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A Simple Intervention With Great Potential

A Simple Intervention With Great Potential 1024 585 Katie Brind'Amour, PhD, MS, CHES

If the CORD-CHD Study meets even a single endpoint, it will represent one of the simplest and most accessible improvements in congenital heart disease management in recent history.

The concept is elegant in its simplicity: delay clamping the umbilical cord for a minute or two after birth to allow a gentle increase in the baby’s blood volume, then reap both physical and neurodevelopmental rewards for years to come.

The idea — already well accepted in healthy infants and in many cases of preterm delivery — has merit for babies with congenital heart disease (CHD), but prior trials exploring the intervention have uniformly excluded this fragile population. The CORD-CHD Study aims to fill in the knowledge gap on delayed clamping so that obstetricians and neonatologists can confidently recommend one course of action over another for these high-risk patients.

“Children with CHD are underrepresented in clinical trials. As a result, we do a lot of things based on intuition, and they’re not always the right thing to do,” explains Kevin Hill, MD, MS, chief of Pediatric Cardiology and co-director of the pediatric and congenital heart disease program at Duke University Medical Center, as well as co-principal investigator for the CORD-CHD study. “This trial will be successful no matter what we learn, because the results will be based on good data specific to this population.”

The randomized trial will compare the impact of a standard 30-second clamp vs a delay of 120 seconds. The extra blood that transfers from the umbilical cord to the infant in the first two minutes after delivery is equivalent to 25% to 33% of a neonate’s typical total blood volume.

“The perceived concerns for delaying clamping in babies with CHD to date have been twofold,” says Mark Galantowicz, MD, chief of Cardiothoracic Surgery and co-director of The Heart Center at Nationwide Children’s Hospital. “One is that the extra volume of blood can overwhelm the circulatory system, which other studies have shown not to be true; the other is that it somewhat concentrates the blood in circulation, causing blood count to increase and potentially causing microvascular complications, which has also turned out not to be the case.”

Infants with CHD have the highest rate of blood transfusions of any pediatric population. Initial research suggests delayed clamping reduces the need for blood transfusions and reduces periods of lower oxygen saturations, which each carry health risks. Preliminary research shows that it also improves neurodevelopmental outcomes in full-term babies and reduces mortality in those born prematurely.

“In infants with CHD, there may be unique risk-benefit profiles, so it is imperative for health care providers to determine at the optimal timing of umbilical cord clamping in these highly vulnerable patients,” says Carl Backes, Jr., MD, MBA, attending neonatologist and cardiologist at Nationwide Children’s, principal investigator in the Center for Perinatal Research at the Abigail Wexner Research Institute (AWRI) and co-principal investigator for the CORD-CHD trial.

One Simple Intervention, Many Things to Consider

Part of the challenge in understanding the impact of delayed clamping in infants with CHD is the heterogeneity of the population. Some children with CHD need minimal attention, while others require immediate resuscitation. The CORD-CHD team has narrowed the focus of the trial to the CHD babies who fall somewhere in between — children with critical CHD that will require intervention and a hospital stay but without life-threatening symptoms expected at the moment of delivery.

The outcomes under study in CORD-CHD also vary considerably, from short-term needs — such as length of stay, need for blood transfusion, readmission or mortality — to long-term developmental outcomes, including age-appropriate motor skills and cognitive processing. CORD-CHD investigators interviewed 100 parents and 100 providers to understand the most important outcomes to each group and incorporated their findings into a novel Global Rank Score, which allows them to assign weighted scores based on the worst outcome experienced. The approach increases statistical power and enables the team to explore factors that might otherwise muddy their findings.

The expectation is that extra blood volume at the start will translate into fewer early complications, giving the brain the greatest chance at normal development over time.

“There is potential for great benefit,” Dr. Backes explains. “Kids with CHD are at 10 times the risk for adverse neurodevelopmental outcomes compared to term babies without CHD, for a number of reasons. If delayed clamping improves outcomes by reducing transfusions or protecting neurodevelopment, then what an easy, safe intervention this would be to offer these families.”

The formal mechanisms behind such potential benefits remain unclear, but possibilities include the increased transfer of the baby’s own stem cells involved in tissue development and repair, increased oxygenation of the brain and other organs, and the implications these two benefits have for subsequent response to surgery, injury, infection, oxygen deprivation and other early stressors.

Furthermore, having more blood to start with also decreases the systemic impact of blood draws and blood loss from surgery. Fetal hemoglobin — the kind present in the baby’s own blood from the placenta — has increased capacity for delivering oxygen compared to the adult hemoglobin given via transfusions. Fetal blood is also richer in iron, a critical component for myelination in health brain development.

The primary goal of the study is to lay to rest the question over when to clamp the cord, but the team hopes to put all collected data to good use.

“There are a host of questions to evaluate, from the early safety of cord clamping for the baby and the mother to secondary endpoints related to intensive care interventions, surgery timing, related complications and hospital discharge,” says Dr. Hill. “There are also many subgroup analyses we can do, looking at benefits by diagnosis, disease severity or specific neurodevelopmental outcomes.”

Foundational Research

“Delayed cord clamping is what all babies used to get — the earliest documentation of delayed clamping goes back to the writing of Aristotle, and even Darwin’s grandfather talked about delaying clamping to resuscitate babies that weren’t breathing,” explains Anup Katheria, MD, director of the Neonatal Research Institute at Sharp Mary Birch Hospital for Women & Newborns and co-principal investigator of CORD-CHD. “Early clinical research suggested its benefits as well. What we’re doing with CORD-CHD is not experimental — we’re just trying to verify whether we should peel back the modern clamping practices that became standard of care without any evidence.”

Concern over possible transfer of the mother’s anesthetics in the 1960s made immediate cord clamping standard practice for all babies for decades — without high-quality data justifying the approach. While delayed clamping has reemerged for term and premature infants in many places, it will take a large, randomized study with high-quality evidence to shift the current cultural hesitation among obstetricians toward waiting to clamp for babies with CHD.

“Delayed clamping could be an important change in practice that could benefit all babies with CHD,” says Dr. Galantowicz of the drug-free, cost-free, globally accessible approach. “There hasn’t ever been something studied that’s so basic, at day one of life, that could have such sweeping benefits.”

The idea began more than 20 years ago with an internally funded, 40-patient pilot study run by Drs. Backes and Galantowicz to explore delayed clamping for blood conservation and transfusion reduction. Years of meticulous planning since then have resulted in a carefully crafted international trial.

Dr. Backes gradually recruited national experts in fetal echocardiography, neurodevelopmental assessment, cord clamping physiology, obstetrics, neonatology, cardiology, endpoint development and data integration. Core teams safeguard study integrity in each area of clinical practice and will also ensure diversity and inclusion for participant recruitment. The trial aims to consent 600 families via 260 study staff at about two dozen hospitals in the United States and Canada. Unlike most pediatric trials, the CORD-CHD study continues to outpace its recruitment targets.

“Coordinators report that moms are responding really well to the invitation to participate,” says Chelsea Cobe, CORD-CHD’s clinical research project manager in the Center for Perinatal Research in AWRI. “It is a scary time for them, and they have no control over that medical diagnosis, but they do have control over this piece of what’s happening during delivery.”

Participating sites also benefit from the study’s “trial within a registry” design, wherein the study’s Data Coordinating Center collects its required information from a registry the sites already take part in, sparing site staff the costly and time-consuming data entry process associated with many trials. The 7-year study is funded by more than $10 million in cooperative agreement (U grant) support from the National Institutes of Health (NIH; UG3HL166794, U24HL166799).

“I am so proud to work at a hospital that has clearly prioritized the integration of clinical research and clinical care,” says Dr. Backes, who commends the Nationwide Children’s Abigail Wexner Research Institute leadership for supporting his early research in this area, as well as supplementing trial costs not covered by the NIH. “I am humbled that this international clinical trial started here at Nationwide Children’s and could impact children across the country and the world. I’m optimistic that CORD-CHD will provide the requisite data to support evidence-based medicine and hopefully lead to better outcomes for CHD infants and their families.”

 

References:

  1. Andersson O, Lindquist B, Lindgren M, Stjernqvist K, Domellöf M, Hellström-Westas L. Effect of Delayed Cord Clamping on Neurodevelopment at 4 Years of Age: A Randomized Clinical Trial. JAMA Pediatr. 2015 Jul;169(7):631-8.
  2. Tarnow-Mordi W, Morris J, Kirby A, Robledo K, Askie L, Brown R, Evans N, Finlayson S, Fogarty M, Gebski V, Ghadge A, Hague W, Isaacs D, Jeffery M, Keech A, Kluckow M, Popat H, Sebastian L, Aagaard K, Belfort M, Pammi M, Abdel-Latif M, Reynolds G, Ariff S, Sheikh L, Chen Y, Colditz P, Liley H, Pritchard M, de Luca D, de Waal K, Forder P, Duley L, El-Naggar W, Gill A, Newnham J, Simmer K, Groom K, Weston P, Gullam J, Patel H, Koh G, Lui K, Marlow N, Morris S, Sehgal A, Wallace E, Soll R, Young L, Sweet D, Walker S, Watkins A, Wright I, Osborn D, Simes J; Australian Placental Transfusion Study Collaborative Group. Delayed versus Immediate Cord Clamping in Preterm Infants. N Engl J Med. 2017 Dec 21;377(25):2445-2455.

Image credit: Adobe Stock

About the author

Katherine (Katie) Brind’Amour is a freelance medical and health science writer based in Pennsylvania. She has written about nearly every therapeutic area for patients, doctors and the general public. Dr. Brind’Amour specializes in health literacy and patient education. She completed her BS and MS degrees in Biology at Arizona State University and her PhD in Health Services Management and Policy at The Ohio State University. She is a Certified Health Education Specialist and is interested in health promotion via health programs and the communication of medical information.

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