Cleft Lip & Palate: From Origin to Treatment, 1st Edition

12. Epidemiology of Oral Clefts: An International Perspective

Peter A. Mossey

Julian Little

Cleft lip with or without cleft palate (CL/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, http://www.census.gov/ipc/www/ibdnew.html, 2001), 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.

Efforts over the years have been made to record the frequency of birth defects, and accurate data on epidemiology are important for documenting the burden in relation to the planning of public health services. They also form the basis for research into causes. The eventual objective must be, from both scientific and humanitarian viewpoints, to advance the knowledge and understanding of causative factors and to institute primary preventive measures. Among the barriers to achieving this objective are (1) the heterogeneity of OCs, (2) the lack of standard criteria for the collection of data, and (3) the lack of and/or failure to apply an internationally comparable OC classification.

Search Strategy for Identification of Relevant Studies

The search strategy began with a free text search of Medline (from 1966, http://www.ncbi.nlm.nih.gov/PubMed/) and EMBASE (from 1989, http://www.silverplatter.com/catalog/embx.htm) and OVID (http://www.ovid.com/sales/medical.cfm), which incorporates Medline, BIDS and a number of university medical databases. The PubMed database was searched with the key words cleft, lip, palate, and incidence, producing 377 records ranked by date. EMBASE was searched using cleft lip or cleft palate combined with prevalence or incidence, yielding a total of 239 references. OVID was searched using cleft lip, cleft palate, and incidence or prevalence, producing a total of 755 references dating back to 1965. In addition, selected literature was hand-searched, including the Cleft Palate Journal dating back to 1960, and references were identified in earlier work on neural tube defects (Elwood et al., 1992). Where available, the following information was also noted: gender distribution, ethnic origin of the parents, and whether the figures included stillbirths and induced abortions. This hand search concentrated on reports from more obscure journals and from various parts of the world, for which the above data sets may not contain complete records. This included the Indian subcontinent, Africa, Asia, and the Middle East. In all searches, there was no restriction on language and original papers were sought. For a small percentage of the literature, only abstracts were reviewed. Bibliographies and review articles from the literature obtained in the hand search enabled identification of any missed articles. The searches are supplemented by EUROCAT (http://www.iph.fgov.be/eurocat/eurocat.htm) and ICBDMS (http://www.icbd.org) reports, in particular for examining time trends.

Among the minimum data required for eligibility were the following:

· Year of publication, reference population, and sample size

· Subdivision into cleft subgroups

· Type of pregnancy outcome included, e.g., live births, stillbirths, induced abortions

Other issues affecting comparison of studies, e.g., ascertainment methods, association of abnormalities or syndromes, family history, were noted but not used as criteria for exclusion.

Methodological Issues Relevant to the Data Presented

Descriptive Epidemiology

The completeness of ascertainment may differ between countries, depending on the number and type of sources of ascertainment, the type of pregnancy outcome (live births, terminations, stillbirths), and the recognition of syndromic individuals. These issues can considerably affect the comparability of such data (McMahon and Pugh, 1970; Leek, 1983). Epidemiological data were derived from OC registries or surgical records, which may be different from the actual number of affected OC individuals. Temporal trends in the prevalence at birth of OCs exist, which can in part be explained by the differing levels of ascertainment within countries as they develop.

Another critical requirement is that the observer defines precisely the population in which the frequency of malformation is measured. A major issue is whether one reports or estimates rates in all recognized conceptuses, all births, or all live births. The term births is somewhat ambiguous because it (usually) included stillbirths, which does not have a uniform definition. In summarizing the data, we have considered issues such as (1) live births vs. stillbirths, (2) associated malformations, and (3) particular factors contributing to the prevalence of isolated CP.

Live Births vs. Stillbirths

The proportion of serious malformations is higher in stillbirths than in live births, so the inclusion of stillbirths tends to elevate the birth prevalence or incidence rates over those derived if only live births are considered. Similarly, inclusion of data on miscarriages and abortions, i.e., losses earlier in gestation, may increase rates over those found if only live births and stillbirths are analyzed.

Vanderas (1987) examined the problem of inclusion or exclusion of stillbirths in the ascertainment of OCs in a number of international studies, some of which included live births, stillbirths, and abortions in their evaluation of prevalence at birth. The OC rates were 6.43/1000 stillbirths vs. 2.16/1000 live births in a study of the white population of Iowa (Hay, 1971). In a study on live births in the pooled data from black, Mexican, and white populations (Lutz and Moor, 1955), rates were 2.72/1000 stillbirths vs. 0.91/1000 live births. The risk of developing clefts in stillbirths and abortions appears therefore to be about three times as frequent as in live births. Also, clefts with associated malformations behaved differently epidemiologically in comparison to clefts without associated malformations.

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. Thus, the lumping of figures that include not only live births but also stillbirths and/or induced abortions will not be comparable to figures for live births only. If fetal deaths or earlier losses are included in summary rates, then this should be noted specifically and rates should be presented separately for live births and for embryonic and fetal deaths.

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. This may explain some of the variation observed in the reporting of the frequency of other abnormalities accompanying OCs (see tables in Appendix I).

Prevalence of Isolated Cleft Palate

There is considerable heterogeneity in what is described as isolated CP. Many figures for isolated CP are provided without an adequate explanation of inclusion/exclusion criteria. 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. Therefore, the authors recommended that future studies on isolated CP distinguish between hard palate, soft palate, and submucous hard palate in an attempt to disclose etiological heterogeneity within secondary palatal clefting.

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.

Geographical Variation in the Epidemiology of Oral Clefts

Epidemiological data for OCs from the three different sources outlined above are presented as follows:

· Peer-reviewed publications, Table 12.1 (complete data shown in Appendix 12.I

· Data from the European Registry of Congenital Anomalies and Twins (EUROCAT) registration system, Appendix 12.II

· Data collected through the National Birth Defects Prevention Network (NBDPN) in the United States, Appendix 12.III

· A series of maps (Figs. 12.1,12.2,12.3,12.4,12.5 and 12.6) are included to illustrate some of the birth prevalence data for isolated CP and cleft lip and palate (CL/P). The data used for the maps were taken from individual reports or from registries that are mentioned in the text of the chapter (Appendix 12.I).

· There is insufficient detail in the maps (Fig. 12.1,12.2,12.3,12.4,12.5,12.6) to reflect regional differences within countries. These maps are intended merely to illustrate general trends in the population distribution of CP and CL/P. They also indicate that there is a dearth of published information available for some countries and geographical areas of the world.

The commentary relates mainly to the peer-reviewed literature, with occasional reference to the other registration systems, and deals with CL/P and CP separately.

Prevalence of Cleft Lip with or without Cleft Palate

United States and Canada

One of the fundamental differences between the OC epidemiology data in Europe and North America is the ethnic heterogeneity that characterizes most of the North American population. It was therefore important to examine the North American data in the light of ethnic origin. The highest prevalence of CL/P was found in British Columbia among Native Americans, 2.73/1000 live births (Lowry and Renwick, 1969). The next highest, 1.99/1000 births, is from the Californian registry in the period 1983-1992 (Croen et al., 1998), representing Native Americans only. The lowest figures are from nonwhite populations in New York [0.29 reported by Conway and Wagner (1966)] and Mississippi [0.30 as reported by Das et al. (1995)].

TABLE 12.1A. Extremes of Cleft Lip with or without Palate Prevalence: Highest and Lowest figures

Continent/Country Total Births Prevalence (per 1000 births) Reference Europe N. Netherlands 60,584 1.46 Cornel et al. (1992) France (Rhone-Alpes-Auvergne) 813,513 0.67 Long et al. (1992) United States and Canada USA California 13,545 1.99 Croen et al. (1998) USA New York (Native American) 344,929 0.29 Conway and Wagner (1966) Central and South America Bolivia 79,296 2.28 Castilla et al. (1999) Caribbean (Santo Domingo) 704,410 0.42 Garcia-Godoy (1980) Oceania Australia (Aborigines) 9,695 2.27 Bower et al. (1989) New Zealand (Maoris) 178,240 0.39 Chapman (1983) Far East Japan (Hiroshima, Nagasaki) 63,806 2.13 Neel (1958) Japan 55,103 0.97 Kondo (1987) Middle East Saudi Arabia 62,557 1.89 Borkar et al. (1993) Israel (Jews) 47,768 0.37 Azaz and Koyoumdjisky-Kaye (1967) Indian Subcontinent India (Maharashtra) 3014 2.32 Chaturvedi and Banerjee (1989) India (Madurai) 11,619 0.77 Kamala et al. (1978) Africa Kenya (Nairobi) 3061 1.63 Khan (1965) South Africa (Johannesburg, blacks) 29,633 0.20 Kromberg and Jenkins (1982)

TABLE 12.1B. Extremes of Cleft Palate Prevalence: Highest and Lowest Figures

Continent/Country Total Births Prevalence Reference Europe Finland 2,258,850 0.97 Rintala (1986) Denmark 1,631,376 0.36 Fogh-Andersen (1961) United States and Canada USA Native Americans 13,545 1.11 Croen et al. (1998) New York (nonwhite) 344,929 0.22 Conway and Wagner (1966) Central and South America Chile 297,583 0.46 Castilla et al. (1999) Peru 72,864 0.06 Castilla et al. (1999) Oceania Australia (Whites) 170,760 0.67 Bower et al. (1989) New Zealand (Maoris) 178,240 0.39 Chapman (1983) Far East Japan (Tokyo) 49,645 0.73 Mitani (1954) China 1,243,284 0.15 Xiao (1989) Middle East Kuwait 53,786 0.42 Srivastava and Bang (1990) Israel (Jews) 47,768 0.17 Azaz and Koyoumdjisky-Kaye (1967) Indian Subcontinent Kanpur 4150 0.48 Mital and Grewal (1969) New Delhi 7590 0.32 Singh and Sharma (1980) Africa Tunisia 10,000 0.40 Khrouf et al. (1986) Zaire 56,637 0.02 Ogle (1993)

FIG. 12.1. Distribution of cleft lip with or without cleft palate for Europe, Africa, Asia, and Australia.

The NBDPN examined OC prevalence by U.S. state. The highest recorded is for New Mexico at 1.73/1000 live births in the 1995–1996 cohort, which included stillbirths as well as live births and is a relatively small sample. In Wisconsin 1989–1995, prevalence was 1.56/1000 with live births and stillbirths combined. The lowest recorded prevalence rate for CL/P was 0.59 in Alaska and Illinois; the Alaskan sample was for 1996 only, while the Illinois sample was a 7-year sample (1989–1996) and included stillbirths.

Central and South America

Most of the registers in South America report through the Latin American Collaborative Study of Congenital Malformations (ECLAMC; Appendix I, Table 12.IC), and the OC figures include associated abnormalities. The highest CL/P prevalence figure is from Bolivia (2.28/1000), with Argentina (1.16/1000) and Chile (1.13/1000) next. These are geographically in the southern, and generally less developed, parts of South America. At the lowest end of the scale is the geographically and genetically different population in Central America and the Caribbean, with Das et al. (1995) reporting a prevalence of 0.42/1000, the next lowest rate is for Venezuela (on the northern coast), with a prevalence of 0.77/1000.

FIG. 12.2. Distribution of cleft palate for Europe, Africa, Asia, and Australia.

FIG. 12.3. Distribution of cleft lip with or without cleft palate for North and South America.

Australia and New Zealand

The figures for Australia and New Zealand recognize the different ethnic origins of the indigenous people of these of islands and the settlers. Prevalence figures range from remarkable extremes for nonsyndromic clefts of 2.27 in Aborigines in a study between 1980 and 1987 (Bower et al., 1989) to the lowest recorded figure outside of Africa of 0.39 in New Zealand Maoris between 1960 and 1976. In the same study, New Zealand whites occupied an intermediate position (1.19) (Chapman, 1983).

FIG. 12.4. Distribution of cleft palate for North and South America.

Europe

The highest birth prevalence of CL/P from all European countries was 1.46 (Cornel et al., 1992). Overall, the areas of highest prevalence within Europe are Norway, Denmark, Sweden, Iceland, and the northern Netherlands. Intermediate levels occur in Central Europe, and the lowest are in southern Europe. In the British Isles, the frequency varies between 0.6 and 1.04, which is nearer to the southern European figures.

Middle East

In the Middle East, the highest record for CL/P prevalence is 1.89/1000 in a Saudi Arabian hospital-based study (Borkar et al., 1993). The next highest is considerably lower (1.06/1000 live births) for nonsyndromic OCs, reported in Kuwait between 1985 and 1987 (Srivastava and Bang, 1990). Taher (1992) reported what he regarded as a cluster in one hospital in Tehran with a prevalence of 3.12/1000. Chemical sulfur mustard gas was implicated in the etiology during this 4-year period, 1983–1988. The lowest prevalence (0.37/1000 live births) was recorded by Azaz and Koyoumdjisky-Kaye (1967) in a hospital-based study of Israeli Jews between 1960 and 1962. The next lowest recorded prevalence was 0.85/1000 live births in Iran (Rajabian and Sherkat, 2000).

FIG. 12.5. Distribution of cleft lip with or without cleft palate for Europe.

FIG. 12.6. Distribution of cleft palate for Europe.

Far East

Data on CL/P prevalence from the Far East are often quoted as single figures with all clefts combined rather than separate figures for CP and CL/P. The highest rate reported is from Japanese data, a hospital-based sample in Hiroshima between 1948 and 1954, revealing a prevalence of 2.13/1000 live births (Neel, 1958). In the Philippines, Murray et al. (1997) reported a prevalence of 1.94/1000 live births in a 7-year survey of hospital records between 1989 and 1996, with this figure including syndromic clefts (21%). The lowest quoted figure is also from a hospital-based study of live births in Japan between 1979 and 1982 (Kondo, 1987), 0.97/1000; the next lowest was reported by Natsume et al. (1987), 1.02/1000 live births, in Haichi, Japan. These studies are not strictly comparable because of differences in ascertainment criteria; they also reveal the difficulty of comparing hospital vs. population-based studies.

Indian Subcontinent

On the Indian subcontinent, highest CL/P prevalences 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 prevalences 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).

Africa

In Africa, the highest figure of 1.63 comes from a relatively small 6-month hospital-based study in Nairobi reported by Khan (1965), which is out of step with other African studies; selection bias is suspected. The next highest rate is from Tunisia in northern Africa, where live births and stillbirths were recorded in a 9-month study, with a prevalence of 1/1000 births (Khrouf et al., 1986). Many of the studies reveal figures less than half of that; e.g., the next highest is from Nigeria (0.47/1000) (Gupta, 1969) and the lowest (0.2, 0.21, and 0.3/1000 live births) were recorded in hospital-based studies in Johannesburg (Kromberg and Jenkins, 1982) and Nigeria (Iregbulem, 1982; Ogle, 1993). All three of these were small studies that may be suspected of underascertainment.

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).

Discussion

Ethnic Origin, Migration, and Population Admixture Studies

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) (Table 12.2). 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.

TABLE 12.2. Prevalence at Birth of Oral Clefts by Ethnic Group of Parents (Birmingham 1960–1984)

Ethnic Group Prevalence at birth (per 10,000) Cleft Lip with or without Cleft Palate Cleft Palate Both parents originating from Europe 10.9 6.6 Indian subcontinent 12.1 7.4 Caribbean 5.2* 2.2* Mother European, father Caribbean 1.5† 6.1 Mother Caribbean, father European 0.0 0.0 *p < 0.05. †p <0.01.

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. This issue is particularly relevant in OC with the known ethnic variations; it is therefore important to pursue clues as to the relative contribution of genetics and environmental factors to the etiology. 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 (Table 12.3) 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).

TABLE 12.3. Number and Rates of Cleft Lip with or without Cleft Palate by State Hispanic Ethnicity (USA National Center for Health Services 1993–1995)

Hispanic all Non-Hispanic white Non-Hispanic black Cases Rate* 95% CI Cases Rate* 95% CI Cases Rate* 95% CI Arizona 78 13.5 10.7–16.9 126 10.8 9.1–13.0 7 9.4 4.1–20.3 California 564 10.4 9.5–11.3 217 10.0 8.8–11.5 5 2 7.8 5.9–10.3 Colorado 48 14.8 11.-19.8 136 11.7 9.9–13.9 3 3.7 1.0–11.9 New Jersey 8 4.3 1.9–8.5 40 6.1 4.4–8.4 7 3.7 1.6–7.9 New York 91 5.8 4.7–7.1 367 10.9 9.9–12.1 63 4.3 3.4–5.6 Texas 52 8.6 6.5–11.3 26 7.6 5.1–11.4 8 5.9 2.7–12.1 Totals 841 9.7 9.0–10.3 912 10.3 9.7–11.0 140 5.4 4.5–6.4 *Rate is quoted per 10,000 births. 95% CI, confidence interval. Source: Kirby et al. (2000).

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; http://www3.ncbi.nlm.nih.gov/omim/).

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. Table 12.4 was compiled from a selection of studies that provide this information and presents in particular the relative frequency of CL and CLP, as well as the overall prevalence of CL/P. 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.

The data in Table 12.4, however, need to be interpreted with caution because of the heterogeneity associated with the ascertainment methods from which the figures were derived. The data are from a range of studies of varying sizes, some looking at nonsyndromic cases only, and some including associated malformations; also, some included stillbirths as well as livebirths and some did not. Since other studies have revealed a greater proportion of associated malformations with the more severe clefts and the milder clefts may not be as easily ascertained in areas with a higher proportion of severe cases, these factors must be accounted for before firm conclusions can be drawn.

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).

TABLE 12.4. Relative Proportions of Cleft Lip Subtypes in a Sample Studies

Country Relative proportions of cleft types (%) Reference Prevalence CL/P CL CLP Ratio CLP:CL New York City (nonwhites) 0.29 27.0 31.0 1.15 Conway and Wagner (1966) Africa (Nigeria) 0.34 49.0 32.0 0.65 Iregbulem (1982) Israeli Jews 0.37 31.0 38.0 1.23 Azaz and Koyoumdjisky-Kaye (1967) Caribbean (Santo Domingo) 0.42 36.4 31.4 0.86 Garcia-Godoy (1980) Africa (Zaire) 0.44 50.0 46.0 0.92 Ogle (1993) New York City (whites) 0.60 33.0 37.0 1.12 Conway and Wagner (1966) Iran 0.85 35.0 48.0 1.37 Rajabian and Sherkat (2000) USA Wisconsin 0.86 26.0 44.0 1.69 Gilmore and Hofman (1966) Denmark 1.08 33.5 41.7 1.27 Fogh-Andersen (1961) Bohemia 1.21 24.3 42.5 1.75 Tolarova (1987) Thailand 1.22 26.0 48.0 1.84 Chuangsuwanich et al. (1998) British Columbia 1.23 23.0 39.0 1.70 Lowry et al. (1989) Australia (non-Aboriginal) 1.24 21.0 44.0 2.09 Bower et al. (1989) Iceland 1.33 25.0 43.8 1.75 Moller (1965) Japan 1.43 41.3 46.0 1.11 Natsume and Kawai (1986) Australia (Aboriginal) 2.27 17.0 59.0 3.47 Bower et al. (1989) Canadian Native Americans 2.73 8.0 78.0 9.75 Lowry et al. (1969) CL, cleft lip; CP, cleft palate; CLP, cleft lip and palate; CL/P, cleft lip with or without cleft palate.

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).

A review of the literature reveals that only a subset of the epidemiological reports sub-divide the primary palatal clefting into CL and CLP. For those that do, there is considerable variation in the gender ratio for CL. There also tends to be less variation in CLP, and by virtue of the fact that CLP is much more common than isolated CL, the gender ratios for CL/P invariably reveal a male predilection. This may, however, mask an important underlying trend in CL gender ratios with considerable variation between ethnic groups. Womersley and Stone, (1987) reported a CL male to female ratio of 3:1 in the west of Scotland, which is considerably higher than other U.K. and European figures. For example, in Czechoslovakia, the CL male to female ratio was 1.5 (Tolarova, 1987) and in Denmark, 1.73 (Melnick et al., 1980). Precisely the same value (1.73) was reported by Woolf et al. (1963) in Utah. Similar gender ratios have been reported in other U.S. studies, such as Gilmore and Hofman (1966) in Wisconsin and Shaw et al. (1991) in California. However, the ratio is much lower in other countries, such as Nigeria (1.1 to 1; Iregbulem, 1982). In China, Yi et al. (1999) reported a male to female ratio of 0.85 to 1. In a 15-year sample of clefts in Iran (Rajabian and Sherkat, 2000) and in a small sample of clefts in the Jewish population in Israel (Azaz and Koyoumdjisky-Kaye, 1967), CL was also more common in females.

Unilateral Clefts and Laterally

The tendency for unilateral CL to be left-sided has proved to be a consistent finding. Of unilateral CL (80%-85% of all CL cases), approximately two-thirds have left-sided defects regardless of sex, ethnic group, and severity of defect (Fogh-Andersen, 1942; Fraser and Calnan, 1961). Since then, this predilection for the left side in unilateral clefts has been a recurrent finding in the OC literature (Bonaiti et al., 1982; Tolarova, 1987; Jensen et al., 1988), and this seems to be a feature in all ethnic groups.

No convincing explanation for these differences has been advanced, but a proposed explanation is that blood vessels, supplying the right side of the fetal head, leave the aortic arch closer to the heart and are perhaps better perfused by blood than those going to the left side (Johnston and Brown, 1980). Therefore, this left-sided characteristic would equally affect males and females, and this was confirmed for both unilateral CL and unilateral CL/P in a study of the Metropolitan Atlanta Congenital Defects Program (Paulozzi and Lary, 1999). An earlier report from the Netherlands by Cornel et al. (1992), however, examined laterality according to gender in an 8-year study and found that the predilection to left-sided clefting was seen only in boys.

Time Trends

The best data on which to base judgments on time trends for OC prevalence at birth are provided by the registries, where the criteria and infrastructure for the collection of data over a time period in a defined geographical area are relatively consistent. 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 (of which the EUROCAT data are regarded as being the most reliable), 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.

Recommendations for Producing Better Descriptive Statistics in Oral Clefts Epidemiology

Oral clefting is a heterogeneous group of defects with a considerable range of severity; therefore, there will inevitably be variability in ascertainment rates. Many earlier publications were less discriminating on the differences in frequency between CP and CL/P, often quoting a combined figure. Many of the more recent papers do differentiate and some subdivide CL and CLP.

For example, the overall data from Europe show a fivefold variation in CL/P and a threefold variation in CP. The explanation for such variation may, at least partly, be due to the variable quality of data. It is therefore important that methods of ascertainment are specified, as well as whether studies were population-based or hospital-based. Accurate data require a recording system using multiple sources of ascertainment.

Population-Based vs. Hospital-Based Registries

In much of the older literature and in current work in less developed countries, data are often available only on births delivered in hospital. Unless almost all births occur in hospital, such data may be biased. However, if hospital confinement is more available to women from the upper socio-economic groups, hospital-derived rates may underestimate those for the community as a whole.

Interpretation of hospital series, therefore, is not straightforward unless the proportion of births in the community delivered in hospital approaches 100%.

Even so, when hospital records alone are searched, the number of cases expressed as a percentage of all known cases found using multiple sources of ascertainment may be low, as indicated by the Hungarian figure of 52.5% based on this one source of ascertainment (Czeizel and Revesz, 1970).

While complete ascertainment is almost impossible to achieve, we can come close to this by pooling data from several overlapping sources. The quality of a population-based perinatal register will depend on how many sources are used and how thorough the ascertainment process is; also, cleft registers or hospital-based registers tend to be a subset, excluding stillbirths, early deaths, minor anomalies not requiring surgery, patients who move away, miscoding, etc. As well as being less complete, a hospital-based registry will tend to have fewer cases with associated abnormalities because of stillbirths and perinatal deaths and because another feature may be more important than the cleft.

Multiple Sources of Ascertainment

Multiple sources of ascertainment from population-based samples should be used for incidence statistics, and complete censuses or representative samples should be employed for prevalence statistics. These constitute the best approaches available for preparing accurate estimates of rates because no single data source has sufficient reliability (Czeizel and Tusnadi, 1971).

In preparing incidence data to support genetic and other etiological studies, all abortions and stillbirths should be included or appropriate adjustments made. Whether terminations and fetal deaths are included, the inclusion criteria, and the methods used should be clarified. Similarly, the effects of differential prenatal and postnatal death rates on the apparent sex ratios for clefts should be documented. All degrees of cleft expression should be diagnosed to prevent underascertainment.

Cleft Type and Associated Malformations

All epidemiological and genetic data should be presented by specific cleft type whenever possible (Fogh-Andersen, 1942; Fraser, 1970). Each cleft type should be subdivided by the presence or absence of associated congenital malformations (Emanuel et al., 1973). Where possible, syndromic cleft cases should be separated from nonsyndromic ones and the classification used and how this was done should be explained, e.g., by a dysmorphologist. Birth prevalence statistics for clefts will further benefit risk factor studies if they are tallied separately for familial and sporadic cases (Melnick et al., 1980; Bixler, 1981), in which the genetic and environmental risk factors may differ, and then for syndromic vs. nonsyndromic status within these categories. Since the major cleft phenotypes are actually heterogeneous entities, disaggregating them for statistical purposes may aid the investigation of unitary disease categories.

Ethnic Grouping

Where possible, data within countries should be presented by ethnic group, although it must be recognized that grouping by ethnic origin is not entirely objective. Also, in light of some emerging evidence, it may be useful to have a record of socioeconomic status. Ideally, data sets containing core information agreed by consensus should be collected, while additional information should be collected for studies in suspected high-risk population subgroups: specific parental genotypes or phenotypes, older parents, medicated mothers, mothers with certain chronic diseases, and parents with unique dietary or other environmental exposures.

Conclusions

The overall conclusions to be drawn from the data presented in this chapter 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.

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Appendix 12.I. international prevalence figures for oral clefts

TABLE 12.IA. International Epidemiology of Oral Clefts—;Europe*

Population Time Period Sources of Ascertainment No. of Births Birth prevalence Associated Abnormalities Reference CL/P CP All Clefts Czech Republic (Bohemia) 1964–1971 Population-based registry 1,831,036 1.21 0.60 1.81 Nonsyndromic Tolarova (1987) 1964–1982 Registry (multiple sources) 689,967 1.28 0.63 1.95 2.1% Syndromic Kjaskova (1973) Croatia 1983–1993 Zagreb Registry EUROCAT 65,100 —† — 1.10 Ligutic et al. (1997) Denmark 1936–1961 Population-based 2,031,559 — 0.47 — Included submucous Christensen and Fogh-Andersen (1994) 1938–1957 Surgical records 1,631,376 1.08 0.36 1.44 Syndromes included Fogh-Andersen (1961) 1941–1968 Population-based 2,066,153 1.30 No data No data Nonsyndromic Melnick et al. (1980) 1942 Population-based 1.25 0.38 1.62 Nonsyndromic Fogh-Andersen (1942) 1962–1987 Population-based 1,761,504 n.d. 0.77 — Nonsyndromic (including submucous) Christensen and Fogh-Andersen (1994) 1976–1981 Population-based 359,027 1.37 0.52 1.89 Included Jensen et al. (1988) England 1940–1950 Multiple sources 218,693 — — 1.30 McMahon and McKeown (1953) Birmingham 1949–1958 Multiple sources 404,124 0.95 0.47 1.42 Knox and Braithwaite (1962) Liverpool 1950–1959 Multiple sources 186,046 — — 1.90 Leek (1969) 1960–1982 Multiple sources 325,727 — — 1.40 Owens et al. (1985) Birmingham 1960–1984 Population-based registry LB + SB 432,778 1.04 0.62 1.66 Included Leek and Lancashire (1995) Trent 1973–1982 Hospital activity analysis 617,940 — — 1.51 Coupland and Coupland (1988) Finland 1948–1975 Population-based registry 2,258,850 0.77 0.97 1.74 — Rintala (1986) 1962–1967 Multiple sources 110,299 — — 1.30 Saxen and Lathi (1974) 1967–1971 Registry 347,316 0.83 0.86 1.72 20% CL/P Saxen and Lathi (1974) Multiple sources 22% CP 1972–1973 Multiple sources 116,407 0.73 0.90 1.63 25% CL/P 30% CP Saxen (1975) 1974–1988 0.81 1.01 1.82 Nonsyndromic Tolarova and Cervenka (1995) France 1978–1987 Registry 813,513 0.67 0.44 1.11 Nonsyndromic Long et al. (1992) Rhone-Alpes/Auvergne Alsace 1979–1987 Registry 118,286 0.98 0.77 1.75 Included Stoll et al. (1991) Strasbourg 1979–1996 Population based 238,942 1.08 0.85 1.93 36.7% Stoll et al. (2000) East Central n.d. Registry 1,460,000 0.56 0.42 0.98 Chromosomal anomalies 4.3% CL/P 4.5% CP Kallen et al. (1996) Hungary (Budapest) 1962–1967 Registry 1.03 0.27 1.30 — Czeizel (1997) 1970–1976 Registry 1.16 0.48 1.64 Included Czeizel (1997) Iceland 1956–1962 Multiple sources LB only 32,979 1.33 0.61 1.94 6.3% Moller (1965) Italy Emilia Romagna 1978–1986 Population-based 150,168 0.75 0.58 1.33 32% Calzolari et al. (1988) Emilia Romagna and northeast Italy) 1981–1989 Hospital and population-based data LB + SB 561,539 0.82 0.61 1.43 23% CL/P 43% CP Milan et al. (1994) Northern Ireland 1980–1990 Regional database 310,838 0.60 0.68 1.28 Nonsyndromic Gregg et al. (1994) Netherlands 1981–1988 Multiple sources LB + SB 73,879 1.46 0.81 2.27 Syndromic (453 SB) 23% CL/P 52% CP Cornel et al. (1992) Norway 1967–1988 Registry 516,657 1.43 0.65 2.08 Included Abyholm (1978) 1974–1988 1.42 0.50 1.92 — Tolarova and Cervenka (1995) Poland 1981–1995 Hospital (surgical cases) 132,783 1.16 0.84 2.00 Nonsyndromic Antoszewski and Kruk-Jeromin (1997) Scotland 1971–1990 Regional database 356,922 0.77 0.63 1.40 Nonsyndromic Bellis and Wohlegemuth (1999) Southeast and Highlands West 1974–1985 Registry 158,333 0.75 0.81 1:56 Nonsyndromic Wormsley and Stone (1987) West 1980–1984 0.74 0.79 1.53 Included 26% CL/P 39.5% CP Fitzpatrick et al. (1994) Slovenia 1973–1993 Cleft registry 179,268 0.98 0.66 1.64 LB Nonsyndromic Kozelj (1996) Sweden (Stockholm) 1958–1970 Cleft registry 253,468 1.17 0.55 1.72 Nonsyndromic Beckman and Myrberg (1972) 1973–1983 Cleft registry 1.00 0.47 1.47 Nonsyndromic McWilliam (1997) 1984–1994 Cleft registry 0.95 0.53 1.48 Nonsyndromic McWilliam (1997) 1991–1995 Population-based LB only 122,148 1.35 0.65 2.00 17% Hagberg et al. (1997) n.d. Registry 2.07 million 1.27 0.65 (includes PR) 1.92 Chromosomal anomalies 2.1% CL/P 2.2% CP Kallen et al. (1996) *CL/P, cleft lip with or without cleft palate; CP, cleft palate LB, live births; SB, stillbirths; PR, Pierre Robin; n.d., not defined. †Data not available.

TABLE 12.IB. International Epidemiology of Oral Clefts—USA and Canada*

Population Time Period Sources of Ascertainment No. of Births Birth prevalence Associated Abnormalities Reference CL/P CP All Clefts Canada 1943–1949 Surgical records 655,322 —† — 1.06 Hixon (1951) Ontario British Columbia 1952–1986 Registry 1,299,495 1.23 0.75 1.98 Nonsyndromic Lowry et al. (1989) Chinese 1952–1971 Multiple sources 12,5000 — — 1.76 Lowry and Trimble (1977) White 1952–1971 Multiple sources 713,316 — — 1.97 Lowry and Trimble (1977) Japanese 1952–1971 Multiple sources 3571 — — 3.36 Lowry and Trimble (1977) 1952–1964 Registry LB + SB 452,147 1.09 0.54 1.63 Included Lowry and Renwick (1969) Native Americans 1952–1964 Registry LB + SB 20,819 2.73 0.44 3.17 Included Lowry and Renwick (1969) Canada 1997 Registry (ICBD) 262,741 0.33 0.74 1.07 ICBDMS (2000) USA n.d. Deliveries 15,565 — — 1.09 Davis (1924) Baltimore White Black n.d. Deliveries 12,500 — — 0.56 Davis (1924) Los Angeles White 1936–1951 Hospital records LB + SB 29,000 — — 1.00 Lutz and Moor (1955) Black 1936–1951 Hospital records LB + SB 16,901 — — 0.71 Lutz and Moor (1955) California 1955 Birth certificates, population-based 313,164 0.82 0.36 1.18 Included 18.2% Wayne Loretz et al. (1961) White 1955 Birth certificates 282,812 — — 1.20 Wayne Loretz et al. (1961) Black 1955 Birth records 21,532 — — 0.60 Wayne Loretz et al. (1961) California 1983–1986 Registry 452,287 0.74 0.38 1.12 Included Shaw et al. (1991) California 1983–1993 Registry 2,509,881 0.77 0.31 1.08 Nonsyndromic Tolarova and Cervenka (1998) California n.d. Registry 1.62 million 1.00 0.57* (includes PR) 1.57 7 Chromosomal anomalies .4% CL/P 8.4% CP Kallen et al. (1996) Hawaii 1948–1966 Multiple sources 67,170 — — 2.65 Ching and Chung (1974) Japanese White 1948–1986 Multiple sources 77,013 — — 1.55 Ching and Chung (1974) Japanese 1974–1977 Birth records 2905 — — 2.41 Tyan (1982) White 1963 Multiple sources 58,686 1.60 0.61 2.21 Included Hay (1971) Mississippi White 1980–1989 Birth certificates 228,156 0.93 0.43 1.36 Nonsyndromic Das et al. (1995) Nonwhite 1980–1989 Birth certificates 211,198 0.30 0.24 0.54 Das et al. (1995) New York City Jan 1952-Dec 1962 Birth certificates 1,478,315 0.60 0.26 0.86 Included Conway and Wagner (1966) White 13% CL/P Nonwhite Jan 1952-Dec 1962 Birth certificates 344,929 0.29 0.22 0.51 27% CP Conway and Wagner (1966) Pennsylvania 1942 Birth records 191,161 — — 1.26 Grace (1943) White Black 1942 Birth records 39,130 — — 0.23 Grace (1943) White 1961 Birth certificates 213,778 — — 1.32 Ivy (1962) Black 1961 Birth certificates 26,086 — — 0.23 Ivy (1962) Black 1961 Birth certificates 28,350 — — 0.95 Ivy (1962) (Utah) (white) Jan 1951-Jan 1961 Nursery records 59,650 1.24 0.27 1.51 Included Woolf et al. (1963) Washington D.C. 1952–1961 Hospital records 79,842 0.49 0.49 0.98 Included Altemus (1966) Black White 1956–1965 Multiple sources 189,096 — — 1.75 Emanuel et al. (1973) Black 1956–1965 Multiple sources 8730 — — 1.26 Emanuel et al. (1973) Chinese 1956–1965 Multiple sources 1,237 — — 4.04 Emanuel et al. (1973) Japanese 1956–1965 Multiple sources 2,538 — — 1.97 Emanuel et al. (1973) Wisconsin (white) 1943–1962 Multiple sources 1,756,409 0.86 0.37 1.23 Included Gilmore and Hofman (1966) USA 1983–1992 Registry 2,221,755 1.07 0.68 1.75 Nonsyndromic Croen et al. (1998) White 1983–1992 Registry 1,005,727 1.05 0.72 1.77 Nonsyndromic Croen et al. (1998) African-American 1983–1992 Registry 172,557 0.62 0.54 1.16 Nonsyndromic Croen et al. (1998) Japanese 1983–1992 Registry 14,314 1.05 0.77 1.82 Nonsyndromic Croen et al. (1998) Chinese 1983–1992 Registry 53,113 0.96 0.60 1.50 Nonsyndromic Croen et al. (1998) Hispanic 1983–1992 Registry 769,866 1.01 0.56 1.57 Nonsyndromic Croen et al. (1998) Filipino 1983–1992 Registry 61,012 1.00 0.92 1.92 Nonsyndromic Croen et al. (1998) Native 1983–1992 Registry 13,545 1.99 1.11 3.10 Nonsyndromic Croen et al. (1998) East Indian 1983–1992 Registry 12,310 1.14 1.06 2.20 Nonsyndromic Croen et al. (1998) Pacific 1983–1992 Registry 11,993 0.83 0.83 1.66 Nonsyndromic Croen et al. (1998) Korean 1983–1992 Registry 15,353 0.65 0.26 0.91 Nonsyndromic Croen et al. (1998) Laotian 1983–1992 Registry 26,735 1.46 0.67 2.13 Nonsyndromic Croen et al. (1998) Vietnamese 1983–1992 Registry 30,779 1.23 0.45 1.68 Nonsyndromic Croen et al. (1998) Cambodian 1983–1992 Registry 12,336 0.97 0.32 1.29 Nonsyndromic Croen et al. (1998) 14 Institutions n.d. Follow-up pregnancies 16,385 — — 1.82 Chung and Myrianthopoulos (1967) Whites Blacks n.d. Follow-up pregnancies 9756 — 0.82 — Chung and Myrianthopoulos (1967) 12 Institutions 1973–1974 Follow-up pregnancies 24,153 — — 2.69 Myrianthopoulos and Chung (1974) Whites Blacks 1973–1974 Follow-up pregnancies 25,149 — 1.67 — Myrianthopoulos and Chung (1974) Native Americans 1963–1966 Population-based 25,341 1.38 0.59 1.97 — Niswander and Adams (1967) *CL/P, cleft lip with or without cleft palate; CP, LB, live births; SB, stillbirths; PR, Pierre Robin; ICBD, International Clearinghouse for Birth Defects; n.d., not defined. †Data not available.

TABLE 12.IC. International Epidemiology of Oral Clefts—Central and South America*

Population Time Period Sources of Ascertainment No. of Births Birth prevalence Associated Abnormalities Reference CL/P CP All Clefts Caribbean (Santo Domingo) 1973–1976 Hospital records 704,410 0.42 0.20 0.62 Nonsyndromic Garcia-Godoy (1980) Mexico (Guadalajara) Nov 1988-June 1991 Hospital registry (4 hospitals) 33,461 1.05 0.27 1.32 Included Perez-Molina et al. (1993) South America 1967–1981 56 hospitals 849,381 0.87 0.13 1.00 Nonsyndromic Menegotto and Salzano (1991) South America 1982–1998 Registry 2,982,893 1.09 0.36 1.45 Included ECLAMC (2000) Argentina 1982–1998 Registry 1,122,870 1.16 0.36 1.52 Included ECLAMC (2000) Bolivia 1982–1998 Registry 79,296 2.28 0.21 2.50 Included ECLAMC (2000) Brazil 1982–1998 Registry 754,657 1.01 0.39 1.40 Included ECLAMC (2000) Chile 1982–1998 Registry 297,583 1.13 0.46 1.59 Included ECLAMC (2000) Colombia 1982–1998 Registry 68,089 1.03 0.30 1.28 Included ECLAMC (2000) Ecuador 1982–1998 Registry 56,199 1.05 0.37 1.42 Included ECLAMC (2000) Paraguay 1982–1998 Registry 94,433 1.19 0.36 1.55 Included ECLAMC (2000) Peru 1982–1998 Registry 72,864 0.81 0.06 0.87 Included ECLAMC (2000) Uruguay 1982–1998 Registry 181,275 0.85 0.37 1.22 Included ECLAMC (2000) Venezuela 1982–1998 Registry 255,627 0.77 0.33 1.10 Included ECLAMC (2000) West Indies (Guadeloupe) July 1979-Feb 1983 Population-based LB only 8,142 —† — 2.08 29% + 41% SB Goulet et al. (1986) *CL/P, cleft lip with or without cleft palate; CP, cleft palate; LB, live births; SB, stillbirths; ECLAMC, Latin American Collaborative Study of Congenital Malformations. †Data not available.

TABLE 12.ID. International Epidemiology of Oral Clefts—Australia and New Zealand*

Population Time Period Sources of Ascertainment No. of Births Birth prevalence Associated Abnormalities Reference CL/P CP All Clefts Australia 1980–1987 Registry 9695 2.27 0.72 2.99 Nonsyndromic Bower et al. (1989) Aboriginal Non-Aboriginal 1980–1987 Registry 170,760 1.24 0.67 1.91 Nonsyndromic Bower et al. (1989) Tasmania (whites) 1945–1957 Multiple sources 96,510 —† — 1.66 Rank and Thomson (1960) New South Wales (Whites) 1964–1966 Hospital records 143,948 — — 1.21 Chi and Godfrey (1970) New South Wales (Whites) 1963–1972 Multiple sources 193,520 0.54 0.68 1.22 Brogan and Woodings (1974) South Australia (whites) 1949–1968 Multiple sources 392,228 — — 1.41 Spry and Nugent (1975) New Zealand (Auckland) 1960–1976 Urban population 178,240 0.39 1.87 2.26 Nonsyndromic Chapman (1983) Maoris Whites 1960–1976 Urban population 26,460 1.19 0.64 1.83 Nonsyndromic Chapman (1983) *CL/P, cleft lip with or without cleft palate; CP, cleft palate. †Data not available.

TABLE 12.IE. International Epidemiology of Oral Clefts—Far East*

Population Time Period Sources of Ascertainment No. of Births Birth prevalence Associated Abnormalities Reference CL/P CP All Clefts China n.d. Hospital births 9876 —† — 1.62 Stevenson et al. (1966) Hong Kong Oct 1986-Sept 1987 945 hospitals 1,243,284 1.67 0.15 1.82 Nonsyndromic Xiao (1989) Shanghai 1980–1989 Population-based cohort 541,504 1.2 — — Nonsyndromic Cooper et al. (2000) Japan n.d. Hospital birth records 16,373 — — 2.41 Tsutsui (1951) Osaka Tokyo 1922–1940 Hospital 49,645 1.17 0.73 1.90 Included Mitani (1954) 1922–1952 Hospital birth records 80,423 — — 1.89 Mitani (1954) 1922–1955 Questionnaire to hospitals 114,815 — — 2.05 Tsukamoto (1956) 1940–1956 Hospital birth records 46,635 — — 2.08 Kobayasi (1958) Nagasaki 1948–1952 Survey of ABCC 27,016 — — 2.48 Hikita (1953) Hiroshima, Nagasaki 1948–1954 Survey of ABCC 63,976 (excluding multiple births) 2.13 0.55 2.68 Included Neel (1958) Okayama 1953–1960 Hospital birth records 35,366 — — 1.64 Kurozumi (1963) 1957–1961 Questionnaire to hospitals 280,000 — — 1.65 Sato (1966) Hokkaido 1965–1967 Questionnaire to hospitals 105,586 — — 1.79 Tanaka (1972) 1979–1982 Hospital LB only 55,103 0.97 0.29 1.26 Nonsyndromic Kondo (1987) Aichi 1982 293 hospitals 40,304 1.02 0.27 1.29 Natsume et al. (1987) 1983 Hospital 39,696 1.43 0.21 1.64 Nonsyndromic Natsume and Kawai (1986) Malaysia (Kuala Lumpur, Chinese) n.d. Hospital births 16,026 — — 1.56 Stevenson et al. (1966) Philippines 1989–1996 Medical records 47,969 1.94 No data No data Included 21% at birth Murray et al. (1997) Singapore 1985–1994 Hospital LB only 474,542 1.59 0.48 2.07 All-inclusive 1.5% of clefts Yi et al. (1999) Chinese n.d. Hospital births 39,655 — — 1.74 Stevenson et al. (1966) 1986–1987 Hospital 33,672 1.04 0.53 1.57 Nonsyndromic Tan (1988) 1986–1987 Hospital 30,411 1.15 0.59 1.74 Tan (1988) Taiwan 1955–1962 Hospital births 14,583 — — 1.92 Wei and Chen (1965) Chinese Chinese 1965–1968 Hospital births 25,517 — — 1.45 Emanuel et al. (1972) Taipei Jan 1965-Jan 1968 6 hospitals LB + SB >28 weeks 25,814 1.29 0.16 1.45 35% Emanuel et al. (1972) Thailand (Siriraj Hospital) 1990–1996 Hospital records 130,236 1.22 0.40 1.62 Included 4.38% Chuangsuwanich et al. (1998) *CL/P, cleft lip with or without cleft palate; CP, cleft palate; LB, live births; SB, stillbirths; ABCC, Atomic Bomb Casualty Committee; n.d., not defined. †Data not available.

TABLE 12.IF. International Epidemiology of Oral Clefts—Middle East*

Population Time Period Sources of Ascertainment No. of Births Birth prevalence Associated Abnormalities Reference CL/P CP All Clefts Iran Aug 1976-Sept 1991 Hospital (surgical cases) 19,369 LB only 0.85 0.18 1.03 7.73% Rajabian and Sherkat (2000) Tehran Tehran 1983–1988 One hospital 21,138 3.12 0.62 3.74 Chemical sulfur mustard gas implicated in CL/P Taher (1992) Israel 1960–1962 6 hospitals 47,768 0.37 0.17 0.54 27% Azaz and Koyoumdjisky-Kaye (1967) Jews Whites 1961–1971 Multiple sources 218,750 —† — 0.80 Tal et al. (1974) Kuwait 1985–1987 Population 53,786 1.06 0.42 1.48 Nonsyndromic Srivastava and Bang (1990) Saudi Arabia 1989–1992 Hospital-based 62,577 1.89 0.30 2.19 CP 21.5% CL/P Borkar et al. (1993) United Arab Emirates 1998 Hospital-based LB + SB 7500 0.40 0.27 0.67 Included ICBDMS (2000) *CL/P, cleft lip with or without cleft palate; CP, cleft palate; LB, live births; SB, stillbirths. †Data not available.

TABLE 12.IG. International Epidemiology of Oral Clefts—Indian Subcontinent*

Population Time Period Sources of Ascertainment No. of Births Birth prevalence Associated Abnormalities Reference CL/P CP All Clefts India Various prospective and retrospective studies Hospital-based LB+SB (meta-analysis) 224,341 1.20 0.44 1.64 Verma and Mathews (1983) Bombay June 1960-Dec 1963 Pregnancy terminations 24,248 1.59 —† — Master-Notani et al. (1968) Calicut Jan 1962-May 1964 Hospital 3721 1.61 — 1.61 (6 clefts) Included Nair and Mathai (1964) Lucknow Sept 1963-Oct 1964 Hospital LB + SB 2851 — — 1.40 (4 clefts) Included Sharma et al. (1972) Patna 1 March 1964–30 Nov 1964 Hospital-based 5376 1.50 — — Khanna and Prasad (1967) Jaipur Jan 1965-Dec 1969 Hospital LB only 28,511 — — 0.70 Included Hemrajani et al. (1971) Kanpur Feb 1967-April 1968 Hospital LB + SB 4150 0.96 0.48 1.44 (6 clefts) Included Mital and Grewal (1969) Rajastan 1969 Hospital LB + SB 2145 0.93 (2 clefts) — — Gupta et al. (1971) New Delhi Dec 1969-March 1973 Hospital LB only 7590 1.05 — — Ghosh et al. (1985) New Delhi 1975–1978 Hospital LB only 6274 1.43 (9 clefts) 0.32 (2 clefts) 1.75 Included Singh and Sharma (1980) Hyderabad April-July 1970 Hospital LB + SB 1060 1.75 0.9 2.65 (4 clefts) Included 2 SB Mathur et al. (1975) Madras 1975–1976 Hospital LB + SB 24,192 — — 1.71 (28 clefts) Included Chandra and Harilal (1977) Haryana Jan 1976-Dec 1977 Population LB only 2409 0.41 0.41 0.82 (2 clefts) Included Kulshrestha et al. (1983) Madurai Jan 1976-July 1977 Hospital-based 11,619 0.77 — — Kamala et al. (1978) Hubli 1 July 1976–30 Sept 1977 Hospital LB + SB 2398 1.25 (3 clefts) — — Goravalingappa and Nashi (1979) Calcutta 1976–1980 Hospital LB + SB termination 21,016 — — 0.62 Choudhury et al. (1984) Malda 1976–1987 6 hospitals LB + SB 126,266 — — 0.74 Choudhury et al. (1989) Maharashtra April 1985-March 1986 Hospital LB + SB 3014 2.32 — 2.32 Nonsyndromic Chaturvedi and Banerjee (1989) *CL/P, cleft lip with or without cleft palate; CP, cleft palate; LB, live births; SB, stillbirths. †Data not available.

TABLE 12.IH. International Epidemiology of Oral Clefts—Africa*

Population Time Period Sources of Ascertainment No. of Births Birth prevalence Associated Abnormalities Reference CL/P CP All Clefts Nairobi 1 Nov 1963–30 April 1964 Hospital-based 3061 1.63 0.33 1.96 Khan (1965) Nigeria 1 Feb-31 July 1964 Adeoyo Hospital 4220 0.47 0.24 0.71 Gupta (1969) Lagos 1966–1967 Hospital LB + SB 16,720 0.36 —† 0.36 (5 clefts) Included Lesi (1969) 1976–1980 Clinical exam at birth 21,624 0.30 0.07 0.37 18% Iregbulem (1982) 1976–1980 Hospital records 973,236 0.3 0.07 0.37 Included Iregbulem (1982) Zaria Hospital 23,512 0.21 0.08 0.29 Included Harrison et al. (1985) South Africa (Johannesburg, blacks) Jan 1976-Dec 1977 Hospital-based 29,633 0.20 0.10 0.30 22% Kromberg and Jenkins (1982) Tunisia 4 Oct 1983–16 July 1984 Hospital LB + SB 10,000 1.00 0.40 1.40 Khrouf et al. (1986) Zaire Jan 1970-Dec 1980 Hospital 64,777 — — 1.20 Nonsyndromic Tandu-Umba et al. (1984) Oct 1977-June 1979 Hospital LB only 56,637 0.44 0.02 0.46 Nonsyndromic Ogle (1993) Zimbabwe March-July 1984 Hospital 18,033 — — 0.16 Included Shija and Kingo (1985) *CL/P, cleft lip with or without cleft palate; CP, LB, live births; SB, stillbirths. †Data not available.

Appendix 12.II. Time Trends for Oral Cleft Prevalence in Europe

TABLE 12.II. Time Trends in Birth Prevalence of Cleft Palate (CP) and Cleft Lip with or without Cleft Palate (CL/P) from Overlapping Time Periods in Consecutive EUROCAT Reports (EUROCAT 1995 = 1980–1992, EUROCAT 1996 = 1990–1994)

Population Time Period Birth prevalence CL/P CP All Clefts Belgium Antwerp 1980–1992/1990–1994 0.97/1.00 0.35/0.30 1.32/1.30 Hainaut-Namur 1980–1992/1990–1994 1.19/1.26 0.61/0.75 1.80/2.01 Denmark (Odense) 1980–1992/1990–1994 1.59/1.29 0.75/0.78 2.34/2.07 France Bouches-du-Rhone 1980–1992/1990–1994 0.87/0.74 0.85/0.86 1.72/1.60 Paris 1980–1992/1990–1994 0.78/0.97 0.47/0.62 1.25/1.59 Strasbourg 1980–1992/1990–1994 1.01/1.25 0.86/0.88 1.87/2.13 Northern Ireland (Belfast) 1980–1992/1990–1994 0.72/0.33 0.61/0.25 1.33/0.58 Ireland Dublin 1980–1992/1990–1994 0.88/0.88 0.70/0.75 1.58/1.63 Galway 1980–1992/1990–1994 0.78/0.62 0.47/0.54 1.25/1.16 Italy (Tuscany) 1980–1992/1990–1994 0.75/0.82 0.58/0.43 1.33/1.25 Malta 1980–1992/1990–1994 0.45/0.65 0.53/0.84 0.98/1.49 Northern Netherlands 1980–1992/1990–1994 1.52/1.53 0.66/0.72 2.18/2.25 Spain Asturias 1980–1992/1990–1994 0.65/0.82 0.61/0.63 1.26/1.45 Basque Country 1980–1992/1990–1994 0.57/0.55 0.43/0.49 1.00/1.04 Switzerland 1980–1992/1990–1994 0.86/0.87 0.66/0.65 1.52/1.43 United Kingdom Glasgow 1980–1992/1990–1994 0.65/0.87 0.84/0.94 1.49/1.93 Sources of ascertainment, regional population-based registry. Associated anomalies: live births, stillbirths, and induced abortions.

Appendix 12.III. Birth Prevalence of Oral Clefts in Selected U.S. States

TABLE 12.III. Birth Defect Surveillance Data from Selected U.S. States, 1989–1996*

Population Time Period Sources of Ascertainment No. of Births Birth prevalence White Other All Clefts CL/P CP CL/P CP Alaska 1996 NBDP LB only 10,041 0.75 0.45 0.30 0.90 1.18 Arizona 1989–1991 NBDP LB only 203,982 1.12 0.49 1.79 0.62 1.73 Arkansas 1993–1996 NBDP LB + SB 141,666 1.26 0.78 1.12 0.56 1.96 California 1989–1995 NBDP LB + SB 2,021,110 1.00 0.75 1.08 0.66 1.73 Colorado 1989–1995 NBDP LB + SB 435,615 1.15 0.80 0.88 0.82 1.98 Connecticut 1993–1994 NBDP LB only 92,453 0.80 1.00 0.46 0.83 1.66 Georgia 1989–1996 NBDP LB only 313,404 1.19 0.58 0.67 0.57 1.51 Hawaii 1989–1996 NBDP LB + SB 167,354 0.79 0.73 1.03 1.18 2.01 Illinois 1989–1996 NBDP LB + SB 1,530,996 0.65 0.41 0.42 0.26 0.96 Iowa 1989–1995 NBDP LB, SB, + terminations 306,265 1.20 0.62 1.10 0.62 1.89 Maryland 1989–1995 NBDP LB + SB 564,152 0.66 0.43 0.53 0.22 0.97 Massachusetts 1994–1996 NBDP LB + SB 246,538 0.65 0.48 1.51 1.33 1.35 Missouri 1989–1996 NBDP LB only 606,325 1.18 0.58 0.76 0.36 1.64 Nebraska 1989–1996 NBDP LB + SB 189,863 1.12 0.82 1.30 0.42 1.90 Nevada 1989–1996 NBDP LB + SB 182,744 0.97 0.67 0.91 New Jersey 1989–1996 NBDP LB only 951,117 0.72 0.69 0.72 0.52 1.39 New Mexico 1995–1996 NBDP LB + SB 55,464 1.57 0.14 0.29 1.91 New York 1989–1996 NBDP LB only 2,263,026 0.75 0.58 0.46 0.40 1.21 North Carolina 1989–1996 NBDP LB + SB 726,358 0.96 0.52 0.62 0.58 1.38 Ohio 1989–1996 NBDP LB + SB 1,488,493 1.00 0.34 —† Oklahoma 1994–1996 NBDP LB + SB 138,100 1.21 0.71 1.50 0.77 1.99 South Carolina 1989–1996 NBDP LB + SB 441,488 0.96 0.43 — Tennessee 1991–1993 NBDP LB + SB 222,073 0.80 0.31 0.48 0.21 1.05 Texas 1995 NBDP LB + SB 112,620 1.27 0.96 0.07 0.03 1.59 Utah 1994–1996 NBDP LB + SB 120,554 0.97 0.45 2.39 0.80 1.51 Virginia 1989–1996 NBDP LB, SB, + terminations 1,053,667 — — — — 1.30 Wisconsin 1989–1995 NBDP LB + SB 563,141 1.62 1.51 1.31 1.56 3.01 *CL/P, cleft lip with or without palate; CP, LB, live births; SB, stillbirths; NBDP, National Birth Defects Prevention Network. †Data not available. Source: National Birth Defects Prevention Network (2000).