Tracheomalacia and tracheomegaly in infants and children with congenital diaphragmatic hernia managed with and without fetoscopic endoluminal tracheal occlusion (FETO): a multicentre, retrospective cohort study.

BACKGROUND: Temporary fetoscopic endoluminal tracheal occlusion (FETO) promotes lung growth and increases survival in selected fetuses with congenital diaphragmatic hernia (CDH). FETO is performed percutaneously by inserting into the trachea a balloon designed for vascular occlusion. However, reports on the potential postnatal side-effects of the balloon are scarce. This study aimed to evaluate the prevalence of tracheomalacia in infants with CDH managed with and without FETO and other consequences related to the use of the balloon. METHODS: In this multicentre, retrospective cohort study, we included infants who were live born with CDH, either with FETO or without, who were managed postnatally at four centres (UZ Leuven, Leuven, Belgium; Antoine Béclère, Clamart, France; BCNatal, Barcelona, Spain; and HCor-Heart Hospital, São Paulo, Brazil) between April 5, 2002, and June 2, 2021. We primarily assessed the prevalence of all (symptomatic and asymptomatic) tracheomalacia as reported in medical records among infants with and without FETO. Secondarily we assessed the prevalence of symptomatic tracheomalacia and its resolution as reported in medical records, and compared tracheal diameters as measured on postnatal x-rays. Crude and adjusted risk ratios (aRRs) and 95% CIs were calculated via modified Poisson regression models with robust error variances for potential association between FETO and tracheomalacia. Variables included in the adjusted model were the side of the hernia, observed-to-expected lung-to-head ratio, and gestational age at birth. Crude and adjusted mean differences and 95% CIs were calculated via linear regression models to assess the presence and magnitude of association between FETO and tracheal diameters. In infants who had undergone FETO we also assessed the localisation of balloon remnants on x-rays, and the methods used for reversal of occlusion and potential complications associated with balloon remnants as documented in clinical records. Finally we investigated whether the presence of balloon remnants was influenced by the interval between balloon removal and delivery. FINDINGS: 505 neonates were included in the study, of whom 287 had undergone FETO and 218 had not. Tracheomalacia was reported in 18 (6%) infants who had undergone FETO and in three (1%) who had not (aRR 6·17 [95% CI 1·83-20·75]; p=0·0030). Tracheomalacia was first reported in the FETO group at a median of 5·0 months (IQR 0·8-13·0). Symptomatic tracheomalacia was reported in 13 (5%) infants who had undergone FETO, which resolved in ten (77%) children by 55·0 months (IQR 14·0-83·0). On average, infants who had undergone FETO had a 31·3% wider trachea (with FETO tracheal diameter 7·43 mm [SD 1·24], without FETO tracheal diameter 5·10 mm [SD 0·84]; crude mean difference 2·32 [95% CI 2·11-2·54]; p<0·0001; adjusted mean difference 2·62 [95% CI 2·35-2·89]; p<0·0001). At birth, the metallic component was visible within the body in 75 (37%) of 205 infants with available thoraco-abdominal x-rays: it was located in the gastrointestinal tract in 60 (80%) and in the lung in 15 (20%). No side-effects were reported for any of the infants during follow-up. The metallic component was more likely to be in the lung than either outside the body or the gastrointestinal tract when the interval between occlusion reversal and birth was less than 24 h. INTERPRETATION: Although FETO was associated with an increased tracheal diameter and an increased probability of tracheomalacia, symptomatic tracheomalacia typically resolved over time. There is a higher risk of retention of metallic balloon components if reversal of the occlusion occurs less than 24 h before delivery. Finally, there were no reported side-effects of the metallic component of the balloon persisting in the body during follow-up. Longer-term follow-up is needed to ensure that no tracheal problems arise later in life. FUNDING: None.

Age and/or postmenopausal status as risk factors for pelvic organ prolapse development: systematic review with meta-analysis.

INTRODUCTION AND HYPOTHESIS: Age is named as a risk factor for pelvic organ prolapse (POP), despite not being the primary outcome for many observational studies. Postmenopausal status is another associated factor but has many confounders. We aimed to systematically review the role of age and/or postmenopausal status in POP development. METHODS: Systematic review addressing age and hormones, more specifically by postmenopausal status, from inception to March 2020 in four databases (PubMed, Embase, WOS, Cochrane Library). Quality of evidence was classified by the ROBINS-I classification for non-randomized studies. Experimental studies, animal studies, studies linking age with recurrent POP and case series were excluded. Effect estimates were collected from adjusted odds ratio plus 95% confidence intervals. Significance level was 5%. A discussion exploring mechanistic factors was also included. RESULTS: Nineteen studies (11 cross sectional, 6 cohort and 2 case control) were included for quantitative analysis. Only two studies presented a low overall risk of bias for age; most of the domains were of moderate risk. Every additional year was responsible for a 10% increase in the risk to develop POP (OR = 1.102 [1.021-1.190]; i2 = 80%, random analysis, p = 0.012). This trend was confirmed when age was dichotomized into a cutoff of 35 (p = 0.035) and 50 (p < 0.001) years. Although an increase in the risk for POP was noted in postmenopausal women, this did not reach statistical significance (OR = 2.080 [0.927-4.668], i2 = 0%, p = 0.076). CONCLUSION: Age is a risk factor for POP; postmenopausal status was not statistically associated with POP, prompting the need for further studies addressing this factor.

A study to assess global availability of fetal surgery for myelomeningocele.

AIM: To establish the provision of fetal surgery for myelomeningocele (MMC) worldwide. METHODS: Through the International Society for Prenatal Diagnosis (ISPD) Fetal Therapy Special Interest Group and the North American Fetal Therapy Network (NAFTNet), fetal therapy centres were surveyed (September 2017-June 2018) regarding availability of fetal MMC surgical repair, patient inclusion criteria, repair techniques, number of cases, and outcome reporting. Responses were summarised on an interactive map on the ISPD website. RESULTS: Forty-four of 59 centres responded (74.6%) of which 34 centres (77.1%) currently offered fetal surgery for MMC and seven centres (15.9%) were awaiting a first case after service set up. Patient inclusion criteria were similar and based on the Management of Myelomeningocele (MOMS) trial. Five centres (14.7%) operated beyond 26 weeks' gestational age, outside the MOMS criteria. Open fetal surgery was provided in 23 centres (67.6%), fetoscopic surgery only in five (14.7%), and six centres offered both types (17.6%). Neurosurgical closure was similar for open surgery but highly variable in fetoscopy surgery. The median number of cases per centre was 21 (range 1-253). CONCLUSIONS: Fetal surgery for MMC is now offered globally. Two thirds of centres offer open repair via hysterotomy using criteria based on the MOMS trial.

Balloon removal after fetoscopic endoluminal tracheal occlusion for congenital diaphragmatic hernia.

BACKGROUND: Isolated congenital diaphragmatic hernia defect allows viscera to herniate into the chest, competing for space with the developing lungs. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension that is lethal in up to 30% of patients. Antenatal measurement of lung size and liver herniation can predict survival after birth. Prenatal intervention aims at stimulating lung development, clinically achieved by percutaneous fetal endoscopic tracheal occlusion under local anesthesia. This in utero treatment requires a second intervention to reestablish the airway, either before birth or at delivery. OBJECTIVE: To describe our experience with in utero endotracheal balloon removal. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data on consecutive patients with congenital diaphragmatic hernia treated in utero by fetal endoscopic tracheal occlusion from 3 centers. Maternal and pregnancy-associated variables were retrieved. Balloon removal attempts were categorized as elective or emergency and by technique (in utero: ultrasound-guided puncture; fetoscopy; ex utero: on placental circulation or postnatal tracheoscopy). RESULTS: We performed 351 balloon insertions during a 144-month period. In 9 cases removal was attempted outside fetal endoscopic tracheal occlusion centers, 3 of which were deemed impossible and led to neonatal death. We attempted 302 in-house balloon removals in 292 fetuses (217 elective [71.8%], 85 emergency [28.2%]) at 33.4 ± 0.1 weeks (range: 28.9-37.1), with a mean interval to delivery of 16.6 ± 0.8 days (0-85). Primary attempt was by fetoscopy in 196 (67.1%), by ultrasound-guided puncture in 62 (21.2%), by tracheoscopy on placental circulation in 30 (10.3%), and postnatal tracheoscopy in 4 cases (1.4%); a second attempt was required in 10 (3.4%) cases. Each center had different preferences for primary technique selection. In elective removals, we found no differences in the interval to delivery between fetoscopic and ultrasound-guided puncture removals. Difficulties during fetoscopic removal led to the development of a stylet to puncture the balloon, leading to shorter operating time and easier reestablishment of airways. CONCLUSION: In these fetal treatment centers, the balloon could always be removed successfully. In 90% this was in utero, with the use of fetoscopy preferred over ultrasound-guided puncture. Ex utero removal was a fall-back procedure. In utero removal does not seem to precipitate immediate membrane rupture, labor, or delivery, although the design of the study did not allow for a formal conclusion. For fetoscopic removals, the introduction of a stylet facilitated retrieval. Successful removal may rely on a permanently prepared team with expertise in all possible techniques.

Amniotic Fluid Derived Stem Cells with a Renal Progenitor Phenotype Inhibit Interstitial Fibrosis in Renal Ischemia and Reperfusion Injury in Rats.

OBJECTIVES: Mesenchymal stem cells derived from human amniotic fluid (hAFSCs) are a promising source for cellular therapy, especially for renal disorders, as a subpopulation is derived from the fetal urinary tract. The purpose of this study was to evaluate if hAFSCs with a renal progenitor phenotype demonstrate a nephroprotective effect in acute ischemia reperfusion (I/R) model and prevent late stage fibrosis. METHODS: A total of 45 male 12-wk-old Wistar rats were divided into three equal groups;: rats subjected to I/R injury and treated with Chang Medium, rats subjected to I/R injury and treated with hAFSCs and sham-operated animals. In the first part of this study, hAFSCs that highly expressed CD24, CD117, SIX2 and PAX2 were isolated and characterized. In the second part, renal I/R injury was induced in male rats and cellular treatment was performed 6 hours later via arterial injection. Functional and histological analyses were performed 24 hours, 48 hours and 2 months after treatment using serum creatinine, urine protein to creatinine ratio, inflammatory and regeneration markers and histomorphometric analysis of the kidney. Statistical analysis was performed by analysis of variance followed by the Tukey's test for multiple comparisons or by nonparametric Kruskal-Wallis followed by Dunn. Statistical significance level was defined as p <0.05. RESULTS: hAFSCs treatment resulted in significantly reduced serum creatinine level at 24 hours, less tubular necrosis, less hyaline cast formation, higher proliferation index, less inflammatory cell infiltration and less myofibroblasts at 48 h. The treated group had less fibrosis and proteinuria at 2 months after injury. CONCLUSION: hAFSCs contain a renal progenitor cell subpopulation that has a nephroprotective effect when delivered intra-arterially in rats with renal I/R injury, and reduces interstitial fibrosis on long term follow-up.

A surgical technique for homogenous renal distribution of substances in rats.

Intra-arterial injection of mesenchymal stem cells has been proven to result in a superior nephroprotection compared to intravenous injection. This avoids initial passage through filter organs such as the lung, liver and spleen. The aim of the present study was to investigate whether suprarenal aortic delivery results in a homogenous distribution to both kidneys. Chinese ink was used to evaluate the renal distribution pattern for the comparison of two retrograde intra-aortic injection methods. In the first, the aorta caudal to the renal branches was temporarily clamped and Chinese ink was injected at the level of the renal arteries. In the second, a distal aortic clamp was combined with alternated clamping of the contralateral arteries. Immediately after injection, kidneys were harvested for histological analysis. Amniotic fluid stem cells labeled with LacZ were injected in the aorta by alternated clamping of the renal arteries in order to track the cells in a rat ischemia/reperfusion model. Without renal artery clamping, intra-aortic administration resulted in a delivery of the ink into the right kidney, whereas administration with alternated clamping of the contralateral renal artery, together with distal aortic artery clamping, resulted in a more homogenous distribution of the ink in both kidneys. Moreover, LacZ-positive cells were found in both kidneys after 6 h of injection. In conclusion, the retrograde administration of Chinese ink in two steps is a fast and reproducible technique, which results in a more homogenous distribution of the stain in both kidneys than a single administration combined by only clamping the aorta.

Risk of perinatal death in early-onset intrauterine growth restriction according to gestational age and cardiovascular Doppler indices: a multicenter study.

OBJECTIVE: To assess the value of gestational age and cardiovascular Doppler indices in predicting perinatal mortality in a multicenter cohort of early-onset intrauterine growth-restricted (IUGR) fetuses. METHODS: A multicenter prospective cohort study including 157 early-onset (<34 weeks) IUGR cases with abnormal umbilical artery (UA) Doppler was conducted. Cardiovascular assessment included the ductus venosus (DV), the aortic isthmus flow index (IFI), and the myocardial performance index (MPI). Isolated and combined values to predict the risk of perinatal death were evaluated by logistic regression and by decision tree analysis, where the gestational age at delivery, UA, and middle cerebral artery (MCA) were also included as covariates. RESULTS: Perinatal mortality was 17% (27/157). All parameters were significantly associated with perinatal death, with individual odds ratios (OR) of 25.2 for gestational age below 28 weeks, 12.1 for absent/reversed DV atrial flow, 5.3 for MCA pulsatility index <5th centile, 4.6 for UA absent/reversed diastolic end-flow, 1.8 for IFI <5th centile, and 1.6 for MPI >95th centile. Decision tree analysis identified gestational age at birth as the best predictor of death (<26 weeks, 93% mortality; 26-28 weeks, 29% mortality, and >28 weeks, 3% mortality). Between 26 and 28 weeks, DV atrial flow allowed further stratification between high (60%) and low risk (18%) of mortality. CONCLUSIONS: Gestational age largely determines the risk of perinatal mortality in early-onset IUGR before 26 weeks and later than 28 weeks of gestation. The DV may improve clinical management by stratifying the probability of death between 26 and 28 weeks of gestation.