Evaluation of the Relationship Between the Thymic–Thoracic Ratio and Perinatal Adverse Outcomes in Fetuses With Congenital Heart Defects

Abstract

Objectives

The aim of this study was to evaluate the thymic–thoracic ratio (TTR) in fetuses with congenital heart defects (CHD) and to investigate the association between TTR and adverse perinatal outcomes.

Methods

This prospective study was conducted at a tertiary care center. A total of 85 participants were enrolled, including 42 fetuses with CHD and 43 healthy controls between 18 and 37 gestational weeks. The TTR was calculated for each case. First, outcomes were compared between the CHD and control groups; subsequently, CHD cases were analyzed in subgroups. Receiver operating characteristic (ROC) analysis was performed to assess the relationship between TTR and perinatal outcomes in the CHD group.

Results

TTR was significantly lower in the fetal CHD group compared with controls (p < .001). In the conotruncal CHD subgroup, TTR values were also significantly lower (p < .001). In the Spearman correlation analysis performed for neonatal intensive care unit (NICU) admission between the study and control groups, TTR showed a negative correlation with NICU admission (r = −0.331, p = .002). ROC analysis indicated that the optimal TTR cut‐off value for predicting NICU admission was 0.41, with 72% sensitivity and 62% specificity (AUC = 0.729; p < .001).

Conclusion

TTR was lower in fetuses with CHD. A decreasing TTR was associated with an increased rate of adverse perinatal outcomes. Assessment of TTR in fetuses with CHD may be a useful tool for predicting adverse perinatal outcomes.

Abbreviations

CHD

congenital heart defects

DORV

double outlet right ventricle

IAA

interrupted aortic arch

ISUOG

International Society of Ultrasound in Obstetrics and Gynecology

ROC

receiver operating characteristic

TAC

truncus arteriosus communis

TGA

transposition of the great arteries

TOF

tetralogy of Fallot

TTR

thymic–thoracic ratio

Congenital heart defects are the most common fetal anomalies. ¹ Although they occur in approximately 8–9 per 1000 live births, the true prevalence is estimated to be 2–3 times higher when intrauterine pregnancy losses are taken into account. ¹ , ²

Conotruncal heart defects constitute approximately 20–30% of all fetal cardiac defects and are associated with a high rate of adverse perinatal outcomes. ³ The fetal heart occupies a substantial proportion of the fetal thorax, and the dimensions and measurements of adjacent organs may be influenced by the anatomical composition of the heart. ⁴ The thymus is located in the superior mediastinum adjacent to the heart, and its assessment may be affected by cardiac anatomy.

Moreover, the thymus and cardiac outflow tracts (aortic and pulmonary outlets) share common embryologic origins, which may further increase the likelihood that measurements of these structures influence one another. ⁵ , ⁶ Therefore, in the presence of cardiac anomalies—particularly conotruncal anomalies that affect the great vessels arising from the heart (tetralogy of Fallot [TOF], double outlet right ventricle [DORV], truncus arteriosus communis [TAC], transposition of the great arteries [TGA], and interrupted aortic arch [IAA])—the thymus may be anatomically affected, or its measurements may vary according to the severity of the cardiac anomaly. ⁷ , ⁸ , ⁹ Consequently, the practical clinical applicability of thymic measurements may be limited.

The thymic–thoracic ratio (TTR), described by Chaoui et al, is calculated in the 3‐vessel–trachea view as the ratio of the anteroposterior thymic diameter to the mediastinal diameter. TTR is considered a practical measurement because it is independent of gestational age and does not require Z‐score calculation. ⁹ , ¹⁰ Recent studies evaluating fetal thymic anatomy and size have highlighted potential associations with antenatal and perinatal outcomes. ¹⁰ , ¹¹ However, data evaluating the relationship between TTR and perinatal outcomes in fetuses with congenital heart defects remain limited. The present study aimed to evaluate TTR in fetuses with congenital heart defects and to assess its association with adverse perinatal outcomes and its predictive value.

Materials and Methods

Study Population

This prospective, single‐center study was conducted at a tertiary care hospital. Pregnant women between 18 and 37 gestational weeks who were followed and treated in the High‐Risk Pregnancy Department of Ankara Bilkent City Hospital between December 2023 and December 2024, and whose fetuses were diagnosed with cardiac anomalies, were included. Written informed consent was obtained from all participants. Ethics committee approval was obtained from Ankara Bilkent City Hospital (E2‐23‐4049). All procedures were performed in accordance with the Declaration of Helsinki.

Gestational age was determined based on the last menstrual period or first‐trimester crown–rump length measurement. For each participant, clinical and demographic variables (maternal age, gravidity, parity, body mass index [BMI]), fetal TTR values, gestational age at delivery, neonatal birth weight, 1‐ and 5‐minute Apgar scores, umbilical arterial cord pH, and neonatal intensive care unit (NICU) admission status were recorded.

Controls were randomly selected from healthy pregnancies. A 1:1 matching approach was used such that each study case had 1 control, and gestational age distribution between groups was balanced.

Exclusion criteria were multiple gestations; maternal obesity; fetuses diagnosed with 22q11.2 syndrome; fetal growth restriction or small‐for‐gestational‐age fetuses; known major fetal chromosomal or extracardiac anomalies; missing/unavailable data; and suboptimal ultrasound imaging preventing adequate measurements.

Ultrasonographic Assessment

Participants were examined between 18 and 37 gestational weeks at the time of fetal CHD diagnosis. All examinations were performed by the same maternal–fetal medicine specialist (ZA) under the supervision of a highly experienced supervisor (DS, professor of maternal–fetal medicine). Voluson E8 ultrasound systems (GE Healthcare, Milwaukee, WI, USA) with a 2–5 MHz convex transducer were used.

Ultrasound examination was conducted in accordance with the recommendations and guidelines of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG). ¹² Each participant was examined once and measurements were recorded. Measurements were obtained during fetal apnea and in the dorsoposterior fetal position. Standard fetal biometry was performed first. The transverse plane of the fetal thorax was then used to obtain the 3‐vessel view. After standard visualization of the 3 great vessels, the thymus was identified as a homogeneous structure in the anterior mediastinum.

The intrathoracic mediastinal diameter was measured along a line drawn parallel to the transverse aortic arch from the anterior border of the thoracic vertebral body to the inner border of the sternum. The anteroposterior thymic diameter was measured from behind the sternum to the edge of the transverse aortic arch. As previously described, the TTR was defined as the ratio of the anteroposterior thymic diameter to the thoracic mediastinal diameter ⁹ , ¹⁰ (Figure 1). Two consecutive measurements were obtained for each participant, and the mean value was used for analysis.

Figure 1.

Ultrasonographic measurement of the thymic–thoracic ratio (TTR) in the 3‐vessel–trachea view.

Statistical Analysis

Sample size calculation was performed using G*Power software (version 3.1; Franz Faul, University of Kiel, Kiel, Germany). Based on a 2‐tailed test with an alpha level of 0.05, power of 95%, and a large effect size (0.80), a minimum sample size of 25 participants per group was estimated.

Statistical analyses were performed using SPSS 22.0 (SPSS Inc., Chicago, IL, USA). Normality was assessed using the Kolmogorov–Smirnov and Shapiro–Wilk tests. The Mann–Whitney U test was used for comparisons of non‐normally distributed variables. Descriptive statistics for non‐normally distributed variables were reported as median (interquartile range, IQR). The chi‐square test was used for categorical variables. Spearman correlation coefficients were calculated. ROC curve analysis was used to determine the optimal TTR cut‐off value for predicting NICU admission. A p value <.05 was considered statistically significant.

Results

A total of 90 participants were initially recruited (45 with CHD and 45 controls). In the CHD group, 1 case was excluded due to DiGeorge syndrome detected on amniocentesis, and 2 cases were excluded due to suboptimal ultrasound imaging caused by fetal position or maternal adiposity. In the control group, 2 cases were excluded because of inadequate ultrasound optimization. The final analysis included 85 participants: 42 fetuses with CHD and 43 controls.

The CHD group was further divided into 2 subgroups: fetuses with conotruncal anomalies (n = 13) and those with non‐conotruncal anomalies (n = 29). First, outcomes were compared between the CHD and control groups; subsequently, subgroup analyses were performed within the CHD cohort. A detailed analysis of fetal CHD patients is presented in Table 1.

Table 1.

Distribution of Detected Fetal Cardiac Anomalies

Cardiac Anomaly Group	N	Percentage %
Ventricular septal defect (VSD), atrioventricular septal defect (AVSD)	14	33.3
Aortic stenosis, aortic coarctation	6	14.3
Double aortic arch, right aortic arch	5	11.9
Hypoplastic left heart syndrome (HLHS)	4	9.5
Conotruncal anomalies (tetralogy of Fallot, TGA, DORV, truncus arteriosus)	13	31.0
Total	42	100.0

DORV, double outlet right ventricle; TGA, transposition of the great arteries.

In the conotruncal fetal CHD group (n = 13), amniocentesis was performed in 11 patients, while 2 patients declined the diagnostic procedure. In the non‐truncal fetal CHD group (n = 29), amniocentesis was carried out in 9 patients, whereas 20 patients declined the recommended procedure for genetic diagnosis. Overall, within the fetal CHD cohort (n = 42), invasive testing for genetic evaluation was performed in 20 patients, while 22 patients refused the procedure. Apart from the excluded case with 22q11.2 deletion syndrome, no additional major chromosomal abnormalities were identified among the cases that underwent invasive genetic testing.

Clinical and demographic characteristics, obstetric and neonatal outcomes, NICU admission rates, and TTR values of the CHD and control groups are presented in Table 2. Gestational age at delivery was earlier in the CHD group (p = .039), and birth weight was lower (p < .001). Compared with controls, the CHD group had lower 1‐ and 5‐minute Apgar scores (p < .001 for both). Umbilical arterial cord pH was lower in the CHD group (p = .024), and NICU admission was more frequent (p < .001). TTR was significantly lower in the CHD group compared with controls (p < .001), as shown in Figure 2A.

Table 2.

Clinical and Neonatal Characteristics and Thymic–Thoracic Ratio (TTR) Values in Fetuses with Congenital Heart Defects (CHD) and Controls

Variables	Fetal CHD (n = 42)	Control (n = 43)	p Value
Age	29.0 (20.0)	27.0 (22.0)	.107
Gravidity	2.0 (2.0)	2.0 (0.0)	.900
Parity	0.0 (1.0)	1.0 (1.0)	.357
Body mass index	26.7 (9.3)	27.3 (5.62)	.344
Gestational age at exam (weeks)	34.3 (6.4)	33.0 (4.6)	.649
Birth weight (g)	2800.0 (630.0)	3352.0 (592.5)	<.001
Gestational age at delivery (weeks)	37.6 (3.0)	38.4 (1.6)	.039
1‐minute Apgar score	6.0 (2.0)	8.0 (1.0)	<.001
5‐minute Apgar score	8.0 (2.0)	9.0 (0.0)	<.001
Umbilical arterial cord pH	7.30 (0.08)	7.32 (0.12)	.024
Umbilical arterial cord base excess (BE)	2.8 (4.3)	0.6 (2.5)	.002
TTR	0.41 (0.07)	0.434 (0.057)	<.001
NICU admission	26 (61.9%)	5 (11.6%)	<.001

Data are presented as median (IQR). TTR values are expressed as decimal ratios (not percentages).

NICU, neonatal intensive care unit.

Figure 2.

Box plots showing thymic–thoracic ratio (TTR) distribution across study groups. A, Comparison between fetuses with congenital heart defects and healthy controls. B, Subgroup analysis within the congenital heart defect (CHD) cohort (conotruncal versus non‐conotruncal anomalies). Boxes represent the interquartile range, horizontal lines indicate medians, and whiskers show minimum and maximum values.

Subgroup analyses of the CHD cohort are shown in Table 3. The conotruncal subgroup had a lower 1‐minute Apgar score (p < .001), lower umbilical cord pH (p = .023), and a higher need for NICU admission (p < .001) compared with the non‐conotruncal subgroup. TTR values were significantly lower in the conotruncal subgroup (p < .001), as shown in Figure 2B.

Table 3.

Clinical and Neonatal Characteristics and TTR Values According to CHD Subtype (Conotruncal versus Non‐Conotruncal)

Variables	Conotruncal CHD (n = 13)	Non‐conotruncal CHD (n = 29)	p Value
Age	25.0 (10.0)	29.0 (12)	.184
Gravidity	1.0 (2.0)	2.0 (2.0)	.232
Parity	0.0 (1.0)	1.0 (1.0)	.246
Body mass index	28.5 (4.7)	26.4 (5.5)	.238
Gestational age at exam (weeks)	35.7 (7.7)	34.1 (6.3)	.841
Birth weight (g)	2790.0 (468.7)	2800.0 (870.0)	.438
Gestational age at delivery (weeks)	37.0 (2.2)	38.0 (4.4)	.846
1‐minute Apgar score	5.5 (1.0)	7.0 (1.0)	<.001
5‐minute Apgar score	7.5 (1.0)	8.0 (2.0)	.020
Umbilical arterial cord pH	7.23 (0.11)	7.32 (0.05)	.023
Umbilical arterial cord base excess (BE)	3.0 (5.45)	2.5 (3.5)	.516
TTR	0.374 (0.086)	0.425 (0.058)	<.001
NICU admission	13 (100%)	13 (44.8%)	<.001

Data are presented as median (IQR). TTR values are expressed as decimal ratios (not percentages).

TTR, thymic–thoracic ratio; CHD, congenital heart defects; NICU, neonatal intensive care unit.

Spearman correlation analysis assessing NICU admission in the study and control groups showed a negative correlation between TTR and NICU admission (r = −0.331, p = .002) (Table 4). ROC analysis demonstrated that the optimal TTR cut‐off value for predicting NICU admission was 0.41, with 72% sensitivity and 62% specificity (AUC = 0.729; p < .001) (Figure 3).

Table 4.

Spearman Correlations Between TTR, NICU Admission, and Other Parameters

Variables	NICU
	r	p
TTR	−0.331	.002
Umbilical cord arterial pH	−0.063	.567
Newborn birth weight	−0.520	<.001
Apgar score (1 minute)	−0.574	<.001
Apgar score (5 minutes)	−0.564	<.001

p < .05 was considered statistically significant.

r, correlation coefficient; NICU, neonatal intensive care unit; TTR, thymic–thoracic ratio.

Figure 3.

Receiver operating characteristic (ROC) curve analysis of thymic–thoracic ratio for the prediction of neonatal intensive care unit admission in fetuses with congenital heart defects.

Discussion

In this study, TTR was evaluated in fetuses with CHD without coexisting DiGeorge syndrome. Outcomes in fetuses with CHD were compared with those in healthy controls; additionally, subgroup analyses were performed to compare TTR values in fetuses with conotruncal anomalies versus other cardiac anomalies, and their associations with perinatal outcomes were examined. TTR was lower in the CHD group compared with controls. In subgroup analyses, TTR was markedly lower in fetuses with conotruncal anomalies than in fetuses with other cardiac anomalies. In both the overall CHD group and the conotruncal subgroup, lower TTR values were associated with adverse perinatal outcomes with moderate sensitivity and specificity.

The fetal thymus has been widely investigated in late gestation from both anatomical and functional perspectives. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ Felker et al first assessed the fetal thymus sonographically and demonstrated that it could be evaluated in many cases even under the technological conditions of that period. ¹⁷ Subsequently, Paladini introduced the “thy‐box” to improve and facilitate visualization of the fetal thymus. ¹⁸ In 2011, Chaoui et al defined TTR and demonstrated that thymic assessment using this index is less influenced by maternal and fetal factors and has the advantage of being independent of gestational age and Z‐scores. ⁹ Despite these advances, data in CHD populations remain limited.

TTR has been investigated in various clinical conditions, including fetal trisomies, IVF pregnancies, preeclampsia, diabetes, and rheumatoid arthritis, where reduced thymic size or lower TTR values have been reported compared with healthy pregnancies. ¹⁴ , ¹⁹ , ²⁰ , ²¹ Collectively, these studies support the feasibility and clinical applicability of TTR as a practical tool for fetal thymus assessment.

Given the close embryologic relationship and anatomical proximity between the fetal thymus and the great‐vessel outflow tracts, we hypothesized that fetal thymus assessment may be useful in CHD and that TTR could be associated with perinatal outcomes in this patient population. Several prior studies have evaluated the thymus in fetuses with CHD. Chaoui et al demonstrated that ultrasound can reliably identify presence or absence/hypoplasia of the thymus in CHD fetuses, ²² and Barrea et al provided supportive evidence. ²³ Li et al assessed the thymus using 2D and 3D ultrasound in fetuses with CHD and reported smaller thymic dimensions in the CHD group, suggesting that 3D assessment is feasible. ⁸ Chaoui et al also showed that TTR is a practical method for thymus assessment in CHD fetuses and is relatively less affected by fetal position or adverse maternal conditions. ⁹ Zhao et al investigated the correlation between fetal cardiac axis and TTR in healthy pregnancies and reported that increasing gestational age did not affect the relationship between TTR and the fetal cardiac axis. ²⁴ Battistoni et al evaluated TTR in fetuses with conotruncal anomalies and found lower TTR values compared with healthy fetuses; they also reported that smaller TTR values were associated with worse outcomes after postnatal surgical procedures. ²⁵

To our knowledge, only 1 study in the past 5 years has specifically examined TTR in fetuses with CHD. Monteiro et al reported lower TTR values in fetuses with conotruncal heart defects, whereas no difference was found for non‐conotruncal defects compared with controls. However, the retrospective design, limited sample size, and absence of genetic testing represent important limitations of that study. ²⁶

These findings support the hypothesis that the observed differences in TTR are primarily driven by conotruncal anomalies and are associated with adverse perinatal outcomes.

The observed diagnostic performance (AUC = 0.729) suggests a moderate discriminative ability of TTR for predicting NICU admission. Therefore, TTR should not be considered a standalone predictive tool but rather a complementary biomarker that may contribute to prenatal risk stratification when interpreted alongside other clinical and ultrasonographic findings.

A relatively broad gestational age range (18–37 weeks) was included in this study. Although TTR is considered largely independent of gestational age, subtle variations related to fetal growth and thoracic development across gestation cannot be entirely excluded and should be considered when interpreting the findings.

The strengths of our study include its prospective design and the availability of genetic evaluation in a substantial proportion of cases. Limitations include the relatively small sample size, the absence of postnatal echocardiographic data, and the lack of neonatal surgical outcome assessment. In addition, the single‐center design may limit the generalizability of our findings. Multicenter studies with larger sample sizes are needed to validate these results.

In conclusion, TTR was lower in fetuses with CHD, and decreasing TTR values were associated with increased adverse perinatal outcomes. We suggest that TTR assessment in fetuses with CHD may be a useful tool for predicting adverse perinatal outcomes. We further argue that a larger prospective study including neonatal echocardiographic findings and neonatal cardiac surgical outcomes would be valuable to strengthen this hypothesis.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.