Lung proliferation is dependent on the duration not the timepoint of tracheal occlusion in nitrofen rats with diaphragmatic hernia.

OBJECTIVE: Prenatal tracheal occlusion (TO) promotes lung growth and is applied clinically in fetuses with congenital diaphragmatic hernia (CDH). Limited data are available regarding the effect of duration versus timepoint of TO. Our objective was to document the impact of TO on lung development in the near-term period in rats with nitrofen-induced CDH. METHOD: Nitrofen was administered on embryonic day (ED)9 and fetal TO was performed on ED18.5, 19, or 20 (term = ED22). Sham-operated and untouched littermates served as controls. Lungs were harvested in 0.5-day steps and only fetuses with a left-sided CDH were included in further analyses. Healthy fetuses provided a reference for normal near-term lung development. RESULTS: Duration of TO in the nitrofen rat model for CDH predicts lung growth in terms of lung-body-weight ratio as well as an increased mRNA level of the proliferation marker Ki67. Longer TO also induced a more complex airway architecture. The timepoint of TO was not predictive of lung growth. CONCLUSION: In the nitrofen rat model of CDH, a longer period of TO leads to enhanced lung growth and more refined airway architecture.

Micro-computed tomography of isolated fetal hearts following termination of pregnancy: A feasibility study at 8 to 12 weeks' gestation.

OBJECTIVES: To assess the feasibility of retrieval of intact human fetal hearts after first trimester surgical termination of pregnancy (TOP) and subsequent anatomical assessment by postmortem micro-computed tomography (micro-CT). METHODS: In a cohort of consenting women undergoing surgical TOP between 8 and 13 weeks' gestation, we attempted the retrieval of the fetal heart from the suction material. Specimens were immersion fixed in 10% formaldehyde, scanned by iodine-enhanced micro-CT and cardiac anatomy assessed by a multidisciplinary team using 3D-multiplanar analysis. RESULTS: The median gestational age at TOP was 10.7 weeks (range 8.3-12.9). In 57 (95.0%) out of 60 suction specimens, the heart could be retrieved. The median cardiac length was 5 mm (range 2-8 mm), in three (5.3%), the heart was too damaged to assess cardiac anatomy and in five (8.7%) only the four chambers could be examined. In the remaining 49 (86.0%) cases, a detailed assessment of cardiac anatomy was possible, showing a major defect in two (4.1%) and a minor defect in four (8.2%). CONCLUSIONS: Fetal hearts can be retrieved after first trimester TOP being intact in the vast majority of cases. Iodine-enhanced, postmortem micro-CT can be used to assess cardiac anatomy from as early as 8 weeks and to describe heart abnormalities.

High-Resolution (1)H NMR Spectroscopy Discriminates Amniotic Fluid of Fetuses with Congenital Diaphragmatic Hernia from Healthy Controls.

Lung hypoplasia in congenital diaphragmatic hernia (CDH) is a life-threatening birth defect. Severe cases can be offered tracheal occlusion to boost prenatal lung development, although defining those to benefit remains challenging. Metabonomics of (1)H NMR spectra collected from amniotic fluid (AF) can identify general changes in diseased versus healthy fetuses. AF embodies lung secretions and hence might contain pulmonary next to general markers of disease in CDH fetuses. AF from 81 healthy and 22 CDH fetuses was collected. NMR spectroscopy was performed at 400 MHz to compare AF from fetuses with CDH against controls. Several advanced feature extraction methods based on statistical tests that explore spectral variability, similarity, and dissimilarity were applied and compared. This resulted in the identification of 30 spectral regions, which accounted for 80% variability between CDH and controls. Combination with automated classification discriminates AF from CDH versus healthy fetuses with up to 92% accuracy. Within the identified spectral regions, isoleucine, leucine, valine, pyruvate, GABA, glutamate, glutamine, citrate, creatine, creatinine, taurine, and glucose were the most concentrated metabolites. As the metabolite pattern of AF changes with fetal development, we have excluded metabolites with a high age-related variability and repeated the analysis with 12 spectral regions, which has resulted in similar classification accuracy. From this analysis, it was possible to distinguish between AF from CDH fetuses versus healthy controls independent of gestational age.

Fetal heart pathology on postmortem 3-T magnetic resonance imaging.

INTRODUCTION: Postmortem magnetic resonance imaging (pmMRI) is increasingly used in perinatology, typically as an alternative or complement to conventional necropsy for central nervous system anomalies. Overall, it provides reliable information on structural malformations but was shown to be of limited use in examining the fetal heart. OBJECTIVE: We aimed to assess the fetal heart on 3-T pmMRI in a consecutive series of fetuses with structural congenital heart defects (CHD) and to determine diagnostic evaluation limits in case of CHD. METHODS: A single-center database was retrospectively reviewed. Only fetuses having CHD of functional significance were included. Fetal cardiac anatomy was assessed on T2-weighted 3D multiplanar reconstructed images acquired using isovolumetric voxel size (0.3-0.8 mm(3) ), which allows to visualize cardiac structures in situ in multiple fetal body planes. Cardiac pathology was classified into complex and isolated CHD. On the basis of clinically relevant findings, pmMRI was considered either diagnostic or not diagnostic. RESULTS: A total of 24 fetuses were included in this study. The median gestational age was 22 weeks and 2 days (range 12w5d-34w6d). The median delay between delivery of the fetus and MR was 6 h and 30 min (range 1 h and 30 min-19 h). PmMRI was diagnostic for 12 out of 13 (92.3%) complex CHD and for 6 out of 11 (54.5%) isolated CHD. In case of valvular malformation, a tentative diagnosis was reached in 7/11 cases (64%) on the basis of indirect features. CONCLUSIONS: Postmortem MRI is a valid diagnostic tool for CHD in fetuses beyond 16 weeks up to term.

A pictorial essay on fetal rabbit anatomy using micro-ultrasound and magnetic resonance imaging.

INTRODUCTION: With this pictorial essay, we aimed to provide gestational age specific reference ranges of relevant fetal structures using micro-ultrasound, as well as its correlation with postmortem MRI and whole body sections. MATERIAL AND METHODS: Time-mated pregnant rabbits (n = 24) were assessed once at various gestational ages in the second half of pregnancy (15, 17, 21 to 23, 25 to 28, and 30 to 31 days; term = 31 days). We obtained biometric data, together with Doppler flow patterns in the ductus venosus, umbilical artery and umbilical vein. After euthanasia, micro-ultrasound images were compared with images obtained by 9.4 Tesla MRI and whole body paraffin sections at 15, 23, 26, and 28 days. RESULTS: We constructed biometric normative curves, which showed a significant correlation with gestational age. The pulsatility index (PI) in the umbilical artery decreased with gestation (PI = 5.746-0.2969(GA) + 0.004931(GA)(2) ; R(2) = 0.30), whereas pulsatility index for veins (PIV) in the ductus venosus remained constant (median PIV = 0.82 (0.60-1.12)). In this report, we provide an anatomical atlas of fetal thoracic development using both micro-ultrasound and MRI. CONCLUSION: We describe anatomical fetal leporine development as can be visualized by micro-ultrasound and MR imaging. The reported reference ranges may be useful for researchers using the fetal rabbit model.

Postmortem high-resolution fetal magnetic resonance imaging in three cases of lower urinary tract obstruction.

In this manuscript we report 3 cases of severe lower urinary tract obstruction diagnosed before 20 weeks of pregnancy. All cases had a very similar prenatal presentation with a megacystis, bilateral hydro-ureteronephrosis and increased echogenicity of the kidneys. High-resolution postmortem magnetic resonance imaging (MRI), following termination of pregnancy, enabled accurate investigation of the underlying cause of the urinary tract obstruction, by depicting the presence of an urethral valve, urethral atresia and cloacal dysgenesis. Postmortem fetal MRI provides high anatomical detail and is very suitable to investigate congenital anomalies of the lower urinary tract. In case (timely or consented) conventional autopsy is not possible, MRI is an excellent alternative.

A morphometric study of the human fetal heart on post-mortem 3-tesla magnetic resonance imaging.

OBJECTIVE: To report on the feasibility of assessing cardiac structures on post-mortem 3-tesla MRI (pmMRI) and to provide morphometric data in fetuses without cardiac abnormalities. METHODS: Retrospective single center study on 3T pmMRI of 39 consecutive fetuses without cardiac abnormalities (13-38 weeks of gestation). Fetal cardiac anatomy was assessed and measurements of cardiac structures were performed on T2-weighted 3D multiplanar reconstructed images. Linear regression analysis was performed to examine changes of cardiac dimensions during gestation. RESULTS: The four-chamber view of the fetal heart could be obtained and the measurements of cardiac chambers and ventricular walls could be performed in all 39 cases. The aorta and the pulmonary artery were visualized and their diameters were measured in 38 (97.4%) fetuses, ductus arteriosus in 32 (82%). All measurements showed strong linear correlation with gestational age. The relationship of the diameters of the pulmonary artery, aorta, and ductus arteriosus remained constant over pregnancy. All these observations are consistent with what is known from prenatal ultrasound. CONCLUSIONS: The present study proves the feasibility of visualizing normal cardiac structures on 3-tesla pmMRI in fetuses beyond 14 weeks. We provide morphometric data that may enable diagnostic evaluation of cardiac abnormalities on pmMRI.

Postmortem fetal imaging of a metabolic pluricystic kidney disease.

Postmortem magnetic resonance images of a pluricystic kidney disease due to an inborn error of the fatty acid metabolism are presented.

The correlation between lung volume and liver herniation measurements by fetal MRI in isolated congenital diaphragmatic hernia: a systematic review and meta-analysis of observational studies.

OBJECTIVE: We conducted a meta-analysis to assess the correlation of lung volume and liver position measured by magnetic resonance imaging (MRI) with survival until discharge in fetuses with isolated congenital diaphragmatic hernia (CDH). METHOD: Systematic searches of MEDLINE and EMBASE from 1 January 1980 to 10 December 2010 were performed. Studies correlating total fetal lung volumes (TFLV, observed/expected (O/E) TFLV) and/or liver position by fetal MRI to survival in expectantly managed fetuses with CDH were included. Data on the side of the defect, position of the liver, TFLV, O/E TFLV, gestational age (GA) at MRI, GA and weight at birth were collected. Odds ratio (OR) for dichotomous data, mean differences (MD) or standardized mean differences (SMD) for continuous variables were determined using RevMan 5.0 software. RESULTS: Nineteen studies (n = 602 fetuses) were included. Survival was associated with left-sided defects (OR 2.52; p = 0.01), "liver down" (OR 0.18; p < 0.00001), a higher TFLV (MD 9.63; p < 0.00001) and O/E TFLV (SMD 0.98; p < 0.00001) as well as higher birth weight (MD 146.60; p = 0.04). GA at MRI (MD 0.70) and GA at birth (MD 0.33) were not correlated with survival. CONCLUSIONS: MRI measurements of fetal lung volumes, liver position and side of the defect correlate well with neonatal survival in fetuses with isolated CDH.

Technical aspects of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia.

In isolated congenital diaphragmatic hernia, prenatal prediction is made based on measurements of lung size and the presence of liver herniation into the thorax. A subset of fetuses likely to die in the postnatal period is eligible for fetal intervention that can promote lung growth. Rather than anatomical repair, this is now attempted by temporary fetal endoscopic tracheal occlusion (FETO). Herein we describe purpose-designed instruments that were developed thanks to a grant from the European Commission. The feasibility and safety of FETO have now been demonstrated in several active fetal surgery programs. The most frequent complication of the procedure is preterm premature rupture of the membranes, which is probably iatrogenic in nature. It does have an impact on gestational age at delivery and complicates balloon removal. FETO is associated with an apparent increase in survival compared with same severity controls, although this needs to be evaluated in a formal trial. The time has come to do so.

Examining the relationship between the lung-to-head ratio measured on ultrasound and lung volumetry by magnetic resonance in fetuses with isolated congenital diaphragmatic hernia.

PURPOSE: In fetuses with isolated congenital diaphragmatic hernia (CDH), lung development can be measured by the lung-to-head ratio (LHR) using ultrasound as well as by lung volumetry determined by fetal magnetic resonance imaging (MRI). We aimed to investigate their relationship as well as to analyze the factors that may have an impact on it. MATERIAL AND METHODS: In 153 consecutive fetuses with isolated CDH, both the LHR and total fetal lung volume (TFLV) were measured. The observed LHR was calculated by dividing the lung area by the head circumference. On MRI, planimetric measurements of ipsilateral, contralateral and TFLV were performed on T(2)-HASTE (half-Fourier acquisition single-shot turbo spin echo) sequences in transverse as well as coronal or sagittal planes. All values were expressed as a ratio of what was observed over what is expected in a gestational age-matched normal fetus. Secondary analyses were performed for right- versus left-sided hernia and for measurements made prior to 25 weeks' gestation. A multivariate linear regression approach was used to determine the influence of the independent variables such as observed/expected (O/E) LHR, gestational age, liver position and CDH side on the dependent variables O/E TFLV and O/E contralateral FLV, and to determine the optimal formulas for calculation of the O/E TFLV as well as contralateral FLV. RESULTS: In total, 200 pairs of measurements were obtained between 20 and 37 weeks' gestation (median 26+6). There was a significant association between the O/E contralateral FLV and O/E LHR (R(2) = 0.44; p < 0.001) as well as between the O/E TFLV and the O/E LHR (R(2) = 0.37; p < 0.001). After adding the independent variables that were first shown to be significant on univariate analysis, the multiple regression analysis demonstrated that gestational age (p = 0.017) and side of the defect (p < 0.001) were predictive of O/E LHR (p < 0.001) and strongly improved the estimation of O/E TFLV (R(2) = 0.43 instead of 0.37 when using O/E LHR only). In terms of estimating O/E contralateral FLV, only the O/E LHR was a significant (p < 0.001) independent predictor (R(2) = 0.44). These correlations also applied when considering only left-sided CDH cases. For measurements done prior to the third trimester, the O/E LHR (p = 0.034), gestational age (p = 0.035) as well as liver herniation (p = 0.029) were significantly correlated to the O/E TFLV (R(2) = 0.33). In terms of predicting the O/E contralateral FLV (R(2) = 0.25), only O/E LHR (p = 0.008) and gestational age (p = 0.037) were useful predictors. CONCLUSION: Measurement of the O/E LHR on ultrasound allows a good estimation of the O/E contralateral FLV as well as TFLV as measured by MRI. Whereas the additional parameters such as gestational age, liver position and side of the defect did not improve the estimation of the contralateral FLV, they did so for estimating the TFLV.

Prenatal anatomical imaging in fetuses with congenital diaphragmatic hernia.

The role of prenatal ultrasound and magnetic resonance imaging in the diagnosis and management of congenital diaphragmatic hernia (CDH) is reviewed. Topics include morphologic imaging and vascular assessment of the developing lung, the value of imaging parameters as prognostic predictors in CDH and the role of imaging following percutaneous fetoscopic endoluminal tracheal occlusion.

Fetal surgery is a clinical reality.

An increasing number of fetal anomalies are being diagnosed prior to birth, some of them amenable to fetal surgical intervention. We discuss the current clinical status and recent advances in endoscopic and open surgical interventions. In Europe, fetoscopic interventions are widely embraced, whereas the uptake of open fetal surgery is much less. The indications for each access modality are different, hence they cannot substitute each other. Although the stage of technical experimentation is over, most interventions remain investigational. Today there is level I evidence that fetoscopic laser surgery for twin-to-twin transfusion syndrome is the preferred therapy, but this operation actually takes place on the placenta. In terms of surgery on the fetus, an increasingly frequent indication is severe congenital diaphragmatic hernia as well as myelomeningocele. Overall maternal safety is high, but rupture of the membranes and preterm delivery remain a problem. The increasing application of fetal surgery and its mediagenicity has triggered the interest to embark on fetal surgical therapy, although the complexity as well as the overall rare indications are a limitation to sufficient experience on an individual basis. We plead for increased exchange between high volume units and collaborative studies; there may also be a case for self-regulation. Inclusion of patients into trials whenever possible should be encouraged rather than building up casuistic experience.