In this study we found that administration of ACS during pregnancy does not appear to be beneficial on short term outcome and can even result in higher rates of adverse outcome in SGA neonates born in the late preterm. Our study showed that the rate of NICU admission was significantly higher among the ACS group along with higher rates of composite neonatal outcome. This association remained significant among fetuses that received a rescue course of ACS in sub-analysis for the ACS group only.
ACS therapy for decreasing neonatal morbidity and mortality is recommended by guidelines around the world and is widely used. Its benefits among intrauterine growth restriction (IUGR) fetuses remains largely unknown, and controversy exists on the benefit of ACS for IUGR/SGA fetuses to improve preterm birth outcome. There is insufficient evidence to withhold routine ACS therapy in cases of suspected IUGR with a high risk of preterm birth.
The benefit of ACS in specific obstetric population such as SGA neonates, is yet to be determined. A previous study by Gyamfi‑Bannerman et al., investigated the effects of ACS for women at risk for late preterm delivery. In this randomized trial, women with a singleton pregnancy who were at high risk for delivery during the late preterm period were recruited. In this study ACS significantly reduced rates of neonatal respiratory complications. It should be noted though that the frequency of IUGR among the ACS group was 3.2% and among the control group was 3.4%, and the impact on ACS on this sub group was not analyzed [3]. Another study by Haviv et al., investigated the role of ACS on late preterm in special populations. They concluded that there is insufficient evidence regarding the benefits or harms of ACS therapy in pregnancies with IUGR, especially in the late preterm period. They recommended an individualized approach when administering corticosteroids at later gestations in specific obstetric populations such as IUGR [10].
Several studies reported no effect of ACS on neonatal morbidity or mortality among IUGR fetuses in the early preterm (up to 34 weeks of gestational age) [8, 11,12,13,14]. Van Stralen et al. demonstrated that administration of ACS to IUGR fetuses does not appear to be beneficial with respect to short term neonatal outcome in preterm deliveries[8]. Another recent study showed the same results where ACS did not improve neonatal morbidities, in SGA neonates delivered between 29 and 34 gestational weeks. Rather, ACS seemed to increase the risk of RDS. They concluded that ACS therapy for women who are at risk for preterm delivery with IUGR fetus, need to be further evaluated, especially after 32 weeks of gestation [13]. A recent meta-analysis, examined 16 observational cohort and case-control studies published from 1995 to 2018, they concluded that ACS reduces neonatal mortality in SGA infants delivered preterm, with no apparent effect on neonatal morbidity (RDS, NEC, IVH and periventricular leukomalacia, bronchopulmonary dysplasia or chronic lung disease of prematurity, or neonatal sepsis). The study concludes that future studies are required on the effect of ACS administration to SGA infants in the late preterm period, because data on this issue is limited [14]
One assumption for our results is that poor intrauterine growth, by itself, actually enhances lung maturation. This assumption has been demonstrated in several studies. The physiological adaptations that growth restricted fetus experience in response to nutrient and oxygen restriction alter the ability to regulate endogenous glucocorticoid availability. As a result, these fetuses may be exposed to higher ACS concentrations, which may result in an exacerbation of the potentially negative side effects of antenatal glucocorticoid treatment, especially in cardiovascular development. Possibly without the full capacity to benefit from the lung maturational effects [15]. Conversely, a previously published study demonstrated that IUGR fetuses accelerate lung maturation is not supported in comparisons of SGA and appropriate for gestational age (AGA) infants of the same gestational age, sex and race [16].
Secondly, it has been suggested that elimination of ACS via the placenta or the blood–brain barrier is impaired with IUGR, and hence, the fetus is exposed to excessive corticosteroids in the lung, brain, and heart tissues [15].
Nevertheless, some studies showed lower risk of adverse outcomes [16,17,18,19,20]. Bernstein et al. demonstrated the association of IUGR fetuses with increased morbidity and mortality. Furthermore, it showed that the benefits of ACS therapy were similar among infants with IUGR and normally grown infants for neonates from 25 to 30 weeks of gestation [19]. A population-based study on singleton infants of 24–31 weeks of gestation, concluded that ACS therapy was associated with significantly reduced mortality and major neonatal morbidities among preterm SGA neonates which was generally similar to the effect in the AGA preterm infants [17]. A previous review (2018) concluded that based on the current clinical evidence, it is reasonable to give a single course of glucocorticoids to pregnant women with IUGR fetuses who are at risk of preterm birth, however there is insufficient evidence to conclude whether repeated or rescue ACS administration is beneficial for IUGR infants [18].
We also found that birth weights were significantly higher among non-ACS group. Our results are aligned with previous studies which have shown that ACS is associated with reduction in birth size for infants born preterm, near term, or at term [21]. These studies even showed reduction in head circumference among preterm newborns [21,22]. However, it is unclear whether this difference in birth weight is a result of the ACS treatment or was it the reason for administering the ACS.
The novelty of the present study is that we examined ACS therapy for SGA fetuses eventually born at late preterm. To the best of our knowledge, all existing studies examined ACS therapy for SGA fetuses in the early preterm. Moreover, most studies refer to IUGR fetuses (defined as an estimated fetal weight <10th percentile) and not SGA fetuses.
Nevertheless, it is not free of limitations. The main limitation of this current study is its retrospective design, which could lead to an unknown selection bias such as the reason for administering or withholding ACS. In addition, the timing of administering ACS was missing. Another limitation is that we only studied short-term neonatal outcomes in this specific population, and the long-term impact of ACS is yet to be determined.
In conclusion, our study demonstrated that ACS did not decrease neonatal morbidity, in SGA neonates at the late preterm. It might be even associated with adverse neonatal outcome. This should be further evaluated in large prospective studies.