We demonstrated an association between radiographic lung area, sPAP values, and death. Among survivors, lung area was also associated with hernia recurrence. As previously reported, our findings suggest a possible role of radiographic measurement as an easy, non-invasive, and reproducible tool in the early prediction of mortality and morbidity among CDH patients15.
Our results confirmed the invariable association between pulmonary hypoplasia, PH, and death risk, as expected on a pathophysiological basis23,25,27.
In our cohort, lower O/E-LHR% in the deceased group indicated a more fetal severe lung impairment, which was then reflected in smaller pulmonary areas at birth. Consequently, lung area and death were inversely related: one cm2 of rising in the ipsilateral area was associated with a 43% reduction in mortality, while variations in the total and contralateral area determined a reduction of 22% and 24%, respectively.
Large-size defects have been previously associated with worse survival and pulmonary hypertension, suggesting that low lung volumes depict the link between these two elements6. Similarly, in our cohort, deceased infants were characterized by persistently higher sPAP values than survivors. In particular, sPAP values at birth showed a decreasing trend by 1.84 mmHg, with each 1 cm2 increase in the ipsilateral area.
Radiographic assessment and first sPAP measurement, both performed within 24 hours after birth, described the lung condition in a defining moment. Subsequently, several factors could influence pulmonary hypertension, such as pharmacological treatments, infections, patency of the ductus arteriosus, or surgery timing. The contribution of these factors could be neither captured nor predicted by the imaging performed at birth. For these reasons, it would be of interest to match lung area assessments and sPAP values at T1, T2, and T3, to clarify if this association is still confirmed over time and define possible trends.
Our findings were consistent with previous literature. A significantly lower CRTA was reported in newborns with CDH who died compared to survivors, and a CRTA greater than 12.99 cm2 was found to predict survival to discharge from NICU better than O/E-LHR% at diagnosis, with 85% sensitivity and 73% specificity16. In our cohort, the best cut off and sensitivity were slightly lower. Even if specificity was higher, it still carried a wide margin of error in identifying patients at risk of death. Probably, the decision to consider only the aerated portions of the lungs led to an underestimation of lung surface, leading to low cut off values and discriminatory capacity.
Finally, after surgical repair, persistently elevated pulmonary pressure carried the highest risk of mortality, with a 16% increase in death risk for each sPAP unitary increment. Several studies have correlated the severity of PH with mortality. Dillon et al. evaluated mortality in a cohort of CDH patients and reported that all those with supra-systemic sPAP died25. Coughlin et al. reported that patients with higher PH at 1 month had a higher incidence of postoperative complications and worse survival, and persistently severe PH at 1 month was associated with increased mortality6. Similarly, looking at our results, we could assume that the most critical factor might not be the absolute value of sPAP or the presence of PH in the first hours after birth, rather its persistence over time6.
Small lung areas at birth result from poor lung development, but the interference of mechanical compression exerted by the herniated organs plays a considerable role. Therefore, after mechanical compression has been removed, the effective lung area’s evaluation could greatly define lung hypoplasia and associated outcome. For example, Dimitriou et al. calculated the difference between the pre- and postoperative radiographic measurements, showing that postoperative improvement was higher in patients with a good outcome. They concluded that poor prognosis was correlated to low postoperative rather than low preoperative values, which was probably more related to mechanical compression than lung hypoplasia14. Therefore, the radiographic assessment of postoperative lung areas and the relative increase from preoperative values should be included in further analysis.
We demonstrated a significant association between preoperative radiographic measurements and hernia recurrence among survivors during the first year of life.
The overall recurrence rate of 20.4% in our cohort was in line with the literature reports17,22,28. In particular, the recurrence rate was higher in those patients with lower final O/E LHR%, prolonged invasive respiratory support, and need for intensive care. Similarly, Al-Iede et al. found a longer duration of mechanical ventilation and hospitalization in children with recurrence19. Notably, these patients showed a significantly lower mean total pulmonary area at birth than non-recurrence, mainly due to a significantly lower ipsilateral pulmonary area.
As a consequence, we respectively observed a 14% and 29% reduction in recurrence risk in our cohort per unit increment of the total and ipsilateral area. Although it showed a lower trend in the recurrence group, the contralateral area did not seem to influence. The total radiographic area showed the best specificity in discriminating those patients at risk of recurrence, while the ipsilateral area showed better sensitivity.
Taken together, the lower ipsilateral area and O/E-LHR% reflected the presence of a large diaphragmatic defect as the cause of poor lung development, indirectly confirming defect size as the leading risk factor for hernia recurrence17–20,22. In other words, we speculate that recurrence patients were somehow “predisposed” to this complication since birth and could have been identified early in the postnatal course.
The recurrence group’s high patching rate suggested the presence of a wide defect, although this difference did not reach statistical significance. We cannot deduce any specific contribution of the patch in determining the recurrence risk due to the low sample size.
We observed that tracheal occlusion improved lung development and outcome through the descriptive comparison between FETO and non-FETO patients’ characteristics.
Since prenatal treatment is reserved for severe cases of CDH, the FETO group included only patients at one end of the spectrum of disease severity26. Nevertheless, final O/E-LHR% before birth was even better in the FETO than in the untreated group, and the total and ipsilateral lung areas at birth did not significantly differ. Likewise, Dassios et al. observed that patients previously submitted to FETO procedure had a CRTA comparable to untreated patients with a similar mortality rate, reflecting a lung catch-up growth favored by the prenatal procedure16.
However, there was an inconsistency among higher mortality rates, similar sPAP values, and prolonged need for pulmonary vasodilators in the FETO group compared to the other. At first impression, we could argue that only a quantitative but not qualitative improvement in lung development was achieved with prenatal intervention since similar lung areas at birth seemed not to guarantee the same survival chances, apparently due to more severe pulmonary hypertension in FETO patients. However, after excluding mild cases, the two groups showed a similar outcome, suggesting that the initial findings were due to many mild cases in the untreated group. The final O/E LHR% dramatically improved after the procedure, but the ipsilateral area was even significantly better in FETO than non-FETO patients.
In our cohort, the non-FETO group, which was primarily constituted by moderate cases, showed a 41.2% survival rate, in line with what is generally expected for this category of CDH2,29,30. As observed by Doneè et al., tracheal occlusion allowed improved outcomes in the operative group, similar to a moderate population expectantly managed31.
Finally, the recurrence risk was around 20% in both populations, despite higher patching in the FETO group, as previously observed by Ali et al. (41). Although it is the leading risk factor, the low recurrence rate suggests other factors besides the patch use as possible determinants of re-herniation18,32. Tsai et al. reported a non-significant difference in recurrence rate between patching and primary repair, despite a higher disease severity in the first group18. Jawaid et al. reported a low incidence of recurrence in patients in which Gore-Tex® patch was inserted32. Although we cannot conclude on the patch’s contribution in determining the risk of re-herniation, we can observe that lower final O/E LHR%, lower radiographic area at birth, and higher patching all suggest a common denominator influencing the risk of this complication 17,19,20,22. Finally, we can speculate that lung catch-up growth in FETO patients conferred the same risk of recurrence as the untreated counterparts.
To the best of our knowledge, our study seems to be the first to evaluate the association between radiographic lung area and two important outcomes affecting newborns with CDH: pulmonary hypertension and hernia recurrence.
The radiographic measurement is easy, rapid, and can be performed soon after birth on the chest X-ray routinely performed at NICU admission. It would contribute to the early identification of infants at greater risk of developing higher sPAP values in the immediate postnatal period and at a higher likelihood of long-term hernia recurrence, as well as higher mortality, with a potential impact on patients’ management. For example, the combined serial evaluation of lung area and sPAP over time could help to define trajectories related to the risk of persistently elevated sPAP and to identify patients evolving towards chronic pulmonary hypertension. Similarly, the preoperative radiographic assessment could help identify a subgroup of patients at higher risk of recurrence, directing them towards a more strict surgical follow-up.
The ipsilateral and contralateral areas were considered separately, evaluating the impact of hernia on each lung. We demonstrated that the ipsilateral area, which is more seriously affected by visceral herniation, has the most significant influence on patient outcomes.
Finally, focusing on FETO patients, we confirm the positive effects of the fetal procedure on lung catch-up growth and patient outcome.
Patients from our cohort showed a broad spectrum of disease severity, including infants requiring fetal surgery and ECMO support, and the standardization of treatment in accordance with international guidelines guarantee uniformity of care.
A certain technical difficulty in tracing the lungs’ perimeter in severe forms must be underlined first among our study’s limitations. We arbitrarily decided to consider only those parts of the radiograms where a lung plot was present, corresponding to those regions effectively recruited and ventilated. This methodological decision could constitute a bias leading to underestimating the lung dimensions since atelectasis areas had been excluded from the measurement.
Another significant limitation is related to the retrospective design of the study. The sample size was limited, and some missing data regarding sPAP estimation could not be integrated with further assessments, nor the number of patients could be incremented. We recognize that several factors could influence pulmonary vascular resistance and mortality throughout the hospital stay. The sample size should then be increased to allow a more unified subgroups analysis.
As research perspectives, serial assessments of the radiographic lung area during the hospital stay, remarkably the comparison between pre- and postoperative condition, could clarify the association between area, sPAP, and mortality, especially in most severe forms. We also aim to investigate the radiographic lung area’s possible role in predicting the need for ECMO support through a prospective multicenter cohort study.
In conclusion, the radiographic pulmonary area on the first day of life reflects impaired lung development during fetal life and the extent of the diaphragmatic defect in CDH patients. Lower lung areas are associated with higher sPAP values at birth, death, and hernia recurrence. Further studies are needed to consolidate these results and define the radiographic lung area’s possible role for CDH early risk assessment, monitoring, and outcome prediction.