Cleft lip and palate in southwestern Iran: an epidemiologic study of live births.

BACKGROUND: Cleft lip with or without cleft palate (CL/P), is the most common congenital anomaly in the head and neck worldwide. We studied the prevalence of cleft lip (CL) and palate (CP) in Shiraz, which is located in southwestern Iran.
METHODS: Data was collected from the teaching hospitals of the Shiraz University of Medical Sciences. Records of 147,608 consecutive live births delivered in three hospitals during the 10 years from November 1993 to November 2003 were reviewed.
RESULTS: One hundred nineteen cases of CL/P or CP alone were registered for a prevalence of 0.80 per thousand live births. The overall male/female ratio was 1.25. The male/female ratio was 1.22 in the CL patients and 1.58 in the CL/P patients. A male predominance was obvious in both groups.
CONCLUSION: This study shows that the prevalence rate of CL and CP in southwestern Iran is closer to the low prevalence reported in African countries and is lower than the prevalence reported in previous reports in Caucasians.

Cleft lip with or without cleft palate (CL/P), is the most common congenital anomaly in the head and neck worldwide.1,2 A multifactorial mode of inheritance is suggested by almost all authors.3–11 Epidemiological studies for prevention of cleft lip (CL) and palate (CP) are lacking while surgical techniques for proper treatment are growing rapidly. There have been few published epidemiologic investigations in Iran.12–14 The objective of this study was to assess data from three maternity university hospitals in Shiraz, which is located in the center of a large province in southwest Iran.

Methods

In a cross-sectional study, we determined the prevalence of CL and CP in 147 608 live births that occurred from 1993 to 2003. The birth records were from three university maternity hospitals in Shiraz, located in the center of Fars province in southwest Iran. The births from these hospitals accounted for the majority of births during this time period. The data elements abstracted were the cleft type, date of birth, sex, and presence of other anomalies. Syndromic clefts were excluded and submucous clefts were not usually diagnosed. The cleft types were classified as CL (right, left, or bilateral), CL and CP (right, left, bilateral), or CP (complete, incomplete). Statistical analysis was carried out with the chi-square test using a frequency table. Probability values of 0.05 or less were taken to be statistically significant.

Results

The overall prevalence of cleft live births over this 10-year period was 0.80 per 1000, or 1 in 1240 live births. The prevalence of cleft births varied from year to year, ranging from 1 in 1487 in 1993, to a high of 1 in 992 in 1999 (Table 1). Among 119 cleft cases, there were 35 cases of CL, 54 cases of CL and palate, and 30 cases of CP (Table 2). The overall male/female ratio was 1.25. The male/female ratio was 1.22 in the CL patients, and 1.58 in the CL and palate patients (Table 3). A male predominance was obvious in both groups. This ratio was 0.88 in the CP babies with a female preponderance. There was no statistically significant correlation with sex and the type of cleft (P=0.44).

Table 1

Cleft births in 147 608 live births, 1993–2003.

Year	Male	Female	Total	Total births	Per 1000 births	Ratio per live births
1993	7	4	11	16361	.672	1:1487
1994	6	6	12	15521	.77	1:1293
1995	5	6	11	15020	.73	1:1365
1996	8	4	12	14343	.83	1:1195
1997	6	4	10	14264	.70	1:1426
1998	11	2	13	14065	.92	1:1081
1999	6	8	14	13893	1.007	1:992
2000	4	6	10	14516	.68	1:1451
2001	6	8	14	14877	.94	1:1062
2003	7	5	12	14748	.81	1:1229
Total	66	53	119	147608	0.80	1:1240

Table 2

Distribution of cleft types

Type	Frequency	Percent (95% confidence interval)
Cleft lip	35	29.41 (21–38)
Cleft lip and palate	54	45.38 (36–54)
Cleft palate	30	25.21 (17–33)
Total	119	100

Table 3

Cleft types by sex.

Type of cleft	Male		Female
	Frequency	%	Frequency	%
Cleft lip	22	55	18	45
Cleft lip and palate	30	61.2	19	38.8
Cleft palate	14	46.7	16	53.3

Unilateral cleft cases (47.05%) occurred more frequently on the left side than on the right side in both CL only and CL and palate patients, but there was no significant correlation between laterality and the type of cleft (Table 4) (P=0.87). Bilateral cleft cases (20.16%) were more frequent in the CL and palate group (31%) than in the only CL group (20%). There was nothing significant in the laterality pattern of deformities in 9 patients (9.24%).

Table 4

Laterality of clefts.

Type of clefts	Unilateral		Bilateral	Uncertain	Total
	Right	Left
Cleft lip	11 (31%)	14 (40%)	7 (20%)	3 (9%)	35 (29.4%)
Cleft lip and palate	13 (24%)	18 (33%)	17 (31%)	6 (11%)	54 (45.4%)
Cleft palate					30 (25.2%)
Total	24 (20.2%)	32 (26.9%)	24 (20.2%)	9 (9.2%)	119 (100%)

Eight of 119 cases (6.72%) of CL (P) were associated with other malformations (Table 5). All these anomalies were single. There were 2 cases of congenital heart diseases and 2 cases of neural tube anomalies, followed by one each ear, gastrointestinal, male genitalia and extremity malformations. Cases with syndromes and chromosomal malformations were not included in this study.

Table 5

Associated malformations in the 119 cases.

Malformation	Frequency	Percent (%)
Neural tube	2	1.68
Cardiac	2	1.68
Ear	1	0.84
Gastrointestinal	1	0.84
Male genitalia	1	0.84
Extremity	1	0.84
Total	8	6.72

Discussion

Birth defects arise from the interplay of multiple genetic and environmental factors. Although such complex traits are characterized by familial aggregation, recurrence rates within families are relatively low; the risk that an affected child will have a sibling who is also affected is typically less than 5 percent.15 Zucchero et al. identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of CL and CP, known as Van der Woude’s syndrome. DNA-sequence variants associated with IRF6 are major contributors to CL/P.16 The most important implication of Zucchero’s study is that it provides a promising lead for identifying other genes linked to CL or CP and for elucidating the mechanisms of environmental exposure, which are substantial steps forward.

CL, CP, or the combination of the two is a common birth defect that varies in prevalence according to ethnicity and geographic origin, with populations of Asian and Amerindian ancestry having the highest rates and groups of African ancestry the lowest.18–31 The prevalence in Caucasian populations varies from 0.6 to 1.89 per 1000, the mean prevalence being approximately 1 per 1000.7,32–48 The reported prevalence in Japanese and Korean populations tends to be higher than in Caucasians,3,49–55 as do rates from Native American populations,52,56–58 being approximately 0.5 per 1000. Several reports from different countries show figures between these two extremes.8,52,59–64

There have been few reports of the birth prevalence of CL/P from Iran12–14 and other countries of Western Asia.22–25,65,66 The recording and documentation of CL and CP in Iran is limited to registration in maternity hospitals. There is no national registration system for congenital anomalies, hence no nationwide epidemiologic study.

In this investigation, the overall prevalence of cleft births over a 10-year period was 0.80 per 1000, which is remarkably lower than previous Iranian reports. The prevalence of CL or CP or both was 1.03 per 1000 births in 1991 (P<0.05).14 We are not sure whether this data resulted from a real reduction in prevalence or a reduction in the number of children delivered. Some have also speculated that a woman who delivers a baby with a cleft as a first child tends not to have another child.

The population in our study was fairly homogenous genetically and has almost the same culture and environment. Thus, we could find no convincing reason for the dramatic variation in cleft prevalence from year to year (Table 1). The distribution of type of cleft (Table 2) and sex ratios (Table 3) in this study were comparable to those observed in a previous Iranian report,14 and in other Caucasian reports.7,32,60,66–68 Both Iranian studies showed a significant predominance of males with CL/P and of females with CP. A higher prevalence of CL in males than in females in this study is compatible with other Caucasian reports, but contrasts with the previous Iranian report, which showed a female preponderance. There was a left-sided predominance of clefts, with a higher frequency of bilaterality (20.16%) compared with the range of 9.6% to 16% in other reports.69–71 The ratio of unilateral left to unilateral right to bilateral clefts was about 4:3:3. Although neural tube and cardiac anomalies had a higher range of occurrence, the result should be interpreted with caution because of the small total number and the absence of adequate control data.

This study shows that the prevalence rate of CL and CP in southwestern Iran is closer to the prevalence reported in African countries and is lower than the prevalence reported in previous reports in Caucasians.