Jean-Luc Bigras

The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects.

Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis. A common variant in MTHFD1, p.Arg653Gln (c.1958G>A), may increase the risk for neural tube defects (NTD). To examine the biological impact of this variant on MTHFD1 function, we measured enzyme activity and stability in vitro and assessed substrate flux in transfected mammalian cells. The purified Arg653Gln enzyme has normal substrate affinity but a 36% reduction in half)life at 42°C. Thermolability is reduced by magnesium adenosine triphosphate and eliminated by the substrate analog folate pentaglutamate, suggesting that folate status may modulate impact of the variant. The mutation reduces the metabolic activity of MTHFD1 within cells: formate incorporation into DNA in murine Mthfd1 knockout cells transfected with Arg653Gln is reduced by 26%±7.7% (P<0.05), compared to cells transfected with wild)type protein, indicating a disruption of de novo purine synthesis. We assessed the impact of the variant on risk for congenital heart defects (CHD) in a cohort of Quebec children (158 cases, 110 controls) and mothers of children with heart defects (199 cases, 105 controls). The 653QQ genotype in children is associated with increased risk for heart defects (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.01–4.42), particularly Tetralogy of Fallot (OR, 3.60; 95% CI, 1.38–9.42) and aortic stenosis (OR, 3.13; 95% CI, 1.13–8.66). There was no effect of maternal genotype. Our results indicate that the Arg653Gln polymorphism decreases enzyme stability and increases risk for CHD. Further evaluation of this polymorphism in folate)related disorders and its potential interaction with folate status is warranted. Hum Mutat 0,1–9, 2008.

Predicting Outcome in Primary Fetal Hydrothorax

Objective: This study examines the role of serial ultrasound in predicting fetal outcomes based on progress, resolution or stability of pleural effusions in primary fetal hydrothorax (PFHT). Methods: Records from consecutive cases of fetal pleural effusions referred to the fetal echocardiography unit over a 12-year period were reviewed. Study patients underwent thorough investigation to rule out secondary causes of pleural effusions. The clinical course was monitored with serial ultrasound studies every 2 weeks until delivery. Pleurocentesis and pleuroamniotic shunts were performed in select cases of PFHT. Fetal survival was the primary outcome variable. Results: Eighteen of 44 patients referred for perinatal evaluation of fetal pleural effusions met the study criteria for PFHT. Diagnosis was made at 28 ± 7 weeks and fetuses delivered at 35 ± 3 weeks’ gestational age. Overall survival was 78%. Effusion progression, greater effusion ratios, earlier gestational age at delivery, and lower Apgar scores at birth were associated with poor outcome. Conservative management was appropriate for most cases. Conclusions: Serial ultrasound studies to evaluate the clinical course of the pleural effusions are essential in the management of PFHT. Expectant management of stable and resolving effusions was appropriate in all cases.

Factors affecting the prognosis of Ebstein's anomaly during fetal life

BACKGROUNDnThe echocardiographic criteria that have been used to evaluate severity of Ebsteins anomaly in utero are the same as those applied after birth.nnnOBJECTIVEnThe objective of this study was to establish prognostic criteria that take into account the peculiarities of the fetal hemodynamics.nnnMETHODnThe video recordings of eight fetuses with Ebsteins anomaly were retrospectively reviewed.nnnRESULTSnThe following indexes had no prognostic significance either on fetal or neonatal outcome: the ratio of functional tricuspid opening over the diameter of the annulus, the degree of displacement of the tricuspid valve opening, and the degree of tricuspid regurgitation. The index of severity (based on the surfaces of right atrium + atrialized right ventricle) and the cardiothoracic ratio had a significant impact only on neonatal survival. The smallest fossa ovalis were found in two fetuses who had hydrops. Fetuses who reached term without problems had higher left ventricular outputs. A positive linear correlation was found between the z score of the left ventricular output and the size of the fossa ovalis (r = 0.81, p < 0.05).nnnCONCLUSIONnThe prognosis of Ebsteins anomaly during fetal life is not influenced by criteria described for postnatal life and may be related to factors that control the volume load of the left ventricle.

Cardiovascular responses to dynamic submaximal exercise in children previously treated with anthracycline

This study assessed the long-term (5-year) outcome of pediatric low-dose anthracycline therapy on the circulatory response to moderate exercise. Thirteen patients (13 +/- 4 years old) and 15 age-matched control subjects completed a maximal cycle ergometer protocol as well as two 5-minute cycling tests at 33% and 66% maximal oxygen uptake (V(O2)max) for determination of cardiac index (carbon dioxide rebreathing). V(O2)max was lower in patients than in control subjects (1.3 +/- 0.5 L/min vs 2.3 +/- 0.6 L/min) (p< 0.05). Smaller relative increases in cardiac index for similar increases in relative exercise intensities were found in patients (33% V(O2)max, 73% vs 116%; 66% V(O2)max, 115% vs 192%), as a result of smaller increases in stroke index from rest (33% V(O2)max, 33% vs 54%; 66% V(O2)max, 33% vs 69%; p< 0.05). Similarly, despite normal resting systolic function, patients exhibited a lower stroke index and higher heart rate for any given value of oxygen uptake (milliliters per minute per square meter). Children who had survived cancer exhibited stroke index impairment during exercise similar in intensity to that of recreational activities or play, attesting to a limited inotropic reserve.

Feasibility and reliability of Doppler flow recordings in the fetal aortic isthmus: a multicenter evaluation

To evaluate the performance of three different centers with respect to their ability to identify the fetal aortic isthmus (AoI) adequately and place a Doppler sample volume in the AoI correctly, and to address the reproducibility of the isthmic flow index (IFI) calculated from Doppler waveforms recorded in the three centers.

Bias Related to Body Mass Index in Pediatric Echocardiographic Z Scores

In pediatric echocardiography, cardiac dimensions are often normalized for weight, height, or body surface area (BSA). The combined influence of height and weight on cardiac size is complex and likely varies with age. We hypothesized that increasing weight for height, as represented by body mass index (BMI) adjusted for age, is poorly accounted for in Z scores normalized for weight, height, or BSA. We aimed to evaluate whether a bias related to BMI was introduced when proximal aorta diameter Z scores are derived from bivariate models (only one normalizing variable), and whether such a bias was reduced when multivariable models are used. We analyzed 1,422 echocardiograms read as normal in children ≤18xa0years. We computed Z scores of the proximal aorta using allometric, polynomial, and multivariable models with four body size variables. We then assessed the level of residual association of Z scores and BMI adjusted for age and sex. In children ≥6xa0years, we found a significant residual linear association with BMI-for-age and Z scores for most regression models. Only a multivariable model including weight and height as independent predictors produced a Z score free of linear association with BMI. We concluded that a bias related to BMI was present in Z scores of proximal aorta diameter when normalization was done using bivariate models, regardless of the regression model or the normalizing variable. The use of multivariable models with weight and height as independent predictors should be explored to reduce this potential pitfall when pediatric echocardiography reference values are evaluated.

Echocardiographic evaluation of fetal hydrothorax: the effusion ratio as a diagnostic tool

Fetal hydrothorax may lead to hydrops and is associated with mortality as high as 50%. The objective of this study was to define the pathophysiology of fetal hydrothorax and its relation to hydrops.

Therapeutic Strategies in Children with an Isolated Unilaterally Absent Proximal Pulmonary Artery

Therapeutic strategies for isolated unilateral absence of a proximal pulmonary artery remain unclear. The natural history of the disease, or thrombosis of primary surgical anastomosis, leads to exclusion of the affected lung with increased risk of intrapulmonary bleeding, impaired quality of life, and shortened life expectancy. We herein describe our two-stage approach in a small series of patients starting with interventional catheterization followed by surgical anastomosis. Other medical interventions, such as anticoagulation and pulmonary vasodilatation, are key factors to successfully restore pulmonary circulation in this rare defect.

Reference Values and Z Scores for Pulsed-Wave Doppler and M-Mode Measurements in Fetal Echocardiography.

BACKGROUNDnFetal echocardiography is now the standard approach for detailed investigations of fetal cardiac anatomy and function. Available studies proposing reference values for pulsed-wave Doppler (PWD) measurements are often focused on few parameters. Furthermore, the methodology used for validating these proposed reference values is sometimes insufficiently described, and parameters necessary to compute Zxa0scores are not always available. Improved definition of reference values with adequate statistical validation is needed for proper interpretation of PWD measurements in a clinical setting. In this study, the authors propose a comprehensive set of reference values and Z score equations for fetal PWD and M-mode measurements with thorough assessment of Z score quality and validity.nnnMETHODSnWomen with normal singleton pregnancies between 18 and 39xa0weeks of gestational age were included. A set of 57 measurements was performed, including PWD, M-mode measurements, and calculation of systolic, diastolic, and global function indices. Several parametric regressions were tested to model each measurement against gestational age. The SD was also modeled to account for heteroscedasticity. Z score equations were computed, and the proposed reference values were tested for residual association, residual heteroscedasticity, and departure from the normal distribution.nnnRESULTSnOne hundred four uncomplicated singleton pregnancies with normal fetal hearts were included. Nonlinear relationships with gestational age were found for most measurements. Parametric normalization was successful for most measurements analyzed, and it was possible to compute Z score equations with minimal residual association with gestational age, no residual heteroscedasticity, and no significant departure from the normal distribution.nnnCONCLUSIONSnThe authors propose a comprehensive set of Z score equations for 57 fetal functional measurements, some of which do not have any published reference values. These Z score equations will allow echocardiographers to more accurately identify measurements that diverge from normal and thus detect earlier potential alterations in fetal heart function.

Echocardiographic Predictors of Outcome in Newborns with Congenital Diaphragmatic Hernia † 143

OBJECTIVEnDespite new treatments, congenital diaphragmatic hernia (CDH) still has high mortality. The aim of this study was to identify echocardiographic predictors of outcome in newborns with an isolated CDH.nnnMETHODSnWe reviewed medical charts and echocardiograms of 40 newborns who presented with CDH in the first 24 hours of life, from 1992 to 1996. We compared the cardiac valves and great arteries diameters, left-ventricular volume and mass, Apgar scores, and modified McGoon index (the combined diameter of hilar pulmonary arteries, indexed to the descending aorta) of survivors and nonsurvivors. We performed Students t test and multiple logistic regression analysis between the 2 groups.nnnRESULTSnFourteen patients died 1 to 33 days after birth (median: 3 days), including 8 from progressive hypoxemia without operation; 26 have survived up to 5 years (median: 2 years) after successful operations. Nonsurvivors had significantly smaller diameters of right and left hilar pulmonary arteries, more frequent right-sided CDH, and lower mean Apgar scores at 1 and 5 minutes. The most significant prognostic factor was the modified McGoon index. A modified McGoon index </=1.3 predicted mortality with a sensitivity of 85% and specificity of 100%.nnnCONCLUSIONnEchocardiographic measurement of hilar pulmonary arteries, which may represent the adequacy of the pulmonary vascular bed, is a strong prognostic factor for newborns with congenital CDH.