Elsevier

The Lancet

Volume 374, Issue 9703, 21–27 November 2009, Pages 1773-1785
The Lancet

Seminar
Cleft lip and palate

https://doi.org/10.1016/S0140-6736(09)60695-4Get rights and content

Summary

Clefts of the lip and palate are generally divided into two groups, isolated cleft palate and cleft lip with or without cleft palate, representing a heterogeneous group of disorders affecting the lips and oral cavity. These defects arise in about 1·7 per 1000 liveborn babies, with ethnic and geographic variation. Effects on speech, hearing, appearance, and psychology can lead to longlasting adverse outcomes for health and social integration. Typically, children with these disorders need multidisciplinary care from birth to adulthood and have higher morbidity and mortality throughout life than do unaffected individuals. This Seminar describes embryological developmental processes, epidemiology, known environmental and genetic risk factors, and their interaction. Although access to care has increased in recent years, especially in developing countries, quality of care still varies substantially. Prevention is the ultimate objective for clefts of the lip and palate, and a prerequisite of this aim is to elucidate causes of the disorders. Technological advances and international collaborations have yielded some successes.

Introduction

Non-syndromic orofacial clefts, which include cleft lip, cleft lip and palate, and cleft palate alone, comprise a range of disorders affecting the lips and oral cavity (figure 1), the causes of which remain largely unknown. Effects on speech, hearing, appearance, and cognition can lead to long-lasting adverse outcomes for health and social integration.

Affected children need multidisciplinary care from birth until adulthood and have higher morbidity and mortality throughout life than do unaffected individuals.1, 2 Findings of studies have shown an increased frequency of structural brain abnormalities3 and that many children and their families are affected psychologically to some extent.4 Although rehabilitation is possible with good quality care, orofacial clefts inevitably pose a burden to the individual, the family, and society, with substantial expenditure in terms of health and related services.

Care for children born with these defects generally includes many disciplines—nursing, plastic surgery, maxillofacial surgery, otolaryngology, speech therapy, audiology, counselling, psychology, genetics, orthodontics, and dentistry—but it forms only a part of the clinical load of every area, meaning that care has tended to be fragmented. This fragmentation of care has led to substantial variations in management, which continue to cause controversy. Furthermore, in both developing and developed countries, standards of care for patients with cleft lip, cleft lip and palate, or cleft palate alone remain a cause for concern.5

Section snippets

Developmental pathogenesis

Development of the lip and palate entails a complex series of events that require close coordination of programmes for cell migration, growth, differentiation, and apoptosis. Neural crest cells, which delaminate from the neural folds, contribute to and migrate through mesenchymal tissue into the developing craniofacial region where, by the 4th week of human embryonic development, they participate in formation of the frontonasal prominence, the paired maxillary processes, and the paired

Descriptive epidemiology

The birth frequency of cleft lip, cleft lip and palate, and cleft palate alone is not known in some parts of the world. In many regions for which information is available, differences in sample source (hospital vs population), duration, method of ascertainment, inclusion criteria, and sampling fluctuation restrict comparability.40 Overall, available findings indicate that orofacial clefts arise in about 1 in 700 livebirths.41 International data from 57 registries for 1993–98 suggest a variation

Lifestyle and environmental risk factors

Epidemiological and experimental data suggest that environmental risk factors might be important in cleft lip and palate, and maternal exposure to tobacco smoke, alcohol, poor nutrition, viral infection, medicinal drugs, and teratogens in the workplace and at home in early pregnancy have all been investigated. This work is reinforced by the finding that pregnancy planning confers protection.56, 57

Maternal smoking during pregnancy has been linked consistently with increased risk of both cleft

Genetic factors

Cleft lip with or without cleft palate is listed as a feature of more than 200 specific genetic syndromes, and isolated cleft palate is recorded as a component of more than 400 such disorders.107 The proportion of orofacial clefts associated with specific syndromes is between 5% and 7%.108 If specific genetic disorders are excluded, the recurrence risk to siblings is greater than that predicted by familial aggregation of environmental risk factors.109 Concordance rates for cleft lip, cleft lip

Gene-environment interaction

Investigation of gene-environment interaction is important for several reasons. First, estimates of the main effects of genes or environment could be biased if interaction is not taken into account.140 Second, our understanding of cause and pathogenesis is enhanced by such studies. Finally, findings of interaction work can inform decisions about public health strategies.

With respect to cleft lip and palate, many potential interactions have been tested. Genes and risk factors investigated in

Clinical management

Services and treatment protocols for management of children with cleft lip and palate can differ remarkably within and between developed countries. In Europe, a networking initiative funded by the European Union in the late 1990s reached consensus on a set of recommendations for cleft care delivery, which were subsequently adopted by WHO.5 However, findings of a network survey indicated that these guidelines were seldom matched in practice.156

The absence of a sound evidence base for selection

Primary prevention of orofacial clefts

Identification of modifiable risk factors for oral clefts is the first step towards primary prevention. Such preventive efforts might entail manipulation of maternal lifestyle, improved diet, use of multivitamin and mineral supplements, avoidance of certain drugs and medicines, and general awareness of social, occupational, and residential risk factors. The proportion of clefts attributable to maternal smoking in populations with a high prevalence of smoking in women of reproductive age was

Conclusions

Large, multicentre, collaborative studies125 are needed to elucidate both environmental (including lifestyle) and genetic risk factors for cleft lip and palate and interactions between them. Exposure measurement is challenging; cleft lip, cleft lip and palate, or cleft palate alone should be encouraged as an endpoint in cohort studies of reproductive outcome, and exposure assessment needs to be harmonised in such studies. The Public Population Project in Genomics is an international consortium

Search strategy and selection criteria

Our search strategy was formulated to identify any meta-analyses and previous systematic reviews in all aspects of orofacial cleft treatment, palatogenesis, and cleft cause and pathogenesis, in addition to all published cohort studies (and where appropriate, comparison groups) and case-control studies. We searched the Cochrane Library, Medline (via PubMed, Internet Grateful Med, OVID, and Knowledgefinder), HealthSTAR, POPLINE, SDILINE, SPACELINE, Embase, OLDMEDLINE, CINAHL, and ASKSAM

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