Supplementary Material for: Isolated Cleft Lip and Palate: Maxillary Gap Sign and Palatino-Maxillary Diameter at 11–13 Weeks

Objective: To evaluate the maxillary gap sign and describe markers for the first-trimester diagnosis of isolated cleft lip and palate (CLP) at 11–13 weeks. Methods: Firstly, this was a prospective assessment of 1,087 fetuses including 5 cases of isolated CLP in 2 centers which were referred for the 11–13 weeks scan. Secondly, intra- and interobserver variability of the maxillary gap sign was evaluated for observers R.L. and A.B. in 2 sessions (affected cases vs. 50 normal fetuses in each session) to reduce the bias of different ultrasound manufacturer visualizations (Philips, GE). Thirdly, the palatino-maxillary diameter (PMD) was examined in stored images, DICOM loops and volumes of the midsagittal and parasagittal view of the fetal head and brain at 11+0–13+6 weeks of gestation from 5 fetuses with isolated CLP and 302 consecutively assessed normal controls. The PMD values in fetuses with isolated CLP and normal controls were compared. Results: Firstly, 5 out of 6 referred pregnancies with isolated CLP were detected prospectively using the midsagittal view for measurement of nuchal translucency due to an abnormal appearance. One out of 6 patients with isolated CLP declined the 11–13 weeks scan. Secondly, intra- and interobserver variability showed no false positive cases; all cases with isolated CLP were identified by both sonographers; however, in 2 cases the maxillary gap sign was doubtful. Therefore, thirdly, we developed the PMD measurement which increased significantly with crown-rump length (CRL) from respective mean values at CRL of 45 mm to 4.66 mm and to 8.95 mm at CRL of 84 mm. In the CLP group, the PMD was below the 5th percentile of the control group in 4 out of 5 (80%) cases. Conclusions: The midsagittal view for measurement of nuchal translucency shows a high reproducibility regarding abnormal views for maxillary gap sign. In the midsagittal view of the fetal head, face, and brain at 11–13 weeks, the majority of fetuses with isolated CLP have a measurable abnormality in addition, the PMD.

研究目的：评估上颌间隙征（maxillary gap sign），并阐述孕11~13周时孤立性唇腭裂（isolated cleft lip and palate, CLP）的孕早期诊断标志物。
研究方法：首先，在2家中心开展前瞻性评估，共纳入1087例接受11~13周超声筛查的胎儿，其中包含5例孤立性唇腭裂病例。其次，为降低不同品牌超声设备（飞利浦（Philips）、通用电气（GE））成像可视化差异带来的偏倚，由观察者R.L.与A.B.分2次评估上颌间隙征的观察者内及观察者间一致性，每次评估均包含受累病例与50例正常胎儿。第三，针对5例孤立性唇腭裂胎儿以及302例连续纳入的正常对照胎儿，在妊娠11+0~13+6周时，对其存储的胎儿颅脑矢状面及旁矢状面图像、DICOM动态序列与容积数据进行腭上颌径（palatino-maxillary diameter, PMD）测量，并对比孤立性唇腭裂胎儿与正常对照胎儿的PMD数值。
研究结果：首先，6例转诊的孤立性唇腭裂妊娠中，有5例因超声表现异常，在用于测量颈项透明层（nuchal translucency）的胎儿矢状面成像中被前瞻性检出；剩余1例孤立性唇腭裂孕妇拒绝接受11~13周超声筛查。其次，观察者间及观察者内一致性评估未出现假阳性病例，2名超声医师均检出了所有孤立性唇腭裂病例，但其中2例的上颌间隙征表现存疑。第三，我们建立的腭上颌径测量值随头臀长（crown-rump length, CRL）显著升高：当CRL为45mm时，PMD均值为4.66mm；当CRL为84mm时，PMD均值为8.95mm。在唇腭裂组中，5例病例中有4例（占比80%）的PMD低于对照组的第5百分位数。
研究结论：用于测量颈项透明层的胎儿矢状面成像，在上颌间隙征异常表现的识别上具有较高的可重复性。在孕11~13周时，对胎儿颅脑、面部的矢状面成像中，多数孤立性唇腭裂胎儿除上颌间隙征外，还存在可被检出的腭上颌径异常。