The equals sign : a novel marker in the diagnosis of fetal isolated cleft palate

Ultrasound Obstet Gynecol 2010; 36: 439 444 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.7704 The equals sign : a novel marker in the diagnosis of fetal isolated cleft palate L. WILHELM and H. BORGERS Centre of Fetal Medicine, Huerth, Germany KEYWORDS: cleft lip and palate; cleft palate; palate; prenatal diagnosis; soft palate; uvula ABSTRACT Objectives To determine the feasibility of visualization of the uvula and the soft palate during routine twodimensional (2D) ultrasound examination and to develop a sonographic procedure that facilitates prenatal detection of isolated fetal cleft palate. Methods We examined 667 consecutive patients with a singleton pregnancy between 20 and 25 weeks of gestation who were referred to our practice for a detailed fetal anomaly scan. The uvula was visualized either in a frontal section through the neck and pharynx or via a transverse section with subsequent slight tilting of the transducer. The soft palate was visualized in a median sagittal section through the head. To test whether the techniques described are suitable for inclusion in routine examinations, the time allowed for a normal ultrasound scan was not changed from 30 min. Results A normal uvula could be visualized with a typical echo pattern (the equals sign ) in 90.7% of the cases and the soft palate could be completely visualized in a median sagittal section in 85.3% of the cases. Visualization of at least one of the two structures (either the uvula or the soft palate) was successful in 98.4% of the cases. In one case an isolated cleft palate (in an otherwise normal fetus) was diagnosed; in one case with a cleft lip and palate, the cleft palate and the completely split uvula were detected. In 1.2% of the cases the examination did not provide sufficient information on either the uvula or the soft palate. Conclusions In a high percentage of cases, relevant soft palate structures can be visualized successfully with 2D ultrasound, permitting cleft palate to be ruled out in routine examinations. Visualization of the equals sign proves an intact palate. Absence of the equals sign indicates cleft palate and should prompt further examination of the soft palate in a median sagittal section. Cleft palate can be confirmed when the soft palate cannot be visualized. This technique also facilitates evaluation of the soft palate in the event of a cleft lip and palate. Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION Facial clefts are among the most frequent congenital malformations, occurring with an incidence of about 1 : 1000 births 1,2. They are present in various forms, whereby from the perspective of pathophysiology, cleft lip and palate (CLP) and isolated cleft palate (CP) are two entirely different defects. CLP always starts at the lip and proceeds to different extents in the dorsal direction (alveolus, hard palate, soft palate). CP always starts at the uvula (uvula bifida as the mildest form) and proceeds along the midline in the anterior direction, affecting either only the soft palate or both the soft and hard palates. Both CLP and CP can occur as isolated defects or as components of chromosomal or syndromal disorders 7.PrenataldetectionofCLP during a detailed ultrasound examination is less difficult than is the evaluation of the palate structures involved in CLP, especially the soft palate. The fact that the prenatal detection rate of CP is very low (0 1.4%) 3 8 demonstrates that there are no satisfactory sonographic indicators of an isolated CP. Because of its dome-shaped structure, the palate cannot be visualized in its entirety by two-dimensional ultrasound (2D). Moreover, ultrasound artifacts from the surrounding osseous structures complicate sonographic assessment. As the whole palate cannot be visualized, the aim of this study was to identify at least one palate structure that could serve as an indicator for the entire palate. Because CP always starts at the uvula, the presence of an unremarkable uvula implies the presence of an intact palate. If the uvula is abnormal or cannot be detected at all, this indicates a defect in the palate. If a cleft is present, it should be detectable along the midline of the soft palate. Correspondence to: Dr L. Wilhelm, Praxis für pränatale Diagnostik und Therapie, Luxemburger Str. 99, 50354 Hürth, Germany (e-mail: info@borgers-wilhelm.de) Accepted: 20 May 2010 Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

440 Wilhelm and Borgers To clarify these hypotheses, our study had to determine the following: how well and reliably the uvula and/or the soft palate can be imaged on 2D ultrasound; whether this procedure can rule out or detect an isolated cleft palate; whether the procedure is reliable, even if scanning conditions are not optimal; and whether the method can be implemented during a routine examination without increasing the time required. METHODS Between May and September 2009, we examined 667 patients referred for various reasons to our practice for a detailed fetal ultrasound examination. We included all patients with a singleton pregnancy between 20 and 25 weeks of gestation (mean gestational age 21 + 5 weeks, mean body mass index 26.1). Gestational age was calculated from menstrual dates or from crown rump length determined in the first trimester. If both methods yielded results different by more than 7 days, the latter method was chosen. The study group included fetuses with varying pathologies (e.g. chromosomal aberrations, abdominal wall defects, brain malformations, heart defects, neural tube defects, malformations of the extremities). The examinations were performed by two investigators (L.W. and H.B.) using a Toshiba Aplio XG ultrasound system (Toshiba Medical Systems Europe, Zoetermeer, The Netherlands). Two different procedures were used to visualize the uvula: 1. A frontal section through the neck and the pharyngeal space, whereby the epiglottis serves as the landmark for identifying the uvula. The pharyngeal space was scanned in the dorsal and ventral directions until the uvula could be visualized cranial to the epiglottis. The echo pattern of the normal uvula is typical and strongly resembles an equals sign (two hyperechoic lines with a hypoechoic intermediate space); therefore, we named the normal uvula the equals sign (Figure 1a and Videoclip S1). 2. A transverse section through the head at the level of the thalamus; the transducer is moved parallel to this plane in the caudal direction until the nasopharynx is visualized in the center. When the transducer is carefully moved further in the caudal direction, the soft palate and the uvula are encountered. The latter can be visualized along its entire length by slightly tilting the transducer. Here, the typical equals sign is also seen (Figure 1b and Videoclip S2). In our experience this technique yields a higher success rate and can be better integrated into routine practice than the frontal approach. Figure 1 Ultrasound images of normal fetal uvula and soft palate. (a) Frontal section through the pharynx for visualization of the uvula ( ); the landmark for orientation is the epiglottis ( ). (b) Transverse section for visualization of the uvula ( ). (c) Mid-sagittal section with visualization of the soft palate ( ) including the uvula ( ); the tongue is indicated ( ).

Equals sign in the prenatal diagnosis of cleft palate 441 Figure 2 (a) Sagittal ultrasound image showing absence of the soft palate ( ), including the uvula, in a case of isolated cleft palate (in the frontal and transverse sections of the pharynx no equals sign was found; see Videoclip S5); the tongue is indicated ( ). (b) Ultrasound image of the same fetus when yawning, clearly demonstrating the absence of the soft palate ( ). (c) Postpartum image of the infant showing the isolated cleft palate with a large defect (image provided by Prof. Braumann, Department of Orthodontology, University of Cologne, Germany). Nasal septum ( ), tongue ( ), maxilla ( ) and cleft palate ( ) are indicated. The objective of this study was to image the uvula irrespective of the plane in which the equals sign could be detected (i.e. in either the frontal plane or the transverse plane). If imaging in one plane was unsuccessful, visualization in the other plane was attempted. As soon as the uvula could be visualized as the equals sign, this was documented and the routine examination was continued. The soft palate was visualized in a median sagittal section. In contrast to conventional visualization of the profile, the ultrasound beam should be directed more towards the chin in order to utilize the ultrasound window between the lower and upper jaws. With a notably overextended head the soft palate can be visualized in a median sagittal section, even if the ultrasound is directed from below the chin (Figure 1c and Videoclips S3 and S4). To test whether the techniques described are suitable for inclusion in routine examinations, the time allowed for a normal ultrasound scan was not changed from 30 min. RESULTS In 90.7% of the cases (605/667) the uvula could be detected as a typical equals sign. Visualization of the soft palate in the median sagittal section was successful in 85.3% of the cases (569/667). Detection of at least one of the two structures (either the uvula in a frontal section or the soft palate in a sagittal section) was successful in 98.4% (656/667) of cases. We found three cases with clefts in our patient series. In one case, in which neither the uvula nor the soft palate could be visualized, a CP was diagnosed and confirmed after birth (Figure 2, Videoclips S5 S7). The fetus was otherwise normal and chromosomal analysis yielded an unremarkable karyotype. In one fetus who exhibited unilateral CLP, our method was used to confirm the involvement of the soft palate and a completely cleft uvula (Figure 3, Videoclips S8 and S9). In a case of bilateral CLP, we were able to correctly diagnose the fully continuous cleft also in the area of the soft palate (Figure 4, Videoclip S10). Either because of the general ultrasound conditions or the unfavorable position of the fetus (significant flexion of the head), in eight cases (1.2%) it was impossible to visualize either the uvula or the soft palate. Therefore, the integrity of the palate could not be assessed. DISCUSSION Prenatal detection of CP is a challenge in prenatal diagnosis. The low detection rate is evidence of the difficulty of visualizing CP during routine examination 3 8.Furthermore, even if a CP is suspected, diagnostic accuracy is low. In a study of nearly 50 000 non-selected deliveries, Offerdal et al. 6 found 25 cases of CP without cleft lip after birth, none of which had been detected prenatally. In a series published by Gillham et al. 7, none of the 252 cases of CP without cleft lip was diagnosed before birth. In another study, Cash et al. 8 reported two out of nine cases of CP, but the diagnosis was made on the basis of an abnormal facial profile and a midline facial defect, and we speculate that neither of the diagnosed cleft palates was an isolated anomaly. Because of the dome-shaped structure of the palate and the associated difficulties in 2D visualization, threedimensional (3D) imaging has provided a new approach in the investigation of the palate. Several studies have focused on 3D visualization of the palate and different techniques have been described 9 16. However, these studies were primarily concerned with the methodology and the sonographic approach used to provide images of the palate structures in normal fetuses; the number of pathologies described was relatively small. Faure et al. 14 and Wong et al. 15 included no pathology. Pilu and Segata 13 reported one case of CLP, while Campbell et al. 11 and Martinez Ten et al. 16 describedeightand10cases,respectively.

442 Wilhelm and Borgers (c) Figure 3 Ultrasound images in a case with unilateral cleft lip and palate (CLP). (a) In the mid-sagittal section, the soft palate ( ) is not visible, but the uvula ( ) is present; the tongue is indicated ( ). (b) The transverse section clearly demonstrates the cleft uvula ( )witha double equals sign. (In Videoclip S9 the changing distance between both parts of the cleft uvula can be seen.) (c) Schematic representation of this case of unilateral CLP. All studies that described structural defects in the palate involved clefts in which the lip was also affected. Of note, none of the studies described an isolated cleft palate. With the exception of Wong et al. 15, all studies were successful in visualizing the hard palate, but had notable difficulties imaging the soft palate. Faure et al. 14 did not describe the soft palate at all. Pilu and Segata 13 pointed out that... it is not certain whether this technique would be helpful in diagnosing isolated clefts of the soft palate. Martinez Ten et al. 16 were able to correctly assess the involvement of the soft palate in only one case out of their series of seven CLPs. Likewise, soft-palate visualization was only possible in 26% of cases of their control sample. Significantly better results regarding 3D visualization of the soft palate and the uvula were shown by Wong et al. 15. The soft palate was visualized in all cases of > 20 weeks of gestation. However, the small number of cases (31 volumes over a time period of 10 months) suggests significant selection with respect to the quality of the volumes. In short, the new 3D techniques also appear to have clear limitations regarding assessment of the soft palate. Importantly, there is no description of a CP visualized using 3D sonography. As all CPs begin at the uvula and then extend a variable distance through the soft palate in the anterior direction, visualization of a normal uvula should be sufficient to rule out a CP. 3D methods are not suitable for the routine detection of isolated CP, for three reasons: first, in screening programs 2D ultrasound is usually used; second, 3D visualization requires good ultrasound conditions and the acquisition of excellent volumes, limiting its routine use 15,16 ; and, third, during visualization of the soft palate in a sagittal section, real-time imaging with its dynamics is very important. Reliable visualization and evaluation frequently occurs during swallowing movements of the fetus when the soft palate is lifted briefly off the tongue. This temporal resolution cannot be achieved with one volume. Imaging rates of the uvula and the soft palate were high in our series, and there are a number of possible reasons for the high success rate observed. The pharynx is mostly fluid-filled, which facilitates differentiation from the surrounding tissues. Ultrasound artifacts caused by osseous structures become more pronounced with increasing gestational age. In the second trimester these phenomena are not yet sufficiently pronounced to significantly interfere with imaging quality. It is our subjective impression that successful imaging of the uvula and the soft palate declines significantly with gestational age. Importantly, we observed a significant training effect during the study period. The examination time required for making appropriate adjustments significantly decreased over time, whereas our ability to interpret ultrasound findings made in poor visual conditions increased significantly. As our study was performed using 2D ultrasound we cannot prove that the exact median sagittal plane was chosen at all times. However, as all CPs lie along the midline, we do not think that this limitation is of practical importance except for very small CPs. The latter are an uncommon occurrence as in most affected cases the cleft is wide and not limited only to the exact median sagittal plane. The study primarily focused on a novel technique to diagnose clefts of the soft palate. It was not designed to describe the extent of the defect in the soft palate. In principle, we expect even small clefts of the soft palate to be visualized using our technique. Importantly, under certain circumstances (e.g. when the fetal head is overextended), the hard palate can also be demonstrated in the sagittal section. In summary, with our new technique we were able to visualize the normal uvula as an equals sign in a large majority of fetuses, even under suboptimal ultrasound conditions. In general, pathology of the uvula (in our example a cleft uvula) can be visualized. If the uvula cannot be visualized in its typical presentation or at all, a CP is not proven but needs to be ruled out. In these

Equals sign in the prenatal diagnosis of cleft palate 443 ACKNOWLEDGMENTS We are grateful to Prof. Braumann for his help in our understanding the pathophysiology of facial clefts and for the postnatal pictures, to Mike Beyer from Toshiba Medical Systems for her support and to Prof. Ralf Schild for his help in revising the manuscript. REFERENCES Figure 4 (a) Mid-sagittal ultrasound image in a case of bilateral cleft lip and palate (CLP). The soft palate including the uvula is not visible ( ); the tongue is indicated ( ). (b) Postpartum image of the same case showing bilateral CLP with a large defect of the palate (image provided by Prof. Braumann, Department of Orthodontology, University of Cologne, Germany). Nasal septum ( ), maxilla ( ) and cleft palate ( ) are indicated. cases the soft palate should be imaged in a median sagittal section to visualize the palate structures in more detail. A secondary, targeted 3D examination may be helpful in this scenario. Larger prospective studies are needed to confirm our results. We are, however, certain that our new technique may improve the prenatal detection rate of isolated cleft palates. 1. Gregg T, Bod D, Richardson A. The incidence of cleft lip and palate in Northern Ireland from 1980 1990. BrJOrthod1994; 21: 387 392. 2. Coupland MA, Coupland AI. Seasonality, incidence and sex distribution of cleft lip and palate birth in Trent region (1973 82). Cleft Palate J 1988; 25: 33 37. 3. Grandjean H, Larroque D, Levi S. The performance of routine ultrasonographic screening of pregnancies in the Eurofetus Study. Am J Obstet Gynecol 1999; 181: 446 454. 4. Clementi M, Tenconie R, Bianchi F, Stoll C. Evaluation of prenatal diagnosis of cleft lip with or without cleft palate and cleft palate by ultrasound: experience from 20 European registries. EUROSCAN study group. Prenat Diagn 2000; 20: 870 875. 5. Shaikh D, Mercer NS, Sohan K, Kyle P, Soothill P. Prenatal diagnosis of cleft lip and palate. Br J Plastic Surg 2001; 54: 288 289. 6. Offerdal K, Jebens N, Syvertsen T, Blaas HG, Johansen OJ, Eik-Nes SH. Prenatal ultrasound detection of facial clefts: a prospective study of 49 314 deliveries in a non-selected population in Norway. Ultrasound Obstet Gynecol 2008; 31: 639 646. 7. Gillham JC, Anand S, Bullen PJ. Antenatal detection of cleft lip with or without cleft palate: incidence of associated chromosomal and structural anomalies. Ultrasound Obstet Gynecol 2009; 34: 410 415. 8. Cash C, Set P, Colemann N. The accuracy of antenatal ultrasound in detection of facial clefts in a low risk screening population. Ultrasound Obstet Gynecol 2001; 18: 432 436. 9. Campbell S. Prenatal ultrasound examination of the secondary palate. Ultrasound Obstet Gynecol 2007; 29: 124 127. 10. Rotten D, Levaillant JM. Two-and three-dimensional sonographic assessment of the fetal face. 2. Analysis of cleft lip, alveolus and palate. Ultrasound Obstet Gynecol 2004; 24: 402 411. 11. Campbell S, Lees C, Moscoso G, Hall P. Ultrasound antenatal diagnosis of cleft palate by a new technique: the 3D reverse face view. Ultrasound Obstet Gynecol 2005; 25: 12 18. 12. Platt LD, DeVore GR, Pretorius DH. Improving cleft palate/cleft lip antenatal diagnosis by three-dimensional sonography. The flipped face view. J Ultrasound Med 2006; 25: 1423 1430. 13. Pilu G, Segata M. A novel technique for visualisation of the normal and cleft fetal secondary palate: angled insonation and three-dimensional ultrasound. Ultrasound Obstet Gynecol 2007; 29: 166 169. 14. Faure JM, Captier G, Bäumler M, Boulot P. Sonographic assessment of normal fetal palate using three-dimensional imaging: a new technique. Ultrasound Obstet Gynecol 2007; 29: 159 165. 15. Wong HS, Tait J, Pringle KC. Examination of the secondary palate on stored 3D ultrasound volumes of the fetal face. Ultrasound Obstet Gynecol 2009; 33: 407 411. 16. Martinez Ten P, Perez Pedregosa J, Santacruz B, Adiego B, Barron E, Sepulveda W. Three-dimensional ultrasound diagnosis of cleft palate: reverse face, flipped face or oblique face which method is best? Ultrasound Obstet Gynecol 2009; 33: 399 406.

444 Wilhelm and Borgers SUPPORTING INFORMATION ON THE INTERNET The following supporting information may be found in the online version of this article: Videoclip S1 Approach for visualization of the uvula using the frontal section through the neck and pharynx. Note the epiglottis as the landmark for orientation. Videoclip S2 Approach for visualization of the uvula using the transverse section (in our experience this technique seems to be easier and more successful than using the frontal section). Videoclips S3 and S4 Normal anatomy in the mid-sagittal section with visualization of the soft palate including the uvula. Note the function of the soft palate in avoiding glossoptosis when swallowing or yawning. Videoclip S5 Frontal section approach through the pharynx for visualization of the uvula in a case of isolated cleft palate. The uvula is not visible (no equals sign ). Videoclip S6 Isolated cleft palate in the mid-sagittal section with the mouth closed. The soft palate and the uvula are not visible. Videoclip S7 Isolated cleft palate in the mid-sagittal section when the fetus is yawning. The soft palate and the uvula are not visible. Note the glossoptosis when yawning. Videoclip S8 Mid-sagittal view in a case of left cleft lip and palate. The anterior part of the soft palate is not visible but the uvula can be demonstrated. Videoclip S9 Investigation of the uvula in a case of left cleft lip and palate. Note the double equals sign and the changing distance between both parts showing the cleft uvula. Videoclip S10 Mid-sagittal view in a case of bilateral cleft lip and palate. The soft palate including the uvula is not visible, indicating the complete defect of the palate.