Epidemiology of Cleft Palate

Cleft lip with cleft palate (C /P) and isolated cleft palate (CP) are serious birth defects, which on

a worldwide level affect approximately 1 in every 600 newborn babies. This means that

assuming a global birth rate of 15,000 children per hour (United States Bureau of the Census), a

child with a cleft is born somewhere in the world every 2.5 min. From birth to maturity, children

with oral clefts (OCs) undergo multidisciplinary surgical and nonsurgical treatment with

considerable disruption to their lives and often adverse psychological consequences to

themselves and their families.

A further study, in Hungary (Czeizel, 1984), reported that the proportion of CP without cleft lip

(CL) was about sevenfold greater in stillbirths (primary fetal deaths 28 weeks or older) than in

live births (2.38/1000 vs. 0.36/1000). In comparison, for CL/P, the ratio was a little less than

threefold (3.17/1000 vs. 1.15/1000). As may be expected, this differential between live births and

stillbirths is greater for individuals with additional malformations elsewhere than for those with

only CL, CP, or both (CLP).

Krause et al. (1963) examined human embryos and fetuses and reported that the frequency of

clefts with associated malformations was 11.61/1000 and that the frequency of clefts without

associated malformations was 7.22/1000. Nishimura et al. (1966) reported the frequency of CL/P

in 1213 voluntarily aborted human embryos to be 14.7/1000. In a separate study of 5117

voluntarily aborted human embryos, Iizuka (1973) found that the prevalence at birth of CL was

4.3/1000, that of CLP was 8.10/1000, and that of isolated CP was 3.2/1000.

Associated Malformations

It is generally accepted that associated malformations occur less frequently in infants who have

CLP than in those who have CP and even less still in those with isolated CL. For example, a 17-

year study in north-eastern France reported rates of associated malformations to be 46.7% in CP,

36.8% in CLP, and 13.6% in CL (Kallen et al., 1996). Cornel et al. (1992) reported associated

abnormalities in 23% of CL/P cases and in 52% of cases with isolated CP. Numerous other

studies also found congenital anomalies to be much more commonly associated with CP than

with CL/P (Ingalls et al., 1964; Drillien et al., 1966; Moller, 1972; Emanuel et al., 1973). In the

Finnish population, however, CL/P was as often associated with other malformations as was CP

(Saxen and Lath, 1974). Familial background was also more often reported in association with

CP than with CL/P in Finland, which contrasts with the findings of others, e.g., Fogh-Andersen

(1942) in Denmark.

Some studies also subdivide CL/P into unilateral and bilateral groups when examining additional

malformations and report an increase in additional malformations in the bilateral subgroup

(Hagberg et al., 1997). Some reports do not define what is meant by associated abnormalities,

while others give ambiguous descriptions. Conway and Wagner (1966) recorded only the ten

most common associated abnormalities listed on birth certificates over an 11-year period.

Prevalence of Isolated Cleft Palate

There is considerable heterogeneity in what is described as isolated CP. For instance, the most

common syndrome with isolated CP as a feature is the Pierre Robin syndrome, and inclusion or

exclusion may make a substantial difference to the figures. This subgroup is also more

susceptible to ascertainment bias as the prevalence of submucous clefting within the general

population is thought to be as common as overt isolated CP. In a detailed study of isolated CP in

Denmark, Christensen and Fogh-Andersen (1994) noted a marked difference in sex ratios for

nonsyndromic overt CP including the hard palate and non-syndromic overt CP of the soft palate

only. This, combined with the tendency for hard palate and soft palate clefts not to occur within

the same families indicates that they may be two etiologically distinct subgroups of CP.

Inclusion of the Robin sequence is also complicated by the fact that its etiology is heterogeneous

and its diagnosis inconsistent. Some authorities state that respiratory distress is an essential part

of the anomaly (Shprintzen and Singer, 1992), while others make a diagnosis on the basis of

glossoptosis and micrognathia with the cleft, whether or not there is respiratory distress

(Caouette-Laberge et al., 1994). The Pierre Robin anomaly also occurs in association with other

monogenie disorders, e.g., Stickler's syndrome.

Further complications in the consideration of isolated CP are two recognized genetic phenomena:

(1) the association of CP with 22qll.2 deletion in the velocardiofacial syndrome and (2) X-linked

clefting. The prevalence at birth of velocardiofacial syndrome in many populations is unknown,

and diagnosis may be delayed, thus affecting the birth prevalence figures. X-linked clefting has

been reported in some populations, e.g., the Icelandic population (Moore et al., 1987), but has

not been investigated in many others. Also, Lowry and Renwick (1969) reported X-linked

submucous CP as part of an X-linked recessive trait, which might complicate the picture

regarding CP birth prevalence and sex ratio figures.

Distribution of cleft lip with or without cleft palate for Europe, Africa, Asia, and Australia

Distribution of cleft palate for Europe, Africa, Asia, and Australia

Distribution of cleft lip with or without cleft palate for North and South America.

Distribution of cleft palate for North and South America.

Distribution of cleft lip with or without cleft palate for Europe.

Distribution of cleft palate for Europe.

Prevalence of Cleft Lip with or without Cleft Palate in Indian Subcontinent

On the Indian subcontinent, highest CL/P prevalence’s were recorded in Maharashtra

(2.32/1000) in a hospital-based study that included live births and stillbirths (Chaturvedi and

Banerjee, 1989). This is followed by a rate of 1.61/1000 in Calcutta in a 29-month hospital-based

study (Nair and Mathai, 1964). The lowest prevalence’s were seen in Madurai (0.77/1000 live

births) in a hospital-based study (Kamala et al., 1978) and in a small 2-year hospital-based study

in New Delhi (0.41/1000 live births) (Kulshrestha et al., 1983).

The survey conducted by Christian Medical College, Vellore reported the incidence of cleft lip

and palate in the regional population as 1:639. Statistics in India are only available in the State of

Tamilnadu and it is approximately 1 in 700 live births. The figures were presented in the Annual

Conference of Association of Plastic Surgeons of India in November 2006 by Dr. K. Sridhar of

Chennai.

Prevalence of Isolated Cleft Palate

United States and Canada

In North America, the highest reported prevalence for CP is 1.11 for Native Americans in the

Californian registry between 1983 and 1992 (Croen et al., 1998). This is followed closely by the

East Indian ethnic subgroup in California in the same study (1.06/1000). The lowest figures

reported are 0.22 for nonwhites in New York City (Conway and Wagner, 1966) and 0.24/1000

for nonwhites in Mississippi in 1980-1989 (Das et al., 1995). In the NBDPN, which compared

the frequency of clefts in various states, the highest reports come from Wisconsin (1.45) and

Connecticut (0.95), with the lowest in New Mexico (0.18) and Tennessee (0.29).

Central and South America

The prevalence of CP in South America shows remarkably little variation, with eight out of the

10 South American countries contributing to the ECLAMC Registry; prevalence rates are

between 0.2 and 0.4/1000 births. The lowest is 0.06/1000 in Peru, while the highest prevalence

was recorded in Chile, 0.46/1000. The figures from Central America for prevalence of isolated

CP were 0.2/1000 in a hospital-based study in the Caribbean (Garcia-Godoy, 1980) and

0.27/1000 in a hospital-based register in Mexico (Perez-Molina et al., 1993).

Australia and New Zealand

In Oceania, a remarkably high figure for isolated CP was reported for the Maoris in New

Zealand, with a prevalence of 1.87/1000 between 1960 and 1976 (Chapman, 1983); figures of

0.64 and 0.67 were reported for whites in New Zealand (Chapman, 1983) and Australia (Bower

et al., 1989), respectively.

Europe

The prevalence of isolated CP is highest in Finland, with a rate of 0.97/1000 from in a study

between 1948 and 1975 (Rintala, 1986); in a later study, between 1974 and 1988, Tolarova and

Cervenka (1995) reported a birth prevalence of 1.01. The next highest rate in Europe was

reported by Womersley and Stone (1987) in the west of Scotland, 0.81, between 1974 and 1985.

The lowest reported European figures come from Denmark (0.36/1000) in a study between 1938

and 1957 (Fogh-Andersen, 1961) and central and eastern France (0.42/1000) (Kallen et al.,

1996). In the EUROCAT regional registry (which does not include Finland), the highest figure is

from Glasgow (western Scotland) (0.94) and the lowest (0.25/1000) is from Northern Ireland in

the same time period (1990 and 1994). In general, the figures from Europe are characterized by

significant variation, not only between countries but also within. For instance, the Paris registry

reveals a relatively low frequency of CP (0.47/1000), while the figure for Strasbourg is

0.88/1000 (ICBDMS, 2000).

Middle East

From the relatively few studies from the Middle East, the extremes in CP birth prevalence range

from a low of 0.17/1000 in a hospital-based study of Israeli Jews (Azaz and Koyoumdjisky-

Kaye, 1967) to a high of 0.42/1000 for nonsyndromic clefts (Srivastava and Bang, 1990) in a

population-based study in Kuwait. Taher (1992) reported what he regarded as a cluster in one

hospital in Tehran with a birth prevalence of 0.62/1000 for CP (and a remarkably high figure of

3.12/1000 for CL/P). Chemical sulfur mustard gas was implicated in the etiology during this 4-

year period (1983-1988).

Far East

The highest recorded figure for isolated CP comes from an 18-year hospital-based study in

Tokyo, in which Mitani (1954) reported 0.73/1000 births. The lowest figure, 0.15/1000 live

births, was recorded by Xiao (1989) in a large cross-sectional study of 945 hospitals in China in

a 12-month period between October 1986 and September 1987. The next lowest figure comes

from a report by Emanuel et al. (1972), who recorded a figure of 0.16/1000 in a hospital-based

study in Taipei (Taiwan).

Indian Subcontinent

Much of the data from India come from relatively small local hospital-based studies recording

the prevalence of birth defects including OCs. While the majority of these studies record figures

for CL/P, many do no record isolated CP. Of those that do, the lowest figure, 0.32/1000, comes

from a study by Singh and Sharma (1980) in New Delhi. The highest figure, 0.48/1000, comes

from a small study in Kanpur by Mital and Grewal (1969). While a meta-analysis was carried out

by Verma and Mathews (1983), this was methodologically flawed and included various

prospective and retrospective studies of live births and stillbirths throughout India. However, the

figures of 1.20/1000 for CL/P and 0.44/1000 for CP appear to be the best available estimates for

OC prevalence in the Indian subcontinent.

Africa

The lowest recorded birth prevalence for OC comes from Africa, and the lowest rate of any study

in the world is that from the hospital live births series reported by Ogle (1993) between October

1977 and June 1979 in a hospital-based study in Nigeria. The prevalence at birth was 0.02/1000

in a study of over 56,000 live births. The next lowest, 0.07/1000, was recorded by Iregbulem

(1982) in another hospital series, in Enugu, Nigeria. The highest prevalence rates come from

Tunisia on the north coast, where Khrouf et al. (1986) recorded 0.4/1000 in a hospital-based

study that included the recording of abnormalities in stillbirths. The next highest, 0.33/1000,

comes from a hospital-based study in Nairobi reported by Khan (1965).

Effect of Ethnic Origin, Migration, and Population on epidemiology of C.P

While only a few studies have been carried out in Africa to examine cleft prevalence, they

suggest a low prevalence of both CP and CL/P. African-Americans have lower rates for both CP

and CLP than whites in the United States, and a study in Birmingham (UK) showed that those

originating from the Caribbean have low OC rates (Leek and Lancashire, 1995). Studies from

Asia reveal high rates of CL/P but not CP in mainly hospital-based series, and similarly higher

rates on the Indian subcontinent. Studies in North America also reveal high rates of CL/P in

persons of Japanese or Chinese origin (Croen et al., 1998; Tolarova and Cervenka, 1998).

Ching and Chung (1974) have shown that the racial differences in CL/P birth prevalence are

likely to have a genetic basis. In an extensive study from Hawaii, they showed that Japanese

immigrants continue to have increased birth prevalence of CL/P and, by studying interracial

crosses, that Caucasian-Japanese matings have intermediate birth prevalence, suggesting that the

racial differences are independent of environment. Support for this theory is provided by Leek

(1972), who showed that the variation in the birth prevalence of CL/P between different ethnic

groups living in the same areas is eight times greater that that among geographically scattered

populations of the same ethnic origin.

Among Filipinos, prevalence data for CL/P revealed a difference by country, with the highest

prevalence observed in the Philippines, an intermediate prevalence Hawaii, and the lowest

prevalence in California (Croen et al., 1998). Such variations in cleft prevalence according to

maternal country of birth may reflect changes in nongenetic risk factors, such as maternal diet,

that may occur following migration. Variations in prevalence may also be related to racial and

ethnic differences in nongenetic factors associated with clefting risk, and this assists with the

formulation of future hypotheses in OC research.

In the United States, Croen et al. (1998) recognized that the considerable population admixture

requires investigation of variation of OC prevalence according to parental race, ethnicity, and

maternal country of birth. Croen and colleagues (1998) subdivided patients in the Californian

birth defects monitoring program into 13 ethnic subsets. They also recorded OC risk according to

whether mother and father were of the same race or ethnicity.

A further study in the United States examined rates of CL/P by state and Hispanic ethnicity by

subdividing the data into three subgroups: Hispanics, non-Hispanic whites, and non-Hispanic

blacks (Kirby et al., 2000). They concluded that CL/P prevalence was greatest among whites

(1.03/1000) and lowest among blacks (0.54/1000), with Hispanics having an intermediate

prevalence (0.97/1000).

Relative Proportions of Different Cleft Types

When considering OC frequency, the proportion of different types of cleft has important

implications for the clinical workload but is also of interest in providing clues about the

underlying etiology. The relative proportions of syndromic clefts and associated abnormalities

are also important in determining etiological factors. European and U.S. studies on

nonsyndromic cleft prevalence in general suggest that unilateral CLP is the most frequent single

type of cleft, accounting for about 30% to 35% of cases. Isolated CL and CP each account for

between 20% to 25%, and bilateral CLP is the most rare (about 10%), with submucous and other

clefts accounting for the rest (Hagberg et al., 1997).

Furthermore, of all CLP cases, 80% are unilateral and 20% are bilateral. Overall, 15% of all OCs

are syndromic (12% of CL/P and 25% of CP). Over 300 syndromes are recognized (involving

the oral, cardiac, skeletal, and other body areas), and of the remaining 85% of OC individuals,

50% have other less welldefined anomalies (OMIM, 2000).

Fogh-Andersen (1942), using data from Denmark, reported a CL: CLP:CP ratio of 1:2:1, which

is often quoted as the normal ratio for the different types of cleft, especially for European or

Caucasian populations. This has on occasion been used as a guide [e.g., Woolf et al. (1963), who

felt that, because of underascertainment of isolated CP in their hospital-based sample in Utah, the

figure should be adjusted in line with this ratio]. It may, however, be erroneous to assume this as

a universal figure, as other studies indicate. A number of Japanese studies (Natsume and Kawai,

1986; Natsume et al., 1987) reveal a much lower prevalence at birth of CP, with a CL:CP ratio of

8:3. Similarly, in Africa, CP is a much lower proportion of the overall prevalence at birth of

clefting, being 4% in a newborn Zairian sample (Ogle, 1993) and 19% in a large Nigerian study

(Iregbulem, 1982). In the latter study, CL was much more common than CLP, the ratios being

49% for CL, 32% for CLP, and 19% for CP.

Closer inspection of the figures in studies that provide a breakdown of clefts into different

subgroups is interesting. The general trend is that in those regions of the world where cleft

prevalence is highest, the ratio of CLP to CL is highest, and in regions of lowest cleft prevalence,

the proportion of the more severe forms of clefting is correspondingly low. This provides

indirect support for the multifactorial threshold model and for the notion of OC being a threshold

characteristic with genetic predisposition.

Gender Ratios in Various Types of Cleft

Among the accepted epidemiological differences between CL/P and isolated CP is the now

widely accepted male predilection for CL/P and female tendency toward CP. Therefore, to quote

a sex ratio for OC as a whole, in view of the acknowledged differences in sex ratios for the

subgroups, is meaningless. The differences in sex ratios within the OC groups have proven to be

more complicated, varying with severity of the cleft, number of affected siblings in a family, and

ethnic origin. In all studies of white populations, CL/P occurs more frequently in males than

females,with an average male to female ratio of 2:1 (Wyszynski et al., 1996). In Japanese

populations, there is a significant male excess in the CLP group but not in the CL only group

(Fujino et al., 1963). In the white population, the male excess in the CL/P group becomes more

apparent with increasing severity of cleft (Fogh-Andersen, 1942) and less apparent when more

than one sibling is affected in the family (Niswander et al., 1972). In both races, there appears to

be a slight excess of affected females in the CP group (Fraser, 1970; Wyszynski et al., 1996),

although there remains some uncertainty and variation in the gender distribution of isolated CL.

No generally accepted explanation for these gender differences exists, although sex differences

in the timing of critical developmental stages in craniofacial development are thought to have an

as yet undefined role in their etiology (Burdi and Silvey, 1969).

It is generally considered that clefts with associated malformations are different

epidemiologically from clefts without associated malformations (Vanderas, 1987). However, the

subdivision of primary palatal clefting into CL and CLP is somewhat controversial. Some argue

that they are embryologically the same structure and the pathogenesis is presumably

chronologically the same, with clefting of the hard palate being a secondary phenomenon

occurring because of the disturbance surrounding the primary palate cleft (Fogh-Andersen,

1942). It is, however, possible to have a CL and/or primary palate and a separate cleft of the soft

palate with an intact hard palate between the two clefts, suggesting that they may be separate

events (Hook and Porter, 1982; Vanderas, 1987; Sayetta et al., 1989).

Time Trends

Data from the EUROCAT registry Report 6 (1980-1992) and Report 7 (1990-1994) provide a

reasonable estimate of time trends in prevalence during these two time periods for CP and CL/P

subgroups. While interesting variations during these time periods can be observed in various

registries, there is no overall consistent trend to suggest that OC is significantly increasing or

reducing in prevalence.

The ICBDMS, like EUROCAT, does not reveal any remarkable time trends in the period 1974-

1998, with the occasional exception, such as the Finnish data. In Finland, the prevalence of CP

has steadily increased over this period and, for CL/P, there is a similar, though lesser, trend. In

contrast, many of the other countries that contribute data to ICBDMS, e.g., the United States and

most of the European countries such as England and Wales, Ireland, northern Netherlands, Italy,

and Hungary, reveal a tendency to reduction in frequency of CL/P. Apart from the

aforementioned trend in Finland, the birth prevalence of CP remains remarkably consistent

throughout this time period.

One of the most comprehensive data sets comes from Denmark, where there is a mandatory

reporting system and a rigorous ascertainment procedure. The reported birth prevalence of OC in

Denmark has risen from 1/667 live-born infants in 1942 to 1/529 in 1981 (Jensen et al., 1988).

This increase may be due to better reporting and recording, decreased neonatal mortality,

increasing environmental teratogens (e.g., drugs), and increased frequency of marriage among

cleft patients because of better care.

The decline in OC in England and Wales apparent in notification data does not appear in the

EUROCAT Registry data from Liverpool or Glasgow (EUROCAT Reports, 1995, 1996).

However, EUROCAT data from Northern Ireland show a consistent decline in birth prevalence

for CP. In parallel with the increased prevalence in Denmark over time between the 1940s and

1970s, increases were also noted in Finland during the same period. Seasonal patterns are little

studied, but where they have been (Saxen and Lathi, 1974), no consistency has been noted.

Genetics and Environmental Factors

The overall variation in craniofacial morphology worldwide is related to ethnicity, and heritable

characteristics (parental craniofacial characteristics being an example) are associated with

ethnicity. The myriad of identifiable environmental causes are not uniform worldwide, individual

countries and regions of countries being subjected to considerably differing lifestyle factors and

environmental conditions. Maternal cigarette smoking and alcohol consumption remain the most

plausible environmental factors in the cause of OC, but the evidence is not entirely consistent

and may differ for CP and CL/P. Gene-environment interactions may also play a role, and in two

studies smoking has been shown to be a more potent risk factor when present in conjunction with

the transforming growth factor-alpha TaqI C2 allele (Hwang et al., 1995; Shaw et al., 1996).

Specific environmental etiologies were implicated in OC in the Tehran study (Taher, 1992), and

Zieglowski and Hemprich (1999) showed a dramatic increase (9.4%) in CLP 1 year after the

Chernobyl nuclear accident, though there may be an element of selection bias in this

figure.Variations in genotype are associated with ethnicity, and thus it is possible that the effects

of gene-environment interactions may vary considerably between ethnic groups. This may also

account for some of the ethnic and geographic variation in the epidemiology of OC.

Socioeconomic Status

A number of studies have speculated on socioeconomic status, but in general, little attempt has

been made to record it accurately or to analyze the correlation with CP or CLP. Croen et al.

(1998) examined variation in the prevalence of CP and CL/P among Filipinos in California,

Hawaii, and the Philippines and demonstrated a gradient, with the highest prevalence observed in

the Philippines, an intermediate prevalence in Hawaii, and the lowest prevalence in California.

They speculated that this variation may reflect differences in environmental risk factors, such as

lack of maternal periconceptional vitamin supplementation.

Womersley and Stone (1987) examined the prevalence of facial clefting within Greater Glasgow

according to housing and social characteristics. The highest rates were observed in areas of high

unemployment, poor housing, and unskilled workers, whereas the lowest rates were found in

affluent areas with large owner-occupied housing and professional or non-manual workers. The

majority of cases examined were CP, and there appeared to be less variation in CL/P cases. The

authors concluded that a deprived environment enhances the susceptibility to CP and that

interaction between low socioeconomic status or a poor environment with a teratogen might

explain Glasgow's high prevalence of CP. Diet, infection, and drugs were suggested.

Sivaloganathan (1972) examined social class and OC in a hospital-based sample in Kuala

Lumpur, Malaysia, between September 1969 and May 1971. They found that 65% of clefts were

from the lower class, 28% from the middle class, and 7% from the upper class, indicating either

that clefting is associated with poor socioeconomic status and environmental factors or that there

is a genetic predisposition. In a similar hospital-based study in Thailand, Chuangsuwanich et al.

(1998) reported that low socio-economic status is also a significant etiological factor for OC.

It might be expected that if low socioeconomic status were a significant factor, time trend data

would reflect this in areas where there have been improvements in living standards. Some trends

are detectable from the available data in Europe, and these show that globally there was no

reduction in the birth prevalence of OC between 1980 and 1996. This is despite considerable

improvements in living conditions and nutrition during this same time period. This might well be

due to a concomitant increase in exposure to other environmental teratogens, or it may be a

genetic phenomenon. In the context of gene-environment interaction, Khoury and James (1993)

state that if genetic susceptibility is not accounted for in the study of environmental factors, the

results may be misleading.

It may be that the factors associated with low socioeconomic status can account for some of the

world-wide variation in the prevalence of OC. The overall conclusion is that socio-economic

status in OC is not well studied. One of the barriers to investigation of the role of socioeconomic

status in OC is that common criteria for the description of low socioeconomic status do not exist.

Also, in those studies where socioeconomic status or social class have been examined, different

criteria have been used, making valid intercenter comparisons impossible.

The overall conclusions to be drawn from the data presented above are as follows:

There is ample evidence of the distinctly different nature of CL/P and CP and emerging

evidence of distinct differences in subgroups within these overall conditions.

There is a great deal of geographical variation, which is more apparent for CL/P than CP.

There is considerable variation in the proportion of OC cases with additional congenital

anomalies and syndromes.

The limited available data suggest that migrant groups retain rates of CL/P similar to

those of their area of origin.

There is no consistent evidence of time trends, nor is there consistent variation by

socioeconomic status or seasonality, but these areas have not been adequately studied.

There is a need to investigate such parameters within as well as between different

populations.

There is considerable international variation in the frequency of OCs, but validity and

comparability of data are adversely affected by numerous factors: source population of

births considered (hospital vs. population), time period, method of ascertainment,

inclusion/exclusion criteria, and sampling fluctuation.

There are many parts of the world for which we have little or no information on the

frequency of OCs, in particular parts of Africa, Asia, and Eastern Europe.