Knowledge Gaps in the Fetal to Neonatal Transition of Infants With a Congenital Diaphragmatic Hernia

Clinical research for infants born with a congenital diaphragmatic hernia (CDH) has until recently mainly focused on advances in prenatal and postnatal treatment. However, during the early perinatal transition period there are major physiological adaptations. For most infants these changes will happen uneventfully, but for CDH infants this marks the beginning of serious respiratory complications. In recent years, there is emerging evidence that the clinical management during the perinatal stabilization period in the delivery room may influence postnatal outcomes. Herein, we discuss major knowledge gaps and novel concepts that aim to optimize fetal to neonatal transition for infants with CDH. One such novel and interesting approach is performing resuscitation with an intact umbilical cord, the efficacy of this procedure is currently being investigated in several clinical trials. Furthermore, close evaluation of neonatal physiological parameters in the first 24 h of life might provide early clues concerning the severity of lung hypoplasia and the risk of adverse outcomes. We will provide an overview of trending concepts and discuss potential areas for future research

Vascular reactivity is altered in the placentas of fetuses with congenital diaphragmatic hernia

Introduction: Infants with congenital diaphragmatic hernia (CDH) often develop pulmonary hypertension but frequently fail to respond to vasodilator therapy, for instance because of an altered pulmonary vasoreactivity. Investigating such alterations in vivo is impossible. We hypothesised that these alterations are also present in fetoplacental vessels, since both vasculatures are exposed to the same circulating factors (e.g. endothelin-1) and respond similarly to certain stimuli (e.g. hypoxia). As proof-of-concept, we compared fetoplacental vasoreactivity between healthy and CDH-affected placentas. Methods: Fetoplacental vascular function of healthy and antenatally diagnosed left-sided CDH fetuses was assessed by wire myography. Placental expression of enzymes and receptors involved in the altered vasoreactive pathways was measured using quantitative PCR. Results: CDH arteries (n = 6) constricted more strongly to thromboxane A2 agonist U46619 (p &lt; 0.001) and dilated less to bradykinin (p = 0.01) and nitric oxide (NO)-donor sodium nitroprusside (p = 0.04) than healthy arteries (n = 8). Vasodilation to prostacyclin analogue iloprost and adenylate cyclase stimulator forskolin, and vasoconstriction to endothelin-1 were not different between both groups. Angiotensin II did not induce vasoconstriction. Phosphodiesterase inhibitors sildenafil and milrinone did not affect responses to sodium nitroprusside, forskolin, or U46619. The mRNA expression of guanylate cyclase 1 soluble subunit alpha 1 (p = 0.003) and protein kinase cyclic guanine monophosphate (cGMP)-dependent 1 (p = 0.02) were reduced in CDH versus healthy placentas. Discussion: The identified changes in the thromboxane and NO-cGMP pathways in the fetoplacental vasculature correspond with currently described alterations in the pulmonary vasculature in CDH. Therefore, fetoplacental arteries may provide an opportunity to predict pulmonary therapeutic responses in infants with CDH.</p

Potential higher risk of tethered spinal cord in children after prenatal surgery for myelomeningocele:A systematic review and meta-analysis

Introduction We performed a systematic review and meta-analysis on the incidence of secondary tethered spinal cord (TSC) between prenatal and postnatal closure in patients with MMC. The objectives was to understand the incidence of secondary TSC after prenatal surgery for MMC compared to postnatal surgery for MMC. Material and methods On May 4, 2023, a systematic search was conducted in Medline, Embase, and the Cochrane Library to gather relevant data. Primary studies focusing on repair type, lesion level, and TSC were included, while non-English or non-Dutch reports, case reports, conference abstracts, editorials, letters, comments, and animal studies were excluded. Two reviewers assessed the included studies for bias risk, following PRISMA guidelines. TSC frequency in MMC closure types was determined, and the relationship between TSC occurrence and closure technique was analyzed using relative risk and Fisher's exact test. Subgroup analysis revealed relative risk differences based on study designs and follow-up periods. A total of ten studies, involving 2,724 patients, were assessed. Among them, 2,293 patients underwent postnatal closure, while 431 received prenatal closure for the MMC defect. In the prenatal closure group, TSC occurred in 21.6% (n = 93), compared to 18.8% (n = 432) in the postnatal closure group. The relative risk (RR) of TSC in patients with prenatal MMC closure versus postnatal MMC closure was 1.145 (95%CI 0.939 to 1.398). Fisher's exact test indicated a statistically non-significant association (p = 0.106) between TSC and closure technique. When considering only RCT and controlled cohort studies, the overall RR for TSC was 1.308 (95%CI 1.007 to 1.698) with a non-significant association (p = .053). For studies focusing on children up until early puberty (maximum 12 years follow-up), the RR for tethering was 1.104 (95%CI 0.876 to 1.391), with a non-significant association (p = 0.409). Conclusion and discussion This review found no significant increase in relative risk of TSC between prenatal and postnatal closure in MMC patients, but a trend of increased TSC in the prenatal group. More longterm data on TSC after fetal closure is needed for better counseling and outcomes in MMC.</p

Physiological-based cord clamping versus immediate cord clamping for infants born with a congenital diaphragmatic hernia (PinC):study protocol for a multicentre, randomised controlled trial

Introduction Pulmonary hypertension is a majordeterminant of postnatal survival in infants with acongenital diaphragmatic hernia (CDH). The current careduring the perinatal stabilisation period in these infantsmight contribute to the development of pulmonaryhypertension after birth—in particular umbilical cordclamping before lung aeration. An ovine model ofdiaphragmatic hernia demonstrated that cord clampingafter lung aeration, called physiological-based cordclamping (PBCC), avoided the initial high pressures in thelung vasculature while maintaining adequate blood flow,thereby avoiding vascular remodelling and aggravationof pulmonary hypertension. We aim to investigate if theimplementation of PBCC in the perinatal stabilisation periodof infants born with a CDH could reduce the incidence ofpulmonary hypertension in the first 24 hours after birth.Methods and analysis We will perform a multicentre,randomised controlled trial in infants with an isolatedleft-sided CDH, born at ≥35.0 weeks. Before birth, infantswill be randomised to either PBCC or immediate cordclamping, stratified by treatment centre and severity ofpulmonary hypoplasia on antenatal ultrasound. PBCCwill be performed using a purpose- built resuscitationtrolley. Cord clamping will be performed when the infantis considered respiratory stable, defined as a heartrate &gt;100 bpm, preductal oxygen saturation &gt;85%,while using a fraction of inspired oxygen of &lt;0.5. Theprimary outcome is pulmonary hypertension diagnosedin the first 24 hours after birth, based on clinical andechocardiographic parameters. Secondary outcomesinclude neonatal as well as maternal outcomes.Ethics and dissemination Central ethical approvalwas obtained from the Medical Ethical Committee ofthe Erasmus MC, Rotterdam, The Netherlands (METC2019-0414). Local ethical approval will be obtained bysubmitting the protocol to the regulatory bodies and localinstitutional review boards

Physiological-based cord clamping in very preterm infants:the Aeration, Breathing, Clamping 3 (ABC3) trial—statistical analysis plan for a multicenter randomized controlled trial

Background: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC. Methods: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data. Discussion: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth. Trial registration: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019.</p

Termination of pregnancy after a prenatal diagnosis of congenital diaphragmatic hernia: Factors influencing the parental decision process

Objective: To evaluate the incidence of termination of pregnancies (TOP) and factors associated with the decision for TOP in prenatally detected congenital diaphragmatic hernia (CDH). Study Design: Single-centre retrospective cohort includes all prenatally detected CDH cases born between January 2009 and December 2021. Parental factors, such as parity, and fetal characteristics, such as disease severity, were collected. Descriptive statistics were used to present the data. Differences between terminated and continued pregnancies were analysed. Results: The study population consisted of 278 prenatally detected CDH cases of which 80% detected <24 weeks of gestation. The TOP rate was 28% in cases that were detected <24 weeks of gestation. Twenty continued pregnancies resulted in either intrauterine fetal demise (n = 6), preterm birth <24 weeks (n = 2), or comfort care after birth (n = 12). The survival rate was 70% in the remaining 195 live born cases. Factors associated with the decision for TOP were additional fetal genetic or anatomical abnormalities (p < 0.0001) and expected severity of pulmonary hypoplasia in left-sided CDH (p = 0.0456). Conclusion: The decision to terminate a pregnancy complicated by fetal CDH depends on the severity of pulmonary hypoplasia and the presence of additional abnormalities. This emphasises the importance of early referral to expertise centres for detailed evaluation and multidisciplinary counselling

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia

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The Oxygen Saturation Index as Early Predictor of Outcomes in Congenital Diaphragmatic Hernia

Objective: The aim of the study was to evaluate the oxygen saturation index (OSI) as an early predictor of clinical deterioration in infants with congenital diaphragmatic hernia (CDH). Methods: A single-center retrospective cohort study was conducted in consecutive infants with isolated CDH with continuous OSI measurements collected in the first 24 h after birth between June 2017 and July 2021. Outcomes of interest were pulmonary hypertension, extracorporeal membrane oxygenation (ECMO)-therapy, and mortality. We evaluated the discriminative values of the maximum OSI value and of mean OSI values with receiver operator characteristic (ROC) analysis and the area under the ROC curve. Results: In 42 infants with 49,473 OSI measurements, the median OSI was 5.0 (interquartile range 3.1-10.6). Twenty-seven infants developed pulmonary hypertension on a median of day 1 (1-1), of which 15 infants had an indication for ECMO-therapy, and 6 infants died. Maximum OSI values were associated with pulmonary hypertension, ECMO-therapy, and mortality. Mean OSI values had an acceptable discriminative ability for pulmonary hypertension and an excellent discriminative ability for ECMO-therapy and mortality. Although OSI measurements were not always present in the first hours after birth, we determined discriminative cut-offs for mean OSI values already in these first hours for pulmonary hypertension, the need for ECMO-therapy, and mortality. Conclusions: Continuous OSI evaluation is a promising modality to identify those infants at highest risk for clinical deterioration already in the first hours after birth. This provides an opportunity to tailor postnatal management based on the individual patient's needs

Newborns with myelomeningocele: their health-related quality of life and daily functioning 10 years later

OBJECTIVE Ten years ago, the authors reported on the outcome of their study investigating the degree of discomfort and pain in newborns with myelomeningocele (MMC), using the parameters of unbearable and hopeless suffering. In the current study, they investigated the quality of life, daily functioning, pain and fatigue, ability to communicate, and number of surgeries in the same cohort of patients. They subdivided their study population into severe (Lorber) and less severe (non-Lorber) cases and compared these cases with a healthy population (non-MMC group) and with each other. METHODS The parents of 22 of 28 patients gave informed consent for this study. The KIDSCREEN-27 and PEDI-CAT (Pediatric Evaluation of Disability Inventory) were used to assess quality of life and daily functioning. Pain and fatigue were self-reported on a 10-point numeric rating scale. Communication and ambulation levels were determined using the Communication Function Classification System (CFCS) and the Hoffer ambulation scale. Using reference data from the KIDSCREEN-27 and PEDI-CAT, the authors created a healthy population comparison group. RESULTS There was no significant difference in health-related quality-of-life (HRQOL) scores between Lorber and non-Lorber patients, except that school environment domain scores were lower in the Lorber group. When comparing the HRQOL of MMC patients with that of the non-MMC group, the physical well-being and parent relations and autonomy domains scored significantly lower. The daily functioning of MMC patients was lower on all domains of the PEDI-CAT compared with the non-MMC group. Lorber MMC patients scored lower on all domains of the PEDI-CAT when compared with non-Lorber patients. All patients were capable of communicating effectively; most patients (n = 18) were considered CFCS level I, and 4 patients were considered CFCS level II. CONCLUSIONS This study shows that MMC is a severe, lifelong condition that affects patients’ lives in many domains. All the patients in this study are capable of effective communication, irrespective of severity of MMC. Overall, the data show that in newborn MMC patients, future unbearable suffering with respect to pain, mobility, cognition, and communication is hard to predict and may not always occur