SARS-CoV-2 positivity in offspring and timing of mother-to-child transmission: living systematic review and meta-analysis

Abstract Objectives To assess the rates of SARS-CoV-2 positivity in babies born to mothers with SARS-CoV-2 infection, the timing of mother-to-child transmission and perinatal outcomes, and factors associated with SARS-CoV-2 status in offspring. Design Living systematic review and meta-analysis. Data sources Major databases between 1 December 2019 and 25 April 2022. Study selection Cohort studies of pregnant and recently pregnant women (including after abortion or miscarriage) who sought hospital care for any reason and had a diagnosis of SARS-CoV-2 infection, and also provided data on offspring SARS-CoV-2 status and risk factors for positivity. Case series and case reports were also included to assess the timing and likelihood of mother-to-child transmission in SARS-CoV-2 positive babies. Data extraction Two reviewers independently extracted data and assessed study quality. A random effects model was used to synthesise data for rates, with associations reported using odds ratios and 95% confidence intervals. Narrative syntheses were performed when meta-analysis was inappropriate. The World Health Organization classification was used to categorise the timing of mother-to-child transmission (in utero, intrapartum, early postnatal). Results 643 studies (343 cohort studies, 300 case series and case reports; 44 552 mothers, 30 822 babies) were included. Overall, 2.7% (95% confidence interval 2.1% to 3.5%; 210 studies, 24 040 babies) born to mothers with SARS-CoV-2 infection tested positive for the virus with reverse transcriptase polymerase chain reaction (RT-PCR). Of the 1107 SARS-CoV-2 positive babies with data on the timing of exposure and type and timing of tests, 32 had confirmed mother-to-child transmission: 20 in utero (857 assessed), three intrapartum (35 assessed), and nine during the early postnatal period (144 assessed). Of the 1213 SARS-CoV-2 positive babies with outcome data, 64 were stillbirths, 36 were neonatal deaths, and nine were early pregnancy losses; 1104 babies were alive at the end of follow-up. Severe maternal covid-19 (odds ratio 3.5, 95% confidence interval 1.5 to 8.1), maternal death (14.1, 4.1 to 48.0), maternal postnatal infection (5.0, 1.2 to 20.1), caesarean section (1.4, 1.1 to 1.8), and preterm delivery (1.5, 1.2 to 1.9) were associated with SARS-CoV-2 positivity in offspring. Positivity rates in offspring using RT-PCR varied between regions, ranging from 0.1% (95% confidence interval 0.0% to 0.5%) in studies from North America to 8.5% (4.6% to 13.3%) in studies from Latin America and the Caribbean. Conclusion SARS-CoV-2 positivity rates are low in babies born to mothers with SARS-CoV-2 infection. Evidence confirms vertical transmission of SARS-CoV-2, although this is rare. Severity of maternal covid-19 is associated with SARS-CoV-2 positivity in offspring. Systematic review registration PROSPERO CRD42020178076. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This version is update 1 of the original article published on 16 March 2022 (BMJ 2022;376:e067696), and previous updates can be found as data supplements (https://www.bmj.com/content/376/bmj-2021-067696/related#datasupp).


DATA EXTRACTION
Two reviewers independently extracted data and assessed study quality.A random effects model was used to synthesise data for rates, with associations reported using odds ratios and 95% confidence intervals.Narrative syntheses were performed when meta-analysis was inappropriate.The World Health Organization classification was used to categorise the timing of mother-to-child transmission (in utero, intrapartum, early postnatal).

WHAT IS ALREADY KNOWN ON THIS TOPIC
In pregnant women with SARS-CoV-2 infection, the virus and viral fragments have been detected in maternal blood, placenta, amniotic fluid, and breast milk, suggesting the potential for mother-to-child transmission Primary studies and systematic reviews provide varied estimates for the rates of neonatal SARS-CoV-2 infection or positivity, or both Current classification systems categorise the timing of SARS-CoV-2 mother-tochild transmission based on timing of exposure to the virus and type and timing of tests in offspring People with severe covid-19 have high viral load

WHAT THIS STUDY ADDS
The overall rates of SARS-CoV-2 positivity in babies born to mothers with infection is low (<3%) Evidence confirms mother-to-child transmission of SARS-CoV-2 through in utero, intrapartum, and early postpartum transmission, but vertical transmission is likely to be rare Maternal factors such as severe covid-19, death, preterm birth, caesarean section, and postnatal infection, were associated with SARS-CoV-2 positivity in offspring The increased risks with preterm birth and caesarean section could be attributed to iatrogenic interventions reflecting severe maternal covid- 19   Breast feeding and keeping the baby with the mother after birth does not appear to increase the risk of SARS-CoV-2 positivity in the baby

Introduction
Maternal infection with SARS-CoV-2 has raised concerns about the potential for mother-to-child transmission of the virus. 1 Although there is robust evidence on the magnitude and modes of SARS-CoV-2 transmission in the general population and the prevalence of test positivity, 2 little is known about the burden of SARS-CoV-2 positivity in babies born to infected women.4][5][6] Our earlier published systematic review on SARS-CoV-2 positivity in offspring and timing of mother-to-child transmission reported low positivity rates, and although evidence suggested vertical transmission of the virus, transmission was thought to be rare. 7Further information is needed on the rates of mother-to-child transmission of the virus following the emergence of SARS-CoV-2 variants of concern, and the roll out of vaccinations globally. 8 9o confirm infection and accurately determine when transmission of SARS-CoV-2 occurs, appropriately timed and repeated tests are needed in relevant samples. 10 11 Furthermore, as timing and route of infection may affect clinical outcomes, we need to be able to differentiate between intrapartum transmission of the virus and infection acquired soon after birth through contact with mother, caregivers, healthcare workers, or the neonate's environment. 14he clinical outcomes in SARS-CoV-2 positive babies and those with confirmed vertical infection also need to be ascertained.The extent to which maternal factors such as severe covid-19, timing of infection, mode of delivery, breastfeeding, and postnatal contact with offspring are associated with SARS-CoV-2 positivity in babies is needs to be known to inform maternal care.
In our living systematic review, we assess the rates of SARS-CoV-2 positivity in babies born to mothers with SARS-CoV-2 infection, the timing of mother-tochild transmission, perinatal outcomes in positive babies, and factors associated with SARS-CoV-2 positivity in offspring.In this update, we address the above unknowns, and additionally investigate the association between SARS-CoV-2 variants and motherto-child transmission of the virus.

Methods
Our systematic review is based on a prospective living protocol (PROSPERO CRD42020178076; registered 22 April 2020).In this paper, we focus on mother-tochild transmission using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) recommendations (see supplementary appendix 1).

Search strategy
We searched major databases, preprint servers, and websites that serve as repositories for covid-

Study selection
Eighteen reviewers contributed to study selection.Two independent reviewers assessed each study using a two stage process.In the first stage, the titles and abstracts of all citations were screened, and the full texts examined for inclusion in the second stage.Disagreements between reviewers were resolved through discussion with a third reviewer (ST, JA, or SF-G).To assess SARS-CoV-2 positivity rates in offspring, we included cohort studies of pregnant and recently pregnant women who sought hospital care for any reason and had a diagnosis of SARS-CoV-2 infection, and where SARS-CoV-2 status was ascertained in the fetus or neonate using RT-PCR (neonatal pharyngeal, rectal, or faecal swabs, neonatal or cord blood, fetal tissue, placental samples, or amniotic fluid) or serological tests (anti-SARS-CoV-2 IgM), or both.We defined cohort studies as those that sampled consecutive women, who were followed-up to ascertain the SARS-CoV-2 status of their offspring within the first 30 days after birth. 17nless specified otherwise, we use the term babies and offspring to denote both fetuses and neonates.In addition to the cohort studies, we included case series and case reports to assess the timing of motherto-child transmission and likelihood of infection.To evaluate maternal risk factors for offspring SARS-CoV-2 positivity, we included cohort studies of pregnant and recently pregnant women with a diagnosis of SARS-CoV-2 infection that reported on maternal and perinatal risk factors such as maternal severe covid-19, admission to an intensive care unit, and death; timing of exposure to the virus (antenatal v postnatal; third v first or second trimester); intrapartum factors (<37 weeks preterm v term); mode of delivery (caesarean section v vaginal birth); timing of cord clamping (immediate v delayed)); postnatal care (skin-to-skin contact v none; not separated v separated at birth; breastfed versus not breastfed); and SARS-CoV-2 infection status of the offspring.In this update, we also extracted information about the SARS-CoV-2 variant and SARS-CoV-2 status of offspring born to mothers who were infected.

Quality assessment and data extraction
We assessed the internal and external validity of non-comparative cohorts using the tool by Hoy et al. 18 For internal validity, we considered studies to be at low risk of bias if data were collected from clinical records or research case report forms (data collection), clearly defined outcomes (case definition), confirmed SARS-CoV-2 infection using laboratory based tests (instrument validity), used same mode of data collection in all participants (ascertainment bias), and had sufficient follow-up, with appropriate numerator and denominator.For external validity, we considered studies to be at low risk of bias if they were representative of the national population for relevant variables (population), representative of the target population (sampling frame), undertook a census (selection bias), and the response rate of individuals with and without the outcome was more than 75% (non-response bias).We assessed the methodological quality of the comparative cohort studies using the Newcastle Ottawa scale for selection, comparability, and outcome ascertainment bias outcome. 19sing a pre-piloted form, six independent reviewers in two sets extracted data on study design, number of pregnant women with SARS-CoV-2 infection, type of SARS-CoV-2 test in mothers and babies (RT-PCR, IgM), maternal characteristics (including stage of pregnancy at diagnosis), severity of covid-19 (as defined by authors), mode of delivery, type of samples tested (neonatal nasopharyngeal, rectal, or faecal swabs, neonatal or cord blood, fetal tissue, placenta, amniotic fluid, vaginal fluid, breast milk), timing of sample collection, and SARS-CoV-2 predominant variant of concern 20  by the dominant variant in the country during the study period using https://covariants.org/). 9We also extracted data on the clinical outcomes of all SARS-CoV-2 positive fetuses and neonates when available, including early pregnancy outcomes of miscarriage and abortion.A detailed deduplication process was used to cross check data against other studies published by the same authors or those that included women from the same institutions.We contacted study authors for unpublished information and to query duplication of data.

Data analysis
We summarised the SARS-CoV-2 positivity rates in offspring identified by RT-PCR or anti-SARS-CoV-2 IgM assays, or both, as a proportion of all babies born to mothers with SARS-CoV-2 infection in cohort studies.After transforming data using Freeman-Tukey double arcsine transformation, we used DerSimonian and Laird random effects meta-analysis to calculate rates and corresponding 95% confidence intervals.Heterogeneity was reported as I 2 and τ 2 estimates.Sensitivity analysis for SARS-CoV-2 positivity rates in babies was done by restricting the analysis to studies at low risk of bias, babies tested at less than 24 h after birth, and babies born to mothers with SARS-CoV-2 infection diagnosed antenatally.The rates of SARS-CoV-2 positivity were also evaluated by subgroups of studies involving babies and mothers from various World Bank regions and by predominant SARS-CoV-2 variants of concern.We ascertained the timing of mother-to-child transmission based on the World Health Organization classification in all studies (cohort, case series, case reports) that reported SARS-CoV-2 positive babies and provided information on the timing of exposure (antenatal, postnatal) and test timings in the babies (see supplementary appendix 3). 21Each baby with a positive test result was placed in mutually exclusive categories for likelihood of infection: confirmed (definite infection), possible (evidence suggestive of infection but not confirmatory), unlikely (infection cannot be ruled out), and indeterminate (tests required to define classification have not been performed) for in utero, intrapartum, or early postnatal transmission.In addition to the specifications in the WHO criteria, we categorised babies to have confirmed or possible in utero infection if they had a positive test result in the first 24 hours after birth and did not have a test between 24 h and 48 h but had a repeat positive test result from a sterile (confirmed) or non-sterile (possible) sample after 48 h and before seven days, with no negative test results before the repeat positive test result.We also added one further "indeterminate" category for intrapartum transmission: when babies had a negative test result or no test in the first 24 h after birth and a single anti-SARS-CoV-2 IgM positive result at 7-14 days with no confirmatory test; and To summarise the associations between maternal and perinatal characteristics and SARS-CoV-2 status in exposed babies, we pooled comparative dichotomous data as odds ratios and 95% confidence intervals using random effects meta-analysis.When metaanalysis was considered inappropriate because of excessive clinical or statistical heterogeneity or when SARS-CoV-2 positive offspring were selectively reported in the cohort studies, we used a narrative descriptive approach to summarise the evidence, such as for clinical outcomes in test positive babies and test positivity in various biological samples.All statistical analyses were performed using Stata (version 16).

Patient and public involvement
This study is supported by Katie's Team (https://www.elly.org.uk/copy-of-research) and The Hilda's (https:// www.dhlnetwork.com/news),dedicated patient and public involvement groups in women's health.The team members were involved in the interpretation and reporting of this living systematic review through participation in virtual meetings.Findings will be made available on our website in a format more suitable for patients and members of the public (www.birmingham.ac.uk/research/who-collaboratingcentre/pregcov/index.aspx).

Results
Overall, we included 643 studies (343 cohort studies, 300 case series and case reports; 44 552 mothers, 30 882 babies) from 941 678 identified articles (fig 1).In 554 studies, women had infections prior to the emergence of any SARS-CoV-2 variants of concern (wild type), six studies during predominance of variants of interest or variants under monitoring, 18 studies during predominance of the alpha variant, two studies each during predominance of the beta and gamma variants, and five studies during predominance of the delta variant.None of the studies was conducted during predominance of the omicron variant, and 56 studies did not report the predominant variant, or provide information required to identify the dominant variant in the country during the study period.A total of 210 cohort studies reported on SARS-CoV-2 positivity status in 24 040 exposed babies.Overall, 1567 babies tested positive for SARS-CoV-2 across all study designs (378 studies; 194 cohorts, 184 case series or case reports).Ninety one comparative cohorts (with 13 683 mother-baby dyads) reported on various maternal and perinatal factors and SARS-CoV-2 positivity in offspring.In 246 cohort studies, SARS-CoV-2 testing of various maternal and perinatal biological samples (placenta, amniotic fluid, maternal vaginal fluid, stool samples, and breast milk) were reported in a proportion of participants (5060 mothers, 4722 babies).3).The likelihood of mother-to-child transmission was classified as indeterminate for 685 babies, mainly owing to the lack of repeat confirmatory testing within the prespecified time points.Table 1 22- 40 and table 2 33 41-46 and supplementary appendix 7 provide the maternal and perinatal characteristics and SARS-CoV-2 test results of the babies with confirmed and possible vertical infection, respectively.

Outcomes of SARS-CoV-2 positive babies
Outcomes were reported for 1213 SARS-CoV-2 positive babies 378 studies including cohort, case series, case reports); 1104 babies were alive at the end of followup, nine early pregnancy losses, 64 stillbirths, and 36 neonatal deaths occurred (table 3).Of the twenty babies with confirmed in utero infection, nine were alive at end of follow-up, one died after delivery, and eight were stillborn, and early pregnancy loss occurred in a set of twin fetuses.All three babies with confirmed intrapartum infection and the nine with early postnatal infection were alive at the end of follow-up (table 1 22- 40 ).Eighty eight babies with symptoms (88/208) were born preterm, and gestational age was not known in another 39 babies.Of the 147 SARS-CoV-2 positive babies in whom radiological findings were reported (as defined by the authors), abnormalities suggestive of    4).Postnatal care, such as skin-to-skin contact was associated with a reduction in SARS-CoV-2 positive status in the babies (0.42; 0.25 to 0.70, I 2 =0%; 3 studies, 1101 women) (table 4).No associations were seen between SARS-CoV-2 positivity in babies and maternal admission to the intensive care unit, the trimester of maternal infection (third versus first or second trimester), breastfeeding or mother-baby separation at birth.(table 4).Subgroup analysis by variants of concern showed most studies were recruited before predominance of any variants of concern (supplementary appendix 9).

SARS-CoV-2 positivity in maternal and perinatal biological samples
In addition to testing infants for SARS-CoV-

Discussion
This update of our living systematic review includes 171 more primary studies (15 600 women, 12 585 babies) than our original review, and 50% more pregnant women with SARS-CoV-2 infection.We found that less than 3% of babies born to mothers seeking hospital care for any reason and with a diagnosis of SARS-CoV-2 infection also tested positive for SARS-CoV-2; the rates were lower (2%) when limited to babies of mothers with antenatal SARS-CoV-2 infection.Confirmed mother-to-child-transmission was noted through in utero, intrapartum, and early postnatal exposure; but the overall risk is low.In addition to severity of maternal covid-19 disease and postnatal maternal infection, which were found to be associated with offspring SARS-CoV-2 positivity in our original review, low gestation at birth and caesarean section were also associated with offspring SARS-CoV-2 positivity in in this update.The risk of a positive test result from offspring was reduced in mothers with skin-to-skin contact compared with no contact, which is usually offered only to mothers who are clinically stable and less likely to have severe covid-19.We did not find any association between SARS-CoV-2 positivity in offspring and trimester of maternal infection, breastfeeding, or mother-baby separation at birth.However, the number of studies reporting on early SARS-CoV-2 exposure were low.SARS-CoV-2 RNA was detected in amniotic fluid, placenta, vaginal fluid, and breast milk, but detection of virus in these biological specimens may not necessarily indicate infection in the baby.Few studies included mothers infected after the emergence of identified SARS-CoV-2 variants.

Strengths and limitations of this review
We carried out a comprehensive review on SARS-CoV-2 positivity rates in babies born to mothers with the infection and assessed the timing of exposure and likelihood of infection.We only included cohort studies for estimating the rates of SARS-CoV-2 positivity in offspring, unlike some of the published systematic reviews, which combined cohort and case-control studies with case series [47][48][49] or reported positivity in babies as neonatal infection. 49 50Our extensive sensitivity and subgroup analyses enabled us to assess the robustness of our findings according to the timing of maternal infection and testing in babies, across regions, and included SARS-CoV-2 variants as they emerged.We used the WHO classification system to ascertain the timing of transmission of SARS-CoV-2 from mother to baby and to confirm infection status, and we included data from any study that reported on babies with a positive test result.We were also able to consult with experts on the revision of the WHO classification to confirm our updates.We assessed the various maternal and perinatal factors that may be associated with SARS-CoV-2 positivity in babies.Our extensive de-duplication process minimised the risk of double counting data.This update has allowed us to seamlessly incorporate new evidence, as well as consider the evolving nature of the pandemic such as the impact of SARS-CoV-2 variants on offspring positivity.
Our review has limitations.We aimed to rapidly update findings since our first review.As a result of the very large number of published studies, requiring intense effort to remove duplicate studies and participants, as well as the need to contact authors for information to classify positive babies, more time was required to prepare and analyse the data than anticipated.Many published primary studies have not kept pace with the evolving nature of the pandemic, resulting in very few studies reporting on women who were infected after the emergence of SARS-CoV-2 variants of concern.Our findings were also limited by heterogeneity in populations, tests, and outcomes.For example, mild and severe covid-19 were variably defined in the studies.Severe disease included severe symptoms, admission to an intensive care unit, and need for extracorporeal membrane oxygenation, and mild symptoms included asymptomatic women.Since almost all women in the studies had a recent diagnosis of SARS-CoV-2 infection, our findings are not applicable to those with infection in early pregnancy who recovered.Similarly, the types and timing of tests used in mothers and babies and their accuracy varied.Several studies did not provide details on the timing of perinatal exposure to SARS-CoV-2, or on the timing of tests, which hindered our ability to determine the timing of mother-to-child transmission of SARS-CoV-2.Even when the babies were tested, confirmatory tests were often not performed, further limiting our ability to use the WHO classification system to confirm infection status.Clinical outcomes of the babies born to mothers with SARS-CoV-2 infection were inconsistently reported, making it challenging to ascertain if the complications including stillbirths and neonatal deaths were related to SARS-CoV-2, other clinical factors or subject to publication bias.We were unable to consider the impact of vaccination status of pregnant women on our findings because of the paucity of available information in studies.Similarly, our subgroup analysis by predominant SARS-CoV-2 variant was limited to analysis of positivity rates and risk factors, and not to timing of mother to child transmission because of the paucity of data.Furthermore, we were unable to limit our analysis for association between postnatal care and offspring SARS-CoV-2 positivity to women with peripartum or postnatal infection because of poor reporting in studies, which could dilute any association between these risk factors and offspring SARS-CoV-2 positivity.

SARS-CoV-2 positivity in offspring and timing of mother-to-child transmission
Our overall findings in this update have remained consistent with our original review.SARS-CoV-2 positivity rates in offspring remain low, and only a small proportion of those infants who had a positive result were from confirmed mother-to-child transmission.Some studies used anti-SARS-CoV-2 IgM antibody testing to diagnose neonatal infection.However, there are concerns about the accuracy of IgM antibody tests to diagnose vertical infection, and often a confirmatory IgM test was not performed. 15Compared with findings in our original review, we noted a smaller percentage of babies tested showed evidence of anti-SARS-CoV-2 specific IgM antibodies in this update, while babies tested in the first 24 h after birth had higher SARS-CoV-2 positivity rates.However, these rates remained below the overall positivity rates across studies.The low SARS-CoV-2 positivity rates in offspring in studies from Europe and North America could reflect the policy of universal maternal screening for SARS-CoV-2, resulting in inclusion of women with mild disease. 51 52ince SARS-CoV-2 positivity in offspring was associated with severity of maternal disease, regions with mostly symptomatic testing of pregnant women were more likely to include women with severe disease, which may be reflected in the higher reported SARS-CoV-2 positivity rates in offspring in those regions.Subgroup analysis by SARS-CoV-2 virus variant was limited by the paucity of data reported.
A previous systematic review that pooled data from all studies, including case series and reports without a formal meta-analysis, reported 70% of the 122 positive babies to have postpartum infections and 9% to have confirmed in utero and intrapartum infection, using the Shah classification. 47But we categorised fewer babies to have confirmed infection using the more stringent WHO criteria.We also refrained from providing the findings of confirmed infection as a proportion of all positive babies, because the selective reporting of SARS-CoV-2 positive babies in the studies affects the reliability of rate estimates.
The observed association between severe maternal disease and test ositivety in offspring could be linked to the prolonged detection of viral RNA in the mothers blood associated with disease severity. 53 54But to date, doi: 10.1136/bmj-2021-067696 | BMJ 2024;384:e067696 | the bmj no clear evidence links the severity of maternal disease to the shedding of SARS-CoV-2, although the duration of shedding appears to be prolonged in individuals with severe covid-19. 55The observed association between postnatal diagnosis of maternal SARS-CoV-2 and neonates who test positive could also be attributed to horizontal transmission from the mother, caregivers, or health workers, or from the neonate's environment.Appropriate measures to reduce the risk of horizontal transmission should be followed if infection is suspected, such as improved ventilation, adequate personal protective equipment including protective masks and mask wearing, hand hygiene, and use of protective clothing during contact with the baby.
In this update, we found an association between preterm birth and caesarean sections with SARS-CoV-2 positivity in offspring.This likely reflects severity of the disease in the mother or fetal distress, resulting in interventional approaches such as iatrogenic preterm delivery (as opposed to spontaneous preterm delivery) or caesarean section by healthcare givers.Other studies have shown that SARS-CoV-2 infection during pregnancy is associated with preterm birth and caesarean section. 56Our review also identified a reduction in risk of test positivity in offspring mothers with a recent diagnosis of SARS-CoV-2 infection and who were allowed skin-to-skin contact with their neonates.Although few studies reported on skin-toskin contact, and there was paucity of information within studies on infection control practices followed by mothers to reduce risk of horizontal transmission, it is reassuring to see that there is no increased risk of test positivity in offspring of mothers allowed skin-toskin contact.It is also likely that only mothers with milder illness are allowed skin-to-skin contact with their babies, which is itself an indication of severity of SARS-CoV-2 infection.
We did not find any association between breastfeeding practice in mothers with a recent diagnosis of SARS-CoV-2 infection and SARS-CoV-2 positivity in neonates, consistent with rare findings of RT-PCR positivity in breast milk samples. 573][14] Studies did not always report whether the maternal or fetal side of the placenta was swabbed, making it difficult to accurately determine placental infection.

Relevance for clinical practice and research
Our review provides estimates on the burden of SARS-CoV-2 positive test results in exposed babies in clinical practice who will require further testing and monitoring.Evidence confirms vertical transmission of SARS-CoV-2 through in utero and intrapartum routes, although the absolute number of confirmed cases is low.SARS-CoV-2 positivity in babies is higher when their mothers have severe covid-19, and relevant testing should be considered in these babies.Very few studies reported on variants and therefore we had limited data to assess their impact on mother to child transmission and positivity rates.Current evidence does not support routine caesarean sections, mother-baby separation at birth, or formula feeding as interventions for avoiding SARS-CoV-2 transmission to babies in mothers with a recent diagnosis of SARS-CoV-2 infection.
Healthcare professionals need to perform further tests in fetuses and babies with a positive result to robustly confirm infection occurred and classify timing of mother-to-child transmission using appropriate samples according to WHO guidance.To reduce the proportion of babies in whom vertical transmission cannot be confirmed despite their initial positive status, repeat tests are needed at various time points in appropriate samples.Further research is needed to assess factors contributing to regional variations, such as different strategies for screening, emerging variants, and vaccination status.Further data are needed on the SARS-CoV-2 positive status of the various biological samples that could be potentially associated with SARS-CoV-2 mother-to-child transmission, and the relationship of sample positivity to fetal or neonatal infection.Future reviews will need to consider the changing landscape of the covid-19 pandemic, including the prevalence of covid-19 in various regions, impact of vaccination, and the effects of known and emerging SARS-CoV-2 variants on mother-to-child transmission.In the absence of individual participant data for synthesis, aggregate data review needs to capture these trends by reporting data according to time of participant recruitment.

Conclusion
The overall rates of SARS-CoV-2 positivity in babies born to mothers with SARS-CoV-2 infection is low.Evidence was found for confirmed vertical transmission of the virus, although the absolute numbers are low.Severe maternal covid-19 was associated with SARS-CoV-2 positivity in babies, but not vaginal birth, keeping the baby with the mother after birth, or breastfeeding.

5629 643
19 studies, including Medline, Embase, Cochrane database, WHO COVID-19 database, Living Overview of the Evidence platform, China National Knowledge Infrastructure Fig 1 | Study selection process in systematic review: SARS-CoV-2 positivity in babies born to mothers with covid-19 and timing of MTCT (mother-to-child transmission).*Seesupplementary figure for details of other sources(CNKI), and Wanfang databases for studies (cohort, case series, and case report) on SARS-CoV-2 infection in pregnant and recently pregnant women (including after abortion or miscarriage).For this update of the living systematic review, we included studies from searches up to 25 April 2022.No language restrictions were applied.Our searches were coordinated with the EPPI-Centre, the WHO (World Health Organization) Library, and the Cochrane Gynaecology and Fertility group (see supplementary appendix 2).

Timing of exposure and test
(as reported by authors, or mapped

Table 1 |
Continued(Continued) a further "indeterminate" category for postpartum transmission: when babies had a negative test result in the first 48 h after birth with a single positive nonsterile sample after 48 h or IgM result at more than 14 days with no or negative confirmatory test result (see supplementary appendix 3 for revised classification).

Table 2 |
Maternal and perinatal characteristics of fetal death with confirmed in utero mother-to-child transmission of SARS-CoV-233 41-46 * Classified as "confirmed" in utero as tests were repeated <24 h, despite not meeting WHO criteria of positive test result at 24-48 h (appendix 3). in the antenatal period, the positivity rate was 2.1%(1.1% to 3.4%); 2.2% (0.7% to 4.4%) when limited to babies tested in the first 24 h after birth (fig2).In the subgroup analyses, SARS-CoV-2 positivity rates by RT-PCR in offspring varied between regions, ranging from 0.1% (0.0% to 0.5%) in studies from North America to 8.5% (4.6% to 13.3%) in studies from Latin America and the Caribbean.Offspring rates of SARS-CoV-2Mother-to-child transmission was according to World Health Organization classification.NP RT-PCR=nasopharyngeal reverse transcriptase polymerase chain reaction; NICU=neonatal intensive care unit; IHC=immunohistochemistry; ISH=in situ hybridisation; GxPx= Gravida number, parity number; IUFD=intra-uterine fetal death; Dx=day number; EM= electron microscopy.*Classified as "confirmed" in utero as tests were repeated <24 h, despite not meeting WHO criteria of positive test result at 24-48 h (appendix 3).

Table 3 |
Outcomes in SARS-CoV-2 positive babies born to mothers with covid-19 in all studies by severity of maternal disease (cohort, case series, and case reports).Values are numbers (percentages) unless stated otherwise

Table 4 |
Maternal and perinatal factors associated with SARS-CoV-2 positive test results in offspring