Perinatal outcomes and sinopharm BBIBP-CorV vaccination during pregnancy

After the outbreak of COVID-19 in December 2019, a huge part of the health care services was dedicated to preventing and treating this disease. In the case of COVID-19 infection, hospitalization and intensive care unit admission are reported more in pregnant individuals [1, 2]. Also, perinatal outcomes such as preterm birth, especially by cesarean section, low 5-minute Apgar score, admission to neonatal intensive care unit, and neonatal death was more common in newborns who were born from mothers infected with COVID-19 during pregnancy [3]. IRAN had one of highest rates of death due to COVID-19 in Eastern Mediterranean Region [4]. Vaccination against SARS-CoV-2 during pregnancy is recognized as a key factor in preventing maternal illness [5]. Nonetheless, the International Federation of Gynecology and Obstetrics and the US Centers for Disease Control and Prevention have since advised unrestricted COVID-19 vaccination in women currently pregnant [6, 7].

Sinopharm (BBIBP‐CorV) is an inactivated virus vaccine with an aluminum hydroxide adjuvant. Although the platform seems safe during pregnancy, the Food and Drug Administration has not yet approved aluminum hydroxide for usage during pregnancy due to the lack of data [8, 9]. The use of the Sinopharm vaccine against COVID-19 has received an interim recommendation from the World Health Organization for emergency use [10]. Sinopharm vaccination in general population seems to be safe with mild and predictable side effects like injection site pain, fatigue, headache and lethargy [11, 12]. For usage during pregnancy, "WHO recommends the use of COVID-19 vaccine Sinopharm in pregnant women when the benefit of vaccination outweighs the potential risks". However, the available information on using the Sinopharm vaccine in pregnant women is insufficient for determining pregnancy-related hazards [13]. After all, due to concerns about the safety of vaccination during pregnancy and lack of evidence, some people may be reluctant to get vaccinated while pregnant [14].

Almost all previous studies about adverse perinatal outcomes were done on mRNA vaccines like Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) or viral vector vaccines like AstraZeneca (AZD1222) [15‐17].

Vaccination of pregnant individuals started in August 2021 with the Sinopharm vaccine in Iran. In this study, the risk of unfavorable perinatal outcomes following SARS-CoV-2 vaccination during pregnancy was examined using data from the maternal vaccination registry and Iranian Maternal and Neonatal (IMaN) Network.

Adverse perinatal outcomes compared between vaccinated and unvaccinated individuals against SARS-CoV-2 included preterm birth (<37 completed gestational weeks), extremely preterm birth (<32 completed gestational weeks), low birth weight (<2500 gr), very low birth weight (<1500 gr), Intrauterine growth restriction [18], stillbirth, neonatal death (death of liveborn infant within first 28 days of life), congenital anomalies, low Apgar score (5-minute Apgar score<7) and neonatal intensive care unit admission.

Congenital malformations were defined as the presence of one or more congenital anomalies in examination at birth. The congenital anomalies in the Iranian Maternal and Neonatal Network included any malformation in the central nervous systems, musculoskeletal, gastrointestinal tract, cardiovascular, genitourinary, respiratory systems, eye-face-ear and skin.

Of all 129,488 singleton births included in this study, 17,485 were among mothers vaccinated against SARS-CoV-2 during pregnancy. In total, 6774(38.74% of vaccinated mothers against SARS-CoV-2) individuals received 1 dose of the Sinopharm vaccine during pregnancy whereas 10711(61.26%) had 2 doses while pregnant. The median gestational age at which vaccinated mothers received their first dose of the Sinopharm vaccine was 24 Weeks (IQR 19-29). This number was 26 Gestational weeks (IQR 21-31) for the second dose.

Among those vaccinated against SARS-CoV-2, 1202 (6.87% of those vaccinated) were vaccinated during the first trimester, 10250 (58.62%) were vaccinated during the second trimester, and 6033 (34.51%) were vaccinated during the third trimester.

Individuals vaccinated during pregnancy were generally multiparous (61.41% of vaccinated vs 54.56% of unvaccinated individuals). They were more likely to have underlying medical conditions (15.46% of vaccinated vs 13.53% of unvaccinated individuals) and less likely to be smokers or substance abusers (0.05% of vaccinated vs 0.22% of unvaccinated individuals). Individuals with a body mass index over 30 are more likely to receive a Sinopharm vaccine compared to the baseline group (individuals with a body mass index between 18.5 to 24.9). Whereas individuals with a body mass index less than 18.5 are less likely to be vaccinated. Vaccinated individuals were usually less educated (Table 1).

Of all births, 8.15% lead to preterm birth (7.98% of vaccinated vs 8.17% of unvaccinated individuals). After adjusted analysis, we observed a statistically significant decrease in the incidence of preterm birth in individuals vaccinated against SARS-CoV-2 during pregnancy (P =0.006, aOR=0.91, [95% CI, 0.85 to 0.97]) (Table 2). Comparing vaccination doses during pregnancy, getting 1 dose of Sinopharm vaccine led to no difference in risk of preterm birth. However, receiving 2 doses was associated with a decrease in incidence of this outcome (Table 3). Adjusted analysis showed that the first-trimester vaccination caused an increase in the incidence of preterm birth. There was no change in the incidence of preterm birth in those vaccinated during the second trimester. However, third-trimester vaccination caused a decrease in the incidence of preterm birth (Table 4).

Extremely preterm birth included 1.26% of all births (0.76% between vaccinated individuals vs 1.34% between unvaccinated individuals). Adjusted analysis indicated a statistically significant decrease in the incidence of extremely preterm birth in individuals vaccinated against SARS-CoV-2 during pregnancy (P =<0.001, aOR=0.55, [95% CI, 0.45 to 0.66]) (Table 2). The protective effect was observed in individuals vaccinated with either 1 or 2 doses (Table 3). Comparing the trimester of pregnancy while vaccinated, there was no significant increase in the incidence of extremely preterm birth associated with vaccination during the first trimester. However, a significant decrease was seen in the risk of extremely preterm birth in those vaccinated during the second and third trimesters (Table 4).

Stillbirth occurred in 0.70% of births (0.51% between vaccinated individuals vs 0.73% between unvaccinated individuals). According to the adjusted analysis, a significant reduction in stillbirths was found among vaccinated individuals (P =<0.001, aOR=0.60, [95% CI, 0.47 to 0.76]) (Table 2). At least receiving 2 doses during pregnancy was required to observe a decrease in stillbirth (Table 3). First-trimester vaccination caused no statistically significant increase in the incidence of stillbirth. However, adjusted analysis indicated a decrease in stillbirth in individuals vaccinated during the second and third trimesters of pregnancy (Table 4).

Unadjusted analysis indicated a decrease in the incidence of LBW, VLBW, and low 5-minute Apgar score. After adjustment for gestational age, this protective effect was not observed. This means there is no difference in the risk of these outcomes in exposed and unexposed neonates with the same gestational age.

Adjusted analysis indicated no statistically significant increase in the risk of congenital anomalies, intrauterine growth restriction, neonatal intensive care unit admission and neonatal death between neonates born from vaccinated and unvaccinated individuals (Table 2). The results were similar for vaccination with 1 or 2 doses (Table 3) and vaccination during all trimesters (Table 4).

This large retrospective cohort study aimed to compare the incidence of adverse perinatal outcomes between individuals vaccinated against SARS-CoV-2 with the Sinopharm vaccine and unvaccinated individuals in Tehran, Iran.

Sinopharm vaccination during the third trimester of pregnancy decreased the incidence of preterm birth. Also, extremely preterm birth declined significantly in those vaccinated during the second and third trimesters. Although at least 2 doses of Sinopharm vaccination were required for a decrease in the risk of preterm birth, only 1 dose can lower the incidence of extremely preterm birth. Similar studies conducted on mRNA vaccines reported no statistically significant increase in the incidence of preterm birth and extremely preterm birth between the vaccinated and unvaccinated groups [15, 20, 21]. Recent studies indicated an association between third-trimester COVID-19 vaccination and lower risk of preterm birth [21]

Nonetheless, a slight increase in preterm birth was observed in individuals vaccinated during the first trimester of pregnancy. This increased risk could be caused by early vaccination. However, such a deduction requires further studies. Articles conducted on mRNA vaccines reported no increase in the risk of preterm birth in the Case of Maternal first-trimester vaccination [16].

The incidence of stillbirth was significantly lower in individuals who received the Sinopharm vaccine while pregnant. At least 2 doses of Sinopharm vaccination during pregnancy were required to observe the protective effects against stillbirth. Similar protective effects were reported in studies conducted on mRNA vaccines [17, 22].

The adjusted analysis indicated a lower risk of preterm birth, extremely preterm birth, and stillbirth. The results can be related to a lower risk of SARS-CoV-2 infection in the vaccinated individuals or antibody transportation to the fetus. The third-trimester vaccination is associated with higher IgG antibody levels in the fetus. Also, Vaccination with 2 doses is associated with higher IgG antibodies in the fetus blood sample compared to vaccination with only 1 dose [23, 24]

There was no statistically significant increase in the risk of IUGR, low 5-minute Apgar score, NICU admission, congenital anomaly, LBW, VLBW, and neonatal death between individuals vaccinated with the Sinopharm vaccine during pregnancy and unvaccinated mothers. Existing articles on the use of mRNA vaccines during pregnancy indicated an association between vaccination and a decreased risk of low 5-minute Apgar score and NICU admission [21, 25] Existing articles indicated no association between vaccination and an increased risk of perinatal outcomes [25, 26].

To our knowledge, this is the first study about adverse perinatal outcomes in individuals vaccinated with the Sinopharm vaccine, which is the main strength of this study. Other strengths are coverage of individuals vaccinated during the first trimester and the population-based setting that led to reduced risk of selection bias.

The following study limitations should be noted. First, data on SARS-CoV-2 infection during pregnancy was unavailable in our study. Exclusion of those infected during pregnancy could lead to more accurate results on the effect of Sinopharm vaccination on perinatal outcomes. Second, although 17,485 mothers were exposed to vaccination during pregnancy, only 1,202 were vaccinated during the first trimester; therefore, the number of newborns exposed in the first trimester is underpowered to detect the incidence of rare adverse perinatal outcomes. Third, although the analysis adjusted for a broad range of potential confounding factors, adjustment could have been conducted for other potential covariates (like household income) if the data was available.

Pregnant women are at risk of severe COVID-19 and related complications [1, 2, 27]. Maternal COVID-19 vaccination during pregnancy reduces COVID-19 complications in infected pregnant individuals [28]. Also, immunization against SARS-CoV-2 during pregnancy has the extra benefit of transferring antibodies to the developing fetus, which can protect the infant against COVID-19 infection for a few months [29, 24].

The results of this study support the safety of vaccination with the Sinopharm vaccine during the second and third trimester of pregnancy. The findings of this study can help healthcare practitioners and policymakers educate pregnant women about the safety and benefits of vaccinations for both themselves and their developing fetuses.

Further studies must focus on the incidence of perinatal outcomes in first-trimester vaccination with the Sinopharm vaccine. Also, the incidence of other perinatal outcomes like miscarriage can be a subject of future studies.

The finding of this study indicated no adverse pregnancy outcome due to vaccination with the Sinopharm vaccine during the second and third trimesters of pregnancy. The overall risk of adverse perinatal outcomes was lower in vaccinated individuals compared to the unvaccinated group. Regarding increased risk of preterm birth related to First-trimester vaccination in this study, further studies are required.