Introduction
Congenital diaphragmatic hernia (CDH) is a life-threatening congenital anomaly, with an incidence of approximately 1:2,500 live births [
1,
2]. Despite advances in antenatal diagnosis and postnatal management, mortality rate remains stable around 40–50% [
1‐
4]. It has been shown that overall survival rate is mainly determined by the rate of antenatal termination, the incidence of CDH associated anomalies, degree of pulmonary hypoplasia and pulmonary hypertension in the neonatal period [
1,
2,
5‐
7]. Reports of improved survival of CDH should be interpreted with caution, as variations in outcomes are more likely to be explained by case selection bias [
2].
The incidence of malformations associated with CDH is 33–50% [
1,
3,
8,
9]. Major anomalies, like cardiovascular defects, intestinal atresias and chromosomal anomalies [
1,
3,
10] may all contribute to a fatal outcome [
1‐
3,
8,
11‐
13]. Several non-life threatening anomalies such as atrial or ventricular septal defect, Meckel’s diverticulum, neurological abnormalities and genito-urinary abnormalities are also more frequently observed in CDH patients [
3,
8].
In the past decades, new pathophysiologic concepts have been developed, leading to a change in therapeutic approach. Before 1985, surgical repair was performed on an emergency basis, because it was believed that removing the abdominal viscera from the chest allowed expansion of the lung on the involved side [
14]. It was observed, however, that the clinical condition of children with CDH rarely, if ever, improved after emergency surgery; in fact, many children were significantly worse postoperatively [
15]. This could be explained by the fact that pulmonary vascular resistance rapidly increases due to a variety of stimuli including endotracheal tube suctioning, loud ambient noise, pain, hypothermia and atelectasis. All of these stimuli are enhanced during repair of the diaphragm. Furthermore it was demonstrated that surgical reduction of the hernia does not improve lung mechanics and may even temporarily decrease the compliance of the chest wall [
16,
17]. This can be explained by increased abdominal pressure associated with reduction of the viscera into the small abdominal cavity [
16,
17].
When it was realized that surgical repair could further decrease lung compliance, which could be fatal in a patient already compromised by pulmonary hypoplasia and persistent pulmonary hypertension, repair was delayed and performed after patients were stabilized and adequately oxygenated with minimal ductal shunting on conventional ventilation [
4,
18]. Delayed surgery is theorized to provide additional time for remodeling of the pulmonary vasculature, leading to a more stable infant, who is better able to tolerate a postoperative decrease in compliance [
16,
19]. Although a significant change in survival after the introduction of delayed surgery was not observed [
4,
20‐
22], a strategy of delaying correction of the defect for some period of time have been adopted by centers, with the majority of patients undergoing operation beyond 24 h of age [
23,
24].
The introduction of ECMO in the early 1980s was expected to improve the outcome for infants with pulmonary hypertension refractory to maximal conventional medical management. Roughly 50% of infants with high-risk CDH are treated with ECMO [
25,
26], the results, however, remain disappointing [
2,
21,
27]. Some authors reported an improved survival rate when incorporating ECMO as a preoperative stabilization or postoperative rescue therapy [
26,
28,
29], while others found a relatively unchanged mortality rate [
2,
21,
22,
27,
30]. It is difficult to accurately compare results of those studies because each center varies in degree of illness, ventilatory management, timing of surgery, ECMO and selection criteria for ECMO. Another confounding feature of reports of survival in CDH patients treated with ECMO is the unreliability of historic controls [
2,
26,
27]. Furthermore, most studies have a relatively short follow-up period, while significant late mortality has been found in CDH patients treated with ECMO [
31]. If the use of ECMO has indeed a beneficial effect on survival, than it might be possible that a larger number of severely affected infants would nowadays survive [
32]. It is likely that these infants will have more severe pulmonary hypoplasia and pulmonary hypertension [
26,
31,
33] implying more serious long-term morbidity [
31].
The last decade fetal endoscopic tracheal occlusion (TO) has been developed as an alternative strategy to promote fetal lung growth by preventing normal outflow of lung fluid. Occlusion of the fetal trachea was shown to stimulate fetal growth in a variety of animal models [
34‐
40]. On the other hand, prematurity caused by the intervention itself can be detrimental. Results of studies regarding survival rate and TO are ambiguous and it is not yet clear whether survival rates will improve with this new technique [
41]. Harrison et al. [
42] showed in a (small) randomized controlled trial comparing fetal endoscopic TO to standard care that mortality is equal. Data concerning long-term outcomes of fetal endoscopic TO are very scarce [
43,
44].
Traditionally most attention has been focused on therapies that reduce perinatal and neonatal mortality, while relatively few studies have addressed the chronic morbidity and long-term outcome. In follow-up of infants born with CDH, many complications have been described. In the following sections, we will describe the pulmonary, cardiovascular and gastro-intestinal morbidity secondary to CDH. We will also discuss failure to thrive, neurodevelopmental outcomes, musculoskeletal abnormalities and health-related quality of life in CDH patients.
Although the prevalence of co-morbidity is high among CDH survivors, little is known about the impact of long-term health problems on overall well being of these patients. There are only two studies describing health-related quality of life (HR-QoL) of CDH patients. Poley et al assessed HR-QoL in 111 CDH patients (4 treated with ECMO), 286 patients with anorectal malformations (ARM) and a healthy control group (age 1–52 years). In children aged 1–4 years, influence of symptoms on HR-QoL, assessed with the TAIQOL (quality of life questionnaire developed for children between ages of 1 and 4 years [
148]), seemed less profound in CDH patients when compared to ARM patients in most domains. Statistically significant differences between the CDH group and the control group were found in five domains of the TAIQOL.
CDH patients aged 5–15 years scored relatively low in the domains “basic motor functioning” and “cognitive functioning” in the TACQOL (quality of life questionnaire developed for children between the ages of 5 and 15) [
149]. Neither the 8 domains of the widely used Short Form 36 (SF-36) domains, used for patients aged 16 years and above, nor the physical summary measure discriminated between CDH patients and the general population [
150].
Koivusalo et al. [
73] studied 69 adult survivors of congenital diaphragmatic defects (CDD) consisting of survivors of CDH and diaphragmatic eventration (DE) in comparison with a healthy control group. None of the patients with DE underwent preoperative stabilization with medication or mechanical ventilation, and only 15% required mechanical ventilation for more than 1 week postoperatively. The frequency of high educational level was significantly lower in patients with CDD than in control subjects, but whether this difference was related to long-term sequelae of CDD remained unclear. A total of 17 of the 69 patients (25%) with CDD had low HR-QoL assessed in one or both of the summary measures Physical Health and Mental Health in SF-36 questionnaires. No statistical difference in quality of life was found between patients with CDH and DE. Incidence of GERD and recurrent intestinal obstruction was most often associated with low HR-QoL and Gastro-Intestinal Quality of Life (GIQLI) scores in patients with CDD. This study indicates that 75% of adult patients born with CDD have good HR-QoL similar to healthy subjects. Practically no or insignificant late sequelae associated with CDD were found. Low HR-QoL was found in 25% of the patients, exceeding the expected figure of 16% [
73].
It is likely that, in the past, major selection took place in the first week of life due to high mortality in patients with severe pulmonary hypoplasia and therapy resistant pulmonary hypertension. ECMO nowadays might enable survival of patients with a relatively poor prognosis leading to iatrogenic morbidity [
150]. While CDH is associated with considerable symptoms, so far available research in adults suggests a favorable long-term outlook for the vast majority of patients [
73,
150], however, there are no studies describing HR-QoL in CDH survivors treated with ECMO.
Conclusion
Despite new therapeutic strategies including ECMO, inhalation of nitric oxide, high frequency oscillation and fetal TO, mortality rate of CDH remains high. Several studies have documented significant long-term morbidity.
Infants born with CDH have pulmonary vascular abnormalities, presumably causing pulmonary hypertension. There is a higher incidence of obstructive airway disease and restrictive lung function pattern among CDH survivors. Gastro-esophageal reflux disease sometimes in combination with failure to thrive is a well recognized complication and several patients require anti-reflux surgery. It is unknown whether GERD has an effect on the pulmonary function.
Pulmonary hypoplasia and persistent pulmonary hypertension predispose children born with CDH to a high risk of hypoxemia, which may result in neurodevelopmental delay.
Chest wall deformities and scoliosis are more common among CDH patients. Deformities are mild and surgery is rarely required.
Despite the significant morbidity due to CDH, limited numbers of quality of life studies in older patients suggest that the majority of patients apparently enjoy quite healthy lives.
It should be realized that, with the introduction of potential mortality reducing new therapies in the acute (neonatal) phase, the balance between decreasing early mortality and potential long-term outcome should be assessed.
It is therefore be, highly recommended that children born with CDH are evaluated periodically in a protocolized multidisciplinary setting to minimize short-term morbidity and to assess long-term morbidity. Particularly the study of long-term sequelae will enable to establish an adequate and focused program for routine follow-up of survivors of a severe congenital anomaly.
Acknowledgments
The authors thank Prof. D. Tibboel, Pediatric Surgical Intensive Care, Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam, for critical comments on earlier versions of this manuscript.