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Hum Vaccin Immunother
Hum Vaccin Immunother
Human Vaccines & Immunotherapeutics
2164-5515
2164-554X
Taylor & Francis

39288786
10.1080/21645515.2024.2403831
2403831
Version of Record
Research Article
Coronavirus
Efficacy of vaccination during pregnancy in reducing the risk of SARS-CoV-2 infection in infants younger than 12 months. Puglia (Italy), 2021–23
C. DE VIRGILIO SUGLIA ET AL.
HUMAN VACCINES & IMMUNOTHERAPEUTICS
De Virgilio Suglia Cesare
https://orcid.org/0000-0002-3279-0196
Stefanizzi Pasquale
Graziano Giusy
Moscara Lorenza
Delle Fontane Arianna
Minelli Martina
Tafuri Silvio
Hygiene Unit - Interdisciplinary Department of Medicine, University of Bari Aldo Moro , Bari, Italy
CONTACT Pasquale Stefanizzi pasquale.stefanizzi@uniba.it Hygiene Unit - Interdisciplinary Department of Medicine, Aldo Moro University of Bari, Piazza Giulio Cesare, 11, Bari 70124, Italy.
17 9 2024
2024
17 9 2024
20 1 2403831Integra17 9 2024
Integra17 9 2024
16 4 2024
03 9 2024
10 9 2024
© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

ABSTRACT

This retrospective cohort study evaluated the effectiveness of maternal vaccination against COVID-19 in reducing the risk of SARS-CoV-2 infection in infants younger than 12 months. The study, conducted at the “Policlinico” University Hospital of Bari, included 3346 newborns and their mothers. The study explored the degree of protection offered by maternal vaccination depending on the timing, type, and trimester of vaccination, also taking into account the mother’s history of infection. We compared the incidence rate of infection between children of vaccinated and unvaccinated mothers; the values were 10.2% and 18.1%, respectively, and the difference was statistically significant. The overall effectiveness of the vaccine against the infection was 45%. Further analysis revealed increasing efficacy as the doses of vaccine administered to the mother increased and in case of a previous history of maternal infection. Dual immune stimulation (vaccination and natural infection) was 83% effective in preventing infection among newborns. The multivariable models confirmed the protective effect of vaccination with all types of vaccines used. The analysis of infection’s incidence in newborns revealed an interesting temporal trend, with increasing incidence with time, suggesting a possible correlation with the persistence of maternal antibodies or with the gradual weaning. The results on the protective capacity of vaccines are in line with the global literature. Strengths of study include sample size, robust methodology, and multivariate analyses. Institutions could intensify awareness campaigns to encourage both pregnant women and all those who would like to become pregnant to receive SARS-CoV-2 vaccination.

KEYWORDS

Influenza
SARS-CoV-2
pregnant
vaccination attitude
communication
hesitancy
public research center on pharmacovigilance activities The research was financed by the Puglia Region, specifically by the public research center on pharmacovigilance activities.
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pmcIntroduction

Vaccine-preventable infectious diseases are responsible for significant maternal, neonatal, and infant morbidity and mortality worldwide.1 Unlike live-attenuated vaccines, many inactivated vaccines, as well as those composed of purified antigens, not only can be safely administered during pregnancy but should be administered based on specific risk factors (e.g. traveling).2,3

The World Health Organization (WHO) recommends maternal immunization both to directly protect the mother against vaccine-preventable infections and to passively protect the newborn through the delivery of specific antibodies to the fetus before birth.4,5 Some vaccines, such as seasonal inactivated influenza vaccine (IIV) and tetanus, diphtheria and pertussis (Tdap), are strongly encouraged in all pregnant women to effectively protect newborns against infections with high risk of morbidity and mortality until active protection develops through child vaccination.3,6–11

Despite robust evidence about safety and effectiveness of vaccination during pregnancy, in terms of both maternal and newborn protection, notwithstanding the specific recommendations provided by the main international scientific societies,2,3,12,13 the percentage of women who are vaccinated during pregnancy remains low, worldwide.6,14 Reasons include an underestimation of the risks of infections during pregnancy, the spreading of diverging opinions among colleagues and relatives, and above all the fear of causing harm to the fetus.15

For example, an Italian study estimated low adherence of pregnant women to the influenza vaccination campaign in 2015, with coverage as low as 2%,16 in contrast with the 75% coverage set as a minimum target by WHO since 2003.17 Another Italian study showed that only 31% of women of childbearing age claimed to have been vaccinated against rubella, while 43% were unaware of their immune status.18,19 Concerning SARS-CoV-2 vaccination, in Italy and the United States, less than half of pregnant women undergo SARS-CoV-2 vaccination.20,21 It should be noted that pregnant women were excluded from pre-marketing clinical trials regarding COVID-19 vaccines.22 Consequently, when the vaccination campaign began, data about safety of the vaccine in pregnancy were scarce, thereby leading to uncertainty in the guidelines and ultimately vaccination hesitancy among healthcare workers and pregnant women.23,24 For example, the Centers for Disease Control and Prevention (CDC) started recommending SARS-CoV-2 vaccination for pregnant women in September 2021,25 several months after the main scientific societies in the fields of pediatrics, neonatology, gynecology, and obstetrics had recommended the importance of carrying out a massive vaccination campaign among pregnant women.26

Indeed, possibly due to physiological changes occurring during pregnancy,27–29 pregnant women have a higher risk of severe COVID-19 compared to non-pregnant peers;30–32 moreover, respiratory infections during pregnancy increase the risk of preeclampsia, gestational diabetes, hospitalization, preterm birth, low birth weight, and interruption of pregnancy.30–33

Furthermore, contrary to popular beliefs, even infants and children can suffer harsh consequences in case of COVID-19. In the United States, a significant increase in hospitalizations was noted during the pandemic period among children under 6 months of age, who were not eligible for SARS-CoV-2 vaccination.34

Thus, maternal SARS-CoV-2 vaccination represents a safe35,36 and effective preventive strategy to reduce the risk of infection and hospitalization in both the mother and the newborn.12,37,38 Indeed, the passage of antibodies into fetal blood across the placenta has been clearly demonstrated.39,40 Furthermore, specific neutralizing IgA and IgG against SARS-CoV-2 were found to persist in breast milk up to 12 months post-partum following booster administration.40 Moreover, antibody levels in breast milk, as well as in blood and umbilical cord, were found to be significantly higher and long-lasting in vaccinated women compared to women with a history of natural infection.41,42

However, immunogenicity data do not always relate to effectiveness;43 clinically speaking, primary (e.g., reducing the risk of developing severe disease) and secondary (e.g., reducing the risk of infection) endpoints need to be established to assess vaccine effectiveness.

To date, four studies44–47 demonstrated a significant reduction in the risk of hospitalization in children younger than 6 months of age born to mothers vaccinated against SARS-CoV-2, compared to that of peers whose mothers were not fully vaccinated. Only one study44 investigated the effectiveness of vaccination during pregnancy in reducing the risk of SARS-CoV-2 infection in newborns, which will thus be the aim of this study.

Materials and methods

We conducted a retrospective cohort study to evaluate the effectiveness of maternal COVID-19 vaccination in reducing the risk of COVID-19 infection in infants younger than 12 months. The study was approved by the Ethics Committee of the “Policlinico” University Hospital of Bari.

We selected all newborns born between February 22, 2021, and December 31, 2022 at the “Policlinico” University Hospital of Bari to include them in the study.

To start the study, we extrapolated from the digital registers of the “Policlinico di Bari” University Hospital all the hospital discharge forms (SDO) drawn up between 22 February 2021 and 31 December 2022 and whose ICD-9 classification code was V30, V31, V33, V34, V36, or V39 including all discharge forms for live newborns. The ICD-9 identification code is found in box B of the hospital discharge form; more precisely, it is inserted in the reference node of the main diagnosis, in the field called “main discharge diagnosis.” V30 refers to a single live birth; V31 refers to a live-born twin; V33 refers to an unspecified twin birth either born alive or stillborn; V34 refers to other multiple births (three or more) all born alive; V36 refers to other multiple births (three or more) live births and stillbirths; V39 refers to “Live births unspecified whether single or multiple.”

At that point, using the unique code present on the hospital discharge forms of the neonatal unit, we were able to match the hospital discharge form of each newborn to that of the mother, obtaining tax codes and date of birth for both.

Thanks to the tax code, it was possible to trace the medical records of the newborn and the mother regarding the history of any previous SARS-CoV-2 infections and vaccination history of the mother. The vaccination data in Puglia are all recorded on a regional IT platform called “GIAVA” vaccinations. The records of the swabs administered to each citizen are collected on a regional site, accessible to healthcare workers, called “IRIS” responsible for the COVID-19 active surveillance system.

We created a database using Microsoft Excel and made sensitive data anonymous by replacing the name, surname, and tax code with progressive codes, thus guaranteeing the anonymity of the patients involved. In the database, we collected for each newborn progressive code, date of birth, history of SARS-CoV-2 infection with date of positive swabs, and for each mother progressive code, date of birth, history of SARS-CoV-2 infection with date of positive swabs, vaccination history with type of vaccine performed, date of administration, and trimester of pregnancy in which the vaccine was administered.

The outcomes considered in this study are the proportion of women vaccinated, the incidence of SARS-CoV-2 infection in newborns in the first 12 months of life, the mothers’ history of infection, and vaccination efficacy.

In particular, we saw whether, in addition to the previous infection, a vaccination could lead to some protection in the newborn in the first year of life.

The overall vaccine efficacy rate of a vaccine was calculated using the following formula:48 Vaccine Effectiveness = Relative Risk Reduction/Attack Rate in Unvaccinated Population × 100. The “Relative Risk Reduction” was calculated as the difference between “Attack Rate in Unvaccinated Group” and “Attack Rate in Vaccinated Group.”

We also took into consideration whether the period of possible infection of the newborn had occurred in a period of large predominance of a specific variant of the virus, considering from January 2021 to June 2021 as a period of large predominance of the “alpha” variant of SARS-CoV-2,” from July 2021 to December 2021 as a period of clear predominance of the “Delta” variant of the virus, while we considered the period from January 2022 to December 2022 as a period of very clear predominance of the “Omicron” variant according to reports of the Italian Higher Institute of Health (ISS).49

Statistical analysis

The descriptive results were synthetized in terms of mean and standard deviation (sd) or percentages, according to the nature of each patient characteristic. The association between the outcome of interest and all the variables in the study were tested with the Chi-square test. To validate the univariate findings while controlling for possible confounding factors, a multivariable logistic regression was carried out. The results were expressed as odds ratios (OR) and their 95% confidence interval (95% CI). All the p-values < 0.05 were considered statistically significant. The data were analyzed with SAS software (release 9.4) (SAS Institute Inc., Cary, NC, USA).

Results

We enrolled a total of 3,346 women in the analysis, of whom more than 87% had been vaccinated. Among vaccinated women, 56% of them had received 3 or more doses of vaccine, while about 40% had received 2 doses and approximately 5% had received only 1 dose of vaccine.

Among women vaccinated before the birth of the child (50% of the total sample), 1049 (63.3%) completed the entire vaccination schedules with the “Comirnaty” vaccine, 157 (9.5%) with the “Spikevax” vaccine, 23 (1.4%) with the “Vaxzevria” or “Janssen” vaccines, while 428 (25.8%) mothers had completed the immunization schedules with two or more different drugs.

Regarding the timing of vaccination, approximately 38% of women were vaccinated before pregnancy, 13.4% in the first trimester, 24.4% in the second trimester, and 24% in the third trimester.

Almost 70% of women had an experience of SARS-CoV-2 infection before the childbirth, mostly earlier than pregnancy (around 71%), while the remaining 29% had contracted the infection during pregnancy, with periods distributed quite equally among the three trimesters of pregnancy.

A history of double immune contact with the virus was found in 1,337 (40%) women, having both contracted the infection and received vaccination before the puerperium.

In the analysis of the incidence of SARS-CoV-2 infection in newborns, we observed that 14% of those born at the Policlinico in the first year of life had contracted the infection. This incidence tended to increase with the child’s age, peaking in the second half of life (Table 1).Table 1. Descriptive statistics.

Variable	Category	N valid	N (%)	
 	 	 	3.346	
Vaccination status of all mothers	Unvaccinated women	3.346	422 (12.6)	
 	Vaccinated women	 	2924 (87.4)	
Number of vaccine doses administered (among vaccinated women)	1	2.924	160 (5.5)	
 	2	 	1127 (38.5)	
 	≥3	 	1637 (56.0)	
Vaccination status of mothers before the birth of the child	Unvaccinated women	3.346	1689 (50.5)	
 	Vaccinated women	 	1657 (49.5)	
Type of vaccine administered (among women vaccinated before the birth of child)	Comirnaty (Pfizer-Biontech)	1.657	1049 (63.3)	
 	Spikevax (Moderna)	 	157 (9.5)	
 	Others (Janssen or Vaxzevria)	 	23 (1.4)	
 	Combination of 2 or more types	 	428 (25.8)	
Vaccination period	Before pregnancy	1.657	634 (38.2)	
 	I trimester	 	622 (13.4)	
 	II trimester	 	404 (24.4)	
 	III trimester	 	397 (24.0)	
Mother’s SARS-CoV-2 infection before childbirth	 	3.346	2321 (69.4)	
Time in which mother contracted COVID-19	Before pregnancy	2.321	1655 (71.3)	
 	I trimester	 	141 (6.1)	
 	II trimester	 	221 (9.5)	
 	III trimester	 	304 (13.1)	
Presence of double immune stimulus for the mother (infection and vaccination)	 	3.346	1337 (40.0)	
SARS-CoV-2 infection of newborns in the first 12 months after birth	 	3.346	474 (14.2)	
Data are absolute frequencies and proportions.

98% of newborns who contracted the infection were infected in a period in which almost all infections were due to the “Omicron” variant of the virus.

As regards the overall effectiveness of maternal vaccination in the prevention of SARS-CoV-2 infection in newborns 12 months after birth, we compared the incidence rate among the children of vaccinated and unvaccinated mothers; the values were of 10.2% and 18.1%, respectively, and the difference was statistically significant (p < .0001).

Overall, vaccine effectiveness against all forms of infection (i.e. symptomatic or asymptomatic) was estimated to be approximately 45% (Figure 1). Figure 1. Effectiveness of maternal vaccination in the prevention of SARS CoV-2 infection.

We then went on to study whether the number of vaccine doses administered to mothers was also relevant for the purposes of protecting the child: the incidence of infection seemed to vary to a statistically significant extent (p < .0001) depending on the number of doses received. The incidence is lower (6.1%) in children whose mothers had received 3 vaccine doses, compared to those born to women who have received 2 doses (13.8%), for which in turn the incidence is lower than children of women who received only one dose (incidence of 15.1%) (Table 2).Table 2. Association between mothers’ characteristics and the history of SARS-CoV-2 infection in newborns at 12 months after birth.

 	 	SARS-CoV-2 infection in newborns 12 months after birth	 	
Variable	Category	No	Yes	p-value	
Previous vaccination of the mother	No	1384 (81.9%)	305 (18.1%)	<.0001	
 	Yes	1488 (89.8%)	169 (10.2%)	 	
Number of doses given to the mother	1	101 (84.9%)	18 (15.1%)	<.0001	
 	2	642 (86.2%)	103 (13.8%)	 	
 	3	745 (93.9%)	48 (6.1%)	 	
Vaccination pregnancy period	Before pregnancy	613 (96.7%)	21 (3.3%)	<.0001	
 	I trimester	203 (91.4%)	19 (8.6%)	 	
 	II trimester	359 (88.9%)	45 (11.1%)	 	
 	III trimester	313 (78.8%)	84 (21.2%)	 	
Mother’s history of infection	Without previous SARS-CoV-2 infection	707 (69.0%)	318 (31.0%)	<.0001	
 	With previous SARS-CoV-2 infection	2165 (93.3%)	156 (6.7%)	 	
Period of pregnancy in which the mother contracted SARS-CoV-2	Before pregnancy	1543 (93.2%)	112 (6.8%)	0,1	
 	I trimester	134 (95.0%)	7 (5%)	 	
 	II trimester	212 (95.9%)	9 (4.1%)	 	
 	III trimester	276 (90.8%)	28 (9.2%)	 	
Presence of double immune stimulus for the mother (infection and vaccination)	No	1604 (79.8%)	405 (20.2%)	<.0001	
 	Yes	1268 (94.8%)	69 (5.2%)	 	
Data are absolute frequencies and proportions. p-values derived from the chi-square test for categorical variables. Statistically significant p-values (p < .05) are in bold.

We then asked ourselves whether the time of the mother’s vaccination was relevant for the protection of the child. The results showed a statistically different (p < .0001) incidence of SARS-CoV-2 infection between the periods considered: it was equal to 3.3% in children born to mothers vaccinated before pregnancy, 8.6% for children of mothers vaccinated in the first trimester of pregnancy, 11.1% for children born to mothers vaccinated in the second trimester, and an incidence of 21.2% for children of women vaccinated in the third trimester of pregnancy.

A natural history of SARS-CoV-2 infection before or during pregnancy seemed to offer some protection against the onset of the infection in newborns. The incidence was significantly lower (p < .0001) among newborns of women who contracted COVID-19 before pregnancy if compared with children born to women who had never encountered the virus (6.7% vs 31%).

As we did for the vaccination trimester, we checked whether the period in which the mother contracted the infection led to a different impact in terms of protection offered. However, no statistically significant differences (p = .1) emerged between women who had the infection before pregnancy and between those who had it in the various stages of pregnancy itself.

We also assessed whether women who had both a vaccination and a history of SARS-CoV-2 infection could offer additional protection to their babies and found that this dual immune stimulation was 83% effective in preventing infection in newborns. Overall, the incidence of SARS-CoV-2 infection in the first year of life was equal to 5.2% for the children of mothers vaccinated and with a previous SARS-CoV-2 infection, while the percentage was higher in case of a single immune stimulation (6.7% with a previous SARS-CoV-2 infection alone and 10.2% in case of vaccination alone) or completely without immune stimulation (20.2% p < .0001) (Table 2).

The first multivariable model, conducted on the overall sample, confirmed that the risk of contracting the infection for the children of unvaccinated women was significantly higher than the risk faced by the children of vaccinated women, after adjusting for previous history of infection among the mothers (OR = 1.28, 95% CI = 1.03-1.59, p = .027). The absence of a maternal previous COVID-19 infection exposed children to a significantly greater risk of contracting the infection in the first 12 months after birth compared to children of women with previous contact with the virus (OR = 5.87, 95% CI = 4.73-7.29, p < .0001).

A second multivariate model, focused on vaccinated women, also confirmed the different degrees of protection offered as the number of doses increased, in particular in the case of three doses (OR = 0.48, 95%CI = 0.25-0.92, p < .05). A significant increase in protection offered by a vaccine administered before pregnancy compared to a drug administered during pregnancy was also proved (OR = 0.3, 95% CI = 0.1;0.4, p-value <.0001).

A previous infection of the mother was confirmed as a variable of strong protection regardless of the type of vaccine, the number of doses administered, the trimester of vaccination, and the period of pregnancy in which the infection was contracted (OR = 0.18, 95% CI = 0.13–0.26, p-value <.0001) (Table 3).Table 3. Multivariable logistic regressions.

A. Overall sample	OR	95% CI	p-value	
Previous vaccination of the mother (No vs Yes)	1.28	(1.03-1.59)	0.027	
Previous COVID-19 infection (No vs Yes)	5.87	(4.73-7.29)	<.0001	
B. Only vaccinated women	OR	95% CI	p-value	
Number of doses	 	 	 	
2 doses vs 1 dose	1	(0.56-1.83)	0.98	
3 doses vs 1 dose	0.48	(0.25-0.92)	0.03	
Vaccination of mothers	 	 	 	
Before pregnancy vs third trimester	0.26	(0.15-0.45)	<.0001	
First trimester vs third trimester	0.72	(0.40-1.28)	0.26	
Second trimester vs third trimester	0.74	(0.48-1.16)	0.18	
Previous COVID-19 infection (Yes vs no)	0.18	(0.13-0.26)	<.0001	
C. Only women with double immune stimulation	OR	95% CI	p-value	
Vaccination of mothers	 	 	 	
Before pregnancy vs third trimester	0.14	(0.06-0.32)	<.0001	
First trimester vs third trimester	0.33	(0.13-0.79)	0.01	
Second trimester vs third trimester	0.87	(0.47-1.60)	0.66	

In the third model, considering instead only women with double immune stimulation, therefore both subjected to vaccination and with a history of previous infection, the only variable for which a significant impact emerges is the vaccination period: the further away from birth vaccination was administered, the greater the newborn protection (p-value <.0001)

Discussion and conclusion

The specific objective of our research was to study the effectiveness of mRNA vaccines administered during pregnancy in reducing the risk of contracting SARS-CoV-2 infection in babies under 12 months.

The effectiveness of the vaccine in preventing infection in newborns was higher than 44%; the incidence of infection was 18.1% among children of unvaccinated women and dropped to 10.2% among children of vaccinated mothers.

The effectiveness of vaccination was confirmed with all types of vaccines used, showing a slight increase in efficacy when the vaccination cycle was completed using 2 or more different vaccines (mostly Spikevax and Comirnaty).

Results were in line with the only other research present in the literature on the topic,44 which highlighted a vaccination efficacy of 41.5% (95% CI, from 22.8% to 55.7%) among children born to mothers vaccinated during pregnancy.

The incidence of SARS-CoV-2 infection in new-borns was significantly lower in the first three months of life and became higher until the second trimester of life, and this temporal trend suggests a possible correlation with the persistence of maternal antibodies. The gradual reduction of circulating levels of maternal antibodies in the infant’s serum had already been studied, and results indicated that antibodies passively transferred via placenta and breast milk tended to progressively fade between 3 and 12 months from birth5,39,40,42 and that this might have consequences on the degree of protection offered.40,45,50 Another hypothesis could concern the progressive weaning, as the neutralizing activity of the antibodies present in breast milk has been widely demonstrated.41

The significant increase in protection offered as the number of vaccine doses administered increased was in line with our expectations and with the scientific literature,12,38,50,51 as the significant additional protection offered by a double immune stimulus was interesting due to its scope: the infection rate among the children of mothers both vaccinated and with previous infection was 5.2%, lower than infection rate among children of unvaccinated mothers without previous infection, which was around 31%.

The state of immune tolerance27,29 developed during pregnancy might alter the immune response following vaccination; in fact, the further away the vaccination event was from birth, the greater the protective capacity of the vaccine seemed to be with respect to the infectious event. This was in line with previous studies that showed that anti-spike IgG titer in newborn is in general higher when the vaccine was administered at a later gestational age.50

At the time of our last check, only four research groups were dedicated to investigating the degree of protection offered by maternal SARS-CoV-2 vaccination to newborns.44–47 One analysis45 showed that the mRNA vaccine administered to mothers was 52% effective in avoiding hospitalization of newborns. In particular, when administered after 20 weeks of gestation, it protected the child by 69%, while before 20 weeks, it demonstrated an efficacy of 38%, a result also confirmed by more recent research.46

This level of effectiveness is not an unexpected result, considering that it had already been shown that flu vaccine administered to pregnant women was as much as 91.5% effective in preventing the hospitalization of their children.47,52

Post-marketing data investigated immunogenicity, safety, and effectiveness of SARS-CoV-2 vaccine in high-risk subgroup, but only one study, published in 2023 by a Singapore research group, investigated the effectiveness of vaccination during pregnancy in reducing the risk of contracting SARS-CoV-2 infection for newborns.44,53–55

However, similar studies have been done on the flu vaccine: one study reported a 70% reduction in infections among the children of vaccinated women,56 but further research should be carried out to demonstrate whether different trimester of vaccination of mothers might correspond to actual differences in clinical protection of newborns.

The strengths of our research is that it was the second to investigate the ability of mRNA vaccines administered during pregnancy to protect newborns from SARS-CoV-2 infection.

The study sample, made up of 3,346 children, offers a clear perspective on the situation in the Puglia region. The methodological approach adopted, which involves cross-referencing data from hospital discharge forms of newborns with information on mothers obtained from sources such as the GIAVA portal for vaccination history and Iris Puglia for previous SARS-CoV-2 infection, showed robustness in the data collected, from which the temporal trend of infections could also be highlighted.

The distribution of vaccinations in the different stages of pregnancy offers a useful temporal framework for evaluating the impact of vaccination in relation to gestational age. The significant presence of pre-pregnancy infections in mothers adds an element of complexity but at the same time offers the opportunity to further explore the protection conferred by vaccination and improves the evaluation of immunogenicity and safety profile. Future studies should extend the knowledge about immunogenicity and safety of SARS-CoV-2, flu, and pertussis vaccines during pregnancy in the case of administration at the same visit.57

The multivariate analysis model validated the results by comparing various possible disturbing variables such as the number of doses administered, the mother’s history of previous infections, the vaccination or infection period in relation to the trimester of pregnancy, and the type of vaccine.

However, it was not possible to take into account the effectiveness of vaccination in different waves in protecting against viral variants other than “Omicron” due to the limited number of cases in the population covered by our study.58,59

Furthermore, as possible confounding factors, behavioral differences between vaccinated and non-vaccinated mothers must be kept in mind, who could differ in the adoption of precautionary measures and in the ability to undergo molecular swabs, which could lead to an underestimation of cases of infection among mothers opposed to vaccination.

Among the weak points of the study, it should also be considered that the evaluation was not enriched with that of the clinical outcomes because obviously an infection with serious symptoms must be considered differently from a completely asymptomatic infection.

This research could be of support for institutions and policymakers in making decisions relating to vaccination policies and the management of maternal and child health. Based on the positive results of the study, institutions could intensify awareness campaigns to encourage pregnant women to receive the SARS-CoV-2 vaccine, improving knowledge and attitude among pregnancy and breastfeeding.48 Communication should highlight the potential benefits for the health of the newborn and underline the importance of vaccination in preventing infection. Furthermore, the observation that an era of early vaccination could offer greater protection could lead to strategies to encourage vaccination in the early stages of pregnancy or to policies that massively promote vaccination for all women intending to become pregnant.

In future research, mothers who contracted SARS-CoV-2 during pregnancy could be retrospectively investigated on how they gave birth. In fact, there are studies that indicate a significant increase in the risk of preterm birth for women who contracted COVID-19 during pregnancy,32,38 a risk that is not present for women who have undergone the vaccine;38,51 in fact, as a secondary output of a forthcoming study is to confirm the safety of the vaccine administered during pregnancy by investigating whether, among vaccinated pregnant women, there is a significant increase in adverse events related to childbirth compared to the unvaccinated population or whether the vaccine could be even considered a protective factor.

With future research, it could also be possible to follow over time the health status of children born to mothers who contracted the COVID-19 infection during pregnancy. As a recent disease, long-term outcomes have not yet been described in infants born to pregnant women infected with COVID-19, but some early reports suggested immune dysregulation and an increased risk of neurological and cardiac-metabolic problems.60

We believe that demonstrating vaccine efficacy in protecting newborns could be a serious incentive for mothers to carry out the recommended vaccination. Various organizational aspects and communication activities should be implemented based on proved action (e.g., active free offer, invite letter, vaccination in hospital during checkup visit to the gynecologist, geographic proximity) in order to improve accessibility to immunization services and to increase compliance to vaccination.61–64

Acknowledgments

Cesare De Suglia: conceptualization, formal analysis, writing – original draft. Pasquale Stefanizzi: supervision, writing – review & editing. Giusy Graziano: Formal analysis. Lorenza Moscara: Investigation, writing - reviewing and Editing, data curation. Arianna Delle Fontane: literature research, acquisition of data. Martina Minelli: literature research, acquisition of data. Silvio Tafuri: Conceptualization, supervision, writing – review & editing.

Stefanizzi qualified in Medicine at the University of Parma in 2014 and he achieved a post degree in Hygiene and Preventive Medicine at the University of Bari in 2019. He is a consultant of the Apulian Observatory for Epidemiology in the field of immunization policies (focus on safety and effectiveness of vaccination programs), surveillance and management of infectious diseases, health organization. From July 2020, he has been the Assistant Professor of Public Health at the School of Medicine in Bari. He works as a medical doctor at the Bari Policlinico General Hospital – Hygiene Unit, in which he is charged of the management of vaccination activities; since March 2020, he is the member of the COVID-19 Control Room Unit.

He is the member of National Group of monitoring safety of vaccines coordinated by National drug Agency.

He is the author or co-author of 120 indexes and scientific papers and over 10 teaching books in the fields of epidemiology and public health.

Disclosure statement

No potential conflict of interest was reported by the author(s).

International committee of medical journal editors requirements

All authors attest they meet the criteria for authorship.
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