Abstract
Background
To investigate the safety of inactivated COVID‐19 vaccine in Chinese pregnant women and their fetuses when inoculated during the peri‐pregnancy period.
Methods
Eligible pregnant women were prospectively collected and divided into a vaccine group (n = 93) and control group (n = 160) according to whether they had been vaccinated against COVID‐19 within 3 months before their last menstruation period (LMP) and after pregnancy. Demographic data of couples, complications during pregnancy and delivery of pregnant women, and data of newborns at birth were collected.
Results
Sixty‐six women were vaccinated with a median time of 35.5 (range = 0–91) days before LMP, and 27 women were vaccinated with a median time of 17 (range = 1–72) days after LMP. The incidence of premature rupture of membrane (PROM) in the vaccine group was significantly higher than that in the control group (16.13% vs. 6.88%, p = 0.019). Multivariate logistic regression analysis revealed that maternal peri‐pregnancy COVID‐19 vaccination was not an independent risk factor for PROM (odds ratio: 2.407, 95% confidence interval: 0.932–6.216, p = 0.069). There was no difference in the incidence of other complications during pregnancy and delivery between the two groups. A total of 253 neonates were delivered, including two cases with congenital abnormalities in each group. The incidence of congenital abnormalities between the two groups was similar (2.15% vs. 1.25%, p = 0.626). There was no difference in neonatal length, weight, head circumference, and Apgar score between the two groups (p > 0.05), but the incidence of neonatal jaundice in the vaccine group was significantly higher than that in the control group (20.43% vs. 7.5%, p = 0.002). Multivariate logistic regression analysis revealed that maternal peri‐pregnancy vaccination, postpartum blood loss, cesarean section, 1‐min Apgar score, and paternal smoking were independent risk factors for neonatal jaundice.
Conclusions
It is safe for pregnant women and their fetuses to be inoculated the inactivated COVID‐19 vaccine during the peri‐pregnancy period, but attention should be paid to neonatal jaundice.
Keywords: COVID‐19, inactivated vaccine, pregnancy, safety, SARS‐CoV‐2
1. INTRODUCTION
The COVID‐19 pandemic remains an overwhelming emergency worldwide. There have been 610 million confirmed cases of COVID‐19 globally, including 6.51 million deaths as of September 26, 2022, and a total of 12.6 billion vaccine doses have been administered as of September 16, 2022. 1 Compared with nonpregnant women, pregnant women have a higher risk of developing severe COVID‐19 when infected with SARS‐CoV‐2. 2 , 3 , 4 COVID‐19 infection increases the rates of premature rupture of membrane (PROM), preterm birth, intrauterine growth restriction, and cesarean section. 5 , 6 , 7 There is evidence of SARS‐CoV‐2 vertical transmission when the infection occurred in the third trimester of pregnancy, and the rate of vertical transmission was reported to be 3.2%. 8 Although placental infection remains an uncommon consequence of maternal COVID‐19 infection, stillbirth caused by placental infection appears to be a rapid evolving inflammatory and destructive process. 9
Vaccination against COVID‐19 is one of the most useful solutions to reduce the incidence of severe illness. However, vaccination may bring up some adverse events, mainly autoimmune‐related diseases. 10 , 11 , 12 , 13 , 14 With concerns about the adverse effects on pregnant women and their fetuses, pregnancy is an exclusion criterion in many current vaccine studies. However, in view of the increased severity of SARS‐CoV‐2 infection during pregnancy, there are suggestions that pregnant women should be included in appropriate populations for vaccination studies. 15 , 16 , 17 There are many studies exploring the safety of messenger RNA (mRNA) COVID‐19 vaccine injection during pregnancy. In a study in two doses of mRNA vaccine recipients, vaccine‐induced antibody titers were equivalent in pregnant and lactating women compared with nonpregnant women, and vaccine‐induced antibody titers were significantly higher than those induced by natural infection. The antibody could transfer to neonates via the placenta and breastmilk. 18 Many studies reported that vaccination did not increase the rate of adverse maternal outcomes, 19 , 20 , 21 , 22 , 23 and COVID‐19 vaccination during the third trimester might decrease the risk of neonatal adverse outcomes. 24 Currently, there are only a few studies about the effects of inactivated vaccines on pregnant women and fetuses. Shi et al. 25 reported that receiving inactivated COVID‐19 vaccine within 60 days before fresh embryo transfer treatment may reduce the clinical pregnancy rate. While Cao et al. 26 found that inactivated COVID‐19 vaccine injected before frozen‐thawed embryo transfer treatment and the interval between vaccination to embryo transfer treatment did not affect the rate of clinical pregnancy, ongoing pregnancy, and live birth, so were the birth length and weight of newborns.
Therefore, we conducted a prospective cohort study to investigate the safety of the Chinese inactivated COVID‐19 vaccine on pregnancy, delivery, and fetal development when inoculated during the peri‐pregnancy period.
2. MATERIALS AND METHODS
2.1. Participants
Eligible pregnant women in Beijing Ditan Hospital, Capital Medical University for prenatal care and delivery from March 1, 2021, to February 2, 2022, were recruited and divided into vaccine group (pregnant women who had been vaccinated against COVID‐19 during the peri‐pregnancy period) and control group (pregnant women who had never been vaccinated against COVID‐19). Peri‐pregnancy refers to 3 months before the last menstruation period (LMP) and during the entire pregnancy.
Inclusion criteria: (1) Pregnant women who inoculated or never inoculated inactivated COVID‐19 vaccine during the peri‐pregnancy period; (2) Pregnant women aged between 20 and 45. Exclusion criteria: (1) Family history of hereditary diseases in one or both families of the couple; (2) Women had delivered babies with congenital abnormalities in the past; (3) The couple had three or more spontaneous abortions in the past; (4) Taking drugs that have a definite effect on fetal development during pregnancy; (5) Exposure to toxic substances (including radiation, toxic chemicals, heavy metals, etc.) in early pregnancy; (6) Associated with malignant tumors; (7) Coinfection with hepatitis C virus, hepatitis D virus, human immunodeficiency virus, syphilis, toxoplasmosis, rubella, or cytomegalovirus.
This study was approved by the Ethics Committee of Beijing Ditan Hospital, Capital Medical University, China. The patients provided their written informed consent to participate in this study. Ethical number: JingDiLunkezi [2021] No. (014)‐01. This study has been registered with clinical registration number: NCT05125770.
2.2. Data collection
All eligible pregnant women completed questionnaires at enrollment which included a history of previous illness, medication history, history of marriage and childbearing, family history, family economic status, smoking and drinking habits, and vaccination status of the couple. Pregnant women had regular prenatal checkups every 4 weeks until 28 weeks gestation and every 1–2 weeks thereafter. All adverse events and laboratory test results during pregnancy and delivery were recorded. Neonatal length, weight, head circumference, Apgar score at birth, congenital malformations, screening for congenital diseases, and other conditions were recorded.
All lab tests for pregnant women were completed at the Clinical Laboratory Center of Ditan Hospital, including blood routine, urine routine, liver function, renal function, coagulation function, thyroid function, blood glucose, HIV, syphilis, hepatitis B, hepatitis C, and other tests. All lab test data was collected from the hospital laboratory information management system.
2.3. Indicators for evaluation
The primary indicator used for evaluation was the incidence of neonatal malformations. The secondary indicator evaluated was the incidence of adverse events during pregnancy and delivery; Indicators of fetal intrauterine development included neonatal length, weight and head circumference at birth, and so on.
2.4. Statistical analysis
Continuous variables were compared using analysis of independent samples t test or Wilcoxon test between two groups, according to whether they are normal distribution. Categorical variables were presented as frequencies and percentages and compared using the χ 2 or Wilcoxon test. Logistics regression was used for analyses of variables associated with the occurrence of complications of pregnancy and childbirth, and the adverse events of infants. Data analyses were performed using the Statistical Package for Social Science for Windows, Version 19.0 (SPSS Inc.). All tests were two‐tailed with 95% confidence interval, and statistical significance was defined as p < 0.05.
3. RESULTS
3.1. Participant demographic and clinical characteristics
In total 253 eligible pregnant women with an average age of 31.86 ± 4.14 years were enrolled, including 93 pregnant women in the vaccine group (29 cases of Sinovac Biotech and 64 cases of Sinopharm Biotech) and 160 cases of pregnant women in the control group (Figure 1). Sixty‐six women were vaccinated with a median time of 35.5 (range = 0–91) days before LMP, and 27 women were vaccinated with a median time of 17 (range = 1–72) days after LMP. The parity of the vaccine group was significantly higher than that of the control group (1.72 ± 0.63 vs. 1.44 ± 0.59, t = 3.501, p = 0.001), and the incidence of autoimmune diseases was significantly lower than that of the control group (0% vs. 3.75%, p = 0.018) because many people with autoimmune diseases refused to vaccinate for safety concerns. There was no difference between the two groups in age, body mass index, gravidity, smoking rate, drinking rate, or laboratory test results. Among the spouses of pregnant women in the two groups, the rate of COVID‐19 vaccination was significantly higher in the vaccine group than that of the control group (61.29% vs. 18.75, p = 0.000), and there was no significant difference in age, body mass index, smoking and drinking rate of the spouses of pregnant women in the two groups (Table 1).
Figure 1.
Flowchart of the patients enrolled in the study
Table 1.
Baseline characteristics of the study group
| Values | All (n = 253) | Vaccine group (n = 93) | Control group (n = 160) | t or χ 2 | p value |
|---|---|---|---|---|---|
| Maternal character | |||||
| Ages (year) | 31.86 ± 4.14 | 31.65 ± 4.36 | 31.98 ± 4.01 | −0.622 | 0.534 |
| Body mass index (kg/m2) | 21.86 ± 3.45 | 21.94 ± 3.49 | 21.81 ± 3.43 | 0.283 | 0.778 |
| Gravidity (times) | 2.23 ± 1.19 | 2.37 ± 1.21 | 2.14 ± 1.17 | 1.434 | 0.152 |
| Parity (times) | 1.55 ± 0.62 | 1.72 ± 0.63 | 1.44 ± 0.59 | 3.501 | 0.001* |
| Smoking before pregnancy (%) | 7 (2.76%) | 5 (5.37%) | 2 (1.25%) | Fisher | 0.104 |
| Alcohol before pregnancy (%) | 4 (1.58%) | 2 (2.15%) | 2 (1.25%) | Fisher | 0.626 |
| Alanine transaminase (U/L) | 21.41 ± 26.31 | 18.24 ± 16.01 | 23.20 ± 30.55 | −1.408 | 0.160 |
| Aspartate transaminase (U/L) | 19.90 ± 16.60 | 17.98 ± 9.86 | 20.99 ± 19.34 | −1.356 | 0.176 |
| Creatinine (umol/L) | 46.32 ± 6.54 | 45.36 ± 6.46 | 46.87 ± 6.54 | −1.678 | 0.095 |
| Hemoglobin (g/L) | 125.23 ± 12.91 | 124.38 ± 15.13 | 125.73 ± 11.47 | −0.789 | 0.431 |
| Platelet (109/L) | 246.01 ± 141.27 | 261.59 ± 216.93 | 237.08 ± 66.35 | 1.314 | 0.190 |
| Thyroid stimulating hormone (µI U/ml) | 1.43 ± 1.32 | 1.63 ± 1.75 | 1.32 ± 0.99 | 1.716 | 0.087 |
| Positive hepatitis B surface antigen (%) | 80 (31.62%) | 23 (24.73%) | 57 (35.63%) | 3.228 | 0.072 |
| HBV DNA (IU/ml) | 2.55 ± 2.85 | 2.10 ± 2.96 | 2.77 ± 2.77 | −1.368 | 0.173 |
| Autoimmune disease (%) | 6 (2.37%) | 0 (0%) | 6 (3.75%) | Fisher | 0.018* |
| Paternal character | |||||
| Ages (year) | 33.46 ± 4.78 | 33.20 ± 5.07 | 33.61 ± 4.61 | −0.660 | 0.510 |
| Body Mass Index (kg/m2) | 24.82 ± 3.81 | 24.47 ± 3.96 | 25.03 ± 3.72 | −1.117 | 0.265 |
| Vaccine injection (%) | 87 (34.39%) | 57 (61.29%) | 30 (18.75%) | 47.137 | 0.000* |
| Smoking before pregnancy (%) | 98 (38.73%) | 41 (44.08%) | 57 (35.62%) | 1.774 | 0.183 |
| Alcohol before pregnancy (%) | 50 (19.76%) | 16 (17.20%) | 34 (21.25%) | 0.607 | 0.436 |
p < 0.05, was considered statistically significant.
3.2. Maternal complications during pregnancy and delivery
The most common adverse events during pregnancy and delivery were gestational diabetes mellitus (29.25%), threatened abortion (15.02%), premature rupture of membrane (PROM, 10.28%), and gestational hypertension (5.14%). A total of 26 pregnant women developed PROM, five cases were preterm PROM with one case in 31 weeks, one case in 33 weeks, and three cases in 36 weeks of pregnancy. The minimal time from vaccination to PROM was 207 days. The incidence of PROM in the vaccine group was significantly higher than that of the control group (16.13% vs. 6.88%, p = 0.019). There was no difference in the incidence of other complications during pregnancy and delivery between the two groups (Table 2).
Table 2.
Complications during pregnancy and delivery
| Values | All (n = 253) | Vaccine group (n = 93) | Control group (n = 160) | χ2 | p value |
|---|---|---|---|---|---|
| Fever in pregnancy (%) | 2 (0.79%) | 0 (0%) | 2 (1.25%) | Fisher | 0.134 |
| Rush in pregnancy (%) | 2 (0.79%) | 0 (0%) | 2 (1.25%) | Fisher | 0.134 |
| Hypertension disorder of pregnancy (%) | 13 (5.14%) | 6 (6.45%) | 7 (4.38%) | Fisher | 0.558 |
| Diabetes (%) | 74 (29.25%) | 24 (25.81%) | 50 (31.25%) | 0.842 | 0.359 |
| Polyhydramnios (%) | 4 (1.58%) | 0 (0%) | 4 (2.5%) | Fisher | 0.300 |
| Oligohydramnios (%) | 1 (0.4%) | 1 (1.08%) | 0 (0%) | Fisher | 0.370 |
| Intrahepatic cholestasis of pregnancy (%) | 5 (1.98%) | 2 (2.15%) | 3 (1.88%) | Fisher | 1.000 |
| Hyperthyroidism (%) | 2 (0.79%) | 0 (0%) | 2 (1.25%) | Fisher | 0.134 |
| Hypothyroidism (%) | 12 (4.74%) | 3 (3.23%) | 9 (5.63%) | Fisher | 0.544 |
| Threatened abortion (%) | 38 (15.02%) | 14 (15.05%) | 24 (15%) | 0.007 | 0.935 |
| Preterm delivery (%) | 18 (7.11%) | 8 (8.60%) | 10 (6.25%) | 0.527 | 0.468 |
| Premature rupture of membranes (%) | 26 (10.28%) | 15 (16.13%) | 11 (6.88%) | 5.462 | 0.019* |
| Postpartum hemorrhage (%) | 22 (8.69%) | 6 (6.45%) | 16 (10.00%) | 0.933 | 0.334 |
p < 0.05, was considered statistically significant.
Univariate logistic regression analysis showed that PROM was significantly associated with maternal peri‐pregnancy vaccination (odds ratio [OR]: 2.693, 95% confidence interval [CI]: 1.156–6.023, p = 0.021), positive hepatitis B surface antigen of mothers (OR: 0.252, 95% CI: 0.073–0.867, p = 0.004), smoking before pregnancy of fathers (OR: 2.771, 95% CI: 1.201–6.390, p = 0.017) and alcohol before pregnancy of fathers (OR: 3.570, 95% CI: 1.522–8.376, p = 0.003).
Variables with p < 0.1 in univariate analysis were included in multivariate logistic regression analysis, and the results showed that, alcohol before pregnancy of father (OR: 3.526, 95% CI: 1.307–9.510, p = 0.013) and positive hepatitis B surface antigen of mother (OR: 0.233, 95% CI: 0.063‐0.857, p = 0.028) were independent risk factors for PROM, but maternal peri‐pregnancy vaccination (OR: 2.407, 95% CI: 0.932–6.216, p = 0.069) was not an independent risk factor for PROM (Table 3).
Table 3.
Multivariate logistic regression analysis of Premature rupture of membranes
| Values | OR | 95% CI | p value |
|---|---|---|---|
| Maternal peri‐pregnancy vaccination | 2.407 | 0.932–6.216 | 0.069 |
| Positive hepatitis B surface antigen of mother | 0.233 | 0.063–0.857 | 0.028* |
| Smoking before pregnancy of father | 2.095 | 0.788–5.567 | 0.138 |
| Alcohol before pregnancy of father | 3.526 | 1.307–9.510 | 0.013* |
p < 0.05, was considered statistically significant.
3.3. Adverse events in newborns
A total of 253 neonates were delivered, including four cases with congenital abnormalities, two cases in the vaccine group (one case of testicular hydrocele and one case of ventricular septal defect), and two cases in the control group (one case of spina bifida occulta and one case of atrial septal defect). There was no difference in the incidence of congenital abnormalities between the two groups (2.15% vs. 1.25%, p = 0.626). There was no significant difference in incidence of neonatal malformations regardless of whether the father had been vaccinated against COVID‐19 or not (3.44% [3/87] vs. 0.60% [1/166], Fisher, p = 0.118). There was no difference in neonatal length, weight, head circumference, and Apgar score at birth between the vaccine group and the control group (p > 0.05), except that the incidence of neonatal jaundice in the vaccine group was significantly higher than that in the control group (20.43% vs. 7.5%, p = 0.002, Table 4). All newborns were discharged without harmful consequences eventually.
Table 4.
Characteristics of newborns
| Values | All (n = 253) | Vaccine group (n = 93) | Control group (n = 160) | t or χ 2 | p value |
|---|---|---|---|---|---|
| Length (cm, mean ± SD) | 49.89 ± 1.54 | 49.69 ± 2.14 | 50.01 ± 1.03 | −1.345 | 0.181 |
| Weight (kg, mean ± SD) | 3.26 ± 0.41 | 3.23 ± 0.48 | 3.27 ± 0.37 | −0.806 | 0.421 |
| Head circumference (cm, mean ± SD) | 33.78 ± 1.17 | 33.61 ± 1.31 | 33.86 ± 1.09 | −1.477 | 0.141 |
| Male (%) | 131 (51.78%) | 44 (47.31%) | 87 (54.38%) | 1.175 | 0.278 |
| Apgar score at 1 min (mean ± SD) | 9.78 ± 0.50 | 9.71 ± 0.56 | 9.83 ± 0.47 | −1.701 | 0.091 |
| Apgar score at 5 min (mean ± SD) | 9.95 ± 0.25 | 9.93 ± 0.29 | 9.96 ± 0.22 | −0.854 | 0.394 |
| Apgar score at 10 min (mean ± SD) | 9.97 ± 0.18 | 9.97 ± 0.17 | 9.98 ± 0.19 | −0.310 | 0.757 |
| Neonatal malformation (%) | 4 (1.58%) | 2 (2.15%) | 2 (1.25%) | Fisher | 0.626 |
| Neonatal jaundice (%) | 31 (12.25%) | 19 (20.43%) | 12 (7.5%) | 9.146 | 0.002* |
p < 0.05, was considered statistically significant.
Univariate logistic regression analysis showed that the incidence of neonatal jaundice was significantly associated with maternal peri‐pregnancy vaccination (OR: 3.167, 95% CI: 1.459–6.872, p = 0.004), postpartum hemorrhage (OR: 1.002, 95% CI: 1.000–1.004, p = 0.018), maternal drinking (OR: 7.586, 95% CI: 1.029–55.934, p = 0.047) and paternal smoking (OR: 2.644, 95% CI: 1.212–5.769, p = 0.015).
Variables with p < 0.1 in univariate analysis were included in multivariate analysis, and the results showed that, maternal peri‐pregnancy vaccination (OR: 2.888, 95% CI: 1.167–7.145, p = 0.022), postpartum blood loss (OR: 1.003, 95% CI: 1.001–1.005, p = 0.016), cesarean section (OR: 2.938, 95% CI: 1.032–8.361, p = 0.043), 1‐min Apgar score (OR: 9.151, 95% CI: 1.163–72.035, p = 0.035) and paternal smoking (OR: 3.167, 95% CI: 1.186–8.456, p = 0.021) were independent risk factors for neonatal jaundice (Table 5).
Table 5.
Multivariate logistic regression analysis of neonatal jaundice
| Values | OR | 95% CI | p value |
|---|---|---|---|
| Maternal peri‐pregnancy vaccination | 2.888 | 1.167–7.145 | 0.022* |
| Postpartum hemorrhage | 1.003 | 1.001–1.005 | 0.016* |
| Cesarean section | 2.938 | 1.032–8.361 | 0.043* |
| Apgar score at 1 min of newborn | 9.151 | 1.163–72.035 | 0.035* |
| Smoking before pregnancy of father | 3.167 | 1.186–8.456 | 0.021* |
p < 0.05, was considered statistically significant.
4. DISCUSSION
Vaccination against COVID‐19 is highly effective in reducing severe diseases. 27 The outcomes of SARS‐CoV‐2 infection vary among different populations. Pregnant women infected with COVID‐19 had higher rates of intensive care unit admission, invasive ventilation, and extracorporeal membrane oxygenation compared to nonpregnant women, 2 and higher rates of premature delivery, pre‐eclampsia, stillbirth, neonatal mortality, and maternal mortality compared to uninfected pregnant women. 28 The perinatal outcomes even deteriorated when pregnant women were infected with postvariant COVID‐19 virus strains. 29 Vaccination can be considered for pregnant women from the second trimester, particularly in the presence of significant risk factors (obesity, diabetes, etc.) for severe COVID‐19 or if there is a high risk of contamination (medical profession, school environment, etc.). 30 Because the vast majority of vaccine‐related clinical trials do not include pregnant women, little is known about the effects of vaccination on pregnancy, delivery, fetal development, and newborns. The safety of prepregnancy vaccination in women of reproductive age remains unclear, especially for inactivated COVID‐19 vaccine.
We recruited pregnant women who had been vaccinated 3 months before pregnancy to the entire pregnancy, because the primordial follicle, the basic female reproductive unit, formed in the female embryo, remains quiescent for decades until puberty. Subsequently, the recruitment of a primordial follicle initiates, then develops under the influence of hormones, going through the process of preantral follicle, antral follicle, preovulatory follicle, and ovulation. It takes more than 9 months for the primordial follicle to develop into the preantral follicle, and then the development accelerates. It takes approximately 85 days, or about 3 months, from the preantral follicle to the preovulatory follicle. Therefore, pregnant women vaccinated 3 months before pregnancy to the entire pregnancy were recruited for observation in this study.
There are currently four COVID‐19 vaccines approved for production in China, namely, the vaccine of Sinopharm Beijing Biotech, the vaccine of Sinopharm Wuhan Biotech, the vaccine of Sinovac Biotech, and the recombinant vaccine of CanSinoBIO respectively, of which the first three are Vero cell inactivated vaccines, and the fourth is adenovirus type 5 vector recombinant COVID‐19 vaccine. All of the pregnant women in this study were inoculated one of the first three vaccines. Compared with other vaccines, inactivated vaccines have more sophisticated manufacturers, elevated safety, and maybe most appropriate for pregnant women.
Our research showed that with inactivated COVID‐19 vaccine inoculated 3 months before pregnancy to the first trimester, the incidence of complications during pregnancy and delivery such as gestational diabetes mellitus, hypertension, threatened abortion, fever, rash, oligohydramnios, hypothyroidism or hyperthyroidism, postpartum hemorrhage was similar, and the incidence of PROM in the vaccine group was significantly higher than that in the control group. Through multivariate logistic regression analysis, maternal peri‐pregnancy COVID‐19 vaccination was not an independent influencing factor of PROM (OR: 2.407, 95% CI: 0.932–6.216, p = 0.069). Since the p value close to 0.05, and other two variables (positive hepatitis B surface antigen and thyroid stimulating hormone level of mother) at baseline between the two groups had p value close to 0.05, therefore, a larger sample size study is needed to confirm the conclusion in this study.
The main purpose of this study is to understand the impact of COVID‐19 vaccination on fetuses during the peri‐pregnancy period. The results showed that vaccination during the peri‐pregnancy period did not increase the incidence of neonatal congenital abnormalities. Neonatal length, weight, head circumference, and incidence of asphyxia in the vaccinated group were similar to those in the unvaccinated group. However, the incidence of neonatal jaundice in the vaccinated group was significantly higher than that in the unvaccinated group, and multivariate logistic regression analysis showed that maternal peri‐pregnancy vaccination was an independent risk factor for neonatal jaundice. Neonatal jaundice is caused by the destruction of red blood cells and the release of bilirubin beyond the metabolic capacity of the liver. COVID‐19 vaccination may trigger pre‐existing underlying autoimmunity diseases or aggravate original autoimmune diseases, such as severe hemolytic paroxysmal nocturnal hemoglobinuria. 10 , 11 , 12 , 13 , 14 , 31 We speculate that after injection of COVID‐19 vaccine, antibodies or other immune response products in mothers might pass through the placenta and enter the fetal blood, causing increased fetal red blood cell destruction, which leads to an increased incidence of neonatal jaundice. Results of multivariate logistic regression analysis showed that cesarean section, paternal smoking before pregnancy, postpartum hemorrhage, and neonatal 1‐min Apgar score were also independent risk factors for neonatal jaundice. In qualitative data, including cesarean section, paternal smoking before pregnancy, postpartum hemorrhage, and maternal peri‐pregnancy vaccination, the OR values of paternal smoking before pregnancy and cesarean section was greater than that of maternal peri‐pregnancy vaccination, it should be considered that peri‐pregnancy COVID‐19 vaccination is not the main factor for neonatal jaundice. Although all the newborns in this study were discharged without harmful consequences, we should continue to visit the subsequent development of these infants.
5. CONCLUSION
In summary, given that PROM and neonatal jaundice are common complications in pregnant women and newborns, the present study indicated that peri‐pregnancy COVID‐19 vaccination is safe for pregnant women and fetuses. Due to the relatively small sample, we will further expand the sample and extend the follow‐up in further study.
AUTHOR CONTRIBUTIONS
Minghui Li, Yao Xie, and Wei Yi contributed to the study concept and design. Jianzhen Hao, Tingting Jiang, Wen Deng, Shiyu Wang and Huihui Lu performed following up with the patients and the data collection. Minghui Li and Wei Yi conducted data analysis. Gang Wan helped to analyze the data. All authors contributed to the article and approved the final version of the manuscript.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGMENTS
The authors thank all study patients and staff participating in the study. This study was funded by the Capital Health Research and Development of Special (2022‐1‐2172), Beijing Science and Technology Commission (Z211100002921059), the Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (XXZ0302 and XXT28), National Science and Technology Major Project of China (2017ZX10201201‐001‐006, 2017ZX10201201‐002‐006, and 2018ZX10715‐005‐003‐005), High‐level Public Health Technical Personnel Training Program of Beijing Municipal Health Commission (2022‐3‐050), and Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (XMLX 202127).
Li M, Hao J, Jiang T, et al. Maternal and neonatal safety of COVID‐19 vaccination during peri‐pregnancy period: a prospective study. J Med Virol. 2022;95:e28378. 10.1002/jmv.28378
Minghui Li, Jianzhen Hao, Tingting Jiang, and Wen Deng contributed equally to this manuscript.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable for this article as no data sets were generated or analyzed during the current study.
REFERENCES
- 1. WHO . https://covid19.who.int/
- 2. Allotey J, Fernandez S, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta‐analysis. BMJ. 2020;370:m3320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Zambrano LD, Ellington S, Strid P, et al. Update: characteristics of symptomatic women of reproductive age with laboratory confirmed SARS‐CoV‐2 infection by pregnancy status United States, January 22‐October 3, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:1641‐1647. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Delahoy MJ, Whitaker M, O'Halloran A, et al. Characteristics and maternal and birth outcomes of hospitalized pregnant women with laboratory‐confirmed COVID‐19‐COVID NET, 13 states, March 1–August 22, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:1347‐1354. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. M J, Ahn JG. Clinical outcomes of 201 neonates born to mothers with COVID‐19: a systematic review. Eur Rev Med Pharmacol Sci. 2020;24:7804‐7815. [DOI] [PubMed] [Google Scholar]
- 6. Di Mascio D, Khalil A, Saccone G, et al. Outcome of coronavirus spectrum infections (SARS, MERS, COVID–19) during pregnancy: a systematic review and meta‐analysis. Am J Obstet Gynecol MFM. 2020;2(2):100107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Zhu H, Wang L, Fang C, et al. Clinical analysis of 10 neonates born to mothers with 2019‐nCoV pneumonia. Transl Pediatr. 2020;9:51‐60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Kotlyar AM, Grechukhina O, Chen A, et al. Vertical transmission of coronavirus disease 2019: a systematic review and meta‐analysis. Am J Obstet Gynecol. 2021;224:35‐53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Fitzgerald B, O'Donoghue K, McEntagart N, et al. Fetal deaths in Ireland due to SARS‐CoV‐2 placentitis caused by SARS‐CoV‐2 alpha. Arch Pathol Lab Med. 2022;146(5):529‐537. [DOI] [PubMed] [Google Scholar]
- 10. Ishay Y, Kenig A, Tsemach‐Toren T, et al. Autoimmune phenomena following SARS‐CoV‐2 vaccination. Int Immunopharmacol. 2021;99:107970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Vogrig A, Janes F, Gigli GL, et al. Acute disseminated encephalomyelitis after SARS‐CoV‐2 vaccination. Clin Neurol Neurosurg. 2021;208:106839. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Vuille‐Lessard É, Montani M, Bosch J, Semmo N. Autoimmune hepatitis triggered by SARS‐CoV‐2 vaccination. J Autoimmun. 2021;123:102710. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Gerber GF, Yuan X, Yu J, et al. COVID‐19 vaccines induce severe hemolysis in paroxysmal nocturnal hemoglobinuria. Blood. 2021;137:3670‐3673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Chen Y, Xu Z, Wang P, et al. New‐onset autoimmune phenomena post‐COVID‐19 vaccination. Immunology. 2022;165:386‐401. [DOI] [PubMed] [Google Scholar]
- 15. Blumberg D, Sridhar A, Lakshminrusimha S, Higgins RD, Saade G. COVID‐19 vaccine considerations during pregnancy and lactation. Am J Perinatol. 2021;38:523‐528. [DOI] [PubMed] [Google Scholar]
- 16. Dashraath P, Nielsen‐Saines K, Madhi SA, Baud D. COVID‐19 vaccines and neglected pregnancy. Lancet. 2020;396(10252):e22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Whitehead CL, Walker SP. Consider pregnancy in COVID‐19 therapeutic drug and vaccine trials. Lancet. 2020;395(10237):e92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Gray KJ, Bordt EA, Atyeo C, et al. Coronavirus disease 2019 vaccine response in pregnant and lactating women a cohort study. Am J Obstet Gynecol. 2021;225:E1‐E17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Male V. Are COVID‐19 vaccines safe in pregnancy? Nat Rev Immunol. 2021;21:200‐201. 10.1038/s41577-021-00525-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Male V. SARS‐CoV‐2 infection and COVID‐19 vaccination in pregnancy. Nat Rev Immunol. 2022;22:277‐282. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Prasad S, Kalafat E, Blakeway H, et al. Systematic review and meta‐analysis of the effectiveness and perinatal outcomes of COVID‐19 vaccination in pregnancy. Nat Commun. 2022;13:2414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Wainstock T, Yoles I, Sergienko R, Sheiner E. Prenatal maternal COVID‐19 vaccination and pregnancy outcomes. Vaccine. 2021;39:6037‐6040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Bookstein Peretz S, Regev N, Novick L, et al. Short‐term outcome of pregnant women vaccinated with BNT162b2 mRNA COVID‐19 vaccine. Ultrasound Obstet Gynecol. 2021;58:450‐456. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Rottenstreich M, Sela H, Rotem R, Kadish E, Wiener‐Well Y, Grisaru‐Granovsky S. Covid‐19 vaccination during the third trimester of pregnancy: rate of vaccination and maternal and neonatal outcomes, a multicentre retrospective cohort study. BJOG: Int J Obstet Gynaecol. 2022;129:248‐255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Shi W, Wang M, Xue X, Li N, Chen L, Shi J. Association between time interval from COVID‐19 vaccination to in vitro fertilization and pregnancy rate after fresh embryo transfer. JAMA Network Open. 2022;5:e2236609. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Cao M, Wu Y, Lin Y, et al. Inactivated Covid‐19 vaccine did not undermine live birth and neonatal outcomes of women with frozen‐thawed embryo transfer. Hum Reprod. 2022:deac220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Fiolet T, Kherabi Y, MacDonald CJ, Ghosn J, Peiffer‐Smadja N. Comparing COVID‐19 vaccines for their characteristics, efficacy and effectiveness against SARS‐CoV‐2 and variants of concern: a narrative review. Clin Microbiol Infect. 2022;28:202‐221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Marchand G, Patil AS, Masoud AT, et al. Systematic review and meta‐analysis of COVID‐19 maternal and neonatal clinical features and pregnancy outcomes up to June 3, 2021. AJOG Global Reports. 2022;2:100049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Sahin D, Tanacan A, Anuk AT, et al. Comparison of clinical features and perinatal outcomes between pre‐variant and post‐variant periods in pregnant women with SARS‐CoV‐2: analysis of 1935 cases. Arch Gynecol Obstet. 2022;306:1939‐1948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Cottin J, Benevent J, Khettar S, Lacroix I. COVID‐19 vaccines and pregnancy: what do we know? Therapies. 2021;76:373‐374. 10.1016/j.therap.2021.05.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Akinosoglou K, Tzivaki I, Marangos M. Covid‐19 vaccine and autoimmunity: awakening the sleeping dragon. Clin Immunol. 2021;226:108721. 10.1016/j.clim.2021.108721 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Data Availability Statement
Data sharing is not applicable for this article as no data sets were generated or analyzed during the current study.