- Email: [email protected]
Predictors of developmental disabilities after open heart surgery in young children with congenital heart defects
Predictors of developmental disabilities after open heart surgery in young children with congenital heart defects Catherine Limperopoulos, PhD, OT(C), Annette Majnemer, PhD, OT(C), Michael I. Shevell, MD, CM, FRCP(C), Charles Rohlicek, MD, CM, PhD, FRCP(C), Bernard Rosenblatt, MD, CM, FRCP(C), Christo Tchervenkov, MD, CM, FRCS(C), and H. Z. Darwish, MD, FRCP(C) Objectives: To determine the prevalence of persistent developmental impairments in children with congenital heart defects and to identify factors that enhance risk for an adverse outcome. Study design: Eligible infants (n = 131) <2 years of age requiring open heart surgery were recruited prospectively. Subjects were assessed during surgery and again 12 to 18 months later with standardized developmental assessments and formal neurologic examinations. Results: Mean age at follow-up testing was 19.1 ± 6.6 months. Assessments indicated that 41% had abnormal neurologic examinations. Gross and/or fine motor delays were documented in 42%, and 23% demonstrated global developmental delay. Univariate and multiple regression models identified the following factors increasing the risk for persistent developmental deficits: preoperative and acute postoperative neurodevelopmental status and microcephaly, type of heart lesion, length of deep hypothermic circulatory arrest, age at surgery, and days in the intensive care unit (P < .05). Conclusions: Children with congenital heart defects commonly have ongoing neurologic, motor, and developmental deficits well after surgical correction. The cause is multifactorial and includes brain injury before, during, and after heart surgery. (J Pediatr 2002;141:51-8) With the advent of technological and surgical advances in the care of the infant born with a congenital heart defect (CHD), mortality rates have decreased
dramatically; however, morbidity remains a concern.1-6 There is controversy regarding the presence and persistence of neurodevelopmental se-
From the School of Physical and Occupational Therapy, Departments of Neurology and Neurosurgery, Cardiovascular and Thoracic Surgery, and Pediatrics, McGill University–Montreal Children’s Hospital, Québec; and the Division of Pediatric Neurology, Alberta Children’s Hospital, Calgary, Canada.
Supported by the National Health Research and Development Program (Health Canada), the Heart and Stroke Foundation, and March of Dimes. Submitted for publication June 28, 2001; revisions received Nov 7, 2001, and Mar 4, 2002; accepted Mar 25, 2002. Reprint requests: Annette Majnemer, PhD, OT(C), Montreal Children’s Hospital, Neurology, Room A-509, 2300 Tupper St, Montreal, Quebec H3H 1P3, Canada. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/21/125227 doi:10.1067/mpd.2002.125227
quelae in children with CHD requiring open heart surgery (OHS). Prospective studies with comprehensive neurodevelopmental assessments of survivors of OHS, as well as standardized procedures, are lacking.1,7 The available evidence in the literature would suggest that developmental problems are common in young children with CHD undergoing OHS.8-12 To date, developmental deficits have largely been attributed to surgical events and procedures without careful consideration of other possible risk factors.1,2,4,7 Few studies have ascertained whether preexisting neurologic abnormalities are evident before OHS, and no study has prospectively examined whether acute neurologic compromise in the perioperative period is an early marker for persisting CHD CPB DHCA GMDS OHS OR OT SES PDMS
Congenital heart defects Cardiopulmonary bypass Deep hypothermic circulatory arrest Griffiths Mental Development Scale Open heart surgery Odds ratio Occupational therapist Socioeconomic status Peabody Developmental Motor Scales
developmental disability. It is important to identify markers of brain injury so that children at high risk for neurodevelopmental sequelae may be targeted for early intervention, to minimize disability. Therefore, the primary objective of this study was to determine the prevalence of persisting neurodevelopmental disabilities in young children with CHD. A secondary objective was 51
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to evaluate whether aspects of the perioperative clinical examinations, indicators of acute or persistent cardiorespiratory compromise, intraoperative procedures, and environmental factors were associated with a greater likelihood for developmental disability.
METHODS In this prospective study, a consecutive series of children with a CHD who were admitted to the Montreal Children’s Hospital for OHS requiring cardiopulmonary bypass (CPB) with or without deep hypothermic circulatory arrest (DHCA) that met our inclusion criteria were recruited. This project was approved by the scientific and ethics review board at our institution. Informed consent was obtained from the families before enrollment into the study (96% participation rate). Neurodevelopmental assessments administered before surgery and acute postoperative assessments just before hospital discharge have been previously reported.13,14 This study examined the neurodevelopmental outcome of this cohort 12 months to 18 months after OHS. A range of outcome measures was used to ascertain the magnitude of persistent developmental impairments and disabilities in neurologic, motor, developmental, and functional domains after heart surgery. Inclusion/exclusion criteria have been reported in detail previously.14 Subjects included term infants with a diagnosis of a CHD undergoing their first corrective or palliative OHS before 2 years of age, with no clinical evidence of a disorder or impairment of the central nervous system due to causes other than complications of the heart defect at the time of admission for heart surgery. Children with hypoplastic left heart syndrome were specifically excluded because the literature suggests a higher prevalence of neurologic morbidity.15-17 At the time of recruitment, there was no systematic genetic and/or neuroimaging screening of all patients with CHD; 52
THE JOURNAL OF PEDIATRICS JULY 2002 however, children who were suspected of having DiGeorge and/or other genetic syndromes were tested. Similarly, those suspected of having brain malformations had imaging performed. Subjects identified as having genetic syndromes or brain malformations in the context of clinical care were specifically excluded. Assessments were carried out at the hospital when convenient for the families. At the time of follow-up, children were between 1 and 3 years of age (most 12-18 months). Subjects were reexamined independently by a neurologist and by an occupational therapist (OT) to determine neuromotor status. Additionally, a psychologist evaluated global development by using the Griffiths Mental Development Scale (GMDS). A cardiologist reviewed medical charts to determine children’s cardiorespiratory status at follow-up. Functional status was also assessed by using the WeeFIM (functional independence measure Uniform Data System, Buffalo, NY) and the Vineland Adaptive Behavior Scale. Functional outcomes have been reported elsewhere.18 The OT, psychologist, and neurologist were not directly involved in the medical care of the subjects. They were blinded at the time of their assessment to type of cardiac defect, operative procedures, and other pertinent medical history, as well as neurodevelopmental findings. The cardiologist conducting the chart reviews was blinded to the results of these evaluations. Assessments took 2 to 2.5 hours to complete. Growth parameters at follow-up testing and number of subsequent hospitalizations were recorded as indexes of overall health. Maternal and paternal education was also ascertained.
Testing Procedures CARDIORESPIRATORY ASSESSMENT. A pediatric cardiologist reviewed the medical chart of each subject at the time of follow-up testing. The presence of congestive heart failure, low arterial
oxygen saturation (<85), and medications in use during this time frame were documented. NEUROLOGIC EXAMINATION. A pediatric neurologist reexamined subjects. The reexamination included the measurement of head circumference and the assessment of muscle power, bulk, and tone; cranial nerves; deep tendon reflexes; activity level; and the presence of any abnormal movement patterns. The presence of motor delays or behavioral difficulties was also documented. The overall examination was scored as normal or abnormal. DEVELOPMENTAL ASSESSMENTS. An OT reevaluated motor skills, using the Peabody Developmental Motor Scales (PDMS). This test objectively evaluates gross motor and fine motor abilities in children from 0 to 7 years of age by using standardized procedures.19 The PDMS has excellent reliability and validity.19,20 Developmental Motor Quotients for each motor domain were derived, and those scoring below 78 (ie, 1.5 SD below the normative mean of 100) were considered as delayed in that motor domain (as recommended in the PDMS manual for identification of a motor delay).19 In addition, a psychologist evaluated 5 separate areas of development (locomotor skills, personal/social skills, hearing and speech, eyehand coordination, adaptive reasoning) using the GMDS.21,22 The GMDS is applicable for children 0 to 8 years of age. A quotient is obtained for each domain, with an overall general quotient as well. Normal values were recently reestablished in a sample of 665 children, with a mean of 111 and an SD of 16. With a 1.5 SD cutoff, scores below 87 were considered an indication of a delay in each domain. This assessment has very good psychometric properties.21-23
Risk Factors A number of baseline factors believed to be associated with greater risk for
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VOLUME 141, NUMBER 1 early brain injury were evaluated for their prognostic value. These risk factors were selected a priori and included (1) the presence of microcephaly at surgery, defined as a head circumference below the 2nd percentile for age/sex,24 (2) preoperative and/or acute postoperative neurodevelopmental status (normal/abnormal), (3) duration of DHCA and CPB (minutes), as increased exposure to these surgical procedures may pose greater risk for hypoxic-ischemic insult, (4) days in the intensive care unit after OHS and duration of hospitalization (days) (as an indicator of medical complications after heart surgery), (5) the type of heart surgery (corrective vs palliative), as palliative procedures may be associated with sustained and cumulative exposure to hypoxia, failure to thrive, and repeated intraoperative insults,5,25 (6) cyanotic versus acyanotic CHD, as the literature would suggest that cyanotic heart lesions are associated with a greater risk for neurodevelopmental abnormalities,26,27 low arterial oxygen saturations (PaO2 <85) before surgery, and (7) socioeconomic status (SES) (maternal/paternal education beyond high school), as this may be an important confounding variable for development.28 Risk factors at the time of follow-up testing that were correlated with outcomes were growth parameters (height/weight <2nd percentile), number of subsequent hospitalizations, persisting cyanosis, and ongoing need for medications.
Table I. Developmental scores 12 to 18 months after OHS
RESULTS
Outcomes
Group Characteristics Of 131 subjects recruited, 13 died and 20 did not undergo follow-up testing. Of 20 children who did not return, 13 lived out of town, 4 could not be reached, and 3 refused participation. The participation rate was 83% (98/118). There were no significant differences between those subjects followed up and not followed up in baseline variables (eg, preoperative and
Developmental outcomes
Mean ± SD
Range
Peabody (gross motor) Peabody (fine motor) Griffiths (locomotor) Griffiths (eye-hand coordination) Griffiths (personal-social) Griffiths (hearing and speech) Griffiths (practical reasoning) Griffiths (developmental quotient)
84.1 ± 14.7 83.1 ± 13.9 102.8 ± 17.5 98.6 ± 16.8 96.2 ± 20.2 96.2 ± 20.2 101.2 ± 20.7 100.6 ± 15.9
65–116 65–117 61–139 55–132 61–139 51–135 37–141 60–128
postoperative neurodevelopmental testing, length of CPB and DHCA, low preoperative oxygen saturations, cyanotic vs acyanotic CHD, palliative vs corrective OHS, length of hospitalizations, subsequent hospitalizations, maternal/paternal education). Not all assessments were carried out on all subjects, depending on the availability of testers at the time of evaluation. All subjects were assessed by at least one evaluator, and 70% were assessed by 2 or 3 evaluators. Of the 98 subjects assessed at follow-up, 45% had undergone OHS in the first month of life, whereas 55% had OHS in infancy. Eighty-nine percent (87) underwent corrective OHS, whereas 11% (11) required palliative heart surgery. Growth parameters at follow-up testing were ascertained, and 21% had weights and 22% had heights <2nd percentile, respectively. Fifty-two percent of fathers and 47% of mothers had post–high school education.
CARDIORESPIRATORY STATUS. Cardiorespiratory status was determined at a mean age of 20.9 ± 8.9 months. Thirteen percent were receiving medications. Twelve percent remained cyanotic and 4% had congestive heart failure. Most children (90%) were noted to have a satisfactory cardiorespiratory status by the cardiologist. NEUROLOGIC STATUS. Neurologic status was documented in 63 subjects at a
Percentage <1.5 SD 42 42 26 24 17 34 24 23
mean age of 19.1 ± 6.6 months, and 41% had an abnormal neurologic examination. Findings included muscle tone abnormalities, which consisted primarily of mild hypotonia (14), severe hypotonia (3), hypertonia (1), motor asymmetry (1), cranial nerve findings (5), decreased muscle bulk (4), decreased muscle power (4), and decreased deep tendon reflexes (4). Severe neurologic sequelae were uncommon and included blindness (1), profound hearing loss (1), spastic quadriparesis (1), and severe developmental delay (3). Behavioral difficulties were noted in 17% of subjects and included an increased activity level (eg, restlessness, decreased attention, irritability) (7), and lethargy (2). Thirty percent of children were microcephalic. MOTOR PERFORMANCE AND BEHAVIOR. Eighty-one children were assessed at a mean age of 20.1 ± 7.8 months. Gross and fine motor performance is summarized in Table I. Within the context of the motor assessment, 10 children were hypotonic, 2 were hypertonic, and 2 had motor asymmetries. Behavioral difficulties were described in 33% and included an increased activity level (15), irritability (6), a decreased activity level (eg, lethargic) (4), and oppositional behavior (1). Feeding difficulties were reported in 7 children, consisting primarily of delays in transitioning to solid foods (4) and decreased feeding efficiency (3). 53
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Table II. Predictors of ongoing neurodevelopmental deficits (univariate analyses)
1-Year outcomes (P values) Risk factors Preoperative neurodevelopment* Preoperative microcephaly* Postoperative neurodevelopment* Postoperative microcephaly* CPB† DHCA† Corrective vs palliative OHS* Cyanotic vs acyanotic CHD* Age at surgery† O2 saturation <85%* Intensive care† Length of hospitalization† Subsequent admissions† Weight† Height† Persisting cyanosis* Ongoing need for medication* Maternal education* Paternal education*
Microcephaly .0008 < .0001 .005 < .0001 NS NS NS NS NS NS NS NS NS .01 NS NS NS NS NS
Neurologic examination .01 .03 .0005 .02 NS .01 .002 NS NS NS .0005 .0002 NS .003 NS .008 NS NS NS
Peabody (GM) .03 NS .04 NS NS .01 NS NS NS NS .007 .004 .04 NS .03 .03 NS NS NS
Peabody (FM) .01 .02 .005 .02 NS < .0001 NS .005 NS NS NS .04 NS .03 .02 NS NS NS NS
Griffiths (DQ) .02 .007 NS .04 NS .01 NS .01 NS NS .01 .01 NS NS NS NS NS NS NS
NS, Nonsignificant; FM, fine motor; GM, gross motor; DQ, developmental quotient. *χ2 test. †t test.
DEVELOPMENTAL STATUS. Sixty-one children were assessed at a mean age of 20.7 ± 8.3 months. Developmental scores are provided in Table I. Clinical observations included behavioral difficulties in 20 children (35%), which included an increased level of activity/decreased attention (14), decreased activity level (4), and oppositional behaviors (2).
Risk Factors Associated with Outcomes Predictors of neurodevelopmental outcomes are summarized in Table II. Perioperative neurodevelopmental status was significantly associated with persisting neurologic abnormalities, microcephaly, gross and fine motor impairments, and developmental delays (P < .05). When the relation between acute postoperative status and subsequent outcomes was examined, postop54
erative assessments were significantly associated with the presence of microcephaly, as well as neurologic and motor performance, but not global developmental deficits. Preoperative and postoperative microcephaly at baseline was highly associated with persistent microcephaly, as well as neurologic sequelae, fine motor delays, and global developmental delays. There was a significant relation between time in the intensive care unit and length of hospitalization, with subsequent neurologic findings, gross/fine motor impairments (for hospitalization only), and global quotients on the GMDS. Lower preoperative oxygen saturation (<85%) did not increase the risk of ongoing developmental morbidity; however, persisting cyanosis at follow-up was associated with neurologic and gross motor delays. In addition, a higher number of subsequent admis-
sions was associated with gross motor delays (P < .05). Children with acyanotic CHD were more likely to have developmental delays. Children with weight <2nd percentile were much more likely to be microcephalic and have neuromotor deficits. Motor scores and developmental quotients in newborn infants were lower than in the infant cohort; however, only gross motor performance was significantly lower in newborns (P < .05). Although neurologic abnormalities and the presence of microcephaly were higher in newborns, this did not reach statistical significance (Table III). Longer duration of DHCA was significantly associated with abnormal neurologic examinations, greater gross/fine motor difficulties, and global delay (P = .01). Children who had palliative procedures were more likely
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VOLUME 141, NUMBER 1 to demonstrate persisting neurologic abnormalities. Maternal and paternal education was not associated with outcomes. Multiple logistic regression analysis demonstrated that baseline examinations (odds ratio [OR], 3.8; CI, 1.212.2), length of DHCA (OR, 1.1; CI, 1.0-1.2), and days in the intensive care unit (OR, 1.5; CI, 1.1-2.2) were strongly predictive of neurologic abnormalities (P < .01). Moreover, multivariate analyses further revealed that preoperative neurodevelopmental status (P < .01; OR, 7.0; CI, 1.5-33.1) and microcephaly (P < .001; OR, 23.6; CI, 4.3130.9) were determinants of persistent microcephaly. Simple logistic regression models identified preoperative neurodevelopmental status and the presence of microcephaly as important markers for gross/fine motor impairments. According to stepwise multiple logistic regression models, determinants of fine motor deficits included DHCA (P < .01; OR, 1.04; CI, 1.0-1.08) for each minute difference, length of stay in the intensive care unit (P < .01; OR, 1.05; CI, 1.01-1.12), preoperative neurodevelopmental status (P < .05; OR, 4.7; CI, 1.1-20.6), and acyanotic defects (P < .01; OR, 9.3; CI, 1.5-58.8). Similarly, for gross motor performance, multiple linear regression models revealed that increasing days in the intensive care unit, acyanotic defects, and increasing age at surgery were associated with gross motor delays. Multiple linear regression analyses identified the following predictor variables as determinants of global delays: oxygen saturations (<85) before surgery (P < .05) and prolonged need for DHCA (P < .01). Simple logistic regression models also supported the finding that preoperative microcephaly (P < .001; OR, 11.5; CI, 2.1-64.9) and abnormal preoperative and postoperative neurodevelopmental performance (P < .05; OR, 10.5; CI, 1.2-88.6) and palliative versus corrective OHS (P < .001; OR,
Table III. Comparison between newborn and infant cohort performance
Outcomes Presence of microcephaly Abnormal neurologic findings Peabody (gross motor)
Peabody (fine motor)
Griffiths (developmental quotient)
Newborn (<1 mo)
Infant (>1 mo)
χ2/t test (P value)
46.0 ± 1.6 cm (31%) 45% 80.5 ± 13.8 (65-111) (50%) 81.1 ± 12.0 (65-111) (45%) 99.8 ± 19.1 (60-128) (21%)
47.2 ± 2.0 cm (29%) 37% 85.2 ± 15.6 (65-117) (33%) 85.2 ± 15.6 (65-117) (38%) 101.4 ± 12.3 (75-121) (27%)
.81* .14* .02†
.19†
.70†
*χ2 test. †t test.
0.1; CI, 0.03-0.47) were important markers for subsequent global delays.
DISCUSSION Cognitive and neurologic outcomes have been the primary areas described in follow-up studies of children with CHD.7 Few studies have characterized global performance across developmental domains. The literature has consistently reported low average mean IQs or normal intelligence with a broader distribution about the mean.8,10,29,30 Mild language delays, especially in expressive skills and vocabulary, have also been documented.9,29,31 Motor difficulties have been identified in these children with estimates of 20% to 50%; however, the exact prevalence and type of motor deficits have not been adequately described. Blackwood et al31 reported that deficits in gross motor areas were common in their cohort at a mean age of 25.5 months. Bellinger et al32 described lower scores on the Bayley Scale at 12 months of age in children randomly assigned to receive a strategy of predominant circulatory arrest versus CPB. Hovels-Gurich et al10 also reported gross and fine motor dysfunction in 23.4% and 22.1%,
respectively. Long-term neurologic abnormalities described in the recent literature have predominantly included developmental delay and hypotonia.8,31,33 Severe abnormalities such as focal findings, cranial nerve abnormalities, ataxia, and abnormalities of the special senses are less prevalent (<10%).8,11 Our results also support the finding that gross and fine motor deficits are prevalent (42% for each) in children with CHD, particularly in the newborn cohort. Neurologic sequelae continue to be evident and encompass a wide spectrum of abnormalities including muscle tone changes, cranial nerve findings, and behavioral difficulties. In addition, persistent microcephaly was documented in 30% of our cohort. Moreover, 23% of our sample demonstrated global developmental delays. Language delays were prevalent, as were difficulties in eye-hand coordination, practical reasoning tasks, locomotor delays, and personal social difficulties. A higher prevalence of disruptive behaviors such as social and emotional maladjustment, increased internalizing and externalizing problems, and greater dependency have been commonly reported 11,32,34,35 Our findings suggest that behavioral problems are evident at 55
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an early age. This area deserves further attention, as some of these difficulties may be secondary and therefore amenable to interventions and anticipatory guidance by health professionals. Several studies have identified surgical and medical risk factors in this population. To date, the emphasis has been placed primarily on intraoperative procedures that enhance risk for neurodevelopmental morbidity. Specifically, a longer DHCA time has been significantly associated with modest risk for lower IQs and Bayley Psychomotor Scores, particularly when DHCA times have exceeded 50 to 60 minutes.6,29,32 A shorter duration of core cooling before DHCA (<20 minutes) correlated with lower developmental scores (r = 0.85).36 Longer exposure to deep hypothermia (>45-60 minutes), particularly during neonatal surgery, has also been linked with greater mortality rates and neurological morbidity.37 In our study, a longer DHCA time was associated with greater neuromotor deficits and global delays. Neuroimaging techniques have been evaluated as predictors of outcome37-39; however, we did not apply these techniques. Electrophysiologic studies have also been carried out,6,40 and our findings are reported elsewhere.41,42 Bloom et al2 reported that a medical risk index and complications of cardiac arrest together accounted for 8% to 18% of the variance for outcome measures of 5 different developmental domains in preschoolers. When SES and parental stress indexes were included in the analyses, these variables accounted for 25% to 61% of the variance, suggesting that both severity of illness and environmental factors contribute to the overall outcome. In our study, SES was not predictive, which was not surprising, given that our subjects were young infants in whom SES has less of an influence.43 Medical factors that augmented the risk of developmental deficits in our cohort included prolonged need for intensive care and ex56
THE JOURNAL OF PEDIATRICS JULY 2002 tended or recurrent hospitalizations, as these may be markers for a more complex medical course. Few studies have examined the preoperative neurodevelopmental status of young infants undergoing OHS with the use of standardized measures.13,14 Results from our study indicate that preoperative neurodevelopmental status is an important marker of subsequent neurologic, motor, and global developmental outcomes. Furthermore, the presence of microcephaly before and/or after surgery was also a strong predictor of outcome. The association between microcephaly and a broad spectrum of long-term deficits is well established in other high-risk populations.44,45 Our findings suggest that multiple causal pathways for microcephaly are plausible. For the newborn, the presence of microcephaly in the first days of life would suggest a congenital intrauterine origin, possibly caused by poor systemic (and cerebral) perfusion or concomitant brain malformation. For the infant, microcephaly may be acquired in association with growth failure, chronic hypoxemia, and other medical complications. Not surprisingly, evidence of poor growth on follow-up was significantly associated with microcephaly and developmental difficulties. Our findings would suggest that although severe impairments are rare, mild to moderate disabilities across domains are highly prevalent. Results from our study demonstrate that factors associated with neurodevelopmental outcomes in these young infants appear to be multifactorial and include preoperative, intraoperative, and postoperative factors. Although we excluded patients with known chromosomal anomalies or brain malformations, we cannot be certain that our cohort was entirely free of such abnormalities. Indeed, the results highlight the importance of systematic genetic and neuroimaging screening of this population. Another limitation of this study is the lack of adequate power to carry out subanalyses on individual
CHD groups. Finally, the long-term implications of these neurodevelopmental concerns in early childhood remain to be determined. Preschool assessments are now underway to address this issue. To date, emphasis of health service delivery for this population has been primarily directed toward the integrity of the heart. It has become increasingly evident that there are cumulative “hits” to the immature brain that collectively result in developmental sequelae. Interdisciplinary efforts are therefore critical to best meet the multiple resource needs of this high-risk group. We thank Dr Marie Beland and Dr Luc Jutras from the Division of Cardiology at the Montreal Children’s Hospital and Johanne Therrien for their assistance in recruitment of subjects. We acknowledge the assistance of Dr Sharon Wood-Dauphinee for the methodological aspects of this project and Dr Harder for follow-up assessments of a subset of our cohort at the Alberta Children’s Hospital. We extend special thanks to Lisa Steinbach for coordination of the project, chart reviews, and data entry and to the Biostatistical Consultation Service at the Montreal Children’s Hospital for statistical consultation. We are especially grateful to the families who participated in the study.
REFERENCES 1. Ferry PC. Neurologic sequelae of openheart surgery in children. Am J Dis Child 1987;141:309-12. 2. Bloom AA, Wright JA, Morris RD, Campbell RM, Krawiecki NS. Additive impact of in-hospital cardiac arrest on the functioning of children with heart disease. Pediatrics 1997;99:390-8. 3. Park L, Sang C, William H. The neurologic complications of congenital heart disease. Neurocardiology 1993;2: 441-62. 4. Ferry PC. Neurologic sequelae of cardiac surgery in children. Am J Dis Child 1990;144:369-73. 5. du Plessis AJ, Johnson M. Hypoxicischemic brain injury in the newborn: cellular mechanisms and potential strategies for neuroprotection. Clin Perinatol 1997;24:627-54. 6. Newburger JW, Jonas RA, Wernovski G, Wypij D, Hickey PR, Kuban CK, et al. A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus
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7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
low-flow cardio-pulmonary bypass in infant heart surgery. N Engl J Med 1993; 329:1057-64. Majnemer A, Limperopoulos C. Developmental progress of children with congenital heart defects requiring open heart surgery. Semin Pediatr Neurol 1999;6:12-9. Bellinger DC, Rappaport LA, Wypij D, Wernovsky G, Newburger JW. Patterns of developmental dysfunction after surgery during infancy to correct transposition of the great arteries. J Dev Behav Pediatr 1997; 18:75-83. Bellinger DC, Wypij D, Kuban KC, Rappaport LA, Wypij PR, Wernovsky G, et al. Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation 1999;100: 526-32. Hovels-Gurich HH, Seghaye MC, Dabritz S, Messmer BJ, von Bernuth G. Cognitive and motor development in preschool and school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg 1991;114: 578-85. O’Dougherty M, Wright FS, Garmezy N, Loewenson RB, Torres F. Later competence and adaptation in infants who survive severe heart defects. Child Dev 1983;54:1129-42. Miller G, Tesman JR, Ramer JC, Baylen BG, Myers JL. Outcome after open-heart surgery in infants and children. J Child Neurol 1996; 11:479-53. Limperopoulos C, Majnemer A, Shevell M, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurologic status of newborns with congenital heart defects prior to open heart surgery. Pediatrics 1999;103:402-8. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurodevelopmental status of newborns and infants with congenital heart defects before and after open heart surgery. J Pediatr 2000;137:638-45. Rogers BT, Msall ME, Buck GM, Lyon NR, Norris MK, Roland JM, et al. Neurodevelopmental outcome of infants with hypoplastic left heart syndrome: J Pediatr 1995;126:496-8. Hagemo P, Rasmussen M, Bryhn G, Vandvik I. Hypoplastic left heart syndrome: multiprofessional followup in the mid-term following palliative procedures. Cardiol Young 1997;7:248-53.
17. Kern JH, Hinton V, Nereo NE, Hayes CJ, Gersony WM. Early developmental outcome after the Norwood procedure for hypoplastic left heart syndrome. Pediatrics 1998;102: 1148-52. 18. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C, et al. Functional limitations in young children with congenital heart defects following cardiac surgery. Pediatrics 2001;108:1325-31. 19. Folio RM, Fewell RR. Peabody Developmental Motor Scales and Activity Cards. Allen (TX): DLM Teaching Resources; 1983. 20. Harrow AW. A taxonomy of the psychomotor domain: a guide for developing behavioral objectives. New York: David McKay Co, Inc; 1972. 21. Griffiths R. The abilities of babies. Association for Research in Infant and Child Development. Clifton Lawns, Amersham, Buckinghamshire: Eden House; 1976. 22. Hanson R. Item reliability for the Griffiths Scales of Mental Development. Child Care Health Dev 1982;8:151-61. 23. Hanson R, Aldridge Smith J. Achievement of infants on items of the Griffiths Scales: 1980 compared with 1950. Child Care Health Dev 1985;11:91-104. 24. Nellhaus G. Head circumference from birth to eighteen years: practical composite international and international graphs. Pediatrics 1986;41:106-14. 25. du Plessis AJ, Johnston MV. The pursuit of effective neuroprotection during infant cardiac surgery. Semin Pediatr Neurol 1999;6:55-63. 26. Casteneda A, Mayer J, Jonas R, Lock JE, Wessel DL, Hickey PR. The neonate with critical congenital heart disease: repair—a surgical challenge. J Thorac Cardiovasc Surg 1989;98: 869-75. 27. Mayer JE. Development, growth and cardiac surgery. Am J Dis Child 1991;145:33-4. 28. Msall ME, Bier J-A, LaGasse L, Tremont M, Lester B. The vulnerable preschool child: the impact of biomedical and social risks on neurodevelopmental function. Semin Pediatr Neurol 1998;5:52-61. 29. Oates RK, Simpson JM, Cartmill TB, Turnbull JA. Intellectual function and age of repair in transposition of the great arteries in children. N Engl J Med 1995;72:298-301. 30. Clarkson PM, MacArthur BA, BarrattBoyes BG, Whitlock RM, Neutze JM. Developmental progress after cardiac surgery in infancy using profound hy-
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
pothermia and circulatory arrest. Circulation 1980;62:855-61. Blackwood MJA, Haka-Iksa K, Steward DJ. Developmental outcome in children undergoing surgery with profound hypothermia. Anesthesiology 1986;65:437-40. Bellinger DC, Jonas RA, Rappaport LA, Wypij D, Wernovsky G, Kuban KC, et al. Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med 1995;334:549-55. Miller G, Tesman JR, Ramer JC, Baylen BG, Myers JL. Outcome after open heart surgery in infants and children. J Child Neurol 1996; 11:49-53. Goldberg S, Janus M, Washingtone J, Simmons RJ, MacLusky I, Fowler RS. Prediction of preschool behavioral problems in healthy and pediatric samples. J Dev Behav Pediatr 1997;18: 304-13. Utens EM, Versluis-Den Bieman HJ, Verhulst FC, Witsenburg M, Bogers AJ, Hess J. Psychological distress and styles of coping in parents of children awaiting elective cardiac surgery. Cardiol Young 2000;10:239-44. Bellinger DC, Wernovsky G, Rappaport LA, Mayer JE, Castaneda AR, Farrell DM. Cognitive development of children following early repair of transposition of the great arteries using deep hypothermic circulatory arrest. Pediatrics 1991;87:701-7. Miller G, Eggli KD, Contant C, Baylen BG, Myers JL. Postoperative neurologic complications after open heart surgery on young infants. Arch Pediatr Adolesc Med 1995;149:764-8. Miller G, Vogel H. Structural evidence of injury or malformation in the brains of children with congenital heart defects. Semin Pediatr Neurol 1999;6:20-6. Ashwal S, Holshouser BA, Hindshaw DB, Schell RM, Bailey L. Proton magnetic resonance spectroscopy in the evaluation of children with congenital heart disease and acute central nervous system injury. J Thorac Cardiovasc Surg 1996;112:403-14. Rosenblatt B. Monitoring the central nervous system in children with congenital heart defects: clinical neurophysiological techniques. Semin Pediatr Neurol 1999;6:27-31. Limperopoulos C, Majnemer A, Rosenblatt B, Shevell M, Rohlicek C, Tchervenkov C. Multimodality evoked 57
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potential findings in infants with congenital heart defects. J Child Neurol 1999;14:702-7. 42. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Association between electroencephalographic findings and neurologic status in infants with con-
58
THE JOURNAL OF PEDIATRICS JULY 2002 genital heart defects. J Child Neurol 2001;16:471-6. 43. Vohr BR, Msall ME. Neurophyschological and functional outcomes of VLBW infants. Semin Perinatol 1997;21:202-20. 44. Dolk H. The predictive value of microcephaly during the first year of
life for mental retardation at seven years. Dev Med Child Neurol 1991;33:267-72. 45. Lipper E, Lee K, Gartier LM, Grellong B. Determinants of neurobehavioral outcomes in low-birthweight infants. Pediatrics 1981; 67:502-5.
dramatically; however, morbidity remains a concern.1-6 There is controversy regarding the presence and persistence of neurodevelopmental se-
From the School of Physical and Occupational Therapy, Departments of Neurology and Neurosurgery, Cardiovascular and Thoracic Surgery, and Pediatrics, McGill University–Montreal Children’s Hospital, Québec; and the Division of Pediatric Neurology, Alberta Children’s Hospital, Calgary, Canada.
Supported by the National Health Research and Development Program (Health Canada), the Heart and Stroke Foundation, and March of Dimes. Submitted for publication June 28, 2001; revisions received Nov 7, 2001, and Mar 4, 2002; accepted Mar 25, 2002. Reprint requests: Annette Majnemer, PhD, OT(C), Montreal Children’s Hospital, Neurology, Room A-509, 2300 Tupper St, Montreal, Quebec H3H 1P3, Canada. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/21/125227 doi:10.1067/mpd.2002.125227
quelae in children with CHD requiring open heart surgery (OHS). Prospective studies with comprehensive neurodevelopmental assessments of survivors of OHS, as well as standardized procedures, are lacking.1,7 The available evidence in the literature would suggest that developmental problems are common in young children with CHD undergoing OHS.8-12 To date, developmental deficits have largely been attributed to surgical events and procedures without careful consideration of other possible risk factors.1,2,4,7 Few studies have ascertained whether preexisting neurologic abnormalities are evident before OHS, and no study has prospectively examined whether acute neurologic compromise in the perioperative period is an early marker for persisting CHD CPB DHCA GMDS OHS OR OT SES PDMS
Congenital heart defects Cardiopulmonary bypass Deep hypothermic circulatory arrest Griffiths Mental Development Scale Open heart surgery Odds ratio Occupational therapist Socioeconomic status Peabody Developmental Motor Scales
developmental disability. It is important to identify markers of brain injury so that children at high risk for neurodevelopmental sequelae may be targeted for early intervention, to minimize disability. Therefore, the primary objective of this study was to determine the prevalence of persisting neurodevelopmental disabilities in young children with CHD. A secondary objective was 51
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to evaluate whether aspects of the perioperative clinical examinations, indicators of acute or persistent cardiorespiratory compromise, intraoperative procedures, and environmental factors were associated with a greater likelihood for developmental disability.
METHODS In this prospective study, a consecutive series of children with a CHD who were admitted to the Montreal Children’s Hospital for OHS requiring cardiopulmonary bypass (CPB) with or without deep hypothermic circulatory arrest (DHCA) that met our inclusion criteria were recruited. This project was approved by the scientific and ethics review board at our institution. Informed consent was obtained from the families before enrollment into the study (96% participation rate). Neurodevelopmental assessments administered before surgery and acute postoperative assessments just before hospital discharge have been previously reported.13,14 This study examined the neurodevelopmental outcome of this cohort 12 months to 18 months after OHS. A range of outcome measures was used to ascertain the magnitude of persistent developmental impairments and disabilities in neurologic, motor, developmental, and functional domains after heart surgery. Inclusion/exclusion criteria have been reported in detail previously.14 Subjects included term infants with a diagnosis of a CHD undergoing their first corrective or palliative OHS before 2 years of age, with no clinical evidence of a disorder or impairment of the central nervous system due to causes other than complications of the heart defect at the time of admission for heart surgery. Children with hypoplastic left heart syndrome were specifically excluded because the literature suggests a higher prevalence of neurologic morbidity.15-17 At the time of recruitment, there was no systematic genetic and/or neuroimaging screening of all patients with CHD; 52
THE JOURNAL OF PEDIATRICS JULY 2002 however, children who were suspected of having DiGeorge and/or other genetic syndromes were tested. Similarly, those suspected of having brain malformations had imaging performed. Subjects identified as having genetic syndromes or brain malformations in the context of clinical care were specifically excluded. Assessments were carried out at the hospital when convenient for the families. At the time of follow-up, children were between 1 and 3 years of age (most 12-18 months). Subjects were reexamined independently by a neurologist and by an occupational therapist (OT) to determine neuromotor status. Additionally, a psychologist evaluated global development by using the Griffiths Mental Development Scale (GMDS). A cardiologist reviewed medical charts to determine children’s cardiorespiratory status at follow-up. Functional status was also assessed by using the WeeFIM (functional independence measure Uniform Data System, Buffalo, NY) and the Vineland Adaptive Behavior Scale. Functional outcomes have been reported elsewhere.18 The OT, psychologist, and neurologist were not directly involved in the medical care of the subjects. They were blinded at the time of their assessment to type of cardiac defect, operative procedures, and other pertinent medical history, as well as neurodevelopmental findings. The cardiologist conducting the chart reviews was blinded to the results of these evaluations. Assessments took 2 to 2.5 hours to complete. Growth parameters at follow-up testing and number of subsequent hospitalizations were recorded as indexes of overall health. Maternal and paternal education was also ascertained.
Testing Procedures CARDIORESPIRATORY ASSESSMENT. A pediatric cardiologist reviewed the medical chart of each subject at the time of follow-up testing. The presence of congestive heart failure, low arterial
oxygen saturation (<85), and medications in use during this time frame were documented. NEUROLOGIC EXAMINATION. A pediatric neurologist reexamined subjects. The reexamination included the measurement of head circumference and the assessment of muscle power, bulk, and tone; cranial nerves; deep tendon reflexes; activity level; and the presence of any abnormal movement patterns. The presence of motor delays or behavioral difficulties was also documented. The overall examination was scored as normal or abnormal. DEVELOPMENTAL ASSESSMENTS. An OT reevaluated motor skills, using the Peabody Developmental Motor Scales (PDMS). This test objectively evaluates gross motor and fine motor abilities in children from 0 to 7 years of age by using standardized procedures.19 The PDMS has excellent reliability and validity.19,20 Developmental Motor Quotients for each motor domain were derived, and those scoring below 78 (ie, 1.5 SD below the normative mean of 100) were considered as delayed in that motor domain (as recommended in the PDMS manual for identification of a motor delay).19 In addition, a psychologist evaluated 5 separate areas of development (locomotor skills, personal/social skills, hearing and speech, eyehand coordination, adaptive reasoning) using the GMDS.21,22 The GMDS is applicable for children 0 to 8 years of age. A quotient is obtained for each domain, with an overall general quotient as well. Normal values were recently reestablished in a sample of 665 children, with a mean of 111 and an SD of 16. With a 1.5 SD cutoff, scores below 87 were considered an indication of a delay in each domain. This assessment has very good psychometric properties.21-23
Risk Factors A number of baseline factors believed to be associated with greater risk for
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VOLUME 141, NUMBER 1 early brain injury were evaluated for their prognostic value. These risk factors were selected a priori and included (1) the presence of microcephaly at surgery, defined as a head circumference below the 2nd percentile for age/sex,24 (2) preoperative and/or acute postoperative neurodevelopmental status (normal/abnormal), (3) duration of DHCA and CPB (minutes), as increased exposure to these surgical procedures may pose greater risk for hypoxic-ischemic insult, (4) days in the intensive care unit after OHS and duration of hospitalization (days) (as an indicator of medical complications after heart surgery), (5) the type of heart surgery (corrective vs palliative), as palliative procedures may be associated with sustained and cumulative exposure to hypoxia, failure to thrive, and repeated intraoperative insults,5,25 (6) cyanotic versus acyanotic CHD, as the literature would suggest that cyanotic heart lesions are associated with a greater risk for neurodevelopmental abnormalities,26,27 low arterial oxygen saturations (PaO2 <85) before surgery, and (7) socioeconomic status (SES) (maternal/paternal education beyond high school), as this may be an important confounding variable for development.28 Risk factors at the time of follow-up testing that were correlated with outcomes were growth parameters (height/weight <2nd percentile), number of subsequent hospitalizations, persisting cyanosis, and ongoing need for medications.
Table I. Developmental scores 12 to 18 months after OHS
RESULTS
Outcomes
Group Characteristics Of 131 subjects recruited, 13 died and 20 did not undergo follow-up testing. Of 20 children who did not return, 13 lived out of town, 4 could not be reached, and 3 refused participation. The participation rate was 83% (98/118). There were no significant differences between those subjects followed up and not followed up in baseline variables (eg, preoperative and
Developmental outcomes
Mean ± SD
Range
Peabody (gross motor) Peabody (fine motor) Griffiths (locomotor) Griffiths (eye-hand coordination) Griffiths (personal-social) Griffiths (hearing and speech) Griffiths (practical reasoning) Griffiths (developmental quotient)
84.1 ± 14.7 83.1 ± 13.9 102.8 ± 17.5 98.6 ± 16.8 96.2 ± 20.2 96.2 ± 20.2 101.2 ± 20.7 100.6 ± 15.9
65–116 65–117 61–139 55–132 61–139 51–135 37–141 60–128
postoperative neurodevelopmental testing, length of CPB and DHCA, low preoperative oxygen saturations, cyanotic vs acyanotic CHD, palliative vs corrective OHS, length of hospitalizations, subsequent hospitalizations, maternal/paternal education). Not all assessments were carried out on all subjects, depending on the availability of testers at the time of evaluation. All subjects were assessed by at least one evaluator, and 70% were assessed by 2 or 3 evaluators. Of the 98 subjects assessed at follow-up, 45% had undergone OHS in the first month of life, whereas 55% had OHS in infancy. Eighty-nine percent (87) underwent corrective OHS, whereas 11% (11) required palliative heart surgery. Growth parameters at follow-up testing were ascertained, and 21% had weights and 22% had heights <2nd percentile, respectively. Fifty-two percent of fathers and 47% of mothers had post–high school education.
CARDIORESPIRATORY STATUS. Cardiorespiratory status was determined at a mean age of 20.9 ± 8.9 months. Thirteen percent were receiving medications. Twelve percent remained cyanotic and 4% had congestive heart failure. Most children (90%) were noted to have a satisfactory cardiorespiratory status by the cardiologist. NEUROLOGIC STATUS. Neurologic status was documented in 63 subjects at a
Percentage <1.5 SD 42 42 26 24 17 34 24 23
mean age of 19.1 ± 6.6 months, and 41% had an abnormal neurologic examination. Findings included muscle tone abnormalities, which consisted primarily of mild hypotonia (14), severe hypotonia (3), hypertonia (1), motor asymmetry (1), cranial nerve findings (5), decreased muscle bulk (4), decreased muscle power (4), and decreased deep tendon reflexes (4). Severe neurologic sequelae were uncommon and included blindness (1), profound hearing loss (1), spastic quadriparesis (1), and severe developmental delay (3). Behavioral difficulties were noted in 17% of subjects and included an increased activity level (eg, restlessness, decreased attention, irritability) (7), and lethargy (2). Thirty percent of children were microcephalic. MOTOR PERFORMANCE AND BEHAVIOR. Eighty-one children were assessed at a mean age of 20.1 ± 7.8 months. Gross and fine motor performance is summarized in Table I. Within the context of the motor assessment, 10 children were hypotonic, 2 were hypertonic, and 2 had motor asymmetries. Behavioral difficulties were described in 33% and included an increased activity level (15), irritability (6), a decreased activity level (eg, lethargic) (4), and oppositional behavior (1). Feeding difficulties were reported in 7 children, consisting primarily of delays in transitioning to solid foods (4) and decreased feeding efficiency (3). 53
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Table II. Predictors of ongoing neurodevelopmental deficits (univariate analyses)
1-Year outcomes (P values) Risk factors Preoperative neurodevelopment* Preoperative microcephaly* Postoperative neurodevelopment* Postoperative microcephaly* CPB† DHCA† Corrective vs palliative OHS* Cyanotic vs acyanotic CHD* Age at surgery† O2 saturation <85%* Intensive care† Length of hospitalization† Subsequent admissions† Weight† Height† Persisting cyanosis* Ongoing need for medication* Maternal education* Paternal education*
Microcephaly .0008 < .0001 .005 < .0001 NS NS NS NS NS NS NS NS NS .01 NS NS NS NS NS
Neurologic examination .01 .03 .0005 .02 NS .01 .002 NS NS NS .0005 .0002 NS .003 NS .008 NS NS NS
Peabody (GM) .03 NS .04 NS NS .01 NS NS NS NS .007 .004 .04 NS .03 .03 NS NS NS
Peabody (FM) .01 .02 .005 .02 NS < .0001 NS .005 NS NS NS .04 NS .03 .02 NS NS NS NS
Griffiths (DQ) .02 .007 NS .04 NS .01 NS .01 NS NS .01 .01 NS NS NS NS NS NS NS
NS, Nonsignificant; FM, fine motor; GM, gross motor; DQ, developmental quotient. *χ2 test. †t test.
DEVELOPMENTAL STATUS. Sixty-one children were assessed at a mean age of 20.7 ± 8.3 months. Developmental scores are provided in Table I. Clinical observations included behavioral difficulties in 20 children (35%), which included an increased level of activity/decreased attention (14), decreased activity level (4), and oppositional behaviors (2).
Risk Factors Associated with Outcomes Predictors of neurodevelopmental outcomes are summarized in Table II. Perioperative neurodevelopmental status was significantly associated with persisting neurologic abnormalities, microcephaly, gross and fine motor impairments, and developmental delays (P < .05). When the relation between acute postoperative status and subsequent outcomes was examined, postop54
erative assessments were significantly associated with the presence of microcephaly, as well as neurologic and motor performance, but not global developmental deficits. Preoperative and postoperative microcephaly at baseline was highly associated with persistent microcephaly, as well as neurologic sequelae, fine motor delays, and global developmental delays. There was a significant relation between time in the intensive care unit and length of hospitalization, with subsequent neurologic findings, gross/fine motor impairments (for hospitalization only), and global quotients on the GMDS. Lower preoperative oxygen saturation (<85%) did not increase the risk of ongoing developmental morbidity; however, persisting cyanosis at follow-up was associated with neurologic and gross motor delays. In addition, a higher number of subsequent admis-
sions was associated with gross motor delays (P < .05). Children with acyanotic CHD were more likely to have developmental delays. Children with weight <2nd percentile were much more likely to be microcephalic and have neuromotor deficits. Motor scores and developmental quotients in newborn infants were lower than in the infant cohort; however, only gross motor performance was significantly lower in newborns (P < .05). Although neurologic abnormalities and the presence of microcephaly were higher in newborns, this did not reach statistical significance (Table III). Longer duration of DHCA was significantly associated with abnormal neurologic examinations, greater gross/fine motor difficulties, and global delay (P = .01). Children who had palliative procedures were more likely
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VOLUME 141, NUMBER 1 to demonstrate persisting neurologic abnormalities. Maternal and paternal education was not associated with outcomes. Multiple logistic regression analysis demonstrated that baseline examinations (odds ratio [OR], 3.8; CI, 1.212.2), length of DHCA (OR, 1.1; CI, 1.0-1.2), and days in the intensive care unit (OR, 1.5; CI, 1.1-2.2) were strongly predictive of neurologic abnormalities (P < .01). Moreover, multivariate analyses further revealed that preoperative neurodevelopmental status (P < .01; OR, 7.0; CI, 1.5-33.1) and microcephaly (P < .001; OR, 23.6; CI, 4.3130.9) were determinants of persistent microcephaly. Simple logistic regression models identified preoperative neurodevelopmental status and the presence of microcephaly as important markers for gross/fine motor impairments. According to stepwise multiple logistic regression models, determinants of fine motor deficits included DHCA (P < .01; OR, 1.04; CI, 1.0-1.08) for each minute difference, length of stay in the intensive care unit (P < .01; OR, 1.05; CI, 1.01-1.12), preoperative neurodevelopmental status (P < .05; OR, 4.7; CI, 1.1-20.6), and acyanotic defects (P < .01; OR, 9.3; CI, 1.5-58.8). Similarly, for gross motor performance, multiple linear regression models revealed that increasing days in the intensive care unit, acyanotic defects, and increasing age at surgery were associated with gross motor delays. Multiple linear regression analyses identified the following predictor variables as determinants of global delays: oxygen saturations (<85) before surgery (P < .05) and prolonged need for DHCA (P < .01). Simple logistic regression models also supported the finding that preoperative microcephaly (P < .001; OR, 11.5; CI, 2.1-64.9) and abnormal preoperative and postoperative neurodevelopmental performance (P < .05; OR, 10.5; CI, 1.2-88.6) and palliative versus corrective OHS (P < .001; OR,
Table III. Comparison between newborn and infant cohort performance
Outcomes Presence of microcephaly Abnormal neurologic findings Peabody (gross motor)
Peabody (fine motor)
Griffiths (developmental quotient)
Newborn (<1 mo)
Infant (>1 mo)
χ2/t test (P value)
46.0 ± 1.6 cm (31%) 45% 80.5 ± 13.8 (65-111) (50%) 81.1 ± 12.0 (65-111) (45%) 99.8 ± 19.1 (60-128) (21%)
47.2 ± 2.0 cm (29%) 37% 85.2 ± 15.6 (65-117) (33%) 85.2 ± 15.6 (65-117) (38%) 101.4 ± 12.3 (75-121) (27%)
.81* .14* .02†
.19†
.70†
*χ2 test. †t test.
0.1; CI, 0.03-0.47) were important markers for subsequent global delays.
DISCUSSION Cognitive and neurologic outcomes have been the primary areas described in follow-up studies of children with CHD.7 Few studies have characterized global performance across developmental domains. The literature has consistently reported low average mean IQs or normal intelligence with a broader distribution about the mean.8,10,29,30 Mild language delays, especially in expressive skills and vocabulary, have also been documented.9,29,31 Motor difficulties have been identified in these children with estimates of 20% to 50%; however, the exact prevalence and type of motor deficits have not been adequately described. Blackwood et al31 reported that deficits in gross motor areas were common in their cohort at a mean age of 25.5 months. Bellinger et al32 described lower scores on the Bayley Scale at 12 months of age in children randomly assigned to receive a strategy of predominant circulatory arrest versus CPB. Hovels-Gurich et al10 also reported gross and fine motor dysfunction in 23.4% and 22.1%,
respectively. Long-term neurologic abnormalities described in the recent literature have predominantly included developmental delay and hypotonia.8,31,33 Severe abnormalities such as focal findings, cranial nerve abnormalities, ataxia, and abnormalities of the special senses are less prevalent (<10%).8,11 Our results also support the finding that gross and fine motor deficits are prevalent (42% for each) in children with CHD, particularly in the newborn cohort. Neurologic sequelae continue to be evident and encompass a wide spectrum of abnormalities including muscle tone changes, cranial nerve findings, and behavioral difficulties. In addition, persistent microcephaly was documented in 30% of our cohort. Moreover, 23% of our sample demonstrated global developmental delays. Language delays were prevalent, as were difficulties in eye-hand coordination, practical reasoning tasks, locomotor delays, and personal social difficulties. A higher prevalence of disruptive behaviors such as social and emotional maladjustment, increased internalizing and externalizing problems, and greater dependency have been commonly reported 11,32,34,35 Our findings suggest that behavioral problems are evident at 55
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an early age. This area deserves further attention, as some of these difficulties may be secondary and therefore amenable to interventions and anticipatory guidance by health professionals. Several studies have identified surgical and medical risk factors in this population. To date, the emphasis has been placed primarily on intraoperative procedures that enhance risk for neurodevelopmental morbidity. Specifically, a longer DHCA time has been significantly associated with modest risk for lower IQs and Bayley Psychomotor Scores, particularly when DHCA times have exceeded 50 to 60 minutes.6,29,32 A shorter duration of core cooling before DHCA (<20 minutes) correlated with lower developmental scores (r = 0.85).36 Longer exposure to deep hypothermia (>45-60 minutes), particularly during neonatal surgery, has also been linked with greater mortality rates and neurological morbidity.37 In our study, a longer DHCA time was associated with greater neuromotor deficits and global delays. Neuroimaging techniques have been evaluated as predictors of outcome37-39; however, we did not apply these techniques. Electrophysiologic studies have also been carried out,6,40 and our findings are reported elsewhere.41,42 Bloom et al2 reported that a medical risk index and complications of cardiac arrest together accounted for 8% to 18% of the variance for outcome measures of 5 different developmental domains in preschoolers. When SES and parental stress indexes were included in the analyses, these variables accounted for 25% to 61% of the variance, suggesting that both severity of illness and environmental factors contribute to the overall outcome. In our study, SES was not predictive, which was not surprising, given that our subjects were young infants in whom SES has less of an influence.43 Medical factors that augmented the risk of developmental deficits in our cohort included prolonged need for intensive care and ex56
THE JOURNAL OF PEDIATRICS JULY 2002 tended or recurrent hospitalizations, as these may be markers for a more complex medical course. Few studies have examined the preoperative neurodevelopmental status of young infants undergoing OHS with the use of standardized measures.13,14 Results from our study indicate that preoperative neurodevelopmental status is an important marker of subsequent neurologic, motor, and global developmental outcomes. Furthermore, the presence of microcephaly before and/or after surgery was also a strong predictor of outcome. The association between microcephaly and a broad spectrum of long-term deficits is well established in other high-risk populations.44,45 Our findings suggest that multiple causal pathways for microcephaly are plausible. For the newborn, the presence of microcephaly in the first days of life would suggest a congenital intrauterine origin, possibly caused by poor systemic (and cerebral) perfusion or concomitant brain malformation. For the infant, microcephaly may be acquired in association with growth failure, chronic hypoxemia, and other medical complications. Not surprisingly, evidence of poor growth on follow-up was significantly associated with microcephaly and developmental difficulties. Our findings would suggest that although severe impairments are rare, mild to moderate disabilities across domains are highly prevalent. Results from our study demonstrate that factors associated with neurodevelopmental outcomes in these young infants appear to be multifactorial and include preoperative, intraoperative, and postoperative factors. Although we excluded patients with known chromosomal anomalies or brain malformations, we cannot be certain that our cohort was entirely free of such abnormalities. Indeed, the results highlight the importance of systematic genetic and neuroimaging screening of this population. Another limitation of this study is the lack of adequate power to carry out subanalyses on individual
CHD groups. Finally, the long-term implications of these neurodevelopmental concerns in early childhood remain to be determined. Preschool assessments are now underway to address this issue. To date, emphasis of health service delivery for this population has been primarily directed toward the integrity of the heart. It has become increasingly evident that there are cumulative “hits” to the immature brain that collectively result in developmental sequelae. Interdisciplinary efforts are therefore critical to best meet the multiple resource needs of this high-risk group. We thank Dr Marie Beland and Dr Luc Jutras from the Division of Cardiology at the Montreal Children’s Hospital and Johanne Therrien for their assistance in recruitment of subjects. We acknowledge the assistance of Dr Sharon Wood-Dauphinee for the methodological aspects of this project and Dr Harder for follow-up assessments of a subset of our cohort at the Alberta Children’s Hospital. We extend special thanks to Lisa Steinbach for coordination of the project, chart reviews, and data entry and to the Biostatistical Consultation Service at the Montreal Children’s Hospital for statistical consultation. We are especially grateful to the families who participated in the study.
REFERENCES 1. Ferry PC. Neurologic sequelae of openheart surgery in children. Am J Dis Child 1987;141:309-12. 2. Bloom AA, Wright JA, Morris RD, Campbell RM, Krawiecki NS. Additive impact of in-hospital cardiac arrest on the functioning of children with heart disease. Pediatrics 1997;99:390-8. 3. Park L, Sang C, William H. The neurologic complications of congenital heart disease. Neurocardiology 1993;2: 441-62. 4. Ferry PC. Neurologic sequelae of cardiac surgery in children. Am J Dis Child 1990;144:369-73. 5. du Plessis AJ, Johnson M. Hypoxicischemic brain injury in the newborn: cellular mechanisms and potential strategies for neuroprotection. Clin Perinatol 1997;24:627-54. 6. Newburger JW, Jonas RA, Wernovski G, Wypij D, Hickey PR, Kuban CK, et al. A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus
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7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
low-flow cardio-pulmonary bypass in infant heart surgery. N Engl J Med 1993; 329:1057-64. Majnemer A, Limperopoulos C. Developmental progress of children with congenital heart defects requiring open heart surgery. Semin Pediatr Neurol 1999;6:12-9. Bellinger DC, Rappaport LA, Wypij D, Wernovsky G, Newburger JW. Patterns of developmental dysfunction after surgery during infancy to correct transposition of the great arteries. J Dev Behav Pediatr 1997; 18:75-83. Bellinger DC, Wypij D, Kuban KC, Rappaport LA, Wypij PR, Wernovsky G, et al. Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation 1999;100: 526-32. Hovels-Gurich HH, Seghaye MC, Dabritz S, Messmer BJ, von Bernuth G. Cognitive and motor development in preschool and school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg 1991;114: 578-85. O’Dougherty M, Wright FS, Garmezy N, Loewenson RB, Torres F. Later competence and adaptation in infants who survive severe heart defects. Child Dev 1983;54:1129-42. Miller G, Tesman JR, Ramer JC, Baylen BG, Myers JL. Outcome after open-heart surgery in infants and children. J Child Neurol 1996; 11:479-53. Limperopoulos C, Majnemer A, Shevell M, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurologic status of newborns with congenital heart defects prior to open heart surgery. Pediatrics 1999;103:402-8. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurodevelopmental status of newborns and infants with congenital heart defects before and after open heart surgery. J Pediatr 2000;137:638-45. Rogers BT, Msall ME, Buck GM, Lyon NR, Norris MK, Roland JM, et al. Neurodevelopmental outcome of infants with hypoplastic left heart syndrome: J Pediatr 1995;126:496-8. Hagemo P, Rasmussen M, Bryhn G, Vandvik I. Hypoplastic left heart syndrome: multiprofessional followup in the mid-term following palliative procedures. Cardiol Young 1997;7:248-53.
17. Kern JH, Hinton V, Nereo NE, Hayes CJ, Gersony WM. Early developmental outcome after the Norwood procedure for hypoplastic left heart syndrome. Pediatrics 1998;102: 1148-52. 18. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C, et al. Functional limitations in young children with congenital heart defects following cardiac surgery. Pediatrics 2001;108:1325-31. 19. Folio RM, Fewell RR. Peabody Developmental Motor Scales and Activity Cards. Allen (TX): DLM Teaching Resources; 1983. 20. Harrow AW. A taxonomy of the psychomotor domain: a guide for developing behavioral objectives. New York: David McKay Co, Inc; 1972. 21. Griffiths R. The abilities of babies. Association for Research in Infant and Child Development. Clifton Lawns, Amersham, Buckinghamshire: Eden House; 1976. 22. Hanson R. Item reliability for the Griffiths Scales of Mental Development. Child Care Health Dev 1982;8:151-61. 23. Hanson R, Aldridge Smith J. Achievement of infants on items of the Griffiths Scales: 1980 compared with 1950. Child Care Health Dev 1985;11:91-104. 24. Nellhaus G. Head circumference from birth to eighteen years: practical composite international and international graphs. Pediatrics 1986;41:106-14. 25. du Plessis AJ, Johnston MV. The pursuit of effective neuroprotection during infant cardiac surgery. Semin Pediatr Neurol 1999;6:55-63. 26. Casteneda A, Mayer J, Jonas R, Lock JE, Wessel DL, Hickey PR. The neonate with critical congenital heart disease: repair—a surgical challenge. J Thorac Cardiovasc Surg 1989;98: 869-75. 27. Mayer JE. Development, growth and cardiac surgery. Am J Dis Child 1991;145:33-4. 28. Msall ME, Bier J-A, LaGasse L, Tremont M, Lester B. The vulnerable preschool child: the impact of biomedical and social risks on neurodevelopmental function. Semin Pediatr Neurol 1998;5:52-61. 29. Oates RK, Simpson JM, Cartmill TB, Turnbull JA. Intellectual function and age of repair in transposition of the great arteries in children. N Engl J Med 1995;72:298-301. 30. Clarkson PM, MacArthur BA, BarrattBoyes BG, Whitlock RM, Neutze JM. Developmental progress after cardiac surgery in infancy using profound hy-
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
pothermia and circulatory arrest. Circulation 1980;62:855-61. Blackwood MJA, Haka-Iksa K, Steward DJ. Developmental outcome in children undergoing surgery with profound hypothermia. Anesthesiology 1986;65:437-40. Bellinger DC, Jonas RA, Rappaport LA, Wypij D, Wernovsky G, Kuban KC, et al. Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med 1995;334:549-55. Miller G, Tesman JR, Ramer JC, Baylen BG, Myers JL. Outcome after open heart surgery in infants and children. J Child Neurol 1996; 11:49-53. Goldberg S, Janus M, Washingtone J, Simmons RJ, MacLusky I, Fowler RS. Prediction of preschool behavioral problems in healthy and pediatric samples. J Dev Behav Pediatr 1997;18: 304-13. Utens EM, Versluis-Den Bieman HJ, Verhulst FC, Witsenburg M, Bogers AJ, Hess J. Psychological distress and styles of coping in parents of children awaiting elective cardiac surgery. Cardiol Young 2000;10:239-44. Bellinger DC, Wernovsky G, Rappaport LA, Mayer JE, Castaneda AR, Farrell DM. Cognitive development of children following early repair of transposition of the great arteries using deep hypothermic circulatory arrest. Pediatrics 1991;87:701-7. Miller G, Eggli KD, Contant C, Baylen BG, Myers JL. Postoperative neurologic complications after open heart surgery on young infants. Arch Pediatr Adolesc Med 1995;149:764-8. Miller G, Vogel H. Structural evidence of injury or malformation in the brains of children with congenital heart defects. Semin Pediatr Neurol 1999;6:20-6. Ashwal S, Holshouser BA, Hindshaw DB, Schell RM, Bailey L. Proton magnetic resonance spectroscopy in the evaluation of children with congenital heart disease and acute central nervous system injury. J Thorac Cardiovasc Surg 1996;112:403-14. Rosenblatt B. Monitoring the central nervous system in children with congenital heart defects: clinical neurophysiological techniques. Semin Pediatr Neurol 1999;6:27-31. Limperopoulos C, Majnemer A, Rosenblatt B, Shevell M, Rohlicek C, Tchervenkov C. Multimodality evoked 57
LIMPEROPOULOS ET AL
potential findings in infants with congenital heart defects. J Child Neurol 1999;14:702-7. 42. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Association between electroencephalographic findings and neurologic status in infants with con-
58
THE JOURNAL OF PEDIATRICS JULY 2002 genital heart defects. J Child Neurol 2001;16:471-6. 43. Vohr BR, Msall ME. Neurophyschological and functional outcomes of VLBW infants. Semin Perinatol 1997;21:202-20. 44. Dolk H. The predictive value of microcephaly during the first year of
life for mental retardation at seven years. Dev Med Child Neurol 1991;33:267-72. 45. Lipper E, Lee K, Gartier LM, Grellong B. Determinants of neurobehavioral outcomes in low-birthweight infants. Pediatrics 1981; 67:502-5.