Antenatal detection of cleft lip with or without cleft palate: incidence of associated chromosomal and structural anomalies

Authors


Abstract

Objective

To ascertain how many fetuses with prenatally diagnosed cleft lip with or without cleft palate have associated congenital structural and/or chromosomal abnormalities and whether there is an association with the anatomical type of cleft lip or palate.

Methods

This was a retrospective review of infants referred to the North-West England Regional Cleft Lip and Palate (CLAP) team between January 2000 and January 2006. Referrals made to the Regional Fetal Management Unit (FMU) in the same time period were investigated to identify the corresponding antenatal ultrasound findings and data on termination of pregnancy and intrauterine fetal death.

Results

Over the 6-year period investigated, 570 infants were referred to the FMU and/or CLAP team. Among these, there were 24 terminations of pregnancy, two intrauterine fetal deaths and one early neonatal death identified. Data on 69 of the 543 patients that survived were incomplete. Of 188 cases with unilateral and 34 cases with bilateral cleft lip ± palate there were no karyotypical abnormalities without other structural abnormalities. The incidence of associated structural abnormalities varied with the anatomical type of cleft: that of unilateral cleft lip ± palate was 9.8% (19/194), that of bilateral cleft lip and palate was 25% (11/44) and that of midline cleft lip and palate was 100% (11/11). None of 252 cases with isolated cleft palate was identified antenatally; of these, 5.6% (n = 14) had either karyotypical or associated structural abnormalities and 21.0% (n = 53) had a genetic syndrome as an underlying diagnosis.

Conclusions

It is essential to tailor the antenatal counseling of patients to the specific scan diagnosis, considering both the anatomical type of cleft and the presence or absence of associated abnormalities. It is inappropriate to offer invasive testing to all patients. The use of three-dimensional ultrasound as an adjunct should be considered in these patients to improve the accuracy of prenatal diagnosis. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.

Introduction

Cleft lip with/without cleft palate (CL ± P) is one of the most common fetal abnormalities, with an incidence of 1 : 700–1 : 1000 and with significant racial and geographic variation. Approximately 80% of cleft lips have an associated cleft palate1. While CL ± P can occur in isolation, associations with more than 100 different chromosomal abnormalities and genetic syndromes have been documented2.

As a result of advances in ultrasound technology and anomaly scan optimum guidelines such as those of the Royal College of Obstetricians and Gynaecologists3, which are utilized in most ultrasound departments in the UK, cases of CL ± P are being diagnosed antenatally more frequently. According to a French study, detection rates increased from approximately 5% in the early 1980s to over 26% in the late 1990s4 and in Norway they were as high as 58% in the late 1990s to 20045.

Generally, the type of cleft is defined by both its laterality (unilateral, bilateral or midline) and its location (cleft lip alone (occurs in 25% of cases of cleft), cleft lip and palate (CL + P) (51%) or isolated cleft palate (24%)5). The ‘cleft palate’ to which we refer in this study is a cleft in the alveolar ridge or primary palate. On ultrasound, cleft lip is best visualized in the coronal plane (Figure 1) and the alveolus is best viewed in the transverse plane. Sagittal views of the fetal head can show abnormalities, particularly if the CL ± P is bilateral or midline, rather than unilateral.

Figure 1.

Coronal views of normal fetal nose and lips (a) and unilateral (b) and bilateral (c) cleft lip.

More information is needed to aid in the prenatal counseling of affected patients and it is important that there is good correlation between prenatal and postnatal findings, allowing confidence in the antenatal diagnosis. It is unclear whether invasive prenatal tests to identify karyotypic abnormalities should be offered in all cases affected by clefting, or whether this should be tailored to the laterality and location of the cleft and the presence of any associated structural abnormalities. Previous studies4, 7–10 have shown a large variation in the incidence of chromosomal abnormalities in CL ± P and to date there has been little effort to segregate the relationship between differing anatomical types of CL ± P with respect to chromosomal abnormalities.

In this study, therefore, we examined the relationship between different anatomical types of CL ± P with associated chromosomal and structural abnormalities. The overall aim was to ascertain how many fetuses with prenatally diagnosed CL ± P have associated congenital structural and/or chromosomal abnormalities and whether the association is linked to the anatomical type of cleft lip or palate. This knowledge would allow more specific antenatal counseling to be given to parents with fetuses found to have different types of CL ± P.

Methods

We conducted a retrospective review of infants referred to the North-West Regional Cleft lip and Palate (CLAP) team between January 2000 and January 2006 and a separate review of all prenatal diagnoses of CL ± P in the North-West Regional Fetal Management Unit (FMU) database. Our regional protocol recommends that any cases suspected of having CL ± P on the 18–20-week fetal ultrasound assessment at a local unit are referred to the FMU for a second opinion, and any such attendances are logged on the FMU database. Thus, the data reflect all cases of prenatally suspected CL ± P in the north-west region. If the pregnancy is ongoing, referral for counseling to the CLAP team is offered. This regional team is a multidisciplinary team of orofacial surgeons, specialist nurses, geneticists, speech and language therapists and audiologists who are involved in all aspects of antenatal support and counseling and all postnatal care, postoperative care and the long-term follow-up of babies diagnosed with a CL ± P. All referrals to the CLAP team (both antenatal and postnatal) are contained on the CLAP database.

The FMU database and the CLAP database were reviewed retrospectively to obtain information on the clinical diagnosis and associated congenital, chromosomal and syndromic abnormalities, and on terminations of pregnancy (TOP) and intrauterine fetal death (IUFD). For infants with an antenatal diagnosis of CL ± P, the ultrasound findings and any results of invasive chromosomal testing were correlated with the postnatal findings. For infants with a postnatal diagnosis only, any associated structural or chromosomal abnormalities were noted. Missing from our series would be the fetuses with a missed diagnosis of CL ± P who were not liveborn and were thus not referred to the CLAP team.

Results

Over the 6-year review period, 570 cases of CL ± P were recorded in the FMU (antenatal detection) and/or CLAP team (ante- or postnatal detection) database. Twenty-four of these underwent TOP: 10 cases of midline CL + P, six cases of unilateral CL ± P and eight of bilateral CL ± P. One of the terminated fetuses with unilateral CL ± P had no associated abnormalities; this TOP was for social reasons. There were two IUFDs in bilateral CL ± P fetuses and one fetus with a midline CL + P died neonatally at 3 h due to prematurity and associated abnormalities. There were incomplete data in 69 patients and these were excluded; data were considered to be incomplete if the maternal ultrasound data (from the FMU) could not be matched confidently with the postnatal infant data (from the Regional CLAP team). This normally occurred if mother and child had different surnames and/or were registered at different addresses. Thus, there were 501 cases included in the final analysis of chromosomal and structural abnormalities, which included the TOPs, IUFDs and neonatal death as well as liveborns with postnatal data (n = 474). These included 188 cases of unilateral CL ± P, analyzed as a group because often palatal involvement cannot be confirmed or refuted using two-dimensional (2D) ultrasound, 34 cases of bilateral CL ± P, similarly analyzed as a group, and 252 cases of isolated cleft palate.

Of the 188 babies seen by the CLAP team with unilateral CL ± P, 41.4% (n = 78) were missed by ultrasound in the antenatal period. One of these babies in which the diagnosis was missed prenatally had associated structural abnormalities (total anomalous pulmonary venous drainage, Case 12, Table 1) and none had an abnormal karyotype. Of the 34 babies with bilateral CL ± P, 26.4% (n = 9) were missed in the antenatal period. Three of these babies in which the diagnosis was missed prenatally had associated structural abnormalities (Cases 9, 10 and 11, Table 2) and none had chromosomal abnormalities. None of the 252 fetuses with an isolated cleft palate was detected in the antenatal period (100% were missed).

Table 1. Associated structural and karyotypic abnormalities in unilateral cleft lip with/without cleft palate
CaseStructural abnormalityKaryotyping
Time of testResult
  1. Ante, antenatal; ASD, atrial septal defect; Post, postnatal; TOP, termination of pregnancy; VSD, ventricular septal defect.

1Unilateral talipesAnteNormal
2Esophageal atresiaAnteNormal
3Unilateral hydronephrosisAnteNormal
4Unilateral dilated renal pelvisPostNormal
5Unilateral talipesPostNormal
6NephromegalyPostNormal
7ASDPostNormal
8Complex cardiac and echogenic bowelAnteNormal
9Unilateral multicystic dysplastic kidneyAnteNormal
10GastroschisisAnteNormal
11Mild ventriculomegalyAnteNormal
12Anomalous pulmonary veinsPostNormal
13VSD, situs inversusAnteTrisomy 18 – TOP
14Agenesis corpus callosum, VSD, horseshoe kidneyAnteTrisomy 13 – TOP
15VSD, horseshoe kidney, polydactylyAnteTrisomy 13 – TOP
16Polycystic kidneysAnteTrisomy 13 – TOP
17Choroid plexus cysts, inferior vermian agenesis, univentricular heartAnteTrisomy 18 – TOP
18PolydactylyPostTrisomy 13
19Tracheo-esophageal atresia, hemivertebraeAnteTOP; karyotyping refused
Table 2. Associated structural and karyotypic abnormalities and genetic syndromes in bilateral cleft lip ± palate
CaseStructural abnormalityKaryotyping
Time of testResult
  1. Ante, antenatal; ASD, atrial septal defect; IVA, inferior vermian agenesis; Post, postnatal; TOP, termination of pregnancy VM, ventriculomegaly; VSD, ventricular septal defect.

1Cord hernia, VM, polydactylyAnteTrisomy 18—TOP
2IVA, VM, polydactyly, VSD, large echogenic kidneysAnteTrisomy 13—TOP
3Holoprosencephaly, polydactyly, duplex kidneyAnteTrisomy 13—TOP
4VM, Dandy–Walker malformation, renal cystAnteNormal—TOP
5Complex cardiac abnormalityAnteNormal—TOP
6HoloprosencephalyAnteNormal—TOP
7Bilateral echogenic kidneysAnteNormal—TOP
8Bilateral talipesAnteNormal—TOP
9Abnormal feet, ectrodactylyPostNormal
10ASD, VSD, hypertelorismPostNormal
11HypertelorismPostNormal; craniofrontonasal dysplasia present
Table 3. Summary of published data on incidence of associated structural and karyotypic abnormalities in cleft lip with/without cleft palate
ReferenceIncidence
Chromosomal abnormalityStructural abnormality
  1. The CL ± P classification system used here is that proposed by Nyberg et al.7, where Type 1 is cleft lip only, Type 2 is unilateral CL ± P, Type 3 is bilateral CL ± P, Type 4 is midline CL + P and Type 5 involves facial defects associated with amniotic bands or limb–body wall complex.

Nyberg et al.7 (1995)Type 1 – 0%Type 1 – 20% (n = 1)
 Type 2 – 20%Type 4 – 100%
 Type 3 – 30%Type 5 – 100%
 Type 4 – 52%Total group—68%
 Type 5 – 0% 
 Total group—20.4% 
 All had additional anomalies, except one fetus with mosaic trisomy 22 
Perrotin et al.9 (2001)Isolated—0%Total group—42%
 Associated with other abnormalities—24% 
Berge et al.8 (2001)Type 1 – 0%Type 1 – 0%
 Type 2 – 32% (all had other abnormalities)Type 2 – 48%
 Type 3 – 59% (all had other abnormalities)Type 3 – 72%
 Type 4 – 82% (all had other abnormalities)Type 4 – 100%
 Isolated defect—0% 
Clementi et al.6 (2000)11% (All types of CL ± P grouped together, all associated with other abnormalities)37% (All types of CL ± P grouped together)
Chmait et al.10 (2006)35% (All types CL ± P grouped together, all associated with other abnormalities)Total group—35.6%; included syndromic/ chromosomal abnormalities
Offerdal et al.5 (2008)Total group—12%Total group—43%

The associated chromosomal and structural abnormalities and genetic syndromes are shown in Tables 1 and 2. Of the 194 cases (188 liveborn and six TOPs) with unilateral CL ± P, there were no associated structural abnormalities in 175, and none of these had associated chromosomal abnormalities. Thus, there were associated structural abnormalities in 9.8% (n = 19, Table 1) and among these the incidence of known chromosomal abnormality was 31.6% (n = 6); in one case karyotyping was refused by the parents.

Of the 44 fetuses with bilateral CL ± P (34 liveborn, eight TOPs and two IUFDs), there were no associated structural abnormalities in 31, and none of these had associated chromosomal abnormalities; however, the numbers were much smaller than in the unilateral CL ± P group. Structural abnormalities were observed in 25% (n = 11, Table 2) and 27.3% (n = 3) of these fetuses had an underlying chromosomal abnormality. One of the 34 (2.9%) fetuses with bilateral CL ± P had an associated genetic syndrome (Case 11). IUFD occurred in two fetuses with isolated bilateral CL ± P, one at 31 and one at 33 weeks' gestation. One had a normal karyotype and the other failed to culture.

All 11 (100%) of the fetuses with a midline CL + P had a structural abnormality. Ten (90.9%) of these underwent TOP. Karyotyping was available for only three of these fetuses and it was abnormal in each case, with one case of trisomy 18 and two of trisomy 13. The 11th patient was liveborn but died neonatally with no CLAP team involvement.

Of the 252 cases of isolated cleft palate, all of which were identified postnatally, 14 (5.6%) had either karyotypical or associated structural abnormalities and 53 (21.0%) had a genetic syndrome (including Pierre–Robin, Sticklers, CHARGE and Asperts syndromes).

Discussion

This is the largest single-country study assessing structural abnormalities associated with CL ± P and the relation with karyotype. The EUROSCAN group6 reported 553 fetuses with a diagnosis of CL ± P and 198 with isolated cleft palate, but this included data from 12 different countries. Our results highlight the need for accurate prenatal diagnosis of the anatomical type of CL ± P. The classification used by Nyberg et al.7, amongst others8, 9, was: Type 1, cleft lip only; Type 2, unilateral CL ± P; Type 3, bilateral CL ± P; Type 4, midline CL + P; Type 5, facial defects associated with amniotic bands or limb–body wall complex. This classification of CL ± P gives a good correlation with ultimate outcome and would aid prenatal counseling. Type 1 defects have the most favorable prognosis and Type 4 and 5 defects are universally associated with other abnormalities and carry an extremely poor prognosis. We, however, chose not to use this classification system because it is not certain whether 2D ultrasound is sufficiently robust to differentiate with absolute confidence between a cleft lip and one with palatal involvement.

Previous studies have quoted a 35% association of CL ± P with an additional structural or syndromic abnormality10 Table 3). However, they grouped together all types of fetal CL ± P, rather than performing subgroup analysis. When counseling patients regarding the association of karyotypic abnormalities and outcome data, it is vital to tailor the discussion according to the anatomical type of CL ± P. As our data show, unilateral and bilateral CL ± P without structural abnormality had no association with abnormal karyotype. This is in agreement with data published by Chmait et al.10, Berge et al.8 and Perrotin et al.9. No abnormal karyotypes were found in fetuses with bilateral CL ± P without structural abnormality; however, as the numbers were small in this group, caution must be applied in the interpretation of these results.

In the presence of a structural abnormality in association with unilateral or bilateral CL ± P, we found a substantially increased risk of a fetus having an underlying abnormal karyotype (31.6% and 27.3%, respectively). In agreement, Nyberg et al.7 found that fetuses with chromosomal abnormalities had an additional one or more ultrasound abnormalities in 96.7% of cases. The exception was one fetus with mosaic trisomy 22 which had a normal antenatal ultrasound examination. In contrast, both in the study of Nyberg et al.7 and in ours, 100% of fetuses with midline CL + P had associated structural abnormalities on ultrasound. This highlights the need for accurate ultrasound diagnosis and identification of associated structural abnormalities and thus offer appropriate, targeted chromosomal testing.

Unfortunately, in all cases, the quality of counseling will be limited by the quality of the ultrasound diagnosis. Overall, 39.2% (87/222) of cases of unilateral or bilateral CL ± P were not detected in the antenatal period. This is similar to recently published data by Demircioglu et al.11. Chmait et al.10 reported a 21.6% rate of undiagnosed associated structural abnormalities. This is similar to our experience, with 23.3% of abnormalities being missed (seven of 30). Berge et al.8 found no cases of aneuploidy in fetuses with an isolated cleft lip; however, they still recommended the offer of karyotype testing as the sensitivity and specificity for cleft palate detection will never be 100%. However, our data suggest that it is more the presence or absence of other abnormalities that is important in determining whether there may be chromosomal abnormalities. Thus, these days, with the availability of tertiary referral centers, better resolution ultrasound machines and three-dimensional (3D) scanning, it is questionable whether routinely karyotyping all cases of CL ± P is necessary. Perrotin et al.9 recommend karyotyping only when a CL ± P is found in association with other abnormalities.

Visualization of the hard palate using ultrasound is challenging. Thus, if a cleft is seen in the soft palate, one has to assume that a cleft of the hard palate is also present. It may be that 3D scanning will play more of a role in this area in the future, as some studies have shown an increased detection rate and accuracy of diagnosis of 3D when compared with 2D scanning12, 13. None of the fetuses with clefting only of the palate was diagnosed antenatally, as reported previously5, 11, 14, 15. Our study shows that these babies have a significant risk of associated abnormalities/syndromes (26.6%). This figure is even higher in other reports. Beriaghi et al.16 found that 38.7% of patients with isolated cleft palate had associated congenital malformations and in the study of Offerdal et al.5, 58% of cases of cleft palate had associated anomalies. However, it is uncertain whether detection of this high-risk group of fetuses in the antenatal period is possible. Wang et al.17 demonstrated that 2D and 3D ultrasound compared with 2D ultrasound alone improved prenatal detection of cleft palate from 22.2% to 88.9%. Yet, identification of patients who would warrant 3D scanning to look for an isolated cleft palate is difficult. Furthermore, although there is a significant association with underlying genetic syndromes, many of these cannot be detected antenatally and are not associated with abnormal karyotype. Thus, prenatal counseling would often be unable to give specific information about the prognosis for the individual fetus. This would obviously increase parental anxiety significantly.

In summary, our data suggest that in the presence of unilateral or bilateral CL ± P without other structural abnormalities there is no association with underlying karyotypical abnormality, although there were fewer cases in our bilateral group. Thus, if the operator has confidence in their ultrasound findings, it may not be appropriate to offer invasive testing in cases with no associated structural abnormalities, given the associated risks of miscarriage or preterm labor. 3D scanning may improve counseling with regard to palatal involvement, although this does not necessarily influence the risk of karyotypic abnormalities. If associated structural abnormalities are found, then counseling should involve discussion of possible associated chromosomal abnormalities, discussion of any other structural abnormalities found and, if normal karyotyping is confirmed or invasive testing is declined, referral to the regional CLAP team should be expedited. As the outcome for midline CL + P is so poor, we would not advocate antenatal referral to the CLAP team, as the majority of these fetuses will have a lethal abnormality.

Acknowledgements

We would like to thank the North-West Regional CLAP team for their help in identifying patients through their database and in accessing records.

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