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

Ultrasound scans in the mid-trimester of pregnancy are now a routine part of antenatal care in most European countries. Using data from registries of congenital anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of cleft lip with or without cleft palate (CL(P)) and cleft palate (CP). All CL(P) and CPs suspected prenatally and identified at birth in the period 1996-98 were registered from 20 Congenital Malformation Registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK, Ukraine. These registries followed the same methodology. A total of 709,027 births were covered; 7758 cases with congenital malformations were registered. Included in the study were 751 cases reported with facial clefts: 553 CL(P) and 198 CP. The prenatal diagnosis by transabdominal ultrasound of CL(P) was made in 65/366 cases with an isolated malformation, in 32/62 cases with chromosomal anomaly, in 30/89 cases with multiple malformations and in 21/36 syndromic cases. The prenatal diagnosis of CP was made in 13/198 cases. One hundred pregnancies were terminated (13%); in 97 of these the cleft was associated with other malformations.     

产前诊断唇腭裂308例回顾性研究

目的:探讨胎儿唇腭裂与染色体异常的关系,为该疾病的临床咨询及预后评估提供依据。方法:回顾性分析我院2008年1月至2016年12月所有超声诊断为唇裂/腭裂/唇腭裂的308例孕妇的产前诊断情况,比较不同类型唇腭裂的超声表型特征及染色体异常的发生率。结果:(1)超声诊断结果显示,在308例唇腭裂胎儿中非综合征型唇腭裂258例(83.77%),综合征型唇腭裂50例(16.23%),其中单纯唇裂40例(12.99%),唇裂合并腭裂266例(86.36%),单纯腭裂2例(0.65%)。(2)同意进行产前诊断137例(44.48%),染色体异常共22例(16.06%),其中23例综合征型唇腭裂中发现染色体异常共12例(52.17%),分别为13-三体8例(66.67%),18-三体2例(16.67%),三倍体2例(16.67%);而在114例非综合征型唇腭裂中发现染色体异常10例(8.77%),分别为18-三体1例,21-三体1例,标记染色体1例,发现基因微缺失微重复等遗传综合征4例(B超检查均无任何软指标及除唇腭裂外的其他结构异常),臂间倒位等染色体多态性3例。染色体基因芯片分析(CMA)检测的染色体异常检出率为16.16%(16/99),染色体核型分析异常检出率为15.79%(6/38)。(3)随访到204例患者,186例患者选择引产,18例患者出生后进行手术干预治疗。结论:唇腭裂胎儿染色体异常发生率较高,建议对所有类型唇腭裂均进行产前诊断;CMA检测可以发现除非整倍体外的拷贝数变异,建议对唇腭裂胎儿优选基因芯片进行产前诊断。     

142例胎儿唇腭裂的超声诊断与遗传因素分析

目的探讨胎儿唇腭裂的影像学特征与遗传基础。方法142例病例均接受产前超声系统检查,经过两级医生检查及会诊做出最终诊断。同时收集活产胎儿的胎儿脐带或引产胎儿的大腿肌肉组织,进行全基因组测序(whole genome sequening,WGS),以发现染色体数目异常和拷贝数异常(copy number variations,CNVs)。结果142例孕妇年龄分布为21~41岁,孕周为12~35周。142例胎儿中,男性94例,女性48例,男女比例为1∶0.51。根据唇腭裂的类型,单纯唇裂有84/142例(59.15%),唇裂合并其他系统畸形情况有31/142例(21.83%)。单纯唇腭裂有14/142例(9.86%),唇腭裂合并其他系统畸形情况有13/142例(9.15%)。9.2%(13/142)的胎儿有染色体数目异常,8.4%(12/142)的胎儿检出了致病性CNV。结论对CNVs的检测可以增加胎儿腭裂的遗传检测诊断率,在临床中应重视检测致病性CNVs。     

Prenatal evaluation of facial clefts with two-dimensional and adjunctive three-dimensional ultrasonography: a prospective trial

OBJECTIVE: The purpose of this study was to compare the prenatal diagnostic capabilities of two-dimensional ultrasonography versus adjunctive three-dimensional ultrasonography for fetal cleft lip and palate. STUDY DESIGN: Fetuses that were suspected of a facial cleft were then examined sequentially with two-dimensional ultrasonography then with a targeted scan of the fetal face with three-dimensional ultrasonography. The images were coded as cleft, no cleft, or equivocal for lip and palate. Postnatal outcome follow-up was obtained. RESULTS: Fifty-three of 57 fetuses had outcome results available. The diagnostic accuracy (true positive + true negative) of adjunct three-dimensional ultrasonography versus two-dimensional ultrasonography alone were improved for cleft lip (100% [53/53 fetuses] vs 91% [48/53 fetuses], P <.05) and cleft palate (89% [47/53 fetuses] vs 57% [30/53 fetuses], P <.05) CONCLUSION: There is significant improvement in diagnostic accuracy with two-dimensional ultrasonography with adjunctive three-dimensional ultrasonography compared with two-dimensional ultrasonography alone for the prenatal evaluation of facial clefts.     

Chromosomal defects and associated malformations in fetal cleft lip with or without cleft palate

OBJECTIVE: To describe the incidence, associated features including chromosomal defects in fetuses, with cleft lip and/or palate and assess the need for karyotyping. METHODS: Retrospective study of 62 cases of prenatally diagnosed facial cleft lip and/or palate in a tertiary fetal medicine unit between January 1991 and December 1999. Chromosome analysis was performed in all fetuses with associated ultrasound findings and in 14 (39%) fetuses with isolated facial clefts. RESULTS: Associated abnormalities were detected in 26 (42%) of the 62 fetuses of which 22 (35%) fetuses had multiple other abnormalities. Central nervous system abnormalities and limb malformations were the most common. Three fetuses had genetic syndromes confirmed after birth. All fetuses with isolated clefts were chromosomally normal, whereas 15 of the 26 with additional abnormalities (58 or 24% of the total group) had chromosomal defects (eight cases of trisomy 13, five of trisomy 18, one unbalanced translocation between chromosomes 7 and 8, and one deletion 4p-). All 22 women who chose not to undergo fetal karyotype analysis delivered phenotypically normal infants. There were five midline clefts; each of them was associated with additional sonographic findings and four were associated with holoprosencephaly. CONCLUSION: Isolated facial clefting is not associated with an increased risk for chromosomal defect. Amniocentesis is recommended when facial cleft is found in association with additional ultrasonographic abnormalities as it is unnecessary for isolated clefts.     

Prenatal sonographic findings in a case of Varadi-Papp syndrome

OBJECTIVES: We aim to describe a case with oral-facial-digital syndrome type VI (OFDS VI) or Varadi-Papp syndrome where the only prenatal findings were cleft lip and palate and a primum type atrial septal defect (ASD). METHODS: A 24-year-old pregnant woman, gravida 1 para 0, attended the prenatal clinic for a routine visit at 16 weeks of gestation. Her medical and family history was unremarkable. There was no history of consanguinity, drug or teratogen exposure. Her triple screening test and other routine biochemical and haematological blood tests did not reveal any abnormal results. During routine prenatal sonographic examination at the 16th gestational week, cleft lip and palate including secondary palate on the right side of the face was detected and ASD was suspected. RESULTS: After delivery, prenatally diagnosed cleft lip and palate and primum ASD were confirmed. Postnatally, minimal micrognathia, posteriorly rotated low-set ears, minimal hypertelorism, epicanthal folds, nystagmus, esotropia, broad nasal tip, intraoral frenula and lobed tongue, shawl scrotum and duplicated nail of the index fingers of both hands were also observed. Radiological examination showed partial agenesis of the corpus callosum and partially duplicated terminal phalanx of the index fingers. A diagnosis of Varadi-Papp syndrome was formulated. At one year of age, there was short stature and delayed mental and motor development. CONCLUSION: Understanding the limitations of prenatal ultrasound is very important for the genetic counselling of prospective parents, since major ultrasound findings can be associated with other minor or undetectable features.     

Detection of fetal structural abnormalities at the 11-14 week ultrasound scan.

The aim of this study was to evaluate the detection of fetal structural abnormalities by the 11-14 week scan. 2853 pregnant women were submitted to a routine ultrasound scan between the 11th and 14th week and the fetal skull, brain, spine, abdominal wall, limbs, stomach and bladder were examined. Following the scans the patients were examined in the second or third trimester of pregnancy. An isolated increased nuchal translucency was not considered an abnormality. However, these patients had an early echocardiography assessment. Fetal structural abnormalities were classified as major or minor and of early or late onset. A total of 130 (4.6%) defects were identified and 29 (22.3%) of these were diagnosed at the 11-14 week scan, including nine cardiac defects associated with increased nuchal translucency. The antenatal ultrasound detection rate was 71.5%, and 31.2% were detected in the first-trimester assessment. 78.8% of the major defects were diagnosed by the prenatal scan and 37.8% by the 11-14 week scan. Fetal structural abnormalities at the 11-14 week scan were detected in approximately 22.3% of the cases, therefore, a second-trimester anomaly scan is important in routine antenatal care to increase the prenatal detection of fetal defects.     

Evaluation of prenatal diagnosis by a registry of congenital anomalies.

Prenatal diagnosis performed by fetal karyotype and ultrasound scan is now a routine part of antenatal care in many countries. How many fetal anomalies are actually detected by these procedures? We have used our registry of congenital malformations to answer this question. In our region, prenatal diagnosis was performed in 23.1 per cent of fetuses with a chromosomal aberration and in 20.1 per cent of fetuses with non-chromosomal anomalies. Only 6.9 per cent of the pregnancies with fetuses with non-chromosomal anomalies were terminated. The sensitivity of prenatal diagnosis by ultrasonographic examination was much lower for isolated malformations (fetuses with only one anomaly) than for multiple malformed children, 15.3 and 48.3 per cent respectively, chromosomal anomalies excluded.     

胎儿期唇裂的诊断和治疗

文章概述了胎儿期唇腭裂的发生、相关因素、诊断和治疗。介绍了胎儿唇腭裂与染色体异常发生率的关系。随着产前诊断技术(超声、MR I等)的提高,越来越多的胎儿唇腭裂得到诊断。胎儿镜等技术促进了胎儿宫内治疗的发展,唇腭裂的宫内治疗亦是一个趋势,但目前大量的研究仍然是局限在动物模型。     

Bilateral cleft lip and palate associated with increased nuchal translucency and maternal cocaine abuse at 14 weeks of gestation

A case of bilateral cleft lip and palate associated with increased fetal nuchal translucency detected at 14 weeks of gestation in a cocaine abusing pregnant woman is presented. There were no other associated structural or chromosomal abnormalities. We propose that systematic examination in both the sagittal and parasagittal plane of the fetal profile and recognition of the characteristic ultrasound appearance of a premaxillary protruding echogenic mass should make detection of this type of cleft relatively easy at the moment of the first trimester scan. First trimester diagnosis of cleft lip and palate can facilitate the parental decision-making process on continuing or terminating the pregnancy and should open the perspective of fetal surgery.     

Prenatal evaluation of facial clefts by three-dimensional extended imaging

OBJECTIVES: To determine the prenatal diagnostic accuracy of two-dimensional ultrasound (2DUS) alone versus 2DUS in conjunction with three-dimensional ultrasonography (3DUS) including orthogonal display (OGD) and three-dimensional extended Imaging for cleft lip and primary palate. MATERIALS AND METHOD: Fetuses being suspected of having a facial cleft by previous ultrasound examination or family history were examined sequentially with 2DUS and then 3DUS. RESULTS: Of a total of 30 infants, 22 had cleft lip and nine also had cleft palate at birth. The use of 2DUS with or without 3DUS correctly identified all cases of cleft lips prenatally. However, the use of 2DUS in conjunction with 3DUS correctly identified more cleft primary palate than 2DUS alone (88.9% vs 22.2%, P < 0.01). Cleft primary palate was well demonstrated in both the multi-slice view (MSV) and OGD modes. In one case, a cleft palate was shown in the MSV mode but not in the Oblique view (OBV) mode. All the unaffected fetuses were reported as no cleft palate with the use of MSV mode. CONCLUSIONS: Combined approach of 2DUS and 3DUS with both OGD and MSV modes significantly improved the prenatal detection rate for a cleft palate compared with 2DUS alone (88.9% vs 22.2%) without decreasing the specificity.     

Are isolated facial cleft lip and palate associated with increased perinatal mortality? A cohort study from the West Midlands Region, 1995-1997.

OBJECTIVE: To investigate the association between cleft lip and/or palate and perinatal mortality. METHODS: A retrospective review was performed of cases of cleft lip/palate born to West Midlands residents from 1995 to 1997. Perinatal mortality for identified cases was compared with all births from 1995 to 1997. RESULTS: 347 cases of cleft lip and/or cleft palate were delivered from 1995 to 1997. Thirty-six pregnancies were terminated due to parental wishes--2 were registerable births. There were 310 spontaneous registerable births (stillbirths/livebirths) with cleft lip and/or palate and 1 further late fetal loss. In 220 (70.5%), the lesion was isolated. Of these, there were 7 perinatal deaths, 5 had post mortems and no additional anomalies were identified. In 92 (29.5%) cases other abnormalities were identified. The overall perinatal mortality rate (PNMR) in the West Midlands, was 10.0/1000 total births. The overall PNMR for babies with facial clefts was 89.7/1000 total births. The PNMR for those with associated anomalies was 228.3/1000 live/still births. The PNMR for isolated facial clefts was 31.8/1000 live/still births, significantly higher than the background population (OR 3.3, 95% CI: 1.5-7.0). CONCLUSION: Consideration should be given to screening the fetus at 20-24 weeks for facial deformity. This has implications for detection both of fetal anomalies and of a population at risk for adverse outcome.     

Prenatal imaging of facial clefts by magnetic resonance imaging with emphasis on the posterior palate

OBJECTIVE: To evaluate the role of Magnetic Resonance Imaging (MRI) in the prenatal diagnosis of facial clefts. MATERIALS AND METHODS: Six fetuses with a sonographic diagnosis of cleft lip and palate underwent MRI at a median age of 30 weeks (range 28-32). The defect was bilateral in two cases. RESULTS: Fetal MRI confirmed the presence of a cleft involving at least the anterior palate in all cases. Distinction between unilateral and bilateral clefts could be made in all cases and was always confirmed after birth. Sagittal views of the fetal face were found to be particularly useful in identifying the degree of extension of the cleft into the palate. The diagnosis was confirmed after birth. CONCLUSION: Our results suggest that MRI may be ancillary to ultrasound in prenatal investigation of a fetus with cleft lip, allowing a better staging of the lesion by demonstrating the degree of involvement of the palate.     

The prenatal diagnosis of Pierre-Robin sequence.

The purpose of this study was to evaluate the spectrum of prenatal sonographic and chromosomal findings, associated anomalies and perinatal and neonatal outcomes in cases with Pierre-Robin sequence. All cases (20) with Pierre Robin sequence, who were born at China Medical College Hospital between 1990 and 1997, were included and analysed in this series. 12 pregnancies (60 per cent) were complicated by polyhydramnios and 9 (45 per cent) were combined with cleft palate. Four cases (20 per cent) with cardiac anomalies were also observed. Two fetuses (10 per cent) had abnormal karyotyping (one trisomy 21, one trisomy 18). All fetuses were delivered at or near term. Male deviation was observed in cases with isolated Pierre-Robin sequence or combined mild anomalies (male female ratio: 13:3). Two neonatal mortalities and three with mental retardation were observed. This investigation provides a basis for counselling patients with fetal micrognathia or neonatal Pierre-Robin sequence. The main prenatal sonographic findings of Pierre-Robin sequence are micrognathia, polyhydramnios and cleft palate. In cases of polyhydramnios, sonographic examination of the facial profile and palate are recommended. After the finding of polyhydramnios, micrognathia, and even cleft palate, clinicians should be aware of the possibility of neonatal Pierre-Robin sequence. Cardiac evaluation and karyotyping is also recommended.     

Sonographic evaluation of fetal clefts of the lip, alveolus and palate

Clefts of the lip, alveolus and palate are among the most common congenital malformations. Due to their frequent combination with other structural anomalies, chromosomal defects and genetic syndromes, the prenatal diagnosis of clefts plays an important role. Furthermore, the prenatal detection of clefts enhances the parents' psychological preparation and enables the planning of postnatal management. This article reviews the occurrence, appearance and pathophysiology of these malformations as well as the different sonographic techniques used to diagnose clefts and their extent. Previously reported 2D- and 3D-techniques as well as our own recent diagnostic approach focussing on the diagnosis of isolated cleft palate are described.     

Prenatal diagnosis of cleft palate by 3D ultrasound

A case of a fetus seen at 33.2 weeks of gestation who was diagnosed with cleft lip in the third quarter by routine ultrasound. Describes the sequential steps that led to a multidisciplinary support the diagnosis of cleft palate by three-dimensional image reconstruction, which were originally obtained to demonstrate the fetal face surface. Birth confirmed the prenatal findings and established the diagnosis of cleft lip and cleft hard and soft palate. It has been reported that the diagnosis of facial clefts can be done with relative ease prenatally, but the detection rate of facial clefts in routine tests is only 20%. Until recently the diagnosis of cleft palate is not considered possible, however in recent years advances in three-dimensional technology has made possible the development of techniques for the assessment of the palate and various authors have reported promising results of ingenious applications that make think that in the near future will approach the palate a fact. We discuss the advantages and disadvantages of these methods are relatively new and highlights how valuable this information is for parents of the affected creature.     

Evaluation of a rapid optical immunoassay-based test for group B streptococcus colonization in intrapartum patients

Objective.?To investigate the association between cleft lip and/or palate and perinatal mortality.

Methods.?A retrospective review was performed of cases of cleft lip/palate born to West Midlands residents from 1995 to 1997. Perinatal mortality for identified cases was compared with all births from 1995 to 1997.

Results.?347 cases of cleft lip and/or cleft palate were delivered from 1995 to 1997. Thirty-six pregnancies were terminated due to parental wishes - 2 were registerable births. There were 310 spontaneous registerable births (stillbirths/livebirths) with cleft lip and/or palate and 1 further late fetal loss. In 220 (70.5%), the lesion was isolated. Of these, there were 7 perinatal deaths, 5 had post mortems and no additional anomalies were identified. In 92 (29.5%) cases other abnormalities were identified. The overall perinatal mortality rate (PNMR) in the West Midlands, was 10.0/1000 total births. The overall PNMR for babies with facial clefts was 89.7/1000 total births. The PNMR for those with associated anomalies was 228.3/1000 live/still births. The PNMR for isolated facial clefts was 31.8/1000 live/still births, significantly higher than the background population (OR 3.3, 95% CI: 1.5–7.0).

Conclusion.?Consideration should be given to screening the fetus at 20–24 weeks for facial deformity. This has implications for detection both of fetal anomalies and of a population at risk for adverse outcome.     

Alpha-tocopherol levels in mothers of children with cleft lip or with cleft lip and palate

OBJECTIVES: Environmental factors may play equally critical role as genes in facial embryogenesis. It was suggested that cleft palate occurring in association with cleft lip may result from environmental factors that affect development of both the lip and the palate. Cleft lip forms from the third through seventh week of embryonic development. During these period fetal nutrition is histotrophic, pressure of oxygen is low, genes for antioxidant enzymes are supressed and alpha-tocopherol play an essential role in the fetal tissues antioxidant capacity. Cleft palate forms from the fifth through twelfth weeks of gestation, when hemonutrition and antioxidant enzymes are developing, and hypothetical deficiency of tocopherol is not so crucial. AIM: The goal of the study was to investigate concentrations of alpha-tocopherol in women who gave birth to a child with cleft lip and mothers of children with cleft lip and palate. MATERIAL AND METHODS: Blood samples from 31 healthy mothers of children with isolated cleft lip (CL) and 29 healthy mothers of children with isolated cleft lip and palate (CLP) were collected. Fasting plasma alpha-tocopherol concentrations were measured by the high performance liquid chromatography. Kolmologorov-Smirnov test with Lilefors correction and k-means cluster analysis were applied to determine differences between the groups of women. RESULTS: We found that alpha-tocopherol concentrations were lower in CL compared to CLP, but the difference did not achieve level of statistical significantly (medians: 15.8 micromol/L vs. 20.0 micromol/L; p = 0.066). There were identified three clusters of alpha-tocopherol concentrations: 14.0 micromol/L (19CL+8CLP), 19.6 micromol/L (8CL+13CLP), and 21.1 micromol/L (4CL+8CLP). The distribution of results to the clusters was dependent on type of the orofacial cleft (chi squared = 6.95 with 2 degrees of freedom, p = 0,031). CONCLUSIONS: Analysis for environmental risk factors should be performed separately for cleft lip and cleft lip and palate because these two conditions appear to be etiologically distinct. The role of a higher periconceptional intake of alpha-tocopherol in reduction of risk of giving birth to a child with cleft lip requires further research.     

Detection of malformations in chromosomally normal fetuses by routine ultrasound at 12 or 18 weeks of gestation-a randomised controlled trial in 39,572 pregnancies

OBJECTIVE: To compare the antenatal detection rate of malformations in chromosomally normal fetuses between a strategy of offering one routine ultrasound examination at 12 gestational weeks (gws) and a strategy of offering one routine examination at 18 gws. DESIGN: Randomised controlled trial. SETTING: Multicentre trial including eight hospitals. POPULATION: A total of 39,572 unselected pregnant women. METHODS: Women were randomised either to one routine ultrasound scan at 12 (12-14) gws including nuchal translucency (NT) measurement or to one routine scan at 18 (15-22) gws. Anomaly screening was performed in both groups following a check-list. A repeat scan was offered in the 12-week scan group if the fetal anatomy could not be adequately seen at 12-14 gws or if NT was >or=3.5 mm in a fetus with normal or unknown chromosomes. MAIN OUTCOME MEASURES: Antenatal detection rate of malformed fetuses. RESULTS: The antenatal detection rate of fetuses with a major malformation was 38% (66/176) in the 12-week scan group and 47% (72/152) in the 18-week scan group (P= 0.06). The corresponding figures for detection at <22 gws were 30% (53/176) and 40% (61/152) (P= 0.07). In the 12-week scan group, 69% of fetuses with a lethal anomaly were detected at a scan at 12-14 gws. CONCLUSIONS: None of the two strategies for prenatal diagnosis is clearly superior to the other. The 12-week strategy has the advantage that most lethal malformations will be detected at <15 gws, enabling earlier pregnancy termination. The 18-week strategy seems to be associated with a slightly higher detection rate of major malformations, although the difference was not statistically significant.     

Prenatal diagnosis of craniofacial malformations with ultrasonography

Although the utility of ultrasound in the prenatal diagnosis of many congenital anomalies is well established, its accuracy in detecting craniofacial malformations has not been examined in a large series. Sonographic examinations of 223 patients at risk for fetuses with craniofacial malformations were performed between 18 and 40 weeks. The risk factors included a familial history of craniofacial malformations, extrafacial anomalies diagnosed on ultrasound, fetal chromosomal aberrations, and maternal drug intake. Sonographic diagnosis was possible in 151 (67.7%) patients on the first scan and in 47 (21.1%) patients on the second scan and was not possible in 25 patients (11.2%). Of the 198 cases diagnosed antenatally, craniofacial malformation was detected in 14 and confirmed postnatally. No false positive diagnoses were made. A negative diagnosis of craniofacial malformation was made in 184 cases with two false negative results (1.0%). Anomalies diagnosed sonographically included anophthalmia, anterior cleft lip and/or palate, hypotelorism, hypertelorism, and micrognathia. The results of this study demonstrate that ultrasound is an accurate and reliable tool for the prenatal diagnosis of craniofacial malformations.