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. 2010;304(8):859-866 (doi:10.1001/jama.2010.1206) JAMA
Björn Pasternak; Anders Hviid
Defects
First Trimester of Pregnancy and the Risk of Birth
Use of Acyclovir, Valacyclovir, and Famciclovir in the
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ORIGINAL CONTRIBUTION
Use of Acyclovir, Valacyclovir, and Famciclovir
in the First Trimester of Pregnancy
and the Risk of Birth Defects
Björn Pasternak, MD, PhD
Anders Hviid, MSc, DrMedSci
ACYCLOVIR, VALACYCLOVIR,and famciclovir are antiviralagents used in the treatmentof herpes simplex and her-
pes zoster infections. For genital and la-
bial herpes, these antivirals are used as
short-course treatment in primary in-
fections and as episodic or chronic sup-
pressive therapy for frequently recur-
ring disease.1,2 In herpes zoster,
antivirals effectively reduce acute symp-
toms as well as the risk for posther-
petic neuralgia.3
The prevalence of herpes simplex is
high4,5 and almost 40% of individuals
with genital herpes experience at least
6 recurrences in the first year after dis-
ease onset,6 which is often the thresh-
old for episodic or chronic suppres-
sive treatment.1 More than 1% of
susceptible women acquire herpes sim-
plex during the first trimester of preg-
nancy7 and the incidence of herpes zos-
ter is 1.5 to 2 per 1000 person-years in
the third and fourth decades of life.8
Given this background, antiviral treat-
ment will be indicated for a significant
number of women in pregnancy.
Although the safety of acyclovir, vala-
cyclovir, and famciclovir in general has
beenwell established,9,10 data on the use
of these antivirals in early pregnancy are
limited. Animal studies, although of un-
certain applicability to humans,11 did
not demonstrate teratogenic effects ini-
tially, whereas later studies suggested
that multiple defects may be induced
with very high doses of acyclovir.12,13
The US Food and Drug Administra-
tion has classified acyclovir, valacyclo-
vir, and famciclovir as category B drugs
in pregnancy.14-16 Information on the
safety of acyclovir, with regard to tera-
togenicity in humans, is mainly based
on data from a pregnancy registryman-
For editorial comment see p 905.
Author Affiliations:Department of Epidemiology Re-
search, Statens Serum Institut, Copenhagen, Den-
mark.
CorrespondingAuthor: Björn Pasternak,MD, PhD,De-
partment of Epidemiology Research, Statens Serum
Institut, Artillerivej 5, 2300 Copenhagen S, Denmark
(bjp@ssi.dk).
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 reg-
istries 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 OutcomeMeasure 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 com-
pared with 19 920 (2.4%) among the unexposed (adjusted POR, 0.89; 95% confi-
dence interval [CI], 0.65-1.22). For individual antivirals, a major birth defect was di-
agnosed 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 expo-
sure was uncommon (n=26), with 1 infant (3.8%) diagnosed with a birth defect. Ex-
ploratory analyses revealed no associations between antiviral drug exposure and 13
different subgroups of birth defects, but the number of exposed cases in each sub-
group 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.
JAMA. 2010;304(8):859-866 www.jama.com
©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, August 25, 2010—Vol 304, No. 8 859
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aged by the drug manufacturer.17 This
study reported that the rate of major
birth defects in 596 pregnancies ex-
posed in the first trimesterwas 3.2%and
compared it to the rate expected (3.2%)
in the general population. In addition
to the lack of a valid control group, re-
cruitment to this study relied on spon-
taneous reporting. Two other acyclo-
vir studies were very limited in size.18,19
There are no published data on vala-
cyclovir in early pregnancy and expe-
rience with famciclovir is limited to 4
pregnancies.19
We conducted a nationwide registry-
based cohort study to assess associa-
tions between acyclovir, valacyclovir,
and famciclovir use in the first trimes-
ter of pregnancy and major birth de-
fects. Our primary objective was to in-
vestigate the risk of any major birth
defects. In secondary explorative analy-
ses, we examined risks in subgroups of
major birth defects by organ system.
METHODS
We used data from nationwide regis-
tries to conduct a historical cohort study
including all infants born alive in
Denmark from January 1, 1996, to Sep-
tember 30, 2008, and evaluated asso-
ciations between exposure to oral acy-
clovir, valacyclovir, and famciclovir in
the first trimester of pregnancy andma-
jor birth defects diagnosed within the
first year of life. In supplementary analy-
ses, we investigated associations be-
tween use of dermatological acyclovir
and penciclovir creams and the risk of
birth defects. Individual-level datawere
linked between registries using the
unique personal identification num-
ber assigned to all inhabitants in Den-
mark. The study was approved by the
Danish Data Protection Agency. Eth-
ics approval is not required for registry-
based research in Denmark.
Study Cohort
TheMedical Birth Register (MBR) con-
tains individual-level information on all
deliveries by women living in Den-
mark,20 including the personal identi-
fication numbers of the parents and the
newborn, date of birth, multiple births,
gestational age, and various physical
characteristics of the newborn. On the
basis of the MBR, we identified a co-
hort of all live births in Denmark from
January 1, 1996, to September 30, 2008.
The date of conception was calculated
by subtracting gestational age fromdate
of birth. For births in which gesta-
tional age was missing (0.9%), we im-
puted the cohort median of 280 days.
TheMBR records gestational age based
on the last menstrual period and cor-
rected by ultrasonographic measure-
ments in most women.21 A validation
study of gestational age registration
in the MBR compared registered data
with medical records and found that
87% of registrations were correct if
agreement was defined as within 1
week.22
Antiviral Drug Exposure
The Prescription Drug Register,23 es-
tablished in 1995, contains individual-
level information on all prescriptions
filled at all Danish pharmacies. Each
record contains the personal identifi-
cation number of the patient, date of
filling the prescription, anatomic thera-
peutic chemical (ATC) code, number
of packages, package size, and num-
ber of daily defined doses in the
prescription. We obtained informa-
tion (ATC code) on oral acyclovir
( J05AB01), valacyclovir ( J05AB11),
famciclovir (J05AB09), and dermato-
logic acyclovir (D06BB03) and penci-
clovir (D06BB06) prescriptions filled by
cohort mothers from 4 weeks before
conception until birth. Systemic acy-
clovir, valacyclovir, and famciclovir are
prescription-only drugs in Denmark,
while dermatological acyclovir andpen-
ciclovir creams have also been avail-
able over the counter since 1993 and
1999, respectively. We lacked infor-
mation on inpatient antiviral drug treat-
ment.
Birth Defects
Cases of birth defects were identified
through the National Patient Register
(NPR),24 which contains individual-
level information on hospital visits
(emergency department and outpa-
tient) and admissions including diag-
noses assigned by clinicians accord-
ing to the International Classification of
Disease (ICD). The NPR does not con-
tain diagnostic data from the primary
care setting, which limits the detec-
tion of diagnoses to those that have been
diagnosed in hospitals. We accessed
NPR data covering January 1, 1996, to
March 31, 2009. For multiple births,
any child was considered as a poten-
tial case. Major birth defects were de-
fined according to the EUROCAT (a
European network for surveillance of
congenital anomalies) classification for
subgroups of major congenital anoma-
lies.25Wemodified the EUROCATpro-
tocol for the purpose of our study: in-
fants with diagnoses of chromosomal
aberrations, genetic disorders, and birth
defect syndromes with known causes
(n=2944), and congenital viral infec-
tions possibly associated with birth de-
fects (n=259) were identified and ex-
cluded (ICD codes are available in
eAppendix, http://www.jama.com).Mi-
nor defects were excluded from evalu-
ation according to the EUROCAT ex-
clusion list.26
Potential Confounders
From theMBR, theCentral PersonReg-
ister,27 and Statistics Denmark, we ob-
tained information onbirth year and the
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. From
theNPR and the PrescriptionDrugReg-
ister, we obtained information on ma-
ternal diseases and drug exposures that
maybe associated bothwithherpes sim-
plex or herpes zoster and birth de-
fects; infectious diseases in the first tri-
mester; history of sexually transmitted
infections, diabetes mellitus, and im-
munodeficiency; and filled prescrip-
tions for antineoplastic and immuno-
modulating agents from 3 months
before conception throughout the first
trimester, oral glucocorticoids in the
first trimester, and oral antibiotics in the
first trimester (ICD and ATC codes in
ANTIVIRAL DRUGS DURING FIRST TRIMESTER AND RISK OF BIRTH DEFECTS
860 JAMA, August 25, 2010—Vol 304, No. 8 (Reprinted) ©2010 American Medical Association. All rights reserved.
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eAppendix). We also identified high-
risk pregnancies and history of birth
defects in siblings back to 1977. We
did not have data on folic acid expo-
sure.
Statistical Analysis
We used logistic regression to esti-
mate prevalence odds ratios (PORs)
with 95% confidence intervals (CIs)
comparing prevalence odds of major
birth defects in infants from pregnan-
cies exposed to antivirals and in in-
fants fromunexposed pregnancies (SAS
software version 9.1, SAS Institute Inc,
Cary, North Carolina). Results were
Table 1. Demographic Characteristics of Participants in a Nationwide Cohort of 837 795 Live Births in Denmark, January 1, 1996, to
September 30, 2008
Characteristic
No. (%)a
Exposed to Antivirals
Unexposed
(n = 832 721)
Weeks 1-4 Before
Conception (n = 1354)
First Trimester
(n = 1804)
Second and Third
Trimesters (n = 2581)
Birth year
1996-1998 165 (12) 205 (11) 386 (15) 200 162 (24)
1999-2001 232 (17) 273 (15) 453 (18) 197 389 (24)
2002-2004 337 (25) 435 (24) 646 (25) 191 931 (23)
2005-Sept 2008 620 (46) 891 (49) 1096 (42) 243 239 (29)
Mother’s age at conception, y
�18 1 (0.1) 3 (0.2) 3 (0.1) 2309 (0.3)
18-24 173 (13) 204 (11) 250 (10) 112 260 (13)
25-29 452 (33) 604 (33) 731 (28) 290 399 (35)
30-34 496 (37) 649 (36) 1025 (40) 293 767 (35)
35-39 204 (15) 307 (17) 489 (19) 115 566 (14)
40-44 26 (2) 35 (2) 80 (3) 17 808 (2)
�45 2 (0.2) 2 (0.1) 3 (0.1) 612 (0.1)
Mother’s level of education
Compulsory school 232 (17) 333 (18) 433 (17) 176 847 (21)
Secondary school 213 (16) 264 (15) 376 (15) 107 116 (13)
Vocational training or short tertiary education 479 (35) 637 (35) 812 (31) 293 525 (35)
Medium or long tertiary education 409 (30) 526 (29) 874 (34) 219 257 (26)
Unknown 21 (2) 44 (2) 86 (3) 35 976 (4)
Mother’s socioeconomic class
Outside of labor marketb 290 (21) 391 (22) 579 (22) 207 396 (25)
Employment with basic or no qualifications 427 (32) 597 (33) 697 (27) 286 969 (35)
Employment with medium-level qualifications 290 (21) 389 (22) 557 (22) 163 442 (20)
Employment with unknown qualifications 92 (7) 131 (7) 199 (8) 51 199 (6)
Self-employed or coworking spouse 47 (3) 56 (3) 81 (3) 20 408 (2)
Top manager 205 (15) 236 (13) 451 (17) 97 751 (12)
Unknown 3 (0.2) 4 (0.2) 17 (0.7) 5556 (0.7)
Mother’s birth place
Denmark 1243 (92) 1660 (92) 2315 (90) 710 962 (85)
Europe and North America 64 (5) 64 (4) 133 (5) 43 156 (5)
Rest of the world 47 (3) 79 (4) 129 (5) 74 531 (9)
Unknown 0 1 (0.1) 4 (0.2) 4072 (0.5)
Mother’s place of residence at the time of conception
Copenhagen 366 (27) 464 (26) 806 (31) 132 328 (16)
Copenhagen suburbs 152 (11) 193 (11) 310 (12) 72 352 (9)
North Sealand 102 (8) 159 (9) 398 (15) 57 704 (7)
East Sealand 51 (4) 84 (5) 98 (4) 32 445 (4)
West and South Sealand 103 (8) 151 (8) 154 (6) 73 221 (9)
Bornholm 6 (0.4) 13 (0.7) 12 (0.5) 4704 (0.6)
Funen 95 (7) 119 (7) 139 (5) 67 957 (8)
North Jutland 105 (8) 128 (7) 99 (4) 82 586 (10)
East Jutland 176 (13) 226 (13) 274 (11) 125 934 (15)
West Jutland 77 (6) 102 (6) 93 (4) 64 436 (8)
South Jutland 118 (9) 162 (9) 161 (6) 104 357 (13)
Unknown 3 (0.2) 3 (0.2) 37 (1) 14 715 (2)
aSome individuals were exposed to antivirals in more than 1 time window. Percentages may not total 100 due to rounding.
bCategory includes students.
ANTIVIRAL DRUGS DURING FIRST TRIMESTER AND RISK OF BIRTH DEFECTS
©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, August 25, 2010—Vol 304, No. 8 861
at University of California - San Francisco on October 28, 2010 www.jama.comDownloaded from
considered statistically significantwhen
the 95%CI did not overlap 1.0 in either
direction. Potential confounders were
included in regression models if they
were significantly (P� .05; 2-sided) as-
sociatedwithmajor birth defects in uni-
variate analyses. P values in univariate
analyses were estimated with missing
values excluded. In adjustedmodels,we
applied multiple imputation for vari-
ables with missing values using the
Markov Chain Monte Carlo method.
Childrenwereobservedforthefirstreg-
istereddiagnosisofamajordefectwithin
1 year after birth. For the primary out-
comemeasureof allmajorbirthdefects,
wecombinedall subgroupsofmalforma-
tions. In preplanned exploratory analy-
sesweevaluatedsubgroupsbyorgansys-
temwithoutcorrectionformultiplecom-
parisons. Any filling of an acyclovir,
valacyclovir, or famciclovirprescription
wasconsideredasexposure.Themainex-
posure timewindowcomprised the first
trimester (12weeks). Analysis of expo-
sure within 4 weeks before conception
andinthesecondandthirdtrimesterswas
performed for comparison. The timing
ofexposurewasdefinedbythedateoffill-
ing theprescription, andanypregnancy
could contribute to any exposure time
window.Incaseapregnancywasexposed
inmore than 1 timewindow, the corre-
sponding PORs (except for crude esti-
mates) were adjusted for effects of each
other. The study had 80% power to de-
tect a 47% relative increase (POR, 1.47)
intheriskofbirthdefectsinthoseexposed
to any antiviral (n=1804; 5% 2-sided �
level; EpiInfo, version3.5.1, http://www
.cdc.gov/epiinfo).
RESULTS
The cohort included 837795 live births
(34 787 multiple births), among whom
19960(2.4%)werediagnosedwithama-
jorbirthdefectduringthefirstyearof life.
TABLE1andTABLE2presentdescriptive
characteristics of cohort participants.
Among 1804 pregnancies exposed to
acyclovir, valacyclovir, or famciclovir at
any time in the first trimester, 40 infants
(2.2%) had a diagnosis of a major birth
defect, comparedwith19920of835991
infants(2.4%)amongtheunexposedpreg-
nancies (crudePOR,0.93;95%CI,0.68-
1.27). Risk estimates for those potential
confoundersthatwerestatisticallysignifi-
cant risk factors for birth defects in uni-
variate analyses are shown in eTable 1.
Adjusting for these variables in a multi-
variatemodel, acyclovir, valacyclovir, or
famciclovir exposure at any time in the
first trimesterwasnot associatedwith in-
creased risk ofmajor birth defects (POR,
0.89; 95% CI, 0.65-1.22), as compared
with unexposed pregnancies. TABLE 3
presents risk estimates for the associa-
tion between use of antivirals and ma-
jor birth defects for the 3 antivirals to-
gether and individually in the different
exposure time windows. First-trimes-
ter use of acyclovir, the most com-
monly prescribed antiviral, was not as-
sociated with major birth defects (32
cases among 1561 exposed [2.0%] vs
2.4% in the unexposed; adjusted POR,
0.82; 95% CI, 0.57-1.17). Neither vala-
cyclovir nor famciclovir were associ-
ated with major birth defects, although
use of the latter was very uncommon.
TheFIGURE shows exploratory analy-
ses of associations between use of
antivirals and major birth defect sub-
Table 2. Clinical Characteristics of Participants in a Nationwide Cohort of 837795 Live Births in Denmark, January 1, 1996, to September 30, 2008
Characteristic
No. (%)a
Exposed to Antivirals
Unexposed
(n = 832 721)
Weeks 1-4 Before
Conception (n = 1354)
First Trimester
(n = 1804)
Second and Third
Trimesters (n = 2581)
Mother’s parity
0 771 (57) 978 (54) 1232 (48) 351 614 (42)
1 403 (30) 550 (30) 920 (36) 299 390 (36)
2 120 (9) 173 (10) 289 (11) 114 993 (14)
�3 23 (2) 52 (3) 75 (3) 43 012 (5)
Unknown 37 (3) 51 (3) 65 (3) 23 712 (3)
Maternal smoking in pregnancy 232 (17) 293 (16) 407 (16) 160 388 (19)
Unknown smoking status in pregnancy 56 (4) 70 (4) 79 (3) 34 947 (4)
History of birth defects in siblings 56 (4) 76 (4) 100 (4) 39 519 (5)
Maternal diseasesb
Diabetes 12 (0.9) 15 (0.8) 25 (1) 9162 (1)
Infectious disease in first trimester 32 (2) 48 (3) 78 (3) 6941 (0.8)
History of sexually transmitted infection 113 (8) 158 (9) 258 (10) 23 087 (3)
History of anogenital herpes 49 (4) 77 (4) 163 (6) 1060 (0.1)
Immunodeficiency 2 (0.2) 2 (0.1) 2 (0.1) 199 (�0.1)
High-risk pregnancy 235 (17) 352 (20) 514 (20) 139 459 (17)
Maternal drug usec
Oral antibiotic in first trimester 208