key: cord-0838173-12e1hgub
authors: Blakeway, Helena; Prasad, Smriti; Kalafat, Erkan; Heath, Paul T.; Ladhani, Shamez N.; Le Doare, Kirsty; Magee, Laura A.; O’brien, Pat; Rezvani, Arezou; Dadelszen, Peter von; Khalil, Asma
title: COVID-19 Vaccination During Pregnancy: Coverage and Safety
date: 2021-08-10
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2021.08.007
sha: b4bdd66130e4579d25fabea8e71b5a6b31e7339d
doc_id: 838173
cord_uid: 12e1hgub

Background Concerns have been raised regarding a potential surge of COVID-19 in pregnancy, secondary to rising numbers of COVID-19 in the community, easing of societal restrictions, and vaccine hesitancy. Even though COVID-19 vaccination is now offered to all pregnant women in the UK, there are limited data on its uptake and safety. Objectives and study design : This was a cohort study of pregnant women who gave birth at St George’s University Hospitals NHS Foundation Trust, London, UK, between March 1st and July 4th 2021. The primary outcome was uptake of COVID-19 vaccination and its determinants. The secondary outcomes were perinatal safety outcomes. Data were collected on COVID-19 vaccination uptake, vaccination type, gestational age at vaccination, as well as maternal characteristics including age, parity, ethnicity, index of multiple deprivation score and co-morbidities. Further data were collected on perinatal outcomes including stillbirth (fetal death ≥24 weeks’ gestation), preterm birth, fetal/congenital abnormalities and intrapartum complications. Pregnant women who received the vaccine were compared with a matched cohort of propensity balanced pregnant women to compare outcomes. Effect magnitudes of vaccination on perinatal outcomes were reported as mean differences or odds ratios with 95% confidence intervals. Factors associated with antenatal vaccination were assessed with logistic regression analysis. Results Data were available for 1328 pregnant women of whom 141 received at least one dose of vaccine before giving birth and 1187 women who did not; 85.8% of those vaccinated received their vaccine in the third trimester and 14.2% in the second trimester. Of those vaccinated, 128 (90.8%) received an mRNA vaccine and 13 (9.2%) a viral vector vaccine. There was evidence of reduced vaccine uptake in younger women (P=0.002), those with high levels of deprivation (i.e., fifth quintile of Index of Multiple Deprivation, P=0.008) and women of Afro-Caribbean or Asian ethnicity, compared to Caucasian ethnicity (P<0.001). Women with pre-pregnancy diabetes had increased vaccine uptake (P=0.008). In the multivariable model adjusting for variables that had a significant effect according to the univariable analysis, fifth deprivation quintile (most deprived) was significantly associated with lower antenatal vaccine uptake (adjusted OR 0.09, 95% CI 0.02–0.39, P=0.002), while pre-pregnancy diabetes was significantly associated with higher antenatal vaccine uptake (adjusted OR 11.1, 95% CI 2.01–81.6, P=0.008). In a propensity score matched cohort, compared with non-vaccinated pregnant women, 133 women who received at least one dose of the COVID-19 vaccine in pregnancy (vs. those unvaccinated) had similar rates of adverse pregnancy outcomes (P>0.05 for all): stillbirth (0.0% vs 0.3%), fetal abnormalities (2.2% vs 2.7%), intrapartum pyrexia (3.7% vs 1.5%), postpartum hemorrhage (9.8% vs 9.5%), cesarean section (30.8% vs. 30.6%), small for gestational age (12.0% vs 15.8%), maternal high dependency unit or intensive care admission (6.0% vs 3.5%) or neonatal intensive care unit admission (5.3% vs 5.4%). Mixed-effects Cox regression showed that vaccination was not significantly associated with birth <40 weeks’ gestation (hazard ratio 0.93, 95% CI 0.71–1.23, P=0.630). Conclusions Of pregnant women eligible for COVID-19 vaccination, less than one third accepted COVID-19 vaccination during pregnancy and they experienced similar pregnancy outcomes. There was lower uptake among younger women, non-white ethnicity, and lower socioeconomic background. This study contributes to the body of evidence that having COVID-19 vaccination in pregnancy does not alter perinatal outcomes. Clear communication to improve awareness among pregnant women and healthcare professionals on vaccine safety is needed, alongside strategies to address vaccine hesitancy. This includes post-vaccination surveillance to gather further data on pregnancy outcomes, particularly after first trimester vaccination, as well as long-term infant follow-up.

The Coronavirus disease 2019 pandemic has caused loss of life and poorer 2 health outcomes, outside and in pregnancy, despite worldwide aggressive public health 3 measures to control the spread. 1 Mass vaccination is a key method by which countries are 4 aiming to control the pandemic. 2 5

Theoretically, COVID-19 vaccines are safe for use in pregnancy, as they do not contain live 6 attenuated virus. 3 For COVID-19 vaccination in pregnancy, there have been no major safety 7 signals from: animal reproductive toxicology studies; the very small number of inadvertent 8 pregnancies in vaccine trials; the Centers for Disease Control and Prevention (CDC) V-safe 9 post-vaccination health checker (with limited data on >30,000 pregnant women, but only 827 10 that have given birth); or a formal pregnancy registry (>1800 enrolled to date). 4 A recent 11 report of American health workers who were pregnant (N=84) or lactating (N=31) when 12 vaccinated, found that compared with non-pregnant controls (N=16), vaccine-induced 13 humoral immunity was similar, antibody titres higher than following actual COVID-19 14 infection, and antibodies were present in umbilical cord blood and breastmilk, suggesting that 15 vaccination can confer maternal and perinatal immunity. 5 16

Based on vast prior experience with other vaccines in pregnancy and no hypothesized 17 mechanisms for harm, similar efficacy and side-effects are anticipated with COVID-19 18 (income, employment, education, health, crime, barriers to housing and services, and living 23 environment) into a single score and is widely used to assess deprivation in the UK. Other 24 data variables included COVID-19 vaccination uptake, vaccination type, and gestational age 25 (GA) at vaccination. Other data of interest included: antenatal complications, including gestational diabetes, obstetric cholestasis and preeclampsia; venous thromboembolism (in 1 view of the association with the Oxford Astra Zeneca vaccine), or myocarditis/pericarditis (in 2 view of the association with the Pfizer/BioNTech vaccine); and antenatal medication, 3

including medications for chronic pre-pregnancy disorders (such as hypothyroidism, epilepsy, 4 diabetes, or depression) or pregnancy conditions (such as gestational hypertension or 5 preeclampsia), but not nutritional supplements, multivitamins, iron replacement, antibiotics, 6 antiemetics, analgesia or anti-D immunoglobulin. 7

Vaccine types included mRNA vaccines (Moderna, Pfizer/BioNTech) and viral vector vaccine 8 (Oxford Astra Zeneca), which are approved for use in the United Kingdom. As for the general 9 population, pregnant women were eligible for vaccination if they: (i) were a health or social 10 care worker which increased their risk of (ii) were at high risk of severe 11 COVID-19 because of personal factors (e.g., non-White ethnicity) or health conditions (e.g., 12

diabetes mellitus or gestational diabetes specifically). From 16 th April 2021, vaccination was 13 offered to those aged 45 years and above, with progressively younger groups offered 14 vaccination from 28 May 2021. 12 From 16 th April, the JCVI has advised that mRNA vaccines 15 should be used in preference in the UK for pregnant women. 9 16

The primary study outcome was COVID-19 vaccine uptake during pregnancy among women 18 eligible for vaccination. Vaccination eligibility was assessed by comparing delivery date with 19 vaccination eligibility date based on the mother's age and priority category. In the UK (2021) 20 women became eligible for vaccination based on clinical risk and maternal age, with 21 vaccination offered to pregnant women at the same time as the rest of the population, as 22 follows: >40 years (from 30 th April), >30 years (26 th May), >25 years (8 th June) and >18 years 23 (18 th June). 13, 14 Women who delivered after the vaccination eligibility date for their age 24 category were considered eligible for antenatal vaccination. Vaccination uptake rate was 25 calculated as the number of women who received at least one dose of any COVID-19 vaccine during pregnancy in a certain group divided by all women eligible for vaccination in 1 that group. 2 Secondary outcomes included perinatal outcomes to assess the safety of COVID-19 3 vaccination, which included stillbirth (fetal death ≥24 weeks' gestation), neonatal death, fetal 4 abnormalities, preterm birth before 37 weeks' gestation, GA at birth in weeks, intrapartum 5 complications (pyrexia, suspected chorioamnionitis, placental abruption, postpartum 6 hemorrhage), birthweight Z-score, mode of birth (cesarean, instrumental, unassisted 7 vaginal), maternal high dependency unit or intensive care unit admission (any indication) and 8 neonatal intensive care unit admission (any indication). Postpartum hemorrhage was defined 9

as estimated blood loss of ≥1 liter regardless of the mode of birth. 10 GA was determined in the first trimester according to the crown-rump length of the fetus 11 (singleton pregnancies) or the larger fetus (twin pregnancies) in cases of spontaneous 12 conception, and according to the embryonic age in pregnancies conceived via assisted 13 reproductive technology (ART). After 14 weeks' gestation GA was determined using the head 14 circumference of the fetus (singleton pregnancies) or of the larger fetus (twin pregnancies) in 15 cases of spontaneous conception, and according to the embryonic age in pregnancies 16 conceived via ART. Birthweight Z-scores were calculated using a reference standard 17 published by Poon et al. 15 18

Continuous variables were represented as median and interquartile range (IQR) regardless 20 of the distribution assumptions. Categorical variables were represented as numbers and 21 percentages of total. Shapiro-Wilk test and visual inspection of quantile-quantile plots were 22 used for verifying normality of continuous variables. Mann-Whitney-U, t-test, chi-squared or 23

Fisher-Freeman-Halton tests were used for group comparisons as appropriate. 24

Factors associated with antenatal vaccination were assessed among all women eligible for 25 vaccination, by logistic regression, with factors significant in univariable analyses assessed in a multivariable model to calculate adjusted odds ratios (OR). Results of regression analyses 1 were reported as mean difference (MD), OR or hazard ratios (HR). 2

The effect of COVID-19 vaccination on perinatal outcomes was assessed among women 3 who had antenatal vaccination, compared with those who did not have the vaccine. 4

Propensity score matching was used to match cases and controls for factors identified from 5 between-group comparisons as potentially differing (P<0.10). Groups were matched 1:3 to 6 simulate the observed vaccination uptake. Success of propensity score matching was 7 assessed with propensity score histograms. After matching, the effect of vaccination was 8 estimated using generalized estimation equations using matched group identifiers as cluster 9 labels. Effect magnitudes of vaccination on perinatal outcomes were reported as MD or OR 10 with 95% confidence intervals (CI). GA at delivery was assessed in a separate cohort 11 matched for expected date of delivery as well as confounders identified for other perinatal 12 outcomes. Mixed-effect Cox regression was used to estimate the effect of vaccination on GA 13 at birth below 40 weeks' gestation. In a sensitivity analysis for pregnancy outcomes, women 14 with antenatal COVID-19 were excluded. 15

All analyses were performed using R for Statistical Computing Software (Version 4.0.2). 16

Between 1 st March and 4 th July 2021, a total of 1328 eligible women with complete 2 vaccination records were identified ( Figure 1 ). This included 141 women who received at 3 least one dose of vaccine in pregnancy before birth, and 1187 women who did not. Table 1  4 shows that women who received antenatal vaccination (vs. those who did not) were slightly 5 older, had less deprivation (i.e., higher IMD scores), and were more likely to be Caucasian 6 than Afro-Caribbean ethnicity. There were no differences in maternal BMI, alcohol 7 consumption, or smoking habits. COVID-19 vaccinated (vs. unvaccinated) women had 8 significantly higher rates of pre-gestational diabetes, as well as antenatal medication use 9 overall and for hypertension specifically. There were no differences in antenatal 10 complications, including antenatal SARS-CoV-2 infection (<3% in each group), gestational 11 diabetes (P=0.522), obstetric cholestasis (P=0.654), or cardiac complications (i.e., 12 arrhythmia) (P=0.868). 13

Among the total cohort of 1328 women, vaccination was accepted by 141 (28.7%) of 492 15 women eligible, based on their age and priority category ( Figure 1 ). Of those vaccinated, 128 16 (90.8%) received an mRNA vaccine and 13 (9.2%) received a viral vector vaccine. 17

Regarding the GA at vaccination, 121 (85.8%) women received the first dose during the third 18 trimester and 20 (14.2%) in the second trimester. None received the vaccine in the first 19 trimester or received a dose pre-pregnancy. The median interval from vaccination to birth 20 was 32.6 days (IQR 20.3 -53.9 days). There were 26 women (18.4%) who had two doses of 21 vaccine during the antenatal period. 22

There were significant trends (Cochrane Armitage test) for reduced antenatal vaccine uptake 23 in younger women (P=0.002), high levels of deprivation (P=0.008) and Afro-Caribbean or 24

Asian ethnicity compared with Caucasian or mixed ethnic background (P<0.001) (Figure 2) . 25

Antenatal vaccine uptake was significantly higher among women with pre-pregnancy 26 J o u r n a l P r e -p r o o f 14 diabetes (OR 5.06, 95% CI 1.31-24.2, P=0.023), and lower among women with maternal age 1 below 30 years (OR 0.37, 95% CI 0.15-0.90, P=0.025), deprivation (OR 0.21, 95% CI 0.06-2 0.59, P=0.005), Afro-Caribbean ethnicity (OR 0.25, 95% CI 0.08-0.60, P=0.005), and obesity 3 (defined as maternal BMI at booking ≥30 kg/m 2 ) (OR 0.55, 95% CI 0.29-1.00, P=0.058) 4 (Table 2 ). Only pre-pregnancy diabetes (adjusted OR 11.1, 95% CI 2.01-81.6, P=0.008) and 5 deprivation (adjusted OR 0.09, 95% CI 0.02-0.39, P=0.002) were significant in multivariable 6 analyses; the maternal age below 30 years (adjusted OR 0.39, 95% CI 0.14-1.09, P=0.067), 7

Afro-Caribbean ethnicity (adjusted OR 0.37, 95% CI 0.10-1.06, P=0.088) or obesity (OR 8 0.67, 95% CI 0.34-1.27, P=0.239) were no longer statistically significant (Table 2) . 9

Women who had antenatal COVID-19 vaccination (vs. those who did not) were matched 1:3 11 using propensity scores calculated from maternal age, IMD quintile, self-reported ethnicity, 12

pre-pregnancy diabetes, antenatal medication (any), and antenatal antihypertensive therapy, 13 with exact matching on antenatal medication use and deprivation quintile. 14 In the propensity score-matched cohort, 133 women who received at least one dose of 15 vaccine before birth were matched with 399 women who did not ( Figure 1 ); a match could 16 not be found for 8 women in the vaccinated group. The propensity score histograms of both 17 groups before and after matching are included in the supplementary material ( Figure S1 ). 18

There were no significant differences in intrapartum complications or perinatal outcomes 19 between women who did (vs. those who did not) receive COVID-19 vaccination during 20 pregnancy (Table 3) . 21

Three fetal abnormalities were reported in the women who received COVID-19 vaccination: 22 spina bifida, ventriculomegaly, and hydronephrosis. The spina bifida case was diagnosed 23 before the pregnant woman received the first dose of the vaccine. The ventriculomegaly case 24 was diagnosed at 37 weeks' gestation and was isolated, with no associated brain abnormalities, as confirmed by fetal brain magnetic resonance imaging. The hydronephrosis 1 was mild, with no other associated abnormalities at birth. 2

The pregnancy outcome findings were unchanged after excluding women who had COVID-3 19 during pregnancy (Supplementary Table 1) . 4

Mixed-effects Cox regression showed that gestational age at delivery below 40 weeks' 5 gestation did not differ between women vaccinated during pregnancy and those who were 6 not (hazard ratio 0.93, 95% CI 0.71-1.23, P=0.630) ( Figure 3 ). The size of the vaccinated 7 cohort (n=133) allowed for estimation of moderate and high effect size greater than 0.25, with 8 80% power. 9 10 COMMENT 11

The overall rate of antenatal COVID-19 vaccine uptake in this cohort of pregnant women who 13 were eligible for vaccination and gave birth in an inner London maternity hospital was 28.7%. 14 The most striking determinants of COVID-19 vaccination uptake when offered during 15 pregnancy were pre-pregnancy diabetes (a facilitator) and deprivation (a barrier). Women 16 from the most deprived socioeconomic background were less likely, while women with pre-17 pregnancy diabetes were more likely, to receive the vaccine. Possible additional factors were 18 maternal age below 30 years and Afro-Caribbean ethnicity, both associated with lower 19 vaccine uptake. Following propensity score-matching for differences between women 20 vaccinated and those not vaccinated, there were no differences seen in pregnancy outcomes 21 associated with COVID-19 vaccination in pregnancy, although 95% CI were wide.

Our study has important implications for improving COVID-19 vaccine uptake among 24 pregnant women by identifying facilitators and barriers to vaccine uptake.

In the UK, the JCVI initially stated that COVID-19 vaccination should be offered only to those 1 pregnant women with underlying health conditions that put them at increased risk of severe 2 COVID-19, or where exposure to COVID-19 could not be avoided. 11 Additionally, pregnant 3 women were excluded from initial COVID-19 vaccine trials, meaning that there are currently 4 limited data on their safety and efficacy in pregnancy. 16 A key factor in determining uptake of 5 these vaccines is public trust. A survey of 16 countries, including the UK, found that 6 scepticism around the disease, concern regarding vaccine safety, and lack of trust in 7 government advice and guidelines were significant indicators in predicting vaccine uptake. 17 8

Consequently, changes in the UK guidance along with the lack of safety and efficacy data 9 likely contributed to vaccine hesitancy among pregnant women. In contrast, this may explain 10 why we found that women with pre-pregnancy diabetes were more likely to have the vaccine; 11 their underlying health condition was an indication for vaccination in and outside pregnancy 12 from the start. Clear government communication and advice is needed to help build trust in 13 the system and improve vaccine uptake. 14 Our results showed that pregnant women of Afro-Caribbean ethnicity were less likely to 15 receive the vaccine; this is consistent with recent questionnaire data both in pregnancy and 16 outside of pregnancy. 8 Yet people from ethnic minority groups are more likely to suffer from 17 severe COVID-19 disease, with increased risk of hospitalization, ICU admission and death 18 being higher in those of South Asian ethnicity in the UK. 18 Of note, ethnicity did not appear as 19

an indication for COVID-19 vaccination in pregnancy until 24 th March 2021, 12 emphasizing 20 the importance of tailoring counseling to individual pregnant women in order to encourage 21

To receive COVID-19 vaccination in the UK, pregnant women must attend a vaccine centre, 23 rather than their local general practitioner. A UK study that interviewed 31 pregnant women 24

in April 2020 about the possibility of a COVID-19 vaccine in pregnancy, identified concern 25 about attending hospital or clinical settings for a vaccine because of the perceived risk of 26 exposure to Additional challenges have included reduced public transport and difficulty in accessing childcare. 21 Importantly, maternity care providers and healthcare 1 professionals in vaccine centers, who are less familiar with maternity care, are not always 2 comfortable discussing the benefits and risks of vaccination in pregnancy, even for the 3 current antenatal immunization programme. 22 This is likely to be the case with the COVID-19 4 vaccine, particularly as it is so new, the advice changes so frequently and, as mentioned 5 before, there are currently no UK data on its safety and efficacy in pregnant women. When 6 the vaccine rollout started in the UK, many pregnant women turned to their midwives and 7 obstetricians advice, but with a lack of clear guidance at that point, it was difficult for 8 healthcare professionals to advise women. 16 9

In addition, safety concerns are cited as a reason why pregnant woman are hesitant to have 10 the COVID-19 vaccine. A multi-methods study into women's views on the COVID-19 vaccine 11

found that 81% of non-pregnant women were willing to accept the vaccine immediately, 12 compared with only 62% of pregnant women for whom vaccine hesitancy was most 13 commonly related to safety concerns; these were particularly related to long-term effects, but 14 also more generally about the speed at which vaccines were developed and tested. 8 There is 15 additional evidence that pregnant women in the UK have concerns about vaccination more 16 generally. While the UK has an extensive antenatal immunization programme, with routine 17 offer of vaccination against pertussis, diphtheria, tetanus, polio and seasonal influenza, 23 a 18 multicenter questionnaire study into vaccine hesitancy for influenza and pertussis vaccination 19 in pregnancy found that, most commonly, vaccination was declined for fear of adverse fetal 20

To date, only observational data have been published on vaccination in pregnancy, including 22 a cohort of 3958 pregnant women, of whom 827 completed their pregnancy. 24 The main 23 focus of that study was safety, but the conclusions drawn are potentially limited as the 24 outcomes of pregnant women were compared to historical background rates instead of a 25 contemporaneous control group. This is also the case for another study which assessed 26

short-term outcomes of COVID-19 vaccination in pregnancy. 25 So far, there is little published evidence comparing outcomes of pregnant women who had the COVID-19 vaccine with 1 other pregnant women who did not have the vaccine but had the same exposure to the 2 pandemic. 24, 25 This is important, as it has been shown that pregnancy outcomes may be 3 altered by the indirect effects of the pandemic, such as changes in the provision of 4 healthcare services and the behavior of pregnant women. 21, 26 5

Our study findings have both clinical and research implications. Ours is the first study with 7 contemporaneous pregnant controls, matched for factors associated with vaccination. This is 8 important, as both vaccinated and unvaccinated pregnant women were equally exposed to 9 the indirect effects of the pandemic on maternity care and outcomes. This means that our 10 findings of no significant difference in perinatal outcomes is more robust. Clinically, 11

healthcare professionals should use this knowledge to encourage pregnant women to accept 12 COVID-19 vaccination and reassure them with the growing evidence that the vaccines are 13 safe during pregnancy. 14 Our study did not include any pregnant women who had the vaccine in the first trimester and 15

there are conflicting reports about the effect of first-trimester COVID-19 infection on 16 miscarriage rates. 27, 28 17

The Royal College of Obstetricians and Gynaecologists (RCOG) currently does not specify 18 any gestation to avoid COVID vaccination, but mentions that in low-risk situations, pregnant 19 women may choose to delay vaccination until 12 weeks of gestation: 'COVID-19 vaccines 20 can be given at any time in pregnancy. In low-risk situations some women may choose to 21 delay vaccination until 12 weeks of gestation, aiming for vaccination as soon as possible 22

thereafter.' 12 More data are needed on safety of the vaccine when administered in the first 23 trimester so that clearer, informed guidance can be developed. Moreover, data on the long-24 term outcomes of infants born following COVID-19 vaccination in pregnancy are needed (as 25 they are for infants born to women who had COVID-19 in pregnancy). It is also important to 26 investigate the safety and efficacy of COVID-19 vaccination in pregnancy in a randomized 1 control trial (RCT) setting. This is currently proposed in a UK multicenter study, PregCOV, as 2 well as in an international RCT by Pfizer and in another trial proposed by Janssen. In the US 3 an observational study of vaccinated pregnant women, sponsored by the National Institutes 4 of Health (NIH), is now underway. 6, 7, 29 5

We conducted this analysis to rapidly evaluate vaccine uptake, factors associated with 7 vaccine acceptance and outcomes in women who received a COVID-19 vaccine compared 8 with a contemporaneous group of pregnant women who were not vaccinated. Vaccine 9 uptake was low at the time, but that may change over time as more data emerge, and 10 women are more reassured with COVID-19 vaccination during pregnancy. We also used a 11 matched cohort of propensity score balanced pregnant women. Propensity score was 12 calculated using variables that were significantly different between vaccinated and 13 unvaccinated women and were likely to affect adverse pregnancy outcomes. Although 14 propensity score matching is no substitute for randomization, it remains one of the best 15 methods for causal inference from observational data. We also provided effect magnitudes 16

with P values, so that the clinical significance of any differences observed could be 17 interpreted, whether statistically significant or not. Finally, a mixed-effects Cox regression 18 was performed in a cohort of expected delivery date matched women to investigate any 19 differences in anticipated delivery date of vaccinated and unvaccinated women. 20

Some limitations apply to our findings. First, the median time to birth after vaccination was 21 only a month. Consequently, insufficient time may have passed between exposure and birth 22

for some outcomes to be affected (e.g. small-for-gestational-age, preterm birth). However, 23 when analyzed on the continuous scale (i.e, for GA at birth and birthweight Z-score), there 24 were no systematic differences. Second, none of the women were vaccinated in the first 25 trimester and only 15% were vaccinated in the second trimester, so our findings apply 26 primarily to women vaccinated in the third trimester. Third, women without vaccination records were not included in this study, which may have led to a selection bias and reduced 1 any potential differences between vaccinated and unvaccinated women. The observed 2 vaccination uptake, however, is similar to vaccination hesitancy rates in the UK according to 3 a recent RCOG survey, 30 so we believe our data are a good approximation of the actual 4 picture. Finally, our sample was powered to detect small-moderate effect sizes down to 5

Cohen's D 0.25, so small and very small differences (< Cohen's D 0.2) may have been 6 undetected, and our 95% CI were wide. However, we also reported effect magnitudes for 7 safety data, and the clinical significance of any Type II error we may have encountered is 8 uncertain. 9

Our findings contribute to mounting evidence that supports the safety of COVID-19 11 vaccination in pregnancy. In our study cohort, less than one third of women who were eligible 12 received the COVID-19 vaccination during pregnancy. This rate is much lower than that for J o u r n a l P r e -p r o o f All values in the comparison number (%), except the birthweight z scores, are presented as median (inter-quartile range (IQR)).

Cases and controls were matched 1:3 using propensity scores calculated from Index of Multiple Deprivation (IMD) quintile, self-reported ethnicity, antenatal medication, pre-gestational diabetes, maternal age and antihypertensive medication.

NE: not estimable, OR: odds ratio, MD: mean difference, CI: confidence interval. All values in the comparison number (%), except the birthweight z scores, are presented as (inter-quartile range (IQR)).Case and controls were matched 1:3 using propensity scores calculated from Index of Multiple Deprivation (IMD) quintile, self-reported ethnicity, antenatal medication, pre-gestational diabetes, maternal age and antihypertensive medication. 

COVID-19 vaccination: a guide to phase 2 of the programme. 2021. 12 14. Coronavirus (COVID-19) vaccines. NHS

Birth weight in live births 14 and stillbirths

SARS-CoV-2 Vaccination During 16 Pregnancy: A Complex Decision. Open Forum Infectious Diseases

COVID-19 vaccine acceptance among pregnant