Self-reported respiratory and gastrointestinal outcomes in children with isolated congenital diaphragmatic hernia: A prospective multicentre study.

OBJECTIVE: To evaluate medium-term self-reported respiratory and gastrointestinal (GI) outcomes in children with congenital diaphragmatic hernia (CDH). DESIGN: Self-reported respiratory and GI outcomes correlated with prenatal severity indicators. SETTING: Prospective study at three fetal medicine units. POPULATION: Families of children prenatally diagnosed with isolated, left-sided CDH surviving for >1 year. METHODS: Families received validated questionnaires for GI outcomes (Infant Gastroesophageal Reflux Questionnaire Revised, I-GERQ-R, for infants aged <2 years, or Paediatric Gastro-oesophageal Symptom and Quality of Life Questionnaire, PGSQ, for children aged aged 2-8 years or >9 years) and respiratory outcomes (preschool respiratory outcome questionnaire, for children aged ≤5 years, or the International Study of Asthma and Allergies in Childhood asthma questionnaire, for children aged 6-8 years or ≥9 years). Prenatal data collected from the medical records included lung size (percentage observed/expected lung-to-head ratio, O/E LHR %), liver position, fetal endoluminal tracheal occlusion (FETO) gestational age (GA) at delivery, and perinatal data included birthweight, location, patch repair and respiratory support. MAIN OUTCOME MEASURES: The GI and respiratory scores were correlated with O/E LHR using linear and logistic regression models. Univariate analysis was used to evaluate associations with perinatal variables. RESULTS: We obtained 142 responses from 342 families (representing a response rate of 45%). The baseline characteristics of participants and non-participants were comparable. No correlations between perinatal variables and respiratory or GI scores were identified. Children aged ≤5 years with lower O/E LHR values reported higher respiratory scores (P = 0.0175); this finding was not reported in older children. Overall, the children who underwent FETO (n = 51) had GI (P = 0.290) and respiratory (P = 0.052) scores that were comparable with those of children who were expectantly managed. CONCLUSIONS: Families and children with prenatally diagnosed CDH reported fewer respiratory symptoms with increasing age. There was no correlation between O/E LHR or the use of FETO and self-reported outcomes.

Brain development is altered in rabbit fetuses with congenital diaphragmatic hernia.

INTRODUCTION: Children with congenital diaphragmatic hernia (CDH) are at risk for neurodevelopmental delay. Some changes are already present prenatally. Herein, we further examined how the brain develops in fetal rabbits with surgically created DH. METHODS: Two fetuses underwent surgical DH creation on day 23 (term = d31). DH pups and littermate controls were harvested at term. Ten DH pups and 11 controls underwent transcardial perfusion for brain fixation and measurement of brain volume, brain folding, neuron and synaptic density, pre-oligodendrocyte count, proliferation, and vascularization. Twelve other DH and 11 controls had echocardiographic assessment of cardiac output and aortic and cerebral blood flow, magnetic resonance imaging (9.4 T) for cerebral volumetry, and molecular assessment of vascularization markers. RESULTS: DH pups had lower lung-to-body weight ratio (1.3 ± 0.3 vs. 2.4 ± 0.3%; p < 0.0001) and lower heart-to-body weight ratio (0.007 ± 0.001 vs. 0.009 ± 0.001; p = 0.0006) but comparable body weight and brain-to-body weight ratio. DH pups had a lower left ventricular ejection fraction, aortic and cerebral blood flow (39 ± 8 vs. 54 ± 15 mm/beat; p = 0.03) as compared to controls but similar left cardiac ventricular morphology. Fetal DH-brains were similar in volume but the cerebellum was less folded (perimeter/surface area: 25.5 ± 1.5 vs. 26.8 ± 1.2; p = 0.049). Furthermore, DH brains had a thinner cortex (143 ± 9 vs. 156 ± 13 µm; p = 0.02). Neuron densities in the white matter were higher in DH fetuses (124 ± 18 vs. 104 ± 14; p = 0.01) with comparable proliferation rates. Pre-oligodendrocyte count was lower, coinciding with the lower endothelial cell count. CONCLUSION: Rabbits with DH had altered brain development compared to controls prenatally, indicating that brain development is already altered prenatally in CDH.

Placenta-associated adverse pregnancy outcomes in women experiencing mild or severe hyperemesis gravidarum - a systematic review and meta-analysis.

BACKGROUND: Nausea and vomiting in pregnancy (NVP) affects 50-80% of pregnant women and is correlated to the level of human chorionic gonadotropin (hCG). Hyperemesis gravidarum (HG) is a severe condition, with an incidence of 0.2-1.5%, characterized by consistent nausea, vomiting, weight loss and dehydration continuing after the second trimester. AIM: The aim of this systematic review was to investigate a potential correlation between NVP or HG with adverse pregnancy outcomes and hCG levels. METHOD: A systematic search in PubMed, Embase and CINAHL Complete was conducted. Studies on pregnant women with nausea in the first or second trimester, reporting either pregnancy outcomes or levels of hCG were included. The primary outcomes were preterm delivery (PTD), preeclampsia, miscarriage, and fetal growth restriction. Risk of bias was assessed using ROBINS-I. The overall certainty of evidence was assessed using GRADE. RESULTS: The search resulted in 2023 potentially relevant studies; 23 were included. The evidence was uncertain for all outcomes, however women with HG had a tendency to have an increased risk for preeclampsia [odds ratio (OR) 1.18, 95% confidence of interval (CI) 1.03 to 1.35], PTD [OR 1.35, 95% CI 1.13 to 1.61], small for gestational age (SGA) [OR 1.24, 95% CI 1.13 to 1.35], and low birth weight (LBW) [OR 1.35, 95% CI 1.26 to 1.44]. Further, a higher fetal female/male ratio was observed [OR 1.36, 95% CI 1.15 to 1.60]. Meta-analyses were not performed for women with NVP; however, most of these studies indicated that women with NVP have a lower risk for PTD and LBW and a higher risk for SGA, and a higher fetal female/male ratio. CONCLUSION: There may be an increased risk in women with HG and a decreased risk in women with NVP for adverse placenta-associated pregnancy outcomes, however the evidence is very uncertain. TRIAL REGISTRATION: PROSPERO: CRD42021281218.

Neurocognitive sequelae of antenatal corticosteroids in a late preterm rabbit model.

BACKGROUND: Late preterm birth is associated with short-term respiratory and adaptive problems. Although antenatal corticosteroids seem to reduce the respiratory burden, this may come at the cost of adverse neuropsychological outcomes later in life. This impact has not been investigated. OBJECTIVE: Herein, we investigate what the short- and long-term neurodevelopmental effects of a single course of betamethasone in simulated late preterm birth. STUDY DESIGN: Time-mated pregnant does received 0.1 mg/kg betamethasone (n=8) or 1 mL saline intramuscular (n=6) at the postconceptional ages of 28 and 29 days. The antenatal corticosteroid dose and scheme were based on previous studies and were comparable with routine clinical use. Cesarean delivery was done on postconceptional age 30 days (term=31 days), and new-born rabbits were foster-cared for 28 days and were thereafter cared for in group housing. Neonatal lung function testing and short-term neurobehavioral testing was done. Open field, spontaneous alternation, and novel object recognition tests were subsequently performed at 4 and 8 weeks of age. On postnatal day 1 and at 8 weeks, a subgroup was euthanized and transcardially perfuse fixated. Ex vivo high-resolution Magnetic Resonance Imaging was used to calculate the Diffusion Tensor Imaging-derived fractional anisotropy and mean diffusivity. Fixated brains underwent processing and were serial sectioned, and a set of 3 coronal sections underwent anti-NeuN, Ki67, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. RESULTS: Antenatal corticosteroid exposure was associated with improved neonatal lung function, yet resulted in a long-term growth deficit that coincided with a persistent neurobehavioral deficit. We demonstrated lower neonatal motor scores; a persistent anxious behavior in the open field test with more displacements, running, and self-grooming episodes; persistent lower alternation scores in the T-Maze test; and lower discriminatory indexes in the novel object recognition. On neuropathological assessment, antenatal corticosteroid exposure was observed to result in a persistent lower neuron density and fewer Ki67+ cells, particularly in the hippocampus and the corpus callosum. This coincided with lower diffusion tensor imaging-derived fractional anisotropy scores in the same key regions. CONCLUSION: Clinical equivalent antenatal corticosteroid exposure in this late preterm rabbit model resulted in improved neonatal lung function. However, it compromised neonatal and long-term neurocognition.

Neurodevelopmental outcomes in children with isolated congenital diaphragmatic hernia: A systematic review and meta-analysis.

BACKGROUND: Congenital diaphragmatic hernia (CDH) reportedly has neurologic consequences in childhood however little is known about the impact in isolated CDH. AIMS: Herein we aimed to describe the risk of neurodevelopmental complications in children born with isolated CDH. MATERIALS & METHODS: We systematically reviewed literature for reports on the neurological outcome of infants born with isolated CDH. The primary outcome was neurodevelopmental delay. Secondary outcomes included, motor skills, intelligence, vision, hearing, language and behavior abnormalities. RESULTS: Thirteen out of 87 (15%) studies reported on isolated CDH, including 2624 out of 24,146 children. Neurodevelopmental delay was investigated in four studies and found to be present in 16% (3-34%) of children. This was mainly attributed to motor problems in 13% (2-30%), whereas cognitive dysfunction only in 5% (0-20%) and hearing in 3% (1-7%). One study assessed the effect of fetal surgery. When both isolated and non-isolated children were included, these numbers were higher. DISCUSSION: This systematic review demonstrates that only a minority of studies focused on isolated CDH, with neurodevelopmental delay present in 16% of children born with CDH. CONCLUSION: To accurately counsel patients, more research should focus on isolated CDH cases and examine children that underwent fetal surgery.

Prenatal cerebellar growth is altered in congenital diaphragmatic hernia on ultrasound.

OBJECTIVE: Children with congenital diaphragmatic hernia (CDH) are at risk for neurodevelopmental delay. Herein we report on prenatal changes in biometry and brain perfusion in fetuses with isolated CDH. STUDY DESIGN: This retrospective study evaluated fetuses with isolated, left-sided CDH in three European referral centers. Abdominal circumference (AC), femur length (FL), head circumference (HC), transcerebellar diameter (TCD), middle cerebral artery (MCA) Doppler, and ventricular width (VW) were assessed during four gestational periods (<24 weeks, 25-28 weeks, 29-32 weeks, >33 weeks). Z-scores were calculated, and growth curves were created based on longitudinal data. RESULTS: In 367 fetuses, HC, AC and FL were within normal ranges throughout gestation. The TCD diminished with advancing gestational age to fall below the fifth percentile after 32 weeks. A less pronounced but similar trend was seen in VW. The peak systolic velocity of the MCA was consistently approximately 10% lower than normal. Disease severity was correlated to TCD (p = 0.002) and MCA doppler values (p = 0.002). There were no differences between fetuses treated with FETO and those managed expectantly. CONCLUSION: Fetuses with isolated left-sided CDH have a small cerebellum and reduced MCA peak systolic velocity. Follow up studies are necessary to determine the impact of these changes on neurodevelopment.

Fetoscopic insufflation of heated-humidified carbon dioxide during simulated spina bifida repair is safe under controlled anesthesia in the fetal lamb.

OBJECTIVE: To assess the safety of Partial-Amniotic-Insufflation-of-heated-humidified-CO2 (hPACI) during fetoscopic spina bifida repair (fSB-repair). METHOD: A simulated fSB-repair through an exteriorized uterus under hPACI was performed in 100-day fetal lambs (term = 145 days) under a laboratory anesthesia protocol (n = 5; group 1) which is known to induce maternal-fetal acidosis and hypercapnia. Since these may not occur clinically, we applied a clinical anesthesia protocol (n = 5; group 2), keeping maternal parameters within physiological conditions, that is, controlled maternal arterial carbon dioxide (CO2) pressure (pCO2  = 30 mmHg), blood pressure (≥67 mmHg), and temperature (37.1-39.8°C). Our superiority study used fetal pH as the primary outcome. RESULTS: Compared to group 1, controlled anesthesia normalized fetal pH (7.23 ± 0.02 vs. 7.36 ± 0.02, p < 0.001), pCO2 (70.0 ± 9.1 vs. 43.0 ± 1.0 mmHg, p = 0.011) and bicarbonate (27.8 ± 1.1 vs. 24.0 ± 0.9 mmol/L, p = 0.071) at baseline. It kept them within clinically acceptable limits (pH ≥ 7.23, pCO2  ≤ 70 mmHg, bicarbonate ≤ 30 mm/L) for ≥120 min of hPACI as opposed to ≤30 min in group one. Fetal pO2 and lactate were comparable between groups and generally within normal range. Fetal brain histology demonstrated fewer apoptotic cells and higher neuronal density in the prefrontal cortex in group two. There was no difference in fetal membrane inflammation, which was mild. CONCLUSION: Fetoscopic insufflation of heated-humidified CO2 during simulated fSB-repair through an exteriorized uterus can be done safely under controlled anesthesia.

Neurodevelopmetal effects of maternal blood pressure management with noradrenaline during general anaesthesia for nonobstetric surgery in the pregnant rabbit model.

In pregnant women, anaesthesia-induced hypotension is commonly treated using phenylephrine or noradrenaline, the rationale being to maintain uterine perfusion pressure and thereby uterine blood flow. Evidence for this strategy during general anaesthesia for nonobstetric surgery is absent. To analyse the effects of treating anaesthesia-induced hypotension with noradrenaline on brain development of rabbit foetuses of mothers subjected to general anaesthesia for nonobstetric surgery. We hypothesised that treatment of maternal hypotension would improve foetal outcomes. Randomised controlled laboratory study using 21 pregnant rabbits (does) at 28 days of gestation. Two hours of sevoflurane anaesthesia for a laparotomy without treatment of anaesthesia-induced hypotension (hypotension group) or with maintaining maternal mean arterial pressure above 80% of the awake value using noradrenaline (noradrenaline group). In the control group, does remained untouched. At term, all pups were delivered by caesarean section. One day later, the neurobehaviour of the pups was assessed and brains were harvested. Neuron density in the frontal cortex for the comparison of noradrenaline groups versus hypotension groups was the primary outcome; the neurobehavioural scores and other histological outcomes were secondary outcomes. In the noradrenaline groups and hypotension groups, neuron density in the frontal cortex was similar (1181 ±â€Š162 versus 1189 ±â€Š200 neurons mm-2, P  = 0.870). However, significantly less foetal survival, lower sensory scores in neurobehavioural assessment and less proliferation were observed in the noradrenaline group when compared with the hypotension group. Neuron densities in other regions, total cell densities, biometrics and synaptogenesis were not affected. There were no differences between the control group and hypotension group. During general anaesthesia for nonobstetric surgery in rabbits, treatment of anaesthesia-induced hypotension using noradrenaline did not affect neuron densities but was associated with impaired foetal outcomes according to several secondary outcome parameters. Further studies are needed to investigate any clinical relevance and to determine the target blood pressure in pregnant women during general anaesthesia.KEY POINTSIn pregnant women, anaesthesia-induced hypotension is commonly treated using phenylephrine or noradrenaline, with the rationale to maintain uterine perfusion pressure and thereby uterine blood flow.Evidence for this strategy during general anaesthesia for nonobstetric surgery is absent.We investigated the effects of treating anaesthesia-induced hypotension with noradrenaline on the brain development of rabbit foetuses, of mothers subjected to general anaesthesia for nonobstetric surgery.We hypothesised that treatment of maternal hypotension would improve foetal outcomes.Neuron densities were similar but significantly less foetal survival, impaired neurobehaviour and less proliferation were observed after treatment of anaesthesia-induced hypotension with noradrenaline, compared with untreated hypotension.

Effects of general anaesthesia during pregnancy on neurocognitive development of the fetus: a systematic review and meta-analysis.

BACKGROUND: The US Food and Drug Administration warned that exposure of pregnant women to general anaesthetics may impair fetal brain development. This review systematically evaluates the evidence underlying this warning. METHODS: PubMed, EMBASE, and Web of Science were searched from inception until April 3, 2020. Preclinical and clinical studies were eligible. Exclusion criteria included case reports, in vitro models, chronic exposures, and exposure only during delivery. Meta-analyses were performed on standardised mean differences. The primary outcome was overall effect on learning/memory. Secondary outcomes included markers of neuronal injury (apoptosis, synapse formation, neurone density, and proliferation) and subgroup analyses. RESULTS: There were 65 preclinical studies included, whereas no clinical studies could be identified. Anaesthesia during pregnancy impaired learning and memory (standardised mean difference -1.16, 95% confidence interval -1.46 to -0.85) and resulted in neuronal injury in all experimental models, irrespective of the anaesthetic drugs and timing in pregnancy. Risk of bias was high in most studies. Rodents were the most frequently used animal species, although their brain development differs significantly from that in humans. In a minority of studies, anaesthesia was combined with surgery. Monitoring and strict control of physiological homeostasis were below preclinical and clinical standards in many studies. The duration and frequency of exposure and anaesthetic doses were often much higher than in clinical routine. CONCLUSION: Anaesthesia-induced neurotoxicity during pregnancy is a consistent finding in preclinical studies, but translation of these results to the clinical situation is limited by several factors. Clinical observational studies are needed. PROSPERO REGISTRATION NUMBER: CRD42018115194.

Fetally-injected drugs for immobilization and analgesia do not modify fetal brain development in a rabbit model.

OBJECTIVE: During fetal surgery, fetuses receive medication (atropine-fentanyl-curare) to prevent fetal pain, movement and bradycardia. Although essential there has been no detailed review of potential side effects. Herein we aimed to assess the effects of this medication cocktail on fetal brain development in a rabbit model. METHODS: Pregnant does underwent laparotomy at 28 days of gestation. Two pups of each horn were randomized to an ultrasound guided injection with medication (atropine-cisatracurium-fentanyl, as clinically used) or saline (sham). The third pup was used as control. At term, does were delivered by cesarean. Outcome measures were neonatal biometry, neuromotoric functioning and neuro-histology (neuron density, synaptic density and proliferation). RESULTS: Maternal vital parameters remained stable during surgery. Fetal heart rates did not differ before and after injection, and were comparable for the three groups. At birth, neonatal body weights and brain-to-body weight ratios were also comparable. Both motor and sensory neurobehavioral scores were comparable. There were no differences in neuron density or proliferation. Sham pups, had a lower synaptic density in the hippocampus as compared to the medication group, however there was no difference in the other brain areas. CONCLUSION: In the rabbit model, fetal medication does not appear to lead to short-term neurocognitive effects.

Effects of Maternal Abdominal Surgery on Fetal Brain Development in the Rabbit Model.

INTRODUCTION: Anesthesia during pregnancy can impair fetal neurodevelopment, but effects of surgery remain unknown. The aim is to investigate effects of abdominal surgery on fetal brain development. Hypothesis is that surgery impairs outcome. METHODS: Pregnant rabbits were randomized at 28 days of gestation to 2 h of general anesthesia (sevoflurane group, n = 6) or to anesthesia plus laparoscopic appendectomy (surgery group, n = 13). On postnatal day 1, neurobehavior of pups was assessed and brains harvested. Primary outcome was neuron density in the frontal cortex, and secondary outcomes included neurobehavioral assessment and other histological parameters. RESULTS: Fetal survival was lower in the surgery group: 54 versus 100% litters alive at birth (p = 0.0442). In alive litters, pup survival until harvesting was 50 versus 69% (p = 0.0352). No differences were observed for primary outcome (p = 0.5114) for surviving pups. Neuron densities were significantly lower in the surgery group in the caudate nucleus (p = 0.0180), but not different in other regions. No differences were observed for secondary outcomes. Conclusions did not change after adjustment for mortality. CONCLUSION: Abdominal surgery in pregnant rabbits at a gestational age corresponding to the end of human second trimester results in limited neurohistological changes but not in neurobehavioral impairments. High intrauterine mortality limits translation to clinical scenario, where fetal mortality is close to zero.

Long-term neurological effects of neonatal caffeine treatment in a rabbit model of preterm birth.

BACKGROUND: Neonatal caffeine treatment might affect brain development. Long-term studies show conflicting results on brain-related outcomes. Herein we aimed to investigate the long-term effects of neonatal caffeine administration in a rabbit model of preterm birth. METHODS: Preterm (born day 29) and term (day 32) pups were raised by wet nurses and allocated to treatment with saline or caffeine for 7 or 17 days. At pre-puberty, neurobehavioral tests were performed and brains were harvested for immunostaining of neurons, synapses, myelin, and astrocytes. RESULTS: Survival was lower in preterm saline pups than in controls, whereas caffeine-treated preterm pups did not differ from term control pups. Preterm saline pups covered less distance compared to controls and were more likely to stay in the peripheral zone of the open field. Corresponding differences were not seen in preterm caffeine pups. Preterm animals had lower neuron density compared to controls, which was not influenced by caffeine treatment. Synaptic density, astrocytes, and myelin were not different between groups. CONCLUSION: Caffeine appeared to be safe. All preterm rabbits had lower neuron density but anxious behavior seen in preterm saline rabbits was not seen in caffeine-treated preterm pups.

Maternal surgery during pregnancy has a transient adverse effect on the developing fetal rabbit brain.

BACKGROUND: Recently, the US Food and Drug Administration called for cautious use of anesthetic drugs during pregnancy. In 0.2-2% of pregnancies, nonobstetric surgery is being performed. The consequences of anesthesia during pregnancy on fetal development remain unclear, and preclinical studies in relevant animal models may help to elucidate them. OBJECTIVE: To assess the effect of maternal anesthesia and surgery during pregnancy on the developing fetal brain, using a rabbit model. MATERIALS AND METHODS: This is a randomized, sham-controlled study in time-mated pregnant does at 28 days of gestation (term = 31 days), which corresponds to the end of the second trimester in humans. Anesthesia was induced in 14 does (155 pups) with propofol and maintained with 4 vol% (equivalent to 1 minimum alveolar concentration) sevoflurane for 2 hours, and a laparotomy with minimal organ manipulation was performed (surgery group). Maternal vital signs (blood pressure, heart rate, peripheral and cerebral oxygen saturation, temperature, end-tidal CO2, pH, lactate) were continuously monitored. Sham controls consisted of 7 does (74 pups) undergoing invasive hemodynamic monitoring for 2 hours without sedation. At term, does underwent cesarean delivery under ketamine-medetomidine sedation and local anesthesia. Pups either underwent motor and sensory neurologic testing followed by euthanasia at day 1 or daily neurodevelopment testing for 2 weeks and extensive neurologic assessment at 5 and 7 weeks (open field and object recognition test, T-maze, and radial-arm maze). Brains were harvested for histologic assessment of neuron density and synaptophysin expression. RESULTS: Blood gases and vital parameters were stable in both groups. On postnatal day 1, surgery pups had significant lower motor (25 ± 1 vs 23 ± 3; P = .004) and sensory (16 ± 2 vs 15 ± 2; P = .005) neurobehavioral scores and lower brain-to-body weight ratios (3.7% ± 0.6% vs 3.4% ± 0.6%; P = .001). This was accompanied by lower neuron density in multiple brain regions (eg, hippocampus 2617 ± 410 vs 2053 ± 492 neurons/mm2; P = .004) with lower proliferation rates and less synaptophysin expression. Furthermore, surgery pups had delayed motor development during the first week of life, for example with hopping appearing later (6 ± 5 vs 12 ± 3 days; P = .011). Yet, by 7 weeks of age, neurobehavioral impairment was limited to a reduced digging behavior, and no differences in neuron density or synaptophysin expression were seen. CONCLUSION: In rabbits, 2 hours of maternal general anesthesia and laparotomy, with minimal organ and no fetal manipulation, had a measurable impact on neonatal neurologic function and brain morphology. Pups had a slower motoric neurodevelopment, but by 7 weeks the effect became almost undetectable.

Maternal complications following open and fetoscopic fetal surgery: A systematic review and meta-analysis.

OBJECTIVE: To establish maternal complication rates for fetoscopic or open fetal surgery. METHODS: We conducted a systematic literature review for studies of fetoscopic or open fetal surgery performed since 1990, recording maternal complications during fetal surgery, the remainder of pregnancy, delivery, and after the index pregnancy. RESULTS: One hundred sixty-six studies were included, reporting outcomes for open fetal (n = 1193 patients) and fetoscopic surgery (n = 9403 patients). No maternal deaths were reported. The risk of any maternal complication in the index pregnancy was 20.9% (95%CI, 15.22-27.13) for open fetal and 6.2% (95%CI, 4.93-7.49) for fetoscopic surgery. For severe maternal complications (grades III to V Clavien-Dindo classification of surgical complications), the risk was 4.5% (95% CI 3.24-5.98) for open fetal and 1.7% (95% CI, 1.19-2.20) for fetoscopic surgery. In subsequent pregnancies, open fetal surgery increased the risk of preterm birth but not uterine dehiscence or rupture. Nearly one quarter of reviewed studies (n = 175, 23.3%) was excluded for failing to report the presence or absence of maternal complications. CONCLUSIONS: Maternal complications occur in 6.2% fetoscopic and 20.9% open fetal surgeries, with serious maternal complications in 1.7% fetoscopic and 4.5% open procedures. Reporting of maternal complications is variable. To properly quantify maternal risks, outcomes should be reported consistently across all fetal surgery studies.

A magnetic resonance multi-atlas for the neonatal rabbit brain.

The rabbit model has become increasingly popular in neurodevelopmental studies as it is best suited to bridge the gap in translational research between small and large animals. In the context of preclinical studies, high-resolution magnetic resonance imaging (MRI) is often the best modality to investigate structural and functional variability of the brain, both in vivo and ex vivo. In most of the MRI-based studies, an important requirement to analyze the acquisitions is an accurate parcellation of the considered anatomical structures. Manual segmentation is time-consuming and typically poorly reproducible, while state-of-the-art automated segmentation algorithms rely on available atlases. In this work we introduce the first digital neonatal rabbit brain atlas consisting of 12 multi-modal acquisitions, parcellated into 89 areas according to a hierarchical taxonomy. Delineations were performed iteratively, alternating between segmentation propagation, label fusion and manual refinements, with the aim of controlling the quality while minimizing the bias introduced by the chosen sequence. Reliability and accuracy were assessed with cross-validation and intra- and inter-operator test-retests. Multi-atlas, versioned controlled segmentations repository and supplementary materials download links are available from the software repository documentation at https://github.com/gift-surg/SPOT-A-NeonatalRabbit.

Antenatal management of congenital diaphragmatic hernia today and tomorrow.

Congenital diaphragmatic hernia is rare birth defect, which can be easily corrected after birth. The main problem is that herniation of viscera during fetal life impairs lung development, leading to a 30% mortality and significant morbidity. In isolated cases the outcome can be accurately predicted prenatally by medical imaging. Cases with a poor prognosis can be treated before birth; clinically this is by fetoscopic endoluminal tracheal occlusion. Obstruction of the airways triggers lung growth. This procedure is currently being evaluated in a global clinical trial for left sided cases; right sided cases with poor prognosis are offered the procedure clinically. The search for more potent and less invasive therapies continues. Prenatal transplacental sildenafil administration will in due course be tried clinically, with the aim to reduce the occurrence of persistent pulmonary hypertension, either alone or in combination with fetal surgery. Other medical approaches are in an earlier translational phase.

Abnormal fetal ultrasound leading to the diagnosis of ADNP syndrome.

ADNP syndrome, also known as the Helsmoortel-Van der Aa syndrome (HVDAS), is a neurodevelopmental disorder characterized by hypotonia, developmental delay, and intellectual disability. Diagnosis is typically made postnatally, and little is known about prenatal presentation of the disorder. We report a child who presented with intrauterine growth restriction, proportionate microcephaly, and an abnormal skull shape on fetal ultrasound. Whole exome sequencing performed on amniotic fluid cells showed a de novo pathogenic variant in the ADNP gene, corresponding to a diagnosis of ADNP syndrome.

Effects of cumulative duration of repeated anaesthesia exposure on foetal brain development in the ovine model.

OBJECTIVE: Anaesthesia is required in 0.4-1% of pregnant women, and prolonged and repeated exposures to anaesthesia may be required. It is unknown whether these exposures may result in foetal neurotoxicity in humans. As sheep have a gestation comparable to that of humans, the objective of this study was to analyse the neurodevelopmental outcome of ovine foetuses that had been exposed in utero to repeated and prolonged anaesthesia. DESIGN: Randomized controlled preclinical study. SETTING: Anaesthesia for non-obstetric surgery during pregnancy. ANIMALS: Twenty-four healthy pregnant Swifter ewes. INTERVENTIONS: The ewes were randomized to no anaesthesia exposure (control-group), single exposure (at gestational age 68-70 days), or repeated exposure (at gestational age 68-70 days and 96-98 days) to 2.5 h of sevoflurane anaesthesia and maternal laparotomy. All lambs were delivered at approximately term gestation (gestational age: 140-143 days). MEASUREMENTS: The primary outcome was neuron density in the frontal cortex 24 h after birth for the control-group versus the repeated-exposure-group. Key secondary outcome was the time needed to achieve the milestone of standing. Secondary outcomes included other neurobehavioural assessments (e.g., motoric milestones) and histological parameters quantified in multiple brain regions (neuron density, total cell density, proliferation, inflammation, synaptogenesis, astrocytes and myelination). MAIN RESULTS: Neuron density in the frontal cortex did not differ between groups (mean ±â€¯standard deviation: control-group: 403 ±â€¯39, single-exposure group: 436 ±â€¯23 and repeated-exposure-group: 403 ±â€¯40 neurons/mm2, control-group versus repeated-exposure-group: p = 0.986, control-group versus single-exposure-group: p = 0.097). No significant difference was observed for the time needed to achieve the milestone of standing. Only very limited differences were observed for other histological outcome parameters and neurobehavioural assessments. CONCLUSIONS: There is no evidence for foetal neuronal injury or neurobehavioural impairments after a cumulative duration of 5 h repetitive prenatal anaesthesia in sheep.

Fetal surgery has no additional effect to general anesthesia on brain development in neonatal rabbits.

BACKGROUND: Fetal surgery is part of modern fetal medicine, and some procedures, such as fetal spina bifida repair, are performed under general anesthesia. Fetuses are operated on in a time window when the developing brain is extremely vulnerable to external, potentially harmful factors. To date, little is known about the effect of fetal surgery on fetal brain development. OBJECTIVE: This study aimed to assess the effect of fetal surgery on the developing fetal brain in the rabbit model. STUDY DESIGN: This was a randomized, sham-controlled study in time-mated pregnant does at 28 days' gestation (term, 31 days), which corresponds to the start of the peak of brain development and end of the second trimester of pregnancy in humans. We included 4 different groups in this experiment: no-surgery, general anesthesia, general anesthesia+hysterotomy, and general anesthesia+fetal surgery. In 11 does, anesthesia was induced using propofol and maintained for 75 minutes with 3.6 vol% (4% is the equivalent of 1 minimum alveolar concentration) sevoflurane. Maternal blood pressure, heart rate, oxygen saturation, temperature, end-tidal CO2 were continuously monitored. For each operated doe, 6 fetuses were part of the experiment. Randomization determined which cornual sac and what opposing third sac were assigned to fetal surgery: hysterotomy, fetal injection (atropine, fentanyl, and cisatracurium), fetal skin incision, and suturing. Only hysterotomy was performed on the opposing cornual and third amniotic sacs of the does. The fetus in these experimental sacs was used as internal unmanipulated control (general anesthesia). All fetuses (n=38) from unmanipulated does (n=4) served as external controls (no-surgery). At term, the does were delivered by cesarean delivery under ketamine-medetomidine sedation and local anesthesia. The pups underwent standardized motoric and sensory neurologic testing on day 1 followed by euthanasia and brain harvesting for histologic assessment of neurons, synapses, proliferation, and glial cells. RESULTS: Maternal vital signs were stable during surgery. Survival was similar in the 4 groups (75%-94%), and brain-to-body weight ratio was comparable; only the no-surgery pups had a higher brain weight. On postnatal day 1, the pups in the 4 groups had a comparable neurobehavioral outcome on both motoric and sensory testing. In the prefrontal cortex, no-surgery pups had significantly higher neuron density than pups who underwent maternal surgery, but there was no difference among pups that underwent general anesthesia, hysterotomy, or fetal surgery. The measurements of proliferation had a similar outcome: a higher proliferation rate in the prefrontal cortex of no-surgery pups. Moreover, synaptic density values were higher in the no-surgery pups, but there was no difference observed among pups who underwent general anesthesia, hysterotomy, and fetal surgery. Lastly, there was no difference in gliosis among the 4 groups. CONCLUSION: In rabbits, fetal surgery through hysterotomy under maternal general anesthesia did not affect brain development, in addition to the effects of general anesthesia per se.