key: cord-0700613-u131tc6p authors: Ben‐Mayor Bashi, Tali; Amikam, Uri; Ashwal, Eran; Hershkovitz, Gal; Attali, Emmanuel; Berkovitz‐Shperling, Roza; Dominsky, Omri; Halperin, Tami; Goldshmidt, Hanoch; Gamzu, Ronni; Yogev, Yariv; Kuperminc, Michael; Hiersch, Liran title: The association of maternal SARS‐CoV‐2 vaccination‐to‐delivery interval and the levels of maternal and cord blood antibodies date: 2021-11-20 journal: Int J Gynaecol Obstet DOI: 10.1002/ijgo.14014 sha: 2b54ed2269adf170766a579f6f526dcaca3853a1 doc_id: 700613 cord_uid: u131tc6p OBJECTIVE: To evaluate the correlation of maternal and cord blood levels of SARS‐CoV‐2 antibodies in pregnant women immunized against COVID‐19. METHODS: A prospective cohort study was performed of pregnant women who delivered at a single university affiliated tertiary medical center. Women who received the COVID‐19 vaccine (BNT162b2 Pfizer©) were approached. The correlation between levels of maternal sera and umbilical cord SARS‐CoV‐2 specific IgG was assessed. RESULTS: Overall, 58 women were included; of them, 19 had received a single dose and 39 received two doses of the COVID‐19 vaccine. Positive levels of umbilical cord IgG were found in 13/19 (68.4%) and 38/39 (97.4%) women after the administration of a single dose and two doses of the vaccine, respectively. The levels of SARS‐CoV‐2 IgG antibodies in the maternal sera of vaccinated women were positively correlated to their respective concentrations in cord blood sera (ρ = 0.857; R(2) linear = 0.719; P < 0.001). Thirteen days after vaccination, the ratio of maternal‐to‐umbilical cord anti Spike IgG antibodies was approximately 1, indicating relatively similar levels in maternal and cord sera. CONCLUSION: After the SARS‐CoV‐2 vaccine, levels of maternal and cord blood antibodies were positively correlated, especially when tested after 13 days following administration of the first dose of the vaccine. BEN-MAYOR BASHI Et Al. population, 2,3 with the Centers for Disease and Control and Prevention (CDC) including pregnancy as one of the factors associated with increased risk for severe COVID-19 illness. 4 Infants and neonates are also reported to be more susceptible to critical illness. 5 However, since the safety and efficacy of the mRNA COVID-19 vaccine was not well studied in the general obstetric population, 6 data are lacking with regard to maternal humoral response to it. Moreover, studies regarding the efficacy of the mRNA COVID-19 vaccine for adequate production of maternal antibodies and the association with levels of cord blood antibodies are scarce. Despite these uncertainties, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recommend that COVID-19 vaccines should not be withheld from pregnant women. 7 Prior studies addressing this issue have reported efficient transplacental transfer of IgG to the infant. However, available studies were limited by small sample size, [8] [9] [10] homogenous population, 8 and lack of data regarding adverse effects and neonatal outcomes. 8, 10 Finally, limited information exists regarding the interval from maternal vaccination to delivery that is associated with adequate levels of cord blood antibodies, which can assist in planning the optimal timing of maternal vaccination before delivery. Thus, the aim of the present study was to evaluate the correlation of maternal and cord blood sera SARS-CoV-2 antibodies levels in pregnant women immunized against COVID-19, to estimate an ideal time for vaccination to achieve adequate levels of antibodies in fetal sera, and to evaluate adverse effects after administration of the vaccine in pregnancy. A prospective cohort study was conducted of pregnant women who delivered at a single university affiliated tertiary medical center in Tel Aviv, Israel from December 2020 to March 2021. The present study was approved by the Institutional Review Board of the Tel-Aviv Sourasky Medical Center (1092-20-TLV; approval date December 29, 2020) and was registered as NCT04724642. All women who received the mRNA COVID-19 vaccine (BNT162b2; manufactured by Pfizer©) during pregnancy were recruited in the delivery room via random questioning. Demographic and clinical information were collected from the electronic medical records. Adverse effects from the vaccination were self-reported. All participants reported they had not had prior COVID-19 infection, which was further validated via serologic testing for the anti-nucleocapsid antibodies. Current infection was excluded using polymerase chain reaction (PCR) nasopharyngeal swabs at the time of admission, routinely taken for all parturients. Maternal blood was collected from each participant during delivery and umbilical vein blood was collected after delivery and before placental detachment. Both blood samples were centrifuged at 400 g for 10 min at room temperature and the sera were stored at -80°C (-112°F). Anti-spike IgG antibodies were provided in arbitrary units (AU/ml) in the range of 0-40 000. Levels of 50 AU/ml and above were considered positive. 11 Anti-nucleocapsid IgG antibodies were provided in relative light units (RLU). Levels above 1.4 RLU were considered positive. 12 Anti-spike IgM antibodies were interpreted as negative when i was less than 1.00 and positive when i was 1.00 or above. 13 The demographic and obstetrical characteristics of the population cohort were described. Additionally, timing and reported adverse effects were reported. Levels of anti-spike IgG were transformed to log10. The correlation between maternal sera and levels of umbilical cord anti-spike IgG were assessed by Spearman test. Curved regression analysis (quadratic model) was used to assess the association between the levels of log10 transformed anti-spike IgG in umbilical cord and the time interval from administration of the first dose of the COVID-19 vaccine to delivery (regression line as well as 95% confidence interval to mean are presented). This model provided the best fit for the data. The cohort was further stratified by the level of umbilical cord blood anti-spike IgG antibodies. Characteristics of cases with levels above 50 AU/ml were compared to those with levels below 50 AU/ ml. For univariate comparisons, χ 2 test or Fisher exact test were used for categorical variables, and Student t-test or Mann-Whitney U-test were used for continuous variables. The predictive values of time elapsed from first dose to delivery in predicting umbilical cord blood level of anti-spike IgG antibodies of 50 AU/ml or greater were calculated, using the cutoff of 14 days or more. Hypotheses were tested using two-tailed tests with a significance level of 0.05. All statistical analyses were performed using the statistical software SPSS version 27 (IBM Corp., Armonk, NY, USA). During the study period, 58 women who were vaccinated against COVID-19 met the inclusion criteria. Of them, 19 were vaccinated with only a single dose and 39 received two doses of the COVID-19 vaccine (doses were given 21 days apart as per the national protocol for vaccination). The demographic, obstetrical, and neonatal characteristics of the study cohort are presented in Table 1 . The characteristics of the vaccine and reported adverse effects are detailed in Table 2 (Table 2 ). Comparing adverse effects after the first and second doses failed to show significance (χ 2 P = 0.706). Levels of SARS-CoV-2 anti-spike IgG in maternal sera were positively correlated to their respective concentrations in cord blood sera (ρ = 0.857; R 2 linear = 0.719; P < 0.001; Figure 1 ). Anti-nucleocapsid IgG was negative in all samples of maternal and umbilical cords, indicating that all women did not acquire COVID-19 infection before delivery. In addition, anti-spike IgM antibodies were negative in all samples of umbilical cord, confirming that no active immunity was induced in the fetus. The correlation of the time interval from the first dose of the vaccination with levels of umbilical anti-spike IgG cord sera was fur- The aim of the present study was to explore the association of Since the emergency-use authorization (EUA) by the FDA for the three mRNA COVID-19 vaccines, there has been substantial need for research regarding efficacy and safety in pregnant and neonatal populations. 14 Furthermore, data are lacking regarding the degree of transplacental passive immunity in vaccinated or infected women. 15 Early on in life, immune protection is accomplished by the transferring of maternal antibodies from mother to offspring. 17 Since the data implicate increased neonatal vulnerability to COVID-19 infection, 18 major concern has risen, and reinforcement of prevention efforts has become a subject of great interest. Efficient placental transfer of IgG antibodies was found in vaccinated women as well as a positive correlation between maternal and umbilical cord antibody ies such as Hepatitis B, rubella, measles, influenza, and pertussis. [19] [20] [21] In the present cohort, the levels of anti-Spike specific IgG in the umbilical cord sera were initially positively correlated to the time interval from first dose to delivery, but an apparent plateauing after approximately 35-40 days was noticed. It is unclear whether a decrease in the levels of antibodies after this period should be expected as the cohort did not include women who were vaccinated more than 55 days before delivery. It is apparent that further studies on this subject are greatly needed. The safety profile for pregnant women is of great concern, and one of the barriers preventing pregnant women from getting vaccinated. 22 The present study did not reveal any alarming adverse effects, similar to the data published in recent studies that evaluated vaccine safety in pregnant women. 9, 14, 23 In accordance with prior studies, it was discov- effect. This result should be interpreted with caution since the women in the present study were vaccinated in the third trimester and were recruited to the study upon entry to the delivery room. Another worthy fact to note is the time interval from administration of the first dose to the achievement of adequate cord immunity. According to previous studies, 8, 10 such an interval exists, and more neonates acquire immunity as time elapses, although a specific cutoff was not calculated. This interval was found to be 13 days, regardless of administration of the second dose. This finding is in accordance with a recent study that showed that an interval of 14 days after a single dose of the vaccine provides immunity against severe disease. 23 A trend towards a plateau in the level of anti-spike IgG antibodies as time elapses after the first dose of the vaccine was also found. A time interval from vaccination to neonatal immunity is important to define the optimal timing of vaccination in pregnant women. Although vaccinating pregnant women is important throughout pregnancy to decrease maternal morbidity, with the hopeful dwindling of the disease in various parts of the world subsequent to vaccination, it may be possible to schedule appropriate vaccination during pregnancy to enhance neonatal immunity. Whether maternal immunity waxes or wanes as the time from vaccination increases may also be discovered. The present study has several strengths. First, while previous stud- The present study has some limitations. Only antibody titer was examined, and not the quality of the antibodies, as may be detected by testing neutralizing antibodies. However, recent data suggest anti-spike IgG can serve as a surrogate marker for virus-neutralizing activity. 24 In addition, all women in the present cohort were vaccinated in the third trimester of pregnancy, a fact that limits the knowledge about the immunity afforded by vaccinations earlier on in pregnancy. Finally, although the present study is the largest to date examining umbilical cord SARS-CoV-2 antibodies in pregnant vaccinated women, the sample size comprised only 58 women. In conclusion, it was demonstrated that vaccination with the mRNA SARS-Cov-2 vaccine has an adequate maternal and obstetric safety profile, in addition to affording maternal and neonatal quantitative immunity. Therefore, and in light of the pandemic that began in December 2019, consideration of vaccination during pregnancy worldwide is recommended, in accordance with results to be obtained in future large prospective studies. The authors have no conflicts of interest. All authors had substantial contribution to this study and gave their final approval of this version to be published. All authors agreed to be accountable for all aspects of the study. Tali Ben-Mayor Bashi https://orcid.org/0000-0001-7182-6107 BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting Disease severity, pregnancy outcomes, and maternal deaths among pregnant patients with severe acute respiratory syndrome coronavirus 2 infection in Washington State Effects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis COVID-19 People with Certain Medical Conditions COVID-19: neonatal-perinatal perspectives PF-07302048). 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