ABSTRACT
This prospective cohort study aimed to evaluate the safety of an inactivated coronavirus disease 2019 (COVID-19) vaccine in pregnant women at a tertiary hospital in Hubei, China. Pregnancy outcomes were compared between pregnant vaccinated and unvaccinated women. Composite adverse pregnancy outcomes were defined as one or more of maternal adverse outcomes (prenatal pyrexia, postpartum hemorrhage, maternal intensive care unit admission, and a prethrombotic state) and adverse neonatal outcomes (premature delivery, intrauterine fetal death or induction of labor, fetal macrosomia, fetal growth restriction, small-for-gestational age, fetal abnormalities, neonatal admission to the neonatal intensive care unit, and birth asphyxia). Of a total of 845 participants in the delivery cohort, 41.2% (348/845) received at least one dose of the COVID-19 vaccination, and 33.6% (284/845) received two doses. In total, 25.3% (88/348) of the vaccinated group were vaccinated at 0–4 weeks of pregnancy. No significant difference was found in the composite adverse outcomes between the vaccinated and unvaccinated participants, regardless of whether vaccination occurred before (44/243 [18.1%] vs. 71/497 [14.3%]; P = .17) or during early pregnancy (14/105 [13.3%] vs. 71/497[14.3%]; P = .79). These findings indicate that the pregnancy outcomes of women who received the COVID-19 vaccination, even if they were vaccinated early in pregnancy, were comparable to those of unvaccinated women. This study was registered with the Chinese Clinical Trial Center (ChiCTR2100051756).
KEYWORDS: COVID-19 vaccination, inactivated vaccines, pregnant women, pregnancy outcome, newborn
Introduction
Coronavirus disease 2019 (COVID-19), an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), is a global pandemic. On November 28, 2022, more than 636 million confirmed cases of COVID-19 and more than 6.6 million deaths had been reported worldwide.1 The SARS-CoV2 exhibits universal susceptibility, high infectiousness, extensive transmission, and rapid variation. A trend toward normalization and repetition is anticipated over the next few years, posing considerable challenges to the global public health care system and economy.2
According to studies, the COVID-19 infection have a temporary effect on the female reproductive system.3,4 There is evidence that owing to physiological changes in the immune, cardiovascular, and respiratory systems, pregnant women are more likely to suffer from COVID-19 and severe complications,5 leading to adverse pregnancy outcomes. The risk of adverse pregnancy outcomes is higher in low- and middle-income countries.6 Compared to the period when wild strains are the main epidemic strains, the risk of critical illness and complications in pregnant women may be higher during the epidemic period of each mutant strain.7–9 Due to the emergency use of the COVID-19 vaccine and the exclusion of pregnant women from phase 3 clinical studies,10 there is still a lack of evidence from randomized clinical trials on the safety and efficacy of vaccination in pregnant women, and there is a lack of standardized recommendations regarding COVID-19 vaccination in pregnant women across different countries.11–14 This inconsistent approach raises considerable challenges for the prevention and control of COVID-19 in pregnant women. Although a small number of studies have shown that the COVID-19 vaccine does not increase the risk of adverse pregnancy outcomes, these studies mostly focused on the mRNA vaccine, and the time of vaccination was mainly during the third trimester.15–17 However, the administration of medication in early pregnancy has the largest effect on embryonic development and growth. Currently, data regarding the safety of COVID-19 vaccination during early pregnancy is limited.
China’ s population is predicted to reach 1.42 billion by 2022, with approximately 10 million pregnancies occurring each year. Predominantly, inactivated vaccines have been used to prevent the spread of COVID-19 in China. This prospective cohort study was conducted to evaluate the association between vaccination with COVID-19 vaccines and adverse pregnancy outcomes in China, with a focus on early pregnancy vaccination.
Materials and methods
This prospective cohort study was conducted at the Maternal and Child Health Hospital of Hubei Province, one of the provinces’ leading providers of prenatal healthcare. The participants were pregnant women registered in the hospital’s Department of Obstetrics and Gynecology between July 2021 and October 2021. Ethical approval for this study was obtained from the Ethics Committee of the Maternal and Child Health Hospital of Hubei Province (2021 IEC XM026). This study was conducted with informed consent of the participants and was recorded in the Chinese Clinical Trial Registry (ChiCTR2100051756).
Subjects of the survey
This study focused on the inactivated COVID-19 vaccine as this is the most common type of COVID-19 vaccine used in China. Of the total cohort of 845 women, 348 women received the COVID-19 vaccine and 497 did not. There was no evidence of previous COVID-19 infection in the participants, although no antibody tests were performed. Participants did not receive another dose of the vaccine after inclusion in the study.
Inclusion criteria: (1) Pregnant women who were not vaccinated with the COVID-19 vaccine or were unknowingly vaccinated with the COVID-19 vaccine and who had a strong desire to give birth. (2) Pre-pregnancy vaccination times of less than 12 weeks.
Exclusion criteria: (1) Women who decided to terminate pregnancy due to a lack of fertility desire. (2) Pregnant women with adverse pregnancy outcomes due to long-term exposure to nicotine and alcohol, use of medications with obvious teratogenic or toxic side effects, and exposure to radioactive or chemical agents. (3) Pregnant women with a history of adverse pregnancy outcomes or family history of adverse pregnancy outcomes; this time, the pregnancy outcome was also adverse.
Source of vaccine
An inactivated COVID-19 vaccine was administered to a total of 348 women via intramuscular injection. The vaccine manufacturer was mainly the Wuhan Institute of Biological Products Co., Ltd.
Clinical data collection
The following data were extracted from questionnaires, telephone follow-ups, and the hospital ‘s electronic medical record system: demographic data on maternal age, body weight, height before pregnancy, and reproductive history, and data on the time and type of COVID-19 vaccination, pregnancy complications, and pregnancy outcomes. Preterm birth, stillbirth, induced labor, small for gestational age, fetal abnormalities, and postpartum hemorrhage were the main indicators used to evaluate adverse pregnancy outcomes. Neonatal asphyxia was determined using the neonatal Apgar score.
Pregnancy outcome analysis
Based on vaccination status, the pregnant women who participated were divided into the vaccination and non-vaccination groups.
Gestational age at the time of drug exposure has been found to be associated with the nature of the injury. Gestational age was estimated based on the date of the last menstrual period, and the participants who were vaccinated were further divided into three subgroups: before pregnancy; 0–4 weeks of pregnancy; and ≥5 weeks of pregnancy in order to examine whether different vaccination times affected pregnancy outcomes.
The outcome index of this study was the composite adverse pregnancy outcomes. Composite adverse pregnancy outcomes are defined as one or more of the following adverse outcomes in mothers and newborns: maternal adverse outcomes were defined as prenatal pyrexia, postpartum hemorrhage, maternal intensive care unit admission, and a prethrombotic state; adverse neonatal outcomes were defined as premature delivery, intrauterine fetal death or induction of labor, fetal macrosomia, fetal growth restriction, small-for-gestational age, fetal abnormalities, neonatal admission to the neonatal intensive care unit, and birth asphyxia.
Statistical analysis
Categorical variables were expressed as percentages and compared using the chi-square or Fisher’s exact test. Continuous variables with normal distribution were expressed as mean and standard deviation, and a two-sample t-test was used for comparison between the two groups. Correlation analysis was used to evaluate the correlation between age, gravidity, conception method, COVID-19 vaccination, and composite adverse pregnancy outcomes. A p value <.05 was considered as statistically significant. Analyses were performed using the SPSS 25. (IBM, Armonk, NY, USA).
Results
This study initially included 863 women. Among them, 8 pregnant women were excluded because of spontaneous abortion or ectopic pregnancy and 10 owing to loss to follow-up. Finally, 845 participants completed the follow-up and had complete follow-up data (Figure 1).
Figure 1.
Study flow chart.
A total of 845 pregnant women who met the inclusion criteria were included in the analysis (348, vaccinated; 497 unvaccinated). In the vaccinated group, 284 women received two doses of the vaccination while the remaining women received one dose only. The essential characteristics and pregnancy complications of all women in this study are shown in Table 1. As shown in Table 1, there were no significant differences between the vaccinated and unvaccinated groups in terms of age, abortion history, mode of delivery, or pregnancy complications.
Table 1.
Background information and obstetric characteristics of the study groups.
| Vaccinated n = 348 | Unvaccinated n = 497 | p | |
|---|---|---|---|
| Background information | |||
| Maternal age, years | 30.03 ± 3.43 | 30.14 ± 3.80 | .67 |
| Abortion history | 102 (29.3%) | 161 (32.4%) | .34 |
| Number of pregnancies, ≥2 | 184 (47.1%) | 236 (52.9%) | .12 |
| Mode of delivery, (Cesarean delivery) | 176 (49.2%) | 235 (50.6%) | .35 |
| Multifetal gestation | 7 (2.0%) | 5 (1.0%) | .36 |
| obstetric characteristics | |||
| Gestational Diabetes Mellitus | 92 (26.4%) | 114 (22.9%) | .24 |
| Virtual hepatitis | 13 (3.7%) | 16 (3.2%) | .69 |
| heart problems | 2 (0.6%) | 2 (0.4%) | 1.00 |
| Pregnancy related hypertensive disorders | 31 (8.9%) | 40 (8.0%) | .66 |
| Hypothyroidism during gestation | 26 (7.5%) | 39 (7.8%) | .84 |
| Anemia | 16 (4.6%) | 12 (2.4%) | .08 |
| premature rupture of membranes | 56 (16.1%) | 80 (16.1%) | .99 |
Data are presented as mean ± standard deviation or number (%). p, p value. The p value is the minimum significance level for rejecting the null hypothesis. In this study, we used an inactivated COVID-19 vaccine. The vaccine manufacturers in this study were mainly the Wuhan Institute of Biological Products Co., Ltd.
Table 2 presents the incidence of adverse maternal and neonatal outcomes in pregnant women who received one or 2 doses of the vaccine compared with those who were not vaccinated. The incidence of composite adverse pregnancy outcomes in the vaccinated group and the unvaccinated group was similar. The pregnancy outcomes of women who received two doses of the vaccine were compared to those of unvaccinated women, the composite adverse pregnancy outcomes for both groups were similar.
Table 2.
Adverse pregnancy outcomes in the study and the 2-dose vaccination group.
| Unvaccinated n = 497 | Vaccinated* n = 348 |
2 doses n = 284 |
|||
|---|---|---|---|---|---|
| case | case | p | case | p | |
| Maternal outcomes | |||||
| Prenatal pyrexia | 2 (0.4%) | 0 | .52 | 0 | .54 |
| Postpartum hemorrhage | 22 (4.4%) | 8 (2.3%) | .10 | 5 (1.8%) | .05 |
| Maternal ICU admission | 7 (1.4%) | 10 (2.9%) | .14 | 9 (3.2%) | .09 |
| Pre-thrombotic status | 2 (0.4%) | 2 (0.6%) | 1.00 | 1 (0.4%) | 1.00 |
| Neonatal outcomes | |||||
| Premature delivery | 32 (6.4%) | 17 (4.9%) | .34 | 16 (5.6%) | .65 |
| Intrauterine fetal death or induction of labor | 2 (0.4%) | 3 (0.9%) | .69 | 1 (0.4%) | 1.00 |
| Fetal macrosomia | 1 (0.2%) | 4 (1.1%) | .17 | 4 (1.4%) | .12 |
| Fetal growth restriction | 7 (1.4%) | 8 (2.3%) | .34 | 8 (2.8%) | .17 |
| SGA | 6 (1.2%) | 2 (0.6%) | .33 | 2 (0.7%) | .76 |
| NICU admission | 10 (2.0%) | 13 (2.3%) | .13 | 8 (2.8%) | .47 |
| Fetal abnormalities | 6 (1.2%) | 4 (1.1%) | 1.00 | 3 (1.1%) | 1.00 |
| Birth asphyxia | 3 (0.6%) | 2 (0.6%) | 1.00 | 2 (0.7%) | 1.00 |
| Composite adverse pregnancy outcomes | 71 (14.3%) | 58 (16.7%) | .34 | 48 (16.9%) | .33 |
*Pregnant women who received at least one dose.
Data are presented as number (%). p, p value. The p value is the minimum significance level for rejecting the null hypothesis. SGA, small for gestational age; NICU, Neonatal Intensive Care Unit. Composite adverse pregnancy outcomes are defined as one or more of the following adverse outcomes in mothers and newborns: maternal adverse outcomes were defined as prenatal pyrexia, postpartum hemorrhage, maternal ICU admission, and a prethrombotic state; adverse neonatal outcomes were defined as premature delivery, intrauterine fetal death or induction of labor, fetal macrosomia, fetal growth restriction, small-for-gestational age, fetal abnormalities, neonatal admission to the NICU, and birth asphyxia.
A comparison of adverse pregnancy outcomes between unvaccinated women and women grouped according to vaccination duration is shown in Table 3. A total of 243 pregnant women were vaccinated against COVID-19 before pregnancy and 105 pregnant women were vaccinated against COVID-19 during pregnancy. Among the 105 women vaccinated during pregnancy, 88 were vaccinated at week 0–4. As shown in Table 3, the incidence of composite adverse pregnancy outcomes in the three vaccinated subgroups was similar to that in the non-vaccinated group. The incidence of preterm births in women who were vaccinated after pregnancy was lower than that in women who were unvaccinated. There were no significant differences in adverse maternal and neonatal outcomes between women who were vaccinated between weeks 0 and 4 of pregnancy and those who were unvaccinated.
Table 3.
Adverse pregnancy outcomes in different vaccination time groups.
| Unvaccinated n = 497 | Before pregnancy n = 243 |
After pregnancy n = 105 |
0–4 weeks* n = 88 |
||||
|---|---|---|---|---|---|---|---|
| case | case | p | case | p | case | p | |
| Maternal outcomes | |||||||
| Prenatal pyrexia | 2 (0.4%) | 0 | 1.00 | 0 | 1.00 | 0 | 1.00 |
| Postpartum hemorrhage | 22 (4.4%) | 7 (2.9%) | .31 | 1 (1.0%) | .16 | 1 (1.1%) | .24 |
| Maternal ICU admission | 7 (1.4%) | 8 (3.3%) | .15 | 2 (1.9%) | 1.00 | 2 (2.3%) | .89 |
| Pre-thrombotic status | 2 (0.4%) | 1 (0.4%) | 1.00 | 1 (1.0%) | .44 | 1 (1.1%) | .39 |
| Neonatal outcomes | |||||||
| Premature delivery | 32 (6.4%) | 16 (4.6%) | .26 | 1 (1.0%) | .03 | 1 (1.1%) | .08 |
| Intrauterine fetal death or induction of labor | 2 (0.4%) | 1 (0.4%) | 1.00 | 2 (1.9%) | .14 | 1 (1.1%) | .39 |
| Fetal macrosomia | 1 (0.2%) | 3 (1.2%) | .21 | 1 (1.0%) | .32 | 1 (1.1%) | .28 |
| Fetal growth restriction | 7 (1.4%) | 5 (1.4%) | 1.00 | 3 (2.9%) | .53 | 2 (2.3%) | .89 |
| SGA | 6 (1.2%) | 1 (0.1%) | 1.00 | 1 (1.0%) | 1.00 | 1 (1.1%) | 1.00 |
| NICU admission | 10 (2.0%) | 9 (3.7%) | 0.17 | 4 (3.8%) | .45 | 3 (3.4%) | .67 |
| Fetal abnormalities | 6 (1.2%) | 3 (1.2%) | 1.00 | 1 (1.0%) | 1.00 | 1 (1.1%) | 1.00 |
| Birth asphyxia | 3 (0.6%) | 2 (0.8%) | 1.00 | 0 | 1.00 | 0 | 1.00 |
| Composite adverse pregnancy outcomes | 71 (14.3%) | 44 (18.1%) | .18 | 14 (13.3%) | .79 | 11 (12.5%) | .66 |
*Pregnant women who received at least one dose.
Data are presented as number (%). p, p value. The P value is the minimum significance level for rejecting the null hypothesis. SGA, small for gestational age; NICU, Neonatal Intensive Care Unit. Composite adverse pregnancy outcomes are defined as one or more of the following adverse outcomes in mothers and newborns: maternal adverse outcomes were defined as prenatal pyrexia, postpartum hemorrhage, maternal ICU admission, and a prethrombotic state; adverse neonatal outcomes were defined as premature delivery, intrauterine fetal death or induction of labor, fetal macrosomia, fetal growth restriction, small-for-gestational age, fetal abnormalities, neonatal admission to the NICU, and birth asphyxia.
The associations among various confounding factors, vaccination, and adverse pregnancy outcomes are shown in Table 4. Polyembryony and assisted reproductive technology were associated with adverse pregnancy outcomes. However, the relationship between COVID-19 vaccination and adverse pregnancy outcomes was not significant.
Table 4.
Correlation analysis between vaccination against COVID-19 and composite adverse pregnancy outcomes.
| r | p | |
|---|---|---|
| Maternal age | 0.060 | .08 |
| Cesarean section history | 0.011 | .74 |
| Abortion history | 0.011 | 10.77 |
| hypertensive disorders of pregnancy | 0.058 | .09 |
| Diabetes（pre-gestational + gestational） | 0.059 | .09 |
| Vaccination | 0.025 | .47 |
| Assisted reproductive technology | 0.160 | <.001 |
| Polyembryony | 0.194 | <.001 |
The correlation coefficient is represented by the r-value, which is defined as the degree of linear correlation between the explanatory and explained variables.
Discussion
If the fetus is administered drugs that are not recommended for use during the embryonic phase, growth and development malformations are likely to occur, and birth defects may occur. The first trimester of pregnancy is an important stage in the formation and differentiation of the embryonic organs. During this stage, if the drug is not applied correctly, fetal malformations may occur. Adverse pregnancy outcomes, such as fetal malformations, are strongly associated with non-indication drug use during pregnancy, which imposes a significant burden on families and society. Therefore, clinically, medication in early pregnancy is more cautious, and pregnant women in early pregnancy will also consciously avoid taking medications.18–20 Due to concerns about the safety of COVID-19 vaccine use during pregnancy, vaccination rates among pregnant women worldwide are relatively low,16,21,22 and research on the safety of the COVID-19 vaccine during early pregnancy has not been reported. Therefore, it is necessary to study the safety of COVID-19 vaccinations during early pregnancy. We conducted a prospective cohort study in China to evaluate the association between vaccination and adverse pregnancy outcomes, focusing on early-pregnancy vaccination.
During the study period, 41.2% of eligible women received at least one dose of the vaccination, and 33.6% received two doses. In the vaccination group, 25.3% of the women were vaccinated at 0–4 weeks of pregnancy. Vaccinated and unvaccinated women had similar comprehensive adverse pregnancy outcomes, regardless of the dose or time of vaccination. Administration of an inactivated COVID-19 vaccine between 0 and 4 weeks of pregnancy did not increase the risk of maternal or neonatal adverse outcomes. Of note, women who were vaccinated after pregnancy had a lower incidence of premature delivery than those who were not.
Furthermore, in 17 women with the COVID-19 vaccine was administered after five weeks of pregnancy. Two of these participants had adverse pregnancy outcomes: there was one case of intrauterine fetal death in late pregnancy and one newborn was transferred to neonatal intensive care unit because the mother was a carrier of hemophilia. In addition to intrauterine fetal death, another patient had a good prognosis.
In this study, three of the vaccinated women required labor induction due to intrauterine fetal death or chromosomal abnormalities. The three cases were first pregnancies, and there was no history of irrational medication during pregnancy or other complications, and there were no obvious abnormalities on the obstetric or imaging examination. Therefore, vaccination was not considered to be related to intrauterine fetal death in the third trimester of pregnancy or to the chromosomal abnormalities.
Considerable advances have been made in the development of COVID-19 vaccines worldwide. As COVID-19 vaccines are promoted worldwide, evidence on their safety and efficacy in pregnant women is being accumulated. The U.S. Centers for Disease Control and Prevention conducted a clinical trial on COVID-19 vaccination during pregnancy using the V-safe surveillance system, V-safe pregnancy registration system, and vaccine adverse event reporting system. A total of 827 participants completed their pregnancies with an abortion, preterm birth, and small for gestational age (SGA) rate of 13.9%, 9.4%, and 3.2%, respectively. No neonatal death occurred during the study period. The incidence of adverse pregnancy outcomes were similar to those previously reported for unvaccinated pregnant women.23 A multi-center study at two university-affiliated medical centers in Jerusalem, Israel, performed a retrospective analysis of the safety of COVID-19 vaccination in the third trimester of pregnancy in 1780 women and found that maternal and infant outcomes of vaccination and non-vaccination groups were similar.24 At the beginning of 2022, JAMA reported a study on the correlation between the administration of COVID-19 vaccination during pregnancy and pregnancy outcomes in Sweden and Norway.25 The study retrospectively analyzed the pregnancy outcomes of 157,521 unvaccinated pregnant women and 28,506 pregnant women who were vaccinated with mRNA or viral vector vaccines during pregnancy and found that the risk of preterm birth, very preterm birth, SGA, and stillbirth were not associated with vaccination. These studies mainly focused on the safety of mRNA vaccination in pregnant women, and the vaccination time was mostly concentrated in the third trimester. Our study investigated the safety of inactivated COVID-19 vaccines during pregnancy and found that vaccination did not increase the risk of adverse outcomes in pregnant women and newborns, including cases with vaccination administered during early pregnancy.
SARS-CoV-2 has not been eradicated and its spread within populations continues. Currently, the aim of the global COVID-19 vaccination is to reduce the gaps in immunization rates among different populations and minimize the risk of severe disease and death. Pregnant women are considered to be a special population group that is susceptible to COVID-19; therefore, strengthening the immunization of pregnant women by administration of the COVID-19 vaccine is important to ensure the safety of this group. Repeated vaccination of pregnant women with high-risk occupations may be an option to ensure maternal and child safety although robust data on vaccine safety are required to support this policy. As the pandemic changes, we may need to comprehensively consider which pregnant women require repeated vaccination based on the factors such as SARS-CoV-2 infection, previous vaccination history, and physical condition. Further evidence on the safety and effectiveness of vaccination is required to develop a safer COVID-19 vaccination program for pregnant women.
This study presents some limitations. The study was conducted at a single center, and all of the patients were from the Maternal and Child Health Hospital of Hubei Province. Clinical diagnosis and treatment may vary depending according to the type of hospital. Therefore, large-sample clinical trials are needed to assess the impact of inactivated vaccination on pregnancy outcomes.
Acknowledgments
We are grateful the teachers of gynecology at the Maternal and Child Health Hospital of Hubei Province for their contributions during data collection.
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.
Funding Statement
This study was supported by Young and Middle-aged Medical Talents Training Project of Wuhan [grant number [2018] 116] and the Maternal and Child Health Hospital of Hubei Province Research Project [grant number 2021SFYM003].
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, [Feng]. The data are not publicly available due to their containing information that could compromise the privacy of research participants.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author, [Feng]. The data are not publicly available due to their containing information that could compromise the privacy of research participants.