Strong heart, fit brain. Cardiac impact on brain development in fetuses with congenital diaphragmatic hernia: a prospective cohort study

Abstract

Purpose

CDH fetuses may present with abnormal brain volume and cerebral fissures. Since cardiac function and size may also be altered, we hypothesized that abnormal cardiac function may contribute to the impaired brain development in these fetuses. The aim of this study is to evaluate whether cardiac dimensions and function correlate with brain development in CDH fetuses.

Materials and Methods

All fetuses with left CDH who underwent ultrasound evaluation of cardiac function and brain development between 2018 and 2023 were included. We analyzed the correlation between cardiac size and function parameters with the parieto-occipital (POF) and Sylvian (SF) fissures and insular depth (ID) in 2 gestational periods (GP). Cardiac and brain anatomical measures were corrected for head circumference, and cardiac function parameters were corrected for estimated fetal weight or GA. Correlations were analyzed using the Pearson test. A p-value <0.05 was considered significant.

Results

24 fetuses with left CDH were included. Between 20 and 24 weeks of gestation, POF, SF, and ID were significantly correlated with aortic flow. Right ventricle E/A was significantly correlated with POF and SF, with a trend toward a correlation with ID, approaching the threshold of significance. In this GP, the ID was also significantly correlated with the left ventricle area, E/A, and E’, S’ and A’. Most correlations were lost in the next GP.

Conclusion

Between 20 and 24 weeks of gestation, brain development in fetuses with CDH is significantly correlated with cardiac function. Most of these correlations were lost at 25–28 weeks of gestation. Further studies are needed to confirm our results and to evaluate whether these findings have postnatal clinical significance.

Zusammenfassung

Ziel

Feten mit angeborener Zwerchfell-Hernie (CDH; „congenital diaphragmatic hernia“) können ein auffälliges Gehirn-Volumen und zerebrale Fissuren aufweisen. Da auch Herzfunktion und -größe verändert sein können, vermuteten wir, dass eine abnormale Herzfunktion zu einer beeinträchtigten Gehirn-Entwicklung bei diesen Feten beiträgt. Ziel dieser Studie ist es zu untersuchen, ob Herzgröße und -funktion mit der Gehirn-Entwicklung bei CDH-Feten in Zusammenhang stehen.

Material und Methoden

Alle Feten mit linksseitiger CDH, bei denen zwischen 2018 und 2023 eine Sonografie zur Beurteilung der Herzfunktion und der Gehirn-Entwicklung durchgeführt wurde, wurden in die Studie eingeschlossen. Wir analysierten die Korrelation zwischen Herzgröße und -funktionsparametern mit den Messungen des Sulcus parietooccipitalis (POF) und der Fissura Sylvii (SF) sowie der Tiefe der Insula (ID) in 2 Gestationsperioden (GP). Die anatomischen Messungen von Herz und Gehirn wurden um den Kopfumfang, die Parameter der Herzfunktion, um das geschätzte fetale Gewicht oder die Schwangerschaftswoche (SSW) korrigiert. Die Korrelationen wurden mit dem Pearson-Test analysiert. Ein p-Wert < 0,05 wurde als signifikant angesehen.

Ergebnisse

Es wurden 24 Feten mit linksseitiger CDH eingeschlossen. Zwischen der 20. und 24. SSW korrelierten POF, SF und ID signifikant mit dem Aortenfluss. Das E/A-Verhältnis des rechten Ventrikels korrelierte signifikant mit POF und SF, mit einer Tendenz zur Korrelation mit der ID nahe der Signifikanz-Schwelle. In dieser GP korrelierte die ID auch signifikant mit der Fläche des linken Ventrikels, E/A sowie E’, S’ und A’. Die meisten Korrelationen gingen in der nächsten GP verloren.

Schlussfolgerung

Zwischen der 20. und 24. SSW korreliert die Gehirn-Entwicklung bei CDH-Feten signifikant mit der Herzfunktion. Die meisten dieser Korrelationen gingen in der 25. bis 28. SSW verloren. Weitere Studien sind erforderlich, um unsere Ergebnisse zu bestätigen und zu bewerten, ob diese Befunde postnatale klinische Bedeutung haben.

Keywords

cerebral fissures - cardiac function - CDH - congenital diaphragmatic hernia

Publication History

Received: 16 September 2024

Accepted after revision: 21 May 2025

Accepted Manuscript online:
21 May 2025

Article published online:
12 November 2025

• References

• 1 Emam D, Aertsen M, Van der Veeken L. et al. Longitudinal MRI Evaluation of Brain Development in Fetuses with Congenital Diaphragmatic Hernia around the Time of Fetal Endotracheal Occlusion AJNR Am. J Neuroradiol 2023; 44 (02) 205-211
• 2 Machado-Rivas F, Jungwhan JC, Bedoya MA. et al. Brain growth in fetuses with congenital diaphragmatic hernia. J Neuroimaging 2023; 33: 617-624
• 3 Fabietti I, Grassini G, Savelli S. et al. Brain cortical assessment by MRI in fetuses with left congenital diaphragmatic hernia. Prenat Diagn 2023; 43 (08) 1002-1007
• 4 Peyvandi S, Xu D, Barkovich A J. et al. Declining Incidence of Postoperative Neonatal Brain Injury in Congenital Heart Disease. J Am Coll Cardiol 2023; 81 (03) 253-266
• 5 Jaimes C, Rofeberg V, Stopp C. et al. Association of Isolated Congenital Heart Disease with Fetal Brain Maturation. AJNR Am J Neuroradiol 2020; 41 (08) 1525-1531
• 6 Jani J, Nicolaides KH, Keller RL. et al. Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet Gynecol 2007; 30 (01) 67-71
• 7 Massolo AC, Romiti A, Viggiano M. et al. Fetal cardiac dimensions in congenital diaphragmatic hernia: relationship with gestational age and postnatal outcomes. J Perinatol 2021; 41 (07) 1651-1659
• 8 Cruz-Lemini M, Valenzuela-Alcaraz B, Granados-Montiel J. et al. Characterizing cardiac dysfunction in fetuses with left congenital diaphragmatic hernia. Prenatal Diagnosis 2018; 38: 422-427
• 9 Bahlmann F, Wellek S, Reinhardt I. et al. Reference values of fetal aortic flow velocity waveforms and associated intra-observer reliability in normal pregnancies. Ultrasound Obstet Gynecol 2001; 17 (01) 42-49
• 10 Kaya B, Tayyar A, Sezer S. et al. The assessment of cardiac function with tissue Doppler imaging in fetuses with congenital diaphragmatic hernia. J Matern Fetal Neonatal Med 2020; 33 (07) 1233-1238
• 11 Paladini D, Lamberti A, Teodoro A. et al. Tissue Doppler imaging of the fetal heart. Ultrasound Obstet Gynecol 2000; 16 (06) 530-535
• 12 Alonso I, Borenstein M, Grant G. et al. Depth of brain fissures in normal fetuses by prenatal ultrasound between 19 and 30 weeks of gestation. Ultrasound Obstet Gynecol 2010; 36 (06) 693-699
• 13 ISUOG Practice Guidelines (updated): sonographic examination of the fetal central nervous system. Part 2: performance of targeted neurosonography. Ultrasound Obstet Gynecol 2021; 57: 661-671
• 14 Morini F, Valfrè L, Bagolan P. Long-term morbidity of congenital diaphragmatic hernia: A plea for standardization. Semin Pediatr Surg 2017; 26 (05) 301-310
• 15 Siebert J R, Haas J E, Beckwith JB. Left ventricular hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 1984; 19 (05) 567-571
• 16 Patel N, Massolo AC, Kraemer US. et al. The heart in congenital diaphragmatic hernia: Knowns, unknowns, and future priorities. Front Pediatr 2022; 10: 890422
• 17 Patel N, Massolo AC, Kipfmueller F. Congenital diaphragmatic hernia-associated cardiac dysfunction. Semin Perinatol 2020; 44 (01) 151168
• 18 Byrne FA, Keller RL, Meadows J. et al. Severe left diaphragmatic hernia limits size of fetal left heart more than does right diaphragmatic hernia. Ultrasound Obstet Gynecol 2015; 46: 688-694
• 19 Vogel M, McElhinney DB, Marcus E. et al. Significance and outcome of left heart hypoplasia in fetal congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2010; 35: 310-317
• 20 Limperopoulos C, Tworetzky W, McElhinney DB. et al. Brain volume and metabolism in fetuses with congenital heart disease: evaluation with quantitative magnetic resonance imaging and spectroscopy. Circulation 2010; 121 (01) 26-33
• 21 Peng Q, Zhou Q, Zang M. et al. Reduced fetal brain fissures depth in fetuses with congenital heart diseases. Prenat Diagn 2016; 36 (11) 1047-1053
• 22 Rollins C K, Ortinau C M, Stopp C. et al. Regional Brain Growth Trajectories in Fetuses with Congenital Heart Disease. Ann Neurol 2021; 89 (01) 143-157
• 23 Kaltman JR, Di H, Tian Z. et al. Impact of congenital heart disease on cerebrovascular blood flow dynamics in the fetus. Ultrasound Obstet Gynecol 2005; 25 (01) 32-36
• 24 Biouss G, Antounians L, Aguet J. et al. Unveiling fetal brain changes in congenital diaphragmatic hernia: Hypoxic injury with loss of progenitor cells, neurons and oligodendrocytes. Sci Rep 2024; 14 (01) 13680
• 25 Kosiv KA, Moon-Grady A, Hogan W. et al. Fetal cerebrovascular impedance is reduced in left congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2021; 57 (03) 386-391
• 26 Karamanoukian HL, Glick PL, Wilcox DT. et al. Pathophysiology of congenital diaphragmatic hernia. XI: Anatomic and biochemical characterization of the heart in the fetal lamb CDH model. J Pediatr Surg 1995; 30 (07) 925-928
• 27 Lantto J, Erkinaro T, Haapsamo M. et al. Foramen ovale blood flow and cardiac function after main pulmonary artery occlusion in fetal sheep. Exp Physiol 2019; 104 (02) 189-198
• 28 Zadka Y, Rosenthal G, Doron O. et al. Limitation of cerebral blood flow by increased venous outflow resistance in elevated ICP. J Appl Physiol (1985) 2024; 136 (01) 224-232
• 29 Egana-Ugrinovic G, Sanz-Cortes M, Figueras F. et al. Fetal MRI insular cortical morphometry and its association with neurobehavior in late-onset small-for-gestational-age fetuses. Ultrasound Obstet Gynecol 2014; 44 (03) 322-329
• 30 Donofrio MT, Bremer YA, Schieken RM. et al. Autoregulation of cerebral blood flow in fetuses with congenital heart disease: the brain sparing effect. Pediatr Cardiol 2003; 24 (05) 436-443