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Three Children’s Mercy Kansas City disciplines — neonatology, fetal cardiology and maternal fetal medicine — are collaborating with hospitals across North America to answer an important question: How does delayed umbilical cord clamping impact the neurodevelopment of babies with congenital heart disease (CHD)? 

Research has established that delaying cord clamping for 30 to 45 seconds or longer benefits both preterm and full-term newborns. Delayed cord clamping can: 

• Preserve the baby’s red blood cells. 
• Reduce the need for transfusions. 
• Improve iron levels, which reduces the risk of anemia and boosts brain development. 
• Decrease the risk of necrotizing enterocolitis. 
• Decrease the risk of brain bleeds. 
• Improve neurological and developmental outcomes. 

Newborns with CHD have been excluded from previous cord-clamping studies because of their complex health variables, including how blood volume affects newborns with cardiac issues.  “The reason they were excluded before is the reason we need the study now,” explained Laura Vricella, MD, FACOG, Medical Director of the Elizabeth J. Ferrell Fetal Health Center. 

“The already established benefits of delayed cord clamping may certainly be favorable to newborns with CHD,” said Maria Kiaffas, MD, PhD, Director of Fetal Cardiology, who outlined some of the hypotheses the study will be able to test.

 “Newborns with certain types of CHD (i.e. cyanotic) do benefit from a robust amount of red blood cells, and the ones that will need surgery may need less transfusions when they start with a good hematocrit. In addition, the decreased risk of necrotizing enterocolitis, a common complication in newborns with CHD, can favorably affect their morbidity and length of hospitalization.” 

“These kids are known to be at higher risk for neurological developmental issues,” said John Daniel, MD, MS, Neonatal ECMO Director. “The brain may receive less oxygen as a fetus in certain CHD types, and then newborns live in a persistently hypoxic state. They often go on cardiopulmonary bypass to have their operations. There are a lot of risk factors.” 

The new multi-site study, “CORD-CHD: Cord clamping among neonates with Congenital Heart Disease,” is led by Carl H. Backes, Jr., MD, from Nationwide Children’s, with Dr. Kiaffas and Dr. Daniel serving as site Principal Investigators at Children’s Mercy. The study is funded through the National Institutes of Health’s National Heart, Lung and Blood Institute. 

The study randomizes participating families into two groups: One where cords are cut after a delay of 30 to 60 seconds and one where cords are cut between 60 and 180 seconds following delivery. Patients will have neurodevelopmental follow-ups at 3-4 months, 9-12 months, and 22 to 26 months of age. The study will recruit participants for five years and run until 2030. With a total sample-size goal of 600, Children’s Mercy is tasked with enrolling 5 to 10 families per year. 

“We’ve sailed past our recruitment goals,” said Cheri Gauldin, BSN, CCRC, Senior Research Nurse Coordinator, Children's Mercy Research Institute. The team started recruiting participants in February and has already enrolled 11 families and completed 10 deliveries — the most of any participating site so far. 

When the team identifies a potential candidate (around 40% of the center’s deliveries have some form of CHD), they explain the study to the family at an interdisciplinary care meeting. Most families have been familiar with delayed cord clamping, either from previous births or by talking to their obstetricians, and have been eager to participate. 

“The Fetal Health Center has done an amazing job,” said Cheri. “They are being very proactive with helping us make sure everybody knows who’s enrolled.”  With the cooperation of today’s Fetal Health Center families, the innovative study will ensure future patients get the best evidence-based care possible. 

“This study wouldn’t be possible without the center,” agreed Dr. Daniel. “As our center continues to grow, we wanted to introduce research that bridges the gap between neonatology and maternal fetal medicine. This is a truly multidisciplinary study, and our Fetal Health Center is uniquely positioned to offer it to families.” 

Learn more about our Heart Center, Neonatology and Fetal Health Center at childrensmercy.org.

 

In recent years there have been marked improvements in survival and outcomes for infants born at less than 30 weeks of gestational age.¹ Despite this positive trend, children born very preterm (VPT) remain at high risk for long-term physical and mental health problems, as well as developmental delays. In longitudinal follow-up studies, VPT children have shown deficits or delays in cognitive, motor and language development and are at increased risk for disorders such as cerebral palsy and autism spectrum disorder.^2-6

However, most studies examining neurodevelopmental outcomes in VPT children report rates of impairment for individual outcomes separately, when in fact it is more likely some outcomes co-occur. An alternative to this approach is to integrate across multiple measures to identify subgroups of children with similar neuroatypical patterns of behavior.

NOVI Studies VPT Infants

The Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) multicenter study enrolled infants born at less than 30 weeks of postmenstrual age (PMA) from nine NICUs affiliated with six universities located throughout the country from April 2014 to June 2016. The regional diversity and volume of patients enrolled are strengths of the NOVI study. Often research into VPT patient outcomes has been limited to single-center studies.

Another unique aspect of the NOVI study is that it not only concerns neonatal-perinatal risk, but the environment of raising the child, exposure to environmental modulators and the frequency and severity of any illness or developmental impairments, as well as therapeutic services utilized.

The Level IV Neonatal Intensive Care Unit at Children’s Mercy Kansas City is one of the sites that originally enrolled VPT infants in this project and continues to follow them to 7 years of age. Brian Carter, MD, Children’s Mercy Neonatologist and Bioethicist, serves as the site’s principal investigator.

Neurodevelopmental Profiles of VPT Infants at 2 Years of Age

The researchers involved in the NOVI study have begun analyzing data gathered from 587 infants born at less than 30 weeks of PMA from the participating sites. To date, they have authored several notable papers, including one recently published online in Pediatric Research that addresses the neurodevelopmental profiles of infants born at less than 30 weeks of gestation at 2 years of age.⁷

Their objective was to describe neurodevelopmental profiles of these children using cognitive, language, motor and behavioral characteristics. Age 2 outcomes included Bayley-III subscale scores, Child Behavior Checklist syndrome scores, diagnosis of cerebral palsy, and positive screen for autism spectrum disorder risk. They used latent profile analysis to group children into mutually exclusive profiles.

What the researchers found were four discrete neurodevelopmental profiles indicating distinct combinations of developmental and behavioral outcomes.

• Two of the profiles included 72.7% of the sample, with most having Bayley scores within the normal range. 
• The other two profiles included the remaining 27.3% of the sample, with most having Bayley scores outside the normal range. Only one profile (11% of sample) comprised children with elevated behavioral problems. These children are most at risk for adverse outcomes. 

While there are additional findings within each profile, this study illustrates the need to move beyond individual variable analysis and toward novel approaches to study different risk profiles in this patient population.

How “Child-Centered" Assessments Could Help VPT Infants

The researchers concluded that “child-centered” analysis techniques may provide clinically useful information and could facilitate the development of targeted intervention strategies for VPT children.

For example, relatively few NICUs across the nation routinely conduct the NICU Network Neurobehavioral Scale (NNNS) assessment before a VPT infant is discharged. This assessment is a valid biomarker for detecting at-risk infants and predicting their outcomes. Results could help identify infants in greatest need for enhanced surveillance in NICU follow-up clinics and determine which infants may benefit most from rapid enrollment in early intervention services, giving them the opportunity for the best possible outcome.

This type of universal screening is consistent with the American Academy of Pediatrics^8,9 promotion of universal screening for a wide range of neurodevelopmental and behavioral conditions that impact children’s long-term developmental and achievement potential and the provision of early intervention referral for high-risk children, even in the absence of a specific diagnosis.

The researchers anticipate additional publications and insights into this important issue as the data collected from this project is further analyzed and published.

Learn more about the Division of Neonatology at Children's Mercy

Brian Carter, MD, Neonatologist; Bioethicist and Co-Director, Pediatric Bioethics Certificate Course, Children’s Mercy Kansas City 

bscarter@cmh.edu

 (816) 731-7028 

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

1. Glass HC, Costarino AT, Stayer SA, Brett CM, Cladis F, Davis PJ. Outcomes for extremely premature infants. Anesth Analg. 2015;120(6):1337–1351. doi:10.1213/ANE.0000000000000705

2. Aarnoudse-Moens CSH, Weisglas-Kuperus N, van Goudoever JB, Oosterlaan J. Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics. 2009;124(2):717–728. doi:10.1542/peds.2008-2816

3. Stephens BE, Vohr BR. Neurodevelopmental outcome of the premature infant. Pediatr Clin North Am. 2009;56(3):631–646. doi:10.1016/j.pcl.2009.03.005

4. Allen MC. Neurodevelopmental outcomes of preterm infants. Curr Opin Neurol. 2008;21(2):123–128. doi:10.1097/WCO.0b013e3282f88bb4

5. Vohr BR, Wright LL, Poole WK, McDonald SA. Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks’ gestation between 1993 and 1998. Pediatrics. 2005;116(3):635–643. doi:10.1542/peds.2004-2247

6. Agrawal S, Rao SC, Bulsara MK, Patole SK. Prevalence of autism spectrum disorder in preterm infants: a meta-analysis. Pediatrics. 2018;142(3):e20180134. doi:10.1542/peds.2018-0134

7. Camerota M, McGowan EC, Hofheimer JA, et al. Neurodevelopmental profiles of infants born <30 weeks gestation at 2 years of age. Pediatric Res. Published online December 9, 2021. doi:10.1038/s41390-021-01871-2

8. Lipkin PH, Macias MM; Council on Children with Disabilities, Section on Developmental and Behavioral Pediatrics. Promoting optimal development: identifying infants and young children with developmental disorders through developmental surveillance and screening. Pediatrics. 2020;145(1):e20193449. doi:10.1542/peds.2019-3449

9. Council on Children with Disabilities; Section on Developmental Behavioral Pediatrics; Bright Futures Steering Committee; Medical Home Initiatives for Children with Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. Pediatrics. 2006;118(1):405–420. doi:10.1542/peds.2006-1231

Participating Centers:

1. Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI

2. Department of Pediatrics, Women & Infants Hospital, Providence, RI

3. Department of Pediatrics, Warren Alpert Medical School of Brown University, Providence, RI

4. Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC

5. Department of Pediatrics-Neonatology, Children’s Mercy Kansas City

6. Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC

7. Department of Pediatrics, University of Hawaii John A. Burns School of Medicine, Honolulu, HI

8. Department of Pediatrics, Spectrum Health-Helen DeVos Hospital, Grand Rapids, MI

9. Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA

Bronchopulmonary dysplasia (BPD) remains the most common complication of premature birth.^1,2 Currently, the most accepted definition of BPD is the need for oxygen or respiratory support at 36 weeks’ postmenstrual age (PMA).

Patients with severe BPD often have severe complications, including pulmonary hypertension, poor growth, long-term pulmonary morbidity, and neurodevelopmental disability.³ The term BPD is often used interchangeably with chronic lung disease of prematurity, or CLD.

Establishing a Multidisciplinary CLD Team

There are a lack of published guidelines and national standards for treating infants with severe BPD/CLD. However, the Children’s Mercy Kansas City Neonatal Intensive Care Unit (NICU), an 84-bed Level IV regional neonatal referral center, saw the need to establish a dedicated multidisciplinary CLD team to care for these infants, and was one of the first in the nation to do so.

Launched in 2010, this team follows a standardized approach to the diagnosis and management of infants with BPD/CLD who do not respond to standard therapies.

Over the past decade, this team has grown to include dedicated neonatologists supported by pediatric pulmonology; cardiology; otolaryngology; a facilitator/coordinator; primary bedside NICU nurses; neonatal nurse practitioners; respiratory therapists; a tracheostomy coordinator; clinical pharmacology; dietary; social work; psychology; a parent advisor group; occupational, speech and language therapies; and members of the infant tracheostomy and home ventilator, pulmonary hypertension and palliative care teams. This group meets biweekly to discuss each case to determine acute and long-term management.

Patient Population Characteristics

To determine whether a multidisciplinary CLD team approach can improve outcomes for this complex infant population, the Children’s Mercy Multidisciplinary CLD team recently published its experience in the Journal of Perinatology.

A total of 267 patients hospitalized from 2008 to 2018 were identified for a retrospective analysis. Patients born from 2008 to 2009 with CLD served as a reference data point but not a comparison group prior to the establishment of the CLD Multidisciplinary team in 2010.

Characteristics of this patient population:

• 56% male; 44% female
• 62.2% Caucasian; 22.8% African American; 5.7% Hispanic; 0.7% Asian; 7.5% other
• 26 weeks median gestational age at birth; mean 28.5 weeks
• 0.85 kg median birth weight; mean birth weight 1.3 kg
• 44% primary respiratory conditions (non-BPD)
• 24% extremely preterm infants (born <28 weeks’ gestation) with severe BPD
• 14% genetic conditions
• 6% cardiac anomalies
• 4% neurologic conditions
• 8% other
• Over 75% of all patients in the cohort received diuretics, systemic and inhaled steroids, and bronchodilators. Pulmonary hypertension was diagnosed in 37.2% of the patient population; 39.7% were treated with inhaled nitric oxide, and <18% required PDE5 inhibitors.⁴

Can a Multidisciplinary CLD Team Improve Outcomes?

Since 2010, mortality has improved for infants with tracheostomy cared for by the dedicated Multidisciplinary CLD team at Children’s Mercy. Most patients were categorized as having primary pulmonary and airway conditions that evolved into what is broadly considered chronic lung disease of infancy (CLDI), while one-quarter of the cohort had the strict definition of severe BPD.

The overall survival rate reported for these infants was 88.8%, with 65% of them being ventilator-dependent through a tracheostomy at the time of NICU discharge. Tracheostomy was not associated with the odds of death prior to NICU discharge. In a cohort of infants with severe BPD/CLD, secondary pulmonary hypertension was strongly associated with the need for a tracheostomy, or death, or tracheostomy and death.

Though not addressed in this study, unique to Children’s Mercy is the continuum of care that extends beyond NICU discharge for these patients via the Infant Tracheostomy and Home Ventilator Program. This neonatology-driven program, led by Winston Manimtim, MD, Neonatologist and Medical Director, is the only one in the U.S. serving as a medical home for these patients in a multidisciplinary setting with other key subspecialists, including pulmonologists, gastroenterologists and otolaryngologists.

This team’s improved survival rates in preterm infants with tracheostomy have been highlighted in other recent studies.

Improving the Odds for Technology-Dependent Infants

A recent survey done by the Children’s Hospital Neonatal Consortium found that among 31 children’s hospital NICUs, 41% had a self-designated multidisciplinary BPD team (unpublished data), indicating that more and more NICUs are realizing the benefits of implementing a consistent, coordinated multidisciplinary approach to caring for these inpatients.

This paper includes resources, such as guidelines and quality improvement projects, to help other providers investigate and develop a multidisciplinary team approach to care for this complex infant population.

To access these supplementary materials, visit https://doi.org/10.1038/s41372-021-00974-2.

Learn more about the Children’s Mercy Multidisciplinary CLD Team

Winston Manimtim, MD, Neonatologist; Medical Director, Infant Tracheostomy and Home Ventilator Program

wmmanimtim@cmh.edu

(816) 302-3592

For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.

References:

Northway WH Jr., Rosan RC, Porter DY. Pulmonary disease following respiratory therapy of hyaline-membrane disease, Bronchopulmonary dysplasia. N Engl J Med. 1967;276:357–68.

Doyle LW, Anderson PJ. Long-term outcomes of bronchopulmonary dysplasia. Semin Fetal Neonatal Med. 2009;14:391–5.

Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116:1353–60.

Hansen TP, Noel-MacDonnell J, Kuckelman S, Norberg M, Truog W, Manimtim W. A multidisciplinary chronic lung disease team in a neonatal intensive care unit is associated with increased survival to discharge of infants with tracheostomy. Journal of Perinatology. https://doi.org/10.1038/s41372-021-00974-2.