Echocardiographic changes in infants with severe congenital diaphragmatic hernia after fetoscopic endoluminal tracheal occlusion (FETO)

doi:10.21203/rs.3.rs-4978354/v1

Background: Fetoscopic endoluminal tracheal occlusion (FETO) induces lung growth and may improve survival in congenital diaphragmatic hernia (CDH) but the effect on post-natal right (RV) and left (LV) ventricular size and cardiac function is unknown.

Methods: Quantitative measures of heart size and function including tricuspid annular plane systolic excursion Z-score (TAPSEZ), RV fractional area change (RVFAC), RV global longitudinal and free wall strain (RVGLS, RVFWS), RV/LV ratio, LV eccentricity index (LVEI), and LV M-mode diastolic and systolic Z-scores (LVIDDZ, LVIDSZ) were compared between FETO and control patients on first post-natal echocardiogram, prior to and post CDH repair, and on last available echocardiogram using non-parametric Wilcoxon rank-sum test in a single-center, retrospective cohort study. Linear regression models evaluated change over time, adjusting for clustering and interaction of echocardiogram parameters with time.

Results: Thirty-two patients (10 FETO, 22 control) met inclusion criteria. At first echocardiogram, FETO patients demonstrated lower RV/LV ratio and LVEI (p=0.01 for both) indicating less RV dilation and less ventricular septal displacement, respectively. LV hypoplasia was less severe in FETO patients (p=0.01 for both LVIDDZ and LVIDSZ) initially. After repair, FETO patients demonstrated better RV systolic function compared to control patients by FAC (p<0.01), RVGLS (p=0.02), and RVFWS (p=0.05). Over time, FETO patients demonstrated greater improvements in RV/LV ratio and LVEI but smaller increases in LV dimensions compared to control patients. Improvements in RV function were similar between the groups.

Conclusion:FETO patients demonstrate differences in cardiac size and function compared to control patients.

congenital diaphragmatic hernia

echocardiogram

pulmonary hypertension

strain

In congenital diaphragmatic hernia (CDH), herniation of abdominal organs into the thorax impairs normal development of the lung and pulmonary vasculature [1]. The triad of pulmonary hypoplasia, pulmonary hypertension (PH), and cardiac ventricular dysfunction is common. Despite improvement in survival over time, overall mortality remains > 25%, higher in patients with the most severe pulmonary hypoplasia [2]. As fetal lung growth is stimulated by tracheal occlusion, the fetoscopic endoluminal tracheal occlusion (FETO) procedure was developed for patients with moderate to severe CDH [3, 4]. The open-label randomized controlled Tracheal Occlusion to Accelerate Lung Growth (TOTAL) trial demonstrated higher survival to neonatal discharge in FETO patients with severe CDH compared to those of similar CDH severity randomized to standard postnatal care, although the incidence of preterm birth was higher in those in the FETO group [5]. In CDH generally, survival varies by category of cardiac ventricular dysfunction [6], however, the impact of FETO on postnatal right (RV) and left (LV) ventricular dysfunction is not known. Quantitative measures of RV and LV size and function by echocardiogram (echo) predict survival and inform treatment decisions regarding pulmonary vasodilators in other forms of pediatric PH [7, 8]. It is critical to describe ventricular function in CDH patients undergoing FETO in order to understand the effect of the treatment strategy on the heart and develop targeted treatment approaches.

Therefore, the objectives of this study were to compare quantitative echo measures of ventricular size, function, and PH in neonates with CDH who underwent FETO patients and control patients of similar CDH severity.

We performed a single-center, retrospective cohort study at the Children’s Hospital of Philadelphia comparing echo findings in left CDH patients who underwent FETO and control patients eligible for the procedure but whose parents declined between September 1, 2016 and November 1, 2021. FETO was offered to families who met the following inclusion criteria: left CDH, intrathoracic liver, observed/expected lung to head ratio < 30%, mother’s age ≥ 18 years, singleton pregnancy, normal fetal karyotype, and gestational age at enrollment < 30 weeks. Patients were not considered for FETO due to maternal contra-indications to fetoscopic surgery, severe maternal medical conditions in pregnancy, technical limitations precluding fetoscopic surgery, preterm labor, or psychosocial concerns that could affect the procedure or post-procedure care. Survival to CDH surgical repair was required for inclusion in this echo study. Relevant demographic and clinical data were extracted from the medical record. All study procedures were approved by the Children’s Hospital of Philadelphia Institutional Review Board in accordance with the Declaration of Helsinki.

Clinically indicated echocardiograms were performed using standard pediatric views with 3–8 MHz transducers on a Phillips IE33 machine (Phillips, Andover, MA, USA) in accordance with our echocardiography laboratory’s standard imaging protocol that was consistent over the study period and digitally stored in the Syngo Dynamics system (Siemens, USA). LV M-mode internal dimension Z-scores in diastole and systole (LVIDDZ, LVIDSZ) and LV shortening fraction were measured at the time of the study as per standard practice [9]. Available echocardiograms were retrospectively reviewed for additional analyses of ventricular function at four time points: baseline/first post-natal echo, closest echo pre-operative to CDH repair, closest echo post-operative from CDH repair, and last available echocardiogram prior to death or neonatal hospital discharge. Two pediatric cardiac sonographers (YW and DA), blinded to clinical characteristics, obtained offline measures of RV size and RV/LV systolic function that predict adverse outcomes in other forms of pediatric PH. RV and LV global longitudinal strain (RVGLS and LVGLS) and RV free wall strain (RVFWS) measurements of systolic myocardial deformation were obtained using Tomtec software (Image Arena 4.6; Munich, Germany). Strain is reported as a negative number, with greater absolute value indicating better systolic function [10]. Absolute value of the strain measures was used in this study [10]. RV systolic function was also assessed by tricuspid annular plane systolic excursion Z-scores (TAPSEZ) [11, 12] and RV fractional area change (RVFAC) calculated as the end-diastolic area minus the end-systolic area divided by the end-diastolic area [13]. Abnormal ventricular septal position was measured by end-systolic LV eccentricity index (LVEI), the ratio of the LV dimension parallel to the ventricular septum to the LV dimension perpendicular to the ventricular septum in parasternal short axis view [13]. In one report, end systolic LVEI of 1.16 best identified the presence of PH [14]. Two-dimensional systolic RV/LV ratio was also measured in the parasternal short axis view [13]. RV/LV ratio increases above 1 with worsening RV dilation. We have previously published excellent intra- and inter-rater reproducibility for LVEI, RV/LV ratio, RV strain and other continuous echocardiographic measures of RV function [15–19].

Descriptive statistics and echocardiographic parameters were summarized using median (25%, 75%) for continuous measures and frequencies for categorical variables. Echocardiographic variables were compared between the FETO and control groups at baseline, prior to CDH repair, post CDH repair, and at last available using non-parametric Wilcoxon rank-sum test. A linear regression model with robust variance and adjustment for the clustered nature of the data was used to evaluate the difference in the change in echocardiographic variables from baseline to last available between the FETO and control groups. A product term of the dichotomous group (FETO vs. control) and time operationalized as a dichotomous variable (baseline vs. last) was included in the model to evaluate differential change in echocardiographic parameters over time. If the interaction term was not statistically significant at the 0.05 level, the models were recalculated without the interaction term to assess if the echocardiographic parameters changed over time and by group. RV/LV ratio and LVEI were adjusted for left ventricular end-systolic Z-score to account for elevation in parameters due to LV hypoplasia. Results with a p-value less than 0.05 were considered as statistically significant.

Ten FETO patients and 22 control patients met inclusion criteria. Demographic and clinical characteristics are described in Table 1. Fetal observed/expected lung-to-head ratio was lower in FETO patients compared to controls [median (25%, 75%): 21.7 (21.4, 25.6) vs. 24.9 (23.5, 27.7), p = 0.06] as was gestational age at delivery [35.1 (34.5, 36.2) vs. 39.2 (38.8, 39.6), p < 0.001]. Extracorporeal membrane oxygenation (ECMO) utilization and pulmonary hypertension medications at discharge were lower in the FETO group compared to control patients (ECMO: 30% vs. 64%; medications: 0% vs. 27%), although these findings did not reach statistical significance. Overall survival was 90% in the FETO group and 82% in the control group.

Table 1

Demographic and clinical characteristics
Variable	FETO (n = 10)	Control (n = 22)	P-value
Sex			0.265
Female	3 (30%)	12 (55%)
Male	7 (70%)	10 (45%)
Race and ethnicity			0.426
Non-Hispanic White	8 (80%)	11 (50%)
Non-Hispanic Black	0 (0%)	3 (14%)
Multi-Racial/Other	1 (10%)	2 (9%)
Hispanic/Latino	1 (10%)	6 (27%)
Initial ultrasound LHR O/E	21.7 (21.4, 25.6)	24.9 (23.5, 27.7)	0.061
Gestational age at delivery, weeks	35.1 (34.5, 36.2)	39.2 (38.8, 39.6)	< 0.001
ECMO	3 (30%)	14 (64%)	0.128
Pulmonary hypertension medications at discharge	0 (0%)	6 (27%)	0.142
Survival
Alive	9 (90%)	18 (82%)	> 0.999
Deceased in NICU after CDH repair	1 (10%)	1 (4%)
Deceased after NICU discharge	0 (0%)	3 (14%)
FETO, fetal endoscopic tracheal occlusion; LHR, lung-to-head ratio; O/E, observed to expected; ECMO, extracorporeal membrane oxygenation; NICU, neonatal intensive care unit; CDH, congenital diaphragmatic hernia

At first echocardiogram, both groups demonstrated RV systolic dysfunction measured by low TAPSEZ, RVFAC, and RV strain (Table 2). RV/LV ratio and LVEI were lower in FETO patients compared to control patients [RV/LV: 1.10 (1.03, 1.24) vs. 1.57 (1.26, 1.76), p = 0.01 and LVEI 1.50 (1.38, 1.57) vs 1.94 (1.56, 2.31), p = 0.01], reflecting less RV dilation and less ventricular septal displacement, respectively. LV hypoplasia measured by 2-dimensional M-mode Z-scores was less severe in FETO patients compared to control patients [LVIDDZ − 2.12 (-3.07, -1.41) vs. -3.50 (-4.48, -2.72), p = 0.01 and LVIDSZ − 1.55 (-2.56, 0.80) vs. -3.93 (-4.69, -2.67), p = 0.01]. While LV shortening fraction was lower in FETO patients [31.0 (25.0, 36.0) vs. 44.5 (36.0, 48.7), p = 0.02], LV function measured by GLS was similar.

Table 2

Pre-operative echocardiographic parameters in FETO vs. control patients
	Baseline/First echo			Pre-operative
	FETO	Control	p value	FETO	Control	p value
Age at echo, d	1 (0.0, 1.0)	1 (1.0, 1.0)	0.22	16.5 (14.5, 22.8)	14.5 (11.0, 18.8)	0.23
TAPSEZ	-3.5 (-4.7, -2.7)	-2.7 (-4.8, -1.1)	0.45	-1.6 (-2.4, -0.9)	-0.9 (-2.9, 0.3)	0.75
RVFAC	28.0 (20.1, 29.2)	26.2 (22.5, 32.1)	0.83	34.4 (31.7, 42.6)	38.9 (34.2, 43.9)	0.49
RVFWS	16.7 (14.0, 18.2)	14.9 (13.3, 17.1)	0.59	20.9 (18.1, 23.8)	23.5 (17.7, 26.2)	0.91
RVGLS	12.9 (10.9, 15.2)	12.5 (10.5, 16.4)	0.87	17.6 (15.4, 22.0)	18.8 (16.2, 23.1)	0.69
RV/LV	1.10 (1.03, 1.24)	1.57 (1.26, 1.76)	0.01	0.84 (0.79, 1.16)	1.01 (0.81, 1.59)	0.44
LVEI	1.50 (1.38, 1.57)	1.94 (1.56, 2.31)	0.01	1.25 (1.14, 1.57)	1.41 (1.21, 1.66)	0.41
LVIDDZ	-2.12 (-3.07, -1.41)	-3.50 (-4.48, -2.72)	0.01	-1.75 (-2.54, -1.34)	-2.02 (-4.54, -1.55)	0.39
LVIDSZ	-1.55 (-2.56, 0.80)	-3.93 (-4.69, -2.67)	0.01	-1.60 (-2.24, -1.19)	-2.76 (-4.43, -0.88)	0.44
LVSF	31.0 (25.0, 36.0)	44.5 (36.0, 48.7)	0.02	39.0 (36.8, 40.0)	45.0 (34.5, 49.5)	0.26
LVGLS	21.8 (11.2, 22.5)	16.1 (10.8, 20.5)	0.42	21.2 (19.8, 27.2)	20.9 (17.8, 21.9)	0.25
FETO, fetal endoscopic tracheal occlusion; d, days; TAPSEZ, tricuspid annular plane systolic excursion Z-score; RV, right ventricular; FAC, fractional area change; FWS, free wall strain; GLS, global longitudinal strain; LV, left ventricular; EI, eccentricity index; LVIDDZ, left ventricular internal dimension in diastole Z-score; LVIDSZ, left ventricular internal dimension in systole Z-score; SF, shortening fraction

The directionality of the effects noted at baseline were similar in the immediate pre-operative period, but there were no statistically significant differences in RV size or ventricular function between the two groups.

In the post-operative period, FETO patients demonstrated better RV function compared to control patients as measured by RVFAC [44.8 (42.8, 49.4) vs. 36.8 (29.4, 39.9), p < 0.01], RVGLS [24.8 (19.9, 26.6) vs. 19.5 (17.3, 21.2), p = 0.02], and RVFWS [28.5 (22.5, 31.5) vs. 23.3 (18.7, 26.3), p = 0.05] (Table 3). However, at last available echocardiogram there were no longer any differences in RV size or ventricular function between the two groups.

Table 3

Post-operative echocardiographic parameters in FETO vs. control patients
	Post-operative			Last available
	FETO	Control	p value	FETO	Control	p value
Age at echo, d	30.0 (25.5, 41.5)	23.5 (17.5, 27.8)	0.02	122 (85.2, 142)	92.5 (46.0, 252)	0.94
TAPSEZ	-0.7 (-1.9, 0.3)	-1.4 (-3.5, 0.8)	0.51	0.4 (-1.7, 1.1)	0.1 (-1.0, 1.3)	0.67
RVFAC	44.8 (42.8, 49.4)	36.8 (29.4, 39.9)	< 0.01	45.2 (40.5, 51.1)	45.1 (40.0, 48.2)	0.69
RVFWS	28.5 [22.5, 31.5)	23.3 (18.7, 26.3)	0.05	27.8 (24.6, 29.0)	24.2 (21.8, 28.1)	0.47
RVGLS	24.8 (19.9, 26.6)	19.5 (17.3, 21.2)	0.02	25.1 (20.9, 26.8)	22.3 (21.3, 25.7)	0.46
RV/LV	0.69 (0.60, 1.00)	0.93 (0.70, 1.10)	0.18	0.66 (0.57, 0.78)	0.65 (0.58, 1.16)	0.64
LVEI	1.11 (1.08, 1.17)	1.29 (1.11, 1.45)	0.09	1.01 (0.95, 1.04)	1.06 (0.99, 1.22)	0.14
LVIDDZ	-1.05 (-2.75, -0.36)	-1.76 (-3.01, -0.89)	0.46	-1.98 (-2.60, -0.58)	-0.43 (-1.66, 0.31)	0.10
LVIDSZ	-1.61 (-2.44, -0.55)	-1.88 (-3.34, -0.49)	0.60	-1.76 (-2.42, -0.69)	-1.28 (-1.96, 0.24)	0.40
LVSF	39.0 (37.0, 43.0)	41.0 (35.0, 45.0)	0.70	38.0 (36.3, 40.8)	40.0 (34.0, 46.0)	0.80
LVGLS	22.7 (21.6, 24.2)	21.2 (18.9, 23.8)	0.16	20.5 (19.1, 22.3)	21.9 (19.0, 23.2)	0.62
FETO, fetal endoscopic tracheal occlusion; d, days; TAPSEZ, tricuspid annular plane systolic excursion Z-score; RV, right ventricular; FAC, fractional area change; FWS, free wall strain; GLS, global longitudinal strain; LV, left ventricular; EI, eccentricity index; LVIDDZ, left ventricular internal dimension in diastole Z-score; LVIDSZ, left ventricular internal dimension in systole Z-score; SF, shortening fraction

Changes in ventricular size and function from first to last echocardiogram differed between the groups. FETO patients demonstrated smaller increases in LV size measured by LVIDDZ and LVIDSZ compared to control patients (Table 4 and Fig. 1). At last available echocardiogram, the increases in LVIDDZ and LVIDSZ from baseline were on average 2.22 and 2.75 units smaller, respectively, in the FETO patients than the control patients. RV/LV ratio and LVEI (adjusted for LV size) improved over time in both groups, but the improvements were greater in the FETO group on average (Table 4 and Fig. 2). Improvements in RV function by TAPSEZ, RVFAC, RVFWS, and RVGLS were similar between the groups.

Table 4. Regression models measuring change in echocardiographic parameters from baseline to last available in FETO vs. controls. Models in (A) include an interaction term to evaluate the change in the variables over the groups, over time. Models in (B) do not include the interaction term as it was not significant in model (A) for that echocardiographic parameter.

A.

Variable

TAPSEZ

RVFAC

RVFWS

RVGLS

RV/LV^[*]

LVEI

LVIDDZ

LVIDSZ

LVSF

LVGLS

Intercept

-2.8

(-3.9, -1.8)

26.4

(22.8, 29.9)

15.4

(13.2, 17.7)

13.1

(11.0, 15.2)

0.91

(0.70, 1.13)

1.49

(1.30, 1.65)

-3.54

(-4.09, -2.99)

-3.35

(-4.50, -2.20)

41.0

(32.4, 49.6)

15.4

(12.4, 18.5)

Visit: Last

3.1

(1.7, 4.5)

17.6

(13.7, 21.6)

10.1

(7.4, 12.8)

10.2

(7.5, 12.9)

-0.25

(-0.48, -0.01)

-0.48

(-0.66, -0.29)

2.62

(1.93, 3.31)

2.05

(0.67, 3.42)

0.00

(-9.8, 9.8)

5.4

(2.0, 8.8)

Group: FETO

-0.7

(-2.3, 1.0)

0.0

(-8.7, 8.8)

1.1

(-3.8, 6.1)

0.4

(-4.2, 5.0)

0.08

(-0.17, 0.32)

-0.06

(-0.26, 0.14)

1.55

(0.34, 2.77)

2.51

(0.66, 4.37)

-11.6

(-21.8, -1.3)

2.1

(-3.7, 7.8)

FETO/Last Interaction

0.3

(-1.7, 2.4)

1.7

(-7.1, 10.4)

-0.1

(-5.2, 5.1)

0.8

(-4.5, 6.0)

-0.35

(-0.67, -0.04)

-0.11

(-0.35, 0.14)

-2.22

(-3.77, -0.67)

-2.75

(-4.98, -0.51)

9.05

(-2.6, 20.7)

-2.2

(-8.4, 3.9)

B.

Variable

TAPSEZ

RVFAC

RVFWS

RVGLS

RV/LV

LVEI

LVSF

LVGLS

Intercept

-2.9

(-3.8, -2.0)

26.1

(22.7, 29.5)

15.4

(13.4, 17.5)

13.0

(11.1, 14.9)

1.53

(1.29, 1.78)

1.51

(1.37, 1.66)

39.0

(32.3, 45.8)

15.8

(13.0, 18.5)

Visit: Last

3.2

(2.1, 4.3)

18.1

(14.5, 21.8)

10.1

(7.8, 12.4)

10.5

(8.2, 12.8)

-0.64

(-0.90, -0.38)

-0.52

(-0.65, -0.39)

3.3

(-3.6, 10.1)

4.8

(1.9, 7.6)

Group: FETO

-0.5

(-1.7, 0.6)

0.8

(-5.3, 7.0)

1.1

(-2.2, 4.4)

0.8

(-2.1, 3.7)

-0.34

(-0.53, -0.14)

-0.12

(-0.22, -0.02)

-6.6

(-11.1, -2.0)

1.0

(-2.3, 4.4)

FETO, fetal endoscopic tracheal occlusion; TAPSEZ, tricuspid annular plane systolic excursion Z-score; RV, right ventricular; FAC, fractional area change; FWS, free wall strain; GLS, global longitudinal strain; LV, left ventricular; EI, eccentricity index; LVIDDZ, left ventricular internal dimension in diastole Z-score; LVIDSZ, left ventricular internal dimension in systole Z-score; SF, shortening fraction

[*] RV/LV ratio and LVEI were adjusted for adjusted for LVIDSZ

This is the first study to describe quantitative changes in heart size and function in patients with severe CDH who underwent the FETO procedure. In this cohort, those who underwent FETO demonstrated less severe RV dilation, less ventricular septal displacement, and less severe LV hypoplasia on first echocardiogram compared to control patients of similar CDH severity. While RV function improved in both groups over time, improvement in RV dilation and septal position measured by LVEI was greater in FETO patients. However, FETO patients demonstrated smaller increases in LV dimensions from first to last echocardiogram compared to control patients. As these echo measures are predictive of adverse outcomes in other forms of pediatric PH, these preliminary findings support future study of the cardiac consequences of this fetal intervention for severe CDH.

PH and ventricular dysfunction are leading determinants of mortality in CDH. Elevated RV afterload results in RV dysfunction, RV dilation, and RV failure. In children with pulmonary arterial hypertension (distinct from CDH-related PH), quantitative measures of ventricular size and function are critical to risk assessment. For example, the RV/LV ratio encompasses both ventricular septal shift and RV dilation and correlates with invasive measures of PH. For every 0.1 unit increase in RV/LV ratio, there is 10% increased hazard of adverse PAH-related events [20]. In other studies, worse RV function by TAPSE, worse RV dilation measured by RV/LV ratio, and smaller LV dimensions are associated with death or lung transplant [7]. These quantitative measures of RV size and systolic function have now been applied in CDH-related PH. Our group has previously applied these measures and demonstrated improvement in TAPSEZ, RVFAC, and RV strain after recovery from hernia repair in CDH patients of varying severity [21]. In the current study, RV function improved over time in patients with repaired severe CDH, but greater improvements in RV/LV ratio and LVEI were seen in those who underwent FETO compared to those who did not. These preliminary findings support future study to determine whether tracheal occlusion and fetal lung growth result in improved pulmonary vascular development and RV hemodynamics.

The impact of LV hypoplasia and dysfunction on CDH outcomes is now recognized. In a multi-center study using site-specific categorical definitions of ventricular dysfunction, survival was 80% in those with normal biventricular function, 74% in those with predominantly RV dysfunction, 57% in those with predominantly LV dysfunction, and only 51% in those with biventricular dysfunction [6]. LV strain was worse (reflecting worse LV systolic function) at 48 hours of life in CDH patients who experienced the composite outcome of ECMO or death [22]. LVs in CDH patients are also often hypoplastic in addition to dysfunctional. LV volumes are smaller in CDH patients compared to control neonates [23]. LV hypoplasia can result in LV diastolic dysfunction, left atrial hypertension, and pulmonary edema [24, 25], critical when considering pulmonary vasodilator therapy. We recently demonstrated that CDH patients with both left heart hypoplasia and LV dysfunction have the highest risk of mortality [26].

In the current study, patients who underwent FETO demonstrated worse LV function by M-mode shortening fraction on initial echocardiogram compared to severe CDH patients who did not undergo FETO. This difference did not persist as LV function by shortening fraction was similar at all other time points, and quantitative strain assessment was similar at baseline and in serial imaging. However, there were differences in LV size between the two groups. On first echo, patients who underwent FETO had less severe LV hypoplasia as indicated by larger (“less negative”) LV end-diastolic and end-systolic dimension Z-scores. Yet, patients with FETO demonstrated smaller increases in LV dimensions from first to last echocardiogram compared to control patients. In FETO patients, median LV end-diastolic dimension Z-score at last echocardiogram was only − 1.98, reflecting a marked shift in LV size. The reasons for this are not clear in this small study. One possible explanation is that patients were born more prematurely after FETO. Some premature infants with bronchopulmonary dysplasia demonstrate LV diastolic dysfunction [27], which may be a manifestation of hypoplasia. There is mounting evidence for LV chamber hypoplasia in formerly preterm adolescents and young adults, even those without bronchopulmonary dysplasia [28]. The FETO procedure is known to result in higher incidence of preterm premature rupture of membranes and preterm birth. Underdevelopment of the LV with subsequent cardiac compromise are important adverse consequences of the intervention that deserve additional investigation.

This study has important limitations. Primarily, the sample size is small. Therefore, although we identified expected differences in clinical variables between the FETO and control patients, we did not adjust for the variables in the regression analyses. Additionally, the cross-sectional design does not allow us to assess the effect of medical or surgical interventions (i.e. pulmonary vasodilators, ECMO) on cardiac function. It is not clear if the improvement in ventricular function in either group is due to the “natural history” of CDH or due to a specific therapy.

FETO patients demonstrated improved RV dilation and ventricular septal position but smaller increases in LV size compared to control patients of similar CDH severity. The impact of premature birth on these findings is not clear. Larger studies should investigate these echocardiographic changes to further understand the effect of FETO on cardiac development and ventricular function in severe CDH.

Competing interests

The authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article.

Funding

This work was supported by the Doris Duke Charitable Foundation through the COVID-19 Fund to Retain Clinical Scientists collaborative grant program

Author Contribution

C.M.A. and H.L.H. conceived of and designed the study S.F., Y.W., and D.A. acquired data C.M.A. and L.M. performed data analysis and interpretationC.M.A. drafted the manuscriptC.M.A., S.F., L.M., J.G., N.E.R., and H.L.H. critically revised the manuscript

Data Availability

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at Children's Hospital of Philadelphia.

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No competing interests reported.

Echocardiographic changes in infants with severe congenital diaphragmatic hernia after fetoscopic endoluminal tracheal occlusion (FETO)

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