To date, the United States has had the highest number of coronavirus disease 2019 (COVID-19) cases.1 Although it appears that the death rate is not increased in pregnant patients, recent Centers for Disease Control and Prevention and UK Obstetric Surveillance System2 data suggest that there is an increased risk for hospitalization, intensive care unit admission, and mechanical ventilation support.3 The pathogenesis of acute respiratory distress syndrome (ARDS) consists of an excessive pulmonary inflammatory response leading to endothelial injury, in situ thrombosis, and exudative pulmonary edema.4,5 In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, a similar picture of an excessive inflammatory response has been described, with elevated markers of both inflammation and coagulation.6,7 Antiinflammatory agents such as corticosteroids are believed to downregulate this massive inflammatory response.
Recent evidence supports the use of an early, short course of glucocorticoids in patients with COVID-19 who require mechanical ventilation or oxygen support.8,9 Based on these results, the National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel recommends dexamethasone 6 mg daily (oral or intravenous) for up to 10 days (or hospital discharge, whichever comes first) in patients with COVID-19 on mechanical ventilation (AI: strong recommendation) or on supplemental oxygen (level of evidence BI: moderate recommendation). The Panel did not recommend using dexamethasone for patients with COVID-19 not requiring supplemental oxygen (level of evidence AI: strong recommendation).10
STEROID THERAPY AND ACUTE RESPIRATORY DISTRESS SYNDROME
The role of corticosteroids in the management of ARDS (not related to COVID-19) has been investigated for decades with contradictory findings, with most studies reporting improved oxygenation but limited effect on mortality.11,12 More recently, the use of daily low-dose methylprednisolone was found to significantly decrease days on mechanical ventilation and mortality among patients with ARDS.13,14 A recent individual patient data metanalysis concludes that administration of prolonged methylprednisolone was associated with fewer days on mechanical ventilation and improved survival.15 Recent guidelines suggest the use of methylprednisolone in patients with moderate ARDS.16 Methylprednisolone was chosen owing to better lung tissue penetration and longer lung residence time.17,18 The most recent clinical trial supports the use of intravenous dexamethasone in patients with moderate ARDS.19 In contrast, the use of glucocorticoids is not recommended in patients with ARDS secondary to community-acquired pneumonia or influenza.18 In summary, current guidelines recommend their use in patients with moderate ARDS, except if associated with influenza.20
STEROID THERAPY AND COVID-19
Until recently, corticosteroid administration in patients with COVID-19 was discouraged because of concerns about potentially delaying viral clearance. Recently, an open-label randomized control trial comparing different treatment modalities with usual care in patients hospitalized with COVID-19 has been completed—the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial.8,9 Eligible participants consisted of hospitalized patients with suspected or laboratory-confirmed SARS-Cov-2 infection, including pregnant or breastfeeding women. Patients with a history of diabetes were not excluded. Preliminary evidence from the RECOVERY trial suggests that patients with COVID-19 who received dexamethasone had a significant reduction in 28-day mortality and that this benefit was greatest among patients receiving invasive mechanical ventilation (rate ratio [RR] 0.64; 95% CI 0.51–0.81), followed by patients receiving supplemental oxygen (RR 0.82; 95% CI 0.72–0.94). Patients not requiring oxygen support did not have such benefit (RR 1.19; 95% CI 0.91–1.55).8,9 In light of these data, the NIH COVID-19 Treatment Guidelines Panel updated their recommendations to include dexamethasone administration in patients with COVID-19 who require oxygen supplementation or ventilatory support.10
OBSTETRIC CONSIDERATIONS IN PATIENTS WITH COVID-19 RECEIVING STEROIDS
The neonatal benefit of antenatal glucocorticoids in women at high risk for preterm delivery within 7 days is well established.21 Of all the corticosteroids, betamethasone and dexamethasone are the only two recommended to induce fetal lung maturity, because they have the highest rate of placental transfer with minimal mineralocorticoid effects.21 For neonatal benefit, the currently accepted regimen is either dexamethasone or betamethasone. Other corticosteroids (eg, methylprednisolone, prednisone, prednisolone, hydrocortisone) are not suitable alternatives, because they are extensively metabolized by placental 11-b-hydroxylase steroid dehydrogenase-2, leading to reduced placental transfer.22
Corticosteroids for fetal lung maturity are not without adverse fetal effects. Exposure to repetitive courses of antenatal glucocorticoids has been associated with adverse neurologic outcomes, small head circumferences, fetal growth restriction,21 and increased risk of neonatal hypoglycemia.23 Considering the potential fetal and neonatal side effects associated with repeated doses of glucocorticoids that efficiently cross the placenta, including the one currently recommended by the NIH for patients with COVID-19 requiring oxygen therapy or mechanical ventilation, an alternative approach for pregnant women is needed.
Pregnancy and breastfeeding were not exclusions in the RECOVERY trial, and the protocol recommended prednisolone 40 mg administered by mouth or intravenous hydrocortisone 80 mg twice daily to be used in these patients. However, the trial included only six pregnant women. In their recommendations, the NIH COVID-19 Treatment Guidelines Panel did not address pregnancy or breastfeeding. Recent guidelines from the Royal College of Obstetricians and Gynecologists suggest the use of intravenous hydrocortisone or oral prednisolone in women who are pregnant or breastfeeding.24 Instead, we suggest using an agent with limited placental transfer and documented efficacy in cases of acute lung injury. Methylprednisolone appears to be the ideal agent.12–16 A total of 32 mg/d of methylprednisolone orally or intravenously (once a day or in divided doses) would be equivalent to the dexamethasone dose used in the RECOVERY trial. If the woman is not a candidate for corticosteroids for fetal lung maturity (not at increased risk for preterm delivery within the next 7 days or is outside the gestational age window) or is breastfeeding, methylprednisolone can be used for the duration of the steroid course (10 days or up to discharge, whichever is sooner). We suggest that, when the RECOVERY trial criteria are met for the administration of glucocorticoids for COVID-19 management (patient requiring oxygen therapy, mechanical ventilation, or both) and the patient is at increased risk for preterm birth between 24 0/7 and 33 6/7 weeks of gestation, a standard regimen of dexamethasone for neonatal benefit should be administered (6 mg intramuscularly every 12 hours for four doses). We believe dexamethasone should be used in lieu of betamethasone owing to a lack of evidence of the latter in patients with acute lung injury. We do not recommend dexamethasone for late preterm gestation, because the ALPS (Antenatal Late Preterm Steroids)25 trial used betamethasone. After the dexamethasone course for lung maturity, we recommend completing the COVID-19 steroid course using methylprednisolone given that 8 additional days of dexamethasone may potentially harm the fetus. The use of short courses of steroids (less than 3 weeks) will not require “stress-dose steroids” at the time of surgery or delivery.26 The 10-day course does not require steroid taper. Owing to the risk of maternal hyperglycemia, we recommend close glucose monitoring with possible insulin administration, particularly in women who are likely to deliver, putting the neonate at risk for hypoglycemia, and in women with diabetes.
A summary of our suggestions is provided in Figure 1.
In conclusion, pregnant women with COVID-19 who require oxygen therapy or mechanical ventilation or both should be considered for steroid therapy. Because in the RECOVERY trial the use of steroids in patients not on oxygen therapy was consistent with a harmful effect, only pregnant patients with a legitimate indication for oxygen therapy (persistent SpO2 values below 94%) should be considered for steroid therapy. During pregnancy, we suggest that, when steroids are required for both fetal lung maturity and COVID-19, a four-dose course of dexamethasone over 2 days be used. After this course, dexamethasone should be replaced with methylprednisolone to complete a 10-day course. Limited data are available supporting the use of dexamethasone in the postpartum period and its effect on breastfeeding infants; hence we suggest using methylprednisolone instead. If the patient is not breastfeeding (eg, on mechanical ventilation), dexamethasone may be used.
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