Breathing Nitric Oxide at High Dose in Severe-Critical COVID-19 During Pregnancy: A Case Series

Introduction: Pregnant patients with a severe form of COVID-19 are at increased risk of maternal and fetal complications. Nitric Oxide (NO) gas is a selective pulmonary vasodilator currently approved to treat newborns with pulmonary hypertension. Inhaled NO has been safely used in patients with severe pneumonia and for cases of pregnant patients with pulmonary hypertension. The antimicrobial effect of NO has been confirmed against bacteria and viruses. In vitro study demonstrated a dose-dependent effect of NO against SARS-CoV-1 and 2. We hypothesize that breathing NO at 160-200 ppm twice daily for 30 minutes in spontaneously breathing pregnant patients might provide a safe and effective treatment for COVID-19. Methods: We retrospectively reviewed the data of 6 pregnant patients hospitalized for COVID-19 treated with inhaled NO. Nitric Oxide was delivered at 160- 200 ppm for 30 minutes twice daily until resolution of respiratory symptoms or negative RT-PCR for SARS-CoV- 2. Demographic and clinical data were collected to assess cardiopulmonary function and safety during the treatment. For safety, we focused on the values of blood methemoglobin (MetHb) and inhaled Nitrogen Dioxide (NO2). Data regarding newborn delivery and health, and 28 days outcomes of mothers and babies were collected. Results: Six pregnant patients were admitted with a severe (2 patients) or critical (4 patients) form of COVID-19 and received inhaled NO therapy between April and June 2020. Two pregnant patients were in the second trimester, while 4 were in the third trimester. A total of 39 treatments were administered. No adverse events were reported relating to NO administration. MetHb peaked at 2.5% (1.95%-3%, safety limit =5%) and inhaled NO2 remained below the safety limit of 2ppm. The patients remained hemodynamically stable;cardiac ultrasound performed in three patients did not detect any rebound pulmonary hypertension after NO interruption. Oxygen saturation improved in hypoxemic patients after the initiation of NO (Figure-1). All patients experienced a reduction in respiratory rate (by a median 4.5breaths/min after NO initiation). Three patients delivered a total of 4 babies (negative for SARS-CoV-2) while the other 3 remained pregnant after hospitalization (gestational age 22-26-33weeks) with normal follow-ups. Five mothers out of 6 tested negative for COVID-19 28 days after hospitalization. Conclusion: Nitric oxide gas at 160-200 ppm was safely administered to pregnant patients with severe-critical COVID-19, improved oxygenation and reduced respiratory rate in all 6 patients. The clinical effectiveness shown suggests inhaled high dose NO as a therapeutic novel therapy for COVID-19 in pregnancy.