In a research letter, Dong et al. reported a possible case of vertical transmission in a 29 year old women with radiographic evidence of pneumonia and a positive NP swab for COVID-19. The mother received antibiotics, oxygen, corticosteroids, and antiviral drugs prior to delivery. The mother wore an N95 mask and did not hold the infant following the delivery. The infant was asymptomatic at birth, had Apgar scores of 9 and 10 and was immediately quarantined. Of note, the infant demonstrated elevated SARS-CoV-2 IgM and IgG levels at two hours of life, but serial NP swabs for SARS-CoV-2 were negative. At time of discharge, immunoglobin levels were still elevated. The presence of IgG levels at two hours of life could be explained by elevated maternal levels, however IgM antibodies do not freely cross the placenta. It is difficult to determine whether the elevated IgM was due to fetal infection, delivery, or an unrelated process. Without testing amniotic fluid or placenta specimens, no definitive conclusions can be drawn. Increased availability of IgG and IgM testing has improved the quality of surveillance and detection of SARS-CoV-2. Zeng et al. reported immunoglobulin levels from six infants born to COVID-19 positive mothers between February 16th and March 6th. All mothers underwent caesarian section and the infants were immediately isolated following delivery. Neonatal viral throat and serum swabs were all negative for SARS-CoV-2, but IgG and IgM were elevated in five and two respectively, out of the six infants. While the sample size is small and no evaluation of the placenta or amniotic fluid occurred, the report raises concern of placental involvement and fetal exposure to the virus.
In the series published by Zhu et al., the clinical status of 10 neonates were reported. None of the infants born to COVID-19 positive mothers demonstrated a positive throat swab PCR. One infant, born at 34 weeks' gestation, developed hemorrhagic shock, secondary to profound gastrointestinal bleeding and ultimately died secondary to multi end organ failure. A second infant, born at 34 week's gestation, developed fever and gastrointestinal (GI) bleeding, but responded to supportive therapies. With negative testing, and without evaluation of placental tissue or amniotic fluid, it is difficult to draw any conclusions regarding the biologic nature of the GI symptoms or any putative relationship to COVID-19 exposure.
Clinical symptoms in neonates are non-specific and appear similar to the classic presentation of respiratory distress syndrome. Additionally, radiologic imaging may demonstrate pneumonia, which is difficult to distinguish from premature lung disease. It is important to have a high degree of suspicion when managing neonates born to positive mothers, while recognizing more information is needed to truly develop a consistent neonatal phenotype.
There is currently no specific treatment for COVID-19 infection, nor access to an available vaccine. The American Academy of Pediatrics (AAP) and the Centers for Disease Control (CDC) have developed guidelines to aid in the care of infants born to COVID-19 positive mothers (Table 4). Recent guidelines prioritize universal maternal testing and recommend a shared decision-making process related to whether the infant should stay with the mother or be isolated. Treatment of patients with active SARS-CoV-2 illness has focused on the provision of supportive care according to illness severity. This may range from oxygen therapy and/or prone positioning to intubation, ICU support in patients with shock or adult respiratory distress syndrome (ARDS). Table 3 provides an overview of current strategies that have been implemented or are under investigation to either mitigate the risk of transmission or modulate the disease course.
Prevention has been used as a primary means to control the growth of COVID-19. As virus spread primarily relates to"person to person" interaction and has demonstrated familial clustering, limitation strategies that minimize human interaction, or social distancing, may help diminish transmission. It has been difficult to accurately determine the basic reproduction number (RO) of SARS-CoV-2, which is used to determine how quickly the virus can spread throughout a population, across various countries and cities with differing population densities. Currently studies indicate the virus has a RO of 2.2, meaning each infected individuals has the potential to spread the virus to 2.2 other individuals. Until the RO drops to less than 1 the outbreak is likely to continue with aggressive spread. Mitigation measures such as social distancing, school closures, quarantine of exposed individuals have been determined through simulation and observational studies to have the potential to reduce transmission of previous pandemics, although there is no published evidence of the efficacy of this strategy in the setting of the current pandemic. Vaccination research has started, with several academic centers and pharmaceutical companies having taken on the challenge, however the timeline needed to ensure patient safety remains considerable.
Modulation of the spread within the health care system is of vital importance. Wu et al. reported that 3.8% of their positive COVID-19 population in China were infected health care personnel. The impact to health care workers in Italy is even greater; in some situations, hospitals have closed because of the magnitude of transmission among health care workers. Protection of healthcare workers has been made especially challenging due to an insufficient global supply of personal protective equipment and disruptions within the supply chain. To help combat this shortage, given that pregnant mothers may be either be asymptomatic carriers or undiagnosed due to limited testing, the vague or mild nature of symptoms, andthe potential for comorbid disease states, it is incumbent on healthcare systems to ensure that neonatal teams have efficient processes to protect vulnerable front-line workers and mitigate both COVID-19 spread and access to healthcare delivery for other neonatal ICU patients.
An array of medications are in current use to treat patients with COVID-19. Anti-viral agents such as oseltamivir, ganciclovir, lopinavir/ritonavir and remdesivir have been used for critically ill patients. Remdesivir is a nucleotide analogue that interferes with viral replication. A clinical trial is currently in progress at multiple centers in Wuhan province. Additionally, the anti-malarial agent chloroquine phosphate has been used to treat pneumonia symptoms, as it possesses anti-viral and anti-inflammatory properties and has demonstrated positive clinical effect in the treatment of COVID-19. Clinical trials of the efficacy of chloroquine are also being conducted in China. Finally, lopinavir has demonstrated inhibition of protease activity in coronavirus species and is currently under investigation. There are no reports of use of these agents in pregnant mothers or their infants.
Use of convalescent plasma, as a means of generating passive immunity, has been the subject of recent investigation. This therapeutic strategy was previously investigated during the SARS and MERS outbreaks; specifically, a metanalysis demonstrated a significant reduction in mortality compared to placebo. In addition, clinical experience from five COVID-19 positive individuals in China with ARDS demonstrated clinical improvement following the receipt of convalescent plasma. While this was not a randomized controlled study, the report is compelling and suggests biological and therapeutic plausibility. While many of the current treatments under investigation hold promise, due diligence and scientific rigor are essential to minimize the potential of unintended or unanticipated patient harm. There is currently no scientific evidence to justify any approach to treatment in pregnant mothers or in neonates. Centers should develop institutional guidelines based on best available evidence and resources available to them.