Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects.
BACKGROUND
Herpes simplex and herpes zoster infections are common and often treated with antiviral drugs including acyclovir, valacyclovir, and famciclovir. Safety of these antivirals when used in the first trimester of pregnancy is insufficiently documented.


OBJECTIVE
To investigate associations between exposure to acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and risk of major birth defects.


METHODS
Population-based historical cohort study of 837,795 live-born infants in Denmark from January 1, 1996, to September 30, 2008. Participants had no diagnoses of chromosomal aberrations, genetic syndromes, birth defect syndromes with known causes, or congenital viral infections. Nationwide registries were used to ascertain individual-level information on dispensed antiviral drugs, birth defect diagnoses (categorized according to a standardized classification scheme), and potential confounders.


METHODS
Prevalence odds ratios (PORs) of any major birth defect diagnosed within the first year of life by exposure to antiviral drugs.


RESULTS
Among 1804 pregnancies exposed to acyclovir, valacyclovir, or famciclovir in the first trimester, 40 infants (2.2%) were diagnosed with a major birth defect compared with 19,920 (2.4%) among the unexposed (adjusted POR, 0.89; 95% confidence interval [CI], 0.65-1.22). For individual antivirals, a major birth defect was diagnosed in 32 of 1561 infants (2.0%) with first-trimester exposure to acyclovir (adjusted POR, 0.82; 95% CI, 0.57-1.17) and in 7 of 229 infants (3.1%) with first-trimester exposure to valacyclovir (adjusted POR, 1.21; 95% CI, 0.56-2.62). Famciclovir exposure was uncommon (n = 26), with 1 infant (3.8%) diagnosed with a birth defect. Exploratory analyses revealed no associations between antiviral drug exposure and 13 different subgroups of birth defects, but the number of exposed cases in each subgroup was small.


CONCLUSIONS
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.
Pasternak
Björn
B
Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark. bjp@ssi.dk
Hviid
Anders
A
D015075:2-Aminopurine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000014:Abnormalities, Drug-Induced / Q000453:epidemiology*; D000212:Acyclovir / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D003718:Denmark / Q000453:epidemiology; D000077595:Famciclovir; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy; D006562:Herpes Zoster / Q000188:drug therapy; D006801:Humans; D008875:Middle Aged; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D012189:Retrospective Studies; D012306:Risk; D000077483:Valacyclovir; D014633:Valine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
D000998:Antiviral Agents; D015075:2-Aminopurine; D014633:Valine; D000077483:Valacyclovir; D000077595:Famciclovir; D000212:Acyclovir