H. Mahallati's research while affiliated with The University of Calgary and other places

Congenital myopathies are a genetically heterogeneous group of neuromuscular disorders that commonly present with congenital hypotonia and weakness but can also present broadly. The most severe presentation is neonatal with arthrogryposis and, rarely, fetal akinesia and pterygia, features also seen in lethal multiple pterygium syndrome (LMPS). We describe two fetuses with similar phenotype, including hydrops fetalis, large cystic hygromas, bilateral talipes, and fetal akinesia in the second trimester. Genetic diagnoses were made using exome sequencing. Both fetuses had a severe form of congenital myopathy. In the first fetus, we identified two novel compound heterozygous likely pathogenic variants consistent with autosomal recessive RYR1 ‐related congenital myopathy (congenital myopathy 1B). In the second fetus, we identified two likely pathogenic variants, one of which is novel, likely in trans consistent with a diagnosis of autosomal recessive NEB ‐related congenital myopathy. Reaching a genetic diagnosis for these fetuses allowed the families to receive accurate genetic counseling for future pregnancies. These fetuses highlight the genetic and phenotypic heterogeneity of LMPS, and support a broad approach to genetic testing.

Objectives: Blood Oxygen Level Dependent (BOLD) functional magnetic resonance imaging (f-MRI) technique allows a non-invasive in-vivo evaluation of placental oxygenation. The aim of this study was to highlight and quantify a relative BOLD effect in response to hyperoxia in the human placenta and to compare it between FGR and non-FGR fetuses (fetal growth restricted). Methods: In a prospective multicenter study (NCT02238301), we included 19 FGR fetuses (cases defined by an ultrasound-based estimated fetal weight (EFW) <5th centile) and 75 non-FGR fetuses (controls). Using a 1.5 Tesla MRI system, the same multi-echo gradient recalled echo (GRE) sequences were performed at both centers to obtain: placental T2* values in baseline and in hyperoxic conditions and the relative BOLD effect according to the following equation: Relative BOLD effect = 100 x (hyperoxicT2*-baseline T2*)/baseline T2*. The baseline T2* values and relative BOLD effect were compared according to fetal weight estimations (between FGR and non-FGR fetuses), presence of Doppler anomalies and according to birth weight (between appropriate and small for gestational age newborns - AGA/SGA). Results: We demonstrate a relative BOLD effect in response to hyperoxia in the human placenta, quantified at 33.8% (22.5;48.0). The relative BOLD effect was not statistically different between FGR and non-FGR fetuses (34.4% (26.1-33.4) versus 33.7% (22.7-139.2), p=0.95). Baseline T2* values Z-score adjusted for gestational age at MRI were significantly lower for FGR fetuses as compared with non-FGR fetuses (-1.27 (-4.87;-0.10) vs 0.33 (-0.81;1.02) respectively, p=0.001). Baseline T2* values Z-score were also significantly lower for the subsequently SGA neonates (-0.75 (-3.48; 0.29 n=23) vs 0.35 (-0.79;-1.05 n=62), p=0.01). Conclusions: Our study confirms a BOLD effect in the human placenta and that baseline T2* values are significantly lower in FGR fetuses. Further studies are needed to evaluate whether such parameters may detect placental insufficiency, before it has a clinical impact on fetal growth. This article is protected by copyright. All rights reserved.

Objective A short corpus callosum (SCC) is defined as a generalized hypoplasia with intact morphology. In the absence of any associated fetal anomaly, its management remains challenging because there is no consensus definition or biometric charts upon which to base the diagnosis, and data regarding outcomes of SCC are scarce. Diffusion Tensor Imaging (DTI) evaluation of corpus callosum (CC) has suggested that the presence of Probst bundles in SCC could help to differentiate between callosal dysplasia and variant of normal CC development. We hypothesized that the DTI metrics, which reflects the integrity of the microstructural of the white matter (WM), would be altered in SCC with Probst bundles (PB) as compared to SCC without PB or normal CC and could help to refine the prognosis of CC abnormalities. The objectives of our study were to compare DTI metrics between SCC and normal CC and between SCC with Probst bundles (PB+) and SCC without Probst bundles (PB‐). Methods This was a retrospective study of fetuses referred to the Necker Hospital (Paris, France) for MRI evaluation of an apparently isolated SCC by sonography between 01/2016 and 12/2022 (IRB 0011928). MRI scans were performed on a 1.5T General Electric Sigma system (GE Healthcare, Waukesha, WI, USA). T2 axial and sagittal sequence of the fetal brain were used to measure the length and the thickness of the CC. 16‐direction DTI axial brain sequences were performed to identify the presence of Probst bundles and to generate quantitative imaging metrics (Fractional Anisotropy [FA], Apparent Diffusion Coefficient [ADC]) of the entire CC, the genu, the body and the splenium. Cases with other associated brain abnormalities seen on MRI were excluded. All cases were matched for GA (Gestational Age) with controls at a 1:3 ratio. These were normal fetuses included in the LUMIERE on the FETUS trial (NCT0414206) who underwent the same MRI‐DTI evaluation of the brain. Comparison between short and normal CC and between SCC with PB and without PB were performed using ANOVA test and adjusted for potential confounders using ANCOVA test. Results 22 SCC were included and compared to 66 fetuses with normal CC. In 10/22(45.4%) SCC, PB were identified. As expected, dimensions of the CC were significantly smaller in case of SCC compared to normal CC (all p<0.01). In SCC with PB, FA values were significantly lower compared to SCC without PB in the entire CC (0.21[0.19‐0.24] vs 0.24[0.22‐0.28], p<0.01), the genu (0.21[0.19‐0.24] vs 0.24[0.17‐0.29], p=0.04), the body (0.21[0.18‐0.23] vs 0.23[0.21‐0.27], p=0.04) and the splenium (0.22[0.16‐0.30] vs 0.25[0.20‐0.29], p=0.03). Also, the ADC values were significantly higher in the entire SCC with PB compared to SCC without PB (all p<0.05). In SCC with PB, all FA values were significantly lower, and the ADC in the body was significantly higher compared to normal CC (all p <0.05). In SCC without PB, there was no difference in FA and ADC compared to normal CC (all p>0.05). Conclusion Fetal DTI evaluation of the SCC showed that the FA was significantly lower and ADC significantly higher compared to normal CC in those cases with PB. These differences may highlight alterations of the WM microstructure in SCC with PB. In contrast, isolated SCC without PB does not demonstrate significant changes in diffusion parameters strengthening the possibility of a normal variant. This article is protected by copyright. All rights reserved.

Objectives: Diffusion tensor imaging (DTI) of the fetal brain is a relatively new technique to study central nervous system white matter tracts throughout pregnancy and also in certain pathological conditions. The objectives of this study were: (1) to evaluate the feasibility of DTI of the spinal cord in utero and (2) to examine age-related changes in the DTI parameters during pregnancy. Methods: As part of the Lumiere on the Fetus trial (NCT04142606), we conducted a prospective study, between December 2021 and June 2022 on the Lumiere Platform in Necker Hospital (Paris, France). We included women between 18 and 36 weeks of gestation, without fetal or maternal conditions. Sagittal diffusion-weighted scans of the fetal spine was acquired on a 1.5T MR imaging scanner without sedation. The imaging parameters were as follow: 15 noncolinear direction diffution-weighted magnetic-pulsed gradients with a b-value=700s/mm2 and one B0 image without diffusion-weighting, slice thickness=3mm, FOV=36mm, voxel size=4.5x2/8x3mm3 , TR=2800ms, TE minimum and acquisition time 2.3 minutes. DTI parameters such as fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were extracted at the cervical, upper thoracic, lower thoracic and lumbar levels of the spinal cord. Cases degraded by motion artifacts or aberrant reconstruction of the spinal cord on tractography were excluded. Pearson's correlations were performed to evaluate age-related changes of the DTI parameters during pregnancy. Results: During the study period, 42 women were included in this study at a median gestational age (GA) of 29.3 [18.1-35.7] weeks of gestation. 5/42 (11.9%) of the patients were not included in the analysis because of fetal movement. 2/42 (4.7%) of the patients with aberrant tractography reconstruction were also excluded from analysis. Acquisition of DTI parameters were feasible in the 100% of the remaining cases (35/35). Increasing GA was correlated with increasing FA averaged over the entire fetal spinal cord (r=0.36, p<0.01) as well as individual regions (cervical level (r=0.519, p<0.01), upper thoracic level (r=0.468, p<0.01), lower thoracic level (r=0,425, p=0.02) and lumbar level (r=0.427, p=0.02)). There was no correlation between ADC values and GA over the entire spinal cord (e=0.01, p=0.99) or the individual cervical, upper or lower thoracic, or lumbar segments (respectively r=-0.109, p=0.56 ; r=-0.226, p=0.22 ; r=-0.052, p=0.78 and r=-0.11, p=0.95). Conclusions: This study shows that DTI of the fetal spinal cord is feasible in normal fetuses under typical clinical practice conditions and allows us to extract DTI parameters of the spinal cord. There is a significant GA-related change of the FA in the spinal cord during pregnancy which may result from decreasing water content as observed during myelination of fiber tracts occurring in utero. This study could serve as a basis for further study of this technique in the fetus, including potential for its use in pathological conditions that impact spinal cord development. This article is protected by copyright. All rights reserved.

Objective: Having adequate reference ranges of the size of corpus callosum (CC) is necessary to better characterize CC abnormalities and improve parental counseling. The objective of this study was to evaluate the methodology used in developing different references charts for CC biometry. Methods: We conducted a systematic review of studies of fetal CC biometry using a set of predefined quality criteria of study design, statistical analysis and reporting methods. We including observational studies whose primary aim was to create ultrasound or MRI charts for size of the CC in normal population of fetuses. Studies were scored against a predefined set of independently agreed methodological criteria and an overall quality score was given to each study. Results: Twelve studies met the inclusion criteria. Quality scores ranged between 17.4% and 95.6%. The highest potential for bias was noted in the following fields : "sample selection" and "sample size calculation" where only 17% of the studies were population-based study with consecutive or random recruitment of patient and with a justification of the sample size; "number of measurement taken for CC biometrics" where in only 17% of the studies more one measure per fetus and per scan were performed; "description of characteristics of the study population" where only 9% of the studies clearly reported a minimum dataset of demographic characteristics. Conclusion: Our review demonstrates substantial heterogeneity in methods and final biometry values of fetal CC measurement. The use of uniform methodology of the highest quality is essential in order to define a "short" CC and provide appropriate parental counseling. This article is protected by copyright. All rights reserved.

Background :Preeclampsia affects between 2% and 5% of pregnancies and is one of the leading causes of perinatal morbidity and mortality worldwide. Despite strong evidence that the combination of systematic preeclampsia (PE) screening based on the Fetal Medicine Foundation (FMF, London UK) preeclampsia risk calculation algorithm with treatment of high-risk patients with low dose aspirin (ASA) reduces the incidence of preterm PE more than currently used risk-factor based screening, real world implementation studies have not yet been done in Canada. Objectives : To assess the operational feasibility of implementing first trimester screening and prevention of preterm preeclampsia (PE) (< 37 weeks) alongside a publicly funded first trimester combined screening (FTS) program for aneuploidies. Study Design : Prospective implementation study. Consecutive pregnant patients referred for FTS (11-13+6 weeks) were offered screening for PE based on the FMF algorithm concomitantly with their aneuploidy screen. Consenting participants were screened using maternal risk factors (MF), mean arterial pressure (MAP), uterine artery Doppler pulsatility index (UTAD PI), pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PLGF). Risk for preterm PE (< 37 weeks) was calculated using the FMF algorithm and individuals with a risk score ≥1/100 were recommended to use aspirin (ASA) (162 mg OD @hs, <16-36 weeks). Implementation metrics assessed included: acceptability; operational impact; proportion of aspirin (ASA) initiation; quality and safety measures; and screen performance. Results : Between Dec 1, 2020-April 23, 2021, 1124 patients consented to PE screening (98.3% uptake) and 92 (8.2%) screened positive. Appointments for patients receiving FTS aneuploidy and PE screening averaged 6 minutes longer than FTS alone, adding UTAD PI averaged 2 minutes. Of 92 patients who screened high-risk for PE, 72 (78.3%) were successfully contacted prior to 16 week's gestation. Of these, 62 (86.1%) initiated aspirin, 10 (13.9%) did not. Performance audit identified a consistent negative bias with MAP measurements (median MOM 10% below 1): other variables were satisfactory. There were seven cases of preterm preeclampsia (0.69%); 5 and 2 in the high and low risk groups respectively. Screening detected 5/7 (71.4 %) of preterm preeclampsia cases, with improved performance after adjustment for ASA treatment effect. Conclusions : This study confirms the operational feasibility of implementing an evidence-based PE screening and prevention program in a publicly funded Canadian setting. This will facilitate implementation into clinical service and the scaling up of this program at a regional and provincial level.

Multiple pregnancies are associated with higher risks for both mother and babies. Women with multiple pregnancies have an increased risk of miscarriage, anemia, hypertensive disorders, haemorrhage, and postnatal illness. These pregnancies are more likely to need an operative delivery, and maternal mortality is generally 2.5 times that of singleton births. Fetuses are at increased risk for anatomic and genetic anomalies, growth abnormalities, prematurity, and several physiological problems related to monochorionicity. This book provides a much needed, up-to-date guide to the management of multiple pregnancies. Presented with a uniform approach to all chapters, information is easily navigable, evidence-based, and highly practical. Heavily illustrated, particularly with ultrasound images – the cornerstone of management of multiple pregnancies - this book will appeal to obstetricians and specialists in maternal-fetal medicine, midwives and ultrasonographers and will improve outcomes for mothers and babies.