Association of Antenatal Steroid Administration with Neonatal Morbidities among Late Preterm Multiple Gestation Infants

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Association of Antenatal Steroid Administration with Neonatal Morbidities among Late Preterm Multiple Gestation Infants

https://doi.org/10.21203/rs.3.rs-4619423/v1

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Background

There is limited evidence on the efficacy of antenatal steroids (ANS) among women with multiple gestations at risk of late preterm delivery.

Study design:

This retrospective study included multiple gestation, late preterm infants (34^0/7-36^6/7 weeks gestational age), born between January 2013 and December 2022. The primary outcome was composite respiratory outcome, defined as the need for respiratory support by 72 hours of age. Logistic and linear regressions were performed to compare the primary and secondary outcomes with and without exposure to any ANS, adjusted for gestational age, sex of infant, histologic chorioamnionitis, and intrauterine growth restriction.

Results

The composite respiratory outcome was significantly lower in any ANS group compared to no ANS group (28.6% vs. 33.7%) [adjusted odds ratio 0.50, 95% CI, 0.33–0.75, p˂0.001].

Conclusion

In late preterm multiple gestation infants, any ANS exposure was associated with lower risk of composite respiratory outcome.

Health sciences/Medical research/Outcomes research

Health sciences/Health care/Paediatrics

antenatal steroids

late preterm infants

betamethasone

multiple gestation

neonatal morbidities

Prematurity is the leading cause of mortality and morbidity among neonates (1). Neonates born between 34^0/7 weeks and 36^6/7 weeks are termed late preterm infants (LPT) (2). In the last two decades, there has been an overall increasing trend in preterm births in the United States, with recent data from Center for Disease Control and Prevention showing 1 in every 10 infants born in the United States is preterm (3), the majority being LPT births (4). These neonates are at increased risks of resuscitation in the delivery room, respiratory morbidities, apnea of prematurity, hyperbilirubinemia, feeding difficulties, hypoglycemia, temperature instability, sepsis, and intracranial hemorrhage (ICH) (5). Compared to term infants, LPT infants are at an increased risk of neurodevelopmental delay (6), cerebral palsy (7), speech and language delay (8), poor school performance (9), and neurobehavioral problems such as autism (10) and attention deficit hyperactivity disorder (11). Multiple gestation may further increase these complications in this vulnerable group (12) (13).

Exposure to ANS among preterm infants born at less than 34 weeks has been associated with lower risks of perinatal and neonatal death, respiratory distress syndrome, need for mechanical ventilation, intracranial hemorrhage, necrotizing enterocolitis (14) (15), and improved neurodevelopmental outcomes (16). Studies have also observed a dose-dependent protective effect of ANS against death and neurodevelopmental impairment in extremely preterm infants (17). There is conflicting data on the efficacy of ANS among singleton LPT infants. In a large (N = 2,831) randomized controlled trial (RCT) exploring the benefits of ANS in late preterm singleton mothers at risk for preterm delivery, Gyamfi-Bannerman et al, noted a significant decrease in the rate of neonatal respiratory complications among infants exposed to ANS (11.6% vs. 14.4%, RR 0.80 (95% CI 0.66–0.97, p = 0.02) (18). In a smaller RCT (n = 273), in singleton LPT mothers at risk for delivery, Porto et al, did not observe any significant difference in rate of respiratory morbidity among LPT infants (25% in ANS vs. 23% in placebo, RR 1.09, 95%CI 0.72 to 1.66, p = 0.69) (19). In another RCT (n = 883) from India that included all LPT mothers at risk for delivery, Yenuberi et al, did not report any difference in respiratory morbidities between infants with and without ANS exposure (4.9% in ANS group vs 4.8% in no ANS group, RR 1.03 95% CI 0.57 to 1.84) (20).

Among LPT multiple gestation infants, the limited evidence from retrospective studies has noted no significant reduction in respiratory morbidities in infants with ANS exposure (21) (22). The American College of Obstetricians and Gynecologists (ACOG) recommends a single course of betamethasone for women between 34^0/7 weeks and 36^6/7 weeks who are at risk for delivery within 7 days and who have not previously received ANS. It, however, acknowledges the lack of evidence for ANS use in women with multiple gestations (23). International Federation of Gynecology and Obstetrics recommends against the routine use of ANS in women at risk for late preterm birth and instead ANS administration should be considered on an individual basis based on risk and benefits (24).

In the setting of limited evidence on the efficacy of ANS in multiple gestation mothers at risk for late preterm delivery, we conducted a retrospective cohort study with the aim to compare the incidence of neonatal respiratory outcomes in late preterm multiple gestation infants with and without exposure to ANS.

We conducted a retrospective cohort study of late preterm multiple gestation infants, 34 0/7 weeks to 36 6/7 weeks at birth, and admitted to Hutzel Women’s Hospital and Children’s Hospital of Michigan, Detroit between January 1, 2013, and December 31, 2022. Institutional Review Board approval was obtained from Central Michigan University before initiation of the study. Infants with unknown timing of ANS administration, major congenital anomaly, and known genetic disorders were excluded from the study.

The primary outcome of composite respiratory outcome defined as the need for respiratory support by 72 hours of age consisting of any of the following: continuous positive airway pressure or high flow nasal cannula for at least two hours, oxygen requirement with FiO₂ ≥ 0.3 for ≥ 4 hours, invasive mechanical ventilation, or the need for extra corporeal membrane oxygenation (ECMO). The secondary outcomes of the study were positive pressure ventilation at delivery, admission to neonatal intensive care unit (NICU) for respiratory distress, highest oxygen requirement and number of hours of any respiratory support that infant received during hospital stay.

Maternal information collected included mother’s age, receipt of prenatal care, race, parity, gestational age, mode of delivery, antenatal diagnosis of intra-uterine growth restriction, insulin-dependent diabetes mellitus, hypertensive disorder in pregnancy, prolonged rupture of membranes (> 18 hours), histological acute chorioamnionitis, administration of antenatal steroids, magnesium sulfate, and antibiotics. Neonatal characteristics collected included birth weight, small for gestational age (SGA) status (defined as < 10th percentile for GA), cord arterial and venous pH, Apgar scores at 1 and 5 minutes after birth, sex, resuscitation at birth, admission to NICU for respiratory distress, respiratory support, highest oxygen support, administration of surfactant, blood glucose, highest white blood cell count, receipt of saline bolus and/or inotropes for hypotension, survival to discharge, and post menstrual age at discharge. Hypoglycemia was defined as blood glucose less than 45 mg/dl in the first 24 hours after birth (25). The lowest blood glucose value was collected among infants with blood glucose less than 45 mg/dl in the first 24 hours after birth. Infants were divided into two groups for comparison based on ANS exposure. Group 1: infants with no ANS exposure and Group 2: infants with any ANS exposure.

Statistical analysis

All analyses were performed using the software package Stata/IC 17.0 (Statacorp, College Station, Tx). The overall rate of respiratory complications in the late preterm infants was estimated to range between 10–25% based on published literature (26) (27) (28) (29). To detect a 10% absolute difference in the primary outcome between the two groups (15% vs. 25%), a sample size of 250 infants was needed in each group, with an alpha of 0.05 and 80% power. The groups were compared using student t-test or Mann–Whitney U test for continuous variables and chi-square test or Fisher exact test for categorical variables. A p-value of < 0.05 was considered statistically significant. Regression analysis was performed on neonatal outcomes adjusting for gestational age, sex of infant, histologic chorioamnionitis, and antenatal diagnosis of intrauterine growth restriction. These variables were selected a-priori based on their reported association with respiratory morbidities in preterm infants.

A total of 568 infants were included: no ANS 306 (54%), any ANS 262 (46%). The study cohort had 44% males, 81% were African Americans, mean GA (SD) was 35.1 (0.82) weeks, and mean birthweight (SD) was 2215 grams (373). Of the 262 infants in the any ANS group 194 (74%) infants were exposed to a complete course of ANS, and 68 infants (26%) were exposed to incomplete course of ANS.

Infants in the any ANS group were significantly lower in gestational age, had lower birth weight, lower 1-minute Apgar score and higher rate of antenatal diagnosis of intra-uterine growth retardation (Table 1). Histologic chorioamnionitis was significantly higher in no ANS group. Neonatal outcomes of infants with any ANS exposure were compared with infants with no exposure to ANS using logistic regression for categorical variables and linear regression for continuous variables as shown in Table 2.

Composite respiratory outcome was significantly lower in the any ANS group, (28.6% vs 33.7%), adjusted odds ratio (aOR) 0.50, 95% confidence interval (CI) 0.33–0.77, p = 0.002]. Infants in any ANS group were less likely to receive positive pressure ventilation after birth (aOR 0.37, 95% CI 0.24–0.57, p < 0.001), and less likely to be admitted to NICU for respiratory distress, (aOR 0.52, 95% CI 0.34–0.64, p = 0.001). Among the infants who received respiratory support, infants in any ANS group compared to no ANS received fewer hours of any respiratory support (β coefficient − 5.5, 95% CI -8.99 to -2.01, p = 0.002). The highest oxygen requirement was lower in any ANS group compared to no ANS, (β coefficient − 0.07, 95% CI -0.09 to -0.04, p ≤ 0.01). In neonates who did not receive ANS, 4.2% of the LPT infants received treatment for hypotension with saline bolus and/or inotrope medication, compared to those who received any ANS. Among infants diagnosed with hypoglycemia, the mean lowest blood glucose was significantly lower in any ANS group, 34.5 mg/dl vs 37.1 mg/dl, p = 0.03. No difference was noted in the postmenstrual age at discharge between the two groups.

In the current single center, retrospective cohort study, we observed the incidence of composite respiratory outcome to be significantly lower in the LPT multiple gestation infants exposed to any ANS. The infants in ANS group had significantly lower number of hours of any respiratory support and required lower levels of maximum oxygen during hospitalization. Infants in any ANS group also had a lower incidence of receipt of positive pressure ventilation in the delivery room compared to infants in the no ANS group.

The evidence for efficacy of ANS in LPT multiple gestation mothers at risk for delivery comes from two retrospective studies. In a large (n = 1974) retrospective cohort study in LPT twin pregnancy from China, Zhu et al, did not observe any significant difference in neonatal respiratory outcomes in infants with and without exposure to ANS (7.8% in ANS group vs 6.2% in no ANS group, weighted odds ratio 1.27, 95% CI 0.60 to 2.76, p = 0.52). The difference in neonatal outcomes in their study compared to the current study could be explained due to many differences in the characteristics of patients included. In their study, more than 57.5% infants in no ANS and 10.6% of infants in ANS group were born at ≥ 37 weeks GA. The mean GA (SD) in our study was 35.1 (0.82) weeks. Only 30% of the infants received a complete course of ANS in their study as compared to 74% infants receiving a complete course in our study. Cesarean delivery was reported in 3.5% of the deliveries in their study compared to 68.8% of the deliveries in the current study (22).

In another retrospective cohort study, (n = 580) in LPT twin pregnancy from Israel, Ben-David et al, did not observe any significant difference in neonatal respiratory morbidities in infants exposed to ANS, (22/144, 15.3%) compared to infants in no ANS group (46/436, 10.5%), AOR 0.81, 95% CI 0.44 to 1.51, p = 0.52 (21). Mean GA in their study was higher than the current study (35.9 weeks vs 35.1 weeks). Moreover, a variation in the definition of respiratory morbidities was noted between the two studies.

The incidence of composite respiratory outcome in our study is higher than the studies mentioned earlier. To the best of our knowledge, there are no published RCT in LPT multiple gestation infants for an actual estimate of respiratory morbidities. Possible explanations for a higher incidence of respiratory morbidity in the current study are lower mean GA compared to other similar retrospective studies in LPT multiple gestation infants, variation in race, and the definition of respiratory morbidities used in different studies. Furthermore, the difference in outcomes in multiple gestation LPT infants compared to singleton LPT infants could be a result of shorter half-life of steroids, changes in maternal blood volume, higher rate of drug clearance in multiple gestation mothers, or other unknown confounding factors.

In the previous studies exploring the effects of ANS in preterm infants, hypoglycemia has been reported with increased frequency among infants exposed to ANS. However, there has been a variation in the definition of neonatal hypoglycemia across these studies. To explore the severity of hypoglycemia, we compared the actual lowest blood glucose values among infants with hypoglycemia and consistent with other studies, we noted that the mean lowest BG was significantly lower in any ANS group (34.5 mg/dl vs 37.1 mg/dl, p = 0.03).

A single center study with consistent practice and care providers with a relatively large sample size to detect the estimated differences are some of the strengths of the current study. Compared to other studies in LPT multiple gestation infants, in the current study 74% of the infants in the ANS group received a complete course. We acknowledge the limitations of our study. A retrospective observational design of the current study suggests association of neonatal morbidities with ANS exposure and does not establish a cause-and-effect relationship. The current study may also have residual confounding due to its retrospective design. Using regression analysis, we tried to control the potential factors that could impact the neonatal morbidities including sex of the infant, gestational age, IUGR, and histologic chorioamnionitis. A single center study with a predominantly African- American population might also affect the generalizability of the study results.

Impact of the Study:

Currently, ACOG recommends a single course of betamethasone to all mothers at late preterm gestation at risk for delivery within 7 days and have not received ANS before. It acknowledges the lack of evidence for ANS in multiple gestation mothers at risk for late preterm delivery. Our study provides evidence in support of its use in this specific population.

In the current retrospective cohort study in LPT multiple gestation infants, any ANS exposure was associated with lower rate of composite respiratory outcome. Exposure to any ANS was also associated with a lower need for positive pressure ventilation in the delivery room, number of hours of any respiratory support, and the highest oxygen requirement in these infants.

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Tables 1-2 are available in the Supplementary Files section.

There is NO conflict of interest to disclose.

Table11.jpg
Table 1.
Table21.jpg
Table 2.

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You are reading this latest preprint version

Association of Antenatal Steroid Administration with Neonatal Morbidities among Late Preterm Multiple Gestation Infants

Status:

Version 1

Abstract

Background

Study Design

Statistical analysis

Results

Discussion

Impact of the Study:

Conclusion

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1