Professional Documents
Culture Documents
ORIGINAL RESEARCH
T
Address correspondence to Juan A. De León- he thymus gland, which is located in the cranial and ventral
Luis, MD, PhD, Fetal Medicine Unit, Department
of Obstetrics and Gynecology, Hospital General
portions of the mediastinum, has a determinant role in the
Universitario Gregorio Marañón, Calle O’Don- development of competent cellular immunity.1 The finding
nell 48, Planta 0, Bloque C, 28009 Madrid, Spain. of thymus agenesis or hypoplasia has been associated with 22q11
E-mail: jdeleonluis@yahoo.es microdeletion in the presence of conotruncal anomalies.2 Thymic
hypoplasia is also a common finding in cases of preterm prelabor
Abbreviations rupture of membranes, intrauterine growth restriction, maternal
GA, gestational age; ICC, intraclass correla- preeclampsia, and fetuses affected with Down syndrome and other
tion coefficient aneuploidies, which may explain the immune function impairment
doi:10.7863/ultra.34.5.853 in those cases.3–10
©2015 by the American Institute of Ultrasound in Medicine | J Ultrasound Med 2015; 34:853–858 | 0278-4297 | www.aium.org
3405jum749-894online_Layout 1 4/22/15 8:11 AM Page 854
Sonographic assessment of the fetal thymus can be described by Paladini14 and measured the fetal thymic
performed by different methods2,11–15; however, it still anteroposterior and transverse diameters in the thy-box
presents some difficulties.6 The perimeter is not always view (Figure 1).
easily defined and occasionally requires too much time.11 To assess interobserver agreement, 39 extra cases
The thymic transverse diameter has the extra difficulty of covering all of the gestational weeks in the study were
the subtle echogenic interphase between the thymus randomly reevaluated by another sonographer (C.B.).
and the lungs, which also varies with gestational age The thymus was measured independently by 2 observers;
(GA).12 The anteroposterior diameter may be narrowed neither of them knew about the results obtained by the
in cases of conotruncal anomalies,13 as the 3 vessels can be other. The agreement was interpreted according to
located ventrally. These difficulties set the need for a com- the criteria of Landis and Koch17 as poor (intraclass
mon anatomic landmark: the thy-box.14,16 correlation coefficient [ICC], <0.21), fair (ICC, 0.21–
The thy-box, described by Paladini,14 sets the bound- 0.40), moderate (ICC, 0.41–0.60), good (ICC, 0.61–0.80),
aries within the thymus and can be easily assessed. or excellent (ICC, >0.80).
Limited on both lateral sides by the internal mammary The feasibility of thy-box visualization and measure-
arteries, on the posterior side by the ductal and aortic arch, ments and their relationship with maternal and fetal vari-
on the ventral side by the sternum, and depicted with color ables (body mass index, uterine anomalies such as uterine
Doppler imaging, the thy-box may be an option for repro- fibroids and congenital malformations, type of pregnancy,
ducible evaluation of the thymus (Figure 1). The aim of our and fetal position) and GA were assessed. P < .05 was con-
study was to evaluate the feasibility and reproducibility of sidered statistically significant.
the thymus visualization in healthy singleton and twin For elaborating the nomograms, we followed the
fetuses from 15 to 37 weeks’ gestation using the thy-box method described by Royston and Wright.18 First, we
sonographic view and to set normative data for thymus selected the lowest polynomial degree (explored up to
diameters with this technique. the third degree) that was best adapted to the data using
the least squares method. Then we explored the residual
Materials and Methods data for any changes in the assumptions of normality and
homoscedasticity. The latter was obtained by using previ-
We conducted a cross-sectional observational study in the ous estimates for scaled absolute residuals and a regression
Fetal Medicine Unit of the Hospital Gregorio Marañón model of these residuals over weeks’ gestation. For inho-
between March 2011 and March 2013. The local Ethics mogeneous variance residuals, we chose to model the scaled
Committee approved the research protocol, and informed absolute residuals so they could be incorporated into the
consent was obtained from all patients. Patients were intervals of normality. Finally, we estimated the 95% con-
recruited consecutively from a cohort of pregnant women fidence intervals for each week of pregnancy.
referred for a routine prenatal sonographic evaluation. The relationship between thymic measurements and
All women had their pregnancies dated during first- GA was also studied according to the type of pregnancy
trimester sonography; in the case of twins, chorionicity was (singleton versus bichorionic/monochorionic twins) and
also determined in this scan. Inclusion criteria were a sono- fetal sex, which was assessed by sonography and checked
graphically confirmed last menstrual period and absence postnatally. By a linear regression model, we extracted the
of major fetal anomalies. Cases affected by intrauterine predicted means and standard deviations of the thymic
growth restriction and twin-twin transfusion syndrome were measurements for each gestational week. Data were ana-
excluded prenatally. Furthermore, cases were excluded post- lyzed with SPSS version 21 software (IBM Corporation,
natally because of preterm birth, adverse perinatal out- Armonk, NY).
comes, and loss of follow-up.
Sonographic examinations were performed by an Results
expert sonographer (F.G.) using 2 ultrasound systems with
transabdominal 4–8-MHz transducers (Voluson Expert; A total of 529 fetuses were initially included in our study;
GE Healthcare, Zipf, Austria; and Aplio 300; Toshiba 192 cases were excluded due to loss of follow-up (19.0%),
Medical Systems Co, Ltd, Tokyo, Japan). In our sono- preterm birth (13.4%), and adverse perinatal outcomes
graphic examinations, fetal biometry was assessed by the (3.0%). A total of 337 fetuses formed the final cohort after
biparietal diameter, abdominal circumference, and femur the exclusion criteria. Clinical and sonographic character-
length. We evaluated the thymus in the thy-box axial view istics of our cohort are shown in Table 1.
Visualization and measurement of both the antero- of the thy-box anatomic frame was limited, as the interphase
posterior and transverse diameters in the thy-box were between the thymic parenchyma and the lungs seemed to
possible in 250 cases (74.2%). In all cases, both diameters exceed the lateral limits of the thy-box, which were the
were equally observed. The interobserver agreement results internal mammary arteries (Figure 2). This finding led us
for the feasibility of the thy-box showed a κ value of 0.80. to truncate the values of the thy-box diameters between 15
Interobserver agreement for the thy-box measurements and 26 weeks’ gestation.
showed high concordance between observers. The ICC No other maternal or fetal factors were associated with
values were 0.81 (95% confidence interval, 0.556–0.923) lower feasibility. We found no significant differences in the
for the anteroposterior diameter and 0.87 (95% confidence feasibility of thy-box measurements regarding the type of
interval, 0.715–0.960) for the transverse diameter. pregnancy (singleton versus twins; P = .48), the presence
The main factors related to an impossibility of assess- of uterine fibroids or uterine malformations (P = .44), or
ing the measurements were an adverse fetal position (anterior the examination time (P = .08).
spine) and advanced GA. Nonfeasibility of the measurements We also assessed thymic anteroposterior and trans-
varied from 60.8% in cases of a fetal anterior spine to 19.8% verse diameters and studied their development through-
in any other fetal position (relative risk, 3.07; P < .001). out gestation. Figure 3 shows the means and standard
Gestational age showed an inverse relationship with the deviations of the anteroposterior and transverse diameters.
possibility of achieving thymus measurements (P = .006). The predicted mean of the anteroposterior diameter was
We also found that after 28 weeks’ gestation, the accuracy calculated as anteroposterior diameter = 0.32 × GA – 1.23
(R2 = 0.26; P < .001; SD = 1.35). The predicted mean of
the transverse diameter was calculated as transverse diam-
Figure 1. View of the thy-box in a 23-week-old fetus. Dashed blue lines
eter = 0.84 × GA – 6.48 (R2 = 0.73; P < .001; SD = 1.33).
show thy-box diameters (A, transverse; B, anteroposterior). IMA
indicates internal mammary artery; IV, innominate vein; T, trachea; and Table 2 shows the predicted means and 5th and 95th
Thy, thymus. percentiles for normal thy-box diameters at each GA.
These results did not differ significantly depending on
the type of pregnancy (singleton versus twins; Figure 4),
chorionicity in twin pregnancies (P = .33), or the fetal sex
(P = .54).
Discussion
related to a decrease in feasibility, similar to other studies twin bichorionic and monochorionic pregnancies, and
that assessed adequate visualization of cardiac anatomy in these findings were consistent with previous data.16,21,22
transverse views in the second trimester.19,20 On the other The thymic transverse diameter also shows a higher variation
hand, advancing GA seems to cause a decrease in the per- throughout pregnancy than the anteroposterior diameter,
centage of thy-box visualization, probably secondary to a which has been described with other techniques as well and
lesser delineation of its limits, as well as impairment of the may be related to the anatomy of the mediastinum.2,12,16,21,23
real contours of the gland and the lateral limits of the thy- According to the results of this study, the thy-box
box (Figure 2). seems to be a feasible and reproducible method not only
In this study, we have shown that thy-box diameters for qualitatively confirming the presence of the fetal thy-
can be obtained by sonography in the second and third mus but also for establishing its dimensions throughout
trimesters of pregnancy. Both thy-box measurements pregnancy. Nevertheless, this technique had certain limi-
showed excellent reproducibility in the interobserver tations. One of the most relevant seems to be that the thy-
study, according to the criteria of Landis and Koch.17 box transverse diameter is not reliable in the third trimester,
As described in previous studies, this gland develops in as we noticed beyond 28 weeks’ gestation. In these cases,
a linear pattern during fetal life,2,11–16 which was also con- the transverse diameter of the thymus exceeds the lateral
firmed in our study (Figure 3). No differences were found limits of the thy-box, which could substantially underesti-
between male and female fetuses or between singleton and mate the true transverse diameter of the gland (Figure 3).
Figure 2. Limitations of the thy-box transverse diameter (TD) in the third trimester. Left, Anatomic transverse thymus diameters in 28- and 30-week-
old fetuses. Right, Thy-box diameters (1, transverse; 2, anteroposterior). The true limits of the fetal thymus are underestimated by the thy-box trans-
verse diameters in the third trimester.
Another factor that can modify the usefulness of the thy- tertiary centers where cases at risk of thymic hypoplasia
box is the need for color Doppler imaging, which means (mainly conotruncal congenital heart disease) are evalu-
that its assessment requires equipment that contains this ated and managed.
tool and sonographer knowledge. Although more and more The thy-box anatomic landmark may establish a con-
units are incorporating color Doppler imaging in routine sensus among sonographers and standardize future studies.
sonographic scans, especially for evaluation of the fetal Thymus evaluation during pregnancy is not performed
heart at 15 to 22 weeks, this method may still be reserved for during routine sonography, but interest in it has increased.
Figure 3. Assessment of thy-box anteroposterior (A) and transverse Table 2. Predicted Means and Percentiles for Anteroposterior and
(B) diameters. Lines represent means and standard deviations. Transverse Diameters
Predicted mean formulas are also shown. APD indicates anteroposte-
GA, wk Mean 5th 95th
rior diameter; and TD, transverse diameter.
Anteroposterior
15 3.52 0.82 6.23
16 3.84 1.13 6.55
17 4.16 1.45 6.87
18 4.48 1.77 7.18
19 4.79 2.08 7.50
20 5.11 2.40 7.82
21 5.43 2.72 8.14
22 5.74 3.03 8.45
23 6.06 3.35 8.77
24 6.38 3.67 9.09
25 6.69 3.99 9.40
26 7.01 4.30 9.72
27 7.33 4.62 10.04
Transverse
15 6.18 3.52 8.84
16 7.02 4.36 9.68
17 7.87 5.21 10.53
18 8.71 6.05 11.37
19 9.56 6.90 12.22
20 10.40 7.74 13.06
21 11.24 8.58 13.90
22 12.09 9.43 14.75
23 12.93 10.27 15.59
24 13.78 11.12 16.44
25 14.62 11.96 17.28
26 15.46 12.80 18.12
27 16.31 13.65 18.97
As Chaoui et al2 established, among fetuses with conotrun- of the fetal immunoendocrine response to malnutrition. Ultrasound Obstet
cal anomalies, thymic hypoplasia or aplasia has sensitivity Gynecol 2009; 33:421–426.
of 90.0%, specificity of 98.5%, a positive predictive value of 7. Eviston DP, Quinton AE, Benzie RJ, Peek MJ, Martin A, Nanan RK.
81.8%, and a negative predictive value of 99.2% for identi- Impaired fetal thymic growth precedes clinical preeclampsia: a case-
fication of fetuses with 22q11 microdeletion. Moreover, control study. J Reprod Immunol 2012; 94:183–189.
there is an association between fetal thymic hypoplasia and 8. Mohamed M, Eviston DP, Quinton AE, et al. Smaller fetal thymuses in
obstetric disorders such as fetal inflammatory response pre-eclampsia: a prospective cross-sectional study. Ultrasound Obstet
syndrome in the context of prolonged premature rupture Gynecol 2011; 37:410–415.
of membranes, intrauterine growth restriction, maternal 9. De León-Luis J, Santolaya J, Gámez F, Pintado P, Pérez R, Ortiz-Quintana
preeclampsia, and chromosomal abnormalities such as L. Sonographic thymic measurements in Down syndrome fetuses.
Down syndrome, suggesting the role of the immune system Prenat Diagn 2011; 31:841–845.
in these disoders.3–10 Under these conditions, sonographic 10. Karl K, Heling KS, Sarut Lopez A, Thiel G, Chaoui R. Thymic-thoracic
assessment of the fetal thymus by the thy-box or any other ratio in fetuses with trisomy 21, 18 or 13. Ultrasound Obstet Gynecol 2012;
method becomes extremely important. Future studies are 40:412–417.
needed to assess thy-box diameters in cases of pathologic 11. Zalel Y, Ganzu R, Mashiach S, Achiron R. The development of the fetal
fetal findings, especially conotruncal anomalies and other thymus: an in utero sonographic evaluation. Prenat Diagn 2002; 22:114–
obstetric and perinatal disorders associated with thymus 117.
hypoplasia.2,16 12. Cho JY, Min JY, Lee IH, McCrindle B, Hornberger LK, Yoo SJ. Diameter
In conclusion, we have shown that visualization of the of the normal fetal thymus on ultrasound. Ultrasound Obstet Gynecol 2007;
thy-box and determination of the anteroposterior and 29:634–638.
transverse diameters is feasible between 15 and 27 weeks 13. Felker RE, Cartier MS, Emerson DS, Brown DL. Ultrasound of the fetal
of pregnancy, with excellent interobserver reproducibility. thymus. J Ultrasound Med 1989; 8:669–673.
The major limitation to its use seems to be an adverse fetal 14. Paladini D. How to identify the thymus in the fetus: the thy-box.
position. The effectiveness of the thy-box is limited in the Ultrasound Obstet Gynecol 2011; 37:488–492.
third trimester, as the transverse diameter of the gland is 15. Li L, Bahtiyar MO, Buhimschi CS, Zou L, Zhou QC, Copel JA.
underestimated. Thy-box measurements could be useful Assessment of the fetal thymus by two- and three-dimensional ultrasound
for sonographic evaluations of fetal thymic development during normal human gestation and in fetuses with congenital heart
and for studies of this gland in pathologic conditions dur- defects. Ultrasound Obstet Gynecol 2011; 37:464–469.
ing the second trimester. Further studies are needed to 16. Mu~noz-Chápuli M, Bravo Arribas C, Gámez-Alderete F, Fernández-
evaluate thy-box diameters in pathologic cases. Pacheco RP, Ortiz-Quintana L, De León-Luis J. Ultrasound scan of the
fetal thymus [in Spanish]. Ginecol Obstet Mex 2014; 82:43–49.
References 17. Landis JR, Koch GG. The measurement of observer agreement for cate-
gorical data. Biometrics 1977; 33:159–174.
1. Di George AM, Lischner HW, Dacou C, Arey JB. Absence of the thymus. 18. Royston P, Wright EM. How to construct “normal ranges” for fetal vari-
Lancet 1967; 1:1387. ables. Ultrasound Obstet Gynecol 1998; 11:30–38.
2. Chaoui R, Heling KS, Sarut Lopez A, Thiel G, Karl K. The thymic-thoracic 19. Schwarzler P, Senat MV, Holden D, Bernard JP, Masroor T, Ville Y.
ratio in fetal heart defects: a simple way to identify fetuses at high risk for Feasibility of the second-trimester fetal ultrasound examination in an uns-
microdeletion 22q11. Ultrasound Obstet Gynecol 2011; 37:397–403. elected population at 18, 20 or 22 weeks of pregnancy: a randomized trial.
3. Musilova I, Hornychova H, Kostal M, Jacobsson B, Kacerovsky M. Ultrasound Obstet Gynecol 1999; 14:92–97.
Ultrasound measurement of the transverse diameter of the fetal thymus 20. DeVore GR, Medearis AL, Bear MB, Horenstein J, Platt LD. Fetal
in pregnancies complicated by the preterm prelabor rupture of echocardiography: factors that influence imaging of the fetal heart during
membranes. J Clin Ultrasound 2013; 41: 283–289. the second trimester of pregnancy. J Ultrasound Med 1993; 12:659–663.
4. Yinon Y, Zalel Y, Weisz B, et al. Fetal thymus size as a predictor of 21. De León-Luis J, Gámez F, Pintado P, et al. Sonographic measurements of
chorioamnionitis in women with preterm premature rupture of mem- the thymus in male and female fetuses. J Ultrasound Med 2009; 28:43–48.
branes. Ultrasound Obstet Gynecol 2007; 29:639–643. 22. Gámez F, De León-Luis J, Pintado P, et al. Fetal thymus size in uncom-
5. El-Haieg DO, Zidan AA, El-Nemr MM. The relationship between sono- plicated twin and singleton pregnancies. Ultrasound Obstet Gynecol 2010;
graphic fetal thymus size and the components of the systemic fetal 36:302–307.
inflammatory response syndrome in women with preterm prelabour rup- 23. Gardiner H, Chaoui R, The fetal three-vessel and tracheal view revisited.
ture of membranes. BJOG 2008; 115:836–841. Semin Fetal Neonatal Med 2013; 18:261–268.
6. Chromi A, Ghezzi F, Raffaelli R, Bergamini V, Siesto G, Bolis P.
Ultrasonographic measurement of thymus size in IUGR fetuses: a marker