Management and implications of severe COVID‐19 in pregnancy in the UK: data from the UK Obstetric Surveillance System national cohort

Abstract Introduction There is a lack of population level data on risk factors and impact of severe COVID‐19 in pregnancy. The aims of this study were to determine the characteristics, and maternal and perinatal outcomes associated with severe COVID‐19 in pregnancy compared with those with mild and moderate COVID‐19 and to explore the impact of timing of birth. Material and methods This was a secondary analysis of a national, prospective cohort study. All pregnant women admitted to hospital in the UK with symptomatic SARS‐CoV‐2 from March 1, 2020 to October 31, 2021 were included. The severity of maternal infection (need for high flow or invasive ventilation, intensive care admission or died), pregnancy and perinatal outcomes, and the impact of timing of birth were analyzed using multivariable logistic regression. Results Of 4436 pregnant women, 13.9% (n = 616) had severe infection. Women with severe infection were more likely to be aged ≥30 years (adjusted odds ratio [aOR] aged 30–39 1.48, 95% confidence interval [CI] 1.20–1.83), be overweight or obese (aOR 1.73, 95% CI 1.34–2.25 and aOR 2.52 95% CI 1.97–3.23, respectively), be of mixed ethnicity (aOR 1.93, 95% CI 1.17–3.21) or have gestational diabetes (aOR 1.43, 95% CI 1.09–1.87) compared with those with mild or moderate infection. Women with severe infection were more likely to have a pre‐labor cesarean birth (aOR 8.84, 95% CI 6.61–11.83), a very or extreme preterm birth (28–31+ weeks’ gestation, aOR 18.97, 95% CI 7.78–14.85; <28 weeks’ gestation, aOR 12.35, 95% CI 6.34–24.05) and their babies were more likely to be stillborn (aOR 2.51, 95% CI 1.35–4.66) or admitted to a neonatal unit (aOR 11.61, 95% CI 9.28–14.52). Of 112 women with severe infection who were discharged and gave birth at a later admission, the majority gave birth ≥36 weeks (85.7%), noting that three women in this group (2.7%) had a stillbirth. Conclusions Severe COVID‐19 in pregnancy increases the risk of adverse outcomes. Information to promote uptake of vaccination should specifically target those at greatest risk of severe outcomes. Decisions about timing of birth should be informed by multidisciplinary team discussion; however, our data suggest that women with severe infection who do not require early delivery have mostly good outcomes but that those with severe infection at term may warrant rapid delivery.


| INTRODUC TI ON
Recent evidence suggests that approximately 8% of pregnant women with COVID-19 on universal screening develop severe infection, [1][2][3] with 3.2% admitted to an intensive care unit (ITU) and 9.2% having pneumonia. 1 In addition to being at increased risk of any infection with SARS-CoV-2 in pregnancy, women aged >35 years (odds ratio [OR] 2.11), that are overweight (body mass index [BMI] >30 kg/ m 2 ; OR 2.71), are of non-white ethnicity (OR 1.66) or that have any preexisting medical comorbidity (OR 1.70), have an increased risk of being admitted to ITU. 1 These data were predominantly from single-center cohorts and included a small number of women with severe outcomes. Evidence regarding the impact of gestational age on severity is also unclear. Although a systematic review reported from four studies that risk was not increased in the third trimester (n = 29), 1 other studies have reported increased prevalence of symptomatic 4 and severe infection in the later stages of pregnancy. 3,5 A high proportion (17%) of women with COVID-19 in pregnancy are reported to have a preterm birth (<37 weeks of pregnancy), which reflects nearly a 50% increase compared with those without COVID-19 (OR 1.47), 1 and the odds of their baby being admitted to a neonatal unit (NNU) are also increased (OR 4.89). 1 Evidence from subsequent small studies suggests that women with severe illness are more likely to have a preterm birth (41.8% vs 15.2%, 2 45.4% vs 5.2% 3 ) and their babies more likely to be admitted to neonatal units (NNU, ie intensive or specialist care) than those with mild illness (50.4% vs 19.2%). 2 However, neither study reported the degree of prematurity or relation to timing of infection. Current guidance states that the decision to initiate birth in order to facilitate maternal resuscitation, at the cost of greater prematurity, should be informed by individual assessment and multidisciplinary team discussion. 6 However, there is a lack of robust data describing the clinical course of severe COVID-19 in pregnancy and the impact of early delivery on maternal and neonatal morbidity and mortality. 7 In the UK, the Delta variant of concern (B.1.617.2) became dominant in late May 2021 8 and the proportion of women that experienced severe disease in pregnancy during this period was significantly increased (35.8% in Alpha-dominant period vs 45.0% in Delta-dominant period; adjusted odds ratio [aOR] 1.53). 9 Therefore, improved knowledge on the risks and outcomes associated with severe infection is urgently required to inform clinical management and prevention policy. The aim of this study was to determine the incidence, characteristics, and maternal and perinatal outcomes of severe COVID-19 in pregnant women admitted to hospital in the UK.
The secondary aim was to explore the impact of timing of birth in relation to maternal and perinatal outcomes.

| MATERIAL AND ME THODS
This study was a secondary analysis of a prospective observational cohort study conducted using the UK Obstetric Surveillance System (UKOSS), across all 194 hospitals in the UK with a consultant-led maternity unit. 10 The methods have been extensively described. 9 All pregnant women admitted to hospital with confirmed SARS-CoV-2 infection between March 1, 2020 and October 31, 2021, were notified to UKOSS. Reporters who had notified a case but not returned data, received email reminders at weekly intervals for 3 weeks. In addition to receipt of real-time reports, zero reports were confirmed to ensure completeness.
Women were defined as having confirmed symptomatic SARS-CoV-2 if they were admitted to hospital during pregnancy or within 2 days of giving birth with symptoms of COVID-19 (fever, cough, sore throat, breathlessness, headache, fatigue, limb or joint pain, vomiting, rhinorrhea, diarrhea, anosmia or SARS CoV-2 pneumonia on imaging) and had a positive SARS-CoV-2 PCR test during their infection who were discharged and gave birth at a later admission, the majority gave birth ≥36 weeks (85.7%), noting that three women in this group (2.7%) had a stillbirth.

Conclusions:
Severe COVID-19 in pregnancy increases the risk of adverse outcomes.
Information to promote uptake of vaccination should specifically target those at greatest risk of severe outcomes. Decisions about timing of birth should be informed by multidisciplinary team discussion; however, our data suggest that women with severe infection who do not require early delivery have mostly good outcomes but that those with severe infection at term may warrant rapid delivery.

K E Y W O R D S
adverse maternal and perinatal outcome, COVID-19, population cohort, pregnancy

Key message
Pregnant women who are ≥30 years old, overweight, of mixed ethnicity or have gestational diabetes have an increased risk of severe COVID-19, which increases adverse outcomes for mother and baby. Information to promote vaccination should especially target these groups.
admission or in the 7 days prior to admission ( Figure S1). Information on women who died or who had a stillbirth or neonatal death, was cross-checked with MBRRACE-UK, the organization that undertakes maternal and perinatal death surveillance in the UK. 11 The primary outcome was a composite outcome indicating severity of SARS-CoV-2 infection as shown in Table 1. Categories were developed based on the World Health Organization criteria. 12 Each of the components of these categories was also analyzed separately, as were pregnancy and perinatal outcomes including mode and gestation of birth, stillbirth, live birth, admission to NNU and neonatal death.  Figure S2). 13,14 Based on this, the model was adjusted for sociodemographics (age, ethnicity, BMI and employment), presence of one or more medical comorbidities that may increase the risk of severe infection (Table S1) were identified as those with strong associations with maternal severity and few levels. 15 Interaction terms were added and subsequent likelihood ratio testing on removal performed, with a P < 0.05 considered as evidence of significant interaction, with none found.

| Statistical analyses
Exploratory analysis was undertaken to examine the impact of timing of birth on pregnancy and perinatal outcomes. Pregnancy and perinatal outcomes were compared for two groups of women: those whose birth was expedited due to maternal COVID-19 disease and those who were discharged following their COVID-19 admission while still pregnant and then gave birth at a later admission. Women who gave birth spontaneously at the time of their infection were excluded from this analysis. Additionally, logistic regression was used to compare the probability of neonatal adverse outcome (admission to NNU or neonatal death) between those with mild/moderate or severe COVID-19, according to the number of days from diagnosis to delivery (divided into quartiles), by inclusion of gestation at time of COVID-19 diagnosis (in weeks) and time to delivery as effect modifiers and adjustment for the final covariate model.  Table 2. After adjustment, women with severe infection were 48% more likely to be aged 30-39 years and 2.6-fold more likely to be 40 years or older compared with those with mild or moderate infection. Overall, nearly two-thirds of women were overweight or obese (65.8%, n = 2792). Women with severe infection were more than twice as likely to be obese compared with those with mild to moderate infection. Women with severe infection were also more likely to be of mixed ethnicity, with a nonsignificant increased odds of being from Black, Asian and other ethnic groups compared with being of white ethnicity (  after diagnosis compared with those that give birth ≤2 days after diagnosis, suggesting that rapid delivery in women with severe infection at term may be beneficial.

| DISCUSS ION
This national cohort study demonstrated that between March 1, 2020 and October 31, 2021 there were 4436 pregnant women admitted to hospital across the UK with confirmed symptomatic COVID-19, more than one in 10 of whom had severe infection.
Women with severe infection were more likely to be aged ≥30 years, be overweight or obese, be of mixed ethnicity, have gestational diabetes and be admitted at earlier gestations than were women with mild or moderate COVID-19.
A high proportion of women with severe infection had pneumonia, required respiratory support and were admitted to intensive care. However, the proportion of women that received treatment with standard pharmacological therapies for COVID-19 was low.
Women with severe infection were more likely to have extreme (<28 weeks' gestation) and very (<32 weeks' gestation) preterm  to be vaccinated. 16 This analysis therefore adds to the field by demonstrating the need to improve vaccine uptake and tackle misinformation in those at greatest risk of severe infection, especially where it is known that current vaccine uptake is low in these groups.
In keeping with other studies, 2,3 a high proportion of women with severe COVID-19 have an iatrogenic preterm birth and evidence on its optimal timing in the presence of severe infection is therefore needed to inform practice. One further study, similar to however, that analysis was limited by failure to report or take account of the gestation at infection. Although it is a strength that our analysis of timing of birth could take account of gestational age and severity of infection, this is likely still limited by residual confounding by indication, in that women with severe infection are most likely to be delivered rapidly regardless of gestation, with adverse impact on the baby, and it is therefore not possible to conclude the optimal timing of delivery in women with severe infection at preterm gestations. Although we provide new, largely reassuring data that the majority of outcomes for women who have severe infection and were discharged from hospital prior to giving birth were good, there was a small number of stillbirths in this group, emphasizing the importance of ongoing monitoring. In addition, taking account of time from diagnosis to delivery has highlighted a trend towards greater neonatal adverse outcomes in women with severe infection who gave birth 3-10 days after diagnosis compared with those that give birth ≤2 days after diagnosis. Therefore, we conclude that decisions around timing of birth are complex and need to be informed by multidisciplinary team discussion.

| CON CLUS ION
Severe COVID-19 in pregnancy is relatively rare but it has a significant negative impact on both mother and baby. A very high proportion of women with severe COVID-19 have a cesarean birth, with their babies born preterm and admitted to the NNU. Prevention of COVID-19 is therefore key. This analysis identifies several characteristics that increase the risk of severe COVID-19 in pregnancy and demonstrates promising vaccine efficacy. Current guidance in the UK recommends vaccination of all pregnant women, and this analysis demonstrates the need to specifically target misinformation and improve vaccine uptake in those identified as being at greatest risk.
In keeping with the wider literature, most women admitted to hospital with COVID-19 are in their third trimester; women should be informed of the greater risk at this time to allow consideration of earlier vaccination and measures to reduce exposure where possible. This analysis provides useful data that most women with severe infection who were discharged pregnant, went on to give birth at term with a low probability of neonatal adverse outcome, but that those with severe infection at term may warrant rapid delivery.
Decisions about timing of birth should continue to be made following individual multidisciplinary team discussion.