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

doi:10.21203/rs.3.rs-769199/v1

There is emerging evidence supporting ventricular function as a prognostic factor in congenital diaphragmatic hernia (CDH). The present systematic review and meta-analysis aimed to determine the predictive value of early ventricular function for survival and extracorporeal membrane oxygenation (ECMO) requirement in newborns with CDH. PubMed, Google Scholar, Cochrane Central Register, Clinical Trial Registry, and Opengrey were accessed. Studies evaluating associations between echocardiographic ventricular function measured ≤ 48 h after birth and survival or ECMO requirement were included. Two independent authors extracted the following data: study and participant characteristics, prognostic factors, and outcome-related data. Eleven studies met the inclusion criteria. Five studies reported on survival, two on ECMO, and four on both outcomes. A moderate risk of bias was found in most of the studies, mainly because of selection, prognostic factors, and confounding biases. For survival (899 participants), pooled sensitivity and specificity were 86% (95% confidence interval [CI], 77–92%) and 44% (95% CI, 25–65%), respectively, in normal left ventricular function. For ECMO need (815 participants), pooled sensitivity and specificity were 39.8% (95% CI, 27–52%) and 88% (95% CI, 80–96%), respectively, in left ventricular dysfunction. Overall certainty of the evidence was graded very low for survival and low for ECMO. Inconsistent reporting of echocardiographic measurements and lack of adjustment for confounding factors were major limitations.

Conclusions: Early ventricular dysfunction is a potential prognostic factor in CDH. Standardized echocardiographic measurement reporting and high-quality studies are needed to further elucidate its prognostic significance.

Pediatrics

congenital diaphragmatic hernia

ventricular function

echocardiography

survival

extracorporeal membrane oxygenation

Evidence supports the predictive value of echocardiographic measurements in CDH ≤ 24–48 h post-birth,
Ventricular dysfunction has been proposed as a prognostic risk factor.

What is New:

Right and left ventricular functions were promising predictors of survival and ECMO requirement in neonates with CDH.
Test characteristics of ventricular function were determined as predictors of survival or need for ECMO. Specific echocardiographic markers of ventricular function can be valuable in determining prognosis.

Despite advances in congenital diaphragmatic hernia (CDH) care, the outcomes in severe cases have remained unchanged. CDH-related mortality is high (30%–40%), with 2 to 6-day-old neonates exhibiting the highest mortality [1, 2]. Survival with extracorporeal membrane oxygenation (ECMO) support remains at 50% [3-5].

Numerous antenatal and postnatal prognostic factors are independently associated with postnatal outcomes in CDH; however, the majority are structural or unmodifiable. The Congenital Diaphragmatic Hernia Study Group (CDHSG) staging system based on diaphragmatic defect size and major cardiac anomalies has an intraoperative limitation [6, 7]. Emerging evidence supports the predictive value of echocardiographic measurements in newborns with CDH during the first 24–48 h of life. Guidelines recommend detailed echocardiographic evaluations in newborns with CDH as early as within 24 h post-birth [8-10]. Randomized trials studying interventions targeting ventricular function (VF) are underway [11]. Quantitative assessment of systolic and diastolic cardiac function and shunt assessment are standard targeted neonatal echocardiographic components [12, 13]. Newer imaging techniques have been employed for assessing cardiac function in CDH [14].

Pulmonary hypertension (PH) in CDH is often refractory and poorly responsive to treatment. Inhaled nitric oxide (iNO) has not improved the combined outcome of death and ECMO use in CDH [15-18]. Pulmonary vasodilators in left ventricular dysfunction (LVD) with concomitant left-to-right shunting potentially cause pulmonary venous hypertension and consequently pulmonary hemorrhage [19, 20]. Early ventricular dysfunction (VD), reported in 39% of CDH cases [21], has been proposed as an independent prognostic risk factor [22-24]. Both right ventricular (RV) and left ventricular (LV) function may be compromised in PH, contributing to higher mortality and morbidity in newborns with CDH [25]. A systematic review did not reveal any clear ECMO benefits in a CDH subgroup [26].

Prognostic factors could help in disease severity definition, disease stratification, early therapeutic strategy planning, and future research development. Therefore, we aimed to determine whether the available evidence adequately supports the importance of early VF as a prognostic factor for determining survival and ECMO requirement in CDH without major cardiac anomalies.

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.

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.

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.

AUC: area under ROC curve

BW: birth weight

CDH: congenital diaphragmatic hernia

CDHSG: Congenital Diaphragmatic Hernia Study Group

CI: confidence interval

DOR: diagnostic Odds ratio

ECMO: extracorporeal membrane oxygenation

EF: ejection fraction

FAC: fractional area change

GA: gestational age

GRADE: Grades of Recommendation, Assessment, Development, and Evaluation

iNO: inhaled nitric oxide

LH+- positive likelihood ratio

LR−: negative likelihood ratio

LV: left ventricle

LVD: left ventricular dysfunction

LVOT: LV outflow tract

MD: mean difference

MeSH: Medical Subject Headings

PH: pulmonary hypertension

QUIPS: Quality in Prognosis Studies

RoB: risk of bias

RV: right ventricle

RVD: right ventricular dysfunction

RVOT: RV outflow tract

SROC: summary receiver operating characteristic

TAPSE: tricuspid annular plane systolic excursion

VD: ventricular dysfunction

VF: ventricular function

VTI: velocity time integer

Funding: No funds, grants, or other support was received.

Conflict of interest/Competing interests: The authors have no conflicts of interest to disclose.

Availability of data and material: All data relevant to the study are included in the article or uploaded as supplementary information.

Code availability: STATA statistical software version 13 (College Station, TX, USA: StataCorp LP) and RevMan

Authors' contributions: Conception (Rameshwar Prasad and Bijan Saha), design (Rameshwar Prasad, Bijan Saha, and Amit Kumar), data acquisition (Rameshwar Prasad and Amit Kumar), analysis (Rameshwar Prasad and Amit Kumar), writing initial draft (Rameshwar Prasad and Amit Kumar), critical revision (Rameshwar Prasad, Bijan Saha, Amit Kumar). All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

Ethics approval: Not applicable

Consent to participate: Not applicable

Consent for publication: Not applicable

Acknowledgements: We thank the authors of the studies who responded to our requests and provided access to additional data.

Harting MT, Lally KP (2014) The Congenital Diaphragmatic Hernia Study Group registry update. Semin. Fetal Neonatal Med. 19:370–375
Politis MD, Bermejo-Sánchez E, Canfield MA, Contiero P, Janet D. Cragan, MDe, Dastgiri S, de Walle H, Feldkamp ML, Nance A, Groismanj B et al (2021) Prevalence and mortality in children with congenital diaphragmatic hernia: a multicountry study. Ann Epidemiol 56:61-69.e3. https://doi.org/10.1016/j.annepidem.2020.11.007
Guner YS, Delaplain PT, Zhang L, Di Nardo M, Brogan TV, Chen Y, Cleary JP, Yu PT, Harting MT, Ford HR et al (2019) Trends in Mortality and Risk Characteristics of Congenital Diaphragmatic Hernia Treated With Extracorporeal Membrane Oxygenation. ASAIO J 65:509–515. https://doi.org/10.1097/MAT.0000000000000834
Barbaro RP, Paden ML, Guner YS, Raman L, Ryerson LM, Alexander P, Nasr VG, Bembea MM, Rycus PT, Thiagarajan RR (2017) Pediatric Extracorporeal Life Support Organization Registry International Report 2016. ASAIO J 63:456–463. https://doi.org/10.1097/MAT.0000000000000603
Tingay DG, Kinsella JP (2019) Heart of the matter? Early ventricular dysfunction in congenital diaphragmatic hernia. Am. J. Respir. Crit. Care Med. 200:1462–1464
Lally KP, Lasky RE, Lally PA, Bagolan P, Davis CF, Frenckner BP, Hirschl RM, Langham MR, Buchmiller TL, Usui N, Tibboel D (2013) Standardized reporting for congenital diaphragmatic hernia - An international consensus. In: Journal of Pediatric Surgery. pp 2408–2415
Putnam LR, Harting MT, Tsao K, Morini F, Yoder BA, Luco M, Lally PA, Lally KP (2016) Congenital Diaphragmatic Hernia Defect Size and Infant Morbidity at Discharge. Pediatrics 138:. https://doi.org/10.1542/peds.2016-2043
Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR (2015) Pediatric pulmonary hypertension. : guidelines from the American heart association and American thoracic Society. Circulation 132:2037–2099
Snoek KG, Reiss IK, Greenough A, Capolupo I, Urlesberger B, Wessel L, Storme L, Deprest J, Schaible T, van Heijst A, Tibboel D (2016) Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update. Neonatology 110:66–74. https://doi.org/10.1159/000444210
Puligandla PS, Skarsgard ED, Offringa M, Adatia I, Baird R, Bailey M (2018) Diagnosis and management of congenital diaphragmatic hernia: a clinical practice guideline. CMAJ 190:E103–E112. https://doi.org/10.1503/cmaj.170206
Lakshminrusimha S, Keszler M, Kirpalani H, Van Meurs K, Chess P, Ambalavanan N, Yoder B, Fraga MV, Hedrick H, Lally KP, Nelin L (2017) Milrinone in congenital diaphragmatic hernia – a randomized pilot trial: study protocol, review of literature and survey of current practices. Matern Heal Neonatol Perinatol 3:. https://doi.org/10.1186/s40748-017-0066-9
Mertens L, Seri I, Marek J, Arlettaz R, Barker P, McNamara P, Moon-Grady AJ, Coon PD, Noori S, Simpson J, Lai WW (2011) Targeted neonatal echocardiography in the neonatal intensive care unit: Practice guidelines and recommendations for training. Eur J Echocardiogr 12:715–736. https://doi.org/10.1093/ejechocard/jer181
Singh Y, Tissot C, Fraga MV, Yousef N, Cortes RG, Lopez J, Sanchez-de-Toledo J, Brierley J, Colunga JM, Raffaj D, Da Cruz E (2020) International evidence-based guidelines on Point of Care Ultrasound (POCUS) for critically ill neonates and children issued by the POCUS Working Group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC). Crit Care 24:1–16. https://doi.org/10.1186/s13054-020-2787-9
Jain A, Mohamed A, El-Khuffash A, Connelly KA, Dallaire F, Jankov RP, McNamara PJ, Mertens L (2014) A comprehensive echocardiographic protocol for assessing neonatal right ventricular dimensions and function in the transitional period: Normative data and z scores. J Am Soc Echocardiogr 27:1293–1304. https://doi.org/10.1016/j.echo.2014.08.018
Galletti MF (2020) Risk factors associated with mortality in newborn infants with congenital diaphragmatic hernia. Arch Argent Pediatr 118:180–186. https://doi.org/10.5546/aap.2020.eng.180
Brindle ME, Cook EF, Tibboel D, Lally PA, Lally KP (2014) A clinical prediction rule for the severity of congenital diaphragmatic hernias in newborns. Pediatrics 134:e413–e419. https://doi.org/10.1542/peds.2013-3367
Barrington KJ, Finer N, Pennaforte T, Altit G (2017) Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst. Rev. 2017
Finer NM (1997) Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics 99:838–845. https://doi.org/10.1542/peds.99.6.838
Nair J, Lakshminrusimha S (2014) Update on PPHN: Mechanisms and treatment. Semin. Perinatol. 38:78–91
Sehgal A, Athikarisamy SE, Adamopoulos M (2012) Global myocardial function is compromised in infants with pulmonary hypertension. Acta Paediatr 101:410–413. https://doi.org/10.1111/j.1651-2227.2011.02572.x
Patel N, Lally PA, Kipfmueller F, Massolo AC, Luco M, Van Meurs KP, Lally KP, Harting MT (2019) Ventricular dysfunction is a critical determinant of mortality in congenital diaphragmatic hernia. Am J Respir Crit Care Med 200:1522–1530. https://doi.org/10.1164/rccm.201904-0731OC
Altit G, Bhombal S, Van Meurs K, Tacy TA (2018) Diminished Cardiac Performance and Left Ventricular Dimensions in Neonates with Congenital Diaphragmatic Hernia. Pediatr Cardiol 39:993–1000. https://doi.org/10.1007/s00246-018-1850-7
Aggarwal S, Stockmann P, Klein MD, Natarajan G (2011) Echocardiographic measures of ventricular function and pulmonary artery size: prognostic markers of congenital diaphragmatic hernia? J Perinatol 31:561–566. https://doi.org/10.1038/jp.2011.3
Kinsella JP, Steinhorn RH, Mullen MP, Hopper RK, Keller RL, Ivy DD, Austin ED, Krishnan US, Rosenzweig EB, Fineman JR, Everett AD (2018) The Left Ventricle in Congenital Diaphragmatic Hernia: Implications for the Management of Pulmonary Hypertension. J Pediatr 197:17–22. https://doi.org/10.1016/j.jpeds.2018.02.040
Aggarwal S, Natarajan G (2015) Echocardiographic correlates of persistent pulmonary hypertension of the newborn. Early Hum Dev 91:285–289. https://doi.org/10.1016/j.earlhumdev.2015.02.008
Mugford M, Elbourne D, Field D (2008) Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants. Cochrane Database Syst. Rev.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R (2021) The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 372
Moons KG, de Groot JA, Bouwmeester W, Vergouwe Y, Mallett S, Altman DG, Reitsma JB, Collins GS (2014) Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies: The CHARMS Checklist. PLoS Med 11:e1001744. https://doi.org/10.1371/journal.pmed.1001744
Riley RD, Moons KG, Snell KI, Ensor J, Hooft L, Altman DG, Hayden J, Collins GS, Debray TP.(2019) A guide to systematic review and meta-analysis of prognostic factor studies. BMJ 364
Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C (2013) Assessing bias in studies of prognostic factors. Ann. Intern. Med. 158:280–286
Grooten WJ, Tseli E, Äng BO, Boersma K, Stålnacke BM, Gerdle B, Enthoven P (2019) Elaborating on the assessment of the risk of bias in prognostic studies in pain rehabilitation using QUIPS—aspects of interrater agreement. Diagnostic Progn Res 3:5. https://doi.org/10.1186/s41512-019-0050-0
Altit G, Bhombal S, Van Meurs K, Tacy TA (2017) Ventricular Performance is Associated with Need for Extracorporeal Membrane Oxygenation in Newborns with Congenital Diaphragmatic Hernia. J Pediatr 191:28-34.e1. https://doi.org/10.1016/j.jpeds.2017.08.060
Lawrence KM, Monos S, Adams S, Herkert L, Peranteau WH, Munson DA, Hopper RK, Avitabile CM, Rintoul NE, Hedrick HL (2020) Inhaled Nitric Oxide Is Associated with Improved Oxygenation in a Subpopulation of Infants with Congenital Diaphragmatic Hernia and Pulmonary Hypertension. J Pediatr 219:167–172. https://doi.org/10.1016/j.jpeds.2019.09.052
Yamoto M, Inamura N, Terui K, Nagata K, Kanamori Y, Hayakawa M, Tazuke Y, Yokoi A, Takayasu H, Okuyama H, Fukumoto K (2016) Echocardiographic predictors of poor prognosis in congenital diaphragmatic hernia. J Pediatr Surg 51:1926–1930. https://doi.org/10.1016/j.jpedsurg.2016.09.014
Sehgal A, Tan K, Ferguson P (2018) Cardiac Function Assessments in Left Bochdalek’s Hernia: Clinical Relevance. Pediatr Cardiol 39:829–836. https://doi.org/10.1007/s00246-018-1834-7
Baptista MJ, Rocha G, Clemente F, Azevedo LF, Tibboel D, Leite-Moreira AF, Guimarães H, Areias JC, Correia-Pinto J (2008) N-terminal-pro-B type natriuretic peptide as a useful tool to evaluate pulmonary hypertension and cardiac function in CDH infants. Neonatology 94:22–30. https://doi.org/10.1159/000112641
Karpuz D, Giray D, Celik Y, Hallioglu O (2018) Prognostic markers in congenital diaphragmatic hernia: Left ventricular diameter and pulmonary hypertension. Pediatr Int 60:122–126. https://doi.org/10.1111/ped.13464
Nagiub M, Klein J, Gullquist S (2018) Echocardiography derived pulmonary artery capacitance and right ventricular outflow velocity time integral on first day of life can predict survival in congenital diaphragmatic hernia. Prog Pediatr Cardiol 48:107–110. https://doi.org/10.1016/j.ppedcard.2018.01.001
Aggarwal S, Shanti C, Lelli J, Natarajan G (2019) Prognostic utility of noninvasive estimates of pulmonary vascular compliance in neonates with congenital diaphragmatic hernia. J Pediatr Surg 54:439–444. https://doi.org/10.1016/j.jpedsurg.2018.08.057
Patel N, Massolo AC, Paria A, Stenhouse EJ, Hunter L, Finlay E, Davis CF (2018) Early Postnatal Ventricular Dysfunction Is Associated with Disease Severity in Patients with Congenital Diaphragmatic Hernia. J Pediatr 203:400-407.e1. https://doi.org/10.1016/j.jpeds.2018.07.062
Wehrmann M, Patel SS, Haxel C, Cassidy C, Howley L, Cuneo B, Gien J, Kinsella JP (2020) Implications of Atrial-Level Shunting by Echocardiography in Newborns with Congenital Diaphragmatic Hernia. J Pediatr 219:43–47. https://doi.org/10.1016/j.jpeds.2019.12.037
Dao DT, Patel N, Harting MT, Lally KP, Lally PA, Buchmiller TL (2020) Early Left Ventricular Dysfunction and Severe Pulmonary Hypertension Predict Adverse Outcomes in “Low-Risk” Congenital Diaphragmatic Hernia. Pediatr Crit care Med a J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc 21:637–646. https://doi.org/10.1097/PCC.0000000000002318
Inamura N, Kubota A, Ishii R, Ishii Y, Kawazu Y, Hamamichi Y, Yoneda A, Kawahara H, Okuyama H, Kayatani F (2014) Efficacy of the circulatory management of an antenatally diagnosed congenital diaphragmatic hernia: outcomes of the proposed strategy. Pediatr Surg Int 30:889–894. https://doi.org/10.1007/s00383-014-3574-y
Gaffar S, Ellini AR, Ahmad I, Chen Y, Ashrafi AH (2019) Left ventricular cardiac output is a reliable predictor of extracorporeal life support in neonates with congenital diaphragmatic hernia. J Perinatol 39:648–653. https://doi.org/10.1038/s41372-019-0348-3
Acker SN, Kinsella JP, Abman SH, Gien J (2014) Vasopressin improves hemodynamic status in infants with congenital diaphragmatic hernia. J Pediatr 165:53-58.e1. https://doi.org/10.1016/j.jpeds.2014.03.059
Aggarwal S, Stockman PT, Klein MD, Natarajan G (2011) The right ventricular systolic to diastolic duration ratio: a simple prognostic marker in congenital diaphragmatic hernia? Acta Paediatr 100:1315–1318. https://doi.org/10.1111/j.1651-2227.2011.02302.x
Bialkowski A, Moenkemeyer F, Patel N (2015) Intravenous sildenafil in the management of pulmonary hypertension associated with congenital diaphragmatic hernia. Eur J Pediatr Surg 25:171–176. https://doi.org/10.1055/s-0033-1357757
Salas GL, Otaño JC, Cannizzaro CM, Mazzucchelli MT, Goldsmit GS (2020) Congenital diaphragmatic hernia: postnatal predictors of mortality. Arch Argent Pediatr 118:. https://doi.org/10.5546/aap.2020.eng.173
Gotteiner NL, Harper WR, Gidding SS, Berdusis K, Wiley AM, Reynolds M, Benson Jr DW (1997) Echocardiographic prediction of neonatal ECMO outcome. Pediatr Cardiol 18:270–275. https://doi.org/10.1007/s002469900173
Inamura N, Kubota A, Nakajima T, Kayatani F, Okuyama H, Oue T, Kawahara H (2005) A proposal of new therapeutic strategy for antenatally diagnosed congenital diaphragmatic hernia. J Pediatr Surg 40:1315–1319. https://doi.org/10.1016/j.jpedsurg.2005.05.018
Kipfmueller F, Heindel K, Schroeder L, Berg C, Dewald O, Reutter H (2018) Early postnatal echocardiographic assessment of pulmonary blood flow in newborns with congenital diaphragmatic hernia. J Perinat Med 46:735–743. https://doi.org/10.1515/jpm-2017-0031
Mandell EW, Kinsella JP (2020) Left Ventricular Dysfunction and Persistent Perfusion Abnormalities in Infants with Congenital Diaphragmatic Hernia. J. Pediatr. 219:7–8
Massolo AC, Paria A, Hunter L, Finlay E, Davis CF, Patel N (2019) Ventricular Dysfunction, Interdependence, and Mechanical Dispersion in Newborn Infants with Congenital Diaphragmatic Hernia. Neonatology 116:68–75. https://doi.org/10.1159/000499347
Partridge EA, Hanna BD, Rintoul NE, Herkert L, Flake AW, Adzick NS, Hedrick HL (2015) Brain-type natriuretic peptide levels correlate with pulmonary hypertension and requirement for extracorporeal membrane oxygenation in congenital diaphragmatic hernia. J Pediatr Surg 50:263–266. https://doi.org/10.1016/j.jpedsurg.2014.11.009
Patel N, Moenkemeyer F, Germano S, Cheung MMH (2015) Plasma vascular endothelial growth factor A and placental growth factor: novel biomarkers of pulmonary hypertension in congenital diaphragmatic hernia. Am J Physiol Lung Cell Mol Physiol 308:L378-83. https://doi.org/10.1152/ajplung.00261.2014
Schroeder L, Reutter H, Gembruch U, Berg C, Mueller A, Kipfmueller F (2018) Clinical and echocardiographic risk factors for extubation failure in infants with congenital diaphragmatic hernia. Paediatr Anaesth 28:864–872. https://doi.org/10.1111/pan.13470
Sernich S, Carrasquero N, Lavie CJ, Chambers R, McGettigan M (2006) Noninvasive assessment of the right and left ventricular function in neonates with congenital diaphragmatic hernia with persistent pulmonary hypertension before and after surgical repair. Ochsner J 6:48–53. https://doi.org/10.1136/jim-52-suppl1-834
Suda K, Bigras JL, Bohn D, Hornberger LK, McCrindle BW (2000) Echocardiographic predictors of outcome in newborns with congenital diaphragmatic hernia. Pediatrics 105:1106–1109. https://doi.org/10.1542/peds.105.5.1106
Tanaka T, Inamura N, Ishii R, Kayatani F, Yoneda A, Tazuke Y, Kubota A (2015) The evaluation of diastolic function using the diastolic wall strain (DWS) before and after radical surgery for congenital diaphragmatic hernia. Pediatr Surg Int 31:905–910. https://doi.org/10.1007/s00383-015-3766-0
Kumar VH., Dadiz R, Koumoundouros J, Lakshminrusimha S (2018) Response to Pulmonary Vasodilators in Infants with Congenital Diaphragmatic Hernia. Pediatrics 142:184–184. https://doi.org/10.1542/PEDS.142.1_MEETINGABSTRACT.184
Moenkemeyer F, Patel N (2014) Right ventricular diastolic function measured by tissue Doppler imaging predicts early outcome in congenital diaphragmatic hernia. Pediatr Crit care Med a J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc 15:49–55. https://doi.org/10.1097/PCC.0b013e31829b1e7a
Bebbington M, Victoria T, Danzer E, Moldenhauer J, Khalek N, Johnson M, Hedrick H, Adzick NS (2014) Comparison of ultrasound and magnetic resonance imaging parameters in predicting survival in isolated left-sided congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 43:670–674. https://doi.org/10.1002/uog.13271
Cochius-den Otter SC, Erdem Ö, van Rosmalen J, Schaible T, Peters NC, Cohen-Overbeek TE, Capolupo I, Falk CJ, van Heijst AF, Schäffelder R, Brindle ME (2020) Validation of a Prediction Rule for Mortality in Congenital Diaphragmatic Hernia. 145 (4) e20192379. https://doi.org/10.1542/peds.2019-2379
Jancelewicz T, Brindle ME, Harting MT, et al (2018) Extracorporeal Membrane Oxygenation (ECMO) Risk Stratification in Newborns with Congenital Diaphragmatic Hernia (CDH). J Pediatr Surg 53:1890–1895. https://doi.org/10.1016/j.jpedsurg.2018.04.014

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

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