Journal of Neonatal-Perinatal Medicine 7 (2014) 107–111 DOI 10.3233/NPM-1474813 IOS Press
Do prenatal steroids improve the survival of late preterm infants with complex congenital heart defects? M.A. Attara,∗ , R.E. Dechertb , R.E. Schumachera and S. Sarkara a Department
of Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, MI, USA b Department of Critical Care Support Services, University of Michigan Health System, Ann Arbor, MI, USA
Received 13 September 2013 Revised 21 November 2013 Accepted 27 February 2014
Abstract. AIM: We evaluated the use of prenatal steroids (PNS) and the effect of that practice on hospital mortality of late preterm infants with complex congenital heart defects (CHD). METHODS: Retrospective review of records of late preterm infants with complex CHD infants that were cared for in a single tertiary perinatal center between 2002 and 2009. Multivariate logistic regression analysis was performed to determine which of the risk factors commonly associated with death prior to discharge from the hospital predict the outcome (hospital death). RESULTS: Of the 106 late preterm infants with complex CHD, 31(29%) died and 15 (14%) received PNS. Endotracheal intubation in the delivery room (42% vs 15%), necrotizing enterocolitis (10% vs 0%) and hypoplastic left heart syndrome (52% vs 25%) were statistically more frequent in non-surviving infants. Non-surviving infants were more frequently treated with PNS (23% vs 11%) but this difference was not statistically significant (p = 0.131). Using logistic regression analysis, delivery room intubation (OR 4.91; 95% CI 1.78 – 13.51) and the hypoplastic left heart syndrome (OR 3.29; 95% CI 1.28 – 8.48), but not prenatal steroids were independently associated with increased risk of hospital death. CONCLUSIONS: In a selected population of late preterm infants with complex CHD, prenatal steroid treatment did not independently influence survival. Keywords: Late preterm infant, congenital heart defect, prenatal steroid, mortality, counseling
1. Introduction Infants born at late preterm (LPT, 34 0/7 to 36 6/7 weeks) are at increased risk for neonatal respiratory morbidities . Infants with complex congenital heart ∗ Corresponding
author: Dr. Mohammad A. Attar, 8621 Mott Hospital, 1540 E. Hospital Drive, Ann Arbor, MI 48109-4254, USA. Tel.: +1 734 763 4109; Fax: +1 734 763 2278; E-mail: [email protected]
defects (CHD) born at LPT gestation have a higher risk of morbidity and mortality compare to those delivered at term . There is limited information on whether the use of prenatal steroids (PNS) significantly decreases pulmonary morbidities associated with LPT birth . The use of PNS at later gestational ages was demonstrated to reduce respiratory distress following elective caesarean section deliveries in a large randomized control
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M.A. Attar et al. / Prenatal steroids for CHD
trial (RCT) . Since pulmonary morbidities (need for endotracheal intubation) is a factor that was associated with increased risk of death of infants with complex CHD , we hypothesized that PNS treatment of infants with complex CHD would decrease their risk of death when born at LPT. The purpose of the study was to evaluate the use of PNS and the effect of that practice on hospital mortality of LPT infants with complex CHD.
2. Methods Retrospective review of infants born at or later than 34–36 weeks’ gestational age (LPT) with complex CHD, cared for in a single subspecialty perinatal center between 2002 and 2009 using the neonatal intensive care unit (NICU) data base. We included in the analysis infants who were considered candidates for surgical repair and had resuscitation attempted at birth. Infants with isolated non- complex cardiac defects, e.g. atrial septal defects, patent ductus arteriosus, ventricular septal defect, coarctation of the aorta, rhythm abnormalities, cardiac myopathies, and infants with other lethal congenital cardiac anomalies (not considered as candidates for surgical repair) were excluded from the analysis. Univariate and multivariate logistic regression analysis was performed to determine which of the univariate elements were independently associated with the outcome of interest (hospital death). Covariates that were included in the logistic regression analysis were receipt of PNS, need for endotracheal intubation in the delivery room for pulmonary insufficiency, gender, race, multiple births, gestational age, birth weight, small for gestational age, mode of delivery, other non-cardiac birth defects, birth location, sepsis, necrotizing enterocolitis (NEC), and subtypes of complex CHD. These perinatal variables have been previously reported to be clinical predictors of mortality in preterm infants . Other variables included in the logistic regression were those that might affect morbidity and mortality such as being SGA, presence of extracardiac anomalies, or having NEC. These have been reported to be more prevalent in preterm infants with complex CHD [6, 7]. We defined hospital mortality as death during the initial NICU hospitalization (before or after surgery). Small for gestational age was defined as birth weight less than the tenth percentile as reported to the cen-
ter by Vermont Oxford Network based on an analysis of the U.S. Vital Statistics Natality data sets for 2001 and 2002 by the National Center for Health Statistics. Infants were considered as having necrotizing enterocolitis (NEC) if they had radiographic evidence (Bell stage 2) and or if they had intraoperative or histopathologic findings of NEC . Sepsis was defined as a positive blood culture. We considered grade 3 or 4 intraventricular hemorrhage (IVH) as severe IVH. Minor anomalies or isolated cleft palate were not considered to be extracardiac congenital anomalies. Univariate analysis was performed employing chi square tests for dichotomous variables and student t-test for continuous variables to determine those variables which demonstrated a significant difference between the populations with and without PNS. Non-parametric tests were used when data were not normally distributed. A critical value (alpha) of 0.05 was used to determine statistical significance for each variable. To assess the influence of covariates on overall mortality, we employed stepwise (forward), multivariate logistic regression to determine which of the univariate elements were independently associated with the outcome of interest (hospital death). A critical value of 0.10 was used to include co-variates in the model development, while a value of 0.20 was used to remove co-variates from model development. A maximum iteration of 20 steps was selected for our model development process. Univariate and multivariate analyses were performed using commercially available statistical software (PASW 18, SPSS Inc. Chicago, Illinois).
3. Results Of the 106 LPT infants with complex CHD, 31(29%) died and 15 (14%) received PNS. Hypoplastic left heart syndrome (HLHS) was the most common type of CHD and carried a hospital mortality rate of 46%. The nature, frequency and hospital mortality of included types of complex CHD are summarized in Table 1. Timing of PNS was recorded in 13 of the 15 treated patients. The median (IQR) duration of PNS to birth was 18 (3–41) days, and in 7 of the 13 infants the duration was more than 14 days. Patient characteristics and hospital course of infants treated and not treated with PNS are described in Table 2. Infants in the PNS treatment group were of a lower gestational ages than those who were not treated
M.A. Attar et al. / Prenatal steroids for CHD Table 1 Frequency and hospital mortality by types of CHD Diagnostic Group
Hypoplastic left heart syndrome Transposition of the great arteries Pulmonary atresia Tetralogy of Fallot Double outlet right ventricle Interrupted aortic arch Truncus arteriosus Common atrioventricular canal Tricuspid atresia Single right ventricle Total anomalous pulmonary veins Pentalogy of Cantrell
Incidence, n (%)
Hospital death per diagnostic group, n (%)
13 (12) 12 (11) 8 (8)
2 (15) 2 (17) 4 (50)
8 (8) 7 (7) 7 (7)
2 (25) 3 (43) 1 (14)
4 (4) 3 (3) 2 (2)
1 (25) 1 (33) 0 (0)
with PNS [median gestational age in weeks (IQR), 34 (34–35) versus 36 (35–36), p = 0.006]. There was a trend for the infants treated with PNS to be more frequently intubated in the delivery room, more frequent death during hospitalization, and more frequent death following surgery; however, the differences in these frequencies were not statistically significant. Univariate analyses of the risk factors for hospital mortality are displayed in Table 3. Endotracheal intubation in the delivery room (DRET) for pulmonary insufficiency, NEC and HLHS were statistically more frequent in non-surviving infants. The regression model’s Cox and Snell r squared was 0.146. The influence (odds) of co-variates that have significant effect on the outcome (death) by logistic regression analysis is presented in Table 4. DRET and the HLHS, but not PNS were independently associated with increased risk of hospital death. Table 3 Univariate analysis of selected death risks
Table 2 Patient characteristics and outcome variables PNS N = 15
No PNS N = 91
Gestational age (weeks)a 34.7 ± 0.8 35.4 ± 0.8 Birth weight (g)a 2448 ± 533 2542 ± 584 White race, n (%) 9 (60) 69 (76) SGA, n (%) 4 (27) 22 (24) Gender (male) 7 (47) 52 (57) C-section, n (%) 10 (67) 47 (52) Multiple births, n (%) 4 (27) 14 (15) Other birth defects 3 (20) 16 (18) (non-cardiac), n (%) Having additional cardiac 3 (9) 14 (7) defects Intubation in delivery room 5 (33) 19 (21) Surfactant 3 (20) 14 (15) Birth location 6 (40) 52 (57) (outborn), n (%) NEC, n (%) 1 (7) 2 (2) Sepsis, n (%) 1 (7) 0 (0) Severe IVH, n (%) 0 (0) 2 (2) Hospital death, n (%) 7 (47) 24 (26) Hospital stay, daysb 18 (8–41) 26 (18–44) Hospital stay for survivorsb 22 (15–40) 26 (18–38) Hospital stay for 8 (4–43) 25 (12–73) non-survivorsb Underwent cardiac surgeries 12 (80) 78 (86) Ventilator days, daysb 8 (4–28) 12 (7–23) Hospital death after surgery 6/12 (50) 21/78 (27) Duration of hospitalization in 29 (15–52) 27 (19–37) survivors, daysb
P value 0.006 0.544 0.198 0.854 0.449 0.298 0.281 0.730 0.719 0.286 0.652 0.217
Gestational age (weeks)a Birth weight (gm)a Gestational age 34 weeks 35 weeks 36 weeks Prenatal Steroids, n (%) White race, n (%) SGA, n (%) Gender (male) C-section, n (%) Multiple births, n (%) Other birth defects (non-heart), n (%) Intubation in delivery room Surfactant Birth location (outborn), n (%) NEC, n (%) Sepsis, n (%) HLHS
Died N = 31
Survived N = 75
35.4 ± 0.8 2525 ± 659
35.2 ± 0.8 2530 ± 542
7 (23) 6 (19) 18 (58) 7 (23) 22 (71) 8 (26) 18 (58) 20 (64) 6 (19) 8 (26)
20 (27) 18 (24) 37 (49) 8 (11) 56 (75) 18 (24) 41 (55) 37 (49) 12 (16) 12 (16)
0.808 0.446 0.522 0.131 0.809 0.805 0.831 0.202 0.777 0.279
13 (42) 7 (23) 15 (48) 3 (10) 0 (0) 16 (52)
11 (15) 10 (13) 43 (57) 0 (0) 1 (1) 19 (25)
0.004 0.255 0.520 0.023 1.000 0.012
0.334 0.013 0.562 0.131 0.205 0.534 0.085
SGA = small for gestational ages, NEC = necrotizing enterocolitis, IVH = intraventricular hemorrhage, a data are expressed in mean ± SD.
0.696 0.543 0.172 0.916
Table 4 Multivariate logistic regression analysis for factors independently associated with death
SGA = small for gestational ages, NEC = necrotizing enterocolitis, IVH = intraventricular hemorrhage. a data are expressed in mean ± SD. b data are expressed in median (interquartile range).
Intubation in the delivery room Hypoplastic left heart syndrome
M.A. Attar et al. / Prenatal steroids for CHD
4. Discussion In a previous report we showed that LPT birth increases the risks for death for infants born with complex CHD . In this analysis, maternal treatment with PNS did not decrease mortality risk in LPT infants with complex CHD, even after accounting for multiple confounding variables for hospital mortality using logistic regression analysis. PNS contributes to decreasing respiratory morbidities and neonatal mortality in very low birth weight infants through multiple mechanisms that include increased alveolar surfactant and enhanced lung water clearance and structural maturity [9–12]. It is a standard of care to treat most women between 24 and 34 weeks of gestation with PNS . PNS, when given at 34–36 weeks of pregnancy, in a randomized controlled trial did not show a significant benefit in decreasing pulmonary morbidities (transient tachypnea or need for support with mechanical ventilation infants delivered at LPT , and this may explain why PNS was not associated with a decreased mortality risk in LPT infants with complex CHD. The low prevalence of 14% use of PNS in the LPT infants in this report is slightly higher compared to that reported for the more mature preterm infants in a population study reported by Malloy et al (7%) and in a single center report by Carreno et al (7%) but closer to another single center report by Fuchs et al (18%) [14–16]. These reports were not able to demonstrate improvement in mortality or respiratory morbidities associated with this treatment. The use of PNS at LPT gestational ages has been evaluated in another congenital malformation in which pulmonary complications could be fatal, congenital diaphragmatic hernia (CDH). PNS did not decrease mortality in CDH in a randomized controlled study . Corticosteroids was started at 34 weeks in the treatment arm of this small study that did not show benefit in decreasing mortality or shortening hospital stay with this treatment. Unlike the population in our report, most patients in Lally et al study were delivered at term. Many mothers in this study received PNS more than 2 weeks prior to delivery. This prolonged period of time between PNS and delivery was shown to be associated with lower efficacy for infants delivered at more than 28–34 weeks of gestation in a retrospective two center cohort study . This could help explain why PNS was not associated with improved outcome in the study infants.
Our report is limited by being a retrospective analysis from a single center. In addition, the long span of time the study covers and due to about half of the study patients were born outside the study institution limited our ability to evaluate maternal factors that contribute to neonatal mortality. However, it is the first report to evaluate the independent effect of PNS on hospital mortality of infants with severe CHD. We did not demonstrate an independent effect of PNS on hospital mortality of LPT infants with severe CHD utilizing logistic regression that accounts for multiple know confounding variables. However, we think that there is a need to evaluate the effect of PNS used closer to the time of delivery using a RCT given the contribution of pulmonary insufficiency (need for endotracheal intubation at birth) to the increased risk of death in this population.
Financial disclosure statement The authors disclose no conflict of interest.
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