Impact of timing from last dose of dexamethasone administration to delivery, different steroid courses, and fetal number on preterm neonatal outcomes

Saifon Chawanpaiboon; Julaporn Pooliam; Monsak Chuchotiros

doi:10.1371/journal.pone.0343138

. 2026 Mar 2;21(3):e0343138. doi: 10.1371/journal.pone.0343138

Impact of timing from last dose of dexamethasone administration to delivery, different steroid courses, and fetal number on preterm neonatal outcomes

Saifon Chawanpaiboon ^1,^*, Julaporn Pooliam ², Monsak Chuchotiros ¹

Editor: Hakan Aylanc³

PMCID: PMC12952613 PMID: 41770776

Abstract

Objectives

To evaluate the impact of the timing from the last dose of dexamethasone to delivery, different steroid courses, and the number of fetuses (singleton vs twin) on preterm neonatal outcomes. This study focused on respiratory complications and associated conditions.

Methods

A retrospective analysis was conducted on 1800 pregnancies, comprising 1585 singleton pregnancies and 215 twin pregnancies, resulting in a total of 2015 neonates. The timing of dexamethasone administration relative to delivery was categorized into intervals: less than 6 hours, between 2 and 7 days, between 8 and 13 days, and 14 days or more. Neonatal outcomes, including respiratory distress syndrome (RDS), continuous positive airway pressure (CPAP) support, bronchopulmonary dysplasia (BPD), pneumothorax, and necrotizing enterocolitis (NEC), were analyzed. Multivariate logistic regression assessed the adjusted odds ratios (AORs) for these outcomes based on timing, steroid course (complete vs partial), and number of fetuses.

Results

Neonates exposed to dexamethasone between 2 and 7 days before delivery showed a reduced need for CPAP support (AOR: 0.65; 95% CI: 0.48–0.88). This group was compared to those exposed for less than 6 hours or more than 14 days before delivery. However, the incidence of RDS did not significantly decrease with the timing of dexamethasone administration. A higher incidence of pneumothorax was observed in neonates born less than 6 hours after an incomplete course (AOR: 1.89; 95% CI: 1.01–3.54). Twin pregnancies delivered within 12 hours of a complete course were at increased risk for NEC (AOR: 2.11; 95% CI: 1.07–4.16). Deliveries occurring more than 14 days after the last dose were associated with increased risks of ventilator support (AOR: 2.11; 95% CI: 1.08–4.11) and BPD. This was particularly evident in cases where multiple courses were administered.

Conclusions

The timing of the last dexamethasone dose is crucial for reducing respiratory complications other than RDS. The optimal window is between 2 and 7 days before delivery. This effect is influenced by the completeness of the steroid course and the number of fetuses. Tailoring dexamethasone administration according to these factors can significantly improve outcomes in preterm neonates, particularly in reducing the severity of respiratory complications.

Thai Clinical Trials Registry (TCTR) number

TCTR20230724002 (Registration date: 24 July 2023) http://thaiclinicaltrials.org/export/pdf/TCTR20230724002

Introduction

In 2014 and 2020, the global preterm birth rate was 10.6% and 9.9%, respectively, accounting for approximately 14.84 million and 13.4 million live preterm births. [1, 2] Although the rate showed a slight decline over time, the overall global burden of preterm birth has not changed substantially. Each year, preterm birth contributes to more than 1 million of the 4 million infant deaths worldwide. [3] The leading causes of these deaths include respiratory distress syndrome (RDS), bronchopulmonary dysplasia, intraventricular hemorrhage and necrotizing enterocolitis. [4] RDS, characterized by underdeveloped lungs or insufficient surfactant production, is a significant concern in preterm infants. [5, 6]

The use of antenatal corticosteroids (ACS) has become a widely adopted strategy to reduce the incidence of neonatal RDS and associated mortality. [4] In preterm singleton infants, the administration of glucocorticoids lowers the risk of RDS by 38%, intraventricular hemorrhage by 48%, necrotizing enterocolitis by 50%, and stillbirth by 25%. [4] Liggins [7] was the first to investigate the potential of glucocorticoids to prevent RDS. These steroid hormones are instrumental in preventing RDS in infants born to mothers at risk of preterm labor, significantly reducing infant morbidity and mortality. [8] Additionally, ACS are recommended to prevent respiratory morbidities, based on the findings of large randomized controlled trials in late preterm infants. [9–11]

However, administering a full course of ACS presents challenges in emergencies. Pregnant women may arrive at the hospital in critical condition and deliver shortly after admission, making it impossible to complete an ACS course. Conversely, some expectant mothers may have hospital stays exceeding 1 week, necessitating an additional rescue course of dexamethasone to increase fetal lung maturity. Despite the widespread use of ACS as a prophylactic treatment for potential preterm births, controversies persist regarding the optimal timing from the last dose to delivery.

This study focused on the effects of the timing between the last dexamethasone dose and delivery on neonatal respiratory complications and other adverse outcomes in preterm neonates between 24⁰ and 36⁶ weeks of gestation.

Materials and methods

Study design and ethics approval

This retrospective study was conducted at the statistical unit of the Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital. Prior to initiation, the study protocol was approved by the Ethics Committee of the Faculty of Medicine Siriraj Hospital (Si754/2023) and registered at the Thai Clinical Trials Registry (TCTR20230724002).

Data collection

Data were collected from hospital records of pregnant women with preterm deliveries between 2016 and 2020. The data were accessed for research purposes on 15 January 2024. Baseline characteristics comprised laboratory blood test results, number of antenatal visits, delivery route, gestational age at delivery, neonatal weight, Apgar scores, and neonatal and maternal complications.

Primary and secondary outcomes

The primary outcome was the effect of the interval between the last dexamethasone dose and delivery on RDS in preterm infants between 24⁰ and 36⁶ weeks of gestation. The secondary outcomes were the effects of different courses and doses of dexamethasone, varying gestational ages at delivery, and other adverse outcomes.

Neonatal and maternal outcomes

For each subgroup, data were collected on Apgar scores less than 7, need for positive pressure ventilation, neonatal intensive care unit admission, respiratory support requirements, RDS, transient tachypnea of the newborn (TTNB), apnea, intraventricular hemorrhage, necrotizing enterocolitis, early-onset neonatal sepsis, and pneumonia. Maternal postpartum complications and length of hospital stay were also analyzed.

Definition

Respiratory distress syndrome (RDS) was diagnosed in preterm infants who presented with clinical signs of respiratory distress, including tachypnea (respiratory rate > 60 breaths per minute), nasal flaring, expiratory grunting, and chest wall retractions and required respiratory support such as continuous positive airway pressure (CPAP), intubation, or surfactant therapy. The diagnosis was confirmed by characteristic chest X-ray findings, including a reticulogranular (ground-glass) appearance and air bronchograms, consistent with surfactant deficiency. [12, 13]
Transient tachypnea of the newborn (TTNB) is characterized by tachypnea (respiratory rate >60 breaths per minute) developing shortly after birth, typically within the first 6 hours, accompanied by mild respiratory distress (grunting, nasal flaring, or retractions) and radiographic findings consistent with pulmonary fluid retention (e.g., prominent vascular markings, interlobar fissure fluid, or hyperinflation). The condition resolves within 72 hours without evidence of infection or structural lung disease. [14]
Apnea of prematurity is defined as a cessation of breathing lasting 20 seconds or longer, or a shorter pause accompanied by bradycardia (heart rate <100 beats/min) and/or oxygen desaturation (SpO₂ < 80%), occurring in infants born before 37 weeks of gestation after exclusion of other causes such as infection or airway obstruction. [15]
Intraventricular hemorrhage (IVH) was classified according to Papile’s grading system (grades I–IV) based on cranial ultrasound findings, with clinically significant IVH defined as grade II or higher. [16, 17]
Necrotizing enterocolitis is diagnosed and staged according to Bell’s classification, with clinically significant disease defined as stage II or higher. [18, 19]
Early-onset neonatal sepsis is defined by sepsis occurring within the first 72 hours of life, confirmed by a positive blood culture or clinical findings consistent with systemic infection (e.g., temperature instability, respiratory distress, or hemodynamic instability). [18, 20]
Neonatal pneumonia is diagnosed by clinical symptoms (tachypnea, grunting, retractions) plus radiographic evidence of pulmonary infiltrates or consolidation, with or without positive cultures. [21]
Maternal postpartum complications: [22]

Common complications evaluated include postpartum hemorrhage (blood loss ≥500 mL after vaginal delivery or ≥1,000 mL after cesarean section), postpartum infection (endometritis, wound infection), hypertensive complications, and readmission due to postpartum morbidity.

Surfactant administration protocol.

At our institution, surfactant is administered selectively to preterm infants with clinically and radiographically confirmed respiratory distress syndrome (RDS) who require intubation and mechanical ventilation, in accordance with the European Consensus Guidelines on the Management of RDS. [12] Infants who can be managed with continuous positive airway pressure (CPAP) alone do not routinely receive surfactant. All infants included in this study were managed under this same standardized institutional protocol. Because the indication and timing of surfactant administration were consistent throughout the study period, this practice is unlikely to have introduced bias or significantly affected comparisons between groups.

Definition of antenatal corticosteroid courses.

A complete course of antenatal corticosteroids (ACS) was defined as four 6-mg intramuscular doses of dexamethasone administered every 12 hours (total 24 mg), according to World Health Organization and American College of Obstetricians and Gynecologists (ACOG) guidelines. [23]
An incomplete course referred to fewer than four doses administered before delivery.
A multiple course was defined as two complete courses of ACS given at least 7 days apart in separate episodes of threatened preterm labor.

Sample size calculation

Our pilot study indicated that 68% of preterm infants with RDS had received a full course of dexamethasone, whereas 50% had received either an incomplete course or multiple courses. To evaluate the impact of these three groups of ACS exposure (incomplete, complete, and multiple courses) on RDS and other outcomes, we calculated the required sample size. We set a significance level of 0.01 (two-sided) and a power of 95%. Using the nQuery Advisor program, we determined that 263 infants with RDS were needed per group. Assuming a 15% incidence of RDS among preterm infants, we required a total of 1753 preterm infants (263 × 100/15). This number was rounded to 1800 to ensure sufficient power to detect differences related to the course of ACS and to accommodate potential variations in the study population.

Statistical analysis

Statistical analyses were performed using PASW Statistics, version 18 (SPSS Inc, Chicago, IL, USA). Demographic data were analyzed with descriptive statistics. Categorical variables are presented as numbers and percentages, whereas continuous variables are reported as means ± standard deviations or as medians and ranges. Baseline data, including qualitative parameters and adverse maternal and neonatal outcomes, were compared via the chi-square test or Fisher’s exact test. Multivariate analysis was conducted using multiple logistic regression for quantitative variables.

Results

Participant characteristics

A total of 1800 pregnant women were recruited across all three groups. Among these, 1585 (88.1%) had singleton pregnancies, and 215 (11.9%) had twin pregnancies, resulting in 2015 neonates.

Timing of dexamethasone administration

The interval from the last dose of dexamethasone to delivery was less than 6 hours in 594 patients (33%). It was between 2 and 7 days in 313 patients (17.4%), as shown in Table 1.

Table 1. Maternal demographic characteristics and neonatal outcomes.

Maternal demographic data	n = 1800	Neonatal outcomes	All newborns (N = 2015)
Age (y)	30.3 ± 6.7	Mean neonatal weight (g)	2178.6 ± 557.4
Pre-pregnancy body weight	56.2 ± 12.6	Apgar at 1 min < 7	341 (16.9%)
BMI	27.1 ± 5.0	Apgar at 5 min < 7	94 (4.7%)
GA delivery (wk)	34.4 ± 2.1	Hemoglobin (g/dL)	16.9 ± 3.2
Dexamethasone		Hematocrit (%)	48.3 ± 8.0
1 course	916 (50.9%)	Microbilirubin (mg/dL)	8.5 ± 3.4
< 1 course	716 (39.8%)	Sex
> 1 course	168 (9.3%)	Male	1037 (51.5%)
Occupation (n = 1792)		Female	978 (48.5%)
Housewife	479 (26.7%)	Primary outcome
Laborer	900 (50.2%)	Primary outcome
Merchant	112 (6.3%)	Respiratory distress syndrome	99 (4.9%)
Government	138 (7.7%)	Respiratory distress syndrome	99 (4.9%)
Personal business	77 (4.3%)	Secondary outcomes
Student	28 (1.6%)	Postnatal adaptation	87 (4.3%)
Other	58 (3.2%)	Transient tachypnea of the newborn	451 (22.4%)
Income (baht/month; n = 1327)
< 10 000	263 (19.8%)	Persistent tachypnea of the newborn	1 (0.05%)
10 000–19 999	497 (37.5%)
20 000–49 999	440 (33.2%)	Bronchopulmonary dysplasia	49 (2.4%)
≥ 50 000	127 (9.5%)
Parity		Pneumothorax	39 (1.9%)
0	971 (53.9%)
≥ 1	829 (46.1%)	Positive pressure ventilation	244 (12.1%)
Pregnancy
Singleton	1585 (88.1%)	Continuous positive airway pressure	451 (22.4%)
Twins	215 (11.9%)
Underlying		Ventilator support	245 (12.2%)
None	1527 (84.8%)
Diabetes mellitus	29 (1.6%)	Pneumonia	64 (3.2%)
Hypertension	99 (5.5%)
Other	145 (8.1%)	Hypothermia	55 (2.7%)
Route of delivery
Vaginal route	725 (40.3%)	Necrotizing enterocolitis	64 (3.2%)
Cesarean section	1063 (59.1%)
Vacuum and forceps assisted	12 (0.6%)	Intraventricular hemorrhage	80 (4.0%)
Time from last dose of dexamethasone to delivery
< 6 h	594 (33.0%)	Sepsis	183 (9.1%)
6– < 12 h	252 (14.0%)
12– < 24 h	81 (4.5%)	Death	44 (2.2%)
24– < 48 h	140 (7.8%)	Phototherapy	1143 (56.7%)
2– < 7 d	313 (17.4%)
7– < 14 d	146 (8.1%)	Neonatal intensive care unit admission	439 (21.8%)
≥ 14 d	274 (15.2%)	Intermediate care unit admission	598 (29.7%)

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Data are presented as mean ± standard deviation (SD) and number (%).

RDS outcomes

RDS occurred in 99 of the 2015 neonates (4.9%). However, the association between the timing of the last dexamethasone dose and the occurrence of RDS was not statistically significant (Table 2).

Table 2. Effect of time from last dexamethasone dose to delivery on respiratory distress syndrome: comparison by steroid course, gestational age, and fetal number.

Time to delivery	Total (n = 1800)		<1 course (n = 716)		1 course (n = 916)		>1 course (n = 168)
	n	RDS rate	n	RDS rate	n	RDS rate	n	RDS rate
<6 h	594	35 (5.9%)	519	31 (6.0%)	52	2 (3.8%)	23	2 (8.7%)
6– < 12 h	252	14 (5.6%)	175	10 (5.7%)	54	1 (1.9%)	23	3 (13.0%)
12– < 24 h	81	4 (4.9%)	8	0 (0%)	60	4 (6.7%)	13	0 (0%)
24– < 48 h	140	3 (2.1%)	4	0 (0%)	118	3 (2.5%)	18	0 (0%)
2– < 7 d	313	19 (6.1%)	8	1 (12.5%)	267	15 (5.6%)	38	3 (7.9%)
7– < 14 d	146	10 (6.8%)	1	0 (0%)	121	6 (5.0%)	24	4 (16.7%)
≥14 d	274	10 (3.6%)	1	0 (0%)	244	9 (3.7%)	29	1 (3.4%)
P value		0.443		0.694		0.926		0.320
Time to delivery	Total (n = 1800)		Extremely to very preterm (GA 24– < 32 wk) (n = 236)		Moderately preterm (GA 32– < 34 wk) (n = 317)		Late preterm (GA 34– < 37 wk) (n = 1247)
	n	RDS rate	n	RDS rate	n	RDS rate	n	RDS rate
<6 h	594	35 (5.9%)	71	16 (22.5%)	90	9 (10%)	433	10 (2.3%)
6– < 12 h	252	14 (5.6%)	35	9 (25.7%)	54	3 (5.6%)	163	2 (1.2%)
12– < 24 h	81	4 (4.9%)	12	1 (8.3%)	30	3 (10.0%)	39	0 (0%)
24– < 48 h	140	3 (2.1%)	37	2 (5.4%)	37	1 (2.7%)	66	0 (0%)
2– < 7 d	313	19 (6.1%)	61	10 (16.4%)	83	3 (3.6%)	169	6 (2.6%)
7– < 14 d	146	10 (6.8%)	14	4 (28.6%)	13	2 (15.4%)	119	4 (3.4%)
≥14 d	274	10 (3.6%)	6	2 (33.3%)	10	2 (20.0%)	258	6 (2.3%)
P value		0.443		0.171		0.222		0.511
Time to delivery	Total (n = 1800)		Singleton (n = 1585)		Twins (n = 317)
	n	RDS rate	n	RDS rate	n	RDS rate
<6 h	594	35 (5.9%)	552	29 (5.3%)	42	6 (14.3%)
6– < 12 h	252	14 (5.6%)	235	13 (5.5%)	17	1 (5.9%)
12– < 24 h	81	4 (4.9%)	75	4 (5.3%)	6	0 (0%)
24– < 48 h	140	3 (2.1%)	123	1 (0.8%)	17	2 (11.8%)
2– < 7 d	313	19 (6.1%)	269	12 (4.5%)	44	7 (15.9%)
7– < 14 d	146	10 (6.8%)	123	7 (5.7%)	23	3 (13.0%)
≥14 d	274	10 (3.6%)	208	6 (2.9%)	66	4 (6.1%)
P value		0.443		0.326		0.605

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Abbreviations: GA, gestational age; RDS, respiratory distress syndrome.

Continuous positive airway pressure support and other respiratory complications

Neonates needed continuous positive airway pressure (CPAP) support more frequently when the interval from the last dexamethasone dose to delivery was between 2 and 7 days. This was in comparison with neonates with intervals of less than 6 hours or 14 days onward (Table 3).

Table 3. Effect of time from last dexamethasone dose to delivery on secondary neonatal outcomes.

Outcomes	Time to delivery
Outcomes	<6 h (n = 594): A	6– < 12 h (n = 252): B	12– < 24 h (n = 81): C	24– < 48 h (n = 140): D	2– < 7 d (n = 313): E	7– < 14 d (n = 146): F	≥14 d (n = 274): G	P value
Apgar at 1 min < 7	100 (16.8%)	41 (16.3%)	12 (14.8%)	37 (26.4%)	67 (21.4%)	18 (12.3%)	52 (19.0%)	0.059
Postnatal adaptation	22 (3.7%)	7 (2.8%)	5 (6.2%)	10 (7.1%)	15 (4.8%)	4 (2.7%)	20 (7.3%)	0.081
Transient tachypnea of the newborn	134 (22.6%)	53 (21.0%)	21 (25.9%)	40 (28.6%)	79 (25.2%)	44 (30.1%)	53 (19.3%)	0.119
Persistent tachypnea of the newborn	1 (0.2%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1.000
Bronchopulmonary dysplasia	14 (2.4%)	7 (2.8%)	6 (7.4%)	4 (2.9%)	11 (3.5%)	4 (2.7%)	2 (0.7%)	0.059
Pneumothorax	9 (1.5%)	1 (0.4%)	1 (1.2%)	1 (0.7%)	18 (5.8%)	3 (2.1%)	6 (2.2%)	0.116
Positive pressure ventilation	76 (12.8%)	37 (14.7%)	12 (14.8%)	24 (17.1%)	42 (13.4%)	18 (12.3%)	26 (9.5%)	0.414
^#Continuous positive airway pressure support	118 (19.9%)	61 (24.2%)	21 (25.9%)	40 (28.6%)	96 (30.7%)	30 (20.5%)	38 (13.9%)	<0.001^ab
Ventilator support	90 (15.2%)	39 (15.5%)	11 (13.6%)	18 (12.9%)	41 (13.1%)	17 (11.6%)	22 (8.0%)	0.132
Pneumonia	16 (2.7%)	10 (4.0%)	2 (2.5%)	8 (5.7%)	12 (3.8%)	7 (4.8%)	6 (2.2%)	0.429
Hypothermia	20 (3.4%)	9 (3.6%)	2 (2.5%)	2 (1.4%)	12 (3.8%)	4 (2.7%)	3 (1.1%)	0.402
Necrotizing enterocolitis	22 (3.7%)	7 (2.8%)	2 (2.5%)	9 (6.4%)	14 (4.5%)	6 (4.1%)	2 (0.7%)	0.068
Intraventricular hemorrhage	30 (5.1%)	11 (4.4%)	7 (8.6%)	7 (5.0%)	17 (5.4%)	4 (2.7%)	2 (0.7%)	0.062
Sepsis	48 (8.1%)	28 (11.1%)	10 (12.3%)	21 (15.0%)	35 (11.2%)	16 (11.0%)	18 (6.6%)	0.074
Death	17 (2.9%)	7 (2.8%)	1 (1.2%)	3 (2.1%)	10 (3.2%)	2 (1.4%)	4 (1.5%)	0.727
Phototherapy	339 (57.1%)	154 (61.1%)	56 (69.1%)	101 (72.1%)	191 (61.0%)	79 (54.1%)	137 (50.0%)	0.174
^#NIC admission	133 (22.4%)	57 (22.6%)	26 (32.1%)	40 (28.6%)	84 (26.8%)	30 (20.5%)	41 (15.0%)	0.003^c
^#Neonatal LOS: median (IQR)	6 (4, 18)	8 (5, 20)	10 (6, 26)	11 (5, 35)	9 (5, 30)	6 (4, 18)	6 (4, 10)	<0.001^de
^#Maternal LOS: median (IQR)	5 (3, 7)	5 (4, 8)	7 (6, 9)	7 (6, 10)	9 (6, 11)	9 (5, 17)	6 (4, 17)	<0.001^fh

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Abbreviations: IQR, interquartile range; LOS, length of hospital stay; NICU, neonatal intensive care unit.

#Significant statistical result

^aDifference between E and A

^bDifference between E and G

^cDifference between G and C, D, E

^dDifference between G and B, C, D, E

^eDifference between A and C, E

^fDifference between A and B, C, D, E, F, G

^hDifference between B and C, D, E, F

Additionally, CPAP support was more common in neonates whose last complete course of dexamethasone was administered between 24 hours and 7 days before delivery than in those who delivered 14 days or more after the last dose.

Bronchopulmonary dysplasia was more common in neonates whose last complete course of dexamethasone was administered 24–48 hours before delivery. This was in comparison with those delivered 14 days or more after the last dose.

Pneumothorax was most prevalent in neonates born between 2 and 7 days after a partial course of dexamethasone. These patients were compared to those born less than 6 hours after the last dose (Table 4).

Table 4. Effect of time from last dose of dexamethasone dose to delivery on key secondary outcomes.

Outcomes	Time to delivery
Outcomes	<6 h (n = 52): A	6– < 12 h (n = 54): B	12– < 24 h (n = 60): C	24– < 48 h (n = 118): D	2– < 7 d (n = 267): E	7– < 14 d (n = 121): F	≥14 d (n = 244): G	P value
Complete 1 course dexamethasone administration
Bronchopulmonary dysplasia	0 (0%)	1 (1.9%)	5 (8.3%)	4 (3.4%)	9 (3.4%)	4 (3.3%)	1 (0.4%)	0.023^d
Continuous positive airway pressure support	14 (26.9%)	12 (22.2%)	18 (30.0%)	33 (28.0%)	81 (30.3%)	22 (18.2%)	35 (14.3%)	<0.001^a
Necrotizing enterocolitis	6 (11.5%)	3 (5.6%)	2 (3.3%)	7 (5.9%)	12 (4.5%)	5 (4.1%)	2 (0.8%)	0.017^b
Intraventricular hemorrhage	4 (7.7%)	3 (5.6%)	5 (8.3%)	6 (5.1%)	14 (5.2%)	2 (1.7%)	1 (0.4%)	0.011^c
Phototherapy	40 (76.9%)	32 (59.3%)	38 (63.3%)	84 (71.2%)	162 (60.7%)	58 (47.9%)	119 (48.8%)	<0.001^ef
NICU admission	17 (32.7%)	11 (20.4%)	20 (33.3%)	31 (26.3%)	68 (25.5%)	22 (18.2%)	34 (13.9%)	0.002^c
Neonatal LOS: median (IQR)	11 (5, 46)	9 (5, 21)	8 (5, 27)	10 (5, 34)	9 (5, 29)	6 (4, 16)	5 (4, 9)	<0.001^g
Maternal LOS: median (IQR)	5 (5, 8)	6 (5, 9)	6 (5, 9)	7 (6, 9)	8 (6, 11)	7 (5, 16)	6 (4, 10)	<0.001^h
^a Difference between G and D, E ^b Difference between G and A ^c Difference between G and A, C, E ^d Difference between G and C ^e Difference between G and A, D ^f Difference between A and F ^g Difference between G and A, B, C, D, E ^h Difference between G and E, F
Outcomes	Time to delivery
Outcomes	<6 h (n = 519): A	6– < 12 h (n = 175): B	12– < 24 h (n = 8): C	24– < 48 h (n = 4): D	2– < 7 d (n = 8): E	7– < 14 d (n = 1): F	≥14 d (n = 1): G	P value
<1 course dexamethasone administration
Pneumothorax	8 (1.5%)	0 (0%)	0 (0%)	0 (0%)	2 (25%)	1 (100%)	0 (0%)	<0.001^a
^a Difference between A and E
Outcomes	Time to delivery
Outcomes	<6 h (n = 23): A	6– < 12 h (n = 23): B	12– < 24 h (n = 13): C	24– < 48 h (n = 18): D	2– < 7 d (n = 38): E	7– < 14 d (n = 24): F	≥14 d (n = 29): G	P value
>1 course dexamethasone administration
Maternal LOS: median (IQR)	10 (4, 19)	10 (8, 26)	14 (7, 20)	12 (8, 21)	12 (9, 24)	21 (13, 38)	23 (11, 42)	0.013^a
^a Difference between A and F, G
Outcomes	Time to delivery
Outcomes	<6 h (n = 47): A	6– < 12 h (n = 51): B	12– < 24 h (n = 57): C	24– < 48 h (n = 105): D	2– < 7 d (n = 233): E	7– < 14 d (n = 102): F	≥14 d (n = 188): G	P value
Singleton and complete 1 course dexamethasone administration
Bronchopulmonary dysplasia	0 (0%)	1 (2.0%)	5 (8.8%)	4 (3.8%)	9 (3.9%)	3 (2.9%)	1 (0.5%)	0.040^b
Continuous positive airway pressure support	11 (23.4%)	10 (19.6%)	16 (28.1%)	29 (27.6%)	65 (27.9%)	15 (14.7%)	21 (11.2%)	<0.001^a
Phototherapy	35 (74.5%)	30 (58.8%)	35 (61.4%)	74 (70.5%)	138 (59.2%)	48 (47.1%)	91 (48.4%)	<0.001 cd
NICU admission	14 (29.8%)	10 (19.6%)	18 (31.6%)	29 (27.6%)	56 (24%)	14 (13.7%)	23 (12.2%)	0.001^a
Neonatal LOS: median (IQR)	9 (5, 38)	9 (5, 20)	8 (5, 24)	9 (5, 34)	8 (4, 26)	5 (4, 12)	5 (3, 7)	<0.001^e
Maternal LOS: median (IQR)	6 (5, 8)	6 (5, 9)	6 (5, 9)	7 (6, 9)	8 (6, 11)	7 (5, 15)	6 (4,10)	<0.001^f
^a Difference between G and C, D, E ^b Difference between G and C ^c Difference between G and A, D ^d Difference between A and F ^e Difference between G and A, B, C, D, E ^f Difference between G and E, F
Outcomes	Time to delivery
Outcomes	<6 h (n = 485): A	6– < 12 h (n = 166): B	12– < 24 h (n = 8): C	24– < 48 h (n = 4): D	2– < 7 d (n = 7): E	7– < 14 d (n = 1): F	≥14 d (n = 1): G	P value
Singleton and <1 course dexamethasone administration
Pneumothorax	7 (1.4%)	0 (0%)	0 (0%)	0 (0%)	1 (14.3%)	1 (100%)	0 (0%)	0.002^a
^a Difference between A and E
Outcomes	Time to delivery
Outcomes	<6 h (n = 5): A	6– < 12 h (n = 3): B	12– < 24 h (n = 3): C	24– < 48 h (n = 13): D	2– < 7 d (n = 34): E	7– < 14 d (n = 19): F	≥14 d (n = 56): G	P value
Twins and complete 1 course dexamethasone administration
Necrotizing enterocolitis	2 (40%)	1 (33.3%)	0 (0%)	2 (15.4%)	1 (2.9%)	2 (10.5%)	1 (1.8%)	0.031^a
^a Difference between G and A, B

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Abbreviations: IQR, interquartile range; LOS, length of hospital stay; NICU, neonatal intensive care unit.

There was no significant difference in neonatal mortality among the groups categorized by the time from the last dexamethasone dose to delivery (P = 0.727) (Table 3).

Outcomes in singleton and twin pregnancies

For singleton pregnancies receiving a complete course of dexamethasone, CPAP support was less frequent when delivery occurred 14 days or more after the last dose than when delivery occurred within 7 days. However, pneumothorax was more common in singleton neonates born less than 6 hours after receiving an incomplete course of dexamethasone. This group was compared to those born between 2 and 7 days after the last dose.

In twin pregnancies with a complete course of dexamethasone, necrotizing enterocolitis was more common in neonates who were delivered less than 12 hours after the last dose. This was in comparison to those delivered 14 days or more after the last dose (Table 4).

Multivariate analysis

Multivariate logistic regression analysis revealed that extremely, very, and moderately preterm births, as well as cesarean sections, were significantly associated with RDS (P < 0.001; Table 5). An interval from the last dexamethasone dose to delivery between day 7–14 days was associated with an increased risk of TTNB. The adjusted odds ratio was 1.658 (95% confidence interval [CI]: 1.028–2.673; P = 0.038).

Table 5. Multivariable logistic regression of significant factors associated with respiratory distress syndrome.

Factors	Respiratory distress syndrome
Factors	Adjusted odds ratio (95% CI)	P value
Time from last dose of dexamethasone to delivery
< 6 h	1.313 (0.536, 3.214)	0.551
6 to <12 h	1.107 (0.431, 2.842)	0.832
12 to <24 h	1.037 (0.319, 3.368)	0.952
24 to <48 h	0.239 (0.053, 1.084)	0.064
2 to <7 d	Reference	–
7 to <14 d	1.977 (0.766, 5.107)	0.159
≥ 14 d	1.842 (0.706, 4.809)	0.212
Dexamethasone
1 course	Reference
< 1 course	1.585 (0.723, 3.471)	0.250
> 1 course	0.966 (0.445, 2.094)	0.930
GA
Extremely to very preterm	13.123 (7.333, 23.482)	<0.001*
Moderately preterm	4.418 (2.329, 8.380)	<0.001*
Late preterm	Reference
Pregnancy
Singleton	Reference
Twin	1.080 (0.557, 2.094)	0.820
Age	0.980 (0.945, 1.017)	0.292
BMI	1.024 (0.979, 1.072)	0.296
Route of delivery
Vaginal route	Reference
Cesarean section	2.129 (1.238, 3.664)	0.006*
Vacuum and forceps assisted	N/A	–
Underlying disease (DM, hypertension)	1.341 (0.743, 2.422)	0.331

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Abbreviations: BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; GA, gestational age.

Delivery within less than 6 hours or 14 days or more after the last dexamethasone dose was associated with a greater likelihood of requiring ventilator support. The adjusted odds ratios were 1.893 (95% CI: 1.011–3.543; P = 0.046) and 2.105 (95% CI: 1.079–4.106; P = 0.029), respectively (Table 6). Moderate, very, and extremely preterm births were also significantly associated with TTNB, persistent tachypnea of the newborn, ventilator support, phototherapy, and neonatal intensive care unit admission (P < 0.001; Table 6), as expected due to increasing immaturity, and are presented here for completeness and comparison across gestational age groups.

Table 6. Multivariable logistic regression of significant factors associated with secondary outcomes.

Factors	Transient tachypnea of the newborn		Positive pressure ventilation support		Continuous positive airway pressure
Factors	Adjusted odds ratio (95% CI)	P value	Adjusted odds ratio (95% CI)	P value	Adjusted odds ratio (95% CI)	P value
Time from last dose of dexamethasone to delivery
< 6 h	0.737 (0.448, 1.214)	0.231	0.838 (0.448, 1.567)	0.579	0.730 (0.425, 1.257)	0.257
6 to <12 h	0.666 (0.398, 1.114)	0.121	0.807 (0.425, 1.534)	0.513	0.809 (0.469, 1.397)	0.447
12 to <24 h	0.853 (0.464, 1.567)	0.609	0.963 (0.454, 2.045)	0.923	0.736 (0.383, 1.412)	0.356
24 to <48 h	1.045 (0.646, 1.689)	0.858	1.058 (0.573, 1.952)	0.857	0.630 (0.369, 1.078)	0.092
2 to <7 d	Reference 1.658 (1.028,	–	Reference 1.062 (0.533,	–	Reference 1.067 (0.601,	–
7 to <14 d	2.673) 1.015 (0.649,	0.038*	2.118) 1.408 (0.763,	0.864	1.897) 1.011 (0.609,	0.824
≥ 14 d	1.588)	0.948	2.596)	0.273	1.679)	0.966
Dexamethasone
1 course	Reference		Reference		Reference
< 1 course	1.559 (1.001, 2.430)	0.049*	1.790 (1.029, 3.113)	0.039*	1.199 (0.739, 1.946)	0.461
> 1 course	1.226 (0.824, 1.823)	0.315	1.148 (0.695, 1.898)	0.590	0.775 (0.496, 1.211)	0.263
GA
Extremely to very preterm	5.228 (3.773, 7.243)	<0.001*	9.670 (6.478, 14.434)	<0.001*	1.199 (0.739, 1.946)	0.461
Moderately preterm	2.304 (1.682, 3.157)	<0.001*	3.756 (2.499, 5.646)	<0.001*	0.775 (0.496, 1.2110	0.263
Late preterm	Reference		Reference		Reference
Pregnancy
Singleton	Reference		Reference		Reference
Twins	0.922 (0.644, 1.320)	0.659	0.404 (0.238, 1.089)	0.065	1.519 (1.028, 2.243)	0.036*
BMI	0.993 (0.969, 1.018)	0.565	1.000 (0.970, 1.032)	0.975	0.971 (0.943, 1.110)	0.053
Route of delivery
Vaginal route	Reference		Reference		Reference
Cesarean section	2.282 (1.736, 2.999)	<0.001*	4.624 (3.104, 6.888)	<0.001*	1.802 (1.330, 2.441)	<0.001*
Vacuum and forceps assisted	N/A	–	7.368 (1.492, 36.385)	0.014*	2.417 (0.493, 11.845)	0.276
Underlying disease (DM, hypertension)	0.907 (0.649, 1.266)	0.565	1.169 (0.780, 1.753)	0.449	1.043 (0.714, 1.523)	0.828
Factors	Ventilator support		Phototherapy		Neonatal intensive care unit admission
Factors	Adjusted odds ratio (95% CI)	P value	Adjusted odds ratio (95% CI)	P value	Adjusted odds ratio (95% CI)	P value
Time from last dose of dexamethasone to delivery
< 6 h	1.893 (1.011, 3.543)	0.046*	1.203 (0.769, 1.883)	0.418	1.130 (0.643, 1.984)	0.671
6 to <12 h	1.743 (0.917, 3.312)	0.090	1.206 (0.764, 1.905)	0.421	0.971 (0.545, 1.730)	0.921
12 to <24 h	1.050 (0.462, 2.385)	0.907	1.404 (0.790, 2.493)	0.248	1.286 (0.668, 2.476)	0.451
24 to <48 h	0.700 (0.351, 1.395)	0.311	1.598 (1.001, 2.554)	0.049*	0.818 (0.463, 1.447)	0.491
2 to <7 d	Reference	–	Reference	–	Reference	–
7 to <14 d	1.471 (0.699, 3.099)	0.309	1.228 (0.799, 1.888)	0.349	1.304 (0.709, 2.397)	0.394
≥ 14 d	2.105 (1.079, 4.106)	0.029*	1.096 (0.764, 1.573)	0.619	1.655 (0.977, 2.805)	0.061
Dexamethasone
1 course	Reference		Reference		Reference
< 1 course	1.132 (0.659,	0.653	0.970 (0.657,	0.880	1.249 (0.761,	0.379
> 1 course	1.944)	0.965	1.433)	0.082	2.048)	0.633
	0.988 (0.582, 1.678)		1.426 (0.956, 2.127)		1.117 (0.709, 1.761)
GA
Extremely to very preterm	24.008 (15.71, 36.69)	<0.001*	6.424 (4.386, 9.409)	<0.001*	40.959 (27.30, 61.44)	<0.001
Moderately preterm	5.318 (3.445, 8.209)	<0.001*	5.976 (4.292, 8.322)	<0.001*	5.545 (3.921, 7.841)	<0.001
Late preterm	Reference		Reference		Reference
Pregnancy
Singleton	Reference		Reference		Reference
Twin	0.646 (0.388, 1.075)	0.093	0.792 (0.569, 1.100)	0.164	0.538 (0.346, 1.034)	0.066
Age	0.989 (0.964, 1.015)	0.415	1.007 (0.991, 1.023)	0.415	1.010 (0.988, 1.032)	0.381
BMI	2.416 (0.289, 20.172)	0.415	1.028 (1.006, 1.050)	0.012*	0.970 (0.941, 1.038	0.059
Route of delivery
Vaginal route	Reference		Reference		Reference
Cesarean section	2.359 (1.631, 3.412)	<0.001*	0.901 (0.720, 1.127)	0.362	2.809 (2.038, 3.870)	<0.001*
Vacuum and forceps assisted	2.416 (0.289, 20.172)	0.415	5.555 (1.188, 25.982)	0.029*	N/A	–
Underlying disease (DM, hypertension)	0.872 (0.552, 1.376)	0.555	1.284 (0.956, 1.724)	0.097	0.915 (0.619, 1.353)	0.657

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Abbreviations: BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; GA, gestational age.

Discussions

Principal findings

Preterm birth (classified as extremely, very, or moderate) and cesarean section were significantly associated with an increased risk of RDS. However, the timing of the last dexamethasone dose did not significantly reduce the incidence of RDS. Instead, it influenced other respiratory complications. Specifically, delivery between 7–14 days after the last dose was associated with an increased risk of TTNB, whereas delivery within 6 hours or 14 days or more after the last dose was linked to a greater need for ventilator support. Additionally, preterm birth was significantly correlated with TTNB, other preterm birth complications, the need for ventilator support, phototherapy, and admission to the neonatal intensive care unit.

The optimal timing of the last dose of ACS for reducing respiratory complications other than RDS was identified as between 2 and 7 days before delivery. Timing outside this window—particularly delivery either less than 6 hours or 14 days or more after the last dose—was associated with increased risks of adverse outcomes. This finding highlights the need for precise timing in the administration of ACS to optimize neonatal respiratory health.

Results in the context of what is known

Our findings align with those of Battarbee et al [24], who concluded that the optimal timing for ACS administration is between 2 and 7 days before delivery. This timing minimizes both short-term and long-term morbidity in preterm neonates. Their study underscores the importance of precisely timing ACS administration to improve neonatal outcomes, which is consistent with our observations regarding dexamethasone timing. The critical window of between 2 and 7 days before delivery appears to be essential for reducing respiratory complications and severe morbidity in preterm infants.

Similarly, Lau et al [25] suggested administering ACS within 7 days of delivery to reduce the risk of RDS, reinforcing the importance of optimal timing. Additionally, research indicates that the most effective timing of 1–7 days is particularly beneficial in cases of preeclampsia, preterm premature rupture of membranes, and fetal growth restriction. [26] These studies advocate for more selective ACS administration to enhance neonatal outcomes and avoid unnecessary interventions, aligning with our findings on the importance of timing.

Outcomes in singleton and twin pregnancies.

Our study revealed that neonates from singleton pregnancies who received a complete course of dexamethasone and were delivered 14 days or more after the last dose had reduced rates of CPAP support. Conversely, neonates who were delivered less than 6 hours after receiving less than a full course had a higher incidence of pneumothorax than those who were delivered between 2 and 7 days after the last dose.

In twin pregnancies with a complete course of dexamethasone, neonates who were delivered less than 12 hours after the last dose had a greater risk of developing necrotizing enterocolitis than those who were delivered 14 days or more after the last dose. These findings suggest that the number of fetuses and the completeness of the steroid course influence outcomes, emphasizing the need for tailored approaches in ACS administration based on pregnancy type.

Implications of incomplete and multiple courses.

Our previous study [27] analyzed the impact of a single complete course, an incomplete course, and multiple courses of dexamethasone on preterm neonates. The investigation found that multiple courses led to worse outcomes, including greater need for ventilation and neonatal intensive care unit admission. Compared with those receiving a complete course, very preterm infants with incomplete courses had higher rates of RDS and ventilatory support. The present study corroborates these earlier findings, indicating that while the timing of dexamethasone did not significantly reduce RDS, the optimal interval of between 2 and 7 days is crucial. Incomplete or multiple courses worsen outcomes, highlighting the importance of both timing and course completeness in managing preterm births.

Clinical significance in twin pregnancies.

The efficacy of ACS in twin pregnancies, particularly with respect to timing compared with that in singleton pregnancies, remains a topic of debate. ACS are similarly effective in reducing the incidence of RDS and neonatal mortality in twins and singletons between 24⁰ and 33⁶ weeks of gestation. [28–30] However, in late preterm twins (34⁰ to 36⁶ weeks), some studies reported no reduction in neonatal respiratory morbidity and even increased neonatal intensive care unit admissions and hypoglycemia. [31, 32]

Recent research suggests that in singleton and twin pregnancies, ACS are most beneficial when they are administered within 7 days of delivery, especially between 2 and 7 days. In twin pregnancies, this timing reduces the incidence of RDS and in-hospital mortality. [29, 30, 33] Conversely, ACS administered more than 7 days before delivery may lead to higher rates of respiratory disorders and longer hospital stays. [34] However, existing studies on twins are often observational with small sample sizes, providing weaker evidence than singleton research does.

As twin pregnancies are at increased risk for suboptimal ACS administration, [35] further research is needed to refine the timing and optimize treatment outcomes. Our study correlates with these findings, indicating that twins receiving multiple ACS courses or those delivered outside the optimal 2- to 7-day window before delivery experienced higher rates of complications. Tailored ACS approaches are necessary to improve neonatal outcomes, especially for twins. [36–38]

Associations with other respiratory complications.

Neonates who received a complete course of dexamethasone 24–48 hours before delivery had a higher incidence of bronchopulmonary dysplasia than those who were delivered 14 days or more after the last dose. Additionally, CPAP support was more common in neonates delivered between 24 hours and 7 days after a complete course. Pneumothorax was more prevalent in those who were delivered between 2 and 7 days after a partial course of dexamethasone. The administration of more than one course was associated with an increased need for ventilator support, especially when the time from the last dose to delivery was less than 6 hours or 14 days or more.

In our cohort, ACS timing was not significantly associated with neonatal mortality, consistent with previous studies showing that while antenatal corticosteroids reduce overall neonatal death, the timing effect within the recommended window may vary depending on gestational age and clinical circumstances. [39]

Comparison with the effective perinatal intensive care in Europe study.

Consistent with our results, the Effective Perinatal Intensive Care in Europe (EPICE) study [40] reported that administration of antenatal corticosteroids (ACS) even shortly before delivery was associated with a marked reduction in in-hospital mortality and severe neonatal morbidity among very preterm infants (24–31 weeks’ gestation). The investigators observed that mortality declined by more than 50% between 18 and 36 hours after ACS administration, suggesting that even brief exposure before birth may provide significant survival and health benefits for very preterm infant.

In comparison, our study found that while the timing of the last dexamethasone dose did not significantly reduce the incidence of RDS, it did influence other respiratory outcomes. Specifically, the time from the last dose to delivery was associated with varying risks of complications such as TTNB and the need for ventilator support.

Both studies underscore the importance of the administration-to-birth interval. The EPICE study emphasized the immediate benefits for very preterm infants. Our findings suggest that careful timing can optimize outcomes across a broader range of respiratory complications, especially in cases involving different steroid courses and multiple gestations.

Considerations on primary outcome and study scope.

Although the primary outcome, respiratory distress syndrome (RDS), did not reach statistical significance among the study groups, several secondary respiratory outcomes, including the need for continuous positive airway pressure (CPAP) support and neonatal intensive care unit (NICU) admission, showed significant differences according to the timing and course of antenatal corticosteroid (ACS) administration. These findings suggest that even in the absence of a clear reduction in RDS incidence, variations in ACS exposure may still influence the severity of neonatal respiratory morbidity.

Clinical implications

Tailored ACS administration.

Our study underscores the critical necessity for individualized approaches to ACS administration. The varying effects of complete versus incomplete steroid courses, along with differences between singleton and twin pregnancies, highlight the need for tailored strategies. While a full course of ACS administered within the optimal window significantly benefits neonatal outcomes, both the timing and the number of courses are pivotal in influencing respiratory and other complications.

Implications for singleton pregnancies.

In singleton pregnancies, our findings suggest that delivery 2–7 days after completing a full course of ACS may be associated with more favorable respiratory outcomes. However, these observations are derived from a retrospective design and therefore may be subject to residual confounding. Prospective studies and randomized controlled trials are needed to confirm whether optimizing timing within this interval leads to improved clinical outcomes.

Implications for twin pregnancies.

In twin pregnancies, adjustments in the timing of ACS administration may be necessary to manage risks such as necrotizing enterocolitis more effectively. The findings suggest that the standard timing optimal for singletons may not directly apply to twins, emphasizing the importance of individualized timing strategies based on fetal number.

Clinical recommendations.

Clinicians should individualize ACS strategies to balance efficacy and safety. Considering the type of steroid course—complete versus incomplete—and the number of fetuses is essential. Healthcare providers can optimize neonatal health outcomes and minimize adverse effects by tailoring ACS administration according to these factors.

Research implications

This study highlights the necessity for further research to refine and optimize ACS protocols. Future studies should examine the differential impacts of complete versus incomplete steroid courses and the timing of administration on neonatal outcomes across both singleton and twin pregnancies. Longitudinal analyses are essential for understanding the long-term effects of various ACS regimens and their interactions with multiple fetal variables. Exploring the underlying mechanisms driving the varying impacts of ACS timing and dosing, particularly in preterm births with complex presentations, could lead to more personalized and effective ACS strategies. Investigating these factors may improve outcomes for preterm infants and inform clinical practice guidelines.

Strengths and limitations

A major strength of this study is its large sample size of 1800 preterm infants, which enhances the robustness and reliability of the findings. The detailed analysis of the timing intervals between the last dose of dexamethasone and delivery contributes valuable insights into the optimal timing for various neonatal outcomes. Additionally, the study accounts for the impact of steroid course completeness and multiple gestations, offering a comprehensive view of how these factors influence neonatal health.

A significant limitation is the lack of a reduction in RDS, which constrains the study’s impact on timing-specific effects for this particular outcome. The retrospective design may be subject to biases and limitations inherent in such studies, such as selection bias and recall bias. Some potential confounders might not have been fully addressed despite controlling for numerous factors. Furthermore, as the research was conducted at a single center, the generalizability of the findings to other settings may be limited.

Conclusions

While the timing of dexamethasone administration did not significantly reduce the incidence of RDS, it did affect other respiratory outcomes. The optimal interval of administering dexamethasone between 2 and 7 days before delivery was associated with better overall respiratory results. These findings underscore the importance of carefully timing steroid administration to manage various respiratory complications in preterm neonates.

Acknowledgments

We thank the Faculty of Medicine Siriraj Hospital, Mahidol University, for the English editing assistance provided by Mr. David Park, and for the administrative support from Ms. Rangsima Srichai.

Data Availability

Due to ethical and legal restrictions related to patient confidentiality, the data supporting the findings of this study are not publicly available. Requests for access to de-identified data may be submitted to the Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University (sirdmu@mahidol.ac.th), which will review requests in accordance with institutional and ethical guidelines.

Funding Statement

The Faculty of Medicine Siriraj Hospital, Mahidol University, provided funding support ([IO] R016733004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0343138.r001

Decision Letter 0

Hakan Aylanc

4 Nov 2025

Dear Dr. Chawanpaiboon,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: Comments to authors

Line 69-70: though the incidence is not significantly different, there is a more recent data on this published in 2023 (Ohuma, Eric O et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. The Lancet, Volume 402, Issue 10409, 1261 – 1271)

Line 74-75: author should provide a more recent article for reference.

Line 116-121: author should provide better clearance on the definition and/or severity of the neonatal outcomes that were evaluated, or provide references for such. For example, what grade of IVH did they look at? What stage of NEC and grade of BPD did they look at? Define or cite reference for definition of BPD? What maternal complications were evaluated? And so on.

Line 125-127: why is chest Xray not included in making diagnosis of RDS

Line 134: author should define the groups before this point

Line 147: I would recommend that the authors discuss association of ACS timing with mortality in their cohort

Line 158-159 (Table 1): author to define what a complete course of ACS is, or cite a reference for it in the method. How many courses of multiple ACS dose were given? At what number of multiple doses did they start to see harm or no benefit?

Line 237-240: It is expected that infants born very or extremely preterm will need NICU admission as well as most likely need resp support. I do not understand why the author analyzed and reported this.

Line 339-346: this is a report of result. It should therefore be under result, and not discussion.

Line 366-389: I disagree with the authors about these clinical implications conclusion as this is a retrospective cohort study. I think an RCT or a meta-analysis will be needed to make such recommendations.

PS: It is important for the authors to describe the practice of surfactant administration in their institution, and what effect does it have on the reported results.

Reviewer #2: The paper is well written in standard English. The statistical analysis is appropriate, however the primary outcome did not reach statistical significance. The subject population consisted primarily of infants of gestational ages for which ACS are not typically given and many were not admitted to the NICU. The conclusions do not add very much to the field as a result.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2026 Mar 2;21(3):e0343138. doi: 10.1371/journal.pone.0343138.r002

Author response to Decision Letter 1

7 Nov 2025

POINT- BY-POINT RESPONSE TO EDITOR AND REVIEWER

RESPONSE TO EDITOR

Comment 1.

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response to editor

Thank you for your guidance. We have revised the manuscript to ensure full compliance with PLOS ONE style requirements. The manuscript has been reformatted according to the provided templates, and all file names have been updated to follow the journal’s naming conventions.

Comment 2.

2. Thank you for stating the following financial disclosure:

The Faculty of Medicine Siriraj Hospital, Mahidol University, provided funding support ([IO] R016733004).

If this statement is not correct you must amend it as needed.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

Response to editor

Thank you for your note. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We have included this statement in the cover letter as requested.

Comment 3.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

The Faculty of Medicine Siriraj Hospital, Mahidol University, provided funding support ([IO] R016733004).

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Response to editor

Thank you for the clarification. We have removed the funding-related text from the Acknowledgments section. The updated Acknowledgment now reads:

“We thank the Faculty of Medicine Siriraj Hospital, Mahidol University, for the English editing assistance provided by Mr. David Park, and for the administrative support from Ms. Rangsima Srichai.”

The Funding Statement remains as follows:

“The Faculty of Medicine Siriraj Hospital, Mahidol University, provided funding support ([IO] R016733004).”

The updated statements have been included in the cover letter as requested.

Comment 4.

4. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

Response to editor

Thank you for your guidance. The ethics statement has been retained only in the Methods section and removed from all other parts of the manuscript, in accordance with PLOS ONE requirements.

Comment 5.

Before we proceed with your manuscript, please address the following prompts:

Please update your Data Availability statement in the submission form accordingly.

Response to editor

Thank you for your note. There are no ethical or legal restrictions on sharing the de-identified data. The data supporting the findings of this study are available from the corresponding author upon reasonable request. The following statement has been included in the manuscript:

Availability of data and materials:

The data supporting the findings of this study are available from the corresponding author upon reasonable request. Researchers may contact the corresponding author directly for data access and further information regarding data sharing arrangements.

Comment 6.

Response to editor

Thank you for the clarification. We have carefully reviewed the publications suggested by the reviewers and have cited only those that are relevant to our study. Irrelevant recommendations were not included, in accordance with PLOS ONE guidelines.

RESPONSE TO REVIEWER 1

Comment 1.

Response to reviewer

We thank the reviewer for this helpful suggestion. The sentence has been revised to include updated global estimates of preterm birth rates and numbers, as follows:

“In 2014 and 2020, the global preterm birth rate was 10.6% and 9.9%, respectively, accounting for approximately 14.84 million and 13.4 million live preterm births (1, 2).”

We have also added the new reference Ohuma et al., 2023 (The Lancet) to provide the most recent global data.

New Corrected data

Introduction part: Line 68-71. In 2014 and 2020, the global preterm birth rate was 10.6% and 9.9%, respectively, accounting for approximately 14.84 million and 13.4 million live preterm births. (1, 2)

Comment 2

Line 74-75: author should provide a more recent article for reference.

Response to reviewer

We appreciate the reviewer’s suggestion to include a more recent reference. The cited article has been updated accordingly. A recent and relevant reference has been added as follows:

Costa, F., Titolo, A., Ferrocino, M., Biagi, E., Dell'Orto, V., Perrone, S., & Esposito, S. (2024). Lung Ultrasound in Neonatal Respiratory Distress Syndrome: A Narrative Review of the Last 10 Years. Diagnostics, 14. https://doi.org/10.3390/diagnostics14242793.

In addition to adding a recent reference, we have also included the original citation that first defined the terminology of respiratory distress syndrome for historical and conceptual accuracy:

Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child. 1959;97(5, Part 1):517–23.

New corrected data

Reference 5. Costa, F., Titolo, A., Ferrocino, M., Biagi, E., Dell'Orto, V., Perrone, S., & Esposito, S. (2024). Lung Ultrasound in Neonatal Respiratory Distress Syndrome: A Narrative Review of the Last 10 Years. Diagnostics, 14. https://doi.org/10.3390/diagnostics14242793.

Comment 3.

Response to reviewer

In the revised manuscript, we have added detailed definitions and corresponding references for all neonatal and maternal outcomes evaluated.

New corrected data

Part of Material and methods, Line 123-158

• Respiratory distress syndrome (RDS) was diagnosed in preterm infants who presented with clinical signs of respiratory distress, including tachypnea (respiratory rate > 60 breaths per minute), nasal flaring, expiratory grunting, and chest wall retractions and required respiratory support such as continuous positive airway pressure (CPAP), intubation, or surfactant therapy. The diagnosis was confirmed by characteristic chest X-ray findings, including a reticulogranular (ground-glass) appearance and air bronchograms, consistent with surfactant deficiency. (12, 13)

• Transient tachypnea of the newborn (TTNB) is characterized by tachypnea (respiratory rate >60 breaths per minute) developing shortly after birth, typically within the first 6 hours, accompanied by mild respiratory distress (grunting, nasal flaring, or retractions) and radiographic findings consistent with pulmonary fluid retention (e.g., prominent vascular markings, interlobar fissure fluid, or hyperinflation). The condition resolves within 72 hours without evidence of infection or structural lung disease. (14)

• Apnea of prematurity is defined as a cessation of breathing lasting 20 seconds or longer, or a shorter pause accompanied by bradycardia (heart rate <100 beats/min) and/or oxygen desaturation (SpO₂ <80%), occurring in infants born before 37 weeks of gestation after exclusion of other causes such as infection or airway obstruction. (15)

• Intraventricular hemorrhage (IVH) was classified according to Papile’s grading system (grades I–IV) based on cranial ultrasound findings, with clinically significant IVH defined as grade II or higher. (16, 17)

• Necrotizing enterocolitis is diagnosed and staged according to Bell’s classification, with clinically significant disease defined as stage II or higher. (18, 19)

• Early-onset neonatal sepsis is defined by sepsis occurring within the first 72 hours of life, confirmed by a positive blood culture or clinical findings consistent with systemic infection (e.g., temperature instability, respiratory distress, or hemodynamic instability). (18, 20)

• Neonatal pneumonia is diagnosed by clinical symptoms (tachypnea, grunting, retractions) plus radiographic evidence of pulmonary infiltrates or consolidation, with or without positive cultures. (21)

• Maternal postpartum complications: (22)

Comment 4.

Line 125-127: why is chest Xray not included in making diagnosis of RDS

Response to reviewer

The definition of respiratory distress syndrome (RDS) has been revised to include chest X-ray findings as part of the diagnostic criteria. The updated definition now states that RDS was diagnosed based on clinical signs of respiratory distress, requirement for respiratory support or surfactant therapy, and characteristic radiographic findings (reticulogranular pattern and air bronchograms) consistent with surfactant deficiency, in accordance with the European Consensus Guidelines on RDS (Sweet et al., 2019) and Wang et al., 2004.

New corrected data

Part of Material and methods, Line 123-158

Respiratory distress syndrome (RDS) was diagnosed in preterm infants who presented with clinical signs of respiratory distress, including tachypnea (respiratory rate > 60 breaths per minute), nasal flaring, expiratory grunting, and chest wall retractions and required respiratory support such as continuous positive airway pressure (CPAP), intubation, or surfactant therapy. The diagnosis was confirmed by characteristic chest X-ray findings, including a reticulogranular (ground-glass) appearance and air bronchograms, consistent with surfactant deficiency.

Comment 5.

Line 134: author should define the groups before this point

Response to reviewer

We thank the reviewer for the helpful suggestion. The groups mentioned in the sample size calculation have now been clearly defined as incomplete, complete, and multiple courses of antenatal corticosteroids (ACS). The paragraph has been revised accordingly to clarify the basis of group comparison in the sample size estimation.

New corrected data

Part of statistical analysis Page 9, Line 162-172

Sample size calculation

Comment 6.

Line 147: I would recommend that the authors discuss association of ACS timing with mortality in their cohort

Response to reviewer

We have now analyzed and reported the association between antenatal corticosteroid (ACS) timing and neonatal mortality.

The Results section includes the following statement: “There was no significant difference in neonatal mortality among the groups categorized by the time from the last dexamethasone dose to delivery (P = 0.727).”

The Discussion section has also been updated to note that ACS timing was not significantly associated with neonatal mortality in our cohort, although prior meta-analyses have shown improved survival when delivery occurs within 1–7 days after ACS administration (McGoldrick et al., 2020).

New corrected data

The result part, Line 216-218.

There was no significant difference in neonatal mortality among the groups categorized by the time from the last dexamethasone dose to delivery (P = 0.727) (Table 3).

The discussion part, Line 382-385.

Comment 7.

Line 158-159 (Table 1): author to define what a complete course of ACS is, or cite a reference for it in the method. How many courses of multipl

Attachment

Submitted filename: Point by point response to editor and reviewers.docx

pone.0343138.s001.docx^{(54KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0343138.r003

Decision Letter 1

Hakan Aylanc

30 Nov 2025

Dear Dr. Chawanpaiboon,

plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
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We look forward to receiving your revised manuscript.

Kind regards,

Hakan Aylanc

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments :

Dear author,

I recommend that you carefully read the referee's comments and review your response to the requested revisions. I look forward to receiving your response. Kind regards.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

Reviewer #1: (No Response)

Reviewer #2: While the authors addressed my previous concerns and revised the primary outcome, the fact remains that one cannot predict when a preterm infant is going to be delivered. The paper provides information regarding optimal timing of ACS, but the information cannot be applied in real practice. I think it is important that they acknowledge this point.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

Reviewer #2: No

**********

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

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PLoS One. 2026 Mar 2;21(3):e0343138. doi: 10.1371/journal.pone.0343138.r004

Author response to Decision Letter 2

26 Dec 2025

Response to Editor and Reviewers

We thank the Academic Editor and reviewers for their valuable comments.

As clarified by the PLOS ONE Editorial Office, Reviewer #1 indicated that all comments had been addressed in the previous revision round, and no further response was required. Reviewer #2 raised one additional concern, which has been addressed in the revised manuscript by acknowledging the limitation of predicting antenatal corticosteroid timing in clinical practice and emphasizing the observational nature of the study.

All requested revisions have been completed, and the revised manuscript, tracked-changes version, and detailed response document have been submitted. We appreciate the opportunity to improve our work.

Attachment

Submitted filename: Final Point by point response to editor and reviewers.docx

pone.0343138.s002.docx^{(54KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0343138.r005

Decision Letter 2

Hakan Aylanc

2 Feb 2026

Impact of timing from last dose of dexamethasone administration to delivery, different steroid courses, and fetal number on preterm neonatal outcomes

PONE-D-25-19075R2

Dear Dr. Chawanpaiboon,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Hakan Aylanc

Academic Editor

PLOS One

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Reviewers' comments:

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Data Availability Statement

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PERMALINK

Impact of timing from last dose of dexamethasone administration to delivery, different steroid courses, and fetal number on preterm neonatal outcomes

Saifon Chawanpaiboon

Julaporn Pooliam

Monsak Chuchotiros

Roles

Abstract

Objectives

Methods

Results

Conclusions

Thai Clinical Trials Registry (TCTR) number

Introduction

Materials and methods

Study design and ethics approval

Data collection

Primary and secondary outcomes

Neonatal and maternal outcomes

Definition

Surfactant administration protocol.

Definition of antenatal corticosteroid courses.

Sample size calculation

Statistical analysis

Results

Participant characteristics

Timing of dexamethasone administration

Table 1. Maternal demographic characteristics and neonatal outcomes.

RDS outcomes

Table 2. Effect of time from last dexamethasone dose to delivery on respiratory distress syndrome: comparison by steroid course, gestational age, and fetal number.

Continuous positive airway pressure support and other respiratory complications

Table 3. Effect of time from last dexamethasone dose to delivery on secondary neonatal outcomes.

Table 4. Effect of time from last dose of dexamethasone dose to delivery on key secondary outcomes.

Outcomes in singleton and twin pregnancies

Multivariate analysis

Table 5. Multivariable logistic regression of significant factors associated with respiratory distress syndrome.

Table 6. Multivariable logistic regression of significant factors associated with secondary outcomes.

Discussions

Principal findings

Results in the context of what is known

Outcomes in singleton and twin pregnancies.

Implications of incomplete and multiple courses.

Clinical significance in twin pregnancies.

Associations with other respiratory complications.

Comparison with the effective perinatal intensive care in Europe study.

Considerations on primary outcome and study scope.

Clinical implications

Tailored ACS administration.

Implications for singleton pregnancies.

Implications for twin pregnancies.

Clinical recommendations.

Research implications

Strengths and limitations

Conclusions

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Hakan Aylanc

Roles

Author response to Decision Letter 1

Decision Letter 1

Hakan Aylanc

Roles

Author response to Decision Letter 2

Decision Letter 2

Hakan Aylanc

Roles

Acceptance letter

Hakan Aylanc

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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