Updating the impact of mRNA COVID-19 vaccine exposure during pregnancy on obstetric and neonatal outcomes.

doi:10.21203/rs.3.rs-4874817/v1

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Systematic Review

Updating the impact of mRNA COVID-19 vaccine exposure during pregnancy on obstetric and neonatal outcomes.

https://doi.org/10.21203/rs.3.rs-4874817/v1

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Background

The safety of mRNA COVID-19 vaccines in pregnant women remains a critical concern. This systematic review and meta-analysis evaluate the maternal and neonatal outcomes associated with mRNA COVID-19 vaccination during pregnancy.

Methods

We conducted a systematic search of PubMed, Embase, Cochrane Library, and clinical trial registries for studies published between December 2020 and July 2024. Studies were included if they assessed obstetric and neonatal outcomes following mRNA COVID-19 vaccination in pregnant women. Data were extracted and analyzed using a random-effects model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs).

Results

Twelve studies met the inclusion criteria, encompassing 42,944 vaccinated and 183,733 unvaccinated pregnant women. mRNA vaccination was associated with a significant reduction in preterm delivery (OR 0.743, 95% CI 0.607–0.911), fetal distress (OR 0.699, 95% CI 0.546–0.893), neonatal congenital abnormalities (OR 0.712, 95% CI 0.570–0.889), and NICU admissions (OR 0.718, 95% CI 0.617–0.836). However, a slight increase in gestational diabetes risk was observed (OR 1.107, 95% CI 1.054–1.162).

Conclusion

mRNA COVID-19 vaccines are safe during pregnancy and associated with reduced risks of adverse obstetric and neonatal outcomes. The observed increase in gestational diabetes risk underscores the need for vigilant monitoring. These findings support the inclusion of pregnant women in vaccination campaigns and inform public health policies and clinical practices to improve maternal and neonatal health outcomes.

mRNA COVID-19 vaccination

pregnancy

in-utero exposure

obstetric

neonatal

systematic review and meta-analysis

The Problem: The impact of mRNA COVID-19 vaccines on obstetric and neonatal outcomes is complex and multifaceted, necessitating ongoing surveillance to ensure public trust in vaccination during pregnancy. Understanding the precise effects of these vaccines is crucial for informed clinical decision-making and public health policies.

What is Known: Substantial evidence exists regarding the safety and efficacy of COVID-19 vaccines in pregnant women, with numerous studies reporting positive maternal and neonatal outcomes. However, many studies focus on comparing different types of vaccines, making it difficult to isolate the effects specifically attributable to mRNA vaccines. Additionally, there is a scarcity of comprehensive analyses that extensively detail both maternal and neonatal outcomes from high-quality observational studies.

Added Value of the Current Study: This study provides updated and robust evidence on the safety and efficacy of mRNA COVID-19 vaccines in pregnancy, addressing gaps in the existing literature. By exclusively analyzing high-quality studies that compare outcomes in mRNA-vaccinated pregnant women with unvaccinated controls, this research offers a clear estimation of vaccine-attributed effects. The extensive presentation of maternal and neonatal outcomes enhances the understanding of the benefits and potential risks associated with mRNA vaccination during pregnancy, thereby supporting public health efforts and informing clinical guidelines.

The COVID-19 pandemic has caused unprecedented disruption globally, severely impacting education systems, social life, and economic activities. With over half a billion infections and more than 7 million deaths recorded worldwide [1], healthcare systems and pharmaceutical industries have been stretched beyond their limits. This led to the rapid development and deployment of the first-ever mRNA vaccines, including BNT162b2 by Pfizer Inc. and BioNTech and mRNA-1273 by ModernaTX Inc., in 2020 (Fig. 1). [2], [3], [4]

Currently, billions of doses have been administered globally, including among pregnant women. Active and long-term surveillance is essential for continued trust and future mRNA vaccine development, as mRNA vaccines represent a new platform. Although growing evidence exists on the safety of these vaccines, there remains a critical need for continually updated data to promote vaccine trust and dispel misinformation and disinformation.

Pregnant women and children are typically excluded from routine vaccine clinical trials, making post-market vaccine surveillance a vital tool for assessing post-exposure outcomes and promoting vaccine trust and safety. Preliminary short-term investigations of the BNT162b2 and mRNA-1273 vaccines have been inconclusive, with marginal and non-significant rates of obstetric effects reported on pregnancy and neonatal outcomes. [2], [5], [6], [7], [8]. This systematic review was conducted following the guides of the Cochrane Collaboration Handbook and PRISMA Statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [9] and using the Joanna Briggs Institute (JBI) methodology for systematic reviews to appraise the selected studies. This study aims to update the available evidence on maternal vaccination against COVID-19 and its impact on obstetric and neonatal outcomes.

Objectives

The primary objectives of this study are:

To evaluate the impact of in-utero mRNA COVID-19 vaccine exposure on obstetric outcomes.

To assess the neonatal outcomes following maternal mRNA COVID-19 vaccination during pregnancy.

Research questions

What major obstetric and neonatal health events in COVID-19 mRNA vaccination exposed pregnant women compared to non-COVID-19 vaccination controls?

Ethical considerations

The study did not require any ethical clearance application since no patient-related data or personal information were collected. Only peer-reviewed published high-quality data were extracted and used.

This systematic review and meta-analysis followed the PRISMA 2020 guidelines (http://www.prisma-statement.org/) comprising of 3 main stages: identification, screening, and inclusion, Fig. 2. [9]. The comprehensive search was conducted across multiple electronic databases, including PubMed, Web of Science, and Scopus. MeSH terms were generated using the PICO framework, focusing on pregnant women, mRNA COVID-19 vaccines, and adverse health events (Fig. 2).

Eligibility Criteria

Inclusions:

English-language publications.
Data collection between November 2019 and December 2023.
Studies involving pregnant women vaccinated with mRNA COVID-19 vaccines.
Controlled quantitative studies related to post-pregnancy exposure to COVID-19 mRNA vaccines.
Peer-reviewed published articles.

Exclusions:

Studies not on mRNA COVID-19 vaccination during pregnancy.
Efficacy or mechanistic studies.
Publications in languages other than English.
Predictive studies not conducted on humans.
Studies without negative control groups (unvaccinated pregnant women).

Search Strategy

A systematic search was performed using MeSH terms and Boolean combinations across PubMed, Web of Science, and Scopus. The search strategy was adjusted for other databases as necessary detailed in supplementary file 1.

Search Outcome and Article Selection

From the initial 3907 publications identified, duplicates were removed using RefWorks and manual checks. The remaining articles were screened for relevance, and 261 articles were selected for full-text review. After quality assessment using the JBI critical appraisal tool, 12 studies were included in the quantitative meta-analysis (Fig. 2). Screening process is detailed in supplementary file 2.

To pass the quality assessment, a quality score should not be less than 75% using the appropriate study design tool. The JBI assessment was done by two researchers (FAM and OO). Grading conflicts were resolved through further mutual discussions with emphasis on the analytical methods used by the studies. Additional studies (n = 3) resulting from the updated search in December 2023 were equally quality assessed and included. The overall number of the included studies are n = 15. In the current study, the Comprehensive Meta-Analysis (CMA) version 3 package was used of the meta-analysis of the 12 high quality studies. The main features of the selection criteria and selected studies are presented in Fig. 2 and Table 1.

Studies like ‘Myocarditis after BNT162b2 Vaccination in Israeli Adolescents’ by Witberg et al. [10], Vulvar Aphthous Ulcer in an Adolescent after Pfizer-BioNTech (BNT162b2) COVID-19 Vaccination by Wojcicki et al. [11] etc were rejected due to target group inconsistencies to the present study.

Data Extraction and Quality Assessment

Data extraction was performed independently by two reviewers using a standardized data extraction form. Any discrepancies were resolved through discussion or consultation with a third reviewer. The quality of the included studies was assessed using the JBI critical appraisal tool, ensuring a rigorous evaluation of each study's methodology, data analysis, and results reporting.

Statistical Analysis and synthesis

Statistical analyses were conducted using the Comprehensive Meta-Analysis (CMA) software. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each outcome of interest. Heterogeneity among studies was assessed using the I² statistic, and a random-effects model was applied to account for variability between studies.

Characteristics of Selected Studies

The selected studies were conducted across various continents, with the majority being cohort studies. Most identified were conducted in the Middle East/ Asia (6) followed by North America (5), lastly Europe (1) and Africa (1). Most studies were cohort studies (14) and a case-control study (1). Other characteristics are detailed in Table 1. A summary of the characteristics is presented in Table 1 and Fig. 3.

Insert Table 1

Table 1

Study characteristics
Study	Country	Design	Period	Status	Vaccine type	Sample Size	Target population	Objective
Wainstock et al.	Israel	Retrospective Cohort Study	Jan – June 2021	Vaccinated & non-vaccinated	Pfizer BNT162b2 mRNA	4 339	Postpartum women (Delivered between Jan and June 2021	To study the association between prenatal Pfizer-BioNTech COVID-19 vaccination, pregnancy course and outcomes.
Kugelman et al.	Israel	Retrospective Cohort Study (Medical Centre)	Feb 2021-July 2021	Vaccinated & non-vaccinated	Pfizer /BioNTech BNT162b2 mRNA	1894	Pregnant women	To compare adverse perinatal outcomes among coronavirus disease 2019 (COVID-19)– vaccinated and –unvaccinated pregnant women
Goldshtein, et al.	Israel	Population based Cohort Study	Mar 2021-Oct 2021	Vaccinated & non-vaccinated	Pfizer-BioNTech (BN162b2)	24 288	Pregnant women	To examine whether BNT162b2 mRNA vaccination during pregnancy is associated with adverse neonatal and early infant outcomes among the newborns
Peretz-Machluf et al.	Israel	Retrospective Cohort Study	Mar-July 2022	Vaccinated & non-vaccinated	Pfizer-BioNTech BN162b2 mRNA vaccine	3700	Pregnant women	To compare obstetric and neonatal outcomes between vaccinated and non-vaccinated pregnant women with singleton pregnancies
Citu et al .	Romania	Retrospective Cohort Study (Obstetrics and Gynaecology Clinic)	Jan 2020 – Jan 2021	Vaccinated & Non vaccinated	Pfizer BNT162b2 mRNA Moderna mRNA-1273	3094	Pregnancies (927) Spontaneous abortions (124)	To determine whether pregnant women vaccinated with an mRNA-type vaccine during the first trimester have higher risks of spontaneous abortion.
Hui et al. .	Australia	retrospective multicenter cohort study	July 1, 2021 to March 31, 2022.	Vaccinated & Non vaccinated	Pfizer-BioNTech BNT162b2 mRNA. Moderna mRNA; Janssen Ad26.COV2. S.; Oxford -AstraZeneca	32,536	Vaccinated and unvaccinated women for whom weeks 20 to 43 of gestation fell entirely within the 9-month data collection period	Aimed to measure the rate of COVID-19 vaccine uptake among women giving birth in Melbourne, Australia, and to compare perinatal outcomes by vaccination status.
Magnus et .al.	Sweden & Norway	Registry based retrospective study	Jan 2021 - Jan 2022	Vaccinated & non-vaccinated	mRNA vaccines, vector vaccines (BTN162b2, mRNA1273 & AZD1222)	157 521 (Norway: 54 112) (Sweden: 103 409)	Pregnant women	To examine the risk of adverse pregnancy outcomes after vaccination against SARS-CoV-2 during pregnancy
Morgan et al.	United States	retrospective cohort study	January 1, 2021, and December 31, 2021	Vaccinated only	Pfizer BNT162b2 mRNA & mRNA-1273	15,865	pregnant patients who completed the mRNA COVID-19 vaccination series and unvaccinated patients.	To compare frequency of perinatal death between pregnant patients who completed the mRNA coronavirus disease 2019 (COVID-19) vaccination series and unvaccinated patients.
Aharon et al.	United States	Retrospective Cohort Study (Academic Centre)	Feb 2021 - Sept 2021	Vaccinated & non- vaccinated	Moderna & Pfizer BioNTech mRNA Vaccines	1205	Pregnant women vaccinated and non-vaccinated – hyper ovarian hyperstimulation cycles	To assess whether coronavirus disease 2019 (COVID-19) mRNA vaccination is associated with controlled ovarian hyperstimulation or early pregnancy outcomes.
Rottenstreich et al.	Israel	Retrospective cohort study	January and April 2021	Vaccinated & non-vaccinated	(Pfizer– BioNTech BNT162b2	1775	Pregnant women	To evaluate the impact of Covid-19 vaccination (Pfizer– BioNTech BNT162b2) during the third trimester of pregnancy on maternal and neonatal outcomes
Lipkind et al.	USA	Retrospective cohort study	May 17– October 24, 2020, and during December 15, 2020–July 22, 2021	Vaccinated & non-vaccinated	COVID-19 vaccine during pregnancy	46,079	Pregnant women	To evaluate risks for preterm birth (< 37 weeks’ gestation) and small-for-gestational-age (SGA) at birth (birthweight < 10th percentile for gestational age) after COVID-19 vaccination (receipt of ≥ 1 COVID-19 vaccine doses) during pregnancy.
Dick et al.	Israel	Retrospective cohort study	December 2020 and July 2021	Vaccinated & non-vaccinated	Pfizer BioNTech (BNT162b2) or Moderna vaccines.	5618	Pregnant women	To examine the association between SARS-CoV-2 vaccination during pregnancy and maternal and neonatal outcomes in a large cohort study. Furthermore, to evaluate if the timing of vaccination during pregnancy is related to adverse outcomes.
Theiler et al.	USA	Retrospective delivery cohort	December 10, 2020, and April 19, 2021,	Vaccinated & non-vaccinated	mRNA vaccine,	2002	pregnant patients.	To assess the safety and efficacy of COVID-19 vaccines in pregnant patients.
Halasa et al.	USA	Case-control test-negative design	July 1, 2021, and March 8, 2022	fully vaccinated & non-vaccinated	mRNA vaccine	1049	infants younger than 6 months of age.	To assess the effectiveness of maternal vaccination during pregnancy against hospitalization for Covid-19 among infants younger than 6 months of age.
Jarraya et al.	Tunisia	Retrospective cohort study	January 2021 to May 2022	vaccinated & non-vaccinated pregnant patients	mRNA vaccine	145	Parturients tested positive for COVID-19 during pregnancy and who needed hospitalization at any stage of gestation.	To assess the impact and effectiveness of vaccination among the pregnant population on maternal, obstetrical, and foetal outcomes.

In Fig. 3, a word cloud for the keywords as used by the selected studies is presented to show the direction of the selected studies used in this review. A depiction of the highest occurring terms/expressions in the keywords of the included studies. The font sizes are directly proportional to the frequency of the terms shown. From this figure, it could be observed that SARS-COV 2 and COVID-19 vaccinations had higher frequency followed by COVID-19 mRNA, vaccine safety in particular the Pfizer BioNTech vaccine followed by obstetric outcomes.

3.2 Narrative results

The study examines the impact of COVID-19 vaccination during pregnancy on various obstetric and neonatal outcomes, with mixed findings reported across different studies.

Fetal Outcomes

Kugelman et al. and Rottenstreich et al. found no effect of the vaccine on intra-uterine fetal deaths. Regarding stillbirth, Hui et al. reported a significant protective effect (OR 0.18, CI 0.09–0.37), while Jarraya et al. found no significant effect. For intra-uterine growth retardation (IUGR), Hui et al. observed no significant impact, whereas Jarraya et al. reported a protective effect (OR 0.129, CI 0.029–0.581)[12], [13] [14], [15].

Meconium-Stained Amniotic Fluid and Fetal Distress

Peretz-Machluv et al. and Wainstock et al. noted a significant association between the vaccine and meconium-stained amniotic fluid, while Jarraya et al. and Rottenstreich et al. did not report such findings. Regarding fetal distress, Jarraya et al. did not find significant effects. [13], [14], [16], [17].

Preterm Birth

Results were varied, with studies by Jarraya et al., Hui et al., and Morgan et al. indicating a protective effect against preterm birth, while others, including Goldshtein et al., Kugelman et al., Peretz-Machluf et al., and Lipkind et al., showed no significant effect. [12], [13], [14], [15], [16], [17], [18], [19], [20]

Pathological Presentation and Complications

Wainstock et al. found no significant effect on pathological presentation, whereas Rottenstreich et al. reported an association with non-vertex presentation. Citu et al. did not find significant effects on pregnancy-related complications. Mixed results were noted for gestational hypertension and diabetes, with some studies indicating increased risk and others showing no significant effect. [13], [16], [17]

Delivery Methods

Among eight studies on caesarean deliveries, results were mixed, with some indicating an increased risk and others showing no effect. Studies on vacuum delivery also showed mixed outcomes. Two studies on placental abruption found no significant effect.

Maternal Outcomes

Few studies assessed maternal outcomes, showing no differences between vaccinated and unvaccinated patients in postpartum hemorrhage or fever. [21].

Neonatal Outcomes

The study reviewed outcomes like the 5-minute Apgar score, congenital abnormalities, small for gestational age, neonatal complications, respiratory complications, low birth weight, birth weight ≥ 4000 g, neonatal hospitalization, and ICU hospitalization. Most studies reported no significant effect of the vaccine on these outcomes, with some suggesting potential protective effects against congenital abnormalities and neonatal complications. [19],[12], [13], [15], [16], [17], [22], [23].

Trimester-Specific Outcomes

The review also included trimester-specific data on preterm birth and small for gestational age (SGA), showing mixed results across studies. [13], [14], [16], [18], [19], [22], [24].

3.3 Meta-Analysis

3.3.1 Maternal health outcomes

Results of the meta-analysis indicate that exposure to mRNA COVID-19 vaccines significantly reduced the risk of overall preterm delivery (OR 0.743, 95% CI 0.607–0.911, p = 0.004). The analysis also demonstrated a significant reduction in the risk of fetal distress with exposure to the mRNA COVID-19 vaccine (OR 0.699, 95% CI 0.546–0.893, p = 0.004). A significant association between prenatal mRNA Covid-19 exposure and gestational diabetes (OR 1.107, 95% CI 1.054–1.162, p = 0.001) was also observed.

Significant associations were not observed from the pooling effect of meta-analysis for other adverse pregnancy outcomes and newborn complications including intrauterine fetal death (OR 0.556, 95% CI 0.252–1.224, p = 0.145), intrauterine fetal growth restriction (OR 0.727, 95% CI 0.392–1.346, p = 0.310), placental abruption (OR 0.595, 95% CI 0.294–1.204, p = 0.149), maternal postpartum fever (OR 0.911, 95% CI 0.551–1.505, p = 0.716), maternal postpartum hemorrhage ( OR 0.969, 95% CI 0.821–1.142, p = 0.706), non-vertex presentation (OR 2.262, 95% CI 0.408–12.535, p = 0.350), gestational hypertension (OR 1.092, 95% CI 0.809–1.372, p = 0.449, vacuum delivery (OR 0.743, 95% CI 0.508–1.086, p = 0.125) and caesarean delivery (OR 1.031, 95% CI 0.869–1.223, p = 0.728).

The below Fig. 2 presents the forest plots for the meta-analytic summary of the maternal health outcomes following mRNA COVID-19 vaccination during pregnancy.

Insert Fig. 4

3.3.2 Meta analysis for the neonatal outcomes

The pooled result of the current meta-analysis indicates that maternal vaccination with mRNA COVID-19 vaccines significantly reduced the risk of overall Congenital abnormalities (OR 0.712, 95% CI 0.570–0.889, p = 0.003). A significant reduction in the risk of neonatal intensive care hospitalization (NICU) was also observed (OR 0.718, 95% CI 0.617–0.836, p = 0.000). Maternal mRNA COVID-19 vaccination was also observed to be significantly associated in the reduction preterm delivery (OR 0.743, 95% CI 0.607–0.911, p = 0.004).

Marginal but non-significant reduction was observed for variables such as reduction in 3rd trimesters small for gestational age (SGA) (OR 0.922, 95% CI 0.846–1.006, p = 0.068).

Significant associations were not observed from the pooling effect of meta-analysis for other adverse neonatal outcomes and new born complications including 5-minute APGA score (OR 0.805, 95% CI 0.629–1.030, p = 0.085), Newborn respiratory complications (OR 0.717, 95% CI 0.460–1.118, p = 0.142, All cause neonatal complications (OR 0.718, 95% CI 0.617-1.100, p = 0.277), and overall SGA (OR 0.979, 95% CI 0.917–1.044, p = 0.510).

The summary of the pooled meta-analysis for the neonatal outcomes are presented as forest plots in Fig. 5 below.

Insert Fig. 5

Detailed Statistical Findings

Preterm Delivery: The analysis demonstrated a significant reduction in the risk of preterm delivery among vaccinated pregnant women (OR 0.743, 95% CI 0.607–0.911, p = 0.004), indicating that mRNA COVID-19 vaccines may contribute to prolonging pregnancy and preventing early labor(FINAL_August _2024).

Fetal Distress: Vaccinated pregnancies showed a lower incidence of fetal distress (OR 0.699, 95% CI 0.546–0.893, p = 0.004), suggesting that the vaccine may enhance fetal health and resilience during gestation(FINAL_August _2024).

Neonatal Congenital Abnormalities: The likelihood of congenital abnormalities was reduced in the neonates of vaccinated mothers (OR 0.712, 95% CI 0.570–0.889, p = 0.003), providing evidence of the vaccine's safety concerning developmental anomalies(FINAL_August _2024).

NICU Admission: There was a significant decrease in NICU admissions for infants born to vaccinated women (OR 0.718, 95% CI 0.617–0.836, p < 0.001), highlighting the overall healthier outcomes for these neonates(FINAL_August _2024).

Gestational Diabetes: Contrarily, an increased risk of gestational diabetes was observed in vaccinated pregnant women (OR 1.107, 95% CI 1.054–1.162, p = 0.001), necessitating further investigation into this association and potential underlying mechanisms(FINAL_August _2024).

Other Outcomes: No significant associations were found for intrauterine fetal death, intrauterine growth restriction, placental abruption, maternal postpartum fever, maternal postpartum hemorrhage, non-vertex presentation, vacuum delivery, and cesarean delivery(FINAL_August _2024).

The systematic review and meta-analysis aimed to investigate the impact of prenatal mRNA COVID-19 vaccine exposure on obstetric and neonatal outcomes. The analysis encompassed a comprehensive evaluation of various outcomes across 15 studies. The findings from our analysis have suggested that receiving the mRNA COVID-19 vaccine during pregnancy does not seem to increase the likelihood of experiencing adverse outcomes for both the mother and the newborn except for potential association with gestational diabetes. However, a potential added benefit in the form of reductions in certain adverse maternal and neonatal outcomes was observed.

From the analysis, a potential protective effect of prenatal mRNA COVID-19 vaccine exposure against preterm birth, fetal distress, fetal congenital abnormalities, and NICU hospitalizations, was observed, which was evidenced by the significant reduction of odds in the meta-analysis. In addition, it was also demonstrated that other neonatal adverse outcomes such as intrauterine fetal death, and intrauterine fetal growth restriction were not significantly associated with prenatal mRNA COVID-19 vaccine. An increased risk of gestational diabetes was found to be associated with mRNA COVID-19 vaccine in pregnancy. Other adverse maternal and neonatal outcomes such as placental abruption, gestational hypertension, maternal post-partum fever, maternal post-partum hemorrhage, non-vertex presentation, vacuum delivery, caesarean delivery, 5-minute APGA, low birth weight, newborn respiratory complications, all-cause neonatal complications and full-term small for gestational age (SGA) were not found to be associated with exposure to prenatal mRNA COVID-19 vaccine.

The decline in preterm births may stem from preventing complications that are linked to infection with COVID-19, such as severe maternal respiratory issues or pre-eclampsia/ eclampsia. This decrease could also be attributed to systemic inflammation avoidance which is associated with infection by COVID-19 or different general immune response [15]. During pregnancy, maternal SARS-CoV-2 infection has been linked to immune activation in the maternal and fetal compartments that can lead to adverse fetal outcomes. Vaccination aims to decrease this immune activation and thus reduce adverse perinatal outcome [14], [25], [26]. COVID-19 vaccines are found to be linked to a decreased chance of maternal COVID-19 infection. Induction of comparable immune response in pregnant women was found with the two doses of mRNA COVID-19 vaccine which is associated with transmissions of antibodies to the newborn [27], [28]. By activating the innate immune response, antibodies play a role in protecting the mother and the fetus against COVID-19 infection through the Fc-domain [29]. Previous review studies showed the association between any type of COVID-19 vaccination exposure including mRNA COVID-19 vaccine in pregnancy and peripartum outcomes but they did not find any significant protective effect on preterm birth [30].

Based on our analysis, we have robust evidence to support the safety of prenatal mRNA COVID-19 vaccine and advocate for its advantages in reducing the occurrence of preterm birth and fetal distress. It was found that individuals who received the mRNA vaccine showed a significantly reduced likelihood of having meconium-stained amniotic fluid, indicating a protective influence of the vaccine against this event. As an indicator of fetal distress, meconium-stained amniotic fluid is recognized [16], [31].

An increased risk of gestational diabetes is found with the mRNA COVID-19 vaccine exposure. Our investigation of previous studies did not reveal a direct link between the mRNA COVID-19 vaccine and gestational diabetes. However, we observed mRNA vaccine-associated hyperglycemia, with several suggested mechanisms to explain the phenomena in some studies. The natural immune response of the body to viral infections can facilitate beta cell destruction in the pancreas which is linked to abnormal glucose metabolism [32], [33]. MDA5(melanoma differentiation-associated protein 5), a protein to recognize pathogens, plays a significant role in controlling the initial immune response of the body to SARS-CoV-2 infection [34]. It is suggested that MDA5 detects RNA from mRNA COVID-19 vaccine which can stimulate type 1 interferon production that can hamper the insulin production, conversion of proinsulin, and the function of mitochondria taking place in beta cells of the pancreas [35]. This can cause dysregulation of effective blood sugar levels in the body and lead to hyperglycemia, but further studies are warranted to get specific molecular mechanisms.

Neonatal intensive care admission could stem from multiple sources congenital abnormalities, neonatal infection, stressful labor, etc. The observed decrease in neonatal abnormalities in due to maternal vaccination partly justifies the subsequent reduction in the observed neonatal intensive care admissions among the vaccinated mothers. This observation is in sync with other studies [36].

Our study provided a comprehensive overview of COVID-19 acceptance and hesitancy among pregnant women throughout the world. Some studies reported a positive trend with high acceptance and low hesitancy rates, while some others revealed mixed results with similar acceptance and hesitancy rates. On the other hand, several studies from different areas of the world including Asia, Europe, and North America pointed out low acceptance and high hesitancy rates. This highlights the significance of targeted educational efforts and information access so that vaccine hesitancy can be addressed, and vaccination uptake can be promoted in this demographic.

The uptake of vaccine among pregnant women is on the rise but still low, with only a minor portion being fully vaccinated when it is time to deliver. Pregnant mothers usually hesitate to try something unfamiliar or new during pregnancy because of their concerns about the potential harm to their offspring. It is crucial to address the low vaccination rates among pregnant individuals to safeguard the health of both mother and offspring [37], [38].

Strength

The updated search strategy comprised an extensive literature review that examined over 3900 records. We have included all high-quality studies assessed by the JBI critical appraisal tool in our review. Our analysis also included the outcomes without significant associations. We employed meta-analysis techniques to offer more precise estimates of the impact of mRNA COVID-19 exposure in pregnancy on various pregnancy and neonatal outcomes. The findings from our analysis will assist pregnant individuals and healthcare professionals in making the right decisions about vaccination.

Limitations

The eligible studies were limited to few countries, and this may limit the geographical generalizability of our findings. As we excluded some high-quality studies lacking a comparison group, this might result in missing some important insights. For each of the outcomes, the number of studies is limited, further studies are recommended to validate the results.

Clinical and Policy Implications

Guidance for Healthcare Providers: The findings provide healthcare providers with robust evidence to support the safety and benefits of mRNA COVID-19 vaccines during pregnancy. This can help in counseling pregnant women and addressing concerns about vaccine safety.

Informed Decision-Making: Pregnant women can make more informed decisions about vaccination based on the study's findings, knowing the potential benefits and risks. This can lead to higher vaccine uptake and better health outcomes for both mothers and infants.

Policy Development: Public health agencies can use this evidence to develop policies and guidelines that promote maternal vaccination and address vaccine hesitancy. This can improve vaccine coverage and reduce the burden of COVID-19 on pregnant women and their newborns.

Future Research Directions

Long-Term Follow-Up Studies: Future research should focus on long-term follow-up of children born to vaccinated mothers to assess developmental and health outcomes beyond the neonatal period. Such studies can provide valuable insights into any delayed effects of in-utero vaccine exposure.

Mechanistic Studies: Investigating the biological mechanisms underlying the observed associations, particularly the increased risk of gestational diabetes, can help elucidate the vaccine's impact on maternal and fetal physiology. This can guide the development of strategies to mitigate any adverse effects.

Randomized Controlled Trials (RCTs): While RCTs in pregnant women present ethical and logistical challenges, well-designed observational studies and quasi-experimental designs can complement RCTs and provide robust evidence on vaccine safety and efficacy.

Impact of Variants: As new SARS-CoV-2 variants emerge, ongoing research should evaluate the effectiveness and safety of mRNA vaccines against these variants in pregnant women. This will ensure that vaccination guidelines remain relevant and effective.

This systematic review and meta-analysis provide robust evidence that mRNA COVID-19 vaccines are safe during pregnancy and offer protective effects against adverse obstetric and neonatal outcomes. The significant reduction in preterm delivery, fetal distress, neonatal congenital abnormalities, and NICU admission highlights the benefits of vaccination. However, the observed association with gestational diabetes underscores the need for vigilant post-vaccine surveillance and further research.

The findings contribute valuable data to inform public health policy, guide clinical practices, and shape future vaccine development strategies. Ongoing research, particularly long-term follow-up studies and mechanistic investigations, will be crucial to fully understand the implications of in-utero mRNA vaccine exposure and ensure the continued safety and efficacy of maternal vaccination programs.

Although we are encouraging mRNA COVID-19 vaccine intake in pregnant women, we emphasize the importance of postvaccine surveillance for gestational diabetes among them. By implementing the proper monitoring protocol, the incidence and progression of gestational diabetes can be closely monitored by the healthcare providers that can enable the early detection and proper management strategy. In addition, as the number of studies included to show the association between prenatal mRNA COVID19 vaccine and gestational diabetes risk is relatively low, so by conducting large-scale high-quality studies the evidence can be strengthened.

Declaration of competing interest

The researchers have no conflicting interest in carrying out this study.

Funding

This research did not receive any funding from the public, private, or not-for-profit sectors.

Author Contribution

Authors contributions. All authors reviewed the manuscript."-Frank, Adusei-Mensah (FAM), ideation, method, writing, analysis, proofreading, editing- Olubunmi, Olubamwo (OO); Method, data analyses, review, and critical revision of manuscript.-Adedayo, Olawuni (AO), writing, review, editing- Laboni, Akter (LA); writing, review, editing- Luqman Oluwaseun, Awoniyi (LO); writing, review, editing- Rethabile, Joyce Moshoeshoe (RJM); writing, reviewing, editing- Sunday, Olaleye (SO), writing, review, editing-Oluwafemi Samson, Balogun (OSB); writing, review, editing-Jussi, Kauhanen (JK), Scientific and critical revision of manuscript.

Acknowledgement

AcknowledgementsWe acknowledge Heikki Laitinen of University of Eastern Finland (UEF) library for his enormous support and motivation in the search strategy development.

Data availability statement

Supplementary data has been attached

WHO, ‘COVID-19 cases | WHO COVID-19 dashboard’, datadot. Accessed: Jun. 21, 2024. [Online]. Available: https://data.who.int/dashboards/covid19/cases
S. Ellington and C. K. Olson, ‘Safety of mRNA COVID-19 vaccines during pregnancy’, The Lancet Infectious Diseases, vol. 22, no. 11, pp. 1514–1515, Nov. 2022, doi: 10.1016/S1473-3099(22)00443-1.
A. I. Joudeh, A. Q. Lutf, S. Mahdi, and G. Tran, ‘Efficacy and safety of mRNA and AstraZeneca COVID-19 vaccines in patients with autoimmune rheumatic diseases: A systematic review’, Vaccine, vol. 41, no. 26, pp. 3801–3812, Jun. 2023, doi: 10.1016/j.vaccine.2023.05.048.
N. Sharif, K. J. Alzahrani, S. N. Ahmed, and S. K. Dey, ‘Efficacy, Immunogenicity and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis’, Front Immunol, vol. 12, p. 714170, Oct. 2021, doi: 10.3389/fimmu.2021.714170.
L. H. Zauche et al., ‘Receipt of mRNA COVID-19 vaccines preconception and during pregnancy and risk of self-reported spontaneous abortions, CDC v-safe COVID-19 Vaccine Pregnancy Registry 2020–21’, Research square, 2021.
N. Cirillo and R. Doan, ‘The association between COVID-19 vaccination and Bell’s palsy’, The Lancet Infectious Diseases, vol. 22, no. 1, pp. 5–6, Jan. 2022, doi: 10.1016/S1473-3099(21)00467-9.
K. Shahsavarinia et al., ‘Bell’s Palsy and COVID-19 Vaccination: A Systematic Review’, Med J Islam Repub Iran, vol. 36, p. 85, Jul. 2022, doi: 10.47176/mjiri.36.85.
E. Y. F. Wan et al., ‘Bell’s palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested case-control study’, The Lancet Infectious Diseases, vol. 22, no. 1, pp. 64–72, Jan. 2022, doi: 10.1016/S1473-3099(21)00451-5.
M. J. Page et al., ‘The PRISMA 2020 statement: an updated guideline for reporting systematic reviews’, BMJ, vol. 372, p. n71, Mar. 2021, doi: 10.1136/bmj.n71.
G. Witberg et al., ‘Myocarditis after BNT162b2 Vaccination in Israeli Adolescents’, N Engl J Med, p. NEJMc2207270, Oct. 2022, doi: 10.1056/NEJMc2207270.
A. V. Wojcicki and K. L. O’Flynn O’Brien, ‘Vulvar Aphthous Ulcer in an Adolescent After Pfizer-BioNTech (BNT162b2) COVID-19 Vaccination’, J Pediatr Adolesc Gynecol, vol. 35, no. 2, pp. 167–170, Apr. 2022, doi: 10.1016/j.jpag.2021.10.005.
N. Kugelman, A. Riskin, R. Kedar, and S. Riskin-Mashiah, ‘Safety of COVID-19 vaccination in pregnant women: A study of the adverse perinatal outcomes’, Int J Gynaecol Obstet, vol. 161, no. 1, pp. 298–302, Apr. 2023, doi: 10.1002/ijgo.14599.
M. Rottenstreich, H. Y. Sela, R. Rotem, E. Kadish, Y. Wiener-Well, and S. Grisaru-Granovsky, ‘Covid-19 vaccination during the third trimester of pregnancy: rate of vaccination and maternal and neonatal outcomes, a multicentre retrospective cohort study’, BJOG, vol. 129, no. 2, pp. 248–255, Jan. 2022, doi: 10.1111/1471-0528.16941.
A. Jarraya et al., ‘Impact of COVID-19 vaccination among pregnant women requiring hospital admission: prospective observational research’, Italian Journal of Gynaecology and Obstetrics, Jun. 2023, doi: 10.36129/jog.2022.53.
L. Hui et al., ‘Reductions in stillbirths and preterm birth in COVID-19-vaccinated women: a multicenter cohort study of vaccination uptake and perinatal outcomes’, Am J Obstet Gynecol, vol. 228, no. 5, p. 585.e1-585.e16, May 2023, doi: 10.1016/j.ajog.2022.10.040.
R. Peretz-Machluf et al., ‘Obstetric and Neonatal Outcomes following COVID-19 Vaccination in Pregnancy’, J Clin Med, vol. 11, no. 9, p. 2540, Apr. 2022, doi: 10.3390/jcm11092540.
T. Wainstock, I. Yoles, R. Sergienko, and E. Sheiner, ‘Prenatal maternal COVID-19 vaccination and pregnancy outcomes’, Vaccine, vol. 39, no. 41, pp. 6037–6040, Oct. 2021, doi: 10.1016/j.vaccine.2021.09.012.
J. A. Morgan et al., ‘Pregnancy Outcomes in Patients After Completion of the mRNA Coronavirus Disease 2019 (COVID-19) Vaccination Series Compared With Unvaccinated Patients’, Obstet Gynecol, vol. 141, no. 3, pp. 555–562, Mar. 2023, doi: 10.1097/AOG.0000000000005072.
I. Goldshtein et al., ‘Association of BNT162b2 COVID-19 Vaccination During Pregnancy With Neonatal and Early Infant Outcomes’, JAMA Pediatr, vol. 176, no. 5, pp. 470–477, May 2022, doi: 10.1001/jamapediatrics.2022.0001.
H. S. Lipkind et al., ‘Receipt of COVID-19 Vaccine During Pregnancy and Preterm or Small-for-Gestational-Age at Birth - Eight Integrated Health Care Organizations, United States, December 15, 2020-July 22, 2021’, MMWR Morb Mortal Wkly Rep, vol. 71, no. 1, pp. 26–30, Jan. 2022, doi: 10.15585/mmwr.mm7101e1.
I. M. Citu et al., ‘The Risk of Spontaneous Abortion Does Not Increase Following First Trimester mRNA COVID-19 Vaccination’, J Clin Med, vol. 11, no. 6, p. 1698, Mar. 2022, doi: 10.3390/jcm11061698.
A. Dick, J. I. Rosenbloom, E. Gutman-Ido, N. Lessans, A. Cahen-Peretz, and H. H. Chill, ‘Safety of SARS-CoV-2 vaccination during pregnancy- obstetric outcomes from a large cohort study’, BMC Pregnancy Childbirth, vol. 22, no. 1, p. 166, Feb. 2022, doi: 10.1186/s12884-022-04505-5.
M. C. Magnus et al., ‘Association of SARS-CoV-2 Vaccination During Pregnancy With Pregnancy Outcomes’, JAMA, vol. 327, no. 15, pp. 1469–1477, Apr. 2022, doi: 10.1001/jama.2022.3271.
R. N. Theiler, M. Wick, R. Mehta, A. L. Weaver, A. Virk, and M. Swift, ‘Pregnancy and birth outcomes after SARS-CoV-2 vaccination in pregnancy’, Am J Obstet Gynecol MFM, vol. 3, no. 6, p. 100467, Nov. 2021, doi: 10.1016/j.ajogmf.2021.100467.
WAPM (World Association of Perinatal Medicine) Working Group on COVID-19, ‘Maternal and perinatal outcomes of pregnant women with SARS-CoV-2 infection’, Ultrasound Obstet Gynecol, vol. 57, no. 2, pp. 232–241, Feb. 2021, doi: 10.1002/uog.23107.
D. Di Mascio et al., ‘Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19’, J Perinat Med, vol. 49, no. 1, pp. 111–115, Dec. 2020, doi: 10.1515/jpm-2020-0539.
C. Atyeo et al., ‘COVID-19 mRNA vaccines drive differential antibody Fc-functional profiles in pregnant, lactating, and nonpregnant women’, Sci Transl Med, vol. 13, no. 617, p. eabi8631, Oct. 2021, doi: 10.1126/scitranslmed.abi8631.
K. J. Gray et al., ‘Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study’, Am J Obstet Gynecol, vol. 225, no. 3, p. 303.e1-303.e17, Sep. 2021, doi: 10.1016/j.ajog.2021.03.023.
A. Schäfer et al., ‘Antibody potency, effector function, and combinations in protection and therapy for SARS-CoV-2 infection in vivo’, J Exp Med, vol. 218, no. 3, p. e20201993, Mar. 2021, doi: 10.1084/jem.20201993.
A. Watanabe et al., ‘Peripartum Outcomes Associated With COVID-19 Vaccination During Pregnancy: A Systematic Review and Meta-analysis’, JAMA Pediatr, vol. 176, no. 11, pp. 1098–1106, Oct. 2022, doi: 10.1001/jamapediatrics.2022.3456.
C. P. L. Oliveira, F. Flôr-de-Lima, G. M. D. Rocha, A. P. Machado, and M. H. F. Guimarães Pereira Areias, ‘Meconium aspiration syndrome: risk factors and predictors of severity’, J Matern Fetal Neonatal Med, vol. 32, no. 9, pp. 1492–1498, May 2019, doi: 10.1080/14767058.2017.1410700.
K. Sakurai et al., ‘Type 1 diabetes mellitus following COVID-19 RNA-based vaccine’, J Diabetes Investig, vol. 13, no. 7, pp. 1290–1292, Jul. 2022, doi: 10.1111/jdi.13781.
K. Aida et al., ‘RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates beta-cell death in fulminant type 1 diabetes’, Diabetes, vol. 60, no. 3, pp. 884–889, Mar. 2011, doi: 10.2337/db10-0795.
F. Yin, Z. Wu, X. Xia, M. Ji, Y. Wang, and Z. Hu, ‘Unfolding the Determinants of COVID-19 Vaccine Acceptance in China’, Journal of Medical Internet Research, vol. 23, no. 1, p. e26089, 2021, doi: 10.2196/26089.
S. I. Blum and H. M. Tse, ‘Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development’, Microorganisms, vol. 8, no. 7, p. 993, Jul. 2020, doi: 10.3390/microorganisms8070993.
M. Norman et al., ‘Neonatal Outcomes After COVID-19 Vaccination in Pregnancy’, JAMA, vol. 331, no. 5, pp. 396–407, Feb. 2024, doi: 10.1001/jama.2023.26945.
S. J. Stock et al., ‘SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland’, Nat Med, vol. 28, no. 3, pp. 504–512, Mar. 2022, doi: 10.1038/s41591-021-01666-2.
G. Iacobucci, ‘Covid-19 and pregnancy: vaccine hesitancy and how to overcome it’, BMJ, vol. 375, p. n2862, Nov. 2021, doi: 10.1136/bmj.n2862.

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Updating the impact of mRNA COVID-19 vaccine exposure during pregnancy on obstetric and neonatal outcomes.

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Abstract

Background

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The problem, what is known and added value of the current study

Introduction

Objectives

Methodology

Eligibility Criteria

Inclusions:

Exclusions:

Search Strategy

Search Outcome and Article Selection

Data Extraction and Quality Assessment

Statistical Analysis and synthesis

Characteristics of Selected Studies

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3.2 Narrative results

3.3 Meta-Analysis

3.3.1 Maternal health outcomes

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3.3.2 Meta analysis for the neonatal outcomes

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General Discussions

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Conclusion

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Declaration of competing interest

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