bmj...2020/05/26 · 0-10, i2=72%) of pregnant and recently pregnant women were admitted to the...

Confidential: For Review OnlyCoronavirus disease (COVID-19) in pregnancy: A living

systematic review on clinical manifestations, maternal and perinatal outcomes

Journal: BMJ

Manuscript ID BMJ-2020-058888

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 26-May-2020

Complete List of Authors: Allotey, John; University of Birmingham, Institute of Applied Health Research; University of Birmingham, WHO Collaborating Centre for Global Women's Health, Institute of Metabolism and Systems ResearchBonet, Mercedes; World Health OrganizationStallings, Elena; Ramon y Cajal University Hospital, Clinical Biostatistics UnitYap, Magnus; University of BirminghamChatterjee, Shaunak; University of BirminghamKew, Tania; University of BirminghamDebenham, Luke; University of BirminghamQiu, Xiu ; Guangzhou Medical University, Division of Birth Cohort Study; Guangzhou Medical University, Department of Woman and Child Health CareYuan, Mingyang; University of Birmingham, Institute of Applied Health Research; Guangzhou Medical University, Division of Birth Cohort StudyCoomar, Dyuti; University of Birmingham, Institute of Applied Health Researchvan Wely, Madelon; University of Amsterdam, Center for Reproductive Medicinevan Leeuwen, Elizabeth ; Amsterdam Universitair Medische Centra, Department of Obstetrics and GynaecologyKostova, Elena; University of Amsterdam, Center for Reproductive MedicineKunst, Heinke; Blizard Institute of Cell and Molecular ScienceKhalil, Asma; St George's Healthcare NHS Trust, Fetal Medicine UnitBrizuela, Vanessa; World Health Organization, Department of Reproductive Health and ResearchBroutet, Nathalie; WHO, RHRKara, Edna; World Health Organization, Department of Reproductive Health and ResearchKim, Caron; World Health Organization, Reproductive Health and ResearchTHORSON, Anna; World Health Organization, Department of Sexual and Reproductive HealthOladapo, Olufemi ; World Health Organization, Reproductive Health and Research

https://mc.manuscriptcentral.com/bmj

BMJ

Confidential: For Review OnlyMofenson, Lynne; Elizabeth Glaser Pediatric AIDS FoundationZamora , Javier ; Clinical Biostatistics Unit, Hospital Ramon y Cajal (IRYCIS) and CIBER Epidemiologia y Salud PublicaThangaratinam, Shakila; University of Birmingham, Institute of Applied Health Research; University of Birmingham, WHO Collaborating Centre for Global Women's Health, Institute of Metabolism and Systems Research

Keywords:COVID-19, Pregnant Women, severe acute respiratory syndrome coronavirus 2, mother to child transmission, SARS-CoV-2, Living Systematic Review

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Confidential: For Review Only

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Coronavirus disease (COVID-19) in pregnancy: A living systematic review on clinical manifestations, maternal and perinatal outcomes

John Allotey, senior research fellow in epidemiology and women’s health,1,2 Mercedes Bonet, medical officer,3 Elena Stallings, researcher,4,5 Magnus Yap, medical student,6 Shaunak Chatterjee, medical student,6 Tania Kew, medical student,6 Luke Debenham, medical student,6 Xiu Qiu, chief consultant of women’s health,7,8,9 Mingyang Yuan, researcher,1,7 Dyuti Coomar, research fellow,1 Madelon van Wely, clinical epidemiologist,10 Elizabeth van Leeuwen, medical specialist,11 Elena Kostova, managing editor,10 Heinke Kunst, senior lecturer and consultant in respiratory medicine,12 Asma Khalil, professor of obstetrics and maternal-fetal medicine,13 Vanessa Brizuela, doctor of public health,3 Nathalie Broutet, medical officer,3 Edna Kara, scientist,3 Caron Rahn Kim, epidemiologist,3 Anna Thorson, professor in global infectious disease epidemiology,3 Olufemi T Oladapo, medical officer,3 Lynne Mofenson, paediatric infectious disease specialist,14 Javier Zamora, senior lecturer in biostatistics 4,5,15 Shakila Thangaratinam, professor of maternal and perinatal health,2,16 for PregCOV-19 LSR Consortium

1Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom. 2WHO Collaborating Centre for Global Women's Health, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom3UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Sexual and Reproductive Health and Research, World Health Organization, Avenue Appia 20, 1211, Geneva, Switzerland4Clinical Biostatistics Unit, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, Spain.5CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain.6Birmingham Medical School, University of Birmingham, Birmingham, United Kingdom.7Division of Birth Cohort Study, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China. 8Department of Woman and Child Health Care, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China.9Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China.10Netherlands Satellite of the Cochrane Gynaecology and Fertility Group, Amsterdam University Medical Center, Amsterdam, The Netherlands.11Department of Obstetrics and Gynaecology, Amsterdam University Medical Center, Amsterdam, The Netherlands12Blizard Institute, Queen Mary University of London, London, United Kingdom.13St George’s University London, London, United Kingdom.14Elizabeth Glaser Pediatric AIDS Foundation, Washington DC, United States.15Women’s Health Research Unit, Queen Mary University of London, London, United Kingdom.16Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom.

Corresponding author: Professor Shakila Thangaratinam, WHO Collaborating Centre for Global Women's Health, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom. Email: [email protected]. Phone: +44 (0) 7887775891

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mailto:[email protected].%20


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Abstract

Objective

To quantify the clinical manifestations, maternal and perinatal outcomes in pregnant and

recently pregnant women with suspected or confirmed coronavirus disease (COVID-19).

Design

Living systematic review and meta-analysis.

Data sources

We searched Medline, Embase, Cochrane database, WHO COVID-19 database, CNKI and

Wanfang databases from inception to 12th May 2020, with additional searches in preprint

servers, social media and reference lists of included studies.

Study selection

We included cohort studies on clinical manifestations (symptoms, laboratory and radiological

findings), maternal and perinatal outcomes in pregnant and recently pregnant women with

suspected or confirmed COVID-19, including those that compared against non-pregnant

women with the disease, and pregnant women without COVID-19. We included studies of

any design (cohort, case-control, randomised studies, case series, case reports) to assess the

risk of mother-to-child transmission of the coronavirus (SARS-CoV-2).

Data extraction

At least two researchers independently extracted the data and assessed the study quality. We

undertook random effects meta-analysis and pooled the estimates as proportions and odds

ratios (OR) with 95% confidence intervals (CI). We qualitatively synthesised the evidence for

mother-to-child transmission. All analyses will be updated monthly.

Findings

From 33,030 citations we included 27 cohort studies (1422 women) on clinical

manifestations of COVID-19; 28 studies (1646 women) on maternal and 24 (900 babies) on

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perinatal outcomes; 87 studies and case reports (1483 women, 869 babies) on mother-to-child

transmission. The commonest manifestations were fever (38%; 95% CI 29-48; range 11-87,

I2=93%), cough (36%; 95% CI 24-49; range 3-100, I2=98%), lymphocytopaenia (49%; 95%

CI 30-68; range 14-100, I2=98%), raised C-reactive protein (52%; 95% CI 45-59; range 11-

71, I2=69%) and abnormal chest CT findings (88%; 95% CI 71-96; range 15-100, I2=99%).

Five maternal deaths were reported across all cohort studies. Overall, 5% (95% CI 3-8; range

0-10, I2=72%) of pregnant and recently pregnant women were admitted to the intensive care

unit; no differences were observed against non-pregnant women with COVID-19 in one

study (OR 0.66, 95% CI 0.31-1.43; I2=0%). Preterm births occurred in 15% (95% CI 10-20;

range 0-40, I2=87%), with higher rates in women with vs without COVID-19 (OR 3.0, 95%

CI 1.2-7.9; I2=1%). The rates of stillbirth and neonatal death were 0.4% (95% CI 0.1-1.1,

I2=0%) and 0.4% (95% CI 0.1-1.3, I2=0%) respectively. The rates of maternal manifestations

and outcomes varied by sampling frames. Overall, 6% (52/869) of babies born to women

diagnosed with COVID-19 in pregnancy and postpartum were suspected to have COVID-19.

Conclusion

Typical COVID-19 symptoms appear to manifest less frequently in pregnant and recently

pregnant women than the general population; less than one in ten women with COVID-19

require treatment in intensive care. The high preterm birth rates could potentially be from

iatrogenic indications related to maternal disease. Mother-to-child transmission of SARS-

CoV-2 requires further evaluation. The living systematic review format will allow us to

continuously and rapidly update the findings as new evidence emerge.

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What is known?

In non-pregnant individuals admitted to the hospitals with coronavirus disease

(COVID-19) caused by SARS-Cov-2 (severe acute respiratory syndrome

coronavirus-2) the commonest symptoms of fever, cough and dyspnoea are

reported in over two-thirds of individuals; 5% (China) to 17% (UK) of individuals

require management in intensive care.

Pregnant women are usually considered to be a high-risk group, and there are

concerns about the potential adverse effect of SARS-Cov-2 on maternal and

perinatal outcomes.

In a few cases, SARS-Cov-2 has been detected in the amniotic fluid, placenta,

vaginal fluid, cord blood, and breast milk samples of mothers with COVID-19.

Published systematic reviews in this field are small, and quickly become outdated

due to the rapid production and publication of evidence.

What does the study add?

Typical COVID-19 symptoms such as fever, cough and dyspnoea appear to

manifest less frequently in pregnant and recently pregnant women than the general

population.

Less than one in ten women admitted to the hospitals for any reason in pregnancy

and diagnosed with COVID-19 require treatment in intensive care. The pregnancy-

related outcomes are heterogeneous and may be influenced by iatrogenic causes

and sampling strategies.

Mother-to-child transmission of COVID-19, if it occurs, appears to be rare.

Our comprehensive living systematic review has summarised the existing evidence

using robust methods, reported the heterogeneity and uncertainty around the

estimates. It will allow us to continuously and rapidly update the findings as new

evidence emerge.

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Introduction

Since the first report of the novel coronavirus disease (COVID-19) caused by severe acute

respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, there has been a rapid

rise in the number of confirmed cases, which contribute to mortality and morbidity.1,2

Pregnant women are considered to be a high-risk group due to concerns about the effect of

COVID-19 on women during pregnancy and afterwards, and on their babies.3 Identification

of the various clinical manifestations of COVID-19 in pregnant and recently pregnant

women, the frequency of their occurrence, and the risks of maternal and perinatal

complications including mother-to-child transmission, is key to planning clinical care and

management in an evolving pandemic scenario.4

There has been a rapid increase in publications on COVID-19 in pregnancy and beyond

through individual case reports, case series, observational studies and systematic reviews. In

two months alone, over ten reviews have been published in this area, 5-10 with a further 50

registered in PROSPERO.8,11 The reviews generally provided limited or no information on

their search strategy, included small numbers of very similar primary studies with no clear

strategies to manage duplicate data, did not robustly assess the quality of the included studies,

synthesised data inappropriately by including case series and case reports, and became

quickly outdated as new evidence emerged. Moreover, primary studies varied in their

sampling frames ranging from universal SARS-CoV-2 testing for all pregnant women

admitted to the hospitals12,13 to symptom-based testing.14,15 The testing strategies also varied

within and between countries, with screening in many early studies based on epidemiological

risk assessment and clinical features without confirmed infection.16 The limitations in the

external and internal validity of studies makes it challenging for guideline developers and

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policymakers to make evidence-based recommendations for the management of pregnant and

recently pregnant women with COVID-19.

We commenced a living systematic review to provide comprehensive evidence on the clinical

manifestations, maternal and perinatal outcomes in pregnant and recently pregnant women

with suspected or confirmed COVID-19, to be updated on a regular basis.

Methods

Our systematic review is based on a prospectively registered protocol (PROSPERO

CRD42020178076; registered 22nd April 2020)17 to evaluate a series of research questions on

COVID-19 during and after pregnancy. In this paper, we report our findings on the clinical

manifestations and maternal and perinatal outcomes in line with the Preferred Reporting

Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (Appendix

1). Each cycle of our living systematic review involves weekly search updates, with analysis

performed every two weeks for our monthly reporting through a dedicated website, or earlier

if new definitive evidence emerges. We plan to review the planned frequency of updates after

two months of commencing the review.

Literature search

A systematic search was performed in major databases including Medline, Embase, Cochrane

database, WHO (World Health Organization) COVID-19 database, China National

Knowledge Infrastructure (CNKI) and Wanfang databases from inception until 12th May

2020 for relevant studies on COVID-19 in pregnancy and afterwards. We co-ordinated our

search efforts with EPPI-Centre, the WHO Library and the Cochrane Gynaecology and

Fertility group to identify potential studies. Additional searches were conducted in preprint

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servers, blogs, social media, guidelines, and reference lists of included studies and

unpublished data. There were no language restrictions. We contacted established groups that

were co-ordinating or conducting surveillance and studies in pregnant women with COVID-

19 such as the WHO Maternal, Newborn, Child and Adolescent health (MNCAH) COVID-

19 research network, and the International Network of Obstetric Survey Systems (INOSS) for

information on published and upcoming data. The detailed search strategies and databases

searched are provided in Appendix 2.

Study selection

Two reviewers independently undertook study selection in a two-stage process: the titles and

abstracts of studies were screened in the first stage (MY and SC), and the full text of the

selected studies were assessed in detail for eligibility in the second stage (TK and LD). Any

disagreements were resolved through discussion with a third reviewer (ST or JA). We

excluded studies if the duplicate data were published elsewhere as reported by the study

authors or when the characteristics of the mother or baby matched the setting, characteristics,

and duration of another study. We contacted the authors of primary studies when there was

uncertainty about duplicate data.

We defined women with confirmed COVID-19 as those with laboratory confirmation of

COVID-19 infection irrespective of clinical signs and symptoms.18 Women with a diagnosis

based on only clinical or radiological findings were defined as suspect COVID-19 cases. We

included women in postpartum and postabortion period as ‘recently pregnant’ group. The

sampling frames for detecting COVID-19 included universal screening and testing where all

women were assessed for COVID-19 using RT-PCR (reverse transcriptase polymerase chain

reaction) for SARS-CoV-2 or chest CT scan, risk-based testing informed by epidemiological

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history and clinical manifestations such as those recommended by National Health

Commission of China (NHCC) guidelines,16 and symptom-based where testing was

performed on symptomatic women. Studies where the testing strategy was not reported were

included in the symptom-based group. We defined the population as ‘selected’ when only

specific groups of women such as those undergoing caesarean section or in third trimester

were included. Studies were categorised under ‘high-risk’ group if it only included women

with any pre-existing medical or obstetric risk factors, ‘low-risk’ if women did not have any

risk factors, and ‘any risk’ if it included all women.

We included cohort studies with a minimum of 10 participants that provided information on

clinical manifestations such as symptoms, laboratory and radiological findings, or maternal

and perinatal outcomes (COVID-19 and pregnancy-related) in pregnant and recently pregnant

women with suspected or confirmed COVID-19. We also included cohort studies with data

on pregnant women with COVID-19 compared against non-pregnant individuals with the

disease or pregnant women without COVID-19. We defined cohort studies as those that

sampled participants based on exposure, followed-up over time, and ascertained the

outcomes.19 The full list of clinical features and outcomes evaluated are provided in

Appendix 3. To assess mother-to-child transmission we included all types of studies

including case reports that reported on the viral status of the babies (cord blood, neonatal

blood, stool, respiratory and skin samples) born to mothers with suspected or confirmed

COVID-19. We also evaluated the evidence for SARS-CoV-2 in the amniotic fluid, placenta

and membranes, vaginal fluid, stool, skin, respiratory samples and breast milk to assess the

risk of mother-to-child transmission.20

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Study quality assessment and data extraction

We assessed the quality of studies reporting on the prevalence of clinical manifestations or

outcomes for internal and external validity.21 We considered the following to be low risk of

bias for internal validity: data collected from clinical records or research case-report forms

(data collection), clearly defined outcomes (case definition), COVID-19 confirmed using

laboratory based tests (instrument validity), same mode of data collection in all participants

(ascertainment bias), sufficient follow-up, and appropriate numerator and denominator. The

following were considered as low risk of bias for external validity: representative of national

population for relevant variables (population), representation of target population (sampling

frame), random selection (selection bias), >75% response rate in individuals with and without

outcome (non-response bias).21 The quality of the comparative cohorts were assessed using

the Newcastle Ottawa Scale (NOS) for selection, comparability and outcome ascertainment

bias.22 Two independent reviewers (JA, ES) undertook data extraction using a pre-piloted

form. For cohort studies on clinical manifestations and outcomes, we collected additional

information on underlying maternal co-morbidities and timing of exposure (periconception,

1st, 2nd, 3rd trimester, postpartum or postabortion period).

Analysis

We reported the findings using aggregate meta-analysis and qualitative synthesis where

appropriate. We summarised the dichotomous data for rates of clinical manifestations,

maternal and perinatal outcomes as proportions with 95% confidence intervals (CI) and

prediction intervals (PI). Comparative dichotomous data were reported using odds ratios

(OR) with 95% CI. We pooled the individual study results using random effects model and

also provided ranges and prediction intervals to summarise the variations in the estimated

effects. Heterogeneity was reported as I2 statistic. We undertook sensitivity analysis by

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restricting the analysis to women with confirmed COVID-19, by sampling frame (universal,

risk-based, and symptom-based testing including not reported), by population (unselected,

selected), by risk status of woman in the studies (high, low, any) and by limiting the analysis

to studies with no suspicion of any potential overlap in the data. All analyses were done with

Stata (version 16).

Patient and public involvement

There were no patients or public involvement in the design, conduct, or reporting of this rapid

systematic review.

Results

From 33,030 citations after removing duplicates, 18,203 unique citations were identified, and

94 studies (34 cohort; 60 case series or case reports) were included in the systematic review

(Figure 1).

Characteristics of the included studies

Of the 94 studies and case reports, 54 (57%) were from China, 12 from USA (13%), seven

from Italy, three from Iran, two each from UK, Portugal and South Korea and one each from

India, Jordan, Australia, Peru, Honduras, Sweden, Turkey, Belgium, Switzerland, Brazil,

Spain and the Netherlands. All studies used RT-PCR tests of respiratory samples for the virus

to confirm the diagnosis of COVID-19; 17 studies additionally diagnosed COVID-19 based

on clinical suspicion. Twenty-seven 12,13,23-47 cohort studies reported on clinical

manifestations (27 on symptoms, 16 on laboratory and 20 on radiological findings); 20

studies 12,15,24,26,28,29,31-33,35,38-41,44-49 on COVID-related maternal outcomes (1467 women); and

24 on pregnancy-related maternal (1337 women) and perinatal outcomes (900 babies)12,23-

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36,38-45,49 (Appendix 4). The sampling frames included universal (9 studies), risk-based (18

studies) where all studies followed the NHCC guidelines, and symptom-based (7 studies)

strategies. Overall, 87 studies (27 cohorts, 60 case series and reports) provided some

information on mother-to-child transmission (1483 women, 869 babies).

Quality of the included studies

Of the 34 cohort studies assessed for external validity, there was low risk of bias for

representativeness in 9% (3/34) of studies, sampling in 29% (10/34), selection in 44%

(15/34), and non-response in 94% (32/34) of studies. For internal validity, there was low risk

of bias for data collection in 94% (32/34) of studies, case definition in 3% (1/34),

measurement in 97% (33/34), differential verification in 100% (34/34), adequate follow-up in

44% (15/34), and appropriate numerator and denominator in 65% (22/34) (Appendix 5). For

comparative cohort studies evaluated using the Newcastle Ottawa Scale, 80% (8/10) of

studies had low risk of bias for study selection, 50% (5/10) for comparability of cohorts and

50% (5/10) for outcome assessment (Appendix 5).

Clinical manifestations of COVID-19

In pregnant and recently pregnant women with COVID-19, the commonest symptom was

fever in 38% (95% CI 29 – 48; range 11-87; I2 = 93%), followed by cough in 36% (95% CI

24 – 49; range 3-100; I2=98%). Figure 2 provides the rates of other symptoms like dyspnoea,

myalgia and diarrhoea along with their 95% PI. One small study (n=28) reported on ageusia

in 4% (95% CI 0.1-18.3) of women.36 About half of all pregnant women had

lymphocytopaenia (49%; 95% CI 30 – 68; I2=98%) and raised C-reactive protein (52%; 95%

CI 45 – 59; I2 = 69%); raised white cell count was observed in 23% (95% CI 12 – 39; I2 =

91%) and abnormal liver function in 17% (95% CI 13 – 23; I2 = 0%). Any abnormal finding

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in chest CT was observed in 88% (95% CI 71-96; I2 = 99%); ground glass appearance was

reported in 83% (95% CI 56 – 95 %; I2 =96%) of women (Figure 2). The odds of fever (OR

0.21, 95% CI 0.09-0.51)33,43 and lymphocytopaenia (OR 0.24, 95% CI 0.06-0.98)33 were

lower in pregnant vs non-pregnant women with COVID-19 (Table 1). Sensitivity analysis

restricted to various sampling frames showed high estimates of fever, cough and dyspnoea in

the symptom-based group (Appendix 6). Radiological changes were reported in a high

proportion of studies using risk-based testing strategy or when CT-scan was used as a

screening tool. The rates of clinical manifestations were similar to the overall estimates when

the analysis was restricted to only RT-PCR confirmed COVID-19 women, unselected

populations, women with any risk, and when we excluded the studies where potential data

overlap cannot be ruled out (Appendix 7).

Maternal and perinatal outcomes

COVID- related maternal outcomes

Overall, 5% (95% CI 3 – 8%; 11 studies, 1093 women, I2=72%) of women with suspected or

confirmed COVID-19 were admitted to intensive care, 2% (95% CI 1 – 7%, I2=NE) required

invasive ventilation, and 52% (95% CI 7 – 94%, I2=99%) received supplemental oxygen

through nasal cannula. Pneumonia was diagnosed in 84% (95% CI 42 – 98%, I2=100%) of

women with suspected or confirmed COVID-19 (Figure 3). We did not observe statistically

significant differences between pregnant and non-pregnant women with COVID-19 in the

risks of admission to the intensive care unit (OR 0.66, 95% CI 0.31 – 1.43; I2= 0%)15,32 or in

invasive ventilation (OR 0.9, 95% CI 0.05 – 15.47) 32 (Table 1). The proportion of women

diagnosed with pneumonia and those needing supplemental oxygen through cannula varied

with sampling strategy; the rates were lower in universally screened and unselected

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populations than the overall estimates (Appendix 8). Analysis restricted to women with

confirmed COVID-19 showed similar findings to the main analyses (Appendix 9).

Pregnancy-related maternal outcomes

The rate of preterm birth (<37weeks) was 15% (95% CI 10 – 20, I2=87%) and preterm

premature rupture of membranes (PPROM) was 5% (95% CI 3 – 8%, I2=13%) in pregnant

women with suspected or confirmed COVID-19; 59% (95% CI 42 – 74%, I2=97%) of all

women delivered by caesarean section (Figure 3). The rates of preterm birth increased 3-fold

in pregnant women with vs without COVID-19 (OR 3.0, 95% CI 1.2 – 7.9; I2= 1%);29,30 there

were no differences in the rates of caesarean section (OR 3.4, 95% CI 0.41 – 27.7; I2= 93%)

between the two groups29,38 (Table 1). The rates of maternal outcomes were similar to the

main estimates when the analysis was limited to women with confirmed COVID-19

(Appendix 9). The rates varied with the sampling strategy, with lower rates of caesarean

section in analysis restricted to studies using universal screening to (43%) and symptom-

based-screening (25%) than the overall estimates. (Appendix 8)

Perinatal outcomes

The rates of stillbirth and neonatal deaths were 4 (95% CI 1 – 11; I2=0%) and 4 (95% CI 1 –

13; I2=0%) per 1000 pregnancies respectively. Overall, 43% (95% CI 8 – 87%, I2=100%) of

newborns were admitted to the neonatal unit (Figure 3). Neonatal sepsis was diagnosed in 4%

(95% CI 1 – 14%, I2=NE) of all babies. Fetal distress was diagnosed in 9% (95% CI 6 – 13%,

I2=0%), with 5’ Apgar score less than 7 in 1% (95% CI 0 – 4%, I2=0%). The rates of

perinatal outcomes appeared broadly similar in various sensitivity analyses to the main

analyses, except for higher rates of admission of the babies to the neonatal unit in in studies

on high-risk women (76%) and lower rates in unselected populations (25%) (Appendix 9).

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Mother-to-child transmission

Eight-seven studies including case reports (1483 women; 869 babies) reported on the viral

status of the mother and baby. Fifty-two (52/869, 6%) babies were suspected or confirmed to

have COVID-19 following exposure to the virus in utero, intrapartum or postnatally. In

babies with suspected infection, 75% (39/52) of their mothers were diagnosed in

pregnancy.26,28,38,39,45,49-70 Of the 39 babies with suspected COVID-19 born to mothers

diagnosed antenatally, 82% (32/39) were born by caesarean section, and 15% (6/39) by

vaginal delivery.

In twenty babies, the nasopharyngeal swabs were positive swabs in the first 24 hours after

birth, eight of whom had positive RT-PCR in nasopharyngeal swabs within the first 12 hours

after birth;26,28,38,49,54,56,58,61,63,66,70 three newborns had IgM antibodies for SARS-CoV-2

within 12 hours of birth (Figure 4).50,57 In the eight babies with SARS-CoV-2 in the

nasopharyngeal swabs within 12 hours after birth,38,58,70 there were no reports of the virus in

the cord blood, neonatal blood, amniotic fluid or placenta. There was one report of SARS-

CoV-2 detection in cord blood, but the baby was asymptomatic and all tests were negative for

the virus in the baby.61 There was evidence of the virus in the placenta or placental

membranes in six women (56 tested),61,71-73 breast milk in two (63 tested),40,61 vaginal fluid in

one (39 tested),35 amniotic fluid in one (62 tested),56 cord blood in one (65 tested),61 neonatal

blood in one (16 tested)60 and neonatal anal or faecal sample in four babies (52 tested).55,59,60

Ninety-four percent (814/869) of the babies tested negative in all samples. Of the 52 babies

with suspected or confirmed COVID-19 born to mothers with the disease either in pregnancy

or postpartum, 19% (10/52) were breast fed. There were two reports of SARS-CoV-2

detection in breast milk, but this was transient and the babies were not infected despite

receiving breast milk.40,61

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Discussion

Summary of findings

Fever, cough, lymphocytopaenia and raised C-reactive protein were the commonest

manifestations of COVID-19 in pregnant women with suspected or confirmed disease and

were present in about half of all women. One in twenty pregnant and recently pregnant

women with COVID-19 required treatment in intensive care. Preterm birth rate was 15%,

with higher rates in pregnant women with COVID-19 than those without the disease; over

half of all affected women delivered by caesarean section. Stillbirth and neonatal deaths were

observed in four per thousand deliveries in women with suspected or confirmed COVID-19.

The findings were similar when analysis was restricted to pregnant and recently pregnant

women with confirmed COVID-19. There was large heterogeneity in the estimates for the

rates of clinical manifestations and outcomes, which varied by sampling frames, selection

and risk factors. About one in twenty babies born to mothers with COVID-19 and exposed

in-utero, intrapartum or postnatally were suspected to have the infection. Viral RNA has been

detected in neonatal respiratory, maternal and neonatal faecal samples, and very rarely in the

amniotic fluid, placenta, membranes, vaginal fluid, cord blood and neonatal plasma.

Strengths and limitations

In this unprecedented pandemic situation, where evidence is rapidly produced and published

in various formats, our living systematic review underpinned by robust methods and

continually updated at regular intervals is relevant for the following reasons. Firstly, it

addresses important research questions relevant for clinical decision-making and policies.

Secondly, uncertainties remain for key outcomes that requires further evidence. Thirdly, the

rapid turn-over of evidence in various formats requires assessments of study qualities and

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regular updating of the findings. Finally, our living systematic review will produce a strong

evidence-base for living guidelines on COVID-19 and pregnancy.

We undertook a comprehensive search and co-ordinated our efforts with key organisations

and research groups like WHO, Cochrane and EPPI-Centre. We restricted our meta-analysis

to cohort studies to minimise the risk of bias and reported the qualities of the included

studies. Our systematic review’s sample size is 3-fold greater than the largest primary study

involving pregnant women with COVID-19.38 Our review helps to understand the variations

in estimates through sensitivity analyses by sampling strategies, population characteristics

and risk factors, and provides more confidence in the rates of reported outcomes. Along with

the 95% confidence intervals and ranges, we also provided 95% prediction intervals to reflect

the study heterogeneity and predict the expected rates in future studies. Caution should be

given to the interpretation of prediction interval when the number of studies is too small or

proportions are too close to 0 or 1. To assess the risk of mother-to-child transmission, we

included all studies including case reports, and comprehensively evaluated the evidence for

the virus in various maternal, placental, cord blood and neonatal samples.

There are limitations in our systematic review. The primary studies identified women with

COVID-19 disease using varied sampling frames, comprised of women with suspected and

confirmed COVID-19 disease, and primarily reported on pregnant women requiring

admissions to the hospitals including for childbirth, affecting the generalisability of the

estimates. Although our sensitivity analyses aimed to address some of these problems, the

numbers and sample sizes of the individual studies were too small to identify differences

between the subgroups. The timing of assessment of the clinical manifestations of disease

was generally not available. The definitions of symptoms, tests and outcomes were

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heterogeneous. Furthermore, poor reporting of the criteria for caesarean section, admission of

babies to the neonatal unit, and the causes of preterm birth, made it difficult to disentangle

iatrogenic effect from the true impact of the disease. There is a paucity of comparative data to

assess the risk of severe disease in the pregnant population compared to the non-pregnant

women in similarly aged groups, and to compare pregnancy outcomes in women with and

without COVID-19. Not many studies reported outcomes by trimester for symptom onset

making it difficult to assess the rates of miscarriage and postpartum complications. Very few

studies robustly evaluated the risks of mother-to-child transmission by testing placenta,

amniotic fluid, cord and neonatal blood, and other neonatal and maternal samples at or near

the time of delivery, making it difficult to robustly confirm presence or absence of

transmission in utero, intrapartum or postpartum. Additionally, reports on the same mother

and baby were reported in multiple studies, often without acknowledging the possibility of

duplicate data.

Comparison to existing evidence

In the recent cohort study of all individuals admitted with COVID-19 in the UK, the cluster

of respiratory symptoms of cough, fever and dyspnoea were observed in over two-thirds of

individuals,74 similar to reported rates in US and China.75-77 But in our review, all three

symptoms were reported in less than half of all women, indicating possible high rates of

asymptomatic presentation in this population. Furthermore, fewer women with COVID-19 in

our review presented with lymphocytopaenia than the general population cohorts. 76,75 In line

with the spread of the pandemic, there has been a shift in the types of studies published, with

initial studies involving pregnant women from epidemic regions in China to recent large

regional and national datasets from the UK, Netherlands and Spain. These variations in the

settings, sampling frames and clinical management may account for the heterogeneity in our

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estimates. Severity of disease as evidenced by admission to intensive care units is similar or

lower to the reported rates in the overall populations with COVID-19 in UK (17%),74 China

(5%)57 and the US (14%).76 However, the populations of adults requiring admission to the

hospital with COVID-19 are skewed towards an older, male population, unlike pregnant

women. The rate of intensive care unit admission for individuals in the 22-44 year-old age

group, which is more comparable to pregnant women, was 2.0-4.2% in the United States,

with mortality rate of 0.1-0.2%.48 The rates of maternal pneumonia appear to be high in the

studies using the risk-based sampling, which may be attributed to the variations in diagnosing

the condition, and the increased use of CT-scan as a screening or diagnostic test, which

detects more radiological changes than chest radiography.28,31,39-41,45,47 Although we found

radiological abnormalities on chest CT scan in over 80% of women, the estimates were

predominantly influenced by studies using risk-factor based testing using the NHCC

guidelines or using a strategy of screening using chest CT scan.

The predicted intervals for pregnancy-related outcomes were very wide reflecting the

uncertainty in the findings. More than half of all women were delivered by caesarean section,

but these estimates were predominantly driven by the studies using the NHCC guidelines,

where COVID-19 may have been an indication for caesarean delivery, particularly in the

initial stages of the global pandemic. The overall rates of stillbirths and neonatal deaths do

not appear higher than the background rates. The high rates of admissions to the neonatal unit

were likely driven by complications of preterm birth and policies of observation and

quarantine infants with SARS-CoV-2 exposure.

To-date, there has been no confirmed maternal-fetal vertical transmission of other

coronaviruses SARS-CoV-1 and MERS.78 Although SARS-CoV-2 infection was suspected in

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babies born to women diagnosed with COVID-19 in pregnancy, determination of in utero

infection is complex, and requires sampling of appropriate tissues or fluids near the time of

birth. Most of the studies that reported detection of SARS-CoV-2 in nasopharyngeal

specimens were from samples taken from infants aged one day or older, and horizontal

transmission cannot be ruled out in such cases. In the three cases detecting SARS-CoV-2

IgM antibody in neonatal blood,50,57 which could indicate possible in utero infection,

neonatal nasopharyngeal tests were negative; the IgM turned negative by 12-28 days, and the

infants had no symptoms. Similarly, in the six reports of detection of the virus in the placenta,

in all cases the babies had multiple negative nasopharyngeal tests and no symptoms.61,71-73

Overall, we consider mother-to-child transmission to be probable or possible, but not

confirmed.

Relevance for clinical practice and research

Healthcare professionals should be aware that at least half, if not more, of pregnant and

recently pregnant women with COVID-19 who are admitted to the hospitals for any reason

may be asymptomatic. While rates of intensive care admissions and mortality in pregnant

women with COVID-19 appear similar to the general population with the disease, it is

important to recognise that there are significant differences in age between pregnant women

and the population hospitalised for COVID-19 and those requiring admission to intensive

care units. It is essential to compare the disease severity to that of age-matched non-pregnant

women with COVID-19. The relatively high rates of preterm birth and caesarean section in

pregnant women with COVID-19 is likely to be iatrogenic with urgent delivery required due

to deteriorating maternal condition, often resulting in fetal distress, than a direct effect of

SARS-CoV-2 infection. The risk of mother-to-child vertical transmission appears to be very

low.

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Whether pregnant women with pre-existing conditions for COVID-19 such as diabetes,

chronic hypertension, obesity, and pregnancy-specific conditions such as pre-eclampsia and

gestational diabetes are at increased the risk of complications needs to be evaluated. As

additional evidence emerges on maternal and neonatal outcomes in women delivering

vaginally, it is likely that we will see a reduction in the rates of caesarean section, iatrogenic

preterm deliveries and newborn admissions to the neonatal special or intensive care units.

Robust collection of maternal data by trimester of exposure including periconception period

is required to determine the effects of COVID-19 on early pregnancy outcomes, fetal growth,

and risk of stillbirth. Any study on mother-to child transmission should obtain relevant

maternal samples including vaginal fluid, placental, amniotic fluid, cord blood, neonatal

blood and other neonatal samples for virological (and immunological studies) at multiple

timepoints starting at birth and evaluated for their infective potential.

Systematic reviews are considered to be the highest quality evidence informing guidelines

and poor-quality reviews will have a direct impact on clinical care. Despite the urgent and

huge need for evidence on the impact of COVID-19 on pregnant women, systematic reviews

and meta-analysis still need to adhere to the reporting guidelines on search, quality

assessment and analysis. This is particularly important as large numbers of non-peer

reviewed scientific papers and reports are currently available in the public domain in multiple

versions. Primary studies need to explicitly state if they have included duplicate data to avoid

double-counting of participants in evidence synthesis. Individual participant data meta-

analysis of the emerging cohorts is critical to assess both differential presentation and

outcomes by underlying risk factors, but also to determine the differential effects of

interventions to reduce the rates of complications. With the establishment of several national

and global prospective cohorts, we expect the sample size of our meta-analysis to further

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increase in the coming months. Our living systematic review with its regular search and

analyses updates is ideally placed to assess the impact of new findings on the growing

evidence base.

Word count: 4544

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Acknowledgment: The Cochrane Gynaecology and Fertility Group would like to acknowledge Marijke Strikwerda and Bethany Clark for helping with searches and data-extraction. The PregCOV-19 LSR Group would also like to acknowledge Prof James Thomas from the EPPI Centre for helping with search updates.

Contributors: ST, MB, JA conceptualised the study. MY, SC, LD, TK undertook study selection. JA and ES extracted the data, JZ conducted the analyses. All co-authors contributed to the writing of the manuscript.

Funding: None

Declaration of Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: Not required.

Transparency: The corresponding author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been disclosed.

Data sharing: No additional data available.

Dissemination: PregCov-19 LSR Group will disseminate the findings through a dedicated website, and social media.

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References

1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 2020; 395(10223): 497-506.2. World Health Organisation (WHO) Coronavirus disease (COVID-19) Pandemic, https://www.who.int/emergencies/diseases/novel-coronavirus-2019 (accessed 7 May 2020) 3. Cabinet Office Guidance Staying alert and safe (social distancing). Coronavirus (COVID-19) Guidance and support Updated 22 May 2020 https://www.gov.uk/government/publications/staying-alert-and-safe-social-distancing/staying-alert-and-safe-social-distancing (Accessed 24 May 2020).4. RCOG Coronavirus (COVID-19) Infection in Pregnancy, https://www.rcog.org.uk/globalassets/documents/guidelines/2020-04-17-coronavirus-covid-19-infection-in-pregnancy.pdf 5. Zaigham M, Andersson O. Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies. Acta obstetricia et gynecologica Scandinavica 2020.6. Parazzini F, Bortolus R, Mauri PA, Favilli A, Gerli S, Ferrazzi E. Delivery in pregnant women infected with SARS-CoV-2: A fast review. Int J Gynaecol Obstet 2020.7. Elshafeey F, Magdi R, Hindi N, et al. A systematic scoping review of COVID-19 during pregnancy and childbirth. Int J Gynaecol Obstet 2020.8. Di Mascio D, Khalil A, Saccone G, et al. Outcome of Coronavirus spectrum infections (SARS, MERS, COVID 1 -19) during pregnancy: a systematic review and meta-analysis. Am J Obstet Gynecol MFM 2020: 100107.9. Della Gatta AN, Rizzo R, Pilu G, Simonazzi G. Coronavirus disease 2019 during pregnancy: a systematic review of reported cases. Am J Obstet Gynecol 2020.10. Cheruiyot I, Henry BM, Lippi G. Is there evidence of intra-uterine vertical transmission potential of COVID-19 infection in samples tested by quantitative RT-PCR? European journal of obstetrics, gynecology, and reproductive biology 2020.11. Gajbhiye R, Modi D, Mahale S. Pregnancy outcomes, Newborn complications and Maternal-Fetal Transmission of SARS-CoV-2 in women with COVID-19: A systematic review of 441 cases. 2020.12. Breslin N, Baptiste C, Gyamfi-Bannerman C, et al. COVID-19 infection among asymptomatic and symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of New York City hospitals. Am J Obstet Gynecol MFM 2020: 100118.13. Vintzileos WS, Muscat J, Hoffmann E, et al. Screening all pregnant women admitted to Labor and Delivery for the virus responsible for COVID-19. Am J Obstet Gynecol 2020.14. Xu L, Yang Q, Shi H, et al. Clinical presentations and outcomes of SARS-CoV-2 infected pneumonia in pregnant women and health status of their neonates. Sci Bull (Beijing) 2020.15. Blitz MJ, Grunebaum A, Tekbali A, et al. Intensive Care Unit Admissions for Pregnant and Non-Pregnant Women with COVID-19. Am J Obstet Gynecol 2020.16. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). Chinese Medical Journal 2020; 133(9): 1087-95.17. Allotey J, Bonet M, Zamora J, Yap M, Yuan M, Debenham L, Kew T, Chatterjee S, Stallings E, Qiu X, Thangaratinam S. COVID-19 in pregnant women: a Living Systematic Review on prevalence, presentation, prognosis and treatment. PROSPERO 2020 CRD42020178076 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020178076.18. World Health Organization. (2020). Global surveillance for COVID-19 caused by human infection with COVID-19 virus: interim guidance, 20 March 2020. World Health

Page 24 of 64


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

https://www.who.int/emergencies/diseases/novel-coronavirus-2019

https://www.gov.uk/government/publications/staying-alert-and-safe-social-distancing/staying-alert-and-safe-social-distancing

https://www.gov.uk/government/publications/staying-alert-and-safe-social-distancing/staying-alert-and-safe-social-distancing

https://www.rcog.org.uk/globalassets/documents/guidelines/2020-04-17-coronavirus-covid-19-infection-in-pregnancy.pdf

https://www.rcog.org.uk/globalassets/documents/guidelines/2020-04-17-coronavirus-covid-19-infection-in-pregnancy.pdf

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020178076


24

Organization. https://apps.who.int/iris/handle/10665/331506. License: CC BY-NC-SA 3.0 IGO.19. Dekkers OM, Egger M, Altman DG, Vandenbroucke JP. Distinguishing case series from cohort studies. Ann Int Med 2012; 156(1 Pt 1): 37-40.20. Shah PS, Diambomba Y, Acharya G, Morris SK, Bitnun A. Classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates. Acta obstetricia et gynecologica Scandinavica 2020; 99(5): 565-8.21. Hoy D, Brooks P, Woolf A, et al. Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement. J Clin Epidemiol 2012; 65(9): 934-9.22. Wells G. Proceedings or the Third Symposium on Systematic Reviews beyond the Basics. SBOD. Improving Quality and Impact; The Newcastle–Ottawa Scale (NOS) for Assessing the Quality of non-randomised Studies in Meta-analysis. 2000 July 3-5 Oxford; 2000 23. Cao D, Yin H, Chen J, et al. Clinical analysis of ten pregnant women with COVID-19 in Wuhan, China: A retrospective study. Int J Infect Dis 2020; 95: 294-300.24. Chen L, Li Q, Zheng D, et al. Clinical Characteristics of Pregnant Women with Covid-19 in Wuhan, China. New Eng J Med 2020.25. Chen R, Zhang Y, Huang L, Cheng BH, Xia ZY, Meng QT. Safety and efficacy of different anesthetic regimens for parturients with COVID-19 undergoing Cesarean delivery: a case series of 17 patients. Can J Anaesth 2020; 67(6): 655-63.26. Ferrazzi E, Frigerio L, Savasi V, et al. Mode of Delivery and Clinical Findings in COVID-19 Infected Pregnant Women in Northern Italy. SSRN Electronic Journal 2020.27. Khalil A, Hill R, Ladhani S, Pattisson K, O'Brien P. SARS-CoV-2 in pregnancy: symptomatic pregnant women are only the tip of the iceberg. Am J Obstet Gynecol 2020.28. Khan S, Jun L, Nawsherwan, et al. Association of COVID-19 with pregnancy outcomes in health-care workers and general women. Clin Microbiol Infect 2020.29. Li N, Han L, Peng M, et al. Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study. Clin Infect Dis 2020.30. Liao J, He X, Gong Q, Yang L, Zhou C, Li J. Analysis of vaginal delivery outcomes among pregnant women in Wuhan, China during the COVID-19 pandemic. Int J Gynaecol Obstet 2020.31. Liu D, Li L, Wu X, et al. Pregnancy and Perinatal Outcomes of Women With Coronavirus Disease (COVID-19) Pneumonia: A Preliminary Analysis. AJR Am J Roentgenol 2020: 1-6.32. Liu F, Liu H, Li J, Hou L, Lan W, Wang D. Clinico-Radiological Features and Outcomes in Pregnant Women with COVID-19: Compared with Age-Matched Non-Pregnant Women. SSRN Electronic Journal 2020.33. Liu H, Liu F, Li J, Zhang T, Wang D, Lan W. Clinical and CT imaging features of the COVID-19 pneumonia: Focus on pregnant women and children. J Infect 2020; 80(5): e7-e13.34. Liu W, Wang J, Li W, Zhou Z, Liu S, Rong Z. Clinical characteristics of 19 neonates born to mothers with COVID-19. Front Med 2020; 14(2): 193-8.35. NVOG: Nederlandse Vereniging voor Obstetrie en Gynaecologie. Update registratie COVID-19 positieve zwangeren in NethOSS Geplaatst op 24 april 2020.36. Qiancheng X, Jian S, Lingling P, et al. Coronavirus disease 2019 in pregnancy. Int J Infect Dis 2020; 95: 376-83.37. Sutton D, Fuchs K, D'Alton M, Goffman D. Universal Screening for SARS-CoV-2 in Women Admitted for Delivery. New Eng J Med 2020.

Page 25 of 64


BMJ

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https://apps.who.int/iris/handle/10665/331506


25

38. Knight M, Bunch K, Vousden N, et al. Characteristics and outcomes of pregnant women hospitalised with confirmed SARS-CoV-2 infection in the UK: a national cohort study using the UK Obstetric Surveillance System (UKOSS). 2020.39. Nie R, Wang S-s, Yang Q, et al. Clinical features and the maternal and neonatal outcomes of pregnant women with coronavirus disease 2019. 2020.40. Wu Y, Liu C, Dong L, et al. Viral Shedding of COVID-19 in Pregnant Women. SSRN Electronic Journal 2020.41. Yan J, Guo J, Fan C, et al. Coronavirus disease 2019 (COVID-19) in pregnant women: A report based on 116 cases. Am J Obstet Gynecol 2020.42. Yang H, Sun G, Tang F, et al. Clinical features and outcomes of pregnant women suspected of coronavirus disease 2019. J Infect 2020.43. Yin M, Zhang L, Deng G, et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection During Pregnancy In China: A Retrospective Cohort Study. 2020.44. Yue L, Han L, Li Q, et al. Anaesthesia and infection control in cesarean section of pregnant women with coronavirus disease 2019 (COVID-19). 2020.45. Zeng L, Xia S, Yuan W, et al. Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China. JAMA pediatrics 2020.46. Wang C, Xian S, Ma M, LIi X, Huang Y, Liu X. Effect of methoxamine on vital signs of severe COVID‐19 pregnant women during cesarean section. Medical Journal of Wuhan University 2020.47. Liu F, Lan W-s, Gan Q. Clinical and CT features of coronavirus disease in pregnant women. Radiol Practice 2020; 35(4).48. Morbidity and Mortality Weekly Report. Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–March 28, 2020. CDC COVID-19 Response Team.49. Pierce-Williams RAM, Burd J, Felder L, et al. Clinical course of severe and critical COVID-19 in hospitalized pregnancies: a US cohort study. Am J Obstet Gynecol MFM 2020: 100134.50. Dong L, Tian J, He S, et al. Possible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn. JAMA 2020.51. Alonso Diaz C, Lopez Maestro M, Moral Pumarega MT, Flores Anton B, Pallas Alonso CR. [First case of neonatal infection due to SARS-CoV-2 in Spain]. An Pediatr (Barc) 2020; 92(4): 237-8.52. Kamali Aghdam M, Jafari N, Eftekhari K. Novel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report. Infect Dis (Lond) 2020; 52(6): 427-9.53. Wang S, Guo L, Chen L, et al. A case report of neonatal COVID-19 infection in China. Clin Infect Dis 2020.54. Alzamora MC, Paredes T, Caceres D, Webb CM, Valdez LM, La Rosa M. Severe COVID-19 during Pregnancy and Possible Vertical Transmission. Am J Perinatol 2020.55. Zeng LK, Tao XW, Yuan WH, Wang J, Liu X, Liu ZS. [First case of neonate with COVID-19 in China]. Zhonghua Er Ke Za Zhi 2020; 58(4): 279-80.56. Zamaniyan M, Ebadi A, Aghajanpoor Mir S, Rahmani Z, Haghshenas M, Azizi S. Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical transmission. Prenat Diagn 2020.57. Zeng H, Xu C, Fan J, et al. Antibodies in Infants Born to Mothers With COVID-19 Pneumonia. JAMA 2020.58. Carosso A, Cosma S, Borella F, et al. Pre-labor anorectal swab for SARS-CoV-2 in COVID-19 pregnant patients: is it time to think about it? Eur J obstetrics, gynecology, and reproductive biology 2020.

Page 26 of 64


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123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


26

59. Zhang ZJ, Yu XJ, Fu T, et al. Novel Coronavirus Infection in Newborn Babies Under 28 Days in China. Eur Respir J 2020.60. Han MS, Seong MW, Heo EY, et al. Sequential analysis of viral load in a neonate and her mother infected with SARS-CoV-2. Clin Infect Dis 2020.61. Buonsenso D, Costa S, Sanguinetti M, et al. Neonatal Late Onset Infection with Severe Acute Respiratory Syndrome Coronavirus 2. American journal of perinatology 2020.62. Sinelli MT, Paterlini G, Citterio M, Di Marco A, Fedeli T, Ventura ML. Early Neonatal SARS-CoV-2 Infection Manifesting With Hypoxemia Requiring Respiratory Support. Pediatrics 2020.63. Kim JH, Shrestha N, Girshin M. Unexpected severe thrombocytopenia in the COVID-19 positive parturient. Anesth Analg 2020.64. Piersigilli F, Carkeek K, Hocq C, et al. COVID-19 in a 26-week preterm neonate. The Lancet Child & Adolescent Health 2020; 4(6): 476-8.65. Sun M, Xu G, Yang Y, et al. Evidence of mother-to-newborn infection with COVID-19. Br J Anaesth 2020.66. Hantoushzadeh S, Shamshirsaz AA, Aleyasin A, et al. Maternal Death Due to COVID-19 Disease. Am J Obstet Gynecol 2020.67. Falcao MB, Pamplona de Goes Cavalcanti L, Filgueiras Filho NM, Antunes de Brito CA. Case Report: Hepatotoxicity Associated with the Use of Hydroxychloroquine in a Patient with Novel Coronavirus Disease (COVID-19). Am J Trop Med Hyg 2020.68. Salvatori G, De Rose DU, Concato C, et al. Managing COVID-19-Positive Maternal-Infant Dyads: An Italian Experience. Breastfeed Med 2020; 15(5): 347-8.69. Wang J, Wang D, Chen GC, Tao XW, Zeng LK. [SARS-CoV-2 infection with gastrointestinal symptoms as the first manifestation in a neonate]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 2020; 22(3): 211-4.70. Li M, Xu M, Zhan W, Han T, Zhang G, Lu Y. Report of the first cases of mother and infant infections with 2019 novel coronavirus in Xinyang City Henan Province.71. Penfield CA, Brubaker SG, Limaye MA, et al. Detection of SARS-COV-2 in Placental and Fetal Membrane Samples. Am J Obstet Gynecol MFM 2020: 100133.72. Algarroba GN, Rekawek P, Vahanian SA, et al. Visualization of SARS-CoV-2 virus invading the human placenta using electron microscopy. Am J Obstet Gynecol 2020.73. Baud D, Greub G, Favre G, et al. Second-Trimester Miscarriage in a Pregnant Woman With SARS-CoV-2 Infection. JAMA 2020.74. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020; 369: m1985.75. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. New Eng J Med 2020; 382(18): 1708-20.76. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 2020.77. Garg S, Kim L, Whitaker M, et al. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 - COVID-NET, 14 States, March 1-30, 2020. MMWR Morb Mortal Wkly Rep 2020; 69(15): 458-64.78. Schwartz DA, Dhaliwal A. Infections in pregnancy with covid-19 and other respiratory rna virus diseases are rarely, If ever, transmitted to the fetus: experiences with coronaviruses, HPIV, HMPV RSV, and INFLUENZA. Arch Pathol Lab Med 2020.

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*Twitter, national reports, blog Thornton J, ObG Project, COVID-19 & Pregnancy Cases, https://www.obgproject.com/2020/04/07/covid-19-research-watch-with-dr-jim-thornton/ (Accessed May 12th 2020)

Citations identified (n=33,030):Electronic databases from inception to 12 May 2020 (n=32,984)Other sources* and reference lists (n=46)

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n

Full-text articles assessed for eligibility (n=708)

Total articles excluded (n= 614)Inappropriate population (n=327)Inappropriate study design (n=215)Duplicate publication (n= 46)Inappropriate outcome (n=17)Inappropriate exposure (n=8)Article not found (n=1)

Studies included (n=94; 2540 women; 1069 babies)

Quantitative synthesis of cohort studiesClinical manifestations of COVID-19 (27 cohort studies; 1422 women)Maternal outcomes (28 cohort studies; 1646 women)Perinatal outcomes (24 cohort studies; 900 babies)Qualitative synthesis Mother-to-child transmission (n= 87; 27 cohort studies, 60 case series and reports; 1483 women; 869 babies)

Total articles excluded (n=32,322)Irrelevant articles (n=17,495)Duplicates (n=14,827)

Figure 1. Study selection process in the living systematic review on clinical manifestations, maternal and perinatal outcomes in pregnant and recently pregnant women with coronavirus

disease (COVID-19)

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https://www.obgproject.com/2020/04/07/covid-19-research-watch-with-dr-jim-thornton/

Confidential: For Review OnlyFig 2. Clinical manifestations of coronavirus disease (COVID-19) in pregnant women and recently pregnant women with suspected or confirmed disease

Dyspnoea

Myalgia

Symptoms

Studies Events/N(*) I-squared 95% PI RangeProportion (95% CI)

Diarrhoea

Fever 25 686/1350 0.38 (0.29, 0.48) 92.7% (0.00; 0.87) (0.11-0.87)

Cough 24 630/1302 0.36 (0.24, 0.49) 98.4% (0.00; 1.00) (0.03-1.00)

17 218/1074 0.09 (0.05, 0.15) 92.6% (0.00; 0.37) (0.00-0.37)

10 86/787 0.10 (0.06, 0.16) 83.3% (0.00; 0.26) (0.00-0.26)

13 44/913 0.05 (0.03, 0.09) 53.1% (0.00; 0.10) (0.00-0.18)

00 .1 .2 .3 .4 .5 .6 .7 .8 .9 1

Proportion

Clinical manifestations

Laboratory findings

Radiological findings

14 236/522 97.9% (0.00; 1.00) (0.14-1.00)0.49 (0.30, 0.68)

Raised white cell count 8 82/410 0.23 (0.12, 0.39) 91.4% (0.00; 0.68) (0.26-0.52)

Lymphocytopaenia

Thrombocytopaenia 3 26/262 87.9% - (0.03-0.18)0.07 (0.03, 0.20)

Abnormal liver function test 7 45/258 0.17 (0.13, 0.23) 0.0% (0.11; 0.23) (0.11-0.23)

Raised C-reactive protein 12 243/464 0.52 (0.45, 0.59) 69.0% (0.21; 0.80) (0.11-0.71)

Raised procalcitonin 1 16/118 0.14 (0.08, 0.21) - (0.14-0.14)-

0.82 (0.56, 0.95) 96.2% (0.15-1.00)12 292/413Ground glass appearance (0.14; 1.00)

CT-chest abnormality 20 636/1119 0.88 (0.71, 0.96) 98.5% (0.08; 1.00) (0.15-1.00)

N* – Number of pregnant or recently pregnant women for whom manifestations were reported; CI – Confidence Interval; PI – Prediction Interval; CT – Computerised tomography

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Confidential: For Review OnlyFig 3. Maternal and perinatal outcomes in pregnant or recently pregnant women with suspected or confirmed coronavirus disease (COVID-19)

COVID-related outcomes

Studies Events/N I-squared 95% PI RangeProportion (95% CI)

00 .1 .2 .3 .4 .5 .6 .7 .8 .9 1

Proportion

Outcomes

Pregnancy-related maternal outcomes

Perinatal outcomes

11 74/1093Admission to intensive care 0.05 (0.03, 0.08) 72.0% (0.00; 0.13) (0.00-0.10)

0.02 (0.01, 0.07) - - (0.02-0.05)Invasive ventilation 2 3/137

-0.01 (0.00, 0.02) 0.0%Need for ECMO 3 4/525 (0.00-0.01)

Oxygen through nasal cannula 7 117/326 0.52(0.07, 0.94) 99.4% (0.00; 1.00) (0.01-1.00)

0.15 (0.09, 0.24)ARDS 2 14/94 - -

13 361/887Pneumonia 0.84 (0.42, 0.98) 99.7% (0.00; 1.00) (0.02-1.00)

0.02 (0.01, 0.07) (0.02-0.02)Cardiac/liver/renal failure 2 2/107 - -

20 184/1207Preterm birth <37 weeks 0.15 (0.10, 0.20) 86.6% (0.00; 0.35) (0.00-0.40)

4 12/268PPROM <37 weeks 0.05 (0.03, 0.08) 12.8% (0.02-0.09)Caesarean section 20 545/1239 0.59 (0.42, 0.74) 97.4% (0.00; 1.00) (0.10-1.00)

Postpartum haemorrhage 3 4/136 0.03 (0.01, 0.08) 0.0% (0.00-0.05)-

Stillbirth 10 3/853 0.00 (0.00, 0.01) (0.00-0.01)0.0% (0.00; 0.01)

17 3/706Neonatal death 0.00 (0.00, 0.01) 0.0% (0.00-0.01)(0.00; 0.01)

Admission to neonatal unit 13 242/628 0.43 (0.08, 0.87) 99.5% (0.00; 1.00) (0.00-1.00)

0.04 (0.01, 0.14) --Neonatal sepsis 2 2/51 (0.03-0.06)

0.01 (0.01, 0.04)11 4/297 0.0% (0.00; 0.03) (0.00-0.06)

7 23/252Fetal distress 0.09 (0.06, 0.13) 0.0% (0.03-0.18)(0.04; 0.12)

Apgar 5’ <7

(0.00-0.22)

(0.00; 0.10)

N – Number of pregnant or recently pregnant women for COVID-related outcomes and for preterm birth, and PPROM outcomes; number of women delivered for caesarean section and postpartum haemorrhage; number of babies born for perinatal outcomes; CI – Confidence Interval; PI – Prediction Interval; ECMO – Extra corporeal membrane oxygenation; PPROM – Preterm premature rupture of membranes; ARDS – Acute Respiratory Distress Syndrome

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Confidential: For Review OnlyFig 4. Details of newborns with suspected coronavirus disease (COVID-19) born to mothers with confirmed COVID-19

C-Caesarean section, V-Vaginal delivery, #delivered in negative pressure room, *mother with personal protection equipment; AN-Antenatal, PN-Postnatal, T-Term, w-weeks of gestation, n/a- not availableAll columns (except quarantined and Breastfed) Green- negative/no, Red- positive/yes, stripes - equivocal; Day in box represents timing of test; †Died ^plateletsQuarantined column: Green - quarantined from birth, Orange -quarantined later, Red - not quarantinedBreastfed column: Green- not breastfed, Red- Breastfed.

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Confidential: For Review OnlyTable 1: Comparison of clinical manifestations and outcomes between pregnant women and non-pregnant women with coronavirus disease (COVID-19), and pregnant women without COVID-19

COVID-19 manifestations and outcomes

No. of studies

Events/N pregnant with COVID-19

Events/N non-pregnant with COVID-19

OR (95% CI) I-squared

Clinical manifestationsFever 2 25/52 44/54 0.21 (0.09, 0.51) 0%Cough 2 21/52 24/54 0.87 (0.40, 1.90) 0%Dyspnoea 2 9/52 10/54 0.99 (0.35, 2.78) 0%Myalgia 1 3/31 6/35 0.52 (0.12, 2.28) NEDiarrhoea 1 2/31 8/35 0.23 (0.05, 1.20) NERaised white cell count 2 16/52 1/54 13.03 (2.15, 79.14) 3.9%Lymphocytopenia 1 10/21 15/19 0.24 (0.06, 0.98) NEAbnormal liver function 1 7/31 4/35 2.26 (0.59, 8.63) NERaised C-reactive protein 1 15/21 10/19 2.25 (0.61, 8.31) NECOVID-related maternal outcomesInvasive ventilation 1 1/21 1/19 0.90 (0.05, 15.47) NEAdmission to intensive care unit 2 9/103 50/351 0.66 (0.31, 1.43) 0%

Outcomes No. of studies

Events/N pregnant with COVID-19

Events/N pregnant without COVID-19

OR (95% CI) I-squared

Pregnancy-related maternal outcomesAdmission to intensive care unit 1 40/427 1/694 71.63 (9.81, 523.06) NEPreterm birth <37 weeks 2 7/44 18/295 3.01 (1.16, 7.85) 0.9%Caesarean section 2 174/461 302/936 3.39 (0.41, 27.74) 93.1%Perinatal outcomesStillbirth 1 3/427 2/694 2.45 (0.41, 14.71) NENeonatal death 1 2/427 1/694 3.26 (0.30, 36.07) NEAdmission to neonatal unit 1 64/427 37/694 3.13 (2.05, 4.79) NEFetal distress 1 3/34 12/242 1.86 (0.50, 6.94) NE

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PRISMA 2009 Checklist

Section/topic # Checklist item Reported on page #

TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. 1ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria,

participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

2-3

INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 5Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons,

outcomes, and study design (PICOS). 6

METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide

registration information including registration number. 6

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

7-8

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

6-7

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

7

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

7-8

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

9

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

8

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

9

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 9-10Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency

(e.g., I2) for each meta-analysis. 9-10

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PRISMA 2009 Checklist

Page 1 of 2

Section/topic # Checklist item Reported on page #

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

9

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

9-10

RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at

each stage, ideally with a flow diagram. 10

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

10

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 11Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each

intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. 11-14

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 11-14Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 11Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 11-14

DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to

key groups (e.g., healthcare providers, users, and policy makers). 15

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

16-17

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 20

FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the

systematic review. 22

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit: www.prisma-statement.org.

Page 2 of 2

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Appendix 2. Details of search strategies used to include studies in the living systematic review on COVID-19 in pregnant and recently pregnant women

1. Cochrane Gynaecology and Fertility

PubmedItem Term

1 pregnancy/2 pregnan*.tw.3 neonatal.tw.4 perinatal.tw.5 mothers/.6 mother.tw.7 maternal.tw.8 obstetric.tw.9 infant, newborn/10 infant.tw.11 newborn.tw.12 child*.tw.13 or/1-1214 COVID-19.tw.15 COVID-2019.tw.16 severe acute respiratory syndrome coronavirus 2.tw.17 2019-nCoV.tw.18 SARS-CoV-2.tw.19 2019nCoV.tw20 or/14-1921 coronavirus.tw.22 2019/12.pd23 2020.pd.24 or/22-2325 21 and 2424 or/20-2525 13 and 24

Google Scholar and GoogleUsing the following text words (pregnancy OR neonatal OR perinatal OR maternal OR obstetric OR newborn) AND (COVID-19 or SARS-Cov-2)

2. EPPI Centre

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The MEDLINE search strategy is the OVID Expert Search as developed by Wolters Kluwer and available at http://tools.ovid.com/coronavirus/

MEDLINE search strategy

1 exp Coronavirus/ 2 exp Coronavirus Infections/ 3 (coronavirus* or corona virus* or OC43 or NL63 or 229E or HKU1 or HCoV* or ncov* or covid* or sars-cov* or sarscov* or Sars-coronavirus* or Severe Acute Respiratory Syndrome Coronavirus*).mp. 4 (or/1-3) and ((20191* or 202*).dp. or 20190101:20301231.(ep).) 5 4 not (SARS or SARS-CoV or MERS or MERS-CoV or Middle East respiratory syndrome or camel* or dromedar* or equine or coronary or coronal or covidence* or covidien or influenza virus or HIV or bovine or calves or TGEV or feline or porcine or BCoV or PED or PEDV or PDCoV or FIPV or FCoV or SADS-CoV or canine or CCov or zoonotic or avian influenza or H1N1 or H5N1 or H5N6 or IBV or murine corona*).mp. 6 ((pneumonia or covid* or coronavirus* or corona virus* or ncov* or 2019-ncov or sars*).mp. or exp pneumonia/) and Wuhan.mp. 7 (2019-ncov or ncov19 or ncov-19 or 2019-novel CoV or sars-cov2 or sars-cov-2 or sarscov2 or sarscov-2 or Sars-coronavirus2 or Sars-coronavirus-2 or SARS-like coronavirus* or coronavirus-19 or covid19 or covid-19 or covid 2019 or ((novel or new or nouveau) adj2 (CoV on nCoV or covid or coronavirus* or corona virus or Pandemi*2)) or ((covid or covid19 or covid-19) and pandemic*2) or (coronavirus* and pneumonia)).mp. 8 COVID-19.rx,px,ox. or severe acute respiratory syndrome coronavirus 2.os. 9 ("32240632" or "32236488" or "32268021" or "32267941" or "32169616" or "32267649" or "32267499" or "32267344" or "32248853" or "32246156" or "32243118" or "32240583" or "32237674" or "32234725" or "32173381" or "32227595" or "32185863" or "32221979" or "32213260" or "32205350" or "32202721" or "32197097" or "32196032" or "32188729" or "32176889" or "32088947" or "32277065" or "32273472" or "32273444" or "32145185" or "31917786" or "32267384" or "32265186" or "32253187" or "32265567" or "32231286" or "32105468" or "32179788" or "32152361" or "32152148" or "32140676" or "32053580" or "32029604" or "32127714" or "32047315" or "32020111" or "32267950" or "32249952" or "32172715").ui. 10 or/6-9 11 5 or 10

The Embase search strategy as at 21st April 2020

1 exp Coronavirus Infections/ 2 exp coronavirinae/ 3 (coronavirus* or corona virus* or OC43 or NL63 or 229E or HKU1 or HCoV* or ncov* or covid* or sars-cov* or sarscov* or Sars-coronavirus* or Severe Acute Respiratory Syndrome Coronavirus*).mp. 4 or/1-3 5 4 not (SARS or SARS-CoV or MERS or MERS-CoV or Middle East respiratory syndrome or camel* or dromedar* or equine or coronary or coronal or covidence* or covidien or influenza virus or HIV or bovine or calves or TGEV or feline or porcine or BCoV or PED or

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PEDV or PDCoV or FIPV or FCoV or SADS-CoV or canine or CCov or zoonotic or avian influenza or H1N1 or H5N1 or H5N6 or IBV or murine corona*).mp. 6 ((pneumonia or covid* or coronavirus* or corona virus* or ncov* or 2019-ncov or sars*).mp. or exp pneumonia/) and Wuhan.mp. 7 (2019-ncov or ncov19 or ncov-19 or 2019-novel CoV or sars-cov2 or sars-cov-2 or sarscov2 or sarscov-2 or Sars-coronavirus2 or Sars-coronavirus-2 or SARS-like coronavirus* or coronavirus-19 or covid19 or covid-19 or covid 2019 or ((novel or new or nouveau) adj2 (CoV on nCoV or covid or coronavirus* or corona virus or Pandemi*2)) or ((covid or covid19 or covid-19) and pandemic*2) or (coronavirus* and pneumonia)).mp. 8 6 or 7 9 5 or 8

3. WHO COVID-19 database

The WHO COVID-19 database contained articles on the novel coronavirus from the following sources:

Web of Science Oxford Academic Journals Pubmed NIH Ishiyaku J Stage Cinii articles Ichushi Web – JAMAS Science Direct Wiley Online Journals JAMA Network British Medical Journal Mary Ann Liebert New England Journal of Medicine Sage Publications Taylor and Francis Online Springer Link Biomed Central MDPI ASM PLOS The Lancet Cell Press Cell Press Search Interface EMBASE KoreaMed Global Index Medics

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MMWR Epidemiology and Health American Chemical Society Eurosurvellance Cambridge Press LWW Airiti JIMR Emerging Infectious Diseases Osong Public Health & Research Perspectives BASE Bielefeld LitCOVID

An additional step using the following search terms was added to the WHO search from 12th May 2020

tw:(newborn* OR mother* OR bab* OR wom* OR pregnan* OR postpart* OR neonat* OR fetus OR fetal OR newborn OR mother OR bab*)

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Appendix 3. Clinical manifestations, maternal and perinatal outcomes in pregnant and postpartum women with coronavirus disease (COVID-19) included in the living

systematic review

Clinical manifestation SymptomsCough, Fever, Breathlessness, Sputum, Myalgia, Fatigue, Diarrhoea, Headache, Sore throat, Chest pain, rigor, Nausea or vomiting, Sequential Organ Failure Assessment (SOFA), Quick SOFA (qSOFA), Ageusia, Anosmia, Asymptomatic

LaboratoryWhite Cell Count, Lymphocyte count, Haemoglobin, Anaemia, Platelet count, Albumin, ALT, AST, C-reactive protein, Creatinine, Lactate dehydrogenase, Creatine kinase, High-sensitivity cardiac troponin, Prothrombin time, D-dimer, Serum, ferritin, Interleukin-6, Procalcitonin

RadiologicalConsolidation, Groundglass opacity, Bilateral pulmonary infiltration, unilateral pulmonary infiltration, abnormal chest x-ray, abnormal chest CT

COVID-related outcomes PrimaryMortality: All-cause mortality, COVID-specific mortalityClinical respiratory syndrome: pneumonia, respiratory failure, ARDS (Acute Respiratory Distress Syndrome) Severe pneumoniaTime from illness onset to outcome (death, recovery)

SecondaryNeed of respiratory support: Invasive ventilation, non-invasive ventilation, oxygenation, Hospitalisation: Admission to ICU (Intensive Care Unit), admission to hospital, ICU length of stayOrgan failure: Sepsis, cardiac failure, septic shock, Coagulopathy, Acute cardiac injury, Acute kidney injury, acute hepatic failure, cytokine storm syndrome (haemophagocytic lymphohistiocytosis) Hypoproteinaemia, Acidosis,Central nervous system manifestations, Secondary infection, Duration of viral shedding after COVID-19 onset,) Long-term respiratory outcomesDelirium, acute neuropsychiatric emergency, agitation, anxiety, depression, psychosis

Pregnancy-related outcomes Primary outcomePregnancy outcome: Miscarriage (spontaneous), induced abortion; preterm delivery (<37w, 36w; spontaneous preterm delivery, induced preterm birth); term delivery

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Pregnancy complications: preterm rupture of membranes, preterm-premature rupture of membranes, prelabour rupture of membranes at(or near) term.Primary cause of maternal death.

Secondary outcomeMode of delivery (vaginal, operative vaginal, Caesarean Section)Onset of labour: spontaneous, induced, CS before labourDirect maternal infections: chorioamnionitis; wound infection, Obstetric complications: pregnancy-induced hypertension, gestational diabetes, antepartum haemorrhage, postpartum haemorrhage

Offspring outcomes Primary outcomeSevere perinatal outcomes: Stillbirth, neonatal death (early, late), fetal distress, fetal growth restriction post infection

Secondary outcomeNeonatal outcomes: Apgar score at 1’, 5’; cord blood pH, gestational age at delivery, birthweight, LGA (large-for-gestational age), SGA (small-for-gestational age), - Congenital malformation,Severe neonatal morbidity: HIE (hypoxic ischaemic encephalopathy), neonatal seizures, neonatal infection (other than COVID), neonatal sepsis, neonatal asphyxia, DIC (Disseminated Intravascular Coagulation), NEC (Necrotising Enterocolitis), RDS (Respiratory distress syndrome),Hospitalisation: admission to the neonatal unit, length of stay in neonatal unit, Primary cause of neonatal death.

Mother-to-child outcomes Viral levels in a.) amniotic fluid, b.) cord blood, c.) vaginal fluids, d.) breast milk, e.) neonatal throat swabs, f.) placentaDuration of viral shedding after COVID-19 symptom onset, after clinical resolution of signs/symptoms

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Study Population Exposure OutcomesAuthor, Year

Study Design

No. ofmothers

No.of babies

Inclusion andexclusion criteria

Diagnosis of COVID-19

Maternal Fetal/Neonatal

Blitz M, 2020USA

Prospective cohort

82 pregnant women with confirmed COVID-19

332 non-pregnant women

All women of reproductive age (defined as between 15-49 years) admitted and tested at 7 hospitals.

Testing carried out on symptomatic patients.

Two groups1) Pregnant women with confirmed COVID-192) Non-pregnant women with confirmed COVID-19

Patients with incomplete data were excluded.

Mothers diagnosed with nasopharyngeal swabs on admission, during hospital stay or after delivery.

COVID-related: admission to ICU

Breslin N, 2020USA**

Retrospective cohort


18 All women attending the Labour and Delivery Triage Unit and tested.

Testing was carried out for women following screening for signs/symptoms, risk factors and travel from 13-21 March. All women tested from 22 March.

Mothers and newborns were diagnosed by nasopharyngeal swabs.

COVID-related: pneumonia, oxygenation, admission to hospital and ICU, acute renal injury

Pregnancy-related: preterm and term birth, spontaneous and induced labour, mode of delivery - caesarean section and vaginal, pregnancy-induced hypertension, pre-labour rupture of membranes at term

Admission into NICU, neonatal sepsis, Apgar scores at 1 and 5 minute, respiratory distress, congenital malformation

Cao D, 2020China*



11 All pregnant women admitted and tested.

Mothers were diagnosed by throat swabs. Some newborns were diagnosed by throat swabs within 24 hours of birth.

Followed diagnostic criteria according to National Health Commission of China.

COVID-related: all-cause mortality, invasive ventilation

Pregnancy-related: preterm birth, mode of delivery – caesarean-section and vaginal, preterm rupture of membranes, gestational diabetes

Neonatal death, neonatal asphyxia, foetal distress, birthweight, gestational age at delivery, Apgar scores at 1 minute and 5 minute

Chen L, 2020China**


118 pregnant women with suspected or confirmed COVID-19:

84 pregnant

70 All laboratory-confirmed and clinically-diagnosed pregnant women admitted at all hospitals in Wuhan.


Laboratory-confirmed women were diagnosed by RT-PCR.

Clinically-diagnosed women diagnosed by chest

COVID-related: all-cause mortality, non-invasive ventilation

Pregnancy-related: miscarriage, induced abortion, induced labour, preterm birth, mode of delivery – caesarean section and vaginal

Neonatal death, neonatal asphyxia, Apgar score at 1 minute

Appendix 4. Characteristics of cohort studies included in the systematic review of COVID-19 in pregnancy and postpartum

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women with confirmed COVID-19

CT imaging.

Some newborns were diagnosed by throat swabs.

Chen R, 2020China**



17 All women admitted for caesarean delivery and tested.

Mothers and newborns diagnosed by nasal swabs.


Pregnancy-related: preterm and term birth, gestational diabetes, mode of delivery – caesarean section, pregnancy-induced hypertension

Admission into NICU, length of stay in NICU, stillbirth, neonatal death, neonatal asphyxia, Apgar scores at 1 minute and 5 minute, birthweight – low-birth weight defined as less than 2 500 grams, cord blood pH – acidosis defined as less than 7.2 in umbilical artery

Chow N, 2020USA



143 All test-positive cases in 50 US states, four US territories and affiliated islands were reported to CDC.

NK- testing criteria COVID-related: admission to hospital and ICU

Cui P, 2020China


35 women with suspected or confirmed COVID-19

27 women with confirmed COVID-19

1 post-natal women with suspected COVID-19

1 All laboratory-confirmed and clinically-diagnosed women with suspicion of COVID-19 who are of reproductive age, postpartum or post-menopausal.

Followed diagnostic criteria according to National HealthCommission of China.

Laboratory-confirmed women were diagnosed by throat swabs.

Clinically-diagnosed women were diagnosed based onepidemiological histories, symptoms, CT imaging and the absence of a positive throat swab.

Newborn was diagnosed by throat swabs.

COVID-related: admission to ICU, invasive ventilation

Pregnancy-related: mode of delivery – caesarean section

Ferrazzi E, 2020Italy

Prospective cohort


5 postnatal women with confirmed COVID-19

42 All women who were admitted for delivery and tested.

Women with positive tests before delivery, 36 hours after delivery and those who delivered during the study were included.

Mother and newborns were diagnosed by throat swabs.

Followed diagnostic criteria according to Italian National Procedures.

COVID-related: pneumonia, oxygenation, admission to ICU Pregnancy-related: preterm and term birth, gestational diabetes, mode of delivery – caesarean section and vaginal, spontaneous and induced labour, postpartum haemorrhage

Admission to NICU, Apgar scores at 5 minute, birthweight

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Khalil A, 2020UK

Prospective cohort

129 pregnant women with suspected or confirmed COVID-19


129 All pregnant women admitted were universally screened.

Mothers were diagnosed by nasopharyngeal swabs. COVID-related: admission to hospital, length of stay

Khan S, 2020China




17 All pregnant women admitted and diagnosed with COVID-19 pneumonia.

Followed diagnostic criteria according to New Coronavirus Pneumonia Prevention and Control Program.


Clinically-diagnosed women were diagnosed by CT imaging.

Newborns were diagnosed by throat swabs collected straight after delivery.

COVID-related: admission to hospital

Pregnancy-related: preterm birth, mode of delivery – caesarean section, preterm rupture of membranes

Neonatal death, stillbirth, neonatal pneumonia, birthweight, Apgar scores at 1 minute and 5 minute

Li N, 2020China*



18 pregnant women with suspected COVID-19

242 pregnant women without COVID-19

17 from confirmed cases

19 from suspected cases

242 from controls

All women admitted to labour and tested during study period.

Two case groups1) Women with confirmed COVID-192) Women with suspected COVID-19

Women aged between 25-35 years randomly selected from records.

Two control groups3) Women admitted during study period4) Women admitted at a similar time of year in 2019



Clinically-diagnosed women were diagnosed by chest CT imaging with negative swabs.

Some newborns were diagnosed by throat swabs.

COVID-related: admission to hospital and ICU, length of hospital stay, oxygenation

Pregnancy-related: preterm delivery, mode of delivery – caesarean section and vaginal, gestational diabetes, preterm rupture of membranes, pregnancy-induced hypertension

Neonatal death, neonatal asphyxia, foetal distress, gestational age at delivery, birthweight – low birth weight defined as less than 2 500 grams, Apgar scores at 1 minute and 5 minute

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Liao J, 2020China


63 pregnant women: 10 women with suspected or confirmed COVID-19

10 (from mothers with suspected or confirmed COVID-19)

Any women admitted and delivered vaginally.

Two groups 1) Women with clinical diagnosis of COVID-19 on obstetric isolation ward.2) Women without COVID-19 on general ward.

Mothers were diagnosed clinically with laboratory results and CT imaging – no throat swab tested.

Followed diagnostic criteria according toNational Health Commission of China.

Isolated newborns tested with throat swabs.

Pregnancy-related: preterm birth,premature rupture of membranes, mode of delivery – vaginal, postpartum haemorrhage

Neonatal death, neonatal asphyxia, gestational age at delivery, birthweight,admission to NICU

Liu D, 2020China



11 Women with COVID-19 pneumonia consecutively admitted to the hospital and were tested.

Mothers were diagnosed with RT-PCR test for SARS-CoV-2.

Followed diagnostic criteria according toNational Health Commission of China.

COVID-related: pneumonia, oxygenation

Pregnancy-related: miscarriage, induced abortion, gestational diabetes, mode of delivery – caesarean section and vaginal

Neonatal death, neonatal asphyxia, Apgar scores at 1 minute and 5 minute

Liu F, 2020China

Prospective cohort


17 Any women admitted who was tested and with complete clinical and CT data.

Two groups:1) Pregnant women with confirmed COVID-192) Age-matched non-pregnant women with confirmed COVID-19

Cases with poor image quality for assessment or infection with another pathogen were excluded.

Mothers were diagnosed with throat swabs. RT-PCR tests carried out according to WHO guideline. Newborns were tested by RT-PCRs.

COVID-related: ventilation, admission to hospital and ICU

Pregnancy-related: preterm and term birth, gestational diabetes, mode of delivery – caesarean section and vaginal, preterm rupture of membranes, pregnancy-induced hypertension

Neonatal death, neonatal asphyxia, neonatal pneumonia, foetal distress, Apgar scores at 1minute and 5 minute

Liu F (1), 2020China*




8 All pregnant women admitted with COVID-19.

Followed diagnostic criteria according to National Health Commission of China

Confirmed women were diagnosed by RT-PCR.

Suspected women were diagnosed by typical chest CT imaging of COVID-19 pneumonia.

Newborns were diagnosed by RT-PCR.

COVID-related: pneumonia

Pregnancy-related: preterm rupture of membranes

Liu H, 2020China*



16 women

16 Any patient with laboratory-confirmed or clinically-diagnosed COVID-19 pneumonia.

The study included pregnant women, non-pregnant adults and children.


Clinically diagnosed mothers were diagnosed with CT imaging according to National Health Commission of China.

COVID-related: admission to ICU

Pregnancy-related: gestational diabetes, pregnancy-induced hypertension

Congenital malformation

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with confirmed COVID-19

One case was excluded due to positive mycoplasmainfection.

Liu W, 2020China



19 All women clinically-diagnosed or laboratory-confirmed during late pregnancy and delivered.

Followed diagnostic criteria according to Coronavirus Pneumonia Prevention and Control Chinese Program.

Clinically-diagnosed women had a fever and/or respiratory symptom, radiological signs of viral pneumonia, low/normal white cell count or low lymphocyte count and no improvementafter treatment for 3 days.

Laboratory-confirmed women had a positive RT-PCR or matched genetic sequence for SARS-CoV-2.

Newborns were tested by RT-PCR on throat swabs, gastric fluid after birth, urine and faeces.

Pregnancy-related: mode of delivery – caesarean section and vaginal, preterm rupture of membranes

Admission to NICU, gestational age at delivery, birthweight, Apgar scores at 1 minute and 5 minute

Nie R, 2020China



28 All consecutive pregnant women diagnosed with COVID-19 at five hospitals in Hubei province.

Followed the diagnostic criteria according to National Health Commission of China.

Some mothers and newborns were diagnosed by throat swabs.

COVID-related: all-cause mortality, pneumonia, non-invasive and invasive ventilation, oxygenation, acute respiratory distress syndrome, admission to ICU

Pregnancy-related: induced abortion, preterm birth, mode of delivery – caesarean section and vaginal, preterm-premature rupture of membranes, gestational diabetes, pregnancy-induced hypertension

Neonatal death, foetal distress, neonatal pneumonia, admission to NICU, birthweight – low birth weight defined as less than 2 500 grams and very low birth weight defined as less than 1 500 grams, Apgar scores at 1 minute and 5 minute, gestational age at delivery – defined either as less than 37 weeks or more than/equal to 37 weeks, respiratory distress syndrome

NethOSS, 2020Netherlands

Prospective cohort


28 All COVID-19 positive women registered in the Netherlands.

COVID-19 was laboratory-confirmed in women and newborns.

COVID-related: all-cause mortality, admission to ICU, oxygenation

Pregnancy-related: preterm birth, mode of delivery – caesarean section and vaginal

Neonatal death, foetal distress, admission to NICU

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Penfield C, 2020USA

Prospective cohort


32 All pregnant women who gave birth admitted and tested.

Mothers were diagnosed by RT-PCR. Newborns were diagnosed by nasopharyngeal swabs between 1-5 days old.

Pregnancy-related: mode of delivery – caesarean section and vaginal

Pierce-Williams R, 2020USA

Prospective cohort


33 All laboratory-confirmed pregnant and postpartum women admitted to 12 US hospitals with severe or critical COVID-19.

Cases with unclear or negative tests, and women diagnosed more than 7 days postpartum were excluded.

Mothers were diagnosed by nasopharyngeal swabs or bronchoalveolar lavage.

COVID-related: all-cause mortality, respiratory failure, acute respiratory distress syndrome, acute cardiac injury, oxygenation,non-invasive and invasive ventilation, length of hospital stay

Pregnancy-related: preterm birth (less than 34 weeks and 37 weeks), mode of delivery – caesarean section and vaginal, pregnancy-induced hypertension, postpartum haemorrhage – defined as blood loss more than 1 000 cc at time of delivery or symptomatic hypovolemia within 24 hours associated with blood loss, chorioamnionitis, preterm-premature rupture of membranes

Stillbirth, neonatal death, admission to NICU, foetal growth restriction, birthweight, gestational age at delivery, Apgar score at 5 minute

Qiancheng X, 2020China



23 All patients consecutively admitted with COVID-19 diagnosis.

The study included pregnant women and non-pregnant women of reproductive age (defined as 18-41 years).

Male patients were excluded.

Mothers were diagnosed by RT-PCR on respiratory samples or IgM serological test for SARS-CoV-2. Followed diagnostic criteria according to National Health Commission of China.

Newborns tested twice by RT-PCR for SARS-CoV-2 24-48 hours apart.

COVID-related: mortality,pneumonia, severe pneumonia, admission to hospital

Pregnancy-related: induced abortion, preterm birth, gestational diabetes, mode of delivery – caesarean section and vaginal, pregnancy-induced hypertension

Stillbirth, neonatal death, neonatal asphyxia, neonatal pneumonia, admission to NICU, birthweight – low birthweight defined as less than 2 500 grams, Apgar scores at 1 minute and 5 minute

Sutton D, 2020USA

Prospective cohort


All women admitted for delivery and tested.

Mothers were diagnosed by nasopharyngeal swabs.

Tassis B, 2020

Prospective cohort


3 pregnant

All women admitted and tested. Mothers were diagnosed by nasopharyngeal swabs.

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women with confirmed COVID-19

UKOSS, 2020UK

Prospective cohort


694 pregnant women without COVID-19 (2017-18 comparison cohort)

244 All pregnant women admitted and tested in all hospitals and obstetrics units in UK.

Testing carried out on symptomatic women.

Comparison cohort of pregnant women from 2017-18 was used.

Mothers were all laboratory-confirmed.

Some newborns were diagnosed by SARS-CoV-2 RNA (at less than 12 hours of age or more than/equal to 12 hours).

COVID-related: COVID-specific mortality, admission to hospital and ICU

Pregnancy-related: preterm birth, mode of delivery – caesarean section, vaginal and operative vaginal, gestational diabetes

Stillbirth, miscarriage, neonatal death, admission to NICU

Vintzileos W, 2020USA




29 All women admitted to labour and delivery and tested.

Testing for all admitted patients.

Mothers and newborns were diagnosed by nasopharyngeal swabs.

WangCY, 2020China


40 pregnant women with confirmedCOVID-19

All laboratory confirmed women who delivered by caesarean section. Eligible patients had a cough, a respiratory rate greater or equal to 30 per minute, typical imaging for COVID-19 pneumonia, normal or reduced white cell count, low lymphopenia and an oxygen saturation of 93% at rest.

Two groups1) Women who inhaled high-flow oxygen before caesarean section (n = 15)2) Women who inhaled high-flow oxygen and injected with methoxamine before caesarean section (n = 25)

Mothers were diagnosed by throat swabs.

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Wu Y, 2020China**

Prospective cohort


5 All pregnant women admitted and tested.


Mothers were diagnosed by throat swabs. Newborns were diagnosed by throat and anal swabs on first and third day after birth.

COVID-related: pneumonia, oxygenation, admission to ICU

Pregnancy-related: miscarriage, preterm birth, mode of delivery – caesarean section and vaginal, preterm rupture of membranes

Stillbirth, neonatal death, neonatal asphyxia, neonatal pneumonia, foetal distress, birthweight – low birth weight defined as less than 2 500 grams, small-for-gestational age – defined as less than 10th percentile, large-for-gestational age – defined as more than 90th percentile, Apgar scores at 1 minute and 5 minute

Xu L, 2020China



5 Any pregnant women admitted and tested. All were more than 34 weeks pregnant with fever or respiratory symptoms.

Mothers were diagnosed by RT-PCR. Newborns were diagnosed by throat swabs.

COVID-related: pneumonia, oxygenation, admission to hospital

Pregnancy-related: miscarriage, induced abortion, preterm birth, mode of delivery – caesarean section and vaginal

Stillbirth, neonatal death, birthweight,Apgar scores at 1 minute and 5 minute

Yan J, 2020China**




100 All consecutive pregnant women laboratory-confirmed or with clinically-diagnosed COVID-19 pneumonia from 25 hospitals inside and outside Hubei province.


Laboratory-confirmed women were tested by throat swabs. Clinically-diagnosed women were those with symptoms, significant history and CT imaging.

Newborns tested by throat swabs straight after delivery in operating room or delivery room.

COVID-related: all-cause mortality, severe, pneumonia, non-invasive and invasive ventilation, oxygenation, admission to ICU, length of ICU stay, hypo-proteinaemia

Pregnancy-related: miscarriage, preterm birth (< 34 weeks and < 37 weeks), preterm-premature rupture of membranes, gestational diabetes, mode of delivery – caesarean section and vaginal

Stillbirth, neonatal death, neonatal asphyxia, admission to NICU, foetal distress, gestational age at delivery, birthweight,Apgar score at 1 minute and 5 minute

Yang H, 2020China*




57 All suspected Chinese pregnant women admitted to an isolated suite and delivered.

Cases were screened based on pulmonary CT scan, routine bloods laboratory tests and signs/symptoms.

Two groups1) Women with confirmed COVID-19


Newborns were diagnosed by throat swabs 24 hours after birth.

Pregnancy-related: preterm-premature rupture of membranes, mode of delivery – caesarean section and vaginal

Gestational age at delivery, admission to NICU, congenital malformation,respiratory distress syndrome, birthweight

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* Study excluded in sensitivity analysis on suspicion of duplication** Selected variables excluded from study in sensitivity analysis on suspicion of duplication

2) Women without COVID-19

Non-Chinese or non-pregnant women were excluded.

Yin M, 2020China



17 All women of childbearing age (defined as between 20-40 years) admitted and tested.

Two groups1) Pregnant women with confirmed COVID-192) Non-pregnant women with confirmed COVID-19

Two cases were excluded due to cancer (one cervical cancer, one lymphoma).

Mothers were diagnosed by throat swabs upon admission. Newborns were diagnosed by throat and anal swabs straight after delivery.


COVID-related: pneumonia, severe pneumonia – defined as the disease when the respiratory rate is equal or greater than 30 per minute, oxygen saturation is less than or equal 93% at rest or when PaO2 is less than or equal to 300 mmHg, length of hospital stay

Pregnancy-related: induced abortion, preterm birth, mode of delivery – caesarean section and vaginal

Stillbirth, neonatal death, neonatal asphyxia, congenital malformation, gestational age at delivery,birthweight – low birthweight defined as less than 2 500 grams,Apgar scores at 1minute and 5 minute

Yue L, 2020China*




32 All women admitted for scheduled or emergency caesarean section and were tested.


Laboratory-confirmed women were diagnosed by RT-PCR tests.

Clinically-diagnosed women were diagnosed by fulfilling at least two points of the criteria (exposure history, fever, lymphopenia or low white cell count, typical chest CT imaging of COVID-19 infection).

COVID-related: pneumonia, respiratory failure, acute respiratory distress syndrome, length of hospital stay

Pregnancy-related: preterm birth, mode of delivery – caesarean section, wound infection, postpartum haemorrhage

Foetal distress, birthweight – low birth weight defined as less than 2 500 grams, respiratory distress syndrome, Apgar scores at 1 minute and 5 minute

Zeng L, 2020China*



33 All neonates born to mothers with COVID-19 at the hospital.

Newborns were diagnosed by nasopharyngeal and anal swabs.

Followed diagnostic criteria according to National Health Commission and Chinese Perinatal-Neonatal SARS-CoV-2 Committee.

COVID-related: pneumonia, admission to ICU Pregnancy-related: preterm birth, mode of delivery – caesarean section and vaginal, preterm rupture of membranes

Stillbirth, neonatal death, neonatal asphyxia, small-for-gestational age, neonatal pneumonia, admission to NICU, length of stay in NICU, neonatal sepsis, respiratory distress syndrome

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Confidential: For Review OnlyAppendix 5: Quality of included studies in the living systematic review on COVID-19

and pregnancy

a. Quality of prevalence studies using the tool by Hoy et al

b. Quality assessment of non-randomised cohort studies using the Newcastle-Ottawa Scale

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Appendix 6. Sensitivity analysis of clinical manifestations by sampling frames to identify pregnant and recently pregnant women with coronavirus disease (COVID-19)

a. symptoms

Cough

Fever

Dyspnoea

Myalgia

Symptoms Studies Events/N(*) I-squared 95% PI RangeProportion (95% CI)

00 .1 .2 .3 .4 .5 .6 .7 .8 .9 1

Diarrhoea

25 686/1350All 0.38 (0.29, 0.48) 92.7% (0.00; 0.87) (0.11-0.87)

Symptom-based / NK176

2275/60960/203

351/538

0.28 (0.19, 0.40)

0.65 (0.61, 0.69)90.5%72.5%

-(0.00; 0.91)(0.00; 0.64)

-(0.15-0.87)(0.11-0.48)

(0.60-0.67)0.39 (0.28, 0.51)

24 630/1302All 0.36 (0.24, 0.49) 98.4% (0.00; 1.00) (0.03-1.00)

174

219/60944/115

0.29 (0.20, 0.39)0.38 (0.30, 0.47)

0.88 (0.37, 0.99)93.2%63.2%

99.1%(0.00; 0.81)

-(0.03-0.70)(0.11-0.44)

(0.57-1.00)Symptom-based / NK 3 367/578

All 17 218/1074 0.09 (0.05, 0.15) 92.6% (0.00; 0.37) (0.00-0.37)

0.09 (0.06, 0.13)0.07 (0.02, 0.24)

28.2%82.5%

(0.01; 0.14)-

(0.00-0.26)(0.00-0.19)

0.37 (0.32, 0.41) -Symptom-based / NK124

44/48616/161

1 158/427

All 10 86/787 0.10 (0.06, 0.16) 83.3% (0.00; 0.26) (0.00-0.26)

0.09 (0.05, 0.14)0.07 (0.01, 0.43)

0.12 (0.09, 0.15)10.3%90.7%

(0.00; 0.14)-

-(0.00-0.20)(0.00-0.26)

-Symptom-based / NK63

18/22018/140

1 50/427

All 13 44/913 0.05 (0.03, 0.09) 53.1% (0.00; 0.16) (0.00-0.18)

0.07 (0.04, 0.12)0.02 (0.01, 0.08)

0.04 (0.02, 0.06)51.8%

-(0.00; 0.16)

-

-(0.00-0.18)(0.00-0.05)


25/3892/97

1 17/427

Proportion

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

(0.00; 0.91)

(0.00; 0.52)

(0.37-0.37)

(0.12-0.12)

(0.04-0.40)

b. laboratory findings

Raised WCC

Lymphocytopaenia

Thrombocytopaenia

Abnormal LFT

Raised CRP

Studies Events/N(*) I-squared RangeProportion (95% CI)

00 .1 .2 .3 .4 .5 .6 .7 .8 .9 1Proportion

All 14 236/522 97.9% (0.00; 1.00) (0.14-1.00)0.49 (0.30, 0.68)


1180/41916/63

40/400.43 (0.30, 0.58)0.25 (0.16, 0.38)

1.00 (0.91, 1.00)85.8%

-

-(0.00; 0.90)

-

-(0.15-0.90)(0.14-0.48)

-

All 8 82/410 0.23 (0.12, 0.39) 91.4% (0.00; 0.68) (0.03-0.52)

62

55/34727/63 0.43 (0.31, 0.55) -

(0.00; 0.60)-

(0.03-0.42)(0.38-0.52)

0.18 (0.08, 0.34) 89.6%

All 3 26/262 87.9% - (0.03-0.18)0.07 (0.03, 0.20)3 26/262 0.07 (0.03, 0.20) 87.9% - (0.03-0.18)

All 7 45/258 0.17 (0.13, 0.23) 0.0% (0.11; 0.23) (0.11-0.23)

52

39/2076/51

0.19 (0.14, 0.25)0.12 (0.05, 0.24)

(0.10; 0.27)-

(0.12-0.23)(0.11-0.12)

0.0%-

All 12 243/464 0.52 (0.45, 0.59) 69.4% (0.22; 0.80) (0.11-0.71)

93

210/39233/72

0.54 (0.47, 0.61)0.42 (0.17, 0.71)

43.1%88.7%

(0.36; 0.72)-

(0.39-0.67)(0.11-0.71)

Sampling frame 95% PI

Raised PCTAll 1 16/118 0.14 (0.08, 0.21) --

1 16/118 0.14 (0.08, 0.21) - -

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

Risk-based

Risk-based0.14-0.140.14-0.14

N* - Number of pregnant women for whom findings were reported; CI – Confidence Interval; PI – Prediction Interval; NK – criteria for testing not known

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Appendix 7. Rates of presentation in pregnant women and recently pregnant women with COVID-19 in various groups

a. Symptoms

Subgroup Studies N Events Proportion 95% CI 95% PI I-squared (p-value) Range

All studies 25 1350 686 0.381 (0.293; 0.477) (0.000; 0.870) 92.7% (p=0.000) (0.111-0.867)

Confirmed COVID

23 1323 615 0.326 (0.231; 0.438) (0.000; 0.920) 95.8% (p=0.000) (0.036-0.867)

Universal screening

6 203 60 0.279 (0.185; 0.398) (0.000; 0.641) 72.5% (p=0.003) (0.111-0.476)

Universal screening with PCR

4 127 39 0.260 (0.131; 0.450) (0.000; 1.000) 82.0% (p=0.001) (0.111-0.476)

Risk-based 17 609 275 0.390 (0.280; 0.512) (0.000; 0.909) 90.5% (p=0.000) (0.147-0.867)

Symptomatic/nk 2 538 351 0.652 (0.611; 0.691) (0.595-0.667)

Selected 15 617 255 0.369 (0.261; 0.492) (0.000; 0.849) 89.9% (p=0.000) (0.121-0.867)

Unselected 9 689 422 0.431 (0.285; 0.591) (0.000; 0.935) 90.9% (p=0.000) (0.111-0.712)

Any risk 23 1303 677 0.399 (0.307; 0.500) (0.000; 0.883) 92.7% (p=0.000) (0.111-0.867)

High risk 2 47 9 0.191 (0.103; 0.329) (0.167-0.235)

Fever

Duplicates excluded

17 1010 570 0.437 (0.319; 0.562) (0.000; 0.946) 92.9% (p=0.000) (0.111-0.867)


All studies 24 1302 630 0.356 (0.244; 0.487) (0.000; 1.000) 98.4% (p=0.000) (0.029-1.000)

Confirmed COVID

22 1275 579 0.316 (0.185; 0.483) (0.000; 1.000) 99.0% (p=0.000) (0.000-1.000)

Universal screening

4 115 44 0.383 (0.298; 0.474) (0.000; 0.913) 63.2% (p=0.043) (0.111-0.442)


3 94 38 0.404 (0.310; 0.506) 73.7% (p=0.022) (0.111-0.442)

Risk-based 17 609 219 0.287 (0.200; 0.393) (0.000; 0.812) 93.2% (p=0.000) (0.029-0.695)

Symptomatic/nk 3 578 367 0.884 (0.368; 0.990) 99.1% (p=0.000) (0.567-1.000)

Selected 14 569 244 0.357 (0.185; 0.574) (0.000; 1.000) 99.1% (p=0.000) (0.029-1.000)

Unselected 9 689 377 0.412 (0.285; 0.551) (0.000; 0.835) 87.7% (p=0.000) (0.100-0.695)

Any risk 21 1215 585 0.359 (0.272; 0.456) (0.000; 0.907) 94.9% (p=0.000) (0.029-0.766)

High risk 3 87 45 0.654 (0.005; 0.998) 99.7% (p=0.000) (0.033-1.000)

Cough

Duplicates excluded

17 1017 563 0.457 (0.324; 0.598) (0.000; 1.000) 97.2% (p=0.000) (0.111-1.000)

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All studies 17 1074 218 0.090 (0.054; 0.147) (0.000; 0.372) 92.6% (p=0.000) (0.000-0.370)

Confirmed COVID

16 1064 212 0.077 (0.041; 0.139) (0.000; 0.357) 93.6% (p=0.000) (0.000-0.370)

Universal screening

4 161 16 0.065 (0.015; 0.244) (0.000; 0.516) 82.5% (p=0.001) (0.000-0.190)


2 85 15 0.176 (0.109; 0.272) (0.163-0.190)

Risk-based 12 486 44 0.087 (0.056; 0.132) (0.006; 0.137) 28.2% (p=0.168) (0.000-0.258)

Symptomatic/nk 1 427 158 0.370 (0.324; 0.418) (0.370-0.370)

Selected 11 421 35 0.069 (0.037; 0.125) (0.000; 0.177) 63.8% (p=0.002) (0.000-0.212)

Unselected 6 653 183 0.148 (0.074; 0.275) (0.000; 0.675) 95.0% (p=0.000) (0.048-0.370)

Any risk 15 1027 216 0.098 (0.057; 0.161) (0.000; 0.400) 93.5% (p=0.000) (0.000-0.370)

High risk 2 47 2 0.043 (0.011; 0.155) (0.033-0.059)

Dyspnoea

Duplicates excluded

11 775 202 0.140 (0.086; 0.220) (0.000; 0.485) 90.7% (p=0.000) (0.000-0.370)


All studies 10 787 86 0.097 (0.057; 0.161) (0.000; 0.262) 83.3% (p=0.000) (0.000-0.256)

Confirmed COVID

10 893 91 0.093 (0.056; 0.151) (0.000; 0.240) 83.2% (p=0.000) (0.000-0.256)

Universal screening

3 140 18 0.074 (0.008; 0.430) 90.7% (p=0.000) (0.000-0.256)


2 85 18 0.212 (0.138; 0.311) (0.167-0.256)

Risk-based 6 220 18 0.086 (0.050; 0.144) (0.000; 0.144) 10.3% (p=0.350) (0.000-0.200)

Symptomatic/nk 1 427 50 0.117 (0.088; 0.151) (0.117-0.117)

Selected 5 155 15 0.071 (0.018; 0.239) (0.000; 0.400) 75.7% (p=0.002) (0.000-0.200)

Unselected 5 632 71 0.109 (0.063; 0.182) (0.000; 0.275) 68.4% (p=0.013) (0.051-0.256)

Any risk 10 787 86 0.097 (0.057; 0.161) (0.000; 0.262) 83.3% (p=0.000) (0.000-0.256)

Myalgia

Duplicates excluded

9 669 80 0.109 (0.063; 0.183) (0.000; 0.309) 85.1% (p=0.000) (0.000-0.256)


All studies 1 28 1 0.036 (0.001; 0.183) (0.036-0.036)

Confirmed COVID

1 28 1 0.036 (0.001; 0.183) (0.036-0.036)

Risk-based 1 28 1 0.036 (0.001; 0.183) (0.036-0.036)

Selected 1 28 1 0.036 (0.001; 0.183) (0.036-0.036)

Any risk 1 28 1 0.036 (0.001; 0.183) (0.036-0.036)

Ageusia

Duplicates excluded

1 28 1 0.036 (0.001; 0.183) (0.036-0.036)

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b. Laboratory findings


All studies 13 913 44 0.051 (0.030; 0.086) (0.000; 0.095) 53.1% (p=0.012) (0.000-0.182)

Confirmed COVID

12 927 39 0.040 (0.022; 0.071) (0.000; 0.079) 51.6% (p=0.019) (0.000-0.182)

Universal screening

2 97 2 0.021 (0.005; 0.079) (0.000-0.048)


1 42 2 0.048 (0.006; 0.162) (0.048-0.048)

Risk-based 10 389 25 0.065 (0.036; 0.116) (0.000; 0.160) 51.8% (p=0.028) (0.000-0.182)

Symptomatic/nk 1 427 17 0.040 (0.023; 0.063) (0.040-0.040)

Selected 8 307 13 0.036 (0.013; 0.097) (0.000; 0.084) 40.8% (p=0.107) (0.000-0.182)

Unselected 5 606 31 0.054 (0.029; 0.099) (0.019; 0.073) 0.0% (p=0.454) (0.040-0.176)

Any risk 12 896 43 0.051 (0.029; 0.088) (0.000; 0.097) 56.4% (p=0.008) (0.000-0.182)

High risk 1 17 1 0.059 (0.001; 0.287) (0.059-0.059)

Diarrhoea

Duplicates excluded

11 742 43 0.068 (0.044; 0.103) (0.031; 0.067) 0.0% (p=0.529) (0.000-0.182)


All studies 8 410 82 0.231 (0.123; 0.391) (0.000; 0.682) 91.4% (p=0.000) (0.026-0.524)

Confirmed COVID

8 410 72 0.204 (0.110; 0.348) (0.000; 0.590) 89.3% (p=0.000) (0.026-0.524)

Universal screening

2 63 27 0.429 (0.313; 0.553) (0.381-0.524)


1 42 16 0.381 (0.236; 0.544) (0.381-0.381)

Risk-based 6 347 55 0.175 (0.082; 0.336) (0.000; 0.604) 89.6% (p=0.000) (0.026-0.415)

Selected 4 227 46 0.224 (0.072; 0.519) (0.000; 1.000) 94.6% (p=0.000) (0.026-0.415)

Unselected 4 183 36 0.232 (0.121; 0.399) (0.000; 0.829) 73.8% (p=0.010) (0.144-0.524)

Any risk 8 410 82 0.231 (0.123; 0.391) (0.000; 0.682) 91.4% (p=0.000) (0.026-0.524)

Raised white cell count

Duplicates excluded

5 232 51 0.238 (0.154; 0.349) (0.000; 0.590) 67.2% (p=0.016) (0.144-0.381)


All studies 14 522 236 0.485 (0.296; 0.679) (0.000; 1.000) 97.9% (p=0.000) (0.143-1.000)

Confirmed COVID

12 495 178 0.388 (0.196; 0.622) (0.000; 1.000) 98.8% (p=0.000) (0.059-1.000)

Universal screening

2 63 16 0.254 (0.162; 0.375) (0.143-0.476)


1 42 6 0.143 (0.054; 0.285) (0.143-0.143)

Risk-based 11 419 180 0.434 (0.300; 0.579) (0.000; 0.896) 85.8% (p=0.000) (0.154-0.900)

Symptomatic/nk 1 40 40 1.000 (0.912; 1.000) (1.000-1.000)

Selected 9 343 163 0.574 (0.276; 0.826) (0.000; 1.000) 98.3% (p=0.000) (0.143-1.000)

Unselected 5 179 73 0.408 (0.338; 0.481) (0.000; 0.817) 64.1% (p=0.025) (0.154-0.600)

Any risk 12 465 191 0.418 (0.284; 0.565) (0.000; 0.906) 88.4% (p=0.000) (0.143-0.900)

High risk 2 57 45 0.789 (0.665; 0.876) (0.294-1.000)

Lymphocytopenia

Duplicates excluded

9 300 137 0.522 (0.221; 0.808) (0.000; 1.000) 98.3% (p=0.000) (0.143-1.000)

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All studies 3 262 26 0.073 (0.025; 0.197) 87.9% (p=0.000) (0.025-0.181)

Confirmed COVID

2 146 4 0.027 (0.010; 0.071) (0.017-0.071)

Risk-based 3 262 26 0.073 (0.025; 0.197) 87.9% (p=0.000) (0.025-0.181)

Selected 2 144 23 0.160 (0.109; 0.229) (0.071-0.181)

Unselected 1 118 3 0.025 (0.005; 0.073) (0.025-0.025)

Any risk 3 262 26 0.073 (0.025; 0.197) 87.9% (p=0.000) (0.025-0.181)

Thrombocytopenia

Duplicates excluded

2 144 23 0.160 (0.109; 0.229) (0.071-0.181)


All studies 7 258 45 0.174 (0.133; 0.226) (0.107; 0.225) 0.0% (p=0.779) (0.111-0.231)

Confirmed COVID

6 241 39 0.162 (0.121; 0.214) (0.092; 0.221) 0.0% (p=0.840) (0.111-0.231)

Universal screening

2 51 6 0.118 (0.054; 0.238) (0.111-0.119)


2 51 6 0.118 (0.054; 0.238) (0.111-0.119)

Risk-based 5 207 39 0.188 (0.141; 0.247) (0.098; 0.268) 0.0% (p=0.797) (0.118-0.231)

Selected 2 70 9 0.129 (0.068; 0.229) (0.119-0.143)

Unselected 5 188 36 0.191 (0.141; 0.254) (0.095; 0.275) 0.0% (p=0.779) (0.111-0.231)

Any risk 7 258 45 0.174 (0.133; 0.226) (0.107; 0.225) 0.0% (p=0.779) (0.111-0.231)

Abnormal liver function test

Duplicates excluded

7 258 45 0.174 (0.133; 0.226) (0.107; 0.225) 0.0% (p=0.779) (0.111-0.231)


All studies 1 118 16 0.136 (0.080; 0.211) (0.136-0.136)

Confirmed COVID

1 118 9 0.076 (0.035; 0.140) (0.076-0.076)

Risk-based 1 118 16 0.136 (0.080; 0.211) (0.136-0.136)

Unselected 1 118 16 0.136 (0.080; 0.211) (0.136-0.136)

Any risk 1 118 16 0.136 (0.080; 0.211) (0.136-0.136)

Raised procalcitonin

Duplicates excluded

1 118 16 0.136 (0.080; 0.211) (0.136-0.136)


All studies 12 464 243 0.522 (0.449; 0.594) (0.221; 0.796) 69.4% (p=0.000) (0.111-0.714)

Confirmed COVID

12 464 175 0.406 (0.305; 0.514) (0.057; 0.750) 79.0% (p=0.000) (0.111-0.714)

Universal screening

3 72 33 0.419 (0.173; 0.713) 88.7% (p=0.000) (0.111-0.714)


2 51 18 0.353 (0.235; 0.492) (0.111-0.405)

Risk-based 9 392 210 0.539 (0.470; 0.607) (0.357; 0.724) 43.1% (p=0.080) (0.385-0.667)

Selected 7 293 145 0.508 (0.429; 0.588) (0.284; 0.742) 49.0% (p=0.068) (0.405-0.667)

Unselected 5 171 98 0.514 (0.336; 0.689) (0.000; 1.000) 82.8% (p=0.000) (0.111-0.714)

Any risk 11 447 236 0.529 (0.453; 0.604) (0.215; 0.816) 71.6% (p=0.000) (0.111-0.714)

High risk 1 17 7 0.412 (0.184; 0.671) (0.412-0.412)

Raised C-reactive protein

Duplicates excluded

7 240 108 0.450 (0.388; 0.513) (0.091; 0.773) 64.7% (p=0.009) (0.111-0.667)

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c. Radiological findings

*CT-thorax for universal screening


All studies 12 413 292 0.825 (0.563; 0.945) (0.135; 1.000) 96.2% (p=0.000) (0.152-1.000)

Confirmed COVID

11 403 187 0.670 (0.324; 0.896) (0.000; 1.000) 98.3% (p=0.000) (0.109-1.000)

Universal* 1 55 32 0.582 (0.441; 0.713) (0.582-0.582)

Risk-based 11 358 260 0.849 (0.565; 0.960) (0.136; 1.000) 96.4% (p=0.000) (0.152-1.000)

Selected 8 315 239 0.897 (0.586; 0.982) (0.172; 1.000) 96.1% (p=0.000) (0.152-1.000)

Unselected 3 54 42 0.755 (0.328; 0.951) 89.2% (p=0.000) (0.400-0.968)

Any risk 11 396 275 0.779 (0.513; 0.922) (0.063; 1.000) 96.4% (p=0.000) (0.152-1.000)

High risk 1 17 17 1.000 (0.805; 1.000) (1.000-1.000)

Ground glass appearance

Duplicates excluded

9 307 226 0.900 (0.577; 0.984) (0.123; 1.000) 97.0% (p=0.000) (0.152-1.000)


All studies 20 1119 636 0.884 (0.713; 0.959) (0.082; 1.000) 98.5% (p=0.000) (0.152-1.000)

Universal* 2 76 71 0.934 (0.851; 0.972) (0.905-0.945)

Risk-based 16 576 424 0.873 (0.670; 0.959) (0.271; 1.000) 95.6% (p=0.000) (0.152-1.000)

Symptomatic/nk 2 467 141 0.302 (0.262; 0.345) (0.237-1.000)

Selected 12 438 364 0.946 (0.779; 0.988) (0.477; 1.000) 94.9% (p=0.000) (0.152-1.000)

Unselected 7 637 261 0.765 (0.439; 0.931) (0.000; 1.000) 98.8% (p=0.000) (0.237-1.000)

Any risk 17 1032 551 0.827 (0.622; 0.933) (0.000; 1.000) 98.5% (p=0.000) (0.152-1.000)

Any CT abnormality

High risk 3 87 85 0.982 (0.836; 0.998) 0.0% (p=0.384) (0.933-1.000)

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Appendix 8. Rates of maternal and perinatal outcomes by various sampling frames to identify pregnant women with coronavirus disease (COVID-19)

a. COVID-related maternal outcomes

Invasive ventilation

Admission to intensive care

Need for ECMO

Oxygen through nasal cannula

Outcomes Studies Events/N(*) I-squared RangeProportion (95% CI)

00 .1 .2 .3 .4 .5 .6 .7 .8 .9 1Proportion

ARDS

Cardiac/renal/liver failure

Pneumonia

11 74/1093All 0.05 (0.03, 0.08) 72.0% (0.00; 0.13) (0.00-0.10)


48/12248/106

58/763

0.08 (0.04, 0.14)

0.07 (0.04, 0.10)57.6%0.0%

75.9%

-(0.00-0.07)(0.05-0.10)

(0.03-0.10)0.00 (0.00, 0.62)

0.02 (0.01, 0.07) - - (0.02-0.05)All 2 3/137

11

2/1161/21

0.02 (0.00, 0.06)0.05 (0.00, 0.24)

--

--

-(0.05, 0.05)

-0.01 (0.00, 0.02) 0.0%All 3 4/525 (0.00-0.01)

0.01 (0.00, 0.02)0.00 (0.00, 0.10)

--

--

(0.00-0.01)Symptom-based / NK 21

4/4910/34

All 7 117/326 0.52(0.07, 0.94) 99.4% (0.00; 1.00) (0.01-1.00)

0.82 (0.05, 1.00)0.09 (0.05, 0.18)

0.81 (0.69, 0.90)99.6%

-

-(0.01-1.00)(0.02-0.17)


57/1778/85

1 52/64

-

0.15 (0.09, 0.24)All 2 14/94 - -

0.22 (0.13, 0.34) - -Symptom-based /NK 1 14/64 (0.22, 0.22)

13 361/887All 0.84 (0.42, 0.98) 99.7% (0.00; 1.00) (0.02-1.00)


2200/33520/85

141/467

0.23 (0.16, 0.34)

0.30 (0.26, 0.35)99.4%

-(0.00; 1.00)

-(0.07-1.00)(0.02-0.45)

0.91 (0.53, 0.99)- -

0.02 (0.00, 0.07) (0.02-0.02)All 2 2/107 - -Universal

11

1/641/43

0.02 (0.00, 0.08)0.02 (0.00, 0.12) -

---

95% PI

Symptom-based / NK

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

Risk-based

(0.00-0.14)

(0.00-0.23)

(0.02, 0.02)

(0.00, 0.00)

(0.00-1.00)(0.81-0.81)

(0.00-0.23)Risk-based 0.00 (0.00, 0.12) - -1 0/30 (0.00, 0.00)

(0.24-1.00)

(0.16-0.16)(0.23-0.23)

N* - Number of pregnant women for whom outcomes were reported; CI – Confidence Interval; PI – Prediction Interval; NK –criteria for testing not known; ECMO – Extracorporeal membrane oxygenation

b. Pregnancy-related maternal outcomes

PPROM <37 weeks

Preterm birth <37 weeks

Caesarean section

Outcomes Studies Events/N(*) I-squared 95% Pl RangeProportion (95% CI)

00 .1 .2 .3 .4 .5 .6 .7 .8 .9 1

Postpartum haemorrhage

20 184/1207All 0.15 (0.10, 0.20) 86.6% (0.00; 0.35) (0.00-0.40)Universal


382/49019/115

83/602

0.11 (0.02, 0.36)

0.09 (0.02, 0.37)41.5%84.2%

97.2%(0.04; 0.27)

-(0.04-0.40)(0.00-0.29)

(0.01-0.30)0.17 (0.13, 0.21)

4 12/268All 0.05 (0.03, 0.08) 12.8% (0.02-0.09)

21

9/1492/55

0.06 (0.03, 0.11)0.04 (0.00, 0.12)

0.02 (0.00, 0.08)

-

-(0.05-0.09)

Symptom-based / NK 1 1/64

---

-

All 20 545/1239 0.59 (0.42, 0.74) 97.4% (0.00; 1.00) (0.10-1.00)

0.73 (0.59, 0.83)0.43 (0.16, 0.74)

90.2%96.4%

(0.26; 1.00)-

(0.31-1.00)(0.16-1.00)

0.25 (0.12, 0.43) 95.8%Symptom-based / NK125

313/46753/170

3 179/602 (0.10-0.38)

All 3 4/136 0.03 (0.01, 0.08) 0.0% (0.00-0.05)-

0.00 (0.00, 0.12)0.02 (0.00, 0.13)

0.05 (0.01, 0.13) --Symptom-based / NK11

0/301/42

1 3/64----

Proportion

Risk-based

(0.00; 1.00)

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

(0.00; 0.80)

(0.00; 0.10)(0.04- 0.04)

(0.02- 0.02)

(0.02-0.02)(0.00- 0.00)(0.05-0.05)

N* – Number of pregnant women for preterm birth and PPROM, and number of women delivered for caesarean section and postpartum haemorrhage; CI – Confidence Interval; PI – Prediction Interval; PPROM – Preterm premature rupture of membranes; NK –criteria for testing not known

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c. Perinatal outcomes

Neonatal death

Stillbirth

Admission to neonatal unit

Neonatal sepsis

Outcomes Studies Events/N(*) I-squared RangeProportion (95% CI)

00 .1 .2 .3 .4 .5 .6 .7 .8 .9 1

Apgar 5’ <7

Fetal distress

All 10 3/853 0.00 (0.00, 0.01) (0.00-0.01)0.0% (0.00; 0.01)

Symptom-based / NK 3

1

3/602

0/9 0.00 (0.00, 0.34)

(0.00-0.01)0.01 (0.00, 0.02)

--

-0.0%6 0/242 0.00 (0.00, 0.02) - - -

17 3/706All 0.00 (0.00, 0.01) 0.0% (0.00-0.01)(0.00; 0.01)

122

1/3320/66

0.00 (0.00, 0.02)0.00 (0.00, 0.05)

0.01 (0.00, 0.03)

-

-(0.00-0.01)


- -

0.0%0.0% (0.00; 0.02)

(0.00-0.01)

All 13 242/628 0.43 (0.08, 0.87) 99.5% (0.00; 1.00) (0.00-1.00)

0.51 (0.04, 0.97)0.29 (0.00, 0.99)

99.2% (0.00; 1.00)-

(0.00-1.00)(0.00-1.00)

0.31 (0.25, 0.36) -Symptom-based / NK74

94/22463/126

2 85/278 (0.26-0.64)

99.6%

0.04 (0.01, 0.14) --All 2 2/51 (0.03-0.06)

0.03 (0.00, 0.16)0.06 (0.00, 0.27)

11

1/331/18

- (0.03-0.03)---

0.01 (0.00, 0.04)All 11 4/297 0.0% (0.00; 0.03) (0.00-0.06)

0.01 (0.00, 0.04)0.03 (0.01, 0.10)

83

2/2202/77

0.0% (0.00; 0.03)(0.00-0.05)(0.00-0.06)

-0.0%

7 23/252All 0.09 (0.06, 0.13) 0.0% (0.03-0.18)(0.04; 0.12)

51

21/2051/17

0.10 (0.07, 0.15)0.06 (0.00, 0.29)

0.03 (0.00, 0.17)

-

-(0.08-0.18)


-

-0.0% (0.03; 0.16)

95% PI

Proportion

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

UniversalRisk-based

(0.00-0.00)

(0.00;1.00)

(0.06-0.06)

(0.06-0.06)

(0.03-0.03)

N* – Number of babies delivered; CI – Confidence Interval; PI – Prediction Interval; NK – criteria for testing not known

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Appendix 9. Rates of maternal and perinatal outcomes in pregnant and recently pregnant women with COVID-19 in various groups

a. COVID-related outcomes


All studies 11 1093 74 0.054 (0.034; 0.084) (0.000; 0.129) 72.0% (p=0.000) (0.000-0.098)

Confirmed COVID

11 1093 72 0.051 (0.032; 0.081) (0.000; 0.124) 71.1% (p=0.000) (0.000-0.098)

Universal screening

3 106 8 0.075 (0.038; 0.144) Not estimable 0.0% (p=0.763) (0.048-0.095)

Universal screening with only PCR

2 85 7 0.082 (0.040; 0.163) Not estimable Not estimable (0.070-0.095)

Risk-based 4 224 8 0.003 (0.000; 0.619) (0.000; 0.135) 57.6% (p=0.070) (0.000-0.069)

Symptomatic/NK 4 763 58 0.066 (0.041; 0.105) (0.000; 0.227) 75.9% (p=0.006) (0.028-0.098)

Selected 6 377 18 0.040 (0.013; 0.118) (0.000; 0.115) 61.2% (p=0.024) (0.000-0.095)

Unselected 5 716 56 0.069 (0.043; 0.109) (0.000; 0.187) 67.8% (p=0.014) (0.028-0.098)

Any risk 11 1093 74 0.054 (0.034; 0.084) (0.000; 0.129) 72.0% (p=0.000) (0.000-0.098)

Admission to intensive care unit

Duplicates excluded

8 975 71 0.064 (0.044; 0.093) (0.000; 0.141) 67.2% (p=0.003) (0.000-0.098)


All studies 2 137 3 0.022 (0.007; 0.066) Not estimable (0.017-0.048)

Confirmed COVID

2 137 3 0.022 (0.007; 0.066) Not estimable (0.017-0.048)

Universal screening

1 21 1 0.048 (0.001; 0.238) (0.048-0.048)

Risk-based 1 116 2 0.017 (0.002; 0.061) (0.017-0.017)

Selected 1 116 2 0.017 (0.002; 0.061) (0.017-0.017)

Unselected 1 21 1 0.048 (0.001; 0.238) (0.048-0.048)

Any risk 2 137 3 0.022 (0.007; 0.066) Not estimable (0.017-0.048)

Invasive ventilation

Duplicates excluded

2 137 3 0.022 (0.007; 0.066) Not estimable (0.017-0.048)


All studies 3 525 4 0.008 (0.003; 0.020) 0.0% (p=0.677) (0.000-0.009)

Confirmed COVID

3 577 5 0.009 (0.004; 0.021) 0.0% (p=0.901) (0.000-0.009)

Risk-based 1 34 0 0.000 (0.000; 0.103) (0.000-0.000)

Symptomatic/nk 2 491 4 0.008 (0.003; 0.021) Not estimable (0.000-0.009)

Selected 2 98 0 0.000 (0.000; 0.037) Not estimable

Unselected 1 427 4 0.009 (0.003; 0.024) (0.009-0.009)


High risk 1 64 0 0.000 (0.000; 0.056) (0.000-0.000)

Need for extracorporeal membrane oxygenation

Duplicates excluded

3 525 4 0.008 (0.003; 0.020) 0.0% (p=0.677) (0.000-0.009)

Oxygen Subgroup Studies N Events Proportion 95% CI 95% PI I-squared (p-value) Range

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All studies 7 326 117 0.524 (0.073; 0.939) (0.000; 1.000) 99.4% (p=0.000) (0.009-1.000)

Confirmed COVID

5 146 64 0.696 (0.102; 0.979) (0.000; 1.000) 99.3% (p=0.000) (0.023-1.000)

Universal screening

2 85 8 0.094 (0.048; 0.177) Not estimable (0.023-0.167)


2 85 8 0.094 (0.048; 0.177) Not estimable (0.023-0.167)

Risk-based 4 177 57 0.816 (0.054; 0.997) (0.000; 1.000) 99.6% (p=0.000) (0.009-1.000)

Symptomatic/nk 1 64 52 0.812 (0.695; 0.899) (0.812-0.812)

Selected 5 270 103 0.496 (0.073; 0.924) (0.000; 1.000) 99.4% (p=0.000) (0.009-0.933)

Unselected 2 56 14 0.250 (0.154; 0.379) Not estimable (0.023-1.000)

Any risk 6 262 65 0.473 (0.037; 0.955) (0.000; 1.000) 99.4% (p=0.000) (0.009-1.000)

High risk 1 64 52 0.812 (0.695; 0.899) (0.812-0.812)

through cannula

Duplicates excluded

7 326 117 0.524 (0.073; 0.939) (0.000; 1.000) 99.4% (p=0.000) (0.009-1.000)


All studies 2 94 14 0.149 (0.090; 0.236) Not estimable Not estimable (0.000-0.219)

Confirmed COVID

1 30 0 0.000 (0.000; 0.116) (0.000-0.000)

Risk-based 1 30 0 0.000 (0.000; 0.116) Not estimable Not estimable (0.000-0.000)

Symptomatic/nk 1 64 14 0.219 (0.125; 0.340) Not estimable Not estimable (0.219-0.219)

Selected 2 94 14 0.149 (0.090; 0.236) Not estimable Not estimable (0.000-0.219)

High risk 2 94 14 0.149 (0.090; 0.236) Not estimable Not estimable (0.000-0.219)

Acute respiratory distress syndrome

Duplicates excluded

1 64 14 0.219 (0.125; 0.340) (0.219-0.219)


All studies 13 887 361 0.844 (0.417; 0.976) (0.000; 1.000) 99.6% (p=0.000) (0.023-1.000)

Confirmed COVID

11 754 316 0.854 (0.374; 0.983) (0.000; 1.000) 99.6% (p=0.000) (0.023-1.000)

Universal screening




Risk-based 9 335 200 0.909 (0.534; 0.989) (0.000; 1.000) 99.4% (p=0.000) (0.069-1.000)

Symptomatic/nk 2 467 141 0.302 (0.262; 0.345) Not estimable Not estimable (0.237-1.000)

Selected 8 343 202 0.937 (0.561; 0.994) (0.000; 1.000) 99.4% (p=0.000) (0.069-1.000)

Unselected 4 500 115 0.219 (0.066; 0.527) (0.000; 1.000) 95.1% (p=0.000) (0.023-0.615)

Any risk 11 817 293 0.753 (0.280; 0.960) (0.000; 1.000) 99.6% (p=0.000) (0.023-1.000)


Pneumonia

Duplicates excluded

9 674 260 0.808 (0.261; 0.980) (0.000; 1.000) 99.6% (p=0.000) (0.023-1.000)



Confirmed COVID

1 43 1 0.023 (0.001; 0.123) (0.023-0.023)

Universal screening

1 43 1 0.023 (0.001; 0.123) (0.023-0.023)

Cardiac, hepatic or renal failure

Universal screening with

1 43 1 0.023 (0.001; 0.123) (0.023-0.023)

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b. Pregnancy-related outcomes

PCR

Symptomatic/nk 1 64 1 0.016 (0.000; 0.084) (0.016-0.016)

Selected 1 64 1 0.016 (0.000; 0.084) (0.016-0.016)

Unselected 1 43 1 0.023 (0.001; 0.123) (0.023-0.023)

Any risk 1 43 1 0.023 (0.001; 0.123) (0.023-0.023)

High risk 1 64 1 0.016 (0.000; 0.084) (0.016-0.016)

Duplicates excluded

2 107 2 0.019 (0.005; 0.072) Not estimable (0.016-0.023)


All studies 20 1207 184 0.145 (0.101; 0.202) (0.000; 0.345) 86.6% (p=0.000) (0.000-0.400)

Confirmed COVID

18 1063 137 0.111 (0.071; 0.170) (0.000; 0.278) 83.7% (p=0.000) (0.000-0.400)

Universal screening

4 115 19 0.106 (0.024; 0.363) (0.000; 0.797) 84.2% (p=0.000) (0.000-0.286)


3 94 13 0.060 (0.007; 0.371) Not estimable 84.9% (p=0.001) (0.000-0.286)

Risk-based 13 490 82 0.167 (0.133; 0.209) (0.036; 0.271) 41.5% (p=0.058) (0.036-0.400)

Symptomatic/nk 3 602 83 0.090 (0.016; 0.368) 97.2% (p=0.000) (0.009-0.297)

Selected 11 518 86 0.146 (0.086; 0.238) (0.000; 0.448) 88.6% (p=0.000) (0.009-0.303)

Unselected 9 689 98 0.142 (0.118; 0.170) (0.000; 0.298) 73.0% (p=0.000) (0.000-0.400)

Any risk 17 1096 156 0.131 (0.086; 0.195) (0.000; 0.323) 86.5% (p=0.000) (0.000-0.400)

High risk 3 111 28 0.252 (0.180; 0.341) 0.0% (p=0.416) (0.176-0.297)

Preterm birth less than 37 weeks

Duplicates excluded

15 982 150 0.130 (0.079; 0.208) (0.000; 0.355) 88.7% (p=0.000) (0.000-0.303)


All studies 4 268 12 0.045 (0.026; 0.077) (0.000; 0.099) 12.8% (p=0.328) (0.016-0.091)

Confirmed COVID

3 183 7 0.038 (0.018; 0.078) 0.0% (p=0.459) (0.026-0.091)

Universal screening

1 55 2 0.036 (0.004; 0.125) (0.036-0.036)

Risk-based 2 149 9 0.060 (0.032; 0.112) Not estimable (0.052-0.091)

Symptomatic/nk 1 64 1 0.016 (0.000; 0.084) (0.016-0.016)

Selected 4 268 12 0.045 (0.026; 0.077) (0.000; 0.099) 12.8% (p=0.328) (0.016-0.091)

Any risk 3 204 11 0.054 (0.030; 0.095) 0.0% (p=0.617) (0.036-0.091)

High risk 1 64 1 0.016 (0.000; 0.084) (0.016-0.016)

Preterm premature rupture of membranes less than 37 weeks

Duplicates excluded

3 213 10 0.047 (0.025; 0.085) 41.5% (p=0.181) (0.016-0.091)


All studies 20 1239 545 0.589 (0.424; 0.736) (0.000; 1.000) 97.4% (p=0.000) (0.099-1.000)

Confirmed COVID

17 1082 411 0.482 (0.332; 0.635) (0.000; 1.000) 98.6% (p=0.000) (0.099-1.000)

Universal screening

5 170 53 0.425 (0.159; 0.743) (0.000; 1.000) 96.4% (p=0.000) (0.164-1.000)

Caesarean section


3 94 35 0.616 (0.096; 0.960) Not estimable 97.5% (p=0.000) (0.186-1.000)

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c. Offspring outcomes

Risk-based 12 467 313 0.725 (0.589; 0.830) (0.262; 1.000) 90.2% (p=0.000) (0.308-1.000)

Symptomatic/nk 3 602 179 0.248 (0.124; 0.433) Not estimable 95.8% (p=0.000) (0.099-0.375)

Selected 11 550 270 0.586 (0.380; 0.766) (0.000; 1.000) 97.6% (p=0.000) (0.099-0.947)

Unselected 9 689 275 0.601 (0.324; 0.825) (0.000; 1.000) 97.4% (p=0.000) (0.186-1.000)

Any risk 19 1175 521 0.603 (0.429; 0.755) (0.000; 1.000) 97.5% (p=0.000) (0.099-1.000)


Duplicates excluded

15 1020 440 0.599 (0.377; 0.787) (0.000; 1.000) 98.8% (p=0.000) (0.099-1.000)


All studies 3 136 4 0.029 (0.011; 0.076) 0.0% (p=0.400) (0.000-0.047)

Confirmed COVID

1 42 1 0.024 (0.001; 0.126) (0.024-0.024)

Universal screening

1 42 1 0.024 (0.001; 0.126) (0.024-0.024)


1 42 1 0.024 (0.001; 0.126) (0.024-0.024)

Risk-based 1 30 0 0.000 (0.000; 0.116) (0.000-0.000)

Symptomatic/nk 1 64 3 0.047 (0.010; 0.131) (0.047-0.047)

Selected 3 136 4 0.029 (0.011; 0.076) 0.0% (p=0.400) (0.000-0.047)

Any risk 1 42 1 0.024 (0.001; 0.126) (0.024-0.024)

High risk 2 94 3 0.032 (0.010; 0.094) Not estimable (0.000-0.047)

Postpartum haemorrhage

Duplicates excluded

2 106 4 0.038 (0.014; 0.096) Not estimable (0.024-0.047)


All studies 10 853 3 0.004 (0.001; 0.011) (0.000; 0.010) 0.0% (p=0.996) (0.000-0.007)

Confirmed COVID

8 711 3 0.004 (0.001; 0.013) (0.000; 0.012) 0.0% (p=0.992) (0.000-0.007)

Universal screening

1 9 0 0.000 (0.000; 0.336) (0.000-0.000)


1 9 0 0.000 (0.000; 0.336) (0.000-0.000)

Risk-based 6 242 0 0.000 (0.000; 0.015) Not estimable

Symptomatic/nk 3 602 3 0.005 (0.002; 0.015) 0.0% (p=0.585) (0.000-0.007)

Selected 6 369 0 0.000 (0.000; 0.010) Not estimable

Unselected 4 484 3 0.006 (0.002; 0.019) (0.000; 0.024) 0.0% (p=0.987) (0.000-0.007)

Any risk 8 772 3 0.004 (0.001; 0.012) (0.000; 0.011) 0.0% (p=0.983) (0.000-0.007)

High risk 2 81 0 0.000 (0.000; 0.045) Not estimable

Stillbirth

Duplicates excluded

9 820 3 0.004 (0.001; 0.011) (0.000; 0.010) 0.0% (p=0.991) (0.000-0.007)

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All studies 17 706 3 0.004 (0.001; 0.013) (0.000; 0.013) 0.0% (p=1.000) (0.000-0.010)

Confirmed COVID

13 467 3 0.006 (0.002; 0.020) (0.000; 0.018) 0.0% (p=1.000) (0.000-0.020)

Universal screening

2 66 0 0.000 (0.000; 0.054) Not estimable Not estimable


1 9 0 0.000 (0.000; 0.336) (0.000-0.000)

Risk-based 12 332 1 0.003 (0.000; 0.021) (0.000; 0.018) 0.0% (p=1.000) (0.000-0.010)

Symptomatic/nk 3 308 2 0.006 (0.002; 0.026) Not estimable 0.0% (p=0.882) (0.000-0.008)

Selected 10 345 1 0.003 (0.000; 0.020) (0.000; 0.017) 0.0% (p=1.000) (0.000-0.010)

Unselected 7 361 2 0.006 (0.001; 0.022) (0.000; 0.019) 0.0% (p=0.998) (0.000-0.008)

Any risk 15 656 3 0.005 (0.001; 0.014) (0.000; 0.014) 0.0% (p=1.000) (0.000-0.010)

High risk 2 50 0 0.000 (0.000; 0.071) Not estimable Not estimable

Neonatal death

Duplicates excluded

12 508 3 0.006 (0.002; 0.018) (0.000; 0.017) 0.0% (p=1.000) (0.000-0.010)


All studies 13 628 242 0.427 (0.079; 0.866) (0.000; 1.000) 99.5% (p=0.000) (0.000-1.000)

Confirmed COVID

11 484 128 0.229 (0.051; 0.619) (0.000; 1.000) 98.4% (p=0.000) (0.000-1.000)

Universal screening

4 126 63 0.286 (0.002; 0.989) (0.000; 1.000) 99.6% (p=0.000) (0.000-1.000)


3 69 6 0.087 (0.040; 0.180) Not estimable 10.8% (p=0.326) (0.000-0.167)

Risk-based 7 224 94 0.514 (0.035; 0.968) (0.000; 1.000) 99.2% (p=0.000) (0.000-1.000)

Symptomatic/nk 2 278 85 0.306 (0.254; 0.362) Not estimable (0.261-0.636)

Selected 10 356 175 0.627 (0.092; 0.965) (0.000; 1.000) 99.5% (p=0.000) (0.000-1.000)

Unselected 3 272 67 0.246 (0.199; 0.301) 84.3% (p=0.002) (0.000-0.261)

Any risk 11 578 204 0.285 (0.041; 0.788) (0.000; 1.000) 99.5% (p=0.000) (0.000-1.000)

High risk 2 50 38 0.760 (0.623; 0.858) Not estimable (0.636-1.000)

Admission to neonatal unit

Duplicates excluded

11 496 192 0.488 (0.054; 0.941) (0.000; 1.000) 99.5% (p=0.000) (0.000-1.000)



Confirmed COVID

2 51 2 0.039 (0.010; 0.144) Not estimable (0.030-0.056)

Universal screening

1 18 1 0.056 (0.001; 0.273) (0.056-0.056)



Risk-based 1 33 1 0.030 (0.001; 0.158) (0.030-0.030)

Selected 1 33 1 0.030 (0.001; 0.158) (0.030-0.030)

Unselected 1 18 1 0.056 (0.001; 0.273) (0.056-0.056)


Neonatal sepsis

Duplicates excluded

2 51 2 0.039 (0.010; 0.144) Not estimable (0.030-0.056)

Abnormal Subgroup Studies N Events Proportion 95% CI 95% PI I-squared (p-value) Range

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NHCC – National Health Commission of China

All studies 11 297 4 0.013 (0.005; 0.035) (0.000; 0.027) 0.0% (p=0.989) (0.000-0.059)

Confirmed COVID

7 146 2 0.010 (0.001; 0.162) (0.000; 0.043) 0.0% (p=0.942) (0.000-0.048)

Universal screening

3 77 2 0.026 (0.007; 0.098) 0.0% (p=0.531) (0.000-0.048)



Risk-based 8 220 2 0.009 (0.002; 0.036) (0.000; 0.028) 0.0% (p=0.993) (0.000-0.059)

Selected 7 231 3 0.013 (0.004; 0.039) (0.000; 0.031) 0.0% (p=0.945) (0.000-0.048)

Unselected 4 66 1 0.015 (0.002; 0.100) (0.000; 0.100) 0.0% (p=0.822) (0.000-0.059)

Any risk 10 280 4 0.014 (0.005; 0.037) (0.000; 0.028) 0.0% (p=0.979) (0.000-0.059)

High risk 1 17 0 0.000 (0.000; 0.195) (0.000-0.000)

Apgar score at 5 minutes less than 7

Duplicates excluded

10 281 4 0.014 (0.005; 0.037) (0.000; 0.028) 0.0% (p=0.979) (0.000-0.059)


All studies 7 252 23 0.091 (0.061; 0.134) (0.035; 0.121) 0.0% (p=0.660) (0.033-0.182)

Confirmed COVID

7 167 18 0.108 (0.069; 0.165) (0.027; 0.133) 0.0% (p=0.458) (0.033-0.182)

Universal screening

1 17 1 0.059 (0.001; 0.287) (0.059-0.059)

Risk-based 5 205 21 0.102 (0.068; 0.152) (0.032; 0.164) 0.0% (p=0.874) (0.083-0.182)

Symptomatic/nk 1 30 1 0.033 (0.001; 0.172) (0.033-0.033)

Selected 5 224 20 0.089 (0.058; 0.134) (0.021; 0.134) 0.0% (p=0.523) (0.033-0.148)

Unselected 2 28 3 0.107 (0.035; 0.284) Not estimable (0.059-0.182)

Any risk 6 220 20 0.091 (0.059; 0.137) (0.027; 0.125) 0.0% (p=0.547) (0.033-0.182)

High risk 1 32 3 0.094 (0.020; 0.250) (0.094-0.094)

Fetal distress

Duplicates excluded

4 173 15 0.087 (0.053; 0.139) (0.000; 0.165) 3.7% (p=0.374) (0.033-0.148)

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