Prospective ultrasound diagnosis of orofacial clefts in the first trimester

Orofacial cleft (OC) is one of the most common congenital anomalies. OC can be an isolated entity or part of genetic syndromes. Early diagnosis of OC is important for etiological testing and parental decision-making. Generally, the midline structures of the fetal face are completely fused by the 7th week of gestation, and the mandible and maxilla can be visualized clearly from the 10th week1, 2, hence allowing the detection of OC during the first trimester. We sought to identify effective sonographic markers of OC during the first trimester. This was a prospective study of 2944 women who underwent ultrasound examination for fetal nuchal translucency (NT) measurement between 11 + 0 and 13 + 6 weeks at the Prenatal Diagnosis Center of Guangzhou Women and Children's Medical Center from May 2018 to August 2019. Four two-dimensional (2D) views of the fetal face, including sagittal view of the palatal line, axial view of the maxilla, coronal view of the retronasal triangle (RNT) and coronal view of the lip, and three-dimensional (3D) images were obtained and evaluated. Having obtained the NT measurement, the integrity of the palatal line in the mid-sagittal and parasagittal views was assessed (Figure 1a). The ultrasound beam was kept at an angle to the palatal line while avoiding shielding by the fetal hands and umbilical cord, so as not to affect visualization of the continuity of the palate. The probe was then rotated by 90° to visualize the maxilla in the axial view (Figure 1d), and the continuity of the alveolar ridge was assessed. A continuous cambered structure indicated normal upper alveolar ridge. Finally, at the fetal forehead, the probe was titled caudally to visualize the RNT in the coronal view (Figure 1b) and to assess its integrity: at the top of the RNT is the bilateral nasal bone, the two sides correspond to the bilateral maxillary rami and the base of the triangle is the alveolar ridge or secondary palate. The examination was continued to obtain the coronal view of the lips (Figure 1c). All ultrasound scans were performed independently by two sonographers certified by The Fetal Medicine Foundation UK using Voluson E8 or E10 ultrasound equipment (GE Healthcare, Zipf, Austria). Fetuses were followed up in the second trimester and postpartum. Fifteen fetuses with OC were identified in the first trimester, including two with unilateral cleft lip and palate (CLP), six with bilateral CLP, six with median CLP and one with isolated cleft palate (CP) (Table 1). The high incidence of OC in our study reflects our status as a referral center. No additional cases were identified at the follow-up, and the postpartum findings of the positive cases were consistent with those of the ultrasound examination in the first trimester. The specificity and sensitivity of screening were thus 100%, indicating the high accuracy of this screening method. We compared the sensitivity of each view for identification of different types of OC among the positive cases and found that the sagittal and coronal RNT views were abnormal in all types of OC, whereas the axial view was abnormal in only 93.3% (14/15) of the positive patients because it did not identify isolated secondary CP. The coronal view of the lip was abnormal in only 66.7% (10/15) of the positive cases. 3D reconstruction of the fetal face and palate was diagnostic in 73.3% (11/15). 4q16.3 deletion (Wolf-Hirschhorn syndrome) Choroid plexus cyst, short limbs Holoprosencephaly, strephenopodia, pleural effusions, ventriculomegaly, spine malformation Polydactyly, single ventricle CHD, micrognathia, low-set ear IUFD/autopsy confirmation, irregular orofacial cleft, 12 MCLP and transverse facial cleft CHD, holoprosencephaly, single umbilical artery, megalocystis Trisomy 13 Images of a normal fetal palate and different types of OC are shown in Figure 2. To date, several effective approaches to ultrasound diagnosis of OC during the first trimester have been reported in the literature, including evaluation of the maxilla–nasion–mandible (MNM) angle, maxillary gap, RNT, axial view of the maxilla and assessment using 3D ultrasound, but there are limitations when these methods are used alone. The MNM angle is applicable only to assess micrognathia and primary CP. Chaoui et al.3 reported that the false-positive rate of the maxillary gap was 7%, because some parts of the normal maxilla may continue to show a lack of ossification of < 1.5 mm in size in the first trimester, which may explain the gap in some normal fetuses; moreover, the vomer bone may be mistaken for the palatal line in the mid-sagittal view. Assessment of the RNT alone may miss a very small primary CP with complete secondary palate, which can be visualized well in the axial view of the maxilla. However, using the axial view of the maxilla alone may misdiagnose a CLP, if the fetal limbs cover the mouth, and may miss isolated CP. The mid-sagittal view of the palatal line and the coronal view of the RNT are most useful for the diagnosis of secondary CP. Lakshmy et al.4 described the absent 'superimposed-line' sign as a novel marker for the early diagnosis of secondary CP. In this study, the coronal view of the fetal lip was difficult to identify before 12 weeks of gestation. 3D ultrasound, a complementary diagnostic tool for CLP, could be used for the evaluation of the secondary palate between 12 and 16 gestational weeks5. 3D images are helpful in the evaluation of OC, especially in the multiplanar mode. In our study, the combination of the four 2D views and 3D reconstruction of the fetal face and palate greatly increased the accuracy of diagnosing OCs, especially when maternal abdominal fat and fetal limbs complicated the examination. Compared with the second trimester, in the first trimester, the facial skull lacks ossification, which reduces sonographic echo loss, and the palate is relatively flat and conducive to observation. With the advent of the higher-frequency transducer, early detection of fetal anomalies has become achievable6. When we screened for fetal OCs in the first trimester, other fetal abnormalities, such as holoprosencephaly, exencephaly, micrognathia, low-set ear, spinal malformation, polydactyly and short limbs were also detected. Many patients with fetal chromosomal defects, multiple fetal malformations or adverse reproductive history chose to terminate the pregnancy. From this, it is evident that early screening for OCs influences the obstetric consultation process and prospective parents' choices.