Acyclovir, Valacyclovir in First Trimester Not Linked to Major Birth Defects

From MedscapeCME Clinical Briefs
News Author: Laurie Barclay, MD
CME Author: Hien T. Nghiem, MD

August 25, 2010 — Exposure to acyclovir or valacyclovir in the first trimester of pregnancy is not associated with an increased risk for major birth defects, according to the results of a large, population-based, historical cohort study reported in the August 25 issue of the Journal of the American Medical Association.

"Herpes simplex and herpes zoster infections are common and often treated with antiviral drugs including acyclovir, valacyclovir, and famciclovir," write Björn Pasternak, MD, PhD, and Anders Hviid, MSc, DrMedSci, from Statens Serum Institut in Copenhagen, Denmark. "Safety of these antivirals when used in the first trimester of pregnancy is insufficiently documented."

The goal of the study was to examine associations between use of acyclovir, valacyclovir, and famciclovir during the first trimester of pregnancy and the risk for major birth defects, using a cohort of 837,795 live-born infants in Denmark from January 1, 1996, to September 30, 2008. Infants diagnosed with chromosomal abnormalities, genetic syndromes, birth defect syndromes of known cause, or congenital virus infections were excluded.

Individual-level data regarding dispensed antiviral drugs, birth defect diagnoses categorized with use of a standardized classification scheme, and potential confounders were derived from nationwide registries. The primary study endpoint was prevalence odds ratios (PORs) of any major birth defect diagnosed before age 1 year within the first year of life, by antiviral drug exposure.

A major birth defect was diagnosed in 40 (2.2%) of 1804 infants whose mothers used acyclovir, valacyclovir, or famciclovir in the first trimester and in 19,920 infants (2.4%) whose mothers were not exposed to these drugs (adjusted POR, 0.89; 95% confidence interval [CI], 0.65 - 1.22).

In the specific antiviral drugs, 32 (2.0%) of 1561 infants with first-trimester exposure to acyclovir were diagnosed with a major birth defect (adjusted POR, 0.82; 95% CI, 0.57 - 1.17), as were 7 (3.1%) of 229 infants with first-trimester exposure to valacyclovir (adjusted POR, 1.21; 95% CI, 0.56 - 2.62). Only 26 infants were exposed to famciclovir during the first trimester; of these, 1 infant (3.8%) was diagnosed with a birth defect. Although no associations between antiviral drug exposure and 13 different subgroups of birth defects were apparent in exploratory analyses, there were only a small number of exposed cases in each subgroup.

"In this large nationwide cohort, exposure to acyclovir or valacyclovir in the first trimester of pregnancy was not associated with an increased risk of major birth defects," the study authors write.

Limitations of this study include inability to capture defects diagnosed after age 1 year, exclusion of abortions, incomplete evaluation of maternal comorbidity, and possible unmeasured confounding. A major limitation is that nonadherence to the dispensed drugs would obscure teratogenic effects, if present. Because there were few exposed cases in each subgroup of major defects, teratogenic effects cannot be ruled out with certainty.

"Our study... has immediate clinical implications and may support informed decisions on safety when prescribing antivirals for herpes infections in early pregnancy," the study authors conclude. "Acyclovir is the most extensively documented antiviral and should therefore be the drug of choice in early pregnancy, while data on valacyclovir and famciclovir are still insufficient.
Future research on antiherpetic antivirals and mother-child health should include safety studies with regard to spontaneous abortion and preterm birth, and during breastfeeding."

Editorial: Still Some Remaining Issues

In an accompanying editorial, James L. Mills, MD, MS, and Tonia C. Carter, PhD, from the National Institutes of Health in Bethesda, Maryland, note that because of limitations, this study does not answer the key question of whether acyclovir is a teratogen.

"[This study] is helpful in demonstrating the safety of acyclovir in pregnancy, but additional strategies must be developed to resolve the remaining issues," Drs. Mills and Carter write. "At a time when the health care system in the United States is facing enormous financial challenges, it is important not to ignore any sources of data that could answer critical medical questions."

The Danish Medical Research Council and the Lundbeck Foundation supported this study. The study authors have disclosed no relevant financial relationships. The editorial work was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development.

JAMA. 2010;304:859-866, 905-906.

Clinical Context

Herpes simplex and herpes zoster infections are common. More than 1% of women acquire herpes simplex during the first trimester of pregnancy. Herpes simplex is often treated with antiviral drugs including acyclovir, valacyclovir, and famciclovir. Individuals who experience at least 6 recurrences of genital herpes within 1 year usually require episodic or long-term suppressive treatment. The US Food and Drug Administration has classified acyclovir, valacyclovir, and famciclovir as category B drugs in pregnancy. However, the safety of these antivirals when used in the first trimester of pregnancy has been insufficiently documented.

The aim of this study was to investigate associations between exposure to acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk for major birth defects.