COVID-19 poses a significant global health threat, impacting both pregnant women and their neonates. While COVID-19 vaccines have proven effective in the general population, their effects on pregnancy and neonatal outcomes remain a crucial area of investigation. Initial COVID-19 vaccine trials excluded pregnant women due to safety concerns, leading to varying vaccination strategies across countries. Although studies suggest COVID-19 vaccination protects pregnant women from severe illness, evidence on neonatal outcomes is limited. Existing observational studies have explored potential impacts on preterm birth, SGA, NICU admission, and Apgar scores. This systematic review and meta-analysis aimed to synthesize data from published studies to clarify the differences in neonatal outcomes between COVID-19 vaccinated and unvaccinated pregnant women.

The introduction cites numerous studies demonstrating the global impact of COVID-19, its risks to pregnant women, and the efficacy of COVID-19 vaccines in the general population. It also highlights the initial exclusion of pregnant women from vaccine trials and the subsequent emergence of data on vaccine safety and efficacy in this group. Several studies exploring the effects of COVID-19 vaccination on neonatal outcomes are mentioned, underscoring the need for a comprehensive meta-analysis.

This systematic review and meta-analysis, registered with PROSPERO (CRD42022343713), followed PRISMA guidelines. Three databases (PubMed, EMBASE, and the WHO COVID-19 Database) were searched up to July 3, 2022, using keywords related to pregnancy, newborns, COVID-19, and vaccines. Studies reporting neonatal outcomes in COVID-19 vaccinated and unvaccinated pregnant women were included. Primary outcomes were preterm birth, SGA, NICU admission, and low 5-minute Apgar score (<7). Secondary outcomes included preterm birth (<34 weeks), low birth weight, very low birth weight, congenital anomalies, jaundice, low 1-minute Apgar score (<7), meconium aspiration syndrome, mechanical ventilation, seizures, hypoglycemia, sepsis, encephalopathy, intracranial hemorrhage, transient tachypnea of the newborn, and respiratory distress syndrome. Studies were screened by two reviewers, with disagreements resolved through consensus or by a third reviewer. Risk of bias was assessed using ROBINS-I. Meta-analysis was performed using RevMan 5.4, with random-effects or fixed-effects models used depending on heterogeneity (I²).

The initial search yielded 399 studies. After removing duplicates and screening based on titles, abstracts, and full texts, 15 studies were included in the meta-analysis, involving 90,443 vaccinated and 265,063 unvaccinated pregnant women. The meta-analysis showed that maternal COVID-19 vaccination was associated with: a 17% reduction in the odds of preterm birth (OR 0.83, 95% CI 0.74-0.95, P=0.004); a 7% reduction in the odds of SGA (OR 0.93, 95% CI 0.90-0.96, P<0.0001); an 8% reduction in the odds of a low 5-minute Apgar score (<7) (OR 0.92, 95% CI 0.86-0.99, P=0.03). There was no significant association between vaccination and NICU admission (OR 0.93, 95% CI 0.82-1.05, P=0.24). Analysis of additional neonatal outcomes showed no increased risk associated with vaccination. Subgroup analysis suggested that vaccination before the third trimester might be particularly beneficial in reducing preterm birth and low Apgar scores. Moderate to high heterogeneity was observed in some outcomes; however, sensitivity analysis showed that the overall effect didn't change after excluding the studies contributing the most to the heterogeneity. Most of the pregnant women in the included studies received mRNA vaccines.

This meta-analysis provides further evidence that maternal COVID-19 vaccination is associated with a reduced risk of several adverse neonatal outcomes, including preterm birth, SGA, and low Apgar scores, without increasing the risk of other adverse effects. These findings should contribute to increasing vaccine acceptance among pregnant women, given the continued concerns regarding vaccine safety. The observed heterogeneity might reflect differences in study designs, populations, or vaccine types. The apparent stronger protective effect of early vaccination (before the third trimester) requires further investigation, as does the impact of different vaccine types and the long-term effects of vaccination.

This meta-analysis of observational studies demonstrates that maternal COVID-19 vaccination is associated with a decreased risk of several adverse neonatal outcomes. The findings support the recommendation for COVID-19 vaccination in pregnant women. Further research focusing on different vaccine types, dosing schedules, and vaccination timing during pregnancy is needed to refine recommendations and address remaining uncertainties.

The main limitations of this study are the reliance on observational studies rather than randomized controlled trials, limited data on specific neonatal outcomes and vaccine types, potential heterogeneity among studies, and the inclusion of data primarily from developed countries and mRNA vaccines, limiting the generalizability of findings. Furthermore, the lack of detailed information about different strains of COVID-19 and the timing of vaccinations during pregnancy prevents a more nuanced understanding of the vaccine's effects.