In isolated CDH, the degree of lung hypoplasia represents the most important independent prognostic factor for neonatal survival (21-23).
Lung development is negatively influenced by the herniation of the abdominal organs through the diaphragmatic defect, displacing the mediastinal structures in the opposite direction. Therefore, the degree of the mediastinal shift is closely related to the total fetal lung volume and was found to be associated with neonatal survival in the recent literature. Our study confirmed an inverse correlation between the MSA and the O/E TFLV assessed at fetal MRI so that the MSA could be considered an indirect measure of lung hypoplasia. Indeed, the MSA and the O/E TFLV were significantly different between survivors and non-survivors. In particular, patients with poor outcomes were characterized by high MSA and low O/E TFLV values. As can be observed in the graphics, almost all high MSA cases had a poor prognosis, while most patients with low MSA survived to discharge.
The study showed an association between increased MSA and postnatal clinical severity. In particular, higher MSA values determined more significant postnatal cardiovascular and respiratory impairment, requiring longer inotropic and vasoactive pharmacological support with dobutamine, dopamine, and hydrocortisone, as well as more prolonged mechanical ventilation and use of pulmonary vasodilators such as nitric oxide, sildenafil, and milrinone. Moreover, patients receiving milrinone infusion were characterized by a more severe mediastinal shift. The same trend was also confirmed for oxygen supplementation, although with a borderline statistical significance.
As expected, the decrease in the O/E TFLV was associated with greater respiratory and cardiocirculatory impairment as well. However, the duration of milrinone administration was not influenced by the O/E TFLV.
Finally, high prenatal MSA and low O/E TFLV both influenced the overall length of hospitalization, although the former at a 10% significance level.
Our results suggest that the MSA reflects hernia severity and is strictly associated with increased mortality and a higher need for neonatal intensive cares. Increased MSA values could help identify a subgroup of patients at higher risk for prolonged NICU stay and second-line treatments, such as milrinone, better than the O/E TFLV alone.
Our findings are in accordance with the recent literature. On fetuses with left isolated CDH, Romiti and colleagues reported a mean MRI-MSA value of 43.7° for deceased and 39.6° for survivors. They identified a cut-off value of 39.1° as having the highest discriminatory power to classify survival correctly (15). However, patients undergoing the FETO procedure in utero were not excluded from the study cohort, and the timing of the MSA assessment (pre- or post-FETO) was not reported. This aspect should be considered when interpreting these results, as the prenatal procedure could alter the MSA measurement by reducing the mediastinal shift and improving lung development.
However, in a previous paper, Savelli and colleagues evaluated the MSA on a cohort of expectantly managed, isolated, left-sided CDH. Both the mean MSA and TFLV were significantly different between survivors and non-survivors, and they identified a cut-off value of 38.2° as having the highest discriminatory power to predict survival to discharge correctly (16). Our study had a similar sample size and mean MSA values. However, a comparison between lung volumes is not possible since Savelli and coll. referred to the absolute lung volume and not to the O/E TFLV, which we consider more appropriate due to the important influence of gestational age on fetal lung development.
Nevertheless, the inverse correlation between MSA and lung volumes and the difference between survivors and non-survivors were confirmed. Finally, we decided not to perform a ROC curve analysis on our cohort due to the low sample size. For the same reason, we believe that the cut-off value identified by Savelli and coll. should be carefully used, as already recognized by the authors themselves, and should be confirmed on a larger CDH population.
Regarding neonatal cardiocirculatory and respiratory impairment, a comparison with the previous literature is not feasible. To our knowledge, the association between fetal MSA and neonatal clinical severity has never been investigated so far.
The presence of the hernia has a negative impact on the development of ipsilateral cardiac structures (24, 25). Compression of heart structures, abnormal cardiac axis, distorted fetal flow, increased pulmonary vascular resistance and decreased left ventricular pre-load contribute to a decreased cardiac output (26). Early ventricular dysfunction is an independent determinant for hernia severity and clinical outcome (26-28). In this regard, the O/E TFLV was shown to correlate with early postnatal left ventricular dysfunction, and both are associated with the need for extracorporeal membrane oxygenation (ECMO) in the neonatal period (3, 28-31). In light of these considerations, we can speculate that the MSA indirectly reflects the mechanical compression of the heart, resulting in a greater need for inotropic and vasoactive pharmacological support, such as dobutamine and dopamine. Patients with CDH have both left and right ventricular dysfunction, and a targeted selection of cardiovascular therapies is of key importance for optimal postnatal management (28). Right ventricular dysfunction requires pulmonary vasodilation to reduce afterload and lusitropic support to improve diastolic function. Instead, systemic vasodilation and inotropic support are required to reduce left ventricular afterload. Therefore, the phosphodiesterase 3 inhibitor milrinone is usually administered in the most severe forms of CDH since it combines all these pharmacological properties (32). Probably, our finding that the MSA was significantly higher in patients requiring milrinone is consistent with these considerations and deserves further analyses. Identifying infants at greater risk for cardiac dysfunction may allow for preventive management, and the MSA could help stratify those patients at a higher likelihood of severe cardiovascular impairment.
However, the relationship between the degree of the mediastinal shift and postnatal respiratory compromise is coherent with the impaired lung development caused by the mechanical compression of the herniated organs. Indeed, lung volume is a well-known marker of CDH severity. For example, lung volumes were found to be significantly lower in patients requiring a patch for hernia repair, who also received longer mechanical ventilation in the postoperative course (33). Moreover, low fetal MRI lung volumes have been associated with a postnatal need for oxygen supplementation and subsequent chronic lung disease development in previous studies (29, 31, 33-36).
Finally, data regarding neonatal mortality are limited to a single-center experience based on a small number of patients. Therefore, our findings may contribute to the definition of the role of the MSA in predicting postnatal survival and the degree of cardiocirculatory and respiratory impairment.
The assessment of the MSA is simple, reproducible, and less time-consuming than lung volume 3D calculation. Moreover, it does not require an experienced operator nor dedicated software but can be easily performed on the most common MRI sequences. Therefore, the MSA assessment could represent an additional or alternative predictive tool, especially for less experienced operators working at peripheral institutions, to allow a prompt referral to a tertiary center for appropriate take in charge of the expecting mother (5). In these cases, the 3D fetal lung volume calculation could represent a second step performed by expert operators, helping in the optimal patient’s pre- and postnatal management decision-making process. For example, it could more accurately identify cases that benefit from fetal balloon treatment or will likely require neonatal ECMO.
However, we also acknowledge some limitations in our study. First, the low sample size prevents us from making a proper statistical inference. Second, we did not consider several postnatal factors that could occur during the hospital course, influencing patient morbidity. Finally, we only performed a descriptive comparison of how MSA and O/E TFLV influenced the postnatal outcome.
To define which of the two measurements carries the highest prognostic capacity and consolidate the results, the MSA should be assessed and compared with lung volumetry on a larger CDH population.
As future directions, we also intend to perform the MSA assessment earlier during the pregnancy, ideally before 27 weeks of gestation for all patients, in order to evaluate if the MSA could correctly identify the candidates for the prenatal treatment and even predict the favorable response to the FETO procedure. We will also investigate a possible role of the MSA in predicting severe cardiorespiratory insufficiency and the need for neonatal ECMO.