Prenatal maternal inactivated COVID-19 vaccination: the maternal and neonatal outcomes, a retrospective cohort study

doi:10.21203/rs.3.rs-2710503/v1

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Research Article

Prenatal maternal inactivated COVID-19 vaccination: the maternal and neonatal outcomes, a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-2710503/v1

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Background

There are very few data on the maternal and neonatal safety effects of inactivated COVID-19 vaccines. Several studies have reported the safety of SARS-CoV-2 vaccination during pregnancy, with no adverse effect on maternal and neonatal outcomes. However, data on the safety of prenatal vaccination are scarce. Therefore, more relevant data are needed to inform maternal, pregnancy, and infant outcomes.

Objective

To evaluate the prenatal maternal inactivated COVID-19 vaccination and the impact on maternal and neonatal outcomes.

Methods

A retrospective cohort study among women who delivered between January and June 2022 at the first affiliated hospital of wenzhou medical university. Those who have completed at least one dose of inactivated vaccine before or during pregnancy were included in “vaccinated group”, and those who were not vaccinated were included in “unvaccinated group”, the maternal, pregnancy and neonatal outcomes were evaluated. Propensity score matching (PSM) was performed to balance the baseline parameters of the two groups.

Results

A total of 1926 women were enrolled in this study, 827 (42.94%) women were prenatally vaccinated, and 1099 (57.06%) unvaccinated. The gestational week of delivery were slightly smaller in the vaccinated group, 38.77 ± 1.83 weeks in the vaccinated group and 39.01 ± 1.45 weeks in the unvaccinated group. There was a higher rate of overall preterm delivery in the vaccinated group (aOR 1.638, 95% CI 1.108–2.422; p = 0.013; Table 3, Fig. 2), however, the probability of delivery before 34 weeks and before 32 weeks (early preterm delivery) were similar (p > 0.05). A total of 2009 infants were born, 851 in the vaccinated group and 1158 in the unvaccinated group. There were similar neonatal outcomes in the two groups.

Conclusions

Although we found a slightly smaller gestational week of delivery and a possible increased rate of late preterm birth in the vaccination group, there was no difference in mean neonatal weight, incidence of low birth weight infants and other neonatal adverse complications. Meanwhile, there was no difference in pregnancy and maternal outcomes between the two groups.

COVID-19

Inactivated vaccine

Maternal outcomes

Pregnancy

Neonatal outcomes

Over the last three years, the COVID-19 outbreaks and pandemics have caused catastrophic damage to health, economy, and all aspects of the society worldwide. Reported to WHO, there have been 754,018,841 confirmed cases of COVID-19, including 6,817,478 deaths[1]. To date, vaccination is the most important method to control pandemics. As of 30 January 2023, a total of 13,168,935,724 vaccine doses have been administered[1]. Despite the high coverage of COVID-19 vaccination, the potential for vaccine-induced adverse effects has not been fully elucidated, particularly in pregnant women who did not participate in the preliminary randomized controlled trial of COVID-19 vaccine safety and efficacy.

Most of the current studies have shown that pregnant women with SARS-CoV-2 infection during pregnancy are not only at increased risk for critical condition, but also for pregnancy complications and adverse neonatal birth outcomes. Higher incidence of morbidity and mortality rates of SARS-CoV-2 infection in pregnancy have been reported in women of childbearing age compared to non-pregnant women[2]. In an exploratory surveillance study conducted in Canada from March 2020 to October 2021, SARS-CoV-2 infection during pregnancy was significantly associated with increased risk of adverse maternal outcomes and preterm birth, including increased risk of SARS-CoV-2 related hospitalization and a significantly increased risk of preterm birth[3]. Meanwhile, a meta-analysis showed there was no evidence of higher risk of adverse perinatal outcomes of COVID-19 vaccines during pregnancy. COVID-19 mRNA vaccination in pregnancy appears to be safe and is associated with a reduction in stillbirth[4]. As a multicentre retrospective cohort study shown, vaccination of the Covid-19 vaccine (BioNTech BNT162b2) during the third trimester of pregnancy was not associated with adverse maternal outcomes, moreover, it decreased the risk for neonatal adverse outcomes[5].

Results from another retrospective cohort study of all women who delivered at Soraka University Medical Center, the largest birthing center in Israel, showed no differences in pregnancy, delivery and neonatal complications, including gestational age at delivery, incidence of small for gestational age and neonatal respiratory complications, with or without Pfizer-BioNTech COVID-19 vaccination[6]. Therefore, an increasing number of countries are recommending vaccination of pregnant women with COVID-19 vaccine.

In China, COVID-19 inactivated vaccine is widely promoted. Diffierent with the mRNA vaccines described above, these inactivated vaccines were developed based on the immune response induced by inactivated SARS-CoV-2 virus. There are very few data on the maternal and neonatal safety effects of inactivated COVID-19 vaccines. Therefore, more relevant data are needed to inform the outcome of mothers, pregnancies and infants. Our research aims to evaluate the prenatal maternal inactivated COVID-19 vaccination and the impact on adverse maternal and neonatal outcomes.

This was a retrospective cohort study, including all women who delivered between January and June 2022 at the First Affiliated Hospital of Wenzhou Medical University. Women who diagnosed with COVID-19 in the past, combined with severe heart disease, liver disease, kidney disease, cerebrovascular events, and malignant tumor, or with unknown vaccination status and pregnancy follow-up information were excluded. Among the enrolled cases, who have completed at least one dose of an inactivated vaccine before or during pregnancy were included in “vaccinated group”, and those who were not vaccinated were included in “unvaccinated group”. All the patients included in this study requested the vaccination voluntarily. The detailed flow chart was shown in Fig. 1.

Detailed vaccination status, including vaccine type, dose, date and manufacturer were ascertained using immunization records, which could be accessed through Zhejiang Province regional health information sharing platform from the electronic medical record system or their smartphone app such as Alipay, WeChat, the health codes of various provinces and cities. For each participating case, demographic characteristics regarding age, weight, height and reproductive history, assisted reproductive status, past medical history, maternal obstetric complications, delivery and newborn details were obtained by searching from the electronic medical record system of the hospital and manually recording.

Fertility treatments included ovulation induction or in-vitro fertilization. Chorioammonitis refers to the cases confirmed by pathology, which was also included in Puerperal infection. Postpartum haemorrhage (PPH, estimated blood loss of > 1000 ml in Caesarean delivery, and > 500 ml in Vaginal delivery). Gestational hypertemsion (gHTN) was defined as an elevated SBP of ≥ 140 mmHg or a DBP of ≥ 90 mmHg occurring on two occasions at least 4h apart after 20 weeks of gestation, which is not associated with proteinuria and no signs or symptoms of end organ damage. Gestational diabetes mellitus (GDM) was defined as glucose intolerance of variable severity with onset or first recognition during pregnancy. Newborn digestive complications included neonatal intestinal obstruction, gastrointestinal dysfunction, allergic enteritis, and gastrointestinal bleeding in this study. Newborn respiratory complications included apnea, dyspnea, shortness of breath, respiratory failure, wet lung, pneumonia, and respiratory distress syndrome. Other composite adverse neonatal outcome refers to the comprehensive situation of multiple diseases related to premature delivery.

Statistical analysis

We compared the following aspects of the vaccinated group versus the unvaccinated group: baseline characteristics, complications during pregnancy, postpartum outcomes, and neonatal outcomes. Quantitative variables described by a normal distribution were presented as Mean ± Standard Deviation (M ± SD), and were presented as median (interquartile range) if not normally distributed. Differences in quantitative variables between the two groups were compared by Kruskal Wallis test. Categorical variables were presented with n(%) and differences between groups were compared using Chi-square test, and Fisher's exact test was used if the count variable had a theoretical number < 10.

Considering the differences in baseline characteristics between eligible participants in the two groups (Table 1), propensity-score matching (PSM) was used to identify a cohort of patients with similar baseline characteristics. The propensity score was calculated by using a multiple logistic regression model, with vaccinated versus unvaccinated serving as the dependent variable, and parity, previous caesarean delivery and fertility treatments serving as independent variables. Matching was performed with the use of a 1:1 matching protocol, with a caliper width of 0.05 of the SD of the logit of the propensity score. SD were estimated for all the baseline covariates before and after matching, SD of less than 10.0% was considered to indicate a balance[7]. Multivariable logistic regression and multiple linear regression were applied to analyze the influence of COVID-19 vaccination on gestational age at delivery, gestational age at delivery < 37 weeks, LBW, VlBW and fetal macrosomia. The following confounding factors are adjusted in the model: female age, male age, parity, fertility treatments, previous caesarean delivery, BMI, previous miscarriages, pre-existing diabetes, hypothyroidism and hypertension.

Table 1

Baseline characteristics of the vaccinated versus the unvaccinated group.
	Before PSM		P value	After PSM		P value
Features	Vaccinated (n = 827)	Unvaccinated (n = 1099)	P value	Vaccinated (n = 761)	Unvaccinated (n = 761)	P value
Female Age, years	30.64 ± 4.77	30.52 ± 4.35	0.883	30.37 ± 4.67	30.39 ± 4.35	0.9366
Male Age, years	32.67 ± 5.19	32.45 ± 4.77	0.488	32.42 ± 5.09	32.33 ± 4.72	0.7301
Parity	1.70 ± 0.65	1.54 ± 0.65	< 0.001	1.66 ± 0.65	1.63 ± 0.65	0.4752
Previous miscarriages	0.70 ± 1.01	0.75 ± 1.05	0.331	0.68 ± 0.99	0.79 ± 1.10	0.0642
BMI, kg/m²	21.46 ± 3.21	21.48 ± 3.19	0.642	21.39 ± 3.22	21.39 ± 3.14	0.9849
Previous caesarean delivery, any	178 (21.5%)	178 (16.2%)	0.003	113 (14.8%)	139 (18.3%)	0.0847
Fertility treatments	50 (6.1%)	256 (23.3%)	< 0.001	50 (6.6%)	50 (6.6%)	1.0000
Pre-existing Hypothyroidism	19(2.3%)	33 (3.0%)	0.345	18 (2.4%)	17 (2.2%)	0.864
Pre-existing Diabetes	13 (1.6%)	15 (1.4%)	0.705	13 (1.7%)	10 (1.3%)	0.6720
Pre-existing hypertension	11 (1.3%)	16 (1.5%)	0.816	103 (13.5%)	114 (15.0%)	0.4635

IBM SPSS Statistics 21 (IBM SPSS, Turkey) program and EmpowerStats software (www.empowerstats.com; X&Y solutions, Inc., Boston MA) were used to analyze all the data. In all analyses, p < 0.05 were considered statistically significant.

During the study period, there were 2036 deliveries in the first affiliated hospital of Wenzhou medical university. A total of 1926 (94.6%) women were enrolled in this study, after excluding patients with incomplete vaccination information, severe heart disease, hematologic disorders, severe liver and kidney disease and with malignant tumor. 827 (42.94%) women were prenatally vaccinated and included in the vaccinated group, and 1099 (57.06%) women were unvaccinated and included in the unvaccinated group. The flow chart of the study was shown in Fig. 1. Women in the two groups had similar demographics, with the exception of parity, previous caesarean delivery and the ratio of fertility treatments (Table 1). We applied the PSM to balance the basic characteristics, and the results showed the baseline and previous obstetric characteristics were well balanced after PSM.

The pregnancy and maternal outcomes were presented in Table 2. After PSM, the gestational weeks of delivery were slightly smaller in the vaccinated group, 38.77 ± 1.83 weeks in the vaccinated group and 39.01 ± 1.45 weeks in the unvaccinated group. There was a higher rate of overall preterm delivery in the vaccinated group (aOR 1.638, 95% CI 1.108–2.422; p = 0.013; Table 3, Fig. 2), however, the probability of delivery before 34 weeks and before 32 weeks (early preterm delivery) were similar (p > 0.05). The results reveal that there were similar rate of multifetal gestation, abnormal fetal presentation, cesarean section and forceps assisted delivery (p > 0.05). There were also similar maternal length of stay (p > 0.05) and similar rates of obstetric complications (p > 0.05) in the two groups, including postpartum hemorrhage, premature rupture of membranes, amniotic fluid contamination, hypoamniotic fluid, gestational hypertension, pre-eclampsia, gestational diabetes mellitus, hypothyroidism in pregnancy, placenta praevia and placental implantation. In addition, there were no diffierence in rate of reproductive tract infection (including mycoplasma infection, streptococcal infection and total incidence of various vaginitis) and puerperal infections during pregnancy (p > 0.05). In the vaccinated group, there was a higher incidence of polyhydramnios (p < 0.05), but the number of cases is relatively small(Table 2).

Table 2

Pregnancy and maternal outcomes of the vaccinated versus the unvaccinated group.
	Before PSM		P value	After PSM		P value
	Vaccinated (n = 827)	Unvaccinated (n = 1099)	P value	Vaccinated (n = 761)	Unvaccinated (n = 761)	P value
Multifetal gestation	24 (2.9%)	59 (5.4%)	0.008	24 (3.2%)	21 (2.8%)	0.7622
Gestational age at delivery	38.74 ± 1.81	38.89 ± 1.57	0.212	38.77 ± 1.83	39.01 ± 1.45	0.0044
Gestational age at delivery <32 weeks	9 (1.1%)	3 (0.3%)	0.024	9 (1.2%)	2 (0.3%)	0.0694
Gestational age at delivery <34 weeks	20 (2.4%)	16 (1.5%)	0.123	19 (2.5%)	9 (1.2%)	0.0860
Gestational age at delivery <37 weeks	83 (10.0%)	91 (8.3%)	0.183	75 (9.9%)	48 (6.3%)	0.0145
Abnormal fetal presentation	29 (3.5%)	53 (4.8%)	0.157	29 (3.8%)	30 (3.9%)	1.0000
Mode of delivery			0.014			0.1374
Caesarean delivery	294 (35.6%)	439 (40.0%)	0.049	238 (31.3%)	274 (36.0%)	0.0576
Vaginal delivery	512 (61.9%)	615 (56.0%)	0.009	502 (66.0%)	465 (61.1%)	0.0552
Forceps assisted delivery	21 (2.5%)	45 (4.1%)	0.063	21 (2.8%)	22 (2.9%)	1.0000
Postpartum hospital stay	3.73 ± 0.93	3.89 ± 1.28	0.004	3.72 ± 0.94	3.75 ± 0.95	0.5343
Puerperal infection	36 (4.4%)	59 (5.4%)	0.308	33 (4.3%)	37 (4.9%)	0.7135
Chorioamnionitis	14 (1.7%)	26 (2.4%)	0.305	13 (1.7%)	13 (1.7%)	1.0000
Postpartum haemorrhage	27 (3.3%)	38 (3.5%)	0.817	27 (3.5%)	27 (3.5%)	1.0000
Placental abruption	16 (1.9%)	14 (1.3%)	0.246	15 (2%)	12 (1.6%)	0.6977
Amniotic fluid pollution	95 (11.5%)	155 (14.1%)	0.091	88 (11.6%)	99 (13%)	0.4349
Premature rupture of membranes	181 (21.9%)	222 (20.2%)	0.368	173 (22.7%)	150 (19.7%)	0.1678
Polyhydramnios	8 (0.9%)	3 (0.3%)	0.045	8 (1.1%)	0 (0)	0.0131
Oligohydramnios	47 (5.7%)	78 (7.1%)	0.212	43 (5.7%)	50 (6.6%)	0.5208
Gestational hypertemsion	28 (3.4%)	41 (3.7%)	0.687	26 (3.4%)	28 (3.7%)	0.8898
Preeclampsia	23 (2.8%)	62 (5.7%)	0.002	23 (3%)	28 (3.7%)	0.5656
Gestational diabetes mellitus	129 (15.6%)	213 (19.4%)	0.032	111 (14.6%)	127 (16.6%)	0.259
Hypothyroidism during pregnancy	110 (13.3%)	173 (15.7%)	0.134	103 (13.5%)	114 (15%)	0.4635
Placenta previa or placenta implantation	2 (0.2%)	9 (0.8%)	0.096	2 (0.3%)	7 (0.9%)	0.1811
Mycoplasma infection during pregnancy	98 (11.9%)	114 (10.4%)	0.305	93 (12.2%)	78 (10.2%)	0.2558
GBS infection during pregnancy	90 (10.88%)	141 (12.83%)	0.193	85 (11.2%)	102 (13.4%)	0.2116
Vaginitis during pregnancy, any	183 (22.1%)	242 (22.0%)	0.955	172 (22.6%)	172 (22.6%)	1.0000

Table 3

Multivariate logistic regression analysis for the association between Covid-19 vaccination and preterm birth (adjusted odds ratio)
	P	OR	95% CI
Vaccine	0.013	1.638	1.108	2.422
Female Age, years	0.419	0.973	0.909	1.040
Male Age, years	0.625	1.015	0.956	1.078
Parity	0.001	0.583	0.422	0.805
Fertility treatments	0.000	0.305	0.175	0.533
Previous caesarean delivery, any	0.995	0.998	0.602	1.656
BMI, kg/m²	0.002	0.916	0.867	0.969
Previous miscarriages	0.848	1.019	0.844	1.230
Pre-existing Diabetes	0.522	1.644	0.359	7.518
Pre-existing Hypothyroidism	0.655	0.883	0.513	1.522
Pre-existing hypertension	0.045	0.303	0.094	0.972

In this study, a total of 2009 infants were born, 851 in the vaccinated group and 1158 in the unvaccinated group. There were similar neonatal outcomes in the two groups before and after PSM. After propensity-score matching, there was no differernce in average weight of newborns, as well as the incidence of macrosomia (aOR = 0.836, 95% CI 0.551–1.268, P = 0.399), low birth weight (aOR = 1.367, 95% CI 0.943–1.983, P = 0.099) and very low birth weight infants (aOR = 1.709, 95% CI 0.618–4.731, P = 0.302) (Table 4, Fig. 2). There was also no difference in the sex ratio of newborns (p > 0.05). There were similar neonatal mortality, hospitalization rate and length of newborn hospitalization in the two groups (p > 0.05). Further detailed data shows that, there were comparable newborn complications in the vaccinated versus the unvaccinated group, including the incidence of jaundice, birth asphyxia, newborn digestive complications, newborn respiratory complications, newborn fever, neonatal heart disease, sepsis, hypolycaemia, hyperglycemia, internal haemorrhage, feeding problems of newborn, aspiration syndrome and other composite adverse neonatal outcomes (p > 0.05) (Table 4).

Table 4

Neonatal outcomes of the vaccinated versus the unvaccinated group
	Before PSM		P value	After PSM		P value
	Vaccinated (n = 851)	Unvaccinated (n = 1158)	P value	Vaccinated (n = 782)	Unvaccinated (n = 785)	P value
Birth weight, g	3220.35 ± 528.64	3211.16 ± 538.42	0.653	3213.98 ± 530.77	3261.66 ± 498.57	0.137
Birthweight > 4000 g	43 (5.1%)	66 (5.7%)	0.527	39 (5.0%)	44 (5.6%)	0.561
Low birth weight, < 2500 g	65 (7.6%)	99 (8.6%)	0.461	63 (8.0%)	44 (5.6%)	0.060
Very low birth weight, < 1500 g	9 (1.1%)	13 (1.1%)	0.890	9 (1.2%)	5 (0.6%)	0.286
Male gender	447 (52.5%)	599 (51.7%)	0.723	410 (52.2%)	405 (51.8%)	0.862
5-minute Apgar score ≤ 7	1 (0.1%)	2 (0.2%)	1.000	1 (0.1%)	2 (0.3%)	0.624
All-cause hospitalizations	210 (24.7%)	328 (28.3%)	0.068	196 (25.0%)	209 (26.7%)	0.427
Length of newborn hospitalization, days	2.17 ± 5.69	2.57 ± 6.37	0.061	2.18 ± 5.74	2.17 ± 5.52	0.623
Infant death over the study period	1 (0.1%)	1 (0.1%)	0.828	1 (0.1%)	1 (0.1%)	0.998
Jaundice	82 (9.6%)	120 (10.4%)	0.592	76 (9.7%)	94 (12.0%)	0.137
Birth asphyxia	7 (0.8%)	8 (0.7%)	0.735	7 (0.9%)	2 (0.3%)	0.178
Newborn digestive complications	3 (0.4%)	9 (0.8%)	0.222	3 (0.4%)	5 (0.6%)	0.506
Newborn respiratory complications	37 (4.4%)	48 (4.2%)	0.823	36 (4.6%)	25 (3.2%)	0.155
Newborn fever	4 (0.5%)	10 (0.9%)	0.295	4 (0.5%)	6 (0.8%)	0.522
Neonatal heart disease	3 (0.4%)	4 (0.4%)	1.000	3 (0.4%)	3 (0.4%)	1.000
Sepsis	1 (0.1%)	6 (0.5%)	0.262	2 (0.3%)	5 (0.6%)	0.287
Hypoglycaemia	5 (0.6%)	8 (0.7%)	0.775	5 (0.6%)	7 (0.9%)	0.558
Hyperglycemia	0 (0.0%)	2 (0.2%)	0.511	0 (0.0%)	2 (0.3%)	0.249
Intracranial haemorrhage	0 (0.0%)	3 (0.3%)	0.267	0 (0.0%)	2 (0.3%)	0.249
Feeding problems of newborn	13 (1.5%)	13 (1.1%)	0.427	13 (1.7%)	7 (0.9%)	0.180
Aspiration syndrome	2 (0.2%)	8 (0.7%)	0.151	2 (0.3%)	5 (0.6%)	0.287
Other composite adverse neonatal outcome	54 (6.4%)	89 (7.7%)	0.248	48 (6.1%)	51 (6.5%)	0.740

To our knowledge, this study is the first to focus on the impact of prenatal inactivated COVID-19 vaccination on maternal and neonatal outcomes. During the study period, 42.9% of women who delivered between 2022.01.01 and 2022.06.30 included in the study received at least one dose of vaccine before delivery. Women in the vaccinated group had a higher number of previous deliveries, a higher percentage of scarred uteruses, and a significantly lower percentage of fertility treatments. Because of these underlying imbalances, we performed multivariate regression analysis and PSM to control the confounding factors that might affect the results. In this study, we found no significant association between vaccination and severe adverse pregnancy outcomes or neonatal complications. Although we found a slightly smaller gestational week of delivery and a possible increased rate of late preterm birth in the vaccination group, there was no difference in mean neonatal weight, incidence of low birth weight infants and other neonatal adverse complications.

Studies show that maternal and fetal outcomes worsened globally during the COVID-19 pandemic, with increases in maternal deaths, stillbirths, ruptured ectopic pregnancies, and maternal depression[8]. A meta-analysis revealed that pregnant women with SARS-CoV-2 infection were at higher risk of preterm delivery, requiring mechanical ventilation, admission to an intensive care unit and death compared to non-pregnant women[9]. As worsening symptoms of maternal infection may lead to more adverse neonatal outcomes. A cohort study involving 43 institutions in 18 countries found that comparing pregnant women with confirmed and undiagnosed COVID-19 identified that COVID-19 during pregnancy was associated with a substantial and sustained increase in severe maternal morbidity and mortality and neonatal complications. In addition, COVID-19 during pregnancy was associated with an increased risk of pregnancy-specific complications of pre-eclampsia, preterm delivery, and stillbirth[10]. Based on the special effects of SARS-CoV-2 infection on maternal and neonatal outcomes, most studies support the safety and protection of COVID-19 vaccine in pregnant women and their newborns[11],

However, the problem is that there is still a lack of evidence on the safety of vaccination and its effects on maternal and neonatal outcomes. A meta-analysis evaluating evidence from 23 studies, including 117,552 pregnant women who received COVID-19 vaccine, showed that the effectiveness of mRNA vaccination was 89.5%. In the vaccinated cohort, the risk of stillbirth was significantly reduced by 15%[4]. Another study showed no differences in prenatal COVID-19 vaccination in terms of pregnancy, delivery, and neonatal complications, including gestational age at delivery, incidence of small for gestational age, and neonatal respiratory complications[12]. It has been reported that vaccination with covid-19 during pregnancy was not associated with a higher risk of preterm delivery, younger gestational age at birth, or risk of stillbirth[13]. A multicenter retrospective study showed that covid19 vaccination was not associated with maternal composite adverse outcomes and a significantly lower risk of neonatal composite adverse outcomes was observed[5]. However, almost all of these above studies and evidence are based on mRNA vaccination.

In China, COVID-19 inactivated vaccine (coronavirus vaccine) is the main type of COVID-19 vaccine available. Studies have shown that COVID-19 inactivated vaccine (coronavirus vaccine) is effective in preventing the transmission of COVID-19, with an efficiency of 65.9% in preventing COVID-19 infection, 87.5% in avoiding hospitalization, 90.3% in preventing ICU hospitalization, and 86.3% in preventing COVID-19 death[14]. Prospective cohort studies have shown that treatment of adults with either of the two inactivated SARS-CoV-2 vaccines significantly reduces the risk of symptomatic COVID-19 with few serious adverse events[15]. However, there are no clinical data to determine whether inactivated vaccination of pregnant women may affect on maternal and neonatal outcomes or not. An animal study showed that human angiotensin-converting enzyme 2 (hACE2) mice vaccinated with inactivated COVID-19 vaccine before and during pregnancy exhibited normal body weight changes and reproductive performance indicators, and the physical development of their offspring was normal. Moreover, after intranasal vaccination with SARS-CoV-2, all pregnant mice in the immunized group survived, and the reproductive performance and physical development of their offspring were normal. In contrast, all mice in the non-immunized group died before delivery. This experiment may recommend that inactivated COVID-19 vaccination is safe and may effectively protects pregnant mice from SARS-CoV2 infection and has no adverse effects on offspring[16]. Huang etal. demonstrates that female vaccination with inactivated COVID-19 vaccine does not have any measurable deleterious effects on in vitro fertilization treatment and has no significant impact on embryonic laboratory parameters or pregnancy outcomes[17]. Another study on the prognosis of inactivated COVID-19 vaccine in frozen-thawed embryos for transfer revealed that live birth rates, sustained pregnancy rates and clinical pregnancy rates in vaccinated women were comparable to those in unvaccinated women, and birth length and birth weight were similar in both groups[18]. However, none of these studies reported maternal-related complications, and only birth weight was analyzed regarding neonatal outcomes.

This study is the first to focus on the effects of prenatal inactivated COVID-19 vaccination on maternal and neonatal outcomes and to analyze the relevant outcomes in detail, with results largely similar to those of similar studies described above. However, it is worth noting that we found an increased risk of overall preterm birth in the vaccinated group compared to unvaccinated women (p < 0.05), and it is important to mention that there was no difference in early preterm birth (< 32 weeks) rate and incidence of preterm birth < 34 weeks, most preterm births were late preterm and there was no difference in neonatal outcomes. Although some studies have shown that vaccination does not increase the risk of preterm birth[6]. The study by Aharon Dick et al. had a similar outcome to ours, although their study population was vaccinated with mRNA vaccine. They included a larger sample and explored the association between risk of preterm birth and vaccination in early, midterm and late pregnancy separately. They found a higher risk of preterm delivery in those who were vaccinated in the midterm of pregnancy (8.1% vs. 6.2%).We therefore hypothesized that unmeasured confounding factors associated with vaccination may have contributed to the results[19].

A large sample size was included in our study, although this was a retrospective study, detailed and accurate vaccination information, including vaccine manufacturer, dosing date, and fertility treatment information were available with the help of an electronic health database to ensure the reliability and authenticity of the retrospective results. However, two limitations of the study should also be noted. First, due to the single-center retrospective nature of the study, some baseline clinical characteristics may not have been adequately balanced. Second, due to the limited sample size, we were unable to match by time of the first vaccination. In addition, early pregnancy outcomes such as miscarriage and ectopic pregnancy cannot be studied.

In this cohort study, the inactivated COVID-19 vaccine appeared to be safe, and although there was an increased incidence of late preterm delivery compared with unvaccinated women, there was no significant increase in other adverse maternal and neonatal outcomes. Future studies that focus on outcomes at the time of vaccination may provide better understanding and more accurate counseling of patients regarding the risks and benefits of vaccination before and during pregnancy.

Ethics approval and consent to participate

Hadassah’s Helsinki committee fle no. HMO-21-0342 approved a waiver of informed consent by participants due to the retrospective nature of the study and anonymization of personal information. All methods were performed in accordance with the relevant guidelines and regulations of the institutional ethical review board and in accordance with the Declaration of Helsinki.

The study was approved by the independent Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (fle no: KY2023-R038) .

Consent for publication

Not applicable.

Availability of Data and Material (ADM)

The data presented in these studies are available on request from the corresponding author.

Competing interests

The authors declare no competing interests.

Funding

None

Authors' contributions

Conceptualization, Y.C.; methodology, Y.C. and W.X.; formal analysis, S.Z., F.X. and L.G.; data curation, X.X., S.W.,Y.C. and W.X.; writing—original draft preparation, Y.C. and W.X.; writing—review and editing, Y.C. , S.W and W.X.; supervision and project administration, W.X. All authors have read and agreed to the published version of the manuscript.

Acknowledgment

Not applicable.

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Prenatal maternal inactivated COVID-19 vaccination: the maternal and neonatal outcomes, a retrospective cohort study

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