DTIC ADA496867: Pregnancy, Birth, and Infant Health Outcomes from the National Smallpox Health Vaccine in Pregnancy Registry, 2003-2006

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by  Defense Technical Information Center

Pregnancy, Birth, and Infant Health

Outcomes from the National Smallpox
Health Vaccine in Pregnancy
Registry, 2003–2006

M. A. K. Ryan

J. F. Seward
For the Smallpox Vaccine in
Pregnancy Registry Team

Naval Health Research Center
Report No. 06-34

. Approved for Public Release; Distribution Unlimited.

Naval Health Research Center
140 Sylvester Road
San Diego, California 92106
SUPPLEMENT ARTICLE
Pregnancy, Birth, and Infant Health Outcomes from
the National Smallpox Vaccine in Pregnancy Registry,
2003–2006
Margaret A. K. Ryan1and Jane F. Seward,2for the Smallpox Vaccine in Pregnancy RegistryTeama
1DepartmentofDefenseCenterforDeploymentHealthResearch,NavalHealthResearchCenter,SanDiego,California;and2NationalCenter
forImmunizationandRespiratoryDisease,CentersforDiseaseControlandPrevention,Atlanta,Georgia
WhentheUnitedStatesimplementedcivilianandmilitarysmallpoxvaccinationprogramsin2003,theNational
Smallpox Vaccine in Pregnancy Registry was established to better evaluate outcomes after the inadvertent
vaccination of pregnant women. Women were referred to the registry by vaccine administrators,healthcare
providers, or state health departmentsorthroughself-referral.Registryprofessionalsactivelyfollowupwith
all enrolled women and collect data on pregnancy,birth, andinfanthealthoutcomes.AsofSeptember2006,
pregnancy outcome data were available from 376 women. Most (77%) were vaccinated near the time of
conception,beforeresultsofastandardpregnancytestwouldhavebeenpositive.Todate,outcomeevaluations
havenotrevealedhigher-than-expectedratesofpregnancyloss(11.9%),pretermbirth(10.7%),orbirthdefects
(2.8%), compared with those in healthy referent populations. No casesoffetalvacciniahavebeenidentified.
TheSmallpoxVaccineinPregnancyRegistrycontinuestoactivelyenrollwomenandfollowinfantandearly-
childhoodhealth outcomes.
In response to concerns about potential biological posure during pregnancy that often results in fetal or
weapons use worldwide, the United States initiated a neonatal death [5, 6]. Fetal vaccinia is postulated to
national smallpox vaccination program in early 2003 occurfollowingmaternalviremiaandismanifestedby
[1].Thevaccineapprovedforthiseffortwasfirstused skinlesionsandinternalorganinvolvement[5,7].On
in 1931, and current stocks were produced as Dryvax thebasis of historicaldata,itisestimatedthattherisk
byWyethLaboratoriesinthelate1970sandearly1980s of fetal vaccinia occurring after smallpox vaccination
[2].Becausethevaccinehadbeenadministeredtobil- inpregnancyrangesfrom1/10,000to1/100,000[6,8–
lions of individuals over nearly half a century, short- 12].Approximately50casesoffetalvacciniahavebeen
term adverse health effects on vaccine recipients are reportedintheworld,and3havebeenreportedinthe
fairlywelldocumented[2–4].Historically,muchlessis United States [4, 5, 7, 12].
describedaboutexposuretosmallpoxvaccineinpreg-
In the absence of clinically apparent fetal vaccinia,
nancy and the potential effects on a developingfetus.
the risk of pregnancy loss after smallpox vaccination
As a live virus product, smallpox vaccine cancause
has notbeenestablished.Althoughsomelargereviews
fetal vaccinia, a rare but serious complication of ex-
arereassuringthatnoincreasedriskexists[8,12],other
reports have cited concern that smallpox vaccination
Theviewsexpressedinthisworkarethoseoftheauthorsanddonotreflect may be associated with spontaneous pregnancy loss
theofficialpolicyorpositionoftheUSDepartmentofDefense,USCentersfor [13–17]. Likewise, the risks of preterm delivery, low
DiseaseControlandPrevention,ortheUSgovernment.
a Membersarelistedattheendofthetext. birth weight, and other birth problems afterexposure
Reprintsorcorrespondence:Dr.MargaretA.K.Ryan,DepartmentofDefense to smallpox vaccine in pregnancy have not been
CenterforDeploymentHealthResearch,NavalHealthResearchCenter,Box85122,
SanDiego,CA92186-5122([email protected]). defined.
ClinicalInfectiousDiseases 2008;46:S221–6 Potential adverse effects on infant health also are a
Thisarticleisinthepublicdomain,andnocopyrightisclaimed. concernaftermaternalexposure.Smallpoxvaccination
1058-4838/2008/4606S3-0009
DOI:10.1086/524744 in pregnancy has been associated with club foot mal-
SmallpoxVaccinationinPregnancy • CID 2008:46 (Suppl3) • S221
formationsinonereport[18];otherreviewshaverefutedsuch viders during and after pregnancy, primarily through confi-
an association [12]. Given that the cause of most congenital dential telephonecontact by registryprofessionals.
anomalies is unknown and that some have argued that live Information sheets were provided to enrollees and their
virusvaccinesgivenduringpregnancymightcausebirthdefects healthcareproviderstodescribetheknownandunknownrisks
[19–22],moreinformationisneededtounderstandtheriskof associated with smallpox vaccine in pregnancy and to answer
infant health problems after maternalsmallpox vaccination. frequently asked questions, such as those relatedtotheuseof
Because of the risk of fetal vaccinia, smallpox vaccine is vaccinia immune globulin [31]. The information sheet also
generallycontraindicatedduringpregnancy.Nonetheless,itwas specified that, in the event of pregnancy loss orotheradverse
anticipated that vaccinating large numbers of youngadultsin outcomes, registry professionals would coordinate laboratory
the national smallpox vaccine program that started in 2003, testing of fetal or infant specimens(e.g.,skinlesions)forvac-
evenwith rigorouspregnancyscreening,wouldresultinsome cinia, if desired. This included viral culture and PCR testing
inadvertentvaccineexposurestopregnantwomen[23–25].Ac- by Laboratory Response Network facilities and/or the CDC
cordingly,theNationalSmallpoxVaccineinPregnancyRegistry Poxvirus Laboratory[32].
was established to identify exposed women and to obtain in- Expected rates for outcomes examined weredeterminedby
formationonpregnancy,birth,andinfanthealthoutcomes.We literature review and by identifying relevant key publications
report the findings from the first 3.5 years of the registry. from subject matter experts. We calculated 95% CIs for di-
chotomous outcomes on the basis of normal approximation
METHODS ofthebinomialdistribution.Foroutcomecellcounts!5,exact
CIs were calculated[33].
The National Smallpox Vaccine in PregnancyRegistrywases-
Thisresearch,performedunderNavalHealthResearchCen-
tablished in concert with the national smallpox vaccine pro-
ter Institutional Review Board–approved protocol 2003.0018,
gram in early 2003. The registry was developed as a collabo-
underworkunit60504,hasbeenconductedincompliancewith
rative effort between the US Department of Defense (DoD)
all applicable federal regulations governing the protection of
and the Centers for Disease Control and Prevention (CDC)
human subjects in research.
andwasmodeledafterpriorregistriesforinadvertentexposure
to vaccines or medications in pregnancy [26]. The establish- RESULTS
ment of the registrywas announcedinCDCpublicationsand
AsofSeptember2006,pregnancyoutcomedatawereavailable
on DoD Web sites [27–29].
for376womenenrolledintheSmallpoxVaccineinPregnancy
Womenwereenrolledintheregistryiftheyreceivedsmallpox
Registry. Women who had not yet reached the 20th week of
vaccine during pregnancy or if they became pregnant within
pregnancy at the time of thisreport(np7),enrolledwomen
28daysofvaccination[28].Conventionally,theestimatedges-
whohadasecondaryexposurefromthehusband’svaccination
tational age (EGA) of a pregnancy is dated from the first day
only(np4),andenrolledwomenwhowerelosttofollow-up
of the last menstrual period of the cycle in which a woman
(np3) are excluded from this report.
conceives; dating of EGA is approximated by ultrasound ex-
Table1showsthecharacteristicsofthe376womenforwhom
aminationwhenthetimingoftheovulatorycycleisuncertain.
pregnancy outcome data were available. Consistent with the
We used clinical reports of EGA for establishing dates of all
pregnancies in the registry. The registry was also designed to
include cases of secondary exposure of pregnant women by, Table 1. Characteristicsof376womeninadvertentlyvaccinated
against smallpox in pregnancy.
for example, close contact with partners who were recently
vaccinated.
Characteristic Value
Womenwerereferredtotheregistrybyvaccineadministra-
Ageatvaccination,meanyears(range) 23.2(17–41)
tors, obstetric providers, other health care providers, state
Vaccinatedaspartofmilitaryservice 365(97.1)
healthdepartments,DoDVaccineHealthcareCenters,theMil-
VaccinatedwhiledeployedoutsideofUnitedStates 91(24.2)
itary Vaccine Agency, the CDC Clinical Information Line, or
Nohistoryofpriorsmallpoxvaccination 354(94.1)
the US Food and Drug Administration; through the Vaccine
Nohistoryofpreviouspregnancies(primigravid) 199(52.9)
AdverseEventReportingSystem[30];orthroughself-referral.
Vaccinatedbefore4weeksEGA 289(76.9)
Registry professionalsactivelysoughtcasesbycommunicating Receivedothervaccinationsinthispregnancya 260(69.1)
with vaccination and obstetric clinics and shared a standard
NOTE. Dataareno.(%)ofwomenunlessotherwiseindicated.EGA,es-
formforcasereporting.Thedata-collectionformincludedde-
timatedgestationalage.
tailsaboutvaccinationandsmallpoxvaccine“take,”aswellas a Receiptofothervaccinationsinpregnancyisbasedontheregistrystan-
dardofexposurewithin28daysbeforestartofEGAoranytimefromcon-
details about pregnancy diagnosis. Consent was requested to
ceptiontotheendofpregnancy.Ifpreconceptionexposuresareexcluded,
follow up with registry participants andtheirhealthcarepro- 162cases(43.1%)hadothervaccinationsinpregnancy.
S222 • CID 2008:46 (Suppl3) • Ryanetal.
USexperiencesince2002,mostwomen(97.1%)receivedsmall- spontaneouslossratemaybemoreappropriatelycalculatedon
poxvaccineaspartoftheirmilitaryservice,andtheremaining the basis of the number of intrauterine pregnanciesthatwere
11 women were vaccinated as civilian health care workers. not electively terminated, yielding a loss rate of 11.9%. Pop-
Ninety-fourpercentofwomenhadnohistoryofpriorsmallpox ulationreferencesforexpectedratesofpregnancylossarealso
vaccination. Prior smallpox vaccination was confirmed byre- shown in table 2 [36–41]. Figure 1 illustrates pregnancy out-
view of personalhistoriesandbyvaccinationrecordsshowing comes, including losses, by timing of maternal exposure to
receipt of the 15-jab inoculation that is consistentwithrevac- smallpoxvaccine.Thelargestpercentageoffetallosses(20.6%)
cination. Among military women, 72% served in the Army, occurred among women vaccinated between 4 and 7 weeks
17% served in the Air Force, and 10% served in the Navy or EGA.Fetaltissuewasavailablefrom5lossesforvacciniatesting;
Marine Corps. Some women (np91) were vaccinated while results of all such testing were negativefor vaccinia virus.
on military duty outside of the United States, and many Birth and infant health outcomes are summarized in table
(np260)receivedothervaccinationsinconjunctionwiththe 2. The percentage of preterm births (10.7%) among registry
smallpoxvaccine.Othervaccinationsreportedbyregistrypar- births, the average birth weight of singleton registry infants
ticipants included anthrax (np228), hepatitis A or B (np (3320 g), and the percentage of infants with low birthweight
50), typhoid (np46), influenza (np34), yellow fever (np (9.1%) may be compared with nationaldatashownintable2
18), meningococcal (np14), tetanus or tetanus-diphtheria [42]. Nearly half (47.9%) of all infants borntowomeninthe
(np8), measles-mumps-rubella (np7), polio (np2), and Smallpox Vaccine in Pregnancy Registry were male; this may
pneumococcal (np1) vaccines. becomparedwiththecurrentUSnationalproportionofmale
Most women (77%) in the registry were vaccinated before births [43].
4 weeks EGA, the time after which resultsofastandardpreg- Finally,importanthealthoutcomesareshownintable2for
nancytestshouldbepositive.Figure1showsthatmostwomen all live-born infants evaluated through the end of infancy or
were vaccinatedvery near the estimatedtime of conception. 12 months of age. Two infants in the registry died of sudden
Pregnancyoutcomesaresummarizedintable2.Among376 infantdeathsyndrome(SIDS),at7weeksand9weeksofage,
pregnant women, 5 had twin pregnancies, for a total of 381 respectively. The expected rate of SIDS is 4.7 per 10,000 live
fetal outcomes. Five ectopic pregnancies represented 1.2% of births[44,45].BothinfantswhodiedofSIDSfromtheregistry
all pregnancies reported to the registry. The 18 elective preg- had postmortem testing for vaccinia virus, and all testresults
nancyterminationsrepresented4.7%ofallfetaloutcomes.No were negative.
registry participants cited their inadvertent smallpoxvaccina- Seven infants (2.8%) had diagnoses of major birth defects,
tionasareasonforpursuingelectiveterminationofpregnancy. as defined by the National Birth Defects Prevention Network
Population references for ectopic pregnancy and elective ter- [46]. Their diagnoses included ventricular septal defects (2
mination are also shown in table 2 [34, 35]. cases),atrialseptaldefect(1case),pulmonaryvalvestenosis(1
Forty-twospontaneousfetallosseswereidentifiedinthereg- case), isolated gastroschisis (1 case), isolated omphalocele (1
istry.Althoughtheserepresent11.0%ofallfetaloutcomes,the case), and omphalocele with Beckwith-Weidemannsyndrome
Figure 1. Pregnancyoutcomesaccordingto estimatedgestationalage (EGA)at the time of maternalsmallpoxvaccination.wk, week.
SmallpoxVaccinationinPregnancy • CID 2008:46 (Suppl3) • S223
Table 2. Pregnancy, birth, and infant health outcomes among those enrolled in the Smallpox
Vaccine in Pregnancy Registry,2003–2006.
Percentage Referencevalue(s)
Outcome Value (95%CI) (source)
Fetaloutcomes(np381)
Ectopicpregnancy 5 1.3(0.2–2.4) 1–2[34]
Electiveabortion 18 5.8a(3.2–8.3) 24.6[35]
Spontaneousabortion(lossbefore20weeksEGA) 37 9.7(6.7–12.7) 9–30[36–40]
Stillbirth(lossafter20weeksEGA) 5 1.0b(0.0–2.1) 0.3–0.7[41]
Fetalvaccinia 0 0.0(0.0–0.9) 0.01–0.001[4]
Livebirthoutcomesc(np309)
Pretermbirth(before37weeksEGA) 33 10.7(7.3–14.1) 12.3[42]
Lowbirthweight(!2500g) 28 9.1(5.9–12.3) 7.9[42]
Meanbirthweight,g 3320 … 3325[42]
Malesexofinfant 148 47.9(42.3–53.6) 52[43]
Infanthealthoutcomesd(np249)
Suddeninfantdeathsyndrome 2 0.8(0.0–2.9) 0.05[44,45]
Majorbirthdefectse 7 2.8(0.8–4.8) 3–5[46]
NOTE. Dataareno.ofcases,unlessotherwiseindicated.EGA,estimatedgestationalage.
a Standardreportingforthismetricistheratioofelectiveabortionsto100livebirths.
b Standardreportingforthismetricistheproportionofsingletonstillbirthsamongallsingletonlivebirthsplusstillbirths.
Onesetofstillborntwinsandalllive-borntwinswereexcludedfromthiscalculation.
c Notethat7casesinlatepregnancyatthetimeofthisreporthadnobirthoutcomesavailable.
d Infanthealthoutcomesreportedforthosewithfollow-upthroughendofinfancyor12monthsofage.
e Amajorbirthdefectisonethataffectssurvival,requiressubstantialmedicalcare,resultsinmarkedphysicalor
psychologicalhandicaps,orinterfereswithababy’sprospectforaproductiveandfulfillinglife[46].
(1 case).Theobservedprevalenceofbirthdefects(2.8%)may cinia,theresultsarevaluableinanumberofways.Asevaluated
be compared with national data, also shown in table 2 [46]. in early 2003, established smallpox vaccine screening and ed-
At all follow-up contacts, registry participants were asked ucation practices appeared to havepreventedmanyexposures
about other indicatorsofinfanthealth,includingskinlesions. in pregnancy [28]. The rate of inadvertent exposure during
Many infants (44%) had some indication of skin findings at pregnancy amongwomenofreproductiveagevaccinateddur-
birthorinearlyinfancy;mostwereconsideredtobebirthmarks ing the first stage of the civilian and DoD programs was ∼1
or benign rashes, and none had diagnoses of fetal vaccinia. per 1000 women, substantially lower than the ∼8 per 1000
womenand12per1000womenestimatedtobeinadvertently
DISCUSSION
exposedtosmallpoxvaccineinthecivilianhealthcareworker
population and in the general population, respectively, in the
The Smallpox Vaccine in Pregnancy Registry was successfully
absence of screening and education [28]. Therefore, most
established in 2003 to evaluate inadvertent vaccine exposures
in pregnancy. The effort has been important in providing a women who were vaccinated were in the very early stages of
better understanding of potential adverse effects of smallpox pregnancy,when pregnancyis typicallynot yet recognized.
vaccinationinavulnerablepopulation.Withnearly400women Theregistrymaybemostvaluablewithregardtoconclusions
enrolled, there have been no cases of fetal vaccinia identified. about pregnancy losses.Themostfrequentlyexpectedadverse
Other adverse outcomes of pregnancy, birth, and infant de- outcome in any cohort of pregnancies is spontaneous preg-
velopment have been observed at rates consistent with those nancy loss, and, as such, pregnancy loss may be one of the
expected in the United States and previously described [34– most importantindicatorsofhazardousexposureinthespec-
46]. Although active vaccination of civilians for publichealth trum of adverse reproductive health outcomes [48]. Without
preparedness is not ongoing in the United States,assmallpox active registry follow-up, mostpregnancy-lossdatawouldnot
vaccinecontinuestobeusedinthemilitaryandvaccineremains have been captured, and it is unlikelythattestingforvaccinia
available for postevent response [47], these registry data will would have been performed on loss cases. The relatively low
be importantin directing public health policy decisions. rateofobservedpregnancylossesmay,therefore,beconsidered
Although the modest numbers ofenrolleesintheSmallpox a reassuringfinding within the registry.
VaccineinPregnancyRegistrydonotallowfordefinitivecon- Itremainsimportanttoconsiderlosses,andalladverseout-
clusions about many important outcomes, such as fetal vac- comes,inrelationtothetimingofexposureinpregnancy.Given
S224 • CID 2008:46 (Suppl3) • Ryanetal.
that fetal development is so dynamic, there are some periods such as spontaneous abortion can vary greatly, dependingon
of pregnancy that represent more vulnerabletimesforcertain the method of ascertainment[36].
adverse outcomes. For this reason, the timing of maternal The Smallpox Vaccine in Pregnancy Registry continues to
smallpox vaccination was explored in relation to pregnancy activelyenrollandfollowupwithwomenwhohavebeenvac-
losses. There were no statistically significant associations be- cinatedinpregnancy,aswellastofollowtheirchildren’shealth
tween timing of exposure and the pregnancy outcomes ex- outcomes.Mostvaccinationsarenowoccurringamongmilitary
amined. However, the small number of cases in which vacci- personnel, although small numbers of civilians may continue
nation occurred later than 4 weeks EGA limited such toreceivesmallpoxvaccineforpublichealthpreparedness.The
firstinfantsborntoregistryparticipantsreached3yearsofage
interpretations. Follow-up of the registry will continue toad-
in 2006. Registry professionals have collected health and de-
dress the issue of exposure timing.
velopmentalinformationaboutthesechildrenatleastannually
Birth outcomes are other important metrics for evaluating
so that, in the future, even more challenging questionsabout
potential hazardous exposures in pregnancy. In the Smallpox
the long-term effects of smallpox vaccination in pregnancy
Vaccine in Pregnancy Registry, the expected rates of all out-
might be explored.
comes examined fell within the 95% CIs of observed rates,
includingmeasuresoflowbirthweightandpretermbirth.The
SMALLPOX VACCINE IN PREGNANCY
proportion of registry infants who were male was within the
REGISTRY TEAM
expected range, and this may also be considered a reassuring
finding, because a reduced proportion of male infant births From the US Department of Defense: Ava Conlin, Brianna
may reflect occult hazardous exposures in a population [49]. Alexander, Rosha Aran-Loach, Katherine Campbell, Shirley
Finally, adverse infant health outcomes are of unique im- Chow, Renata Engler, John Grabenstein, Gia Gumbs, Mary
portance,becausetheyrepresentsomeofthemostvisibleand Minor, Peter Napolitano, Brian Pierce, Jessica Rubin, Cheryl
costly negative reproductive health outcomes. The absence of Rudy-Goodness, Tyler Smith, Kathy Snell, Christina Spooner,
cases of fetal vaccinia in the Smallpox Vaccine in Pregnancy Victor Stiegman,Jennifer Strickler,and JeannetteWilliams.
Registrytodateisnotunexpected,giventhelowestimatedrisk From the US Centers for Disease Control and Prevention:
for fetal vaccinia. Although 7 infants with birth defects were MariaCano,SandraS.Chaves,SonjaS.Hutchins,KristinKen-
yan, Sheryl B. Lyss, and Joseph Mulinare.
identified,theratesanddistributionofthesebirthdefectswere
notoutsideofexpectedranges[46].The2casesofSIDS,how-
Acknowledgments
ever, were unexpected occurrenceswithinthissmallcohortof
infants. Given the uncertain etiology of most SIDS cases and We gratefullyacknowledgethesupportofalloftheprofessionalswho
the uncertain effects of maternal smallpox vaccination, these havecontributedtotheSmallpoxVaccineinPregnancyRegistry,especially
thewomenandfamilieswhosharetheirhealthinformationwiththereg-
cases may illustrate the important value of the registry’s co-
istry.Wealsogreatlyappreciatetheassistanceofthefollowingstafffrom
ordinationofvacciniatestinginhelpingtoevaluateanunusual theCentersforDiseaseControlandPrevention:LouisaChapman,Riduan
association. Joesef,SusanGoldstein,KarenBroder,IngerDamon,RussellRegnery,and
SherifZaki;professionalsfromtheUSDepartmentofDefenseCenterfor
The following limitationsshouldbeconsideredwheninter-
Deployment Health Research; the US Department of Defense Vaccine
pretingthesedata.First,themajorityofwomenwerevaccinated HealthcareCentersNetwork;theMilitaryVaccineAgency;andtheHenry
M.JacksonFoundationfortheAdvancementofMilitaryMedicine.
early in pregnancy, before 4 weeks EGA. This period of preg-
Financialsupport. TheworkreportedherewassupportedbytheUS
nancyincludesweeksbeforetheembryoimplants;thus,trans-
Department of Defense and the US Department of Health and Human
mission of vaccinia virus from mother to embryo would be Services.ThisresearchwasperformedunderNavalHealthResearchCenter
institutionalreviewboard–approvedprotocol2003.0018,underworkunit
unlikely.Smallnumbersofcaseslimitedourabilitytoexamine
60504.
possibleeffectsofsmallpoxvaccineexposurelaterinpregnancy, Supplementsponsorship. Thisarticlewaspublishedaspartofasup-
when maternal viremia may be more likely to resultintrans- plement entitled “Posteradication Vaccination against Smallpox,” spon-
soredbytheNationalCenterforImmunizationandRespiratoryDiseases,
missionacrosstheplacentaandwhenoutcomesmayalsodiffer.
CoordinatingCenterforInfectiousDiseases,CentersforDiseaseControl
We could not determine the capture rate of all eligible cases andPrevention(CDC),andbytheCoordinatingOfficeforTerrorismPre-
fortheregistry.Therateofcaptureofmilitarycases,however, ventionandEmergencyResponse,CDC.
Potentialconflictsofinterest. M.A.K.R.andJ.F.S.:noconflicts.
isbeingevaluatedthroughaseparateeffort,outsideofthescope
of this report. There are limitations to relying on prior
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S226 • CID 2008:46 (Suppl3) • Ryanetal.
REPORT DOCUMENTATION PAGE
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1. Report Date (DD MM YY) T 2. Report Type 3. DATES COVERED (from - to)
17 10 06 New 2003-2006
4. TITLE AND SUBTITLE 5a. Contract Number:
Pregnancy, Birth, and Infant Health Outcomes from the National Smallpox 5b. Grant Number:
Vaccine in Pregnancy Registry, 2003-2006 5c. Program Element:
6. AUTHORS 5d. Project Number:
Margaret A. K. Ryan & Jane F. Seward for the Smallpox Vaccine in Pregnancy 5e. Task Number:
Registry Team 5f. Work Unit Number: 60504
7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)
Naval Health Research Center
P.O. Box 85122
San Diego, CA 92186-5122 9. PERFORMING ORGANIZATION REPORT
NUMBER
8. SPONSORING/MONITORING AGENCY NAMES(S) AND ADDRESS(ES) Report No. 06-34
Commanding Officer Commander
Naval Medical Research Center Navy Medical Support Command
503 Robert Grant Ave P O Box 240 10. Sponsor/Monitor's Acronyms(s)
Silver Spring, MD 20910-7500 Jacksonville, FL 332212 0140 NMRC/NMSC
11. Sponsor/Monitor's Report Number(s)

12 DISTRIBUTION/AVAILABILITY STATEMENT
Will be approved for public release with distribution unlimited AFTER accepted for publication and released from journal
embargo period.
13. SUPPLEMENTARY NOTES
Published in: Clinical Infectrious Diseases, 2008,15(46), (Suppl 3) S22-16
14. ABSTRACT (maximum 200 words)
Background: Little information is available to describe the risks of smallpox vaccine administered in pregnancy, with the
exception of known, rare cases of fetal vaccinia. When the United States implemented a smallpox vaccination program in
2003, the Smallpox Vaccine in Pregnancy Registry was established to better evaluate outcomes after the inadvertent
vaccination of women in pregnancy.
Methods: The Registry developed a modified Vaccine Adverse Event Reporting System report to collect information from
pregnant women after smallpox vaccination. Military healthcare providers were engaged to identify cases, since most
smallpox vaccines were administered to military service members. Registry professionals actively follow all enrolled
women through and after pregnancy.
Results: As of September 2006, pregnancy outcome data were available from 376 women followed by the Registry. Most
(77%) were vaccinated near the time of conception, before a standard pregnancy test would have been positive.
Evaluations of outcomes to date have not revealed higher-than-expected rates of pregnancy loss (11.9%), preterm birth
(10.7%), or birth defects (2.8%), when compared to healthy referent populations. No cases of fetal vaccinia have been
identified.
Conclusions: Close follow-up of women inadvertently vaccinated against smallpox during pregnancy, to date, has not
revealed pregnancy, birth, or infant health problems attributable to smallpox vaccine exposure. The Smallpox Vaccine in
Pregnancy Registry continues to actively enroll and follow women and infant and early childhood health outcomes.
15. SUBJECT TERMS
smallpox vaccine, vaccinia, pregnancy, reproductive health
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