Feasibility of 4D-Spatio Temporal Image Correlation (STIC) in the Comprehensive Assessment of the Fetal Heart Using FetalHQ®.

Fetal Heart Quantification (FetalHQ®) is a novel speckle tracking software that permits the study of global and regional ventricular shape and function from a 2D four-chamber-view loop. The 4D-Spatio Temporal Image Correlation (STIC) modality enables the offline analysis of optimized and perfectly aligned cardiac planes. We aimed to evaluate the feasibility and reproducibility of 4D-STIC speckle tracking echocardiography (STE) using FetalHQ® and to compare it to 2D STE. We conducted a prospective study including 31 low-risk singleton pregnancies between 20 and 40 weeks of gestation. Four-chamber view volumes and 2D clips were acquired with an apex pointing at 45° and with a frame rate higher than 60 Hz. Morphometric and functional echocardiography was performed by FetalHQ®. Intra- and interobserver reproducibility were evaluated by the intraclass correlation coefficient (ICC). Our results showed excellent reproducibility (ICC > 0.900) for morphometric evaluation (biventricular area, longitudinal and transverse diameters). Reproducibility was also good (ICC > 0.800) for functional evaluation (biventricular strain, Fractional Area Change, left ventricle volumes, ejection fraction and cardiac output). On the contrary, the study of the sphericity index and shortening fraction of the different ventricular segments showed lower reproducibility (ICC < 0.800). To conclude, 4D-STIC is feasible, reproducible and comparable to 2D echocardiography for the assessment of cardiac morphometry and function

Study protocol for a randomised controlled trial: treatment of early intrauterine growth restriction with low molecular weight heparin (TRACIP)

Introduction: The incidence of intrauterine growth restriction (IUGR) is estimated at about 3% of pregnancies, and it is associated with 30% of all perinatal mortality and severe morbidity with adverse neurodevelopmental and cardiovascular health consequences in adult life. Early onset IUGR represents 20%-30% of all cases and is highly associated with severe placental insufficiency. The existing evidence suggests that low molecular weight heparin (LMWH) has effects beyond its antithrombotic action, improving placental microvessel structure and function of pregnant women with vascular obstetric complications by normalising proangiogenic and antiapoptotic protein levels, cytokines and inflammatory factors. The objective of our study is to demonstrate the effectiveness of LMWH in prolonging gestation in pregnancies with early-onset IUGR. Methods and analysis: This is a multicentre, triple-blind, parallel-arm randomised clinical trial. Singleton pregnancies qualifying for early (20-32 weeks at diagnosis) placental IUGR (according to Delphi criteria) will be randomised to subcutaneous treatment with bemiparin 3500 IU/0.2 mL/day or placebo from inclusion at diagnosis to the time of delivery. Analyses will be based on originally assigned groups (intention-to-treat). The primary objective will be analysed by comparing gestational age and prolongation of pregnancy (days) in each group with Student's t-tests for independent samples and by comparing Kaplan-Maier survival curves (from inclusion to delivery, log-rank test). A linear regression model for gestational age at birth will consider the following covariates: gestational age at inclusion (continuous) and pre-eclampsia (binary). Ethics and dissemination: The study will be conducted in accordance with the principles of Good Clinical Practice. This study was approved by the Clinical Research Ethics Committee (CEIC) of Sant Joan de Déu Hospital, on 13 July 2017. The trial is registered in the public registry www.clinicaltrial.gov. according to Science Law 14/2011, and the results will be published in an open access journal

Brain Oxygen Perfusion and Oxidative Stress Biomarkers in Fetuses with Congenital Heart Disease-A Retrospective, Case-Control Pilot Study.

Fetuses with congenital heart disease (CHD) have circulatory changes that may lead to predictable blood flow disturbances that may affect normal brain development. Hypoxemia and hypoperfusion may alter the redox balance leading to oxidative stress (OS), that can be assessed measuring stable end-products. OS biomarkers (OSB) were measured in amniotic fluid in fetuses with (n = 41) and without CHD (n = 44) and analyzed according to aortic flow, expected cyanosis after birth, and a CHD classification derived from this. Birth head circumference (HC) was used as a neurodevelopment biomarker. CHD fetuses had higher levels of ortho-Tyrosine (o-Tyr) than controls (p = 0.0003). There were no differences in o-Tyr levels considering aortic flow obstruction (p = 0.617). Fetuses with expected extreme cyanosis presented the highest levels of o-Tyr (p = 0.003). Among groups of CHD, fetuses without aortic obstruction and extreme cyanosis had the highest levels of o-Tyr (p = 0.005). CHD patients had lower HC than controls (p = 0.023), without correlation with OSB. Patients with HC < 10th percentile, presented high levels of o-Tyr (p = 0.024). Fetuses with CHD showed increased OSB and lower HC when compared to controls, especially those with expected extreme cyanosis. Our results suggest that increased levels of OSB are more influenced by the effect of low oxygenation than by aortic flow obstruction. Future studies with larger sample size are needed to further investigate the role of OSB as an early predictor of neurodevelopmental problems in CHD survivors

Lethal congenital contracture syndrome 11: A case report and literature review

Lethal congenital contracture syndrome 11 (LCCS11) is caused by homozygous or compound heterozygous variants in the GLDN gene on chromosome 15q21. GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report a fetus with ultrasound alterations detected at 28 weeks of gestation. The fetus exhibited hydrops, short long bones, fixed limb joints, absent fetal movements, and polyhydramnios. The pregnancy was terminated and postmortem studies confirmed the prenatal findings: distal arthrogryposis, fetal growth restriction, pulmonary hypoplasia, and retrognathia. The fetus had a normal chromosomal microarray analysis. Exome sequencing revealed two novel compound heterozygous variants in the GLDN associated with LCCS11. This manuscript reports this case and performs a literature review of all published LCCS11 cases

Estudi del desenvolupament cerebral en els fetus afectes de cardiopatia congènita

[cat] Les CC són les malformacions congènites més freqüents i la principal causa de mortalitat per anomalia congènita durant el primer any de vida. Durant les últimes dècades, l’augment de la supervivència com a conseqüència de la millora de les tècniques quirúrgiques i de les mesures de suport postoperatòries ha fet desviar l’atenció cap a l’elevada xifra de morbiditat neurològica que presenten aquests infants. Inicialment, aquesta morbididitat neurològica era atribuïda a la cirurgia cardíaca i les seves complicacions, però en els últims anys ha aparegut cada vegada més evidència a favor de que els nadons amb CC ja presenten anomalies cerebrals immediatament després de néixer i abans de la cirurgia cardíaca. D’aquesta manera s’ha focalitzat l’atenció cap a un possible origen prenatal de la lesió cerebral que presenten aquest infants. Aquest concepte, conegut com "programació fetal", és un dels enfocs més importants de cares a la prevenció de les malalties durant l’edat adulta. El desenvolupament cerebral durant la vida fetal és un procés molt complex que requereix un equilibri adequat en l’aportació d’oxigen i nutrients. Les condicions adverses durant l'embaràs, com per exemple la presència d’una CC, poden condicionar un desenvolupament cerebral anormal que posteriorment pot acabar desembocant en els diferents tipus i graus de morbiditat neurològica que presenten els nadons i infants amb CC. En aquesta tesi hem demostrat que és possible identificar canvis en el desenvolupament cerebral dels fetus amb CC des d’etapes molt precoces de la gestació fins a terme utilitzant diferents tècniques d’imatge (ecografia i ressonància magnètica). A més hem demostrat com, a part del tipus de CC, existeixen altres variables (biometries cefàliques i variables de l’estudi Doppler) que ens poden ajudar a identificar de manera molt precoç quins fetus amb CC presentaran més risc de presentar alteracions en el desenvolupament cerebral. La informació presentada obre les portes per la introducció d’aquestes variables dins de l’avaluació inicial de les CC, en el moment de diagnòstic, permetent així identificar de manera precoç els fetus amb més risc de desenvolupar anomalies del sistema nerviós central que condicionin posteriorment l’aparició d’alteracions en el neurodesenvolupament. La identificació precoç dels fetus amb risc de presentar un neurodesenvolupament anormal permetrà, per una banda, millorar de manera significativa l’assessorament familiar en el moment del diagnòstic de la CC i, per altre banda, permetrà iniciar intervencions (programes d’estimulació precoç) per tal de millorar el resultat neurològic final d’aquests infants.[eng] Congenital heart disease (CHD) are the most common congenital malformations and the main cause of mortality for congenital anomaly during the first year of life. During the past decades, the increase of survival of these babies, as a result of improved surgical techniques and postoperative support measures, has diverted the attention to the high number of these children that presents neurological impairment. Initially, this neurological morbidity was attributed to cardiac surgery and its complications, but in recent years several studies has showed that babies with CHD already have brain abnormalities immediately after birth and before cardiac surgery. These findings have focused the attention on a possible prenatal origin of brain injury in these babies. In this thesis we demonstrated that it is possible to identify changes in brain development of fetuses with CHD from very early stages of pregnancy to term using different imaging techniques (ultrasound and MRI). We have also shown how, regardless of the type of CHD, there are other variables (cephalic biometry and brain Doppler) that can help us to identify which fetuses with CHD present greater risk of abnormal brain development. From a clinical perspective, the use of specific brain predictors might be incorporated as part of the comprehensive assessment at the time of clinical diagnosis of CHD. An individualized prediction of the risk of abnormal neurodevelopment could improve parental counseling and facilitate early-life interventions that have been shown to improve brain development in other infants at risk

Corpus callosum size by neurosonography in fetuses with congenital heart defect and relationship with expected pattern of brain oxygen supply

Objective: To evaluate corpus callosum (CC) size by neurosonography (NSG) in fetuses with an isolated major congenital heart defect (CHD) and explore the association of CC size with the expected pattern of in-utero oxygen supply to the brain. Methods: A total of 56 fetuses with postnatally confirmed isolated major CHD and 56 gestational-age-matched controls were included. Fetuses with CHD were stratified into two categories according to the main expected pattern of cerebral arterial oxygen supply: Class A, moderately to severely reduced oxygen supply (left outflow tract obstruction and transposition of the great arteries) and Class B, near normal or mildly impaired oxygenated blood supply to the brain (other CHD). Transvaginal NSG was performed at 32–36 weeks in all fetuses to evaluate CC length, CC total area and areas of CC subdivisions in the midsagittal plane. Results: CHD fetuses had a significantly smaller CC area as compared to controls (7.91 ± 1.30 vs 9.01 ± 1.44 mm2; P < 0.001), which was more pronounced in the most posterior part of the CC. There was a significant linear trend for reduced CC total area across the three clinical groups, with CHD Class-A cases showing more prominent changes (controls, 9.01 ± 1.44 vs CHD Class B, 8.18 ± 1.21 vs CHD Class A, 7.53 ± 1.33 mm2; P < 0.05). Conclusions: Fetuses with major CHD had a smaller CC compared with controls, and the difference was more marked in the CHD subgroup with expected poorer brain oxygenation. Sonographic CC size could be a clinically feasible marker of abnormal white matter development in CHD.Peer ReviewedPostprint (published version