Overview of epidemiology and aetiology of orofacial clefts

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Julian Little
Canada Research Chair in Human Genome Epidemiology
University of Ottawa

Approximately 400-500 babies with orofacial clefts (OC), comprising cleft lip with or without associated cleft palate (CL/P) or cleft palate (CP), are born each year in Canada (1). O rofacial clefts pose a substantial burden to affected individuals and their families. Individuals with OC require multidisciplinary surgical and non-surgical care, and they and their families may suffer psychological effects (2). Affected individuals have been observed to have an increased risk of death throughout childhood and adulthood (3). OC also require significant expenditure in terms of health and related services. For example, in the USA , the average lifetime medical cost per OC was estimated as US$100,000 per child (4).

International data from 57 registries for the period 1993-8 (5) suggest considerable geographic variation in the prevalence at birth of OC, ranging between 3.4 and 22.9 per 10,000 births for CL/P, and 1.3-25.3 per 10,000 for CP. This might reflect a greater impact of differences in methods of ascertainment for CP than for CL/P. Higher CL/P prevalences were observed in parts of Latin America and the Far East and lower rates in Israel , South Africa and southern Europe . Higher CP rates were reported for Canada and parts of northern Europe and lower rates from parts of Latin America and South Africa . Overall, migrant groups have rates of CL/P closer to the area from which they originated than those in the area into which they have moved (6-9).

In combined data from European registries over the period 1995-1999, 3.5% of cases of CL/P were stillborn, and 9.4% from terminated pregnancies; the corresponding proportions for CP were 2.4% and 8.1%. No consistent time trends (10, 11) or seasonal patterns (12-14) in the prevalence at birth of OC have been observed.

There has been a male predominance for CL/P in most studies, and many but not all studies suggest a female preponderance for CP (5, 15-17). The sex ratio varies with severity of the cleft, presence of additional malformations, the number of affected siblings in a family, ethnic origin and possibly paternal age (5, 17-21).

CL/P and CP frequently occur in association with other major congenital anomalies. In general, the proportion of cases with additional anomalies appears to be higher for CP than CL/P (5, 15). In a study of almost 4000 cases of CP in Europe , 55% occurred as isolated, 18% in association with other anomalies, and 27% as part of recognized conditions (16).

In a meta-analysis, increased birth order was associated with OC (22), although data regarding important co-variates were not included in the majority of the studies, and so the analyses were unadjusted. These authors noted that several studies suggested no association with maternal age but a positive association with birth order. However, there is debate about the relationship between OC and maternal age (23, 24). Consistent associations between OC and socio-economic status have not been established (25, 26)

Maternal smoking during pregnancy has been consistently associated with increased risk for OC, with a population attributable risk of about 20% (27, 28). This association may be underestimated because passive exposure to smoke has not usually been assessed. CL/P has been found to be associated with heavy maternal alcohol intake or binge drinking (29-31). There is no consistent association between OC and moderate alcohol intake (32-40).

There is a positive association between OC and maternal use of anti-convulsant drugs (41-43). A positive association between OC and maternal corticosteroid use in pregnancy has been reported in a meta-analysis (44), but caution is needed in interpreting this result because of possible publication bias. Maternal occupational exposures to organic solvents (45-50) and parental exposure to agricultural chemicals (51-56) have been inconsistently associated with OC.

Maternal use of multivitamin supplements in early pregnancy has been associated with a reduced risk of OC in most studies (37, 57-68). A randomized controlled trial (RCT) of periconceptional multivitamins for the primary prevention of birth defects (69) and a subsequent cohort study (70) lacked statistical power for OC. A large study of the effect of a multivitamin supplement containing a high dose (10mg) of folic acid (71) was carried out in women with a family history of OC, but important design limitations make the results un-interpretable (72). Other trials of maternal multivitamin supplementation for the prevention of OC have been too small and the data presented insufficient for evaluation (73-76).

Folate deficiency is known to cause OC in animals (77) and folate antagonists are associated with increased risk of OC in humans (78). The role of dietary or supplemental intake of folic acid in OC is uncertain and case-control studies of folic-acid containing multivitamin supplements (58, 59, 60, 62, 66, 79), maternal dietary folate intake (59, 61, 79) and red cell and plasma folate (80-83) are inconsistent. Moreover, in Ontario , the prevalence at birth of OC did not change following the introduction of food fortification with folic acid (84). Other nutrients which may be involved in the aetiology of OC include vitamin B-6 (81, 83), zinc (68, 85) and, controversially, vitamin A (67, 86-89).

Increasingly, studies of genetic polymorphisms have been included in etiological studies. Some of the products of the genes investigated are growth factors (e.g. TGFα, TGFβ3), some are transcription factors (e.g. MSX1, SATB2), and some influence xenobiotic metabolism (e.g. CYP1A1, GSTM1, NAT2), nutrient metabolism (e.g. MTHFR, RARA) or immune response (PVRL1, IRF6). The most intensively investigated variants have been of the TGFα (90) and MTHFR (91) genes. The results have been inconsistent, reflecting the challenges of investigating gene-disease associations and related interactions (92). For example, a meta-analysis suggested interaction between presence of the TGFα Taq1 C2 allele and maternal smoking for CP, but with marked variation between studies (90); there was no evidence of interaction for CL/P.

In addition to possible prevention, management is relevant to the control of OC. Variation in management of OC does not appear to have been systematically addressed in North America (93). In Europe , considerable variation in management and outcome has been observed (94), which has stimulated a set of RCTs of primary surgery of OC (95). A WHO Working Group concluded that there is an urgent need for the creation of collaborative groups in order to assemble a critical mass of expertise and to enable adequately-powered clinical trials (72).

To conclude, there appears to be marked international variation in the prevalence at birth of OC. On the basis of data for the period 1993-8 from 57 registries which were members of either the International Clearinghouse for Birth Defects Monitoring Systems or EUROCAT, Canada appears to have a particularly high prevalence at birth of CP (5). It is important to determine whether this is due solely to differences in completeness of ascertainment or differences in the coding of OC when the infant also has anomalies of other systems (1) , or if other explanations need to be considered. Smoking is consistently associated with an increased risk for OC, and multivitamin supplements with reduced risk. Apart from these observations, the picture is of inconsistencies. These may in part be resolved through careful meta-analyses, and pooled analyses of individual patient data.

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