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Abstract Fetal growth restriction (FGR) remains one of the main obstetrical problems worldwide, with consequences beyond perinatal life. Animal models with developmental and structural similarities to the human are essential to understand FGR long-term consequences and design novel therapeutic strategies aimed at preventing or ameliorating them. Herein, we described the long-term consequences of FGR in pulmonary function, structure, and gene expression, and characterized neurodevelopmental sequelae up to preadolescence in a rabbit model. FGR was induced at gestational day 25 by surgically reducing placental blood supply in one uterine horn, leaving the contralateral horn as internal control. Neonatal rabbits born near term were assigned to foster care in mixed groups until postnatal day (PND) 21. At that time, one group underwent pulmonary biomechanical testing followed by lung morphometry and gene expression analysis. A second group underwent longitudinal neurobehavioral assessment until PND 60 followed by brain harvesting for multiregional oligodendrocyte and microglia quantification. FGR was associated with impaired pulmonary function and lung development at PND 21. FGR rabbits had higher respiratory resistance and altered parenchymal biomechanical properties in the lungs. FGR lungs presented thicker alveolar septal walls and reduced alveolar space. Furthermore, the airway smooth muscle content was increased, and the tunica media of the intra-acinar pulmonary arteries was thicker. In addition, FGR was associated with anxiety-like behavior, impaired memory and attention, and lower oligodendrocyte proportion in the frontal cortex and white matter. In conclusion, we documented and characterized the detrimental pulmonary function and structural changes after FGR, independent of prematurity, and beyond the neonatal period for the first time in the rabbit model, and describe the oligodendrocyte alteration in pre-adolescent rabbit brains. This characterization will allow researchers to develop and test therapies to treat FGR and prevent its sequelae.

Congenital diaphragmatic hernia (CDH) is a congenital malformation characterized by pulmonary hypoplasia, pulmonary hypertension, and cardiac dysfunction. Pulmonary hypertension represents the major cause of neonatal mortality and morbidity. Prenatal diagnosis allows assessment of severity and selection of foetal surgery candidates. We have shown that treprostinil, a prostacyclin analogue with an anti-remodelling effect, attenuates the relative hypermuscularization of the pulmonary vasculature in rats with nitrofen-induced CDH. Here we confirm these observations in a large animal model of surgically-created CDH. In the rabbit model, subcutaneous maternal administration of treprostinil at 150 ng/kg/min consistently reached target foetal concentrations without demonstrable detrimental foetal or maternal adverse effects. In pups with CDH, prenatal treprostinil reduced pulmonary arteriolar proportional medial wall thickness and downregulated inflammation and myogenesis pathways. No effect on alveolar morphometry or lung mechanics was observed. These findings provide further support towards clinical translation of prenatal treprostinil for CDH.

Abstract Fetal growth restriction is one of the leading causes of perinatal mortality and morbidity and has consequences that extend well beyond the neonatal period. Current management relies on timely delivery rather than improving placental function. Several prenatal strategies have failed to show benefit in clinical trials after promising results in animal models. Most of these animal models have important developmental and structural differences compared to the human and/or are insufficiently characterized. We aimed to describe placental function and structure in an FGR rabbit model, and to characterize the early brain and lung developmental morbidity using a multimodal approach. FGR was induced in time-mated rabbits at gestational day 25 by partial uteroplacental vessel ligation in one horn. Umbilical artery Doppler was measured before caesarean delivery at gestational day 30, and placentas were harvested for computed microtomography and histology. Neonates underwent neurobehavioral or pulmonary functional assessment the day after delivery, followed by brain or lung harvesting, respectively. Neuropathological assessment included multiregional quantification of neuron density, apoptosis, astrogliosis, cellular proliferation, and oligodendrocyte progenitors. Brain region volumes and diffusion metrics were obtained from ex-vivo brain magnetic resonance imaging. Lung assessment included biomechanical tests and pulmonary histology. Fetal growth restriction was associated with labyrinth alterations in the placenta, driven by fetal capillary reduction, and overall reduced vessels volume. FGR caused altered neurobehavior paralleled by regional neuropathological deficits and reduced fractional anisotropy in the cortex, white matter, and hippocampus. In addition, FGR kittens presented functional alterations in the peripheral lung and structurally underdeveloped alveoli. In conclusion, in a uteroplacental insufficiency FGR rabbit model, placental vascular alterations coincide with neurodevelopmental and pulmonary disruption.

IntroductionOne of the drawbacks of fetoscopic endoluminal tracheal occlusion (FETO) for congenital diaphragmatic hernia is the need for a second invasive intervention to reestablish airway patency. The "Smart-TO" (Strasbourg University-BSMTI, France) is a new balloon for FETO, which spontaneously deflates when positioned near a strong magnetic field, e.g., generated by a magnetic resonance image (MRI) scanner. Translational experiments have demonstrated its efficacy and safety. We will now use the Smart-TO balloon for the first time in humans. Our main objective is to evaluate the effectiveness of prenatal deflation of the balloon by the magnetic field generated by an MRI scanner.Material and methodsThese studies were first in human (patients) trials conducted in the fetal medicine units of Antoine-Béclère Hospital, France, and UZ Leuven, Belgium. Conceived in parallel, protocols were amended by the local Ethics Committees, resulting in some minor differences. These trials were single-arm interventional feasibility studies. Twenty (France) and 25 (Belgium) participants will have FETO with the Smart-TO balloon. Balloon deflation will be scheduled at 34 weeks or earlier if clinically required. The primary endpoint is the successful deflation of the Smart-TO balloon after exposure to the magnetic field of an MRI. The secondary objective is to report on the safety of the balloon. The percentage of fetuses in whom the balloon is deflated after exposure will be calculated with its 95% confidence interval. Safety will be evaluated by reporting the nature, number, and percentage of serious unexpected or adverse reactions.ConclusionThese first in human (patients) trials may provide the first evidence of the potential to reverse the occlusion by Smart-TO and free the airways non-invasively, as well a safety data.

We previously reported the multi-system sequelae of fetal growth restriction, induced by placental underperfusion, in near-term born rabbits, in the immediate neonatal period and up to pre-adolescence. Herein, we describe the pulmonary and neurodevelopmental consequences of FGR in rabbits born preterm. We hypothesize that FGR has an additional detrimental effect on prematurity in both pulmonary function and neurodevelopment. FGR was induced at gestational day (GD) 25 by placental underperfusion, accomplished by partial uteroplacental vessel ligation in one uterine horn. Rabbits were delivered by cesarean section at GD 29, and placentas were harvested for histology. Neonates underwent neurobehavioral or pulmonary functional assessment at postnatal day 1, followed by brain or lung harvesting, respectively. The neurodevelopmental assessment included neurobehavioral testing and multiregional quantification of cell density and apoptosis in the brain. Lung assessment included functional testing, alveolar morphometry, and airway histology. FGR was associated with higher perinatal mortality, lower birth and placental weight, and a similar brain-to-body weight ratio compared to controls. Placental underperfusion decreased labyrinth and junction zone volumes in FGR placentas. FGR impaired pulmonary function, depicted by higher parenchymal resistance, damping, and elastance. Alveolar morphometry and airway smooth muscle content were comparable between groups. Neurobehavioral tests showed motoric and sensorial impairment in FGR rabbits. In FGR brains, cell density was globally reduced, with higher apoptosis in selected areas. In conclusion, in preterm-born rabbits, placental underperfusion leads to higher mortality, FGR, and impaired lung and brain development in early assessment. This study complements previous findings of placental, pulmonary, and neurodevelopmental impairment in near-term born rabbits in this model.

The objective of the study was to describe a case-series of neural tube defects (NTD) with an abnormal intracranial translucency (IT) detected during the first-trimester ultrasound scan, performed on a low-risk obstetric population in Mexico. Certified Fetal Medicine specialists performed all US scans; the IT was assessed using the mid-sagittal view of the fetal head, which is already systematically used for nuchal translucency and nasal bone evaluation. During the study, we were able to find that eight fetuses had an absence of the intracranial translucency, out of which two were reassessed at 14 weeks′ gestation and IT was normal, six of them were later diagnosed to have an NTD that consisted in spina bifida aperta (n = 5) and encephalocele (n = 1). Conclusion: As previous studies have shown, IT evaluation during the first-trimester US routine scan may be a useful screening marker for early detection of NTDs.