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An epidemiological study of orofacial clefts in Croatia 1988–1998
ARTICLE IN PRESS Journal of Cranio-Maxillofacial Surgery (2005) 33, 85–90 r 2005 European Association for Cranio-Maxillofacial Surgery doi:10.1016/j.jcms.2005.01.002, available online at http://www.sciencedirect.com
An epidemiological study of orofacial clefts in Croatia 1988–1998 Marija MAGDALENIC´-MESˇTROVIC´1,, Marijo BAGATIN2 Zagreb Dental Policlinic, (Chairman: Boris Klaic´), Zagreb, Croatia; 2Bagatin Policlinic for Maxillofacial, General and Plastic Surgery, (Chairman: Marijo Bagatin), Zagreb, Croatia 1
SUMMARY. Introduction: The objective of this epidemiological study was to assess the incidence at birth of orofacial clefts in Croatia. Aim: The aim of the present study was to analyse the character and incidence of orofacial clefts in Croatia and to compare the data with reports from other countries. Material and methods: All the material for the epidemiological study was retrieved from the documented files from all the neonatal units and hospitals in Croatia providing surgical treatment. Results: A total of 525,298 livebirths were documented during 11 years (1988–1998); 903 among them with orofacial clefts, 24 (2.7%) of them twins. Sixty (6.6%) infants died between birth and the age of 6 months. The incidence of orofacial clefts during the study period was 1.71 per thousand. When eliminating syndromic clefts, the incidence of non-syndromic clefts was 1.56 per thousand. Analysis of cleft lip with or without cleft palate (CL7P) and isolated cleft palate only (CP) revealed their incidence to be 1.05 and 0.66 per 1000, respectively. Of all types of clefting, CL and CLA was found in 17.2%, CL7P in 43.9%, CP in 38.2% and atypical facial clefts (AFC) in 0.8% of children. Left-sided clefts were most common (51%), followed by bilateral (30.5%) and right-sided (18.5%) clefts. The male to female ratio was 1.3. CL7P predominated in male and CP in female children. In 220 cases (24.4%) orofacial clefts were either associated with other anomalies or the clefts occurred as one feature of a syndrome. Conclusion: Data obtained from different sources yielded a cleft incidence of 1.71 per 1000 in Croatia. There were no differences in the incidences of orofacial clefts in comparison with similar data from other European countries. r 2005 European Association for Cranio-Maxillofacial Surgery
Keywords: Cleft lip and palate; Epidemiology; Associated anomalies; Syndrome
register of malformations, the study was based on data collected from several medical sources. The aim of the present study was to analyse the character and incidence of orofacial clefts in Croatia and to compare them with those from other countries.
INTRODUCTION Orofacial clefts are the most common facial malformations in all populations and ethnic groups. Every day some 700 children with cleft lip and/or cleft palate are born in the world, which means that a baby with cleft is born every 2 min or 240,000 children per year (Tolarova et al., 2002). Cleft lip and/or cleft palate account for 65% of all head and neck anomalies (Gorlin et al., 2001). The location makes these anomalies readily recognizable at birth. Clefts can occur as isolated malformations (nonsyndromic clefts) and associated with other malformations. Sometimes they are a feature of a specific malformation syndrome (syndromic clefts; Cohen, 1978; Duarte and Leal, 1999; Gorlin et al., 2001). The aetiology of cleft of lip, alveolus and palate is very complex and includes environmental effects in addition to the interaction of genetic predisposition. This holds also true for isolated clefts of the palate (Christensen, 1999). In Caucasian populations, the incidence of clefts ranges from 1.0 to 2.21 per 1000 livebirths (Gorlin et al., 1971;Vanderas, 1987; Derijcke et al., 1996; Tolarova and Cervenka, 1998; Table 1). No comprehensive epidemiological study has yet been conducted on the incidence of clefts in Croatia, nor are there reliable data. As there is no national
MATERIAL AND METHODS This epidemiological study covers the period between January 1, 1988, and December 31, 1998. Due to the lack of a national malformation registry, the study relied on data obtained from neonatal units at departments of gynaecology and obstetrics from all hospitals in Croatia (23 hospitals and two medical centers). The data were supplemented with those from the four surgical treatment centres (all those providing surgical treatment of orofacial clefts in Croatia). The study included only children born to mothers whose permanent residence was in Croatia at the time of delivery. The data were collected by the authors, who visited all neonatal and operative treatment centres in Croatia and obtained data from the hospital charts and birth certificates for entry into the computer database. The data obtained were statistically 85
ARTICLE IN PRESS 86 Journal of Cranio-Maxillofacial Surgery Table 1 – Previously reported Cleft Lip and Palate studies (from north to south)
only (CP) accounted for the highest proportion of these unrecorded cases (46; 57.5%), followed by cleft lip (CL+CLA) in 19 (23.8%), and cleft lip, alveolus and palate (CLAP) in 15 (18.7%) cases. Another 78 (8.6%) cleft patients who had apparently been treated at the surgical centres were not recorded there, but were recorded at the neonatal units. CP accounted again for the highest proportion of those (43;55.1%), followed by CLAP in 24 (30.7%), and cleft lip (CL+CLA) in 11 (14.1%) cases. Out of these, 60 infants (6.6%) who had been recorded at the neonatal units have died from other disorders before the age of 6 months (all livebirths). These data indicate the actual drop-out of 18 (2%) patients who were not recorded in the registries of the surgical centres.
Country
Incidence per 1000 live births
Author
Finland Sweden Norway Denmark
1.74 1.72 2.08 1.89
Scotland
1.40–1.53
England The Netherlands Belgium France Germany, Federal Republic German Democratic Republic Poland
1.00–1.40 1.47 1.47 1.75 1.48
Rintala (1986) Milerad et al. (1997) Derijcke et al. (1996) Jensen et al. (1988), Christensen (1999) Womersley and Stone (1987), Fitzpatrick et al. (1994), Bellis and Wohlgemuth (1999) Owens et al. (1985) Derijcke et al. (1996) Derijcke et al. (1996) Long et al. (1992) Hillig (1991)
1.77
Andra¨ et al. (1988)
Incidence
2.00–2.11
Czechoslovakia Hungary Slovenia Northern Italy
1.81–2.03 1.45 1.64 1.33
Antoszewski and KrukJeromin (1997), Tolarova and Cervenka (1998) Tolarova (1987) Hillig (1991) Kozˇelj (1996) Calzolari et al. (1988)
There were 525,298 livebirths to Croatian mothers from 1988 until 1998. The diagnosis of an orofacial cleft was made in 903 newborns, yielding an incidence of one neonate with orofacial cleft per 581 livebirths or 1.717 per 1000. The incidence varied according to years, from 1.43 per 1000 livebirths in 1989 to 2.02 per 1000 livebirths in 1992 (Table 2). When classifying orofacial clefts into syndromic and non-syndromic clefts, the latter as an isolated anomaly had an incidence of 1.56 per 1000 or 1 per 641 livebirths. When orofacial clefts were divided into cleft lip with or without cleft palate (CL7P) and isolated CP, the incidence was l.05 per 1000 and 0.66 per 1000, respectively. Of the 903 identified patients with orofacial clefts, 24 (2.7%) were twins. The data about the incidence for every year, since 1988 to 1998, location and gender are given in Tables 3 and 4.
analysed by use of w2-test. p o0.05 was accepted as statistically significant. The proportion of children born out of hospital and medical centers was between 1.5 and 2%, and was considered insignificant. Data on children with non-syndromic and syndromic clefts were included in the study. Data on the number of newborns in Croatia were obtained from the National Bureau of Statistics and National Institute of Public Health. Orofacial clefts were classified into four groups according to Robertson (1983):
primary cleft palate (CL or CLA), primary and secondary cleft palate (CLAP), i.e. combined clefts of lip, alveolus and palate (left or right – unilateral; bilateral), secondary cleft palate (CP), i.e. isolated cleft palate (hard palate, soft palate, submucous cleft); cleft uvula was not included; and atypical facial clefts (AFC).
RESULTS Analysis of the data collected showed that 903 children with congenital orofacial clefts were born during the study period (from January 1988 until December 1998). However, comparison of data received from various sources revealed some discrepancies: 80 cases of orofacial clefts had not been recorded in the neonatal units, but were recorded in surgical treatment centres, which accounted for 8.9% of the total number of recorded cases. Cleft palate
Cleft type Cleft lip (including clefts of lip and alveolus) was present in 17.2%, cleft lip, alveolus and palate in 43.9%, isolated CP in 38.2%, and AFC in 0.8% of study subjects. Cleft location According to location, left-sided orofacial clefts were most common (51%), followed by bilateral (30.5%) and right-sided (18.5%) clefts. Isolated CP most commonly involved the entire palate (74.8%), whereas soft palate involvement alone was recorded in 20% of cases. Submucous clefts were less frequently observed (5.2%). The male-to-female (M/F) ratio was 1.3. During the 11-year study period, the incidence of orofacial clefts was 1.8 and 1.5 per 1000 livebirths according to gender, male and female, respectively (Fig. 1). CL7P showed a male predominance (M/F ratio 1:9) and CP a female predominance (F/M ratio 1:4). That was a statistically significant (po0:001) difference regarding type of cleft and gender (Table 4).
ARTICLE IN PRESS study of orofacial clefts in Croatia 87 Table 2 – Incidence of orofacial clefts in Croatia, 1988 to 1998 Years
Incidence
11
Mean
Standard deviation
1.717
0.162
Range Minimum
Maximum
1.43 (1989)
2.02 (1992)
Table 3 – Number of orofacial clefts from 1988 to 1998, according to cleft type Year
Cleft type CL(A)
1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998
18 (18.2%) 16 (22.2%) 21 (22.1%) 12 (13.8%) 13 (15.3%) 19 (23.8%) 7 (9.6%) 16 (21.6%) 13 (17.1%) 11 (13.4%) 9 (11.3%)
Total
155 (17.2%)
Total
CLAP
CP
45 30 42 37 37 32 31 34 29 42 37
35 26 30 38 34 29 34 23 33 29 34
(45.5%) (41.7%) (44.2%) (42.5%) (43.5%) (40.0%) (42.5%) (45.9%) (38.2%) (51.2%) (46.3%)
396 (43.9%)
AFC (35.4%) (36.1%) (31.6%) (43.7%) (40.0%) (36.3%) (46.6%) (31.1%) (43.4%) (35.4%) (42.5%)
345 (38.2%)
1 (1%) 2 (2.1%) 1 (1.2%) 1 (1.4%) 1 (1.4%) 1 (1.3%)
7 (0.8%)
99 72 95 87 85 80 73 74 76 82 80 903
Table 4 – Distribution of the subjects according to cleft type, location and gender Cleft type
Cleft location
Gender
Total
Male
Female
Left Right Bilateral
70 15 11 96 (18.9%)
40 12 7 59 (15%)
110 27 18 155
(71%) (17.4%) (11.6%) (17.2%)
Left Right Bilateral
122 42 101 265 (52.1%)
49 33 49 131 (33.2%)
171 75 150 396
(43.2%) (18.9%) (37.9%) (43.9%)
Hard and soft Soft only Submucous
Subtotal
107 33 6 146 (28.7%)
151 36 12 199 (50.5%)
258 69 18 345
(74.8%) (20.0%) (5.2%) (38.2%)
AFC
2 (0.4%)
5 (1.3%)
Total
509 (56.4%)
394 (43.6%)
CL(A) Subtotal CLAP Subtotal CP
7
(0.8%)
903
(100%)
Orofacial clefts and associated anomalies
Fig. 1 – Cleft incidence according to gender, 1988–1998.
In 220 (24.4%) cases, clefts were either associated with other anomalies or they occurred as a symptom of a malformation syndrome (syndromic cleft). In 10% of these, the cleft occurred in chromosomal aberrations, whereas in 11.8%, it was associated with single gene inheritance. The anomalies occurring in a so-called sequence (numerous defects caused by a known mechanical or primarily structural factor) and multiple congenital anomalies of unknown aetiology involving more than two organs were diagnosed in
ARTICLE IN PRESS 88 Journal of Cranio-Maxillofacial Surgery Table 5 – Incidence of associated anomalies in patients with orofacial clefts Type of anomalies
Number of newborns
Percentage of the total (percentage among syndromic clefts)
Chromosomal aberrations Monogenic syndromes Sequences Multiple congenital anomalies Congenital cardiac anomalies Other single organ anomalies
22
2.4 (10)
26
2.9 (11.8)
36 36
4.0 (16.4) 4.0 (16.4)
24
2.7 (10.9)
76
8.4 (34.5)
16.5% of cases each. Congenital cardiac anomalies of unknown aetiology were detected in 10.9% and other single organ anomalies in 34.5% of cases. Distribution of associated anomalies is given in Table 5.
DISCUSSION Collecting data for an epidemiological study presents numerous problems, although at first it may appear simple. Clefts are generally diagnosed either at birth or subsequently at institutions offering treatment (Kozˇelj and Vegnuti, 2000). It is considered that perinatal registries include some 60–80% of all cleft cases (Rintala and Stegars, 1982). Complete recognition of this entity is impossible: in addition to readily identifiable cases there are also minimal forms of cleft lip or submucous cleft palate (Bagatin, 1985a,b). When reviewing the registries of patients submitted for surgical treatment, it becomes apparent that data on lethal outcomes between two surgical procedures or postoperative control examinations are inconsistent. In addition, these registries provide only partial insight into other anomalies associated with the cleft. Neonatal registries of maternity wards did not contain records on 80 (8.9%) newborns with a cleft. This is comparable to findings from neighbouring Slovenia, where Kozˇelj (1996) reported on 78 (8.6%) neonates with clefts who were not recorded in the registries of hospitals providing surgical treatment but were recorded in neonatal registries. Comparison of the data obtained from different registries in Croatia revealed that subsequent information was missing on 2% of children with orofacial clefts. This is less than the percentage reported by Christensen (1999). Lethal outcome shortly after birth up to the age of 6 months was recorded in 60 (6.6%) patients, which is consistent with Christensen’s results (1999) in the Danish population with orofacial clefts. However, Kozˇelj (1996), and Bellis and Wohlgemuth (1999) reported on a lower postnatal mortality rate in cleft children in Slovenia and southeast Scotland, respectively.
In this study, 24 (2.7%) of 903 patients with orofacial clefts were born as twins, which is in accordance with the results published by Akker et al. (1987) and Menegotto and Salzano (1991). A somewhat lower percentage of twins in children with congenital orofacial clefts has been reported by Rintala (1986) in Finland and Jensen et al. (1988) in Denmark. In Croatia, the incidence of orofacial clefts during the 1988–1998 period was 1.71 per 1000 livebirths. In the studies performed in various European countries the respective incidence ranged from 1.30 per 1000 through 1.94 per 1000 livebirths (Vanderas, 1987; Hagberg et al., 1988; Hillig, 1991; Derijcke et al., 1996). The incidence of orofacial clefts of 1.64 per 1000 livebirths was recorded in Slovenia during the 1973–1993 period (Kozˇelj, 1996), and of 1.33 per 1000 livebirths in northern Italy during the 1978–1986 period (Calzolari et al., 1988), both being lower than the rate recorded in this study. A lower incidence of congenital orofacial clefts was also found in the epidemiological studies carried out in Great Britain (Owens et al., 1985), southeast Scotland (Womersley and Stone, 1987; Bellis and Wohlgemuth, 1999), Hungary (Hillig, 1991), France (Long et al., 1992), West Scotland (Fitzpatrick et al., 1994) and Belgium (Derijcke et al., 1996). Rintala (1986) reported on a cleft incidence of 1.74 per 1000 in Finland, whereas Milerad et al. (1997) found 1.7 per 1000 in neighbouring Sweden, which is in accordance with our results. A higher incidence was found in former Czechoslovakia (Tolarova, 1987) and Denmark (Jensen et al., 1988; Christensen, 1999). According to the classification of orofacial clefts that has been most widely used in epidemiological studies, CLAP was the most common type, followed by isolated CP and cleft lip (CL+CLA), whereas AFC was the most uncommon type. The mean CLAP proportion reported is 35–55%. In this study, CLAP was diagnosed in 43.9% of cases, corresponding to the rate reported in the literature (Owens et al., 1985; Womersley and Stone, 1987; Kozˇelj, 1996; Milerad et al., 1997; Bellis and Wohlgemuth, 1999). In the present study, isolated CP was found in 38.2% of cases, which is higher than the proportion reported by Owens et al. (1985; 33.5%), Womersley and Stone (1987; 32.2%) and Jones (1988; 32.5%), similar to the values recorded by Kozˇelj (1996; 39.1%) and Milerad et al. (1997; 39%), but lower than the data reported by Bellis and Wohlgemuth (1999; 45%) and Stoll et al. (2000; 43.7%). Submucous cleft palate has been rarely described in the literature and refers to a small group of patients. Rintala and Stegars (1982) found submucous clefts in 13.8% of patients with an isolated CP, which exceeds the proportion recorded in the present study (5.2%). In this study, the incidence of isolated cleft lip (CL+CLA) was 17.2%, which is lower than the rates reported in the literature (Owens et al., 1985; Kozˇelj, 1996; Milerad et al., 1997; Bellis and Wohlgemuth, 1999; Stoll et al., 2000), with the exception of Womersley and Stone (1987) who have reported on a lower rate of CL+CLA.
ARTICLE IN PRESS study of orofacial clefts in Croatia 89
In the present study, atypical cleft forms such as oblique facial cleft, horizontal cleft, cleft of lower lip, etc. were recorded in 0.8% of cases, which is generally in accordance with literature data (1.4% Jones, 1988 and 1.0% Kozˇelj, 1996). However, Tolarova and Cervenka (1998) reported only 0.29% of AFC. Gender distribution of particular orofacial clefts showed a male predominance in the CL7P group and female predominance in the CP group, which is in accordance with literature data on Caucasian populations (Ross and Johnson, 1972; Tarallo et al., 1998; Shapira et al., 1999). In this study, the M/F ratio for isolated cleft lip (CL+CLA) was 1.63, similar to the result reported by Jensen et al. (1988). A higher prevalence of cleft lip with or without cleft palate (CL7P) in males was recorded by Owens et al. (1985); Tolarova (1987); Calzolari et al. (1988); Baird and Sadovinck (1994); Bellis and Wohlgemuth (1999); Rajabian and Sherkat (2000) and Long et al. (1992) reported on a M/F ratio of 1.9, which is in accordance with the results of this study (1.9). Isolated CP was more common in females, yielding a F/M ratio of 1.4, which is also consistent with literature reports (Coupland and Coupland, 1988; Long et al., 1992; Croen et al., 1998; Bellis and Wohlgemuth, 1999; Shapira et al., 1999; Rajabian and Sherkat, 2000). The percentage of children with syndromic clefts and of those with clefts associated with other malformations varies greatly from 3.8% in the study of Jensen et al. (1988) in Denmark through 44–64% in the overview presented by Wyszynski et al. (1996). However, most authors report on the prevalence of syndromic clefts and of associated anomalies with clefts to range from 20 to 39%, which is in accordance with the rate of 24.4% recorded in the present study.
CONCLUSION The present study points to the need to establish a national cleft registry to ensure reliable recording of patients with these congenital anomalies. Comparison of data obtained from different sources yielded a cleft incidence of 1.71 per 1000 in Croatia. There were no differences in the incidences of orofacial clefts in comparison with similar data from other European countries.
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ARTICLE IN PRESS 90 Journal of Cranio-Maxillofacial Surgery Ross RB, Johnson MC: Cleft Lip and Palate. Williams & Wilkins, Baltimore, 1972 Shapira Y, Lubit E, Kuflinec M, Borell G: The distribution of clefts of the primary and secondary palates by sex, type, and location. Angle Orthod 69: 523–528, 1999 Stoll C, Alembik Y, Dott B, Roth MP: Associated malformations in cases with oral clefts. Cleft Palate Craniofac J 37: 41–47, 2000 Tarallo D, Giuftre G, Franzese I, Tarallo MR, Maresca L, Langella G, De Carlo F, Grandi E, Tarallo S: Cheilognathopalatoschisis: its embryology, epidemiology, etiology, clinical picture and therapy. The experience of a division of pediatrics. Pediatr Med Chir 20: 281–284, 1998 Tolarova M: A study of the incidence, sex ratio, laterality, and clinical severity in 3660 probands with facial clefts in Czechoslovakia. Acta Chir Plast 29: 77–87, 1987 Tolarova MM, Cervenka J: Classification and birth prevalence of orofacial clefts. Am J Med Genet 75: 126–137, 1998 Tolarova MM., Mosby T, Pastor L, Armentano V, Oh H, Guinazu M: Prevention of cleft lip and palate — the plan for today, the goal for the future. Paper no. 114, 2nd World Cleft Congress, Munich, September 15–19, 2002.
Vanderas AP: Incidence of cleft lip and cleft lip and palate among races: a review. Cleft Palate J 24: 216–225, 1987 Womersley J, Stone DH: Epidemiology of facial clefts. Arch Dis Child 62: 717–720, 1987 Wyszynski DF, Beaty TH, Maestri NE: Genetics of nonsyndromic oral clefts revisited. Cleft Palate Craniofac J 33: 406–417, 1996
Dr. Marija MAGDALENIC`-MESˇTROVIC` Brune Bus˘ ic´a 36 HR-10020 Zagreb Croatia Tel.: +237 385 1 6636 851 E-mail: [email protected] Paper received 18 May 2004 Accepted 17 November 2004
An epidemiological study of orofacial clefts in Croatia 1988–1998 Marija MAGDALENIC´-MESˇTROVIC´1,, Marijo BAGATIN2 Zagreb Dental Policlinic, (Chairman: Boris Klaic´), Zagreb, Croatia; 2Bagatin Policlinic for Maxillofacial, General and Plastic Surgery, (Chairman: Marijo Bagatin), Zagreb, Croatia 1
SUMMARY. Introduction: The objective of this epidemiological study was to assess the incidence at birth of orofacial clefts in Croatia. Aim: The aim of the present study was to analyse the character and incidence of orofacial clefts in Croatia and to compare the data with reports from other countries. Material and methods: All the material for the epidemiological study was retrieved from the documented files from all the neonatal units and hospitals in Croatia providing surgical treatment. Results: A total of 525,298 livebirths were documented during 11 years (1988–1998); 903 among them with orofacial clefts, 24 (2.7%) of them twins. Sixty (6.6%) infants died between birth and the age of 6 months. The incidence of orofacial clefts during the study period was 1.71 per thousand. When eliminating syndromic clefts, the incidence of non-syndromic clefts was 1.56 per thousand. Analysis of cleft lip with or without cleft palate (CL7P) and isolated cleft palate only (CP) revealed their incidence to be 1.05 and 0.66 per 1000, respectively. Of all types of clefting, CL and CLA was found in 17.2%, CL7P in 43.9%, CP in 38.2% and atypical facial clefts (AFC) in 0.8% of children. Left-sided clefts were most common (51%), followed by bilateral (30.5%) and right-sided (18.5%) clefts. The male to female ratio was 1.3. CL7P predominated in male and CP in female children. In 220 cases (24.4%) orofacial clefts were either associated with other anomalies or the clefts occurred as one feature of a syndrome. Conclusion: Data obtained from different sources yielded a cleft incidence of 1.71 per 1000 in Croatia. There were no differences in the incidences of orofacial clefts in comparison with similar data from other European countries. r 2005 European Association for Cranio-Maxillofacial Surgery
Keywords: Cleft lip and palate; Epidemiology; Associated anomalies; Syndrome
register of malformations, the study was based on data collected from several medical sources. The aim of the present study was to analyse the character and incidence of orofacial clefts in Croatia and to compare them with those from other countries.
INTRODUCTION Orofacial clefts are the most common facial malformations in all populations and ethnic groups. Every day some 700 children with cleft lip and/or cleft palate are born in the world, which means that a baby with cleft is born every 2 min or 240,000 children per year (Tolarova et al., 2002). Cleft lip and/or cleft palate account for 65% of all head and neck anomalies (Gorlin et al., 2001). The location makes these anomalies readily recognizable at birth. Clefts can occur as isolated malformations (nonsyndromic clefts) and associated with other malformations. Sometimes they are a feature of a specific malformation syndrome (syndromic clefts; Cohen, 1978; Duarte and Leal, 1999; Gorlin et al., 2001). The aetiology of cleft of lip, alveolus and palate is very complex and includes environmental effects in addition to the interaction of genetic predisposition. This holds also true for isolated clefts of the palate (Christensen, 1999). In Caucasian populations, the incidence of clefts ranges from 1.0 to 2.21 per 1000 livebirths (Gorlin et al., 1971;Vanderas, 1987; Derijcke et al., 1996; Tolarova and Cervenka, 1998; Table 1). No comprehensive epidemiological study has yet been conducted on the incidence of clefts in Croatia, nor are there reliable data. As there is no national
MATERIAL AND METHODS This epidemiological study covers the period between January 1, 1988, and December 31, 1998. Due to the lack of a national malformation registry, the study relied on data obtained from neonatal units at departments of gynaecology and obstetrics from all hospitals in Croatia (23 hospitals and two medical centers). The data were supplemented with those from the four surgical treatment centres (all those providing surgical treatment of orofacial clefts in Croatia). The study included only children born to mothers whose permanent residence was in Croatia at the time of delivery. The data were collected by the authors, who visited all neonatal and operative treatment centres in Croatia and obtained data from the hospital charts and birth certificates for entry into the computer database. The data obtained were statistically 85
ARTICLE IN PRESS 86 Journal of Cranio-Maxillofacial Surgery Table 1 – Previously reported Cleft Lip and Palate studies (from north to south)
only (CP) accounted for the highest proportion of these unrecorded cases (46; 57.5%), followed by cleft lip (CL+CLA) in 19 (23.8%), and cleft lip, alveolus and palate (CLAP) in 15 (18.7%) cases. Another 78 (8.6%) cleft patients who had apparently been treated at the surgical centres were not recorded there, but were recorded at the neonatal units. CP accounted again for the highest proportion of those (43;55.1%), followed by CLAP in 24 (30.7%), and cleft lip (CL+CLA) in 11 (14.1%) cases. Out of these, 60 infants (6.6%) who had been recorded at the neonatal units have died from other disorders before the age of 6 months (all livebirths). These data indicate the actual drop-out of 18 (2%) patients who were not recorded in the registries of the surgical centres.
Country
Incidence per 1000 live births
Author
Finland Sweden Norway Denmark
1.74 1.72 2.08 1.89
Scotland
1.40–1.53
England The Netherlands Belgium France Germany, Federal Republic German Democratic Republic Poland
1.00–1.40 1.47 1.47 1.75 1.48
Rintala (1986) Milerad et al. (1997) Derijcke et al. (1996) Jensen et al. (1988), Christensen (1999) Womersley and Stone (1987), Fitzpatrick et al. (1994), Bellis and Wohlgemuth (1999) Owens et al. (1985) Derijcke et al. (1996) Derijcke et al. (1996) Long et al. (1992) Hillig (1991)
1.77
Andra¨ et al. (1988)
Incidence
2.00–2.11
Czechoslovakia Hungary Slovenia Northern Italy
1.81–2.03 1.45 1.64 1.33
Antoszewski and KrukJeromin (1997), Tolarova and Cervenka (1998) Tolarova (1987) Hillig (1991) Kozˇelj (1996) Calzolari et al. (1988)
There were 525,298 livebirths to Croatian mothers from 1988 until 1998. The diagnosis of an orofacial cleft was made in 903 newborns, yielding an incidence of one neonate with orofacial cleft per 581 livebirths or 1.717 per 1000. The incidence varied according to years, from 1.43 per 1000 livebirths in 1989 to 2.02 per 1000 livebirths in 1992 (Table 2). When classifying orofacial clefts into syndromic and non-syndromic clefts, the latter as an isolated anomaly had an incidence of 1.56 per 1000 or 1 per 641 livebirths. When orofacial clefts were divided into cleft lip with or without cleft palate (CL7P) and isolated CP, the incidence was l.05 per 1000 and 0.66 per 1000, respectively. Of the 903 identified patients with orofacial clefts, 24 (2.7%) were twins. The data about the incidence for every year, since 1988 to 1998, location and gender are given in Tables 3 and 4.
analysed by use of w2-test. p o0.05 was accepted as statistically significant. The proportion of children born out of hospital and medical centers was between 1.5 and 2%, and was considered insignificant. Data on children with non-syndromic and syndromic clefts were included in the study. Data on the number of newborns in Croatia were obtained from the National Bureau of Statistics and National Institute of Public Health. Orofacial clefts were classified into four groups according to Robertson (1983):
primary cleft palate (CL or CLA), primary and secondary cleft palate (CLAP), i.e. combined clefts of lip, alveolus and palate (left or right – unilateral; bilateral), secondary cleft palate (CP), i.e. isolated cleft palate (hard palate, soft palate, submucous cleft); cleft uvula was not included; and atypical facial clefts (AFC).
RESULTS Analysis of the data collected showed that 903 children with congenital orofacial clefts were born during the study period (from January 1988 until December 1998). However, comparison of data received from various sources revealed some discrepancies: 80 cases of orofacial clefts had not been recorded in the neonatal units, but were recorded in surgical treatment centres, which accounted for 8.9% of the total number of recorded cases. Cleft palate
Cleft type Cleft lip (including clefts of lip and alveolus) was present in 17.2%, cleft lip, alveolus and palate in 43.9%, isolated CP in 38.2%, and AFC in 0.8% of study subjects. Cleft location According to location, left-sided orofacial clefts were most common (51%), followed by bilateral (30.5%) and right-sided (18.5%) clefts. Isolated CP most commonly involved the entire palate (74.8%), whereas soft palate involvement alone was recorded in 20% of cases. Submucous clefts were less frequently observed (5.2%). The male-to-female (M/F) ratio was 1.3. During the 11-year study period, the incidence of orofacial clefts was 1.8 and 1.5 per 1000 livebirths according to gender, male and female, respectively (Fig. 1). CL7P showed a male predominance (M/F ratio 1:9) and CP a female predominance (F/M ratio 1:4). That was a statistically significant (po0:001) difference regarding type of cleft and gender (Table 4).
ARTICLE IN PRESS study of orofacial clefts in Croatia 87 Table 2 – Incidence of orofacial clefts in Croatia, 1988 to 1998 Years
Incidence
11
Mean
Standard deviation
1.717
0.162
Range Minimum
Maximum
1.43 (1989)
2.02 (1992)
Table 3 – Number of orofacial clefts from 1988 to 1998, according to cleft type Year
Cleft type CL(A)
1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998
18 (18.2%) 16 (22.2%) 21 (22.1%) 12 (13.8%) 13 (15.3%) 19 (23.8%) 7 (9.6%) 16 (21.6%) 13 (17.1%) 11 (13.4%) 9 (11.3%)
Total
155 (17.2%)
Total
CLAP
CP
45 30 42 37 37 32 31 34 29 42 37
35 26 30 38 34 29 34 23 33 29 34
(45.5%) (41.7%) (44.2%) (42.5%) (43.5%) (40.0%) (42.5%) (45.9%) (38.2%) (51.2%) (46.3%)
396 (43.9%)
AFC (35.4%) (36.1%) (31.6%) (43.7%) (40.0%) (36.3%) (46.6%) (31.1%) (43.4%) (35.4%) (42.5%)
345 (38.2%)
1 (1%) 2 (2.1%) 1 (1.2%) 1 (1.4%) 1 (1.4%) 1 (1.3%)
7 (0.8%)
99 72 95 87 85 80 73 74 76 82 80 903
Table 4 – Distribution of the subjects according to cleft type, location and gender Cleft type
Cleft location
Gender
Total
Male
Female
Left Right Bilateral
70 15 11 96 (18.9%)
40 12 7 59 (15%)
110 27 18 155
(71%) (17.4%) (11.6%) (17.2%)
Left Right Bilateral
122 42 101 265 (52.1%)
49 33 49 131 (33.2%)
171 75 150 396
(43.2%) (18.9%) (37.9%) (43.9%)
Hard and soft Soft only Submucous
Subtotal
107 33 6 146 (28.7%)
151 36 12 199 (50.5%)
258 69 18 345
(74.8%) (20.0%) (5.2%) (38.2%)
AFC
2 (0.4%)
5 (1.3%)
Total
509 (56.4%)
394 (43.6%)
CL(A) Subtotal CLAP Subtotal CP
7
(0.8%)
903
(100%)
Orofacial clefts and associated anomalies
Fig. 1 – Cleft incidence according to gender, 1988–1998.
In 220 (24.4%) cases, clefts were either associated with other anomalies or they occurred as a symptom of a malformation syndrome (syndromic cleft). In 10% of these, the cleft occurred in chromosomal aberrations, whereas in 11.8%, it was associated with single gene inheritance. The anomalies occurring in a so-called sequence (numerous defects caused by a known mechanical or primarily structural factor) and multiple congenital anomalies of unknown aetiology involving more than two organs were diagnosed in
ARTICLE IN PRESS 88 Journal of Cranio-Maxillofacial Surgery Table 5 – Incidence of associated anomalies in patients with orofacial clefts Type of anomalies
Number of newborns
Percentage of the total (percentage among syndromic clefts)
Chromosomal aberrations Monogenic syndromes Sequences Multiple congenital anomalies Congenital cardiac anomalies Other single organ anomalies
22
2.4 (10)
26
2.9 (11.8)
36 36
4.0 (16.4) 4.0 (16.4)
24
2.7 (10.9)
76
8.4 (34.5)
16.5% of cases each. Congenital cardiac anomalies of unknown aetiology were detected in 10.9% and other single organ anomalies in 34.5% of cases. Distribution of associated anomalies is given in Table 5.
DISCUSSION Collecting data for an epidemiological study presents numerous problems, although at first it may appear simple. Clefts are generally diagnosed either at birth or subsequently at institutions offering treatment (Kozˇelj and Vegnuti, 2000). It is considered that perinatal registries include some 60–80% of all cleft cases (Rintala and Stegars, 1982). Complete recognition of this entity is impossible: in addition to readily identifiable cases there are also minimal forms of cleft lip or submucous cleft palate (Bagatin, 1985a,b). When reviewing the registries of patients submitted for surgical treatment, it becomes apparent that data on lethal outcomes between two surgical procedures or postoperative control examinations are inconsistent. In addition, these registries provide only partial insight into other anomalies associated with the cleft. Neonatal registries of maternity wards did not contain records on 80 (8.9%) newborns with a cleft. This is comparable to findings from neighbouring Slovenia, where Kozˇelj (1996) reported on 78 (8.6%) neonates with clefts who were not recorded in the registries of hospitals providing surgical treatment but were recorded in neonatal registries. Comparison of the data obtained from different registries in Croatia revealed that subsequent information was missing on 2% of children with orofacial clefts. This is less than the percentage reported by Christensen (1999). Lethal outcome shortly after birth up to the age of 6 months was recorded in 60 (6.6%) patients, which is consistent with Christensen’s results (1999) in the Danish population with orofacial clefts. However, Kozˇelj (1996), and Bellis and Wohlgemuth (1999) reported on a lower postnatal mortality rate in cleft children in Slovenia and southeast Scotland, respectively.
In this study, 24 (2.7%) of 903 patients with orofacial clefts were born as twins, which is in accordance with the results published by Akker et al. (1987) and Menegotto and Salzano (1991). A somewhat lower percentage of twins in children with congenital orofacial clefts has been reported by Rintala (1986) in Finland and Jensen et al. (1988) in Denmark. In Croatia, the incidence of orofacial clefts during the 1988–1998 period was 1.71 per 1000 livebirths. In the studies performed in various European countries the respective incidence ranged from 1.30 per 1000 through 1.94 per 1000 livebirths (Vanderas, 1987; Hagberg et al., 1988; Hillig, 1991; Derijcke et al., 1996). The incidence of orofacial clefts of 1.64 per 1000 livebirths was recorded in Slovenia during the 1973–1993 period (Kozˇelj, 1996), and of 1.33 per 1000 livebirths in northern Italy during the 1978–1986 period (Calzolari et al., 1988), both being lower than the rate recorded in this study. A lower incidence of congenital orofacial clefts was also found in the epidemiological studies carried out in Great Britain (Owens et al., 1985), southeast Scotland (Womersley and Stone, 1987; Bellis and Wohlgemuth, 1999), Hungary (Hillig, 1991), France (Long et al., 1992), West Scotland (Fitzpatrick et al., 1994) and Belgium (Derijcke et al., 1996). Rintala (1986) reported on a cleft incidence of 1.74 per 1000 in Finland, whereas Milerad et al. (1997) found 1.7 per 1000 in neighbouring Sweden, which is in accordance with our results. A higher incidence was found in former Czechoslovakia (Tolarova, 1987) and Denmark (Jensen et al., 1988; Christensen, 1999). According to the classification of orofacial clefts that has been most widely used in epidemiological studies, CLAP was the most common type, followed by isolated CP and cleft lip (CL+CLA), whereas AFC was the most uncommon type. The mean CLAP proportion reported is 35–55%. In this study, CLAP was diagnosed in 43.9% of cases, corresponding to the rate reported in the literature (Owens et al., 1985; Womersley and Stone, 1987; Kozˇelj, 1996; Milerad et al., 1997; Bellis and Wohlgemuth, 1999). In the present study, isolated CP was found in 38.2% of cases, which is higher than the proportion reported by Owens et al. (1985; 33.5%), Womersley and Stone (1987; 32.2%) and Jones (1988; 32.5%), similar to the values recorded by Kozˇelj (1996; 39.1%) and Milerad et al. (1997; 39%), but lower than the data reported by Bellis and Wohlgemuth (1999; 45%) and Stoll et al. (2000; 43.7%). Submucous cleft palate has been rarely described in the literature and refers to a small group of patients. Rintala and Stegars (1982) found submucous clefts in 13.8% of patients with an isolated CP, which exceeds the proportion recorded in the present study (5.2%). In this study, the incidence of isolated cleft lip (CL+CLA) was 17.2%, which is lower than the rates reported in the literature (Owens et al., 1985; Kozˇelj, 1996; Milerad et al., 1997; Bellis and Wohlgemuth, 1999; Stoll et al., 2000), with the exception of Womersley and Stone (1987) who have reported on a lower rate of CL+CLA.
ARTICLE IN PRESS study of orofacial clefts in Croatia 89
In the present study, atypical cleft forms such as oblique facial cleft, horizontal cleft, cleft of lower lip, etc. were recorded in 0.8% of cases, which is generally in accordance with literature data (1.4% Jones, 1988 and 1.0% Kozˇelj, 1996). However, Tolarova and Cervenka (1998) reported only 0.29% of AFC. Gender distribution of particular orofacial clefts showed a male predominance in the CL7P group and female predominance in the CP group, which is in accordance with literature data on Caucasian populations (Ross and Johnson, 1972; Tarallo et al., 1998; Shapira et al., 1999). In this study, the M/F ratio for isolated cleft lip (CL+CLA) was 1.63, similar to the result reported by Jensen et al. (1988). A higher prevalence of cleft lip with or without cleft palate (CL7P) in males was recorded by Owens et al. (1985); Tolarova (1987); Calzolari et al. (1988); Baird and Sadovinck (1994); Bellis and Wohlgemuth (1999); Rajabian and Sherkat (2000) and Long et al. (1992) reported on a M/F ratio of 1.9, which is in accordance with the results of this study (1.9). Isolated CP was more common in females, yielding a F/M ratio of 1.4, which is also consistent with literature reports (Coupland and Coupland, 1988; Long et al., 1992; Croen et al., 1998; Bellis and Wohlgemuth, 1999; Shapira et al., 1999; Rajabian and Sherkat, 2000). The percentage of children with syndromic clefts and of those with clefts associated with other malformations varies greatly from 3.8% in the study of Jensen et al. (1988) in Denmark through 44–64% in the overview presented by Wyszynski et al. (1996). However, most authors report on the prevalence of syndromic clefts and of associated anomalies with clefts to range from 20 to 39%, which is in accordance with the rate of 24.4% recorded in the present study.
CONCLUSION The present study points to the need to establish a national cleft registry to ensure reliable recording of patients with these congenital anomalies. Comparison of data obtained from different sources yielded a cleft incidence of 1.71 per 1000 in Croatia. There were no differences in the incidences of orofacial clefts in comparison with similar data from other European countries.
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Dr. Marija MAGDALENIC`-MESˇTROVIC` Brune Bus˘ ic´a 36 HR-10020 Zagreb Croatia Tel.: +237 385 1 6636 851 E-mail: [email protected] Paper received 18 May 2004 Accepted 17 November 2004