Review Article
Review Article
Review Article
Review Article
Safety and Immunogenicity of Pertussis Vaccine
Immunization during Pregnancy: A Meta-Analysis of Randomized
Clinical Trials
Aidibai Simayi ,1,2 Liguo Zhu ,3,4 and Hui Jin 1,2
1
Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, No. 87 Dingjiaqiao,
Nanjing, China
2
Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University,
Nanjing, China
3
Department of Acute Infectious Disease Control and Prevention, Jiangsu Provincial Center for Disease Control and Prevention,
Nanjing, China
4
National Health Commission (NHC) Key Laboratory of Enteric Pathogenic Microbiology,
Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
Received 28 January 2022; Revised 6 April 2022; Accepted 8 April 2022; Published 21 December 2022
Copyright © 2022 Aidibai Simayi et al. Tis is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Te objective of this meta-analysis is to assess the safety and immunogenicity of maternal pertussis vaccination based on randomized
clinical trials. PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Internet, and Wan Fang Database were
searched from inception up to the 8th of October 2021, using a protocol registered on PROSPERO with no. 42021287717, and a meta-
analysis was conducted. We measured pooled geometric mean concentrations (GMCs) for IgG antibodies against pertussis and the
incidence of serious adverse events (SAEs). We identifed a total of 522 publications, and after a strict screening, we found that 6 RCTs
were eligible for our meta-analysis. GMCs were determined with a standardized mean diference (SMD), and the pooled SMD of anti-
PT, anti-FHA, and anti-PRN IgG from cord blood were 0.91 (95% CI: 0.58, 1.24), 1.03 (95% CI: (0.70, 1.35)), and 1.55(95% CI: 1.22,
1.88), respectively. Te pooled OR of SAEs of women and infants did not show a statistical diference; the pooled ORs were 1.26 (95% CI:
0.78, 2.05); P � 0.35) and 0.61 (95% CI: 0.37, 1.01); p � 0.053), respectively. Infants of immunized women have signifcantly higher
transplacental antibodies for protection against pertussis disease during the frst 2 months of life.
mortality rate [9]. Meanwhile, maternal immunization is 2.3. Quality Assessment. Te methodological quality of each
increasingly being recommended as a strategy to protect trial was evaluated for risk of bias using standard criteria:
young infants from infectious diseases [10]. It was also re- method of randomization; allocation concealment; patient,
ported that vaccination during pregnancy results in high investigator, and outcome assessor blinding; selective out-
levels of antibodies in the mother and the newborn. Fur- come reporting; incomplete outcome ascertainment; and
thermore, maternal tetanus, diphtheria, and acellular per- other potential sources of bias as recommended by the
tussis (Tdap) vaccination ofers protection for neonates Cochrane Collaboration [22]. Each domain was categorized
against clinical pertussis until primary vaccinations. Te as low, high, or unclear.
pertussis vaccine exists in both whole-cell (Tdwp) and
acellular (Tdap) forms. Te Tdap form has fewer adverse 2.4. Data Extraction. Te data were carefully evaluated and
efects and seems to be as efective as the Tdwp formulation. extracted independently from all the eligible publications.
As a result, the Tdwp preparation is only recommended Te following data were collected from each study: (a) name
when the Tdap form is not available [11]. Trough trans- of the frst author, year of publication, and geographic
placental transfer, antipertussis antibodies pass to the fetus, setting; (b) study design; (c) type of vaccine during preg-
which is protected at the time of birth and during the frst nancy; (d) study period; (e) the number of subjects in each
months of life [12]. However, performing clinical trials in group; (f ) registration number of the trial; (g) gestational age
pregnant women is challenging [13]; hence, the vast majority in weeks of vaccination. To evaluate maternal pertussis
of immunogenicity and safety data has come from obser- vaccine immunogenicity, geometric mean concentrations
vational studies, which are prone to bias [14]. (GMCs) for IgG antibodies against pertussis toxin (PT),
So far, several systematic reviews have investigated the flamentous haemagglutinin (FHA), and pertactin (PRN) in
efectiveness and/or safety of pertussis vaccination during infants for all vaccine antigens were extracted from the trials.
pregnancy [15–20]. And yet none of them were specifcally Te following outcomes were considered for the meta-
conducted as randomized clinical trials (RCT) or addressed analysis: GMC after the infant series (at delivery, before
the quantitative immune response comprising safety as well primary vaccination, and after primary vaccination) of the
as immunogenicity for mother and child. Terefore, we Tdap vaccine. To evaluate safety, we measured the incidence
performed a meta-analysis of RCTs to compare the im- of serious adverse events (SAEs) for women and their
munogenicity and safety of pertussis vaccination during infants.
pregnancy.
4. Discussion
3.4. Meta-Analysis of Immunogenicity. Five studies were
included in the analysis of anti-PT and anti-PRN IgG GMCs To the best of our knowledge, this is the frst meta-analysis
of infants from cord blood, and four studies reported the exploring the immunogenicity and safety of maternal per-
related GMCs for the FHA. Te pooled SMD of anti-PT IgG tussis vaccination based on RCTs. Tis meta-analysis syn-
from cord blood was 0.91 (95% CI: 0.58, 1.24; P < 0.0001). thesized evidence about the immunogenicity and safety of
Te pooled SMD of GMC for anti-FHA from cord blood was Tdap vaccination during pregnancy in 6 studies involving
1.03 (95% CI: 0.70, 1.35; P < 0.00001). Also, the pooled SMD more than 1400 pregnant women and infants. We used
of anti-PRN IgG from cord blood was 1.55 (95% CI: 1.22, a systematic strategy and broad search terms in multiple
1.88; P < 0.00001). A random-efects model was employed databases to identify as many published clinical trials as
due to the signifcant heterogeneity between diferent an- possible. Maternal pertussis immunization has undergone
tibody responses among these studies (I2 � 80.5%, 73.7%, a paradigm shift in recent years as evidence emerges of
and 77.2%, respectively) (Figure 2). We removed the open- robust efectiveness and safety in protecting young infants
label trial of Barug et al. [26] for each analysis, and the and their mothers against pertussis [32]. GMCs against
heterogeneity of anti-PT and anti-PRN both sharply pertussis were assessed by performing an ln transformation,
4
-2 0 2
NOTE: Weights are from random-effects model
-2 0 2
NOTE: Weights are from random-effects model
-2 0 2
NOTE: Weights are from random-effects model
Figure 2: Forest plots of GMCs for pertussis antibodies in infants from cord blood.
to get a more intuitional understanding of the immuno- 2 months of life until they get primary vaccinated. Tis
genicity of vaccines. supports the recommendation of Tdap vaccination during
For immunogenicity, our results from the analysis of 6 pregnancy to prevent early-infant pertussis disease.
RCTs suggested that GMCs of anti-PT, anti-FHA, and anti- For safety, signifcant diferences were demonstrated in
PRN were higher in the Tdap group than the control group the comparisons of the incidence of serious SAEs, which
at delivery and before primary vaccination of infants, which mainly included pregnancy-induced hypertension, pancre-
is consistent with the included studies [26–31]. However, atitis, acute appendicitis, fetal distress resulting in a C-
after primary vaccination, anti-PT and anti-PRN did not section, congestive heart failure, and gastroenteritis. Both
show statistical diferences between the Tdap group and the SAEs of pregnant women and their infants showed no
control group, and GMCs of anti-FHA were statistically less signifcant diferences. According to the included studies,
in the Tdap group than the control group, suggesting that none of the SAEs in women and their infants were judged to
maternal immunization with Tdap resulted in high con- be attributable to the Tdap vaccine, except that four of these
centrations of pertussis antibodies in infants during the frst pregnancy-related SAEs were assessed as possible vaccine-
6 Journal of Tropical Medicine
Table 2: Meta-analysis results of GMCs for pertussis antibodies before and after primary vaccination of infants.
Pooled SMD
Study number P value I2 (%) Efect model
(95% CI)
Before primary vaccination
Anti-PT 4 0.75 (0.28, 1.22) 0.002 86.3 Random
Anti-FHA 3 0.90 (0.41, 1.39) <0.0001 80.9 Random
Anti-PRN 4 1.37 (0.90, 1.83) <0.0001 84.0 Random
After primary vaccination
Anti-PT 4 −0.016 (−0.32, −0.01) 0.059 0 Fixed
Anti-FHA 3 −0.20 (−0.39, −0.01) 0.039 10.8 Fixed
Anti-PRN 4 −0.05 (−0.50, 0.40) 0.819 85.7 Random
.125 1 8
NOTE: Weights are from Mantel-Haenszel model
.125 1 8
NOTE: Weights are from Mantel-Haenszel model
related (preeclampsia, premature delivery, and HELLP complications in the Tdap and control groups; however,
syndrome (hemolysis, elevated liver enzymes, low platelet there were no signifcant diferences between them, and
count) in 1 Td recipient and gestational hypertension in 1 the reported data were not eligible for meta-analysis; thus,
Tdap recipient) [31]. Hoang et al.’s study [28] reported 7 we did not perform meta-analysis based on obstetric or
SAEs but did not reveal the distribution of the incidences, so fetal complications.
we did not include this in the meta-analysis. Other included Several limitations of the present study must be ac-
studies also reported the incidence of non-SAEs [26, 28, 30], knowledged. First, we searched only six databases, and some
mainly redness and mild local pain, but they were either unpublished studies or publications in other databases may
without signifcant diferences between the Tdap group and not have been identifed. Second, only a limited number of
control group or without eligible data for pooled analysis; published RCTs directly compare the immunogenicity and
therefore, we did not perform a meta-analysis about non- safety of Tdap maternal vaccination. While RCTs are de-
SAEs. Overall, our results of the Tdap vaccine’s safety are sirable for addressing the impacts of antenatal vaccination
consistent with the included studies. timing on vaccine immunogenicity, there are limitations on
Infants are specifcally prone to bradycardia, hypo- study design due to the ethical issues raised by delaying
tension, and cardiac arrest from pertussis. Te develop- vaccination. Tird, there was signifcant heterogeneity
ment of pulmonary hypertension has been increasingly among the studies that evaluated GMCs of pertussis anti-
recognized as a factor contributing to infant mortality at bodies in cord blood and after primary vaccination. Te
an early age, as it may lead to worsening systemic hy- result of the sensitivity analyses that were performed in-
potension and hypoxia [33]. Some of the included studies dicated that the possible reason for the heterogeneity was
[27, 30, 31] reported the occurrence of obstetric or fetal a diferent trial design; however, the overall conclusions were
Journal of Tropical Medicine 7
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