Physiological Umbilical Cord Clamping in Patients With Congenital Diaphragmatic Hernia. Clinical Trial

Congenital diaphragmatic hernia (CDH) is a malformation that affects 1 in every 3000 newborns. The diaphragm does not complete its closure during embryogenesis, which allows the abdominal organs to herniate into the thoracic cavity altering lung development. The lungs of patients with CDH are small, with a decreased surface area for gas exchange and developmental impair of the pulmonary vasculature, resulting in respiratory failure and pulmonary hypertension shortly after birth. When clamping the umbilical cord, a large part of the preload is abruptly excluded, generating an increase in vascular resistance, which in turn increase the afterload, resulting in a decrease in cardiac output. The output is restored by decreasing vascular resistance in pulmonary circuit after lung aeration upon receiving the preload of the right atrium, increasing pulmonary flow and thus sustaining the preload of the left ventricle. If pulmonary aeration occurs before clamping the umbilical cord, the pulmonary blood flow increases before placenta flow is lost, thus avoiding a decrease in cardiac output. This modality has been called physiological base cord clamping (PFC). The hypothesis is that PFC once ventilation has been established could prevent hypoxia and improve cardiac output in newborns with CDH and secondarily improve their hemodynamic parameters, stabilizing gas exchange and pulmonary hypertension during the first 24 hours of birth.

Study Overview

• Status: Recruiting
• Conditions: Congenital Diaphragmatic Hernia; Umbilical Cord Clamping; Delayed Umbilical Cord Separation
• Intervention / Treatment: Procedure: Physiological cord clamping

Detailed Description

• Type of study: Randomized clinical trial
• Primary objective: To establish the effectiveness of PFC in reducing hypoxia and improving cardiac output compared to immediate postintubation clamping in newborns with CDH. To establish the safety and feasibility of PFC after pulmonary recruitment achieved post intubation.
• Secondary objectives: describe the evolution of patients with CDH 24 hours after birth under pre-established conditions. Relate prenatal indices to the subsequent evolution of these patients. Describe maternal evolution and postpartum complications.
• Population: Patients who attend the Fetal Diagnosis and Treatment program of Garrahan Children's Hospital and undergo prenatal diagnosis of CDH are possible candidates. The study will be carried out in the Neonatal Intensive Care Unit of said hospital.
• Scope of the study: Garrahan Children's Hospital is a level 3 B pediatric hospital and national referral center located in Autonomous City of Buenos Aires, Argentina. Center that receives neonates with CDH referred from all over the country as well as from other countries in the region and carries out the relevant training for equal reception.
• Block randomization: will be carried out on the same day, 2 hours before entering the delivery room
• Intervention: Immediately after birth, the newborn will be placed on a mobile table, made to received these patients in the delivery room, at the level of the mother's womb, leaving the umbilical cord intact, intubated and gently ventilated (positive inspiration pressure (PIM) 15/25 - positive end expiratory pressure (PEEP)4 - fraction of inspired oxygen inspired oxygen fraction (FiO2) 50%), until saturation >85% and heart rate (HR) >100 or 10 timed minutes pass, whichever occurs first, the umbilical cord will be clamped and continued with the usual reception steps in accordance with the unit´s CDH reception protocol.
• Sample size: To calculate the sample size, a prevalence of hemodynamic alterations of 60% was considered in the first 24 hours of life of patients with CDH, following unit statistics and the aforementioned bibliography. The estimated sample size with a relative reduction of 50%: reduction from 60% to 30% of hemodynamic alterations - Power of 80% - Two-tailed test - alpha 5%. 40 patients required in each branch.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mariela Jozefkowicz; Phone Number: +5491164646270; Email: mjozefkowicz@garrahan.gov.ar
• Study Contact Backup: Name: Maria T Mazzucchelli; Phone Number: +5491149170437; Email: mtmazzu@gmail.com

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1245AAM
    • Recruiting
    • Hospital de Pediatría S.A.M.I.C. "Prof. Dr. Juan P. Garrahan"
    • Contact: Mariela Jozefkowicz; Phone Number: +5491164646270; Email: mjozefkowicz@garrahan.gov.ar
    • Contact: Maria T Mazzucchelli; Phone Number: +5491149170437; Email: mtmazzu@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Prenatal diagnosis of congenital diaphragmatic hernia
• gestational age >34 weeks
• Informed consent signed by the patient's parents

Exclusion Criteria:

• Multiple gestation
• Major malformation or fetal genetic anomaly diagnosed in the prenatal stage
• Emergency cesarean section or maternal condition that prevents the approach
• Lack of informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: physiological umbilical cord clamping; Immediately after birth, the newborn will be placed on a mobile table, made to receive these patients in the delivery room, at the level of the mother's womb, leaving the umbilical cord intact and will be intubated. The patient will be gently ventilated (PIM 15/25 - PEEP 4 - Fio2 50%), until saturation >85% and HR>100 or 10 timed minutes have elapsed, whichever occurs first, the umbilical cord will be clamped and the procedures continued usual reception steps according to the unit´s CDH reception protocol.	Procedure: Physiological cord clamping; Immediately after birth, the newborn with prenatal diagnosis of CDH will be placed on a mobile table, made to receive these patients in the delivery room, at the level of the mother's womb, leaving the umbilical cord intact and intubated. The patient will be gently ventilated (PIM 15/25 - PEEP 4 - Fio2 50%), until saturation >85% and HR>100 or 10 timed minutes have elapsed, whichever occurs first, the umbilical cord will be clamped.
No Intervention: usual reception; Immediately after birth, the newborn is placed on a mobile table, made to receive these patients in the delivery room, at the level of the mother's womb, leaving the umbilical cord intact will be intubated. According to the unit´s CDH reception protocol, patients with CDH cord clamping is done post intubation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemodynamic deterioration in the first 24 hours of life	Hemodynamic deterioration in the first 24 hours of life (meeting 3 of 4 of the following criteria or entry to extracorporeal membrane oxygenation (ECMO) or Death).; Pre/post ductal saturation difference >10%; Oxygenation index (IO) >20; mean arterial pressure < Percentile 50 or inotrope requirement; Lactic acid >3 mmol/l	24 hours of life
complete delivery according group	Complete the protocol in the delivery room pre-established according to randomization (yes/no)	delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational age at diagnosis	Gestational age at diagnosis of CDH in weeks	1st day of life
Lung heart rate index observed/expected LHR O/E	lung heart rate index observed/expected (LHR O/E)	from 26 to 32 weeks of gestational age
liver in thorax	liver in thorax (yes/no) and %	from 26 to 32 weeks of gestational age
stomach herniation	stomach herniation (yes/no) and %	from 26 to 32 weeks of gestational age
lung volumen	lung volumen in RMI	from 26 to 32 weeks of gestational age
Mcgoon	Mcgoon Index in fetal echocardiogram	from 26 to 32 weeks of gestational age
maternal hematocrit	maternal hematocrit in gr/dl	1 day before delivery
Intubation time	Time to intubation (minutes, seconds)	From delivery to intubation
Cord clamping time	Cord clamping time (minutes, seconds)	from delivery to cord clamping
Advance resuscitation need on delivery room	Requirement for advanced resuscitation (yes/no) (compressions, drugs, hypothermia)	from delivery to 30 minutes of life
Time to reach heart rate (HR) >100	Time to reach HR >100 (minutes, seconds)	from delivery to 30 minutes of life
Time to reach saturation (SAT) >85%	Time to reach SAT >85% (minutes, seconds)	from delivery to 30 minutes of life
Cord PH value	cord ph value	inmediatly after cord clampping
Cord lactic acid value	cord lactic acid value in mmol/l	inmediatly after cord clampping
saturation at 10 minutes	pre and post ductal saturation %	10 minutes of life
Arterial pressure at 10 minutes	mean arterial tension in mmhg	10 minutes of life
placenta abruption	Time for placental abruption (minutes, seconds)	30 minutes of life
Mother arterial tension after delivery	mothers arterial mean tension after delivery in mmhg	10 minutes after delivery
Uterotonic use	uterotonics use on mothers after delivery (yes/no)	30 minutes after delivery
Evolution of patient Blood preassure (BP)	Blood pressure in mmhg	2 - 4 hours and 24 hours of life
Evolution of patient inotropes required	Inotrope requirement (yes/no)	2 - 4 hours and 24 hours of life
Inhaled nitric oxide (NOi) requirement	NOi requirement (yes/no)	2 - 4 hours and 24 hours of life
ventilation requirements on the first day	Ventilatory mode / mean airway pressure (MAP)/ FIo2 %	2 - 4 hours and 24 hours of life
Oxygenation on the first day	Partial arterial pressure of oxygen (PaO2) mmhg	2 - 4 hours and 24 hours of life
Oxygenation index (OI) on the first day	OI	2 - 4 hours and 24 hours of life
near-infrared spectroscopy (Nirs) on the first day	Cerebral and somatic NIRS	2 - 4 hours and 24 hours of life
B natriuretic peptide (BNP) on the first day	B natriuretic peptide (BNP)	24 hours of life
PH value on the first day	echocardiographic pulmonary hypertension PH (<50% of systemic pressure, between 50-80% of systemic pressure, between 80 and 100% of systemic pressure, systemic, suprasystemic)	6 and 24 hours of life
cardiac malformations	cardiac malformation (yes/no)	6 hours of life
Mortality	Mortality (yes/no)	through study completion, an average of 1 year
Admission to ECMO	Admission to ECMO after the first 24 hours (yes/no)	through study completion, an average of 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
maternal age	maternal age during pregnancy	through study completion, an average of 1 year
maternal history	maternal pathological history during pregnancy (yes/no)	through study completion, an average of 1 year
baby weight	Weight in grams	30 minutes of life
Patent ductus arteriosus (PAD) on the first day (size)	Patent ductus arteriosus (PAD): size in milimeters	6 and 24 hours of life
Patent ductus arteriosus (PAD) on the first day (gradient)	Patent ductus arteriosus (PAD): gradient	6 and 24 hours of life
Patent ductus arteriosus (PAD) on the first day (shunt direction)	Patent ductus arteriosus (PAD): shunt direction	6 and 24 hours of life
Patent foramen ovale (PFO) on the first day (shunt direction)	Patent foramen ovale (PFO): shunt direction.	6 and 24 hours of life
Right ventricle (RV) on the first day diameter	Right ventricle (RV): RV diameter in milimeters	6 and 24 hours of life
Right ventricle (RV) on the first day TAPSE	Right ventricle (RV): TAPSE	6 and 24 hours of life
Tricuspide Insufitienty	tricuspide insufitienty	6 and 24 hours of life
Right ventricle funtion	Right ventricle global disfuntion : no, mild, moderate or severe	6 and 24 hours of life
Left ventricle (LV) on the first day (eccentricity index)	Left ventricle (LV): eccentricity index	6 and 24 hours of life
Left ventricle (LV) on the first day (ejection fraction)	Left ventricle (LV): ejection fraction (EF)	6 and 24 hours of life
Left ventricle (LV) on the first day global funtion	Left ventricle (LV) global disfuntion : no, global disfuntion : no, mild, moderate or severe	6 and 24 hours of life
Interventricular septum (IS) on the first day	Interventricular septum: configuration	6 and 24 hours of life
Pulmonary hypertation grade on the first day	Pulmonary hypertation: no, mild, moderate or severe	6 and 24 hours of life
Associated malformations	Associated malformations (yes/no), which	24 hours of life
Chromosomopathy or genetic alteration	Chromosomopathy or genetic alteration (yes/no), which	through study completion, an average of 1 year
Hyperbilirubinemia	Hyperbilirubinemia requiring phototherapy or exchange transfusion (yes/no)	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
Early sepsis	Early sepsis (yes/no)	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
Omphalitis	Omphalitis (yes/no)	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
CDH surgery	CDH surgery (yes/no), days of life	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
Surgical classification	Surgical classification of CDH (a-b-c-d)	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
Days in neonatal intensive care unit (NICU)	Days in NICU	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

Collaborators and Investigators

• Sponsor: Hospital JP Garrahan
• Investigators: Principal Investigator: Mariela Jozefkowicz, Hospital JP Garrahan

Publications and helpful links

General Publications

• Bhatt S, Alison BJ, Wallace EM, Crossley KJ, Gill AW, Kluckow M, te Pas AB, Morley CJ, Polglase GR, Hooper SB. Delaying cord clamping until ventilation onset improves cardiovascular function at birth in preterm lambs. J Physiol. 2013 Apr 15;591(8):2113-26. doi: 10.1113/jphysiol.2012.250084. Epub 2013 Feb 11.
• Hooper SB, Polglase GR, te Pas AB. A physiological approach to the timing of umbilical cord clamping at birth. Arch Dis Child Fetal Neonatal Ed. 2015 Jul;100(4):F355-60. doi: 10.1136/archdischild-2013-305703. Epub 2014 Dec 24.
• Polglase GR, Dawson JA, Kluckow M, Gill AW, Davis PG, Te Pas AB, Crossley KJ, McDougall A, Wallace EM, Hooper SB. Ventilation onset prior to umbilical cord clamping (physiological-based cord clamping) improves systemic and cerebral oxygenation in preterm lambs. PLoS One. 2015 Feb 17;10(2):e0117504. doi: 10.1371/journal.pone.0117504. eCollection 2015.
• Wyckoff MH, Aziz K, Escobedo MB, Kapadia VS, Kattwinkel J, Perlman JM, Simon WM, Weiner GM, Zaichkin JG. Part 13: Neonatal Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015 Nov 3;132(18 Suppl 2):S543-60. doi: 10.1161/CIR.0000000000000267. No abstract available.
• Snoek KG, Reiss IK, Greenough A, Capolupo I, Urlesberger B, Wessel L, Storme L, Deprest J, Schaible T, van Heijst A, Tibboel D; CDH EURO Consortium. Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update. Neonatology. 2016;110(1):66-74. doi: 10.1159/000444210. Epub 2016 Apr 15.
• Hooper SB, Te Pas AB, Lang J, van Vonderen JJ, Roehr CC, Kluckow M, Gill AW, Wallace EM, Polglase GR. Cardiovascular transition at birth: a physiological sequence. Pediatr Res. 2015 May;77(5):608-14. doi: 10.1038/pr.2015.21. Epub 2015 Feb 4.
• Katheria A, Poeltler D, Durham J, Steen J, Rich W, Arnell K, Maldonado M, Cousins L, Finer N. Neonatal Resuscitation with an Intact Cord: A Randomized Clinical Trial. J Pediatr. 2016 Nov;178:75-80.e3. doi: 10.1016/j.jpeds.2016.07.053. Epub 2016 Aug 26.
• Duley L, Dorling J, Pushpa-Rajah A, Oddie SJ, Yoxall CW, Schoonakker B, Bradshaw L, Mitchell EJ, Fawke JA; Cord Pilot Trial Collaborative Group. Randomised trial of cord clamping and initial stabilisation at very preterm birth. Arch Dis Child Fetal Neonatal Ed. 2018 Jan;103(1):F6-F14. doi: 10.1136/archdischild-2016-312567. Epub 2017 Sep 18.
• Katheria AC, Brown MK, Faksh A, Hassen KO, Rich W, Lazarus D, Steen J, Daneshmand SS, Finer NN. Delayed Cord Clamping in Newborns Born at Term at Risk for Resuscitation: A Feasibility Randomized Clinical Trial. J Pediatr. 2017 Aug;187:313-317.e1. doi: 10.1016/j.jpeds.2017.04.033. Epub 2017 May 16.
• Winter J, Kattwinkel J, Chisholm C, Blackman A, Wilson S, Fairchild K. Ventilation of Preterm Infants during Delayed Cord Clamping (VentFirst): A Pilot Study of Feasibility and Safety. Am J Perinatol. 2017 Jan;34(2):111-116. doi: 10.1055/s-0036-1584521. Epub 2016 Jun 15.
• Langham MR Jr, Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic hernia. Epidemiology and outcome. Clin Perinatol. 1996 Dec;23(4):671-88.
• Keller RL. Antenatal and postnatal lung and vascular anatomic and functional studies in congenital diaphragmatic hernia: implications for clinical management. Am J Med Genet C Semin Med Genet. 2007 May 15;145C(2):184-200. doi: 10.1002/ajmg.c.30130.
• Horn-Oudshoorn EJJ, Knol R, Te Pas AB, Hooper SB, Cochius-den Otter SCM, Wijnen RMH, Schaible T, Reiss IKM, DeKoninck PLJ. Perinatal stabilisation of infants born with congenital diaphragmatic hernia: a review of current concepts. Arch Dis Child Fetal Neonatal Ed. 2020 Jul;105(4):449-454. doi: 10.1136/archdischild-2019-318606. Epub 2020 Mar 13.
• Lefebvre C, Rakza T, Weslinck N, Vaast P, Houfflin-Debarge V, Mur S, Storme L; French CDH Study Group. Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH). Resuscitation. 2017 Nov;120:20-25. doi: 10.1016/j.resuscitation.2017.08.233. Epub 2017 Aug 30.
• Rabe H, Gyte GM, Diaz-Rossello JL, Duley L. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev. 2019 Sep 17;9(9):CD003248. doi: 10.1002/14651858.CD003248.pub4.
• McGillick EV, Davies IM, Hooper SB, Kerr LT, Thio M, DeKoninck P, Yamaoka S, Hodges R, Rodgers KA, Zahra VA, Moxham AM, Kashyap AJ, Crossley KJ. Effect of lung hypoplasia on the cardiorespiratory transition in newborn lambs. J Appl Physiol (1985). 2019 Aug 1;127(2):568-578. doi: 10.1152/japplphysiol.00760.2018. Epub 2019 Jun 13.
• Kashyap AJ, Hodges RJ, Thio M, Rodgers KA, Amberg BJ, McGillick EV, Hooper SB, Crossley KJ, DeKoninck PLJ. Physiologically based cord clamping improves cardiopulmonary haemodynamics in lambs with a diaphragmatic hernia. Arch Dis Child Fetal Neonatal Ed. 2020 Jan;105(1):18-25. doi: 10.1136/archdischild-2019-316906. Epub 2019 May 23.
• Sakurai Y, Azarow K, Cutz E, Messineo A, Pearl R, Bohn D. Pulmonary barotrauma in congenital diaphragmatic hernia: a clinicopathological correlation. J Pediatr Surg. 1999 Dec;34(12):1813-7. doi: 10.1016/s0022-3468(99)90319-6.
• Foglia EE, Ades A, Hedrick HL, Rintoul N, Munson DA, Moldenhauer J, Gebb J, Serletti B, Chaudhary A, Weinberg DD, Napolitano N, Fraga MV, Ratcliffe SJ. Initiating resuscitation before umbilical cord clamping in infants with congenital diaphragmatic hernia: a pilot feasibility trial. Arch Dis Child Fetal Neonatal Ed. 2020 May;105(3):322-326. doi: 10.1136/archdischild-2019-317477. Epub 2019 Aug 28.
• Le Duc K, Mur S, Rakza T, Boukhris MR, Rousset C, Vaast P, Westlynk N, Aubry E, Sharma D, Storme L. Efficacy of Intact Cord Resuscitation Compared to Immediate Cord Clamping on Cardiorespiratory Adaptation at Birth in Infants with Isolated Congenital Diaphragmatic Hernia (CHIC). Children (Basel). 2021 Apr 26;8(5):339. doi: 10.3390/children8050339.

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: January 22, 2024
• First Submitted That Met QC Criteria: May 6, 2024
• First Posted (Actual): May 10, 2024

Study Record Updates

• Last Update Posted (Actual): May 10, 2024
• Last Update Submitted That Met QC Criteria: May 6, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Congenital Abnormalities; Pathological Conditions, Anatomical; Internal Hernia; Hernia; Hernias, Diaphragmatic, Congenital; Hernia, Diaphragmatic
• Other Study ID Numbers: 1362; 6721 (Other Identifier: PRIISA BA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No