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Impact of antenatal corticosteroids-to-delivery interval on very preterm neonatal outcomes: a retrospective study in two tertiary centers in Japan

BMC Pregnancy and Childbirth volume 24, Article number: 607 (2024) Cite this article

Abstract

Background

Antenatal corticosteroids (ACS) are administered to prevent neonatal complications and death in women at risk of imminent preterm birth. Internationally, the optimal interval from ACS to delivery (ACS-to-delivery interval) is within seven days; however, evidence in Asian populations specifically is limited. This study aimed to investigate the association between ACS-to-delivery interval and the incidence of neonatal complications in Japan.

Methods

This retrospective observational study enrolled singleton neonates born preterm at < 32 weeks of gestational age between 2012 and 2020 at two tertiary centers. A total of 625 neonates were divided into the following four groups according to the timing of ACS (measured in days): no ACS (n = 145), partial ACS (n = 85), ACS 1–7 (n = 307), and ACS ≥ 8 (n = 88). The following outcomes were compared between the groups: treated respiratory distress syndrome (RDS), severe intraventricular hemorrhage (IVH), treated patent ductus arteriosus (PDA), necrotizing enterocolitis, sepsis, bronchopulmonary dysplasia (BPD), treated retinopathy of prematurity (ROP), periventricular leukomalacia, and death discharge.

Results

The ACS 1–7 group had significantly decreased adjusted odds ratios (ORs) for treated RDS (0.37 [95% confidence interval: 0.23, 0.57]), severe IVH (0.21 [0.07, 0.63]), treated PDA (0.47 [0.29, 0.75]), and treated ROP (0.50 [0.25, 0.99]) compared with the no ACS group. The ACS ≥ 8 group also showed significantly reduced adjusted ORs for RDS (0.37 [0.20, 0.66]) and treated PDA (0.48 [0.25, 0.91]) compared with the no ACS group. However, the adjusted ORs for BPD significantly increased in both the ACS 1–7 (1.86 [1.06, 3.28]) and ACS ≥ 8 groups (2.94 [1.43, 6.05]) compared to the no ACS group.

Conclusions

An ACS-to-delivery interval of 1–7 days achieved the lowest incidence of several complications in preterm neonates born at < 32 weeks of gestational age. Some of the favorable effects of ACS seem to continue even beyond ≥ 8 days from administration. In contrast, ACS might be associated with an increased incidence of BPD, which was most likely to be prominent in neonates delivered ≥ 8 days after receiving ACS. Based on these findings, the duration of the effect of ACS on neonatal complications should be studied further.

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Background

Neonates born very preterm (< 32 weeks of gestation) are at a higher risk of death and other medical complications [1], including respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), sepsis, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and periventricular leukomalacia (PVL). These complications have significant implications on the quality of life during childhood and well-being of their parents, and inflict an economic burden associated with care [2,3,4].

The introduction of antenatal corticosteroids (ACS) represented a pivotal intervention in the mitigation of complications in preterm neonates [5, 6]; ACS have recently been recommended in several guidelines worldwide [7,8,9,10]. The World Health Organization Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns (ACTION-I) trial demonstrated that among women, even in low-resource countries, ACS administration reduced neonatal death without inducing maternal infection [11]. However, recent publications have recognized the need for new research on optimizing regimens [12, 13].

The optimal interval from ACS administration to delivery (ACS-to-delivery interval) is unclear [14]. Several current guidelines suggest 1–7 days as optimal interval in accordance with the subgroup analysis in Cochrane review 2006 [6]. However, this review cautioned ACS-to-delivery interval as a post-randomization variable, and the evidence about optimal interval is no longer supported by current updated Cochrane reviews in 2017 and 2020 [15, 16]. Optimal ACS-to-delivery interval is difficult to study in RCTs, because the precise prediction of the timing of preterm delivery is often challenging in clinical settings. Furthermore, a recent systematic review of RCTs and observational studies concluded that optimal interval was not detected because of heterogeneity in included ACS-to-delivery interval among publications [14]. To examine the optimal ACS-to-delivery interval, it may be appropriate to treat the ACS-to-delivery interval as a continuous variable [17]. Since there are only a few such reports, one of the objectives of this study was to visualize the association of ACS-to-delivery interval as a continuous variable with each outcome.

Furthermore, expect for the ACTION-I trial, most of the evidence on ACS or ACS-to-delivery intervals is based on Caucasian results, and evidence in Asians is limited [14, 15]. Indeed, Japan has demonstrated a low rate of ACS administration despite a low neonatal mortality and minimal occurrence of severe neurological injuries [18]. Thus, the significance of the ACS-to-delivery interval in preventing neonatal complications in the Japanese population remains uncertain.

To date, only two single-center studies have reported a relationship between ACS-to-delivery interval and neonatal outcomes in Japan [19, 20]. Yasuhi et al. investigated the incidence of RDS in 117 infants, and reported that the odds ratio (OR) for RDS when infants received ACS 7–14 days or > 14 days before delivery significantly increased compared with that when ACS was administered within 7 days [19]. However, Yasuhi et al. did not investigate other neonatal complications. In contrast, Tomotaki et al. investigated the incidence of refractory hypotension in 115 very low birth weight infants [20], reporting that ACS administration within 7 days before delivery was associated with a significantly lower incidence of refractory hypotension during the first week of life. These two reports encompassed approximately 100 neonates each, suggesting the need for an investigation with a larger sample size to thoroughly examine the association between ACS-to-delivery interval and various neonatal complications.

In this context, we conducted a study at two tertiary centers with a larger study population to accumulate evidence on the relationship between ACS-to-delivery interval and neonatal outcomes in Asians.

Methods

Study design and study population

This retrospective observational study was conducted at two tertiary centers in Japan to investigate the association between ACS-to-delivery interval and neonatal outcomes. We enrolled singleton neonates born at < 32 weeks of gestation at Nagoya University Hospital and the Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital between 2012 and 2020. In this study, neonates born at < 32 weeks were focused as previously reported [21]. In accordance with the relevant Japanese guidelines [7, 22, 23], ACS was administrated to pregnant women who were imminent for preterm birth within a week. The ACS regimen comprised two doses of betamethasone phosphate (12 mg) administered via intramuscular injection 24 h apart [7]. The exclusion criteria were as follows: congenital dysfunction or chromosomal abnormalities, neonates who received repeated courses of the ACS regimen, regimens other than those mentioned above, or those with missing data for the covariates included in the main analysis.

We categorized neonates into four groups based on the timing of ACS administration, as previously described [24]: The "no ACS" group comprised neonates born without receiving ACS; the "partial ACS" group included neonates who received the first dose of betamethasone phosphate, but were born within a 24-h interval before receiving the second dose; the "ACS 1–7" group comprised neonates who received the complete course of ACS and were born within 7 days of administration; and the "ACS ≥ 8" group encompassed neonates who received the complete ACS regimen and were born later than 7 days after administration.

Outcome measures

The primary outcome was treated RDS, diagnosed by clinicians based on clinical findings, including X-ray chest scan findings, microbubble test results, and the need for surfactant administration [25], since RDS is the main target of the preventive effect of ACS [15]. The secondary outcomes were severe IVH (grade ≥ 3 on the Papile classification [26]), treated PDA (requiring therapeutic indomethacin or surgery), NEC (grade ≥ 2 on the Bell classification [27]), neonatal sepsis (positive blood culture within the first 28 days of life) with classifying into early-onset (< 72 h after birth) and late-onset (≥ 72 h after birth) [28], BPD (requiring supplemental oxygen and/or positive-pressure respiratory support at 36 weeks of postmenstrual age [29, 30]), treated ROP (photocoagulation or use of vascular endothelial growth factor) [31], PVL (cystic PVL diagnosed by sonographic scan or magnetic resonance imaging) [32], death discharge, severe neurological injuries (including severe IVH, PVL, or death discharge), and the severe composite outcome (including severe IVH, NEC, neonatal sepsis, BPD, treated ROP, PVL, and death discharge). In addition, the composite outcomes of BPD or death, ROP or death, and PVL or death were evaluated, since BPD, ROP, and PVL could not be diagnosed after early neonatal death. Furthermore, severe composite outcome without BPD (a composite outcome of severe IVH, NEC, neonatal sepsis, treated ROP, PVL, and death discharge) was also assessed, due to the opposite effect of ACS on BPD.

Data collection

The following data were collected from the clinical records: ACS administration, maternal age, primiparity, delivery mode, spontaneous preterm birth, hypertensive disorders of pregnancy (HDP), histological chorioamnionitis (hCAM), funisitis, sex, gestational age at birth, birth weight, small for gestational age (SGA), Apgar score at 5 min, umbilical cord pH, and neonatal complications as the outcomes (treated RDS, severe IVH, treated PDA, NEC, neonatal sepsis, BPD, treated ROP, PVL, and death discharge from NICU).

The definitions for each diagnosis were as follows: SGA, birth weight below the 10th percentile according to a Japanese chart [33]; spontaneous preterm birth, birth due to spontaneous preterm labor starting with regular uterine contractions and cervical changes; HDP was defined according to the International Society for the Study of Hypertension in Pregnancy 2018 standards [34]; hCAM, stage ≥ II on the Blanc classification [35].

Our respiratory management

Although the attending physician has a certain degree of discretion, respiratory management is basically as follows:

  • In the case where there is only a decrease in SpO2 without respiratory distress such as retractions or tachypnea, oxygen therapy alone is administered.

  • If respiratory distress is observed, continuous positive airway pressure (CPAP), synchronized nasal intermittent positive pressure ventilation (SNIPPV), or high-flow nasal cannula (HFNC) is used.

  • In the acute phase, FiO2 and mean airway pressure (MAP) are adjusted to maintain SpO2 above 90–95.

  • If respiratory distress does not improve with CPAP, SNIPPV, or HFNC, intubation and mechanical ventilation are performed.

  • Although management with synchronized intermittent mandatory ventilation (SIMV) is primarily used during the acute phase, switching to high-frequency oscillatory ventilation (HFO) is considered if severe respiratory distress is present.

  • If high settings are necessary in the subacute phase or later with SIMV, consider changing to HFO or neurally adjusted ventilatory assist (NAVA).

  • In the subacute phase or later, adjust FiO2 and MAP to maintain SpO2 between 85–95.

Statistical analysis

Statistical analysis was performed using RStudio 2023.06.1 + 524 (Posit Software, MA, U.S.A.) and Easy R version 1.54 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a modified version of R and R Commander [36]. To assess the adjusted OR and 95% confidence interval (CI) of the incidence of each complication in the partial ACS, ACS 1–7, ACS ≥ 8 group compared with the no ACS group, logistic regression analysis was performed using gestational age at birth, sex, delivery type, SGA, and hCAM as covariates. These covariates were reportedly associated with multiple neonatal morbidities [37,38,39,40]. Multivariate analysis for neonatal sepsis was only performed for neonatal sepsis as a whole due to the small number of patients with early-onset sepsis. To assess the difference in intubation days between groups, multiple regression analysis was performed with the same covariates.

In the subsequent analyses, restricted cubic splines methods using the rms package in R were employed to create non-linear figures expressing the adjusted OR (with 95% CI) of the incidences of the complications at each time point from ACS administration [21]. The adjusted OR at each time point was calculated from the logistic regression model. The incidence of each complication in the no ACS group was set as a reference. The covariates for calculating adjusted OR were the same with logistic regression analyses as described above. Statistical significance was determined using a 95% CI.

Results

Study cohort and characteristics

The analysis included 625 neonates (Fig. 1). Table 1 presents the characteristics of the study participants. The overall rate of ACS administration was 76.8% (480/625), whereas the rate of ACS administration within 1–7 days before preterm birth was 49.1%. The four groups exhibited similar characteristics in terms of maternal age, primiparity, sex, and birth weight. Notably, the ACS ≥ 8 group had an earlier gestational age at the time of receiving ACS and at birth than the other groups. The partial ACS group was less likely to have undergone delivery via cesarean section. The ACS 1–7 group comprised a higher proportion of infants with HDP and who were SGA. Patients in the no ACS and partial ACS groups were less likely to experience hCAM and funisitis. Furthermore, the no ACS group was more likely to have a low Apgar score at 5 min and an umbilical cord pH < 7.1.

Fig. 1
figure 1

Flow chart of patient enrollment. ACS, antenatal corticosteroids

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Table 1 Background characteristics of the study participants
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Neonatal complications

Each incidence of treated RDS and the other complications is presented in Table 2. The overall incidence of treated RDS, BPD, and treated PDA was 48.5%, 33.9%, and 27.5%, respectively, whereas the overall incidence of severe IVH, NEC, PVL, and discharge due to death was relatively low (< 5%). The ACS 1–7 group had the lowest incidence of severe IVH (2.0%), treated PDA (22.5%), treated ROP (15.7%), and PVL (1.0%) among the four groups. The partial ACS group had the highest incidence of neonatal sepsis (both early- and late-onset neonatal sepsis).

Table 2 Incidence of neonatal complications
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In the adjusted model, the ACS 1–7 group showed a significantly decreased adjusted OR for RDS (0.36 [95% confidence interval: 0.23, 0.57]) compared with the no ACS group (Table 3). The ACS 1–7 group also showed significantly decreased adjusted ORs of severe IVH (0.21 [0.07, 0.63]), treated PDA (0.49 [0.31, 0.78]), and treated ROP (0.50 [0.25, 0.99]) compared with the no ACS group (Table 3). The ACS ≥ 8 group further showed significantly reduced adjusted ORs for RDS (0.37 [0.20, 0.66]) and treated PDA (0.52 [0.28, 0.98]) compared with the no ACS group. Conversely, the adjusted OR for BPD was significantly higher in ACS 1–7 (1.86 [1.06, 3.28]) and ACS ≥ 8 (2.94 [1.43, 6.05]) groups than that in the no ACS group. The partial ACS group had a higher trend of OR for the incidence of neonatal sepsis (3.22 [1.00, 10.4]), but this was not statistically significant. Total intubation days were not significantly different between groups after multiple regression analysis (Table S1).

Table 3 Multivariable analysis of the association between the ACS-to-delivery interval and adverse neonatal outcomes
Full size table

Missing data for BPD (n = 9), treated ROP (n = 11), and PVL (n = 7) because of death were observed in several patients. Therefore, we conducted further analyses of the composite outcomes, including BPD or death, treated ROP or death, and PVL or death (Table S2). This revealed that the ACS 1–7 group had a significantly lower OR for treated ROP or death (0.50 [0.26, 0.96]). Conversely, the ACS ≥ 8 group had a significantly higher OR for BPD or death (2.54 [1.23, 5.27]). Compared with the no ACS group, only the ACS 1–7 group had significantly lower adjusted OR for severe neurological injuries (0.44 [0.22, 0.90]) and severe composite outcomes without BPD (0.54 [0.31, 0.94]). However, in the analysis of severe composite outcomes, including BPD, the adjusted ORs were not significantly different among the four groups.

Subsequent analysis treating the ACS-to-delivery interval as a continuous variable revealed that the trough of adjusted ORs for certain outcomes occurred within 7 days of ACS administration (Fig. 2, Figure S1). The adjusted ORs for treated RDS (Fig. 2A), severe IVH (Fig. 2B), treated PDA (Fig. 2C), severe neurological injuries (Figure S1D), and severe composite outcomes without BPD (Figure S1E) were significantly reduced within 7 days of ACS administration. The risk reduction for RDS plateaued at 4–5 days post-ACS administration, and remained significant beyond 7 days following ACS administration (Fig. 2A). The decrease in the risk of severe IVH (Fig. 2B), treated PDA (Fig. 2C), severe neurological injuries (Figure S1D), and severe composite outcomes without BPD (Figure S1E) plateaued at 3 days post-ACS administration; however, its significance did not persist beyond 7 days. Similar trends were observed for treated ROP (Fig. 2G) and treated ROP or death (Figure S1B); however, these differences did not reach statistical significance. Conversely, the risk of BPD (Fig. 2F) and a composite of BPD or death (Figure S1A) increased significantly within 7 days following ACS administration and continued to increase beyond this period. The effects of ACS on NEC (Fig. 2D), neonatal sepsis (Fig. 2E), PVL (Fig. 2H), PVL or death (Figure S1C), death (Fig. 2I), and severe composite outcomes (Figure S1F) were not significant.

Fig. 2
figure 2

Association between timing of ACS and outcomes in infants born very preterm. The reference-adjusted OR (dashed line) represents the no ACS group. The curves for the adjusted ORs show the mean and 95% CI bands. A–E, n = 625. F, n = 613. G, n = 603. H, n = 618. I, n = 625. ACS, antenatal corticosteroids; OR, odds ratio; RDS, respiratory distress syndrome; IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; BPD, bronchopulmonary dysplasia; ROP, retinopathy of prematurity; PVL, periventricular leukomalacia

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Discussion

The present study demonstrated that the adjusted ORs for treated RDS and the other outcomes, such as severe IVH, treated PDA, treated ROP, composite of treated ROP or death, severe neurological injuries, and severe composite outcome without BPD were significantly lower in the ACS 1–7 group than those in the no ACS group among Japanese infants. Some of these values were less than half of those in the no ACS group. Furthermore, the adjusted ORs of treated RDS and treated PDA were significantly reduced in the ACS ≥ 8 groups compared with those in the no ACS group. In contrast, the adjusted OR of BPD was approximately threefold and twofold higher in the ACS ≥ 8 and ACS 1–7 groups, respectively, compared with that in the no ACS group. The adjusted OR of a composite of BPD or death was also higher in the ACS ≥ 8 group. Moreover, partial ACS administration showed no significant effect on outcomes compared with the no ACS group but showed a higher trend in neonatal sepsis. A subsequent analysis considering the ACS-to-delivery interval as a continuous variable corroborated these findings and illustrated the temporal changes in the effect of ACS.

Both our and prior studies showed that the effect of ACS on reducing RDS is likely to continue even after eight days following treatment. In 2006, a Cochrane review using a subgroup analysis suggested that the optimal ACS-to-delivery interval to prevent RDS was 1–7 days [6]. However, a recent systematic review speculated that RDS might be reduced when ACS were administered at 1–7 and ≥ 8 days before delivery, although it concluded that the optimal interval was difficult to identify [14]. These reviews included studies mostly from Western countries; however, the findings of the present study conducted in Japan are in agreement with these past reviews.

The effect of ACS on reducing severe IVH and severe neurological injuries followed a similar trend to its effect on RDS. In the present study, a significant reduction in the incidence of severe IVH and severe neurological injuries from day 1 to 7 of ACS administration and a trend toward reduction after day 8 were observed; however, the latter did not reach significance. These results are consistent with the findings of previous large observational studies [21, 24]. Additionally, our previous report demonstrated an association between ACS and lower levels of brain injury markers in cord blood when administered within 1–7 days of delivery; however, this was not significant at ≥ 8 days [41]. In a recent systematic review of 20 cohort studies, optimal ACS-to-delivery intervals for preventing IVH were 1–7 days in six studies and ≥ 8 days in five studies [14]. These inconsistencies may be related to variations in study populations, such as differences in the gestational weeks in the inclusion criteria or in the prevalence of IVH or severe neurological injuries between countries. The present study suggested that the effects of reducing severe IVH and severe neurological injuries were gradually attenuated after day 3 of ACS administration, which is consistent with a previous report conducted in European countries [21].

The present study demonstrated that ACS was significantly associated with a reduced incidence of treated PDA within days 1–7 and after day 8 of ACS administration, which is consistent with previous studies [42, 43]. However, the effects of ACS on PDA remain controversial. In a small cohort study of neonates with and without hCAM, ACS was associated with an increased and decreased incidence of PDA, respectively [44]. Indeed, a meta-analysis reported no association between ACS and the incidence of PDA; however, this meta-analysis included only three observational studies for the adjusted analysis [45]. A more recent observational study in Korea enrolling 2,961 infants born at 22–29 weeks of gestation showed that complete ACS was significantly associated with a reduced incidence of symptomatic PDA [46]. This effect was also observed in a subgroup analysis at 26–29 weeks, but not at 22–25 weeks [46]. These inconsistent results may depend on the differences in the effect of ACS on ductus constriction at various gestational ages [43].

The adjusted OR for neonatal sepsis tended to be higher in the partial ACS group. While some studies have reported an increase in neonatal sepsis following multiple courses of ACS after premature rupture of membranes, the incidence of neonatal sepsis by two courses of ACS has been reported to be equivalent to that by a single course [47]. Additionally, neonatal sepsis did not increase after a single course of ACS [48, 49]. Thus, the rationale for the higher adjusted OR for neonatal sepsis in the partial ACS group remains unclear. Clinical reasons for not administering ACS in full may also have influenced the incidence of neonatal sepsis. Further studies are needed to confirm the association between the ACS-to-delivery interval and neonatal sepsis.

Two recent meta-analyses supported the association between ACS and a lower incidence of ROP [50, 51]. However, few studies have indicated an association between the ACS-to-delivery interval and ROP incidence as a single outcome. Herein, we showed that the adjusted ORs of treated ROP and the composite of treated ROP or death were reduced by approximately half in the ACS 1–7 group compared with that in the no ACS group, with significant differences observed in the composite outcome. Similarly, Melamed et al. reported the incidence of stage ≥ 3 ROP according to ACS-to-delivery intervals; however, they did not find any effect of ACS administration being superior at any interval when compared with the no ACS administration as reference [24]. In the present study, treated ROP was defined as a treatment at any stage, which may explain the variation in the study results. Current ROP management guidelines, influenced by The Early Treatment for Retinopathy Of Prematurity (ETROP) study, recommend treating not only stage 3 ROP but also cases of stages 1 and 2 ROP, depending on the zone and prevalence of plus disease [52]. Therefore, our definition may better reflect clinical practice.

This study further showed that ACS might increase the incidence of BPD and a composite of BPD or death. Furthermore, the adjusted OR for BPD was higher in the ACS ≥ 8 group than that in the ACS 1–7 group, consistent with a previous study [53]. In agreement, a meta-analysis failed to demonstrate a reduced incidence of BPD due to ACS [15]. Furthermore, it has been repeatedly shown that ACS is associated with an increased risk of BPD in nationwide studies in Japan [25, 54] and Switzerland [55]. Another meta-analysis showed an association between ACS and an increased incidence of BPD in neonates born at < 25 weeks of gestation [56], despite strong evidence of the preventive effect of ACS on RDS. This paradoxical effect of ACS on BPD may be due to the increased survival of very immature infants at a high risk of BPD [57], although our data showed an increased composite outcome of BPD or death. The complete pathological mechanisms underlying the role of ACS in BPD development remain largely unknown. A previous animal study showed that ACS acutely promotes fetal lung maturation, but subsequently inhibits alveolarization and lung growth [58]. They further reported that ACS suppressed endotoxin-induced inflammation in the fetal lung 1 day after treatment, but paradoxically amplified endotoxin-induced lung inflammation at 5 and 15 days after treatment [59]. Although these phenomena have not been directly investigated in humans, the results of animal studies support our findings. As inflammation is not only the main cause of preterm birth, but is also believed to be central to the pathogenesis of BPD [60], the paradoxical enhancement lung inflammation by ACS may lead to BPD. Our data suggest that an ACS-to-delivery interval of no more than 7 days may minimize the potential risk of ACS in BPD. To prevent BPD, medications other than ACS administration may be required [60]. Furthermore, the present study failed to show a reducing effect of ACS on severe composite outcomes, including BPD, as an increase in BPD offset the reduction in other complications, including neurological complications. However, the preventative effect of ACS on severe IVH and severe brain injury cannot be ignored, and the results of present study certainly do not negate the efficacy of ACS. Consequently, it may be essential to reevaluate the impact of ACS during each week of gestation, considering the extent of influence of each complication on the quality of life and specific weeks when they most commonly occur.

Several guidelines recommend that a single repeat course of ACS should be considered in women at < 34 weeks of gestation who received a prior course of ACS more than 7 or 14 days previously and are still at risk of preterm birth within 7 days. However, our data suggest that the preventive effects of ACS on RDS and PDA may continue even longer than 7 days of administration. Recently, the secondary analysis of The Multiple Courses of Antenatal Corticosteroids for Preterm Birth (MACS) trial was published, with the results demonstrating that neonatal mortality and severe morbidities were not improved by a second course of ACS [61]. These findings suggest the need to reconsider the timing and dosage of a single repeat course of ACS.

This study had certain limitations. First, although, to the best of our knowledge, it is the largest investigation of the association between ACS-to-delivery interval and neonatal outcomes in Japan, the number of neonates with complications may not have been sufficient for a robust analysis. This limitation may explain the loss of significance in some of the results when the ACS-to-delivery interval was analyzed as a continuous variable. Second, there were several potential selection biases exist in this study. For example, the ACS ≥ 8 group had an earlier gestational age at the time of receiving ACS and at birth, and hCAM was more common in the ACS 1–7 and ACS ≥ 8 groups. Although we have endeavored to minimize bias by performing multivariate analysis, both small gestational age and hCAM were reportedly associated with the development of BPD [58, 60]. Third, postnatal treatments were not included in the analysis, as in previous reports [21, 24]. However, as this was a collaborative study of two tertiary centers, as opposed to a national survey, we believe that the impact of differences in neonatal treatment strategies on the results would be minimal. At least, there was no significant difference among four groups for prophylactic indomethacin administration (p = 0.296, chi-square test, data not shown). Fourth, although a reducing effect on RDS and treated PDA was shown even beyond 8 days after ACS administration, we could not determine how long the effect of ACS would continue after treatment. Further studies are required to confirm the duration of the effects of ACS in Asian populations.

Conclusions

This study investigated the effect of the ACS-to-delivery interval on complications in very early preterm infants in Japan. Overall, our results showed that an ACS-to-delivery interval of 1–7 days achieved the lowest incidence of RDS, other several complications, and severe composite outcomes without BPD in preterm neonates born at < 32 weeks of gestation. Further analysis revealed that some of the favorable effects of ACS continue even beyond ≥ 8 days from administration. In contrast, ACS might be associated with the increased incidence of BPD, and this effect was most prominent in neonates delivered ≥ 8 days after receiving ACS. However, we believe it is not yet appropriate to withhold the use of ACS for the purpose of the prevention of BPD. Based on these findings, the duration of the effect of ACS on neonatal complications should be studied further, particularly in Asian populations where data is limited.

Availability of data and materials

The data supporting the findings of this study are available in the Supplementary Material.

Data availability

Data is provided within supplementary information.

Abbreviations

RDS:

Respiratory distress syndrome

IVH:

Intraventricular hemorrhage

PDA:

Patent ductus arteriosus

NEC:

Necrotizing enterocolitis

BPD:

Bronchopulmonary dysplasia

ROP:

Retinopathy of prematurity

PVL:

Periventricular leukomalacia

ACS:

Antenatal corticosteroids

ACS-to-delivery interval:

Interval from ACS administration to delivery

NICU:

Neonatal intensive care unit

HDP:

Hypertensive disorders in pregnancy

hCAM:

Histological chorioamnionitis

SGA:

Small for gestational age; OR, odds ratio

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Acknowledgements

We would like to thank Dr. Fumie Kinoshita (Department of Advanced Medicine, Data Science Division, Data Coordinating Center, Nagoya University Hospital, Nagoya) for her advice on the analysis of the restricted cubic spline method. We would like to thank Editage (www.editage.jp) for English language editing.

Funding

This work was supported by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (grant number 22K09638).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan

    Kazuya Fuma, Tomomi Kotani, Sho Tano, Takafumi Ushida, Kenji Imai & Hiroaki Kajiyama

  2. Division of Reproduction and Perinatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8560, Japan

    Tomomi Kotani & Takafumi Ushida

  3. Department of Obstetrics and Gynecology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, 453-8511, Japan

    Hiroyuki Tsuda

  4. Department of Pediatrics, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, 453-8511, Japan

    Makoto Oshiro

  5. Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Aichi, Japan

    Yoshiaki Sato

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  1. Kazuya Fuma
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Contributions

KF: conceptualization, investigation, writing—original draft. TK: conceptualization, investigation, project administration, writing—original draft, review and editing, funding acquisition. HT: investigation, data curation, project administration, writing—review and editing, MO: investigation, data curation, writing—review and editing. ST: data curation, investigation, investigation, writing—review and editing. TU: investigation, writing—review and editing. KI: data curation, investigation, writing—review and editing. YS, investigation, data curation, writing—review and editing. HK: investigation, writing—review and editing, supervision.

Corresponding author

Correspondence to Tomomi Kotani.

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Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki and all other relevant guidelines and regulations, and was approved by The Institutional Ethics Boards of Nagoya University Hospital (approval numbers: 2018–0026) and Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital (approval numbers: 2022–460). The requirement for informed consent was waived by these two Institutional Ethics Boards in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan.

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Fuma, K., Kotani, T., Tsuda, H. et al. Impact of antenatal corticosteroids-to-delivery interval on very preterm neonatal outcomes: a retrospective study in two tertiary centers in Japan. BMC Pregnancy Childbirth 24, 607 (2024). https://doi.org/10.1186/s12884-024-06790-8

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BMC Pregnancy and Childbirth

ISSN: 1471-2393

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