Effectiveness of Prenatal Tetanus, Diphtheria, and Acellular Pertussis Vaccination on Pertussis Severity in Infants
Effectiveness of Prenatal Tetanus, Diphtheria, and Acellular Pertussis Vaccination on Pertussis Severity in Infants
accepted 1 3
published online 1
. Correspondence: K. Winter 1
California Department of Public Health 1
Marina Bay Pkwy 1
(). Clinical Infectious Diseases® 1
0 Department of Epidemiology, University of Kentucky , Lexington
1 The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions , e-mail
2 David Geffen School of Medicine at UCLA , Los Angeles, California
3 California Department of Public Health , Immunization Branch, Richmond
Background. All US women are recommended to receive a tetanus, diphtheria, and acellular pertussis (Tdap) vaccine at 27-36 weeks gestation during each pregnancy to reduce the risk of pertussis to their infants. The impact of this strategy on severity of disease among infected infants has not been evaluated. Methods. We use a retrospective cohort study design evaluating whether pertussis-infected infants born in 2011-2015 whose mothers received Tdap vaccine during pregnancy had less severe pertussis, resulting in a lower risk of hospitalization or intensive care unit admission compared with infants born to unvaccinated mothers. Results. Infected infants of vaccinated mothers were significantly less likely to be hospitalized and had significantly shorter hospital stays compared with infants born to unvaccinated mothers, after adjustment for chronological and gestational age and receipt of diphtheria and tetanus toxoids and acellular pertussis vaccine. Unadjusted and adjusted vaccine effectiveness for preventing hospitalization among infants with pertussis was 72% (95% confidence interval [CI], 49%-85%) and 58% (95% CI 15%-80%), respectively. No infants born to vaccinated mothers required intubation or died of pertussis. Conclusions. Infants with pertussis whose mothers received Tdap during pregnancy had a significantly lower risk of hospitalization and intensive care unit admission and shorter hospital stays. Prenatal Tdap vaccination is a critical strategy for reducing the morbidity and mortality from pertussis.
Young infants are at greatest risk of severe disease and death
from pertussis [1–8]. From 1994 to 2004, 58% of infant pertussis
deaths in the United States occurred in infants <2 months of age
 and in 2010 in California, 10 deaths from pertussis occurred
in infants <8 weeks of age .
Passively acquired maternal antibodies against many
infectious diseases offer protection during the first months of life
. In the United States, women are recommended to receive
tetanus, diphtheria, and acellular pertussis (Tdap) vaccine at
27–36 weeks gestation during each pregnancy to protect infants
through transplacental transfer of antibodies . Data from the
United Kingdom show that this strategy reduces the risk of
pertussis among infants <2 months of age [13, 14]. However, to our
knowledge, no studies have evaluated the impact of this strategy
on the outcomes of infected infants. Studies have shown that
infants who develop pertussis after receiving the first dose of
diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine
have lower risks of hospitalization and death than unvaccinated
infants [8, 15]. It is possible that, although still infected, these
infants receive sufficient antibody to pertussis toxin to prevent
development of severe leukocytosis, which can lead to irreversible
pulmonary hypertension and death [16, 17].
In the baboon model, infant baboons born to mothers
vaccinated against pertussis in the third trimester of pregnancy were
protected against leukocytosis after a direct challenge with Bordetella
pertussis . Similarly, infants born to women who receive
Tdap vaccine during pregnancy who are infected with B. pertussis
may obtain sufficient antibody to pertussis toxin and other
antigens to prevent severe disease and death [19, 20]. In the current
study, we retrospectively evaluate a cohort of infants with pertussis
to determine whether those whose mothers received Tdap vaccine
during pregnancy had less severe pertussis illness than those
whose mothers were unvaccinated during pregnancy.
By California statute, laboratories and clinicians must report
suspected cases of pertussis to local public health departments;
all cases with an acute cough illness meeting the Council of State
and Territorial Epidemiologists clinical case definition  or
with laboratory detection of B. pertussis by culture or polymerase
chain reaction are subsequently reported to the California
Department of Public Health (CDPH). Local health department
investigators complete case report forms containing demographic,
Infants, No. (%)a
Complete Tdap Data (n = 420)
Missing Tdap Data (n = 303)
clinical, laboratory, and epidemiologic data through patient and
provider interviews and medical record reviews. In addition,
medical records are requested and reviewed by CDPH staff to
ensure accuracy of the surveillance data for hospitalized cases
occurring in young infants. We evaluated the cohort of infants
reported in California with pertussis onset occurring at <63
days of age and born from 1 January 2011 through 31 December
2015. We used an age cutoff of 63 days because most infants
receive the first dose of DTaP vaccine at about 2 months of
age, and we sought to minimize potential confounding effects
of protection from routine active immunization.
CDPH pertussis surveillance reports were linked to birth
certificate records from the CDPH Center for Health Statistics for
the mother and infant and California Immunization Registry
(CAIR) Tdap immunization records for the mother using a
matching algorithm consisting of combinations of the following
Infants, No. (%)a
Prenatal Tdap (n = 49)
No Prenatal Tdap (n = 371)
RR (95% CI)
variables: infant’s last name, infant’s first name, infant’s date of
birth, infant’s sex, mother’s last name, mother’s first name,
mother’s date of birth, father’s last name, and city of residence.
Symptoms, clinical course, DTaP vaccination, and outcomes
were reported on surveillance reports and verified through
medical record review. Length of hospital stay was calculated as the
number of days between admission and discharge dates and
summed across hospital stays for multiple admissions or transfers.
The infant’s gestational age and birth weight, and maternal age,
country of birth, date of last menses, and number of prenatal visits
were reported on the birth certificate. Maternal Tdap vaccination
histories were self-reported on public health case investigation
reports or verified by the provider through documentation in the
mother or infant’s medical record or in CAIR.
Mothers were considered to have had prenatal Tdap if they
self-reported or had documented receipt of Tdap vaccine in
Maternal receipt of Tdap
vaccine during pregnancy
Infant chronological age
Infant receipt of DTaP vaccine
≥14 d before pertussis
OR (95% CI)
Model 1: Risk of
Model 2: Risk of ICU
Abbreviations: CI, confidence interval; DTaP, diphtheria and tetanus toxoids and acellular
pertussis; ICU, intensive care unit; OR, odds ratio; Tdap, tetanus, diphtheria, and acellular
a Infant chronological and gestational age were recorded in weeks.
b DTaP vaccination was dropped from the model to allow for convergence.
their medical record or in CAIR at any point during the
pregnancy for the infected infant. Where available, the trimester and
date of Tdap receipt were recorded; week of gestation for the
dose administration was calculated as the number of weeks
between the date of last menses reported on the birth certificate
and Tdap dose.
Mothers were considered unvaccinated if they self-reported
or had with documentation in their medical record of not
receiving Tdap vaccine during pregnancy (eg, vaccine refusal).
In addition, mothers who had documentation in their medical
record or CAIR of receipt of Tdap within 2 weeks after the
delivery were assumed to have been unvaccinated during the
pregnancy, because postpartum Tdap is recommended only for
unvaccinated mothers. If no Tdap dose was recorded on the
surveillance report, medical records, or CAIR and the mother
did not recall Tdap receipt during or immediately after
pregnancy, prenatal Tdap was considered unknown.
Bivariate comparisons of demographics, symptoms, clinical
course and outcomes between infants born to vaccinated and
unvaccinated mothers were calculated using χ2 and Fisher
exact tests; associated relative risk (RR) and 95% confidence
intervals (CIs) were constructed. Two-sided P values were
calculated using analysis of variance or the Wilcoxon-Mann–
Whitney test for continuous variables and the
CochranArmitage test to evaluate trends, as appropriate.
To avoid misclassification of Tdap vaccination, infants were
excluded from analyses if their mother’s vaccination status was
unknown. To assess potential bias due to missing data, bivariate
comparisons of demographics, birth and clinical characteristics
of infant pertussis cases with and without known exposure data
were evaluated and associated odds ratios (ORs) were
calculated. In addition, birth certificate records were unavailable for
infants born in 2015 or born outside California and were excluded
from estimations requiring maternal age, maternal country of
birth, number of prenatal visits, gestational age, and birth
The primary outcomes of interest were hospitalization for
≥24 hours, length of hospital stay, admission to an intensive
care unit (ICU) for any length of time, intubation, and death
from pertussis. Using multivariate logistic regression, we
calculate ORs and 95% CIs to estimate the effect of prenatal Tdap
vaccination on risk of (1) hospitalization and (2) ICU
admission, while simultaneously adjusting for the important
covariates of infant’s chronological age, gestational age, and receipt
of DTaP vaccine.
The vaccine effectiveness (VE) of prenatal Tdap in
preventing hospitalization among infants with pertussis was calculated
as (1 – OR) × 100% . VE estimates adjusted for
chronological and gestational age of the infant and receipt of DTaP were
also calculated. A subanalysis included only infants whose
mothers received Tdap vaccine during the third trimester.
A total of 752 infants born from 1 January 2011 through 31
December 2015 were reported with pertussis at <63 days of age.
Among those with complete information, 495 (68%) were
hospitalized, 25% of whom required intensive care. Forty-four
infants (7%) required intubation, and 6 (1%) died. Four (1%)
received the first dose of DTaP vaccine ≥14 days before onset
of pertussis illness. Three infants were born outside California,
and 116 were born in 2015 and did not have available birth data.
Of the remaining 633 infants, 607 (96%) were successfully
linked to their birth certificate record.
A total of 420 (56%) infants had known maternal vaccination
status. Comparisons of infants with and without complete data
are presented in Table 1. Characteristics were similar between
these 2 groups, but infants with missing exposure data were
Timing of Maternal Tdap Vaccination
Mothers Vaccinated, No.
Unadjusted VE (95% CI), %
Any point in pregnancyb
3rd trimester onlyc
Abbreviations: CI, confidence interval; Tdap, tetanus, diphtheria, and acellular pertussis; VE, vaccine effectiveness.
a Adjusted for infant’s chronological age, gestational age, and receipt of diphtheria and tetanus toxoids and acellular pertussis vaccine.
b Calculations based on 420 (unadjusted) and 344 (adjusted) infants.
c Calculations based on 406 (unadjusted) and 330 (adjusted) infants.
Adjusted VE (95% CI), %a
52.1 (−.16 to 80.3)
significantly more likely to be preterm, have apnea, be admitted
to the ICU, have seizures, or die (Table 1).
Of the 420 infants with complete maternal vaccination data,
49 (12%) had mothers who received Tdap during pregnancy,
whereas the remaining mothers were unvaccinated or
vaccinated post partum. Among those vaccinated during pregnancy, 8
(16%) received Tdap during the first or second trimester, 37
(76%) received Tdap during the third trimester, and 4 (8%)
received Tdap at an unknown point during the pregnancy.
Among the 18 mothers vaccinated during the third trimester
with documented administration dates, 14 (78%) received
Tdap during the recommended window of 27–36 weeks
gestation, and 4 (22%) received Tdap after 36 weeks gestation; ≥5
infants (10%), including all 4 whose mothers were vaccinated
after 36 weeks gestation, were born <14 days after maternal
Vaccinated mothers were less likely to have Medicaid
insurance (RR, 0.6; 95% CI, .4–.9). There was no difference in age,
country of birth, or number of prenatal visits between
vaccinated and unvaccinated mothers (Table 2). Infants born to
vaccinated mothers were older when they developed pertussis
(P = .03) but did not differ with regard to race or ethnicity,
sex, gestational age, birth weight, or DTaP vaccination (Table 2).
Clinical symptoms differed between the groups, and infants
born to vaccinated mothers were less likely to have the classic
pertussis symptoms of paroxysmal cough (RR, 0.41; 95% CI,
.25–.68), apnea (0.66; .47–.91), cyanosis (0.53; .39–.73), or
whoop (0.78; .62–.99), although the frequency of posttussive
vomiting was similar between groups (Table 2).
Infants whose mothers received prenatal Tdap had
significantly lower risk of hospitalization (RR, 0.5; 95% CI, .4–.6) or
ICU admission (0.8; .7–.9). Among hospitalized infants, those
whose mothers were vaccinated had shorter hospitalization
stays (median 3 vs 6 days; P = .02). No infants born to
vaccinated mothers had seizures, required intubation, or died (Table 2).
In the first multivariate regression model (model 1), infants
whose mothers received Tdap vaccine during pregnancy were
significantly less likely to have been hospitalized (OR, 0.4;
95% CI, .2–.9) after adjustment for the infant’s chronological
and gestational age and receipt of DTaP (Table 3). In model
2, no infants who received DTaP were admitted to an ICU;
this was dropped from the model to allow for convergence.
After adjustment for the infant’s chronological and gestational
age, prenatal Tdap was associated with a lower odds of ICU
admission (OR, 0.5; 95% CI, .2–1.2), but the CI included the null
value (Table 3).
The overall VE for preventing hospitalization among infants
with pertussis was 72% (95% CI, 49%–85%); after adjustment
for the infant’s chronological and gestational age and receipt
of DTaP vaccine, it was 58% (15%–80%) (Table 4). VE estimates
remained similar when restricted to infants whose mothers were
known to have received Tdap vaccine during the third trimester.
This is the first known study demonstrating that prenatal Tdap
vaccination of mothers reduces the severity of disease in infants
who are infected with pertussis. Infected infants whose mothers
received Tdap during pregnancy had a lower risk of
hospitalization and ICU admission and shorter hospital stays than infants
whose mothers were unvaccinated. No infected infants born to
vaccinated mothers required intubation or died. Classic
pertussis symptoms were observed less frequently among infants born
to vaccinated mothers, suggesting that they had more mild
Among the women vaccinated with Tdap during pregnancy,
≥24% were vaccinated outside the recommended window of
27–36 weeks gestation, and ≥5 (10%) infants were born <14
days after vaccination; it is possible that optimal timing of
vaccination could have prevented pertussis infection for these
infants altogether. Recently, high pertussis antibody titers were
observed in infants born to mothers vaccinated late in the
second or early in the third trimester , stressing the importance
of prompt vaccination. All pregnant women should be offered
Tdap vaccination during routine prenatal visits at the earliest
opportunity, starting at 27 weeks gestation.
This study has several important limitations. Foremost,
misclassification of Tdap immunization could have occurred
because maternal vaccination histories were not exclusively
provider verified, and there may have been recall bias if mothers
of severely ill infants reported Tdap vaccination differently from
mothers of infants with more mild disease. However, the use of
several overlapping data sources, including those with provider
verification to obtain maternal vaccination histories, reduced
the risk of recall bias and exposure misclassification.
Complete maternal Tdap immunization data were available
for only 56% of infants with pertussis, and some differences
were observed between infants with and those without complete
data. Infants with known maternal Tdap status were more likely
than with missing data to be admitted to the ICU, have seizures,
or die. It is possible that public health investigators were more
persistent in obtaining maternal vaccination histories for more
severe cases. Hospital admission records for infants were
available as an additional data source for more severe cases. There
may have been differential completeness of the exposure data
because documentation of nonreceipt of vaccine (eg, notation
of refusal or postpartum vaccination) was necessary to
determine nonexposure. Therefore, it is possible that more infants
with unknown maternal Tdap status were born to unvaccinated
mothers. Most characteristics were similar between our infants
with and those without maternal Tdap data, so it unclear
whether incomplete data had a meaningful impact on our
The cohort of infected infants in this study includes only
those with reported pertussis, so some cases may have been
missed. However, because pertussis reporting is mandated by
both laboratories and clinicians and ill infants in this age
group are often brought to medical attention, underreporting,
particularly of hospitalized infants, is probably lessened. In
addition, routine surveillance activities include reviews of hospital
discharge and death certificate databases to identify possible
infant pertussis cases that may not have been initially reported.
Finally, our VE is only a partial estimate of the true impact of
prenatal Tdap vaccination. All the infants in our cohort were
infected with pertussis; therefore, we are unable to estimate
the effect of prenatal Tdap on preventing pertussis illness in
infants. Many mothers received postpartum Tdap but
information on breastfeeding status was not collected, so we could
not evaluate possible protective effects of postpartum Tdap or
antibodies transferred via breast milk, which may have lowered
the VE estimates presented here.
California is a large state with a diverse population; therefore
our findings should be generalizable to other populations.
Other countries experiencing a high incidence of pertussis
should consider recommending routine Tdap vaccination of
pregnant women. These findings should be communicated to
both prenatal care providers and pregnant women to encourage
uptake of Tdap vaccine during each pregnancy.
In conclusion, prenatal Tdap vaccination was 58% effective
in preventing hospitalizations in infants infected with
pertussis. Infected infants whose mothers did not receive Tdap
during pregnancy had a higher risk of hospitalization and ICU
admission and longer hospital stays. No infants born to
vaccinated mothers required intubation or died of pertussis.
Prenatal Tdap vaccination of mothers is a critical strategy for
reducing morbidity and mortality rates associated with
Acknowledgments. We are grateful for Rosie Glenn-Finer from CDPH
for her assistance with data collection and to Arthur Reingold from the
University of California, Berkeley, School of Public Health for his critical review
of this manuscript. We are indebted to the 61 local health jurisdictions for
their ongoing pertussis surveillance and vaccination efforts.
Potential conflicts of interest. J. D. C. has served as a consultant for
GlaxoSmithKline and as a speaker for Sanofi Pasteur, outside the submitted
work. All other authors report no potential conflicts. All authors have
submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Conflicts that the editors consider relevant to the content of the manuscript
have been disclosed.
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