Pregnancy outcomes after SARS-CoV-2 infection in periods dominated by delta and omicron variants in Scotland: a population-based cohort study.

BACKGROUND: Evidence suggests that the SARS-CoV-2 omicron (B.1·1.529) is associated with lower risks of adverse outcomes than the delta (B.1.617.2) variant among the general population. However, little is known about outcomes after omicron infection in pregnancy. We aimed to assess and compare short-term pregnancy outcomes after SARS-CoV-2 delta and omicron infection in pregnancy. METHODS: We did a national population-based cohort study of women who had SARS-CoV-2 infection in pregnancy between May 17, 2021, and Jan 31, 2022. The primary maternal outcome was admission to critical care within 21 days of infection or death within 28 days of date of infection. Pregnancy outcomes were preterm birth and stillbirth within 28 days of infection. Neonatal outcomes were death within 28 days of birth, and low Apgar score (<7 of 10, for babies born at term) or neonatal SARS-CoV-2 infection in births occurring within 28 days of maternal infection. We used periods when variants were dominant in the general Scottish population, based on 50% or more of cases being S-gene positive (delta variant, from May 17 to Dec 14, 2021) or S-gene negative (omicron variant, from Dec 15, 2021, to Jan 31, 2022) as surrogates for variant infections. Analyses used logistic regression, adjusting for maternal age, deprivation quintile, ethnicity, weeks of gestation, and vaccination status. Sensitivity analyses included restricting the analysis to those with first confirmed SARS-CoV-2 infection and using periods when delta or omicron had 90% or more predominance. FINDINGS: Between May 17, 2021, and Jan 31, 2022, there were 9923 SARS-CoV-2 infections in 9823 pregnancies, in 9817 women in Scotland. Compared with infections in the delta-dominant period, SARS-CoV-2 infections in pregnancy in the omicron-dominant period were associated with lower maternal critical care admission risk (0·3% [13 of 4968] vs 1·8% [89 of 4955]; adjusted odds ratio 0·25, 95% CI 0·14-0·44) and lower preterm birth within 28 days of infection (1·8% [37 of 2048] vs 4·2% [98 of 2338]; 0·57, 95% CI 0·38-0·87). There were no maternal deaths within 28 days of infection. Estimates of low Apgar scores were imprecise due to low numbers (5 [1·2%] of 423 with omicron vs 11 [2·1%] of 528 with delta, adjusted odds ratio 0·72, 0·23-2·32). There were fewer stillbirths in the omicron-dominant period than in the delta-dominant period (4·3 [2 of 462] per 1000 births vs 20·3 [13 of 639] per 1000) and no neonatal deaths during the omicron-dominant period (0 [0 of 460] per 1000 births vs 6·3 [4 of 626] per 1000 births), thus numbers were too small to support adjusted analyses. Rates of neonatal infection were low in births within 28 days of maternal SARS-CoV-2 infection, with 11 cases of neonatal SARS-CoV-2 in the delta-dominant period, and 1 case in the omicron-dominant period. Of the 15 stillbirths, 12 occurred in women who had not received two or more doses of COVID-19 vaccination at the time of SARS-CoV-2 infection in pregnancy. All 12 cases of neonatal SARS-CoV-2 infection occurred in women who had not received two or more doses of vaccine at the time of maternal infection. Findings in sensitivity analyses were similar to those in the main analyses. INTERPRETATION: Pregnant women infected with SARS-CoV-2 were substantially less likely to have a preterm birth or maternal critical care admission during the omicron-dominant period than during the delta-dominant period. FUNDING: Wellcome Trust, Tommy's charity, Medical Research Council, UK Research and Innovation, Health Data Research UK, National Core Studies-Data and Connectivity, Public Health Scotland, Scottish Government Health and Social Care, Scottish Government Chief Scientist Office, National Research Scotland.

A population-based matched cohort study of early pregnancy outcomes following COVID-19 vaccination and SARS-CoV-2 infection.

Data on the safety of COVID-19 vaccines in early pregnancy are limited. We conducted a national, population-based, matched cohort study assessing associations between COVID-19 vaccination and miscarriage prior to 20 weeks gestation and, separately, ectopic pregnancy. We identified women in Scotland vaccinated between 6 weeks preconception and 19 weeks 6 days gestation (for miscarriage; n = 18,780) or 2 weeks 6 days gestation (for ectopic; n = 10,570). Matched, unvaccinated women from the pre-pandemic and, separately, pandemic periods were used as controls. Here we show no association between vaccination and miscarriage (adjusted Odds Ratio [aOR], pre-pandemic controls = 1.02, 95% Confidence Interval [CI] = 0.96-1.09) or ectopic pregnancy (aOR = 1.13, 95% CI = 0.92-1.38). We undertook additional analyses examining confirmed SARS-CoV-2 infection as the exposure and similarly found no association with miscarriage or ectopic pregnancy. Our findings support current recommendations that vaccination remains the safest way for pregnant women to protect themselves and their babies from COVID-19.

Second-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.

We investigated thrombocytopenic, thromboembolic and hemorrhagic events following a second dose of ChAdOx1 and BNT162b2 using a self-controlled case series analysis. We used a national prospective cohort with 2.0 million(m) adults vaccinated with two doses of ChAdOx or 1.6 m with BNT162b2. The incidence rate ratio (IRR) for idiopathic thrombocytopenic purpura (ITP) 14-20 days post-ChAdOx1 second dose was 2.14, 95% confidence interval (CI) 0.90-5.08. The incidence of ITP post-second dose ChAdOx1 was 0.59 (0.37-0.89) per 100,000 doses. No evidence of an increased risk of CVST was found for the 0-27 day risk period (IRR 0.83, 95% CI 0.16 to 4.26). However, few (≤5) events arose within this risk period. It is perhaps noteworthy that these events all clustered in the 7-13 day period (IRR 4.06, 95% CI 0.94 to 17.51). No other associations were found for second dose ChAdOx1, or any association for second dose BNT162b2 vaccination. Second dose ChAdOx1 vaccination was associated with increased borderline risks of ITP and CVST events. However, these events were rare thus providing reassurance about the safety of these vaccines. Further analyses including more cases are required to determine more precisely the risk profile for ITP and CVST after a second dose of ChAdOx1 vaccine.

Vaccine effectiveness of two-dose BNT162b2 against symptomatic and severe COVID-19 among adolescents in Brazil and Scotland over time: a test-negative case-control study.

BACKGROUND: Little is known about vaccine effectiveness over time among adolescents, especially against the SARS-CoV-2 omicron (B.1.1.529) variant. This study assessed the associations between time since two-dose vaccination with BNT162b2 and the occurrence of symptomatic SARS-CoV-2 infection and severe COVID-19 among adolescents in Brazil and Scotland. METHODS: We did test-negative, case-control studies in adolescents aged 12-17 years with COVID-19-related symptoms in Brazil and Scotland. We linked records of SARS-CoV-2 RT-PCR and antigen tests to national vaccination and clinical records. We excluded tests from individuals who did not have symptoms, were vaccinated before the start of the national vaccination programme, received vaccines other than BNT162b2 or a SARS-CoV-2 booster dose of any kind, or had an interval between their first and second dose of fewer than 21 days. Additionally, we excluded negative SARS-CoV-2 tests recorded within 14 days of a previous negative test, negative tests recorded within 7 days after a positive test, any test done within 90 days after a positive test, and tests with missing sex and location information. Cases (SARS-CoV-2 test-positive adolescents) and controls (test-negative adolescents) were drawn from a sample of individuals in whom tests were collected within 10 days of symptom onset. We estimated the adjusted odds ratio and vaccine effectiveness against symptomatic COVID-19 for both countries and against severe COVID-19 (hospitalisation or death) for Brazil across fortnightly periods. FINDINGS: We analysed 503 776 tests from 2 948 538 adolescents in Brazil between Sept 2, 2021, and April 19, 2022, and 127 168 tests from 404 673 adolescents in Scotland between Aug 6, 2021, and April 19, 2022. Vaccine effectiveness peaked at 14-27 days after the second dose in both countries during both waves, and was significantly lower against symptomatic infection during the omicron-dominant period in Brazil (64·7% [95% CI 63·0-66·3]) and in Scotland (82·6% [80·6-84·5]), than it was in the delta-dominant period (80·7% [95% CI 77·8-83·3] in Brazil and 92·8% [85·7-96·4] in Scotland). Vaccine efficacy started to decline from 27 days after the second dose for both countries, reducing to 5·9% (95% CI 2·2-9·4) in Brazil and 50·6% (42·7-57·4) in Scotland at 98 days or more during the omicron-dominant period. In Brazil, protection against severe disease remained above 80% from 28 days after the second dose and was 82·7% (95% CI 68·8-90·4) at 98 days or more after receiving the second dose. INTERPRETATION: We found waning vaccine protection of BNT162b2 against symptomatic COVID-19 infection among adolescents in Brazil and Scotland from 27 days after the second dose. However, protection against severe COVID-19 outcomes remained high at 98 days or more after the second dose in the omicron-dominant period. Booster doses for adolescents need to be considered. FUNDING: UK Research and Innovation (Medical Research Council), Scottish Government, Health Data Research UK BREATHE Hub, Fiocruz, Fazer o Bem Faz Bem programme, Brazilian National Research Council, and Wellcome Trust. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

BNT162b2 and ChAdOx1 nCoV-19 vaccinations, incidence of SARS-CoV-2 infections and COVID-19 hospitalisations in Scotland in the Delta era.

Background: The emergence of the B.1.617.2 Delta variant of concern was associated with increasing numbers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and COVID-19 hospital admissions. We aim to study national population level SARS-CoV-2 infections and COVID-19 associated hospitalisations by vaccination status to provide insight into the association of vaccination on temporal trends during the time in which the SARS-CoV-2 Delta variant became dominant in Scotland. Methods: We used the Scotland-wide Early Pandemic Evaluation and Enhanced Surveillance (EAVE II) platform, covering the period when Delta was pervasive (May 01 to October 23, 2021). We performed a cohort analysis of every vaccine-eligible individual aged 20 or over from across Scotland. We determined the vaccination coverage, SARS-CoV-2 incidence rate and COVID-19 associated hospitalisations incidence rate. We then stratified those rates by age group, vaccination status (defined as "unvaccinated", "partially vaccinated" (1 dose), or "fully vaccinated" (2 doses)), vaccine type (BNT162b2 or ChAdOx1 nCoV-19), and coexisting conditions known to be associated with severe COVID-19 outcomes. Results: During the follow-up of 4 183 022 individuals, there were 407 405 SARS-CoV-2 positive cases with 10 441 (2.6%) associated with a hospital admission. Those vaccinated with two doses (defined as fully vaccinated in the current study) of either vaccine had lower incidence rates of SARS-CoV-2 infections and much lower incidence rates of COVID-19 associated hospitalisations than those unvaccinated in the Delta era in Scotland. Younger age groups were substantially more likely to get infected. In contrast, older age groups were much more likely to be hospitalised. The incidence rates stratified by coexisting conditions were broadly comparable with the overall age group patterns. Conclusions: This study suggests that national population level vaccination was associated with a reduction in SARS-CoV-2 infections and COVID-19 associated hospitalisation in Scotland throughout the Delta era.

Two-dose ChAdOx1 nCoV-19 vaccine protection against COVID-19 hospital admissions and deaths over time: a retrospective, population-based cohort study in Scotland and Brazil.

BACKGROUND: Reports suggest that COVID-19 vaccine effectiveness is decreasing, but whether this reflects waning or new SARS-CoV-2 variants-especially delta (B.1.617.2)-is unclear. We investigated the association between time since two doses of ChAdOx1 nCoV-19 vaccine and risk of severe COVID-19 outcomes in Scotland (where delta was dominant), with comparative analyses in Brazil (where delta was uncommon). METHODS: In this retrospective, population-based cohort study in Brazil and Scotland, we linked national databases from the EAVE II study in Scotland; and the COVID-19 Vaccination Campaign, Acute Respiratory Infection Suspected Cases, and Severe Acute Respiratory Infection/Illness datasets in Brazil) for vaccination, laboratory testing, clinical, and mortality data. We defined cohorts of adults (aged ≥18 years) who received two doses of ChAdOx1 nCoV-19 and compared rates of severe COVID-19 outcomes (ie, COVID-19 hospital admission or death) across fortnightly periods, relative to 2-3 weeks after the second dose. Entry to the Scotland cohort started from May 19, 2021, and entry to the Brazil cohort started from Jan 18, 2021. Follow-up in both cohorts was until Oct 25, 2021. Poisson regression was used to estimate rate ratios (RRs) and vaccine effectiveness, with 95% CIs. FINDINGS: 1 972 454 adults received two doses of ChAdOx1 nCoV-19 in Scotland and 42 558 839 in Brazil, with longer follow-up in Scotland because two-dose vaccination began earlier in Scotland than in Brazil. In Scotland, RRs for severe COVID-19 increased to 2·01 (95% CI 1·54-2·62) at 10-11 weeks, 3·01 (2·26-3·99) at 14-15 weeks, and 5·43 (4·00-7·38) at 18-19 weeks after the second dose. The pattern of results was similar in Brazil, with RRs of 2·29 (2·01-2·61) at 10-11 weeks, 3·10 (2·63-3·64) at 14-15 weeks, and 4·71 (3·83-5·78) at 18-19 weeks after the second dose. In Scotland, vaccine effectiveness decreased from 83·7% (95% CI 79·7-87·0) at 2-3 weeks, to 75·9% (72·9-78·6) at 14-15 weeks, and 63·7% (59·6-67·4) at 18-19 weeks after the second dose. In Brazil, vaccine effectiveness decreased from 86·4% (85·4-87·3) at 2-3 weeks, to 59·7% (54·6-64·2) at 14-15 weeks, and 42·2% (32·4-50·6) at 18-19 weeks. INTERPRETATION: We found waning vaccine protection of ChAdOx1 nCoV-19 against COVID-19 hospital admissions and deaths in both Scotland and Brazil, this becoming evident within three months of the second vaccine dose. Consideration needs to be given to providing booster vaccine doses for people who have received ChAdOx1 nCoV-19. FUNDING: UK Research and Innovation (Medical Research Council), Scottish Government, Research and Innovation Industrial Strategy Challenge Fund, Health Data Research UK, Fiocruz, Fazer o Bem Faz Bem Programme; Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Association between multimorbidity and mortality in a cohort of patients admitted to hospital with COVID-19 in Scotland.

OBJECTIVES: We investigated the association between multimorbidity among patients hospitalised with COVID-19 and their subsequent risk of mortality. We also explored the interaction between the presence of multimorbidity and the requirement for an individual to shield due to the presence of specific conditions and its association with mortality. DESIGN: We created a cohort of patients hospitalised in Scotland due to COVID-19 during the first wave (between 28 February 2020 and 22 September 2020) of the pandemic. We identified the level of multimorbidity for the patient on admission and used logistic regression to analyse the association between multimorbidity and risk of mortality among patients hospitalised with COVID-19. SETTING: Scotland, UK. PARTICIPANTS: Patients hospitalised due to COVID-19. MAIN OUTCOME MEASURES: Mortality as recorded on National Records of Scotland death certificate and being coded for COVID-19 on the death certificate or death within 28 days of a positive COVID-19 test. RESULTS: Almost 58% of patients admitted to the hospital due to COVID-19 had multimorbidity. Adjusting for confounding factors of age, sex, social class and presence in the shielding group, multimorbidity was significantly associated with mortality (adjusted odds ratio 1.48, 95%CI 1.26-1.75). The presence of multimorbidity and presence in the shielding patients list were independently associated with mortality but there was no multiplicative effect of having both (adjusted odds ratio 0.91, 95%CI 0.64-1.29). CONCLUSIONS: Multimorbidity is an independent risk factor of mortality among individuals who were hospitalised due to COVID-19. Individuals with multimorbidity could be prioritised when making preventive policies, for example, by expanding shielding advice to this group and prioritising them for vaccination.

Temporal trends and forecasting of COVID-19 hospitalisations and deaths in Scotland using a national real-time patient-level data platform: a statistical modelling study.

BACKGROUND: As the COVID-19 pandemic continues, national-level surveillance platforms with real-time individual person-level data are required to monitor and predict the epidemiological and clinical profile of COVID-19 and inform public health policy. We aimed to create a national dataset of patient-level data in Scotland to identify temporal trends and COVID-19 risk factors, and to develop a novel statistical prediction model to forecast COVID-19-related deaths and hospitalisations during the second wave. METHODS: We established a surveillance platform to monitor COVID-19 temporal trends using person-level primary care data (including age, sex, socioeconomic status, urban or rural residence, care home residence, and clinical risk factors) linked to data on SARS-CoV-2 RT-PCR tests, hospitalisations, and deaths for all individuals resident in Scotland who were registered with a general practice on Feb 23, 2020. A Cox proportional hazards model was used to estimate the association between clinical risk groups and time to hospitalisation and death. A survival prediction model derived from data from March 1 to June 23, 2020, was created to forecast hospital admissions and deaths from October to December, 2020. We fitted a generalised additive spline model to daily SARS-CoV-2 cases over the previous 10 weeks and used this to create a 28-day forecast of the number of daily cases. The age and risk group pattern of cases in the previous 3 weeks was then used to select a stratified sample of individuals from our cohort who had not previously tested positive, with future cases in each group sampled from a multinomial distribution. We then used their patient characteristics (including age, sex, comorbidities, and socioeconomic status) to predict their probability of hospitalisation or death. FINDINGS: Our cohort included 5 384 819 people, representing 98·6% of the entire estimated population residing in Scotland during 2020. Hospitalisation and death among those testing positive for SARS-CoV-2 between March 1 and June 23, 2020, were associated with several patient characteristics, including male sex (hospitalisation hazard ratio [HR] 1·47, 95% CI 1·38-1·57; death HR 1·62, 1·49-1·76) and various comorbidities, with the highest hospitalisation HR found for transplantation (4·53, 1·87-10·98) and the highest death HR for myoneural disease (2·33, 1·46-3·71). For those testing positive, there were decreasing temporal trends in hospitalisation and death rates. The proportion of positive tests among older age groups (>40 years) and those with at-risk comorbidities increased during October, 2020. On Nov 10, 2020, the projected number of hospitalisations for Dec 8, 2020 (28 days later) was 90 per day (95% prediction interval 55-125) and the projected number of deaths was 21 per day (12-29). INTERPRETATION: The estimated incidence of SARS-CoV-2 infection based on positive tests recorded in this unique data resource has provided forecasts of hospitalisation and death rates for the whole of Scotland. These findings were used by the Scottish Government to inform their response to reduce COVID-19-related morbidity and mortality. FUNDING: Medical Research Council, National Institute for Health Research Health Technology Assessment Programme, UK Research and Innovation Industrial Strategy Challenge Fund, Health Data Research UK, Scottish Government Director General Health and Social Care.

Impact of COVID-19 on accident and emergency attendances and emergency and planned hospital admissions in Scotland: an interrupted time-series analysis.

OBJECTIVES: Following the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and the subsequent global spread of the 2019 novel coronavirus disease (COVID-19), health systems and the populations who use them have faced unprecedented challenges. We aimed to measure the impact of COVID-19 on the uptake of hospital-based care at a national level. DESIGN: The study period (weeks ending 5 January to 28 June 2020) encompassed the pandemic announcement by the World Health Organization and the initiation of the UK lockdown. We undertook an interrupted time-series analysis to evaluate the impact of these events on hospital services at a national level and across demographics, clinical specialties and National Health Service Health Boards. SETTING: Scotland, UK. PARTICIPANTS: Patients receiving hospital care from National Health Service Scotland. MAIN OUTCOME MEASURES: Accident and emergency (A&E) attendances, and emergency and planned hospital admissions measured using the relative change of weekly counts in 2020 to the averaged counts for equivalent weeks in 2018 and 2019. RESULTS: Before the pandemic announcement, the uptake of hospital care was largely consistent with historical levels. This was followed by sharp drops in all outcomes until UK lockdown, where activity began to steadily increase. This time-period saw an average reduction of -40.7% (95% confidence interval [CI]: -47.7 to -33.7) in A&E attendances, -25.8% (95% CI: -31.1 to -20.4) in emergency hospital admissions and -60.9% (95% CI: -66.1 to -55.7) in planned hospital admissions, in comparison to the 2018-2019 averages. All subgroup trends were broadly consistent within outcomes, but with notable variations across age groups, specialties and geography. CONCLUSIONS: COVID-19 has had a profoundly disruptive impact on hospital-based care across National Health Service Scotland. This has likely led to an adverse effect on non-COVID-19-related illnesses, increasing the possibility of potentially avoidable morbidity and mortality. Further research is required to elucidate these impacts.

Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II): protocol for an observational study using linked Scottish national data.

INTRODUCTION: Following the emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 and the ensuing COVID-19 pandemic, population-level surveillance and rapid assessment of the effectiveness of existing or new therapeutic or preventive interventions are required to ensure that interventions are targeted to those at highest risk of serious illness or death from COVID-19. We aim to repurpose and expand an existing pandemic reporting platform to determine the attack rate of SARS-CoV-2, the uptake and effectiveness of any new pandemic vaccine (once available) and any protective effect conferred by existing or new antimicrobial drugs and other therapies. METHODS AND ANALYSIS: A prospective observational cohort will be used to monitor daily/weekly the progress of the COVID-19 epidemic and to evaluate the effectiveness of therapeutic interventions in approximately 5.4 million individuals registered in general practices across Scotland. A national linked dataset of patient-level primary care data, out-of-hours, hospitalisation, mortality and laboratory data will be assembled. The primary outcomes will measure association between: (A) laboratory confirmed SARS-CoV-2 infection, morbidity and mortality, and demographic, socioeconomic and clinical population characteristics; and (B) healthcare burden of COVID-19 and demographic, socioeconomic and clinical population characteristics. The secondary outcomes will estimate: (A) the uptake (for vaccines only); (B) effectiveness; and (C) safety of new or existing therapies, vaccines and antimicrobials against SARS-CoV-2 infection. The association between population characteristics and primary outcomes will be assessed via multivariate logistic regression models. The effectiveness of therapies, vaccines and antimicrobials will be assessed from time-dependent Cox models or Poisson regression models. Self-controlled study designs will be explored to estimate the risk of therapeutic and prophylactic-related adverse events. ETHICS AND DISSEMINATION: We obtained approval from the National Research Ethics Service Committee, Southeast Scotland 02. The study findings will be presented at international conferences and published in peer-reviewed journals.