Journal of Pediatric Surgery 50 (2015) 898–903
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Neurodevelopmental outcome at one year of age in congenital diaphragmatic hernia infants not treated with extracorporeal membrane oxygenation Enrico Danzer ⁎, Marsha Gerdes, Jo Ann D’Agostino, Judy Bernbaum, Casey Hoffman, Lisa Herkert, Natalie E. Rintoul, William H. Peranteau, Alan W. Flake, N. Scott Adzick, Holly L. Hedrick The Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA
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Article history: Received 24 February 2015 Accepted 10 March 2015 Key words: Congenital diaphragmatic hernia Neurodevelopmental outcome Bayley Scales of Infant Development Hypotonicity Pulmonary hypoplasia ECMO
a b s t r a c t Background: We evaluated the neurodevelopmental (ND) outcome at one year of age for congenital diaphragmatic hernia (CDH) children who have not undergone extracorporeal membrane oxygenation (ECMO) treatment during the neonatal period. Material and methods: Between 01/2005 and 06/2012, 63 consecutive CDH patients underwent ND assessment using the BSID-III at a median age of 12 months. ND delay was defined by a score of ≤85 in any of the composite scales. Severe impairment was defined as a score of ≤69 in at least one domain. Results: Mean ± SD cognitive, language, and motor functions were 94 ± 14, 86 ± 14, 90 ± 15, respectively (normal 100 ± 15, P b 0.01 for each). Forty-three-percent scored within the average range for all scales. Forty-fourpercent had mild, and 13% had severe delays in at least one domain. Prolonged NICU stay, intubation and O2 requirement, fundoplication, abnormal BAERs, and tracheostomy were associated with lower scores in all domains. Right-sided CDH, male gender, lower 5 min APGAR, pulmonary hypertension, and delayed start of enteral feeding were predictive of lower cognitive and/or language scores. Conclusion: At one year of age, a high percentage of CDH children whose illness did not necessitate ECMO have below normal ND scores. Modifiable and non-modifiable factors are significant determinants of adverse outcomes. © 2015 Elsevier Inc. All rights reserved.
Advances in neonatal care and surgical management for children with congenital diaphragmatic hernia (CDH) have led to improved survival, along with an increased recognition of associated morbidities [1]. Neurocognitive and functional delays, learning disabilities, behavioral disorders, and hearing impairments are increasingly recognized among the spectrum of developmental problems in CDH survivors [2–8]. Although the etiology of developmental abnormalities is most likely multifactorial, several risk factors have been identified. One of the most important risk factors associated with impaired neurological outcome is the use of extracorporeal membrane oxygenation (ECMO) [2,3,6–8]. In general, ECMO is reserved for CDH neonates when conventional treatment of severe pulmonary hypertension fails. Whether the increased incidence of adverse outcome in CDH children following neonatal ECMO therapy is the result of disease severity necessitating ECMO rather than of the treatment itself remains under discussion. The majority of outcome studies in CDH survivors combine data from ECMO treated and non-ECMO treated patients [2,3,6–8]. Information on neurological outcome of non-ECMO-treated CDH survivors is scarce [5,9–14]. Furthermore, these studies are limited by small sample size, incomplete ⁎ Corresponding author at: The Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, 5th Floor Wood Center, Philadelphia, PA, 19104-4318. Tel.: +1 215 590 2733; fax: +1 215 590 2447. E-mail address: [email protected] (E. Danzer). http://dx.doi.org/10.1016/j.jpedsurg.2015.03.040 0022-3468/© 2015 Elsevier Inc. All rights reserved.
cohorts, and wide age range at neurological evaluation. Consequently, one of the major challenges is to prognosticate developmental outcome and to provide appropriate counseling for parents of CDH children not treated with ECMO. The primary objective of this study was to evaluate the neurodevelopmental outcome at one year of age for CDH children who have not undergone ECMO treatment. The secondary objective was to examine both modifiable and non-modifiable patient, clinical and operative factors associated with adverse neurological outcome. 1. Material and methods 1.1. Ethical statement The Institutional Review Board, Committee for Protection of Human Subjects of The Children’s Hospital of Philadelphia approved this study (IRB 2004-5-3779). Informed consent was obtained from the parent or guardian. 1.2. Patient population This was a cross-sectional review of prospectively collected data on neurodevelopmental outcome in CDH survivors enrolled in our Pulmonary
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Hypoplasia Program between January 2005 and June 2012. All CDH survivors born during the study period who enrolled in the follow-up program were eligible. Among this cohort, subjects who underwent neurodevelopmental assessment at a median age of 12 months (range 10–14) and did not undergo ECMO therapy were identified and form the study population for this report. 1.3. Perinatal and postnatal management As described elsewhere, CDH patients are treated according to a specific CDH management protocol [1]. Briefly, the initial evaluation of all CDH patients referred to the Center for Fetal Diagnosis and Treatment at the Children’s Hospital of Philadelphia includes detailed fetal ultrasonography, echocardiography, and ultrafast MRI [15]. Assessment includes confirmation of diagnosis, the type of CDH, liver position, lung-to-head ratio (LHR), observed over expected LHR, observed over expected LHR MRI lung volumes, and the presence of other fetal anomalies. After evaluation, all patients undergo nondirective counseling for pregnancy management options. The postnatal ventilatory management in the neonatal intensive care unit utilizes a lung-preservation strategy similar to that of infants with other causes of pulmonary hypoplasia [1–3]. Postnatal echocardiography is performed early to establish the presence and severity of pulmonary hypertension. The operating surgeon determines the timing of repair based upon co-morbidities and clinical stability. The need for patch is based upon the size of the diaphragmatic defect. 1.4. Data collection Perinatal, perioperative and postnatal factors that might independently affect neurodevelopmental and neuromotor outcome were obtained from maternal prenatal charts and neonatal hospital records. 1.5. Follow-up assessment Growth parameters including weight, length, and head circumference were measured and compared to standard reference curves. Developmental assessment was performed using the Bayley Scales of Infant Development, 3rd Edition (BSID-III) [16]. The normalized population mean and standard deviation (SD) of each composite score are 100 ± 15 [16]. As described previously, overall scores were grouped as average, borderline, and delayed based on SD intervals (85–115, 70–84, and ≤69, respectively) [2,3]. To minimize observer bias, neurodevelopmental testing was administered by either a trained psychologist or psychometrist not involved in the neonatal care of these patients and supervised by a pediatric psychologist (M.G.). The neuromuscular examination (active tone, passive tone, reflexes, gross motor abilities, and fine motor abilities) was classified as normal if no abnormalities affecting motor skills were noted, suspect if a moderate degree of abnormality was noted, and abnormal if functionally significant abnormalities of tone, reflexes, or motor skills were present. Autism was diagnosed if the child met the symptom criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [17]. 1.6. Definition of developmental delay In order to capture the majority of CDH survivors who would be expected to experience at least some degree of impairments, neurological delay was defined by a score of ≤85 in any of the evaluated composite scores. Severe impairments were defined as a score of ≤69 in at least one domain tested. 1.7. Statistical analysis Continuous data are presented as means ± SD (median, range). Categorical data are presented as proportions. The differences between
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groups were determined using a chi-square test, Student’s t, Wilcoxon rank-sum, one-way ANOVA, or Kruskall–Wallis non-parametric oneway ANOVA, depending on the outcome variable and number of groups. Prediction of outcome variables used linear regression, logistic regression, or ordinal logistic regression, depending on the type of outcome variable. One-sample t-test was used to compare the mean BSID-III score of outcome to the population mean. P values less than .05 were considered statistically significant and were not corrected for multiple tests. All analyses were conducted in Stata version 12.0. 2. Results 2.1. Patient population During the study period, a total of 83 CDH survivors enrolled in our follow-up program underwent neurodevelopmental assessment at a median age of 12 (range, 10–14). Of those, 20 (24%) required ECMO therapy during the neonatal period and were subsequently excluded. The remaining 63 (76%) children present the study cohort. A total of 38 (60%) underwent prenatal evaluation and postnatal care at our institution. Twenty-five (40%) CDH neonates were referred to our center shortly after birth for management. Baseline characteristics are summarized in Table 1. 2.2. General neurodevelopmental outcome At the time of assessment the mean weight percentile for age and height percentile for age were 16 (2–96) and 25 (2–97), respectively. Head circumference was assessed as a surrogate for brain growth. The median head circumference was 50 (range, 4–98). Microcephaly, defined as head circumference percentile ≤ 5%, was present in 3 (5%) patients. Cranial imaging (brain US and/or MRI) was available in 57 (90%) patients. No signs of intraventricular hemorrhage (IVH) were found 50 (88%), while 7 (12%) developed various grades of IVH (Grade I: 5, Grade II: 1, and Grade III: 1). Small foci of periventricular leukomalacia were identified in 3 (5%) neonates. An underdeveloped or “open” opercula, a marker for brain immaturity associated with adverse neurodevelopmental outcome, was found in 8 (14%) of children studied. Neuromuscular hypotonicity was found in 20 (32%) children. Various degrees of delayed motor coordination were documented in 11 (17%) patients. While no association between delayed motor coordination and clinical demographics was found (data not shown), neuromuscular hypotonicity was more often diagnosed in CDH children that required a prolonged NICU stay (OR 5.6, 95% CI 1.70–18.4, P = 0.005), patch repair (OR 3.55, 95% CI 1.15–11.0, P = 0.03), prolonged supplemental O2 requirement (OR 5.14, 95% CI 1.56–17.0, P = 0.007), pulmonary hypertension (OR 3.44, 95% CI 1.11–10.6, P = 0.03), fundoplication (OR 10.5, 95% CI 1.10–101.2, P = 0.04), and are enrolled in physical therapy (OR 6.5 95% CI 1.66–25.41). There was a trend towards increased risk of neuromuscular hypotonicity in right-sided CDH infants (OR 3.39, 95% CI 0.79–14.47, P = 0.09). Visual impairment was diagnosed in one (2%) patient. Autism was suspected in one (2%). Sixtytwo (98%) completed BAER hearing assessment prior to discharge. Of those, 3 (5%) patients failed the assessment. 2.3. BSID-III developmental outcome Although the mean composite and subdomain scores were within the low average range, BSID-III mean scores for the entire cohort were significantly lower than the expected population norms of 100 ± 15 (Table 2). The language composite function was more severely affected than cognitive and motor outcome (P = 0.002). Twenty-seven (43%) scored within the average range for all scales. Twenty-eight (44%) had mild deficits and 8 (13%) had severe delays in at least one domain. Four (6%) had severe neurodevelopmental and neurofunctional deficits.
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2.4. Predictors of adverse developmental outcome
Table 1 Clinical description of the CDH cohort. Study subjects (n = 63) Sex Male Female Ethnicity Non-Hispanic white Non-Hispanic black Asian-Pacific, Hispanic, Native Other Pregnancy Single Twins Karyotype Normal Abnormal Gestational age (wk) Birth weight (g) CDH Right Left LHRa Liver position Intrathoracic Intraabdominal AGPAR 1 (min)a APGAR 5 (min)a First pH on ABGa Age at surgery (d) Need for patch repair Ventilation setting SIMV HFOV Length of ventilation (d) Tracheostomy Need for supplemental oxygen beyond 30 DOL Preoperative Sildenafil Postoperative Sildenafil Preoperative inotropes Postoperative inotropes Age at initial enteral feed Age at full enteral feed GERD Anti-acid medication Fundoplication LOS Abnormal BAERs Enrollment in EI Enrollment in PT
34 (54) 29 (46) 50 (79) 2 (3) 1 (2) 10 (16) 53 (84) 10 (16) 62 (98) 1 (2) 37.2 ± 2.9 (24–40) 2969.9 ± 664 (1000–4192) 9 (14) 54 (86) 1.5 ± 0.7 (0.72–4.60) 22 (35) 41 (65) 6 (1–9) 9 (5–9) 7.21 (6.8–7.42) 5 (1–56) 26 (41) 49 (78) 14 (22) 11 (2–118) 3 (5) 17 (27) 7 (11) 8 (13) 34 (54) 28 (45) 10 (2–79) 18 (4–180) 38 (60) 5 (8) 29 (7–205) 3 (5) 23 (37) 12 (19)
Data presented either as mean ± SD (range), n (%), or median (range) as appropriate. wk, weeks; g, gram; min, minutes; d, days; m, months; SIMV, synchronized intermittent mandatory ventilation; HFOV, High frequency oscillatory ventilation; DOL, day of life; GERD, Gastroesophageal reflux disease; LOS, length of stay; BAERs, brainstem auditory evoked responses; EI, early intervention; PT, physical therapy. a Based on 38 CDH patients that underwent prenatal evaluation at our institution.
CDH infants that met criteria for neurological delay scored significantly lower in all domains compared to those that scored within the average range for all composite and subdomain scores (Table 3).
Patient-related and procedure-related variables associated with adverse neurological outcome are listed in Table 4. Modifiable (neonatal course) and non-modifiable (gender, CDH-side) factors were significant determinants of adverse outcomes. Prolonged length of stay, prolonged intubation, O2 requirement beyond 30 days of life, gastroesophageal reflux disease requiring fundoplication, presence of pulmonary hypertension, abnormal BAERs, and tracheostomy placement were associated with lower scores in all domains. Presence of right-sided CDH, male gender, lower 5 min APGAR, and delayed start of enteral feeding, were predictive of lower cognitive and/ or language scores, while the need for patch repair and delayed advancement to full enteral feeding were associated with lower than expected motor function.
3. Discussion This study provides an examination of one-year neurological outcomes in a relatively large cohort of CDH survivors who have not undergone ECMO therapy during the neonatal period. Although the mean BSID-III composite scores for these infants were within the low average range, it should be noted that these scores were significantly lower compared to population norms. Language skills appeared to be more impaired then cognitive and motor outcome. Furthermore, the number of children with moderate (43%) to severe delays (13%) in at least one domain was greater than expected for the general population (7% and 1% respectively). Consequently, less than half of our cohort performed well within the normal range. A third of our population was found to have neuromuscular hypotonicity. Even though hypotonicity was described as being mild-to-moderate in severity, it appears that it was clinically significant enough to interfere with the acquisition and quality of gross and fine motor milestones, which in turn increases the risks of neuromotor disabilities. Our data suggest that considerable short-term neurological morbidity exists in CDH children whose illness did not necessitate neonatal ECMO. These findings have important implications for families and health care providers as there has been a general perception that nonECMO treated CDH children have a better prognosis and are less likely to experience co-morbidities that impact on long-term outcome than their ECMO counterparts. Given the importance of early identification of adverse neurological outcome [2], all CDH survivors should be considered at risk for developmental delay and followed closely by an interdisciplinary team to promptly identify and effectively treat morbidities before additional disabilities evolve. Studies describing the neurological outcome of CDH survivors not treated with neonatal ECMO are limited. Bouman and colleagues [5] studied 11 CDH children between 8 and 12 years of age and found that only 45% had IQ scores with the normal range. Similarly Crankson et al. [13] reported moderate to severe long-term delays in 23% of non-ECMO treated CDH survivors, described as global neurological
Table 2 BSID-III outcomes of the entire cohort as compared to population norms [16].
Cognitive composite scorea Language composite scorea Motor composite scorea Receptive language scoreb Expressive language scoreb Fine motor scoreb Gross motor scoreb
BSID-III score
P-value
Proportion N1 SD and b2 SD below mean, %
Proportion N2 SD below mean, %
93.7 85.9 89.6 7.4 8.0
0.001 0.0001 0.0001 0.0001 0.0001
14 32 24 13 19
8 11 8 7 9
0.002 0.0001
5 12
3 14
± ± ± ± ±
14.4 (55–115) 13.8 (56–124) 14.6 (46–124) 2.4 (1–13) 2.6 (2–13)
8.9 ± 2.5 (1–15) 7.8 ± 3.2 (1–13
Data presented as mean ± SD (range) or proportions as appropriate. a Mean ± SD of expected normal score of reference population is 100 ± 15. b Mean ± SD of expected normal score of reference population is 10 ± 3.
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Table 3 Comparison of neurodevelopmental and functional scores between CDH children with average outcome in all BSID-III domains versus survivors with borderline or delayed outcome in at least one category.
Cognitive composite score Language composite score Motor composite score Receptive language score Expressive language score Fine motor score Gross motor score
Average (n = 27)
Borderline/delayed (n = 36)
P-value
100.9 96.2 97.7 8.5 9.7 9.8 9.5
88.1 77.5 83.2 6.3 6.4 8.2 6.4
b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 0.01 b0.0001
± ± ± ± ± ± ±
7.9 (85–115) 8.4 (86–124) 10.4 (82–124) 1.2 (7–12) 1.4 (7–13) 1.9 (8–15) 1.8 (7–13)
± ± ± ± ± ± ±
15.9 (55–115) 11.5 (56–97) 14.4 (46–112) 2.8 (1–13) 2.5 (2–11) 2.8 (1–13) 3.5 (1–12
Data presented as mean ± SD (range).
impairment, problems in language and visual motor skills and/or hearing impairment. Jakobson and associates [10] found that compared to a control group, CDH adolescents were more likely to have delayed oralmotor and visual motor integration skills. Finally, in a study by Frisk et al. [11] 14 of the 27 survivors required placement in special educational classes due to significant impairments. While these long-term results are similar to the short-term neurological data presented in the current study, two recent reports from European centers show somewhat different results in school-aged CDH children without ECMO use with normal neurocognitive outcome and IQ scores of 103 and 100, respectively [9,14]. The discrepancies in outcome between studies might be in part explained by differences in methodologies across the studies, potential selection bias due to incomplete data from small sample size, and the wide range of assessment combining outcome data from infancy throughout adolescent age. The current study demonstrates that both modifiable and nonmodifiable factors are important determinants of neurological outcome. Similar to previous reports on developmental sequelae in CDH that combine the results of ECMO and non-ECMO treated children, surrogate markers of disease severity and degree of pathophysiological disruption correlate with the severity of neurodevelopmental delays [7]. Indeed, prolonged neonatal resuscitation and hospitalization, prolonged ventilatory support and O2 supplementation, pulmonary hypertension, tracheostomy, feeding difficulties, and others presumably reflecting the severity of disease have been associated with poorer outcomes in our study. Our results also show that the hypothesis that adverse neurological outcomes reflect only neonatal intervention seems unlikely; coexistent pathology and genetic predisposition are contributing factors. For
example, males and children with right-sided diaphragm defects, both non-modifiable patient-specific factors unrelated to surgical management were also significant predictors of adverse outcome. It is well known that genetic predisposition and factors other than neonatal events are important determinants in children with congenital heart disease [18]. Our findings would suggest that this might be true for CDH children as well, however additional studies that include risk-stratification for genetic and other patientspecific factors that may alter the risk of adverse neurological outcomes are warranted. Strengths of the current study include the standardized comprehensive neurodevelopmental assessment at a uniform age in a large heterogeneous CDH population; including children with low birth weight, different ethnicity, and various degrees of pulmonary hypoplasia. This increases the potential for generalization of our findings to the larger CDH population. The early enrollment in our follow-up program and early assessment of outcome provide a basis for ongoing research and intervention and may allow timely recognition of impairments before additional disabilities evolve and optimize long-term academic achievements. We previously followed a cohort of 47 CDH survivors with and without neonatal ECMO treatment during the first 3 years of life and demonstrated that over time neurodevelopmental scores improve; with the majority of children scoring within the average to low average range at the preschool age [2]. In accordance with our previous studies [2,3,7] not only CDH survivors with identified adverse outcome early in life should be placed under close neurodevelopmental surveillance, but also those with mild deficits or even with average scores. Early assessment could be a useful tool in alerting physicians to follow up
Table 4 OLS regression modeling the relationship between the Bayley scores and predictors of adverse neurodevelopmental and functional outcomes at one year of age in nonECMO treated CDH children. Bayley Cognitive Score
Male Gender Right-sided CDH APGAR at 5 minutes Low pH on first ABG Length of NICU stay Need for patch repair Prolonged ventilatory support GERD requiring fundoplication Abnormal BAERs Delayed start of enteral feeding Delayed advancement to full enteral feeding Need for tracheostomy Enrolled in early intervention Need for physical therapy Pulmonary hypertension Supplemental O2 requirement beyond 30 DOL
Bayley Language Score
Bayley Motor Score
Coefficient (95% CI)
P value
Coefficient (95% CI)
P value
Coefficient (95% CI)
P value
−11.01 (−17.79 to −4.23) −13.72 (−22.87 to −4.58) 4.48 (1.45 to 7.51) 28.91 (0.33 to 57.48) −0.17 (−0.24 to −0.90) −2.65 (−10.14 to 4.83) −0.32 (−0.51 to −0.14) −21.45 (−33.82 to −9.10) −26.60 (−42.48 to −10.71) −0.38 (−0.66 to −0.99) −0.13 (−0.27 to 0.02) −26.60 (−42.55 to −10.64) −7.42 (−14.97 to 0.11) −13.89 (−22.5 to −5.28) −14.81 (−25.20 to −4.41) −12.7 (−20.28 to −5.13)
0.002 0.004 0.004 0.05 b0.0001 0.48 0.001 0.001 0.001 0.009 0.08 0.001 0.05 0.002 0.006 0.001
−7.54 (−14.36 to −0.72) −7.29 (−17.02 to 2.44) 3.01 (0.06 to 5.97) 30.2 (2.70 to 57.65) −0.13 (−0.21 to −0.58) −5.03 (−12.1 to 2.02) −0.27 (−0.46 to −0.09) −20.76 (−34.13 to −7.39) −29.3 (−47.98 to −10.6) −0.17 (−0.45 to 0.11) −0.78 (−0.22 to 0.07) −29.47 (−48.13 to −10.80) −11.46 (−18.3 to −4.61) −16.54 (−24.41 to −8.66) −12.48 (−22.6 to −2.33) −11.26 (−18.81 to −3.72)
0.03 0.14 0.05 0.03 0.001 0.16 0.004 0.003 0.003 0.22 0.29 0.003 0.001 b0.0001 0.02 0.004
−5.81 (−13.24 to 1.62) −.95 (−18.6 to 2.71) 2.79 (−0.48 to 6.07) 28.78 (−0.35 to 57.91) −0.20 (−0.29 to −0.11) −10.75 (−17.96 to −3.55) −0.33 (−0.52 to −0.14) −18.6 (−33.05 to −4.1) −24.81 (−45.15 to −4.47) −0.29 (−0.38 to 0.00) −0.15 (−0.29 to −0.02) −24.68 (−44.87 to −4.48) −6.95 (−14.67 to 0.76 −13.3 (−22.467 to −4.08) −10.90 (−22.52 to 0.78) −14.12 (−21.88 to −6.37)
0.12 0.14 0.09 0.05 b0.0001 0.004 0.001 0.01 0.02 0.05 0.05 0.02 0.08 0.005 0.07 0.001
GERD, gastroesophageal reflux disease; BAERs, brainstem auditory evoked responses; DOL, day of life.
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neurodevelopment to facilitate initiation of early intervention, better test interpretation, and parent counseling. Although our study provides strong evidence that CDH survivors not requiring neonatal ECMO are at risk of neurological impairment, there are several limitations. Our study cohort nearly doubles the patient population enrolled in the next largest report, but we were unable to perform meaningful multiregression statistical analysis to further narrow the spectrum of significant predictors of adverse outcome. Nevertheless it is important to review the above mentioned factors for their relevance from a clinical standpoint. For example, a child who has a complicated and prolonged NICU course and/or requires tracheostomy placement will have accumulated multiple risk factors for adverse outcome. Therefore, these complications must suggest to clinicians that a patient's severity of illness puts that patient at extremely high risk for impaired neurological function. Of note, non-ECMO treated CDH survivors appear to be at similar risk as children that underwent surgical intervention for other congenital malformations during the neonatal period and also require prolonged hospitalization during the first year of life [19]. Thus, further research is needed to fully delineate whether the underlying malformation, its treatment, or both impact on short-term neurological outcome. 4. Conclusion Our data suggest that considerable short-term neurological morbidity exists in CDH children whose illness did not necessitate neonatal ECMO. A high percentage of CDH children have below normal developmental scores during the first year of age. Neuromuscular hypotonicity is common. Modifiable and non-modifiable factors are associated with adverse outcomes. These findings have important implications for families and health care providers as there has been a general perception that non-ECMO treated CDH children have a better prognosis and are less likely to experience co-morbidities that impact on long-term outcome than their ECMO counterparts. Given the importance of early identification of adverse neurological outcome [2], all CDH survivors should be considered at risk for developmental delay and followed closely by an interdisciplinary team to promptly identify and effectively treat morbidities before additional disabilities evolve. Reevaluation throughout childhood may enhance identification of significant deficits, allowing for appropriate therapies to enhance later academic functioning. Acknowledgement We greatly appreciate the statistical advice and analysis provided by Mark S. Cary, PhD, Sr. Staff Biostatistician Biostatistics Analysis Center, Center for Clinical Epidemiology and Biostatistics, The Perelman School of Medicine at The University of Pennsylvania. We also thank Norma Rendon for superb administrative assistance. Appendix A. Discussions Presenter: Enrico Danzer, MD (Philadelphia, PA) MODERATOR: This paper is now open for questions. When would you recommend the earliest screening after the patient's been born? Response: DR. DANZER: Follow-up starts at around six months of age. Thus far more than 300 patients enrolled in this follow-up program. Not all of them are able to return at the adjusted time. Discussant: DR. CHARLES STOLER (Santa Barbara, CA): I encourage you when you look at outcomes for diaphragmatic hernia; in a paper we presented here about 15 years ago when we looked at kids reaching school age, the most important predictors of neurodevelopmental outcome are really the educational age of the primary caretaker. It was the eighth grade. If the primary caretaker has an educational age of eighth grade and is home
with the child seven days a week, that had the biggest impact on outcome than any of these other things. If you compare diaphragmatic hernia to any other neonatal illness – omphalocele, necrotizing enterocolitis, esophageal atresia – outcomes are the same. They all are challenged in a neurodevelopmental outcome. What unifies them is having been a sick baby. It's not unique to diaphragmatic hernia. So the outcome measure you need to add to this is what's the educational age of the primary caretaker. Response: DR. DANZER: That's a very good point, and it's wellknown. Unfortunately, not all of our families have completed the socioeconomic questionnaires, so we couldn't include this data in the presentation. Discussant: DR. FRANCESCO MORINI (Rome, Italy): Thank you for your presentation; I enjoyed it very much. We presented a couple of years ago at the EUPSA meeting a cohort of CDH patients in which we analyzed the neurodevelopmental outcome at one year of age, and we found a little bit less pessimistic figures, maybe because we did not look at the language side of the neurodevelopmental outcome. How reliable do you think is the study of language at one year of age in the definition of the neurodevelopment outcome as far as language is concerned at that age? They are very young Response DR. DANZER: it's a very good question. In one of our pre vious studies that we evulated the longitudinal neurodevelopmental outcome in CDH during the first three years of life. We found that nearly 10% improve their cognitive and language scores over time. You are correct, given the young age re-evaluation during preschool or school age will be important.
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Neurodevelopmental outcome at one year of age in congenital diaphragmatic hernia infants not treated with extracorporeal membrane oxygenation Enrico Danzer ⁎, Marsha Gerdes, Jo Ann D’Agostino, Judy Bernbaum, Casey Hoffman, Lisa Herkert, Natalie E. Rintoul, William H. Peranteau, Alan W. Flake, N. Scott Adzick, Holly L. Hedrick The Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia and The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA
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Article history: Received 24 February 2015 Accepted 10 March 2015 Key words: Congenital diaphragmatic hernia Neurodevelopmental outcome Bayley Scales of Infant Development Hypotonicity Pulmonary hypoplasia ECMO
a b s t r a c t Background: We evaluated the neurodevelopmental (ND) outcome at one year of age for congenital diaphragmatic hernia (CDH) children who have not undergone extracorporeal membrane oxygenation (ECMO) treatment during the neonatal period. Material and methods: Between 01/2005 and 06/2012, 63 consecutive CDH patients underwent ND assessment using the BSID-III at a median age of 12 months. ND delay was defined by a score of ≤85 in any of the composite scales. Severe impairment was defined as a score of ≤69 in at least one domain. Results: Mean ± SD cognitive, language, and motor functions were 94 ± 14, 86 ± 14, 90 ± 15, respectively (normal 100 ± 15, P b 0.01 for each). Forty-three-percent scored within the average range for all scales. Forty-fourpercent had mild, and 13% had severe delays in at least one domain. Prolonged NICU stay, intubation and O2 requirement, fundoplication, abnormal BAERs, and tracheostomy were associated with lower scores in all domains. Right-sided CDH, male gender, lower 5 min APGAR, pulmonary hypertension, and delayed start of enteral feeding were predictive of lower cognitive and/or language scores. Conclusion: At one year of age, a high percentage of CDH children whose illness did not necessitate ECMO have below normal ND scores. Modifiable and non-modifiable factors are significant determinants of adverse outcomes. © 2015 Elsevier Inc. All rights reserved.
Advances in neonatal care and surgical management for children with congenital diaphragmatic hernia (CDH) have led to improved survival, along with an increased recognition of associated morbidities [1]. Neurocognitive and functional delays, learning disabilities, behavioral disorders, and hearing impairments are increasingly recognized among the spectrum of developmental problems in CDH survivors [2–8]. Although the etiology of developmental abnormalities is most likely multifactorial, several risk factors have been identified. One of the most important risk factors associated with impaired neurological outcome is the use of extracorporeal membrane oxygenation (ECMO) [2,3,6–8]. In general, ECMO is reserved for CDH neonates when conventional treatment of severe pulmonary hypertension fails. Whether the increased incidence of adverse outcome in CDH children following neonatal ECMO therapy is the result of disease severity necessitating ECMO rather than of the treatment itself remains under discussion. The majority of outcome studies in CDH survivors combine data from ECMO treated and non-ECMO treated patients [2,3,6–8]. Information on neurological outcome of non-ECMO-treated CDH survivors is scarce [5,9–14]. Furthermore, these studies are limited by small sample size, incomplete ⁎ Corresponding author at: The Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, 5th Floor Wood Center, Philadelphia, PA, 19104-4318. Tel.: +1 215 590 2733; fax: +1 215 590 2447. E-mail address: [email protected] (E. Danzer). http://dx.doi.org/10.1016/j.jpedsurg.2015.03.040 0022-3468/© 2015 Elsevier Inc. All rights reserved.
cohorts, and wide age range at neurological evaluation. Consequently, one of the major challenges is to prognosticate developmental outcome and to provide appropriate counseling for parents of CDH children not treated with ECMO. The primary objective of this study was to evaluate the neurodevelopmental outcome at one year of age for CDH children who have not undergone ECMO treatment. The secondary objective was to examine both modifiable and non-modifiable patient, clinical and operative factors associated with adverse neurological outcome. 1. Material and methods 1.1. Ethical statement The Institutional Review Board, Committee for Protection of Human Subjects of The Children’s Hospital of Philadelphia approved this study (IRB 2004-5-3779). Informed consent was obtained from the parent or guardian. 1.2. Patient population This was a cross-sectional review of prospectively collected data on neurodevelopmental outcome in CDH survivors enrolled in our Pulmonary
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Hypoplasia Program between January 2005 and June 2012. All CDH survivors born during the study period who enrolled in the follow-up program were eligible. Among this cohort, subjects who underwent neurodevelopmental assessment at a median age of 12 months (range 10–14) and did not undergo ECMO therapy were identified and form the study population for this report. 1.3. Perinatal and postnatal management As described elsewhere, CDH patients are treated according to a specific CDH management protocol [1]. Briefly, the initial evaluation of all CDH patients referred to the Center for Fetal Diagnosis and Treatment at the Children’s Hospital of Philadelphia includes detailed fetal ultrasonography, echocardiography, and ultrafast MRI [15]. Assessment includes confirmation of diagnosis, the type of CDH, liver position, lung-to-head ratio (LHR), observed over expected LHR, observed over expected LHR MRI lung volumes, and the presence of other fetal anomalies. After evaluation, all patients undergo nondirective counseling for pregnancy management options. The postnatal ventilatory management in the neonatal intensive care unit utilizes a lung-preservation strategy similar to that of infants with other causes of pulmonary hypoplasia [1–3]. Postnatal echocardiography is performed early to establish the presence and severity of pulmonary hypertension. The operating surgeon determines the timing of repair based upon co-morbidities and clinical stability. The need for patch is based upon the size of the diaphragmatic defect. 1.4. Data collection Perinatal, perioperative and postnatal factors that might independently affect neurodevelopmental and neuromotor outcome were obtained from maternal prenatal charts and neonatal hospital records. 1.5. Follow-up assessment Growth parameters including weight, length, and head circumference were measured and compared to standard reference curves. Developmental assessment was performed using the Bayley Scales of Infant Development, 3rd Edition (BSID-III) [16]. The normalized population mean and standard deviation (SD) of each composite score are 100 ± 15 [16]. As described previously, overall scores were grouped as average, borderline, and delayed based on SD intervals (85–115, 70–84, and ≤69, respectively) [2,3]. To minimize observer bias, neurodevelopmental testing was administered by either a trained psychologist or psychometrist not involved in the neonatal care of these patients and supervised by a pediatric psychologist (M.G.). The neuromuscular examination (active tone, passive tone, reflexes, gross motor abilities, and fine motor abilities) was classified as normal if no abnormalities affecting motor skills were noted, suspect if a moderate degree of abnormality was noted, and abnormal if functionally significant abnormalities of tone, reflexes, or motor skills were present. Autism was diagnosed if the child met the symptom criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [17]. 1.6. Definition of developmental delay In order to capture the majority of CDH survivors who would be expected to experience at least some degree of impairments, neurological delay was defined by a score of ≤85 in any of the evaluated composite scores. Severe impairments were defined as a score of ≤69 in at least one domain tested. 1.7. Statistical analysis Continuous data are presented as means ± SD (median, range). Categorical data are presented as proportions. The differences between
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groups were determined using a chi-square test, Student’s t, Wilcoxon rank-sum, one-way ANOVA, or Kruskall–Wallis non-parametric oneway ANOVA, depending on the outcome variable and number of groups. Prediction of outcome variables used linear regression, logistic regression, or ordinal logistic regression, depending on the type of outcome variable. One-sample t-test was used to compare the mean BSID-III score of outcome to the population mean. P values less than .05 were considered statistically significant and were not corrected for multiple tests. All analyses were conducted in Stata version 12.0. 2. Results 2.1. Patient population During the study period, a total of 83 CDH survivors enrolled in our follow-up program underwent neurodevelopmental assessment at a median age of 12 (range, 10–14). Of those, 20 (24%) required ECMO therapy during the neonatal period and were subsequently excluded. The remaining 63 (76%) children present the study cohort. A total of 38 (60%) underwent prenatal evaluation and postnatal care at our institution. Twenty-five (40%) CDH neonates were referred to our center shortly after birth for management. Baseline characteristics are summarized in Table 1. 2.2. General neurodevelopmental outcome At the time of assessment the mean weight percentile for age and height percentile for age were 16 (2–96) and 25 (2–97), respectively. Head circumference was assessed as a surrogate for brain growth. The median head circumference was 50 (range, 4–98). Microcephaly, defined as head circumference percentile ≤ 5%, was present in 3 (5%) patients. Cranial imaging (brain US and/or MRI) was available in 57 (90%) patients. No signs of intraventricular hemorrhage (IVH) were found 50 (88%), while 7 (12%) developed various grades of IVH (Grade I: 5, Grade II: 1, and Grade III: 1). Small foci of periventricular leukomalacia were identified in 3 (5%) neonates. An underdeveloped or “open” opercula, a marker for brain immaturity associated with adverse neurodevelopmental outcome, was found in 8 (14%) of children studied. Neuromuscular hypotonicity was found in 20 (32%) children. Various degrees of delayed motor coordination were documented in 11 (17%) patients. While no association between delayed motor coordination and clinical demographics was found (data not shown), neuromuscular hypotonicity was more often diagnosed in CDH children that required a prolonged NICU stay (OR 5.6, 95% CI 1.70–18.4, P = 0.005), patch repair (OR 3.55, 95% CI 1.15–11.0, P = 0.03), prolonged supplemental O2 requirement (OR 5.14, 95% CI 1.56–17.0, P = 0.007), pulmonary hypertension (OR 3.44, 95% CI 1.11–10.6, P = 0.03), fundoplication (OR 10.5, 95% CI 1.10–101.2, P = 0.04), and are enrolled in physical therapy (OR 6.5 95% CI 1.66–25.41). There was a trend towards increased risk of neuromuscular hypotonicity in right-sided CDH infants (OR 3.39, 95% CI 0.79–14.47, P = 0.09). Visual impairment was diagnosed in one (2%) patient. Autism was suspected in one (2%). Sixtytwo (98%) completed BAER hearing assessment prior to discharge. Of those, 3 (5%) patients failed the assessment. 2.3. BSID-III developmental outcome Although the mean composite and subdomain scores were within the low average range, BSID-III mean scores for the entire cohort were significantly lower than the expected population norms of 100 ± 15 (Table 2). The language composite function was more severely affected than cognitive and motor outcome (P = 0.002). Twenty-seven (43%) scored within the average range for all scales. Twenty-eight (44%) had mild deficits and 8 (13%) had severe delays in at least one domain. Four (6%) had severe neurodevelopmental and neurofunctional deficits.
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2.4. Predictors of adverse developmental outcome
Table 1 Clinical description of the CDH cohort. Study subjects (n = 63) Sex Male Female Ethnicity Non-Hispanic white Non-Hispanic black Asian-Pacific, Hispanic, Native Other Pregnancy Single Twins Karyotype Normal Abnormal Gestational age (wk) Birth weight (g) CDH Right Left LHRa Liver position Intrathoracic Intraabdominal AGPAR 1 (min)a APGAR 5 (min)a First pH on ABGa Age at surgery (d) Need for patch repair Ventilation setting SIMV HFOV Length of ventilation (d) Tracheostomy Need for supplemental oxygen beyond 30 DOL Preoperative Sildenafil Postoperative Sildenafil Preoperative inotropes Postoperative inotropes Age at initial enteral feed Age at full enteral feed GERD Anti-acid medication Fundoplication LOS Abnormal BAERs Enrollment in EI Enrollment in PT
34 (54) 29 (46) 50 (79) 2 (3) 1 (2) 10 (16) 53 (84) 10 (16) 62 (98) 1 (2) 37.2 ± 2.9 (24–40) 2969.9 ± 664 (1000–4192) 9 (14) 54 (86) 1.5 ± 0.7 (0.72–4.60) 22 (35) 41 (65) 6 (1–9) 9 (5–9) 7.21 (6.8–7.42) 5 (1–56) 26 (41) 49 (78) 14 (22) 11 (2–118) 3 (5) 17 (27) 7 (11) 8 (13) 34 (54) 28 (45) 10 (2–79) 18 (4–180) 38 (60) 5 (8) 29 (7–205) 3 (5) 23 (37) 12 (19)
Data presented either as mean ± SD (range), n (%), or median (range) as appropriate. wk, weeks; g, gram; min, minutes; d, days; m, months; SIMV, synchronized intermittent mandatory ventilation; HFOV, High frequency oscillatory ventilation; DOL, day of life; GERD, Gastroesophageal reflux disease; LOS, length of stay; BAERs, brainstem auditory evoked responses; EI, early intervention; PT, physical therapy. a Based on 38 CDH patients that underwent prenatal evaluation at our institution.
CDH infants that met criteria for neurological delay scored significantly lower in all domains compared to those that scored within the average range for all composite and subdomain scores (Table 3).
Patient-related and procedure-related variables associated with adverse neurological outcome are listed in Table 4. Modifiable (neonatal course) and non-modifiable (gender, CDH-side) factors were significant determinants of adverse outcomes. Prolonged length of stay, prolonged intubation, O2 requirement beyond 30 days of life, gastroesophageal reflux disease requiring fundoplication, presence of pulmonary hypertension, abnormal BAERs, and tracheostomy placement were associated with lower scores in all domains. Presence of right-sided CDH, male gender, lower 5 min APGAR, and delayed start of enteral feeding, were predictive of lower cognitive and/ or language scores, while the need for patch repair and delayed advancement to full enteral feeding were associated with lower than expected motor function.
3. Discussion This study provides an examination of one-year neurological outcomes in a relatively large cohort of CDH survivors who have not undergone ECMO therapy during the neonatal period. Although the mean BSID-III composite scores for these infants were within the low average range, it should be noted that these scores were significantly lower compared to population norms. Language skills appeared to be more impaired then cognitive and motor outcome. Furthermore, the number of children with moderate (43%) to severe delays (13%) in at least one domain was greater than expected for the general population (7% and 1% respectively). Consequently, less than half of our cohort performed well within the normal range. A third of our population was found to have neuromuscular hypotonicity. Even though hypotonicity was described as being mild-to-moderate in severity, it appears that it was clinically significant enough to interfere with the acquisition and quality of gross and fine motor milestones, which in turn increases the risks of neuromotor disabilities. Our data suggest that considerable short-term neurological morbidity exists in CDH children whose illness did not necessitate neonatal ECMO. These findings have important implications for families and health care providers as there has been a general perception that nonECMO treated CDH children have a better prognosis and are less likely to experience co-morbidities that impact on long-term outcome than their ECMO counterparts. Given the importance of early identification of adverse neurological outcome [2], all CDH survivors should be considered at risk for developmental delay and followed closely by an interdisciplinary team to promptly identify and effectively treat morbidities before additional disabilities evolve. Studies describing the neurological outcome of CDH survivors not treated with neonatal ECMO are limited. Bouman and colleagues [5] studied 11 CDH children between 8 and 12 years of age and found that only 45% had IQ scores with the normal range. Similarly Crankson et al. [13] reported moderate to severe long-term delays in 23% of non-ECMO treated CDH survivors, described as global neurological
Table 2 BSID-III outcomes of the entire cohort as compared to population norms [16].
Cognitive composite scorea Language composite scorea Motor composite scorea Receptive language scoreb Expressive language scoreb Fine motor scoreb Gross motor scoreb
BSID-III score
P-value
Proportion N1 SD and b2 SD below mean, %
Proportion N2 SD below mean, %
93.7 85.9 89.6 7.4 8.0
0.001 0.0001 0.0001 0.0001 0.0001
14 32 24 13 19
8 11 8 7 9
0.002 0.0001
5 12
3 14
± ± ± ± ±
14.4 (55–115) 13.8 (56–124) 14.6 (46–124) 2.4 (1–13) 2.6 (2–13)
8.9 ± 2.5 (1–15) 7.8 ± 3.2 (1–13
Data presented as mean ± SD (range) or proportions as appropriate. a Mean ± SD of expected normal score of reference population is 100 ± 15. b Mean ± SD of expected normal score of reference population is 10 ± 3.
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Table 3 Comparison of neurodevelopmental and functional scores between CDH children with average outcome in all BSID-III domains versus survivors with borderline or delayed outcome in at least one category.
Cognitive composite score Language composite score Motor composite score Receptive language score Expressive language score Fine motor score Gross motor score
Average (n = 27)
Borderline/delayed (n = 36)
P-value
100.9 96.2 97.7 8.5 9.7 9.8 9.5
88.1 77.5 83.2 6.3 6.4 8.2 6.4
b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 0.01 b0.0001
± ± ± ± ± ± ±
7.9 (85–115) 8.4 (86–124) 10.4 (82–124) 1.2 (7–12) 1.4 (7–13) 1.9 (8–15) 1.8 (7–13)
± ± ± ± ± ± ±
15.9 (55–115) 11.5 (56–97) 14.4 (46–112) 2.8 (1–13) 2.5 (2–11) 2.8 (1–13) 3.5 (1–12
Data presented as mean ± SD (range).
impairment, problems in language and visual motor skills and/or hearing impairment. Jakobson and associates [10] found that compared to a control group, CDH adolescents were more likely to have delayed oralmotor and visual motor integration skills. Finally, in a study by Frisk et al. [11] 14 of the 27 survivors required placement in special educational classes due to significant impairments. While these long-term results are similar to the short-term neurological data presented in the current study, two recent reports from European centers show somewhat different results in school-aged CDH children without ECMO use with normal neurocognitive outcome and IQ scores of 103 and 100, respectively [9,14]. The discrepancies in outcome between studies might be in part explained by differences in methodologies across the studies, potential selection bias due to incomplete data from small sample size, and the wide range of assessment combining outcome data from infancy throughout adolescent age. The current study demonstrates that both modifiable and nonmodifiable factors are important determinants of neurological outcome. Similar to previous reports on developmental sequelae in CDH that combine the results of ECMO and non-ECMO treated children, surrogate markers of disease severity and degree of pathophysiological disruption correlate with the severity of neurodevelopmental delays [7]. Indeed, prolonged neonatal resuscitation and hospitalization, prolonged ventilatory support and O2 supplementation, pulmonary hypertension, tracheostomy, feeding difficulties, and others presumably reflecting the severity of disease have been associated with poorer outcomes in our study. Our results also show that the hypothesis that adverse neurological outcomes reflect only neonatal intervention seems unlikely; coexistent pathology and genetic predisposition are contributing factors. For
example, males and children with right-sided diaphragm defects, both non-modifiable patient-specific factors unrelated to surgical management were also significant predictors of adverse outcome. It is well known that genetic predisposition and factors other than neonatal events are important determinants in children with congenital heart disease [18]. Our findings would suggest that this might be true for CDH children as well, however additional studies that include risk-stratification for genetic and other patientspecific factors that may alter the risk of adverse neurological outcomes are warranted. Strengths of the current study include the standardized comprehensive neurodevelopmental assessment at a uniform age in a large heterogeneous CDH population; including children with low birth weight, different ethnicity, and various degrees of pulmonary hypoplasia. This increases the potential for generalization of our findings to the larger CDH population. The early enrollment in our follow-up program and early assessment of outcome provide a basis for ongoing research and intervention and may allow timely recognition of impairments before additional disabilities evolve and optimize long-term academic achievements. We previously followed a cohort of 47 CDH survivors with and without neonatal ECMO treatment during the first 3 years of life and demonstrated that over time neurodevelopmental scores improve; with the majority of children scoring within the average to low average range at the preschool age [2]. In accordance with our previous studies [2,3,7] not only CDH survivors with identified adverse outcome early in life should be placed under close neurodevelopmental surveillance, but also those with mild deficits or even with average scores. Early assessment could be a useful tool in alerting physicians to follow up
Table 4 OLS regression modeling the relationship between the Bayley scores and predictors of adverse neurodevelopmental and functional outcomes at one year of age in nonECMO treated CDH children. Bayley Cognitive Score
Male Gender Right-sided CDH APGAR at 5 minutes Low pH on first ABG Length of NICU stay Need for patch repair Prolonged ventilatory support GERD requiring fundoplication Abnormal BAERs Delayed start of enteral feeding Delayed advancement to full enteral feeding Need for tracheostomy Enrolled in early intervention Need for physical therapy Pulmonary hypertension Supplemental O2 requirement beyond 30 DOL
Bayley Language Score
Bayley Motor Score
Coefficient (95% CI)
P value
Coefficient (95% CI)
P value
Coefficient (95% CI)
P value
−11.01 (−17.79 to −4.23) −13.72 (−22.87 to −4.58) 4.48 (1.45 to 7.51) 28.91 (0.33 to 57.48) −0.17 (−0.24 to −0.90) −2.65 (−10.14 to 4.83) −0.32 (−0.51 to −0.14) −21.45 (−33.82 to −9.10) −26.60 (−42.48 to −10.71) −0.38 (−0.66 to −0.99) −0.13 (−0.27 to 0.02) −26.60 (−42.55 to −10.64) −7.42 (−14.97 to 0.11) −13.89 (−22.5 to −5.28) −14.81 (−25.20 to −4.41) −12.7 (−20.28 to −5.13)
0.002 0.004 0.004 0.05 b0.0001 0.48 0.001 0.001 0.001 0.009 0.08 0.001 0.05 0.002 0.006 0.001
−7.54 (−14.36 to −0.72) −7.29 (−17.02 to 2.44) 3.01 (0.06 to 5.97) 30.2 (2.70 to 57.65) −0.13 (−0.21 to −0.58) −5.03 (−12.1 to 2.02) −0.27 (−0.46 to −0.09) −20.76 (−34.13 to −7.39) −29.3 (−47.98 to −10.6) −0.17 (−0.45 to 0.11) −0.78 (−0.22 to 0.07) −29.47 (−48.13 to −10.80) −11.46 (−18.3 to −4.61) −16.54 (−24.41 to −8.66) −12.48 (−22.6 to −2.33) −11.26 (−18.81 to −3.72)
0.03 0.14 0.05 0.03 0.001 0.16 0.004 0.003 0.003 0.22 0.29 0.003 0.001 b0.0001 0.02 0.004
−5.81 (−13.24 to 1.62) −.95 (−18.6 to 2.71) 2.79 (−0.48 to 6.07) 28.78 (−0.35 to 57.91) −0.20 (−0.29 to −0.11) −10.75 (−17.96 to −3.55) −0.33 (−0.52 to −0.14) −18.6 (−33.05 to −4.1) −24.81 (−45.15 to −4.47) −0.29 (−0.38 to 0.00) −0.15 (−0.29 to −0.02) −24.68 (−44.87 to −4.48) −6.95 (−14.67 to 0.76 −13.3 (−22.467 to −4.08) −10.90 (−22.52 to 0.78) −14.12 (−21.88 to −6.37)
0.12 0.14 0.09 0.05 b0.0001 0.004 0.001 0.01 0.02 0.05 0.05 0.02 0.08 0.005 0.07 0.001
GERD, gastroesophageal reflux disease; BAERs, brainstem auditory evoked responses; DOL, day of life.
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neurodevelopment to facilitate initiation of early intervention, better test interpretation, and parent counseling. Although our study provides strong evidence that CDH survivors not requiring neonatal ECMO are at risk of neurological impairment, there are several limitations. Our study cohort nearly doubles the patient population enrolled in the next largest report, but we were unable to perform meaningful multiregression statistical analysis to further narrow the spectrum of significant predictors of adverse outcome. Nevertheless it is important to review the above mentioned factors for their relevance from a clinical standpoint. For example, a child who has a complicated and prolonged NICU course and/or requires tracheostomy placement will have accumulated multiple risk factors for adverse outcome. Therefore, these complications must suggest to clinicians that a patient's severity of illness puts that patient at extremely high risk for impaired neurological function. Of note, non-ECMO treated CDH survivors appear to be at similar risk as children that underwent surgical intervention for other congenital malformations during the neonatal period and also require prolonged hospitalization during the first year of life [19]. Thus, further research is needed to fully delineate whether the underlying malformation, its treatment, or both impact on short-term neurological outcome. 4. Conclusion Our data suggest that considerable short-term neurological morbidity exists in CDH children whose illness did not necessitate neonatal ECMO. A high percentage of CDH children have below normal developmental scores during the first year of age. Neuromuscular hypotonicity is common. Modifiable and non-modifiable factors are associated with adverse outcomes. These findings have important implications for families and health care providers as there has been a general perception that non-ECMO treated CDH children have a better prognosis and are less likely to experience co-morbidities that impact on long-term outcome than their ECMO counterparts. Given the importance of early identification of adverse neurological outcome [2], all CDH survivors should be considered at risk for developmental delay and followed closely by an interdisciplinary team to promptly identify and effectively treat morbidities before additional disabilities evolve. Reevaluation throughout childhood may enhance identification of significant deficits, allowing for appropriate therapies to enhance later academic functioning. Acknowledgement We greatly appreciate the statistical advice and analysis provided by Mark S. Cary, PhD, Sr. Staff Biostatistician Biostatistics Analysis Center, Center for Clinical Epidemiology and Biostatistics, The Perelman School of Medicine at The University of Pennsylvania. We also thank Norma Rendon for superb administrative assistance. Appendix A. Discussions Presenter: Enrico Danzer, MD (Philadelphia, PA) MODERATOR: This paper is now open for questions. When would you recommend the earliest screening after the patient's been born? Response: DR. DANZER: Follow-up starts at around six months of age. Thus far more than 300 patients enrolled in this follow-up program. Not all of them are able to return at the adjusted time. Discussant: DR. CHARLES STOLER (Santa Barbara, CA): I encourage you when you look at outcomes for diaphragmatic hernia; in a paper we presented here about 15 years ago when we looked at kids reaching school age, the most important predictors of neurodevelopmental outcome are really the educational age of the primary caretaker. It was the eighth grade. If the primary caretaker has an educational age of eighth grade and is home
with the child seven days a week, that had the biggest impact on outcome than any of these other things. If you compare diaphragmatic hernia to any other neonatal illness – omphalocele, necrotizing enterocolitis, esophageal atresia – outcomes are the same. They all are challenged in a neurodevelopmental outcome. What unifies them is having been a sick baby. It's not unique to diaphragmatic hernia. So the outcome measure you need to add to this is what's the educational age of the primary caretaker. Response: DR. DANZER: That's a very good point, and it's wellknown. Unfortunately, not all of our families have completed the socioeconomic questionnaires, so we couldn't include this data in the presentation. Discussant: DR. FRANCESCO MORINI (Rome, Italy): Thank you for your presentation; I enjoyed it very much. We presented a couple of years ago at the EUPSA meeting a cohort of CDH patients in which we analyzed the neurodevelopmental outcome at one year of age, and we found a little bit less pessimistic figures, maybe because we did not look at the language side of the neurodevelopmental outcome. How reliable do you think is the study of language at one year of age in the definition of the neurodevelopment outcome as far as language is concerned at that age? They are very young Response DR. DANZER: it's a very good question. In one of our pre vious studies that we evulated the longitudinal neurodevelopmental outcome in CDH during the first three years of life. We found that nearly 10% improve their cognitive and language scores over time. You are correct, given the young age re-evaluation during preschool or school age will be important.
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