Keywords
COVID-19 - corticosteroids - prematurity - betamethasone - dexamethasone
The field of medicine is facing an unprecedented challenge rapidly adapting current
medical practice in caring for novel coronavirus disease 2019 (COVID-19) patients.
The field of obstetrics is no different. Current treatment algorithms and protocols
must be evaluated and modified to account for what is being learned and already known
about COVID-19. One of our common practices in obstetrics is to give corticosteroids
for fetal lung maturity to those at risk of delivering prematurely. Unfortunately,
corticosteroid use in COVID-19 may be tied to worse patient outcomes, including death.
Therefore, it is imperative that our field evaluates our current treatment paradigm
and make appropriate modifications to best balance risks and benefits.
Outcomes are worse for patients with COVID-19 with corticosteroid use ([Tables 1] and [2]).[1]
[2] This was demonstrated in several studies; however, these studies were unable to
control for underlying medical comorbidities, ventilation, or intensive care unit
(ICU) status. It is therefore unclear at this time as to whether the steroids were
given because the baseline condition was worse or if giving the steroids caused worse
outcomes. Additionally, none of the patients were pregnant and the dosing for glucocorticoids
in an ICU setting are different than for obstetric indications. The typical obstetrical
dosing of betamethasone and dexamethasone in methylprednisolone equivalents is 60 mg.
This dosage is similar to that listed in [Table 2] (40–80 mg/day); however, the duration of treatment is different (4–11 days of treatment).[2] Therefore, the typical corticosteroids used in pregnant women are roughly one-fourth
to one-tenth of the amount used in these publications. While it may seem reasonable
to continue our practice of steroids for fetal lung maturity, given its shorter duration,
despite similar daily dosages, there is limited evidence at this time to confirm whether
this is the case. Therefore, a careful assessment of maternal risk versus neonatal
benefit should be undertaken.
Table 1
Disease severity and adverse composite outcome in COVID-19 patients treated with systemic
glucocorticoids[1]
|
Variable
|
All patients
n = 1,099
n (%)
|
Disease severity
|
Presence of composite primary end point[a]
|
|
Nonsevere
n (%)
|
Severe
n (%)
|
Yes
n (%)
|
No
n (%)
|
|
Systemic glucocorticoids
|
204 (18.6)
|
127 (13.7)
|
77 (44.5)
|
35 (52.2)
|
169 (16.4)
|
|
Individual aspects of the composite outcomes
|
|
ICU admission
|
33 (16.2%)
|
|
Invasive ventilation
|
17 (8.3%)
|
|
ECHMO[b]
|
5/77 (0.5%)
|
|
Death
|
5 (2.5%)
|
Abbreviations: COVID-19, novel coronavirus disease 2019; ECHMO, extracorporeal membrane
oxygenation; ICU, intensive care unit.
a Primary composite endpoint was admission to an ICU, use of mechanical ventilation,
or death.
b ECHMO was used in severe patients; % calculated from n = 77.
Table 2
Treatment with systemic glucocorticoids by severity[2]
|
Survivors
|
Deaths
|
|
Mild
|
Severe
|
|
Corticosteroid therapy
|
Yes
|
No
|
Yes
|
No
|
Yes
|
No
|
|
Number (%)
|
76 (34)
|
150 (66%)
|
77 (55)
|
62 (45)
|
43 (84)
|
8 (16)
|
|
Usage of corticosteroids
|
|
|
Dosage (mg/d)
|
40.0 (32.2–40.0)[a]
|
–
|
38.7 (29.7–4.2)[a]
|
–
|
65.0 (40.0–80.0)
|
–
|
|
Treatment period (d)
|
6.0 (4.0–9.0)
|
–
|
8.0 (5.5–11.0)
|
–
|
7.0 (4.0–9.0)
|
–
|
|
Hospitalization (d)
|
12.0 (9.0–16.0)[b]
|
10.0 (8.0–13.0)
|
14.0 (10.0–18.0)[b]
|
11.0 (9.0–13.0)
|
11.0 (7.0–13.0)
|
11.5 (8.0–16.0)
|
|
Days from corticosteroids to temperature restore
|
2.0 (1.0–4.0)[a]
|
–
|
2.0 (1.0–4.0)[a]
|
–
|
6.5 (1.0–11.0)
|
–
|
Note: All data expressed as n (%) or median (interquartile range).
a
p < 0.05 vs. death in patients with corticosteroids therapy group.
b
p < 0.05 vs. the same group without corticosteroid therapy.
In examining the data, there are numerous studies demonstrating neonatal benefit to
corticosteroid use.[3]
[4]
[5]
[6]
[7] Because of this, it has become the standard of care to give betamethasone (or dexamethasone)
to women at risk for delivering prematurely between 23 and 36 weeks of gestation.[3]
[8]
[9] In fact, corticosteroids are such an ingrained part of obstetric practice, we give
them out more than it is truly necessary. In evaluating obstetricians' use of betamethasone,
several studies have examined how poorly steroids are timed (<7 days from administration
to delivery) for imminent delivery. Two of these studies found that betamethasone
was only given within the effective window 45.4 to 80% of the time.[10]
[11] In this pandemic, given that obstetricians are faced with two patients, mom and
baby, it is necessary to balance the risks and benefits for each patient, which means
evaluating how and when it is necessary to give them. In examining corticosteroids
by gestational age, the absolute risk of neonatal complications and improved neonatal
benefit by gestational age should be considered. Travers et al demonstrated that the
lowest gestations receive the largest benefit from corticosteroids.[12] In this large prospective cohort of 117,941 infants, neonatal death before discharge
did not demonstrate a statistically significant reduction at or beyond 31 weeks. Additionally,
survival without morbidity also did not reach statistical significance after 28 weeks.
Indeed, the number of mothers needed to treat with corticosteroids to prevent one
neonatal death is six at 23 to 24 weeks but can increase to 798 women at 34 weeks.[12] Given this delicate balance of choosing between neonatal benefit and possible maternal
harm, it is prudent that obstetricians become more cautious with their betamethasone
administration during this time. Weighing the risks and benefits, our institution
has recommended that no women COVID-19 positive or person under investigation (PUI)
receive corticosteroids beyond 320/7 weeks. We acknowledge that it may be difficult to determine whether a maternal fever
in labor is chorioamnionitis or COVID-19. Given the experience of those in New York
with asymptomatic COVID-19 patients at the outset of labor, we recommend treating
with antibiotics as is standard for chorioamnionitis, but also treating the patient
as a PUI and obtaining a COVID-19 test. We also recommend ([Table 3]) a maternal fetal medicine consultation for decisions regarding corticosteroid administration
for pregnancies <32 weeks in women at risk of preterm delivery who are COVID-19 positive
or PUI as individualization of care is necessary to take into account the unique risks
of corticosteroids for the mother verses the benefit for the fetus.
Table 3
Recommendations for corticosteroid use during the COVID-19 pandemic
|
• We recommend that no women COVID19 positive or PUI receive corticosteroids beyond
320/7 wk.
|
|
• We recommend an MFM consultation for decisions regarding corticosteroid administration
for pregnancies <32 wk in women at risk of preterm delivery who are COVID-19 positive
or PUI as individualization of care is necessary to take into account the unique risks
of corticosteroids for the mother vs the benefit for the fetus.
|
|
• We recommend against tocolysis in women who are COVID-19 positive or PUI who are
not receiving corticosteroids.
|
Abbreviations: COVID-19, novel coronavirus disease 2019; MFM, maternal-fetal medicine;
PUI, person under investigation.
When corticosteroids are not given, tocolysis should also not be undertaken given
that the endpoint for tocolysis is to achieve steroid administration. When giving
corticosteroids and utilizing tocolysis, consideration for risks and benefits of each
tocolytic is prudent. Currently, the most efficacious tocolytic is indomethacin for
achieving steroid benefit.[13] While there was concern about nonsteroidal anti-inflammatory drugs (NSAIDs) in the
setting of COVID-19, the Food and Drug Administration (FDA) has recently stated that
there are no data to suggest NSAID use should be altered at this time.[14] Other tocolytics, such as nifedipine, would also be reasonable to use, as there
is some preliminary suggestions that nifedipine may be beneficial in COVID-19 patients
due to its efficacy in the treatment of high-altitude pulmonary edema, which has clinical
similarities to the lung manifestations of COVID-19.[15] However, if a women is already hypotensive or tachycardic, nifedipine should not
be used. Magnesium is a less effective tocolytic than indomethacin and nifedipine,[13] and given the recommendation for conservative fluid management is less than ideal
choice. Finally, betamimetics should not be used as they cause significant maternal
hypotension, tachycardia, and pulmonary edema which should be avoided in someone who
is has COVID-19.[16] The discussions regarding corticosteroid administration and tocolysis should involve
a multidisciplinary team including maternal fetal medicine, obstetrics, critical care
physician, infectious disease specialists, and neonatologists. These decisions are
of critical importance to serve both the interests of the mother and the fetus.
