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Learn more: PMC Disclaimer | PMC Copyright Notice BMC Pregnancy Childbirth . 2026 Mar 12;26:403. doi: 10.1186/s12884-026-08909-5 Search in PMC Search in PubMed View in NLM Catalog Add to search Association between timing of antenatal corticosteroid and developmental outcomes in children born late preterm by high-risk pregnancies Hao-Wei Chung Hao-Wei Chung 1 Department of Pediatrics, Division of Neonatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 2 Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan 3 Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Find articles by Hao-Wei Chung 1, 2, 3, 4 , Chia-Hung Yu Chia-Hung Yu 5 Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan 6 Department of Computer Science and Information Engineering, Southern Taiwan University of Science and Technology, Tainan, Taiwan Find articles by Chia-Hung Yu 5, 6 , Chiao-Yun Huang Chiao-Yun Huang 7 Department of Public Health, College of Health Sciences, Kaohsiung Medical University, No. 100, TzYou 1st Rd, Kaohsiung, 80756 Taiwan Find articles by Chiao-Yun Huang 7 , Fu-Wen Liang Fu-Wen Liang 7 Department of Public Health, College of Health Sciences, Kaohsiung Medical University, No. 100, TzYou 1st Rd, Kaohsiung, 80756 Taiwan 8 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 9 Center for Big Data Research, Kaohsiung Medical University, Kaohsiung, Taiwan Find articles by Fu-Wen Liang 7, 8, 9, ✉ Author information Article notes Copyright and License information 1 Department of Pediatrics, Division of Neonatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 2 Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan 3 Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan 6 Department of Computer Science and Information Engineering, Southern Taiwan University of Science and Technology, Tainan, Taiwan 7 Department of Public Health, College of Health Sciences, Kaohsiung Medical University, No. 100, TzYou 1st Rd, Kaohsiung, 80756 Taiwan 8 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 9 Center for Big Data Research, Kaohsiung Medical University, Kaohsiung, Taiwan ✉ Corresponding author. Received 2025 Apr 30; Accepted 2026 Mar 3; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13077810 PMID: 41820888 Abstract Objective High-risk pregnancies often receive antenatal corticosteroids (ACS) before 34 weeks, even when delivery occurs in the late preterm period. We aimed to evaluate whether the timing of ACS exposure is associated with developmental delay in late preterm infants born to high-risk mothers. Methods We conducted a national, retrospective cohort study of 40,119 singleton late preterm (LPI) live births born in Taiwan between January 1, 2004, and December 31, 2011, followed up until December 31, 2018. We defined high-risk pregnancies based on four clinical conditions: diabetes mellitus, advanced maternal age, hypertensive complications, and cesarean delivery, identified from claims data . The primary outcome is developmental delay (DD). Results Among 40,119 LPI, 4,730 (11.8%) had exposure to ACS, with the majority (68.4%) exposed to ACS before 34 weeks. Compared to LPT without ACS exposure, those exposed to ACS at 34–36 weeks showed no increased risk of DD (aHR: 0.93[95% CI, 0.80–1.09]), whereas those with ACS before 34 weeks had significantly elevated risk of DD (aHR: 1.12 [95% CI, 1.01–1.24]), especially in infants born to diabetic or older age mothers (aHR: 1.43 [95% CI, 1.13–1.80]; 1.48 [95% CI, 1.11–1.97]). Conclusion Exposure to ACS at 34–36 weeks was not associated with an increased risk of DD in any high-risk pregnancy subgroup. In contrast, ACS exposure before 34 weeks, particularly among infants born to mothers with diabetes or of advanced maternal age, was associated with a modestly elevated risk. These findings suggest potential susceptibility in specific high-risk groups not previously recognized, underscoring the need for further research. Keywords: Antenatal Corticosteroid, Late Preterm Infants, Development Delay Article summary Antenatal corticosteroids before 34 weeks are associated with an increased risk of developmental delay in late preterm infants, particularly in diabetic mothers and elder pregnant women whereas exposure during the late preterm period had no significant effect. What’s known on this subject An inconclusive relationship between developmental delay in late preterm infants and antenatal corticosteroid treatment, especially regarding different timings of exposure and complicated pregnancies, impacts weighing the benefits and harms of corticosteroids for late preterm laboring mothers. What this study adds Antenatal corticosteroid treatment before 34 weeks increases the risk of developmental delay in late preterm infants, especially infants born by diabetic mothers. Corticosteroid treatment at 34–36 weeks had no association with developmental delay in late preterm infants . Introduction Since the first clinical trial in 1972, supporting evidence has revealed that antenatal corticosteroids (ACS) reduce the risk of perinatal death, neonatal death, and respiratory distress syndrome in preterm infants before 34 weeks of gestation [ 1 , 2 ]. Late preterm infants (LPI), born between 34 weeks 0 days (34 + 0 ) and 36 weeks 6 days (36 + 6 ) gestation, comprise nearly 75% of preterm birth and account for 8% of total deliveries [ 3 ]. Although respiratory conditions in LPI are typically less severe than in very preterm infants, studies have shown that the use of ACS can reduce hospital costs, short-term morbidity, and mortality in this population [ 4 – 6 ]. Given these benefits, the use of ACS has steadily increased among women at risk of late preterm delivery over the years [ 7 ]. However, despite these benefits, the routine use of ACS for late preterm remains inconclusive [ 8 , 9 ]. A primary concern arises regarding the long-term sequelae, because studies have shown adverse neurological effects in animals exposed to ACS [ 10 ]. Additionally, a meta-analysis of 30 studies revealed a correlation between ACS exposure and a higher risk of neurodevelopmental impairment in LPI [ 11 ]. As a result, several committees have revisited their recommendations regarding the administration of ACS to women likely to deliver after 34 weeks of gestation [ 12 ]. In addition to concerns about long-term neurodevelopment, growing evidence has shown that the timing of ACS exposure may also influence short-term neonatal outcomes, even among term-born infants. A recent population-based study found that infants exposed to ACS between 28 and 33 weeks of gestation had higher risks of respiratory complications and jaundice, despite ultimately being delivered at term [ 13 ]. These findings underscore the importance of considering gestational age at the time of ACS administration, beyond simply whether or not ACS was given. Most existing studies have treated ACS exposure as a binary variable, regardless of the gestational timing of administration. Yet, in real-world clinical practice, especially among high-risk pregnancies with diabetes, hypertensive disorders, or advanced maternal age, ACS is often administered before 34 weeks in anticipation of earlier delivery, even when delivery ultimately occurs in the late preterm window. This mismatch between exposure and birth timing introduces uncertainty regarding the true neurodevelopmental risk of ACS in LPI . The gap between current evidence and practice lies in the lack of detailed information regarding the timing of ACS administration in most studies [ 11 , 12 ]. For better clarification between anticipated benefits and potential risks, it is essential to assess how different timing of exposure to ACS for late preterm birth influences fetal brain development. This study aims to examine whether different exposure periods of ACS in LPI are linked with developmental delay (DD) in a large, population-based birth cohort in Taiwan. Materials and methods Data source and study population To prepare data for this retrospective cohort study, we used several population-based data sources provided by the Health and Welfare Data Science Center, Ministry of Health and Welfare [ 14 ], including the Birth Notification Database (BND), the Taiwan Maternal and Child Health Database (TMCHD), and the National Health Insurance Research Database (NHIRD). According to Taiwanese law, hospitals or clinics are obligated to notify the health department when delivering a birth with a birth weight of more than 500 g or gestational age(GA) of more than 20 weeks. The BND encompasses maternal demographics, health behaviors, obstetric complications, intrapartum interventions, fetal anomalies, and birth outcomes. The TMCHD provides parent-child pairings, enabling us to identify children’s scramble IDs for each specific mother. In Taiwan, the National Health Insurance (NHI)program covered 99% of the 23.74 million residents, with up to 97% of medical records from the insured population being recorded in the NHIRD [ 14 , 15 ]. The diagnostic codes were based on the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes (or ICD-10-CM since 2016), and the accuracy of diagnosis in NHIRD has been validated in previous studies [ 16 ]. In this nationwide study, we first included all singleton live births listed in the linked TMCHD and BND between 2004 and 2011. We included infants born between 34 + 0 and 36 + 6 weeks of gestation to mothers who were hospitalized during pregnancy with a diagnosis of threatened preterm labor (ICD-9-CM code 644.x), representing those at risk of preterm birth . Births delivered by women who had chemotherapy or radiotherapy during pregnancy, those without a risk of early or threatened labor during pregnancy, those not born at 34 to 36 weeks of gestation, or those with congenital anomalies were excluded, leaving 50,645 LPI eligible for enrollment. All subjects were followed up until December 31, 2018. The Institutional Review Board of the Chi Mei Medical Center approved this study (IRB number: 11105-E04) and waived the requirement of informed consent because the retrospective patient information was de-identified. Exposure to ACS Maternal ACS use was obtained from the hospital prescription database in NHIRD, which provided the name of the drug with cumulative dosage during hospitalization. In Taiwan, pregnant women at risk of preterm labor would receive either two doses of 12-mg betamethasone every 24 h or four doses of 6-mg dexamethasone every 12 h, in accordance with the guidelines of American College of Obstetricians and Gynecologists [ 17 ]. To investigate the effect of ACS, mothers were considered to have received ACS for preterm labor if they were admitted with a diagnosis of preterm labor (ICD-9-CM: 644) and received the recommended dosage of betamethasone or dexamethasone (ATC code: H2AB01, H02AB02). We excluded infants born to women receiving ACS before 21 weeks of gestation or both before and after 34 weeks. Infants were categorized into three groups: those born to women never exposed to ACS, those born to women who received ACS before 34 weeks, and those born to women who received ACS between 34 and 36 weeks. Outcome The study defined the outcome of interest as the presence of DD (ICD-9-CM codes 315.0- 315.9), which was confirmed by at least two ambulatory clinic visits. Standardized diagnostic tools, widely available across professional departments in Taiwan, supported these assessments. Since formal diagnostic codes for developmental conditions can only be issued by licensed child psychologists, and pediatrician, the criteria and assessment processes have been regularly reviewed and updated through collaboration between government authorities and assessment centers since 1996 . Covariates Potential maternal confounders included age at delivery (< 35 vs. ≥35 years), mode of delivery (cesarean section vs. spontaneous vaginal delivery), parity (nulliparous vs. multiparous), level of urbanization (cities, towns, rural areas) [ 18 ] determined by the mother’s place of residence, family income status, preterm premature rupture of membranes (PPROM) (ICD-9-CM code 658.1), gestational diabetes mellitus/diabetes mellitus (GDM/DM) (ICD-9-CM code 648 and 250), hypertensive complications including chronic hypertension, pregnancy-induced hypertension, and preeclampsia (ICD-9-CM codes 401–405 and 642), mental and behavioral disorders (ICD-9-CM codes 290–319), and autoimmune disease (ICD-9-CM codes 340, 710.0–4,714.3, 555. X, and 556. X). Neonatal characteristics included GA at birth (weeks), sex, 5-minute Apgar score (< 7 vs. ≥7), small for gestational age (SGA) (birth weight < 10th percentile for gestational age according to national reference), admission to NICU, resuscitation, mechanical ventilation, and nasal prong continuous positive airway pressure (NCPAP), were considered as the potential confounders. All covariates were derived from the National Health Insurance claims database or the Birth Notification Database using standardized coding and procedures routinely applied in Taiwan. Variables lacking universally accepted definitions were operationalized according to local clinical guidelines and dataset coding conventions. Statistical analysis Maternal and neonatal characteristics were presented as numbers and percentages, and the associations between these characteristics and maternal ACS exposure were examined using the test. The multivariable Cox proportional hazards model was used to estimate the hazard ratios and 95% confidence intervals (CI) for the association between exposure to maternal ACS and childhood developmental delay considering potential confounders. The proportionality assumption for the Cox regression model was assessed graphically by examining log-log survival curves and formally tested by including interactions between predictors and event time in the proportional hazards model. No obvious violation was found. All data linkages and analyses were performed from Jan 21 to Sep 29, 2022, using SAS 9.4 (SAS Institute Inc., Cary, North Carolina). Results Characteristics of ACS-exposed and non-exposed late preterm infants Of 50,645 infants born between 34 + 0 through 36 + 6 weeks of gestation from 2004 to 2011, 40,119 were eligible for analysis. Among the 4,730 children born to women receiving ACS, 1,495 (31.6%) were exposed to ACS between 34 and 36 weeks, while 3,235 (68.4%) were exposed before 34 weeks (Fig. 1 ). Fig. 1. Open in a new tab Flowchart of the study population selection. TMCHD: Taiwan Maternal and Child Health Database; BND: Birth Notification Database; ACS: Antenatal corticosteroids The maternal and neonatal characteristics of the two exposed groups and the non-exposed group are reported in Table 1 . Women who received ACS before 34 weeks delivered infants earlier in gestation (34.7% at 34 weeks of gestation), had a lower rate of GDM/DM (10.3%), and were more often primiparous (66.0%). LPI born to women who received ACS before 34 weeks were less likely to be SGA (7.6%), but were more often received NCPAP (14.4%) and be admitted to the NICU (57.9%). Mothers who did not receive ACS had higher rates of hypertensive complication (7.6%) and PPROM (12.6%). Most babies in the non-exposed group were born later in gestation (64.5% at 36 weeks) and were male (56.6%). Women who received ACS at 34–36 weeks were younger, less likely to reside in urban areas, and experienced less labor induction (3.8%) and cesarean Sect. (37.3%). All the children were followed for a median of 9.7 years (interquartile range, 7.3–12.3). Table 1. Characteristics of the study population according to timing of exposure to antenatal corticosteroids treatment Variables Non-exposed N = 35,389 Exposed P -value Before 34 weeks N = 3,235 34–36 weeks N = 1,495 Maternal Age ≧ 35 6,691 (18.9) 589 (18.2) 212 (14.2) < 0.001 Urbanization < 0.001 Cities 19,302 (54.5) 1,641 (50.7) 656 (43.9) Towns 12,498 (35.3) 1,222 (37.8) 629 (42.1) Rural areas 3,589 (10.1) 372 (11.5) 210 (14.1) Low income 274 (0.8) 17 (0.5) 7 (0.5) 0.130 Comorbidities Hypertensive complications a 2,693 (7.6) 138 (4.3) 64 (4.3) < 0.001 GDM/DM 4,241 (12.0) 332 (10.3) 174 (11.6) 0.015 Autoimmune disease 541 (1.5) 56 (1.7) 24 (1.6) 0.660 Obstetric condition Primiparous 22,519 (63.6) 2,136 (66.0) 906 (60.6) 0.001 Induction labor 2,532 (7.2) 198 (6.1) 57 (3.8) < 0.001 PPROM 4,461 (12.6) 224 (6.9) 52 (3.5) < 0.001 Caesarean section 14,721 (41.6) 1,380 (42.7) 557 (37.3) 0.002 Hospital level < 0.001 Hospital 34,205 (96.6) 2,924 (90.4) 1,299 (86.9) Clinic or other 1,184 (3.4) 311 (9.6) 196 (13.1) Week < 0.001 34 3,612 (10.2) 1,123 (34.7) 153 (10.2) 35 8,957 (25.3) 760 (23.5) 663 (44.4) 36 22,820 (64.5) 1,352 (41.8) 679 (45.4) Neonatal condition Male 20,035 (56.6) 1,911 (59.1) 872 (58.3) 0.013 SGA 3,669 (10.4) 247 (7.6) 171 (11.4) < 0.001 5 min Apgar score < 7 323 (0.9) 25 (0.8) 9 (0.6) 0.347 Resuscitation 186 (0.5) 14 (0.4) 12 (0.8) 0.258 NICU admission 18,947 (53.5) 1,873 (57.9) 736 (49.2) < 0.001 NCPAP 3,723 (10.5) 467 (14.4) 135 (9.0) < 0.001 Mechanical ventilation 1,451 (4.1) 139 (4.3) 54 (3.6) 0.542 Open in a new tab GDM Gestational diabetes mellitus, DM Diabetes mellitus, PRROM Preterm premature rupture of membrane, SGA Small for gestational age, NICU Neonatal intensive care unit, NCPAP Nasal continuous airway pressure a Includes chronic hypertension, pregnancy-induced hypertension, and preeclampsia Developmental delay in different timing of ACS-exposed and non-exposed late preterm infants In the overall cohort, the crude rate of DD significantly differed among the three groups (p-value = 0.007). LPI exposed to ACS before 34 weeks had the highest rate of DD (13.5%) compared with 11.8% in the non-exposed LPIs and 10.7% in those exposed at 34–36 weeks (Fig. 2 ). We further observed that the cumulative incidence of DD for ACS exposed LPI before 34 weeks was significantly greater than that for the non-exposed LPI (p-value = 0.002), but no significant difference was found between the LPI exposed to ACS between 34 and 36 weeks and non-exposed LPI (p-value = 0.277) (Fig. 3 ). In multivariable Cox regression adjusting for potential covariates, ACS exposure before 34 weeks was associated with an increased risk of DD (adjusted hazard ratio (aHR): 1.12 [95% CI, 1.01–1.24]), whereas exposure between 34 and 36 weeks was not significantly different from non-exposure (aHR: 0.93[95% CI, 0.80–1.09]). (Fig. 2 ). Fig. 2. Open in a new tab Unadjusted cumulative incidence curves and adjusted hazard ratios for developmental delay in childhood among late preterm infants by timing of antenatal corticosteroid exposure. *Adjusted hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards models, controlling for maternal and neonatal covariates listed in Table 1 . Abbreviations: ACS, antenatal corticosteroids; DD, developmental delay Fig. 3. Open in a new tab Comparison of cumulative incidence of DD between different timing of ACS exposure and non-exposed infants. a exposed at 34-36 weeks. b exposed before 34 weeks. ACS: Antenatal corticosteroids DD: developmental disorders.DD: developmental disorders The effect of ACS timing on development delay among specific late-preterm subgroups In subgroup analysis, variations were observed in both crude proportions and adjusted risks of developmental delay among specific late-preterm groups (Fig. 2 ). Among LPI born to mothers aged 35 years or older, the crude proportions of DD were 15.2% for those exposed to ACS before 34 weeks, 11.8% for those exposed between 34 and 36 weeks, and 10.9% for non-exposed LPIs, with a significant difference across the three groups (p-value = 0.0012). In multivariable Cox regression, ACS exposure before 34 weeks remained associated with an increased risk of DD compared with non-exposure. By contrast, there was no significant differences in crude DD proportions among LPI born to mothers with GDM/DD (p-value = 0.057), those with hypertensive complications (p-value = 0.429), or those delivered via caesarean section (p-value = 0.131). After adjusting for covariates, ACS exposure before 34 weeks was associated with higher risks of DD among LPI born to women with GDM/DM compared to non-exposed LPI. No significant associations were observed among LPI born to women with hypertensive complications (aHR: 1.10[95%CI, 0.73–1.67]) or those delivered by cesarean section (aHR: 1.09[95%CI, 0.94–1.26]). For ACS exposure between 34 and 36 weeks, no significant differences in DD risk were observed within any of the subgroups. Discussion In this large population-based cohort, we found no statistically significant association between ACS administration at 34 to 36 weeks’ gestation and the incidence of DD among LPI. However, we did observe a higher risk of DD in LPI exposed to ACS before 34 weeks’ gestation compared with those not exposed. We further found that the effect of ACS exposure on the risk of DD varied across several LPI subgroups. Compared with the non-exposed group, LPI born to women with GDM/DM or advanced maternal age had a higher risk of DD when exposed to ACS before 34 weeks. However, our study did not find a significant adverse effect of ACS exposure among LPI born to women with hypertensive complications or cesarean sections, nor did it find any significant effect based on infant gender. A large cohort study in Finland found an association between preterm infants exposed to ACS and an increased risk of psychological development disorders [ 19 ]. The meta-analysis concluded that ACS for LPI increased the risk of neurocognitive disorders based on retrospective studies ( n = 25,668 children: aHR: 1.12 [95% CI, 1.05–1.20]) [ 11 ]. However, most of these studies did not report the timing of ACS exposure and did not specifically focus on LPI. A general population study in Taiwan demonstrated that exposure to ACS during late preterm periods did not increase the risk of any specific mental disorder for LPI [ 20 ]. The follow-up study of the antenatal late preterm steroids (ALPS) randomized trial demonstrated that infants who received ACS did not exhibit significant impact on neurodevelopment outcomes [ 21 ]. Hutcheon et al. found that exposure to ACS immediately before and after 34 weeks of gestation resulted in no difference in child development test scores at school age using linked population health and education databases from British Columbia, Canada [ 22 ]. In addition, our findings are consistent with those of a national retrospective study conducted in Canada, which revealed that children born late preterm and exposed to ACS before 34 weeks had an increased adjusted risk of developing neurocognitive disorders [ 23 ]. In specific subgroups, associations indicating an increased risk of DD among infants exposed to ACS before 34 weeks of GA were found for those whose mother were older or had GDM/DM. According to current guidelines, ACS administration in diabetic mothers for preterm birth between 24 and 34 weeks is well established, and there are no specific cautions regarding maternal age [ 16 ]. Additionally, an observational study conducted in the general population in the UK found that increasing maternal age was positively associated with improved health and development outcomes in children up to 3 years of age, particularly in language development and reduced social-emotional difficulties [ 24 ]. However, when considering the steroid hormones at the maternal-fetal interface, studies have revealed that elevated androgen levels in women of advanced maternal age exhibit a positive correlation with adverse pregnancy complications [ 25 ]. The presence of diabetes in mother has been recognized as a risk factor of developing neurodevelopmental disorders for children in the general population [ 26 ]. Although maternal diabetes does not seem to alter the neonatal impact of ACS for short-term morbidities [ 26 , 27 ], the long-term impact of ACS in these infants remains inconclusive. The proposed mechanism by which ACS influence fetal brain development involves modulation of neurogenesis and gliogenesis during a critical stage when gyral and sulcal formation is still ongoing, accounting for approximately 65% of the term brain weight [ 28 ]. Besides, excess steroid would make maternal hormonal disequilibrium leading to an elevation in glucocorticoid release, impairing progesterone secretion, and potentially initiating intrauterine inflammation [ 29 ]. An adverse intrauterine environment in these specific pregnant women could be a possible mediator of lasting effects on the child’s developmental and health outcomes [ 30 ]. A national cohort study from Taiwan demonstrated that among infants born at term, ACS exposure before 34 weeks was associated with a higher risk of childhood mental disorders, particularly ADHD and developmental delay (DD), but only in early-term births—not in those born full term [ 31 ]. All of these demonstrate that, despite the safety and potential benefits of ACS use in specific groups at risk of preterm birth [ 32 ], further research is needed to investigate long-term effects, taking individual characteristics such as maternal conditions into consideration. Our research findings highlight the importance of conducting a thorough investigation into the effects of ACS on LPI with identical exposure times. Therefore, future research should aim to elucidate the mechanisms underlying these effects, as well as to develop strategies to mitigate potential harm to fetal health and development. The present study has several notable strengths. This nationwide cohort study interlinked data among the Birth Notification, NHI medical claims, and Maternal and Child Health databases, providing comprehensive information about parent-child pairs and considerably reducing the likelihood of incomplete information due to follow-up loss. Unlike most studies, this study exclusively selected children born to women ever admitted for threatened preterm labor to ensure comparability in the control group. Despite the selection criteria, this population-based study included a large number of participants, thereby providing sufficient statistical power to detect even small magnitudes of increased risks of DD. Furthermore, the study examined the timing of ACS administration and the outcome of LPI born to mothers with different complicated, offering valuable insights for further investigation into the knowledge gap surrounding the use of ACS in these populations. This study has several limitations inherent to its retrospective design. First, all covariates, including the definition of high-risk pregnancy, were identified primarily using ICD and management codes. While this approach is common in administrative data, some maternal diagnoses may be misclassified or underestimated due to limited clinical detail, despite using a nationwide, single-payer insurance database [ 33 ]. Second, some residual confounding factors related to adverse childhood neurodevelopment could not be captured due to data limitations. These include neonatal hypoglycemia and neonatal infection, for which specific clinical or laboratory details were not available. While NICU admission was included as a proxy for neonatal illness severity, we were unable to isolate the independent effects of specific complications. Other unmeasured factors include maternal obesity, smoking, parental education level, paternal disease history, and family environment [ 34 ]. In addition, data on children’s participation in rehabilitation program were not available and may have influenced the ascertainment of DD diagnosis. Third, while multiple courses of ACS are no longer recommended in current guidelines [ 35 ], our dataset only allowed us to identify the first recorded maternal ACS prescription with appropriate dosage. Infants exposed to ACS before 34 weeks may have been more likely to receive repeat or “rescue” courses, which could partially account for the increased risk of developmental delay observed in this subgroup. However, we were unable to distinguish whether multiple courses were administered, a limitation given that repeated ACS exposure has been associated with poorer neurodevelopmental outcomes in term-born infants at five years of age [ 36 ]. Furthermore, we were unable to ascertain the clinical indications for ACS administration, particularly for mothers without documented threatened preterm labor, such as those with preeclampsia or fetal distress. These indications may reflect underlying pregnancy severity and thus represent potential unmeasured confounders in our analysis. Fourth, although NHIRD had been validated for high-quality diagnoses, validation of pediatric neurodevelopmental disorders has not been performed. In Taiwan, after the amendment of the “Child Welfare Law” announced in 1993, an early intervention protocol for all insured children with DD was established [ 37 ]. However, DD is a descriptive clinical condition rather than a specific diagnosis and may encompass a wide range of underlying disorders. Due to limitations in coding and data availability, our study could not assess the association between ACS timing and specific neurodevelopmental disorders such as autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD). Further research using validated diagnostic criteria and more detailed neurodevelopmental outcome measures is warranted. Fifth, our cohort spanned an eight-year period (2004–2011), during which clinical practices regarding ACS use, particularly beyond 34 weeks, were evolving. As such, temporal differences in provider behavior, awareness, and policy may have introduced residual confounding related to the timing of ACS administration . Lastly, because 96% of births in Taiwan are to native-born mothers [ 38 ], our findings may not be generalizable to populations with more racial or ethnic diversity. Further studies in more diverse populations are warranted. Conclusion In a large population-based cohort of late preterm infants, our study found that exposure before 34 weeks was linked to a higher risk of DD, particularly in subgroups of LPI born to diabetic or older-age mothers. Notably, these high-risk pregnancies are more likely to receive ACS earlier in gestation due to a higher baseline risk of preterm birth. However, our findings suggest that the long-term neurodevelopmental impact of ACS exposure is not uniform across different maternal conditions, as no significant associations were observed in subgroups with hypertensive disorders or cesarean delivery, nor among those exposed between 34 and 36 weeks. These findings highlight the significance of our study in elucidating the nuanced impacts of ACS exposure, particularly about the timing of exposure and the specific subgroups of LPI affected. Such insights should be considered in further deliberations regarding the use of ACS after 34 weeks’ gestation, especially when weighing the potential benefits and risks of corticosteroid use for this population. Furthermore, it’s important to note that up to 10% of fetus with threatened preterm labor are ultimately delivered at term [ 7 ], our findings highlight the need for more nuanced risk assessments that account for maternal health characteristics. This study contributes valuable evidence for future deliberations regarding the use of ACS in late preterm pregnancies and underscores the importance of incorporating maternal profiles into individualized risk–benefit evaluations before 34 weeks’ gestation. Acknowledgements The authors thank the Health and Welfare Data Science Center, Ministry of Health and Welfare, for providing administrative and technical support, and the Kaohsiung Medical University for providing administrative and partial funding support. Abbreviations aHR Adjusted hazard ratios ATC Anatomical Therapeutic Chemical ACS Antenatal corticosteroid BND Birth Notification Database CI Confidence intervals DD Developmental delay DM Diabetes mellitus GA Gestational age GDM Gestational diabetes mellitus ICD-9-CM International Classification of Disease, Ninth Revision, Clinical Modification LPI Late preterm infants NCPAP Nasal prong continuous positive airway pressure NHI National Health Insurance NHIRD National Health Insurance Research Database NICU Neonatal intensive care unit PPROM Preterm Premature Rupture of Membrane SGA Small for Gestational Age TMCHD Taiwan Maternal and Child Health Database Authors’ contributions HWC and FWL were responsible for conceptualizing and designing the study, interpreting the results, drafting the initial manuscript, and critically reviewing and revising it. CHY and CYH were responsible for cleaning the data and carrying out the analyses, and they also critically reviewed and revised the manuscript. All authors have approved the final manuscript as submitted and have agreed to be accountable for all aspects of the work. Funding This study was funded by Chi Mei Medical Center (grant No. 111CM-KMU-09 and 114CM-KMU-05), Kaohsiung Medical University Research Foundation (NCTUKMU108-BIO-02), Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUH SI11010) and the National Science and Technology Council (grant No. MOST NSTC 113-2314-B-037-072 and NSTC114-2314-B-037-029). Data availability The BND, the TMCHD, and the NHIRD are not publicly available, and restrictions apply to the availability of the databases. Only analyzed data that are de-identified are released to the researchers. All data containing relevant information to support the study findings are provided in the manuscript. Declarations Ethics approval and consent to participate The Institutional Review Board of the Chi Mei Medical Center approved this study (IRB number: 11105-E04) and waived the requirement of informed consent because the retrospective patient information was de-identified. This research was conducted following the principles outlined in the Declaration of Helsinki. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Footnotes Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50(4):515–25. [ PubMed ] [ Google Scholar ] 2. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. 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