neurologic examination at 8 months of age (6).
A prospective, double-blind, placebo controlled trial was conducted to estimate the efficacy of valacyclovir to reduce HSV infection at delivery (7). Valacyclovir 500 mg twice daily (N = 170) or placebo (N = 168) was given from 36 weeks’ gestation until delivery. Compared with controls, valacyclovir significantly reduced HSV shedding and need for cesarean section. There were no differences between the groups in terms of delivery and neonatal outcomes (7).
A 2009 review of genital herpes concluded that the benefits from the use of acyclovir or valacyclovir for the treatment of the virus in pregnancy far outweighed the potential fetal risks (8). Because there was no evidence to suggest a risk of major defects with acyclovir, the reviewers also concluded that the pro-drug valacyclovir, even though the pregnancy experience was limited, could be viewed similarly.
A 2010 study used a population-based historical cohort of 837,795 liveborn infants in Denmark to determine if there were associations between 1st trimester exposure to acyclovir, valacyclovir, and famciclovir and major birth defects (9). Subjects were excluded if they had chromosomal abnormalities, genetic syndromes, birth defect syndromes, or congenital viral infections. Among 1804 pregnancies exposed to one of the antivirals, there were 40 (2.2%) infants with a major birth defect compared with 19,920 (2.4%) among those unexposed (adjusted prevalence odds ratio [POR] 0.89, 95% confidence interval [CI] 0.65–1.22). In the valacyclovir group, 7 (3.1%) infants had a major defect from the 229 with 1st trimester exposure (POR 1.21, 95% CI 0.56–2.62). The prevalence of major defects with acyclovir and famciclovir were 2.0% (POR 0.82, 95% CI 0.57–1.17) and 3.8%, respectively, but only 26 pregnancies (1 infant with a defect) were exposed to famciclovir. The study limited the evaluation to 13 major birth defect types by organ system. For any antiviral drug, POR >1 were found for defects of the nervous system, eye, abdominal wall, urinary tract, and a miscellaneous group of defects; none reached statistical significance. The authors concluded that 1st trimester exposure to valacyclovir and acyclovir was not associated with an increased risk of major birth defects (9). The authors of an accompanying editorial thought that the large number of exposures during organogenesis without an overall increased risk of major defects was reassuring, especially for acyclovir. However, more data were needed to examine the associations with individual defects (10).
BREASTFEEDING SUMMARY
Valacyclovir is rapidly and nearly completely converted to acyclovir and the amino acid, L-valine. Acyclovir is concentrated in human milk with milk:plasma ratios in the range 3–4 (see Acyclovir).
In a 2002 study, five healthy postpartum women who were breastfeeding were given valacyclovir (500 mg) twice daily for 7 days (11). Maternal serum and milk samples were collected after the first dose, on day 5, and 24 hours after the last dose. Infant urine samples were collected on day 5. All samples were analyzed for acyclovir. The peak milk concentration occurred 4 hours after the first dose (milk:serum ratio 3.4), whereas the peak serum level occurred at 2 hours. At steady state, the milk:serum ratio was about 1.9. The median infant urine acyclovir concentration was 0.74 mcg/mL. Twenty-four hours after the last dose, the milk:serum ratio was 0.25. The estimated infant dose (based on a consumption of 750 mL/day of milk by a 2.75-kg infant) would be about 0.2% of the therapeutic dose for neonates (11).
Because acyclovir has been used to treat herpesvirus infections in the neonate, and because of the lack of adverse effects in reported cases in which acyclovir was used during breastfeeding, the American Academy of Pediatrics classifies acyclovir as compatible with breastfeeding (see Acyclovir). Valacyclovir also appears to be compatible with breastfeeding.
References
1.American College of Obstetricians and Gynecologists. Management of herpes in pregnancy. ACOG Practice Bulletin. No. 82, June 2007.
2.Product information. Valtrex. Glaxo Wellcome, 1997.
3.Kimberlin DF, Weller S, Andrews WW, Hauth JC, Whitley RJ, Lakeman F, Miller G, Lee C, Goldenberg RL. Valaciclovir pharmacokinetics in late pregnancy (abstract). Am J Obstet Gynecol 1998;178:S12.
4.Kimberlin DF, Weller S, Whitley RJ, Andrews WW, Hauth JC, Lakeman F, Miller G. Pharmacokinetics of oral valacyclovir and acyclovir in late pregnancy. Am J Obstet Gynecol 1998;179:846–51.
5.Acyclovir Pregnancy Registry and Valacyclovir Pregnancy Registry. Final study report. 1 June 1984 through 30 April 1999. Glaxo Wellcome, 1999.
6.Anderson R, Lundqvist A, Bergstrom T. Successful treatment of generalized primary herpes simplex type 2 infection during pregnancy. Scand J Infect Dis 1999;31:201–2.
7.Sheffield JS, Hill JB, Hollier LM, Laibl VR, Roberts SW, Sanchez PJ, Wendel GD Jr. Valacyclovir prophylaxis to prevent recurrent herpes at delivery. Obstet Gynecol 2006;108:141–7.
8.Nath AK, Thappa DM. Newer trends in the management of genital herpes. Indian J Dermatol Venereol Leprol 2009;75:566–74.
9.Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. JAMA 2010;304:859–66.
10.Mills JL, Carter TC. Acyclovir exposure and birth defects—an important advance, but more are needed. JAMA 2010;304:905–6.
11.Sheffield JS, Fish DN, Hollier LM, Cadematori S, Nobles BJ, Wendel GD Jr. Acyclovir concentrations in human breast milk after valaciclovir administration. Am J Obstet Gynecol 2002;186:100–2.