Long-term follow up of infants with congenital diaphragmatic hernia

With improving treatment strategies for congenital diaphragmatic hernia (CDH) infants, an increase in survival of more severely affected patients can be expected. Consequently, more attention is now focused on long-term follow up of these patients. Many reports have emphasized associated morbidity, including pulmonary sequelae, neurodevelopmental deficits, gastrointestinal disorders, and other abnormalities. Therefore, survivors of CDH remain a complex patient population to care for throughout infancy and childhood, thus requiring long-term follow up. Much information has been provided from many centers regarding individual institutional improvements in overall survival. Few of these, however, have reported long-term follow up. The aim of this review is to describe the long-term outcome of survivors with CDH and to suggest a possible follow-up protocol for these patients.     

The long-term follow-up of patients with a congenital diaphragmatic hernia: a broad spectrum of morbidity

Congenital diaphragmatic hernia (CDH) is a life-threatening anomaly with a mortality rate of approximately 40-50%, depending on case selection. It has been suggested that new therapeutic modalities such as nitric oxide (NO), high frequency oxygenation (HFO) and extracorporal membrane oxygenation (ECMO) might decrease mortality associated with pulmonary hypertension and the sequelae of artificial ventilation. When these new therapies indeed prove to be beneficial, a larger number of children with severe forms of CDH might survive, resulting in an increase of CDH-associated complications and/or consequences. In follow-up studies of infants born with CDH, many complications including pulmonary damage, cardiovascular disease, gastro-intestinal disease, failure to thrive, neurocognitive defects and musculoskeletal abnormalities have been described. Long-term pulmonary morbidity in CDH consists of obstructive and restrictive lung function impairments due to altered lung structure and prolonged ventilatory support. CDH has also been associated with persistent pulmonary vascular abnormalities, resulting in pulmonary hypertension in the neonatal period. Long-term consequences of pulmonary hypertension are unknown. Gastro-esophageal reflux disease (GERD) is also an important contributor to overall morbidity, although the underlying mechanism has not been fully understood yet. In adult CDH survivors incidence of esophagitis is high and even Barrett's esophagus may ensue. Yet, in many CDH patients a clinical history compatible with GERD seems to be lacking, which may result in missing patients with pathologic reflux disease. Prolonged unrecognized GERD may eventually result in failure to thrive. This has been found in many young CDH patients, which may also be caused by insufficient intake due to oral aversion and increased caloric requirements due to pulmonary morbidity. Neurological outcome is determined by an increased risk of perinatal and neonatal hypoxemia in the first days of life of CDH patients. In patients treated with ECMO, the incidence of neurological deficits is even higher, probably reflecting more severe hypoxemia and the risk of ECMO associated complications. Many studies have addressed the substantial impact of the health problems described above, on the overall well-being of CDH patients, but most of them concentrate on the first years after repair and only a few studies focus on the health-related quality of life in CDH patients. Considering the scattered data indicating substantial morbidity in long-term survivors of CDH, follow-up studies that systematically assess long-term sequelae are mandatory. Based on such studies a more focused approach for routine follow-up programs may be established.     

Long-term outcome following extracorporeal membrane oxygenation for congenital diaphragmatic hernia: the UK experience

OBJECTIVE: We evaluated the long-term outcome of neonates receiving extracorporeal membrane oxygenation (ECMO) for congenital diaphragmatic hernia (CDH).Study design A retrospective review of all 73 neonates with CDH supported with ECMO in the United Kingdom between 1991 and 2000, with follow-up to January 2003. Information was from hospital charts and from communication with family doctors and pediatricians. Median follow-up period for survivors was 67 months. RESULTS: 46 infants (63%) were weaned from ECMO, 42 (58%) survived to hospital discharge, and 27 (37%) survived to age 1 year or more. A higher birth weight, higher 5-minute Apgar score, and postnatal diagnosis were "pre-ECMO" predictors of long-term survival. Comorbidity was common in long-term survivors: 13 (48%) had respiratory symptoms, 16(59%) had gastrointestinal problems, and 6 (19%) had severe neurodevelopmental problems. Only 7 children were free of significant neurodevelopmental deficit and required no further medical or surgical intervention. CONCLUSION: Using the current referral criteria, ECMO can be used to support the sickest neonates with CDH. However, there is significant mortality in the first year of life, and long-term physical and neurodevelopmental morbidity remains in the majority of survivors.     

Long-term follow-up of childhood cancer survivors: future directions for clinical care and research

Improvement in survival after childhood cancer has resulted in a growing population of childhood cancer survivors, causing the healthcare community to focus on providing appropriate care to the survivors, and addressing issues related to the etiology and prevention of long-term sequelae of cancer and its treatment. The overarching goal is to decrease the morbidity related to cancer treatment, and improve the overall quality of life, such that cancer survivors can successfully integrate back into society and lead productive lives. In order to achieve this goal, several issues need to be addressed, such as education of survivors and healthcare providers regarding the potential late effects; provision of standardized guidelines for appropriate follow-up of the survivors in a setting that is feasible and practical for the cancer survivor; ongoing communication between the cancer center that provided acute care for the patient and the healthcare facility providing follow-up care. Several challenges remain in addressing these issues, and will be the focus of this article.     

Follow-up of the term infant after hypoxic-ischemic encephalopathy

While the number of survivors of term hypoxic-ischemic encephalopathy (HIE) is lower than the number of survivors of extreme prematurity, the proportion of neonates with long-term sequelae is higher. All neonates with Sarnat stages 2 (moderate) and 3 (severe) should be enrolled in follow-up programs. The present paper discusses the clinical and imaging diagnostic criteria for HIE, which are essential to decisions about follow-up. Prognostic indicators are also summarized. The recommendations for follow-up and intervention are based on the clinical condition of the baby at the time of discharge from intensive care, including an assessment of feeding, vision, hearing and whether seizures continue to be present. Early assessments (at four to eight months) focus on head growth, general health and motor neurodevelopment. Assessments at 12 to 24 months focus on cognitive skills and language development. Preschool assessments are also strongly recommended to provide for the identification of children requiring early education programs. Knowledge of long-term outcome and its secular changes enhance prognostication, and the evaluation of new preventive and therapeutic approaches.     

Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature

The development of curative therapy for most pediatric malignancies has produced a growing population of childhood cancer survivors who are at increased risk for a variety of health problems resulting from their cancer or its treatment. Because of the fact that many treatment-related sequelae may not become clinically apparent until the survivor attains maturity or begins to age, the ability of primary care providers to anticipate late effects of treatment is essential for providing timely interventions that prevent or correct these sequelae and their adverse effects on quality of life. Altered bone metabolism during treatment for childhood cancer may interfere with attainment of peak bone mass, potentially predisposing to premature onset of and more severe complications related to osteopenia and osteoporosis. Bone mineral deficits have been reported after treatment for a variety of pediatric malignancies and represent morbidity that can be reduced or prevented through lifestyle changes and attention to other common cancer-related sequelae such as hypogonadism. The Children's Oncology Group long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers provide risk-based surveillance recommendations that are based on expert opinion and review of the scientific literature for potential late effects of pediatric cancer therapy including osteopenia. This review summarizes the existing literature that has defined characteristics of cancer survivors at risk for bone mineral deficits and contributed to the surveillance and counseling recommendations outlined in the Children's Oncology group long-term follow-up guidelines.     

Prospective evaluation of late effects after childhood cancer therapy with a follow-up over 9 years

Intensive multimodality treatment has led to a remarkable improvement of prognosis in paediatric cancer patients, however, a great number of long-term survivors suffer from considerable tumour- or treatment-related late effects. Between January 1990 and December 1998, 223 consecutive survivors of childhood malignancies entered a prospective follow-up study designed to evaluate the frequency and severity of tumour- and/or therapy-related long-term sequelae. After cessation of therapy and subsequently once a year, all patients underwent a detailed examination programme including physical examination, laboratory tests, abdominal sonography, echocardiography, electrocardiography, electroencephalography, spirometry, audiometry, ophthalmological examination and endocrine stimulation tests. Median follow-up was 5 years (range 0.4 to 9.6 years). A total of 167 patients (75%) had at least one chronic medical problem of whom 80 needed permanent medical support. The organ systems most frequently affected were the nervous system in 39%, the endocrine system in 32%, the ears/eyes in 22%, the kidneys in 17%, and the liver in 12% of the patients. Some late effects (endocrine deficits, hearing loss, tubulopathy) were primarily diagnosed only several years after the end of oncological therapy. Conclusion The results of this study indicate that a considerable number of former paediatric cancer patients suffer from remarkable long-term side-effects. Since life quality is an important parameter of cancer survival, careful follow-up of long-term survivors is mandatory with the aim to reduce or even abrogate possible side-effects at the earliest time. Received: 8 December 1999 and in revised form: 1 March 2000 / Accepted: 31 March 2000     

Physical Activity and Late Effects in Childhood Acute Lymphoblastic Leukemia Long-Term Survivors

In the present study the authors evaluated therapy-related long-term adverse effects and physical activity in a cohort of long-term survivors of childhood acute lymphoblastic leukemia (ALL), diagnosed in their center between March 1991 and August 2000, treated according to the AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) ALL 91 or 95 study protocol and regularly seen in the authors’ long-term follow-up unit. The authors analyzed the long-term sequelae of major body systems in this cohort of subjects and administered an “ad hoc” questionnaire concerning sport. The authors found that 70 patients out of 102 (68.5%) showed no late effects, 10% presented only instrumental or neuropsychological test abnormalities, and 21.5% had 1 or more clinical late sequelae. None of the evidenced late effects represented a contraindication to do physical activity. Sixty-one percent of survivors do physical activity, most of them regularly. Sixty-one percent of males and 18.5% of females (P < .005) do competitive sport (sports rates are similar to those of the general age-matched population). Nearly all subjects spontaneously choose to do sport and think physical exercise is an important and useful resource for their health. The authors conclude that the more recent therapy regimens for leukemia treatment, excluding bone marrow transplantation, do not seem to cause such late effects as to prevent survivors from doing sport. Therefore, in the care of ALL survivors, physical activity is not only not contraindicated, but should also be promoted as much as possible. The development of specific educational programs is warranted as part of the care of cancer survivors.     

Physical activity and late effects in childhood acute lymphoblastic leukemia long-term survivors

In the present study the authors evaluated therapy-related long-term adverse effects and physical activity in a cohort of long-term survivors of childhood acute lymphoblastic leukemia (ALL), diagnosed in their center between March 1991 and August 2000, treated according to the AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) ALL 91 or 95 study protocol and regularly seen in the authors' long-term follow-up unit. The authors analyzed the long-term sequelae of major body systems in this cohort of subjects and administered an "ad hoc" questionnaire concerning sport. The authors found that 70 patients out of 102 (68.5%) showed no late effects, 10% presented only instrumental or neuropsychological test abnormalities, and 21.5% had 1 or more clinical late sequelae. None of the evidenced late effects represented a contraindication to do physical activity. Sixty-one percent of survivors do physical activity, most of them regularly. Sixty-one percent of males and 18.5% of females (P < .005) do competitive sport (sports rates are similar to those of the general age-matched population). Nearly all subjects spontaneously choose to do sport and think physical exercise is an important and useful resource for their health. The authors conclude that the more recent therapy regimens for leukemia treatment, excluding bone marrow transplantation, do not seem to cause such late effects as to prevent survivors from doing sport. Therefore, in the care of ALL survivors, physical activity is not only not contraindicated, but should also be promoted as much as possible. The development of specific educational programs is warranted as part of the care of cancer survivors.     

Outcome of paediatric intensive care survivors

The development of paediatric intensive care has contributed to the improved survival of critically ill children. Physical and psychological sequelae and consequences for quality of life (QoL) in survivors might be significant, as has been determined in adult intensive care unit (ICU) survivors. Awareness of sequelae due to the original illness and its treatment may result in changes in treatment and support during and after the acute phase. To determine the current knowledge on physical and psychological sequelae and the quality of life in survivors of paediatric intensive care, we undertook a computerised comprehensive search of online databases for studies reporting sequelae in survivors of paediatric intensive care. Studies reporting sequelae in paediatric survivors of cardiothoracic surgery and trauma were excluded, as were studies reporting only mortality. All other studies reporting aspects of physical and psychological sequelae were analysed. Twenty-seven studies consisting of 3,444 survivors met the selection criteria. Distinct physical and psychological sequelae in patients have been determined and seemed to interfere with quality of life. Psychological sequelae in parents seem to be common. Small numbers, methodological limitations and quantitative and qualitative heterogeneity hamper the interpretation of data. We conclude that paediatric intensive care survivors and their parents have physical and psychological sequelae affecting quality of life. Further well-designed prospective studies evaluating sequelae of the original illness and its treatment are warranted.     

Dental abnormalities in long-term survivors of head and neck rhabdomyosarcoma

To define the long-term dental sequelae of therapy for childhood rhabdomyosarcoma of the head and neck, and to identify factors in their development, we retrospectively reviewed the serial panoramic radiographs and clinical records of 22 survivors of head or neck rhabdomyosarcoma who had been followed for at least 5 years. Patients were divided into four groups based upon age at the time of therapy and three groups based upon radiation doses. All patients had received similar multiagent chemotherapy. Dental sequelae of oncotherapy occurred in over half of the long-term survivors of head and neck rhabdomyosarcoma. The abnormalities comprised root stunting in 54%, microdontia in 23%, and hypodontia in 50% of patients; 36% had multiple abnormalities. Microdontia and multiple abnormalities were more prevalent in patients treated at the earliest age, and abnormalities tended to be more prevalent with increasing doses of radiation. Five patients (23%) developed severe cosmetic and/or functional sequelae necessitating surgical and/or orthodontic intervention. The high frequency of dental sequelae we observed suggests that meticulous long-term dental and radiographic follow-up are needed. Early detection and treatment of the complications of therapy will expedite their correction and minimize morbidity. © 1995 Wiley-Liss, Inc.     

The neurodevelopmental sequelae of childhood leukaemia and its treatment

The overall survival of childhood leukaemia has increased dramatically over recent decades. With the increasing number of survivors, chemotherapy protocols are designed not only to improve cure rates but also to minimise long-term sequelae. Central-nervous-system-directed therapy given as intrathecal chemotherapy and/or cranial irradiation plays a crucial part in acute leukaemia treatment but can also result in adverse effects on the developing brain. The elimination of cranial irradiation from current treatment protocols has improved the neurocognitive outcome without compromising survival rates. Although neurodevelopmental long-term sequelae after chemotherapy-only central-nervous-system-directed therapies may be more subtle, survivors of childhood leukaemia will continue to require methodical follow-up and appropriate rehabilitation.     

Neurodevelopmental outcome in congenital diaphragmatic hernia: Evaluation,predictors and outcome

To review the reported neurodevelopmental outcome of congenital diaphragmatic hernia (CDH) survivors, identify important predictors of developmental disabilities, and describe the pathophysiological mechanisms contributing to adverse outcome. A Medline search was performed for English-language articles cross-referencing CDH with pertinent search terms. Retrospective, prospective, and longitudinal follow-up studies were examined. The reference lists of identified articles were also searched. Neurodevelopmental dysfunction has been recognized as one of most common and potentially most disabling outcome of CDH. Intelligence appears to be in the low normal to mildly delayed range. Neuromotor dysfunction is common during early childhood. Behavioral problems, hearing impairment, and quality of life related issues are frequently encountered in older children and adolescence. Disease severity correlates with the degree of neurological dysfunction. Neurodevelopmental follow-up in CDH children should become standard of care to identify those who would benefit from early intervention services and improve neurological outcomes.     

Risk of respiratory syncytial virus in survivors with severe congenital diaphragmatic hernia

Background: During the follow-up period in surviving patients with severe congenital diaphragmatic hernia (CDH), respiratory complications, such as recurrence of CDH or chronic lung disease, have been reported to occur as a late complication. Although some risk factors for deterioration of respiratory condition have been reported in CDH, the risk of respiratory syncytial virus (RSV) in postoperative CDH patients has not as yet been reported upon.
Methods: In 21 survivors with severe CDH, which had been detected antenatally, and whose lung:thoracic ratio was <0.2, the risk of RSV infection in those patients was investigated.
Results: Five survivors with severe CDH had RSV infection and three patients needed hospitalization due to bronchiolitis during the follow-up period. In two patients the recurrence of CDH after the infection resulted in the need to perform a re-operation for CDH. All patients often suffered from chronic wheezing requiring medication after the first RSV infection.
Conclusion: RSV infection is a risk for deterioration of postoperative respiratory condition in severe CDH survivors. Considering the presence of pulmonary hypoplasia in severe CDH, the routine use of monoclonal antibody for RSV (palivizumab) might be effective for patients with severe CDH in the high season of RSV, similar to the patients with chronic lung disease, although further large multicenter studies are needed to clarify this hypothesis.     

Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of childhood cancer: a report from the Children's Oncology Group

With modern therapies and supportive care, survival of childhood cancer has increased considerably. Patients who have survived cancers involving the central nervous system or who have received therapy toxic to the developing brain are at risk of long-term neurocognitive sequelae. Negative outcomes are observed most frequently in survivors of acute lymphoblastic leukemia and brain tumors. The Children's Oncology Group Long-term Follow-up Guidelines Task Force on Neurocognitive/Behavioral Complications After Childhood Cancer has generated risk-based, exposure-related guidelines designed to direct the follow-up care of survivors of pediatric malignancies based on a comprehensive literature review and expert opinion. This article expands on these guidelines by reviewing the risk factors for the development of neurocognitive sequelae and describing the expected pattern of these disabilities. We herein present recommendations for the screening and management of neurocognitive late effects and outline important areas of school and legal advocacy for survivors with disabilities. Finally, we list resources that can guide patients, their parents, and their medical caregivers as they face the long-term neurocognitive consequences of cancer therapy.     

Gastrointestinal sequelae in survivors of congenital diaphragmatic hernia.

BACKGROUND: Gastrointestinal sequelae have been sporadically reported in survivors of congenital diaphragmatic hernia (CDH). The aim of the present paper was to evaluate the gastrointestinal morbidity in infant, adolescent and adult patients who had undergone repair of CDH. METHODS: Thirty-one of 38 survivors after left-side CDH repair were followed up. They were subdivided in two groups. Group A consisted of 12 patients (39%) with a mean age of 4.5 years and group B, 19 patients (61%) with a mean age of 21.0 years. Patients underwent physical examination, barium meal study, gastroesophageal scintigraphy, esophageal pH monitoring and manometry of the esophagus and stomach. Upper intestinal endoscopy was performed in patients with confirmed gastroesophageal reflux (GER). RESULTS: All patients were within the normal range for height or weight. A total of 41.7% of group A and 15.8% of group B had typical symptoms suggesting GER. Barium meal study was pathological in 33.3% of group A and 21% of group B patients. In 58% of group A and 42% of group B, GER was documented on scintigraphy. In 41.7% of group A and 47% of group B the time taken for the stomach to empty half of its radioactive content (T(1/2)) was pathological. On 24 h pH monitoring pathological GER was documented in 54.5%, whereas in group B it was present in 33.3%. In 36.4% of group A and 46.7% of group B alteration of peristalsis of the stomach was recorded. Endoscopy showed esophageal pathology in 33%. CONCLUSIONS: Foregut dysmotility and GER are major sequelae in survivors of CDH repair. Long-term follow up of patients with CDH is recommended.     

Mid- and long-term effects on pulmonary perfusion,anatomy and diaphragmatic motility in survivors of congenital diaphragmatic hernia

The aim of the present study was to evaluate the pulmonary sequelae and diaphragmatic motility in infant, adolescent and adult patients (pts) who had undergone the repair of a congenital diaphragmatic hernia. Thirty-one (81.5%) out of 38 survivors after left side CDH repair, without using a patch, were followed-up. They were subdivided in two groups. Group A (mid-term follow-up): 12 pts (39%) (5 males, 7 females) with a mean age of 4.5 years; Group B (long-term follow-up): 19 pts (61%) (9 males, 10 females) with a mean age of 21.0 years. All pts underwent physical examination, chest X-ray, diaphragmatic ultrasonographic (US) examination, pulmonary perfusion scintigraphy. Patients of the group B were also submitted to spirometry. All pts had a normal life-style and no one complained of respiratory symptoms. The chest X-ray revealed pathologic findings in 12 pts (39%). 8 pts (26%) showed chest wall alterations. The profile of the left diaphragmatic dome appeared irregular in 9 pts (29%). In all pts M-mode sonography disclosed a reduced diaphragmatic motility on the treated side. The mean pulmonary perfusion scintigraphy value on the affected side was 39.2±0.7%. The spirometric study showed normal values. We noted that the lung perfusion significantly and rapidly improved after CDH repair even the apparently hypoplastic and small lungs, the diaphragm maintained a good contractility during forced respiration. An erratum to this article can be found at     

Gastroesophageal reflux and diaphragmatic motility after repair of congenital diaphragmatic hernia.

At the Department of Pediatric Surgery in Graz, 31 boys and 23 girls were operated on for congenital diaphragmatic hernia (CDH) from 1978 to 1994. In 49 patients the defect was on the left, in five on the right side. In 46 cases, the hernia was diagnosed within the first week of life; in eight children at a later date. 19 children (35%) died. 25 of the 35 survivors (71%) came to a follow-up examination on average 9.4 (1-17) years after the operation. 24 h pH-monitoring or manometry and Upper G.I. series revealed pathological gastroesophageal reflux (GER) in 16 patients. Nine children were treated conservatively; in seven patients an antireflux procedure was performed. A thoracic position of the stomach or left liver lobe, presence of a hernial sac, gestational age, prenatal diagnosis, use of a patch or severity of lung hypoplasia did not significantly influence the incidence of GER. In three patients, a hiatal hernia was found. The motility of the diaphragm was documented with M-mode sonography (n = 18); a restricted motility could be demonstrated in five patients. GER is very common in patients after repair of CDH. We recommend long-term follow-up with special interest in respect of GER.     

Monitoring for cardiovascular disease in survivors of childhood cancer: report from the Cardiovascular Disease Task Force of the Children's Oncology Group

Curative therapy for childhood cancer has improved significantly in the last 2 decades such that, at present, approximately 80% of all children with cancer are likely to survive > or = 5 years after diagnosis. Prevention, early diagnosis, and treatment of long-term sequelae of therapy have become increasingly more significant as survival rates continue to improve. Cardiovascular disease is a well-recognized cause of increased late morbidity and mortality among survivors of childhood cancer. The Children's Oncology Group Late Effects Committee and Nursing Discipline and Patient Advocacy Committee have recently developed guidelines for follow-up of long-term survivors of pediatric cancer. A multidisciplinary task force critically reviewed the existing literature to evaluate the evidence for the cardiovascular screening recommended by the Children's Oncology Group guidelines. In this review we outline the clinical manifestations of late cardiovascular toxicities, suggest modalities and frequency of monitoring, and address some of the controversial and unresolved issues regarding cardiovascular disease in childhood cancer survivors.     

The immediate and long-term outcomes of newborns with congenital diaphragmatic hernia

In spite of the innovations in the management of newborns with congenital diaphragmatic hernia (CDH) presenting with respiratory distress at birth, mortality and ongoing morbidity still remain high. This is a retrospective analysis of newborns with CDH to determine the immediate and long-term outcomes among survivors. Medical records of newborns with CDH and respiratory distress at birth between January 1993 and March 2002 were reviewed retrospectively. There were 45 newborns, 29 males and 16 females. Eleven newborns (24%) died during the period of preoperative stabilization, 9 from pulmonary hypoplasia and 2 with complex anomalies who were not resuscitated. Surgery was performed in 34 newborns (76%). Three died postoperatively from severe pulmonary hypoplasia and pulmonary hypertension. Eleven newborns (24%) had sepsis from coagulative-negative staphylococci. Thirty-one of 43 newborns (72%) with isolated CDH were discharged home. Twenty-seven of 31 survivors (87%) had adverse long-term outcome and 2 late deaths were from pulmonary complications. Twenty-nine of 43 newborns (67%) with isolated CDH survived. The principal determinant of survival was pulmonary hypoplasia. Eighty-seven percent of survivors have associated morbidity including ongoing pulmonary, nutritional and neuro-developmental problems. Nevertheless preoperative stabilization and delayed surgery have been a satisfactory mode of management.