Antenatal steroid

Adverse effects

Preliminary research has suggested that the use of antenatal corticosteroids may have adverse long-term effects. In animals, antenatal corticosteroid use has been associated with adverse effects on the cardiometabolic system and inhibited growth of the brain, as well as worsened memory and learning difficulties. While it is not yet certain if human fetuses would experience these same effects, some literature has found that human preterm fetuses treated with antenatal corticosteroids may be at greater risk of developing mental and behavioural disorders during childhood, as these drugs are able to enter the fetus' brain and could affect neurodevelopment. In both humans and animals, research has suggested that repeated doses of antenatal corticosteroids could lead to an increased risk of vision and hearing issues in the long-term.

Contraindications

Contraindications to the administration of antenatal corticosteroids include:

• Systemic maternal infection
• Maternal chorioamnionitis

Drugs

Corticosteroids encourage the development of the lungs in a premature fetus before birth, and are administered when the premature fetus is expected to be delivered within 24 to 48 hours. The period of optimal benefit begins 24 hours after administration and lasts 7 days. In some parts of the world, antenatal steroids are used at up to 36 weeks of pregnancy. The time between administration of steroids and delivery may alter the effectiveness of the steroids.

Choice of steroid

Common corticosteroids include dexamethasone and betamethasone. Dexamethasone is often recommended over the latter due to its increased efficacy and safety, wide availability, and low cost, while betamethasone is better at preventing the softening of the brain in premature fetuses. Both drugs share certain commonalities, including the ability to traverse the placenta, as well as a very similar molecular structure. In fact, the two steroids are identical save for a single additional methyl group on betamethasone. Although betamethasone has an increased half-life, there is no significant evidence indicating that one might be better than the other. Literature on the subject is limited and inconsistent. A Cochrane review (2022) found that it was unclear if there were significant differences, while other studies determined that betamethasone results in improved longer term outcomes.

Mechanism of action

In order to generate improved respiratory outcomes, antenatal steroids act on cells called type II pneumocytes which are located within the alveoli of infant lungs. Glucocorticoids both increase rates of cell maturation, as well as increase the production of mRNA coding for proteins required for the synthesis of surfactant. Surfactant is a phospholipid-rich substance secreted by the lungs in order to increase elasticity and decrease surface tension, consequently generating more efficient rates of ventilation. Additionally, surfactant lines the insides of alveoli in the lungs and as a result, prevents alveoli from collapsing during exhalation. Since infants born preterm often have immature or incompletely developed lungs, the surfactant coating of the alveoli is similarly insufficient, resulting in poor respiratory outcomes or the development of respiratory distress syndrome. The administration of antenatal corticosteroids increases production of surfactant (decreasing the need to use surfactant after birth), and therefore result in better health outcomes for preterm infants.

History

In 1969, Graham Liggins, a medical research scientist, began investigating the effects of dexamethasone administration on the timing of labor in pregnant sheep. Liggins conducted this experiment in the hopes of proving his hypothesis that the fetus, and not the mother, is responsible for inducing labour. Liggins found that dexamethasone caused pregnant sheep to deliver their fetuses prematurely, however, despite the fact that the lamb fetus was extremely premature, it was delivered alive.

With the help of his colleague, pediatrician Ross Howie, Liggins conducted a similar experiment with 282 human women, all of whom were projected to have a preterm delivery. This preliminary trial showed that the administration of corticosteroids, specifically betamethasone, resulted in immediate improvements that were statistically significant, such as:

• Lowered neonatal mortality rate
• Reduced incidence of respiratory distress syndrome, but only in fetuses who had
  1. Undergone less than 32 weeks of gestation, and;
  2. Were treated for a minimum 24 hours before they were delivered
• Reduced incidence of intraventricular cerebral hemorrhage

These findings were first reported in the article A Controlled Trial of Antepartum Glucocorticoid Treatment for Prevention of the Respiratory Distress Syndrome in Premature Infants, published in the journal Pediatrics in 1972. Liggins and Howie's research proved that antenatal corticosteroids were able to decrease respiratory complications and infant mortality by inducing cellular differentiation, and thus maturation, in the lungs. However, these results were not incorporated into clinical practice in the United States until over two decades later.