SARS-CoV-2 infections among neonates born to women with SARS-CoV-2 infection: maternal, pregnancy and birth characteristics

Background: Multiple reports have described neonatal SARS-CoV-2 infection, including likely in utero transmission and early postnatal infection. Most neonatal infections reported to date have been asymptomatic or mild disease; however, severe cases, including respiratory failure requiring intensive care unit admission, have been described. Objectives: To describe maternal, pregnancy and infant characteristics among neonates born to women with SARS-CoV-2 infection during pregnancy by neonatal SARS-CoV-2 testing results. Methods: Using aggregated data from the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET) from March 29, 2020–August 6, 2021, we identi�ed neonates who were: 1) born to women who were SARS-CoV-2 positive by RT-PCR at any time during their pregnancy, and 2) tested for SARS-CoV-2 by RT-PCR during the birth hospitalization. Results: Among 25,896 neonates of mothers with SARS-CoV-2-infection, 3,381 (13%) underwent PCR testing. One hundred thirty-six neonates (4%) were PCR-positive. Neonates testing positive were born to both symptomatic and asymptomatic women, and 95% were born to women with infection identi�ed ≤ with 14 days of delivery. Conclusions: While perinatal SARS-CoV-2

and control measures in delivery and outpatient pediatric settings, as well as counselling for persons who acquire COVID-19 during pregnancy about potential risk to their neonates.Moreover, pregnant people and those wanting to become pregnant should be vaccinated against COVID-19 in order to protect themselves and their infants.

Synopsis Study question
We sought to describe maternal, pregnancy and infant characteristics among neonates born to women with SARS-CoV-2 infection during pregnancy by infant SARS-CoV-2 testing results at birth.What's already known?Multiple reports have described perinatal SARS-CoV-2 infection, including likely in utero transmission and early postnatal infection.Most neonatal infections reported to date have been asymptomatic or mild disease; however, severe cases, including respiratory failure requiring intensive care unit admission, have been described.
What this study adds?Among 25,896 neonates of mothers with SARS-CoV-2 infection, 3,381 (13%) underwent PCR testing with reported results.One hundred thirty-six neonates (4%) were PCR-positive and were born to both symptomatic and asymptomatic women.Nearly all PCR-positive neonates (95%) were born to women with infection identi ed ≤14 days of delivery.

Background
2][3] Multiple reports have described perinatal infection, including likely in utero transmission and early postnatal infection. 3,4Most neonatal infections reported to date have been asymptomatic or mild disease; however, severe cases, including respiratory failure requiring intensive care unit (ICU) admission, have been described. 5The American Academy of Pediatrics (AAP) and the Centers for Disease Control and Prevention (CDC) recommend all neonates born to women with suspected or con rmed COVID-19 be tested for SARS-CoV-2 by real-time reverse transcription polymerase chain reaction (RT-PCR). 6,7However, data describing factors associated with infection among exposed neonates are limited.We sought to describe maternal, pregnancy and infant characteristics among neonates born to women with SARS-CoV-2 infection during pregnancy by neonatal SARS-CoV-2 testing results.

Cohort Selection
The Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET) is a collaboration between CDC and state, local, and territorial health departments to conduct linked-longitudinal surveillance of pregnant women and their infants to understand the effects of emerging and reemerging threats, including COVID-19. 8Pregnant women with laboratory con rmed SARS-CoV-2 infection from January 20 to December 31, 2020, are retrospectively ascertained through reporting of pregnancy in COVID-19 surveillance and cross-matching of COVID-19 surveillance data with local data systems that contained data on births to assess pregnancy status.The data are then enhanced through a variety of supplemental data sources at the jurisdiction level including, but not limited to, vital statistics, prenatal screening data, administrative datasets, electronic laboratory reporting, and maternal and neonatal medical record review.The aggregated SET-NET data contain variables on maternal demographics and prenatal history, maternal SARS-CoV-2 infection (e.g., timing of infection relative to pregnancy, severity), neonatal characteristics (e.g., gestational age, SARS-CoV-2 testing), among others.This activity was reviewed by CDC and conducted consistent with applicable federal law and policy. 9posure Using aggregated SET-NET data compiled through August 6, 2021, we identi ed neonates who were: 1) born to women who were SARS-CoV-2 RT-PCR positive at any time during their pregnancy, and 2) tested for SARS-CoV-2 by RT-PCR during the birth hospitalization.For neonates with extended hospitalization at birth (>14 days) or whose date of discharge was unknown, only SARS-CoV-2 tests conducted ≤14 days following birth were included in order to focus on infections from perinatal transmission, rather than community transmission.

Statistical analysis
We describe neonates by SARS-CoV-2 testing.We focused on SARS-CoV-2 positive neonates and described maternal and birth characteristics, including maternal demographics, maternal COVID-19 disease severity, 10 timing of maternal infection relative to delivery (determined by date of rst positive SARS-CoV-2 or symptom onset, if testing date was missing) and pregnancy complications (e.g., preeclampsia).We assessed neonatal characteristics including gestational age and birthweight.We also described these characteristics among neonates who were tested by SARS-CoV-2 RT-PCR following birth but who tested negative.Because negative results are not reported consistently to all jurisdictions, the group of test-negative neonates are not representative of all neonates testing negative.Therefore, we did not perform statistical comparisons between neonates testing positive and negative for SARS-CoV-2.Nevertheless, the SET-NET data offer a glimpse of the current state of perinatal SARS-CoV-2 RT-PCR testing of neonates, and neonates with negative results are included here for context.
Of the 3,362 neonates with test results, 3,226 had only negative RT-PCR results reported, and 136 (4.0%) had at least one positive RT-PCR result, representing 0.5% [136/25,896] of livebirths reported.Of these 136 neonates, 90 (66.2%) had only positive RT-PCR results and 46 (33.8%) had both positive and negative results.Of the latter group, 20 neonates tested negative one day before testing positive and nine neonates tested positive one day before testing negative.Four neonates had a positive and a negative PCR on the same day.
Maternal demographics and underlying conditions are summarized in the Table .The most frequent maternal race/ethnicity was Hispanic or Latina.Of SARS-CoV-2 positive neonates with date of maternal infection reported (n=133), 95.5% were born to women with either initial positive testing or symptom onset occurring ≤14 days before delivery.Six infected neonates were born to women with initial positive SARS-CoV-2 testing >14 days before delivery.Three of these women remained SARS-CoV-2 positive within two days prior to delivery.The percent positivity among neonates tested for SARS-CoV-2 was 0.9% (6/644), 3.2% (10/317), 4.6% (19/409), and 5.0% (98/1967) for those born to women with infection diagnosed >14 days, 7-14 days, 3-6 days and 0-2 days before delivery.Of neonates testing positive whose maternal disease severity was known (n=85), 42 (49.4%)were born to mothers reported to be asymptomatic at time of COVID-19 diagnosis.
The timing of RT-PCR testing was similar for neonates testing negative.

Comment
Principal ndings SARS-CoV-2 infection among neonates born to women with COVID-19 during pregnancy was uncommon, occurring in 4.0% of neonates known to be tested for the virus.However, this is likely an overestimate because negative test results are less frequently reported to health departments; the true percentage lies between 4.0% and 0.5% (the total neonates testing PCR-positive among all livebirths).While uncommon, neonatal infection was more frequent among neonates born to mothers diagnosed with COVID-19 close to delivery (<7 days) and among neonates born preterm (<37 weeks).Neonatal positivity occurred regardless of maternal symptom status.
Strengths of the study SET-NET is one of the largest cohorts of pregnant women with laboratory con rmed SARS-CoV-2 infections in the U.S. The mother baby linked longitudinal surveillance allows for case identi cation of infection during pregnancy and follow-up to the birth hospitalization using existing data sources including laboratory reporting.

Limitations of the data
Limitations of our analysis include the inability to assess route of SARS-CoV-2 transmission (e.g., in utero, peripartum, postnatal), given lack of immunoglobulin-M serology and RT-PCR testing data on sterile specimens (e.g., blood). 11We were also not able to assess infection prevention and control (IPC) measures implemented during delivery hospitalization, which may vary.Lastly, testing practices of both pregnant women and their neonates likely varied throughout the course of the pandemic, by facility, and by maternal or neonatal characteristics (e.g., symptom status, ICU admission). 12terpretation Previous studies of pregnant women with SARS-CoV-2-infection have suggested higher prevalence of preterm birth, and potentially other adverse outcomes, compared to pregnant women without infection or national baseline estimates. 2,13However, much remains unknown about the frequency and risk factors of transmission of SARS-CoV-2 from a pregnant person to their fetus or neonate.Our ndings that neonates with positive SARS-CoV-2 testing were born to both symptomatic and asymptomatic women underline the need for IPC measures in delivery and outpatient pediatric settings, as well as counselling for persons who acquire COVID-19 during pregnancy about potential risk to their neonates.
Identi cation of neonates with SARS-CoV-2 infection will be in uenced by testing practices.Although these data are not representative of all perinatal testing practices, they indicate that RT-PCR SARS-CoV-2 testing of neonates born to women with SARS-CoV-2 infection during pregnancy primarily occurred for women with third trimester infection, especially for women with infection identi ed within 14 days of delivery.These testing patterns are consistent with the idea that transmission from mother to neonate through respiratory droplets is most likely to occur during the mother's infectious period. 14Nearly all neonates born to women with infection occurring more than 14 days prior to delivery tested negative; one possible additional explanation is protection against SARS-CoV-2 infection by transplacental transfer of maternal antibodies, 15 but further studies are needed.

Conclusion
Previous studies have demonstrated that risk of postnatal transmission from a mother infected with SARS-CoV-2-to neonate is low when appropriate IPC is followed. 3The AAP and CDC recommend that mothers with COVID-19 utilize appropriate IPC measures (e.g., masks, hand hygiene) when rooming in with their infants, 6,7 even if the mother is asymptomatic.Neonates born to women with COVID-19 should be tested for SARS-CoV-2, 6,7 particularly those born to women with infection identi ed close to delivery or who are born preterm.Future studies that compare infected with SARS-CoV-2 infection to a representative sample of neonates without infection are needed to identify risk factors for neonatal SARS-CoV-2 infection and other neonatal adverse outcomes.Additionally pregnant people and those wanting to become pregnant should be vaccinated against COVID-19 in order to protect themselves and their infants.

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Table Table .
16 Declarations 16.Centers for Disease Control and Prevention.COVID-19 Vaccines While Pregnant or Breastfeeding.Updated August 11, 2021.Accessed August 27, 2021.https://www.cdc.gov/coronavirus/2019ncov/vaccines/recommendations/pregnancy.htmlMaternal demographics, maternal disease characteristics, and neonate characteristics by neonate real-time polymerase chain reaction (RT-PCR) test results -SET-NET, 20 a , March 29, 2020 -August 6, 2021 Inclusive of preeclampsia, eclampsia, or HELLP (hemolysis, elevated liver enzymes and low platelet) syndrome.Does not include chronic hypertension.Hypertensive disorders of pregnancy were only considered underlying conditions for women with third trimester infection.Categories of disease severity were based on modi ed National Institute of Health and World Health Organization criteria as described in Galang et al 9 .Women were considered asymptomatic if reported as having an absence of symptoms using a symptom status variable rather than solely absence of individual symptoms reported.Criteria were applied to classify severity using submitted data including De ned as weight <10th percentile for sex (presumed female if missing) and gestational age using the INTERGROWTH-21st online percentile calculator http://intergrowth21.ndog.ox.ac.uk.Some gestational ages were reported in completed weeks only (rather than in weeks and days).
c d symptoms, intensive care unit admission, invasive ventilation, use of COVID-19 therapies, complications associated with COVID-19, and death.e