1. Use of Acyclovir, Valacyclovir, and Famciclovir in the First Trimester of Pregnancy and the Risk of Birth Defects Björn Pasternak; Anders Hviid R3 Jungwook Kim / Prof. Misuk Lee Journal of the American Medical Association 2010;304(8):859-866

2. Background  Acyclovir, Valacyclovir, and famiciclovir ► Herpes simplex & Herpes zoster infection  H.simplex → prevalence ↑ → almost 40% of individuals with genital herpes : at least 6 recur in 1 st year after onset : episodic or chronic suppressive treatment → 1% ↑ of susceptible women during the 1 st trimester of pregnancy (incidence of Zoster : 1.5~2 /1000 person-years in 3 rd & 4 th decades)  Safety of acyclovir, valacyclovir, and famciclovir ► in general : well established ► in early pregnancy : limited ► Animal studies : No teratogenic effects initially : multiple defects may be induced with very high doses of acyclovir

3. Background  Acyclovir, valacyclovir, and famciclovir - US FDA : Category B Drugs in pregnancy - information on the safety of Acyclovir → mainly based on data from pregnancy registry managed by drug manufacturer → the rate of major birth defect in 596 pregnancies exposed in the 1 st trimester 3.2% (vs 3.2% expected in the general population) ⇒ lack of a valid control group recruitment relied on spontaneous reporting very limited in size

4. Background  Nationwide registry based cohort study to assess associations between acyclovir, valacyclovir, and famciclovir use in the 1 st trimester of pregnancy and major birth defects  Primary objective : to investigate the risk of any major birth defects  Secondary explorative analyses : risks in subgroups of major birth defects by organ system

5. Methods  Participants ► Data from nationwide registries ► historical cohort study ► all infants born alive in Denmark (Jan 1,1996 ~ Sep 30,2008)  Exposure to oral antivirals in 1 st trimester ⇔ Major birth defects diagnosed within the 1 st year of life  Use of dermatological acyclovir/penciclovir creams ⇔ risk of birth defects

6. Methods  Study Cohort ► Medical Birth Register (MBR) 1) all deliveries by women living in Denmark 2) personal identification No. of parents / newborn date of birth, multiple birth, gestational age, various physical characteristics of the newborn.  Antiviral Drug Exposure ► Prescription Drug Register 1) all prescriptions filled at all Danish pharmacies 2) personal ID No, date of prescription, anatomic therapeutic chemical (ATC) code, number of packages, package size number of daily defined doses

7. Methods  Birth Defects ► National Patient Register (NPR) : individual level information on hospital visits admission including Dx (ICD) ► Major birth Defects : defined according to the EUROCAT (European network for surveillance of congenital anomalies)  Potential confounders ► MBR, Central Person Register, Statistics Denmark birth year, mother’s parity, age at conception, smoking status during pregnancy, country or continent of origin, place of residence at the time of conception, and educational level and socioeconomic class in the year of conception

8. Results

9. Demographic Characteristics of Participants

11. Clinical Characteristics of Participants

12. Association Between antiviral Drugs & Major Birth Defects

13. Any viral drugs & subgroups of Major birth defects by organ system

14. Acyclovir & subgroups of Major birth defects by organ system

15. Association Between use of Dermatologic Acyclovir and Penciclovir Creams & Major Birth Defects

16. Results  Alternative analyses to test the robustness of result 1. restricted to those who used antivirals exclusively in the 1 st trimester 2. antiviral prescription at any time in the period of maximal susceptibility to teratogenic agents, 2 to 8 weeks after conception 3. excluding multiple births 4. restricted to mothers without a history of antiviral use 5. restricted to cohort participants without any missing values ⇒ antiviral exposure was not associated with major birth defects

17. 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.