Perinatal outcomes after admission with COVID-19 in pregnancy:  a UK national cohort

doi:10.21203/rs.3.rs-3785899/v1

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Perinatal outcomes after admission with COVID-19 in pregnancy: a UK national cohort

https://doi.org/10.21203/rs.3.rs-3785899/v1

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published 15 Apr, 2024

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BACKGROUND

There are few population-based studies of sufficient size and follow-up duration to have reliably assessed perinatal outcomes for pregnant women admitted to hospital with SARS-CoV-2 infection.

METHODS

The United Kingdom Obstetric Surveillance System (UKOSS) includes all 194 consultant-led UK maternity units. From March 2020 to March 2022, pregnant women admitted with a positive SARS-CoV-2 PCR test within seven days before or during admission were included and categorised by dominant SARS-CoV-2 variant, severity of maternal COVID-19 and vaccination status.

RESULTS

In total, 16,351 infants were born to 16,627 women; women with symptomatic COVID-19 contributed 7,116 (43.3%) births, 111 of which were stillborn. Infection during the delta variant period was associated with increased risk of stillbirth irrespective of infection severity compared to mild wild-type infection (mild wildtype 0.8% vs. mild delta 3%, adjusted risk ratio [aRR] 3.57, 95% confidence interval [CI] 1.66 to 7.67; vs. moderate to severe delta, 1.9%, aRR2.41; 95%CI 1.03 to 5.60). All variants were associated with increased risk of preterm birth in women with moderate to severe infection compared to women with mild infection in the wildtype period. After introduction of vaccination during pregnancy, 91.2% (83/91) of stillbirths and 92.1% (422/459) of preterm births < 34 weeks’ gestation were in symptomatic women with no documented vaccination or with unknown vaccine status.

CONCLUSION

COVID-19 variant, severity, and no or unknown maternal vaccinations were key risk factors for adverse perinatal outcomes. There is strong evidence for continued recommendation of SARS-CoV-2 vaccination during pregnancy to protect women and their babies.

Health sciences/Medical research/Epidemiology

Health sciences/Diseases/Infectious diseases/Viral infection

During the course of the pandemic, evolving variants of SARS-CoV-2 were associated with higher risk of severe maternal disease and adverse perinatal outcomes, but short observation time and lack of outcome data for continuing pregnancies were likely to bias results towards pregnancies ending at an earlier gestation and with more severe perinatal outcomes.^1–4

The latest update of the World Health Organization (WHO) systematic review of coronavirus disease in pregnancy included studies published early in the alpha-dominant period.⁵ Few of the studies in the WHO review were population-based or based on European data, and concerns have been raised about the conduct of other systematic reviews and the quality of included studies.⁶

Several of the larger multinational registry studies of COVID-19 in pregnancy lacked information about the source population and relied on passive, voluntary reporting,^7–9 and studies linking national routine health registry data have been unclear whether hospital admission was related to COVID-19 or pregnancy complications.^10–13 Robust evidence is needed to inform the care of pregnant women and counselling regarding vaccination,^14–16 particularly given the current increase in hospitalisations due to the omicron (XBB) lineage viruses and new emerging variants such as “pirola“ (BA.2.86).^{17 18}

Therefore, this study aimed to assess perinatal outcomes for mothers admitted to hospital with SARS-CoV-2 infection using a population-based national cohort with comprehensive follow-up.

STUDY DESIGN AND OVERSIGHT

The United Kingdom Obstetric Surveillance System (UKOSS) has a source population of all women giving birth or being admitted to one of the 194 consultant-led maternity units in England, Northern Ireland, Scotland and Wales, approximately 720,000 maternities annually.^19–22 A protocol for active surveillance of pregnant women admitted to hospital with viral infection was planned in 2012, approved by the ethical review board (HRA NRES Committee East Midlands, Nottingham 1 (Ref. Number: 12/EM/0365) and hibernated (https://doi.org/10.1186/ISRCTN40092247). The protocol was activated for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) from March 1, 2020, and concluded on March 31, 2022. Routines were in place to ensure complete reporting (online supplementary),³ and follow-up information about birth outcomes up to December 31, 2022, were retrieved from clinical records until April 24, 2023. Maternal and perinatal deaths were cross-checked with the MBRRACE-UK mortality surveillance. (https://www.npeu.ox.ac.uk/mbrrace-uk). The corresponding author vouches for the accuracy and completeness of the data and reporting. Patients and public were part of the UKOSS steering committee and involved in study design, oversight, reporting and dissemination of study findings but not in the conduct of the study. The funder played no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication.

STUDY POPULATION AND GROUPS

Pregnant women were included if admitted to hospital with a positive SARS-CoV-2 reverse transcriptase polymerase chain reaction (PCR) test within seven days of admission, during admission or up to two days after giving birth. Women were further classified according to their SARS-CoV-2 symptoms (symptomatic/asymptomatic); severity of infection (mild/moderate to severe); and the dominant viral variant in UK at the time of the PCR test (wild-type March 1 to November 30 2020; alpha December 1 2020, to May 15 2021; delta May 16 to December 14 2021; omicron December 15 2021, to March 31 2022).²³

SEVERITY OF MATERNAL COVID-19

Moderate to severe maternal COVID-19 was defined according to modified WHO criteria as maternal death, maternal intensive care admission, peripheral oxygen saturation below 95% at admission, pneumonia on radiological imaging or need for respiratory support (either oxygen supplementation, non-invasive ventilation (high flow nasal oxygen or continuous positive airway pressure), mechanical ventilation or extracorporeal membrane oxygenation (ECMO)).²⁴

MATERNAL CHARACTERISTICS AND MEDICAL RISK FACTORS

The sociodemographic characteristics and medical risk factors recorded were maternal age, maternal body mass index (kg/m²), employment, ethnic background, smoking, pre-existing medical conditions (no medical conditions (reference) vs asthma, hypertension, cardiac disease or diabetes), preeclampsia, gestational diabetes, parity, plurality and gestational age at admission (categorised by completed weeks into < 22, 22 to 27, 28–33, 34–36 and ≥ 37 weeks).

Vaccination status was recorded from January 2021 after vaccination was recommended for pregnant women in risk groups in the UK from December 22, 2020.²⁵

PREGNANCY AND PERINATAL OUTCOMES

Pregnancy outcomes examined were pregnancy loss (< 24 weeks’ gestation), gestational age at birth, expedited birth due to COVID-19, and mode of birth (spontaneous vaginal, operative vaginal, caesarean section prior to or during labor). The perinatal outcomes were stillbirth at ≥ 24 weeks’ gestation, preterm birth (< 34 weeks’ and 34^+ 0 to 36^+ 6 weeks’ gestation), neonatal unit admission, and neonatal death within seven days after birth.

STATISTICAL ANALYSES

Percentages and frequencies were computed by symptom group, and for symptomatic women by severity of infection, dominant variant, and vaccination status. Where data were missing, percentages are presented as the proportion of cases known.

Risk ratios (RR) with 95% confidence intervals (CI) for stillbirth, preterm birth and admission to neonatal unit for births to symptomatic women were computed using symptomatic mild infection during the wild-type period as the reference category with the lowest absolute risk. Since severity and variant were known risk factors, we included a preplanned interaction analysis to assess the combined effect of these factors.^2,4 Several models were run: models with dominant variant only (crude RR), disease severity only (crude RR), and with an interaction term for variant and severity (interaction without covariates (model 1); adjusted for selected covariates without vaccination status (model 2); and adjusted for selected covariates and vaccination status using mild infection during the alpha period as reference (model 3).

Multilevel Poisson or multinomial regression model as appropriate was used with random intercept to account for clustering effect among multiple pregnancies. The multivariable model for stillbirth was adjusted for maternal age, ethnicity, employment status, body mass index, plurality, smoking, parity, medical conditions prior to or during pregnancy and gestational age at admission. The preterm birth model included the above except gestational age at admission, and the model for neonatal unit admission was adjusted for gestational age at birth, parity, and medical conditions. Statistical analyses were performed using STATA version 18 (Statacorp, TX, USA).

Among a source population of approximately 1.5 million maternities,^20–22 16,627 women were included (Supplementary Figure S1). Their characteristics are shown by symptom status and severity in Table 1. A higher proportion of women with moderate to severe COVID-19 were overweight or obese, had diabetes or asthma, and were of a minority ethnic background compared with women with asymptomatic or mild infection. Women with moderate to severe infection were more likely to be admitted prior to 37 weeks’ gestation (77.3%) compared with asymptomatic women (24.9%) and women with mild infection (51.3%). Vaccination coverage increased gradually amongst women admitted with SARS-CoV-2 from May 2021 onwards (Fig. 1).

Table 1

Characteristics of pregnant women admitted with SARS-CoV-2, by symptom group, March 1, 2020, to March 31, 2022, United Kingdom.
Symptom group	Asymptomatic (N = 9374)	Mild infection (N = 4901)	Moderate to severe infection^* (N = 2352)
Age (years) - no. (%)
< 20	231 (2.5)	100 (2.0)	21 (0.9)
20–34	6685 (71.5)	3583 (73.2)	1544 (65.8)
≥35	2438 (26.1)	1210 (24.7)	782 (33.3)
Missing	20	8	5
Body Mass Index (BMI) (kg/m²) - no. (%)
Underweight (< 18.5)	229 (2.5)	101 (2.1)	17 (0.8)
Normal (18.5 to < 25)	3599 (39.7)	1829 (38.5)	529 (23.4)
Overweight (25 to < 30)	2702 (29.8)	1467 (30.9)	714 (31.6)
Obese (≥ 30)	2528 (27.9)	1357 (28.5)	1000 (44.3)
Missing	316	147	92
Woman or partner in paid work - no. (%)	7010 (74.8)	3788 (77.3)	1791 (76.2)
Ethnic Group - no. (%)
White	6107 (66.7)	3134 (65.4)	1350 (58.9)
Asian	1689 (18.5)	934 (19.5)	519 (22.6)
Black	825 (9.0)	418 (8.7)	254 (11.1)
Chinese/Other	282 (3.1)	178 (3.7)	110 (4.8)
Mixed	249 (2.7)	129 (2.7)	59 (2.6)
Missing	222	108	60
Current smoking - no. (%)	1547 (17.0)	626 (13.1)	178 (7.8)
Missing	294	138	68
Pre-existing medical conditions - no. (%)
Asthma	552 (5.9)	375 (7.7)	231 (9.8)
Hypertension	155 (1.7)	80 (1.6)	55 (2.3)
Cardiac disease	114 (1.2)	68 (1.4)	38 (1.6)
Diabetes	132 (1.4)	71 (1.5)	60 (2.6)
Medical conditions during pregnancy - no. (%)
Pre-eclampsia	141 (1.5)	73 (1.5)	49 (2.1)
Gestational diabetes	595 (6.4)	354 (7.2)	263 (11.2)
Multiparous - no. (%)	5749 (61.9)	3038 (62.4)	1626 (69.8)
Missing	90	35	22
Multiple pregnancy - no. (%)	140 (1.5)	96 (2.0)	51 (2.2)
Gestation at admission (weeks^days) - no. (%)
< 22	463 (5.0)	468 (9.6)	194 (8.3)
22–27^+ 6	300 (3.2)	445 (9.1)	415 (17.8)
28–33^+ 6	639 (6.9)	863 (17.7)	738 (31.7)
34–36^+ 6	915 (9.8)	729 (14.9)	455 (19.5)
37 or more	6987 (75.1)	2374 (48.7)	529 (22.7)
Missing	70	22	21
Evidence of pneumonia on imaging - no. (%)	-	-	1695 (72.1)
Respiratory support required - no. (%)	-^†	-	1709 (76.2)
Intensive Care Unit admission - no. (%)	-^†	-	771 (32.8)
Maternal Death - no. (%)	1 (0.01)	-	38 (1.6)
Vaccination status - no. (%)
Unvaccinated	6099 (65.1)	3424 (69.9)	1785 (75.9)
1 dose	620 (6.6)	271 (5.5)	72 (3.1)
2 doses	835 (8.9)	290 (5.9)	41 (1.7)
3 doses	140 (1.5)	53 (1.1)	4 (0.2)
Not known/ not documented	1680 (17.9)	863 (17.6)	450 (19.1)
^*Moderate to severe Covid-19 was defined as one or more of the following: maternal death, intensive care unit admission, peripheral oxygen saturation below 85% at admission, pneumonia on imaging, or need for respiratory support with either oxygen, high flow nasal cannula or continuous positive pressure mask, mechanical ventilation or extracorporeal membrane oxygenation. ^† 27 (0.3%) asymptomatic women needed respiratory support or were admitted to ICU for other reasons and one of them died from other causes than Covid-19.

Of the 16,386 (98.6%) women with known pregnancy outcomes, 1.9% (n = 319) experienced a pregnancy loss (Supplementary Figure S1) and the remaining 16,067 women gave birth to 16,351 infants of whom 190 were stillborn. Pregnancy outcomes for symptomatic women are shown by variant and severity in Table 2, and for asymptomatic women in Supplementary Table S1. Women with moderate to severe COVID-19 were more likely to give birth prior to 37 weeks, have an expedited birth due to COVID-19 and a pre-labour caesarean birth than women with mild disease.

Table 2

Maternal and pregnancy outcomes for women with symptomatic SARS-CoV-2 by severity, March 1, 2020 to March 31, 2022, United Kingdom.
Severity	Mild infection (N = 4901)	Moderate to severe infection^* (N = 2352)
Pregnancy outcome - no. (%)
Birth	4710 (96.1)	2264 (96.3)
Pregnancy loss	92 (1.9)	26 (1.1)
Birth outcome unknown	99 (2.0)	62 (2.6)
Gestation at birth (weeks^+ days)^† - no. (%)
22^+ 0 – 27^+ 6	47 (1.0)	49 (2.2)
28^+ 0 – 33^+ 6	180 (3.8)	305 (13.6)
34^+ 0 – 36^+ 6	441 (9.4)	395 (17.6)
37^+ 0 or more	4022 (85.8)	1490 (66.6)
Missing	20	24
Birth expedited due to COVID-19^† - no. (%)	80 (1.7)	601 (26.6)
Mode of birth^† - no. (%)
Pre-labour Caesarean	1246 (26.6)	1129 (50.4)
Caesarean after labour onset	702 (15.0)	260 (11.6)
Operative vaginal	491 (10.5)	141 (6.3)
Spontaneous vaginal	2239 (47.9)	712 (31.8)
Missing	32	21
*Moderate to severe Covid-19 defined as one or more of the following. maternal death, intensive care unit admission, peripheral oxygen saturation below 85% at admission, pneumonia on imaging, or need for respiratory support with oxygen, high flow nasal cannula or continuous positive pressure mask, mechanical ventilation or extracorporeal membrane oxygenation. ^† Pregnancy loss excluded from denominator

The perinatal outcomes for births to symptomatic women are shown in Table 3 and for births to asymptomatic women in Supplementary Table S2. Amongst the 7,116 infants born to 6,974 symptomatic women, 1.6% (n = 111) were stillborn and 8.2% (n = 581) were born prior to 34 weeks’ gestation (Table 3).

Table 3

Perinatal outcomes for babies of women admitted to hospital with symptomatic SARS-CoV-2 by dominant variant period and severity of maternal infection, March 1, 2020, to March 31, 2022, United Kingdom.
SARS-CoV-2 dominant variant	Wild-type period		Alpha period		Delta period		Omicron period
Severity*	Mild (N = 1067)	Moderate to severe^* (N = 370)	Mild (N = 1220)	Moderate to severe^* (N = 678)	Mild (N = 1420)	Moderate to severe^* (N = 1055)	Mild (N = 1098)	Moderate to severe^* (N = 208)
Stillbirths - no. (%)	9 (0.8)	6 (1.6)	12 (1.0)	9 (1.3)	42 (3.0)	20 (1.9)	8 (0.7)	5 (2.4)
Model 1^†: RR (95% CI	[Ref]	1.93 (0.68–5.38)	1.17 (0.49–2.76)	1.57 (0.63–3.95)	3.49 (1.70–7.18)	2.25 (1.03–4.92)	0.86 (0.32–2.34)	2.86 (0.96–8.46)
Model 2^‡: RR (95% CI)	[Ref]	1.90 (0.61–5.88)	1.20 (0.49–2.97)	1.68 (0.63–4.51)	3.57 (1.66–7.67)	2.41 (1.03–5.60)	0.96 (0.35–2.66)	2.62 (0.79–8.69)
Model 3^§: RR (95% CI)	NA	NA	[Ref]	0.99 (0.33–3.01)	2.82 (1.29–6.16)	1.89 (0.81–4.40)	0.79 (0.25–2.47)	2.07 (0.64–6.76)
Preterm live birth^¶ - no. (%)
< 34 weeks’ GA	56 (5.3)	57 (15.5)	56 (4.6)	121 (18.1)	92 (6.5)	177 (16.9)	41 (3.7)	17 (8.2)
Model 1^†: RR (95% CI)	[Ref]	3.74 (2.52–5.55)	0.87 (0.59–1.27)	4.41 (3.15–6.17)	1.27 (0.90–1.79)	4.26 (3.10–5.85)	0.69 (0.46–1.04)	1.83 (1.04–3.24)
Model 2^‡: RR (95% CI)	[Ref]	3.46 (2.24–5.34)	0.84 (0.56–1.27)	5.03 (3.51–7.20)	1.37 (0.95–1.97)	4.94 (3.52–6.94)	0.66 (0.42–1.03)	2.02 (1.13–3.63)
Model 3^§: RR (95% CI)	NA	NA	[Ref]	6.84 (4.42–10.59)	1.92 (1.24–2.96)	7.01 (4.65–10.59)	0.98 (0.59–1.63)	2.98 (1.57–5.65)
34^+ 0 – 36^+ 6 weeks’ GA	104 (9.8)	65 (17.7)	120 (9.9)	105 (15.7)	153 (10.8)	201 (19.2)	101 (18.0)	41 (19.8)
Model 1^†: RR (95% CI)	[Ref]	2.30 (1.63–3.23)	1.00 (0.76–1.32)	2.06 (1.54–2.77)	1.14 (0.87–1.48)	2.60 (2.01–3.37)	0.92 (0.69–1.22)	2.38 (1.59–3.56)
Model 2^‡: RR (95% CI)	[Ref]	2.36 (1.62–3.42)	1.00 (0.74–1.34)	2.38 (1.73–3.26)	1.18 (0.89–1.57)	2.92 (2.22–3.86)	1.04 (0.77–1.42)	2.55 (1.67–3.87)
Model 3^§: RR (95% CI)	NA	NA	[Ref]	2.32 (1.63–3.31)	1.23 (0.90–1.67)	3.00 (2.21–4.06)	1.20 (0.85–1.69)	2.81 (1.81–4.35)
Neonatal unit admission^\|\| - no. (%)	144 (13.6)	120 (33.1)	160 (13.3)	231 (34.5)	180 (13.1)	349 (33.7)	105 (9.6)	50 (24.5)
Model 1^†: RR (95% CI)	[Ref]	2.43 (1.97- 3.00)	0.98 (0.79–1.20)	2.53 (2.11–3.05)	0.96 (0.78–1.18)	2.47 (2.08–2.94)	0.71 (0.56–0.90)	1.80 (1.35–2.39)
Model 2^‡: RR (95% CI)	[Ref]	1.61 (1.32–1.96)	0.99 (0.81–1.21)	1.61 (1.35–1.93)	0.88 (0.73–1.08)	1.52 (1.28–1.81)	0.76 (0.61–0.95)	1.51 (1.16–1.97)
Model 3^§: RR (95% CI)	NA	NA	[Ref]	1.60 (1.30–1.97)	0.92 (0.73–1.14)	1.57 (1.28–1.94)	0.77 (0.60–0.99)	1.55 (1.16–2.07)
Neonatal death^** - no. (%)^††	4 (0.4)	1 (0.3)	0	2 (0.3)	6 (0.4)	3 (0.3)	2 (0.2)	0
Abbreviations: gestational age (GA), risk ratio (RR), confidence interval (CI), Not available (NA) Moderate to severe Covid-19 defined as one or more of the following. maternal death, intensive care unit admission, peripheral oxygen saturation below 85% at admission, pneumonia on imaging, or need for respiratory support with oxygen, high flow nasal cannula or continuous positive pressure mask, mechanical ventilation or extracorporeal membrane oxygenation. ^†Model 1: Variant + severity + interaction term for variant and severity. ^‡Model 2: Stillbirth: Model 1 + maternal age, ethnicity, employment status, body mass index, multiple pregnancy, smoking, parity, pre-existing medical conditions, pre-eclampsia, gestational diabetes, and gestational age at admission Preterm birth: Model 1 + maternal age, ethnicity, employment status, body mass index, multiple pregnancy, smoking, parity, pre-existing medical conditions, and pre-eclampsia. Neonatal admission: Model 1 + gestational age at birth, parity, and pre-existing medical conditions ^§Model 3: Model 2 + vaccination status. Vaccination started from January 1, 2021, so mild alpha infection was used as reference group. ^¶ 45 infants born to symptomatic women had missing data for gestational age at birth. ^\|\| 112 infants born to symptomatic women had missing data for admission to neonatal unit. ^* 75 infants born to symptomatic women had missing data for neonatal death. ^†† risk ratios were not calculated due to low numbers.

The absolute risk of stillbirth among symptomatic women was 0.8% for mild infection in the wild-type period and 1.6%, 1.3%, 1.9% and 2.4% with moderate to severe maternal infection in the wild-type, alpha, delta and omicron variant periods, respectively (Table 3). Compared to women with mild infection during the wild-type period, there was no evidence for a statistically significant increased risk of stillbirth for women with moderate to severe infection, except for during the delta period, noting that smaller numbers impacted the study power to detect differences as statistically significant. After adjusting for maternal risk factors, there was an increased risk of stillbirth during the delta period irrespective of infection severity (mild RR 3.57; 95%CI 1.66 to 7.67 and moderate to severe RR 2.41; 95%CI 1.03 to 5.60) when compared with mild infection during the wild-type period. (Table 3, model 2).

The risk of being born prior to 34 weeks’ gestation was 7.9% in the wild-type period and 9.4% with alpha (crude RR 1.21; 95%CI 0.94 to 1.55), 10.9% with delta (crude RR 1.49; 95%CI 1.18 to 1.87) and 4.5% with omicron (crude RR 0.53; 95%CI 0.38 to 0.74). The risk of being born at 34^+ 0-36^+ 6 weeks’ gestation was 11.8% in the wild-type period and 11.9% with alpha (crude RR 1.03; 95%CI 0.83 to 1.87), 14.4% with delta (crude RR 1.31; 95%CI 1.07 to 1.59) and 10.9% with omicron (crude RR 0.87; 95%CI 0.69 to 1.11) (Supplementary Table S3). Compared with births among women with mild infection, infants born to women with moderate to severe infection had a fourfold increased risk of birth before 34 weeks’ gestation and a nearly doubled risk of birth at 34^+ 0-36^+ 6 weeks’ gestation in the crude risk ratio analyses (Supplementary Table S4).

When the association was examined by variant period and infection severity, the risk of being born preterm prior to 34 weeks’ gestation was 5.3% with mild maternal infection during the wild-type period, and 15.5%, 18.1%, 16.9% and 8.2% with moderate to severe maternal infection in the wild-type, alpha, delta and omicron variant periods, respectively. We found evidence of a multiplicative interaction between variant period and infection severity on the risk of preterm birth. The risk of birth before 34 weeks’ was five times higher among infants born to women with moderate to severe infection during the alpha and delta periods, compared with women with mild infection during the wild-type period, after adjusting for maternal risk factors (alpha RR 5.03; 95%CI 3.51 to 7.20; delta RR 4.94; 95%CI 3.52 to 6.94) (Table 3, model 2) whereas this risk was doubled during the omicron period (RR 2.02; 95%CI 1.13 to 3.63) (Table 3, model 2). The risk increase was two-to-threefold for birth between 34^+ 0 to 36^+ 6 weeks’ gestation among women with moderate to severe infection across all periods when compared to mild wild-type infection (Table 3, model 2).

We also found evidence of a multiplicative interaction between variant period and infection severity on neonatal unit admission. Compared with women with mild infection in the wild-type period, analyses accounting for both severity and variant in a model adjusted for maternal risk factors and gestational age at birth (model 2) showed 1.5 times higher risk of neonatal unit admission across all variant periods in neonates born to women with moderate to severe infection (Table 3, model 2). These patterns for preterm birth and neonatal unit admission persisted after accounting for vaccination status (Table 3, model 3). Neonatal deaths at less than seven days of age were rare, with a total of 18 deaths among babies born to symptomatic women (Table 3).

Amongst 5,185 births to symptomatic women from January 1, 2021 onwards, when vaccination was recommended for pregnant women in risk groups, there were 91 stillbirths among symptomatic women; 91.2% (83/91) occurred to women with no documented vaccine or unknown vaccination status (Table 4). Women who were unvaccinated or had unknown vaccination status also gave birth to 92.1% (422/458) of the infants born before < 34 weeks’ gestation in the symptomatic group. Perinatal outcomes and maternal vaccination status for asymptomatic women are reported in online supplementary Table S5; 75% (49/65) of the stillbirths and 78.1% (249/319) of infants born prior to 34 weeks were born to women with no documented vaccination or unknown vaccination status.

Table 4

Perinatal outcomes in births to women with symptomatic SARS-CoV-2 admitted to hospital by number of documented maternal vaccination doses, from January 1, 2021, to March 31, 2022, United Kingdom
Vaccination status	Unvaccinated (N = 3184)	Vaccine status unknown (N = 1275)	1 dose (N = 347)	2 doses (N = 319)	3 doses (N = 60)
Stillbirth - no. (%)	64 (2.0)	19 (1.5)	3 (0.9)	5 (0.6)	0
Preterm births^* - no. (%)
< 34 weeks	299 (9.5)	123 (9.7)	13 (3.8)	20 (6.3)	3 (5.0)
34^+ 0 − 36^+ 6 weeks’	443 (14.0)	152 (12.0)	34 (9.9)	26 (8.2)	7 (11.7)
Admission to Neonatal Unit^† - no. (%)	620 (19.9)	270 (21.5)	40 (11.7)	40 (12.7)	9 (15.0)
Neonatal Death^‡ - no. (%)	6 (0.2)	3 (0.2)	2 (0.6)	1 (0.3)	0
^* 45 infants born to symptomatic women had missing data for gestational age at birth ^† 112 infants born to symptomatic women had missing data for admission to neonatal unit. ^‡ 77 infants born to symptomatic women had missing data for neonatal death

This national cohort study of pregnant women admitted to hospital with SARS-CoV-2 shows that compared with women with mild infection in the wild-type period there was increased risk of stillbirth for women with mild and moderate to severe infection during the delta period. The risk of preterm birth was increased for babies born to women with moderate to severe infection across all periods. Omicron was considered to be a variant with lower risk of adverse perinatal outcomes,²⁶ yet we observed a threefold increase in risk of birth prior to 34 weeks’ gestation for women with moderate to severe COVID-19 in this period compared with mild infection in the wild-type period, after accounting for vaccination status. Unvaccinated women were at higher risk of stillbirth and preterm birth.

The key strengths of this study are that birth outcomes were available for almost all the included women. The large sample size provides sufficient statistical power to detect a difference in stillbirth during the delta period. We observed an increase in risk of preterm birth with moderate to severe maternal infection across all variant periods, demonstrating the merit of a nuanced analysis taking variant and severity into account.

In addition, the availability of data about symptom status, severity of infection and vaccination status allowed robust regression models. The UKOSS system of active and uniform case identification across all pregnant women admitted to hospital in the UK that tested positive for SARS-CoV-2 reduces the risk of selection bias compared with other studies. Finally, the clinical information reduced the risk of misclassification bias, such as attributing adverse outcomes associated with pregnancy-related admission incorrectly to COVID-19.

Several limitations also need to be considered. First, perinatal outcomes in births to pregnant women with SARS-CoV-2 who were not admitted to hospital at the time of infection could not be assessed. There would likely be few adverse outcomes in this group, as studies from other countries did not find an increased risk of adverse perinatal outcomes with a test-delivery interval exceeding ten days.²⁷ Second, we have included time periods when the variants of SARS-CoV-2 were dominant as proxy for individual variant sequencing data which were not available. Third, whilst providing robust data about the prevalence of stillbirth in women with COVID-19, we do not have clinical information to assess the cause of death and differentiate iatrogenic and spontaneous nature of the preterm birth

We adjusted for known confounders, but there could be time-dependent changes that were unmeasured and may be important underlying causes of stillbirth and preterm birth. For example, indirect impacts of the pandemic such as competing hospital pressures, differing practice around intrapartum fetal monitoring for women with COVID-19, or delay in seeking care may contribute to the higher proportion of stillbirths observed in women with COVID-19 during the delta period, but this does not explain the increase in preterm births.

The proportion of stillbirths observed in women with asymptomatic infection during the wild-type period was comparable to nationally-reported figures in the UK (4/1000 total births versus 3.5/1000 total births, respectively).²⁸ Recent UK-wide surveillance of perinatal deaths identified an increase in the perinatal mortality rate during 2021.²⁸ The current study indicates that COVID-19 in unvaccinated pregnant women could have contributed to this increase.

This study significantly adds to the field since previous cohort studies that ended during earlier variant periods reported stillbirth rates comparable with pre-pandemic periods,^12,19,29 thus demonstrating the need for ongoing surveillance of perinatal outcomes during a pandemic to inform care. Similarly, other studies with shorter³⁰ or unclear³¹ duration of follow up after admission with infection have had insufficient data to reliably compare severe perinatal outcomes and did not account for severity of maternal infection.

By January 2022, 50.6% of the women who gave birth in England had received two vaccine doses.³² Previous cohort studies have demonstrated the benefit of maternal SARS-CoV-2 vaccination to prevent hospital admission due to COVID-19 in pregnant women,³³ reduce moderate to severe maternal COVID-19,^2,4 and reduce infant hospitalization for COVID-19, severe neonatal morbidity and death.^3,34,35 The current study clearly demonstrates the benefit of maternal vaccination on perinatal outcomes, showing a large proportion of stillbirths in women with no documented vaccination in both those with and without any symptoms of COVID-19.

Preterm birth is also associated with adverse short-term³⁶ and long-term^37,38 health outcomes and the need for neonatal unit admissions increases demand and economic impact on the health services.³⁹ With ongoing increasing SARS-CoV-2 infections, it is paramount to ensure that pregnant women are prioritised for vaccination, and that messaging around safety and access to vaccines is clear and readily available.

In this large national cohort comprising two years’ active surveillance over four SARS-CoV-2 variant periods and with near complete follow-up of pregnancy outcomes for included women, severe perinatal outcomes were more common in women with moderate to severe COVID-19, during the delta dominant period and among unvaccinated women. We provide strong evidence to recommend continuous surveillance of pregnancy outcomes in future pandemics and to continue to recommend vaccination in pregnancy to protect both mothers and babies.

Study registration number: (https://doi.org/10.1186/ISRCTN40092247)

Ethics approval: HRA NRES Committee East Midlands – Nottingham 1 (Ref. Number: 12/EM/0365). Information about ethnicity was self-determined according to the UK standard census categories (List of ethnic groups - GOV.UK (ethnicity-facts-figures.service.gov.uk)

Rema Ramakrishnan, Hilde Engjom, Nicola Vousden and Marian Knight analysed the data.

The study protocol was published at the study start and is available on the UKOSS website https://www.npeu.ox.ac.uk/ukoss/completed-surveillance/covid-19-in-pregnancy

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Yes there is potential Competing Interest. All authors have completed the ICMJE uniform disclosure form www.icmje.org/coi_disclosure.pdf and declare: MK, MQ, PB, PO’B, JJK received grants from the NIHR in relation to the submitted work. HME participated in this work as academic visitor to the NPEU with funding from The Norwegian Research Council, grant no 320181. KB, NV, RR, NS, CG have no conflicts of interest to declare. EM was Trustee and President of RCOG, Trustee of British Menopause Society and Chair of the Board of Trustees Group B Strep Support. PO’B was Vice President of RCOG and Co-Chair of the RCOG Vaccine Committee. No other relationships or activities that could appear to have influenced the submitted work.

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Perinatal outcomes after admission with COVID-19 in pregnancy: a UK national cohort

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Abstract

BACKGROUND

METHODS

RESULTS

CONCLUSION

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Introduction

Methods

STUDY DESIGN AND OVERSIGHT

STUDY POPULATION AND GROUPS

SEVERITY OF MATERNAL COVID-19

MATERNAL CHARACTERISTICS AND MEDICAL RISK FACTORS

PREGNANCY AND PERINATAL OUTCOMES

STATISTICAL ANALYSES

Results

Discussion

Conclusion

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