Of note, women with pregestational diabetes were excluded from the study and, in routine practice, inclusion of such patients may further increase the risk of neonatal hypoglycemia.
There are few data on the prognostic significance of neonatal hypoglycemia in preterm infants, with the exception of a single study, the results of which show that it is associated with adverse neurodevelopment at 18 months of age.10
In spite of strict protocol specifications to increase the probability of delivery before 37 weeks’ gestation, 16% of women in the trial delivered at term. Investigators of prior randomized studies of ACS, aimed at reducing the risks of prematurity, have reported a rate of term delivery of about one-third,4,11 and in routine practice, administration of ACS after 34 weeks may be associated with even higher rates of term delivery.
This is important because recent evidence shows an unfavorable impact of ACS exposure in term-born children.12 The 5-year follow-up of the largest randomized trial in which multiple ACS courses were used noted that babies born at term had a 4-fold increased odds ratio for neurosensory disability.11 There was no dose−response interaction, with the same adverse odds ratio after 1 or 4 additional ACS courses. This observation was consistent with a previously reported Swedish national cohort, pointing to an unfavorable impact of even a single course of ACS in term-born children, with a greater likelihood of harm than benefit.13
In a UK follow-up of children aged 8 to 15 years who were enrolled in an RCT of ACS before cesarean delivery at term, low academic achievement was significantly more common in the group whose mothers had received ACS.14 In another study of 304 children born at term after exposure to a single course of ACS, investigators noted significantly increased cortisol reactivity to acute psychological stress at ages 6 to 11 years in the ACS-exposed patients, compared with 212 babies of women with threatened preterm labor who did not receive ACS and 372 babies from uncomplicated term pregnancies.15
The relevance of such study findings extends beyond childhood given the fact that elevated hypothalamic-pituitary-adrenal (HPA) axis reactivity has been linked to the pathogenesis of metabolic syndrome and depression in adult life.16 As recently as 2015, investigators of a randomized trial of ACS in 6 low- and middle-income countries highlighted their concern regarding “potentially harmful use of antenatal corticosteroids for infants not delivered preterm.”17
The effects of ACS are more pleiotropic than those reflected in a lower incidence of respiratory difficulties. Knowledge of the overall consequences of ACS exposure in infants born late-preterm or at term is still limited. The close-to-term fetus exposed to exogenous corticosteroids is also exposed to the physiologic endogenous surge of cortisol known to occur in the maternal circulation in late pregnancy, which reaches levels 3 times higher than those seen in nonpregnant women.18 Although placental 11 beta-hydroxysteroid dehydrogenase type 2 plays a protective role by allowing no more than 10% to 20% of maternal corticosteroids to cross the placenta, fetal overexposure from concomitant exogenous maternal corticosteroid administration remains a theoretical concern close to term. This is especially worrisome if there is a gestational age−related increase in the sensitivity to corticosteroid-induced in utero fetal programming. It has been reported that fetal overexposure to corticosteroids in late pregnancy can permanently increase the activity of the HPA-axis, with likely consequences in adult life.19
Another concern relates to oligodendrocytes development. Although the neuronal division process in humans usually is completed by 24 weeks’ gestation, the most rapid growth for oligodendrocytes occurs between 34 and 36 weeks’ gestation; these are the cells responsible for the synthesis of myelin. Overexposure to corticosteroids at this vulnerable time in the late preterm fetus potentially may have unanticipated negative neurologic consequences.20
If a pregnant woman previously has delivered a baby beyond 34 weeks who developed a need for respiratory support, and the woman was again at risk for a late preterm delivery, it may be reasonable to offer her corticosteroids with full informed consent.
This is the only scenario in which we feel antenatal corticosteroids could be used in a fetus aged 34 weeks to 36 weeks 5 days. In the setting of a scheduled cesarean delivery between 34 weeks and 35 weeks, the concerns relative to term delivery after corticosteroid exposure may not apply, but the concerns in relation to the administration of corticosteroid in the late preterm period—which is a time of possibly increased neurohormonal and neurologic vulnerability—still apply. With regard to the risk of neonatal hypoglycemia, one might argue that close neonatal monitoring of babies so exposed may ensure that any associated neonatal hypoglycemia does not go unnoticed or untreated. However, the prognostic significance of even short periods of neonatal hypoglycemia has not been established.
