The onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which causes coronavirus disease 2019 (COVID-19), has led to severe disruption to social and economic life, as well as over 2.7 deaths reported worldwide. Researchers are still examining the impact of the virus on different population groups, including pregnant women.
A new paper published in the Journal of Multidisciplinary Healthcare describes the outcome of corticosteroid use in pregnancy.
Varying impact of COVID-19 with stage of pregnancy
COVID-19 may have different effects at different stages of pregnancy. This is because pregnancy is associated with wide-ranging hemodynamic and immunological changes, among others. The latter may predispose the pregnant woman to greater severity of disease following viral infection.
Pregnancy has not been associated with a higher risk of mortality, though disease severity may be higher in the latter half of pregnancy. The risk of hospitalization and admission to intensive care is also increased in pregnancy complicated by COVID-19.
COVID-19 beyond 20 weeks of pregnancy is associated with a five-fold risk of ICU admission, but very few women have required oxygen supplementation and mechanical ventilation.
The risk of preterm delivery is three-fold increased in this infection, but are mostly due to medical decisions intended to improve the mother’s health. Cesarean sections are also increased in this condition.
Few cases of vertical transmission from the pregnant mother to the baby have been documented, while increased rates of miscarriages and perinatal death have not been reported so far.
Nonetheless, COVID-19 in most pregnancies is an asymptomatic illness, and many others have mild symptoms. The risk for this condition is thus similar to that of the general population.
Corticosteroids in preterm delivery
The increased rate of iatrogenic preterm delivery has led to the exposure of these pregnant women to corticosteroids, which are routinely used to accelerate fetal lung maturation and reduce the risk of neonatal respiratory distress due to surfactant deficiency. The evidence on the use of these drugs in pregnancy is summed up in the current paper.
Steroids are also used to treat COVID-19 patients, in order to avert the hyperinflammatory syndrome called acute respiratory distress syndrome (ARDS). This is characterized by tachypnea, respiratory hypoxemia and diffuse opacities in the lung on chest X-rays and occurs in many other viral infections as well.
In COVID-19 patients, this condition is characterized by the triggering of an abnormally hyperactive cascade of inflammatory mediators and cytokines – the so-called cytokine storm – with secondary haemophagocytic lymphohistiocytosis.
Corticosteroids in the management of severe COVID-19
The powerful immunosuppressive action of corticosteroids has led to their deployment in the management of the ARDS associated with severe COVID-19, to avert this vicious cycle of cytokine-mediated inflammatory damage to the lungs and other organs, which in turn results in the release of still more cytokines.
Corticosteroids have thus been used at low doses in early COVID-19 with ARDS, to bring down the overall mortality. In pregnancy-associated COVID-19, the corticosteroid used must be one that has the greatest potential for benefit coupled with the least potential harm to the fetus.
The RECOVERY trial showed that the potent corticosteroid dexamethasone, at a low dose of 6 mg, reduced the death rate associated with COVID-19 among those patients who required mechanical ventilation by a third. Moreover, it reduced mortality among those on supplemental oxygen by a fifth.
In mild COVID-19, no benefit was observed.
Risks of corticosteroids
Dexamethasone cannot be used for prolonged periods in pregnancy as it rapidly crosses the placenta and is teratogenic. As a result, even though it is useful in reducing the duration of mechanical ventilation in patients with ARDS, provided its use is started early in moderate to severe COVID-19, its use in pregnant COVID-19 women is controversial.
The risks of placenta-crossing corticosteroids in pregnancy may include higher rates of endometritis and chorioamnionitis if the membranes are ruptured prior to the onset of labor; high levels of amino acids, and high blood sugar levels.
If repeatedly used, these drugs may limit fetal breathing and body movements, cause intrauterine growth restriction, often resulting in low birth weight. Other consequences may include fetal hypoglycemia, and a higher risk of early-onset neonatal sepsis.
Prednisolone, hydrocortisone and methylprednisolone
The Royal College of Obstetricians and Gynecology (RCOG) therefore recommends oral prednisolone or intravenous hydrocortisone for pregnant women with moderate to severe COVID-19, while another study prefers methylprednisolone instead.
The Society of Critical Care Medicine and European Society of Intensive Care Medicine had earlier issued its guideline on the use of intravenous methylprednisolone in ARDS, because of the improvement in this condition, spanning multiple outcomes, including healthcare use and death rate.
The latter drug has been proved to be effective in acute lung injury. Moreover, it does not cross the placenta into the fetus to any significant extent. However, it is more expensive than the others, an important consideration in low-resource settings.
The placenta also metabolizes many corticosteroids, including both prednisolone and dexamethasone, but not budesonide or fluticasone. Prednisolone is more extensively metabolized than dexamethasone, however.
“It implies that the placenta helps protect the fetus from the corticosteroid side effects through this extensive metabolism to inactive products.” This increases the acceptability of prednisolone.
The World Health Organization (WHO) recommends either oral dexamethasone or intravenous hydrocortisone in patients with severe COVID-19. While also recommending the use of corticosteroids in pregnant women who are likely to have preterm deliveries, it does not specifically name the drug of choice in pregnancy complicated by moderate to severe COVID-19.
The ideal corticosteroid?
Methylprednisolone is concentrated to higher levels in the lungs compared to prednisolone, being more extensively distributed by volume, remaining in the lung tissues for a longer time and being lipid-soluble.
It has a low albumin binding affinity, albumin being its plasma transporter molecule, but this is compensated for by its high binding capacity. Prednisolone is carried in plasma in bound form to transcortin, on the other hand, having high binding affinity but low capacity.
The result is increased avidity of methylprednisolone for the lung tissue. However, both are probably present in the fetal circulation at equivalent levels.
The ideal corticosteroid for the treatment of pregnancy with moderate-to-severe COVID-19 would thus be one that distributes well in the lung parenchyma but does not cross the placental barrier significantly. If the steroid is being given to hasten fetal lung maturity, because of impending preterm delivery, a short-term course of dexamethasone or betamethasone should be given, followed by methylprednisolone.
The few studies that are currently available on corticosteroid use in pregnancy complicated by COVID-19 are insufficient to provide authoritative guidelines. Further data is necessary to arrive at a firm estimate of the risk associated with this infection at various points of pregnancy.
The lack of data from Africa, despite its excessively high maternal mortality and morbidity, is also disturbing and mandates more studies on the incidence and patterns of COVID-19 in this population.
Finally, the role of corticosteroids in this condition should be explored further with respect to severe COVID-19 in pregnant women. This is especially important in low- and middle-income countries, which should take efforts to provide these drugs to patients with moderate to severe disease.