COVID-19 Therapeutics in Pregnancy and Lactation: Corticosteroids

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Corticosteroids consist of steroid hormones, either produced endogenously (in the body) in the adrenal cortex (the outer layer of the adrenal glands), or made synthetically and causing effects in the body similar to those of endogenous corticosteroids. Of the two main categories of corticosteroids —glucocorticoids and mineralocorticoids— glucocorticoids are the category used in the treatment of COVID-19.

Glucocorticoids produce the following effects:

Immunosuppression and anti-inflammation: At normal concentrations in the body, this helps the immune system function normally, but excessive concentrations resulting from various medical conditions lead to a weakening of immunity. For the same reason, administration of pharmacologic doses of glucocorticoids are used commonly as treatments against conditions featuring too much inflammation. This includes the inflammatory phase of COVID-19.

Metabolism of glucose (blood sugar) and fat: Glucocorticoids stimulate the mobilization of energy storage molecules and the production of glucose molecules. This results in the production of glucose molecules from other molecules, the breakdown of fat in adipose (fat) cells, the breakdown of protein in muscles, the breakdown of muscle cell glycogen to release glucose, and the production of glycogen from glucose in the liver.

Fetal lung maturation: During pregnancy, glucocorticoids stimulate the lungs of the fetus to mature and produce needed quantities and types of surfactant, a soapy substance that enables the lungs to stretch when the newborn inhales. Surfactant production is one of the main reasons why fetuses are not viable before generally around 24 weeks gestation, and why glucocorticoids are given to pregnant women to accelerate fetal lung maturation in cases when preterm is anticipated, or needed.

A handful of synthetic glucocorticoids constitute a mainline treatment in COVID-19 that has progressed to the point that the person requires supplemental oxygen.

Pregnancy and lactation status do not have a direct influence on whether or not a women suffering from COVID-19 will receive corticosteroid treatment, because the corticosteroids used —mostly dexamethasone and methylprednisolone— are considered to be safe in pregnant and lactating women. Moreover, as noted above, glucocorticoid therapy is given particularly to pregnant women who have a high risk of delivering preterm. In such cases, the glucocorticoid given is either betamethasone or dexamethasone, because both transfer well through the placenta to the fetus and have very minimal mineralocorticoid effects.

At the same time, pregnant and recently-pregnant women are more vulnerable than their non-pregnant counterparts to developing severe COVID-19 disease, if they become infected with SARS-CoV2 (the virus that causes COVID-19). Additionally, maternal COVID-19 puts the fetus at greatly elevated risk of preterm delivery, which entails various health and mental consequences. However, data from the RECOVERY trial have demonstrated that the administration of dexamethasone substantially improves the outcomes of those COVID-19 patients receiving oxygen and especially those on invasive mechanical ventilation. These are the patients in whom COVID-19 has progressed to a point that an inflammatory process, triggered by the virus, either has led to acute respiratory distress syndrome (ARDS) or is headed toward ARDS. In contrast, dexamethasone treatment is not beneficial in those with a SARS-CoV2 infection that has not (at least yet) warranted supplemental oxygen, meaning that their oxygen saturation (O2 sat) has not dropped below 92 percent when they are breathing room air.

In fact, in such cases (mild COVID-19), the use of corticosteroids actually has a detrimental effect. It makes outcomes worse, which is thought to be the result of immunosuppression. Every drug entails a tradeoff between beneficial and detrimental effects. Early in the course of the disease, if a person’s immunity is strong, there is still ample opportunity to fight off the virus and keep from progressing to a stage when inflammation in the lower respiratory system and other systems puts life at risk. Administration of corticosteroids at this stage blunts the immune response with no benefit on the flip side. Once the O2 saturation has fallen into the low 90s, however, it means that the inflammatory process in the lungs has ramped up to a point that the movement of oxygen from the air to the blood is difficult, which is also a reflection of inflammation causing various non-pulmonary problems. Consequently, when dexamethasone is given at this point, when inflammation is threatening life, the benefits of the treatment outweigh the detrimental effects.

Specifically, the RECOVERY trial found low-dose dexamethasone (6 mg) to reduced mortality by up to 33 percent in COVID-19 patients who are invasive mechanical ventilation and by 20 percent in patients receiving supplemental oxygen, but without mechanical ventilation. In the same trial, pregnant women actually received oral prednisolone, or intravenous hydrocortisone, because of pre-COVID-19 experience with these drugs for lung conditions in cases when women are not considered to be at risk for premature delivery. This has led some researchers to suggest that pregnant women with COVID-19 on supplemental oxygen or mechanical ventilation should receive methylprednisolone (which reaches the lungs better than prednisolone) when glucocorticoids are not indicated for maturing the fetal lungs, and dexamethasone initially, followed by methylprednisolone, in cases glucocorticoids are indicated for helping the fetal lungs. However, the National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel currently call for dexamethasone 6 mg (oral or intravenous) per day for up to 10 days (or up to hospital discharge, whichever is sooner) in COVID-19 patients on mechanical ventilation or on supplemental oxygen without ventilation. Given a high amount of evidence that dexamethasone is effective and safe particularly in cases of lung injury, as occurs in COVID-19, it has been proposed that dexamethasone is particularly appropriate for pregnant women who suffer from COVID-19 severe enough to warrant corticosteroid treatment, and, because of their COVID-19, are also at high risk of delivering early. In a very high proportion of cases of moderate to severe COVID-19 in pregnant women, glucocorticoid treatment for fetal lung maturity is going to be indicated anyway.

Although all of the glucocorticoids mentioned above can transfer from the mother’s blood into breastmilk, in practice they transfer in only very tiny amounts. Consequently, these medications are considered safe in lactating women.

References

Committee on Obstetric Practice. Committee Opinion No. 713: Antenatal Corticosteroid Therapy for Fetal Maturation. Obstet Gynecol. 2017 Aug;130(2):e102-e109. doi: 10.1097/AOG.0000000000002237. PMID: 28742678.

Mitra AR, Gellatly R, Rowe H, Johnson SR. Corticosteroids in the Management of Pregnant Patients With Coronavirus Disease (COVID-19). Obstet Gynecol. 2021 Feb 1;137(2):379-380. doi: 10.1097/AOG.0000000000004271. PMID: 33481519.

National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. Retrieved December 14, 2021

RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.

David Warmflash
Dr. David Warmflash is a science communicator and physician with a research background in astrobiology and space medicine. He has completed research fellowships at NASA Johnson Space Center, the University of Pennsylvania, and Brandeis University. Since 2002, he has been collaborating with The Planetary Society on experiments helping us to understand the effects of deep space radiation on life forms, and since 2011 has worked nearly full time in medical writing and science journalism. His focus area includes the emergence of new biotechnologies and their impact on biomedicine, public health, and society.

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