A single course of antenatal corticosteroid (ACS) treatment has become the standard of care for women at risk of imminent or anticipated preterm delivery, particularly before 32–34 weeks' gestation [1], representing an effective therapy for respiratory distress syndrome (RDS) and improving morbidity and mortality in preterm babies. Based on a double-blind, placebo-controlled, randomized clinical trial suggesting that betamethasone can be beneficial in pregnant women at high risk of late preterm birth [2], the American Congress of Obstetricians and Gynecologists (ACOG) has released a practice advisory that the “administration of betamethasone may be considered in women with a singleton pregnancy between 34 and 36 complete weeks of gestation at imminent risk of preterm birth within 7 days” [3]. However, there are no randomized studies on the effect of ACS in preterm small-for-gestational-age (SGA) cases. The first randomized controlled trial of ACS in 1972 [4] not only demonstrated a reduction in RDS in preterm infants but also suggested an excess of fetal death in cases of pregnancy-related hypertension and fetal growth restriction (FGR) treated with corticosteroid. However, many of the subsequent clinical trials on the effect of ACS excluded pregnancies with such complications. In a recent meta-analysis, effects of ACS use were still inconclusive for cases with SGA [5]. In the extreme preterm birth before 29 weeks, the benefit might outweigh the possible harm, considering lung development. However, we need to consider potential risks and benefits of ACS to FGR or small-for-gestational-age (SGA) infants, especially after 32 weeks [6]. Thus, our aim was to assess the association of ACS, when administrated within the ideal interval of 1–7 days before birth, with the outcomes of preterm SGA neonates. We also evaluated the effect of ACS on SGA neonates who born at 32 weeks of gestation. At this age, the level of surfactant started to increase in the amniotic fluid [7].

In this study, we observed that the exposure of preterm SGA fetuses to ACSs between 29 and 34 weeks of gestation was not associated with a significant decrease or increase in the odds of NICU admission, mechanical ventilation, sepsis, seizure, IVH, ROP, NEC, PPHN, feeding difficulties, neonatal death, or hypoglycemia. However, the frequency of RDS was notably increased in the group that received ACS. Although this result was adjusted with gestational age and birth weight, it is thought that the group that received ACS included more newborns that were born earlier and weighed less. And exposure of preterm SGA fetuses to ACSs before birth between 32 and 34 weeks of gestation was associated with neonatal hypoglycemia.

Retarded fetal growth is associated with chronic hypoxia and acidosis. Because SGA fetuses might be already exposed to elevated endogenous corticosteroid levels, ACS can cause too much burden including fetal hemodynamics and neurologic development [9]. There are many evidences from basic science and observational studies for potential fetal harms [6]. It has been reported that restricted fetal growth is related with adult hypertension, atherosclerosis, type 2 diabetes, and metabolic derangement [1011], although the degree to which low birth weight mediates adult disease is controversial. Also, it was reported that ACS was associated with increased cortisol reactivity to acute psychosocial stress in 6–11 years old [12]. The effect of ACS on the developing brain is controversial [6]. Multiple courses of ACS have been associated with decreased weight, length, and fetal head circumference at birth, and increased risk of neurodevelopmental and neurosensory impairment by 5 years of age [1314]. A recent meta-analysis suggested that a single course of ACSs in women at high risk for preterm birth appears to improve most neurodevelopmental outcomes in offspring born before 34 weeks of gestation [15]. Growth restricted fetal brain might be more vulnerable to oxidative damage, as an experimental sheep model of FGR has demonstrated the relationship between betamethasone and disturbed neuronal integrity and enhanced cell death in the brain due to increased cerebral oxidative stress [9]. However, the effects of ACS on the brain of human growth-restricted fetuses remain largely understudied. The effects of ACS on the hemodynamics of the growth restricted fetuses were evaluated with end-diastolic flow of umbilical artery after ACS, using Doppler ultrasonography. While there were higher risks of neonatal morbidity associated with lack of return of end-diastolic flow after ACS in growth-restricted fetuses, the mechanisms and the long-term impact are still unknown [1617]. The only data available about long-term neurocognitive outcomes after late preterm administration of ACSs vs. placebo come from the initial corticosteroids study [4], which showed no difference between exposure groups, in cognitive functioning, working memory and attention, and other neurocognitive assessments. Considering the proven mechanisms and effects of ACS on developing brain, we should be cautious when we give ACS in the premature FGR cases [18]. There are 2 recent retrospective studies reporting that ACS significantly reduced mortality and severe morbidities among preterm SGA neonates [1920]. However, one study included SGA neonates within 24–31 weeks' gestation, while the other study included SGA neonates from 24 to 33 weeks' gestation. The present study included SGA neonates from 29 to 34 weeks' gestation, which might present less mortality and severe morbidities. Low incidence of mortality and morbidity might be the reason that we could not find the benefit of ACS. The gestational age and birth weight of the group that did not receive ACS were significantly higher than those of the group that received ACS, which could act as a selection bias. However, even after the adjustment by gestational age, birth weight including other clinical confounding factors, there was no significant difference between ACS group and no ACS group. In addition, the risk of neonatal hypoglycemia was significantly higher in the ACS group, between 32 and 34 weeks' gestation, in logistic regression analysis. Also, small sample size of this study is our limitation. A previous study from Japan showed that ACS does not affect short- or long-term outcome in SGA infants when the birth weight is less than 1,500 g [21]. These similar results can be related with ethnic difference. So, data on the efficacy and safety of ACS in pregnancies complicated by FGR or SGA are limited and conflicting. SGA includes growth restricted and constitutionally small fetuses. Our study has limitation in that it cannot distinguish between FGR and constitutionally small fetuses. Therefore, it is needed to evaluate the effects of ACS on the severe FGR cases, which have abnormal flow patterns in umbilical and middle cerebral arteries.

Our study demonstrated that ACS could not decrease neonatal mortality and morbidities, in SGA neonates delivered between 29 and 34 weeks of gestation. And the risk of neonatal hypoglycemia was increased in ACS group, in SGA neonates delivered between 32 and 34 weeks of gestation. Although a single course of ACS has become the standard of care in most high-income countries for cases of imminent or anticipated preterm delivery, particularly before 32–34 weeks' gestation and ACOG expanded a recommendation of ACS to women with a singleton pregnancy between 34 and 36 weeks of gestation at imminent risk of preterm birth within 7 days, ACS in women at preterm FGR need to be further evaluated, especially after 32 weeks' gestation.