Natalie E. Rintoul

Neurodevelopmental outcome of infants with congenital diaphragmatic hernia prospectively enrolled in an interdisciplinary follow-up program.

PURPOSE The purpose of the study was to evaluate the neurodevelopmental outcome in infants with congenital diaphragmatic hernia (CDH). METHODS Between June 2004 and September 2007, 41 CDH survivors were prospectively enrolled in an interdisciplinary follow-up program. Neurodevelopmental status was evaluated using the Bayley Scales of Infant Development II (prior 2006, n = 9), the Bayley Scales of Infant Development III (after 2006, n = 27), or the Wechsler Preschool and Primary Scale of Intelligence III (children older than 4 years, n = 5). Scores were grouped as average, mildly delayed, and severely delayed by standard deviation intervals (115-85, 71-84, <70), and mixed if average and mildly delayed in either cognitive or language. RESULTS Median age at last assessment was 24 months (range, 6-62). Average, mixed, mildly delayed, and severely delayed scores for neurocognitive and language skills were found in 49%, 19%, 17%, and 15%, respectively. Psychomotor scores were normal, mildly delayed, and severely delayed in 46%, 23%, and 31%, respectively. Autism was present in 7%. Abnormal muscle tonicity was found in 51% (49% hypotonic, 2% hypertonic). Multivariate risk factors for borderline or delayed neurodevelopmental, neurocognitive, and/or psychomotor outcome were intrathoracic liver position (P = .02), presence of a right-sided CDH (P = .02), extracorporeal membrane oxygenation need (P < .001), Gore-Tex patch repair (P = .02), O(2) requirement at 30 days of life (P < .01), and hypotonicity (P < .01). CONCLUSIONS The prospective evaluation in an interdisciplinary follow-up program uncovered striking morbidities in neurodevelopmental status in approximately half of the CDH infants. The most common neurologic sequelae are neuromuscular hypotonicity and psychomotor dysfunction. Patient-specific factors are important determinants of adverse neurologic outcome.

Percutaneous sclerotherapy in neonatal and infant head and neck lymphatic malformations: a single center experience

PURPOSE To evaluate the clinical outcomes of percutaneous sclerotherapy for congenital head and neck lymphatic malformations in our institution. MATERIALS AND METHODS Over a 7-year period, 17 children (10 M, 7 F) mean age 5.8 months (5 days to 13 months) underwent 49 sclerotherapy procedures for congenital head and neck malformations. The imaging and clinical records were reviewed for each patient. Ten of 17 had macrocystic disease; 7 of 17 had microcystic disease. Imaging response was categorized by volume reductions of 0% to 25%, 25% to 50%, 50% to 75%, or 75% to 100%. A concentration of 10 mg/mL doxycycline was used routinely via catheter in 3 instillations with a dose range of 50 to 500 mg per session as per our standard protocol in 17 of 17 patients. In more recent patients, systemic doxycycline levels were obtained after instillations. Additional treatments included direct injection doxycycline (10/17), instillation of absolute ethanol (7/17) or sodium tetradecyl sulfate (4/17), or a combination of these methods. RESULTS Imaging improvement of ≥ 76% was noted in 11 of 17. Of these, 8 of 11 had macrocystic disease. Four of 17 had 51% to 75% resolution, of which 3/4 were mixed. Two of 17 children had 25% to 50% resolution with a mixed lesion. Seven of 49 peri-procedural complications: hemolytic anemia in 2 infants, hypoglycemic and metabolic acidosis in 3 neonates aged 7 to 10 days, transient hypotension during absolute alcohol instillation in 1 neonate, and self-limiting skin excoriation secondary to peri-catheter leakage of doxycycline in one neonate. Neonates prone to these systemic complications had doxycycline doses of greater than 250 mg and resulted in serum levels of >5 μg/mL but as high as 21 μg/mL. Delayed neural complications occurred in 7 of 49 procedures, Horners syndromes in 4 of 49 procedures, transient left lip weakness in 1 of 49 procedures, right facial nerve palsy in 1 of 49 procedures, and transient left hemidiaphragm paralysis in 1/49 procedures. CONCLUSION Our experience with catheter directed doxycycline sclerotherapy provides excellent results for large macrocystic head and neck lymphatic malformations. Microcystic and mixed lesions continue to provide a therapeutic challenge.

Fetal Myelomeningocele Repair: The Post-MOMS Experience at the Children's Hospital of Philadelphia

Background: Fetal myelomeningocele (fMMC) repair has become accepted as a standard of care option in selected circumstances. We reviewed our outcomes for fMMC repair from referral and evaluation through surgery, delivery and neonatal discharge. Material and Methods: All patients referred for potential fMMC repair were reviewed from January 1, 2011 through March 7, 2014. Maternal and neonatal data were collected on the 100 patients who underwent surgery. Results: 29% of those evaluated met the criteria and underwent fMMC repair (100 cases). The average gestational age was 21.9 weeks at evaluation and 23.4 weeks at fMMC repair. Complications included membrane separation (22.9%), preterm premature rupture of membranes (32.3%) and preterm labor (37.5%). Average gestational age at delivery was 34.3 weeks and 54.2% delivered at ≥35 weeks. The perinatal loss rate was 6.1% (2 intrauterine fetal demises and 4 neonatal demises); 90.8% of women delivered at the Childrens Hospital of Philadelphia and 3.4% received transfusions. With regard to the neonates, 2 received ventriculoperitoneal shunts prior to discharge; 71.1% of neonates had no evidence of hindbrain herniation on MRI. Of the 80 neonates evaluated, 55% were assigned a functional level of one or more better than the prenatal anatomic level. Conclusion: In an experienced program, maternal and neonatal outcomes for patients undergoing fMMC repair are comparable to results of the MOMS trial.

Reversal of Hindbrain Herniation after Maternal-fetal Surgery for Myelomeningocele Subsequently Impacts on Brain Stem Function

The aim of our study was to delineate whether the reversal of hindbrain herniation (HH) following fetal myelomeningocele (fMMC) closure subsequently reduces the incidence and severity of HH-associated brainstem dysfunction (BSD). Prior to the NIH-sponsored Management of Myelomeningocele Study (MOMS) trial, 54 children underwent fMMC closure at our institution. Forty-eight (89%) families participated in a structured survey focusing on HH-associated BSD (e.g., apnea, neurogenic dysphagia [ND], gastro-esophageal reflux disease [GERD], neuro-ophthalmologic disturbances [NOD]). Median age at follow-up was 72 months (range: 46-98). Fifty-percent required shunting. HH-related symptoms were completely absent in 15 (63%) non-shunted and 10 (42%) shunted children (P=0.15). No HH-related death occurred and none developed severe persistent cyanotic apnea. ND was reported in 2 (8%) non-shunted and 9 (38%) shunted infants (P=0.03). Mild GERD (medically managed) developed in 2 (8%) without and 6 (25%) with shunt placement (P=0.24). NOD was found in 6 (25%) and 13 (54%) of non-shunted and shunted children, respectively (P=0.07). The majority of fMMC children developed no or only mild BSD at follow-up. Our data support the hypothesis that neurodevelopmental deficits associated with MMC are at least partially acquired and that reversal of HH following fMMC surgery may help to reduce the incidence and severity of BSD.

Fetal MRI-Calculated Total Lung Volumes in the Prediction of Short-Term Outcome in Giant Omphalocele: Preliminary Findings

Objective: To determine the value of fetal MRI-calculated total lung volumes (TLV) in the prediction of short-term outcome in patients with giant omphalocele (GO). Material and Methods: We reviewed all cases of GO undergoing fetal MRI after 21 weeks’ gestation and receiving postnatal care at our institution between 2003 and 2010. Observed/expected (O/E) TLV was calculated using age-matched TLV normograms [Radiology 2001;219:236–241]. Postnatal outcomes were stratified based on O/E TLV above or below 50% of expected. Results: Seventeen GO cases fulfilled the entry criteria. The mean age at fetal MRI evaluation was 25.8 ± 4.8 weeks’ gestation. The mean GO TLV (21.0 ± 13.2) was lower than age-matched population norms (p < 0.001), resulting in a mean O/E TLV of 52.3 ± 16.8%. The mean gestational age at delivery was 36.8 ± 1.6 weeks. Overall survival was 94%. Fourteen (88%) infants underwent staged reduction, and 2 underwent silver sulfadiazine treatment and delayed repair. Infants with ≤50% of predicted O/E TLV (n = 11, 65%) had lower Apgar scores at birth (p = 0.03), prolonged ventilatory support (p = 0.004), delayed oral intake (p = 0.03), and longer hospitalization (p = 0.03) compared to patients with ≥50% of expected O/E TLV. Two infants (both O/E TLV <50%) required tracheostomy placement. Conclusion: In the assessment of GO fetuses, MRI-based O/E TLV of <50% was predictive of increased postnatal morbidity.

Longitudinal neurodevelopmental and neuromotor outcome in congenital diaphragmatic hernia patients in the first 3 years of life

Objective:The objective of this study was to longitudinally evaluate the neurodevelopmental (ND) outcome in congenital diaphragmatic hernia (CDH) survivors during the first 3 years of life.Study Design:The study cohort consists of 47 CDH survivors that were enrolled in our prospective, follow-up program between July 2004 and September 2010, and underwent serial ND evaluations during the first 3 years of life. ND outcomes were evaluated using the Bayley Scales of Infant Development (BSID)-II or BSID-III. Persistent ND impairment was defined as a score that remained ⩽79 for the cognitive, language and psychomotor domains at the most recent follow-up visit compared with the first assessment.Result:The median age at first and last evaluation was 8 (range, 5 to 15) and 29 (range, 23 to 36) months, respectively. During the follow-up, ND scores improved to average in 17%, remained average in 60%, remained delayed in 10%, improved from severely delayed to mildly delayed in 2% and deteriorated from average to delayed in 15%. Motor scores improved to average in 26%, remained average in 55%, remained delayed in 8% and improved from severely delayed to mildly delayed in 11%. Intrathoracic liver position (P=0.004), preterm delivery (P=0.03), supplemental O2 requirement at day of life 30 (P=0.007), age at discharge (P=0.03), periventricular leukomalacia (PVL; P=0.004) and initial neuromuscular hypotonicity (P=0.01) were associated with persistent motor delays. No relationship was found between patient’s characteristics and the risk of persistent cognitive and language delays.Conclusion:(1) The majority of children with CDH are functioning in the average range by early preschool age, (2) most children who had early delays showed improvement in their ND outcome, (3) children showing delays in all the three domains were the least likely to show improvement and (4) CDH severity appears to be predictive of persistent psychomotor delays.

Preschool neurological assessment in congenital diaphragmatic hernia survivors: Outcome and perinatal factors associated with neurodevelopmental impairment

OBJECTIVE To evaluate the preschool neurodevelopmental outcome in CDH survivors between 2 and 5 years of age and to identify perinatal and postnatal factors that may be predictive of persistent neurological deficits. METHODS The study cohort consists of 60 CDH survivors that were enrolled in our prospective, follow-up program between January 2006 and September 2012. Developmental assessment of study participants between 2 and 3 years of age was performed using the Bayley Scales of Infant Development, 3rd Edition (BSID-III). Cognitive outcomes of CDH children older than 3 years of age were evaluated using The Wechsler Preschool and Primary Scale of Intelligence, 3rd Edition (WPPSI-III). Neurodevelopmental delay was defined by a score of ≤ 85 in any of the evaluated composite scores. Severe impairments were defined as a score of ≤ 69 in at least one domain tested. RESULTS Mean follow-up for children assessed by BSID-III (n=42) and WPPSI-III (n=18) was 28 ± 4.5 months and 58 ± 4.0 months, respectively. As a group, mean composite and subdomain BSID-III and WPPSI-III scores were within the expected normal range. For the BSID-III group, 9 (22%) had mild deficits in at least one domain, and 6 (14%) had severe deficits in at least one. Only 3 (7%) patients demonstrated severe neurological delays for all BSID-III composite scales. For the WPPSI-III group, 4 (22%) patients scored within the borderline-delayed range for at least one subscale and only one (6%) child had a WPPSI-III VIQ score in the severe delay range. Abnormal muscle tonicity was found in 35% (hypotonicity 33%, hypertonicity 2%). Need for ECMO, prolonged ventilation, hypotonicity, and other surrogate markers of disease severity (P<0.05) were associated with borderline or delayed neurological outcome. CONCLUSION The majority of CDH children are functioning in the average range at early preschool and preschool age. Neuromuscular hypotonicity is common in CDH survivors. CDH severity appears to be predictive of adverse neurodevelopmental outcome.

Prospective, interdisciplinary follow-up of children with prenatally diagnosed giant omphalocele: short-term neurodevelopmental outcome.

PURPOSE The objective of this study is to determine the short-term neurodevelopmental outcome in infants with giant omphalocele (GO). MATERIALS AND METHODS Between January 2002 and December 2007, 31 consecutive infants with GO received prenatal and postnatal care at our institution. Overall survival was 81% (25/31). Twenty (80%) of the survivors were enrolled in a prospective interdisciplinary follow-up program. Fifteen were at least 6 months of age and received detailed neurodevelopmental evaluation using the Bayley Scales of Infant Development II (BSID-II [before 2006, n = 3]) or BSID-III (after 2006, n = 12). Scores were grouped as average, mildly delayed, and severely delayed by SD intervals (115-85, 71-84, <70). Scores were considered mixed if cognitive or language skills were in different ranges. RESULTS Median age at evaluation was 12 months (range, 6-26 months). Average, mildly delayed, and severely delayed scores for cognitive and language skills were found in 6 (40%), 2 (13%), and 6 (40%), respectively. One child had mixed scores (severely delayed for cognitive and mildly delayed for language skills). Motor scores were normal, mildly delayed, and severely delayed in 6 (40%), 2 (13%), and 7 (47%), respectively. The neuromuscular examination was abnormal in 8 patients (62%). Five (33%) scored within the average range, whereas 6 (40%) demonstrated severe delays for cognitive, language, and motor outcome. Of the 6 children with severe delays, 2 (13% of total) have autism, 4 required tracheostomy, and 1 was diagnosed with Williams syndrome. CONCLUSIONS The presence of GO is associated with deficits in developmental achievements in most of the affected infants ranging from mild to profound delays. These findings underscore the importance of early and standardized neurodevelopmental evaluation throughout childhood for all survivors with GO. Larger studies are warranted for risk factor stratification.

Duplication of chromosome region 4q28.3-qter in monozygotic twins with discordant phenotypes

We describe monozygotic twins with partially discordant phenotypes who were found to have a duplication of chromosome region 4q28.3-qter. The duplicated region of chromosome 4 resulted from an unbalanced segregation of a balanced maternal (4;22)(q28.3;p13) translocation. Duplication of the long arm of chromosome 4 has been described in >60 patients; however, it usually results from the unbalanced segregation of a parental balanced translocation and has an associated monosomy. Twenty cases of dup 4q without an associated monosomy have been reported, and this is the only case of dup 4q28. 3-qter. All cases of dup 4q are reviewed, and phenotypic aspects are analyzed. Issues of monozygotic twinning and other birth defects also are addressed.

Timing of repair of congenital diaphragmatic hernia in patients supported by extracorporeal membrane oxygenation (ECMO)

PURPOSE The optimal timing of repair for congenital diaphragmatic hernia (CDH) in patients requiring extracorporeal membrane oxygenation (ECMO) is controversial. Repair during ECMO may improve respiratory function by restoring normal anatomy. However, there is increased risk of complications including surgical bleeding. The purpose of this study was to examine the impact of timing of CDH repair on outcomes in a large cohort of patients treated at a single institution. METHODS We retrospectively reviewed charts of all CDH patients in our Pulmonary Hypoplasia Program from 2004 to 2013. Categorical variables were analyzed by Fishers exact test and continuous variables by Mann-Whitney t-test (p<0.05). RESULTS A total of 77 CDH patients required ECMO support during the study dates. Of these, 16 patients did not survive to repair, 3 patients were repaired prior to cannulation, 41 patients were repaired during ECMO, and 17 patients were repaired after decannulation. Survival was 67%, 43.9%, and 100% for those repaired prior to, during, or post ECMO, respectively, with statistical significance associated with repair after decannulation (P<0.0001). Operative bleeding requiring transfusion occurred in 12 patients repaired on ECMO, while no significant bleeding occurred in patients repaired after decannulation (P=0.003). CONCLUSION Outcomes were improved in CDH patients undergoing surgical repair following ECMO with significantly increased survival, lower rates of surgical bleeding, and decreased total duration of ECMO therapy compared to patients repaired on ECMO. In patients who can be successfully weaned from ECMO, our study supports a role for delayed repair off ECMO with reduced operative morbidity and increased survival.