key: cord-0946537-k4ttbbix
authors: GUROL-URGANCI, Ipek; JARDINE, Jennifer E.; CARROLL, Fran; DRAYCOTT, Tim; DUNN, George; FREMEAUX, Alissa; HARRIS, Tina; HAWDON, Jane; MORRIS, Edward; MULLER, Patrick; WAITE, Lara; WEBSTER, Kirstin; VAN DER MEULEN, Jan; KHALIL, Asma
title: Maternal and perinatal outcomes of pregnant women with SARS-CoV-2 infection at the time of birth in England: national cohort study
date: 2021-05-20
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2021.05.016
sha: c3b692cecec24cfb21d9a1bbedc8cf01464d89cd
doc_id: 946537
cord_uid: k4ttbbix

Objective The aim of this study was to determine the association between SARS-CoV-2 infection at the time of birth and maternal and perinatal outcomes. Methods This is a population-based cohort study in England. The inclusion criteria were women with a recorded singleton birth between 29th May 2020 and 31st January 2021 in a national database of hospital admissions. Maternal and perinatal outcomes were compared between pregnant women with a laboratory-confirmed SARS-CoV-2 infection recorded in the birth episode and those without. Study outcomes were fetal death at or beyond 24 weeks’ gestation (stillbirth), preterm birth (<37 weeks gestation), small for gestational age infant (SGA; birthweight <10th centile), preeclampsia/eclampsia, induction of labor, mode of birth, specialist neonatal care, composite neonatal adverse outcome indicator, maternal and neonatal length of hospital stay following birth (3 days or more), 28-day neonatal and 42-day maternal hospital readmission. Adjusted odds ratios (aOR) and their 95% confidence interval (CI) for the association between SARS-CoV-2 infection status and outcomes were calculated using logistic regression, adjusting for maternal age, ethnicity, parity, pre-existing diabetes, pre-existing hypertension and socioeconomic deprivation measured using Index of Multiple Deprivation 2019. Models were fitted with robust standard errors to account for hospital-level clustering. The analysis of the neonatal outcomes was repeated for those born at term (≥ 37 weeks’ gestation) since preterm birth has been reported to be more common in pregnant women with SARS-CoV-2 infection. Results The analysis included 342,080 women, of whom 3,527 had laboratory-confirmed SARS-CoV-2 infection. Laboratory-confirmed SARS-CoV-2 infection was more common in women who were younger, of non-white ethnicity, primiparous, residing in the most deprived areas, or had comorbidities. Fetal death (aOR, 2.21, 95% CI 1.58-3.11; P<0.001) and preterm birth (aOR 2.17, 95% CI 1.96-2.42; P<0.001) occurred more frequently in women with SARS-CoV-2 infection than those without. Risk of preeclampsia/eclampsia (aOR 1.55, 95% CI 1.29-1.85; P<0.001), birth by emergency Cesarean delivery (aOR 1.63, 95% CI 1.51-1.76; P<0.001) and prolonged admission following birth (aOR 1.57, 95%CI 1.44-1.72; P<0.001) were significantly higher for women with SARS-CoV-2 infection than those without. There were no significant differences in the rate of other maternal outcomes. Risk of neonatal adverse outcome (aOR 1.45, 95% CI 1.27-1.66; P<0.001), need for specialist neonatal care (aOR 1.24, 95% CI 1.02-1.51; P=0.03), and prolonged neonatal admission following birth (aOR 1.61, 95% CI 1.49-1.75; P<0.001) were all significantly higher for infants with mothers with laboratory-confirmed SARS-CoV-2 infection. When the analysis was restricted to pregnancies delivered at term (≥37 weeks), there were no significant differences in neonatal adverse outcome (P=0.78), need for specialist neonatal care after birth (P=0.22) or neonatal readmission within four weeks of birth (P=0.05). Neonates born at term to mothers with laboratory-confirmed SARS-CoV-2 infection were more likely to have prolonged admission following birth (21.1% compared to 14.6%, aOR 1.61, 95% CI 1.49-1.75; P<0.001). Conclusions SARS-CoV-2 infection at the time of birth is associated with higher rates of fetal death, preterm birth, preeclampsia and emergency Cesarean delivery. There were no additional adverse neonatal outcomes, other than those related to preterm delivery. Pregnant women should be counseled regarding risks of SARS-COV-2 infection and should be considered a priority for vaccination.

Methods: This is a population-based cohort study in England. The inclusion criteria were 28 women with a recorded singleton birth between 29 th May 2020 and 31 st January 2021 in a 29 national database of hospital admissions. Maternal and perinatal outcomes were compared 30 between pregnant women with a laboratory-confirmed SARS-CoV-2 infection recorded in the 31 birth episode and those without. Study outcomes were fetal death at or beyond 24 weeks' 32 gestation (stillbirth), preterm birth (<37 weeks gestation), small for gestational age infant 33 (SGA; birthweight <10 th centile), preeclampsia/eclampsia, induction of labor, mode of birth, 34 specialist neonatal care, composite neonatal adverse outcome indicator, maternal and 35 neonatal length of hospital stay following birth (3 days or more), 28-day neonatal and 42-day 36 maternal hospital readmission. Adjusted odds ratios (aOR) and their 95% confidence interval 37 (CI) for the association between SARS-CoV-2 infection status and outcomes were calculated 38 using logistic regression, adjusting for maternal age, ethnicity, parity, pre-existing diabetes, 39

pre-existing hypertension and socioeconomic deprivation measured using Index of Multiple 40 Deprivation 2019. Models were fitted with robust standard errors to account for hospital-level 41

clustering. The analysis of the neonatal outcomes was repeated for those born at term (≥ 37 42 weeks' gestation) since preterm birth has been reported to be more common in pregnant 43 women with SARS-CoV-2 infection. for infants with mothers with laboratory-confirmed SARS-CoV-2 infection. When the analysis 61 was restricted to pregnancies delivered at term (≥37 weeks), there were no significant 62 differences in neonatal adverse outcome (P=0.78), need for specialist neonatal care after 63 birth (P=0. 22) women with severe COVID-19, leading to an observed increase in preterm birth and 86 neonatal unit admission for infants of infected mothers. 1, [4] [5] [6] In the general population, 87 advanced age, obesity, minority ethnic origin, socioeconomic deprivation and comorbidities 88 including diabetes and hypertensive disease are associated with higher risk of severe 89 disease, a pattern which is also seen in pregnant women. 1, 7 Neonatal SARS-CoV-2 infection 90

has not been associated with adverse outcomes for the newborn. 8 

A recent international registry study demonstrated an increase in adverse maternal and 92 neonatal outcomes for mothers infected with COVID-19 in pregnancy; 4 and a study using 93 national data from Sweden demonstrated an increase in adverse neonatal outcomes for 94 infants born to women with SARS-CoV-2 infection, a finding largely mediated by increased 95 rates of preterm birth. 9 96

We aimed to investigate maternal and perinatal outcomes of pregnant women with SARS-97

CoV-2 infection in England using data available from routinely collected electronic healthcare 98 records. 99 100

This study is a national population-based cohort study using Hospital Episode Statistics 103 (HES) data from 29 th May 2020 to 31 st January 2021. HES contains records of all inpatient 104 J o u r n a l P r e -p r o o f admissions to National Health Service (NHS) hospitals in England including data on patient 105 demographics (age, sex and ethnicity), the admission (date of admission and discharge) and 106 clinical information. On the 29 th May 2020, the Royal College of Obstetricians and 107

Gynaecologists recommended universal screening of all women admitted to maternity 108 services with a PCR test, in line with recommendations from NHS England to test all hospital 109 admissions. 10,11 110 Diagnostic information is coded using the International Classification of Diseases, 10th 111 revision (ICD-10). 12 Operative procedures are described using the UK Office for Population 112

Censuses and Surveys classification, 4th revision (OPCS-4). 13 Further details about the 113 labor and birth are captured in the episode record (e.g., gestational age, birthweight) in 114 supplementary data fields known as the HES 'maternity tail'. HES data is sufficiently 115 accurate to be used for research and managerial decision-making. 14 116

The inclusion criteria were women who had a HES record of a singleton birth between 29 th 118

May 2020 and 31 st January 2021. HES includes births which occur in NHS hospitals and 119 hospital-associated community care in England. Only 0.3% of births in England in 2020 120 occurred in non-NHS organizations. 15 121 A maternity episode was defined as any record that contained valid information about mode 122 of birth in either the procedure fields (OPCS-4 codes: R171 to R259) or the HES maternity 123 tail. Multiple births, which were excluded, were defined as maternity episodes with an ICD 124 code for a multiple birth (Z37.2-Z37.7) or strong evidence of a multiple birth in the maternity 125 tail (more than one distinct birthweight, birth order, and infant recorded in the same birth 126 episode). A neonatal episode was defined as any record that contained a newborn, defined 127 as being less than one day of age at episode onset. Maternal and neonatal episodes were 128 linked using encrypted versions of the mother's and infant's NHS number (a unique national 129 identifier for each individual NHS user, assigned at birth) 16 birth if the ICD-10 code "COVID-19, virus identified" (U07.1) was recorded in the birth 134 episode. 18 The test used to confirm infection in NHS hospital admissions is a nasal/throat 135 swab examined using PCR. 11 136

The study outcomes derived for the cohort identified by the maternity episode included fetal 137 death at or beyond 24 weeks' gestation (stillbirth), preterm birth (less than 37 weeks, 138 liveborn or stillborn), small for gestational age at birth (SGA; defined as birthweight <10 th 139 centile using UK-WHO paediatric growth charts 19 ), maternal diagnosis with preeclampsia or has previously been validated in HES. 20 The definitions and coding of all study outcomes are 147 specified in Supplementary Table 1 . This dataset does not contain sufficient information to 148 distinguish between antepartum and intrapartum fetal death (stillbirth); in England in 2018 149 (the latest date for which this information is available), nine in every ten stillbirths were 150 antepartum. 21 

Maternal age was grouped into five-year periods, with women under 20 and over 40 years 152 being aggregated into single categories. Parity was defined using records of previous births 153 through a 'look-back' approach in HES, and handled in three categories: primiparous, 154 multiparous without previous Cesarean delivery, and multiparous with previous Cesarean 155 delivery. 22, 23 Maternal ethnicity was coded using the Office for National Statistics logistic regression, adjusting for maternal age, ethnicity, parity, pre-existing diabetes, pre-171 existing hypertension and socioeconomic deprivation measured using IMD. Models were 172 fitted with robust standard errors to account for hospital-level clustering. The analysis of the 173 neonatal outcomes was repeated for those born at term (at or beyond 37 weeks' gestation) 174 since preterm birth has been reported to be more common in pregnant women with SARS-175

CoV-2 infection. 176

Data were complete for all variables except maternal ethnicity (89.1% complete) and IMD 177 (99.4% complete). For regression analyses, missing values of ethnicity and IMD were 178 imputed using chained equations to generate 10 datasets; estimates from these datasets 179 were pooled using Rubin's rules. 25 Stata 16 was used for all analyses. A P value of less than 180 0.05 was assumed to represent statistical significance. Table 1 ). 191

Laboratory-confirmed SARS-CoV-2 infection was more likely in younger women, women 192 from non-white ethnicity, those with pre-existing diabetes, pre-existing hypertension and 193 women residing in the most socioeconomically deprived areas (Table 1) . 194 

In this population-based study of women giving birth to a singleton infant in England in 2020-227 2021, we report that women with a record of laboratory-confirmed SARS-CoV-2 infection at 228 the time of birth were more than twice as likely as women without SARS-CoV-2 infection to 229 have fetal death or preterm birth. Women with SARS-CoV-2 infection were also more likely 230

to have preeclampsia and to give birth by emergency Cesarean delivery. Both women and 231 their neonates were more likely to have prolonged hospital stay of three days or more, and 232 mothers were more likely to be readmitted to hospital in the postnatal period. There was no 233 significant difference in rates of induction of labor, instrumental vaginal delivery or SGA 234 between women who did and did not have SARS-CoV-2 infection at the time of birth. The 235 composite neonatal adverse outcome and specialist neonatal care were significantly higher 236 in pregnancies with SARS-CoV-2 infection at the time of birth. However, when the analysis 237 was restricted to term deliveries, neonatal outcomes were similar for those born to mothers 238 with and without SARS-CoV-2 infection. 239

Our findings concur with those of an ongoing living systematic review which estimates the 241 pooled association between COVID-19 and fetal death at OR 2.84 (95% CI 1.25 to 6.45); 1 242 with a more recent multinational case-control study which reports an association between 243 COVID-19 and a composite neonatal adverse outcome of RR 2.14 (95% CI 1.66 to 2.75 4 ); 244 and with a recent population level study reporting an increase in adverse neonatal outcomes 245

for infants born to women with COVID-19 infection. 9 However, the systematic review is 246 limited by the size and number of studies available, with only nine women experiencing a 247 stillbirth in the COVID-19 group of the pooled dataset; 1 and the case-control study was 248 unable to report on fetal death alone, instead incorporating it into an adverse outcome 249 including intrauterine or neonatal death, prolonged neonatal stay, or severe neonatal 250 morbidity. 4 In the population-level study, as in our study, almost all of the association 251 between maternal COVID-19 infection and adverse neonatal outcome was explained by 252 increased risk of preterm birth. 9 In our study we were not able to stratify preterm birth into 253 spontaneous and indicated/iatrogenic (where birth is initiated by the clinician); other studies 254 have suggested that the increase in preterm birth is due to indicated delivery to improve 255 maternal condition. 1 256

The key potential bias in our study comes from misclassification of the exposure; this could 257 be caused by selective testing (whether the chance of a woman having been tested for 258 SARS-CoV-2 was dependent on her pregnancy outcome), selective recording (whether the 259 chance of a woman who tested positive had that result recorded in HES was dependent on 260 J o u r n a l P r e -p r o o f her pregnancy outcome) or missed cases (women who had SARS-CoV-2 infection but were 261 not recorded as such). 262

It is unlikely that either selective testing or recording fully explain our results. First, 263 throughout the pandemic there was a statutory requirement to report cases of SARS-CoV-2 264 infection in healthcare settings. 26 admissions was fully implemented during this period. 28 The slightly higher rate may be 272 attributed to women of childbearing age likely to be living with children and to be required to 273 leave the house to interact with healthcare providers. 29 

These results provide further evidence that SARS-CoV-2 infection increases the risk of fetal 275 death. The potential mechanisms may be pregnancy-specific, including placental disease 276 with reports of abnormal inflammation of the placenta in association with maternal COVID-277 19. 30, 31 However, the association may also be a more generic consequence of severe 278 maternal illness in pregnancy, given that women who become seriously unwell with other 279

illnesses are known to be at higher risk of perinatal morbidity and mortality. 32 

The finding that women with a recorded SARS-CoV-2 infection at the time of birth may have 289 an increased risk of fetal death and other adverse maternal and perinatal outcomes concurs 290 with a recent international case-control study 4 and will be of particular concern to pregnant 291 women and healthcare professionals. The overall numbers of fetal deaths are too small to 292 impact the overall national rate of stillbirth in the UK, as seen in provisional national reports 293 for 2020. 33 It is therefore important to carefully contextualise these findings when counselling 294 pregnant women. The use of administrative data including diagnostic and procedure codes to establish 324 exposures and outcomes (including in our study pre-eclampsia, neonatal adverse outcome, 325

and SARS-CoV-2 status) has inherent limitations as the primary purpose of data recording is 326 for payment rather than clinical research; known limitations include under-recording and 327 misclassification. 41 This may particularly affect pre-eclampsia where there is variation in 328 diagnostic criteria and thresholds; gestational hypertension may be conflated with pre-329 eclampsia. 42 

While in our study we were able to adjust for many potential confounders, we had no 331 information on the severity of COVID-19 illness or maternal body mass index (BMI) in our 332 dataset. Maternal obesity is a risk factor for both severe COVID-19 and fetal death. 1, 43 It is 333 therefore possible that the observed association could be partially accounted for by 334 differences between groups of women. 335

Our results should be strictly interpreted as being related to the result of a test for SARS-336

CoV-2 at the time of birth, rather than to any infection which occurred during pregnancy. This 337 is an important feature given that some of the observations in women who tested positive for 338 SARS-CoV-2, especially the increases in risk of stillbirth and preterm birth in women with a 339 positive test, may be partly explained by variations in the rate of SARS-CoV-2 infection 340 according to gestational age. This is different from other studies which seek to understand 341 effects on women who are infected with SARS-CoV-2 at any point during their pregnancy, 342 and from studies which assess population risks of fetal death measuring both direct and 343 indirect effects. 44-46 344 Conclusions 345

Our results demonstrate that women who have laboratory-confirmed infection with SARS-346

CoV-2 at the time of birth have higher rates of fetal death and preterm birth, preeclampsia 347 and emergency Cesarean delivery, as well as prolonged maternal and neonatal admission 348 following birth, compared to those without SARS-CoV-2 infection. There were no additional 349 adverse neonatal outcomes, other than those related to preterm delivery. These findings All singleton births with non-missing date of discharge information and date of delivery before 19 th December 2020 (to allow for six-week follow up). Women who died before discharge or were not discharged within 42 days of delivery were excluded. within 42 days of birth.

Numerator / coding Denominator / coding Using maternal-neonatal linked data: Neonatal specialist care Neonatal specialist care is defined using the "neocare" variable in HES, and includes values 1=Special care: care given in a special nursery, transitional care ward or postnatal ward, which provides care and treatment exceeding normal routine care; 2 = Level 2 intensive care (high dependency intensive care); and 3 = Level 1 intensive care (maximal intensive care) All liveborn singleton term births with nonmissing information on gestational age and birthweight Neonatal length of stay post birth (3 or more days)

Length of stay is defined as the number of days between date of discharge and date of admission for the birth episode.

All singleton births with non-missing date of discharge information and date of birth before 28 th January 2021 (to allow for 3day follow up) Neonatal readmission (28days) Neonatal readmission is defined as unplanned, overnight readmission to hospital within 28 days of birth, excluding those accompanying an unwell mother. Babies readmitted with the following admission method codes: 21, 22, 23, 24, 28, 2A, 2B, 2D, 31, 32, 82, 83 within 28 days of birth.

All singleton neonates with non-missing date of discharge information and date of birth before 3 rd January 2021 (to allow for four-week follow up). Babies who died before discharge or were not discharged within 28 days of birth were excluded.

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