Ventricular Function in Congenital Diaphragmatic Hernia: A Systematic Review and Meta-Analysis

Materials And Methods

This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline [27] and was registered in PROSPERO (CRD 42021233726).

Inclusion criteria

Observational and interventional studies were retrieved. We included studies and/or subgroups if they reported echocardiographic VF measurements ≤ 48 h of birth (qualitative or quantitative) and postnatal outcomes (survival and/or ECMO).

Participants

We included studies on newborns with CDH (excluding major cardiac malformations affecting both VF and outcomes), regardless of the defect side, fetal intervention, CDH severity, and lung hypoplasia degree.

Prognostic tests

VF at ≤ 48 h post-birth was considered in order to minimize any possible confounding effect of interventions; further, this measurement may aid in stratifying CDH severity early and in guiding further intervention. We extracted prognostic factors as continuous or categorical variables and any reported cutoff points.

Exclusion criteria

We excluded studies without echocardiographic cardiac function assessments or reports of echocardiography timing. We excluded case reports, case series, reviews or articles without full text, unpublished manuscripts, conference abstracts, and studies lacking information regarding relevant prognostic factor-outcome data.

Primary outcomes

The primary outcomes were survival and ECMO requirement. Survival was defined as survival until discharge or as defined in the included study. ECMO requirement was defined as any instance of ECMO need during the hospital stay.

Search strategy

A search for studies published from inception to March 2021 was performed on MEDLINE via PubMed, Google Scholar, The Cochrane Central Register of Controlled Trials (CENTRAL), Clinical Trial Registry, and Opengrey (Supplement Table 1).

Study selection

We selected studies in two phases: (1) title and abstract screening and (2) full-text screening. Two reviewers (R.P. and B.S.) independently screened articles. Disagreements were resolved by discussion or by a third reviewer (A.K.). In the case of overlapping studies, only the largest and most complete dataset was included to avoid cohort double counting.

Data extraction and management

Two authors (R.P. & A.K.) independently extracted and recorded data from included studies using a data extraction sheet, which we previously piloted. Extracted data were compared, and discrepancies were resolved through discussion. If relevant information was missing, we contacted the corresponding author through two e-mails sent 14 days apart.

We extracted data from each study based on Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies modified for prognostic factors (CHARMS-PF) [28, 29]. Data on participant characteristics, test characteristics, methodological variables, and primary and secondary outcomes were extracted.

Risk of bias (RoB) assessment

Two authors (R.P. and B.S.) independently evaluated the RoB in each study. Disagreements were resolved by consensus or a third author’s vote (A.K.). The Quality in Prognosis Studies (QUIPS) tool with relevant modifications for our review was applied [30, 31] (Supplement Table 2A & 2B).

Effect measures

To determine the prognostic significance of VF in predicting outcomes, a summary receiver operating characteristic curve (SROC) and pooled estimates of sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), area under the ROC curve (AUC), and diagnostic odds ratio (DOR), with 95% confidence intervals (CIs) were computed. A random-effects model was used considering the heterogeneity among studies. STATA statistical software version 13 (College Station, TX, USA: StataCorp LP) and RevMan 5.4.1 were used for statistical analyses.

If an association between a prognostic factor and an outcome of interest was presented across three or more studies reporting sufficient data to construct a 2 ´ 2 diagnostic table, the results were statistically combined. If combining data was deemed inappropriate (due to substantial heterogeneity in prognostic factor–outcome combinations), the results were reported qualitatively.

Synthesis methods

We divided the prognostic factors into three broad categories: RV function, LV function, and combined RV and LV function. We then grouped studies according to these prognostic factor categories and primary outcomes.

Heterogeneity assessment

The between-study variance was estimated using both Q statistic and I². If heterogeneity was found, we performed meta-regression.

Results

Search results

We identified 526 records through electronic searches and three records through other sources. We excluded 477 records based on title and abstract screening and 18 duplicates. We assessed 34 full-text articles, of which 15 were possibly eligible for inclusion. In six studies, we contacted the authors for additional information [21, 23, 32-35]; authors of four studies responded [21, 32-34]. Additional relevant data were provided by one author [34]. Finally, 11 studies were included in this review (Table 1) [33, 34, 36-44]. Fig. 1 outlines the study selection.

Excluded studies

We excluded 23 studies [21-24, 32, 35, 45-61]after full text retrieval. Reasons for exclusion are listed in Supplement Table 3.

Characteristics of included studies

Of the 11 studies [33, 34, 36-44], ten had a retrospective design, and one had a prospective cohort design. Among the multicenter studies, one was a registry-based international CDHSG collaboration [42]. Of the included articles, five reported the association of VF with survival, two with ECMO need, and four with both outcomes. Two single-center studies [40,43] had overlapping cohorts with two multicentric studies [34,42]. These were included for qualitative synthesis as they reported various echocardiographic parameters and outcomes. However, they were not included in the meta-analysis. One study involved survival analysis [38], and two studies involved adjusted analysis [34, 42].

Participants’ characteristics

Most studies included CDH cases ≥ 34 gestational age (GA). Mean GA was 38 weeks, and mean birth weight (BW) was 2.8 kg. Comorbidities are summarized in Supplement Table 4. Dao et al. included only low-risk CDH cases (type A and B) [42]. Wehrmann et al. [41] exclusively studied patients with measurable right-to-left or left-to-right atrial shunts. Lawrence et al. limited their analysis to iNO-treated CDH [33].

Prognostic factors

There were significant variations in echocardiographic parameters among studies (Table 2). Two studies reported RV function [38, 39], four reported LV function [33, 34, 37, 43],and five reported both RV and LV function [36, 40-42, 44]. Two studies defined LVD a priori [33, 41]. LVD [34] and RV dysfunction (RVD) [38] were defined based on ROC curve analysis in two studies. One study defined abnormal VF as < 1 standard deviation below the mean derived from control data [40]. One study reported VD as a dichotomous variable (present or absent) based on qualitative and quantitative echocardiographic assessments [42]. This study specified neither echocardiographic parameters nor the systolic or diastolic nature of the dysfunction. Only one study described isolated RVD and LVD separately [40]. Studies mostly reported systolic function.

RoB

The methodological quality was evaluated using QUIPS [30, 31] (Supplement Fig. 1A & 1B). Overall, ten studies had moderate RoB, and one had low RoB. This was commonly due to selection, confounding factors, statistical analysis and reporting, and prognostic factor measurement biases. Only one study had low RoB in all six domains.

Findings

LV function and survival

Nine studies reported the association of VF (any reported VF measurement) with survival [33, 34, 36-42]. Four studies with 899 participants (range, 51–674), including 856 who survived, were pooled. We included only LV function data in the pooled analysis if a study reported both RV and LV function. The pooled sensitivity and specificity of normal LV function for survival prediction were 86% (95% CI, 77%–92%) and 44% (95% CI, 25%–65%), respectively. Summary LR+ and LR- were 1.5 (95% CI, 1.1–2.1) and 0.32 (95% CI, 0.21–0.50), respectively. Pooled analysis-derived AUC and DOR were 75% (95% CI, 71%–78%) and 5 (95% CI, 2–9), respectively (Fig. 2A & 2B and Supplement Table 5).

The proportion of heterogeneity likely due to the threshold effect was 100. To explore other potential heterogeneities, meta-regression was conducted (Supplement Fig. 2). Overall, the test performances did not vary by GA, BW, sex, and liver herniation. Two studies provided data for predicting survival using RV function [38, 42]. Both studies showed a significant survival-related predictive value of normal VF (Supplement Fig. 3).

VF and ECMO requirement

Six studies reported an association between LV function and ECMO requirement [33, 40-44]. Three studies (111 out of 815 participants requiring ECMO) could be pooled for meta-analysis [33, 41, 42]. ECMO use ranged from 9.2%–40% among three studies. The overall sensitivity and specificity of LVD for ECMO requirement prediction were 39.8% (95% CI, 27%–52%) and 88% (95% CI, 80%–96%), respectively. Sensitivity ranged from 35%–62%, and specificity from 71%–93%. Summary LR+ and LR- were 2.9 (95% CI, 1.8–4.1) and 0.68 (95% CI, 0.58–0.78), respectively. Pooled analysis-derived DOR was 5.6 (95% CI, 2.5–8.8) (Fig. 3A & 3B).

In one study [42], RVD was predictive of ECMO need with sensitivity and specificity of 0.45 (95% CI, 0.32%–0.58%) and 0.82 (95% CI, 0.79%–0.85%), respectively (Supplement Fig. 4).

Among studies pooled for meta-analysis, one study [42] included participants with low-risk CDHSG type A and B, and another [33] included only severe CDH cases. Four studies had moderate RoB, and one had low RoB. LVD can be complicated by concomitant RVD.

Results of the remaining seven studies were not pooled because of high heterogeneity in the reported echocardiographic markers and continuous variable-related results or because of overlapping cohorts (Supplement Table 6).

Among the reported echocardiographic parameters, higher RV outflow tract velocity time integer (RVOT VTI) (MD, 3.30; 95% CI, 0.54%–6.06%), RV fractional area change (FAC) (MD, 14.40; 95% CI, 8.69%–20.11%), and tricuspid annular plane systolic excursion (TAPSE) (MD, 0.30; 95% CI, 0.14%–0.46%) were predictive of survival. Low LV outflow tract VTI (LVOT VTI) (MD, -4.15; 95% CI, -6.18% to -2.12%) and LV cardiac index (MD, -0.47; 95% CI, -0.91% to -0.03%) were predictive of ECMO need.

Secondary outcomes

Survival without ECMO vs. death/ECMO

Two studies reported survival without ECMO and death/ECMO [39, 40]. Aggarwal et al. [39] reported associations of lower RV FAC, TAPSE, and RVOT VTI with the combined outcome of death/ECMO, and Patel et al. [40] reported the association of lower LV global longitudinal strain with this outcome.

GRADE assessment

We additionally performed a GRADE assessment of our review. All studies were observational. There were serious concerns due to RoB, inconsistency, and survival-related imprecision. The overall certainty of the evidence was very low. For ECMO requirements, imprecision was not detected, and the certainty of evidence was low.

Discussion

In our review, RV and LV functions were promising ECMO requirement predictors. LV function had fair discriminative power (AUC, 0.76) in predicting mortality. Normal LV function fairly accurately discriminates CDH with better outcomes. In most cases, associations between specific echocardiographic parameters and outcomes were only reported by one study each.

The included studies were limited by the selection, prognostic factor measurement, and confounding biases. In our review, the majority of the population had low-risk CDH, was late preterm or term, and had normal BW. Further, we were able to perform a pooled analysis of only LV function data in this group. We also observed statistical heterogeneity among studies, likely due to different cutoff values.

To our knowledge, there have not been similar systematic reviews evaluating the predictive accuracy of prognostic factors in CDH. The most commonly used validated CDH prognostic predictors, lung head ratio, and observed/expected LHR, have fair discriminatory power (AUC, 0.70) for predicting survival to discharge [62]. Among prediction models, the AUC of the CDHSG prediction rule and modified CDHSG prediction rule for mortality was 79.0% and 84.6%, respectively [63]. The C-statistic of the validated pre-ECMO risk model was 82.4% for ECMO use in newborns with CDH [64]. These results are difficult to compare with our meta-analysis results.

Strengths

This systematic review condenses existing knowledge on the prognostic utility of VF in CDH. It included a comprehensive search strategy and rigorous study selection and quality assessment in line with the most recent guidelines; further, it was conducted according to registered protocol and provides the most up-to-date results. No language or time restrictions were applied. We attempted to contact authors, and additional data were obtained. We performed diagnostic test accuracy analysis, thereby obtaining a better overview of test performance.

Limitations

This review highlights major lacunae in current knowledge of the predictive value of early VF in CDH. Lack of standardized CDH severity reporting in many studies was a major limitation. VD definition criteria varied across studies. Studies were limited by lack of standardization and inconsistencies in echocardiographic measurement reporting and adjusting for important confounding variables. LVD can be complicated by concomitant RVD and vice versa. We did not include unpublished studies in our review. The small number of studies and high heterogeneity in reported prognostic factor-outcome data limited our ability to evaluate test performance according to study design, participant characteristics, prognostic factor characteristics, and different interventions. We could not examine publication bias and perform sensitivity analyses as well.

Implication for further research

To determine the prognostic accuracy of VF in CDH more precisely, there is a need for prospective cohort studies with adequate sample sizes, predefined cutoff values, investigator blinding, and high quality. Our findings also highlight the need for echocardiographic assessment protocol standardization, reporting consistency, and VF assessment tool validation in CDH.

To further demonstrate VF prognostic value, all these data must be available at the individual level, and studies should control for potential confounders. Randomized clinical trials investigating VF-targeted interventions are needed. Data presentation should facilitate the investigation of all possible cutoff values, and all measurement time points should be available. Isolated RVD and LVD should also be reported. The presence of major cardiac anomalies itself can affect outcomes through treatment withholding or ECMO contraindication.

Implications for practice

The main advantage of ventricular function assessment over other prognostic factors in CDH is its modifiable nature. Previous reports suggest that relationship between ventricular function and PH in CDH is not linear. Many echocardiographic parameters have been used for the assessment of VF in newborns with CDH. This systematic review suggests that survival and need for ECMO can be predicted by early ventricular function assessment. Both right and left ventricular function needs to be assessed. Echocardiographic measurements of cardiac output, TAPSE, RV FAC and strain pattern may be valuable in identifying CDH cases with poor outcome.

In conclusion, our systematic review suggests that VF within 48 h of life in newborns with CDH has the potential to be a prognostic marker for ECMO requirement and survival. Additional information from echocardiographic VF measurements should be utilized for clinically managing CDH until more high-quality evidence is available.

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Tables

Table 1. Characteristics of included studies

Study ID/year	Center & Country	Study design	Sample size	Out-born /inborn	Inclusion criteria	Exclusion criteria
A. Survival
Baptista,[36] 2008	Single, Portugal	Prospective cohort	18	-	Left-sided CDH	CHD
Yamoto,[34] 2016	Multi, Japan (9 centers)	Retrospective cohort^a	84	-	Isolated left-sided CDH	Severe CHD/ chromosomal aberrations, incomplete ECHO
Karpuz,[37] 2018	Single, Turkey	Retrospective cohort	35	-	Isolated left-sided CDH	GA < 36 weeks, severe IUGR, severe CHD/congenital malformations, incomplete ECHO
Nagiub,[38] 2018	Single, USA	Retrospective cohort	20	-	CDH patients admitted to NICU	genetic syndrome, hereditary upper/lower airways malformation, pulmonary vein stenosis, aorto-pulmonary collaterals, CHD (except PDA/PFO/ASD), incomplete ECHO, meconium aspiration, perinatal hypoxia, hypothermia, hypercarbia, sepsis, high frequency ventilated neonates
Aggarwal,[39] 2019	Single, USA	Retrospective cohort	47	-	CDH neonates admitted to NICU	CDH (except PDA/PFO) Inadequate ECHO (Inadequate TRV jet/ PV Doppler)

Study ID	Center & Country	Study design	Sample size	Out-born /Inborn	Inclusion criteria	Exclusion criteria
B. Survival + extracorporeal membrane oxygenation
Patel,[40] 2018	Single, UK	Retrospective cohort	25	Out-born + inborn	Patients with CDH	Severe CDH (except VSD), major chromosomal anomalies
Lawrence,[33] 2020	Single, USA	Retrospective cohort	Recruited = 95, Eligible= 90	Inborn	Patients with CDH treated with iNO	Out-born palliative delivery, cyanotic CHD, GA ≤ 34 weeks, iNO initiation at ≥ 7 DOL
Wehrmann,[41] 2020	Single, USA	Retrospective cohort	51	-	Patients with CDH with left-to-right or right-to-left atrial-level shunting	Severe CDH (except ASD/small muscular VSD), GA < 34 weeks, chromosomal abnormality, bidirectional atrial-level shunting/intact atrial septum, ECMO at first ECHO,
Dao,[42] 2020	Multi	Retrospective cohort	LV function (n = 674), RV function (n = 667)	384^b (50.7%) n = 758	Patients in the CDHSG registry, only defect size A and B included.^c	chromosomal anomalies Severe CHD (cyanotic congenital heart defects, hypoplastic left heart syndrome, coarctation of the aorta, double outlet right ventricle)
C. Extracorporeal membrane oxygenation
Inamura,[43] 2014	Single, Japan	Retrospective cohort	Recruited = 61, Eligible = 4	Inborn	Antenatally diagnosed CDH	Complex CHD/ chromosomal aberrations
Gaffar,[44] 2019	Single, USA	Retrospective cohort	27	22^b (81%)	All newborns with CDH	CHD (except PDA/PFO/ASD) GA < 35 weeks, weight < 1.8 kg, severe cerebral hemorrhage

CDH, congenital diaphragmatic hernia; Multi, multicenter; CHD, congenital heart disease; CDHSG, CDH study group; GA, gestational age; IUGR, intrauterine growth retardation; NICU, newborn intensive care unit; PDA, patent ductus arteriosus; PFO, patent foramen ovale; ASD, atrial septal defect; VSD, ventricular septal defect; TRV, tricuspid valve regurgitation velocity; PV, pulmonary valve; iNO, inhaled nitric oxide; ECHO, echocardiogram; ECMO, extracorporeal membrane oxygenation; USA, United States of America; UK, United Kingdom

^aquestionnaire survey.

^binborn percentage.

^cCDHSG defect type.

Table 2. Echocardiographic parameters and reported outcomes

Study ID/ year	Index test^a		Measurement/ definition	Investigator blinded to outcome
Study ID/ year	RV function	LV function	Measurement/ definition	Investigator blinded to outcome
A. Survival
Baptista,[36] 2008	RV Tei index, Tricuspid E/A ratio	LV Tei index, Mitral E/A ratio	Mean (SD)	NS

Yamoto,[34] 2016	NS	EF (M mode), FS^g(M mode)	Mean (SD) EF < 45% (ROC)^b, FS < 23% (ROC)^b	NS
Kapruz,[37] 2018	NS	LV EF (Simpson), FS (M mode)	Mean (SD)	NS
Nagiub,[38] 2018	RVOT VTI, RV Tei index, SD/DD ratio	NS	Mean (SD) RVOT VTI ≤ 10.5 ml (ROC)^b	Yes

Aggarwal,[39] 2019	RV FAC, TAPSE,RVOT VTI	NS	Median (IQR)	Yes
B. Survival + extracorporeal membrane oxygenation
Patel,[40] 2018	RV GLS	LV- GLS	Mean (SD) cut off for RV and LV GLS (1 SD < mean from control)	NS
Lawrence,[33] 2020 and	NS	LV FS	LV FS < 28%	NS
Wehrmann,[41] 2020	NS	EF	LV EF < 55%	NS
Study ID/ year	Index test^a		Measurement/ definition	Investigator blinded to outcome
Study ID/ year	RV function	LV function	Measurement/ definition	Investigator blinded to outcome
Dao,[42] 2020	RV dysfunction	LV dysfunction	NS	NS
C. Extracorporeal membrane oxygenation
Inamura,[43] 2014	NS	LV EF (M mode), LV Tei index	Mean (SD)	NS
Gaffar,[44] 2019	RVOT VTI, RV cardiac index	LV cardiac output, LV cardiac index, LVOT VTI, LV EF (Simpson), mitral E/A	Median (IQR)	Yes

RV, right ventricle; LV, left ventricle; ECMO, extracorporeal membrane oxygenation; SD, standard deviation; NS, not specified; EF, ejection fraction; FS, fractional shortening; RVOT VTI, right ventricular outflow tract velocity time integral; SD/DD, systolic duration to diastolic duration; GLS, global longitudinal strain; FAC, fractional area change; IQR, interquartile range; TAPSE, tricuspid annular plane systolic excursion; LVOT VIT, left ventricular outflow tract velocity time integral

^aechocardiographic parameters for ventricular function and reported outcome in the study.

^b measurement/definition of abnormal function reported by author.

^creceiver operating characteristic curve derived cutoff value.

Ventricular Function in Congenital Diaphragmatic Hernia: A Systematic Review and Meta-Analysis

Abstract

What is Known

Introduction