No observable influence of COVID-19 inactivated vaccines on pregnancy and birth outcomes in the first trimester of gestation

ABSTRACT

Background

While studies have demonstrated that certain COVID-19 vaccines administered during pregnancy did not affect neonatal or maternal outcomes significantly, the safety of inactivated SARS-CoV-2 vaccines in China, given during the first trimester, remains to be fully elucidated.

Method

A retrospective cohort study was conducted involving female participants who gave birth from January to October 2021. The study compared pregnancy, delivery, and neonatal outcomes between subjects who received one or two doses of the inactivated COVID-19 vaccines during their first trimester and unvaccinated control subjects.

Results

A total of 2658 pregnant women was recruited. Among them, 2358 (88.7%) reported ongoing pregnancies; 326 (13.8%) of these were vaccinated. Additionally, 277 (10.4%) experienced spontaneous miscarriages between 6 to 20 gestational weeks; 40 (14.4%) of these were vaccinated, yielding an odds ratio of 0.67–1.36 (95% confidence interval) for COVID-19 vaccination. The comparison of neonatal complications, including an Apgar score less than 7, preterm birth, low birth weight, and newborn respiratory complications, between unvaccinated and vaccinated participants revealed no statistical significance.

Conclusion

The administration of COVID-19 inactivated vaccines during the first trimester of pregnancy is not associated with adverse pregnancy or neonatal outcomes, providing a substantial ground for pertinent health education.

KEYWORDS:

• First trimester
• COVID-19 inactivated vaccine
• birth outcome
• pregnancy
• birth defect

1. Introduction

COVID-19 has caused millions of deaths worldwide and is a global pandemic [1]. Previous studies have shown that COVID-19 infection during pregnancy may increase adverse pregnancy outcomes for both mothers and infants, such as premature delivery, abortion, restricted fetal growth, and maternal respiratory failure [2–5]. To defeat the pandemic, COVID-19 inactivated vaccines, such as CoronaVac (Sinovac Biotech, Beijing, China), have been approved by the Chinese government and the World Health Organization for emergency use to prevent COVID-19 [6–8]. Both Sinopharm vaccines and Sinovac-CoronaVac are inactivated vaccines used in China, which can prevent the infection of viruses. The second phase of clinical evaluation results showed that the efficacy rate of the Sinovac COVID-19 vaccine was 78%, and the effective rate of the national drug vaccine was 79%, both of which could have a good effect in preventing the transmission of COVID-19 [9,10]. Although the safety of such inactivated COVID-19 vaccines, as commonly used in China, has not been tested in pregnant women, medical organizations and health managing committees of different levels recommend its use in pregnant women.

However, there is still a significant amount of hesitation toward recommendations for maternal COVID-19 vaccination. Studies have investigated pregnancy outcomes in COVID-19 vaccinated individuals, which observed no evidence of adverse maternal or neonatal outcomes; however, most of the participants involved in the reported studies had been vaccinated with mRNA vaccines at gestational stages after the first trimester [11]. Early pregnancy is a critical period of fetal development, therefore pregnant women at this stage have more doubts and resistance to vaccination. Thus far, data on the side effects of administering inactivated COVID-19 vaccines during the first trimester have been limited. In this study, we executed a retrospective analysis to elucidate the potential risks associated with exposure to inactivated COVID-19 vaccines during the first trimester. This encompassed both pregnancy and birth complications among Chinese women who delivered in a hospital in Soochow, a well-developed city in eastern China.

2. Materials and methods

2.1. Study design and patients

A retrospective cohort study was performed, including all women who were termed for delivery between January and October 2021 at the First Affiliated Hospital of Soochow University, Soochow, China. Women who had a history of COVID-19 infection were currently diagnosed as having multiple pregnancies, recently receiving a prescription for teratogenic medication, with exposure to radiation during pregnancy, or without information regarding COVID-19 vaccination, pregnancy follow-up data, periodical antenatal examination, or clear newborn prognosis were all excluded from the study. None of the participants had a smoking history. A total of 2658 pregnant women, aged 28.3 years on average, were recruited. Of them, 2269 subjects (85.4%) did not receive COVID-19 vaccination, while 389 (14.6%) were vaccinated during the first trimester. Of the 389 vaccinated subjects, 23 (5.9%) requested and received induced abortion surgery to end a pregnancy (for fear of the adverse impact of vaccines on the fetus); of the rest vaccinated 366 subjects, 326 (89.1%) delivered live neonates, while 40 lost pregnancy by spontaneous abortions. Of the 2269 unvaccinated subjects, 2032 (89.6%) delivered living neonates, and the remaining 237 experienced spontaneous abortions (shown in Figure 1). Pregnancies that ended with live birth were related to infant birth data. Birth weight and gestational age were required to evaluate the low-birth-weight babies and preterm birth. To assess major structural birth defects, which occur in China at the rate of about 2%, infants who survived the first year were required to have at least one outpatient visit in the first year. We excluded infants with chromosome disorders. These endpoints are considered secondary outcomes potentially related to COVID-19 vaccination during pregnancy. The vaccines administered were exclusively inactivated COVID-19 vaccines (Sinopharm from Beijing Bio-Institute Ltd., Beijing, China; and CoronaVac from Sinovac Biotech Ltd., Beijing, China) as these were the only options provided for free by the Chinese government; vaccines produced in other countries were largely unavailable in China. The standard vaccination regimen encompassed two doses administered with a minimum interval of 28 days between them. Regarding the vaccination in pregnant women, the internationally commonly accepted clinical practice is that pregnancy is not contradictory to COVID-19 vaccination; what is more, pregnant women are recommended for vaccine boosters at least 6 months after the primary series of vaccination [12]. In China, some how (probably due to cultural and health belief variations in this particular country) COVID-19 vaccination is not recommended for pregnant women, except for those with heightened risk factors for COVID-19 infection, such as hospital nurses and doctors. There were cases where women, unaware of their early pregnancy stage, received the first dose during the first trimester. However, they did not proceed with the second dose upon confirming their pregnancy. As a result, those women who received COVID-19 vaccines were vaccinated unexceptionally from 14 days before the first day of the last menstrual period to the end of 12^th gestational week. The electronic database ‘Zhen Ding’ provides pregnancy follow-up and vaccination information. ‘Zhen Ding’ is the most extensive database in Suzhou, covering all the information on pregnant women in Suzhou. Delivery and newborn information were also available from this database. The study protocol had been approved by the committee of The First Affiliated Hospital of Soochow University, and the informed consent of each participant had been obtained. Pregnancy, delivery, and neonatal characteristics and complications were compared between the participants who received COVID-19 vaccines during the first trimester and the unvaccinated participants.

Figure 1. The process of study cohort formation from the recruited pregnant women.

2.2. Variables definitions

Obesity was defined as maternal body mass index (BMI) > 30; miscarriages were pregnancy losses with detectable intrauterine gestational sacs within the 20^th gestational week. Live birth was defined as the delivery of a live newborn after the 28^th gestational week. According to clinical assessment, preterm birth was defined as a live birth before 37 gestational weeks. Low birth weight was defined as a newborn’s weight lower than 2500 g. Validated defect-specific algorithms were used to identify major structural birth defects. The definition of pregnancy-related hypertension disease was either mild or severe preeclampsia or eclampsia; pathological fetal position referred to a nonvertex presentation including breech, oblique, and transverse position; newborn respiratory complications included dyspnea, tachypnea, apnea, and respiratory distress syndrome.

2.3. Statistical analysis

All statistical analysis was performed by using SPSS (version 23.0, IBM Inc., U.S.A.). Normally distributed quantitative parameters were expressed as means±SD, and each parameter was compared between different groups using the Student’s t-test or the one-way ANOVA as appropriate. The Mann – Whitney U test was used for those data without normal distribution. Quantal data are expressed as percentages, and the comparisons of frequencies and proportions between groups were made by using the chi-square test. P < 0.05 was defined for statistically significant differences. Multivariable logistic regressions were performed to determine the independent impact of COVID-19 vaccination status on miscarriage outcomes, using data presented as adjusted odds ratios (ORs) and 95% confidence intervals (CI).

3. Results

A total of 3,531 women were supposed to deliver babies during the study period, 1,098 (31.2%) of whom were excluded because of a lack of complete data concerning COVID-19 vaccination status and pregnancy follow-up, including spontaneous and induced abortions. Of the remaining 2,433 (68.8%) pregnancies, 61 (1.7%) were further excluded for multiple pregnancies and 14 (0.4%) for exposure to an abortifacient or teratogenic medication. The final cohort study population comprised 2,358 women with live birth. Of them, 326 (13.8%) received at least one dose of a COVID-19 inactivated vaccine, whose ages ranged from 21 to 42 years, with a median age of 31. All vaccinations were given during the first trimester. The remaining 2,032 (86.2%) were not vaccinated against COVID-19 during or before pregnancy, the median age being 28 years (ranging from 20 to 43 years).

The comparison of maternal demographics, pregnancy complications, and newborn characteristics between unvaccinated and vaccinated participants is presented in Table 1. Vaccinated subjects were, on average, slightly older than unvaccinated ones (30.85 vs. 27.90 years, p < 0.01), exhibited higher educational attainment, and a greater proportion were multiparous. The incidence rates of various adverse outcomes – encompassing pregnancy complications (such as pregnancy-related hypertensive disorders, gestational diabetes mellitus, oligohydramnios, polyhydramnios), delivery complications (including preterm birth, cesarean delivery, forceps delivery, and postpartum hemorrhage), and newborn complications (like Apgar scores less than 7, low birth weight, newborn respiratory complications, stillbirth/neonatal death, and major birth defects) – were comparable between the two groups, lacking statistical significance.

Table 1. Pregnancy and birth outcomes in unvaccinated and vaccinated subjects.

	COVID-9 vaccination during the first trimester
Pregnancy and birth outcomes	No (n = 2032)	Yes (n = 326)	Total (n = 2358)	P value
Maternal background characteristics
Maternal age at delivery (y)	27.9	30.85	28.3	<0.01
Education, ≥ 12 (y)	998 (49.1)	185 (56.7)	1183 (50.2)	0.01
Obesity	203 (10.0)	34 (10.4)	228 (9.7)	0.81
Exposure to primigravida	1068 (52.6)	145 (44.5)	1213 (51.4)	<0.01
Pregnancy complications diagnosed in late pregnancy
Pregnancy-related hypertensive disorders	107 (5.3)	19 (5.8)	126 (5.3)	0.68
Gestational diabetes mellitus	130 (6.4)	23 (7.1)	153 (6.5)	0.66
Oligohydramnios	58 (2.9)	11 (3.4)	69 (2.9)	0.61
Polyhydramnios	54 (2.7)	8 (2.5)	62 (2.6)	0.83
Pathological fetal positions	67 (3.3)	12 (3.7)	79 (3.4)	0.72
Meconium-stained amniotic fluid	89 (4.4)	14 (4.3)	103 (4.4)	0.96
Delivery and postpartum characteristics
Gestational age <37 week	229 (11.3)	40 (12.3)	269 (11.4)	0.60
Cesarean delivery	701 (34.5)	128 (39.3)	829 (35.2)	0.09
Forceps delivery	22 (1.1)	5 (1.5)	27 (1.1)	0.48
Postpartum hemorrhage ≥1000 ml	70 (3.4)	12 (3.7)	82 (3.5)	0.72
Newborn characteristics
Apgar score < 7 at 5 min	20 (1.0)	6 (1.8)	26 (1.1)	0.17
Low birth weight (<2500 g)	19 (0.9)	6 (1.8)	25 (1.2)	0.14
Newborn respiratory complications	32 (1.6)	7 (2.1)	39 (1.7)	0.45
Stillbirth or neonatal death Major structural birth defects	0 (0.0) 31 (1.5)	0 (0.0) 7 (2.1)	0 (0.0) 38 (1.6)	0.41

Of the 2358 live births with sufficient follow-up data, birth defects (as listed in Table 2) were rare in both groups and unrelated to the exposure of COVID-19 inactivated vaccine in early pregnancy (p = 0.41).

Table 2. List of major structural birth defects occurring in subjects unvaccinated (no) and vaccinated with COVID-19 inactivated vaccines (yes).

Major structural birth defects	No (n = 31)	Yes (n = 7)
Atrial septal defect	10	2
Ventricular septal defect	5	2
Patent ductus arteriosus	1	0
Fallot’s tetrad	1	0
accessory earlobe malformation	6	1
Cleft lip and palate	1	0
Polydactyly	1	1
Hypospadias	3	1
strephenopodia	1	0
Syndactyly	1	0
forearm Dysplasia	1	0

Additionally, we analyzed the role of the inactivated COVID-19 vaccine in early miscarriage (now spontaneously occurring in China at the rate of about 2.9%) in the valid participants involved in our investigation, including both vaccinated and unvaccinated subjects. As indicated in Table 3, 277 participants reported spontaneous miscarriages (experienced mostly before 12 weeks of gestation), 40 of which were vaccinated in the period ranging from 14 days before the first day of the last menstrual period to the 12^th gestational week. Among the 277 women with spontaneous miscarriages, the odds ratio for COVID-19 inactivated vaccine injection was 0.95 (with its 95% confidence interval ranging from 0.67 to 1.36).

Table 3. Odds ratios for COVID-19 inactivated vaccine exposure regarding miscarriage or ongoing pregnancy.

Subjects’ vaccination status	Number of ongoing pregnancies	Number of miscarriages	Odds ratio (95% CI) *
Unvaccinated	2032	237	Reference
Vaccinated	326	40	0.95 (0.67–1.36)

4. Discussion

In this observational retrospective cohort study, the administration of the COVID-19 inactivated vaccine during the first trimester of pregnancy was relatively rare, with 366 vaccinated compared to 2358 unvaccinated pregnant women. This discrepancy is likely due to vaccine safety concerns during early pregnancy [13]. The embryo/fetus is particularly susceptible to teratogenesis during the first trimester, and many pregnant women have an incomplete understanding of how various medications might affect fetal development. This lack of knowledge often leads to a blanket refusal of any medical procedures or treatments during the first trimester. Consequently, ‘vaccine hesitancy’ among pregnant women remains a global issue. However, several reports suggest that immunization with inactivated vaccines does not cause significant adverse maternal or fetal effects, leading to the consensus that they are safe for pregnant and periconceptional women [14,15]. The main adverse reactions of COVID-19 inactivated vaccines include redness, swelling, hardness, pain at the vaccine injection site, and a few systemic side effects, such as fever, fatigue, nausea, headache, and muscle soreness. Based on the results of previous clinical trials with COVID-19 inactivated vaccines, the occurrence of these common adverse reactions is similar to that of other vaccines that have been widely used. In addition, some studies performed in western countries have shown that the incidence of severe complications related to COVID-19 infection, including severe conditions with hospitalization and perinatal death, was significantly lower in pregnant women who had been vaccinated (with mRNA vaccines) than in infected pregnant women who had received the vaccination [16]. The COVID-19 inactivated vaccine may induce strong antibody immunity to protect the body against SARS-CoV-2, and particularly in pregnant women, IgG can be transmitted to the embryo/fetus through the placenta. In a study, blood samples from 1,471 pregnant women were analyzed, 83 of which contained COVID-19 antibodies at delivery, and IgG was detected in the cord blood of 72 of 83 newborns [17]. It was inferred that maternal antibodies to COVID-19 can cross the placenta, potentially protecting the fetus from infection. The uptake of vaccines during an early gestational period may offer continuous protection against COVID-19 during the later stages of pregnancy and lactation for both the maternal and the fetal/infant side. Pregnant women may benefit from the inactivated vaccine with safety and protection. However, vaccine hesitation still exists. Our findings from this study provide some evidence for the safety of the COVID-19 inactivated vaccine applied during the first trimester, which could help to improve the acceptance of COVID-19 inactivated vaccines. It will also add practical evidence for physicians to implement health consultations about the potential risks and benefits of the vaccines.

Another exciting discovery of our study is that maternal background characteristics, including older age, higher level of maternal education, and being a multipara, are associated with increased COVID-19 vaccination rates in pregnancy. This means that this part of pregnant women may have more confidence in the safety and/or effectiveness of COVID-19 inactivated vaccines. A possible reason is that compared with younger and less educated women, they have more access to knowledge about vaccines and are more open to accepting new things.

In this study, the COVID-19 inactivated vaccine applied to pregnant women during the first trimester was not associated with an increased rate of miscarriage, adverse immediate pregnancy outcomes, or newborn complications. In 2022, Cao et al. reported the clinical, including vaccination, records of 2,574 couples with the female side receiving transferred embryos. In this study, COVID-19 (in inactivated forms) vaccinated women had comparable rates of live birth, ongoing pregnancy, and successful conception; meanwhile, the newborns’ birth length and weight from vaccinated mothers were not statistically different from those from unvaccinated mothers [18]. On the other hand, a recent study by Shi et al. suggests that receipt of the first dose of inactivated COVID-19 vaccine within 60 days prior to fertilization treatment is associated with a reduced rate of pregnancy [19]. Clinical pregnancy or live birth could be influenced by multiple factors, not just a particular vaccination status. Besides, reports from some Western countries suggest that pregnant women exposed to mRNA COVID-19 vaccines did not influence the rate of spontaneous abortions during early pregnancy [20–22]. Moreover, COVID-19 vaccination during early pregnancy was not associated with an increased risk of fetal structural anomalies [23,24]. However, almost all existing evidence is focused on mRNA COVID-19 vaccines or women receiving implantation of in vitro fertilized embryos. To the best of our knowledge, this study is the first to describe adverse pregnancy and birth outcomes of the inoculation of COVID-19 inactivated vaccines in pregnant women during the first trimester. Furthermore, for the first time, according to the results from this study, the inactivated COVID-19 vaccines applied to naturally conceived women might be similar to the mRNA COVID-19 vaccines for women treated with human-assisted reproduction regarding the risk of adverse maternal and fetal outcomes. The data we used included more than 2,000 cases of live births with credible follow-up data to evaluate consequences, including birth defects, which is supportive of the reliability of the observed results; thus, this study may provide new evidence for obstetrical consultation after exposure to COVID-19 inactivated vaccines during the first gestational trimester.

5. Limitations

Several limitations are present in this study. (1) COVID-19 vaccination was limited to the first trimester of pregnancy, while the effects of vaccination during later stages of pregnancy could not be studied in this study. (2) Subjects receiving one dose and two doses of vaccines were pooled together instead of being analyzed separately. (3) We did not analyze the chromosomal abnormalities in subjects with miscarriages or exclude vaccinated pregnancies outside the teratogenesis window (3 to 8 weeks of gestation) due to the lack of data. (4) We used one-way analysis of variance to analyze the associations of individual potential factors one by one with the maternal and fetal outcomes rather than using logistic regression to study the interactive influence of different factors altogether due to the lack of other relevant data (e.g. smoking status, weight before pregnancy, and weight before delivery).

6. Conclusions

Our findings suggest that administering inactivated COVID-19 vaccines during the first trimester of pregnancy does not increase the rate of miscarriage, nor does it elevate the risk of obstetric/neonatal complications or birth defects. This evidence contributes to our understanding of the safety of inactivated COVID-19 vaccines when administered to pregnant women, either inadvertently or by prescription, during the first trimester.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

All authors have made a significant contribution to the work reported; Ting Du performed the research, and wrote the paper. Qiuxia Qu and Yawen Zhang analyzed the data. Qin Huang reviewed the manuscript. Ting Du and Qin Huang designed and conceptualized the study and confirmed the authenticity of the raw data. All authors have read and approved the final manuscript.All agree to take responsibility and be accountable for the contents of the article and to share responsibility to resolve any questions raised about the accuracy or integrity of the published work.

Data availability statement

The datasets that support the findings of this study are managed by Suzhou Municipal Health Commission and can be requested from the corresponding author upon reasonable request.

Additional information

Funding

This paper was funded by the First Affiliated Hospital of Soochow University.