Fariha Sheikh

Fetal MRI lung volumes are predictive of perinatal outcomes in fetuses with congenital lung masses.

PURPOSE The purpose of this study was to evaluate fetal magnetic resonance imaging (MRI) as a modality for predicting perinatal outcomes and lung-related morbidity in fetuses with congenital lung masses (CLM). METHODS The records of all patients treated for CLM from 2002 to 2012 were reviewed retrospectively. Fetal MRI-derived lung mass volume ratio (LMVR), observed/expected normal fetal lung volume (O/E-NFLV), and lesion-to-lung volume ratio (LLV) were calculated. Multivariate regression and receiver operating characteristic analyses were applied to determine the predictive accuracy of prenatal imaging. RESULTS Of 128 fetuses with CLM, 93% (n=118) survived. MRI data were available for 113 fetuses. In early gestation (<26weeks), MRI measurements of LMVR and LLV correlated with risk of fetal hydrops, mortality, and/or need for fetal intervention. In later gestation (>26weeks), LMVR, LLV, and O/E-NFLV correlated with neonatal respiratory distress, intubation, NICU admission and need for neonatal surgery. On multivariate regression, LMVR was the strongest predictor for development of fetal hydrops (OR: 6.97, 1.58-30.84; p=0.01) and neonatal respiratory distress (OR: 12.38, 3.52-43.61; p≤0.001). An LMVR >2.0 predicted worse perinatal outcome with 83% sensitivity and 99% specificity (AUC=0.94; p<0.001). CONCLUSION Fetal MRI volumetric measurements of lung masses and residual normal lung are predictive of perinatal outcomes in fetuses with CLM. These data may assist in perinatal risk stratification, counseling, and resource utilization.

Predictors of poor prognosis in prenatally diagnosed sacrococcygeal teratoma: A multiinstitutional review

INTRODUCTION Attempts at defining predictors of poor outcome in fetal sacrococcygeal teratoma (SCT) have been hampered by small patient numbers. We sought to validate the utility of tumor volume to fetal weight ratio (TFR) as a predictor of poor prognosis and to identify other morphological outcome predictors in a multicenter series. METHODS Records of prenatally diagnosed SCT at three fetal centers from 1986 to 2011 were reviewed. Prenatal imaging characteristics including TFR, morphology, hydrops, and placentomegaly were assessed. Poor prognosis was defined as fetal demise, need for fetal intervention, or perinatal death. Receiver operating characteristic (ROC) analysis was used to select a TFR cutoff value. RESULTS Seventy-nine fetuses with SCT were evaluated. Eleven pregnancies ending in elective termination were excluded. ROC analysis revealed that TFR >0.12 prior to 24 weeks gestation was predictive of poor prognosis (AUC=0.913; Sensitivity=91.7%, Specificity=76.2%, PPV=86.8%; NPV=84.2%). Solid tumor morphology and presence of hydrops were found to be predictors of poor prognosis. None of the factors associated with poor prognosis were independent predictors on multivariate analysis. CONCLUSION This study validates TFR >0.12 prior to 24 weeks gestation as an objective predictor of outcomes in fetuses with SCT that can be easily applied in most clinical settings.

Low Abdominal NIRS Values and Elevated Plasma Intestinal Fatty Acid-Binding Protein in a Premature Piglet Model of Necrotizing Enterocolitis

To identify early markers of necrotizing enterocolitis (NEC), we hypothesized that continuous abdominal near-infrared spectroscopy (A-NIRS) measurement of splanchnic tissue oxygen saturation and intermittent plasma intestinal fatty-acid binding protein (pI-FABP) measured every 6 hours can detect NEC prior to onset of clinical symptoms. Premature piglets received parenteral nutrition for 48-hours after delivery, followed by enteral feeds every three hours until death or euthanasia at 96-hours. Continuous A-NIRS, systemic oxygen saturation (SpO2), and heart rate were measured while monitoring for clinical signs of NEC. Blood samples obtained at 6-hour intervals were used to determine pI-FABP levels by ELISA. Piglets were classified as fulminant-NEC (f-NEC), non-fulminant-NEC (nf-NEC) and No-NEC according to severity of clinical and histologic features. Of 38 piglets, 37% (n=14) developed nf-NEC, 18% (n=7) developed f-NEC and 45% (n=17) had No-NEC. There were significant differences in baseline heart rate (p=0.008), SpO2 (p<0.001) and A-NIRS (p<0.001) among the three groups. A-NIRS values of NEC piglets remained lower throughout the study with mean for f-NEC of 69±3.8%, 71.9±4.04% for nf-NEC, and 78.4±1.8% for No-NEC piglets (p<0.001). A-NIRS <75% predicted NEC with 97% sensitivity and 97% specificity. NEC piglets demonstrated greater variability from baseline in A-NIRS than healthy piglets (10.1% vs. 6.3%; p=0.04). Mean pI-FABP levels were higher in animals that developed NEC compared to No-NEC piglets (0.66 vs. 0.09 ng/mL;p<0.001). In f-NEC piglets, pI-FABP increased precipitously after feeds (0.04 to 1.87 ng/mL;p<0.001). pI-FABP levels increased in parallel with disease progression and a value >0.25ng/mL identified animals with NEC (68% sensitivity and 90% specificity). NIRS is a real-time, non-invasive tool that can serve as a diagnostic modality for NEC. In premature piglets, low A-NIRS in the early neonatal period and increased variability during initial feeds are highly predictive of NEC, which is then confirmed by rising plasma I-FABP levels. These modalities may help identify neonates with NEC prior to clinical manifestations of disease.

Prenatally diagnosed neck masses: long-term outcomes and quality of life.

PURPOSE To determine long-term outcomes of fetuses with neck masses (NM), including functional and cosmetic results. METHODS A retrospective review was performed of all fetuses evaluated for NM from November 2001 to March 2014. Quality of life (QOL) was evaluated using the validated PedsQL™ questionnaire. RESULTS Of 35 fetuses evaluated, 9 died perinatally and 1 died late from tracheostomy complications. NM ranged from 4 to 20cm (mean, 9.1cm); 18 were delivered by EXIT. Of 25 surviving patients, 22 had mass resection, 7 requiring more than one procedure. Surviving patients with lymphatic malformations (LM) had the highest incidence of moderate and severe disfigurement and a higher rate of persistent/recurrent disease (100% vs. 31%, p=0.002) and cranial nerve dysfunction (50% vs. 0%, p=0.005) compared to those with non-LM diagnoses. Of 9 children attending school, 78% achieve grades of A/Bs. QOL for 13 patients revealed a mean score of 83/100 for physical and 78/100 for psychosocial functioning. Median follow-up was 6 years (7 months-17 years). CONCLUSION Unlike those with teratoma or other lesions, children with congenital cervicofacial LM are at high-risk for persistent disease, nerve dysfunction and moderate-severe disfigurement. There is substantial perinatal morbidity for fetuses with neck masses, but for those surviving, the long-term functional and cognitive outcomes are good.

Are all pulmonary hypoplasias the same? A comparison of pulmonary outcomes in neonates with congenital diaphragmatic hernia, omphalocele and congenital lung malformation

INTRODUCTION Patients with congenital diaphragmatic hernias (CDH), omphaloceles, and congenital lung malformations (CLM) may have pulmonary hypoplasia and experience respiratory insufficiency. We hypothesize that given equivalent lung volumes, the degree of respiratory insufficiency will be comparable regardless of the etiology. METHODS Records of all fetuses with CDH, omphalocele, and CLM between January 2000 and June 2013 were reviewed. MRI-based observed-to-expected total fetal lung volumes (O/E-TFLV) were calculated. An analysis of outcomes in patients with O/E-TFLV between 40% and 60%, the most inclusive range, was performed. RESULTS 285 patients were evaluated (161, CDH; 24, omphalocele; 100, CLM). Fetuses with CDH had the smallest mean O/E-TFLV. CDH patients were intubated for longer and had a higher incidence of pulmonary hypertension. Fifty-six patients with the three diagnoses had an O/E-TFLV of 40%-60%. The need for ECMO, supplemental oxygen at 30days of life, and 6-month mortality were similar among groups. CDH patients had a significantly longer duration of intubation and higher incidence of pulmonary hypertension than the other two diagnoses. CONCLUSION Given equivalent lung volumes (40%-60% of expected), CDH patients require more pulmonary support initially than omphalocele and CLM patients. In addition to lung volumes, disease-specific factors, such as pulmonary hypertension in CDH, also contribute to pulmonary morbidity and overall outcome.

Repeated isoflurane exposure and neuroapoptosis in the midgestation fetal sheep brain

BACKGROUND Advances in surgery and technology have resulted in increased in-utero procedures. However, the effect of anesthesia on the fetal brain is not fully known. The inhalational anesthetic agent, isoflurane, other gamma amino butyric acid agonists (benzodiazepines, barbiturates, propofol, other inhalation anesthetics), and N-methyl D aspartate antagonists, eg, ketamine, have been shown to induce neuroapoptosis. The ovine model has been used extensively to study maternal-fetal physiologic interactions and to investigate different surgical interventions on the fetus. OBJECTIVE The purpose of this study was to determine effects of different doses and duration of isoflurane on neuroapoptosis in midgestation fetal sheep. We hypothesized that repeated anesthetic exposure and high concentrations of isoflurane would result in increased neuroapoptosis. STUDY DESIGN Time-dated, pregnant sheep at 70 days gestation (term 145 days) received either isoflurane 2% × 1 hour, 4% × 3 hours, or 2% × 1 hour every other day for 3 exposures (repeated exposure group). Euthanasia occurred following anesthetic exposure and fetal brains were processed. Neuroapoptosis was detected by immunohistochemistry using anticaspase-3 antibodies. Fetuses unexposed to anesthesia served as controls. Another midgestation group with repeated 2% isoflurane exposure was examined at day 130 (long-term group) and neuronal cell density compared to age-matched controls. Representative sections of the brain were analyzed using Aperio Digital imaging (Leica Microsystems Inc, Buffalo Grove, IL). Data, reported by number of neurons per cubic millimeter of brain tissue are presented as means and SEM. Data were analyzed using the Mann-Whitney U and Kruskal-Wallis tests as appropriate. RESULTS A total of 34 fetuses were studied. There was no significant difference in neuroapoptosis observed in fetuses exposed to 2% isoflurane for 1 hour or 4% isoflurane for 3 hours. Increased neuroapoptosis was observed in the frontal cortex following repeated 2% isoflurane exposure compared to controls (1.57 ± 0.22 × 10(6)/mm(3) vs 1.01 ± 0.44 × 10(6)/mm(3), P = .02). Fetuses at 70 days gestation with repeated exposure demonstrated decreased frontal cortex neurons at day 130 when compared to age-matched controls (2.42 ± 0.3 × 10(5)/mm(3) vs 7.32 ± 0.4 × 10(5)/mm(3), P = .02). No significant difference in neuroapoptosis was observed between the repeated exposure group and controls in the hippocampus, cerebellum, or basal ganglia. CONCLUSION Repeated isoflurane exposure in midgestation sheep resulted in increased frontal cortex neuroapoptosis. This persisted into late gestation as decreased neuronal cell density. While animal studies should be extrapolated to human beings with caution, our findings suggest that the number of anesthetic/sedative exposures should be considered when contemplating the risks and benefits of fetal intervention as certain fetal therapies may need to be repeated.

Assessment of quality of life outcomes using the pediatric quality of life inventory survey in prenatally diagnosed congenital diaphragmatic hernia patients.

INTRODUCTION Congenital diaphragmatic hernia patients can have significant postnatal morbidity. To date, there has been no quality of life (QOL) study in a prenatally diagnosed CDH patient population, assessing prenatal disease severity and QOL. The purpose of this pilot study was to assess the QOL in a single institution fetal center CDH experience. METHODS The study was a retrospective cohort study of CDH patients diagnosed by fetal ultrasound and MRI at a fetal center between March 2002-March 2014. Parents of children ≥2years were contacted by telephone to participate in the validated Pediatric Quality of Life Inventory (PedsQL™, Version 4.0). RESULTS Of 95 CDH survivors, 68 met inclusion criteria, of which 28 (42%) completed the survey (mean age, range: 5.5, 2.3-11.7years). Based on prenatal markers of disease severity, there were no differences in performance between those with mild or severe forms of CDH. Overall, patients had minimal QOL limitations, but those with limitations had a higher risk for oxygen dependence at 30days of life (71%v. 29%, OR 0.16, CI, 0.031-0.82, p=0.02). ECMO was not associated with significantly worse QOL in physical or psychosocial functioning. Cronbachs alpha reliability coefficient yielded a correlation of 0.951 for the overall survey, 0.911 for physical functioning, and 0.901 for psychosocial functioning questions. CONCLUSIONS Patients that are prenatally diagnosed with severe forms of CDH have similar QOL outcomes across all categories of physical and psychosocial functioning. This pilot study is encouraging and may allow improved counseling for expectant parents of CDH patients.

Persistent hypercarbia after resuscitation is associated with increased mortality in congenital diaphragmatic hernia patients

BACKGROUND Within congenital diaphragmatic hernia (CDH) care, there have been attempts to identify clinical parameters associated with patient survival, including markers of postnatal pulmonary gas exchange. This study aimed to identify whether postnatal pulmonary gas exchange parameters correlated with CDH patient survival. METHODS A retrospective review was performed of isolated CDH neonates treated at a single institution from 1/2007 to 12/2013. Patient demographics, prenatal imaging, and postnatal clinical parameters, including arterial blood gas values within the first 24hours of life, were collected. RESULTS Seventy-four patients with isolated CDH were identified. Fifty-seven had fetal MRI. Overall, 30-day patient survival was 85%. Sixteen infants (22%) required ECMO within 24hours. Mean initial PaCO2 in nonsurvivors was higher, and infants who remained hypercarbic postresuscitation (72±19mmHg) had a worse prognosis than those who resuscitated to a normal PaCO2 (39±1.6mmHg) (p<0.001). Prenatal fetal lung volumes measured by MRI were not strongly correlated with PaCO2 levels. CONCLUSION CDH nonsurvivors are unable to maintain sufficient pulmonary gas exchange during the first 24hours of resuscitation. Furthermore, prenatal fetal lung volumes are weakly correlated with actual pulmonary gas exchange. These data may be useful for patient counseling during the resuscitative phase of CDH care.

Predictive Value of MRI Findings for the Identification of a Hernia Sac in Fetuses With Congenital Diaphragmatic Hernia

OBJECTIVE The purpose of this study was to identify MRI features of diaphragmatic hernia sac, as well as to assess the accuracy of diagnosing a sac prenatally. MATERIALS AND METHODS All fetal MRI examinations performed for intrapleural congenital diaphragmatic hernia (CDH) from 2004 to 2013 were retrospectively reviewed by two pediatric radiologists blinded to the hernia sac status (defined intraoperatively or at autopsy). Reviewers noted whether a sac was present on the basis of identification of the following four MRI findings: 1, meniscus of lung posterior or apical to the hernia contents; 2, encapsulated appearance of hernia contents, exerting less than expected mass effect on the heart and mediastinum; 3, presence of pleural fluid outlining a sac from above; and 4, presence of ascites outlining a sac from below. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each finding and for various combinations. Contingency tables, chi-square testing, and logistic regression were applied to calculate the probability of a sac. RESULTS Ninety patients were included: 21 with and 69 without a sac. The first three MRI findings correlated with the presence of a sac. Logistic regression yielded high predicted probability of a sac when one finding was identified (finding 1, 94.4%; finding 2, 96.2%). Adding a second and a third finding improved the probability to 99.7% and 99.9%, respectively. Sensitivity and specificity for the presence of a sac were 0.43 and 0.97, respectively. PPV and NPV were 83.8% and 80%, respectively. CONCLUSION On fetal MRI, presence of a hernia sac in CDH can be diagnosed with high specificity when indicative findings are present.

5, 4, 3, 2, 1: embryologic variants of pentalogy of Cantrell

BACKGROUND The purpose of this study was to evaluate our experience with pentalogy of Cantrell and the various embryologic variants. MATERIALS AND METHODS Patient charts and diagnostic imaging studies of all fetuses evaluated at Texas Childrens Fetal Center for pentalogy of Cantrell between April 2004 and June 2014 were reviewed retrospectively. Data collected from patient charts included demographic information, clinical presentation, fetal and postnatal imaging findings, operative treatment, pathologic evaluation, and outcomes. RESULTS There were 10 patients who presented with embryologic variants of pentalogy of Cantrell over a 6-y period. Two cases displayed the full range of embryologic defects observed, and eight cases exhibited variants of the classic pentalogy. Sternal and pericardial defects were each present in 40% of patients. Additional anomalies present included pulmonary hypoplasia, pulmonary artery stenosis, and chromosomal abnormalities. Four patients presented with diaphragmatic defects but no defect in the pericardium, and one patient presented with a defective pericardium but no associated diaphragmatic defect, suggesting highly specific losses of somatic mesoderm during embryologic development. One patient was lost to follow-up, and a second patient underwent termination of pregnancy. Five of the remaining eight patients survived, one of which had the full range of embryologic defects and now attends preschool but requires speech and occupational therapy. The remaining surviving patients have developed without serious sequelae. CONCLUSIONS This report highlights the spectrum of anomalies observed in the pentalogy of Cantrell and demonstrates that these fetuses can survive but with substantial morbidity.