UPDATED 2020: The Neuro-Developmental Consequences of Congenital Heart Disease

The Neuro-Developmental Consequences of Congenital Heart Disease -

Updated here, including over 75 recent references and scientific studies: Professional Version

Gil Wernovsky, MD, FACC, FAAP; Senior Consultant in Pediatric Cardiac Critical Care and Pediatric Cardiology at Childrens National Hospital

[email protected]

Background

Children with complex congenital heart defects (CHD) are now surviving neonatal and infant surgery with a frequency thought to be impossible only a generation ago. While advances in medicine and surgery have allowed the ability to “mend” children born with CHD, the increasing number of survivors has created a growing population of children in our primary and secondary school systems and young adults entering the work force.

In the United States alone, over 35,000 infants are born each year with CHD, and more than a third of these infants will undergo temporary or corrective surgical interventions in the first year of life. It is estimated that there are more than 1.5 million adults now living in the US with a variety of congenital heart defects. This figure includes over 200,000 adults living with “complex CHD (cCHD)” - CHD severe enough to require surgery in the first 6 months of life. Due to improved survival rates in the past decade, there are even larger numbers of school-age children with increasingly complex forms of CHD. As survival rates have increased, additional attention has been directed toward understanding and treating the long-term challenges for these children and their families, including behavioral problems, academic performance and quality of life.

Much of the information I will summarize below is relatively new; unknown to most doctors and nurses 15-25 years ago. Internationally, many centers are now actively pursuing research in this area, which can be broken down into four main areas:

1. What are the types of difficulties that children with cCHD have, and how frequently do they occur?

2. What are the causes of these difficulties?

3. What are the best treatments for these problems?

4. How may we decrease the frequency and severity of these problems in the future?

What are the types of difficulties that children with complex CHD have, and how frequently do they occur?

As a group, children with cCHD have a higher likelihood of academic, behavioral, emotional and coordination problems compared to children without CHD. This does not mean that all children with cCHD have these difficulties (in fact, depending upon the severity of the CHD, about ?-? have normal development in every respect), but the percentage of children with these difficulties is significantly higher than the percentage seen in the general population. These problems are more prevalent in children with cCHD compared to less severe forms of CHD that either don't require surgery, can be repaired during a heart catheterization (for example, an atrial septal defect or patent ductus arteriosus), or don't require surgery until later childhood.

In infancy, problems that are more prevalent include feeding difficulties (perhaps in ? of all children requiring heart surgery as newborns) and delays in reaching some motor milestones such as rolling over, crawling or walking. Most newborns achieve full feedings by mouth shortly after discharge from the hospital, but some require supplemental feedings through a feeding tube into later infancy and beyond. While delays in motor skills are extremely common, most of the infant's milestones are delayed by only a few months or so. Following heart surgery in the infant, many heart centers now recommend speech, occupational and physical therapy consultations for evaluation and treatment recommendations.

In preschool, there is a growing recognition of delays in certain elements of speech and language. To greatly oversimplify, speech and language can be broken down into two components: receptive language (the child hears and understands words), and expressive language (getting the words out with proper grammar and pronunciation). In many children with cCHD, receptive language is normal (e.g., if you say “point to the apple”, the child will point to the apple). However, expressive language may be delayed (e.g., when you point to an apple and say “what is that?”, even though the child knows it's an apple, he or she can't seem to “find the word”). Importantly, recent work has suggested that up to ? of children with cCHD have some form of hearing loss after surgery; a formal hearing evaluation should be part of the routine follow-up of these children.

In addition to delays in expressive language, some preschool children with cCHD (probably less than ?) have ongoing difficulties with motor skills, including large motor delays (clumsiness) and fine motor delays (drawing, cutting). In most children, these problems improve by the time they enter school.

As children with cCHD enter primary and secondary school in larger numbers, there is a growing recognition of a combination of challenges that may combine to cause academic and social problems. Attention deficit/hyperactivity disorder (ADHD) is a term that may be over applied in our current society and is an extremely complicated combination of environmental, learning and behavioral interactions. Again, to greatly oversimplify, the main components are impulsiveness, easy distractibility and hyperactivity. As we look more carefully at children with cCHD, various aspects of ADHD occur in perhaps one third to one half of children, which is perhaps two to three times higher than that seen in the general population. It is not clear if continued frustrations with speech and fine motor (handwriting) control are related to the higher incidence of ADHD—in other words, which is the chicken and which is the egg? 

Two related issues are now also being seen in larger numbers of school age children with cCHD: problems with visual-motor integration and executive function. Visual-motor integration relates to the ability to coordinate thoughts and images into motor action. In adults, for example, driving a car represents an example of highly complex visual motor integration. In school-age children, however, learning handwriting represents a particular challenge: seeing handwriting on the board, knowing that it's a particular letter, and getting the hand to make the letter can be very frustrating to an otherwise bright child. As you can see, handwriting is a common theme, and many parents have told me that their child's handwriting is “one of the worst in the class”. Executive function (sometimes referred to as "metacognition") is a feature that allows us to hypothesize, determine "what if", plan out a course of action, among others. For example, "first I will get dressed, then I will go eat breakfast, then I will pack my bag, and then head off to school". As the number of tasks increases, it becomes increasingly difficult for many children with cCHD to coordinate and execute. Some children with cCHD have a particular problem in this area, but the exact frequency of this problem is currently unknown. Finally, there are no studies as of yet to determine whether ‘higher order’ intellectual functions (such as complex mathematics or learning a second language), or artistic talents (such as painting, cooking or music) will be affected in our children with cCHD - either negatively OR positively.

Figure below shows the Frequency of Neurodevelopmental Abnormalities Increases with the Complexity of the CHD. From Wernovsky G. Current insights regarding neurological and developmental abnormalities in children and young adults with complex congenital cardiac disease.  Cardiol Young. 2006;16 Suppl 1:92-104.

Finally, there are challenges related to comfort and skill with social interactions (“social cognition”) and mood disorders (anxiety, depression) in many teens and young adults with cCHD.

What are the causes of these problems?

Although it is tempting to point at “one” feature as "the cause" of the problems I've outlined above, that would be a terrible oversimplification. We are only now beginning to recognize that the effects of cCHD on the developing brains of children are multiple, and cumulative over the early years of development.

Following conception, the preliminary portions of the brain form at exactly the same time that the heart forms, in the first trimester. In most cases, whatever caused the CHD has "left its mark" on the heart by the end of the first trimester; in most cases cCHD is essentially determined by the end of the 8th week of gestation. In contrast, the brain continues to develop and mature throughout pregnancy. We are just beginning to learn that the abnormal circulation caused by cCHD in the fetus is responsible for some of the brain abnormalities present at birth. It is now recognized that “congenital heart disease” and “congenital brain disease” go together in many children. Does the same factor or factors that cause CHD also cause brain abnormalities as well? Is the brain “wired” the same way in children with CHD compared to normal? Does the abnormal fetal circulation put an abnormal fetal brain at greater risk for other stressors? These are questions that are only now being investigated, as technologies such as magnetic resonance imaging (MRI) in the fetus and newborn have become more routinely available. Recent studies suggest that the brain is either structurally or functionally abnormal at birth in up to 25% of newborns with cCHD. The brain of many newborns delivered at term appears ‘immature’, multiple studies have now shown that the brain of a full-term infant with cCHD has the complexity (or “maturity”) of the brain of a 35-36 week gestation infant without cCHD. This has led to a paradigm shift over the past few decades to encourage delivery as close to term (39-40 weeks) as possible, unless there are maternal or fetal reasons to recommend earlier delivery.

In addition, children with cCHD have an increased incidence of other congenital abnormalities, abnormal genetics, and other syndromes which may effect the developing brain....both in the womb and after birth

In newborns with cCHD, so many things happen so quickly that it is impossible to sort out their relative contribution to long-term outcomes. These factors may include, but are not limited to:

• The effects on the heart and lungs of the transition from the fetal circulation
• Treatment and/or procedures that may be necessary urgently after birth, such as mechanical ventilation (breathing tube), catheterization, etc.
• The effects of the heart lung machine (cardiopulmonary bypass) during surgery
• The effects of abnormal function of the heart before and/or after surgery
• Medications necessary to minimize pain and sedation
• Limited mobility and stimulation in the early postoperative period
• Seizures and/or stroke that may occur before, during or after surgery
• Nutritional deficiencies, "failure to thrive"
• The combined effects of a long stay in the intensive care unit and hospital on both the baby and the family, including post-traumatic stress disorder in parents

In past research, much attention was paid to the way the heart-lung machine was used: how long was the operation, how low was the body temperature during surgery (hypothermia), did the circulation need to be stopped completely (hypothermic circulatory arrest) during the most delicate part of surgery, etc. While these factors are certainly important to the brain and later development, we now realize that many other factors, both before and after surgery, play an even bigger role. 

A considerable amount of research has been done on the use of the heart-lung machine (cardiopulmonary bypass) in general and the use of “hypothermic circulatory arrest” in particular. While it is beyond the scope of this summary to go into all of the details, the majority of studies have shown little to no effects on the brain during and after short periods of cardiopulmonary bypass and/or circulatory arrest. In fact, recent studies suggest that <5% of the variability in later developmental outcomes is related to cardiopulmonary bypass. Importantly, it would be na?ve and far too simplistic to point at a particular "cutoff" as being “too long”; if one chose, for example, 45 minutes, does that mean that 44 minutes is ‘safe’ and 46 minutes is ‘dangerous’? Of course not. However; there is general agreement that shorter periods of both cardiopulmonary bypass and hypothermic circulatory arrest are preferable to longer periods; exactly how long and in what combination continues to be a subject of research and controversy. Importantly, in the most fundamental terms, the most important factor in cardiac surgery and recovery is the technical success of the operation itself, so that the postoperative period is less likely to be rocky.

Finally, recent studies are showing that longer overall stays in the intensive care unit and hospital as a newborn are associated with worse school performance years later. As above, this most likely reflects the cumulative effects of the CHD and its treatment, and also includes:

• Increased exposure to noise
• Increased duration of a bland, minimally stimulating environment
• Prolonged mechanical ventilation
• Limited mobility
• Additional exposures to sedatives, analgesics, other medications, plastics, etc.

Research is currently very active in this area – to reduce hospital length of stay.

What are the best treatments for these problems?

Unfortunately, the research into the treatment of the problems I've outlined above is still in its infancy. It has only been in the recent decade that the increased incidence of hyperactivity, school, behavioral and emotional difficulties has been recognized. Prior to that time, there were simply not enough children old enough who survived with different forms of cCHD for this to be fully recognized. Recently, the American Heart Association and American Academy of Pediatrics have recommended formal developmental testing in infancy and the preschool years to identify potential problems and institute therapies such as speech therapy, occupational and physical therapy, and to recommend changes in learning environments that facilitate learning in children with different strengths and challenges. 

In 2012, the American Heart Association and the American Academy of Pediatrics both endorses a Scientific Statement (written by Dr. Bradley Marino and colleagues) can be found here: https://circ.ahajournals.org/content/126/9/1143.full.pdf?download=true

Updated, formal testing recommendations for children age 0-5 years from the Cardiac Neurodevelopmental Outcome Collaborative (www.cardiacneuro.org) will be forthcoming by the end of 2020/beginning of 2021.

In my opinion, there is insufficient data at the current time to comment on the safety and/or potential benefits of the psychotropic drugs (for example, stimulant medications for ADHD, anti-depressants, etc.) in children with cCHD, and this must be an individual decision with a child’s cardiologist. Many of the medications currently available for children with structurally normal hearts slightly increase the risk of rhythm problems and high blood pressure; and some children with CHD are possibly at increased risk for rhythm disturbances when using these medications. It must be emphasized that no large study has determined the safety and efficacy of these drugs specifically in children with cCHD, or even if they work the same way as in children with structurally normal hearts. The decision to use medications to deal with behavioral issues or ADHD must be individualized to the child, balancing the unknown risks of these medications in children with CHD against the lifelong implications of academic and social difficulties. Close follow-up, planning and surveillance are warranted when beginning any new medication.

Some investigators are currently researching whether increasing flow to the brain of a fetus with cCHD can be safely accomplished with medicines administered to the mother. Also, there is growing evidence in studies across the globe, that treatments geared toward decreasing maternal worry and parental mental health show the most promise in this area (see below), including prenatal counseling, pre- and post-operative support with clergy and palliative care teams, and increased contact with advanced practice nurses prior to and after hospital discharge.

How can we decrease the frequency and severity of these problems in the future?

In my view, having been in practice for 35 years, the outlook for children with cCHD remains quite optimistic, and is constantly improving. Many are now adults and are engineers, nurses, doctors, government workers, social workers, and teachers; many are parents themselves, and lead happy, productive lives. Nonetheless, there are ongoing challenges for those of us who care for these children to improve overall quality of life. It is important to emphasize that patients are surviving in numbers thought impossible one or two decades ago, and compared with older children with cCHD repaired in the 1980s and 1990s, studies continue show improvement in many areas of functioning for children born more recently. Thus, it must be emphasized that results we expect for children born today, are likely to be significantly better than are being reported in adolescents (managed between 1980-2000) and young adults (managed in the 1970's-1990's). This is due to the many nearly simultaneous important improvements in the last three decades—including more frequent prenatal diagnosis, research into the developing brain before and after surgery, a better understanding of anesthesia and cardiopulmonary bypass, improved post-operative care, the implementation of developmental care in the intensive care unit, and the benefits of structured follow-up programs after discharge. A number of additional factors will ultimately contribute to the academic success of our children, including parent and teacher expectations. Again, I want to emphasize that it is highly likely that the group of babies born today will have better outcomes than those born just a generation before.

It has also been learned that - not surprisingly - the severe stress of having a child with cCHD on moms and dads is certainly understandable, predictable, and at times severe and long-lasting.  Importantly, taking steps to improve parental mental health (mindfulness techniques, meditation, trauma therapy, etc.) improve the child’s long-term outlook! (see references). As is said when you board an airplane: “Put your own mask on first before helping others”.  I cannot emphasize the importance of self-care enough – both physically and mentally – in improving the outlook for your child with cCHD (and for you as well!).

Finally, the best way to improve the outcomes for future generations is a continued and long-term partnership between patients, parents, researchers, nurses and physicians. Advocacy at the government level for continued research funding by physicians, nurse scientists, parents and patients is crucial to continue to pursue the causes and treatment of heart disease in children, as well as the secondary effects on the brain and quality of life. Philanthropic contributions play a significant role in start-up funds for research as well. Finally, if families and children are willing, voluntary participation in clinical research studies remains the cornerstone of the process.

Summary of Current Findings, 2020

?   In the absence of an associated structural brain abnormality or genetic syndrome, cognitive function (IQ, intelligence) is typically within the normal range for most children with CHD

?   Parental education, mental health and socioeconomic status are consistently the most strongly associated factors in the long-term outcomes for children with cCHD, rather than the type of CHD or its management. Of these, only parental mental health is likely to be modifiable in the short term

?   Behavior problems, especially impulse control and attention difficulties, are prevalent

?   Deficits in visual-motor integration and language skills are common

?   Executive functioning—the ability to plan and perform complex tasks—is impaired in some children

?   Some identified risk factors for academic and behavioral difficulties include highly complex CHD requiring multiple procedures, a long hospital stay, and family PTSD. Health-related quality of life is also affected by the number of medications necessary and number of doctor visits per year. 

?   The association between open heart surgery and postoperative care with later cognitive, language, or behavior difficulties continues to be an area of investigation

Updated data and references here: https://bit.ly/CANDOatCNMC

Gil Wernovsky, MD, FACC, FAAP

Senior Consultant in Cardiac Intensive Care and Pediatric Cardiology

Children's National Heart Institute of the Children’s National Health System

Washington, DC, USA

[email protected]