Infant Outcomes Following Maternal Infection with SARS-CoV-2: First Report from the PRIORITY Study

Infant outcomes after maternal SARS-CoV-2 infection are not well-described. In a prospective U.S. registry of 263 infants born to mothers testing positive or negative for SARS-CoV-2, SARS-CoV-2 status was not associated with birth weight, difficulty breathing, apnea or upper or lower respiratory infection through 8 weeks of age.


Introduction
Maternal viral infection in pregnancy and the peripartum and postpartum periods can adversely affect infant outcomes. While studies have reported that maternal SARS-CoV-2 infection increases the risk of preterm birth 1 and can be vertically transmitted, [2][3][4][5] overall risks for infants born to mothers with SARS-CoV-2 are not yet well-described. Currently, national and international guidelines for management of infants born to mothers with SARS-CoV-2 [6][7][8] are based on limited data without outcomes reported past the neonatal period. A more complete understanding of infant outcomes after maternal SARS-CoV-2 infection would inform guidelines and policies to manage this important and growing segment of the population.
To address this urgent need, we report here early findings from infants born to mothers enrolled in the PRegnancy CoronavIrus Outcomes RegIsTrY (PRIORITY), an ongoing nationwide study of pregnant or recently pregnant women who have confirmed or suspected SARS-CoV-2.

Methods
PRIORITY is a prospective cohort study enrolling U.S. individuals 13 years old with suspected or confirmed SARS-CoV-2 during pregnancy or in the first 6 weeks after pregnancy. This manuscript reports infant outcomes for live births occurring to 179 mothers who had a positive test for SARS-CoV-2 and 84 mothers who had a negative test for SARS-CoV-2 and excludes live births of 10 mothers suspected of SARS-CoV-2 who were not tested. Maternal outcomes from PRIORITY will be reported separately.
Mothers were recruited nationally through outreach by professional organizations, traditional media, social media, and word of mouth to healthcare providers. Once recruited, informed consent was obtained by the study team from the mother, for herself and her infant; births occurred at over 100 hospitals across the U.S. PRIORITY was approved by the University of California San Francisco Institutional Review Board (IRB #20-30410).  Table 1 for infant questionnaire items and the dates that their collection was initiated. PRIORITY enrollment and follow up is ongoing; for this manuscript, we report data available by June 22, 2020.
We calculated the incidence and associated 95% confidence intervals for adverse outcomes using exact binomial techniques. We used chi-square analysis and Fisher's exact test to compare the proportion of outcomes between infants whose mothers tested positive for the virus and those whose mothers tested negative.
A c c e p t e d M a n u s c r i p t 5 See the Table for other clinical and demographic characteristics by maternal SARS CoV-2 status.
In this cohort of 263 infants, 44 infants (17%) were admitted to the NICU; fast breathing or difficulty breathing was reported for 14 (11%) of 127 infants surveyed after expansion of the birth questionnaire, and apnea was reported for 2 (1.6%). These characteristics did not differ between mothers testing positive for SARS-CoV-2 compared to those who tested negative. Among infants born to mothers who first tested positive 0-14 days prior to delivery, 20 (26.0%) of 77 were admitted to the NICU compared to 10 (12.2%) of 82 born to mothers who first tested positive more than 14 days prior to delivery (p=0.04). Infants born to mothers who first tested positive 0-14 days prior to delivery were also born earlier as compared to infants born to mothers who first tested positive more than 14 days prior to delivery (mean 37.5 versus 39 week gestation, p=0.0009). Additionally in this cohort, 16 mothers first tested positive for SARS-CoV-2 after delivery; the positive test for this subgroup occurred a median of 6 days after delivery with an interquartile range of 1-12 days after delivery. Infants born to mothers who first tested positive 0-14 days prior to delivery were less likely to room in with mothers than were those born to mothers who first tested positive more than 14 days prior to delivery or after delivery (see Supplemental Table 2).
Two infants born to mothers who tested positive for SARS-CoV-2 in the third trimester were reported to have birth defects, each with multiple congenital anomalies reported. One of these had cardiac, vertebral, renal and pulmonary anomalies while the other had facial, genital, renal, brain and cardiac anomalies. One mother who tested negative for SARS-CoV-2 also reported an infant with gastrointestinal, renal and cardiac anomalies.

Discussion
Among 263 initial infants enrolled in the PRIORITY study, adverse outcomes, including preterm birth, NICU admission, and respiratory disease did not differ between those born to mothers testing positive for SARS-CoV-2 and those born to mothers testing negative. No pneumonia or lower respiratory tract infection was reported in this cohort through 6-8 weeks of age. Among infants born to mothers who tested positive for SARS-CoV-2, the estimated incidence of a positive infant SARS-CoV-2 test was low at 1.1% (0.1%, 4.0%), and infants had minimal symptoms. Overall, these results are reassuring and suggest that infants born to mothers infected with SARS-CoV-2 generally do well in the first 6-8 weeks after birth.
Our study has several limitations. First, we are unable to estimate the incidence of infant SARS-CoV-2 infection because infant testing was incomplete and might be biased by both false-positive and false-negative results. Further research is needed to report infant incidence of SARS-CoV-2 after maternal infection. Second, since PRIORITY's control group includes both symptomatic and asymptomatic women testing negative for SARS-CoV-2, it may not be representative of all U.S. pregnancies. However, these inclusion criteria allowed sampling of control mothers who were more similar to the exposed group in all respects A c c e p t e d M a n u s c r i p t 7 except for SARS-CoV-2 test results, which may enhance causal inference for the effect of SARS-CoV-2 on infant outcomes. Third, PRIORITY's current racial and ethnic distribution underrepresents maternal Latina ethnicity and Black race compared to a concurrent CDC assessment of U.S. pregnant women infected with SARS-CoV-2 that reported race/ethnicity as 46% Hispanic, 22% Black and 23% White. 9 Barriers to registry participation are expected given the historical harm related to research participation and systemic racism experienced by Black, Indigenous, People of Color communities and the current burden of SARS-CoV-2 in these communities and may impact the generalizability of our findings. 10 In May 2020, PRIORITY launched a Reproductive Health Equity and Birth Justice Core to increase enrollment of underrepresented groups and engage with partners in highly impacted communities. Fourth, the timing of maternal testing in this cohort was determined at the clinical sites and may not have coincided with the onset of illness. Therefore, while we found that NICU admission and earlier gestational age were more common for infants born to mothers testing positive for SARS-CoV-2 0-14 days before delivery than for those testing positive at other times, these associations may reflect hospital practices for management of mothers testing positive for SARS-CoV-2 rather than infant physiology.
Overall, PRIORITY's initial findings regarding infant health are reassuring. Further investigation with longer follow up periods and larger sample sizes will be needed to make a definitive determination of the risk of vertical transmission, neonatal illness, and the incidence of congenital anomaly and are planned for the PRIORITY cohort.