Background
Congenital heart disease is associated with an increased risk of smaller brain volumes and structural brain damage, and impaired growth of supratentorial brain structures in utero has been linked to poor neurodevelopmental outcomes. However, little is known on brainstem and cerebellar volumes in fetuses with congenital heart disease. Moreover, it is not clear whether impaired infratentorial growth, if present, is associated with only certain types of fetal cardiac defects or with supratentorial brain growth, and whether altered biometry is already present before the third trimester.
Objective
This study aimed to investigate brainstem and cerebellar volumes in fetuses with congenital heart disease and to compare them to infratentorial brain volumes in fetuses with normal hearts. Secondarily, the study aimed to identify associations between infratentorial brain biometry and the type of cardiac defects, supratentorial brain volumes, and gestational age.
Study Design
In this retrospective case-control study, 141 magnetic resonance imaging studies of 135 fetuses with congenital heart disease and 141 magnetic resonance imaging studies of 125 controls with normal hearts at 20 to 37 gestational weeks (median, 25 weeks) were evaluated. All cases and controls had normal birthweight and no evidence of structural brain disease or genetic syndrome. Six types of congenital heart disease were included: tetralogy of Fallot (n=32); double-outlet right ventricle (n=22); transposition of the great arteries (n=27); aortic obstruction (n=24); hypoplastic left heart syndrome (n=22); and hypoplastic right heart syndrome (n=14). First, brainstem and cerebellar volumes of each fetus were segmented and compared between cases and controls. In addition, transverse cerebellar diameters, vermian areas, and supratentorial brain and cerebrospinal fluid volumes were quantified and differences assessed between cases and controls. Volumetric differences were further analyzed according to types of cardiac defects and supratentorial brain volumes. Finally, volume ratios were created for each brain structure ([volume in fetus with congenital heart disease/respective volume in control fetus] × 100) and correlated to gestational age.
Results
Brainstem (cases, 2.1 cm 3 vs controls, 2.4 cm 3 ; P <.001) and cerebellar (cases, 3.2 cm 3 vs controls, 3.4 cm 3 ; P <.001) volumes were smaller in fetuses with congenital heart disease than in controls, whereas transverse cerebellar diameters ( P =.681) and vermian areas ( P =.947) did not differ between groups. Brainstem and cerebellar volumes differed between types of cardiac defects. Overall, the volume ratio of cases to controls was 80.8% for the brainstem, 90.5% for the cerebellum, and 90.1% for the supratentorial brain. Fetuses with tetralogy of Fallot and transposition of the great arteries were most severely affected by total brain volume reduction. Gestational age had no effect on volume ratios.
Conclusion
The volume of the infratentorial brain, which contains structures considered crucial to brain function, is significantly smaller in fetuses with congenital heart disease than in controls from midgestation onward. These findings suggest that impaired growth of both supra- and infratentorial brain structures in fetuses with congenital heart disease occurs in the second trimester. Further research is needed to elucidate associations between fetal brain volumes and neurodevelopmental outcomes in congenital heart disease.
Introduction
Fetuses with congenital heart disease (CHD) often show altered brain development, and children with CHD are at risk of impaired neurocognitive outcomes. , Structural brain anomalies are present on magnetic resonance imaging (MRI) in up to 25% of fetuses with CHD, , and some of these CHDs have been associated with decreased brain volume, abnormal cortical folding, and abnormal brain metabolism in the third trimester. , Although even subtle brain structures, such as the hippocampi, have been increasingly well studied, the potential impact of CHD on infratentorial brain development has been less commonly evaluated. Cerebellar volumes in cases of fetal CHD were reported to be smaller or unchanged, and few studies assessed brainstem development in these fetuses. , , Moreover, most previous studies focused on third-trimester fetuses with hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), or tetralogy of Fallot (TOF), whereas others grouped mixed types of CHD according to hemodynamics or uni- vs biventricular physiology.
Why was this study conducted?
Fetal congenital heart disease (CHD) has been linked to smaller supratentorial brain volumes and neurodevelopmental delay; however, little is known about the growth of infratentorial brain structures in fetal CHD.
Key findings
Infratentorial brain volumetry in fetal CHD revealed a significant reduction of brainstem (−19.2%) and cerebellar (−9.5%) volumes at fetal magnetic resonance imaging. Among 6 types of CHD, fetuses with tetralogy of Fallot and transposition of the great arteries were most severely affected by total brain volume reductions. Fetal age from 20 to 37 week’s gestation had no influence on infratentorial volume ratios compared with normal controls.
What does this add to what is known?
Smaller volumes of infratentorial brain structures from 20 weeks of gestation onward suggest that, in the presence of fetal CHD, mechanisms affecting brain growth may originate from early to mid-gestation, and not only from the third trimester.
Infratentorial structures are crucial in brain function and neurodevelopment, , which may be altered in children with CHD. , The brainstem is a crossway for motor and sensory systems, whereas the cerebellum plays a critical role in motor control, memory, attention, and language. In adolescents and young adults with CHD, significant correlations between posterior cerebellar volumes and poorer executive function were identified. In Fontan circulation, cerebellar volumes showed strong associations with neurocognition, reinforcing the cerebellar role in neurocognitive processes.
To date, no study has focused on infratentorial volumetry in fetuses with different types of CHD and at an early gestational age. The aims of this study were to define brainstem and cerebellar volumes on MRI in fetuses with CHD, and to investigate associations with different types of CHD, supratentorial brain volumetry, and gestational age. We hypothesized that: (1) brainstem and cerebellar volumes in fetuses with CHD would be smaller than those in an age- and sex-matched control group without CHD; (2) volumetric measures of the brainstem, cerebellum, supratentorial brain, and cerebrospinal fluid (CSF) spaces would differ between types of CHD; and (3) relative differences in brainstem and cerebellar volumes between fetuses with CHD and controls would increase with advancing gestation.
Materials and Methods
Subjects
In this retrospective single-center study, approved by the local institutional review board (ethics committee number, 1148/2020), fetal MRI examinations performed between 2007 and 2020 at the Department of Biomedical Imaging and Image-guided Therapy and the Division of Obstetrics and Feto-Maternal Medicine of the Medical University of Vienna were evaluated. Potential subjects without structural brain anomalies, as assessed by ultrasound and MRI, were identified retrospectively in the hospitaĺs database.
We investigated 6 specific types of CHD with a potential impact on brain growth and commonly detected on fetal echocardiography at our center: TOF; double-outlet right ventricle (DORV; including DORV/TGA-type, DORV/Fallot-type, and complex DORV); TGA; aortic obstruction (AoOb; including aortic coarctation and hypoplasia); HLHS; and hypoplastic right-heart syndrome (HRHS, including tricuspid and pulmonary atresia with hypoplastic right ventricle). All consecutive fetuses with the ultrasound diagnosis (and postnatal confirmation) of 1 of these 6 types of CHD who had prenatally undergone fetal MRI (at least of the fetal brain) were eligible for the analysis. Postnatal confirmation of the specific CHD diagnosis on echocardiography, cardiac surgery, or autopsy were inclusion criteria, but cardiac surgery for live births was not. Of the 135 fetuses included in the analysis, 5 with aortic coarctation (and 6 fetal MRIs) had postnatal confirmation of the CHD, but did not require surgery. All other live births with CHD underwent postnatal surgical correction or palliation. Eleven cases of fetuses with TOF, previously published by our group, were also included. The fetuses had no extracardiac or structural brain anomalies, and normal birthweight.
Maternal exclusion criteria were pregnancies with maternal infections or chronic disease, preexisting or gestational diabetes mellitus, and preexisting or gestational hypertension or preeclampsia. Fetal/neonatal exclusion criteria comprised multiple pregnancies, fetal growth restriction below the 5th percentile, or macrosomia above the 95th percentile at the time of fetal MRI, the presence of brain anomalies on ultrasound or fetal MRI, absence of fetal and neonatal cardiac evaluation, known genetic anomalies, clinical suspicion of syndromic disease postnatally, extracardiac anomalies (only for the CHD group), and birthweight below the fifth percentile (for both groups). Cardiac and extracardiac diagnoses were based on a combination of pre- and postnatal assessment, and gestational age was determined by biometry at first-trimester ultrasound screening.
The control group was selected retrospectively from fetuses who underwent detailed ultrasound and MRI evaluation primarily for body malformations or premature rupture of membranes, without known associations with abnormal brain development, normal fetal echocardiography, and absence of cardiac dysfunction (also in fetuses with abnormal cardiac positioning caused by chest masses like diaphragmatic hernia or congenital pulmonary airway malformation) according to the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guidelines. Fetuses for the control group were age- and sex-matched to the respective gestational age of the CHD fetuses at MRI, allowing a maximum of 2 days’ age difference between cases and controls. Matching according to fetal sex was performed whenever possible.
Fetal magnetic resonance imaging
All fetal MRI examinations were clinically indicated and referred after standard neurosonography (screening examination; all fetuses) or targeted, multiplanar fetal neurosonography (on indication). All mothers gave written informed consent for the fetal MRI and agreed to the scientific use of their imaging data. Fetal MRI examinations were performed using an Ingenia 1.5T scanner (Koninklijke Philips N.V., Amsterdam, Netherlands) or an Achieva 3T scanner (Koninklijke Philips N.V.) in accordance with the ISUOG practice guidelines. A body coil was used and T2-weighted turbo spin-echo sequences (in-plane resolution, 0.62/0.62–1.17/1.17 mm; slice thickness, 2.0–4.5 mm; matrix size, 256 × 256; field of view, 200–230 mm; relaxation time, ≤20,000 ms; echo time, 100–140 ms) were acquired in the 3 orthogonal planes. MRI images were reviewed by an experienced neuroradiologist for the absence of structural brain anomalies before the image export. Technical exclusion criteria were marked motion artifacts with poor image quality, oblique image planes, and irretrievable MRI images.
Biometric and volumetric measurements
All segmentations and measurements were performed by 1 trained observer (G.H.), blinded to cardiac diagnoses, using the open-source software ITK-SNAP version 3.8.0 (University of Pennsylvania, Pennsylvania, PA). Individual brain regions were segmented, including the brainstem, cerebellum, supratentorial brain, ventricles, and supra- and infratentorial extraaxial CSF spaces, and their volume was used for further calculations ( Figure 1 ). The total brain volume included all parenchymal brain regions. Total intracranial volume was calculated as the sum of all 5 compartments. Furthermore, the area of the cerebellar vermis (on the midsagittal plane) and the transverse cerebellar diameter (TCD) (on the coronal plane) were measured ( Figure 2 ).
To establish biometric and volumetric reproducibility and reliability of the measurements, 14 randomly selected cases were assessed independently by 2 trained examiners (G.H., T.Z.) blinded to gestational age and the fetal diagnosis.
Statistical analysis
SPSS Statistics for Windows (version 26; IBM Corp, Armonk, NY) was used for statistical analyses, with a significance threshold set at P ≤.05. Descriptive statistics were reported as absolute frequencies and percentages for qualitative variables and as median values and interquartile ranges (IQR) for quantitative data. Medians and IQRs were chosen because data were not normally distributed ( Supplementary Document 1 ). An intraclass correlation coefficient (ICC) between the 2 observers was calculated to determine interrater variability. An ICC above 0.75 was considered an excellent agreement. Volume ratios (VR) were determined by dividing the absolute volumetric data of cases by their age- and sex-matched controls, and expressed as percentages for each assessed brain compartment. Crosstabs and chi square tests were used to compare independent samples with regard to nominal data. The Wilcoxon matched-pairs signed-ranks test was used to assess differences in volumetric and biometric ratios between cases and controls. We also used Mann–Whitney U tests to compare 2 independent sample groups or Kruskal–Wallis tests for more than 2 independent groups. Correlation coefficients according to Spearman rank correlation were calculated to assess any effects of gestational age on brain VR between cases and controls.
Results
Study population
Initially, we found 268 fetuses in our database who had 1 of the 6 predefined types of CHD and were referred for fetal MRI, of whom 145 were enrolled ( Figure 3 ). We excluded 9 fetuses (6.2%) because the T2-weighted sequence was irretrievable or oblique, and 1 fetus (0.7%) was excluded because of marked motion artifacts. After accounting for MRI exclusion criteria, 135 fetuses with CHD were included and contributed a total of 141 MRI studies to the analysis. The CHD group comprised TOF (n=32; 16/32 [50%] male), DORV (n=22; 14/22 [64%] male), TGA (n=27; 17/27 [63%] male), AoOb (n=24; 12/24 [50%] male), HLHS (n=22; 15/22 [68%] male), and HRHS (n=14; 5/14 [36%] male). In the control group ( Supplementary Table 1 ), 125 fetuses with a total of 141 age- and sex-matched MRI studies were included.
All 135 fetuses with CHD and 125 controls underwent fetal MRI, with a median age of 25+0 gestational weeks (GW; range, 20+2 to 37+0 weeks). Demographic data are given in Table 1 and available fetal outcome data are presented in Supplementary Document 2 . The groups were similar with respect to maternal characteristics and cesarean delivery rates. The CHD group was more likely to have undergone prenatal genetic testing than the control group. Subjects with low birthweight were excluded, and there were no differences in absolute birthweight and neonatal head circumference. Head circumference percentiles were lower among neonates with CHD than among controls.
| Characteristics | CHD (n=135) | Control (n=125) | P value a |
|---|---|---|---|
| Maternal parameters | |||
| Maternal age | 30.7±5.4 | 31.3±6.1 | .379 |
| Maternal smoking, n (%) | 13 (9.6) | 20 (16.0) | .123 |
| Maternal BMI in kg/m 2 | 25.3±4.5 | 25.3±5.3 | .929 |
| Primiparity, n (%) | 68 (50.4) | 68 (54.4) | .516 |
| Fetal parameters | |||
| Fetal male sex, n (%) | 76 (56.3) | 68 (54.4) | .759 |
| GA at MRI in wk | 25/0 (22/5–29/6) | 25/0 (22/6–29/5) | .428 |
| Prenatal genetic testing, n (%) b | 79 (58.5) | 39 (31.2) | <.001 |
| TOP/IUFD, n (%) | 10 (7.4) | — | — |
| Lost to follow-up, n (%) | 3 (2.2) | — | — |
| Perinatal parameters of live births | n=122 | n=125 | |
| GA at birth in wk | 38.6 (38.1–39.9) | 38.3 (36.7–39.3) | .428 |
| Cesarean delivery, n (%) | 55 (45.1) | 65 (52.0) | .277 |
| Birthweight in g | 3197 (2908–3494) | 3190 (2850–3550) | .986 |
| Birthweight percentile | 34.0 (16.0–63.3) | 44.0 (30.0–69.0) | .061 |
| Neonatal head circumference in cm | 34.0 (33.0–35.0) | 34.5 (34.0–35.0) | .121 |
| Head circumference percentile | 29.0 (12.0–60.0) | 50.0 (30.0–67.0) | .012 |
| Neonatal acidosis, n (%) c | 1 (0.8) | 1 (0.8) | .986 |
| APGAR score <7 at 5 min, n (%) | 2 (1.6) | — | — |
a Student t -test was used for independent samples
b Including noninvasive prenatal testing (n=6 in CHD group and n=7 in control group)
Supratentorial brain, cerebrospinal fluid, total brain, and total intracranial volume
The CHD group had significantly smaller supratentorial brain, total brain, and total intracranial volumes compared with the control group ( P <.001) ( Table 2 ), whereas CSF volumes were similar between groups. When comparing the different types of CHD to their matched controls, both supratentorial brain and total brain volumes were smaller in fetuses with TOF, DORV, TGA, HLHS, and HRHS, and similar between controls and fetuses with AoOb. CSF volume was larger in fetuses with TGA and smaller in those with HRHS, but similar between controls and fetuses with all other types of CHD. Total intracranial volume was smaller in fetuses with TOF and HRHS and did not differ between fetuses with any other type of CHD and the respective controls.
| Gestational age at MRI | Supratentorial brain volume (cm 3 ) | CSF volume (cm 3 ) | Total brain volume (cm 3 ) | Total intracranial volume (cm 3 ) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Mean (SD) | Median (IQR) | Mean (SD) | Median (IQR) | Mean (SD) | Median (IQR) | Mean (SD) | Median (IQR) | Mean (SD) | Median (IQR) | |
| Tetralogy of Fallot (n=32) | ||||||||||
| Cases | 25.6 (3.6) | 24+6 (22+4–26+6) | 81.0 (44.3) | 67.0 (46.1–90.7) | 55.2 (23.5) | 51.1 (36.7–64.8) | 86.4 (47.4) | 70.4 (49.4–96.8) | 141.6 (69.8) | 121.7 (85.1–154.6) |
| Controls | 25.6 (3.6) | 24+5 (22+5–27+0) | 94.4 (54.0) | 77.9 (55.6–101.0) | 57.3 (30.4) | 47.3 (35.6–64.6) | 101.8 (58.5) | 84.3 (58.9–107.5) | 159.1 (87.7) | 136.4 (95.3–168.0) |
| P value | .894 | <.001 a | .793 | <.001 a | .004 a | |||||
| Double outlet right ventricle (n=22) | ||||||||||
| Cases | 27.9 (4.5) | 28+3 (23+1–31+2) | 114.5 (62.5) | 115.8 (48.6–147.6) | 79.3 (38.2) | 82.2 (36.8–110.2) | 123.0 (67.5) | 123.9 (52.1–157.8) | 202.3 (100.4) | 214.2 (88.6–273.9) |
| Controls | 27.9 (4.6) | 28+4 (23+1–31+1) | 123.2 (61.8) | 120.0 (55.2–172.7) | 73.3 (35.8) | 7v4.5 (35.4–93.2) | 132.6 (67.1) | 129.2 (59.3–186.9) | 205.9 (99.0) | 213.8 (93.9–270.8) |
| P value | .731 | .012 a | .178 | .011 a | .506 | |||||
| Transposition of the great arteries (n=27) | ||||||||||
| Cases | 25.6 (3.6) | 24+1 (22+5–28+0) | 85.1 (46.1) | 68.9 (49.8–129.6) | 62.3 (26.8) | 53.2 (38.0–86.3) | 91.0 (49.7) | 74.1 (53.2–137.3) | 153.2 (74.1) | 127.3 (91.7–222.4) |
| Controls | 25.7 (3.5) | 24+1 (22+6–28+0) | 96.6 (46.6) | 78.1 65.1–118.6) | 58.4 (29.0) | 43.4 (38.4–72.3) | 103.3 (50.5) | 82.7 (69.4–127.0) | 161.7 (77.0) | 126.5 (106.0–199.2) |
| P value | .084 | <.001 a | .039 a | <.001 a | .136 | |||||
| Aortic obstruction (n=24) | ||||||||||
| Cases | 28.6 (4.4) | 28+6 (24+6–32+4) | 130.6 (60.8) | 126.4 (78.0–184.8) | 74.8 (30.7) | 72.2 (48.4–96.2) | 140.0 (65.6) | 135.4 (83.1–201.1) | 214.8 (94.2) | 214.9 (137.9–290.4) |
| Controls | 28.6 (4.4) | 28+4 (24+6–32+4) | 139.8 (70.4) | 126.4 (87.1–198.9) | 75.1 (29.3) | 77.1 (44.7–103.7) | 150.2 (76.1) | 135.0 (92.2–213.9) | 225.3 (101.5) | 212.8 (135.6–329.6) |
| P value | .883 | .440 | .775 | .361 | .424 | |||||
| Hypoplastic left heart syndrome (n=22) | ||||||||||
| Cases | 26.9 (4.9) | 24+4 (23+5–31+5) | 106.3 (64.1) | 75.5 (64.6–158.9) | 59.0 (30.9) | 45.2 (37.2–83.1) | 114.2 (69.2) | 81.4 (68.8–170.1) | 173.2 (96.1) | 130.0 (106.6–256.7) |
| Controls | 26.9 (5.0) | 24+5 (23+5–31+4) | 116.9 (72.5) | 80.9 (67.3–187.1) | 62.0 (30.6) | 48.2 (33.3–94.8) | 125.6 (78.4) | 85.8 (72.8–200.3) | 187.6 (108.0) | 137.5 (109.7–291.4) |
| P value | .469 | .005 a | .685 | .006 a | .050 a | |||||
| Hypoplastic right heart syndrome (n=14) | ||||||||||
| Cases | 23.7 (3.8) | 22+5 (21+0–24+0) | 64.6 (51.5) | 47.2 (35.6–65.3) | 38.5 (22.2) | 31.6 (24.2–42.9) | 69.7 (56.0) | 50.9 (38.5–70.0) | 108.2 (77.4) | 82.2 (62.7–112.9) |
| Controls | 23.7 (3.9) | 22+5 (21+0–24+1) | 73.2 (58.7) | 57.1 (35.6–74.3) | 42.2 (22.4) | 35.1 (24.5–47.3) | 78.4 (62.8) | 60.8 (39.3–79.1) | 120.6 (84.2) | 97.2 (63.6–128.2) |
| P value | 1.00 | .004 a | .004 a | .003 a | .002 a | |||||
| All fetuses | ||||||||||
| Cases | 26.5 (4.4) | 25+0 (22+5–29+6) | 97.8 (58.6) | 76.1 (48.9–133.7) | 62.6 (31.5) | 53.2 (36.9–86.3) | 104.8 (63.2) | 81.2 (52.5–143.4) | 167.4 (92.7) | 134.9 (90.3–236.4) |
| Controls | 26.5 (4.4) | 25+0 (22+6–29+5) | 108.6 (63.9) | 86.7 (57.1–149.2) | 62.3 (31.8) | 52.1 (36.1–85.0) | 116.5 (69.1) | 91.6 (60.8–159.4) | 178.8 (98.3) | 140.7 (97.3–244.1) |
| P value | .428 | <.001 a | .557 | <.001 a | <.001 a | |||||
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