Advances in Neonatology

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been linked to poor outcomes in pregnancy, maternal morbidity and mortality, and complications in newborns, but how the virus affects a fetus is unclear. The majority of newborns born to mothers who are positive for COVID-19 are asymptomatic at birth, and those who do test positive follow a benign neonatal course.

In the 16 months since the start of the pandemic, more than 250 newborns were tested for COVID-19 at NewYork-Presbyterian Komansky Children’s Hospital using SARS CoV-2 nasal polymerase chain reaction (PCR); all results were negative. SARS-CoV-2 virus has been found in the nostrils of infants born to mothers with active COVID-19 at delivery, likely attributed to transmission of the pathogen to the infant after birth by direct or indirect contact. Compared to older children infected with SARS-CoV-2, the rates of hospitalization and admission to intensive care are higher in children under the age of one who have the virus.

Studies have shown that proinflammatory cytokines play a fundamental role in the immune response to pathogens. Interleukin-6 (IL-6) is an innate proinflammatory cytokine produced by innate immune cells such as macrophages during the severe phase of infection. Excessive production of IL-6, as seen in critical cases of COVID-19, can lead to cytokine storms, autoimmunity, and chronic inflammation. Interleukin-1-beta (IL-1β) contributes to the pathogenesis of gastrointestinal disease. Interferon-gamma (IFN-γ) is another cytokine that is a powerful activator of macrophages. Both IL-6 and IFN-γ have been shown to be upregulated in cases of viral infection and viral and bacterial gastroenteritis in children younger than two years of age. Notable increases in inflammatory markers, including IL-6 and IFN-γ, in cytokine storms play an integral role in the immunopathology of COVID-19; this may be influenced by changes in the gut microbiome or potential gut viral reservoirs.

Dr. Melody Zeng

Dr. Jeffrey Perlman

Melody Y. Zeng, PhD, Assistant Professor of Immunology in Pediatrics, in collaboration with Jeffrey M. Perlman, MB, ChB, a neonatologist and Professor of Pediatrics at Weill Cornell Medicine, have been building a biobank of human neonatal stool samples from infants admitted to the Neonatal Intensive Care Unit or the Well Baby Nursery at NewYork-Presbyterian/Weill Cornell Medical Center. In July 2020, Dr. Perlman and Dr. Zeng, along with Jenny C. Jin, MD, a neonatologist in the Division of Newborn Medicine at NewYork-Presbyterian Komansky Children’s Hospital, and colleagues in the Division of Gastroenterology and Hepatology, and the Departments of Pathology and Laboratory Medicine and Cell and Developmental Biology at Weill Cornell Medicine, sought to test the stool specimens of preterm and term infants with a goal to explore their gut microbiome. Unexpectedly, the Weill Cornell Medicine researchers discovered in their initial studies highly elevated inflammatory cytokines – IL-6 and IFN-γ – as early as day one of life mainly from premature newborns born to mothers who had resolved COVID-19 weeks prior to delivery.

“This study is a great demonstration of cross-disciplinary collaboration. The clinical implications of the findings of these researchers will spur further investigations in exploring the mechanisms of in utero transmission of SARS-CoV-2 in women with COVID-19 during pregnancy.” — Dr. Camilia Martin

This information led them to further examine whether newborns of mothers who had COVID-19 during earlier stages of pregnancy might have SARS-CoV-2 in their gastrointestinal tract. In a cohort study led by Dr. Perlman and Dr. Zeng, the researchers investigated stool from 14 newborns of gestational age (25 to 41 weeks) delivered between July 2020 and May 2021 who were born to mothers who had COVID-19 during their pregnancy. The study results, which were published in the August 19, 2022, issue of Pediatric Research, found:

• Despite negative SARS CoV-2 nasal PCRs from all newborns, viral RNAs and the Spike protein, a SARS-CoV-2 surface protein that mediates viral entry, were detected at high levels in the stool of 11 out of 14 newborns as early as the first day of life and increased over time in 6 newborns.
• Stool homogenates from all 14 newborns induced elevated levels of proinflammatory IL-6 and IFN-γ from immune cells.
• The majority of newborns were clinically well except for one death from gestational autoimmune liver disease and another who developed necrotizing enterocolitis.

The Weill Cornell Medicine researchers maintain that these novel findings point to the risk of in utero SARS-CoV-2 transmission to the fetal intestine during earlier gestation due to maternal infection and the risk of persistent viral reservoirs in the newborn’s intestine after birth. The authors write, “Currently, our understanding of the impact of antenatal COVID-19 on the newborn is limited. SARS CoV-2 nasal PCRs performed in the immediate post-natal period of this cohort of newborns born to mothers with COVID-19 during gestation at our institution have been negative at the time of data analysis. However, negative nasal PCRs do not exclude the possibility of SARS-CoV-2 present in other tissues of the newborn, which have not been rigorously studied.”

The investigators also emphasize that early development of the immune system is strongly influenced by the gut microbiome. However, the impact of persistent viral reservoirs on the development of the immune system in these infants may not be fully understood for years to come.

“This study is a great demonstration of cross-disciplinary collaboration,” says Camilia R. Martin, MD, MS, Chief of Newborn Medicine at NewYork-Presbyterian Komansky Children’s Hospital. “The clinical implications of the findings of these researchers will spur further investigations in exploring the mechanisms of in utero transmission of SARS-CoV-2 in women with COVID-19 during pregnancy.”