To date, many studies around the world have been conducted to evaluate the health and economic effects of ACS administered to a special population of late preterm infants. The supplementation of pregnant women with antenatal corticosteroids between 34 weeks and 36 weeks 6 days was accepted as an effective approach that can significantly reduce the cost and acute morbidity associated with late preterm birth [12]. The mechanism that causes respiratory distress in babies born between 22 weeks and 34 weeks of gestation, including surfactant deficiency and immature development of the fetal lung, can also affect late preterm infants. Lack of the epithelial sodium channel responsible for clearance of the fluid and deficiency of pulmonary surfactant plays a key role in the pathophysiology of respiratory morbidity [2]. Antenatal corticosteroids may have an impact on both surfactant maturity and fetal lung fluid clearance in late preterm newborns [13]. Currently, Vietnam is a lower middle-income country, but preterm newborn care is still limited. The economic costs of preterm birth are large in terms of neonatal intensive care and long-term complications [1]. Therefore, a low-cost intervention, such as antenatal dexamethasone, may indeed help to alleviate the neonatal interventions needed in Vietnam.
Our study objective was to determine the efficacy of antenatal dexamethasone in reducing the rate of respiratory distress in late preterm infants. As mentioned above, we found that dexamethasone administration to women at risk at 34 0/7 weeks − 36 6/7 weeks of gestation reduced the rate of respiratory distress (RR, 0.44; 95% CI, 0.21–0.96; p = 0.03). Previously, Yinon et al. (2012) conducted a retrospective cohort study to compare the outcomes of infants born between 34 and 37 weeks of gestation who had either received betamethasone or not. The rate of the composite respiratory morbidity outcome was significantly higher in the nontreatment group than in the betamethasone group (21% vs. 8.4%, respectively; p = 0.02). However, this was a retrospective cohort study design, and the authors could not control for potential confounding factors [14]. According to Attawattanakul (2015), dexamethasone administration in late preterm labor significantly decreased the rate of respiratory distress without increasing the rate of adverse events. Furthermore, only 6% of participants completed the full course of antenatal dexamethasone [15]. Most recently, both Gyamfi-Bannerman et al. (2016) and Uquillas et al. (2020) found that antenatal betamethasone decreased the need for substantial respiratory support during the first 72 hours of late preterm newborns after birth (p = 0.02) [8], [16]. Uquillas et al’s study was also a retrospective cohort study, so they could not control for differences in subgroup gestational age (34 weeks, 35 weeks and 36 weeks of gestation). Despite being the largest trial, it is important to note that only 60% of the study group completed the full course of betamethasone in the Gyamfi-Bannerman et al’ trial.
In addition, there are other studies that reported opposite results. A randomized controlled trial conducted by Porto et al showed that the rate of respiratory morbidity was similar between betamethasone and placebo groups (25% vs. 23%, respectively). They concluded that antenatal treatment with corticosteroids was not effective in reducing neonatal respiratory morbidity. However, 43 pregnant women (13%) were discharged and lost to follow-up. [17]. Recently, Balreldin et al. (2020) even concluded that the rate of respiratory distress in the group using ACS was higher than in the group without ACS (6% vs. 4.7%, respectively) [18]. These differences may be due to the different sample sizes and trial designs. Balreldin et al pointed out that the weakness in their study was the limited sample size; therefore, their analysis had inadequate power to identify differences. In addition, our study is the first in Vietnam to use dexamethasone to determine the benefits of antenatal corticosteroids on respiratory distress reduction in late preterm infants.
In our matched cohort study, there were no significant differences between groups in baseline characteristics, including maternal age, history of prematurity, gravidity, and method of delivery. The most frequent cause of delivery was premature rupture of the membranes (43.6%), followed by preterm labor (42.9%). Compared to the matched group, the incidence of membrane rupture in the dexamethasone group was lower (p < 0.0001), but the incidence of preterm labor was higher (p = 0.02). These differences may be explained by the longer the rupture of membranes, the more limited the indication of dexamethasone to be used.
In our findings, there was a difference in the level of breathing difficulty related to respiratory distress in late preterm infants between the two groups. In particular, there were 2 infants with moderate levels in the dexamethasone group and 10 infants with moderate levels in the matched group. Two cases with severe breathing difficulty in the two groups were due to respiratory distress syndrome (stage III) and were treated with mechanical ventilation and surfactant therapy. As mentioned above, dexamethasone primarily reduced the moderate level of breathing difficulty. Although the difference was not statistically significant, antenatal dexamethasone may help improve the level of breathing difficulty in late preterm newborns.
Our study showed that there was a significant reduction in the rate of respiratory distress. Nevertheless, the rate of NICU admission, the need for respiratory support, respiratory distress syndrome, surfactant use, and Apgar score < 7 were not significantly different between the dexamethasone and matched control groups. We found that there were cases of neonatal respiratory distress at different levels, but Apgar score ≥ 7 at 1 minute and 5 minutes after birth accounted for the majority in the two groups. Although good resuscitation at birth significantly improved the Apgar score, some infants showed signs of respiratory distress within 72 hours after birth (tachypnea, grunting, chest indrawing, etc.) and the need for respiratory support. Table 2 also shows that dexamethasone did not shorten the length of hospital stay for infants. This could be explained by many other factors affecting the length of hospital stay of late preterm newborns, including gestational age, birth weight, sex, method of delivery and neonatal complications [19].
Furthermore, administration of dexamethasone did not significantly improve the rates of short-term morbidity or complications of late preterm infants, consisting of jaundice requiring phototherapy, early-onset neonatal sepsis, intraventricular hemorrhage, necrotizing enterocolitis and neonatal death. Notably, the rate of neonatal hypoglycemia was higher in the dexamethasone group than in the control group (25.6% vs. 12.8%, respectively; RR, 2.00; 95% CI, 1.00–3.99; p = 0.04). Few trials of antenatal corticosteroids have recorded the same result on neonatal hypoglycemia in the late preterm period. According to Ramadan et al. (2016), infants in the betamethasone group had a higher incidence of neonatal hypoglycemia (p = 0.04) [20]. Gyamfi-Bannerman (2016) also demonstrated that betamethasone increased the rate of neonatal hypoglycemia (24.0% vs. 15.0%, respectively; RR, 1.60; 95% CI, 1.60–1.87; p < 0.001), although there were no reported adverse events related to neonatal hypoglycemia, and the condition was self-limiting [8]. Our findings are consistent with the results of Gyamfi-Bannerman. Accordingly, we support monitoring blood glucose of newborns in the late preterm period who were exposed to antenatal dexamethasone.
The results in Table 4 show that dexamethasone administration did not increase the risk of infection for the mother. There was only 1 case of chorioamnionitis in the control group, and there were no diagnosed endometritis cases in either group. These findings are consistent with the results of Gyamfi-Bannerman et al. [8]. There was no significant between-group difference in the incidence of retained placenta. The maternal length of hospital stay after delivery in the dexamethasone group was slightly higher than in the matched group, but the difference was not statistically significant (p > 0.05). This could be explained by the higher rate of cesarean delivery in the dexamethasone group than in the matched group (38.5% vs. 28.2%, respectively). In clinical practice at our study center, the maternal length of hospital stay after birth is usually 5 days for cesarean delivery and 3 days for normal delivery. Therefore, dexamethasone was not associated with an increased length of hospital stay of the mother after delivery.
A previously published study evaluated the long-term impact of antenatal corticosteroids. In 2013, a follow-up study was conducted to evaluate the long-term behavioral, cognitive and developmental outcomes of children aged 8–15 years who were born preterm in a previous study with corticosteroid administration, and they did not exhibit any adverse events [21]. In this study, only short-term complications of late preterm infants within 72 hours after birth were assessed, not long-term complications. Another limitation is the nature of matched-cohort studies rather than randomized control trials to increase the power of the study results.