key: cord-0738565-rm6av6sj
authors: Stock, Sarah J.; Carruthers, Jade; Calvert, Clara; Denny, Cheryl; Donaghy, Jack; Goulding, Anna; Hopcroft, Lisa E. M.; Hopkins, Leanne; McLaughlin, Terry; Pan, Jiafeng; Shi, Ting; Taylor, Bob; Agrawal, Utkarsh; Auyeung, Bonnie; Katikireddi, Srinivasa Vittal; McCowan, Colin; Murray, Josie; Simpson, Colin R.; Robertson, Chris; Vasileiou, Eleftheria; Sheikh, Aziz; Wood, Rachael
title: SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland
date: 2022-01-13
journal: Nat Med
DOI: 10.1038/s41591-021-01666-2
sha: d4265216b3fec01c4e742def9409a16c2883c0be
doc_id: 738565
cord_uid: rm6av6sj

Population-level data on COVID-19 vaccine uptake in pregnancy and SARS-CoV-2 infection outcomes are lacking. We describe COVID-19 vaccine uptake and SARS-CoV-2 infection in pregnant women in Scotland, using whole-population data from a national, prospective cohort. Between the start of a COVID-19 vaccine program in Scotland, on 8 December 2020 and 31 October 2021, 25,917 COVID-19 vaccinations were given to 18,457 pregnant women. Vaccine coverage was substantially lower in pregnant women than in the general female population of 18−44 years; 32.3% of women giving birth in October 2021 had two doses of vaccine compared to 77.4% in all women. The extended perinatal mortality rate for women who gave birth within 28 d of a COVID-19 diagnosis was 22.6 per 1,000 births (95% CI 12.9−38.5; pandemic background rate 5.6 per 1,000 births; 452 out of 80,456; 95% CI 5.1−6.2). Overall, 77.4% (3,833 out of 4,950; 95% CI 76.2−78.6) of SARS-CoV-2 infections, 90.9% (748 out of 823; 95% CI 88.7−92.7) of SARS-CoV-2 associated with hospital admission and 98% (102 out of 104; 95% CI 92.5−99.7) of SARS-CoV-2 associated with critical care admission, as well as all baby deaths, occurred in pregnant women who were unvaccinated at the time of COVID-19 diagnosis. Addressing low vaccine uptake rates in pregnant women is imperative to protect the health of women and babies in the ongoing pandemic.

C omprehensive whole-population data on COVID-19 vaccine uptake in pregnancy and SARS-CoV-2 infection rates and COVID-19 outcomes are lacking 1 . Such data are required to help guide decision making by women, clinicians and policymakers on measures to prevent and control COVID-19 in pregnancy, in particular, vaccination.

The first case of SARS-CoV-2 in Scotland was identified on 1 March 2020. Different SARS-CoV-2 variants have predominated in subsequent waves of infection, with wild type predominant initially, the Alpha variant dominant from January 2021 and the Delta variant dominant from May 2021. SARS-CoV-2 testing was initially restricted due to limited availability, with availability in the community for any symptomatic adult available from 18 May 2020. Although not uniformly implemented in all maternity units, routine SARS-CoV-2 testing of maternity admissions was instituted from 1 December 2020.

Pregnant women do not seem to be more susceptible to SARS-CoV-2 infection than non-pregnant women, but they are at higher risk of severe COVID-19 disease [2] [3] [4] . Compared to non-pregnant women of reproductive age, pregnant women with SARS-CoV-2 infection are more likely to be admitted to critical care, receive invasive ventilation and extracorporeal membrane oxygenation and die 2, 3 . COVID-19 in pregnancy is associated with increased risk of the pregnancy specific complications pre-eclampsia, preterm birth and stillbirth 2, [5] [6] [7] [8] [9] [10] .

Despite widespread recognition of potential vulnerability to COVID-19, pregnant women were excluded from pre-marketing clinical trials studying COVID-19 vaccines 11, 12 . As a result, evidence to inform decision making on vaccination was largely absent when vaccination programs started and recommendations on vaccination in pregnancy have varied over time as well as by country 13 . Post-marketing surveillance data suggest that COVID-19 vaccine effectiveness is broadly similar to that in non-pregnant individuals 14, 15 . Data on the safety of vaccines in pregnancy comes from preclinical studies of COVID-19 vaccines in animals 16 , findings from women who had unanticipated pregnancies while participating in clinical trials 17 and accumulating pharmacovigilance data [18] [19] [20] [21] , all of which are reassuring regarding COVID-19 vaccine safety in pregnancy.

The COVID-19 vaccination program in Scotland commenced on 8 December 2020 and policies on the provision of COVID-19 vaccination to pregnant women evolved over time (Fig. 1) . From 16 April 2021 the recommendation has been that women who are pregnant should be offered vaccination at the same time as non-pregnant women, based on their age and clinical risk group and no pregnancy specific pre-vaccination counseling is required.

The COVID-19 in Pregnancy in Scotland (COPS) study (a sub-study of EAVE II (Early Pandemic Evaluation and Enhanced Surveillance of COVID- 19) 22, 23 ) is a national, prospective dynamic cohort of all women who were pregnant on, or became pregnant after, 1 March 2020; linked to SARS-CoV-2 infection data and

Cohort. We used the COPS database linked to records of COVID-19 vaccinations delivered and SARS-CoV-2 infections diagnosed up OCT. 30 Clarification that pregnant women in priority risk groups could be offered vaccine Infection and vaccination in pregnancy was defined as infection diagnosed or vaccination given at any point from the date of conception (2 + 0 weeks gestation) to the date the pregnancy ends inclusive. The date of first positive viral RT−PCR sample collection was taken as the date of onset of the first episode of COVID-19. Subsequent episodes were recorded if a positive viral RT−PCR sample was taken ≥90 d after a first positive sample.

To explore the impact of vaccination status on SARS-CoV-2 infection, women were grouped as follows: unvaccinated (no previous COVID-19 vaccination before the date of onset of COVID-19 or with one dose of vaccination ≤21 d before the date of onset); partially vaccinated (one dose of vaccination >21 d before the date of onset of COVID-19 or two doses of vaccination with the second dose administered ≤14 d before the date of onset); or fully vaccinated (two doses of vaccination with the second dose >14 d before the date of onset of . We also report the number of third or booster doses given, but have not included these in definitions of vaccination status, as third and booster doses in Scotland were only recommended from 14 and 20 September 2021, respectively. We used two different metrics to describe vaccination in pregnancy, monthly uptake in women who were pregnant during the month and coverage (the proportion of women who, at the time of giving birth, had been vaccinated, whether vaccination was before or during pregnancy). Uptake and coverage data in the general female population of reproductive age (18−44 years) were provided for context, generated from data collected by Public Health Scotland 26 .

COVID-19 vaccine uptake among pregnant women each month was consistently lower than that in the general female population of reproductive age (Fig. 3a) . Vaccine uptake was consistently lowest in younger (≤20 years) pregnant women and those living in the most deprived areas of Scotland (Fig. 3b,c) .

COVID-19 vaccine coverage increased over time, but has consistently been substantially lower among pregnant women than in the general female population of reproductive age (Fig. 3d) 

women. Between 1 March 2020 and 31 October 2021, there were 5,653 confirmed SARS-CoV-2 infections in pregnancy. Overall, rates of SARS-CoV-2 infection in pregnancy showed similar patterns to those in the general female population of reproductive age, with peaks of infection in October 2020, January 2021 and September 2021 (Fig. 4a ). SARS-CoV-2 infection rates have been consistently highest in pregnant women living in the most deprived areas and in younger, compared to older, pregnant women (Fig. 4b,c) .

Early in the pandemic, it is highly likely that there was under-ascertainment of cases of SARS-CoV-2 infection due to limited test availability and testing capacity (Fig. 4a) . Restricting the COPS cohort to only data from 1 December 2020 onward (the date that routine SARS-CoV-2 testing was recommended for all admissions to maternity care and the COVID-19 vaccination program started in Scotland) reduces the size of the cohort, but allows more comparable estimation of rates of severe outcomes (hospital admission, critical care admission and perinatal mortality) associated with SARS-CoV-2 infection in vaccinated and unvaccinated women. From 1 December 2020 onward, the COPS database included linked data on a total of 91,183 pregnancies in 87,694 women.

There were 4,950 confirmed SARS-CoV-2 infections in pregnancy from 1 December 2020. SARS-CoV-2 infections were relatively evenly spread throughout pregnancy (1,543 (31.2%; 95% CI 29.9−32.5) diagnosed in the first trimester of pregnancy; 1,850 (37.4%; 95% CI 36.0−38.7) in the second trimester; and 1,557 (31.5%; 95% CI 30.2−32.8) in the third trimester). Overall, 823 of the 4,950 SARS-CoV-2 infections in pregnancy from 1 December 2020 onward (16.6%; 95% CI 15.6−17.7) were associated with any hospital admission (date of onset of infection occurred during a hospital admission or within 14 d before admission) and 104 SARS-CoV-2 infections in pregnancy (2.1%; 95% CI 1.7−2.6) were associated with a critical care admission (date of onset of infection occurred during a critical care admission or within 21 d before admission). In first trimester SARS-CoV-2 infections, 6.7% (103 out of 1,543; 95% CI 5.5−8.1) were associated with any hospital admission, compared to 10.7% (198 out of 1,850 cases; 95% CI 9.3−12.2) of those in the second trimester and 33.5% (522 out of 1,557; 95% CI 31. To date, there has been one maternal death following SARS-CoV-2 infection in pregnancy in Scotland.

A total of 2,364 babies have been born to women who had SARS-CoV-2 infection in pregnancy between 1 December 2020 and 31 October 2021. Of these, 2,353 were live births, of which 241 were preterm births (<37 weeks gestation; preterm birth rate 10.2%; 95% CI 9.1−11.6). Overall, 610 of the live births and 101 of the preterm births occurred within 28 d of the date of onset of the mother's SARS-CoV-2 infection, giving a preterm birth rate among babies born within 28 d of SARS-CoV-2 infection of 16.6% (95% CI 13.7−19.8).

Of the 2,364 total births, 11 were stillbirths (deaths in utero ≥ 24 weeks gestation) and eight live births resulted in neonatal deaths (death within 28 d of birth), giving an extended perinatal mortality rate of 8.0 per 1,000 births following SARS-CoV-2 infection at any point in pregnancy (19 out of 2,364; 95% CI 5.0−12.8). Ten of the stillbirths and four neonatal deaths occurred in babies born within 28 d of the onset of maternal infection, giving an extended perinatal mortality rate of 22.6 per 1,000 births (14 out of 620, 95% 12.9−38.5) in this population. All perinatal deaths following SARS-CoV-2 infection in pregnancy occurred in women who were unvaccinated at the time of SARS-CoV-2 infection. We do not have access to detailed clinical records to assess whether COVID-19 directly or indirectly contributed to the preterm births and deaths seen following maternal infection.

For comparison, the background preterm birth rate during the pandemic (from 1 March 2020 to 31 October 2021) was 8.0% (6,381 out of 80,183 live births; 95% CI 7.8−8.1) and the extended perinatal mortality rate was 5.6 per 1,000 births (452 out of 80,456 total births; 95% CI 5.1−6.2). When restricted to babies born to women with no confirmed SARS-CoV-2 infection during pregnancy the preterm birth rate was 7.9% (6,083 out of 77,209 live births; 95% CI 7.7−8.1) and the extended perinatal mortality was 5.6 per 1,000 births (432 out of 77,470 total births; 95% CI 5.1−6.1). These preterm and perinatal mortality rates are shown in Fig. 5 , along with the preterm birth and extended perinatal mortality rates in women who received the COVID-19 vaccine in pregnancy (preterm birth rate of 8.6% (495 out of 5,752 live births in women who received COVID-19 vaccination in pregnancy; 95% CI 7.9−9.4) and 8.2% (134 out of 1,632 live births within 28 d of COVID-19 vaccination in pregnancy; 95% CI 7.0−9.6); and extended perinatal mortality of 4.3 per 1,000 births (25 out of 5,766 total births in women who received COVID-19 vaccination in pregnancy; 95% CI 2.9−6.4) and 4.3 per 1,000 births (7 out of 1,635 births within 28 d of COVID-19 vaccination; 95% CI 1.9−9.2)).

These population data provide new national evidence of low levels of vaccine uptake in pregnancy in Scotland, at a time when the Delta variant dominated, with only 32.3% of pregnant women giving birth in October having had two doses of the vaccine. Rates were lowest in younger women and populations who lived in the most deprived areas. SARS-CoV-2 infection rates in pregnancy closely mirrored those in the general population throughout the pandemic, when different SARS-CoV-2 variants predominated in Scotland (wild type initially, Alpha dominant from January 2021 and Delta dominant from May 2021). We found that severe complications known to be associated with COVID-19 in pregnancy (critical care admission and perinatal mortality) were more common in women who were unvaccinated at the time of COVID-19 diagnosis than in vaccinated pregnant women. Our data support the importance of women being vaccinated in pregnancy to prevent adverse outcomes associated with COVID-19. For extended perinatal mortality, for example, we find substantially elevated rates among women who had SARS-CoV-2 within 28 d of birth; conversely, for women who had COVID-19 vaccination, extended perinatal morality rates were similar to background rates and among women with no confirmed SARS-CoV-2. Although surveillance studies, which have mainly been based on women admitted to hospital, have suggested that pregnant women are at highest risk of severe COVID-19 disease in the third trimester 9 , these Scottish population data, capturing all virologically confirmed infections in a setting where testing has been widely available in hospital and the community, show that SARS-CoV-2 infections were relatively evenly spread throughout pregnancy. However, in line with findings from other studies, SARS-CoV-2 associated with hospital and critical care admission was more common as pregnancy progressed 4, 9 .

A strength of this study is that it used population data with high data completeness. Another strength is that the data describe changes in vaccine uptake over time, with most contemporary data available included. A caveat is that due to source data latency, the most recent 3 months' pregnancy data may be less complete (there may be some under-ascertainment of the most recent pregnancies and end of pregnancy outcomes). A limitation of our study is that the data presented are descriptive and we have not adjusted for the potential confounding influence of demographics, obstetric or medical conditions. A fully adjusted analysis of all pregnancy outcomes (including early pregnancy outcomes) is planned 27 when a greater number of end of pregnancy events have accumulated to ensure sufficient power, with appropriate historic comparison groups included 28 . Another limitation of our study is that we were unable to differentiate between hospital and critical care admissions due to SARS-CoV-2 infection from admissions for obstetric care with coincidental SARS-CoV-2 infection. SARS-CoV-2 infection in pregnancy may require admission in its own right for COVID-19 treatment; may trigger obstetric complications that require admission for maternity care or critical care (for example pre-eclampsia or delivery) or may be an incidental finding on admission. Due to this complexity, routine population data coding was not sufficiently detailed to identify coincidental infections. Nevertheless, comparison of hospital and critical care admissions within 28 d of SARS-CoV-2 infection, to those within 28 d of COVID-19 vaccination show different patterns (Fig. 6) . Given the established safety profile of vaccinations 18-21 , we would anticipate that post-vaccination admissions are likely to be predominantly for obstetric indications. The higher levels of second and third trimester hospital and critical care admissions following SARS-CoV-2 infections compared to vaccinations suggests that management of COVID-19 or its obstetric sequelae is the most likely reason for excess admissions. Our findings emphasize the need for continued efforts to increase vaccination uptake in pregnant women, especially in younger and more deprived populations 29 . The percentage of pregnant women vaccinated each month has declined since August 2021, reflecting the roll out of the vaccination program and the likelihood that an increasing proportion of women entering pregnancy are fully vaccinated. However, vaccine coverage, although increasing, remains low, with only a minority of pregnant women fully vaccinated by the time of delivery. Vaccine hesitancy in pregnancy thus requires addressing, especially in light of new recommendations for booster vaccination administration 3 months after the initial vaccination course to help protect against new variants such as Omicron 30 . Low levels of vaccine uptake in Scotland are likely to be representative of those in the United Kingdom and other high-income countries 31 (Public Health Wales, personal communication). Addressing low vaccine uptake in pregnant women is imperative to protect the health of women and babies.

Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at https://doi.org/10.1038/ s41591-021-01666-2.

Ethics and data governance. COPS is a sub-study of EAVE II, using unconsented data that is covered by National Research Ethics Service Committee, South East Scotland 02 approval reference REC 12/SS/0201: SA 2. COPS has been approved by the Public Benefit and Privacy Panel approval reference 2021-0116. Public Health Scotland and the Chief Medical Officer for Scotland are both (independent) data controllers for the national Abortion Act Scotland (AAS) database of termination of pregnancy notifications, thus the Chief Medical Officer has been informed of the use of AAS records. All data were housed within a secure trusted research environment within Public Health Scotland and accessed only by approved researchers.

Study design and population. COPS is a prospective dynamic pregnancy cohort, identifying all ongoing and completed pregnancies in Scotland, United Kingdom, since 1 March 2020 (ref. 24 ). In this manuscript we used the COPS database as updated in mid-November 2021 linked to records of COVID-19 vaccinations delivered and SARS-CoV-2 infections diagnosed up to and including 31 October 2021. Further detail on the datasets used are in the published protocol 24 . The COPS data dictionary is available online 28 .

Maternity data sources and linkage. Ongoing pregnancies were identified using antenatal booking appointment data. Completed pregnancies were identified using multiple sources, specifically general practitioner records, general acute hospital discharge records, Scottish Morbidity Record (SMR) 01; maternity hospital discharge records, SMR 02; notification of termination data as governed by AAS; National Records of Scotland (NRS) statutory live birth registrations; NHS Scotland live births; and NRS statutory stillbirth registrations. These datasets capture miscarriage, molar pregnancy or ectopic pregnancy requiring any general practitioner or hospital-based care, a termination of pregnancy, a live birth or a stillbirth.

The CHI number is a unique patient identifier used across all health records in Scotland, enabling integration of healthcare data. All source data incorporated into COPS were subject to a CHI-seeding process in which reported CHIs are reconciled to a contemporaneous unique patient identifier to ensure accurate linkage across sources.

Where multiple records within a data source pertained to the same woman, records were subject to event resolution, in which an iterative grouping procedure assigned records occurring within 83 d (less than 12 weeks) to a single healthcare event with its own universally unique identifier. The estimated date of conception was used to resolve records to a single pregnancy with a single universally unique identifier when gestation information was available and multiple records within a data source pertained to the same woman. Following event resolution, records from each individual data source were linked together to create a comprehensive record for each pregnancy and birth.

The COPS cohort is updated monthly and although source data latency means there is some instability in data for the most recent months, data are generally complete for conceptions and end of pregnancy events occurring up to 3 months previously.

National resources for SARS-CoV-2 infection data and COVID-19 vaccination data were incorporated into the study using CHI linkage.

Results are based on simple descriptive statistics, for example calculation of the proportion of vaccination events occurring by trimester, or the extended perinatal mortality rate following maternal infection, with relevant definitions provided. Wilson score estimates were used for 95% confidence intervals. All analyses were performed in R version 3.6.1.

Infection and vaccination in pregnancy was defined as infection diagnosed or vaccination given, at any point from the date of conception (2 + 0 weeks gestation) to the date the pregnancy ends inclusive (censoring infections and vaccinations occurring at 44 + 0 weeks gestation or over as it is very likely that these women have completed their pregnancy, but the end of pregnancy record has not yet been received by Public Health Scotland). The date of first positive viral RT−PCR sample collection was taken as the date of onset of the first episode of COVID-19. Subsequent episodes were recorded if a positive viral RT−PCR sample was taken ≥90 d after a first positive sample. Lateral flow test results were not considered. For the duration of our study period, anyone in Scotland having a positive lateral flow test was advised to have a follow up RT-PCR test to confirm COVID-19.

Vaccination status was defined as unvaccinated (no previous COVID-19 vaccination before the date of onset of COVID-19 or with one dose of vaccination ≤21 d before the date of onset), partially vaccinated (one dose of vaccination >21 d before the date of onset of COVID-19 or two doses of vaccination with the second dose ≤14 d before the date of onset) or fully vaccinated (two doses of vaccination with the second dose >14 d before the date of onset of COVID-19).

Monthly vaccine uptake was calculated as the number of pregnant women vaccinated during the month divided by the number of women with ongoing pregnancies at the start of the month of interest. Coverage of vaccination at delivery, was calculated as the proportion of women who, at the time of giving birth, have been vaccinated, whether vaccination was before or during pregnancy. Uptake in the general female population of reproductive age (18−44 years) was calculated as the number of women 18−44 years of age vaccinated during the month divided by the total number of women 18−44 years of age. Coverage in the general female population of reproductive age (18−44 years) was calculated as the cumulative number of women 18−44 years of age vaccinated by the end of each month divided by the total number of women 18−44 years of age. Numbers of women 18−44 years were derived from 2020 mid-year population estimates 26 . Although pregnant women 11−55 years of age were included in the COPS cohort, the comparator group was restricted to women 18−44 years. This is the Public Health Scotland standard definition of women of reproductive age and helps avoid bias in comparisons that could result from very low numbers of pregnancies at the extremes of reproductive age.

National hospital discharge records were linked to pregnancy SARS-CoV-2 RT−PCR testing data to identify women who were admitted to hospital around the time of infection. Admissions to general acute units (SMR 01) and maternity units (SMR 02) were included. SARS-CoV-2 infection was defined as associated with a hospital admission if the woman was admitted to hospital ≤14 d after the date of onset of COVID-19 or if the date of onset occurred at any point during a hospital admission (as per Public Health Scotland standard definition). National critical care discharge records from the Scottish Intensive Care Society Audit Group were used to identify women who were admitted to critical care. Completed admissions to all intensive care units and general (non-obstetric) high-dependency units across Scotland were included. Completed admissions to the seven obstetric high-dependency units that contribute data to Scottish Intensive Care Society Audit Group (collectively covering around 60% of deliveries in Scotland) were also included. SARS-CoV-2 infection was defined as associated with a critical care admission if the woman was admitted to critical care ≤21 d after the date of onset of COVID-19 or if the date of onset occurred at any point during a critical care admission (as per Public Health Scotland standard definition).

Comparator data. Comparator data from the general population of women of reproductive age (taken as 18−44 years for these analyses) were obtained from Public Health Scotland Open data with mid-year population estimate denominators (2020) 26 .

Data quality and completeness. The national Scottish data used within this study undergo regular assessment and quality assurance with high level of completeness and accuracy 32,33 . The CHI number was used to link the SARS-CoV-2 PCR testing data and COVID-19 vaccination records to the pregnancy records. Quality of linkage was assured by the testing, vaccination and pregnancy records including complete and accurate information on individuals' CHI number, as confirmed in the Results section.

Reporting Summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Aggregate data files of infections among pregnant women and the general population and vaccinations delivered to pregnant women and the general population are available here: https://www.opendata.nhs.scot/organization/health_ protection. Patient-level data underlying this article cannot be shared publicly due to data protection and confidentiality requirements. Public Health Scotland and the Chief Medical Officer for Scotland are the data holders for the data used in this study. Data can be made available to approved researchers for analysis after securing relevant permissions from the data holders via the Public Benefit and Privacy Panel. Enquiries regarding data availability should be directed to phs.edris@phs.scot.

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Research and Innovation. COPS has received additional funding from Tommy's charity and support from Sands charity

The funders had no role in the writing of the manuscript or the decision to submit it for publication. B.A. was supported by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 813546, the Baily Thomas Charitable Fund TRUST/VC/AC/ SG/469207686, the Data Driven Innovation and the UK Economic and

interpreted data and revised the manuscript for important intellectual content

Metadata and code are available at https://github.com/Public-Health-Scotland/ COPS-public.

We thank the EAVE II Patient Advisory Group and Sands charity for their support. COPS is a sub-study of EAVE II, which is funded by the Medical Research Council 

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A.S. and C.R. are members of the Scottish Government's COVID-19 Advisory Group. A.S. and C.R. are members of the New and Emerging Respiratory Virus Threats Advisory Group risk stratification subgroup. C.R. is a member of the Scientific Pandemic Influenza Group on Modeling. A.S. is a member of AstraZeneca's Thrombotic Thrombocytopenic Advisory Group. All roles are unremunerated. R.W. and C.R. are employed by Public Health Scotland. S.J.S. has received research grants paid to the institution from Wellcome Trust, Scottish Chief Scientist Office, National Institute of Healthcare Research and Tommy's during the course of this study. The remaining authors declare no competing interests.

The online version contains supplementary material available at https://doi.org/10.1038/s41591-021-01666-2.Correspondence and requests for materials should be addressed to Sarah J. Stock.Peer review information Nature Medicine thanks Gianluca Trifirò, Deborah Money and Denise Jamieson for their contribution to the peer review of this work. Jennifer Sargent was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.Reprints and permissions information is available at www.nature.com/reprints.