This was a retrospective cohort study conducted on women who delivered singleton late preterm infants (34 + 0 to 36 + 6 weeks of gestation) at Seoul National University Bundang Hospital from May 2016 to October 2021 (Fig. 1). The inclusion criteria were as follows: completion of the initial cycle of ACS in the early preterm period (before 34 + 0 weeks of gestation). The exclusion criteria were as follows: (1) patients who were not exposed to ACS during pregnancy; (2) patients who were provided with initial ACS during the late preterm period (33 + 6/7–36 + 5/7 weeks of gestation); (3) patients who received rescue ACS for more than one cycle; and (4) patients who received both initial and rescue ACS during the early preterm period (before 34 + 0/7 weeks of gestation).

Fig. 1.

Flow chart of the study.

Data on maternal baseline characteristics, such as age, parity, mode of delivery, gestational age at delivery, gestational age at initial ACS, and gestational age at rescue ACS, were obtained from medical records. Data regarding the presence or absence of pregnancy-related complications and risk factors, such as hypertensive disorder of pregnancy, gestational diabetes, and indication for initial ACS, were also collected. The study protocol was approved by the Institutional Review Board of Seoul National University Bundang Hospital (B-1905-540-005). The need for obtaining informed consent from the study participants was waived due to the retrospective nature of this study.

Based on the ALPS trial, we administered a course of ACS to patients in the late preterm period (34 + 0/7–36 + 6/7 weeks in gestation) who were at risk of delivery within 7 days or before 37 weeks of gestation in our institution since May 2016 [9]. In some cases, rescue ACS was also administered to late preterm infants based on the physician’s decision, although it is not recommended by guidelines [6, 8]. For this study, rescue ACS in the late preterm period was defined as the administration of at least one of two doses of 12 mg (3 mL) betamethasone, which is sodium phosphate 5.2 mg (betamethasone 4.0 mg) in 1 ample (1 mL), produced by Dawon Parm (Seoul, Korea), intramuscularly every 24 h between 34 + 0/7 and 36 + 6/7 weeks of gestation.

The primary outcomes assessed were RDS and neonatal hypoglycemia. RDS, typically caused by surfactant deficiency, was diagnosed clinically if the neonate exhibited respiratory distress requiring surfactant replacement at least once [14, 15]. Neonatal hypoglycemia was defined as a glucose level $\le$40 mg/dL within the first 24 h of life, based on consultation with the neonatologists at our institution [16, 17]. Our secondary outcomes included neonatal hypoglycemia, defined as a glucose level $\le$60 mg/dL within the first 24 h of life; birth weight; 1-min Apgar score less than 7; 5-min Apgar score less than 7; and TTN [16, 17, 18, 19]. Serum glucose tests were routinely conducted for all neonates within 24 h of birth. TTN, resulting from delayed resorption and clearance of fetal alveolar fluid, typically resolves spontaneously or with supportive care [15]. We diagnosed TTN clinically if the neonate exhibited respiratory distress requiring respiratory support but not surfactant administration.

Continuous variables were compared using the Mann–Whitney U test, and categorical variables were assessed using the Chi-square test. Fisher’s exact test was used in cases where the frequency was less than 5 or when the sample size of any variable was below 20% of the total sample size. Multivariate logistic regression was used to determine the factors associated with neonatal outcomes. Multivariate modeling with inclusion of the following factors was applied: variables with p 0.2 in the univariate analysis and with exclusion of variables showing multicollinearity. Statistical significance was set at p 0.05. Statistical analysis was performed using SPSS version 25 (IBM SPSS Inc., Armonk, NY, USA).

In this study, neonates who received late preterm rescue ACS had a lower occurrence of RDS. Other neonatal outcomes, including TTN of the newborn and hypoglycemia (glucose level $\le$40 mg/dL and $\le$60 mg/dL), demonstrated no differences between the two groups. However, in the multivariate modeling of the risk factors for RDS, late preterm rescue ACS tended to reduce neonatal RDS, but the difference was not statistically significant. Hypoglycemia (glucose level $\le$40 mg/dL and $\le$60 mg/dL) also did not show an association in the multivariate modeling.

ACS administration may cause temporary maternal hyperglycemia, leading to fetal hyperinsulinemia and subsequent hypoglycemia [20].

In the ALPS trial, hypoglycemia (glucose level $\le$40 mg/dL) was more frequent in neonates exposed to late preterm ACS than in those in the control group (24.0% vs. 15.0%, p 0.001) [9]. In a prospective cohort study, Ramadan et al. [21] reported that neonates born to mothers receiving ACS (two doses of 12 mg of betamethasone administered intramuscularly 24 h apart) in late preterm showed a higher incidence of hypoglycemia (glucose level $\le$40 mg/dL) within 1 h of life (20.3% vs. 10.9%; OR, 2.09; 95% CI, 1.03–4.24; p = 0.039). Similarly, Dude et al. [10] performed a retrospective cohort study comparing the neonatal outcomes of late preterm infants by dividing them before and after the APLS trial into mothers with pre-gestational diabetes and mothers with gestational diabetes. They reported that the post-protocol group exposed to ACS experienced hypoglycemia (glucose level $\le$60 mg/dL) more frequently than the pre-protocol group (59.7% vs. 79.6%; OR, 2.82; 95% CI, 1.19–6.72; p = 0.03) [10].

Gyamfi-Bannerman et al. [22] re-analyzed the data of infants enrolled in the ALPS trial and reported no significant difference in the incidence of neonatal hypoglycemia between the betamethasone and placebo groups (29.3% vs. 17.3%; relative risk (RR), 1.69; 95% CI, 1.46–1.96). In addition, most cases of neonatal hypoglycemia resolved spontaneously within 24 h in both groups, and the time to resolution was shorter in the betamethasone group than that for the placebo group (2.80 h [interquartile range: 2.03–7.03] vs. 3.74 h [interquartile range: 2.15–15.08]; p = 0.002) [13].

In our study, late preterm rescue ACS was not associated with hypoglycemia (glucose level $\le$40 mg/dL) or hypoglycemia (glucose level $\le$60 mg/dL).

ACS administration accelerates alveolization by promoting normal thinning of the double capillary loops, forming thin gas-exchanging walls of alveoli, and inducing lung maturation by promoting pneumocyte II maturation and pulmonary surfactant generation [23, 24].

The efficacy of ACS in late preterm infants remains controversial, and there are few studies on rescue ACS in late preterm infants. According to the ALPS trial, ACS in late preterm infants reduces the risk of composite RDS, TT of the newborn, or apnea (13.9% vs. 17.8%; RR, 0.78; 95% CI, 0.66–0.93; p = 0.004) [9]. Mansouri et al. [25] reported that the incidence of neonatal RDS was significantly lower in the group administered betamethasone (12 mg/kg/BW twice every 24 h) at 35–36 weeks compared to in the untreated group in a double-blind randomized controlled trial (8% vs. 20%, p 0.01).

Shanks et al. [26] conducted a randomized controlled study that compared the surfactant-to-albumin ratio (TDx-FLM-II), a laboratory marker that is useful for determining fetal lung maturity, depending on ACS administration in pregnant women at 34 + 0/7–36 + 6/7 weeks. They showed that the surfactant-to-albumin ratio (TDx-FLM-II) significantly increased in the group exposed to ACS after 34 weeks (28.37 mg/g vs. 9.76 mg/g, p 0.002) [26]. In a randomized controlled trial, Ontela et al. [27] argued that late preterm ACS was not associated with composite respiratory morbidity (RR, 0.91; 95% CI, 0.7–1.2; p = 0.49). Additionally, Ramadan et al. [21] reported that late preterm ACS did not increase the incidence of RDS in neonates (8.1% vs. 6.8%; OR, 1.21; 95% CI, 0.452–3.25; p = 0.702) (hypoglycemia, no RDS).

In our study, we found that late preterm ACS might be associated with a reduced risk of RDS; however, the results were not statistically significant in the multivariate analysis (OR, 0.07; 95% CI, 0.00–1.48; p = 0.087). It is presumed that the small sample size was insufficient to obtain statistical significance. Through this study, we were not able to definitively prove whether mothers who have already received steroids once during the early preterm period, when labor is predicted, can definitely have reduced RDS or TTN by receiving rescue steroids when labor is predicted in the late preterm period. Additionally, we could not establish a correlation of late preterm ACS with increased neonatal hypoglycemia. Therefore, we believe that future large-scale studies are needed to investigate the efficacy or potential adverse effects of administering rescue steroids in women with singleton pregnancies.

Although studies on the efficacy of late preterm ACS have been actively conducted before and after the ALPS trial, there have been few studies on the efficacy of rescue ACS in late preterm infants. The major strength of our study is being the first to evaluate the benefits and side effects of rescue ACS in late preterm infants. Our findings may shed some light on rescue ACS use in late preterm infants.

However, this study had a few limitations. First, as this was a retrospective hospital-based cohort study, the number of patients who were exposed to rescue ACS in late preterm was insufficient to reach statistical significance. Further studies with a larger number of pregnant women are needed to verify the efficacy of late preterm rescue for ACS. A second potential limitation is that we only collected data from neonates within 24 h of birth. Potential long-term outcomes, such as neurodevelopmental outcomes, need to be evaluated in future studies. Third, residual disturbances due to other factors or interventions, such as fetal anomalies and antibiotic treatment, and maternal factors of gestational diabetes or pregestational diabetes were not addressed but cannot be excluded.