Role of Umbilical Cord Milking in the Management of Hypoxic-ischemic Encephalopathy in Neonates

Hypoxic-Ischemic Encephalopathy Clinical Trial

Official title:

Role of Umbilical Cord Milking in the Management of Hypoxic-ischemic Encephalopathy in Neonates: a Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03123081
• Other study ID #: JubileeMMCRI
• Status: Recruiting
• Phase: N/A
• Start date: January 1, 2018
• Est. completion date: July 1, 2022

Study information

• Verified date: February 2021
• Source: Jubilee Mission Medical College and Research Institute
• Contact: Manoj Varanattu, M D
• Phone: +919388407588
• Email: manojvaranattu[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to investigate the efficacy and safety of umbilical cord milking in depressed neonates at birth for prevention of hypoxic ischemic encephalopathy.

Description:

Hypoxic-ischemic encephalopathy (HIE) is a brain injury caused by inadequate supply of oxygen and blood to the brain of a newborn baby. Therapeutic hypothermia is the only proven therapy for these infants. Even after receiving therapeutic hypothermia, 50% of all infants with moderate and severe HIE die or develop neurological and functional impairment. There is a need for a new intervention for neonatal HIE, which is readily available in developing countries and can complement hypothermia. The American College of Obstetricians and Gynecologists and American Academy of Pediatrics recommend a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30-60 seconds after birth. Immediate umbilical cord clamping is contraindicated in maternal hemodynamic instability, need for immediate resuscitation of the newborn and in conditions where placental circulation is not intact. Umbilical cord milking (UCM) is a simple method of delivering volume and possibly stem cells to those neonates, where resuscitation cannot be postponed for obtaining the benefits of delayed cord clamping. We hypothesize that depressed neonates who receive umbilical cord milking will have lower incidence and severity of hypoxic ischemic encephalopathy compared to depressed neonates who receive immediate cord clamping.We propose to investigate the safety and effectiveness of UCM in term and late preterm (≥35 week's gestation) infants who are depressed at birth, in preventing the development and/or progression of hypoxic ischemic encephalopathy. The need for immediate resuscitation measures, abnormal parameters (clinical, hematological and biochemical) and neuroimaging will be compared in depressed neonates with and without UCM. If UCM is found to be safe and beneficial, it can be a useful substitute for delayed cord clamping in depressed neonates worldwide. Conditions: Depressed neonate, Hypoxic-ischemic encephalopathy Intervention: Umbilical cord milking Study Design Study Type: Interventional Study Design: Allocation: Randomized Endpoint Classification: Efficacy/Safety Study Intervention Model: Parallel Assignment Number of Arms: 2 Masking: Single Blind (Subject) Primary Purpose: Prevention Enrollment: 400 [Anticipated] Arms and Interventions: Arms:2, Assigned Interventions: 1. Experimental: Umbilical Cord Milking and 2. No Intervention: Immediate Umbilical Cord Clamping 1. Experimental: Umbilical Cord Milking,Other Name: Umbilical cord stripping Umbilical Cord Milking involves milking a 30 cm long segment of umbilical cord at birth, after initiation of ventilation Procedure: Umbilical Cord Milking (UCM) At birth the umbilical cord of a depressed newborn is clamped immediately and cut 30 cm from the umbilicus and the neonate placed on the resuscitation table. After completion of initial steps, if the baby does not have adequate spontaneous respirations and a heart rate of 100 bpm or higher, positive pressure ventilation (PPV) is given for 30 seconds, along with UCM. The cord is untwisted and held in a vertical position. It is milked 3 times towards the baby at a speed of 10 cm/s and then clamped 3 cm from the umbilicus. The time of cord clamping will be recorded using a timer. After completion of PPV along with UCM, if the baby requires further resuscitation, the NRP 2015 guidelines will be followed. Depressed newborns who respond to initial steps of resuscitation with normal breathing and heart rate of 100 bpm or higher, will receive UCM after this. 2. No Intervention: Immediate Umbilical Cord Clamping, Other Name: routine clamping of the umbilical cord Procedure: Immediate Cord Clamping, At birth the umbilical cord of a depressed newborn is clamped immediately (current recommendation) and cut 3 cm from the umbilicus and the neonate placed on the resuscitation table. The time of cord clamping will be recorded using a timer. After completion of initial steps, if the baby requires further resuscitation, the NRP 2015 guidelines will be followed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: July 1, 2022
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 24 Weeks

Eligibility

Inclusion Criteria:

• Neonates of =35 week's gestation and born depressed (defined by NRP 2015 criteria: as those neonates who doesn't cry or breathe at birth and whose tone is poor) in the hospital

Exclusion Criteria:

• MCDA Twin pregnancy (DCDA twins are included)
• Triplet or quadruplet pregnancy
• Presence of IUGR in antenatal scans (< 10th Centile)
• Short umbilical cord length (<30 cm)
• Rh-negative or retrovirus positive mothers
• Major chromosomal or congenital anomalies
• Hydrops fetalis
• Severe placental abruption
• Cord prolapse and cord abnormalities such as true knots
• Culture positive early onset neonatal sepsis

Related Conditions & MeSH terms

• Brain Diseases
• Brain Ischemia
• Hypoxia
• Hypoxia-Ischemia, Brain
• Hypoxic-Ischemic Encephalopathy
• Ischemia

Intervention

Procedure:
• Umbilical Cord Milking
At birth the cord of a depressed newborn is clamped immediately and cut 30 cm from the umbilicus. After completion of initial steps, if required, positive pressure ventilation (PPV) is given for 30 seconds, along with UCM. The cord is untwisted and held in a vertical position. It is milked 3 times towards the baby at a speed of 10 cm/s and then clamped 3 cm from the umbilicus. After completion of PPV along with UCM, if the baby requires further resuscitation, the NRP 2015 guidelines will be followed. Depressed newborns who respond to initial steps of resuscitation with normal breathing and heart rate of 100 bpm or higher, will receive UCM after this.

Locations

Country	Name	City	State
India	Jubilee Mission Medical College & Research Institute	Thrissur	Kerala

Sponsors (1)

Lead Sponsor	Collaborator
Jubilee Mission Medical College and Research Institute

Country where clinical trial is conducted

India, 

References & Publications (10)

Aridas JD, McDonald CA, Paton MC, Yawno T, Sutherland AE, Nitsos I, Pham Y, Ditchfield M, Fahey MC, Wong F, Malhotra A, Castillo-Melendez M, Bhakoo K, Wallace EM, Jenkin G, Miller SL. Cord blood mononuclear cells prevent neuronal apoptosis in response to perinatal asphyxia in the newborn lamb. J Physiol. 2016 Mar 1;594(5):1421-35. doi: 10.1113/JP271104. Epub 2015 Dec 14. — View Citation

Barkovich AJ, Hajnal BL, Vigneron D, Sola A, Partridge JC, Allen F, Ferriero DM. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am J Neuroradiol. 1998 Jan;19(1):143-9. — View Citation

Dalili H, Nili F, Sheikh M, Hardani AK, Shariat M, Nayeri F. Comparison of the four proposed Apgar scoring systems in the assessment of birth asphyxia and adverse early neurologic outcomes. PLoS One. 2015 Mar 26;10(3):e0122116. doi: 10.1371/journal.pone.0122116. eCollection 2015. — View Citation

Erickson-Owens DA, Mercer JS, Oh W. Umbilical cord milking in term infants delivered by cesarean section: a randomized controlled trial. J Perinatol. 2012 Aug;32(8):580-4. doi: 10.1038/jp.2011.159. Epub 2011 Nov 17. — View Citation

Hong Huang, Nicholas Eastman, Brandon Schanbacher et al. Impact of Delayed Cord Clamping on Circulating Progenitor Cells in Extremely Premature Infants. E-PAS 2016:3821.208

Jaiswal P, Upadhyay A, Gothwal S, Singh D, Dubey K, Garg A, Vishnubhatala S. Comparison of two types of intervention to enhance placental redistribution in term infants: randomized control trial. Eur J Pediatr. 2015 Sep;174(9):1159-67. doi: 10.1007/s00431-015-2511-y. Epub 2015 Mar 24. — View Citation

Mercer JS, Erickson-Owens DA. Is it time to rethink cord management when resuscitation is needed? J Midwifery Womens Health. 2014 Nov-Dec;59(6):635-44. doi: 10.1111/jmwh.12206. Epub 2014 Oct 8. — View Citation

Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976 Oct;33(10):696-705. — View Citation

Upadhyay A, Gothwal S, Parihar R, Garg A, Gupta A, Chawla D, Gulati IK. Effect of umbilical cord milking in term and near term infants: randomized control trial. Am J Obstet Gynecol. 2013 Feb;208(2):120.e1-6. doi: 10.1016/j.ajog.2012.10.884. Epub 2012 Oct 31. — View Citation

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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence and severity of HIE in depressed neonates with and without umbilical cord milking	The severity of HIE if any will be assessed by modified Sarnat staging which is based on level of consciousness, spontaneous activity, neuromuscular control, primitive reflexes, autonomic function and seizures.; [Designated as safety issue: No]; Ref:Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976; 33:696-705. PMID: 987769	72 hours
Secondary	The resuscitation interventions required and the short term outcomes for depressed newborns with and without umbilical cord milking.	The resuscitation interventions required (use of CPAP, oxygen, mask and bag ventilation, endotracheal intubation and ventilation, chest compressions, drugs, and fluid boluses) and the short term outcomes of resuscitation will be assessed using the validated Combined Apgar score (consisting of the Expanded and Specified Apgar scoring systems) introduced by Rudiger et al, in depressed neonates with and without UCM.; [Designated as safety issue: No]; Ref:Dalili H, Nili F, Sheikh M, Hardani AK, Shariat M, Nayeri F (2015) Comparison of the Four Proposed Apgar Scoring Systems in the Assessment of Birth Asphyxia and Adverse Early Neurologic Outcomes. PLoS ONE 10(3): e0122116	20 minutes after delivery
Secondary	Requirement of Neonatal Intensive Care Unit (NICU) admission	Requirement of Neonatal Intensive Care Unit (NICU) admission [Designated as safety issue: No]	1st 24 hours after delivery
Secondary	Blood lactate at 24 hours	Lactate in the peripheral blood at 24 hours after birth in neonates with any grade of HIE.; [Designated as safety issue: No]	1st 24 hours after delivery
Secondary	CD34+ stem cell count at 24 hours	CD34+ stem cell count in the peripheral blood at 24 hours after birth in neonates with any grade of HIE.; [Designated as safety issue: No]	24 hours after birth
Secondary	The number of neonates with symptomatic polycythemia	The number of neonates with symptomatic polycythemia defined as lethargy, plethora, jitteriness, tachycardia, tachypnea and with venous hematocrit > 65%.; [Designated as safety issue: No];	48 hours after birth
Secondary	The number of neonates with hyperbilirubinemia requiring phototherapy or exchange transfusion.	Neonates requiring phototherapy or exchange transfusion will be evaluated according to the NICE/AAP guidelines and serum bilirubin levels will be interpreted according to the baby's age in hours. Physicians who assess the neonate and advice phototherapy or exchange transfusion will be blinded to the intervention.; [Designated as safety issue: No]	72 hours after birth
Secondary	The number of neonates with anemia	The number of neonates with anemia defined as venous hemoglobin < 12.5 g/dL [Designated as safety issue: No];	2 hours after birth
Secondary	MRI changes in the brain of neonates with moderate and severe degrees of HIE who underwent whole body hypothermia.	MRI examination will be performed in neonates who underwent whole body hypothermia 7-14 days after birth and the changes in brain scored as per a validated MR scoring system (Barkovich et al, Am J Neuroradiol 1998;19:143-9) by a neuroradiologist blinded to the intervention.; [Designated as safety issue: No]; Ref:Barkovich AJ, Hajnal BL, Vigneron D, Sola A, Partridge JC, Allen F, et al. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. Am J Neuroradiol 1998;19:143-9. [PubMed: 9432172]	14 days after birth
Secondary	Duration of hospital stay in neonates with any grade of HIE.	Duration of hospital stay in neonates with any grade of HIE. [Designated as safety issue: No]	Duration of hospital stay, an expected average of 7-14 days
Secondary	Survival at 6 weeks of age	Survival at 6 weeks of age [Designated as safety issue: No]	6 weeks after birth
Secondary	Haemoglobin levels at 6 weeks of age	Haemoglobin levels at 6 weeks of age [Designated as safety issue: No]	6 weeks after birth
Secondary	Serum ferritin levels at 6 weeks of age	Serum ferritin levels at 6 weeks of age [Designated as safety issue: No]	6 weeks after birth