Can High Dose Nitric Oxide Improve Respiratory Function in Pregnant Women with Severe COVID-19?

PURPOSE:

• There is limited data on how best to manage respiratory failure in pregnant women with COVID-19
• Safaee Fakhr et al. sought to determine if administering high concentrations of nitric oxide could improve the clinical course of pregnant women with respiratory failure  

METHODS:

• Case series (April to June 2020)
• 6 pregnant patients admitted with severe or critical COVID-19
• Patients received high-dose (160–200 ppm) nitric oxide by mask twice daily
  • Treatment sessions lasted 30 minutes to 1 hour
  • For those patients requiring mechanical ventilation, the high dose regimen was stopped and restarted after extubation | During intubation, the patients received continuous low dose nitric oxide through the ventilator

RESULTS:

• Total of 39 treatments
• Cardiopulmonary function improved with administration of nitric oxide
  • Systemic oxygenation: Improved following each administration session in hypoxemic patients
  • Tachypnea: Reduced among all patients each session
• 3 deliveries while in hospital
  • 4 neonates
  • 28-day follow-up: All mothers and infants in good condition at home
• 3 remaining patients:
  • Discharged home and still pregnant at time of publication  
• There were no adverse events documented

CONCLUSION:

• While acknowledging the small cohort size, the authors also conclude that

Nitric oxide at 160–200 ppm is easy to use, appears to be well tolerated, and might be of benefit in pregnant patients with COVID-19 with hypoxic respiratory failure

Learn More – Primary Sources:

High Concentrations of Nitric Oxide Inhalation Therapy in Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19)

Pregnant Women with COVID-19 at Time of Delivery: NYC Cohort Characteristics and Outcomes

BACKGROUND AND PURPOSE:

• Khoury et al. (Obstetrics & Gynecology, 2020) characterized clinical features and disease course among the initial cohort of pregnant women during the COVID-19 pandemic in New York City admitted for delivery

METHODS:

• Prospective cohort study (March 13 to April 12, 2020 with follow-up completed April 20, 2020)
• Setting
  • Five New York City medical centers
• Participants
  • Pregnant women admitted for delivery
  • Confirmed COVID-19  
• Study design
  • Data collected: Demographics | Presentation | Comorbidities | Maternal and Neonatal outcomes | COVID-19 clinical course
• COVID-19 cases were defined as
  • Asymptomatic
  • Mild: no additional oxygen supplementation required
  • Severe: Dyspnea | Respiratory rate ≥30 breaths | Oxygen saturation ≤93% | Pneumonia
  • Critical: Respiratory failure | Septic shock | Multiple organ dysfunction or failure

RESULTS:

• 241 women included
  • Asymptomatic on admission: 61.4% | 69% remained asymptomatic
• Clinical status at time of hospitalization for delivery
  • Mild: 26.5%
  • Severe: 26.1%
  • Critical: 5%
• Singleton preterm birth rate: 14.6%
• Critical outcomes
  • ICU admission: 7.1% of women (17 women)
  • Intubation during delivery: 3.7% (9 women)
  • Maternal deaths: 0 women
• BMI ≥30 associated with COVID-19 severity (P=0.001)
• Cesarean delivery rates
  • Severe COVID-19: 52.4%
  • Critical COVID-19: 91.7%
  • Linear trend across COVID-19 severity groups for cesarean risk (P<.001)
• 245 liveborn neonates
  • Resuscitation at delivery beyond normal requirements: 30%
  • NICU admission: 25.7% | Hospitalization <2 days in 62.4%
• Newborn outcomes
  • Prematurity and low birth weight: 8.7% (most common complications)
  • RDS: 5.8%
  • No complications: 79.3%
• 97.5% of newborns tested negative for SARS-CoV-2 at 24 to 96 hours  
• IUFD: 2 cases
  • Case 1: 38 weeks without fetal movement | Symptoms of COVID-19 pneumonia including chest imaging | No supplemental oxygen required | Patient declined autopsy and further work up for COVID-19 | No abnormalities were seen on placental pathology
  • Case 2: 29 weeks of gestation | FGR <1%tile | HELLP syndrome | Severe COVID-19 pneumonia

CONCLUSION:

• Majority of pregnant women admitted for delivery were asymptomatic for COVID-19  
  • Approximately 1/3 remained asymptomatic
• Obesity was associated with COVID-19 severity
• For women with COVID-19 (particularly severe and critical) there is an increased risk for cesarean and preterm birth

Learn More – Primary Sources:

Characteristics and Outcomes of 241 Births to Women With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection at Five New York City Medical Centers

Mode of Delivery in the Setting of COVID-19

BACKGROUND AND PURPOSE:

• Ferrazzi et al. (BJOG, 2020) report on the mode of delivery and immediate neonatal outcomes in women infected with COVID-19 in Lombardy, Italy

METHODS:

• Retrospective study
• Setting
  • 12 hospitals in northern Italy
• Participants
  • Confirmed COVID-19 prior to or within 36 hours after delivery
  • Delivered from March 1 to March 20, 2020
  • All consecutive cases admitted to maternity ward for delivery
• Study design
  • Data derived from clinical records
    • General maternal characteristics | Medical or obstetric co-morbidity | Course of pregnancy | Clinical signs and symptoms | Treatment of COVID 19 infection | Mode of delivery | Neonatal data and breastfeeding
• Primary outcome
  • Mode of delivery
  • Neonatal outcome

RESULTS:

• Total 42 women with COVID-19
  • Mean maternal age: 32.9 years (range 21 to 44 years)
• COVID-19 diagnosis
  • Known before admission: 19 cases
  • On hospital admission: 10 cases
  • Delivery room: 27 cases
  • Within 36 hours of delivery: 5 cases (patients still admitted)
• Maternal clinical features
  • Most common symptoms: Fever, cough and mild dyspnoea (80%)
  • Pneumonia: 45.2%
    • Oxygen support: 36.8%
    • Critical care unit: 21.1%
• Mode of delivery
  • Vaginal: 57.1%
  • Elective cesarean: 42.9% (18 women)
    • COVID-19 indication (e.g. worsening dyspnea): 10 cases
    • Unrelated to COVID-19: 8 cases
• Neonatal outcomes
  • Spontaneous term: 30 cases (71.4%)
  • Spontaneous preterm birth: 5 cases
  • Elective cesarean: 6 cases
  • Two women breastfed without a mask because COVID-19 infection was diagnosed in the postpartum period
    • Their newborns tested positive for COVID-19 (days 1 and 3)
  • In one case, a newborn had a positive test after a vaginal operative delivery | Mother did not breastfeed
    • Symptoms day 3 | Recovered after 1 day of mechanical ventilation

CONCLUSION:

• Authors acknowledge that vertical transmission risk with vaginal delivery cannot be excluded
• However, results from this study would suggest that vaginal delivery is associated with a low risk of COVID-19 transmission
• In addition, the author conclude that

Vaginal delivery is appropriate in mild cases and caesarean section should be reserved for women with severe respiratory problems, where delivering the baby will allow improved ventilation

Learn More – Primary Sources:

Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis

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COVID-19: The SMFM/SOAP Guidelines for Labor and Delivery

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date

SUMMARY:

SMFM and Society for Obstetric and Anesthesia and Perinatology (SOAP) have released COVID-19 guidelines for obstetric professionals, including anesthesiologists. The following are highlights. The complete document link can be found in ‘Learn More – Primary Sources’. The guideline is not proscriptive with an understanding that they “may not apply in your clinical setting”

• Initial Assessment and Intake
• Patient Rooms
• PPE for Health Care Workers
• Preterm Medications
• Labor and Delivery
• Postpartum Care

Initial Assessment and Intake

• Initial assessment performed upon patient arrival
  • Personnel should maintain distance (>6 feet if possible)
  • Limit duration of encounter
  • Limit number of support persons
    • Develop policies locally | There may be state restrictions as well
    • Screen visitors for symptoms of respiratory illness before entering the healthcare facility
    • Provide exceptions for bereavement
• Log staff entering and leaving cohorted rooms
• Consider staggering staff schedule to limit exposure
  • Example: Rotate telehealth team with in-person team every 2 weeks
• Testing of women admitted to labor and delivery
  • Prioritize pregnant women with exposure to or symptoms of COVID-19
  • Universal testing “may be considered due to the potential for asymptomatic patients to present, particularly in areas of high community prevalence”

Patient Rooms

• Confirmed COVID-19 and PUI: “Ideally” should be placed in isolation room
• Airborne infection isolation rooms
  • In general
    • Droplet and contact precautions
  • If aerosol-generating procedure is anticipated
    • Single-patient negative-pressure rooms | Minimum of 6 air changes per hour
• “Crash Rooms”
  • Negative-pressure ORs should not have open surgical equipment

PPE for Health Care Workers

Women with Confirmed Covid-19 Or PUI

• Should wear a surgical mask

Health Care Workers Caring for Women Who are Positive for SARS-CoV2 or PUIs

• Use droplet and contact precautions with eye protection: Gown | Gloves | Surgical mask | Face shield or goggles
• High-risk obstetrical scenarios
  • Use respirators (e.g., N95 masks) in any room where there is performance or anticipation of aerosol generating procedure (e.g., intubation)
  • Obstetrical examples include
    • Cesarean deliveries
    • Twin vaginal deliveries
    • Women brought to OR for management of PPH
    • Intubation (actual or anticipated)
• Second stage of labor and deep respiratory effort
  • SMFM/SOAP states that healthcare workers

…should use N95 (or facemasks if N95 is not available), eye protection, gloves, and gowns during the second stage of labor, in addition to other personal protective equipment that may be typically indicated for labor and delivery

Surgical drapes could be used as an additional physical respiratory droplet barrier during the second stage and at delivery

KEY POINTS:

Preterm Medications

• Antenatal corticosteroids
  • Use with caution in ICU/acute care setting
  • Balance risks and benefits and adjust protocols accordingly (e.g., >34 weeks and repeat courses)
• Magnesium for fetal neuroprotection
  • Concern regarding maternal respiratory depression | Adjust accordingly based on clinical scenario, including gestational age and increasing maternal oxygen demands
  • Assess renal function | If mild respiratory distress, single 4 g bolus “may serve as an alternative”
• NSAIDs restriction
  • Document considers restricting NSAIDs to be controversial because data lacking to support this practice
• Prenatal ultrasonography
  • Use in settings where sonography would likely impact care

Labor and Delivery

• Follow standard guidelines for the following practices (based on availability, which may change over time)
  • Amniotomy
  • Internal monitoring (may change with more data but currently no evidence that there is an increased risk for transmission)
  • Operative vaginal deliveries
  • Magnesium for preeclampsia/seizure prophylaxis
    • In absence of severe features of preeclampsia, “avoidance of magnesium seems prudent”
    • Be cognizant of potential renal dysfunction and adjusts dosing accordingly
  • Epidural
    • Consider early epidural to mitigate risks of general anesthesia including increased risk of aerosol-generating procedures such as intubation
• Nitrous Oxide
  • Currently, limited data regarding use of nitrous oxide in patients with COVID-19
  • Patients with confirmed COVID-19 | Suspected COVID-19 | Unconfirmed COVID-19 negative status
    • “…may consider suspending use of nitrous oxide”
  • Patients with COVID-19 confirmed negative result
    • Nitrous oxide remains an option
• Oxygen for fetal indications
  • While considered controversial, “suspend” use of high flow nasal cannula or face mask | Consider oxygen in the setting of maternal hypoxia
• Worsening maternal respiratory status
  • Uterine decompression to improve maternal respiratory status
    • Data are unclear
  • Risk for fetal hypoxemia
    • Must be balanced against risks of preterm birth and maternal compromise

Postpartum Care

• CDC recommendation regarding mother/infant separation has been updated since SMFM/SOAP Statement posted
  • CDC guideline now recommends that separation be based on ‘shared decision making’ | For those mothers who wish to room in, use mask/gloves and maintaining bassinet distance
  • Use expedited testing to determine COVID-19 status
• Breastfeeding
  • Breastfeeding (with appropriate precautions) or pumping for women for confirmed COVID-19 or PUI is recommended
  • The document notes there may be risk to infant associated with direct breast feeding
• NSAIDs
  • Increased risk with opioids vs NSAIDs
  • The document states “For women who are asymptomatic, mildly symptomatic, or moderately symptomatic who require analgesic medication beyond acetaminophen, nonsteroid anti-inflammatory drugs (NSAIDs) should be used if there are no other contraindications because systemic opioids likely pose more clinical risks”
• Postpone postpartum tubal ligations if alternatives available
• Circumcisions
  • Infants are considered PUIs
  • Decision “should be made in communication with the pediatric team, and appropriate PPE must be worn”

Learn More – Primary Sources

Society for Maternal-Fetal Medicine and Society for Obstetric and Anesthesia and Perinatology – Labor and Delivery COVID-19 Considerations

Vertical Transmission in Pregnancies with Confirmed COVID-19

PURPOSE:

• Chen at al. (Lancet, 2020)  sought to assess vertical transmission in the initial cohort of pregnant patients in Wuhan (capital of Hubei province) with confirmed COVID-19 infection

METHODS:

• Participants 
  • 9 pregnant patients who were admitted with  COVID-19 pneumonia  
• The following  were tested for virus to determine  intrauterine vertical  transmission 
  • Amniotic fluid | Cord blood | Neonatal throat swab | Breastmilk samples after the first lactation 

RESULTS:

• Gestational age range: 36w0d to 39w4d  
• All 9  patients had a caesarean  delivery  in their third trimester for the following indications   
  • Severely elevated ALT or AST | COVID-19 pneumonia 
  • Mature | COVID-19 pneumonia 
  • History of C-section (×2) | COVID-19 pneumonia 
  • Pre-eclampsia | COVID-19 pneumonia 
  • Fetal distress | COVID-19 pneumonia 
  • History of stillbirth (×2) | COVID-19 pneumonia 
  • PROM | COVID-19 pneumonia 
  • Fetal distress | COVID-19 pneumonia 
  • PROM | COVID-19 pneumonia 

Note:  The authors state that “Uncertainty about the risk of intrapartum mother-to-child transmission by vaginal delivery ” was  the reason  COVID-19 pneumonia was considered an indication for cesarean delivery  

• Presenting maternal symptoms 
  • Fever:  7  patients 
  • Lymphopenia  (<1.0 × 10⁹ cells per L): 5 patients   
  • Cough: 4 patients 
  • Myalgia: 3 patients 
  • Sore throat: 2 patients  
  • Malaise: 2 patients 

Note:  None of the patients progressed to severe pneumonia   

• Fetal  status 
  • “Fetal distress”: 2 cases  
  • 9 live births, all with normal Apgar scores (8  to  9  at 1 min  and 9 to 10  at 5 min)  
  • No neonatal asphyxia  
  • All samples tested negative for the virus  

CONCLUSION:

• Presentation and clinical findings for  COVID-19 pneumonia  showed no difference between pregnant women and the general population 
• No evidence (in this small study) of intrauterine infection attributable to  vertical transmission  

Learn More – Primary Sources

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

COVID-19 Case Series: Pregnancy and Infant Outcomes

PURPOSE:

• Chen et al. (Frontiers in Pediatrics) provide an update on 4 infants, born to women with COVID-19

METHODS:

• Case series from city of Wuhan (capital of Hubei province)
• Participants
  • Infants of mothers had tested positive for COVID-19

RESULTS:

• 4 mothers tested positive | Symptomatic | Infected with COVID-19 during the 3rd trimester

Maternal Findings

• Symptoms were typical of COVID-19
  • Fever: 3/4 patients
  • Cough: 2/4 patients
  • Myalgia or fatigue: 2/4 patients
  • Headache: 2/4 patients
  • Dyspnea: 1 patient
• Labs
  • Lymphocytes below the normal range (lymphocyte count <1.1 × 109/L): 4/4 patients
  • Lymphopenia (lymphocyte count <1.0 × 109/L): 2/4 patients
  • Anemia: 1/4 patients
• Imaging
  • Bilateral abnormalities on chest CT images: 4/4 patients
• Fetal assessment
  • Reduced fetal movement (1 patient)

Delivery

• Mode of delivery
  • Cesarean delivery: 3/4 patients
  • Vaginal delivery: 1/4 patients (patient presented in labor)
  • 4 full-term infants (3 male and 1 female) | Immediately isolated from mothers

Maternal Outcome

• Maternal recovery: 3 of 4 patients were discharged between days 3 to 5 following delivery
• Respiratory support: 1 patient required respiratory support but did survive
• All mothers were healthy on discharge and at follow-up visit

Infant Outcome

• Normal Apgar scores | None had serious clinical symptoms (e.g., fever)
• 3 infants tested negative for COVID-19 | 1 infant not tested because there was no consent
• Two infants with rashes of different shape and distribution
  • 1 infant: Maculopapules scattered all over the body and facial skin ulceration on the forehead (size about 0.3 × 0.5 cm2) | Resolved without treatment
  • 1 infant: Day 2 appearance of small miliary red papules with resolution on day 10 without treatment (Table 2) | Transient tachypnea of the newborn (TTN) requiring nasal- Continuous Positive Airway Pressure (nCPAP) | Discharged day 7
• All infants were healthy at time of post-discharge follow-up visit

CONCLUSION:

• Authors recognize limited dataset
• Unclear if there is any relationship between rash and COVID-19
• No vertical transmission noted and children all discharged from hospital in good health

Learn More – Primary Sources:

Infants Born to Mothers With a New Coronavirus (COVID-19)