Uses and safety of acyclovir in pregnancy

Journal of Family Practice, Feb, 1994 by John G. Spangler, Julienne K. Kirk, Mark P. Knudson

Acyclovir, an antiviral nucleoside analogue, is a widely used agent highly specific for herpes simplex and varicella-zoster viruses. Unintended exposure to acyclovir early in pregnancy, which is not uncommon, may cause excessive maternal and physician anxiety. This drug has not been studied prospectively in large numbers of pregnant women and lacks the Food and Drug Administration's approval for gestational use unless benefits clearly outweigh potential fetal harm. However, data published since acyclovir became available do not indicate increased adverse effects related to its use in pregnancy, especially if prescribed in selected situations, such as disseminated primary herpes simplex infections or maternal varicella pneumonia. This article reports the impact of inadvertent acyclovir exposure on a woman during the first trimester of pregnancy and reviews the literature on acyclovir's pharmacology, safety profile, and potential uses during pregnancy.

Key words. Acyclovir; pregnancy trimester, first; herpes simplex; herpes genitalis; varicella-zoster virus.

Acyclovir is a widely used antiviral agent of low toxicity available in oral and intravenous forms and used in the United States mainly for suppression of recurrent genital herpes. Up to 50% of users are women of child-bearing age,[1] making unsuspected fetal exposure during the first trimester of pregnancy a common occurrence and increasing the prospect of maternal or physician anxiety. Although the drug has not been approved by the Food and Drug Administration (FDA) for use during pregnancy, the literature cites several situations in which it might have therapeutic value. The purpose of this paper is to present a case illustrating the emotional impact of exposure to acyclovir during the first trimester, to review available data on the drug's pharmacology and safety during pregnancy, and to discuss situations in which its use during pregnancy appears warranted.

Case Report

A 29-year-old [G.sub.3][P.sub.1] white woman came to our clinic for pregnancy testing. Her most recent menstrual period had been 5 weeks earlier. A positive pregnancy test and an initial examination confirmed a pregnancy of 5 weeks' gestation.

The patient, who had a history of recurrent lingual herpes simplex infections, developed pain and burning on the right lateral aspect of her tongue, typical of her herpetic prodrome 10 days prior to the visit. She initiated treatment with acyclovir 200 mg orally five times daily, which she continued until she became aware of missing a menstrual period, at which time she discontinued taking the acyclovir.

The patient's pregnancy was subsequently complicated by an appendectomy performed at 8 weeks' gestation and a low maternal [alpha]-fetoprotein test. She refused amniocentesis. An ultrasound at 17 weeks' gestation was unremarkable for developmental abnormalities, but the early exposure to acyclovir caused the patient marked emotional anxiety regarding the health and viabilty of the fetus. She was enrolled in the Acyclovir in Pregnancy Registry, a program made available by the manufacturer (Burroughs Wellcome Company) to provide information to patients so that they can make informed choices. At 40 weeks' gestation, she gave birth to a healthy female infant. Two years of follow-up have revealed no abnormalities of growth or development.

Discussion

Acyclovir, a synthetic purine nucleoside analogue introduced in 1982, is the first antiviral agent to possess broad activity against the two types of herpes simplex virus. HSV-1 and HSV-2, and varicella-zoster virus (VZV). Acyclovir is a highly selective agent for the herpes viruses with low toxicity toward the host cell: it inhibits the replication of HSV-1 and HSV-2 but cannot eradicate the latent viral reservoir. This agent has proven to be the most effective and least toxic antiviral agent available for HSV infections.

Pharmacokinetics in Pregnancy

Acyclovir is cleared primarily by the renal route through glomerular filtration and tubular secretion. Absorption or oral acyclovir from the gastrointestinal tract is variable and incomplete with an estimated bioavailability of 15% to 30%, probably caused by a saturable process in which the drug's bioavailability decreases with increasing doses.[2] The average serum half-life used in obstetrics and gynecology is between 2.1 and 3.5 hours.[3] The 50% inhibitory dose for HSV-1 and HSV-2 is 0.1 to 3 [mu]mol/L and for VZV is 3 to 4 [mu]mol/L.[2]

Acyclovir is known to cross the placenta to the fetus. Frenkel et al[4] reported the specific pharmacokinetics of acyclovir in pregnant patients with recurrent HSV receiving either 200 or 400 mg of acyclovir orally every 8 hours from 38 weeks' gestation until delivery. Doses of 200 mg and 400 mg produced mean peak maternal serum concentrations of 1.7 [ or -] 0.6 [mu]mol/L and 2.3 [ or -] 1.0 [mu]mol/L, respectively. Amniotic fluid levels were 2 to 8 times higher than those in maternal plasma, and maternal-to-cord ratios at delivery were between 1.07 and 1.90 [mu]mol/L. Additional trough steady-state acyclovir concentrations for 200 mg and 400 mg doses were reported as 0.7 [ or -] 0.3 and 0.8 [ or -] 0.6 [mu]mol/L, respectively; peak concentrations were 1.9 [ or -] 1.0 and 3.3 [ or -] 1.0 [mu]mol/L, respectively.