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

Implementation of Delayed Cord Clamping for 3 Min During Term Cesarean Sections Does Not Influence Maternal Blood Loss

Background: To assess maternal safety outcomes after a local protocol adjustment to change the interval of cord clamping to 3 min after term cesarean section.Design, Setting, and Patients: A retrospective cohort study in a tertiary referral hospital (Erasmus MC, Rotterdam). We included pregnant women who gave birth at term after cesarean section. A cohort (Nov 2016–Oct 2017) prior to the protocol implementation was compared to a cohort after its implementation (Nov 2017–Nov 2018). The study population covered 789 women (n = 376 pre-cohort; n = 413 post-cohort).Interventions: Implementation of a local protocol changing the interval of cord clamping to 3 min in all term births.Main outcome measures: Primary outcomes were the estimated maternal blood loss and the occurrence of postpartum hemorrhage (blood loss &gt;1,000 ml). Secondary outcomes included both maternal as well as neonatal outcomes.Results: Estimated maternal blood loss was not significantly different between the pre-cohort and post-cohort (400 mL [300–600] vs. 400 mL [300–600], p = 0.52). The incidence of postpartum hemorrhage (26 [6.9%] vs. 35 (8.5%), OR 1.24, 95% CI 0.73–2.11) and maternal blood transfusion (9 [2%] vs. 13 (3%), OR 1.33, 95% CI 0.56–3.14) were not different. Hemoglobin change was significantly higher in the post-cohort (−0.8 mmol/L [−1.3 to −0.5] vs. −0.9 mmol/L [−1.4 to −0.6], p = 0.01). In the post-cohort, neonatal hematocrit levels were higher (51 vs. 55%, p = 0.004) and need for phototherapy was increased (OR 1.95, 95% CI 0.99–3.84).Conclusion: Implementation of delayed cord clamping for 3 min in term cesarean sections was not associated with increased maternal bleeding complications

Perinatal stabilisation of infants born with congenital diaphragmatic hernia: A review of current concepts

Congenital diaphragmatic hernia (CDH) is associated with high mortality rates and significant pulmonary morbidity, mainly due to disrupted lung development related to herniation of abdominal organs into the chest. Pulmonary hypertension is a major contributor to both mortality and morbidity, however, treatment modalities are limited. Novel prenatal and postnatal interventions, such as fetal surgery and medical treatments, are currently under investigation. Until now, the perinatal stabilisation period immediately after birth has been relatively overlooked, although optimising support in these early stages may be vital in improving outcomes. Moreover, physiological parameters obtained from the perinatal stabilisation period could serve as early predictors of adverse outcomes, thereby facilitating both prevention and early treatment of these conditions. In this review, we focus on the perinatal stabilisation period by discussing the current delivery room guidelines in infants born with CDH, th

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

Spontaneous breathing approach in mild congenital diaphragmatic hernia: A resuscitation algorithm

BackgroundInfants with a congenital diaphragmatic hernia (CDH) and expected mild pulmonary hypoplasia have an estimated survival rate of 90%. Current guidelines for delivery room management do not consider the individual patient's disease severity, but an individualized approach with spontaneous breathing instead of routine mechanical ventilation could be beneficial for the mildest cases. We developed a resuscitation algorithm for this individualized approach serving two purposes: improving the success rate by structuring the approach and providing a guideline for other centers.MethodsAn initial algorithm was discussed with all local stakeholders. Afterwards, the resulting algorithm was refined using input from international experts.ResultsEligible CDH infants: left-sided defect, observed to expected lung-to-head ratio ≥50%, gestational age at birth ≥37.0 weeks, and no major associated structural or genetic abnormalities. To facilitate fetal-to-neonatal transition, we propose to start stabilization with non-invasive respiratory support and to adjust this individually.ConclusionsInfants with mild CDH might benefit from an individualized approach for neonatal resuscitation. Herein, we present an algorithm that could serve as guidance for centers implementing this

Oxygen Saturation Index in Neonates with a Congenital Diaphragmatic Hernia: A Retrospective Cohort Study

Introduction: The oxygenation index (OI) is a marker for respiratory disease severity and adverse neonatal outcomes. The oxygen saturation index (OSI) is an alternative that allows for continuous noninvasive monitoring, but evidence for clinical use in critically ill neonates is scarce. The aim of this study was to evaluate the OSI as compared to the OI in term neonates with a congenital diaphragmatic hernia (CDH). Methods: A single-center retrospective cohort study was conducted including all live-born infants with an isolated CDH between June 2017 and December 2020. Paired values of the OI and OSI in the first 24 h after birth were collected. The relation between OI and OSI measurements was assessed, taking into account arterial pH, body temperature, and preductal versus postductal location of oxygen saturation measurement or arterial blood sampling. The predictive values for pulmonary hypertension, need for extracorporeal membrane oxygenation therapy, and survival at discharge were evaluated. Results: Of 33 subjects included, 398 paired values of the OI (median 5.8 [3.3-17.2]) and OSI (median 7.3 [3.6-14.4]) were collected. The OI and OSI correlated strongly (r = 0.77, p < 0.001). The OSI values corresponding to the clinically relevant OI values (10, 15, 20, and 40) were 8.9, 10.9, 12.9, and 20.9, respectively. The predictive values of the OI and OSI were comparable for all adverse neonatal outcomes. No difference was found in the area under the receiver operating characteristic curves for the OI and the OSI for adverse neonatal outcomes. Conclusions: The OSI could replace the OI in clinical practice in infants with a CDH

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

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