Abstract
Objective:
The study aims to evaluate the role of the posterior hard palate angle in the prenatal diagnosis of cleft palate.
Study Design:
Stored images of the axial transverse view of the fetal secondary palate, obtained at three-level obstetric ultrasounds, were used to evaluate the posterior border of the hard palate. The study population comprised 63 consecutive pregnancies of unaffected cases and 17 pregnancies suspected for a cleft palate without cleft lip, including 7 cases of cleft palate, 4 cases of high-arched palate, and 6 false-positive cases.
Results:
The posterior angle of the hard palate was significantly larger in the cleft palate group than in the healthy controls and false-positive cases: 227° (±51°) vs 160° (±16°), p < 0.0001; and 173° ± 18°, p < 0.0001, respectively. Regression analysis revealed that reflex angle remained an independent risk factor for cleft palate (odds ratio, 58.67 (95% confidence interval 10–341)). The sensitivity and specificity of the posterior angle assessment were 73% and 96%, respectively.
Conclusions:
The posterior hard palate angle could be an ultrasound marker of cleft palate without a cleft lip.
Introduction
According to the literature, the prevalence of isolated cleft palate is slightly lower than that of cleft lip. 1 However, the prenatal detection rate of cleft palate is relatively modest compared to that of cleft lip, probably because of the lack of a standardized approach for hard palate assessment. 2 At present, visualization of the hard palate is not routinely performed in the mid-trimester fetal ultrasound scan. 3
Faure et al. 4 described three-dimensional (3D) ultrasound semiology of the cleft palate. They defined cleft palate as a disruption in the horizontal plate of the secondary palatine bone. Three-dimensional imaging is easy to implement. Nevertheless, 3D ultrasound is not always accessible and thus is not routinely performed. Furthermore, good 3D ultrasound practice requires perfect two-dimensional (2D) ultrasound settings and a clear interpretation of 2D images.
Although hard palate visualization is not mandatory, many professionals who perform prenatal ultrasounds assess it as a part of fetal evaluation. Currently, there is no uniformity in antenatal diagnosis of cleft palate. Some of the existing 2D techniques aim to detect fetuses at high risk of cleft palate: The jaw index and inferior facial angle provide an accurate diagnostic for micrognathia and retrognathia.5,6 The “equals sign” and the absence of a “superimposed-line” sign indicate indirect ultrasound signs of cleft palate.7,8 Fuchs et al.9,10 recently published a feasible method for directly assessing the fetal hard palate on 2D in the second-trimester scan: the axial transverse view.
The aim of our retrospective study was to describe an additional key point in the prenatal diagnosis of cleft palate without cleft lip to expand the ultrasound semiology of the axial transverse view of the fetal hard palate.
Materials and methods
We conducted a retrospective cohort study at a single center. The study population comprised 17 patients suspected of having cleft palate without cleft lip referred to our Multidisciplinary Center for Prenatal Diagnosis between January 2019 and January 2023. We compared the suspected group with 63 unaffected consecutive and unselected singleton pregnancies between 17 and 37 weeks, identified from our ultrasound database from June 2022 to August 2022. The exclusion criteria for the control group were major congenital anomaly or chromosomal aberration, premature rupture of the membranes, fetal demise, and age under 18 years. If the available images did not allow the complete evaluation of the hard palate, the case was also excluded from further consideration.
According to our local protocol, all patients underwent precise examination of the fetal lip and palate to screen for clefts. The initial suspicion of cleft palate prior to the measurement of the hard palate angle was based on the presence of interruption or lack of visualization of the horizontal hyperechoic plate of the palatine bone. The characterization of true- and false-positive cases was based on whether the initial suspicion of cleft palate was correct.
Ultrasound examinations were performed using a General Electric Medical Systems (Zipf, Austria) ultrasound machine and a RM7 C 2- to 8‑ MHz or a RM6 C 2- to 7-MHz curved array transducers. All examinations and images of the fetal palate were performed by a single experienced sonographer. The palate assessments followed the method recently published by Fuchs et al. 9 for assessing the fetal hard palate on 2D: the axial transverse view (Figure 1). The magnification was maximal, so that the hard palate occupied at least one-third of the image. The insonation was perpendicular to the palatine bone, and the alveolar ridge of the superior maxilla was well visualized.
Diagram illustrating the method by Fuchs et al. 9 for assessing the fetal hard palate on 2D: the axial transverse view; the yellow lines demonstrate the posterior borders of the palatine bones; the asterisks illustrate the alveolar ridge; and arrows show the pterygoid processes.
Stored images of the axial transverse view were examined retrospectively. The soft-to-hard palate interface has been studied. We assessed the visualization of the posterior nasal spine and the presence of a gap within the hard palate. We also measured the posterior angle of the hard palate, formed by the posterior borders of the palatine bones, just next to the most posterior midpoint of the palatine bone. When the measurement of the angle was slightly less than or equal to 180°, it was determined to be a straight-angle type. The reflex angle type was defined as an angle with a measurement greater than 180° (Figure 2).
Axial transverse view of the hard palate demonstrating the posterior hard palate angle. (a) Normal orientation of the posterior borders of the palatine bones (yellow lines) in a fetus at 23 weeks of gestation. The yellow arrow indicates the nasal spine. The diagram in the right upper corner shows the disposition of the alveolar ridge, posterior borders of the palatine bones, and pterygoid processes in this case. (b) Normal hard palate with no visualization of the nasal spine and straight angle of the posterior borders (yellow lines) at 21 weeks of gestation. (c) Reflex angle in a fetus with cleft palate at 22 weeks of gestation. The diagram in the right upper corner shows the disposition of the alveolar ridge, posterior borders of the palatine bones, and pterygoid processes.
Demographic data and pregnancy outcomes were collected from the hospital maternity records. The study was approved by the local ethics committee. The study complied with the World Medical Association Declaration of Helsinki regarding the ethical conduct of research involving human subjects. All the patients included in our study gave their oral consent for their data use.
To assess the interobserver agreement, we performed a study with 34 fetuses from the study population. Random sampling was performed using R version 3.3.3 for Windows. After brief training, two operators independently evaluated the posterior hard palate angle as straight or reflex. The interoperator agreement was assessed using the kappa concordance coefficient.
Distributions were tested for normality using the Kolmogorov-Smirnov test. Statistical comparisons were performed using the unpaired t-test for continuous variables, the Mann–Whitney U test for non-normally distributed data, and the Fisher exact and chi-square tests for categorical variables. All analyses were two-tailed, and p < 0.05 was used to define statistical significance. The statistical software package IBM SPSS Statistics 24.0 was used for data analysis.
Results
The median gestational age at assessment was 25 weeks (interquartile range, 21–31). The quality of the hard palate assessment was sufficient in 63 out of 74 cases (85%) in the control group of unaffected cases. The study population comprised 80 pregnancies, including 63 (79%) unaffected cases and 17 (21%) suspected cases, represented by 11 (13%) true-positive cases and 6 (8%) false-positive cases, confirmed in the newborn infant physical examination or fetal autopsy. The group of true-positive cases contained seven cases of cleft palate without cleft lip and four cases of high-arched palate.
Interobserver agreement of the subjective evaluation of the posterior hard palate angle type as straight or reflex was good (Kappa = 0.53 and the number of discordant pairs was 5 out of 34).
The characteristics of the study population are presented in Table 1. We found no significant differences in age, height, body mass index, and gestational age. There was a higher prevalence of major associated anomalies and genetic disorders in the affected and false-positive groups (54% and 83% vs 0%; p < 0.001, 54% and 33% vs 0%; p < 0.001). The proportion of pregnancy termination was higher in the affected group than that in the false-positive and control groups (36% vs 17% and 0%, respectively; p < 0.001).
Maternal clinical characteristics of the study population of pregnant women by unaffected, true-positive and false-positive cases.
Data are given as mean ± SD, median (interquartile range), or n (%). Comparisons between groups by chi-square or Fisher’s exact tests for categorical variables and the Mann–Whitney U-test and unpaired t-tests for continuous variables. BMI, body mass index.
p < 0.05.
Table 2 shows the fetal ultrasound characteristics of the hard palate by group. The posterior angle of the hard palate was straight in the control group and reflexed in the true-positive group (95% and 80%, respectively; p < 0.001). The nasal spine was visualized in half of the control group, and only one-fifth of the true-positive group (p = 0.02). In the false-positive group, there was always a gap within the palate (100%, p < 0.001), but the posterior angle of the hard palate was straight (100%, p < 0.001).
Fetal ultrasound characteristics of the hard palate in the study population of pregnant women by unaffected, true-positive, and false-positive cases.
Data are given as mean ± SD, median (interquartile range), or n (%). Comparisons between groups by chi-square or Fisher’s exact tests for categorical variables and the Mann–Whitney U-test and unpaired t-tests for continuous variables.
p < 0.05.
The posterior angle of the hard palate data was normally distributed in the control group. The posterior angle of the hard palate was significantly larger in the cleft palate group than in the healthy controls and false-positive cases: 227 (±51°) vs 160° (±16°), p < 0.0001; and 173° ± 18°, p < 0.0001, respectively (Figure 3). The results of univariate regression analysis for the diagnosis of cleft are presented in Table 3. Regression analysis revealed that reflex angle remained an independent risk factor for cleft palate (odds ratio, 58.67 (95% confidence interval 10–341)).
Scatterplot of posterior angle of the hard palate measurements in normal fetuses (circles) and affected fetuses (triangles) according to gestational age (in weeks).
Univariate regression analysis in prediction of cleft palate.
p < 0.05.
The sensitivity and specificity for the presence of a gap in the palate were 73% and 86%, respectively. The sensitivity and specificity of posterior angle assessment were 73% and 96%, respectively.
Discussion
The aim of this retrospective cohort study was to describe a key factor in the prenatal diagnosis of isolated cleft palate on the axial transverse view, to provide a better understanding, detection, and diagnosis of this anomaly. Here, we demonstrate that the posterior angle of the hard palate assessment is a reliable tool that provides a valuable addition to the existing gold standard of a gap within the hard palate.
Our accuracy in prenatal ultrasound diagnosis of cleft palate is moderate, with a misdiagnosis rate of 35%. This misdiagnosis rate is due to a high false-positive rate. According to previously described ultrasound features, we diagnosed the cleft palate based on the presence of a gap within or nonvisualization of the posterior border of the hard palate. 11 However, visualization of the posterior part of the hard palate could be hindered by technical difficulties related to maternal obesity, advanced gestational age, and fetal head position. Furthermore, we speculate that acoustic shadowing can explain the visualization of a gap which is not real. Thus, in the case of major fetal malformation, the observer-expectancy effect may influence some diagnostic conclusions. These facts could explain why a gap within the palate was present in all our false-positive cases.
On the other hand, in some of our true-positive cases, there was no gap, or the nasal spine was visualized. These cases concern fetuses with intact hard palate such as severe high-arched palate or type 1 cleft palate (Figure 4). Our experience shows that the presence of a reflexed angle may improve the accuracy in discriminating between acoustic shadowing due to the surrounding bone structures and true palate anomaly. Three-dimensional ultrasound allows prenatal anatomic classification of cleft palate with a high level of concordance with postnatal findings. 4 It is a commonly held opinion that the combination of 2D and 3D ultrasound scans improves the visualization of the fetal palate and is considered the best diagnostic tool for cleft palate without a cleft lip. 12 Nevertheless, we believe that 3D ultrasound has a better performance because it is frequently used by experienced and trained sonographers at the expert level. Besides, 3D ultrasound faces the same technical limitations as those of 2D ultrasound. We consider that improvement in the detection and diagnosis of isolated cleft palate requires the development of 2D techniques accessible to sonographers who do not have all expert skills.
A case of a fetus at 33 weeks with type I cleft palate (midline cleft of the soft palate and intact hard palate). The arrow shows the nasal spine. The inclined palatine bones of the horizontal plate form a reflex angle.
Our successful acquisition rate of the axial transverse view was slightly lower than that in studies by Fuchs et al. 9 and Wilhelm et al. 7 (85% vs 95% and 91%), but we would like to emphasize that our sample consist of 59% pregnancies after 24 weeks of gestation, contrary to that in the works of Fuchs et al. and Wilhelm et al., who included fetuses before 24 and 25 weeks, respectively. We think that advanced ossification during the third trimester of pregnancy may explain this finding. As routine fetal ultrasound scans in France are performed at 21–25 weeks and 31–35 weeks, level III ultrasound is frequently required during the third trimester of pregnancy. Our experience shows that the acquisition of the axial view of the hard palate during late pregnancy requires deflection of the fetal head in order to direct the ultrasound beam parallel to the hard palate and to pass through the acoustic window between the lower and upper lips. Two-dimensional image processing could be improved owing to the brief moments of opening of the fetal mouth.
As previously stated in the literature, our data show that fetal cleft palate is strongly associated with other major anomalies and genetic disorders. 13 Thus, the diagnostic accuracy of cleft palate without cleft lip can play an important role in prenatal counseling and decisions, including the use of whole-genome sequencing or parents’ choice for termination of pregnancy.
Strengths and limitations
First, we included the high-arched palate cases in the “true-positive” group for cleft palate. We considered this approach because high-arched and cleft palate seem to be the result of the same process. 14 Our experience shows that they are diagnosed and managed similarly during the prenatal period (Figure 5). The Online Mendelian Inheritance in Men (OMIM) database lists over 667 genetic syndromes, in which high-arched palate is reported in combination with other phenotypical features.
(a) Axial transverse view of the hard palate in a fetus with arthrogryposis at 21 weeks of gestation showing abnormal orientation of the posterior borders of the palatine bones forming a reflex angle but no gap within the bony secondary palate. Cleft palate was suspected prenatally, but the fetal autopsy revealed a high-arched palate. (b) The same findings were observed in a fetus at 23 weeks of gestation with U-shaped type III cleft palate (cleft of the soft palate and the secondary hard palate). The yellow lines demonstrate the posterior borders of the palatine bones.
Second, we reported an extremely high prevalence of minor fetal anomalies in the control group. This finding could be explained by the fact that the control group involved high-risk pregnancies referred to our Center for Prenatal Diagnosis. Nevertheless, newborn infant physical examination of the palate was normal in this group. Third, as there was missing information about the false-negative cases in our unit between January 2019 and January 2023, we could not evaluate the positive and negative predicted values of the reflexed angle of the hard palate. Finally, we would like to emphasize that this study does not provide a nomogram of the posterior hard palate angle but rather highlights the clinical utility of this aspect regardless of the absolute value of the angle assessment. We recommend direct visualization of the palate as a part of detailed fetal anatomic ultrasound in cases of fetal micrognathia/retrognathia or major structural anomalies.
Conclusion
The reflexed angle of the posterior border of the hard palate on the axial transverse view is a strong sonographic marker of cleft palate. We propose a new and accessible ultrasound tool for the improvement of prenatal diagnosis of isolated cleft palate. Our study provides some key information for the successful evaluation of the fetal hard palate at third trimester of pregnancy. Large prospective studies are needed to evaluate the performance of the posterior angle of the hard palate in the screening and diagnosis of cleft palate.
Footnotes
Acknowledgements
The author thanks Dr Mercier Marion for her participation in the assessments for interobserver variability.
Author’s Note
The findings of the paper were presented at the ISPD 27th International Conference on Prenatal Diagnosis and Therapy, 18–21 June 2023 with submission ID number 198.
Contributors
IIS-B researched literature and conceived the study. IIS-B was involved in protocol development, gaining ethical approval, patient recruitment, and data analysis. IIS-B wrote the first draft of the manuscript.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval
The study was approved by the CNIL (Commission Nationale de l’Informatique et des Libertés), France, approval number 2211250v0, 23.01.2019. The study was also registered with the ClinicalTrials.gov registry (NCT05785338).
Guarantor
Iglika Simeonova-Brachot
