Ernst M. Schoonderwaldt

Prenatal detection and outcome of congenital diaphragmatic hernia (CDH) associated with deletion of chromosome 15q26: two patients and review of the literature.

Congenital diaphragmatic hernia (CDH) is a severe birth defect characterized by a defect in the diaphragm with pulmonary hypoplasia and postnatal pulmonary hypertension. Approximately 50% of CDH cases are associated with other non‐pulmonary congenital anomalies (so called non‐isolated CDH) and in 5–10% of cases there is a chromosomal etiology. The majority of CDH cases are detected prenatally. In some cases prenatal chromosome analysis reveals a causative chromosomal anomaly, most often aneuploidy. Deletion of 15q26 is the most frequently described structural chromosomal aberration in patients with non‐isolated CDH. In this paper we report on two patients with a deletion of 15q26 and phenotypes similar to other patients with CDH caused by 15q26 deletions. This phenotype consists of intra‐uterine growth retardation, left‐sided CDH, cardiac anomalies and characteristic facial features, similar to those seen in Fryns syndrome. We propose that when this combination of birth defects is identified, either pre‐ or postnatally, further investigations to confirm or exclude a deletion of 15q26 are indicated, since the diagnosis of this deletion will have major consequences for the prognosis and, therefore, can affect decision making.

Human fetal amino acid metabolism at term gestation.

BACKGROUND Knowledge on human fetal amino acid (AA) metabolism, largely lacking thus far, is pivotal in improving nutritional strategies for prematurely born infants. Phenylalanine kinetics is of special interest as is debate as to whether neonates will adequately hydroxylate phenylalanine to the semiessential AA tyrosine. OBJECTIVE Our aim was to quantify human fetal phenylalanine and tyrosine metabolism. DESIGN Eight fasted, healthy, pregnant women undergoing elective cesarean delivery at term received primed continuous stable-isotope infusions of [1-(13)C]phenylalanine and [ring-D(4)]tyrosine starting before surgery. Umbilical blood flow was measured by ultrasound. Maternal and umbilical cord blood was collected and analyzed by gas chromatography-mass spectrometry for phenylalanine and tyrosine enrichments and concentrations. Data are expressed as medians (25th-75th percentile). RESULTS Women were in a catabolic state for which net fetal AA uptake was responsible for > or = 25%. Maternal and fetal hydroxylation rates were 2.6 (2.2-2.9) and 7.5 (6.2-15.5) micromol phenylalanine/(kg . h), respectively. Fetal protein synthesis rates were higher than breakdown rates: 92 (84-116) and 73 (68-87) micromol phenylalanine/(kg . h), respectively, which indicated an anabolic state. The median metabolized fraction of available phenylalanine and tyrosine in the fetus was <20% for both AAs. CONCLUSIONS At term gestation, fetuses still show considerable net AA uptake and AA accretion [converted to tissue approximately 12 g/(kg . d)]. The low metabolic uptake (AA usage) implies a very large nutritional reserve capacity of nutrients delivered through the umbilical cord. Fetuses at term are quite capable of hydroxylating phenylalanine to tyrosine.

Amino Acid Metabolism in the Human Fetus at Term: Leucine, Valine, and Methionine Kinetics

Human fetal metabolism is largely unexplored. Understanding how a healthy fetus achieves its fast growth rates could eventually play a pivotal role in improving future nutritional strategies for premature infants. To quantify specific fetal amino acid kinetics, eight healthy pregnant women received before elective cesarean section at term, continuous stable isotope infusions of the essential amino acids [1-13C,15N]leucine, [U-13C5]valine, and [1-13C]methionine. Umbilical blood was collected after birth and analyzed for enrichments and concentrations using mass spectrometry techniques. Fetuses showed considerable leucine, valine, and methionine uptake and high turnover rates. α-Ketoisocaproate, but not α-ketoisovalerate (the leucine and valine ketoacids, respectively), was transported at net rate from the fetus to the placenta. Especially, leucine and valine data suggested high oxidation rates, up to half of net uptake. This was supported by relatively low α-ketoisocaproate reamination rates to leucine. Our data suggest high protein breakdown and synthesis rates, comparable with, or even slightly higher than in premature infants. The relatively large uptakes of total leucine and valine carbon also suggest high fetal oxidation rates of these essential branched chain amino acids.

Reproducibility of echocardiographic measurements of human fetal left ventricular volumes and ejection fractions using four-dimensional ultrasound with the spatio-temporal image correlation modality.

OBJECTIVES To determine the reproducibility, both reliability and agreement, of measurements of fetal left ventricular parameters from volumes obtained by spatio-temporal image correlation (STIC) acquisition applying virtual organ computer-aided analysis (VOCAL) and Simpsons rule (method of discs). Furthermore the success rate of STIC acquisition was determined. STUDY DESIGN In 84 pregnancies between 20 and 34 weeks of gestation the fetal heart was scanned using the STIC modality. An optimal four-chamber view in end-diastole and end-systole was obtained. Left ventricular end-diastolic volume, left ventricular end-systolic volume, stroke volume and ejection fraction were determined. For calculations based on Simpsons rule only one plane was traced, whereas for VOCAL six planes were traced. To quantify the reliability intraclass correlation coefficients were calculated for both intra- and inter-observer measurements. Agreement of measurements was evaluated by Bland-Altman plots. RESULTS The STIC volumes of 54 women (64%) were excluded from the study because of poor quality, leaving 30 volumes for further analysis. Intraclass correlation coefficients for intra-observer reliability for VOCAL and Simpson were 0.99 and 0.99 for left ventricular end-diastolic volume, 0.95 and 0.92 for left ventricular end-systolic volume, 0.98 and 0.97 for stroke volume, 0.76 and 0.77 for ejection fraction, respectively. Intraclass correlation coefficients for inter-observer reliability for VOCAL and Simpson were 0.97 and 0.86 for left ventricular end-diastolic volume, 0.97 and 0.86 for left ventricular end-systolic volume, 0.95 and 0.81 for stroke volume, 0.68 and 0.63 for ejection fraction, respectively. According to Bland-Altman plots, the mean percentage difference and 95% limits of intra- and inter-observer agreement for left ventricular stroke volume measurements using VOCAL were -0.2 (-25.1, 24.7)% and 2.8 (-34.2, 39.8)%, respectively. For left ventricular stroke volume measured with Simpson versus VOCAL the mean percentage difference and 95% limits of agreement were -1.8 (-22.1, 18.5)%. CONCLUSIONS 4D STIC enables reproducible measurements of left ventricular volumes. Reliability of the VOCAL mode is not essentially different from the single-plane method used in Simpsons rule. The large percentage of poor quality STIC volumes and the wide limits of inter-observer agreement would create obstacles for the clinical applicability of this technique.

First-trimester detection of surface abnormalities: A comparison of 2- and 3-dimensional ultrasound and 3-dimensional virtual reality ultrasound

The aim was to determine the diagnostic performance of 3-dimensional virtual reality ultrasound (3D_VR_US) and conventional 2- and 3-dimensional ultrasound (2D/3D_US) for first-trimester detection of structural abnormalities. Forty-eight first trimester cases (gold standard available, 22 normal, 26 abnormal) were evaluated offline using both techniques by 5 experienced, blinded sonographers. In each case, we analyzed whether each organ category was correctly indicated as normal or abnormal and whether the specific diagnosis was correctly made. Sensitivity in terms of normal or abnormal was comparable for both techniques (P = .24). The general sensitivity for specific diagnoses was 62.6% using 3D_VR_US and 52.2% using 2D/3D_US (P = .075). The 3D_VR_US more often correctly diagnosed skeleton/limb malformations (36.7% vs 10%; P = .013). Mean evaluation time in 3D_VR_US was 4:24 minutes and in 2D/3D_US 2:53 minutes (P < .001). General diagnostic performance of 3D_VR_US and 2D/3D_US apparently is comparable. Malformations of skeleton and limbs are more often detected using 3D_VR_US. Evaluation time is longer in 3D_VR_US.

OC019: Reproducibility of echocardiographic measurements of human fetal left ventricular volumes and ejection fractions using 4D ultrasound with the STIC modality

Male n = 65 13.1 23.0 ± 6.7 41.1 ± 11.3 0.559 ± 0.08 6.6 ± 1.8 0.349 ± 0.16 23.0 ± 6.7 41.1 ± 11.3 0.559 ± 0.08 6.6 ± 1.8 0.349 ± 0.16 1.5 ± 0.7 Male n = 55 20.3 24.5 ± 6.3 41.9 ± 8.1 0.585 ± 0.11 6.2 ± 1.3 0.304 ± 0.14 27.2 ± 6.9 45.4 ± 6.8 0.601 ± 0.11 6.4 ± 1.9 0.387 ± 0.4 1.56 ± 0.7 Female n = 39 13.2 21.2 ± 6.5 39.0 ± 9 0.542 ± 0.11 7.5 ± 2 0.337 ± 0.12 23.5 ± 7.65 41.1 ± 11.7 0.576 ± 0.10 ± 2.1 0.358 ± 0.12 1.56 ± 0.6 Female n = 20 20.6 21.7 ± 6.2 40.9 ± 12.6 0.562 ± 0.12 6.0 ± 1.4 0.329 ± 0.1 24.3 ± 7.7 43.5 ± 11.1 0.551 ± 0.11 6.5 ± 1.4 0.403 ± 0.17 1.64 ± 0.5

Biomarkers of the one-carbon pathway in association with congenital diaphragmatic hernia

Homocysteine is an intermediate of the one-carbon (1-C) pathway and increased concentrations have been related to neural crest-related congenital anomalies. The neural crest and the 1-C pathway might be involved also in the etiology of Congenital Diaphragmatic Hernia (CDH). In 22 CDH and 28 control newborns and their mothers, general characteristics were obtained by standardized questionnaires. The 1-C pathway intermediates total homocysteine (tHcy), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were determined in cord blood. Correlations between maternal and newborn factors and risk estimates were investigated by univariate and multivariable logistic regression analyses. Birth weight (2962 vs. 3418 gram; p < 0.001) was lower and gestational age (270 vs. 277 days; p = 0.006) was shorter in case children. Control mothers were slightly older (32 vs. 35 year; p = 0.05). Other characteristics were comparable between case and control children and mothers. The concentrations of homocysteine, SAM and SAH, and the SAM/SAH ratio were comparable (tHcy: 8.57 vs. 8.56 μmol/l, p = 0.99; SAM: 152.7 vs. 157.3 nmol/l, p = 0.76; SAH: 43.5 vs. 48.9, p = 0.26; ratio: 3.8 vs. 3.5, p = 0.50). Maternal and newborn characteristics were not correlated to the biomarker concentrations. In conclusion, the biomarkers of methylation determined in cord blood are not associated with CDH risk. Maternal and child characteristics could not predict newborn biomarker concentrations of the 1-C pathway.