Maternal and Neonatal Outcomes in Pregnant Women Vaccinated Against COVID-19 Compared to an Unvaccinated Group

Introduction

Significant progress was made in combating COVID-19 by early 2022, marked by a decline in daily reported cases and a nearly 27.9% reduction in hospitalizations. These improvements are largely credited to the broad application of large-scale public health measures against COVID-19, including maintaining communication with authorities, vaccination, correct use of recommended masks, avoiding crowded areas, and physical distancing.^1–4

Pregnant women are recognized as a population at high risk for severe outcomes from coronavirus disease 2019 (COVID-19).^5–7 Pregnancy involves physiological and immune adjustments to accommodate the developing fetus, which can heighten susceptibility to infections and lead to severe maternal and fetal complications.⁸ Drawing from experiences with the outbreak of SARS-CoV-1 in 2002, associated with high mortality among pregnant women, it became clear that pregnant individuals represent a vulnerable demographic for COVID-19.^9,10 Tossetta et al demonstrated that a greater frequency of preeclampsia occurred in pregnancies complicated by COVID-19 than in COVID-19-negative pregnancies.¹¹

Managing COVID-19 in pregnant patients presents a significant challenge for clinicians because of the risk of adverse maternal, fetal, and neonatal effects.^12,13 Various medications, such as ribavirin, a frequently utilized antiviral for SARS-CoV-2, which is not recommended during pregnancy because of its established teratogenic effects.^4,14,15 Furthermore, clinical trials often exclude pregnant individuals for safety considerations.¹⁶ Consequently, medications that may be effective for the general population cannot be readily administered to pregnant women because of insufficient data on side effects in this specific group. As noted by Costantine et al,¹⁷ this “protection by exclusion” of pregnant individuals from clinical therapeutic trials can be inappropriate and unfounded, preventing pregnant women with COVID-19 from accessing potentially beneficial interventions and complicating the assessment of drug safety and efficacy in pregnancy exceedingly difficult. Despite these challenges, the fight against COVID-19 has largely relied on repurposing existing drugs, with the scientific community shifting focus towards vaccine development rather than specific antiviral agents.^18,19

Over 50 COVID-19 vaccines have gained approval from national regulatory authorities worldwide, with most demonstrating efficacy.^13,20 Moreover, over half of the global population has been administered at least one dose of a vaccine.²¹ However, many individuals have refrained from receiving an optimal vaccine dosage for various reasons, including misinformation regarding its safety and long-term effects. Whatever the reason, when individuals opt out of vaccination, there are significant consequences.²² COVID-19 outbreaks are more prevalent in communities with low vaccination rates. This not only places unvaccinated individuals at risk but also elevates the likelihood of disease transmission to others, including those at low risk.²³

Pregnant women are a high-risk group; infection with COVID-19 while pregnant can result in more severe clinical manifestations compared to non-pregnant women, significantly increasing hospitalizations, ICU admissions, need for assisted ventilation, and even mortality in this population. Other complications associated with COVID-19 in pregnant women, such as preterm labor and preeclampsia, are linked to the activation of inflammatory processes. While there was initially limited information regarding clinical adverse events from vaccination, a now substantial body of observational data and systematic reviews has provided reassuring evidence on vaccine safety in pregnancy.^24,25 However, this evidence is predominantly from studies of mRNA vaccines conducted in Western populations, which have found no increased risk for major adverse outcomes like miscarriage, stillbirth, or congenital anomalies.^26,27

This existing literature highlights a critical knowledge gap. In countries like Iran, which have utilized non-mRNA vaccines (eg, inactivated virus vaccines), specific safety data is less abundant. This uncertainty is compounded by a reluctance from some manufacturers to report potential adverse effects for pregnant women. Therefore, the primary objective of this study was to evaluate the association between COVID-19 vaccination (the exposure) and a comprehensive set of maternal and neonatal events (the outcomes) in an Iranian cohort. Specifically, we aimed to compare these outcomes in vaccinated pregnant women with those in a contemporary control cohort of unvaccinated pregnant women.

Materials and Methods

This retrospective cohort study analyzed pregnant women delivering at Amir-Al-Momenin Hospital in Semnan, Iran, between March 2020 and March 2022 (corresponding to Iranian calendar years 1399–1400). Patients were identified from hospital records using a convenience sampling method of all eligible deliveries within the study period. Based on an estimated complication rate and a precision of 5% at a 95% confidence level, a target sample size of 400 individuals was determined.

Inclusion criteria were maternal age between 15–45 years, singleton pregnancy, and no major anomalies reported in the 18th-week ultrasound. Mothers who had a confirmed COVID-19 infection during pregnancy were excluded (Figure 1).

Figure 1 The study selection process.

Data were gathered via a standardized checklist from archived hospital records. Baseline information included age, gestational age at birth, BMI, gravidity, parity, and history of underlying diseases (diabetes, hypertension, heart or thyroid disease). Exposure status (COVID-19 vaccination) was ascertained from medical records, including the number of doses received and vaccine type. Outcomes were defined based on standard clinical criteria and diagnostic codes documented in the records. Maternal outcomes included miscarriage, preeclampsia, premature rupture of membranes (PROM), maternal infections, vaginal bleeding, thromboembolism, and uterine contractions. Neonatal complications included stillbirth, preterm birth, intrauterine growth restriction (IUGR), small or large for gestational age (SGA/LGA), in-hospital neonatal death, need for NICU admission, respiratory distress, 1- and 5-minute Apgar scores, and congenital anomalies. It is a limitation that neonatal outcomes beyond the immediate hospitalization period were not assessed.

Data Analysis

Quantitative data were expressed as mean ± standard deviation (SD), and categorical data were expressed as number and percentage (%). To compare quantitative variables between groups, the independent t-test or Mann–Whitney U-test was used as appropriate. For categorical variables, the Chi-square test or Fisher’s exact test was employed. To analyze the impact of vaccination on binary maternal and neonatal outcomes, multivariable logistic regression analysis was used to calculate Odds Ratios (ORs) and 95% Confidence Intervals (CIs). Regression models were adjusted for potential confounders that showed baseline imbalances or were clinically relevant (eg, maternal age, parity). To analyze the influence of the number of vaccine doses on outcomes, logistic regression was used, with the number of doses treated as a categorical variable. All data analyses were conducted using SPSS software version 27, and a p-value of less than 0.05 was considered statistically significant.

Ethical Considerations

This research commenced following approval from the Research Council at the Abnormal Uterine Bleeding Research Center and the University Research Council, with ethics code IR.SEMUMS.REC.1401.042 from the University Ethics Committee. A waiver of the requirement for guardian consent for participants under 18 was granted by the Institutional Review Board (IRB), as all were legally emancipated minors (married, pregnant, and self-supporting). Confidentiality was maintained throughout the data collection process using anonymous checklists.

Results

This study included 404 pregnant women, consisting of 300 vaccinated individuals and 104 who were unvaccinated. The mean ± standard deviation (SD) age of the mothers in the study was 29.23 years (with a range of 15–45 years), while the mean ± SD gestational age stood at 34.23 weeks, and the mean ± SD BMI was recorded as 28.74 kg/m². No cases of smoking or alcohol consumption were observed among the mothers, and only one vaccinated patient reported drug use. No statistically significant differences were found between the vaccinated and unvaccinated groups in terms of mean age, gestational age, BMI, gravidity, type of delivery, employment status, education level, and underlying diseases (diabetes, hypertension, and hypothyroidism) (Table 1). The overall comparison of delivery types yielded p=0.093; however, a specific comparison of natural delivery rates showed a higher frequency in vaccinated mothers (45% vs 33.4%, p=0.043), consistent with detailed subgroup analysis in the records.

Table 1 Demographic and Baseline Characteristics of the Studied Mothers

In the vaccinated mothers group, 177 (59%) had no pregnancy complications, and 123 (41%) experienced pregnancy complications, among whom 16 patients experienced more than one complication. In the unvaccinated mothers group, 56 (53.8%) had no pregnancy complications, and 46 (44.2%) experienced pregnancy complications, among whom 11 patients experienced more than one. The most prevalent pregnancy complications in both vaccinated and unvaccinated pregnant mothers were gestational diabetes, bleeding, and preeclampsia, respectively. Among pregnancy complications, miscarriage was observed in 12 patients from the vaccinated group, but no cases of miscarriage were seen in the unvaccinated group (p=0.038). The frequency of other pregnancy complications did not differ significantly between the two groups of vaccinated and unvaccinated pregnant mothers (p > 0.05) (Table 2).

Table 2 Frequency Distribution and Comparison of Pregnancy Complications in Vaccinated and Unvaccinated Pregnant Mothers

The 1-minute Apgar score in neonates born to vaccinated and unvaccinated mothers did not differ significantly. In neonates born to vaccinated mothers, the 5-minute Apgar score was slightly lower than in neonates born to unvaccinated mothers (p=0.031); however, the difference was small and likely clinically insignificant, given the study’s sample size and wide confidence intervals. Comparison of the frequency of various neonatal complications in neonates born to vaccinated and unvaccinated mothers showed that intrauterine growth restriction (IUGR) was more common in neonates born to unvaccinated mothers than in neonates from the vaccinated mothers group (p=0.005). The frequency of other neonatal complications did not differ significantly between the two groups of vaccinated and unvaccinated mothers (p > 0.05) (Table 3).

Table 3 Frequency Distribution of Neonatal Complications in Neonates Born to Vaccinated and Unvaccinated Pregnant Mothers

The most common type of vaccine received was Sinopharm in 299 patients, and only one patient had received the AstraZeneca vaccine. Vaccination coverage was 99.7% for the first dose, 80.0% for the second dose, and 16.7% for the third dose. Comparison of the frequency of various neonatal complications in neonates born to vaccinated mothers according to the number of doses received showed that the incidence of neonatal complications did not differ significantly among mothers receiving one, two, or three doses of the vaccine (p > 0.05) (Table 4).

Table 4 Frequency Distribution of Neonatal Complications in Neonates Born to Vaccinated Pregnant Mothers by Dose Received

Table 5 Frequency Distribution of Maternal Complications in Vaccinated Pregnant Mothers by Dose Received

Comparison of the frequency of various maternal complications in vaccinated pregnant mothers according to the number of doses received showed that the incidence of maternal complications during pregnancy did not differ significantly among mothers receiving one, two, or three doses of the vaccine (p > 0.05) (Table 5).

Logistic regression analysis, adjusting for baseline characteristics such as age, gestational age, BMI, gravidity, and parity to account for potential imbalances, showed that vaccination did not have an effect on maternal outcomes, and the rate of maternal complications showed no statistical difference between the two cohorts of vaccinated and unvaccinated mothers; in other words, vaccination did not change the rate of maternal complications (Table 6).

Table 6 Logistic Regression Results for the Effect of Vaccination on Maternal Pregnancy Complications and Outcomes

Logistic regression analysis, similarly adjusted for baseline characteristics, showed that vaccination was associated with some neonatal outcomes. In neonates born to vaccinated mothers, the 5-minute Apgar score was lower, while intrauterine growth restriction and the need for NICU admission were higher in neonates born to unvaccinated mothers (Table 7).

Table 7 Logistic Regression Results for the Effect of Vaccination on Neonatal Complications and Outcomes

In linear regression analysis, selected for its ability to model the continuous relationship between dose number and outcomes despite the binary nature of some variables (with robustness checks confirming no significant impact on conclusions), the number of vaccine doses received was not associated with maternal outcomes during pregnancy or neonatal complications and outcomes.

Discussion

In this study, 404 pregnant women were studied in two groups: vaccinated and unvaccinated. We found that vaccination against COVID-19 was not associated with an overall increase in maternal or neonatal complications. Our findings, primarily reflecting outcomes following the Sinopharm vaccine, contribute important regional data to the global understanding of vaccine safety in pregnancy.

The baseline characteristics of our vaccinated and unvaccinated cohorts were largely comparable, minimizing the risk of significant confounding. The high vaccination uptake (75%) in our cohort is notable compared to rates reported in other studies. Research from Tamar Wainstock et al in 2021 reported a COVID-19 vaccination coverage rate of about 21%.²⁸ In a study by Megan E. Trostle et al in 2021, 82.1% had received two doses.²⁹ M. Rottenstreich et al (2022) reported a vaccination coverage of one or both doses at 40.2% in their study.³⁰ Seravalli et al (2024) reported COVID-19 vaccination coverage of about 80%, with inadequate education, fear of adverse vaccine reactions, and worries about fetal effects being the most important factors influencing vaccine hesitancy.³¹ Vaccination coverage is a health and development indicator, and vaccine hesitancy has been identified as a public health challenge in specific communities.³² Local-level inequalities exist in the development and implementation of public health measures, and COVID-19 vaccination coverage is no exception. These inequalities, along with racial and ethnic differences, act as barriers to healthcare access, creating mistrust and depriving some groups of vaccination.^33,34 Pregnant individuals face a greater risk of severe COVID-19. Although vaccination is recommended, uptake among pregnant individuals remains lower than in the general non-pregnant population. The main concern for vaccine refusal is safety concerns, and education and public health interventions are effective methods to increase vaccine acceptance rates.³⁵

In our cohort, we observed a trend toward a higher rate of natural delivery in vaccinated mothers (45% vs 33.4%); however, the overall comparison of delivery types was not statistically significant. The study by M. Rottenstreich et al (2022) indicated that receiving the COVID-19 vaccine was linked to reduced rates of cesarean delivery and vacuum-assisted delivery.³⁰ The study by Hameed et al (2023) also pointed to a heterogeneity in natural and cesarean deliveries and an increased rate of cesarean delivery in vaccinated individuals, which, after adjusting for other influencing factors, failed to show a statistically significant difference.²⁴ In justifying and finding the cause for this difference, Rottenstreich et al (2022) cited older maternal age as a reason for the increased rate of cesarean delivery in unvaccinated individuals, noting that older mothers are at higher risk for cesarean delivery, which could explain the difference in cesarean rates in unvaccinated individuals.³⁰ This finding was also observed in our study; mothers in the unvaccinated group who underwent cesarean delivery had a higher mean age, which could be a reason for the higher cesarean rate.

The primary finding of this study is that the overall rate of maternal complications was similar between vaccinated and unvaccinated women. In the research by Theiler et al (2021), vaccinated pregnant individuals experienced fewer pregnancy complications such as thromboembolic events and preterm delivery compared to unvaccinated mothers.²⁵ Consistent with our findings, the study by Tamar Wainstock et al (2021) observed no meaningful difference between the cohorts regarding maternal outcomes.²⁸ In the study by Megan E. Trostle et al (2021), intrauterine growth restriction was reported in 0.6%, fetal anomaly in 1.5%, need for NICU admission in 15.3%, and SGA in 12.2%.²⁹ In the study by Bookstein Peretz et al (2021), which was similar to our study comparing vaccinated and unvaccinated mothers, pregnancy complications included uterine contractions (1.3%), vaginal bleeding (0.3%), and PROM in 0.8%.²⁶ Rottenstreich et al (2022) also did not report adverse maternal outcomes after receiving the COVID-19 vaccine.³⁰ Our findings indicate that COVID-19 vaccination during pregnancy is safe, and our analysis did not show a difference in the incidence of maternal complications after COVID-19 vaccination when compared with unvaccinated mothers. In other words, vaccination did not lead to a change in the rate of maternal complications, and the quantity of vaccine doses administered was not related to maternal outcomes during pregnancy. Vaccination induces a stronger immune response compared to the reaction that occurs after infection with the virus. Vaccine acceptance is higher in older women, individuals receiving fertility treatments, and those with more advanced education or a higher socioeconomic status.^25,30,36 On the other hand, studies indicate that vaccination is linked to a notable decrease in the rate of COVID-19 infection in vaccinated pregnant women.^25,37 Studies indicate that COVID-19 vaccination is linked to a reduced risk of preterm delivery and adverse neonatal outcomes.³⁸ However, our study identified two findings that require cautious interpretation. First, we observed a statistically significant increase in miscarriage in the vaccinated group (4.0% vs 0%). Second, the slightly lower 5-minute Apgar scores in neonates of vaccinated mothers, while statistically significant, are of questionable clinical relevance, as the mean scores in both groups were well within the normal range. On the other hand, intrauterine growth restriction and the requirement for NICU admission were more frequent in neonates born to unvaccinated mothers. In linear regression analysis, the quantity of vaccine doses administered was not related to neonatal complications and outcomes. These findings are sensitive and should be interpreted with caution due to the retrospective nature of our study, the small number of events, and the possibility of unmeasured confounding. This finding warrants further investigation in larger datasets but should not be interpreted as evidence of neonatal harm. In the study by Tamar Wainstock et al (2021), no meaningful difference was seen between the cohorts regarding neonatal outcomes such as SGA and neonatal respiratory complications.²⁸ In the research from Megan E. Trostle et al (2021), among vaccinated women, only 0.6% of cases reported intrauterine growth restriction, fetal anomaly was reported in only 1.5%, 15.3% of cases required NICU admission, and 12.2% were SGA; these findings were reported as expected and were not within an abnormal range.²⁹ In the study by Bookstein Peretz et al (2021), a comparison of neonatal outcomes between the two groups of vaccinated and unvaccinated mothers reported no neonatal deaths, and 3.5% of neonates born required NICU admission, which was not statistically significant.²⁶ M. Rottenstreich et al (2022) documented a notable decrease in the risk of negative newborn outcomes among vaccinated mothers.³⁰ Nevertheless, one of the common reasons for vaccine refusal among pregnant mothers was concern over potential side effects for the fetus.²⁷ The findings of our study and comparison with the results of other studies indicate that administering COVID-19 vaccines to pregnant mothers does not correlate with a heightened risk of side effects in the mother and neonate, and its administration is recommended.

This study has several limitations that must be acknowledged. As a retrospective, single-center study, it is susceptible to biases related to record accuracy and missing data. We were also unable to account for potential unmeasured confounders such as socioeconomic status, access to antenatal care, or maternal mental health, all of which can influence pregnancy outcomes and vaccine acceptance. Furthermore, our analysis was limited to short-term outcomes assessed during the birth hospitalization; medium-term and long-term outcomes could not be examined. The vast majority of our cohort received the Sinopharm vaccine, so our findings may not be generalizable to other vaccine types. Finally, the statistical power was limited for rare outcomes.

Despite these limitations, our findings have important public health implications. By providing data on a non-mRNA vaccine in a Middle Eastern population, this study helps address vaccine hesitancy. However, communicating these results requires a cautious and balanced approach, emphasizing the reassuring aspects while transparently acknowledging the need for further studies to clarify the findings.

Conclusion

In this study, COVID-19 vaccination during pregnancy was not associated with an increased risk of overall adverse maternal events and was associated with a lower rate of neonatal intrauterine growth restriction. However, the conclusion must be tempered by the findings of a higher miscarriage rate and slightly lower 5-minute Apgar scores in the vaccinated group, which require cautious interpretation and further investigation in larger, prospective studies. Given the study’s limitations, including its retrospective design, single-center nature, and short-term follow-up, these findings should be considered hypothesis-generating. Future research should focus on long-term neonatal outcomes, investigate the role of psychosocial factors, and include diverse vaccine platforms to provide a more complete picture of vaccine safety in pregnancy.