Introduction: The purpose was to compare thymus size measured during second trimester screening of fetuses who were subsequently small for gestational age at birth (weight below 10th percentile, SGA group) with fetuses with normal birth weight (control group). We hypothesized that measuring the fetal thymic-thoracic ratio (TT-ratio) might help predict low birth weight. Methods: Using three-vessel view echocardiograms from our archives, we measured the anteroposterior thymus size and the intrathoracic mediastinal diameter to derive TT-ratios in the SGA (n = 105) and control groups (n = 533) between 19+0 and 21+6 weeks of gestation. We analyzed the association between TT-ratio and SGA adjusted to the week of gestation using logistic regression. Finally, we determined the possible TT-ratio cut-off point for discrimination between SGA and control groups by means of receiver operating characteristics (ROC) curve analysis. Results: The TT-ratio was significantly higher in the SGA group than in the control group (p < 0.001). An increase of the TT-ratio by 0.1 was associated with a 3.1-fold increase in the odds of diagnosing SGA. We determined that a possible discrimination cut-off point between SGA and healthy controls was achieved using a TT-ratio of 0.390 (area under the ROC curve 0.695). Conclusion: An increased TT-ratio may represent an additional prenatal screening parameter that improves the prediction of birth weight below the 10th percentile. Prospective studies are now needed to evaluate the use of fetal thymus size as predictive parameter for adverse fetal outcome.

Mini-Summary

What does this study add to current knowledge?

• We found a significantly higher TT-ratio in fetuses with later diagnosis of SGA than in the control group during second trimester screening.

What are the main clinical implications?

• Using a standard plane in ultrasound examinations of pregnancy, the parameter is measured in an easy way. The TT-ratio in fetuses between 19+0 and 21+6 may become an additional and affordable prediction marker or a part of screening during pregnancy. It may possibly enable earlier prenatal diagnosis of SGA and FGR fetuses.

Small for gestational age (SGA) is usually defined as an estimated fetal weight below the 10th percentile [1, 2] and has to be distinguished from the term fetal growth restriction (FGR), which denotes a pathologically small fetal size due to not achieving full growth potential. These fetuses often develop abnormal fetomaternal Doppler indices, indicating severe placental insufficiency, which in turn is correlated with complications, such as an adverse perinatal outcome and stillbirth [1, 3, 4]. Furthermore, FGR has lifelong negative effects regarding coronary heart disease and other chronic diseases [5]. In contrast, 70% of SGA fetuses survive without serious morbidity [6]. Unfortunately, definition of SGA and FGR is not consistent in the literature and international and national guidelines.

The thymus is a primary lymphatic organ in the anterior mediastinum and plays a central role in the differentiation of T lymphocytes. Felker et al. [7] published the first research results on the subject of the fetal thymus in ultrasound examinations in 1989. Further studies were performed by various research groups, which used different methods to measure the thymus size [8‒10]. Alterations of thymus size have been observed in pregnancies complicated with fetal inflammatory response syndrome [11, 12], preterm premature rupture of membranes, and chorioamnionitis [13], as well as in fetuses with congenital heart defects in connection with microdeletion 22q11 [10]. Also, conception with assisted reproductive technologies (ART) and maternal diseases such as diabetes mellitus and infection with human immunodeficiency virus (HIV) have been associated with a decreased (ART, diabetes mellitus) or increased thymus size (HIV) [14‒16].

In several previous studies, a correlation between thymus size and SGA/FGR has been examined [17‒19]. Cromi et al. [17] and Ekin et al. [18] showed a lower thymus size in fetuses with FGR, whereas Brandt et al. [19] did not find a significant difference between SGA fetuses and controls. However, none of these studies assessed the thymus size in pregnancies considered normal between 19+0 and 21+6 weeks of gestation which later developed a fetal weight below the 10th percentile.

We therefore conducted this study with the objective of comparing the thymus size of normal fetuses to fetuses with later diagnosis of SGA. We hypothesized that an altered thymic-thoracic ratio (TT-ratio) would be present in the second trimester screening in these fetuses prior to the development of growth retardation in terms of SGA.

For this retrospective study, we extracted all data from the database of the University Hospital Münster, Department for Gynecology and Obstetrics (ViewPoint®, General Electric Healthcare, Fairfield, CT, USA). The ultrasound examinations were performed by experienced practitioners between June 2005 and December 2017. Our study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of our institution (Reference Number: 2019-691-f-S).

In this study, we compared the thymus size of normal fetuses (control group) with fetuses with a later diagnosis of SGA (SGA group). We included singleton pregnancies between 19+0 and 21+6 weeks of gestation. At the time of the routine ultrasonography, no relevant pathological finding existed. Exclusion criteria were preterm birth, the diagnosis of fetal chromosomal aberrations or major anomalies, as well as maternal diseases such as diabetes mellitus, infection with human immunodeficiency virus (HIV), cytomegalovirus (CMV), and other chronic inflammatory diseases. A history of smoking or ART was also exclusion criteria as well as insufficient quality of the sonogram. For the SGA group, we included cases with a fetal birth weight below the 10th percentile. Only five of the 105 fetuses in the SGA group presented with pathological Doppler indices, e.g., absent or reverse umbilical end-diastolic flow (AEDF/REDF) or pathological Doppler of the middle cerebral artery, thus fulfilling the diagnosis criteria for FGR (estimated weight <3rd percentile +/− pathological Doppler indices). The remaining 100 fetuses in the SGA group did not show pathological Doppler indices.

Measurements of the thymus size were performed in the three-vessel view by the same reviewer and controlled by a second independent reviewer. In this plane, three vessels (the pulmonary artery, aorta, and superior vena cava), the vertebral body, sternum, and thymus had to be visible as well as the contour of the thoracic wall in a way similar to that of Chaoui et al. [10], the difference being that we used a line crossing the middle of the aorta rather than the aortic arch. We measured the anteroposterior thymus diameter and intrathoracic mediastinal diameter in this plane. The intrathoracic mediastinal diameter is defined as the distance between the anterior edge of the vertebral body and the inner edge of the sternum. The straight line has to cross the middle of the aorta. As a parallel to this, the line of the anteroposterior thymus diameter is drawn from the anterior aortic wall to the inner edge of the sternum, shown in Figure 1. We calculated the TT-ratio as a quotient of these variables:
TTratio=AnteroposteriorthymusdiameterIntrathoracicmediastinaldiameter
Fig. 1.

Three-vessel view of a fetus of SGA group at the 21st week of gestation. The anteroposterior thymus diameter (9.6 mm) and the intrathoracic mediastinal diameter (21.9 mm) are displayed. The TT-ratio is 0.44.

Fig. 1.

Three-vessel view of a fetus of SGA group at the 21st week of gestation. The anteroposterior thymus diameter (9.6 mm) and the intrathoracic mediastinal diameter (21.9 mm) are displayed. The TT-ratio is 0.44.

Close modal

We used the TT-ratio, which was our primary target variable, to compare the thymus size between fetuses.

Statistical Analysis

The statistical analysis of the data was performed with IBM SPSS Statistics for Windows, version 27.0 (IBM Corporation, Armonk, NY, USA). All p values and confidence limits were two-sided and were intended to be exploratory, not confirmatory. Therefore, no adjustment for multiplicity was made. Exploratory two-sided p values ≤0.05 were considered statistically noticeable.

Continuous variables were described using median and interquartile range (IQR; 25% quantile–75% quantile). Mann-Whitney U tests were used to compare the continuous variables between the SGA and control group (gestational age at screening, gestational age at delivery, pH umbilical artery, birth weight, birth weight percentile, Apgar score at 5 min, and TT-ratio). The correlation between the TT-ratio and gestational age at screening in the SGA and control group was analyzed using Spearman’s correlation coefficient. Corresponding 95% confidence intervals were estimated from 10,000 bootstrap samples using the bias-corrected and accelerated (BCA) method.

Additionally, a multivariable logistic regression was applied to evaluate the adjusted effect of the TT-ratio on SGA or FGR compared to normal growth, accounting for an influence of the gestational age at screening. Results are presented as odds ratios with corresponding 95% confidence intervals (95% CI) and p values of the Wald test. Sensitivity, specificity, and positive predictive value were calculated.

Finally, receiver operating characteristics (ROC) analysis was applied to examine the diagnostic value of the TT-ratio for differentiation between fetuses with SGA or FGR and fetuses with normal growth. Results are reported as area under the curve (AUC) and corresponding 95% confidence limits. Youden’s index was used to determine a possible cut-off point.

We included 638 fetuses in our study, which were divided into two groups (SGA group: n = 105, control group: n = 533). The characteristics of the SGA and control groups are presented in Table 1. They did not differ in regard to the APGAR score at 5 min, the age at delivery, and the intrathoracic mediastinal diameter. The pH umbilical artery, birth weight, and birth weight percentile were lower in the SGA group than in the control group (7.28 [IQR 7.23–7.33] vs. 7.30 [IQR 7.25–7.35], p = 0.004); (2,695 g [IQR 2,380–2,880] vs. 3,260 g [IQR 3,000–3,470], p < 0.001); and (5 [IQR 2–7] vs. 35 [IQR 22–48], p < 0.001), respectively. Furthermore, the gestational age at screening was higher in the SGA group than in the control group (20.6 [IQR 20.0–20.9] vs. 19.7 [IQR 19.4–19.9], p < 0.001). The TT-ratio was increased in the SGA group (0.39 [IQR 0.34–0.43]) compared to the control group (0.34 [IQR 0.30–0.37], p < 0.001). In Figure 2, the distribution of the TT-ratios in both groups over all weeks (20th up to 22nd) is visualized. Figure 3 presents the distribution of the TT-ratio grouped by the gestational age at screening. The SGA group showed higher TT-ratios than the control group in the 21st and 22nd weeks of gestation (p = 0.004, p = 0.011, respectively). It should be noted that in the 20th week of gestation, the TT-ratio values were similar in both groups (p = 0.876).

Table 1.

Characteristics of the SGA and control group

Parameter (20th–22nd week)SGA group (n = 105)Control group (n = 533)p valuea
GA at screening, weeks 20.6 (20.0–20.9) 19.7 (19.4–19.9) <0.001 
 n = 105 n = 533  
GA at delivery, weeks 39.0 (37.8–40.1) 39.3 (38.0–40.4) 0.156 
 n = 105 n = 533  
pH umbilical artery 7.28 (7.23–7.33) 7.30 (7.25–7.35) 0.004 
 n = 100 n = 476  
Birth weight, g 2,695 (2,380–2,880) 3,260 (3,000–3,470) <0.001 
 n = 105 n = 533  
Birth weight percentile 5 (2–7) 35 (22–48) <0.001 
 n = 105 n = 533  
Apgar score at 5 min 10 (9–10) 10 (9–10) 0.142 
 n = 105 n = 516  
TT-ratio 0.39 (0.34–0.43) 0.34 (0.30–0.37) <0.001 
 n = 105 n = 533  
IMD, mm 20.7 (19.0–22.1) 20.5 (18.9–22.5) 0.881 
 n = 105 n = 533  
Thymus diameter, mm 7.9 (6.6–9.3) 7.0 (6.1–7.9) <0.001 
 n = 105 n = 533  
Parameter (20th–22nd week)SGA group (n = 105)Control group (n = 533)p valuea
GA at screening, weeks 20.6 (20.0–20.9) 19.7 (19.4–19.9) <0.001 
 n = 105 n = 533  
GA at delivery, weeks 39.0 (37.8–40.1) 39.3 (38.0–40.4) 0.156 
 n = 105 n = 533  
pH umbilical artery 7.28 (7.23–7.33) 7.30 (7.25–7.35) 0.004 
 n = 100 n = 476  
Birth weight, g 2,695 (2,380–2,880) 3,260 (3,000–3,470) <0.001 
 n = 105 n = 533  
Birth weight percentile 5 (2–7) 35 (22–48) <0.001 
 n = 105 n = 533  
Apgar score at 5 min 10 (9–10) 10 (9–10) 0.142 
 n = 105 n = 516  
TT-ratio 0.39 (0.34–0.43) 0.34 (0.30–0.37) <0.001 
 n = 105 n = 533  
IMD, mm 20.7 (19.0–22.1) 20.5 (18.9–22.5) 0.881 
 n = 105 n = 533  
Thymus diameter, mm 7.9 (6.6–9.3) 7.0 (6.1–7.9) <0.001 
 n = 105 n = 533  
Parameter (20th week of gestation)SGA group (n = 22)Control group (n = 443)p valuea
TT-ratio 0.34 (0.29–0.37) 0.33 (0.30–0.37) 0.876 
 n = 22 n = 443  
IMD, mm 19.0 (17.1–21.1) 20.5 (18.8–22.5) 0.010 
 n = 22 n = 443  
Thymus diameter, mm 6.5 (5.2–7.9) 6.9 (5.9–7.8) 0.236 
 n = 22 n = 443  
Parameter (20th week of gestation)SGA group (n = 22)Control group (n = 443)p valuea
TT-ratio 0.34 (0.29–0.37) 0.33 (0.30–0.37) 0.876 
 n = 22 n = 443  
IMD, mm 19.0 (17.1–21.1) 20.5 (18.8–22.5) 0.010 
 n = 22 n = 443  
Thymus diameter, mm 6.5 (5.2–7.9) 6.9 (5.9–7.8) 0.236 
 n = 22 n = 443  
Parameter (21st week of gestation)SGA group (n = 57)Control group (n = 55)p valuea
TT-ratio 0.40 (0.36–0.45) 0.36 (0.34–0.39) 0.004 
 n = 57 n = 55  
IMD, mm 20.7 (18.9–21.7) 20.4 (19.1–22.2) 0.868 
 n = 57 n = 55  
Thymus diameter, mm 8.1 (7.1–9.3) 7.5 (6.7–8.5) 0.091 
 n = 57 n = 55  
Parameter (21st week of gestation)SGA group (n = 57)Control group (n = 55)p valuea
TT-ratio 0.40 (0.36–0.45) 0.36 (0.34–0.39) 0.004 
 n = 57 n = 55  
IMD, mm 20.7 (18.9–21.7) 20.4 (19.1–22.2) 0.868 
 n = 57 n = 55  
Thymus diameter, mm 8.1 (7.1–9.3) 7.5 (6.7–8.5) 0.091 
 n = 57 n = 55  
Parameter (22nd week of gestation)SGA group (n = 26)Control group (n = 35)p valuea
TT-ratio 0.39 (0.34–0.41) 0.35 (0.31–0.38) 0.011 
 n = 26 n = 35  
IMD, mm 22.0 (20.6–23.5) 21.1 (19.2–22.8) 0.089 
 n = 26 n = 35  
Thymus diameter, mm 8.2 (7.6–9.9) 7.4 (6.5–8.2) 0.005 
 n = 26 n = 35  
Parameter (22nd week of gestation)SGA group (n = 26)Control group (n = 35)p valuea
TT-ratio 0.39 (0.34–0.41) 0.35 (0.31–0.38) 0.011 
 n = 26 n = 35  
IMD, mm 22.0 (20.6–23.5) 21.1 (19.2–22.8) 0.089 
 n = 26 n = 35  
Thymus diameter, mm 8.2 (7.6–9.9) 7.4 (6.5–8.2) 0.005 
 n = 26 n = 35  

Data presented as median (25% quantile–75% quantile).

GA, gestational age; TT-ratio, thymic-thoracic ratio; IMD, intrathoracic mediastinal diameter.

aUnivariate p values are from Mann-Whitney U tests.

Fig. 2.

Boxplots of the TT-ratio in the control and SGA groups. The distribution of the TT-ratio is statistically noticeably different between the two groups (Mann-Whitney U test: p < 0.001). SGA, small for gestational age; TT-ratio, thymic-thoracic ratio.

Fig. 2.

Boxplots of the TT-ratio in the control and SGA groups. The distribution of the TT-ratio is statistically noticeably different between the two groups (Mann-Whitney U test: p < 0.001). SGA, small for gestational age; TT-ratio, thymic-thoracic ratio.

Close modal
Fig. 3.

Distribution of the TT-ratio grouped by the gestational age at screening in weeks. The SGA group showed higher TT-ratios than the control group in the 20th and 21st weeks of gestation (p = 0.004, p = 0.011, respectively). In the 19th week of gestation, the TT-ratio values were comparable between both groups (p = 0.876). SGA, small for gestational age; TT-ratio, thymic-thoracic ratio.

Fig. 3.

Distribution of the TT-ratio grouped by the gestational age at screening in weeks. The SGA group showed higher TT-ratios than the control group in the 20th and 21st weeks of gestation (p = 0.004, p = 0.011, respectively). In the 19th week of gestation, the TT-ratio values were comparable between both groups (p = 0.876). SGA, small for gestational age; TT-ratio, thymic-thoracic ratio.

Close modal

The correlation between the TT-ratio and the gestational age at screening is presented in the scatterplot in Figure 4. We found a low correlation between the gestational age at screening and the TT-ratio [Spearman’s correlation coefficient 0.217, bootstrapped 95% confidence interval (CI): 0.141–0.291].

Fig. 4.

Scatterplot of the TT-ratio and gestational age in the scontrol and SGA group. SGA, small for gestational age; TT-ratio, thymic-thoracic ratio.

Fig. 4.

Scatterplot of the TT-ratio and gestational age in the scontrol and SGA group. SGA, small for gestational age; TT-ratio, thymic-thoracic ratio.

Close modal

In the logistic regression adjusted for the gestational week, the odds of an SGA diagnosis increased by the factor 3.095 per increase of TT-ratio by 0.1 units, if age is kept constant [odds ratio (OR): 3.056, 95% CI: 1.982–4.711, p < 0.001]. Notably, the OR was higher in the 22nd week of gestation (OR: 3.896) than in the 20th week (OR: 1.341) as it is shown in Table 2.

Table 2.

Results of the logistic regression for SGA including TT-ratio and gestational week at screening as influencing factors

Dependent variable: SGA groupOdds ratio95% Wald confidence limitsp value (Wald test)
20th–22nd week 
 TT-ratio (x+0.1 vs. x units) 3.056 1.982 4.711 <0.001 
 Gestational age at screening (x+1 vs. x days) 1.207 1.154 1.262 <0.001 
20th week 
 TT-ratio (x+0.1 vs. x units) 1.341 0.633 2.844 0.444 
21st week 
 TT-ratio (x+0.1 vs. x units) 2.521 1.194 5.321 0.015 
22nd week 
 TT-ratio (x+0.1 vs. x units) 3.896 1.282 11.842 0.016 
Dependent variable: SGA groupOdds ratio95% Wald confidence limitsp value (Wald test)
20th–22nd week 
 TT-ratio (x+0.1 vs. x units) 3.056 1.982 4.711 <0.001 
 Gestational age at screening (x+1 vs. x days) 1.207 1.154 1.262 <0.001 
20th week 
 TT-ratio (x+0.1 vs. x units) 1.341 0.633 2.844 0.444 
21st week 
 TT-ratio (x+0.1 vs. x units) 2.521 1.194 5.321 0.015 
22nd week 
 TT-ratio (x+0.1 vs. x units) 3.896 1.282 11.842 0.016 

TT-ratio, thymic-thoracic ratio.

The results of the AUC calculation are presented in Table 3. The AUC was 0.695 [95% CI: 0.636–0.728] and higher in the 21st and 22nd than in the 20th week of gestation. The maximal Youden’s index was 0.34. The TT-ratio of 0.390 was chosen as a possible discrimination cut-off point, with a sensitivity of 51% (95% CI: 41–61%) and a specificity of 82% (95% CI: 79–86%).

Table 3.

Optimal cut-off values of the TT-ratio to predict SGA determined by Youden’s index

Week of gestationCut-off value for TT-ratioSensitivity, % (95% CI)Specificity, % (95% CI)AUC (95% CI)Youden’s index
All weeks 0.390 51.4 (41.5, 61.3) 82.4 (78.9, 85.5) 0.695 (0.636, 0.755) 0.338 
20th 0.410 22.7 (7.8, 45.4) 91.9 (88.9, 94.2) 0.510 (0.373, 0.646) 0.146 
21st 0.400 54.4 (40.7, 67.6) 85.5 (73.3, 93.5) 0.657 (0.552, 0.762) 0.398 
22nd 0.390 53.8 (33.4, 73.4) 85.7 (69.7, 95.2) 0.691 (0.553, 0.829) 0.396 
Week of gestationCut-off value for TT-ratioSensitivity, % (95% CI)Specificity, % (95% CI)AUC (95% CI)Youden’s index
All weeks 0.390 51.4 (41.5, 61.3) 82.4 (78.9, 85.5) 0.695 (0.636, 0.755) 0.338 
20th 0.410 22.7 (7.8, 45.4) 91.9 (88.9, 94.2) 0.510 (0.373, 0.646) 0.146 
21st 0.400 54.4 (40.7, 67.6) 85.5 (73.3, 93.5) 0.657 (0.552, 0.762) 0.398 
22nd 0.390 53.8 (33.4, 73.4) 85.7 (69.7, 95.2) 0.691 (0.553, 0.829) 0.396 

SGA, small for gestational age; TT-ratio, thymic-thoracic ratio; CI, confidence interval; AUC, area under the curve.

Five fetuses in the SGA group fulfilled the criteria of FGR. The analysis of these fetuses showed that the TT-ratio was noticeably higher in the FGR group than in the control group (0.41 [IQR 0.35–0.45] and 0.34 [IQR 0.30–0.37] respectively, p < 0.001). The 5 cases were not excluded, as they did not distort the statistical results. Due to the low number of cases, a further statistical evaluation of the subgroups was not performed.

In this study, we found an increased TT-ratio between 19+0 and 21+6 weeks of gestation in fetuses which later developed low birth weight (SGA group) compared to the control group. Several previous studies have shown a decreased thymus size in FGR and SGA fetuses. Cromi et al. [17] suggested that thymic involution in FGR is part of a neuroendocrine response to malnutrition in utero. Ekin et al. [18] hypothesized that leptin may be a vital mediator in this neuroendocrine response and that an imbalance between leptin and cortisol concentration may be caused by syncytiotrophoblasts failing to adequately convert maternal cortisol to less-active glucocorticosteroid metabolites [18, 20]. Olearo et al. [21] argue that placental dysfunction may be due to a specific “trigger,” such as an infection, causing intrauterine stress, which in turn results in thymic involution.

However, not all published studies found a smaller thymus: Brandt et al. [19] observed no association between measurements of the organ in the second trimester and preterm birth as primary outcome or SGA as one of the secondary outcomes. They explain this result by the fact that most fetuses with birth weight below the 10th percentile are constitutionally small and not suffering from pathological growth restriction. The authors also postulate that thymus involution may be more apparent and more closely correlated to fetal growth in the third trimester of pregnancy and thus not apparent in the second trimester screening.

In contrast to Brandt et al. [19], we observed an increased TT-ratio in the second trimester screening in the SGA group in this study. Contrary to Cromi et al. [17] and Ekin et al. [18], we collected data of thymus size between 19+0 and 21+6 weeks of gestation, several weeks prior to the diagnosis of SGA or FGR. It is known that adverse conditions like clinical diseases and nutritional disorders, as well as placental dysfunction, play a role in etiology of growth restriction and can be stressful for the fetus [22]. The thymus as an endocrine organ reacts sensitively to hormonal changes with increase and decrease of size, respectively [23].

In general, it should be noted that fetuses in our SGA group could be constitutionally small, as Brandt et al. [19] argued. Furthermore, a review about normal and abnormal thymus size makes so-called thymic rebound hyperplasia in children and adults the subject of discussion. After a period of stress and following decrease of thymus due to pneumonia, for example, the thymus increases to its original size or even larger within the convalescence period [24, 25]. Therefore, we suggest that some sort of stress might be an explanation for our observation of increased thymus size in the SGA group in comparison to the control group. In this case, the cause of stress remains unknown, but as a result, a thymic rebound hyperplasia, consistent with our measurements, appears. If further stress in pregnancy cannot be compensated, this could lead to above-mentioned thymus involution in the third trimester of pregnancy found in other studies.

In the context of this hypothesis, leptin as a protector against thymic involution could play a role in our findings of increased thymus size. Gruver et al. [26] conducted a study with mice in which thymus atrophy was triggered by lipopolysaccharide (LPS). They showed an expression of leptin receptor molecules in medullary thymic epithelial cells (mTECs) and the ability of leptin to indirectly protect thymus cells against apoptosis. Leptin treatment was also associated with elevated cytokine levels, especially interleukin-7 (IL-7). Tagoma et al. [27] observed an increase of IL-7 in healthy pregnancies during the second trimester. They pointed out the protective and supporting function of IL-7 as a growth factor, especially for T-cells, which mature in the thymus. It is possible that IL-7 and leptin could positively affect the growth of the thymus.

A review on the therapeutic potential of IL-7 against thymic atrophy showed auspicious results in mouse models; however, human clinical trials have not been able to reproduce these results. Due to inconsistent data, the role of IL-7 should be assessed in further studies [28].

Limitations of our study are following: The retrospective design leads to the risk of selection bias. There were only five FGR fetuses in our SGA group due to the strict exclusion criteria, e.g., preterm birth. Besides, the AUC should be larger for a better discrimination between SGA and normal fetuses. A further study with more cases of FGR is needed to adequately estimate the TT-ratio in these fetuses. It should be a prospective study to get reliable data and evaluate the practicability of focused measuring of the TT-ratio in the three-vessel view. Moreover, the value of the TT-ratio as a predictive marker was greater in the 21st week of gestation than in earlier weeks because the difference between the SGA and control group in the 20th week was weak. Thus, this parameter is of limited use for discrimination between both groups before the 21st week of gestation. Furthermore, retrospective design caused difficulties regarding the appropriate planes for ultrasound examination. The ultrasound examinations were performed in a single dimension; due to its amorphous shape of the thymus, it would be more accurately assessed if several measurement planes were combined. Besides, it is sometimes difficult to distinguish clearly between the thymus and its surrounding structures due to limitations of ultrasound technique.

Nevertheless, the advantage of our measurement method is that it is easy to learn, as the three-vessel view is a standard plane in ultrasound examinations of pregnancy and the inter- and intra-observer variability is low [29]. Furthermore, the investigator does not face the problem of an irregular thymus contour as only the thymic and thoracic diameters have to be measured. The small difference in the examination and measurement methods of Chaoui et al. [10] might explain the apparently different values of the TT-ratio in our study.

In conclusion, our study suggests that measurements of increased TT-ratio in the second trimester can be associated with birth weight below the 10th percentile, regardless of the estimated fetal weight at examination. An early detection of fetuses at risk of growth retardation is important to prevent pregnancy complications and improve maternal and fetal outcome [30]. The TT-ratio, as an additional prediction marker or as a part of screening with various parameters, may possibly enable earlier prenatal diagnosis of SGA and FGR fetuses. Additional investigation is needed to assess correlation between TT-ratio and FGR and to confirm the relation between TT-ratio and SGA in a prospective study.

We thank everyone who voluntarily dedicated their time and effort.

All procedures performed in this study were planned in accordance with the World Medical Association Declaration of Helsinki from 1964 and its later amendments or comparable ethical standards. This study was approved by the Ethics Committee of our institution, “Ethik-Kommission der Ärztekammer Westfalen-Lippe und der Westfälischen Wilhelms-Universität” (Reference Number: 2019-691-f-S). The review board approved this study and required neither patient approval nor informed consent for our retrospective analysis of data that was obtained using a standard-of-care clinical protocol. The study was planned in accordance with the ethical standards of the Institutional Research Committee and the Declaration of Helsinki.

The authors have no conflicts of interest to declare.

No funding was received.

J.M. Kim: data collection, data management, data analysis, and manuscript writing. M. Möllers: project development, data collection, manuscript editing, and manuscript revision. R. Schmitz: project development, data collection, and manuscript revision. W. Klockenbusch and H.A. Köster: manuscript revision. K. Oelmeier, K. Hammer, J. Braun, and J. Steinhard: data collection and manuscript revision. R. Koch: statistical support, data analysis, and manuscript revision.

All data generated or analyzed during this study are included in this article. There is no supplementary material for publication. Further inquiries can be directed to the corresponding author.

1.
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Daly
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