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Isolated left congenital diaphragmatic hernia (CDH) is associated with a high risk of neonatal mortality and morbidity, mainly owing to pulmonary hypoplasia and/or hypertension[1-3]. In an attempt to improve postnatal survival and lower morbidity, therapy with fetoscopic tracheal occlusion (FETO) is offered in cases with estimated chances of poor neonatal survival, demonstrating an increment of around 25% in survival rate. In spite of an overall improvement in outcomes, FETO is associated with huge variability in the pulmonary response after tracheal occlusion and in the degree of postnatal morbidity and mortality. The identification of clinical predictors to refine individualized prognoses is on the agenda of many research groups and would be of great help in making clinical and patient decisions.
In terms of perinatal mortality, the best predictor of response to fetal therapy is lung area on the side contralateral to the hernia (measured as the lung area-to-head circumference ratio and expressed as a ratio between observed and expected-for-gestational-age value, O/E-LHR)[6, 7]. In addition, evaluation of the intrapulmonary circulation has been suggested as a promising predictor of neonatal prognosis in CDH[8-12]. Thus, recent studies suggest that abnormalities in lung Doppler velocimetry discriminate between cases with moderate to high survival rates and those with extremely low chances of survival after FETO.
Aside from mortality, information on the risks of serious postnatal morbidity might be of interest to patients when considering the option of prenatal therapy. While O/E-LHR has been shown to be a good predictor of neonatal morbidity among survivors managed expectantly, in a recent study it failed to predict morbidity in fetuses treated with FETO. With respect to intrapulmonary Doppler, there are no studies evaluating its value as a predictor of morbidity after FETO.
In the present study we evaluated the ability of O/E-LHR and of intrapulmonary artery Doppler velocimetry to predict neonatal morbidity in survivors in a consecutive cohort of fetuses with left-sided CDH treated with FETO.
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A total of 51 fetuses fulfilled the entry criteria. In all cases FETO was successfully performed and the overall mortality rate was 49.0% (25/51), leaving a final study population of 26 survivors. Table 1 shows the maternal and neonatal clinical characteristics of the study population. Among survivors, only one case required ECMO; 15 (57.7%) required HFV, eight (30.8%) required oxygen support at 28 days of age, nine (34.6%) showed gastroesophageal reflux and four (15.4%)needed tube feeding at discharge. The O/E-LHR values before FETO ranged from 17.7 to 40.5%. In addition, Doppler values before therapy were normal in 18 (69.2%) and abnormal in eight (30.8%) fetuses.
Table 1. Maternal and neonatal clinical characteristics of the study group of fetuses with left-sided congenital diaphragmatic hernia (CDH)
|Characteristic||Survivors (n = 26)||Non-survivors (n = 25)||P|
|GA at first scan (weeks)||25.4 (19.4–30.3)||24.3 (18.3–28.4)||0.18|
|Maternal age (years)||29.4 (18.0–39.8)||29.5 (17.5–39.6)||0.96|
|Primiparity||12 (46.2)||9 (36.0)||0.46|
|Non-Caucasian ethnicity||6 (23.1)||3 (12.0)||0.30|
|O/E lung-to-head ratio||28.0 (17.7–40.5)||27.0 (14.3–44.9)||0.59|
|GA at FETO (weeks)||29.4 (26.4–33.3)||29.1 (26.0–32.9)||0.61|
|Length of occlusion (days)||28.2 (9–49)||29.3 (9–69)||0.78|
|GA at occlusion removal (weeks)||33.4 (30.3–35.4)||33.4 (28.6–36.4)||0.99|
|PPROM||10 (38.5)||14 (56.0)||0.21|
|GA at PPROM (weeks)||33.7 (29.9–36.3)||31.9 (28.3–35.0)||0.08|
|Postnatal balloon removal||1 (3.8)||5 (20.0)||0.07|
|Cesarean section||6 (23.1)||11 (44.0)||0.11|
|GA at delivery (weeks)||36.8 (32.7–40.4)||35.2 (28.6–40.3)||0.06|
|Birth weight (g)||2584 (1680–4010)||2280 (1100–3100)||0.09|
|5-min Apgar score < 7||2 (7.7)||9 (36.0)||0.01|
|Neonatal age at CDH repair (days)||2.0 (1–8)||15.1 (1–63)||< 0.01|
|Need for patch at surgical correction||22/26 (64.6)||8/10* (80.0)||0.74|
|Extracorporeal membrane oxygenation||1 (3.8)||6 (24.0)||0.04|
|Inhaled nitric oxide used||12 (46.2)||22 (88.0)||< 0.01|
|High-frequency ventilation||15 (57.7)||23 (92.0)||< 0.01|
|Neonatal age at extubation (days)||16.6 (2–63)||35.8 (2–64)||0.03|
|Conventional ventilation (days)||11.2 (1–38)||5.5 (1–64)||0.14|
|Oxygen therapy at 28 days||8 (30.8)||N/A||—|
|Gastroesophageal reflux||9 (34.6)||N/A||—|
|Time in neonatal intensive care unit (days)||42.8 (12–120)||18.1 (1–84)||< 0.01|
|Tube feeding at discharge||4 (15.4)||N/A||—|
While gestational age at birth was only significantly associated with the duration of conventional ventilation (P = 0.040) and oxygen support (P = 0.038), regression analysis adjusted for gestational age at birth showed no significant association between O/E-LHR and any of the analyzed outcomes, including days of mechanical ventilation (P = 0.28), conventional ventilation (P = 0.29), HFV (P = 0.96), INO therapy (P = 0.26), oxygen support (P = 0.06), parenteral nutrition (P = 0.83), length of stay in neonatal intensive care unit (P = 0.20), frequency of gastroesophageal reflux (P = 0.61), oxygen requirement at age 28 days (P = 0.86) or tube feeding at discharge (P = 0.49).
Table 2 shows the neonatal clinical characteristics of CDH cases with normal and abnormal intrapulmonary artery Doppler parameters. Cases with abnormal lung Doppler required significantly higher duration of mechanical ventilation, conventional ventilation, HFV, oxygen support, parenteral nutrition and longer stay in the neonatal intensive care unit. After adjustment for gestational age at birth, linear regression analysis showed that the group with abnormal intrapulmonary Doppler findings was significantly associated with an increase in the duration of: mechanical ventilation (average increase of 21.2 (95% CI, 9.99–32.5) days; P = 0.001), conventional ventilation (15.2 (95% CI, 7.43–23.0) days; P = 0.001), HFV (6.34 (95% CI, 0.69–11.99) days; P = 0.04), nitric oxide therapy (5.73 (95% CI, 0.60–10.9) days; P = 0.03), oxygen support (36.5 (95% CI, 16.3–56.7) days; P = 0.001), parenteral nutrition (19.1 (95% CI, 7.53–30.7) days; P = 0.002) and stay in neonatal intensive care unit (42.7 (95% CI, 22.9–62.6) days; P < 0.001) when compared with the group with normal intrapulmonary Doppler values.
Table 2. Fetal and neonatal clinical characteristics for congenital diaphragmatic hernia (CDH) survivors with normal and abnormal intrapulmonary artery Doppler velocimetry
|Characteristic||Normal lung Doppler (n = 18)||Abnormal lung Doppler (n = 8)||P*|
|GA at ultrasound (weeks)||25.3 ± 3.1||25.6 ± 2.9||0.80|
|GA at FETO (weeks)||29.2 ± 1.6||29.7 ± 2.1||0.54|
|Length of occlusion (days)||29.1 ± 10.6||26.3 ± 9.9||0.53|
|GA at occlusion removal (weeks)||33.4 ± 1.5||33.4 ± 1.8||0.93|
|PPROM||5 (27.8)||5 (62.5)||0.09|
|GA at PPROM (weeks)||34.4 ± 2.6||32.9 ± 1.2||0.28|
|GA at delivery (weeks)||37.3 ± 2.4||35.5 ± 2.0||0.07|
|Birthweight (g)||2630 ± 738||2480 ± 433||0.60|
|5-min Apgar score < 7||1 (5.6)||1 (12.5)||0.54|
|Neonatal age at CDH repair (days)||1.7 ± 1.1||2.6 ± 2.4||0.20|
|Need for patch||15 (83.3)||7 (87.5)||0.79|
|Oxygen support (days)||19.7 ± 14.9||45.9 ± 33.7||0.01|
|Mechanical ventilation (days)||11.4 ± 6.6||27.6 ± 19.2||< 0.01|
|High-frequency ventilation (days)||3.39 ± 4.9||8.63 ± 7.4||0.04|
|Conventional ventilation (days)||7.53 ± 4.5||19.0 ± 13.6||< 0.01|
|Inhaled nitric oxide (days)||2.44 ± 4.9||5.88 ± 7.1||0.16|
|Parenteral nutrition (days)||17.1 ± 7.1||33.9 ± 17.8||< 0.01|
|Time in neonatal intensive care unit (days)||31.2 ± 13.3||67.5 ± 32.4||< 0.01|
Figure 2 shows the frequency of adverse neonatal outcomes for CDH cases classified according to the presence or absence of abnormal intrapulmonary artery Doppler velocimetry. CDH fetuses with abnormal lung Doppler velocimetry had a significantly higher rate of HFV (87.5 vs 44.4%; P = 0.040), oxygen requirement at 28 days of age (75.0 vs 11.1%; P = 0.009), gastroesophageal reflux (62.5 vs 22.2%; P = 0.038) and tube feeding at discharge (37.5 vs 5.56%; P = 0.045) than those with normal intrapulmonary Doppler.
Figure 2. Frequency of adverse neonatal outcome for congenital diaphragmatic hernia survivors with normal () and abnormal () intrapulmonary artery Doppler velocimetry. *P < 0.05, adjusted for gestational age at birth by multiple logistic regression analysis.
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Clinical experience has demonstrated that there is wide individual variability in the response to FETO in human fetuses. A subgroup of survivors still presents serious neonatal morbidity, mainly in the form of pulmonary but also with gastrointestinal complications. This study provides evidence that intrapulmonary artery Doppler velocimetry is an independent predictor of neonatal prognosis, discriminating a subgroup of CDH fetuses with liver herniation treated with FETO that is associated with decreased survival and increased neonatal morbidity.
The findings of the study in relation to the predictive value of O/E-LHR in fetuses treated with FETO are in agreement with a previous study in which O/E-LHR did not show any correlation with the likelihood of neonatal morbidity. On the contrary, among CDH cases managed expectantly, Jani et al. reported a significant negative correlation between O/E-LHR with days of assisted ventilation needed and the need for supplemental oxygen at 28 days. The discrepancy between reports with treated and untreated cases could be explained by differences in the population characteristics with respect to average O/E-LHR values. Thus, the study on expectantly managed cases included higher O/E-LHR values, ranging from 15 to 83%. Concerning the value of Doppler velocimetry, this is the first study on the prediction of morbidity, and therefore we cannot compare the findings with previous studies. However, Doppler velocimetry has previously been shown to add valuable information when used in combination with O/E-LHR for predicting mortality in fetuses treated with FETO. In a recent study we demonstrated that, in fetuses with O/E-LHR below 26%, a combination of O/E-LHR with intrapulmonary Doppler helped to stratify the probability of survival. Among the small series of survivors, Doppler velocimetry did not appear to add any benefit in cases with O/E-LHR above 26%, since this subgroup was already associated with a mean survival rate of over 90% after FETO.
Previous studies have demonstrated that CDH is associated with profound changes in the pulmonary vasculature in the form of a decreased number of arterial branches and increased muscular thickness in the wall of the intrapulmonary vessels[23-25]. Vascular anomalies are thought to be the main reason for the high prevalence of pulmonary hypertension, which in many cases determines the degree of morbidity and mortality, more so than pulmonary insufficiency. However, in human CDH, the degree of vascular changes, and consequently the severity of pulmonary hypertension, may show important individual variation, which seems not to be fully identifiable by lung size and O/E-LHR measurement. The present study showed that intrapulmonary artery Doppler predicted neonatal pulmonary morbidity in survivors after FETO, while O/E-LHR did not. These findings confirm previous studies that fetuses with similar lung sizes, as assessed by O/E-LHR, may present substantial differences in the intrapulmonary impedance as measured by Doppler, and possibly in the degree of primary vascular disease. Doppler studies add to the body of evidence suggesting that the diagnostic category of CDH includes several related diseases with various pathophysiological origins and a mixed component of mechanical lung compression with primary lung anomalies, which are not completely reflected in lung size.
Interestingly, Doppler velocimetry also predicted the prevalence of gastrointestinal complications. Gastroesophageal reflux disease requiring antacid medication is the major contributor to non-pulmonary neonatal morbidity in CDH. It has been reported in up to 40% of cases, of which 50% required antireflux medication at discharge[26, 27]. We hypothesize that the association of lung Doppler velocimetry with the risk of gastrointestinal morbidity could reflect an indirect association between the degree of pulmonary morbidity, which includes prolonged ventilatory support and use of a nasogastric tube, and the development of gastroesophageal reflux disease[26, 28, 29]. Aside from a direct relationship between therapeutic aggressiveness and consequent morbidity, the relationship between lung Doppler and gastroesophageal reflux could represent an example of the theory of gastric CO2 ventilation, which postulates coordination of respiratory and digestive control networks regulating CO2 elimination during respiratory acidosis, and which has been proposed to partially explain the frequent co-expression of pulmonary disease and chronic respiratory acidosis with gastroesophageal reflux disease.
From a clinical perspective, the results of this study, if confirmed by others, might be useful for counseling patients. Previous studies on CDH survivors with severe lung hypoplasia have shown a 40% risk of late gastroesophageal reflux disease, 25% risk of sensorineural hearing loss in childhood and 30% risk of adverse neurodevelopment at 6–16 years of age. Since such long-term morbidity is especially increased in cases with severe lung hypoplasia requiring prolonged respiratory support[29, 33, 34], lung Doppler abnormalities could assist in the identification of cases at highest risk and may be of help in making clinical and patient decisions.
This study has several limitations. Firstly, sample size was not sufficiently large to evaluate other associations such as the potential existence of differences in the use of ECMO. Secondly, since there was no control group we cannot establish comparisons with contemporary cases managed expectantly. Thirdly, we acknowledge that insonation of the fetal intrapulmonary vasculature is technically difficult. It requires training to achieve competence and strict criteria for acquisition in order to ensure reproducibility, and therefore its clinical use is not widely applicable. We have recently reported that lung Doppler velocimetry in CDH is reliable after a substantial number of examinations. Once competence has been achieved, Doppler velocimetry can be performed in the proximal branch of the intrapulmonary artery with near zero angle on virtually all occasions and with a good degree of agreement between experienced examiners[10, 36].
In conclusion, the present study suggests a new clinical application of intrapulmonary artery Doppler velocimetry in the identification of survivors at the highest risk of neonatal morbidity. Integration of lung Doppler into clinical prognosis algorithms at the time of considering FETO could contribute to improving clinical management and to refining the design of future clinical trials.