Effect of Antenatal Steroids on Respiratory Morbidity of Late Preterm Newborns: A Randomized Controlled Trial

Effect of Antenatal Steroids on Respiratory Morbidity of Late Preterm Newborns: A Randomized... Abstract Objective The objective of this article was to study the effect of antenatal dexamethasone on the respiratory morbidity of late preterm newborns. Study design A randomized controlled trial, conducted in Obstetrics and Gynecology Department in collaboration with Neonatology department at JIPMER, India. In total, 155 women were studied in each group. Intention to treat analysis and per protocol analysis were done. Results Overall 31 (10%) newborns were admitted to intensive care unit. The composite respiratory morbidity (defined as respiratory distress syndrome and/or transient tachypnea of newborn) was observed in 64 (41.6%) infants in the study and 56 (36.2%) infants in the control group. On multivariable-adjusted analysis, use of steroids was not found to be associated with decrease in composite respiratory morbidity [adjusted relative risk 0.91 (95% confidence interval: 0.7–1.2)]. Conclusions Antenatal dexamethasone does not reduce the composite respiratory morbidity of babies born vaginally or by emergency cesarean to women with late preterm labor. late preterm, antenatal steroids, transient tachypnea of newborn, respiratory distress syndrome INTRODUCTION Worldwide prevalence of preterm birth is 9.6%. More than 1 million preterm newborns die each year [1]. In a retrospective cohort study of 18 years, the authors found that late preterm deliveries complicate 9% of all deliveries, and further, three-fourth of all preterm deliveries are late preterm [2]. India has a high preterm birth rate with an incidence of around 13.0% [3]. In a recent study from India, late preterm deliveries were found to be 14% of all deliveries [4]. Late preterm infants (those between 34 and 36+6/7 weeks of gestation) face a significantly greater risk of adverse respiratory outcomes compared with term infants [5–7]. Antenatal corticosteroid (ACS) therapy has been one of the major breakthroughs in improving perinatal outcome for preterm infants. The benefit of ACS before 34 weeks to mitigate the morbidity of prematurity is well established [7, 8, 9]. There are few completed trials addressing the effect of ACS on the late preterm newborns [10]. Balci and colleagues [11] found ACS to be beneficial, but their sample size was small, and nearly one-third of women in both the groups had been delivered by scheduled cesarean section. Porto and colleagues [12], on the other hand, did not find any benefit of antenatal betamethasone on transient tachypnea or respiratory distress syndrome among the late preterm newborns. This randomized controlled trial (RCT) was undertaken to study the effect of antenatal dexamethasone on composite respiratory morbidity among the late preterm babies born vaginally or by emergency cesarean section to women with preterm labor. MATERIAL AND METHODS Trial design and study setup We conducted this RCT (parallel allocation with 1:1 ratio) in Obstetrics and Gynaecology Department in collaboration with the Department of Neonatology at the Jawaharlal Nehru Institute of Postgraduate Medical Education and Research (JIPMER) from February 2015 to June 2016. It is a tertiary care institute of National importance. It caters to the poor population free of cost. The institute ethics committee approved the study, and it is registered with the Clinical Trials Registry-India (Clinical Trials Registry-India: http://ctri.nic.in/Clinicaltrials/login.php CTRI no 2016/12/007570). Screening and recruitment We screened all women admitted to labor ward with the risk of late preterm delivery. We included women admitted to the labor room with a period of gestation between 34 and 36 + 6 weeks with a singleton pregnancy with risk of preterm delivery either spontaneously or requiring termination for maternal (or) fetal indication. We calculated gestational age as per the last menstrual period or early pregnancy scan. Those who were far advanced in labor (5 cm or more dilated) or had received the previous course of steroids or had chorioamnionitis at admission were considered ineligible. We excluded women with multiple gestations, gestational diabetes and diabetes mellitus, major congenital malformations in the fetus and those undergoing a pre-labor scheduled cesarean section. Randomization and intervention Among the 1575 women screened, 1265 were either ineligible or excluded (Fig. 1). After informing study details and obtaining informed consent, we randomized 310 eligible women into ACS group, and non-ACS group using computer-generated random numbers (generated and provided in a sequentially numbered, sealed, opaque envelopes, from an independent data coordinating party, from the Department of Preventive and Social Medicine). Women randomized to study group received four doses of dexamethasone (hospital supply given free of cost for patients), 6 mg administered intramuscularly 12 hourly. Control group did not receive steroids or placebo. We administered tocolytics and antibiotics as per the department protocol. There was no loss to follow-up after randomization. One case in the study group was excluded from analysis because it was stillborn. Fig 1. View largeDownload slide CONSORT diagram of the study. Fig 1. View largeDownload slide CONSORT diagram of the study. Study outcomes Structured pro forma was used to collect the data. The primary outcome measure was composite respiratory morbidities (transient tachypnea; respiratory distress syndrome). Transient tachypnea of the newborn was defined as the presence of clinical signs of respiratory distress at birth without any significant radiological changes or with a feature of hyperinflation/interlobar fluid that resolved within 72 h. Respiratory distress syndrome was defined as signs of respiratory distress at birth along with radiological evidence of decreased air entry of diffuse granular infiltrates. Other complications such as hypoglycemia, hypothermia, poor feeding, sepsis and neonatal mortality were also noted. We followed up all the babies until discharge from the hospital. Sample size calculation Based on the literature, the composite respiratory morbidity in the unexposed group is 25% [13]. A 50% reduction is expected with the intervention. So, for 80% power and an alpha error of 0.05, based on Kelsey and Fleiss continuity correction, a sample size of 155 was required in each group. Thus, we included 155 women in each group (total sample size of 310). Analysis The analysis was performed using SPSS version 19.0. Continuous variables were described using mean and SD as well as the median for gestational age and birth weight and compared with unpaired t-test or Wilcoxon rank sum (Mann–Whitney U) test. We compared categorical variables using chi-square test. We performed an intention to treat analysis for comparing the primary outcome. We calculated relative risk (RR) with 95% confidence intervals (CIs). A p-value of <0.05 was taken as statistically significant. To adjust for the baseline differences between the two groups, adjusted RRs with 95% CIs were calculated using log-binomial regression. Intention to treat analysis (irrespective of the number of doses of steroids) and per protocol analysis (including only those who received all four doses of steroids) were done. RESULTS In total, 155 women were randomly assigned to each group. In the study group, 108 women (70%) completed the full dexamethasone course before delivery (Fig. 1). None of the subjects in either group delivered after 37 weeks. Therefore, 154 in the study group and all 155 in the control group were analyzed. Most of the baseline characters (Table 1) were comparable in the two groups. However, a significant number of women in the study group underwent emergency cesarean section (p < 0.001). In our study, 5 of 155 (3.2%) in control and 4 of 154(2.6%) in steroid group had intrauterine growth-retarded babies. This difference is not statistically significant (p-value = 0.74), though the mean birth weight was significantly higher in the study group (p < 0.001). This s a statistical difference and is not of clinical significance (2.4 vs. 2.36 kg). We did not observe any serious side effect or short-term adverse effect of the steroid injection to the women. Table 1 Baseline characteristics of study population Outcome  Study group (N = 154) (%)  Control group (N = 155) (%)  p-value  Maternal age (years) (SD)  24.3 (3.74)  24.1 (2.93)    Gravidity n =(%)         1  81 (52.6)  71 (45.8)     >1  73 (47.4)  84 (54.2)    Medical disorders  28. (18.2)  19 (12.3)    Hypertensive disorders  16 (10.4)  11 (7.1)    Median period of gestation(interquartile range) (weeks)  35.4 (34–36.9)  35.9 (34–36.9)  0.001  Antibiotic usage  107 (69.5)  91 (58.7)    Tocolytic usage  8 (5.2)  9 (5.8)    Mode of delivery         Vaginal delivery  128 (83.1)  142(91.6)  0.02   Emergency cesarean section  26 (16.9)  13 (8.4)    Mean duration of labor (hours)  9.64  9.56    Liquor color         Meconium  4 (2.6)  4 (2.6)     Clear  150 (97.4)  150 (96.8)     Blood stained  0  1 (0.6)    Sex of baby (%)         Male  78(50.6)  78 (50.6)     Female  49.4 (76)  49.4 (77)    Mean birth weight kg (SD)  2.4 (1.92)  2.36 (0.202)  0.001  PROM  59 (41.5%)  83 (58.5%)    Admission to delivery interval (hours)  50.6  19.8  0.001  Outcome  Study group (N = 154) (%)  Control group (N = 155) (%)  p-value  Maternal age (years) (SD)  24.3 (3.74)  24.1 (2.93)    Gravidity n =(%)         1  81 (52.6)  71 (45.8)     >1  73 (47.4)  84 (54.2)    Medical disorders  28. (18.2)  19 (12.3)    Hypertensive disorders  16 (10.4)  11 (7.1)    Median period of gestation(interquartile range) (weeks)  35.4 (34–36.9)  35.9 (34–36.9)  0.001  Antibiotic usage  107 (69.5)  91 (58.7)    Tocolytic usage  8 (5.2)  9 (5.8)    Mode of delivery         Vaginal delivery  128 (83.1)  142(91.6)  0.02   Emergency cesarean section  26 (16.9)  13 (8.4)    Mean duration of labor (hours)  9.64  9.56    Liquor color         Meconium  4 (2.6)  4 (2.6)     Clear  150 (97.4)  150 (96.8)     Blood stained  0  1 (0.6)    Sex of baby (%)         Male  78(50.6)  78 (50.6)     Female  49.4 (76)  49.4 (77)    Mean birth weight kg (SD)  2.4 (1.92)  2.36 (0.202)  0.001  PROM  59 (41.5%)  83 (58.5%)    Admission to delivery interval (hours)  50.6  19.8  0.001  PROM: Premature Rupture of Membranes. Table 1 Baseline characteristics of study population Outcome  Study group (N = 154) (%)  Control group (N = 155) (%)  p-value  Maternal age (years) (SD)  24.3 (3.74)  24.1 (2.93)    Gravidity n =(%)         1  81 (52.6)  71 (45.8)     >1  73 (47.4)  84 (54.2)    Medical disorders  28. (18.2)  19 (12.3)    Hypertensive disorders  16 (10.4)  11 (7.1)    Median period of gestation(interquartile range) (weeks)  35.4 (34–36.9)  35.9 (34–36.9)  0.001  Antibiotic usage  107 (69.5)  91 (58.7)    Tocolytic usage  8 (5.2)  9 (5.8)    Mode of delivery         Vaginal delivery  128 (83.1)  142(91.6)  0.02   Emergency cesarean section  26 (16.9)  13 (8.4)    Mean duration of labor (hours)  9.64  9.56    Liquor color         Meconium  4 (2.6)  4 (2.6)     Clear  150 (97.4)  150 (96.8)     Blood stained  0  1 (0.6)    Sex of baby (%)         Male  78(50.6)  78 (50.6)     Female  49.4 (76)  49.4 (77)    Mean birth weight kg (SD)  2.4 (1.92)  2.36 (0.202)  0.001  PROM  59 (41.5%)  83 (58.5%)    Admission to delivery interval (hours)  50.6  19.8  0.001  Outcome  Study group (N = 154) (%)  Control group (N = 155) (%)  p-value  Maternal age (years) (SD)  24.3 (3.74)  24.1 (2.93)    Gravidity n =(%)         1  81 (52.6)  71 (45.8)     >1  73 (47.4)  84 (54.2)    Medical disorders  28. (18.2)  19 (12.3)    Hypertensive disorders  16 (10.4)  11 (7.1)    Median period of gestation(interquartile range) (weeks)  35.4 (34–36.9)  35.9 (34–36.9)  0.001  Antibiotic usage  107 (69.5)  91 (58.7)    Tocolytic usage  8 (5.2)  9 (5.8)    Mode of delivery         Vaginal delivery  128 (83.1)  142(91.6)  0.02   Emergency cesarean section  26 (16.9)  13 (8.4)    Mean duration of labor (hours)  9.64  9.56    Liquor color         Meconium  4 (2.6)  4 (2.6)     Clear  150 (97.4)  150 (96.8)     Blood stained  0  1 (0.6)    Sex of baby (%)         Male  78(50.6)  78 (50.6)     Female  49.4 (76)  49.4 (77)    Mean birth weight kg (SD)  2.4 (1.92)  2.36 (0.202)  0.001  PROM  59 (41.5%)  83 (58.5%)    Admission to delivery interval (hours)  50.6  19.8  0.001  PROM: Premature Rupture of Membranes. Table 2 shows the neonatal outcome. There was no statistical difference in the study and the control group for Apgar scores, admission to neonatal intensive care unit (NICU) and resuscitation steps. None of the babies who developed transient tachypnea required a bag and mask ventilation and intubation. Among those who developed respiratory distress syndrome, seven needed a bag and mask ventilation and four required intubation. The composite respiratory morbidity was maximum in the babies born between 34 and 34 + 6 weeks compared with higher periods of gestation, though it was not of statistical significance. None of the babies among the two groups developed morbidities like hypoglycemia and hypothermia during the period of stay in the hospital. Table 2 Perinatal outcomes of late preterm newborns Outcome  Study group (N = 154)  Control group (N = 155)  RR (95% CIa)  p-value  N (%)  N (%)  Transient tachypnea of the newborn (TTN)  51 (33.1)  46 (29.7)  1.12 (0.80–1.55)  0.51  Respiratory distress syndrome (RDS)  13 (8.4)  10 (6.5)  1.31 (0.59–2.89)  0.50  Composite respiratory morbidity (TTN+RDS)  64 (41.6)  56 (36.2)  1.15 (0.87–1.52)  0.32  Bag and mask  7 (4.5)  4 (2.6)  1.76 (0.53–5.90)  0.35  Ventilatory support  2 (1.3)  2 (1.3)  1.01 (0.14–7.06)  0.99  Admission to NICUb  18 (11.7)  13 (8.4)  1.39 (0.71–2.74)  0.33  Apgar score Mean (SD)           1 min  7.8 (0.68)  7.8 (0.70)  –  0.98   5 min  8.9 (0.36)  8.9 (0.58)  –  0.7  Downe’s score Median (range)  2 (0–6)  2 (0–8)  –  0.24  Outcome  Study group (N = 154)  Control group (N = 155)  RR (95% CIa)  p-value  N (%)  N (%)  Transient tachypnea of the newborn (TTN)  51 (33.1)  46 (29.7)  1.12 (0.80–1.55)  0.51  Respiratory distress syndrome (RDS)  13 (8.4)  10 (6.5)  1.31 (0.59–2.89)  0.50  Composite respiratory morbidity (TTN+RDS)  64 (41.6)  56 (36.2)  1.15 (0.87–1.52)  0.32  Bag and mask  7 (4.5)  4 (2.6)  1.76 (0.53–5.90)  0.35  Ventilatory support  2 (1.3)  2 (1.3)  1.01 (0.14–7.06)  0.99  Admission to NICUb  18 (11.7)  13 (8.4)  1.39 (0.71–2.74)  0.33  Apgar score Mean (SD)           1 min  7.8 (0.68)  7.8 (0.70)  –  0.98   5 min  8.9 (0.36)  8.9 (0.58)  –  0.7  Downe’s score Median (range)  2 (0–6)  2 (0–8)  –  0.24  a Confidence Interval (CI), b Neonatal Intensive Care Unit (NICU). Table 2 Perinatal outcomes of late preterm newborns Outcome  Study group (N = 154)  Control group (N = 155)  RR (95% CIa)  p-value  N (%)  N (%)  Transient tachypnea of the newborn (TTN)  51 (33.1)  46 (29.7)  1.12 (0.80–1.55)  0.51  Respiratory distress syndrome (RDS)  13 (8.4)  10 (6.5)  1.31 (0.59–2.89)  0.50  Composite respiratory morbidity (TTN+RDS)  64 (41.6)  56 (36.2)  1.15 (0.87–1.52)  0.32  Bag and mask  7 (4.5)  4 (2.6)  1.76 (0.53–5.90)  0.35  Ventilatory support  2 (1.3)  2 (1.3)  1.01 (0.14–7.06)  0.99  Admission to NICUb  18 (11.7)  13 (8.4)  1.39 (0.71–2.74)  0.33  Apgar score Mean (SD)           1 min  7.8 (0.68)  7.8 (0.70)  –  0.98   5 min  8.9 (0.36)  8.9 (0.58)  –  0.7  Downe’s score Median (range)  2 (0–6)  2 (0–8)  –  0.24  Outcome  Study group (N = 154)  Control group (N = 155)  RR (95% CIa)  p-value  N (%)  N (%)  Transient tachypnea of the newborn (TTN)  51 (33.1)  46 (29.7)  1.12 (0.80–1.55)  0.51  Respiratory distress syndrome (RDS)  13 (8.4)  10 (6.5)  1.31 (0.59–2.89)  0.50  Composite respiratory morbidity (TTN+RDS)  64 (41.6)  56 (36.2)  1.15 (0.87–1.52)  0.32  Bag and mask  7 (4.5)  4 (2.6)  1.76 (0.53–5.90)  0.35  Ventilatory support  2 (1.3)  2 (1.3)  1.01 (0.14–7.06)  0.99  Admission to NICUb  18 (11.7)  13 (8.4)  1.39 (0.71–2.74)  0.33  Apgar score Mean (SD)           1 min  7.8 (0.68)  7.8 (0.70)  –  0.98   5 min  8.9 (0.36)  8.9 (0.58)  –  0.7  Downe’s score Median (range)  2 (0–6)  2 (0–8)  –  0.24  a Confidence Interval (CI), b Neonatal Intensive Care Unit (NICU). In both unadjusted analysis and adjusted analysis, mode of delivery is associated with composite respiratory morbidity. We agree that emergency caesarean section numbers are high in the study group. However, this difference is taken care of/adjusted in the multivariable analysis, and the independent effect of steroids is estimated. In adjusted analysis (Table 3), after adjusting for effect of mode of delivery, birth weight and period of gestation, use of steroids was not found to be statistically associated with a decrease in composite respiratory morbidity [adjusted RR: 0.91 (95% CI: 0.7–1.2)]. Table 3 Multivariable analysis (intention to treat analysis) for effect of antenatal steroids on composite respiratory morbidity Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=154)  0.91 (0.7–1.2)  0.49  0.92 (0.67–1.23)  0.61  0.86 (0.40–1.83)  0.69   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.43 (0.34–0.55)  <0.001  0.42 (0.31–0.57)  <0.001  0.49 (0.20–1.22)  0.13   LSCSc  1    1    1    Birth weight (kg)  0.21 (0.11–0.39)  <0.001  0.28 (0.13–0.60)  0.001  0.06 (0.007–0.46)  0.007  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.22 (0.89–1.69)  0.22  1.34 (0.90–2.17)  0.14  0.85 (0.36–1.97)  0.69   36–36 + 6  0.96 (0.66–1.39)  0.82  1.13 (0.70–1.82)  0.63  0.55 (0.22–1.4)  0.21  Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=154)  0.91 (0.7–1.2)  0.49  0.92 (0.67–1.23)  0.61  0.86 (0.40–1.83)  0.69   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.43 (0.34–0.55)  <0.001  0.42 (0.31–0.57)  <0.001  0.49 (0.20–1.22)  0.13   LSCSc  1    1    1    Birth weight (kg)  0.21 (0.11–0.39)  <0.001  0.28 (0.13–0.60)  0.001  0.06 (0.007–0.46)  0.007  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.22 (0.89–1.69)  0.22  1.34 (0.90–2.17)  0.14  0.85 (0.36–1.97)  0.69   36–36 + 6  0.96 (0.66–1.39)  0.82  1.13 (0.70–1.82)  0.63  0.55 (0.22–1.4)  0.21  a Relative Risk (RR), b Confidence Interval (CI), c Lower segment caesarean section. Table 3 Multivariable analysis (intention to treat analysis) for effect of antenatal steroids on composite respiratory morbidity Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=154)  0.91 (0.7–1.2)  0.49  0.92 (0.67–1.23)  0.61  0.86 (0.40–1.83)  0.69   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.43 (0.34–0.55)  <0.001  0.42 (0.31–0.57)  <0.001  0.49 (0.20–1.22)  0.13   LSCSc  1    1    1    Birth weight (kg)  0.21 (0.11–0.39)  <0.001  0.28 (0.13–0.60)  0.001  0.06 (0.007–0.46)  0.007  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.22 (0.89–1.69)  0.22  1.34 (0.90–2.17)  0.14  0.85 (0.36–1.97)  0.69   36–36 + 6  0.96 (0.66–1.39)  0.82  1.13 (0.70–1.82)  0.63  0.55 (0.22–1.4)  0.21  Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=154)  0.91 (0.7–1.2)  0.49  0.92 (0.67–1.23)  0.61  0.86 (0.40–1.83)  0.69   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.43 (0.34–0.55)  <0.001  0.42 (0.31–0.57)  <0.001  0.49 (0.20–1.22)  0.13   LSCSc  1    1    1    Birth weight (kg)  0.21 (0.11–0.39)  <0.001  0.28 (0.13–0.60)  0.001  0.06 (0.007–0.46)  0.007  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.22 (0.89–1.69)  0.22  1.34 (0.90–2.17)  0.14  0.85 (0.36–1.97)  0.69   36–36 + 6  0.96 (0.66–1.39)  0.82  1.13 (0.70–1.82)  0.63  0.55 (0.22–1.4)  0.21  a Relative Risk (RR), b Confidence Interval (CI), c Lower segment caesarean section. We observed similar findings in per protocol analysis (Table 4) that included only those (107 women analyzed) who received all four doses of steroids. Table 4 Multivariable analysis (per protocol analysis) for effect of antenatal steroids on composite respiratory morbidity among mothers who received four doses of steroids Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=107)  0.99 (0.75–1.33)  0.98  0.95 (0.67–1.36)  0.78  1.15 (0.53–2.47)  0.73   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.49 (0.38–0.64)  <0.001  0.45 (0.32–0.63)  <0.001  0.72 (0.28–1.82)  0.49   LSCSc  1    1    1    Birth weight (kg)  0.18 (0.09–0.37)  <0.001  0.29 (0.12–0.68)  0.005  0.04 (0.005–0.27)  0.001  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.34 (0.95–1.89)  0.10  1.6 (0.95–2.6)  0.08  0.95 (0.4–2.29)  0.91   36–36 + 6  1.06 (0.71–1.57)  0.78  1.23 (0.74–2.17)  0.39  0.64 (0.26–1.59)  0.33  Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=107)  0.99 (0.75–1.33)  0.98  0.95 (0.67–1.36)  0.78  1.15 (0.53–2.47)  0.73   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.49 (0.38–0.64)  <0.001  0.45 (0.32–0.63)  <0.001  0.72 (0.28–1.82)  0.49   LSCSc  1    1    1    Birth weight (kg)  0.18 (0.09–0.37)  <0.001  0.29 (0.12–0.68)  0.005  0.04 (0.005–0.27)  0.001  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.34 (0.95–1.89)  0.10  1.6 (0.95–2.6)  0.08  0.95 (0.4–2.29)  0.91   36–36 + 6  1.06 (0.71–1.57)  0.78  1.23 (0.74–2.17)  0.39  0.64 (0.26–1.59)  0.33  a Relative Risk (RR), b Confidence Interval (CI), c Lower segment caesarean section. Table 4 Multivariable analysis (per protocol analysis) for effect of antenatal steroids on composite respiratory morbidity among mothers who received four doses of steroids Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=107)  0.99 (0.75–1.33)  0.98  0.95 (0.67–1.36)  0.78  1.15 (0.53–2.47)  0.73   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.49 (0.38–0.64)  <0.001  0.45 (0.32–0.63)  <0.001  0.72 (0.28–1.82)  0.49   LSCSc  1    1    1    Birth weight (kg)  0.18 (0.09–0.37)  <0.001  0.29 (0.12–0.68)  0.005  0.04 (0.005–0.27)  0.001  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.34 (0.95–1.89)  0.10  1.6 (0.95–2.6)  0.08  0.95 (0.4–2.29)  0.91   36–36 + 6  1.06 (0.71–1.57)  0.78  1.23 (0.74–2.17)  0.39  0.64 (0.26–1.59)  0.33  Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=107)  0.99 (0.75–1.33)  0.98  0.95 (0.67–1.36)  0.78  1.15 (0.53–2.47)  0.73   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.49 (0.38–0.64)  <0.001  0.45 (0.32–0.63)  <0.001  0.72 (0.28–1.82)  0.49   LSCSc  1    1    1    Birth weight (kg)  0.18 (0.09–0.37)  <0.001  0.29 (0.12–0.68)  0.005  0.04 (0.005–0.27)  0.001  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.34 (0.95–1.89)  0.10  1.6 (0.95–2.6)  0.08  0.95 (0.4–2.29)  0.91   36–36 + 6  1.06 (0.71–1.57)  0.78  1.23 (0.74–2.17)  0.39  0.64 (0.26–1.59)  0.33  a Relative Risk (RR), b Confidence Interval (CI), c Lower segment caesarean section. DISCUSSION In this RCT, we found that there is no statistically significant difference in the Apgar score, NICU admission or steps of resuscitation in the two groups. Further, antenatal dexamethasone was not found to reduce respiratory morbidity (transient tachypnea of newborn of respiratory distress syndrome) in the babies born after late preterm labor. In the present study, though the mean birth weight of babies was significantly lower in the control group, the absolute difference was only 90 g. The strength of our study is that 68% of the study group received the complete course of steroids. We excluded the factors such as multiple gestations, maternal diabetes mellitus (gestational and pregestational), major congenital malformations in the fetus and pre-labor planned cesarean section that affect the respiratory morbidity in newborns. The attempt to administer all four doses probably significantly increased the mean interval from admission to delivery in the study group. There have been four RCTs that were completed and published in English language and that have compared the effect of steroids on late preterm newborns. The study setup, primary outcomes, type of steroids and actual percentage of the primary outcome are summarized in Table 5. Table 5 Summary of the study characteristics and setup of the previous RCTs and the present study Study  Balci 2010 [11]  Porto 2011 [12]  Attwatantakul 2015 [14]  Gyamfi-Bannerman 2016 [15]  Present  Study setup  Single-center, Turkey, open-label RCT  Single-center, Brazil, double-blind RCT  Single-center, Chonburi, Thailand, open-label RCT  17 centers, USA, double-blind RCT  Single-center, Puducherry, India, open-label RCT  Numbers (study vs. control)  50 vs. 50  143 vs. 130  96 vs. 90  1427 vs. 1400  155 vs. 155  Type of steroids  Single dose of betamethasone  Two doses of betamethasone  Four doses of dexamethasone  Two doses of betamethasone  Four doses of dexamethasone  Loss to follow-up/exclusion after randomization  30% excluded after randomization  13%  0  0.1%  0  1 stillbirth excluded in study group  Women with diabetes (n)  Excluded  5 (3 vs. 2)  Excluded  153 gestational diabetes in both groups  Excluded  % of women completing the steroid course in the study group  100  78  6  60  68  Women with pre-labor caesarean section  20 vs. 15 (40 vs. 30%)  None  None  62 of 244 (25%) vs. 92 of 291 (32%) of those with primary or secondary outcome  None  Primary outcome  RDS  RDS  Respiratory distress at birth  Composite of need for respiratory support, still birth and neonatal death  TTN and RDS  Rate of RDS  8 (16%) vs. 2 (4%)  36 (25%) vs. 30 (23%)  5 in each group  79 (5.5%) vs. 89 (6.4%)  13 (8.4%) vs. 10 (6.5%)  Study  Balci 2010 [11]  Porto 2011 [12]  Attwatantakul 2015 [14]  Gyamfi-Bannerman 2016 [15]  Present  Study setup  Single-center, Turkey, open-label RCT  Single-center, Brazil, double-blind RCT  Single-center, Chonburi, Thailand, open-label RCT  17 centers, USA, double-blind RCT  Single-center, Puducherry, India, open-label RCT  Numbers (study vs. control)  50 vs. 50  143 vs. 130  96 vs. 90  1427 vs. 1400  155 vs. 155  Type of steroids  Single dose of betamethasone  Two doses of betamethasone  Four doses of dexamethasone  Two doses of betamethasone  Four doses of dexamethasone  Loss to follow-up/exclusion after randomization  30% excluded after randomization  13%  0  0.1%  0  1 stillbirth excluded in study group  Women with diabetes (n)  Excluded  5 (3 vs. 2)  Excluded  153 gestational diabetes in both groups  Excluded  % of women completing the steroid course in the study group  100  78  6  60  68  Women with pre-labor caesarean section  20 vs. 15 (40 vs. 30%)  None  None  62 of 244 (25%) vs. 92 of 291 (32%) of those with primary or secondary outcome  None  Primary outcome  RDS  RDS  Respiratory distress at birth  Composite of need for respiratory support, still birth and neonatal death  TTN and RDS  Rate of RDS  8 (16%) vs. 2 (4%)  36 (25%) vs. 30 (23%)  5 in each group  79 (5.5%) vs. 89 (6.4%)  13 (8.4%) vs. 10 (6.5%)  Table 5 Summary of the study characteristics and setup of the previous RCTs and the present study Study  Balci 2010 [11]  Porto 2011 [12]  Attwatantakul 2015 [14]  Gyamfi-Bannerman 2016 [15]  Present  Study setup  Single-center, Turkey, open-label RCT  Single-center, Brazil, double-blind RCT  Single-center, Chonburi, Thailand, open-label RCT  17 centers, USA, double-blind RCT  Single-center, Puducherry, India, open-label RCT  Numbers (study vs. control)  50 vs. 50  143 vs. 130  96 vs. 90  1427 vs. 1400  155 vs. 155  Type of steroids  Single dose of betamethasone  Two doses of betamethasone  Four doses of dexamethasone  Two doses of betamethasone  Four doses of dexamethasone  Loss to follow-up/exclusion after randomization  30% excluded after randomization  13%  0  0.1%  0  1 stillbirth excluded in study group  Women with diabetes (n)  Excluded  5 (3 vs. 2)  Excluded  153 gestational diabetes in both groups  Excluded  % of women completing the steroid course in the study group  100  78  6  60  68  Women with pre-labor caesarean section  20 vs. 15 (40 vs. 30%)  None  None  62 of 244 (25%) vs. 92 of 291 (32%) of those with primary or secondary outcome  None  Primary outcome  RDS  RDS  Respiratory distress at birth  Composite of need for respiratory support, still birth and neonatal death  TTN and RDS  Rate of RDS  8 (16%) vs. 2 (4%)  36 (25%) vs. 30 (23%)  5 in each group  79 (5.5%) vs. 89 (6.4%)  13 (8.4%) vs. 10 (6.5%)  Study  Balci 2010 [11]  Porto 2011 [12]  Attwatantakul 2015 [14]  Gyamfi-Bannerman 2016 [15]  Present  Study setup  Single-center, Turkey, open-label RCT  Single-center, Brazil, double-blind RCT  Single-center, Chonburi, Thailand, open-label RCT  17 centers, USA, double-blind RCT  Single-center, Puducherry, India, open-label RCT  Numbers (study vs. control)  50 vs. 50  143 vs. 130  96 vs. 90  1427 vs. 1400  155 vs. 155  Type of steroids  Single dose of betamethasone  Two doses of betamethasone  Four doses of dexamethasone  Two doses of betamethasone  Four doses of dexamethasone  Loss to follow-up/exclusion after randomization  30% excluded after randomization  13%  0  0.1%  0  1 stillbirth excluded in study group  Women with diabetes (n)  Excluded  5 (3 vs. 2)  Excluded  153 gestational diabetes in both groups  Excluded  % of women completing the steroid course in the study group  100  78  6  60  68  Women with pre-labor caesarean section  20 vs. 15 (40 vs. 30%)  None  None  62 of 244 (25%) vs. 92 of 291 (32%) of those with primary or secondary outcome  None  Primary outcome  RDS  RDS  Respiratory distress at birth  Composite of need for respiratory support, still birth and neonatal death  TTN and RDS  Rate of RDS  8 (16%) vs. 2 (4%)  36 (25%) vs. 30 (23%)  5 in each group  79 (5.5%) vs. 89 (6.4%)  13 (8.4%) vs. 10 (6.5%)  Balci et al. [11] found steroids to be beneficial in reducing respiratory distress at birth. However, the sample size was small. There was post-randomization exclusion of cases, and nearly one-third of the cases were scheduled planned cesarean section. Porto and colleagues [12] did not observe any significant difference in the respiratory morbidity, transient tachypnea or respiratory distress syndrome among the steroid group. Total 78% had completed the steroid dose. However, 43 women (13%) were lost to follow-up. In the trial by Attawattanakul and Tansupswatdikul [14], though the authors observed significantly higher NICU admissions and respiratory distress (primary outcome) at birth in the control group, the rate of transient tachypnea and respiratory distress was comparable in the two groups. Further, only 6% of the study completed the course of steroids. In the largest trial involving 17 centers, the authors [15] observed that steroids significantly reduced the respiratory problems. However, it is important to note that only 60% participants completed the full course of steroids. In their trial, 25% of those with the primary outcome and 32% of those with secondary outcome had planned elective cesarean deliveries. The role of steroids for preterm scheduled cesarean section is well established [16–20]. Thus, though the largest trial [15] has concluded that steroids are beneficial in preventing respiratory problems, it is important to note that scheduled planned cesarean section was not excluded in this study. We excluded all planned cesarean section in our study and found that steroids could not improve the respiratory morbidity in the late preterm newborns. The limitation of our study is that we did not have a placebo group. Further, the enrolment and the allocation to the intervention were done by the same author, which could be a source of bias. Our study focused only on the respiratory morbidity. We did not study the other beneficial effects of steroids. We conclude that administration of antenatal dexamethasone does not reduce the composite respiratory morbidity of babies born to women with late preterm labor and those who have not been delivered by scheduled cesarean section. We recommend more RCTs to study the effect of antenatal steroids on respiratory morbidity among newborns born late preterm labor excluding planned cesarean section and with the use of tocolysis and antibiotics as that would reflect the real-time scenarios before any changes in existing guidelines on this subject are considered. We also recommend studies to compare the impact of the rescue dose alone with that of a full course of antenatal steroids to women in late preterm labor on respiratory morbidity of newborns. ACKNOWLEDGEMENTS The authors acknowledge the authorities of JIPMER for allowing us to use the infrastructure of JIPMER for carrying out the study. REFERENCES 1 Lawn JE, Gravett MG, Nunes TM, et al.   Global report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data. BMC Pregnancy Childbirth  2010; 10(Suppl. 1): S1. Google Scholar CrossRef Search ADS PubMed  2 McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol  2008; 111: 35– 41. doi: 10.1097/01.AOG.0000297311.33046.73. Google Scholar CrossRef Search ADS PubMed  3 Born Too Soon. The Global Action Report for Preterm Birth . New York, NY: MoD, PMNCH, Save the Children, WHO; 2012. 4 Shaikh N, Faizi S, Rai L. Respiratory morbidity in late-preterm births: a prospective observational study at a Tertiary Care Hospital. J Obstet Gynecol India  2016; 66: 301– 6. Published online 2016 May 4. doi: 10.1007/s13224-016-0893-z. Google Scholar CrossRef Search ADS   5 Bastek JA, Sammel MD, Paré E, et al.   Adverse neonatal outcomes: examining the risks between preterm, late preterm, and term infants. Am J Obstet Gynecol  2008; 199: 367.e1– 8. Google Scholar CrossRef Search ADS   6 Hibbard JU, Wilkins I, Sun L, et al.   Respiratory morbidity in late preterm births. JAMA  2010; 304: 419– 25. http://dx.doi.org/10.1001/jama.2010.1015 Google Scholar CrossRef Search ADS PubMed  7 Picone S, Paolillo P. Neonatal outcomes in a population of late-preterm infants. J Matern Fetal Neonatal Med  2010; 23: 116– 20. http://dx.doi.org/10.3109/14767058.2010.509921 Google Scholar CrossRef Search ADS PubMed  8 Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev  2006; 3: CD004454. 9 ACOG Committee on Obstetric Practice. ACOG Committee Opinion No.475: antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol  2011; 117: 422– 4. CrossRef Search ADS PubMed  10 Opiyo N, Stones W. Corticosteroids for preterm deliveries: missing evidence [editorial]. Cochrane Database Syst Rev  2017; 5: ED000121. 10.1002/14651858.ED000121p. Google Scholar PubMed  11 Balci O, Ozdemir S, Mahmoud AS, et al.   The effect of antenatal steroids on fetal lung maturation between the 34th and 36th week of pregnancy. Gynecol Obstet Invest  2010; 70: 95– 9. doi: 10.1159/000295898. Google Scholar CrossRef Search ADS PubMed  12 Porto AMF, Coutinho IC, Correia JB, Amorim MMR. Effectiveness of antenatal corticosteroids in reducing respiratory disorders in late preterm infants: randomized clinical trial. BMJ  2011; 342: d1696. doi: 10.1136/bmj.d1696. Google Scholar CrossRef Search ADS PubMed  13 Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics  2004; 114: 372– 6. http://dx.doi.org/10.1542/peds.114.2.372 Google Scholar CrossRef Search ADS PubMed  14 Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al.   Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med  2016; 374: 1311– 20. http://dx.doi.org/10.1056/NEJMoa1516783 Google Scholar CrossRef Search ADS PubMed  15 Stutchfield P, Whitaker R, Russell I. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomized trial. BMJ  2005; 331: 662– 8. doi: 10.1136/bmj.38547.416493.06. Google Scholar CrossRef Search ADS PubMed  16 Sotiriadis A, Makrydimas G, Papatheodorou S, Ioannidis JP. Corticosteroids for preventing neonatal respiratory morbidity after elective caesarean section at term. Cochrane Database Syst Rev  2009; 4: CD006614. 17 American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 561: nonmedically indicated early-term deliveries. Obstet Gynecol  2013; 121: 911– 15. doi: 10.1097/01. AOG.0000428649.57622.a7. CrossRef Search ADS PubMed  18 Ahmed MR, Sayed Ahmed WA, Mohammed TY. Antenatal steroids at 37 weeks, does it reduce neonatal respiratory morbidity? A randomized trial. J Matern Fetal Neonatal Med  2015; 28: 1486– 90. doi: 10.3109/14767058.2014.958461 Google Scholar CrossRef Search ADS PubMed  19 Nada AM, Shafeek MM, El Maraghy MA, et al.   Antenatal corticosteroid administration before elective caesarean section at term to prevent neonatal respiratory morbidity: a randomized controlled trial. Eur J Obstet Gynecol Reprod Biol  2016; 199: 88– 91. doi: 10.1016/j.ejogrb.2016.01.026. Google Scholar CrossRef Search ADS PubMed  20 Attawattanakul N, Tansuspswatdikul P. Effect of Antenatal Dexamethasone on Respiratory distress in Late Preterm Infant: A Randomized controlled trial. Thai J Obstet Gynecol  2015; 23: 25– 33. © The Author(s) [2018]. Published by Oxford University Press. All rights reserved. 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Effect of Antenatal Steroids on Respiratory Morbidity of Late Preterm Newborns: A Randomized Controlled Trial

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Abstract

Abstract Objective The objective of this article was to study the effect of antenatal dexamethasone on the respiratory morbidity of late preterm newborns. Study design A randomized controlled trial, conducted in Obstetrics and Gynecology Department in collaboration with Neonatology department at JIPMER, India. In total, 155 women were studied in each group. Intention to treat analysis and per protocol analysis were done. Results Overall 31 (10%) newborns were admitted to intensive care unit. The composite respiratory morbidity (defined as respiratory distress syndrome and/or transient tachypnea of newborn) was observed in 64 (41.6%) infants in the study and 56 (36.2%) infants in the control group. On multivariable-adjusted analysis, use of steroids was not found to be associated with decrease in composite respiratory morbidity [adjusted relative risk 0.91 (95% confidence interval: 0.7–1.2)]. Conclusions Antenatal dexamethasone does not reduce the composite respiratory morbidity of babies born vaginally or by emergency cesarean to women with late preterm labor. late preterm, antenatal steroids, transient tachypnea of newborn, respiratory distress syndrome INTRODUCTION Worldwide prevalence of preterm birth is 9.6%. More than 1 million preterm newborns die each year [1]. In a retrospective cohort study of 18 years, the authors found that late preterm deliveries complicate 9% of all deliveries, and further, three-fourth of all preterm deliveries are late preterm [2]. India has a high preterm birth rate with an incidence of around 13.0% [3]. In a recent study from India, late preterm deliveries were found to be 14% of all deliveries [4]. Late preterm infants (those between 34 and 36+6/7 weeks of gestation) face a significantly greater risk of adverse respiratory outcomes compared with term infants [5–7]. Antenatal corticosteroid (ACS) therapy has been one of the major breakthroughs in improving perinatal outcome for preterm infants. The benefit of ACS before 34 weeks to mitigate the morbidity of prematurity is well established [7, 8, 9]. There are few completed trials addressing the effect of ACS on the late preterm newborns [10]. Balci and colleagues [11] found ACS to be beneficial, but their sample size was small, and nearly one-third of women in both the groups had been delivered by scheduled cesarean section. Porto and colleagues [12], on the other hand, did not find any benefit of antenatal betamethasone on transient tachypnea or respiratory distress syndrome among the late preterm newborns. This randomized controlled trial (RCT) was undertaken to study the effect of antenatal dexamethasone on composite respiratory morbidity among the late preterm babies born vaginally or by emergency cesarean section to women with preterm labor. MATERIAL AND METHODS Trial design and study setup We conducted this RCT (parallel allocation with 1:1 ratio) in Obstetrics and Gynaecology Department in collaboration with the Department of Neonatology at the Jawaharlal Nehru Institute of Postgraduate Medical Education and Research (JIPMER) from February 2015 to June 2016. It is a tertiary care institute of National importance. It caters to the poor population free of cost. The institute ethics committee approved the study, and it is registered with the Clinical Trials Registry-India (Clinical Trials Registry-India: http://ctri.nic.in/Clinicaltrials/login.php CTRI no 2016/12/007570). Screening and recruitment We screened all women admitted to labor ward with the risk of late preterm delivery. We included women admitted to the labor room with a period of gestation between 34 and 36 + 6 weeks with a singleton pregnancy with risk of preterm delivery either spontaneously or requiring termination for maternal (or) fetal indication. We calculated gestational age as per the last menstrual period or early pregnancy scan. Those who were far advanced in labor (5 cm or more dilated) or had received the previous course of steroids or had chorioamnionitis at admission were considered ineligible. We excluded women with multiple gestations, gestational diabetes and diabetes mellitus, major congenital malformations in the fetus and those undergoing a pre-labor scheduled cesarean section. Randomization and intervention Among the 1575 women screened, 1265 were either ineligible or excluded (Fig. 1). After informing study details and obtaining informed consent, we randomized 310 eligible women into ACS group, and non-ACS group using computer-generated random numbers (generated and provided in a sequentially numbered, sealed, opaque envelopes, from an independent data coordinating party, from the Department of Preventive and Social Medicine). Women randomized to study group received four doses of dexamethasone (hospital supply given free of cost for patients), 6 mg administered intramuscularly 12 hourly. Control group did not receive steroids or placebo. We administered tocolytics and antibiotics as per the department protocol. There was no loss to follow-up after randomization. One case in the study group was excluded from analysis because it was stillborn. Fig 1. View largeDownload slide CONSORT diagram of the study. Fig 1. View largeDownload slide CONSORT diagram of the study. Study outcomes Structured pro forma was used to collect the data. The primary outcome measure was composite respiratory morbidities (transient tachypnea; respiratory distress syndrome). Transient tachypnea of the newborn was defined as the presence of clinical signs of respiratory distress at birth without any significant radiological changes or with a feature of hyperinflation/interlobar fluid that resolved within 72 h. Respiratory distress syndrome was defined as signs of respiratory distress at birth along with radiological evidence of decreased air entry of diffuse granular infiltrates. Other complications such as hypoglycemia, hypothermia, poor feeding, sepsis and neonatal mortality were also noted. We followed up all the babies until discharge from the hospital. Sample size calculation Based on the literature, the composite respiratory morbidity in the unexposed group is 25% [13]. A 50% reduction is expected with the intervention. So, for 80% power and an alpha error of 0.05, based on Kelsey and Fleiss continuity correction, a sample size of 155 was required in each group. Thus, we included 155 women in each group (total sample size of 310). Analysis The analysis was performed using SPSS version 19.0. Continuous variables were described using mean and SD as well as the median for gestational age and birth weight and compared with unpaired t-test or Wilcoxon rank sum (Mann–Whitney U) test. We compared categorical variables using chi-square test. We performed an intention to treat analysis for comparing the primary outcome. We calculated relative risk (RR) with 95% confidence intervals (CIs). A p-value of <0.05 was taken as statistically significant. To adjust for the baseline differences between the two groups, adjusted RRs with 95% CIs were calculated using log-binomial regression. Intention to treat analysis (irrespective of the number of doses of steroids) and per protocol analysis (including only those who received all four doses of steroids) were done. RESULTS In total, 155 women were randomly assigned to each group. In the study group, 108 women (70%) completed the full dexamethasone course before delivery (Fig. 1). None of the subjects in either group delivered after 37 weeks. Therefore, 154 in the study group and all 155 in the control group were analyzed. Most of the baseline characters (Table 1) were comparable in the two groups. However, a significant number of women in the study group underwent emergency cesarean section (p < 0.001). In our study, 5 of 155 (3.2%) in control and 4 of 154(2.6%) in steroid group had intrauterine growth-retarded babies. This difference is not statistically significant (p-value = 0.74), though the mean birth weight was significantly higher in the study group (p < 0.001). This s a statistical difference and is not of clinical significance (2.4 vs. 2.36 kg). We did not observe any serious side effect or short-term adverse effect of the steroid injection to the women. Table 1 Baseline characteristics of study population Outcome  Study group (N = 154) (%)  Control group (N = 155) (%)  p-value  Maternal age (years) (SD)  24.3 (3.74)  24.1 (2.93)    Gravidity n =(%)         1  81 (52.6)  71 (45.8)     >1  73 (47.4)  84 (54.2)    Medical disorders  28. (18.2)  19 (12.3)    Hypertensive disorders  16 (10.4)  11 (7.1)    Median period of gestation(interquartile range) (weeks)  35.4 (34–36.9)  35.9 (34–36.9)  0.001  Antibiotic usage  107 (69.5)  91 (58.7)    Tocolytic usage  8 (5.2)  9 (5.8)    Mode of delivery         Vaginal delivery  128 (83.1)  142(91.6)  0.02   Emergency cesarean section  26 (16.9)  13 (8.4)    Mean duration of labor (hours)  9.64  9.56    Liquor color         Meconium  4 (2.6)  4 (2.6)     Clear  150 (97.4)  150 (96.8)     Blood stained  0  1 (0.6)    Sex of baby (%)         Male  78(50.6)  78 (50.6)     Female  49.4 (76)  49.4 (77)    Mean birth weight kg (SD)  2.4 (1.92)  2.36 (0.202)  0.001  PROM  59 (41.5%)  83 (58.5%)    Admission to delivery interval (hours)  50.6  19.8  0.001  Outcome  Study group (N = 154) (%)  Control group (N = 155) (%)  p-value  Maternal age (years) (SD)  24.3 (3.74)  24.1 (2.93)    Gravidity n =(%)         1  81 (52.6)  71 (45.8)     >1  73 (47.4)  84 (54.2)    Medical disorders  28. (18.2)  19 (12.3)    Hypertensive disorders  16 (10.4)  11 (7.1)    Median period of gestation(interquartile range) (weeks)  35.4 (34–36.9)  35.9 (34–36.9)  0.001  Antibiotic usage  107 (69.5)  91 (58.7)    Tocolytic usage  8 (5.2)  9 (5.8)    Mode of delivery         Vaginal delivery  128 (83.1)  142(91.6)  0.02   Emergency cesarean section  26 (16.9)  13 (8.4)    Mean duration of labor (hours)  9.64  9.56    Liquor color         Meconium  4 (2.6)  4 (2.6)     Clear  150 (97.4)  150 (96.8)     Blood stained  0  1 (0.6)    Sex of baby (%)         Male  78(50.6)  78 (50.6)     Female  49.4 (76)  49.4 (77)    Mean birth weight kg (SD)  2.4 (1.92)  2.36 (0.202)  0.001  PROM  59 (41.5%)  83 (58.5%)    Admission to delivery interval (hours)  50.6  19.8  0.001  PROM: Premature Rupture of Membranes. Table 1 Baseline characteristics of study population Outcome  Study group (N = 154) (%)  Control group (N = 155) (%)  p-value  Maternal age (years) (SD)  24.3 (3.74)  24.1 (2.93)    Gravidity n =(%)         1  81 (52.6)  71 (45.8)     >1  73 (47.4)  84 (54.2)    Medical disorders  28. (18.2)  19 (12.3)    Hypertensive disorders  16 (10.4)  11 (7.1)    Median period of gestation(interquartile range) (weeks)  35.4 (34–36.9)  35.9 (34–36.9)  0.001  Antibiotic usage  107 (69.5)  91 (58.7)    Tocolytic usage  8 (5.2)  9 (5.8)    Mode of delivery         Vaginal delivery  128 (83.1)  142(91.6)  0.02   Emergency cesarean section  26 (16.9)  13 (8.4)    Mean duration of labor (hours)  9.64  9.56    Liquor color         Meconium  4 (2.6)  4 (2.6)     Clear  150 (97.4)  150 (96.8)     Blood stained  0  1 (0.6)    Sex of baby (%)         Male  78(50.6)  78 (50.6)     Female  49.4 (76)  49.4 (77)    Mean birth weight kg (SD)  2.4 (1.92)  2.36 (0.202)  0.001  PROM  59 (41.5%)  83 (58.5%)    Admission to delivery interval (hours)  50.6  19.8  0.001  Outcome  Study group (N = 154) (%)  Control group (N = 155) (%)  p-value  Maternal age (years) (SD)  24.3 (3.74)  24.1 (2.93)    Gravidity n =(%)         1  81 (52.6)  71 (45.8)     >1  73 (47.4)  84 (54.2)    Medical disorders  28. (18.2)  19 (12.3)    Hypertensive disorders  16 (10.4)  11 (7.1)    Median period of gestation(interquartile range) (weeks)  35.4 (34–36.9)  35.9 (34–36.9)  0.001  Antibiotic usage  107 (69.5)  91 (58.7)    Tocolytic usage  8 (5.2)  9 (5.8)    Mode of delivery         Vaginal delivery  128 (83.1)  142(91.6)  0.02   Emergency cesarean section  26 (16.9)  13 (8.4)    Mean duration of labor (hours)  9.64  9.56    Liquor color         Meconium  4 (2.6)  4 (2.6)     Clear  150 (97.4)  150 (96.8)     Blood stained  0  1 (0.6)    Sex of baby (%)         Male  78(50.6)  78 (50.6)     Female  49.4 (76)  49.4 (77)    Mean birth weight kg (SD)  2.4 (1.92)  2.36 (0.202)  0.001  PROM  59 (41.5%)  83 (58.5%)    Admission to delivery interval (hours)  50.6  19.8  0.001  PROM: Premature Rupture of Membranes. Table 2 shows the neonatal outcome. There was no statistical difference in the study and the control group for Apgar scores, admission to neonatal intensive care unit (NICU) and resuscitation steps. None of the babies who developed transient tachypnea required a bag and mask ventilation and intubation. Among those who developed respiratory distress syndrome, seven needed a bag and mask ventilation and four required intubation. The composite respiratory morbidity was maximum in the babies born between 34 and 34 + 6 weeks compared with higher periods of gestation, though it was not of statistical significance. None of the babies among the two groups developed morbidities like hypoglycemia and hypothermia during the period of stay in the hospital. Table 2 Perinatal outcomes of late preterm newborns Outcome  Study group (N = 154)  Control group (N = 155)  RR (95% CIa)  p-value  N (%)  N (%)  Transient tachypnea of the newborn (TTN)  51 (33.1)  46 (29.7)  1.12 (0.80–1.55)  0.51  Respiratory distress syndrome (RDS)  13 (8.4)  10 (6.5)  1.31 (0.59–2.89)  0.50  Composite respiratory morbidity (TTN+RDS)  64 (41.6)  56 (36.2)  1.15 (0.87–1.52)  0.32  Bag and mask  7 (4.5)  4 (2.6)  1.76 (0.53–5.90)  0.35  Ventilatory support  2 (1.3)  2 (1.3)  1.01 (0.14–7.06)  0.99  Admission to NICUb  18 (11.7)  13 (8.4)  1.39 (0.71–2.74)  0.33  Apgar score Mean (SD)           1 min  7.8 (0.68)  7.8 (0.70)  –  0.98   5 min  8.9 (0.36)  8.9 (0.58)  –  0.7  Downe’s score Median (range)  2 (0–6)  2 (0–8)  –  0.24  Outcome  Study group (N = 154)  Control group (N = 155)  RR (95% CIa)  p-value  N (%)  N (%)  Transient tachypnea of the newborn (TTN)  51 (33.1)  46 (29.7)  1.12 (0.80–1.55)  0.51  Respiratory distress syndrome (RDS)  13 (8.4)  10 (6.5)  1.31 (0.59–2.89)  0.50  Composite respiratory morbidity (TTN+RDS)  64 (41.6)  56 (36.2)  1.15 (0.87–1.52)  0.32  Bag and mask  7 (4.5)  4 (2.6)  1.76 (0.53–5.90)  0.35  Ventilatory support  2 (1.3)  2 (1.3)  1.01 (0.14–7.06)  0.99  Admission to NICUb  18 (11.7)  13 (8.4)  1.39 (0.71–2.74)  0.33  Apgar score Mean (SD)           1 min  7.8 (0.68)  7.8 (0.70)  –  0.98   5 min  8.9 (0.36)  8.9 (0.58)  –  0.7  Downe’s score Median (range)  2 (0–6)  2 (0–8)  –  0.24  a Confidence Interval (CI), b Neonatal Intensive Care Unit (NICU). Table 2 Perinatal outcomes of late preterm newborns Outcome  Study group (N = 154)  Control group (N = 155)  RR (95% CIa)  p-value  N (%)  N (%)  Transient tachypnea of the newborn (TTN)  51 (33.1)  46 (29.7)  1.12 (0.80–1.55)  0.51  Respiratory distress syndrome (RDS)  13 (8.4)  10 (6.5)  1.31 (0.59–2.89)  0.50  Composite respiratory morbidity (TTN+RDS)  64 (41.6)  56 (36.2)  1.15 (0.87–1.52)  0.32  Bag and mask  7 (4.5)  4 (2.6)  1.76 (0.53–5.90)  0.35  Ventilatory support  2 (1.3)  2 (1.3)  1.01 (0.14–7.06)  0.99  Admission to NICUb  18 (11.7)  13 (8.4)  1.39 (0.71–2.74)  0.33  Apgar score Mean (SD)           1 min  7.8 (0.68)  7.8 (0.70)  –  0.98   5 min  8.9 (0.36)  8.9 (0.58)  –  0.7  Downe’s score Median (range)  2 (0–6)  2 (0–8)  –  0.24  Outcome  Study group (N = 154)  Control group (N = 155)  RR (95% CIa)  p-value  N (%)  N (%)  Transient tachypnea of the newborn (TTN)  51 (33.1)  46 (29.7)  1.12 (0.80–1.55)  0.51  Respiratory distress syndrome (RDS)  13 (8.4)  10 (6.5)  1.31 (0.59–2.89)  0.50  Composite respiratory morbidity (TTN+RDS)  64 (41.6)  56 (36.2)  1.15 (0.87–1.52)  0.32  Bag and mask  7 (4.5)  4 (2.6)  1.76 (0.53–5.90)  0.35  Ventilatory support  2 (1.3)  2 (1.3)  1.01 (0.14–7.06)  0.99  Admission to NICUb  18 (11.7)  13 (8.4)  1.39 (0.71–2.74)  0.33  Apgar score Mean (SD)           1 min  7.8 (0.68)  7.8 (0.70)  –  0.98   5 min  8.9 (0.36)  8.9 (0.58)  –  0.7  Downe’s score Median (range)  2 (0–6)  2 (0–8)  –  0.24  a Confidence Interval (CI), b Neonatal Intensive Care Unit (NICU). In both unadjusted analysis and adjusted analysis, mode of delivery is associated with composite respiratory morbidity. We agree that emergency caesarean section numbers are high in the study group. However, this difference is taken care of/adjusted in the multivariable analysis, and the independent effect of steroids is estimated. In adjusted analysis (Table 3), after adjusting for effect of mode of delivery, birth weight and period of gestation, use of steroids was not found to be statistically associated with a decrease in composite respiratory morbidity [adjusted RR: 0.91 (95% CI: 0.7–1.2)]. Table 3 Multivariable analysis (intention to treat analysis) for effect of antenatal steroids on composite respiratory morbidity Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=154)  0.91 (0.7–1.2)  0.49  0.92 (0.67–1.23)  0.61  0.86 (0.40–1.83)  0.69   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.43 (0.34–0.55)  <0.001  0.42 (0.31–0.57)  <0.001  0.49 (0.20–1.22)  0.13   LSCSc  1    1    1    Birth weight (kg)  0.21 (0.11–0.39)  <0.001  0.28 (0.13–0.60)  0.001  0.06 (0.007–0.46)  0.007  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.22 (0.89–1.69)  0.22  1.34 (0.90–2.17)  0.14  0.85 (0.36–1.97)  0.69   36–36 + 6  0.96 (0.66–1.39)  0.82  1.13 (0.70–1.82)  0.63  0.55 (0.22–1.4)  0.21  Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=154)  0.91 (0.7–1.2)  0.49  0.92 (0.67–1.23)  0.61  0.86 (0.40–1.83)  0.69   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.43 (0.34–0.55)  <0.001  0.42 (0.31–0.57)  <0.001  0.49 (0.20–1.22)  0.13   LSCSc  1    1    1    Birth weight (kg)  0.21 (0.11–0.39)  <0.001  0.28 (0.13–0.60)  0.001  0.06 (0.007–0.46)  0.007  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.22 (0.89–1.69)  0.22  1.34 (0.90–2.17)  0.14  0.85 (0.36–1.97)  0.69   36–36 + 6  0.96 (0.66–1.39)  0.82  1.13 (0.70–1.82)  0.63  0.55 (0.22–1.4)  0.21  a Relative Risk (RR), b Confidence Interval (CI), c Lower segment caesarean section. Table 3 Multivariable analysis (intention to treat analysis) for effect of antenatal steroids on composite respiratory morbidity Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=154)  0.91 (0.7–1.2)  0.49  0.92 (0.67–1.23)  0.61  0.86 (0.40–1.83)  0.69   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.43 (0.34–0.55)  <0.001  0.42 (0.31–0.57)  <0.001  0.49 (0.20–1.22)  0.13   LSCSc  1    1    1    Birth weight (kg)  0.21 (0.11–0.39)  <0.001  0.28 (0.13–0.60)  0.001  0.06 (0.007–0.46)  0.007  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.22 (0.89–1.69)  0.22  1.34 (0.90–2.17)  0.14  0.85 (0.36–1.97)  0.69   36–36 + 6  0.96 (0.66–1.39)  0.82  1.13 (0.70–1.82)  0.63  0.55 (0.22–1.4)  0.21  Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=154)  0.91 (0.7–1.2)  0.49  0.92 (0.67–1.23)  0.61  0.86 (0.40–1.83)  0.69   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.43 (0.34–0.55)  <0.001  0.42 (0.31–0.57)  <0.001  0.49 (0.20–1.22)  0.13   LSCSc  1    1    1    Birth weight (kg)  0.21 (0.11–0.39)  <0.001  0.28 (0.13–0.60)  0.001  0.06 (0.007–0.46)  0.007  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.22 (0.89–1.69)  0.22  1.34 (0.90–2.17)  0.14  0.85 (0.36–1.97)  0.69   36–36 + 6  0.96 (0.66–1.39)  0.82  1.13 (0.70–1.82)  0.63  0.55 (0.22–1.4)  0.21  a Relative Risk (RR), b Confidence Interval (CI), c Lower segment caesarean section. We observed similar findings in per protocol analysis (Table 4) that included only those (107 women analyzed) who received all four doses of steroids. Table 4 Multivariable analysis (per protocol analysis) for effect of antenatal steroids on composite respiratory morbidity among mothers who received four doses of steroids Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=107)  0.99 (0.75–1.33)  0.98  0.95 (0.67–1.36)  0.78  1.15 (0.53–2.47)  0.73   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.49 (0.38–0.64)  <0.001  0.45 (0.32–0.63)  <0.001  0.72 (0.28–1.82)  0.49   LSCSc  1    1    1    Birth weight (kg)  0.18 (0.09–0.37)  <0.001  0.29 (0.12–0.68)  0.005  0.04 (0.005–0.27)  0.001  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.34 (0.95–1.89)  0.10  1.6 (0.95–2.6)  0.08  0.95 (0.4–2.29)  0.91   36–36 + 6  1.06 (0.71–1.57)  0.78  1.23 (0.74–2.17)  0.39  0.64 (0.26–1.59)  0.33  Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=107)  0.99 (0.75–1.33)  0.98  0.95 (0.67–1.36)  0.78  1.15 (0.53–2.47)  0.73   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.49 (0.38–0.64)  <0.001  0.45 (0.32–0.63)  <0.001  0.72 (0.28–1.82)  0.49   LSCSc  1    1    1    Birth weight (kg)  0.18 (0.09–0.37)  <0.001  0.29 (0.12–0.68)  0.005  0.04 (0.005–0.27)  0.001  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.34 (0.95–1.89)  0.10  1.6 (0.95–2.6)  0.08  0.95 (0.4–2.29)  0.91   36–36 + 6  1.06 (0.71–1.57)  0.78  1.23 (0.74–2.17)  0.39  0.64 (0.26–1.59)  0.33  a Relative Risk (RR), b Confidence Interval (CI), c Lower segment caesarean section. Table 4 Multivariable analysis (per protocol analysis) for effect of antenatal steroids on composite respiratory morbidity among mothers who received four doses of steroids Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=107)  0.99 (0.75–1.33)  0.98  0.95 (0.67–1.36)  0.78  1.15 (0.53–2.47)  0.73   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.49 (0.38–0.64)  <0.001  0.45 (0.32–0.63)  <0.001  0.72 (0.28–1.82)  0.49   LSCSc  1    1    1    Birth weight (kg)  0.18 (0.09–0.37)  <0.001  0.29 (0.12–0.68)  0.005  0.04 (0.005–0.27)  0.001  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.34 (0.95–1.89)  0.10  1.6 (0.95–2.6)  0.08  0.95 (0.4–2.29)  0.91   36–36 + 6  1.06 (0.71–1.57)  0.78  1.23 (0.74–2.17)  0.39  0.64 (0.26–1.59)  0.33  Variable  Composite respiratory morbidity   Transient tachypnea of newborn   Respiratory distress syndrome   Adjusted RRa (95% CIb)  p-value  Adjusted RR (95% CI)  p-value  Adjusted RR (95% CI)  p-value  Group               Steroid (n=107)  0.99 (0.75–1.33)  0.98  0.95 (0.67–1.36)  0.78  1.15 (0.53–2.47)  0.73   Control (n=155)  1    1    1    Mode of delivery               Vaginal  0.49 (0.38–0.64)  <0.001  0.45 (0.32–0.63)  <0.001  0.72 (0.28–1.82)  0.49   LSCSc  1    1    1    Birth weight (kg)  0.18 (0.09–0.37)  <0.001  0.29 (0.12–0.68)  0.005  0.04 (0.005–0.27)  0.001  Period of gestation               34–34 + 6  1    1    1     35–35 + 6  1.34 (0.95–1.89)  0.10  1.6 (0.95–2.6)  0.08  0.95 (0.4–2.29)  0.91   36–36 + 6  1.06 (0.71–1.57)  0.78  1.23 (0.74–2.17)  0.39  0.64 (0.26–1.59)  0.33  a Relative Risk (RR), b Confidence Interval (CI), c Lower segment caesarean section. DISCUSSION In this RCT, we found that there is no statistically significant difference in the Apgar score, NICU admission or steps of resuscitation in the two groups. Further, antenatal dexamethasone was not found to reduce respiratory morbidity (transient tachypnea of newborn of respiratory distress syndrome) in the babies born after late preterm labor. In the present study, though the mean birth weight of babies was significantly lower in the control group, the absolute difference was only 90 g. The strength of our study is that 68% of the study group received the complete course of steroids. We excluded the factors such as multiple gestations, maternal diabetes mellitus (gestational and pregestational), major congenital malformations in the fetus and pre-labor planned cesarean section that affect the respiratory morbidity in newborns. The attempt to administer all four doses probably significantly increased the mean interval from admission to delivery in the study group. There have been four RCTs that were completed and published in English language and that have compared the effect of steroids on late preterm newborns. The study setup, primary outcomes, type of steroids and actual percentage of the primary outcome are summarized in Table 5. Table 5 Summary of the study characteristics and setup of the previous RCTs and the present study Study  Balci 2010 [11]  Porto 2011 [12]  Attwatantakul 2015 [14]  Gyamfi-Bannerman 2016 [15]  Present  Study setup  Single-center, Turkey, open-label RCT  Single-center, Brazil, double-blind RCT  Single-center, Chonburi, Thailand, open-label RCT  17 centers, USA, double-blind RCT  Single-center, Puducherry, India, open-label RCT  Numbers (study vs. control)  50 vs. 50  143 vs. 130  96 vs. 90  1427 vs. 1400  155 vs. 155  Type of steroids  Single dose of betamethasone  Two doses of betamethasone  Four doses of dexamethasone  Two doses of betamethasone  Four doses of dexamethasone  Loss to follow-up/exclusion after randomization  30% excluded after randomization  13%  0  0.1%  0  1 stillbirth excluded in study group  Women with diabetes (n)  Excluded  5 (3 vs. 2)  Excluded  153 gestational diabetes in both groups  Excluded  % of women completing the steroid course in the study group  100  78  6  60  68  Women with pre-labor caesarean section  20 vs. 15 (40 vs. 30%)  None  None  62 of 244 (25%) vs. 92 of 291 (32%) of those with primary or secondary outcome  None  Primary outcome  RDS  RDS  Respiratory distress at birth  Composite of need for respiratory support, still birth and neonatal death  TTN and RDS  Rate of RDS  8 (16%) vs. 2 (4%)  36 (25%) vs. 30 (23%)  5 in each group  79 (5.5%) vs. 89 (6.4%)  13 (8.4%) vs. 10 (6.5%)  Study  Balci 2010 [11]  Porto 2011 [12]  Attwatantakul 2015 [14]  Gyamfi-Bannerman 2016 [15]  Present  Study setup  Single-center, Turkey, open-label RCT  Single-center, Brazil, double-blind RCT  Single-center, Chonburi, Thailand, open-label RCT  17 centers, USA, double-blind RCT  Single-center, Puducherry, India, open-label RCT  Numbers (study vs. control)  50 vs. 50  143 vs. 130  96 vs. 90  1427 vs. 1400  155 vs. 155  Type of steroids  Single dose of betamethasone  Two doses of betamethasone  Four doses of dexamethasone  Two doses of betamethasone  Four doses of dexamethasone  Loss to follow-up/exclusion after randomization  30% excluded after randomization  13%  0  0.1%  0  1 stillbirth excluded in study group  Women with diabetes (n)  Excluded  5 (3 vs. 2)  Excluded  153 gestational diabetes in both groups  Excluded  % of women completing the steroid course in the study group  100  78  6  60  68  Women with pre-labor caesarean section  20 vs. 15 (40 vs. 30%)  None  None  62 of 244 (25%) vs. 92 of 291 (32%) of those with primary or secondary outcome  None  Primary outcome  RDS  RDS  Respiratory distress at birth  Composite of need for respiratory support, still birth and neonatal death  TTN and RDS  Rate of RDS  8 (16%) vs. 2 (4%)  36 (25%) vs. 30 (23%)  5 in each group  79 (5.5%) vs. 89 (6.4%)  13 (8.4%) vs. 10 (6.5%)  Table 5 Summary of the study characteristics and setup of the previous RCTs and the present study Study  Balci 2010 [11]  Porto 2011 [12]  Attwatantakul 2015 [14]  Gyamfi-Bannerman 2016 [15]  Present  Study setup  Single-center, Turkey, open-label RCT  Single-center, Brazil, double-blind RCT  Single-center, Chonburi, Thailand, open-label RCT  17 centers, USA, double-blind RCT  Single-center, Puducherry, India, open-label RCT  Numbers (study vs. control)  50 vs. 50  143 vs. 130  96 vs. 90  1427 vs. 1400  155 vs. 155  Type of steroids  Single dose of betamethasone  Two doses of betamethasone  Four doses of dexamethasone  Two doses of betamethasone  Four doses of dexamethasone  Loss to follow-up/exclusion after randomization  30% excluded after randomization  13%  0  0.1%  0  1 stillbirth excluded in study group  Women with diabetes (n)  Excluded  5 (3 vs. 2)  Excluded  153 gestational diabetes in both groups  Excluded  % of women completing the steroid course in the study group  100  78  6  60  68  Women with pre-labor caesarean section  20 vs. 15 (40 vs. 30%)  None  None  62 of 244 (25%) vs. 92 of 291 (32%) of those with primary or secondary outcome  None  Primary outcome  RDS  RDS  Respiratory distress at birth  Composite of need for respiratory support, still birth and neonatal death  TTN and RDS  Rate of RDS  8 (16%) vs. 2 (4%)  36 (25%) vs. 30 (23%)  5 in each group  79 (5.5%) vs. 89 (6.4%)  13 (8.4%) vs. 10 (6.5%)  Study  Balci 2010 [11]  Porto 2011 [12]  Attwatantakul 2015 [14]  Gyamfi-Bannerman 2016 [15]  Present  Study setup  Single-center, Turkey, open-label RCT  Single-center, Brazil, double-blind RCT  Single-center, Chonburi, Thailand, open-label RCT  17 centers, USA, double-blind RCT  Single-center, Puducherry, India, open-label RCT  Numbers (study vs. control)  50 vs. 50  143 vs. 130  96 vs. 90  1427 vs. 1400  155 vs. 155  Type of steroids  Single dose of betamethasone  Two doses of betamethasone  Four doses of dexamethasone  Two doses of betamethasone  Four doses of dexamethasone  Loss to follow-up/exclusion after randomization  30% excluded after randomization  13%  0  0.1%  0  1 stillbirth excluded in study group  Women with diabetes (n)  Excluded  5 (3 vs. 2)  Excluded  153 gestational diabetes in both groups  Excluded  % of women completing the steroid course in the study group  100  78  6  60  68  Women with pre-labor caesarean section  20 vs. 15 (40 vs. 30%)  None  None  62 of 244 (25%) vs. 92 of 291 (32%) of those with primary or secondary outcome  None  Primary outcome  RDS  RDS  Respiratory distress at birth  Composite of need for respiratory support, still birth and neonatal death  TTN and RDS  Rate of RDS  8 (16%) vs. 2 (4%)  36 (25%) vs. 30 (23%)  5 in each group  79 (5.5%) vs. 89 (6.4%)  13 (8.4%) vs. 10 (6.5%)  Balci et al. [11] found steroids to be beneficial in reducing respiratory distress at birth. However, the sample size was small. There was post-randomization exclusion of cases, and nearly one-third of the cases were scheduled planned cesarean section. Porto and colleagues [12] did not observe any significant difference in the respiratory morbidity, transient tachypnea or respiratory distress syndrome among the steroid group. Total 78% had completed the steroid dose. However, 43 women (13%) were lost to follow-up. In the trial by Attawattanakul and Tansupswatdikul [14], though the authors observed significantly higher NICU admissions and respiratory distress (primary outcome) at birth in the control group, the rate of transient tachypnea and respiratory distress was comparable in the two groups. Further, only 6% of the study completed the course of steroids. In the largest trial involving 17 centers, the authors [15] observed that steroids significantly reduced the respiratory problems. However, it is important to note that only 60% participants completed the full course of steroids. In their trial, 25% of those with the primary outcome and 32% of those with secondary outcome had planned elective cesarean deliveries. The role of steroids for preterm scheduled cesarean section is well established [16–20]. Thus, though the largest trial [15] has concluded that steroids are beneficial in preventing respiratory problems, it is important to note that scheduled planned cesarean section was not excluded in this study. We excluded all planned cesarean section in our study and found that steroids could not improve the respiratory morbidity in the late preterm newborns. The limitation of our study is that we did not have a placebo group. Further, the enrolment and the allocation to the intervention were done by the same author, which could be a source of bias. Our study focused only on the respiratory morbidity. We did not study the other beneficial effects of steroids. We conclude that administration of antenatal dexamethasone does not reduce the composite respiratory morbidity of babies born to women with late preterm labor and those who have not been delivered by scheduled cesarean section. We recommend more RCTs to study the effect of antenatal steroids on respiratory morbidity among newborns born late preterm labor excluding planned cesarean section and with the use of tocolysis and antibiotics as that would reflect the real-time scenarios before any changes in existing guidelines on this subject are considered. We also recommend studies to compare the impact of the rescue dose alone with that of a full course of antenatal steroids to women in late preterm labor on respiratory morbidity of newborns. ACKNOWLEDGEMENTS The authors acknowledge the authorities of JIPMER for allowing us to use the infrastructure of JIPMER for carrying out the study. 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Journal of Tropical PediatricsOxford University Press

Published: Jan 22, 2018

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