“Long-Term Outcomes of Tetralogy of Fallot: A Study From the Pediatric Cardiac Care Consortium” (2019), by Clayton A. Smith, Courtney McCracken, Amanda S. Thomas, Logan G. Spector, James D. St Louis, Matthew E. Oster, James Moller, and Lazaros Kochilas

In 2019, US-based pediatric heart doctor Clayton Smith and colleagues published “Long-Term Outcomes of Tetralogy of Fallot: A Study From the Pediatric Cardiac Care Consortium,” hereafter, “Long-Term Outcomes,” in JAMA Cardiology. The Tetralogy of Fallot, or TOF, is a group of four congenital anatomical heart abnormalities, all of which lead to the circulation of oxygen-poor blood throughout the body. Congenital conditions are ones that are present from birth. The researchers, who at the time of publication were all affiliated with US medical schools or hospitals, investigated the long-term outcomes of individuals who underwent several different types of complete repair surgery, which is the surgery that remedies all four TOF defects, within the first three months of life. Prior to the release of “Long-Term Outcomes,” studies of TOF outcomes used data from single centers in the US or non-US patient cohorts. “Long-Term Outcomes” was one of the largest US-based, multicenter studies to evaluate the effectiveness of different strategies of complete surgical repair in remedying TOF, a condition that affects around 1,700 infants born in the US every year.

1. Background and Context
2. Article Summary
3. Impacts

Background and Context 

The TOF is a complex condition caused by four anatomical abnormalities in the heart that surgeons can fix through a complete repair surgery, an open-heart surgery that they usually perform within the first six months of life. The first abnormality is pulmonary stenosis, which is the narrowing of the opening that typically allows oxygen-poor blood to travel from the heart to the lungs to pick up oxygen. Because of the narrow opening, the right ventricle works harder to push blood through the opening, which can strain the heart over time. The condition also causes less oxygenated blood to circulate throughout the body and contributes to the cyanotic, or blue, appearance of TOF infants. A surgeon remedies the stenosis by adding a balloon to the defective pulmonary valve, increasing its diameter and reestablishing normal blood flow.

The second component of the TOF is the ventricular septal defect, or VSD, which is a hole in the wall that separates the left and right ventricles of the heart. VSD allows deoxygenated blood and oxygenated blood to mix with each other, and the body pumps extra blood in the right ventricle into the lungs, which strains the blood vessels in the lungs. The mixed oxygen-rich and oxygen-poor blood can also flow into the left ventricle and circulate throughout the body. VSD effectively lowers the concentration of oxygen in the blood pumped throughout the body, contributing to cyanosis. A surgeon can fix VSD using stitches or a patch.

The third component of the TOF is right ventricular hypertrophy, or RVH, which is a thickening of the muscle around the right ventricle. Excess stress from pulmonary stenosis on the right ventricle causes RVH. The condition reduces the pumping efficiency of the right ventricle, which pumps deoxygenated blood to the lungs through the pulmonary valve. Since the right ventricle cannot pump as efficiently, the body pushes less deoxygenated blood to the lungs, reducing the amount of oxygenated blood that the body eventually pumps out it. Surgeons often remedy RVH by treating the underlying cause of the hypertrophy.

The fourth and final abnormality of the TOF is an overriding aorta, which is when the aorta, or the main artery through which oxygenated blood leaves the heart, is over the VSD and pumps out the oxygenated and deoxygenated blood mixture caused by the VSD. Typically, the aorta is over the heart’s left side and pumps out oxygenated blood from the left ventricle. During the complete repair surgery, fixing VSD and pulmonary stenosis often helps manage the other two abnormalities, so the surgeon may or may not need to address the overriding aorta during surgery, depending on severity.

Doctors can choose several different approaches for conducting a complete repair, depending on the case. For example, some infants are not strong enough to sustain a complete repair performed all at once, termed a primary repair. In those cases, doctors may choose to conduct the surgery using a staged repair approach, meaning they complete the surgery in two steps. First, a surgeon inserts a shunt, or passageway, that increases the flow of deoxygenated blood through the pulmonary artery to help more blood receive oxygen in the lungs. The shunt is a temporary fix that allows the infant to develop further for a period of time and gain strength to endure the complete repair surgery at a later stage, at which point they remove the shunt and fix the TOF abnormalities in the heart directly through surgery. Another consideration relevant to the surgery is the status of the pulmonary valve. In some patients, however, a surgeon may elect to remove and replace the pulmonary valve completely, known as non-valve sparing surgery. Some surgeons may try to fix the valve instead of replacing it completely, which is known as valve sparing. Smith and his colleagues assessed the effect of all of those surgical strategies on patient survival in the short- and long-term.

At the time of publication, Smith worked as a fellow in the department of pediatrics at Emory University School of Medicine in Atlanta, Georgia. Courtney McCracken was the director of the Pediatrics Biostatistics Core at Emory University School of Medicine. Amanda S. Thomas also worked at Emory University School of Medicine. Logan Spector was a professor in the division of pediatric epidemiology and clinical research at the University of Minnesota in Minneapolis, Minnesota. James D. St Louis was a cardiac, thoracic, and congenital heart surgeon affiliated with the department of pediatric surgery at the University of Missouri in Kansas City, Missouri. Matthew E. Oster was a professor of pediatrics at the Emory School of Medicine and associate professor of epidemiology in the School of Public Health. James H. Moller was a pediatric cardiologist affiliated with the department of internal medicine at the University of Minnesota. Lazaros Kochilas was a pediatric cardiologist and an associate professor of pediatrics at Emory University School of Medicine, whose research focused on the long-term effects of congenital heart defects. Kochilas was the senior author on the study.

Before the publication of “Long-Term Outcomes,” many of the TOF patient surgery survival studies had fewer than 200 individuals and were from a single US center, meaning researchers could not necessarily apply the data and conclusions to the US at large. Physicians knew that a complete repair surgery often allowed patients with TOF to survive and lead relatively normal lives. However, “Long-Term Outcomes” was one of the first studies to quantitatively demonstrate, with a large, multi-center approach, the effectiveness of the complete repair surgery for TOF across the US, and to evaluate several factors that impacted survival. The research team combined data from multiple sources, such as the Pediatric Cardiac Care Consortium and the National Death Index.

Article Summary

The authors organize “Long-Term Outcomes” into five sections. The first section, titled “Introduction,” outlines the need for a large, multicenter study consisting of thousands of patients and explains the rationale behind the data sources that the researchers used to conduct the study. The second section, “Methods,” outlines the criteria for inclusion in the study as well as the specific statistical models implemented. In the third section, titled “Results,” the authors discuss the high survival rate of patients who underwent complete repair surgery as well as factors like genetic abnormalities and surgical strategy that may influence patient outcomes. In the fourth section, “Discussion,” the researchers address the early, post-surgical phase and long-term outlooks for patients with a primary complete repair versus a staged repair, and pulmonary valve replacement versus valve-sparing surgery. They also state that the causes of death following TOF complete repair include sudden death, heart arrhythmia, and congestive heart failure, while addressing the limitations and strengths of their study. Finally, in the fifth section, titled “Conclusions,” Smith and his colleagues explain that long-term survival following TOF complete repair is excellent, at 94.5 percent, but recommend continuous investigation of the TOF patient population examined in the present study to identify any other risk factors resulting from cardiovascular aging.

In the first section, “Introduction,” Smith and colleagues begin by explaining that the TOF is the most prevalent cyanotic heart condition affecting newborns. Next, they state that existing studies of long-term outcomes following complete repair surgery for TOF suffer from being limited to a single medical center in the US, having low sample sizes, or from using non- US data. Thus, the authors indicate that they chose to conduct a US-based survival study with more than 3,000 patients from the Pediatric Cardiac Care Consortium, or PCCC. The PCCC is one of the largest clinical registries for congenital heart disease in the US. The researchers conclude the section by explaining that they used the National Death Index, or NDI, and the Organ Procurement and Transplantation Network, or OPTN, as supplementary data sources to evaluate long-term survival, need for a heart transplant, and causes of death in their US cohort of TOF patients.

In the “Methods” section, Smith and his colleagues write that the data used in “Long-Term Outcomes” came retrospectively from the PCCC, and prospectively from the NDI and OPTN. Next, in the subsection titled “Cohort Selection,” the researchers explain that the only patients they included in the study were simple TOF repair patients, defined as VSD closure and right ventricular outflow tract, or RVOH, reconstruction. Fixing RVOH also typically requires a pulmonary valve replacement and remedies the RVH, as the right ventricle does not need to pump as hard to push blood to the lungs and the overriding aorta, since the aorta pumps only oxygenated blood after VSD closure. Using data in the PCCC, the researchers were able to split the patients into two groups based on whether they received one surgery to fix both defects, called primary repair, or if they had to get a shunt placed in a procedure first before they could undergo the complete repair surgery, called staged repair. They selected only patients who had their TOF repairs done before the age of twenty-one in the US and were US residents. If patients met those inclusion criteria but did not have sufficient identifiers to find their information in the NDI and OPTN, the researchers excluded those patients.

In the next subsection of “Methods,” titled “Data Collection,” the authors outline the variables they collected for analysis in “Long-Term Outcomes.” Those variables were sex, age at repair, decade of the surgical procedure, surgical strategy, pulmonary valve repair approach, and presence of a genetic condition such as a chromosomal abnormality that might affect the outcome of surgery. They explain that by using the PCCC codes for each patient, they were able to extract all of the information regarding surgical strategy. In the subsection titled “Ascertainment of Death or Transplant Events,” the authors indicate that they extracted information on patient deaths and the need for a heart transplant by matching patient information from the PCCC to the NDI and OPTN.

In the next subsection of “Methods,” titled “Causes of Death,” Smith and colleagues indicate that they determined causes of death from the death certificates of each patient. They define the cause of death as the injury or disease that initiated the progression of events that culminated in a patient’s death. For the purposes of “Long-Term Outcomes,” the researchers grouped causes of death into multiple specific categories, such as congenital heart disease, which included TOF, other cardiovascular disorders, congenital noncardiac malformations, respiratory disease, and infection, among others. The researchers conclude the next section with “Statistical Methods,” where they describe statistical analysis methods.

In the next section, “Results,” Smith and his colleagues indicate that 3,894 patients met the inclusion criteria described in the “Methods” section. Specifically, they included 3,168 patients who underwent primary repair and 726 who underwent staged repair. Following the procedure, forty-seven patients in the staged repair group and 114 patients in the primary repair group died in the hospital. Of the remaining 3,733 patients who doctors discharged from the hospital, 3,283 patients had sufficient information to match them to the NDI and OCTN, so those were the patients that the authors included in the study. The authors emphasize that over a median follow-up period of 18.5 years, 145 patients died. Additionally, five of the patients included in the study underwent heart transplant procedures later in life.

In the first subsection of “Results,” titled “In-Hospital Mortality after TOF Repair,” the authors report that the rate of in-hospital death was 4.1 percent. They found that death occurred more commonly in infants, in patients who underwent staged repair, in patients who weighed below 2.5 kilograms, in patients who underwent the procedure in the 1980s and 1990s, and in patients who had a concurrent genetic condition.

In the second subsection, titled “Long-term Survival After Complete TOF Repair,” the researchers report the survival rates of patients after complete repair at intervals of one, five, ten, twenty, and twenty-five years after surgery. For those intervals, survival rates were 98.6 percent, 97.8 percent, 97.1 percent, 95.5 percent, and 94.5 percent, respectively. The researchers also found that the risk of dying in their patient cohort was highest right after surgery but fell sharply during the first year after surgery and reached its lowest point at four years, rising slowly thereafter.

In the third subsection, titled “Factors Associated With Long-term Mortality,” the authors report that they observed a lower survival rate within two years of surgery for patients who had a staged repair or a valve replacement surgery compared with those who had primary repair or a valve-sparing surgery. The presence of a genetic abnormality significantly lowered survival rates throughout the entire post-operative period. Additionally, early post-operative mortality was higher in earlier decades, but long-term survival rates were similar across decades. In the later years, however, only the presence of a genetic abnormality increased the risk of death.

In the fourth subsection, “Causes of Death,” Smith and his colleagues indicate that 43.4 percent of deaths among those surviving repair surgery were directly or indirectly attributed to TOF. The direct cause of death was congenital heart disease, meaning that TOF is what ultimately led to the progression of events that ended with the patient’s death. Other contributing cardiovascular diseases include cardiac arrest, or heart attack, arrhythmia, or abnormal heart rhythms, and congestive heart failure, a condition characterized by inefficient pumping of blood. While 15.2 percent of deaths resulted from a cardiovascular disease without mention of TOF, 41.4 percent resulted from conditions not related to either TOF or any cardiac condition, such as other congenital anomalies, external causes like physical injury, and other medical causes.

In the next main section, “Discussion,” the researchers indicate that “Long-Term Outcomes” is one of the largest long-term studies of TOF patients. Next, they report that their major finding, which is that more than 94 percent of patients survive at least 25 years after TOF repair, is in agreement with results from smaller, single-center US studies and international studies published previously, which report a 30-year survival rate between 80 and 98 percent.

In the first subsection of “Discussion,” titled “Patterns of Long-term Survival after TOF Repair,” the authors note that TOF patients who undergo complete repair surgery have the highest risk of dying within the first year of the surgery, with the risk dropping to its lowest point by four years post-surgery, and then slowly increasing after six years post-surgery. They note that the late-phase survival and causes of death have not changed significantly across the decades, despites improvements in treatment. They note that a major risk factor for death in both early and later years is the presence of a genetic anomaly. The authors draw attention to the fact that the risk of death was higher for those undergoing staged repair or valve-replacement surgery compared with those receiving primary repair or valve-sparing surgery. The researchers state that other studies are inconsistent in their findings of mortality differences in staged and primary repairs. In the subsection “Causes of Death after TOF repair,” the authors confirm that deaths after TOF surgery were related to TOF, and the causes of deaths matched a similar study conducted in Taiwan.

In the subsection titled “Strengths and Limitations,” Smith and colleagues state that the main strengths of the present study are the large cohort of more than 3,000 patients as well as the length of follow-up. However, they state that their study does have some limitations. For example, the PCCC registry lacks information regarding presurgical variables that may have influenced surgical strategy, as well as subsequent procedures the patient may have undergone, and socioeconomic variables. Additionally, limited information on the status of the right ventricular outflow tract in patients following surgery exists. The authors also indicate that they may have misclassified some of the causes of death collected for the present study on the NDI, while stating that the classifications generally correlate well with other methods of cause of death determination.

In “Conclusions,” Smith and colleagues reemphasize their finding that patients undergoing staged and valve-replacement surgeries have slightly worse survival rates in the early years compared with those receiving primary repair and valve-sparing repair surgeries. Long-term survival of patients receiving complete surgery for TOF is excellent, with the presence of a genetic condition being a major risk factor for higher mortality. The authors indicate that within the twenty-five-year period, most deaths were due to TOF as well as other heart conditions. The authors conclude by recommending further monitoring of TOF patients post-surgery to identify other risk factors that impact long-term survival.

Impacts

As of 2025, “Long-Term Outcomes” has been viewed on the JAMA Cardiology website more than 18,000 times since its publication and cited 173 times according to Google Scholar. As Smith and colleagues indicate in the article, “Long-Term Outcomes” was one of the largest studies examining long-term patient survival as well as the factors that influence survival after TOF repair. It showed that when a patient receives a complete repair surgery, typically between three and six months of age, they have a very good chance of surviving for at least twenty-five years, with their chance of mortality increasing as they develop other cardiovascular conditions.

Additionally, subsequent studies citing “Long-Term Outcomes” further elucidated the role of risk factors and more specific surgical strategies, such as the method of valve-sparing repair, in influencing patient survival. For example, in a paper citing “Long-Term Outcomes,” Anne Bassett of the department of medicine at the University of Toronto in Toronto, Ontario, and colleagues reported some other risk factors for TOF patients, such as specific genetic mutations, that influence survival following surgery. Another study, citing “Long-Term Outcomes,” conducted by Simon G. Williams of the University of Manchester in Manchester, United Kingdom, and colleagues, found that, in patients with COVID-19, congenital heart anomalies such as TOF increase their chance of hospitalization by fifty to seventy-five percent. Together, those studies have helped scientists to learn more about TOF survival and surgery risk as well as the underlying genetic causes of TOF.

Sources

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