Impact of in utero exposure to SARS-CoV-2 on children’s hospital admission: National birth cohort study of 262,000 children in England

Impact of in utero exposure to SARS-CoV-2 on children’s hospital admission: National birth cohort study of 262,000 children in England | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Impact of in utero exposure to SARS-CoV-2 on children’s hospital admission: National birth cohort study of 262,000 children in England Mengyun Liu, Fariyo Abdullahi, Charlotte Jackson, Jeannie Collins, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8823144/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 16 You are reading this latest preprint version Abstract Objective To examine the impact of in utero exposure to SARS-CoV-2 virus on children’s emergency and planned hospital admissions up to 40 months of age. Design, Setting, and Participants Nationwide, birth cohort study using multiple linked administrative datasets in England. Children with conception start dates between 1 st February and 31 st July 2020 and born alive to mothers residing in England, followed for 40 months. Exposure In utero SARS-CoV-2 exposure (i.e., maternal infection in pregnancy) during wild-type or Alpha variant dominant periods, characterised via linkage to national testing and hospital data. Main Outcome Measures First emergency or planned admission before 40 months of age. Results Of the 262,086 children included, 14,717 (5.6%) were exposed to SARS-CoV-2 in utero: 6,888 (2.6%) during the wild-type period and 7,829 (3.0%) during the Alpha period. Overall, 89,189 children (34.0%) had at least one emergency admission and 24,635 (9.4%) had at least one planned admission. After adjusting for socio-demographic characteristics and maternal chronic conditions, compared to children unexposed during either period, children exposed in utero during the wild-type period showed no difference in time to the first emergency admission, while Alpha-period exposure was associated with an 8% lower hazard (adjusted HR: 0.92, 99% CI: 0.87 to 0.97). No difference was found in the time to the first planned admission between in utero exposed groups and the unexposed group, nor in the time to either the first emergency or planned admission based on the trimester of in utero exposure. Conclusions In this large national birth cohort in England, we did not find an increased hazard of hospital admission by 40 months of age associated with in utero exposure to SARS-CoV-2, in the absence of maternal vaccination. Further follow-up is needed to assess late-onset outcomes and the effect of later circulating SARS-CoV-2 variants. Continued investment in linked maternal-child health data is essential to monitor both immediate and long-term effect of emerging infections during pregnancy. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Risk factors COVID-19 Respiratory tract infections pregnancy complications health services public health Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction SARS-CoV-2-related disease has been shown to be more severe in pregnant than non-pregnant women 1 . However, much less is known about the outcomes for children who were exposed to SARS-CoV-2 during pregnancy. According to the Developmental Origins of Health and Disease hypothesis, periconceptual and foetal exposures may cause irreversible genetic and epigenetic programming changes, increasing the risk of chronic diseases later in life 2,3 . Maternal respiratory viral infections during pregnancy have been shown to be associated with a higher risk of neurodevelopmental disorders 4,5 and leukaemia in offspring 6–8 , although findings are not always consistent across studies. Vertical transmission is one mechanism by which maternal infection in pregnancy affects foetus and child, but this is rare in the case of SARS-CoV-2 9–12 . However, maternal infections in pregnancy, including SARS-CoV-2, even in the absence of vertical transmission, may also negatively affect foetal and infant outcomes through pathways linked to immune activation and inflammation, including inflammatory cytokines signalling, placental dysfunction, and altered foetal immune programming 13–15 . In a meta-analysis of 117 studies, an estimated 7% (95% confidence interval: 6% to 8%) of pregnant women globally were infected with SARS-CoV-2 between December 2019 and April 2021 1 . Given the global scale of the pandemic and the continued circulation of SARS-CoV-2 virus, the potential long-term consequences for child health warrant rigorous investigation. A systematic review including 204 studies from 36 countries, mostly only including children exposed in utero to SARS-CoV-2 in the third trimester, demonstrated inconsistent findings with respect to adverse birth and neonatal outcomes. However, the review reported a pooled estimate of 1.93 (95% confidence interval [CI]: 1.33 to 2.80) times higher odds of premature delivery and 3.35 (0.84 to 13.36) times higher odds of neonatal intensive care unit (NICU) admission among children exposed to SARS-CoV-2 in utero 16 . The authors attributed the increased NICU admission rate to prematurity, for isolation and observation purposes, or for care of a baby whose mother could not care for the baby herself due to COVID-19 disease 16 . Further studies, mostly with limited sample size, suggest that infants whose mothers had SARS-CoV-2 infection in pregnancy may have an increased risk of respiratory disease in the neonatal period and developmental disorders in infancy, including developmental disorders of speech and language and motor function 16–18 . No association has been shown between SARS-CoV-2 infection during the first trimester of pregnancy and risk of congenital anomalies in children 19 . The vast majority of existing studies have focused on health outcomes in the perinatal and neonatal period 16,17,20–23 . While a few studies from high-income countries have followed children beyond this period, they have typically examined a limited set of prespecified outcomes, mostly neurological disorders 18,19,24–27 . We aimed to examine the impact of in utero exposure to maternal SARS-CoV-2 infection during pregnancy on children’s emergency and planned hospital admissions up to age 40 months in England. We focused on women infected during the wild-type and Alpha waves of the COVID-19 pandemic, before the recommendation that pregnant women receive COVID-19 vaccines 28,29 . Data and Methods Data sources This cohort study used multiple linked public national administrative health datasets, including Hospital Episode Statistics Admitted Patient Care dataset (HES APC, from here on referred to as HES for brevity) for hospital admissions, Second Generation Surveillance System (SGSS, ‘Pillar 1’l; see below for an explanation of the pillars) and Non-hospital Antigen Testing Results (‘Pillar 2’) for SARS-CoV-2 testing, the birth notification, death registration, and mother-baby linkage developed by Feng et al. 30,31 . Figure 1 illustrates the linkage between these datasets and how we derived exposure and outcome variables. A description of data sources and approaches to identify birth cohorts and estimate date of birth is presented in Supplementary Methods (Table A1 and Figure A1). We derived a national birth cohort of all babies born in England from birth notifications32 and a HES mother-baby linked dataset within HES30,31. Births recorded in either source were included. Children were followed up using HES data and death registration data linked to the birth cohort. Cleaning and linking HES episodes into continuous inpatient admissions episodes used an algorithm developed by Hardelid et al 33,34 (Table A2 in Supplementary Methods). Hospital transfers and admissions within one day were treated as one inpatient admission. Maternal SARS-CoV-2 infections were determined via linkage between maternal HES records and Pillar 1 and 2 datasets that contain information on SARS-CoV-2 test results. Pillar 1 was introduced in March 2020, initially prioritising individuals with a medical need and critical key workers. This dataset was expanded in May 2020 following the introduction of universal testing of all hospital-admitted patients, including admissions to maternity services for delivery. This routine asymptomatic testing for hospital-admitted patients came to an end in August 202235,36. The Pillar 1 dataset contains data on positive SARS-CoV-2 tests reported by NHS virology laboratories to the Public Health England (the national infectious disease surveillance agency), predominantly based on polymerase chain reaction (PCR) testing37–39. Pillar 2 community testing was launched in April 2020, initially using PCR testing for symptomatic key workers and general public via local test centres40. Lateral flow testing (rapid antigen tests) was introduced in December 2020 and gradually expanded to include asymptomatic individuals, with universal access implemented in April 2021 continuing until April 202241–43. The Pillar 2 dataset contains data on positive and negative SARS-CoV-2 tests conducted in the community (e.g., home testing, drive-through and mobile test centres) 37–39,44. Note that lateral flow test results conducted at home relied on individuals' self-reporting test results online. Key changes to Pillar 1 and Pillar 2 testing policies were summarised in Figure A2, and the individuals included in each exposure group during the intervals between policy changes are described in Table A3 in Supplementary Tables and Figures. Study population We included all babies in the birth cohort with an estimated conception date between 1st February and 31st July 2020, ensuring most births occurred before the COVID-19 vaccine rollout. The date of conception was defined as 2+0 weeks gestation45, where the start of gestation was calculated using the estimated date of birth and gestational age at birth in weeks. We defined the birth cohort by date of conception rather than date of birth to avoid unbalanced distribution on gestational age and thus reduce fixed cohort bias46. Multiple births, stillbirths, and children whose mothers were residents outside England at delivery were excluded. Rules for identifying stillbirths and multiple births in HES are presented in Table A4 in Supplementary Methods. Outcomes The primary outcome was children’s first emergency admission after discharge from delivery. We had two secondary outcomes: children’s first planned (elective) admission and overall admission rates (including emergency and planned) according to primary diagnosis. Emergency and planned admissions were distinguished using the ‘admimeth’ variable (Table A5 in Supplementary Methods). Birth admissions, between-hospital transfer, and unclassified admissions were excluded from follow-up. Exposure The primary exposure was exposure to SARS-CoV-2 variants in utero, determined by combining the mother’s information from Pillar 1, Pillar 2 and hospital diagnoses in HES during pregnancy. SARS-CoV-2 infections identified through linked testing were supplemented by COVID-19 diagnoses recorded in maternal HES records (International Classification of Diseases 10th version, ICD-10 codes U07.1- U07.2) during pregnancy, with the episode start date considered as the date of infection. De-duplication and cleaning of Pillar 1 and 2 data are described in Supplementary Methods (Table A6 and A7). The first positive test or COVID-19 diagnosis since conception was defined as the start of the first SARS-CoV-2 infection during pregnancy. Two positive tests 90 days or less apart were considered part of the same infection episode47. Children whose mothers were tested for SARS-CoV-2 during pregnancy with unknown results were excluded from the analysis. Children exposed more than once in utero in both the wild-type and the Alpha-period were excluded. In utero positive exposure status was classified according to the dominant circulating variant at the time of the first positive test or the first admission date with an ICD-10 diagnosis of SARS-CoV-2 infection within each infection episode during pregnancy : “positive, wild-type” (from outbreak start to 15th December 2020) or “positive, Alpha” (16th December 2020 to 15th May 202148–50). Children whose mothers had a negative test result in Pillar 2 at any point during pregnancy and no positive test result or diagnosis throughout pregnancy were classified as the “test-negative” group, irrespective of timing of the negative test; and the remaining children whose mothers had no record of either a positive or negative test result, nor a diagnosis in HES during pregnancy were classified as the “no recorded result” group. The four exposure groups are mutually exclusive. All pregnancies included in this study had progressed beyond the first trimester before the Alpha period began, due to the conception date inclusion criterion. Follow up Children were followed from the day after their estimated date of birth until the first occurrence of the outcome event, death, or reaching 40 months of age, whichever occurred first. To estimate admission rates, we included admissions from the day after their estimated date of birth until death or reaching 40 months of age, whichever occurred first. Covariates We used Directed Acyclic Graphs to identify confounders for inclusion in the statistical models (Figure A3 in Supplementary Methods)51. Gestational age (preterm birth: 42 weeks) lies on the causal pathway between in utero exposure to SARS-CoV-2 and child hospital admission, so it was not considered a confounder. However, we present the distribution of gestational ages in each exposure group. To minimise missing data for these covariates, we integrated information from children’s HES admissions records within the first month of life, birth notification, mother’s delivery records, and the mother-baby linkage31 when available. The included confounders, definitions and the source of information are presented in Table 1. Table 1. Definition of confounders and the source of information Confounders Definition Source of information Mother’s ethnicity Ethnicity of the mother: White, Asian, Black, mixed, or other 52 Mothers’ HES delivery records; if missing, replace with children’s ethnicity in children’s HES admissions within 28 days of birth; if missing, replace with children’s ethnicity in birth notification. Area deprivation decile Deciles of the Index of Multiple Deprivation (IMD), measured at the Lower Super Output Area (LSOA) level (an average size of 1500 residents or 650 households 52–54 Area deprivation decile in mother’s HES delivery records; if missing, replace with area deprivation decile in children’s HES admissions within 28 days of birth; if missing, replace with IMD decile in the mother-baby link developed by Feng et al. Maternal chronic condition Presence of chronic condition defined by Charlson Comorbidities Classification based on diagnoses recorded in HES up to three years before conception 55,56 ICD-10 disease codes in mother’s HES admissions up to 3 years before conception. Maternal age Age of the mother at delivery: <25, 25-29, 30-34, 35-39, and ≥40 years The most common value in children’s HES admissions within 28 days of birth; if missing, replace with maternal age from the mother-baby link developed by Feng et al.; if missing, replace with maternal age in the mother’s HES delivery admission. Whether the child was a London resident Government office region, LSOA, or postcode district is Greater London area. The most common value in children’s admissions within 28 days of birth; if missing, replace with mother’s residence area in delivery records. Month and year of conception Month-year of the estimated date of conception Children’s birth admissions in HES and birth notification. Statistical analysis We plotted the number of conceptions, births, in utero exposure to SARS-CoV-2, and emergency and planned admissions against calendar dates. To understand testing policies over time, we also plotted the number of SARS-CoV-2 tests and COVID-19 diagnoses recorded for mothers in each dataset over the study period. We compared the distribution of the key variables of interest and the extent of missing data among children in the birth cohort based on their in utero SARS-CoV-2 exposure status (positive, wild-type; positive, Alpha; test-negative; no recorded result). We plotted the Kaplan-Meier curves for time to first emergency and planned admission. We calculated rates of emergency admissions and planned admissions per 1000 child years, respectively, stratified by exposure status (including all admissions, not just the first; details in Supplementary Methods). We examined the association between in utero SARS-CoV-2 exposure and time to first emergency or planned admission using Cox proportional hazards regression models with robust standard errors, separately for emergency and planned admissions. For each outcome, we first fitted an unadjusted model including the main exposure (exposure to SARS-CoV-2; coded into four groups: positive, wild-type; positive, Alpha; test-negative; no recorded result), followed by an adjusted model incorporating potential confounders listed in Table 1. The proportional hazards assumption was assessed by comparing models with and without an interaction term between exposure status and time (child’s age), using likelihood ratio tests. We also conducted trimester-specific analyses among children with a record of in utero exposure to SARS-CoV-2. Trimester of exposure was determined by the timing of the first positive test result of each episode of infection. We constructed Cox proportional hazard regression models among children exposed in utero to examine the effect of timing of in utero exposure on the time to first emergency or planned admissions. Models initially included the variant period of exposure (wild-type vs. Alpha period) and the trimester of exposure (first trimester: conception to 12 weeks; second trimester [reference]: 13 to 27 weeks; third trimester: 28 weeks to birth), and were subsequently adjusted for confounders listed in Table 1. Children who were unexposed or whose mothers had multiple episodes of infection in different trimester were excluded from the trimester-specific analyses. To calculate admission rates by primary diagnosis, we classified the primary diagnosis of the first episode of each admission into disease groups according to ICD-10 chapters57 (Table A8 in Supplementary Methods). Admission rates were calculated for each disease group, including all emergency and planned admissions per 1000 child years. To account for multiple tests, we used 99% confidence intervals (CI). All counts smaller than five were reported as “<5” to minimise the potential of re-identification58. All regression models included only children with complete data for all covariates. All analyses were done using STATA 18.0 (StataCorp LLC, College Station, Texas). The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist is presented in Supplementary STROBE Checklist)59. Sensitivity analysis To rule out the influence of hospital admissions due to COVID-19, we performed a sensitivity analysis excluding COVID-19-related admissions in children (definitions provided in Supplementary Sensitivity Analysis). To address the potential violation of the proportional hazard assumption, we performed a sensitivity analysis using logistic regression models, assuming equal follow-up time for all children. To account for potential overestimation of person-time caused by excluding neonatal admissions immediately after birth, we performed a sensitivity analysis excluding admissions within the first 7 days of life, with follow-up starting from day 8. To address potential selection bias arising from changes in SARS-CoV-2 testing policies and capacities across variant periods, models were constructed and admissions rates calculated separately for the wildtype and Alpha periods, using children whose mothers tested negative during pregnancy within the corresponding variant period as the comparator group. Patient and public involvement Whilst patients and the public have not been involved with this specific piece of research, the study team met with the Great Ormond Street Hospital Biomedical Research Centre Parents’ and Carers’ Advisory Group in April 2022 to discuss the overall project and discuss the use of linked administrative health data to address research questions relating to the child and maternal health impacts of SARS-CoV-2 infection. Ethical approval and consent to participate This study used pseudonymised NHS data which was provided within the terms of a data sharing agreement (DARS-NIC-393510-D6H1D-v9.3) by NHS England, collected for the purposes of providing patient care. Pseudonymised HES data were obtained as part of the standard NHS Digital data access request process. NHS Research Authority suggests that ethical approval was not required as the study involved secondary analysis of pseudonymised data only60. Consent for research was waived as data were pseudonymised. Results This study included 262,086 children born between June 2020 and May 2021 to 261,797 mothers (Figure B1). Table 2 summarises children’s characteristics by exposure status. A higher proportion of children exposed in utero were from ethnic minority groups, compared to children in the no recorded result and test-negative groups. Children exposed in utero were more likely to be born in deprived areas than children in the no-recorded-result and test-negative groups (percentage of children from the 10% most deprived areas: 19.7% in the wild-type group and 16.8% in the Alpha group vs. 13.8% in the no-recorded-result group and 11.4% in the test-negative group). The test-negative group had a higher proportion of children whose mothers had chronic conditions (4.8%) and tended to be conceived later than the other three groups. The number of positive tests increased markedly at the onset of the Alpha wave in January 2021, coinciding with the expansion of community testing and wider use of Pillar 2 testing (Figure B2 in Supplementary Tables and Figures). A total of 43,225 (16.5%) children were in the test-negative exposure group, while 5.6% were exposed to SARS-CoV-2 in utero at least once, with 6,888 (2.6%) exposed in the wild-type period and 7,829 (3.0%) in the Alpha period. Among exposed children, the positive maternal test was reported in the second trimester for 29.5% (n=4,343), in the third for 67.4% (n=9,925), with only 4.1% of children exposed in the first trimester (Figure 2). Ten mothers tested positive in both the first and second trimesters, <5 in the first and the third trimesters, and 140 in the second and third trimesters. Table 2. Distribution of the characteristics by in-utero exposure status to SARS-CoV-2 during pregnancy Characteristics Number of children (column percentage) Total (column percentage) Test-negative Positive, wild-type Positive, Alpha No recorded result Number of children 43,225 6,888 7,829 204,144 262,086 Number of children with emergency admission 16,023 (37.1) 2,646 (38.4) 2,634 (33.6) 67,886 (33.3) 89,189 (34.0) Number of children with planned admission 4,164 (9.6) 716 (10.4) 745 (9.5) 19,010 (9.3) 24,635 (9.4) Area of residence London 6,294 (14.6) 983 (14.3) 2,266 (28.9) 38,979 (19.1) 48,522 (18.5) Non-London 36,931 (85.4) 5,905 (85.7) 5,563 (71.1) 165,165 (80.9) 213,564 (81.5) Ethnicity of mother White 35,647 (82.5) 4,572 (66.4) 5,151 (65.8) 151,853 (74.4) 197,223 (75.3) Asian 4,269 (9.9) 1,533 (22.3) 1,514 (19.3) 27,189 (13.3) 34,505 (13.2) Black 1,125 (2.6) 278 (4.0) 530 (6.8) 10,552 (5.2) 12,485 (4.8) Mixed 1,011 (2.3) 175 (2.5) 210 (2.7) 5,443 (2.7) 6,839 (2.6) Others 1,172 (2.7) 330 (4.8) 424 (5.4) 9,100 (4.5) 11,026 (4.2) Missing <5 (<0.05) 0 (0) 0 (0) 7 (<0.05) 8 (<0.01) Area deprivation decile Most deprived10% 4,923 (11.4) 1,359 (19.7) 1,315 (16.8) 28,177 (13.8) 35,774 (13.7) 10% to 20% 4,788 (11.1) 975 (14.2) 1,213 (15.5) 25,775 (12.6) 32,751 (12.5) 20% to 30% 4,650 (10.8) 820 (11.9) 1,003 (12.8) 23,700 (11.6) 30,173 (11.5) 30% to 40% 4,466 (10.3) 732 (10.6) 886 (11.3) 21,489 (10.5) 27,573 (10.5) More deprived 40% to 50% 4,273 (9.9) 614 (8.9) 720 (9.2) 19,742 (9.7) 25,349 (9.7) Less deprived 40%-50% 4,264 (9.9) 572 (8.3) 659 (8.4) 18,254 (8.9) 23,749 (9.1) 30%-40% 4,068 (9.4) 512 (7.4) 547 (7.0) 17,269 (8.5) 22,396 (8.6) 20% to 30% 4,002 (9.3) 486 (7.1) 560 (7.2) 16,935 (8.3) 21,983 (8.4) 10% to 20% 4,026 (9.3) 442 (6.4) 486 (6.2) 16,977 (8.3) 21,931 (8.4) Least deprived10% 3,758 (8.7) 375 (5.4) 437 (5.6) 15,800 (7.7) 20,370 (7.8) Missing 7 (0.02) <5 (<0.05) <5 (<0.05) 26 (0.01) 37 (0.01) Mother’s chronic condition Yes 2,063 (4.8) 264 (3.8) 267 (3.4) 7,175 (3.5) 9,769 (3.7) No 41,162 (95.2) 6,624 (96.2) 7,562 (96.6) 196,969 (96.5) 252,317 (96.3) Year-Month of conception Feb 2020 3,307 (7.7) 1,011 (14.7) 0 (0) 39,098 (19.2) 43,416 (16.6) Mar 2020 4,564 (10.6) 1,403 (20.4) 98 (1.3) 37,195 (18.2) 43,260 (16.5) Apr 2020 5,844 (13.5) 1,163 (16.9) 1,163 (14.8) 32,654 (16.0) 40,824 (15.6) May 2020 8,135 (18.8) 1,117 (16.2) 2,099 (26.8) 32,549 (15.9) 43,900 (16.8) Jun 2020 10,150 (23.5) 1,147 (16.7) 2,164 (27.6) 32,006 (15.7) 45,467 (17.4) Jul 2020 11,225 (26.0) 1,047 (15.2) 2,305 (29.4) 30,642 (15.0) 45,219 (17.3) Maternal age <25 5,775 (13.4) 1,090 (15.8) 1,382 (17.7) 30,868 (15.1) 39,115 (14.9) 25-29 11,445 (26.5) 2,039 (29.6) 2,130 (27.2) 53,271 (26.1) 68,885 (26.3) 30-34 15,380 (35.6) 2,208 (32.1) 2,529 (32.3) 68,275 (33.4) 88,392 (33.7) 35-39 8,079 (18.7) 1,142 (16.6) 1,318 (16.8) 38,741 (19.0) 49,280 (18.8) >=40 1,772 (4.1) 298 (4.3) 328 (4.2) 9,204 (4.5) 11,602 (4.4) N missing values 774 (1.8) 111 (1.6) 141 (1.8) 3,785 (1.9) 4,812 (1.8) Gestational age (weeks) Preterm birth (42) 28 (0.1) 7 (0.1) 9 (0.1) 139 (0.1) 183 (0.1) In total, 89,189 children (34.0%) had at least one emergency admission before age 40 months: 55,663 (21.2%) had a single emergency admission, while 33,526 (12.8%) had two or more. A total of 24,635 children (9.4%) had at least one planned admission, with 16,881 (6.4%) having one planned admission and 7,754 (3.0%) having two or more (Table 2 and Figure 4). About two-thirds (n=162,293; 61.9%) of children had no admissions, while 14,031 (5.4%) children had both emergency and planned admissions. More than half (n=14,031; 57.0%) of children with a planned admission also had an emergency admission. Kaplan-Meier curves for emergency and planned admissions are shown in Figures B3 and B4 in the Supplementary Tables and Figures. Children with in utero exposure during the Alpha period and those without a maternal test result had lower emergency admission rates (169.6 per 1000 child-years [99% CI: 163.2 to 176.3] and 170.7 [169.4 to 172.0], respectively) than those exposed during the wild-type period and those unexposed during either period (209.1 [201.4 to 217.0] and 200.4 [197.4 to 203.5] respectively). Planned admission rates were lower among children exposed in utero during the Alpha period (45.4 [42.1 to 48.9]), while rates were similar across the other three groups (Table 3). Table 3. Hospital admission rates by in utero SARS-CoV-2 exposure status (all admissions other than birth admissions were included) In-utero exposure status Number of children Number of child-year (*1000) Number of admissions Rate per 1000 child-years (99% CI) Emergency admissions Test-negative 43,225 143.8 28,825 200.4 (197.4, 203.5) Positive, Wild-type 6,888 22.9 4,786 209.1 (201.4, 217.0) Positive, Alpha 7,829 26.1 4,418 169.6(163.2, 176.3) No-recorded-result 204,144 678.4 115,783 170.7 (169.4, 172.0) Total 262,086 871.2 153,812 176.6 (175.4, 177.7) Planned admission Test-negative 43,225 143.9 7,346 51.1 (49.5, 52.6) Positive: Wild-type 6,888 22.9 1,258 54.9 (51.1, 59.1) Positive: Alpha 7,829 26.1 1,183 45.4 (42.1, 48.9) No-recorded-result 204,144 678.6 33,979 50.1 (49.4, 50.8) Total 262,086 871.5 43,766 50.2 (49.6, 50.8) A total of 257,241 children (98.2%) with complete data for all covariates were included in the Cox proportional hazard regression models. There was no evidence for a difference in the time to the first emergency admission between children exposed in utero during the wild-type period and children unexposed in either period (i.e., test-negative group) (Figure 3 and Table B2 in Supplementary Tables and Figures). However, children exposed during the Alpha variant period and those in the no-recorded-result group had 8% (adjusted HR=0.92, 99% CI: 0.87 to 0.97) and 12% (aHR=0.88, 0.86 to 0.90) lower hazard of first emergency admission than the test-negative group, respectively. Children in the no-recorded-result group had a 5% lower hazard of first planned admission compared with the test-negative group, while no significant difference was observed between the two positive groups and the test-negative group, regardless of adjustment (Figure 3 and Table B1). The proportional hazard assumption was met for the model examining emergency admissions but was violated for the planned admissions model in the no-recorded-result group (Table B2). Only 603 children were exposed during the first trimester, all during the wild-type period. Similar numbers of exposed children were observed during the wild-type period in the second (n=3,035) and third trimesters (n=3,333) (Table B3). A total of 14,306 children with confirmed in utero exposure and complete data for all covariates were included in the trimester-specific regression analyses, after excluding 154 children where exposure spanned two trimesters. Among in utero exposed children, no evidence was found for a difference in time to first emergency or planned admissions by trimester of exposure, while children in utero exposed during the Alpha period showed a 16% lower hazard of the first emergency admission, compared with those exposed during the wild-type period (aHR=0.84, 0.75 to 0.93) (Figure 4). Children with in utero exposure during the wild-type period had the highest admission rate (264.1 per 1000 child-years, 99% CI: 255.5 to 272.9), followed by those whose mothers tested negative during pregnancy (251.5, 248.2 to 255.0). Lower admission rates were observed among children exposed in utero during the Alpha period (215.0, 207.7 to 222.5) and those with no recorded maternal test during pregnancy (220.8, 219.3 to 222.2) (Table 4). Across all disease groups, the highest admission rates were for diseases of the respiratory system (52.9 per 1,000 child-years, 99% CI: 52.3 to 53.6), while the lowest were for mental and behavioural disorders (0.4, 0.4 to 0.5) and diseases of the circulatory system (0.5, 0.5 to 0.6 for heart diseases and 0.4, 0.4 to 0.5 for circulatory diseases). Children exposed in utero during the wild-type period had higher admissions rates for malignant neoplasms (based on 195 disease cases), diseases of the blood and blood-forming organs and certain immune disorders, and injury, poisoning, and certain other consequences of external causes, but lower admission rates for benign neoplasms; while children exposed in utero during the Alpha period had lower admission rates for diseases of the respiratory system. Table 4. Admission rates per 1000 child-years (99% CI) by primary diagnosis, including all emergency and planned admissions up to 40 months old Disease group Number of disease cases Number of admissions Test-negative Positive: Wild-type Positive: Alpha No-recorded-result Total Certain infectious and parasitic diseases Bacterial infectious diseases 7,692 8,880 11.6 (10.9,12.4) 14.0 (12.1,16.2) 9.9 (8.4,11.6) 9.8 (9.5,10.1) 10.2 (9.9,10.5) Non-bacterial infectious diseases 13,955 19,337 24.0 (23.0,25.1) 27.7 (25.0,30.7) 20.6 (18.4,23.0) 21.7 (21.2,22.1) 22.2 (21.8,22.6) Neoplasms Malignant neoplasms 193 4,420 5.3 (4.8,5.8) 11.0 (9.3,12.9) - # 5.0 (4.8,5.2) 5.1 (4.9,5.3) Benign neoplasms 906 1,501 2.5 (2.2,2.8) 1.1 (0.7,1.8) 1.9 (1.3,2.8) 1.6 (1.5,1.7) 1.7 (1.6,1.8) Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism 806 2,502 1.9 (1.6,2.2) 4.4 (3.4,5.7) 2.8 (2.0,3.7) 3.0 (2.9,3.2) 2.9 (2.7,3.0) Endocrine, nutritional and metabolic diseases 1,228 2,373 3.0 (2.7,3.4) 2.2 (1.5,3.1) 2.6 (1.9,3.6) 2.7 (2.5,2.8) 2.7 (2.6,2.9) Mental and behavioural disorders 330 360 0.4 (0.3,0.6) 0.2 (0.0,0.6) 0.3 (0.1,0.7) 0.4 (0.4,0.5) 0.4 (0.4,0.5) Diseases of the nervous system 1,902 3,435 4.1 (3.7,4.6) 5.0 (4.0,6.4) 3.8 (3.0,5.0) 3.9 (3.7,4.1) 3.9 (3.8,4.1) Diseases of the eye and adnexa 1,596 1,907 2.4 (2.1,2.7) 2.6 (1.9,3.7) 1.9 (1.3,2.8) 2.1 (2.0,2.3) 2.2 (2.1,2.3) Diseases of the ear and mastoid process 2,258 2,626 3.6 (3.2,4.0) 3.9 (3.0,5.2) 2.6 (1.9,3.6) 2.9 (2.7,3.0) 3.0 (2.9,3.2) Diseases of the circulatory system Heart diseases 268 461 0.5 (0.4,0.7) 0.4 (0.2,0.9) 0.3 (0.1,0.8) 0.5 (0.5,0.6) 0.5 (0.5,0.6) Circulatory diseases 290 358 0.5 (0.4,0.7) 0.4 (0.2,0.9) 0.6 (0.3,1.1) 0.4 (0.3,0.4) 0.4 (0.4,0.5) Diseases of the respiratory system 31,816 45,898 64.0 (62.3,65.7) 59.7 (55.7,64.0) 55.4 (51.7,59.2) 50.0 (49.3,50.7) 52.7 (52.1, 53.3) Diseases of the digestive system 7,534 9,762 12.4 (11.7,13.2) 12.8 (11.1,14.9) 10.8 (9.3,12.6) 10.9 (10.6,11.2) 11.2 (10.9,11.5) Diseases of the skin and subcutaneous tissue 3,330 3,954 4.7 (4.2,5.1) 5.7 (4.6,7.2) 4.5 (3.5,5.7) 4.5 (4.3,4.7) 4.5 (4.4,4.7) Diseases of the musculoskeletal system and connective tissue 805 1,040 1.1 (0.9,1.3) 1.3 (0.8,2.1) 1.5 (1.0,2.3) 1.2 (1.1,1.3) 1.2 (1.1,1.3) Diseases of the genitourinary system 3,482 5,436 6.1 (5.6,6.7) 6.0 (4.8,7.5) 5.6 (4.6,7.0) 6.3 (6.0,6.5) 6.2 (6.0,6.5) Certain conditions originating in the perinatal period 19,576 22,541 27.2 (26.1,28.3) 28.2 (25.5,31.2) 24.5 (22.1,27.1) 25.4 (24.9,25.9) 25.8 (25.3,26.2) Congenital malformation, deformations and chromosomal abnormalities 7,247 11,366 13.8 (13.0,14.6) 12.8 (11.1,14.9) 12.1 (10.4,13.9) 12.9 (12.6,13.3) 13.0 (12.7,13.4) Injury, poisoning, and certain other consequences of external causes 8,608 9,990 11.5 (10.8,12.3) 14.3 (12.4,16.5) 10.2 (8.7,12.0) (11.1,11.8) 11.5(11.2,11.8) Total 95,715 197,735 251.5 (248.2,255.0) 264.1 (255.5,272.9) 215.0 (207.7,222.5) 220.8 (219.3,222.2) 226.8 (225.5,228.1) # There was no malignant neoplasm case up to 40 months old among children in utero exposed to SARS-CoV-2 during the Alpha period. Sensitivity analysis After excluding 1,648 emergency admissions (1.1% of all first emergency admissions) and 101 planned admissions (0.2% of all first planned admissions) that were COVID-19 related, the sensitivity analysis restricted to non-COVID-19-related admissions showed results consistent with the main analysis (Figure C1 and C2 in Supplementary Sensitivity Analysis). Sensitivity analysis excluding admissions and deaths within the first 7 days of life, with follow-up beginning on day 8, also produced similar findings (Figure C3). Findings from logistic regression models were consistent with those from the Cox proportional hazard models used in the main analysis (Figure C4). When restricting the comparator group to children whose mothers tested negative during the same variant period as those who tested positive, all hazard ratios were slightly attenuated, and children exposed in utero during the Alpha period no longer showed a lower hazard of emergency admissions than the unexposed children (Figure C5 and Table C1). The overall conclusion remained unchanged. Discussion Key findings Based on our England cohort of a quarter of a million children with a pregnancy start date in the first six months of the COVID-19 pandemic, 5% of children had a record of exposure to in utero SARS-CoV-2. We found no evidence of increased risk of either first emergency or planned admission up to 40 months of age associated with in utero exposure to SARS-CoV-2 during the wild-type and Alpha periods. Compared with unexposed children, children exposed in utero during the Alpha period had a slightly lower overall emergency admission rate, while no difference was observed for those exposed during the wildtype period. Within the exposed groups, no differences were found in the hazard of first emergency or planned admissions according to trimester of maternal SARS-CoV-2 infection. Diagnosis-specific admission rates showed modest differences, with some elevated rates of malignant neoplasms and injury-related admissions among children in utero exposed during the wild-type period, and blood and immune disorders among children in utero exposed during either period. Strengths and limitations A key strength of this study is the use of multiple, national linked administrative health datasets, thereby ensuring representativeness and minimising loss to follow-up. The follow-up period of 40 months is longer than similar studies published to date. Our examination of both emergency and planned admissions capture any potential severe health outcomes requiring hospital admission. By defining the cohort based on the timing of conception rather than birth, we minimised fixed cohort bias 46,61 . We combined mother-baby linkage derived from HES 31 with those recorded in birth notification data 62 to maximise cohort coverage, and integrated information from various databases to minimise missing data. Analyses adjusted for key maternal and sociodemographic confounders, and multiple sensitivity analyses supported the robustness of the findings. Our study has some limitations. First, although we used two COVID-19 surveillance datasets and hospital admission data to ascertain maternal infection status, we were unable to capture asymptomatic infections that were not tested or test-positive cases from the community that were not reported; those infections were included in the “no reported result” group. Underreporting may have been a particular issue during the wild-type period, when testing capacity was limited (February to April 2020) and community testing was not widespread (before 2020) 63–65 . In particular, since we found that children whose mothers had a negative test reported were less likely to live in deprived areas, but more likely to have chronic conditions recorded, some differential misclassification of infection status reflecting different testing and healthcare seeking behaviours among pregnant women is likely. Second, in utero exposure was classified by the dominant circulating variant at the time of testing or diagnosis, as laboratory confirmation of variants was not available. However, given the high transmissibility and rapid dominance of the Alpha variant in the UK, the risk of variant misclassification is likely to be minimal 66–68 . Our findings are limited to the wildtype and Alpha period and may not be generalisable to later variants or to pregnancies in vaccinated women, as we focused on pregnancies prior to vaccine rollout to avoid any impact of vaccination on child health outcomes 69,70 . Further studies, including linked vaccination data, are required to confirm whether out findings are applicable to Delta and Omicron SARS-CoV-2 variants. Third, our outcome measures were limited to hospital admissions. We were unable to access primary or outpatient care use or developmental or health outcomes not requiring hospital admissions. Lastly, as the cohort was followed from birth rather than conception, findings are conditional on live births and do not account for the competing risks of stillbirth and pregnancy loss, the risk of which may increase by SARS-CoV-2 infection during pregnancy. For example, a population-based study of 0.8 million pregnancies in England and Wales showing an association between maternal COVID-19 diagnosis and stillbirth within 14 days of infection 71 . Further studies could integrate abortion and stillbirth data to fully describe the effect of SARS-CoV-2 infection during pregnancy. Comparison with other studies Several studies have investigated health outcomes in neonates and infancy following in-utero exposure to SARS-CoV-2, but few have examined long-term, all-cause outcomes separately for emergency and planned hospital admissions using population-wide data. A small cohort study of 339 children (96 exposed and 243 unexposed) born in England and Wales between March 2020 and February 2021 - spanning the wild-type and Alpha variant periods - found higher admission rates by 21 months of age among those with perinatal exposure to SARS-CoV-2 (38% of exposed vs. 21% of unexposed children had at least one admission) 72 . However, it remains unclear whether these differences were driven by in utero exposure, neonatal infection, or both. Though findings were not consistent across all studies, the majority of studies worldwide reported a higher risk of neonatal intensive care unit admission in babies exposed to SARS-CoV-2 in utero compared to unexposed babies, primarily due to conditions such as respiratory distress and hyperbilirubinemia 1,16,17,73–75 . This increased risk is thought to be largely driven by preterm delivery, often resulting from clinical decisions related to maternal health complications or medically induced preterm birth, rather than a direct viral effect on the foetus 76–79 . Our study, with a longer follow-up of 40 months, found no evidence of an increased overall hazard of hospital admission, particularly for diseases of the respiratory system, among children born to mothers who tested positive for SARS-CoV-2 during pregnancy compared with those born to test-negative mothers. Note that any admission within one day of the birth admission was also excluded, as part of our linkage of HES episodes into admissions, which may account for part of the discrepancy with earlier studies. Differences in findings may also reflect variation in follow-up duration and control group selection. Some previous studies 17,80 compared test-positive pregnancies with a broader reference group that included both test-negative women and those without any recorded test results during pregnancy – a heterogeneous group likely comprising true negatives, under-ascertained positives, and pregnant women with diverse health status, exposure risks, and testing and care-seeking behaviours. In contrast, we restricted our control group to test-negative pregnancies who actively engaged with testing, thereby reducing potential selection bias related to differential healthcare access and care-seeking behaviour. Clear socio-demographic differences between the no-recorded-result and test-negative groups in our data indicate that it is not appropriate to assume the former were necessarily uninfected. Results related to the no-recorded-result group in this study should therefore be interpreted with caution. Existing research on the impact of in utero exposure to SARS-CoV-2 has primarily focused on developmental delays in gross and fine motor, problem-solving, communication, and social skills, assessed with various scales 18,19,24,25,27,81–86 . However, these studies mostly had relatively short follow-up periods and reported mixed findings. A systematic review of 17 studies published up to June 2023 reported mild delays in gross and fine motor skills up to six months of age and in social and language domains between six and 12 months 81 . In contrast, three subsequent studies - including two prospective cohorts from Canada and the US with a 24-month follow-up period 24,26 and a Scottish population-based retrospective cohort with a follow-up period of 13 to 15 months 25 – found no association between in utero exposure to SARS-CoV-2 and developmental concerns. Unlike these studies, our analysis was limited to hospital admissions and therefore only captured severe cases of neurological disorders requiring hospital admission, making direct comparisons difficult. This study observed a lower hazard of emergency hospital admission among children with in utero exposure during the Alpha period compared to those with no exposure. One reason for observing this difference during the Alpha, but not wild-type, period may be that our comparator group (test-negative) likely included symptomatic women tested in the community, particularly during the wild-type period when testing was limited to symptomatic individuals. This may represent a less healthy comparator group than that included during the Alpha period when broader community testing was in place. Further, during the wild-type period, limited testing likely captured more severe infections or high-risk pregnancies, while broader testing during the Alpha period identified a more heterogeneous group of possibly healthier exposed pregnancies. In the sensitivity analysis using children whose mothers tested negative during the same variant period as those who tested positive as the comparator group, the lower hazard of emergency admissions among children in utero exposed during the Alpha period no longer exists. Whether neonatal outcomes differ by variant following in utero exposure remains inconsistent and evidence comparing different variants is limited 50,62,87–90 . For example, research from Italy and Scotland showed a higher risk of premature births 91,92 , small-for-gestational age 92 , and low Apgar score 91 and evidence from France, Switzerland 62 , and Malawi 93 showed higher stillbirth rates associated with the Delta variant, while a US study showed no difference in Apgar scores, NICU admissions or need for respiratory support between the pre-Delta and Delta variants, although with longer hospital stay in neonates born during the Delta period 88 . Our study, focusing on longer-term outcomes after birth, found broadly similar crude admission rates between exposed and unexposed children across most disease groups. However, children exposed in utero during the wild-type period had higher crude admission rates for malignant neoplasms and diseases of the blood and blood-forming organs, and certain disorders involving the immune mechanism. We did not observe this finding for children exposed to SARS-CoV-2 in utero during the Alpha wave. We consider it unlikely to be due to SARS-CoV-2 exposure during pregnancy, but instead may reflect changes in healthcare delivery for children with cancer earlier in the pandemic, or potentially in exposure to infections in early life (which has been associated with leukaemia risk 94–97 ) due to the changes in seasonality of common infections seen during and after the COVID pandemic. These impacts may well be differential by exposure group, due to the complex changes in SARS-CoV-2 circulation, testing availability, and healthcare availability over time. The concurrent increase in admission rates for injury, poisoning, and certain other consequences of external causes, along with the absence of malignant neoplasm cases among children exposed in utero during the Alpha period, raises the possibility of unadjusted confounding between exposure groups. Further studies, including linkage to cancer registration data to obtain the date of cancer diagnosis, rather than the date of hospital admission with cancer diagnosis recorded, are required. Our study shows no difference in the hazards of first admission in early childhood by trimester of in-utero exposure, after adjusting for the variants exposed and other maternal and sociodemographic confounders. However, interpretation of the potential impact of the first-trimester exposure should be cautious, as the number of cases exposed in early pregnancy was small and confined to the wild-type period. Pregnancies affected in the first trimester may be more likely to result in early pregnancy loss, which is not captured in our live-birth cohort and may lead to underestimation of adverse outcomes associated with early pregnancy exposure. Despite these limitations, our findings align with most previous studies that reported no consistent evidence of trimester-specific effects on a range of perinatal and early childhood outcomes 26,72,98 . Clinical and policy implications Overall, findings from this study suggest no evidence for increased risk of emergency or planned hospital admission in children with in utero SARS-CoV-2 exposure during the wild-type and Alpha period up to 40 months of age, providing reassurance to families affected by maternal COVID-19 infection in the early pandemic period. These findings support ongoing public health messaging that maternal SARS-CoV-2 infection, at least in its earlier variants, does not indicate an increased risk of children exposed in utero requiring hospital admission. Further studies with longer follow-up are needed to assess the health consequences of in utero SARS-CoV-2 exposure with onset in later childhood or adulthood, ideally accounting for survivorship bias. Conclusion In conclusion, our study, the largest population-based cohort with the longest follow-up period, found no evidence for an increase in children’s emergency or planned admission rates up to 40 months of age, following in utero SARS-CoV-2 exposure during the wild-type and Alpha periods. No differences in either emergency or planned admissions rates were observed across trimesters of exposure. Further studies should examine disease-specific outcomes and in utero exposure to SARS-CoV-2 during later variant periods. Declarations Acknowledgement We acknowledge funding from the European Union’s Horizon Grant and support from the SARS-CoV-2 variants Evaluation in Pregnancy and Paediatrics cohorts (VERDI) project. This work used data provided by the public and patients and collected by the NHS as part of their care and support. NHS Hospital Episode Statistics data was provided within the terms of a data-sharing agreement (DARS-NIC-393510-D6H1D-v9.3) to the researchers by NHS England. We acknowledge the help and support of Dr. Linda Wijlaars and Dr. Professor Darren Hargrave. Author contributions PH, CT and ML contributed to the development and conduct of the study. ML and FA contributed to the data cleaning and analyses. ML wrote the first draft of the manuscript with contributions from PH and CT. All authors edited drafts of the manuscript and approved the final version of the article. The corresponding author attested that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Pia Hardelid is the guarantor. Funding This work is part of the VERDI project (101045989) which is funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. The funder played no role in study design, data collection, analysis, interpretation of the result, writing of the paper, or decision to submit the paper for publication. Competing interests All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare they have no competing interests. Transparency statement The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Dissemination to participants and related patient and public communities Dissemination to participants is not possible as this study analysed pseudonymised data only. Dissemination to women, families, and healthcare practitioners will be undertaken via social media and the programme website (https://verdiproject.org/) and through summary articles for professional and third-sector organisations. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. Data availability The data is provided by patients and collected by the NHS as part of their care and support. Details about Hospital Episode Statistics can be found here: https://digital.nhs.uk/services/data-access-request-service-dars/dars-products-and-services/data-set-catalogue/hospital-episode-statistics. Details about data from COVID-19 Second Generation Surveillance System (Pillar 1) can be found here: https://digital.nhs.uk/services/data-access-request-service-dars/dars-products-and-services/data-set-catalogue/covid-19-second-generation-surveillance-system-sgss, and details about Non-hospital Antigen Testing Results (Pillar 2) can be found here: https://digital.nhs.uk/services/data-access-request-service-dars/dars-products-and-services/data-set-catalogue/covid-19-uk-non-hospital-antigen-testing-results-pillar-2. The data that support the findings of this study are available from NHS England but restrictions apply to the availability of these data, which were used under licence for the current study (DARS-NIC-393510-D6H1D-v9.3), and so are not publicly available. The data governance arrangements for the study do not allow us to redistribute HES data to other parties. 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Mass asymptomatic Covid-19 testing: Strategy and accuracy. https://commonslibrary.parliament.uk/research-briefings/cbp-9223/ (2025). Hull University Teaching Hospital. Maternity guidance during coronavirus (COVID-19): changes to our services. Hull University Teaching Hospitals NHS Trust https://www.hey.nhs.uk/patient-leaflet/maternity-guidance-during-coronavirus-covid-19-changes-to-our-services/ (2021). Volz, E. et al. Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England. Nature 593 , 266–269 (2021). Davies, N. G. et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science 372 , eabg3055 (2021). Our World in Data. SARS-CoV-2 variants in analyzed sequences. Our World in Data https://ourworldindata.org/grapher/covid-variants-area?country=~GBR. Kirsebom, F. C. M. et al. Vaccine effectiveness against mild and severe covid-19 in pregnant individuals and their infants in England: test negative case-control study. BMJ Med 3 , e000696 (2024). Fernández-García, S. et al. Effectiveness and safety of COVID-19 vaccines on maternal and perinatal outcomes: a systematic review and meta-analysis. BMJ Glob Health 9 , (2024). Raffetti, E. et al. COVID-19 diagnosis, vaccination during pregnancy, and adverse pregnancy outcomes of 865,654 women in England and Wales: a population-based cohort study. The Lancet Regional Health - Europe 45 , 101037 (2024). Jackson, R. et al. Association of antenatal or neonatal SARS-COV-2 exposure with developmental and respiratory outcomes, and healthcare usage in early childhood: a national prospective cohort study. eClinicalMedicine 72 , (2024). Vousden, N. et al. The incidence, characteristics and outcomes of pregnant women hospitalized with symptomatic and asymptomatic SARS-CoV-2 infection in the UK from March to September 2020: A national cohort study using the UK Obstetric Surveillance System (UKOSS). PLoS ONE 16 , e0251123 (2021). Smith, E. R. et al. Adverse maternal, fetal, and newborn outcomes among pregnant women with SARS-CoV-2 infection: an individual participant data meta-analysis. BMJ Glob Health 8 , (2023). Hudak, M. L. et al. Maternal and Newborn Hospital Outcomes of Perinatal SARS-CoV-2 Infection: A National Registry. Pediatrics 151 , e2022059595 (2023). Smith, L. H., Dollinger, C. Y., VanderWeele, T. J., Wyszynski, D. F. & Hernández-Díaz, S. Timing and severity of COVID-19 during pregnancy and risk of preterm birth in the International Registry of Coronavirus Exposure in Pregnancy. BMC Pregnancy and Childbirth 22 , 775 (2022). Fallach, N. et al. Pregnancy outcomes after SARS-CoV-2 infection by trimester: A large, population-based cohort study. PLOS ONE 17 , e0270893 (2022). Oğuz Arslan, B. G. Comparison of perinatal and neonatal outcomes of symptomatic pregnancy infected with SARS-CoV-2. https://www.jtgga.org/articles/comparison-of-perinatal-and-neonatal-outcomes-of-symptomatic-pregnancy-infected-with-sars-cov-2/doi/jtgga.galenos.2024.2023-6-4 (2024) doi:10.4274/jtgga.galenos.2024.2023-6-4. Gurol-Urganci, I. et al. Maternal and perinatal outcomes of pregnant women with SARS-CoV-2 infection at the time of birth in England: national cohort study. Am J Obstet Gynecol 225 , 522.e1-522.e11 (2021). Lindsay, L. et al. Neonatal and maternal outcomes following SARS-CoV-2 infection and COVID-19 vaccination: a population-based matched cohort study. Nat Commun 14 , 5275 (2023). Veloso, A. H. N., Barbosa, A. de M., Ribeiro, M. F. M. & Gervásio, F. M. Neurodevelopment in the first year of children exposed to SARS-CoV-2 during intrauterine period: systematic review. Rev. Gaúcha Enferm. 45 , e20240020 (2024). Hessami, K. et al. COVID-19 Pandemic and Infant Neurodevelopmental Impairment: A Systematic Review and Meta-analysis. JAMA Network Open 5 , e2238941 (2022). Leyser, M., Marques, F. J. P. & Nascimento, O. J. M. do. Potential risk of brain damage and poor developmental outcomes in children prenatally exposed to sars-cov-2: a systematic review. Rev Paul Pediatr 40 , e2020415 (2021). Jackson, R. et al. Antenatal and neonatal exposure to SARS-CoV-2 and children’s development: a systematic review and meta-analysis. Pediatr Res 96 , 40–50 (2024). Fajardo-Martinez, V. et al. Neurodevelopmental delay in children exposed to maternal SARS-CoV-2 in-utero. Sci Rep 14 , 11851 (2024). Santos, C. A. D. et al. Developmental impairment in children exposed during pregnancy to maternal SARS-COV2: A Brazilian cohort study. International Journal of Infectious Diseases 139 , 146–152 (2024). Mosnino, E. et al. Impact of SARS-CoV-2 Alpha and Gamma Variants among Symptomatic Pregnant Women: A Two-Center Retrospective Cohort Study between France and Brazil. Journal of Clinical Medicine 11 , 2663 (2022). Morris, C., Doshi, H. & Liu, W. F. Impact of COVID-19 in pregnancy on maternal and perinatal outcomes during the Delta variant period: a comparison of the Delta and pre-delta time periods, 2020–2021. matern health, neonatol and perinatol 10 , 20 (2024). Deng, J. et al. Association of Infection with Different SARS-CoV-2 Variants during Pregnancy with Maternal and Perinatal Outcomes: A Systematic Review and Meta-Analysis. IJERPH 19 , 15932 (2022). Vousden, N. et al. Severity of maternal infection and perinatal outcomes during periods of SARS-CoV-2 wildtype, alpha, and delta variant dominance in the UK: prospective cohort study. bmjmed 1 , (2022). Stock, S. J. et al. Pregnancy outcomes after SARS-CoV-2 infection in periods dominated by delta and omicron variants in Scotland: a population-based cohort study. Lancet Respir Med 10 , 1129–1136 (2022). Incognito, G. G. et al. Comparison of Maternal and Neonatal Outcomes between SARS-CoV-2 Variants: A Retrospective, Monocentric Study. J Clin Med 12 , 6329 (2023). Mndala, L. et al. Comparison of maternal and neonatal outcomes of COVID-19 before and after SARS-CoV-2 omicron emergence in maternity facilities in Malawi (MATSurvey): data from a national maternal surveillance platform. The Lancet Global Health 10 , e1623–e1631 (2022). Gao, L. et al. Impact of COVID-19 infection on Kawasaki disease and immune status in children. Sci Rep 15 , 6417 (2025). Kosmeri, C., Koumpis, E., Tsabouri, S., Siomou, E. & Makis, A. Hematological manifestations of SARS-CoV-2 in children. Pediatric Blood & Cancer 67 , e28745 (2020). Rotulo, G. A. & Palma, P. Understanding COVID-19 in children: immune determinants and post-infection conditions. Pediatr Res 94 , 434–442 (2023). Greaves, M. A causal mechanism for childhood acute lymphoblastic leukaemia. Nat Rev Cancer 18 , 471–484 (2018). Candel-Pau, J. et al. Do timing and severity of gestational COVID-19 impact perinatal and neonatal outcomes? J Perinatol 1–8 (2024) doi:10.1038/s41372-024-02179-9. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8823144","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":632014924,"identity":"05487c35-9390-43fb-9391-3e5b101a2059","order_by":0,"name":"Mengyun Liu","email":"","orcid":"","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Mengyun","middleName":"","lastName":"Liu","suffix":""},{"id":632014925,"identity":"e94dbe75-b510-482b-89da-8e3174f03e8d","order_by":1,"name":"Fariyo Abdullahi","email":"","orcid":"","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Fariyo","middleName":"","lastName":"Abdullahi","suffix":""},{"id":632014926,"identity":"c79716ae-63e5-4f13-a004-9d6ad11bc531","order_by":2,"name":"Charlotte Jackson","email":"","orcid":"","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Charlotte","middleName":"","lastName":"Jackson","suffix":""},{"id":632014927,"identity":"710337e1-2834-420a-a9f0-f565e1f3c597","order_by":3,"name":"Jeannie Collins","email":"","orcid":"","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Jeannie","middleName":"","lastName":"Collins","suffix":""},{"id":632014928,"identity":"d1a86150-270d-42f8-b0ca-cb7f2d012400","order_by":4,"name":"Claire Thorne","email":"","orcid":"","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Claire","middleName":"","lastName":"Thorne","suffix":""},{"id":632014929,"identity":"79cd1627-5de4-4ab0-80b8-c21187cb85e2","order_by":5,"name":"Pia Hardelid","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYFACHiBmY5BhY0g+wMBQABZiJkoLDxtDWgIDgwEpWhgYcgyI02LOwHvwc0WZDQ8fe843iR8GDPL8DTzGBvi0WDbwJUueOZfGw8bzdptkjwGD4YwDPMYJ+LQYHOAxkGxsO8zDJpG7TRroMMYNDDzGBwhoMf7Z2PYfqCXnGUiLPTFazIC2HABpYQNpSQRpweswy2YeM8uGc8lAvzwztuwxkEiecZitGK/3zdl7jG82lNnJybcnP7zxo8LGtr+9ebMEXoehxYEE4YjE64RRMApGwSgYBWAAAE+eOQMLhoOhAAAAAElFTkSuQmCC","orcid":"","institution":"University College London","correspondingAuthor":true,"prefix":"","firstName":"Pia","middleName":"","lastName":"Hardelid","suffix":""}],"badges":[],"createdAt":"2026-02-08 16:53:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8823144/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8823144/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108406731,"identity":"c64f7d3b-5a3b-4dde-80fb-a253e2a1b307","added_by":"auto","created_at":"2026-05-04 09:45:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":481593,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLinkage between data sources to derive the exposure and outcome variables\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8823144/v1/202521563e4425bae31aef85.png"},{"id":108406728,"identity":"8071a05a-86af-4466-9946-b37eab936229","added_by":"auto","created_at":"2026-05-04 09:45:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":468951,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of conceptions, births, maternal SARS-CoV-2 infections in pregnancy and emergency and planned admissions in the study cohort. From top panel to bottom panel: the number of conceptions and births; the number of maternal SARS-CoV-2 infections in pregnancy; the number of emergency admissions and planned admissions in children. \u003c/strong\u003eTransparent bars show daily counts, and solid lines show the 15-day rolling average of daily counts (a week before + the index day + a week after).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8823144/v1/8bcbb8e5d7e172f0cc4338e6.png"},{"id":108492667,"identity":"9210bdc2-edc9-485e-b15a-a6b93c1e8bdf","added_by":"auto","created_at":"2026-05-05 09:58:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":93663,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime to child’s first emergency and planned admission up to 40 months old: hazard ratio and 99% confidence interval by in utero SARS-CoV-2 exposure status, children conceived and born between February 2020 and April 2021 in England. Reference=Test-negative group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNote: Results based on Cox proportional hazard regression models. \u0026nbsp;Adjusted models include maternal ethnicity, area deprivation decile, mother’s history of chronic conditions, maternal age, London residence, and month of conception. A total of 257,249 children with complete data for all covariates were included.\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8823144/v1/37893ef537fea7084c321f48.png"},{"id":108804348,"identity":"8f69970f-1b0a-4f85-a025-2eb0467e62cf","added_by":"auto","created_at":"2026-05-08 15:19:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":109330,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe impact of variant and timing of SARS-CoV-2 exposure in utero on time to the first emergency and planned admissions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNote: Results based on Cox proportional hazard regression models. Adjusted models include maternal ethnicity, deprivation decile, maternal chronic conditions, maternal age, London residence, and month of conception. A total of 14,306 children with complete data for all covariates were used.\u003c/p\u003e","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8823144/v1/8f3206d7545a33986c227cc5.png"},{"id":108809518,"identity":"c88cefa1-588e-4834-9c7e-9fb72fb8c237","added_by":"auto","created_at":"2026-05-08 15:53:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1916674,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8823144/v1/29d1f94f-d301-4f07-81de-652e074ffb2d.pdf"},{"id":108492674,"identity":"9a2528e1-4d03-43ac-9ce8-0930e073d6c7","added_by":"auto","created_at":"2026-05-05 09:58:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1572392,"visible":true,"origin":"","legend":"","description":"","filename":"appendix.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8823144/v1/496de6ff4e289f690c19152c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of in utero exposure to SARS-CoV-2 on children’s hospital admission: National birth cohort study of 262,000 children in England","fulltext":[{"header":"Introduction ","content":"\u003cp\u003eSARS-CoV-2-related disease has been shown to be more severe in pregnant than non-pregnant women\u003csup\u003e1\u003c/sup\u003e. However, much less is known about the outcomes for children who were exposed to SARS-CoV-2 during pregnancy. According to the Developmental Origins of Health and Disease hypothesis, periconceptual and foetal exposures may cause irreversible genetic and epigenetic programming changes, increasing the risk of chronic diseases later in life\u003csup\u003e2,3\u003c/sup\u003e. Maternal respiratory viral infections during pregnancy have been shown to be associated with a higher risk of neurodevelopmental disorders\u003csup\u003e4,5\u003c/sup\u003e and leukaemia in offspring\u003csup\u003e6\u0026ndash;8\u003c/sup\u003e, although findings are not always consistent across studies. Vertical transmission is one mechanism by which maternal infection in pregnancy affects foetus and child, but this is rare in the case of SARS-CoV-2\u003csup\u003e9\u0026ndash;12\u003c/sup\u003e. However, maternal infections in pregnancy, including SARS-CoV-2, even in the absence of vertical transmission, may also negatively affect foetal and infant outcomes through pathways linked to immune activation and inflammation, including inflammatory cytokines signalling, placental dysfunction, and altered foetal immune programming\u003csup\u003e13\u0026ndash;15\u003c/sup\u003e. In a meta-analysis of 117 studies, an estimated 7% (95% confidence interval: 6% to 8%) of pregnant women globally were infected with SARS-CoV-2 between December 2019 and April 2021\u003csup\u003e1\u003c/sup\u003e. Given the global scale of the pandemic and the continued circulation of SARS-CoV-2 virus, the potential long-term consequences for child health warrant rigorous investigation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA systematic review including 204 studies from 36 countries, mostly only including children exposed in utero to SARS-CoV-2 in the third trimester, demonstrated inconsistent findings with respect to adverse birth and neonatal outcomes. However, the review reported a pooled estimate of 1.93 (95% confidence interval [CI]: 1.33 to 2.80) times higher odds of premature delivery and 3.35 (0.84 to 13.36) times higher odds of neonatal intensive care unit (NICU) admission among children exposed to SARS-CoV-2 in utero\u003csup\u003e16\u003c/sup\u003e. The authors attributed the increased NICU admission rate to prematurity, \u0026nbsp;for isolation and observation purposes, or for care of a baby whose mother could not care for the baby herself due to COVID-19 disease\u003csup\u003e16\u003c/sup\u003e. Further studies, mostly with limited sample size, suggest that infants whose mothers had SARS-CoV-2 infection in pregnancy may have an increased risk of respiratory disease in the neonatal period and developmental disorders in infancy, including developmental disorders of speech and language and motor function\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e. No association has been shown between SARS-CoV-2 infection during the first trimester of pregnancy and risk of congenital anomalies in children\u003csup\u003e19\u003c/sup\u003e. The vast majority of existing studies have focused on health outcomes in the perinatal and neonatal period\u003csup\u003e16,17,20\u0026ndash;23\u003c/sup\u003e. While a few studies from high-income countries have followed children beyond this period, they have typically examined a limited set of prespecified outcomes, mostly neurological disorders\u003csup\u003e18,19,24\u0026ndash;27\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe aimed to examine the impact of in utero exposure to maternal SARS-CoV-2 infection during pregnancy on children\u0026rsquo;s emergency and planned hospital admissions up to age 40 months in England. We focused on women infected during the\u0026nbsp;wild-type and Alpha waves of the COVID-19 pandemic, before the recommendation that pregnant women receive COVID-19 vaccines\u003csup\u003e28,29\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e"},{"header":"Data and Methods ","content":"\u003ch3\u003eData sources\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eThis cohort study used multiple linked public national administrative health datasets, including Hospital Episode Statistics Admitted Patient Care dataset (HES APC, from here on referred to as HES for brevity) for hospital admissions, Second Generation Surveillance System (SGSS, \u0026lsquo;Pillar 1\u0026rsquo;l; see below for an explanation of the pillars)\u0026nbsp;and Non-hospital Antigen Testing Results (\u0026lsquo;Pillar 2\u0026rsquo;)\u0026nbsp;for SARS-CoV-2 testing, the birth notification, death registration, and mother-baby linkage developed by Feng et al.\u003csup\u003e30,31\u003c/sup\u003e. Figure 1 illustrates the linkage between these datasets and how we derived exposure and outcome variables. A description of data sources and approaches to identify birth cohorts and estimate date of birth is presented in Supplementary Methods (Table A1 and Figure A1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe derived a national birth cohort of all babies born in England from birth notifications32 and a HES mother-baby linked dataset within HES30,31. Births recorded in either source were included. Children were followed up using HES data and death registration data linked to the birth cohort. Cleaning and linking HES episodes into continuous inpatient admissions episodes used an algorithm developed by Hardelid et al 33,34 (Table A2 in Supplementary Methods). Hospital transfers and admissions within one day were treated as one inpatient admission.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMaternal SARS-CoV-2 infections were determined via linkage between maternal HES records and Pillar 1 and 2 datasets that contain information on SARS-CoV-2 test results. Pillar 1 was introduced in March 2020, initially prioritising individuals with a medical need and critical key workers. This dataset was expanded in May 2020 following the introduction of universal testing of all hospital-admitted patients, including admissions to maternity services for delivery. This routine asymptomatic testing for hospital-admitted patients came to an end in August 202235,36. The Pillar 1 dataset contains data on positive SARS-CoV-2 tests reported by NHS virology laboratories to the Public Health England (the national infectious disease surveillance agency), predominantly based on polymerase chain reaction (PCR) testing37\u0026ndash;39.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePillar 2 community testing was launched in April 2020, initially using PCR testing for symptomatic key workers and general public via local test centres40. Lateral flow testing (rapid antigen tests) was introduced in December 2020 and gradually expanded to include asymptomatic individuals, with universal access implemented in April 2021 continuing until April 202241\u0026ndash;43. The Pillar 2 dataset contains data on positive and negative SARS-CoV-2 tests conducted in the community (e.g., home testing, drive-through and mobile test centres) 37\u0026ndash;39,44. Note that lateral flow test results conducted at home relied on individuals\u0026apos; self-reporting test results online. Key changes to Pillar 1 and Pillar 2 testing policies were summarised in Figure A2, and the individuals included in each exposure group during the intervals between policy changes are described in Table A3 in Supplementary Tables and Figures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudy population\u003c/p\u003e\n\u003cp\u003eWe included all babies in the birth cohort with an estimated conception date between 1st February and 31st July 2020, ensuring most births occurred before the COVID-19 vaccine rollout. The date of conception was defined as 2+0 weeks gestation45, where the start of gestation was calculated using the estimated date of birth and gestational age at birth in weeks. We defined the birth cohort by date of conception rather than date of birth to avoid unbalanced distribution on gestational age and thus reduce fixed cohort bias46. Multiple births, stillbirths, and children whose mothers were residents outside England at delivery were excluded. Rules for identifying stillbirths and multiple births in HES are presented in Table A4 in Supplementary Methods.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOutcomes\u003c/p\u003e\n\u003cp\u003eThe primary outcome was children\u0026rsquo;s first emergency admission after discharge from delivery. We had two secondary outcomes: children\u0026rsquo;s first planned (elective) admission and overall admission rates (including emergency and planned) according to primary diagnosis. Emergency and planned admissions were distinguished using the \u0026lsquo;admimeth\u0026rsquo; variable (Table A5 in Supplementary Methods). Birth admissions, between-hospital transfer, and unclassified admissions were excluded from follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExposure\u003c/p\u003e\n\u003cp\u003eThe primary exposure was exposure to SARS-CoV-2 variants in utero, determined by combining the mother\u0026rsquo;s information from Pillar 1, Pillar 2 and hospital diagnoses in HES during pregnancy. SARS-CoV-2 infections identified through linked testing were supplemented by COVID-19 diagnoses recorded in maternal HES records (International Classification of Diseases 10th version, ICD-10 codes U07.1- U07.2) during pregnancy, with the episode start date considered as the date of infection. De-duplication and cleaning of Pillar 1 and 2 data are described in Supplementary Methods (Table A6 and A7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe first positive test or COVID-19 diagnosis since conception was defined as the start of the first SARS-CoV-2 infection during pregnancy. Two positive tests 90 days or less apart were considered part of the same infection episode47. Children whose mothers were tested for SARS-CoV-2 during pregnancy with unknown results were excluded from the analysis. Children exposed more than once in utero in both the wild-type and the Alpha-period were excluded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn utero positive exposure status was classified according to the dominant circulating variant at the time of the first positive test or the first admission date with an ICD-10 diagnosis of SARS-CoV-2 infection within each infection episode during pregnancy : \u0026ldquo;positive, wild-type\u0026rdquo; (from outbreak start to 15th December 2020) \u0026nbsp;or \u0026ldquo;positive, Alpha\u0026rdquo; (16th December 2020 to 15th May 202148\u0026ndash;50). Children whose mothers had a negative test result in Pillar 2 at any point during pregnancy and no positive test result or diagnosis throughout pregnancy were classified as the \u0026ldquo;test-negative\u0026rdquo; group, irrespective of timing of the negative test; and the remaining children whose mothers had no record of either a positive or negative test result, nor a diagnosis in HES during pregnancy were classified as the \u0026ldquo;no recorded result\u0026rdquo; group. The four exposure groups are mutually exclusive. All pregnancies included in this study had progressed beyond the first trimester before the Alpha period began, due to the conception date inclusion criterion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFollow up\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChildren were followed from the day after their estimated date of birth until the first occurrence of the outcome event, death, or reaching 40 months of age, whichever occurred first. To estimate admission rates, we included admissions from the day after their estimated date of birth until death or reaching 40 months of age, whichever occurred first.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCovariates\u003c/p\u003e\n\u003cp\u003eWe used Directed Acyclic Graphs to identify confounders for inclusion in the statistical models (Figure A3 in Supplementary Methods)51. Gestational age (preterm birth: \u0026lt;37 weeks, term birth: 37-42 weeks, post-term birth: \u0026gt;42 weeks) lies on the causal pathway between in utero exposure to SARS-CoV-2 and child hospital admission, so it was not considered a confounder. However, we present the distribution of gestational ages in each exposure group. To minimise missing data for these covariates, we integrated information from children\u0026rsquo;s HES admissions records within the first month of life, birth notification, mother\u0026rsquo;s delivery records, and the mother-baby linkage31 when available. The included confounders, definitions and the source of information are presented in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Definition of confounders and the source of information\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConfounders\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDefinition\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSource of information \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eMother\u0026rsquo;s ethnicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eEthnicity of the mother: White, Asian, Black, mixed, or other\u003csup\u003e52\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003eMothers\u0026rsquo; HES delivery records; if missing, replace with children\u0026rsquo;s ethnicity in children\u0026rsquo;s HES admissions\u0026nbsp;within 28 days of birth; if missing, replace with children\u0026rsquo;s ethnicity in birth notification.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eArea deprivation decile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eDeciles of the Index of Multiple Deprivation (IMD), measured at the Lower Super Output Area (LSOA) level (an average size of 1500 residents or 650 households\u003csup\u003e52\u0026ndash;54\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003eArea deprivation decile in mother\u0026rsquo;s HES delivery records; if missing, replace with area deprivation decile in children\u0026rsquo;s HES admissions within 28 days of birth; if missing, replace with IMD decile in the mother-baby link developed by Feng et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eMaternal chronic condition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003ePresence of chronic condition defined by Charlson Comorbidities Classification based on diagnoses recorded in HES up to three years before conception\u003csup\u003e55,56\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003eICD-10 disease codes in mother\u0026rsquo;s HES admissions up to 3 years before conception.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eMaternal age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eAge of the mother at delivery: \u0026lt;25, 25-29, 30-34, 35-39, and\u0026nbsp;\u0026ge;40 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003eThe most common value in children\u0026rsquo;s HES admissions within 28 days of birth; if missing, replace with maternal age from the mother-baby link developed by Feng et al.; if missing, replace with maternal age in the mother\u0026rsquo;s HES delivery admission. \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eWhether the child was a London resident\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eGovernment office region, LSOA, or postcode district is Greater London area.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003eThe most common value in children\u0026rsquo;s admissions within 28 days of birth; if missing, replace with mother\u0026rsquo;s residence area in delivery records.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eMonth and year of conception\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eMonth-year of the estimated date of conception\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 311px;\"\u003e\n \u003cp\u003eChildren\u0026rsquo;s birth admissions in HES and birth notification.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eStatistical analysis \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe plotted the number of conceptions, births, in utero exposure to SARS-CoV-2, and emergency and planned admissions against calendar dates. To understand testing policies over time, we also plotted the number of SARS-CoV-2 tests and COVID-19 diagnoses recorded for mothers in each dataset over the study period. We compared the distribution of the key variables of interest and the extent of missing data among children in the birth cohort based on their in utero SARS-CoV-2 exposure status (positive, wild-type; positive, Alpha; test-negative; no recorded result). We plotted the Kaplan-Meier curves for time to first emergency and planned admission. We calculated rates of emergency admissions and planned admissions per 1000 child years, respectively, stratified by exposure status (including all admissions, not just the first; details in Supplementary Methods).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe examined the association between in utero SARS-CoV-2 exposure and time to first emergency or planned admission using Cox proportional hazards regression models with robust standard errors, separately for emergency and planned admissions. For each outcome, we first fitted an unadjusted model including the main exposure (exposure to SARS-CoV-2; coded into four groups: positive, wild-type; positive, Alpha; test-negative; no recorded result), followed by an adjusted model incorporating potential confounders listed in Table 1. The proportional hazards assumption was assessed by comparing models with and without an interaction term between exposure status and time (child\u0026rsquo;s age), using likelihood ratio tests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe also conducted trimester-specific analyses among children with a record of in utero exposure to SARS-CoV-2. Trimester of exposure was determined by the timing of the first positive test result of each episode of infection. We constructed Cox proportional hazard regression models among children exposed in utero to examine the effect of timing of in utero exposure on the time to first emergency or planned admissions. Models initially included the variant period of exposure (wild-type vs. Alpha period) and the trimester of exposure (first trimester: conception to 12 weeks; second trimester [reference]: 13 to 27 weeks; third trimester: 28 weeks to birth), and were subsequently adjusted for confounders listed in Table 1. Children who were unexposed or whose mothers had multiple episodes of infection in different trimester were excluded from the trimester-specific analyses.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo calculate admission rates by primary diagnosis, we classified the primary diagnosis of the first episode of each admission into disease groups according to ICD-10 chapters57 (Table A8 in Supplementary Methods). Admission rates were calculated for each disease group, including all emergency and planned admissions per 1000 child years.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo account for multiple tests, we used 99% confidence intervals (CI). All counts smaller than five were reported as \u0026ldquo;\u0026lt;5\u0026rdquo; to minimise the potential of re-identification58. All regression models included only children with complete data for all covariates. All analyses were done using STATA 18.0 (StataCorp LLC, College Station, Texas). The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist is presented in Supplementary STROBE Checklist)59.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSensitivity analysis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo rule out the influence of hospital admissions due to COVID-19, we performed a sensitivity analysis excluding COVID-19-related admissions in children (definitions provided in Supplementary Sensitivity Analysis). To address the potential violation of the proportional hazard assumption, we performed a sensitivity analysis using logistic regression models, assuming equal follow-up time for all children. To account for potential overestimation of person-time caused by excluding neonatal admissions immediately after birth, we performed a sensitivity analysis excluding admissions within the first 7 days of life, with follow-up starting from day 8. To address potential selection bias arising from changes in SARS-CoV-2 testing policies and capacities across variant periods, models were constructed and admissions rates calculated separately for the wildtype and Alpha periods, using children whose mothers tested negative during pregnancy within the corresponding variant period as the comparator group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatient and public involvement\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhilst patients and the public have not been involved with this specific piece of research, the study team met with the Great Ormond Street Hospital Biomedical Research Centre Parents\u0026rsquo; and Carers\u0026rsquo; Advisory Group in April 2022 to discuss the overall project and discuss the use of linked administrative health data to address research questions relating to the child and maternal health impacts of SARS-CoV-2 infection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthical approval and consent to participate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study used pseudonymised NHS data which was provided within the terms of a data sharing agreement (DARS-NIC-393510-D6H1D-v9.3) by NHS England, collected for the purposes of providing patient care. Pseudonymised HES data were obtained as part of the standard NHS Digital data access request process. NHS Research Authority suggests that ethical approval was not required as the study involved secondary analysis of pseudonymised data only60. Consent for research was waived as data were pseudonymised.\u003c/p\u003e"},{"header":"Results ","content":"\u003cp\u003eThis study included 262,086 children born between June 2020 and May 2021 to 261,797 mothers (Figure B1). Table 2 summarises children\u0026rsquo;s characteristics by exposure status. A higher proportion of children exposed in utero were from ethnic minority groups, compared to children in the no recorded result and test-negative groups. Children exposed in utero were more likely to be born in deprived areas than children in the no-recorded-result and test-negative groups (percentage of children from the 10% most deprived areas: 19.7% in the wild-type group and 16.8% in the Alpha group vs. 13.8% in the no-recorded-result group and 11.4% in the test-negative group). The test-negative group had a higher proportion of children whose mothers had chronic conditions (4.8%) and tended to be conceived later than the other three groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe number of positive tests increased markedly at the onset of the Alpha wave in January 2021, coinciding with the expansion of community testing and wider use of Pillar 2 testing (Figure B2 in Supplementary Tables and Figures).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA total of 43,225 (16.5%) children were in the test-negative exposure group, while 5.6% were exposed to SARS-CoV-2 in utero at least once, with 6,888 (2.6%) exposed in the wild-type period and 7,829 (3.0%) in the Alpha period. Among exposed children, the positive maternal test was reported in the second trimester for 29.5% (n=4,343), in the third for 67.4% (n=9,925), with only 4.1% of children exposed in the first trimester (Figure 2). Ten mothers tested positive in both the first and second trimesters, \u0026lt;5 in the first and the third trimesters, and 140 in the second and third trimesters.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Distribution of the characteristics by in-utero exposure status to SARS-CoV-2 during pregnancy\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"99%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of children (column percentage)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (column percentage)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTest-negative\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive, wild-type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive, Alpha\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo recorded result\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of children\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e43,225\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e6,888\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e7,829\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e204,144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e262,086\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of children with emergency admission\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e16,023 (37.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e2,646 (38.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e2,634 (33.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e67,886 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e89,189 (34.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of children with planned admission\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,164 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e716 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e745 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e19,010 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e24,635 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArea of residence\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;London\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e6,294 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e983 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e2,266 (28.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e38,979 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e48,522 (18.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Non-London\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e36,931 (85.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e5,905 (85.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e5,563 (71.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e165,165 (80.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e213,564 (81.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEthnicity of mother\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;White\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e35,647 (82.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,572 (66.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e5,151 (65.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e151,853 (74.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e197,223 (75.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Asian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,269 (9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,533 (22.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1,514 (19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e27,189 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e34,505 (13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Black\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,125 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e278 (4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e530 (6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e10,552 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12,485 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Mixed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,011 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e175 (2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e210 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e5,443 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e6,839 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,172 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e330 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e424 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e9,100 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11,026 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Missing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;5 (\u0026lt;0.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e7 (\u0026lt;0.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e8 (\u0026lt;0.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArea deprivation decile\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Most deprived10%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,923 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,359 (19.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1,315 (16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e28,177 (13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e35,774 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;10% to 20%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,788 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e975 (14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1,213 (15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e25,775 (12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e32,751 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;20% to 30%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,650 (10.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e820 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1,003 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e23,700 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e30,173 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;30% to 40%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,466 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e732 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e886 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e21,489 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e27,573 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;More deprived 40% to 50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,273 (9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e614 (8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e720 (9.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e19,742 (9.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e25,349 (9.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Less deprived 40%-50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,264 (9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e572 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e659 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e18,254 (8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e23,749 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;30%-40%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,068 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e512 (7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e547 (7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e17,269 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e22,396 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;20% to 30%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,002 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e486 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e560 (7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e16,935 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e21,983 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp;10% to 20%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,026 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e442 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e486 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e16,977 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e21,931 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Least deprived10%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e3,758 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e375 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e437 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e15,800 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e20,370 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; Missing\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e7 (0.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;5 (\u0026lt;0.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026lt;5 (\u0026lt;0.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e26 (0.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e37 (0.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMother\u0026rsquo;s chronic condition\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e2,063 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e264 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e267 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e7,175 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e9,769 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e41,162 (95.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e6,624 (96.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e7,562 (96.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e196,969 (96.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e252,317 (96.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYear-Month of conception\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Feb 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e3,307 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,011 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0 (0)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e39,098 (19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e43,416 (16.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Mar 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e4,564 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,403 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e98 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e37,195 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e43,260 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Apr 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e5,844 (13.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,163 (16.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1,163 (14.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e32,654 (16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e40,824 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;May 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e8,135 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,117 (16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e2,099 (26.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e32,549 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e43,900 (16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Jun 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e10,150 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,147 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e2,164 (27.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e32,006 (15.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e45,467 (17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Jul 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e11,225 (26.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,047 (15.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e2,305 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e30,642 (15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e45,219 (17.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMaternal age\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026lt;25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e5,775 (13.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,090 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1,382 (17.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e30,868 (15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e39,115 (14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;25-29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e11,445 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e2,039 (29.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e2,130 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e53,271 (26.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e68,885 (26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;30-34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e15,380 (35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e2,208 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e2,529 (32.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e68,275 (33.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e88,392 (33.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;35-39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e8,079 (18.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,142 (16.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1,318 (16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e38,741 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e49,280 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026gt;=40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1,772 (4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e298 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e328 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e9,204 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e11,602 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; N missing values\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e774 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e111 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e141 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e3,785 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e4,812 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGestational age (weeks)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Preterm birth (\u0026lt;37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e2,071 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e460 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e615 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e12,998 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e16,144 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Term birth (34-42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e41,126 (95.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e6,421 (93.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e7,205 (92.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e191,007 (93.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e245,759 (93.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Post-term birth (\u0026gt;42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e28 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e7 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e9 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e139 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e183 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIn total, 89,189 children (34.0%) had at least one emergency admission before age 40 months: 55,663 (21.2%) had a single emergency admission, while 33,526 (12.8%) had two or more. A total of 24,635 children (9.4%) had at least one planned admission, with 16,881 (6.4%) having one planned admission and 7,754 (3.0%) having two or more (Table 2 and Figure 4). About two-thirds (n=162,293; 61.9%) of children had no admissions, while 14,031 (5.4%) children had both emergency and planned admissions. More than half (n=14,031; 57.0%) of children with a planned admission also had an emergency admission. Kaplan-Meier curves for emergency and planned admissions are shown in Figures B3 and B4 in the Supplementary Tables and Figures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChildren with in utero exposure during the Alpha period and those without a maternal test result had lower emergency admission rates (169.6 per 1000 child-years [99% CI: 163.2 to 176.3] and 170.7 [169.4 to 172.0], respectively) than those exposed during the wild-type period and those unexposed during either period (209.1 [201.4 to 217.0] and 200.4 [197.4 to 203.5] respectively). Planned admission rates were lower among children exposed in utero during the Alpha period (45.4 [42.1 to 48.9]), while rates were similar across the other three groups (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Hospital admission rates by in utero SARS-CoV-2 exposure status (all admissions other than birth admissions were included)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIn-utero exposure status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of children\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of child-year (*1000)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of \u0026nbsp; \u0026nbsp; admissions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRate per 1000 child-years (99% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEmergency admissions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003eTest-negative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e43,225\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e143.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e28,825\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e200.4 (197.4, 203.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003ePositive, Wild-type\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e6,888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e22.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e4,786\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e209.1 (201.4, 217.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003ePositive, Alpha\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e7,829\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e26.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e4,418\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e169.6(163.2, 176.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003eNo-recorded-result\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e204,144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e678.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e115,783\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e170.7 (169.4, 172.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e262,086\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e871.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e153,812\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e176.6 (175.4, 177.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlanned admission\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003eTest-negative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e43,225\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e143.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e7,346\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e51.1 (49.5, 52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003ePositive: Wild-type\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e6,888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e22.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1,258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e54.9 (51.1, 59.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003ePositive: Alpha\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e7,829\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e26.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1,183\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e45.4 (42.1, 48.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003eNo-recorded-result\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e204,144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e678.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e33,979\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e50.1 (49.4, 50.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 23px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e262,086\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e871.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e43,766\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e50.2 (49.6, 50.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eA total of 257,241 children (98.2%) with complete data for all covariates were included in the Cox proportional hazard regression models. There was no evidence for a difference in the time to the first emergency admission between children exposed in utero during the wild-type period and children unexposed in either period (i.e., test-negative group) (Figure 3 and Table B2 in Supplementary Tables and Figures). However, children exposed during the Alpha variant period and those in the no-recorded-result group had 8% (adjusted HR=0.92, 99% CI: 0.87 to 0.97) and 12% (aHR=0.88, 0.86 to 0.90) lower hazard of first emergency admission than the test-negative group, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChildren in the no-recorded-result group had a 5% lower hazard of first planned admission compared with the test-negative group, while no significant difference was observed between the two positive groups and the test-negative group, regardless of adjustment (Figure 3 and Table B1). The proportional hazard assumption was met for the model examining emergency admissions but was violated for the planned admissions model in the no-recorded-result group (Table B2). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOnly 603 children were exposed during the first trimester, all during the wild-type period. Similar numbers of exposed children were observed during the wild-type period in the second (n=3,035) and third trimesters (n=3,333) (Table B3). A total of 14,306 children with confirmed in utero exposure and complete data for all covariates were included in the trimester-specific regression analyses, after excluding 154 children where exposure spanned two trimesters.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong in utero exposed children, no evidence was found for a difference in time to first emergency or planned admissions by trimester of exposure, while children in utero exposed during the Alpha period showed a 16% lower hazard of the first emergency admission, compared with those exposed during the wild-type period (aHR=0.84, 0.75 to 0.93) (Figure 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChildren\u0026nbsp;with\u0026nbsp;in utero\u0026nbsp;exposure\u0026nbsp;during the wild-type period\u0026nbsp;had\u0026nbsp;the highest admission rate (264.1 per 1000 child-years, 99% CI: 255.5 to 272.9), followed by those\u0026nbsp;whose mothers\u0026nbsp;tested negative during pregnancy (251.5, 248.2 to 255.0). Lower admission rates were observed among\u0026nbsp;children exposed in utero during the Alpha period (215.0, 207.7 to 222.5) and those with no recorded maternal test during pregnancy (220.8, 219.3 to 222.2) (Table 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcross all disease groups, the highest admission rates were\u0026nbsp;for\u0026nbsp;diseases of the respiratory system (52.9 per 1,000 child-years, 99% CI: 52.3 to 53.6), while\u0026nbsp;the lowest\u0026nbsp;were for\u0026nbsp;mental and behavioural disorders (0.4, 0.4 to 0.5) and diseases of the circulatory system (0.5, 0.5 to 0.6 for heart diseases and 0.4, 0.4 to 0.5 for circulatory diseases).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChildren exposed in utero during the wild-type period had higher admissions rates for malignant neoplasms (based on 195 disease cases), diseases of the blood and blood-forming organs and certain immune disorders, and injury, poisoning, and certain other consequences of external causes, but lower admission rates for benign neoplasms; while children exposed in utero during the Alpha period had lower admission rates for diseases of the respiratory system.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Admission rates per 1000 child-years (99% CI) by primary diagnosis, including all emergency and planned admissions up to 40 months old\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"937\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of disease cases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of admissions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTest-negative\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eWild-type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive:\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAlpha\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo-recorded-result\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCertain infectious and parasitic diseases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u0026nbsp; Bacterial infectious diseases\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e7,692\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e8,880\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e11.6 (10.9,12.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e14.0 (12.1,16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e9.9 (8.4,11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e9.8 (9.5,10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e10.2 (9.9,10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u0026nbsp; Non-bacterial infectious diseases\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e13,955\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e19,337\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e24.0 (23.0,25.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e27.7 (25.0,30.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e20.6 (18.4,23.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e21.7 (21.2,22.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e22.2 (21.8,22.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeoplasms\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u0026nbsp; Malignant neoplasms\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e193\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e4,420\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e5.3 (4.8,5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e11.0 (9.3,12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e5.0 (4.8,5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e5.1 (4.9,5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u0026nbsp; Benign neoplasms\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e906\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1,501\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e2.5 (2.2,2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e1.1 (0.7,1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e1.9 (1.3,2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.6 (1.5,1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e1.7 (1.6,1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the blood and blood-forming organs and\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ecertain disorders involving the immune mechanism\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e806\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2,502\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e1.9 (1.6,2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e4.4 (3.4,5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e2.8 (2.0,3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3.0 (2.9,3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e2.9 (2.7,3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndocrine, nutritional and metabolic diseases \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1,228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2,373\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e3.0 (2.7,3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e2.2 (1.5,3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e2.6 (1.9,3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2.7 (2.5,2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e2.7 (2.6,2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMental and behavioural disorders\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e330\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0.4 (0.3,0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0.2 (0.0,0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0.3 (0.1,0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.4 (0.4,0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e0.4 (0.4,0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the nervous system\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1,902\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3,435\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e4.1 (3.7,4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e5.0 (4.0,6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e3.8 (3.0,5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3.9 (3.7,4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e3.9 (3.8,4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the eye and adnexa\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e1,596\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1,907\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e2.4 (2.1,2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e2.6 (1.9,3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e1.9 (1.3,2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2.1 (2.0,2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e2.2 (2.1,2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the ear and mastoid process\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e2,258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2,626\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e3.6 (3.2,4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e3.9 (3.0,5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e2.6 (1.9,3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2.9 (2.7,3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e3.0 (2.9,3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the circulatory system\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u0026nbsp; Heart diseases\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e268\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e461\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0.5 (0.4,0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0.4 (0.2,0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0.3 (0.1,0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.5 (0.5,0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e0.5 (0.5,0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u0026nbsp; Circulatory diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e290\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e358\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0.5 (0.4,0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0.4 (0.2,0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0.6 (0.3,1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.4 (0.3,0.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e0.4 (0.4,0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the respiratory system \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e31,816\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e45,898\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e64.0 (62.3,65.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e59.7 (55.7,64.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e55.4 (51.7,59.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e50.0 (49.3,50.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e52.7 (52.1, 53.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the digestive system\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e7,534\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e9,762\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e12.4 (11.7,13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e12.8 (11.1,14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e10.8 (9.3,12.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e10.9 (10.6,11.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e11.2 (10.9,11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the skin and subcutaneous tissue\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e3,330\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3,954\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e4.7 (4.2,5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e5.7 (4.6,7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e4.5 (3.5,5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e4.5 (4.3,4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e4.5 (4.4,4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the musculoskeletal system and connective tissue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e805\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1,040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e1.1 (0.9,1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e1.3 (0.8,2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e1.5 (1.0,2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.2 (1.1,1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e1.2 (1.1,1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of the genitourinary system\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e3,482\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e5,436\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e6.1 (5.6,6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e6.0 (4.8,7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e5.6 (4.6,7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e6.3 (6.0,6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e6.2 (6.0,6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCertain conditions originating in the perinatal period \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e19,576\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e22,541\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e27.2 (26.1,28.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e28.2 (25.5,31.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e24.5 (22.1,27.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e25.4 (24.9,25.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e25.8 (25.3,26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCongenital malformation, deformations and chromosomal abnormalities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e7,247\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e11,366\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e13.8 (13.0,14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e12.8 (11.1,14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e12.1 (10.4,13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e12.9 (12.6,13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e13.0 (12.7,13.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInjury, poisoning, and certain other consequences of external causes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e8,608\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e9,990\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e11.5 (10.8,12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e14.3 (12.4,16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e10.2 (8.7,12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003col start=\"11\"\u003e\n \u003cli\u003e(11.1,11.8)\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e11.5(11.2,11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 268px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 72px;\"\u003e\n \u003cp\u003e95,715\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 76px;\"\u003e\n \u003cp\u003e197,735\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e251.5 (248.2,255.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e264.1 (255.5,272.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 102px;\"\u003e\n \u003cp\u003e215.0 (207.7,222.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 104px;\"\u003e\n \u003cp\u003e220.8 (219.3,222.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e226.8 (225.5,228.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003e#\u003c/sup\u003e There was no malignant neoplasm case up to 40 months old among children in utero exposed to SARS-CoV-2 during the Alpha period.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter excluding 1,648 emergency admissions (1.1% of all first emergency admissions) and 101 planned admissions (0.2% of all first planned admissions) that were COVID-19 related, the sensitivity analysis restricted to non-COVID-19-related admissions showed results consistent with the main analysis (Figure C1 and C2 in Supplementary Sensitivity Analysis). Sensitivity analysis excluding admissions and deaths within the first 7 days of life, with follow-up beginning on day 8, also produced similar findings (Figure C3). Findings from logistic regression models were consistent with those from the Cox proportional hazard models used in the main analysis (Figure C4). When restricting the comparator group to children whose mothers tested negative during the same variant period as those who tested positive, all hazard ratios were slightly attenuated, and children exposed in utero during the Alpha period no longer showed a lower hazard of emergency admissions than the unexposed children (Figure C5 and Table C1). The overall conclusion remained unchanged.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion ","content":"\u003ch3\u003eKey findings\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eBased on our England cohort of a quarter of a million children with a pregnancy start date in the first six months of the COVID-19 pandemic, 5% of children had a record of exposure to in utero SARS-CoV-2. We found no evidence of increased risk of either first emergency or planned admission up to 40 months of age associated with in utero exposure to SARS-CoV-2 during the wild-type and Alpha periods.\u0026nbsp;Compared with unexposed children, children exposed in utero during the Alpha period had a\u0026nbsp;slightly\u0026nbsp;lower\u0026nbsp;overall\u0026nbsp;emergency admission rate, while no difference was observed for those exposed during the wildtype period.\u0026nbsp;Within the exposed groups, no differences were found in the hazard of first emergency or planned admissions according to trimester of maternal SARS-CoV-2 infection. Diagnosis-specific admission rates showed modest differences, with some elevated rates of malignant neoplasms and injury-related admissions among children in utero exposed during the wild-type period, and blood and immune disorders among children in utero exposed during either period.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eStrengths and limitations\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eA key strength of this study is the use of multiple, national linked administrative health datasets, thereby ensuring representativeness and minimising loss to follow-up. The follow-up period of 40 months is longer than similar studies published to date.\u0026nbsp;Our examination of both emergency and planned admissions capture any potential severe health outcomes requiring hospital admission. By defining the cohort based on the timing of conception rather than birth, we minimised fixed cohort bias\u003csup\u003e46,61\u003c/sup\u003e.\u0026nbsp;We combined mother-baby linkage derived from HES\u003csup\u003e31\u003c/sup\u003e with those recorded in birth notification data\u003csup\u003e62\u003c/sup\u003e to maximise cohort coverage, and integrated information from\u0026nbsp;various databases to minimise missing\u0026nbsp;data.\u0026nbsp;Analyses\u0026nbsp;adjusted\u0026nbsp;for key maternal and sociodemographic confounders, and\u0026nbsp;multiple\u0026nbsp;sensitivity analyses\u0026nbsp;supported\u0026nbsp;the robustness of\u0026nbsp;the\u0026nbsp;findings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study has some limitations.\u0026nbsp;First, although we used two COVID-19 surveillance datasets and hospital admission data to ascertain maternal infection status, we were unable to capture asymptomatic infections that were not tested or test-positive cases from the community that were not reported; those infections were included in the \u0026ldquo;no reported result\u0026rdquo; group.\u0026nbsp;Underreporting\u0026nbsp;may have been a particular issue during the wild-type period, when testing capacity was limited (February to April 2020) and community testing was not widespread (before 2020)\u003csup\u003e63\u0026ndash;65\u003c/sup\u003e. In particular, since we found that children whose mothers had a negative test reported were less likely to live in deprived areas, but more likely to have chronic conditions recorded, some differential misclassification of infection status reflecting different testing and healthcare seeking behaviours among pregnant women is likely.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecond, in utero exposure was classified by the dominant circulating variant at the time of testing or diagnosis, as laboratory confirmation of variants was not available. However, given the high transmissibility and rapid dominance of the Alpha variant in the UK, the risk of variant misclassification is likely to be minimal\u003csup\u003e66\u0026ndash;68\u003c/sup\u003e. Our findings are limited to the wildtype and Alpha period and may not be generalisable to later variants or to pregnancies in vaccinated women, as we focused on pregnancies prior to vaccine rollout to avoid any impact of vaccination on child health outcomes\u003csup\u003e69,70\u003c/sup\u003e. \u0026nbsp;Further studies, including linked vaccination data, are required to confirm whether out findings are applicable to Delta and Omicron SARS-CoV-2 variants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThird, our outcome measures were limited to hospital admissions. We were unable to access primary or outpatient care use or developmental or health outcomes not requiring hospital admissions. Lastly,\u0026nbsp;as the cohort was followed from birth rather than conception, findings are conditional on live births and do not account for the competing risks of stillbirth and pregnancy loss, the risk of which may increase by SARS-CoV-2 infection during pregnancy. For example, a population-based study of 0.8 million pregnancies in England and Wales showing an association between maternal COVID-19 diagnosis and stillbirth within 14 days of infection\u003csup\u003e71\u003c/sup\u003e. Further studies could integrate abortion and stillbirth data to fully describe the effect of SARS-CoV-2 infection during pregnancy.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eComparison with other studies\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eSeveral studies have investigated health outcomes in neonates and infancy following in-utero exposure to SARS-CoV-2, but few have examined long-term, all-cause outcomes separately for emergency and planned hospital admissions using population-wide data. A small cohort study of 339 children (96 exposed and 243 unexposed) born in England and Wales between March 2020 and February 2021 - spanning the wild-type and Alpha variant periods - found higher admission rates by 21 months of age among those with perinatal exposure to SARS-CoV-2 (38% of exposed vs. 21% of unexposed children had at least one admission)\u003csup\u003e72\u003c/sup\u003e. However, it remains unclear whether these differences were driven by in utero exposure, neonatal infection, or both.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThough findings were not consistent across all studies, the majority of studies worldwide reported a higher risk of neonatal intensive care unit admission in babies exposed to SARS-CoV-2 in\u0026nbsp;utero compared to unexposed babies, primarily due to conditions such as respiratory distress and hyperbilirubinemia\u003csup\u003e1,16,17,73\u0026ndash;75\u003c/sup\u003e. This\u0026nbsp;increased risk is thought to be largely\u0026nbsp;driven by preterm delivery, often resulting\u0026nbsp;from\u0026nbsp;clinical decisions related to maternal health complications or medically induced preterm birth, rather than a direct viral effect on the foetus\u003csup\u003e76\u0026ndash;79\u003c/sup\u003e.\u0026nbsp;Our study, with a longer follow-up of 40 months, found no evidence of an increased overall hazard of hospital admission, particularly for diseases of the respiratory system, among children born to mothers who tested positive for SARS-CoV-2 during pregnancy compared with those born to test-negative mothers. Note that any admission within one day of the birth admission was also excluded, as part of our linkage of HES episodes into admissions, which may account for part of the discrepancy with earlier studies. Differences in findings may also reflect variation in follow-up duration and control group selection. Some previous studies\u003csup\u003e17,80\u003c/sup\u003e compared test-positive pregnancies with a broader reference group that included both test-negative women and those without any recorded test results during pregnancy \u0026ndash; a heterogeneous group likely comprising true negatives, under-ascertained positives, and pregnant women with diverse health status, exposure risks, and testing and care-seeking behaviours. In contrast, we restricted our control group to test-negative pregnancies who actively engaged with testing, thereby reducing potential selection bias related to differential healthcare access and care-seeking behaviour. Clear socio-demographic differences between the no-recorded-result and test-negative groups in our data indicate that it is not appropriate to assume the former were necessarily uninfected. Results related to the no-recorded-result group in this study should therefore be interpreted with caution.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExisting research on the impact of in utero exposure to SARS-CoV-2 has primarily focused on developmental delays in gross and fine motor, problem-solving, communication, and social skills, assessed with various scales\u003csup\u003e18,19,24,25,27,81\u0026ndash;86\u003c/sup\u003e. However, these studies mostly had relatively short follow-up periods and reported mixed findings. A systematic review of 17 studies published up to June 2023 reported mild delays in gross and fine motor skills up to six months of age and in social and language domains between six and 12 months\u003csup\u003e81\u003c/sup\u003e. In contrast, three subsequent studies - including two prospective cohorts from Canada and the US with a 24-month follow-up period\u003csup\u003e24,26\u003c/sup\u003e and a Scottish population-based retrospective cohort with a follow-up period of 13 to 15 months\u003csup\u003e25\u003c/sup\u003e \u0026ndash; found no association between in utero exposure to SARS-CoV-2 and developmental concerns. \u0026nbsp;Unlike these studies, our analysis was limited to hospital admissions and therefore only captured severe cases of neurological disorders requiring hospital admission, making direct comparisons difficult. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study observed a lower hazard of emergency hospital admission among children with in utero exposure during the Alpha period compared to those with no exposure. One reason for observing this difference during the Alpha, but not wild-type, period may be that our comparator group (test-negative) likely included symptomatic women tested in the community, particularly during the wild-type period when testing was limited to symptomatic individuals. This may represent a less healthy comparator group than that included during the Alpha period when broader community testing was in place. Further, during the wild-type period, limited testing likely captured more severe infections or high-risk pregnancies, while broader testing during the Alpha period identified a more heterogeneous group of possibly healthier exposed pregnancies.\u0026nbsp;In the sensitivity analysis using children whose mothers tested negative during the same variant period as those who tested positive as the comparator group, the lower hazard of emergency admissions among children in utero exposed during the Alpha period no longer exists. Whether neonatal outcomes differ by variant following in utero exposure remains inconsistent and evidence comparing different variants is limited\u003csup\u003e50,62,87\u0026ndash;90\u003c/sup\u003e. For example, research from Italy and Scotland showed a higher risk of premature births\u003csup\u003e91,92\u003c/sup\u003e, small-for-gestational age\u003csup\u003e92\u003c/sup\u003e, and low Apgar score\u003csup\u003e91\u003c/sup\u003e and evidence from France, Switzerland\u003csup\u003e62\u003c/sup\u003e, and Malawi\u003csup\u003e93\u003c/sup\u003e showed higher stillbirth rates associated with the Delta variant, while a US study showed no difference in Apgar scores, NICU admissions or need for respiratory support between the pre-Delta and Delta variants, although with longer hospital stay in neonates born during the Delta period\u003csup\u003e88\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study, focusing on longer-term outcomes after birth, found broadly similar crude admission rates between exposed and unexposed children across most disease groups. However, children exposed in utero during the wild-type period had higher crude admission rates for malignant neoplasms and diseases of the blood and blood-forming organs, and certain disorders involving the immune mechanism. We did not observe this finding for children exposed to SARS-CoV-2 in utero during the Alpha wave. We consider it unlikely to be due to SARS-CoV-2 exposure during pregnancy, but instead may reflect changes in healthcare delivery for children with cancer earlier in the pandemic, or potentially in exposure to infections in early life (which has been associated with leukaemia risk\u003csup\u003e94\u0026ndash;97\u003c/sup\u003e) due to the changes in seasonality of common infections seen during and after the COVID pandemic. These impacts may well be differential by exposure group, due to the complex changes in SARS-CoV-2 circulation, testing availability, and healthcare availability over time. The concurrent increase in admission rates for injury, poisoning, and certain other consequences of external causes, along with the absence of malignant neoplasm cases among children exposed in utero during the Alpha period, raises the possibility of unadjusted confounding between exposure groups. Further studies, including linkage to cancer registration data to obtain the date of cancer diagnosis, rather than the date of hospital admission with cancer diagnosis recorded, are required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study shows no difference in the hazards of first admission in early childhood by trimester of in-utero exposure, after adjusting for the variants exposed and other maternal and sociodemographic confounders. However, interpretation of the potential impact of the first-trimester exposure should be cautious, as the number of cases exposed in early pregnancy was small and confined to the wild-type period. Pregnancies affected in the first trimester may be more likely to result in early pregnancy loss, which is not captured in our live-birth cohort and may lead to underestimation of adverse outcomes associated with early pregnancy exposure. Despite these limitations, our findings align with most previous studies that reported no consistent evidence of trimester-specific effects on a range of perinatal and early childhood outcomes\u003csup\u003e26,72,98\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eClinical and policy implications\u003c/h3\u003e\n\u003cp\u003eOverall, findings from this study suggest no evidence for increased risk of emergency or planned hospital admission in children with in utero SARS-CoV-2 exposure during the wild-type and Alpha period up to 40 months of age, providing reassurance to families affected by maternal COVID-19 infection in the early pandemic period. These findings support ongoing public health messaging that maternal SARS-CoV-2 infection, at least in its earlier variants, does not indicate an increased risk of children exposed in utero requiring hospital admission. Further studies with longer follow-up are needed to assess the health consequences of in utero SARS-CoV-2 exposure with onset in later childhood or adulthood, ideally accounting for survivorship bias.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study, the largest population-based cohort with the longest follow-up period, found no evidence for an increase in children\u0026rsquo;s emergency or planned admission rates up to 40 months of age, following in utero SARS-CoV-2 exposure during the wild-type and Alpha periods. No differences in either emergency or planned admissions rates were observed across trimesters of exposure. Further studies should examine disease-specific outcomes and in utero exposure to SARS-CoV-2 during later variant periods.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgement \u003c/h2\u003e\n\u003cp\u003eWe acknowledge funding from the European Union’s Horizon Grant and support from the SARS-CoV-2 variants Evaluation in Pregnancy and Paediatrics cohorts (VERDI) project. This work used data provided by the public and patients and collected by the NHS as part of their care and support. NHS Hospital Episode Statistics data was provided within the terms of a data-sharing agreement (DARS-NIC-393510-D6H1D-v9.3) to the researchers by NHS England. We acknowledge the help and support of Dr. Linda Wijlaars and Dr. Professor Darren Hargrave. \u003c/p\u003e\n\u003ch2\u003eAuthor contributions\u003c/h2\u003e\n\u003cp\u003ePH, CT and ML contributed to the development and conduct of the study. ML and FA contributed to the data cleaning and analyses. ML wrote the first draft of the manuscript with contributions from PH and CT. All authors edited drafts of the manuscript and approved the final version of the article. The corresponding author attested that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Pia Hardelid is the guarantor. \u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis work is part of the VERDI project (101045989) which is funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. The funder played no role in study design, data collection, analysis, interpretation of the result, writing of the paper, or decision to submit the paper for publication. \u003c/p\u003e\n\u003ch2\u003eCompeting interests \u003c/h2\u003e\n\u003cp\u003eAll authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eTransparency statement \u003c/h2\u003e\n\u003cp\u003eThe lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.\u003c/p\u003e\n\u003ch2\u003eDissemination to participants and related patient and public communities\u003c/h2\u003e\n\u003cp\u003eDissemination to participants is not possible as this study analysed pseudonymised data only. Dissemination to women, families, and healthcare practitioners will be undertaken via social media and the programme website (https://verdiproject.org/) and through summary articles for professional and third-sector organisations.\u003c/p\u003e\n\u003cp\u003eThis is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.\u003c/p\u003e\n\u003ch2\u003eData availability \u003c/h2\u003e\n\u003cp\u003eThe data is provided by patients and collected by the NHS as part of their care and support. Details about Hospital Episode Statistics can be found here: https://digital.nhs.uk/services/data-access-request-service-dars/dars-products-and-services/data-set-catalogue/hospital-episode-statistics. Details about data from COVID-19 Second Generation Surveillance System (Pillar 1) can be found here: https://digital.nhs.uk/services/data-access-request-service-dars/dars-products-and-services/data-set-catalogue/covid-19-second-generation-surveillance-system-sgss, and details about Non-hospital Antigen Testing Results (Pillar 2) can be found here: https://digital.nhs.uk/services/data-access-request-service-dars/dars-products-and-services/data-set-catalogue/covid-19-uk-non-hospital-antigen-testing-results-pillar-2. \u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from NHS England but restrictions apply to the availability of these data, which were used under licence for the current study (DARS-NIC-393510-D6H1D-v9.3), and so are not publicly available. The data governance arrangements for the study do not allow us to redistribute HES data to other parties. Researchers interested in accessing HES data can apply for access through NHS Digital’s Data Access Request Service (DARS) https://dataaccessrequest.hscic.gov.uk. \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAllotey, J. \u003cem\u003eet al.\u003c/em\u003e Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. \u003cem\u003eBMJ\u003c/em\u003e \u003cstrong\u003e370\u003c/strong\u003e, m3320 (2020).\u003c/li\u003e\n\u003cli\u003eLangley-Evans, S. C. \u0026amp; McMullen, S. Developmental Origins of Adult Disease. \u003cem\u003eMedical Principles and Practice\u003c/em\u003e \u003cstrong\u003e19\u003c/strong\u003e, 87\u0026ndash;98 (2010).\u003c/li\u003e\n\u003cli\u003eLacagnina, S. 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A causal mechanism for childhood acute lymphoblastic leukaemia. \u003cem\u003eNat Rev Cancer\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 471\u0026ndash;484 (2018).\u003c/li\u003e\n\u003cli\u003eCandel-Pau, J. \u003cem\u003eet al.\u003c/em\u003e Do timing and severity of gestational COVID-19 impact perinatal and neonatal outcomes? \u003cem\u003eJ Perinatol\u003c/em\u003e 1\u0026ndash;8 (2024) doi:10.1038/s41372-024-02179-9.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, Respiratory tract infections, pregnancy complications, health services, public health","lastPublishedDoi":"10.21203/rs.3.rs-8823144/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8823144/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective \u003c/strong\u003eTo examine the impact of in utero exposure to SARS-CoV-2 virus on children’s emergency and planned hospital admissions up to 40 months of age.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDesign, Setting, and Participants \u003c/strong\u003eNationwide, birth cohort study using multiple linked administrative datasets in England. Children with conception start dates between 1\u003csup\u003est\u003c/sup\u003e February and 31\u003csup\u003est\u003c/sup\u003e July 2020 and born alive to mothers residing in England, followed for 40 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExposure \u003c/strong\u003eIn utero SARS-CoV-2 exposure (i.e., maternal infection in pregnancy) during wild-type or Alpha variant dominant periods, characterised via linkage to national testing and hospital data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMain Outcome Measures \u003c/strong\u003eFirst emergency or planned admission before 40 months of age.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eOf the 262,086 children included, 14,717 (5.6%) were exposed to SARS-CoV-2 in utero: 6,888 (2.6%) during the wild-type period and 7,829 (3.0%) during the Alpha period. Overall, 89,189 children (34.0%) had at least one emergency admission and 24,635 (9.4%) had at least one planned admission. After adjusting for socio-demographic characteristics and maternal chronic conditions, compared to children unexposed during either period, children exposed in utero during the wild-type period showed no difference in time to the first emergency admission, while Alpha-period exposure was associated with an 8% lower hazard (adjusted HR: 0.92, 99% CI: 0.87 to 0.97). No difference was found in the time to the first planned admission between in utero exposed groups and the unexposed group, nor in the time to either the first emergency or planned admission based on the trimester of in utero exposure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003eIn this large national birth cohort in England, we did not find an increased hazard of hospital admission by 40 months of age associated with in utero exposure to SARS-CoV-2, in the absence of maternal vaccination. Further follow-up is needed to assess late-onset outcomes and the effect of later circulating SARS-CoV-2 variants. Continued investment in linked maternal-child health data is essential to monitor both immediate and long-term effect of emerging infections during pregnancy.\u003c/p\u003e","manuscriptTitle":"Impact of in utero exposure to SARS-CoV-2 on children’s hospital admission: National birth cohort study of 262,000 children in England","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-04 09:45:15","doi":"10.21203/rs.3.rs-8823144/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-08T01:05:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T16:48:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T15:20:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T13:40:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T21:11:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"176022421243231341945895519021373106072","date":"2026-04-24T12:54:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"275624554223951961776604449716737488326","date":"2026-04-24T12:35:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"276362631124354785927054004207936553653","date":"2026-04-24T12:27:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-22T17:10:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"126047104065329315766117985138530396336","date":"2026-04-22T17:04:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"258571838138724907212657443503396514365","date":"2026-04-22T13:31:49+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-22T12:06:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-22T12:01:48+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-18T23:26:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-16T13:58:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-02-16T13:53:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"25c902b4-96ef-4bcd-8509-588202f798b1","owner":[],"postedDate":"May 4th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-08T01:05:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T16:48:02+00:00","index":128,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T15:20:51+00:00","index":127,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T13:40:02+00:00","index":126,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T21:11:29+00:00","index":125,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":67272227,"name":"Health sciences/Diseases"},{"id":67272228,"name":"Health sciences/Health care"},{"id":67272229,"name":"Health sciences/Medical research"},{"id":67272230,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2026-05-08T01:10:06+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-04 09:45:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8823144","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8823144","identity":"rs-8823144","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}