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To determine the relative contribution of clinical data versus head ultrasound (HUS) in predicting neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.
2103 ELBW infants (<1000g) admitted to a National Institute of Child Health and Human Development Neonatal Research Network center who had a HUS within the first 28 days, a repeat one around 36 weeks’ post-menstrual age, and neurodevelopmental assessment at 18–22 months corrected age were selected. Multivariate logistic regression models were developed using clinical and/or HUS variables. The primary outcome was the predictive abilities of the HUS done before 28 days after birth and closer to 36 weeks post-menstrual age, either alone or in combination with “Early” and “Late” clinical variables.
Models using clinical variables alone predicted NDI better than models with only HUS variables at both 28 days and 36 weeks (both p < 0.001), and addition of the HUS data did not improve prediction. NDI was absent in 30% and 28% of the infants with grade IV intracranial hemorrhage or periventricular leukomalacia, respectively, but was present in 39% of the infants with a normal head ultrasound.
Clinical models were better than head ultrasound models in predicting neurodevelopment.
Advances in perinatal care have increased survival of extremely low birth weight (ELBW) infants (< 1000 grams).1,2 However, improvements in survival have not led to better neurodevelopmental outcomes.3,4 Many ELBW infants who survive develop major physical or behavioral disabilities such as severe neurological impairment, cerebral palsy, deafness, or blindness.4–6 In addition to these neurodevelopmental disabilities, survivors are at high risk for learning difficulties leading to school failure, stressed families, and increased health care costs.7–11
Clinicians have attempted to predict neurodevelopmental impairment using many perinatal risk factors such as gestational age, race, maternal socioeconomic status, antenatal steroid use, mode of delivery, low Apgar scores, birth weight, severe intracranial hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, nosocomial sepsis, and necrotizing enterocolitis. 4,12–15 Decisions to limit therapeutic interventions to avoid futile therapy and postponement of death are often based on a prediction of mortality and neurodevelopmental impairment. Identification of abnormal head ultrasound findings such as severe intracranial hemorrhage (grades III or IV) and periventricular leukomalacia are generally considered strong predictors of handicap 4,14,16 and mortality.17,18 However, the variance in neurodevelopmental impairment explained by severe intracranial hemorrhage/periventricular leukomalacia has been generally low in these studies − 8% for a low mental developmental index (<70 or below 2 Standard Deviations of the mean) at 2 years of age 14 and 5–7% for cognitive, language, and achievement performance at 8 years of age.19 The existing literature on the predictive ability of head ultrasound for neurodevelopmental outcome consists mostly of studies from single centers with small numbers of patients. Identification of severe intracranial hemorrhage (grades III or IV) and periventricular leukomalacia may occur early in the first few hours after birth or later in the clinical course,20 with progression or resolution commonly observed. 16,21–23
Despite the uncertainty regarding the prediction of neurodevelopmental outcome, decisions to withdraw or withhold life-saving support are frequently based, at least in large part, on neurosonographic findings.17,18,24–26 Therefore, this study was designed to compare clinical variables and head ultrasound data in the prediction of neurodevelopmental impairment at 18–22 months corrected age.
This study analyzed data from a retrospective cohort of all ELBWinfants (401–1000 g) who were admitted (both inborn and outborn) to any of the 19 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network from January 1, 1998 to June 30, 2001. Infants were included if they had at least two head ultrasounds, one within 28 days after birth and a later ultrasound close to 36 weeks postmenstrual age, as well as follow-up assessment at 18–22 months corrected age. Exclusion criteria were lethal congenital malformations and chromosomal abnormalities. Data were routinely collected by trained research personnel and entered into a database as previously described.4 Data collection was approved by the institutional review board at each of the participating institutions.
A comprehensive assessment was performed at 18–22 months corrected age. This assessment consisted of medical history, physical and neurologic examinations, and developmental assessment. The neurologic assessment (including muscle tone, strength, reflexes, angle, and posture) was performed using the Amiel-Tison method.27 Cerebral palsy was defined as a non-progressive central nervous system disorder characterized by abnormal muscle tone in at least one extremity and abnormal control of movement and posture. The developmental assessment consisted of the Bayley Scales of Infant Development II, 28 which included the mental and psychomotor developmental indices. Hearing impairment was defined as the use of hearing aids. Visual impairment was defined as blind with some functional vision or no useful vision. Neurodevelopmental impairment was defined as the infant having one or more of the following: psychomotor developmental index <70, mental developmental index <70, cerebral palsy, and hearing or visual impairment. Functional status was assessed by the presence or absence of independent walking and independent feeding.
According to the standardized Neonatal Research Network data collection procedures, early head ultrasound (HUS-28) was the most abnormal head ultrasound obtained within the first 28 days after birth, and head ultrasound closer to 36 weeks (HUS-36) was the head ultrasound obtained after day 28 and closest to 36 weeks post-menstrual age. HUS-28 data were classified as: normal, blood/echodensity in germinal matrix/subependymal area (grade I), blood/echodensity in the ventricles (grade II), ventricular size enlarged (grade III), blood/echodensity in the parenchyma (grade IV), cystic area in the parenchyma (if a previous grade IV hemorrhage was documented previously), and/or periventricular leukomalacia (cystic area in the parenchyma was also considered periventricular leukomalacia if no grade IV was documented previously) by trained research nurses based on local radiology reports. HUS-36 data were classified as: normal, ventricular size enlarged, cystic area in the parenchyma (if a grade IV was documented previously), cystic periventricular leukomalacia, porencephalic cyst, and/or shunt. Data on size or location of the lesions were not collected. Central readers were not used. The specific frequency and timing of the head ultrasounds was based on clinical status and local protocols at each Network center.
The variables analyzed were those that have been reported as associated with poor neurodevelopmental outcome by other investigators. Clinical variables were grouped as “Early” if they could be assessed by postnatal day 28. These included maternal education, antenatal steroids, antenatal antibiotics, mode of delivery, outborn, male, race, gestational age, 1 minute Apgar score <3, 5 minute Apgar score <3, 5 minute Apgar score 3–6, intubation at delivery, medications for resuscitation, birth weight (in 100 gram increments), intrauterine infection, breech presentation, surfactant, indomethacin <24 hours, indomethacin for patent ductus arteriosus treatment, early sepsis (culture positive), late onset sepsis (culture positive), proven necrotizing enterocolitis (≥ Bell Stage II), seizures, pneumothorax, conventional ventilation, and high frequency ventilation. Clinical variables were grouped as “All” if they could be assessed before discharge home, death, and at 120 days, and included the “Early” clinical variables as well as supplemental O2 at 36 weeks postmenstrual age, steroids for bronchopulmonary dysplasia, and threshold retinopathy of prematurity. Head ultrasound variables were grouped as early (HUS-28) or late (HUS-36) depending on ultrasound timing.
The data were randomly divided into a development set of 70% of the population (n=1472) and a validation set of 30% (n=631). Stepwise variable selection was performed on the development set to obtain clinical and/or sonographic variables significantly associated with neurodevelopmental impairment, at p = 0.1 for the entry and exit criteria. For the combined head ultrasound/clinical models, the head ultrasound variables were forced to remain in the model. Using the selected clinical and head ultrasound variables, multiple logistic regression analysis was performed to develop a regression equation on the development set. This equation was applied to the validation set to predict neurodevelopmental impairment and its components. Neurodevelopmental impairment was defined as mental developmental index<70, psychomotor developmental index<70, cerebral palsy, deafness and/or blindness. The process was repeated for HUS-28 and “Early” clinical variables, as well as for HUS-36 and “All” clinical variables alone and in combination. Predictive abilities of the different models were compared using the area under the curve of the receiver operating characteristic curves.
Of 5867 ELBWinfants admitted to any of the participating centers, 3096 infants had both HUS-28 and HUS-36 (Figure). HUS-28 was done before 7 days in 50%, 39% between 7 and 14 days, and 12% between 15 and 28 days of age. The median age at HUS-36 was day 57 (25th–75th centile of 37–74 days).
Of the 3009 infants without major malformations/syndromes, death before and after discharge occurred in 6.6% of the patients with normal head ultrasound or grade I intracranial hemorrhage, 11% of those with grade II intracranial hemorrhage, and 14% and 18% of those with grade III and IV intracranial hemorrhage, respectively. Cystic periventricular leukomalacia was noted in 5% of patients who died. 2,271 infants survived to follow-up at 18 to 22 month corrected age. Some or all neurodevelopmental impairment data were missing in 168 infants. Thus, a total of 2,103 infants were included in the analysis of neurodevelopmental impairment. A comparison of the infants lost to follow-up to those followed up shows that infants were comparable for birth weight and grade of intracranial hemorrhage, but there was a lower incidence of periventricular leukomalacia in infants lost to follow-up (Table I).
The mean gestational age for the study population was 26 weeks (± 1.8 weeks SD) and the mean birth weight was 773 grams (± 136 g SD). Eighty percent of the infants were exposed to at least one dose of antenatal steroids, 22% were multiple births, 53% were females, and 47% were black/non-Hispanic.
The overall rate of the combined outcome of death or neurodevelopmental impairment was 50%, with 45% (638/1430) infants with a normal HUS-28, 46% (121/266) of those with grade I intracranial hemorrhage, 58% (102/176) with grade II, 63% (163/259) with grade III, and 76% (140/184) with grade IV having neurodevelopmental impairment or death (p<0.0001 for death or neurodevelopmental impairment by grade of intracranial hemorrhage). 77% (127/164) of those with periventricular leukomalacia and 81% (50/62) of those with cystic periventricular leukomalacia also either died or developed neurodevelopmental impairment. Overall, 2.3% (50/2153 infants) died after discharge, and the post-discharge death rate was comparable among those with normal HUS-28 (2.2%), grade 4 intracranial hemorrhage (2.7%) and those with periventricular leukomalacia (2.2%).
Neurodevelopment impairment increased with worse head ultrasound findings (Table II). However, neurodevelopmental impairment was not present in 30% and 24% of the infants with grade IV intracranial hemorrhage and cystic periventricular leukomalacia, respectively, but was present in 39% of infants with normal head ultrasounds.
The “Early” and “All” clinical models were better predictors of neurodevelopmental impairment (areas under the curve = 0.68 for both), compared with the corresponding HUS-28 (areas under the curve = 0.58) and HUS-36 models (areas under the curve = 0.57) (p<0.001 vs. the clinical models) (Figure 2[L1]). The HUS-36 model did not improve prediction of neurodevelopmental impairment when compared to the HUS-28 model (p=0.4). The combined head ultrasound and clinical models were comparable to isolated clinical models for neurodevelopmental impairment prediction for both “Early” (0.68 vs 0.68, p=0.5) and “All” models (0.68 vs. 0.68, p=0.9).
Predictions of the major neurological outcomes were comparable for the HUS-36 model and HUS-28 model except for non-independent walking for which the HUS-36 model was superior (0.71 vs. 0.65, p<0.01). There was an improvement in the predictive ability for mental developmental index<70 (0.72 vs. 0.69, p<0.05), cerebral palsy (0.78 vs. 0.72, p<0.01), and non-independent walking (0.79 vs. 0.74, p<0.01) for the HUS-36/“All” clinical model as compared to the HUS-28/“Early” clinical model.
Multiple logistic regression analyses controlling for clinical variables and timing of head ultrasound revealed that only periventricular leukomalacia and shunt placement in HUS-36 were significantly associated with neurodevelopmental impairment (Table III; available at www.jpeds.com). Head ultrasound and clinical variables findings were significantly associated with various components of neurodevelopmental impairment.
This study addresses the ability of clinical models, head ultrasound models, and their combination to predict neurodevelopmental impairment at 18–22 months corrected age. Many ELBW infants with a normal head ultrasound later develop neurodevelopmental impairment, although some infants with abnormal head ultrasounds do not have significant impairment. Clinical models were stronger predictors for neurodevelopmental impairment and its components than head ultrasound models. Isolated head ultrasound findings had a poor predictive ability for neurodevelopmental outcome when compared to clinical data and generally demonstrated no improvement in predictive ability over time. Only when combined with clinical data was a head ultrasound closer to 36 weeks post-menstrual age better than an ultrasound in the first 28 days for the prediction of low mental developmental index, cerebral palsy, and non-independent walking. Overall, these models are not optimal for use in individual neonates due to lack of sufficient accuracy, but the models are suitable for evaluation of the relative importance of the predictors.
Periventricular leukomalacia was an important risk factor for neurodevelopmental impairment and its components but only if considered after the first 28 days. Echodensities diagnosed early in life may partially or completely resolve and consequently may not predict neurodevelopmental impairment.22,29,30 Independent of the time of the exam, enlarged ventricles was the only head ultrasound finding that predicted poor neurodevelopmental outcome. It is possible that enlarged ventricles may be a marker of abnormal white matter development. 23,31
Infants with normal head ultrasound and grades I and II intracranial hemorrhage had an incidence of neurodevelopmental impairment ranging from 39% to 51%. When corrected for other variables by regression analysis, a normal head ultrasound was not associated with normal outcome, which is consistent with the recent work by Laptook et al,32 who demonstrated that nearly 30% of ELBW infants with a normal head ultrasound had either cerebral palsy or a low MDI. It is likely that neurodevelopmental impairment will not always be preceded by abnormal ultrasound findings. Detection of subtle white matter damage may be better with magnetic resonance imaging.33,34
Severe intracranial hemorrhage and periventricular leukomalacia are believed to be strong predictors of poor neurodevelopmental outcome.4,14–19 Abnormal ultrasonographic findings are considered often in decisions to withdraw or withhold therapy. Clinicians may consider the cranial ultrasound to provide additional prognostic data to the “pre-test probability” estimated based upon multiple clinical variables (birth weight, antenatal variables, need for resuscitation, severity of illness). The current study shows that head ultrasounds do not reliably predict neurodevelopmental impairment in survivors. When controlled for clinical variables and timing of the exam, only periventricular leukomalacia diagnosed closer to 36 weeks and shunt placement were significantly associated with subsequent neurodevelopmental impairment. The high prevalence of neurodevelopmental impairment in infants with normal head ultrasound or minor grades of intracranial hemorrhage, and the frequent absence of severe neurodevelopmental impairment despite grade IV intracranial hemorrhage and/or periventricular leukomalacia indicate that the association between head ultrasound findings and neurodevelopmental outcome is not as strong as previously believed.14,19
A limitation of this study is that the analysis was constrained to already existing data; however, the database was comprehensive and collected by trained personnel. Although head ultrasound interpretations are subject to interobserver variability35,36 and central readers were not used, the effect of inter-reader variability was minimized by using a predefined classification. Our study may also more closely approximate routine clinical practice as central readers are not used for clinical decision making. Another limitation is that the timing of the head ultrasound (both early and late) were variable, and this variability in timing may influence the observations. Again, however, this may more closely approximate routine clinical practice in which timing is variable. Only infants who survived to follow-up were evaluated. Therefore, differential bias is possible as infants in whom support was withdrawn as a result of severe intracranial hemorrhage would not have been included. Differential bias is also possible in this study as examiners during follow-up were not masked to the infants’ clinical course, head ultrasound findings, or clinical findings on prior evaluations.
Important strengths of the current study include the analysis of a large multicenter cohort of ELBWinfants with a standardized and comprehensive evaluation of neurodevelopment at 18–22 months corrected age. Furthermore, the analyses performed on head ultrasound findings were controlled not only for clinical variables but also for the time of the exam.
Clinical variables were stronger predictors than head ultrasound findings as the addition of head ultrasound data did not improve the predictive abilities of models with only clinical variables. The poor predictive ability for head ultrasound may be partly explained by the use of a classification that considers increasing grades of IVH as a progression of a single disease with cumulative effect.37 Ventriculomegaly is considered a consequence of intraventricular hemorrhage although it may represent atrophy secondary to white matter damage from other causes.31 In addition to the anatomical site and extension of the hemorrhage,38,39 a classification that considers the degree of white matter damage,22 its location,40 and whether these findings are persistent or transient41 may improve the prediction of neurologic outcome. Additional limitations of the current methods of ultrasound analysis include the lack of standardization in determination of ventricular size and of reporting of cerebellar lesions. It is possible that a classification of head ultrasound that takes into account the site, extension, and persistence of the hemorrhage as well as the degree of white matter damage may correlate better with longer-term outcome.
Clinicians often overestimate the incidence of major disability or death in these extremely sick babies, and this may lead to restriction of life support therapies.42,43 The current study documents that head ultrasound findings are poor predictors of outcome and indicates that decisions on withdrawal or withholding support in preterm infants should not be made based solely on head ultrasound findings. A large study with more accurate imaging techniques and/or classifications is required to identify specific characteristics that may improve the predictive ability of imaging studies for neurodevelopmental outcomes.
Funding Sources: Supported by cooperative agreements with the National Institute of Child Health and Human Development: U10 HD34216 (Dr. Carlo), U10HD27853 (Dr. Donovan), U10HD40461 (Dr. Finer), U10HD21364 (Dr. Fanaroff), U10HD40461 (Dr. Goldberg), U10HD27851 (Dr. Stoll), U10HD27856 (Dr. Lemons), U10HD21397 (Dr. Duara), U10DH27881 (Dr. Papile), U10HD40521 (Dr. Phelps), U10HD27880 (Dr. Stevenson), U10HD21415 (Dr. Korones), U10HD40689 (Dr. Laptook), U10HD21373 (Dr. Tyson), U10HD40498 (Dr. O’Shea), U10HD21385 (Dr. Shankaran), U10HD27904 (Dr. Oh), U10HD27871 (Dr. Ehrenkranz)
|Center||Principal Investigator (PI)||Follow up Principal Investigator (FPI)||Network Coordinator (NC)||Follow-up Coordinator (FC)|
|1||Brown University||William Oh, MD||Betty Vohr, MD||Angelita Hensman, RNC||Lucy Noel, RNC|
|2||Case Western Reserve University||Avroy A. Fanaroff, MB BCh||Dee Wilson, MD||Nancy Newman, RN||Bonnie Siner, RN|
|3||Duke University||Ronald N Goldberg, MD||Ricki Goldstein, MD||Kathy Auten, RN, BS||Melody Lohmeyer, RN|
|4||Emory University||Barbara J. Stoll, MD||Barbara J. Stoll, MD||Ellen Hale, RNC, BS||Ellen Hale, RNC, BS|
|5||Harvard University||Ann R. Stark, MD||Ann R. Stark, MD||Kerri Fournier, RN|
|6||Indiana University||James A. Lemons, MD||Anna Dusick, MD||DeeDee Appel, RN||Leslie Richards, RN|
|7||Stanford University||David K. Stevenson, MD||Susan Hintz, MD||Bethany Ball, RN, BS||Bethany Ball, RN, BS|
|8||University of Alabama||Waldemar A. Carlo, MD||Kathy Nelson, MD||Monica Collins, RN||Vivien Phillips, RN|
|9||University of California, San Diego||Neil N. Finer, MD||Yvonne Vaucher, MD||Chris Henderson, RN||Martha Fuller, RN|
|10||University of Cincinnati||Edward F. Donovan, MD||Jean Steichen, MD||Cathy Grisby, RN||Tari Gratton, RN|
|11||University of Miami||Shahnaz Duara, MD||Charles Bauer, MD||Ruth Everett, RN||Mary Allison, RN|
|12||University of New Mexico||Lu-Ann Papile, MD||Lu-Ann Papile, MD||Conra Backstrom, RN|
|13||University of Rochester||Dale L. Phelps, MD||Gary Myers, MD||Linda Reubens, RN||Diane Hust, RN|
|14||University of Texas. Houston||Jon E. Tyson, MD, MPH||Brenda Morris, MD||Georgia McDavid, RN||Shannon Rossi|
|15||Wake Forest University||T. Michael O’Shea, MD||Robert Dillard, MD||Nancy Peters, RN||Barbara Jackson, RN|
|16||Wayne State University||Seetha Shankaran, MD||Yvette Johnson, MD||Gerry Muran, BSN||Debbie Kennedy, RN|
|17||Yale University||Richard A. Ehrenkranz, MD||Linda Mayes, MD||Pat Gettner, RN||Elaine Romano, MSN|
|18||NICHD||Linda L. Wright, MD, Rosemary D. Higgins, MD||Beth B. McClure, MS|
|19||Research Triangle Institute||W. Kenneth Poole, PhD||W. Kenneth Poole, PhD||Betty Hastings, Carolyn Petrie, MS||Beth B. McClure, MS|
Presented in part at the Pediatric Academic Societies’ Meeting, San Francisco, CA, 2004
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