Use of Acyclovir, Valacyclovir, and Famciclovir in the First Trimester of Pregnancy and the Risk of Birth Defects | Congenital Defects | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 18.207.108.182. Please contact the publisher to request reinstatement.
[Skip to Navigation Landing]
1.
Sen P, Barton SE. Genital herpes and its management.  BMJ. 2007;334(7602):1048-105217510153PubMedGoogle ScholarCrossref
2.
Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infections: an evidence-based review.  Arch Intern Med. 2008;168(11):1137-114418541820PubMedGoogle ScholarCrossref
3.
Wareham DW, Breuer J. Herpes zoster.  BMJ. 2007;334(7605):1211-121517556477PubMedGoogle ScholarCrossref
4.
Smith JS, Robinson NJ. Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review.  J Infect Dis. 2002;186:(suppl 1)  S3-S2812353183PubMedGoogle ScholarCrossref
5.
Xu F, Sternberg MR, Kottiri BJ,  et al.  Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States.  JAMA. 2006;296(8):964-97316926356PubMedGoogle ScholarCrossref
6.
Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection.  Ann Intern Med. 1994;121(11):847-8547978697PubMedGoogle ScholarCrossref
7.
Brown ZA, Selke S, Zeh J,  et al.  The acquisition of herpes simplex virus during pregnancy.  N Engl J Med. 1997;337(8):509-5159262493PubMedGoogle ScholarCrossref
8.
Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland  MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction.  Mayo Clin Proc. 2007;82(11):1341-134917976353PubMedGoogle ScholarCrossref
9.
Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years' experience with acyclovir.  J Infect Dis. 2002;186:(suppl 1)  S40-S4612353186PubMedGoogle ScholarCrossref
10.
Saltzman R, Jurewicz R, Boon R. Safety of famciclovir in patients with herpes zoster and genital herpes.  Antimicrob Agents Chemother. 1994;38(10):2454-24577840587PubMedGoogle ScholarCrossref
11.
Buhimschi CS, Weiner CP. Medications in pregnancy and lactation: part 1 teratology.  Obstet Gynecol. 2009;113(1):166-18819104374PubMedGoogle Scholar
12.
Moore HL Jr, Szczech GM, Rodwell DE, Kapp  RW Jr, de Miranda P, Tucker WE Jr. Preclinical toxicology studies with acyclovir: teratologic, reproductive and neonatal tests.  Fundam Appl Toxicol. 1983;3(6):560-5686662297PubMedGoogle ScholarCrossref
13.
Chahoud I, Stahlmann R, Bochert G, Dillmann I, Neubert D. Gross-structural defects in rats after acyclovir application on day 10 of gestation.  Arch Toxicol. 1988;62(1):8-143190462PubMedGoogle ScholarCrossref
14.
US Food and Drug Administration.  Zovirax (acyclovir product information), GlaxoSmithKline, 2005. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018828s030,020089s019,019909s020lbl.pdf. Accessed July 5, 2010
15.
US Food and Drug Administration.  Valtrex (valacyclovir product information), GlaxoSmithKline, 2008. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020487s016lbl.pdf. Accessed July 5, 2010
16.
US Food and Drug Administration.  Famvir (famciclovir product information), Novartis, 2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020363s036lbl.pdf. Accessed July 5, 2010
17.
Stone KM, Reiff-Eldridge R, White AD,  et al.  Pregnancy outcomes following systemic prenatal acyclovir exposure: conclusions from the international acyclovir pregnancy registry, 1984-1999.  Birth Defects Res A Clin Mol Teratol. 2004;70(4):201-20715108247PubMedGoogle ScholarCrossref
18.
Ratanajamit C, Vinther Skriver M,  et al.  Adverse pregnancy outcome in women exposed to acyclovir during pregnancy: a population-based observational study.  Scand J Infect Dis. 2003;35(4):255-25912839155PubMedGoogle ScholarCrossref
19.
Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England.  Br J Obstet Gynaecol. 1998;105(8):882-8899746382PubMedGoogle ScholarCrossref
20.
Knudsen LB, Olsen J. The Danish Medical Birth Registry.  Dan Med Bull. 1998;45(3):320-3239675544PubMedGoogle Scholar
21.
Jørgensen FS. Ultrasonography of pregnant women in Denmark 1999-2000: description of the development since 1980-1990.  Ugeskr Laeger. 2003;165(46):4409-441514655565PubMedGoogle Scholar
22.
Kristensen J, Langhoff-Roos J, Skovgaard LT, Kristensen FB. Validation of the Danish Birth Registration.  J Clin Epidemiol. 1996;49(8):893-8978699210PubMedGoogle ScholarCrossref
23.
Danmarks Statistik.  Research databases: data sources available at Statistics Denmark [in Danish] (ISBN 8701-501-1301-1). http://www.dst.dk/upload/forskningsdatabaser.pdf. Accessed August 2, 2010
24.
Andersen TF, Madsen M, Jørgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register: a valuable source of data for modern health sciences.  Dan Med Bull. 1999;46(3):263-26810421985PubMedGoogle Scholar
25.
Eurocat Network.  Chapter 3.3: coding of Eurocat subgroups of congenital anomalies, issued on January, 03, 2007. http://www.eurocat-network.eu/content/EUROCAT-Guide-1.3.pdf. Accessed March 3, 2010
26.
Eurocat Network.  Chapter 3.2: minor anomalies for exclusion, issued on 31-08-2007. http://www.eurocat-network.eu/content/EUROCAT-Guide-1.3.pdf. Accessed March 3, 2010
27.
Pedersen CB, Gøtzsche H, Møller JO, Mortensen PB. The Danish Civil Registration System: a cohort of eight million persons.  Dan Med Bull. 2006;53(4):441-44917150149PubMedGoogle Scholar
28.
Larsen H, Nielsen GL, Bendsen J, Flint C, Olsen J, Sørensen HT. Predictive value and completeness of the registration of congenital abnormalities in three Danish population-based registries.  Scand J Public Health. 2003;31(1):12-1612623519PubMedGoogle ScholarCrossref
29.
Jepsen B, Jepsen P, Johnsen SP, Espersen GT, Sørensen HT. Validity of diagnoses of cardiac malformations in a Danish population-based hospital-discharge registry.  Int J Risk Saf Med. 2006;18(2):77-81Google Scholar
Original Contribution
August 25, 2010

Use of Acyclovir, Valacyclovir, and Famciclovir in the First Trimester of Pregnancy and the Risk of Birth Defects

Author Affiliations

Author Affiliations: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

JAMA. 2010;304(8):859-866. doi:10.1001/jama.2010.1206
Abstract

Context 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.

Design, Setting, and Participants 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.

Main Outcome Measure 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.

Conclusion 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.

×