Discussion
Main
findings
This study provided a unique prospective assessment of accurate
pregnancy and infant data with confirmed maternal vaccination status.
The analytical framework treated pertussis vaccination as a time-varying
exposure and computed time at risk windows for each of the time
sensitive outcomes of interest and adjusted for a comprehensive set of
confounding factors to reaffirm that maternal pertussis vaccination is
safe for both the mothers and their newborn infants.
Strengths and
Limitations
The major strength of this study is the prospective cohort design that
recruited a large number of nulliparous women with singleton pregnancies
at low risk for obstetric complications at two major maternity
hospitals. Vaccinated women in our study were more likely to engage in
healthy lifestyles i.e. pregnancy micronutrient supplementation, regular
exercise, non-smoking than unvaccinated women. The analysis framework
used herein adjusted for putative risk factors, including psychosocial
factors, to mitigate the impact of any ‘healthy vaccinee bias’ on our
findings. However, we cannot rule out the possibility of residual
confounding. Our use of Cox proportional-hazards models accounting for
time-varying vaccine exposure during pregnancy minimized the
introduction of immortal time bias in our data.25 The
potential for this bias arises because the opportunity for vaccination
increases the longer a woman remains pregnant.28Furthermore, many studies use the earliest recommended maternal
pertussis vaccination time (i.e. 28 weeks’ gestation in this case) as a
cut-off point to restrict their data but pregnancies must survive within
the recommended timeframe (i.e. 28-32 weeks’ gestation) to be eligible
to receive the vaccines. Hence, immortal time bias may also be present
in studies of maternal pertussis vaccination evaluating adverse
pregnancy outcomes that develop in mid-to-late pregnancy, including PE
and GH, where the bias may attenuate the true relative risk. Our
analytic approach used 32 instead of 28 weeks’ gestation as the cut-off
point in order to allow all women to have had the chance to receive the
recommended pertussis vaccination in that optimal 4-week window. This
may have reduced the introduction of immortal time bias in our analyses.
Additionally, including follow-up time during which pregnancies are no
longer at risk of some adverse outcomes (e.g. gestation after 37 weeks
considered for PTB outcomes) can lead to incorrect estimation of the
effect of maternal vaccination on the outcome of interest but our
time-to-event analytic approach minimized the risk of these biases
occurring. Another major strength of our study is confirmed maternal
vaccination status. As this study was a secondary analysis, we did not
conduct an a priori power analysis to show sample size adequacy.
A post-hoc power analysis was not conducted as there is a rich
literature, in both medical and statistical journals, warning against
post-hoc power calculations.29, 30 However, the cohort
was originally powered on the basis of 25% of women affected by
pregnancy complications (preeclampsia, small for gestational age birth,
spontaneous preterm birth and gestational diabetes
mellitus).19
Interpretation
Our Cox proportional hazards models accounting for the time-dependent
nature of exposure to vaccination during pregnancy, thereby avoiding the
introduction of immortal time bias to our analyses, found no association
between maternal pertussis vaccination and PTB, spontaneous PTB, nor
PPROM, reaffirming the conclusion from previous systematic reviews.11-14
In keeping with previous studies11, 12, our findings
demonstrated no association between maternal pertussis vaccination and
gestational hypertensive disorders. The new Australian guidelines
recommend pregnant women to receive a pertussis vaccine from 20 weeks of
gestation rather than 28 weeks’ to maximize the opportunity for
vaccination to protect all infants, including preterm
infants.31 Administration of maternal pertussis
vaccination from 20 weeks’ can align with other key routine antenatal
visits such as morphology scanning and gestational diabetes testing,
potentially improving the uptake of pertussis vaccination among pregnant
women. However, there is a need for continued surveillance and
monitoring to confirm that a broader window for pertussis vaccination
during pregnancy is safe for the pregnant mother and the newborn.
Our study demonstrates that maternal pertussis vaccination was not
associated with chorioamnionitis. In contrast, three large retrospective
studies15-17conducted in the USA showed receipt of
pertussis vaccination during pregnancy was associated with a small but
significant increase in risk of developing chorioamnionitis. These
studies15-17 used commercial health data and ICD codes
for identifying chorioamnionitis from electronic medical records with no
clinical case definition. Coding for commercial reasons, such as
insurance claims, is potentially subject to favoring more severe
diagnoses and might be prone to poor external validity, selection bias,
confounding and misclassification bias.32 Furthermore,
these studies did not find an association with an increased risk of PTB,
which is an expected major clinical sequel of chorioamnionitis and most
women with chorioamnionitis had at least one pre-existing risk factor
for this complication. This suggests the observed relation between
receipt of pertussis vaccination during pregnancy and chorioamnionitis
was unlikely to be casual, and is probably more reflective of residual
confounding affecting the results in these studies.
In our study, we found an association between maternal pertussis
vaccination during pregnancy and longer gestation. There are no known
biologically plausible direct effects of pertussis vaccination on
pregnancy duration but women who remained pregnant longer have more
opportunity to have received pertussis vaccine in the late third
trimester of pregnancy. This may have created a spurious relationship
between pregnancy duration and time-varying pertussis vaccine exposure
during pregnancy because linear regression analysis is not suited to
include both the event and time aspects in the model.
Our study provides further assurance that pertussis vaccination during
pregnancy is not associated with any adverse birth outcomes including
LBW or SGA births, consistent with previous
findings.11-14 Receipt of pertussis vaccination during
pregnancy was not associated with increased risk of perinatal outcomes
including admission to the neonatal care unit, respiratory distress,
Apgar scores <7 nor need for mechanical ventilation at birth
compared with infants born to unvaccinated women.11-14