Prenatal detection of associated anomalies in ... - Wiley Online Library

Ultrasound Obstet Gynecol 2006; 27: 173–176 Published online 24 October 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.2593

Prenatal detection of associated anomalies in fetuses diagnosed with cleft lip with or without cleft palate in utero R. CHMAIT*, D. PRETORIUS†, T. MOORE‡, A. HULL‡, G. JAMES‡, T. NELSON† and M. JONES§ *Florida Institute for Fetal Diagnosis and Therapy, Tampa, FL, †Department of Radiology, University of California, San Diego, ‡Division of Reproductive Medicine, University of California, San Diego and §Children’s Hospital of San Diego, Department of Pediatrics, San Diego, CA, USA

K E Y W O R D S: associated anomalies; cleft lip; cleft palate; fetus; ultrasound

ABSTRACT Objective The aim of this study was to determine the prenatal detection rate of associated anomalies in fetuses with a suspected cleft lip with or without cleft palate. Methods Fetuses with a suspected cleft lip with or without cleft palate, determined by prenatal ultrasound, were prospectively enrolled. Additional anomalies suspected by ultrasound or genetic testing were recorded. Postnatal outcome was obtained. Results Forty-five fetuses with a cleft lip with or without cleft palate, diagnosed prenatally with either twodimensional and/or three-dimensional ultrasound, were studied. Postnatal follow-up revealed that 16 (35.6%) of these 45 fetuses had an additional structural or syndromic abnormality. Of the 37 fetuses with prenatally determined ‘isolated’ cleft lip with or without cleft palate, eight (21.6%) had an additional malformation identified after delivery. Conclusion In pregnancies complicated by a cleft lip with or without cleft palate, patients should be informed of the risks of associated anomalies, some of which may be undetected prenatally. Copyright  2005 ISUOG. Published by John Wiley & Sons, Ltd.

INTRODUCTION Facial clefting is attributed to failure of the nasal and maxillofacial processes to fuse during embryological development. The cleft lip with or without cleft palate may be isolated with no other congenital abnormalities present1 , or be one component of a more global fetal abnormality. Approximately 350 syndromes have been

linked with facial clefting, some of which may result in death or severe morbidity2 . Previous studies have shown that the rate of associated anomalies for cleft lips with or without cleft palate range between 35–63%3,4 . Ultrasound has played a key role in prenatal identification of cleft lip with or without cleft palate5,6 . In a previous study in which we prospectively enrolled patients that were referred to our unit with a suspected cleft lip with or without cleft palate, we found that two-dimensional (2D) ultrasound with adjunct threedimensional (3D) ultrasound of the fetal face detected all of the fetuses with a cleft lip and 90% with a cleft primary palate6 . Although location and extent of the cleft lip with or without cleft palate is important with regard to prognosis, the presence or absence of an associated anomaly is equally if not more critical to the outcome of the fetus. The prenatal identification of facial clefting with or without associated anomalies is essential for prenatal counseling and planning obstetrical and neonatal management. The aim of this study was to determine the prenatal detection rate of associated anomalies in fetuses with a suspected cleft lip with or without cleft palate.

METHODS The study was conducted between April 1994 and January 2001 with approval from the institutional investigational review board. After informed consent had been obtained, women carrying fetuses with a cleft lip with or without cleft palate suspected on a previous ultrasound examination were prospectively enrolled into the study. Twenty-eight of these fetuses had been included in another study7 . Fetuses referred for evaluation were examined sequentially with 2D ultrasound followed by 3D ultrasound. All

Correspondence to: Dr D. Pretorius, Department of Radiology, University of California, 9500 Gilman Dr., 0610, La Jolla, CA 92093-0610, USA (e-mail: [email protected]) Accepted: 30 January 2005

Copyright  2005 ISUOG. Published by John Wiley & Sons, Ltd.

ORIGINAL PAPER

Chmait et al.

174

the scans were performed transabdominally; one was also performed transvaginally. The 2D ultrasound scans were carried out with 128XP (Acuson, Mountain View, CA, USA), HDI (Advanced Technology Laboratories, Bothell, WA, USA), or Elegra (Siemens, Erlangen, Munich, Germany) ultrasound machines. A detailed fetal anatomical survey was performed with 2D ultrasound. The integrity of the fetal lip was then assessed via the acquisition and analysis of frontal and transverse image planes. The fetal primary palate was evaluated using the transverse image planes through the upper lip and anterior alveolar ridge; specifically, the tooth germs were assessed for continuity. Each 2D examination was interpreted at the time of the study by a perinatalogist or radiologist staffing the clinic. A focused 3D ultrasound examination of the fetal face was then performed by a sonologist trained and experienced with 3D obstetric imaging. The results of the 2D ultrasound were not blinded. The 3D ultrasound images were obtained with a Combison 530 (Kretztechnik, Zipf, Austria) or a Voluson 530D (Medison, Seoul, Korea) scanner. The techniques for 3D ultrasound image acquisition of the fetal face using both multiplanar imaging and surface-rendered views have been previously described6 – 11 . Families were shown volume-rendered images of their fetuses during counseling sessions. A data sheet was prospectively generated for each fetus evaluated for a cleft lip with or without cleft palate, which contained the following information: gestational age at time of evaluation; 2D ultrasound cleft lip/palate results; 3D ultrasound cleft lip/palate results; and any other fetal abnormalities detected prenatally, including other structural anomalies detected by either 2D or

3D ultrasound and fetal karyotype results obtained by invasive genetic testing. The outcome was determined by a variety of methods, including a review of autopsy reports, clinical genetics evaluation, and contact with primary care providers. The majority of surviving infants had been treated through the Cleft Palate Treatment Program at the Children’s Hospital, permitting assessment of neurobehavioral development.

RESULTS Forty-five fetuses with cleft lip with or without cleft palate prenatally diagnosed using either 2D and/or 3D ultrasound were included in the study. Postnatal followup revealed that 16 (35.6%) of these 45 fetuses had an additional structural or syndromic abnormality. All 16 fetuses had both a cleft lip and palate. Of these 16 fetuses, five had a chromosomal abnormality (one case has been reported in detail12 ), four had primarily a central nervous abnormality, two had primarily a cardiac anomaly, one had a renal abnormality, two had a known genetic syndrome, and two had dysmorphic features suggestive of an unknown multiple malformation syndrome. These cases are summarized in Table 1. Of the 45 prenatally diagnosed cases of cleft lip with or without cleft palate, eight cases were determined to have an associated abnormality via sonographic examination or genetic testing during the antenatal period. However, an additional eight (21.6%) cases of the remaining 37 with presumed ‘isolated’ cleft lip with or without cleft palate had an unrecognized associated anomaly. A 41-year-old woman who had refused both a triple marker screen and genetic amniocentesis delivered

Table 1 List of cases with a facial cleft and an additional fetal anomaly

Case 1 2 3 4 5

Additional malformation detected prenatally by ultrasound or genetic testing

7 8

Anencephaly, holoprosencephaly Holoprosencephaly, hypoplastic left heart Dandy–Walker malformation Hypoplastic left heart Holoprosencephaly, absent orbit, clubfeet, absent stomach Encephalocele, hypoplastic left heart, absent stomach, polyhydramnios Scoliosis Bilateral clubfeet

9 10 11 12 13 14

None* None* None None None None

15 16

None None

6

Postnatal diagnosis

Outcome

Ring chromosome 18 abnormality Trisomy 13 Unbalanced chromosome 13–14 translocation Peters plus syndrome Undefined multiple malformation syndrome, NK

ND ND TOP ND TOP

Undefined multiple malformation syndrome, NK

ND

Hemivertebra, unilateral renal agenesis, NK Short palpebral fissures, ear malformation, bilateral clubfeet, NK Trisomy 21 Trisomy 21 Van der Woude syndrome Lobar holoprosencephaly, NK Panhypopituitary, septo-optic dysplasia, NK d-transposition of the great vessels, ventricular septal defect, NK Atrial septal defect, clinodactyly, NK Hypertelorism, periauricular tag, atrial septal defect, dysplasia of pons, NK

IUFD ND Alive Alive TOP ND Alive ND TOP TOP

*Twin pregnancy of an advanced maternal age mother, genetic amniocentesis declined. IUFD, intrauterine fetal demise; ND, neonatal demise; NK, normal karyotype; TOP, termination of pregnancy.


Ultrasound Obstet Gynecol 2006; 27: 173–176.

Associated anomalies in fetuses with cleft lip twins diagnosed with trisomy 21 after birth; however, no sonographic features of trisomy 21 were noted on any prenatal sonograms. The infants with the lobar holoprosencephaly and septo-optic dysplasia were diagnosed via magnetic resonance imaging and clinical presentation (diabetes insipidus and panhypopituitarism, respectively). No sonographic evidence of these lesions was noted upon re-review of the prenatal images. The cardiac views of the infant with the undetected transposition of the great vessels were suboptimal, partly because the scan was performed at 34 weeks. Midtrimester termination via dilation and evacuation for presumed isolated cleft lip and palate revealed additional anomalies in three fetuses. One abortus had a lip pit suggestive of Van der Woude syndrome. The second abortus had an unrecognized pattern of malformation, including hypertelorism, periauricular tag, atrial septal defect, and dysplasia of the pons. The third abortus had fifth finger clinodactyly and a moderately large secundum atrial septal defect. Regarding outcome, only three of the 16 fetuses with a cleft lip with or without cleft palate and an associated anomaly survived through the neonatal period. There were seven neonatal demises, five termination of pregnancies, and one intrauterine fetal demise (Table 1). The three survivors were in the group that was classified as ‘isolated’ facial cleft. Two survivors were twins with trisomy 21. The third child had septo-optic dysplasia, was mildly developmentally delayed with visual impairment, and was on multiple hormones for panhypopituitarism.

DISCUSSION Previous studies have noted a varying rate of associated anomalies in prenatally detected cleft lip with or without cleft palate. In a retrospective review of 4180 patients, multiple anomalies were found in 35% of patients with a cleft lip with or without cleft palate and 54% of cleft palate patients3 . Similarly, in a study of 238 942 consecutive deliveries in northeastern France between 1979 and 1996, 460 infants had clefts. Of the total cleft cases, 36.7% had associated defects. The rate of associated malformation was 13.6% for cleft lip, 36.8% for cleft lip and palate, and 46.7% for cleft palate alone13 . The rate of associated anomalies in our study group was 35.6%. All the cases in our study that had an additional abnormality had both a cleft lip and primary cleft palate. Of concern was that, in half of these fetuses, the additional malformation was not detected prenatally despite the fact that these fetuses were examined on multiple occasions with 2D ultrasound. In this study 3D ultrasound was used to visualize the fetal face only. Thus, of the 37 cases of presumed ‘isolated’ cleft lip with or without cleft palate, eight (21.6%) were found to have an associated anomaly after delivery. The 21.6% rate of undiagnosed associated anomalies in cases with a cleft lip with or without cleft palate is in line with previous studies that have shown the relative insensitivity of ultrasound in prenatal diagnosis14,15 . This


175

finding warrants guarded optimism when counseling patients regarding prognosis of prenatally diagnosed cleft lip with or without cleft palate. The natural history of fetuses with a cleft lip with or without cleft palate and an additional anomaly is unfavorable both in utero and in the neonatal period. This was borne out in our study in which, excluding the five cases that underwent pregnancy termination, eight of the remaining 11 fetuses had an intrauterine or neonatal demise. Analysis of the lower half of Table 1, which lists the cases of facial clefts with prenatally undiagnosed associated anomalies, shows that the diagnoses of several of the associated anomalies may have been obtainable prenatally under optimal conditions. This is especially true regarding the twins with trisomy 21 in which an amniocentesis would have elucidated the karyotypic abnormality. However, the realities of prenatal diagnosis may preclude the prenatal identification of severe yet diagnosable abnormalities. In the case with transposition of the great vessels (Case 14), prenatal evaluation of the fetus did not occur until 34 weeks’ gestation and views of the fetal heart were limited by fetal position. Understanding these limitations and conveying them to the patient is imperative. Three of the eight cases with presumed ‘isolated’ cleft lip with or without cleft palate underwent termination of pregnancy. Pathological evaluation of these three cases revealed the additional abnormalities. Although in Case 11 the additional abnormality was only a lip pit, this finding prompted the diagnosis of Van der Woude syndrome, an autosomal dominant trait, to be made. Similarly, the other two termination cases had multiple malformations suggestive of a syndromic abnormality. This has important implications regarding reproductive counseling. Postnatal follow-up may help discriminate between etiological and syndromic diagnoses. The empirical recurrence risk for nonsyndromic fetal cleft lip with or without primary cleft palate is approximately 4% if the family history is negative for an oral cleft. Recurrence risk for syndromic causes is specific to the diagnosis. We found that 21.6% of fetuses with a presumed ‘isolated’ cleft lip with or without cleft palate had an additional anomaly; this has important implications regarding prenatal diagnosis and counseling of patients. All efforts should be made to assess the entire fetus for an additional anomaly if a cleft lip with or without cleft palate is detected. Although associated anomalies were only seen in fetuses with cleft lip and palate in this study, fetal chromosomal evaluation should be considered for cleft lip only as well as cleft lip and palate since both anomalies are part of the same developmental spectrum. The patient should also be instructed of the limitations of current diagnostic capabilities, and that additional malformation may be discovered postnatally. Also, the patient should be informed of the inability of the prenatal sonogram to reliably evaluate the secondary palate. The presence of an additional malformation may significantly alter the prognosis. Referral to a dysmorphologist is prudent to assess associated anomalies and to establish recurrence risk.


Chmait et al.

176

REFERENCES 1. Jones MC. Facial clefting. Etiology and developmental pathogenesis. Clin Plast Surg 1993; 20: 599–606. 2. Gorlin RJ, Cohen MM, Hennekam RCM. Syndromes of the Head and Neck (4th edn). Oxford University Press: New York, 2001; 859. 3. Rollnick BR, Prusansky S. Genetic services at a center for craniofacial anomalies. Cleft Palate J 1981; 18: 304–313. 4. Shprintzen RJ, Siegel-Sadewitz VL, Amato J, Goldberg RB. Anomalies associated with cleft lip, cleft palate, or both. Am J Med Genet 1985; 20: 585–595. 5. Clementi M, Tenconi R, Bianchi F, Stoll C. 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. Prenat Diagn 2000; 20: 870–875. 6. Chmait R, Pretorius D, Jones M, Hull A, James G, Nelson T, Moore T. Prenatal evaluation of facial clefts with twodimensional and adjunctive three-dimensional ultrasonography: A prospective trial. Am J Obstet Gynecol 2002; 187: 946–949. 7. Johnson DD, Pretorius DH, Budorick NE, Jones MC, Lou KV, James GM, Nelson TR. Fetal lip and primary palate: Threedimensional versus two-dimensional ultrasound. Radiology 2000; 217: 236–239. 8. Pretorius DH, House M, Nelson TR, Hollenbach KA.


9.

10.

11.

12.

13.

14.

15.

Evaluation of normal and abnormal lips in fetuses: comparison between three and two-dimensional sonography. AJR Am J Roentgenol 1995; 165: 1233–1237. Pretorius DH, Nelson TR. Fetal face visualization using threedimensional ultrasonography. J Ultrasound Med 1995; 14: 349–356. Bronshtein M, Blumenfeld I, Kohn J, Blumenfeld Z. Detection of cleft lip by early second-trimester transvaginal sonography. Obstet Gynecol 1994; 84: 73–76. Nyberg DA, Hegge FG, Kramer D, Mahony BS, Kropp RH. Premaxillary protrusion: a sonographic clue to bilateral cleft lip and palate. J Ultrasound Med 1993; 12: 331–335. Bird LM, Pretorius DH, Mendoza AE, Jones MC. Anencephaly with holoprosencephalic facies due to ring chromosome 18. Clin Dysmorphol 1997; 6: 351–358. Stoll C, Alembik Y, Dott B, Roth MP. Associated malformations in cases with oral clefts. Cleft Palate Craniofac J 2000; 37: 41–47. Crane JP, LeFevre ML, Winborn RC, Evans JK, Ewigman BG, Bain RP, Frigoletto FD, McNellis D. A randomized trial of prenatal ultrasonographic screening: impact on the detection, management, and outcome of anomalous fetuses. Am J Obstet Gynecol 1994; 171: 392–399. Porter HJ, Weston M, Andrews J, Berry PJ. Is ultrasound scanning an adequate antenatal diagnostic and screening technique: Review of 150 abnormal fetuses. Pediatr Pathol 1992; 12: 897–898.
