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Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate

Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate
Literature review current through: Jan 2024.
This topic last updated: Jun 09, 2023.

INTRODUCTION — The oral cleft is the most common craniofacial malformation in the newborn. The three main types of oral clefts are cleft lip alone, cleft palate alone, and cleft lip with cleft palate (figure 1). Cleft lip with or without a cleft palate (CL/P) and cleft palate alone (CP) differ with respect to embryology, etiology, candidate genes, associated abnormalities, and recurrence risk.

This topic will discuss issues related to development, prenatal diagnosis, and prenatal management of CL/P and CP. Specific syndromes associated with facial clefts are reviewed separately. (See "Syndromes with craniofacial abnormalities".)

PREVALENCE — The reported prevalence of oral clefts varies by country, method of ascertainment, and classification. In the United States, the most recent prevalence report from the National Birth Defects Prevention Network included the following estimates for 2007 to 2011 [1]:

Oral clefts (CL/P and CP): 14.5 per 10,000 live births (1 in 690 births)

CL alone: 3.1 per 10,000 live births

CL with CP: 5.6 per 10,000 live births

CP alone: 5.9 per 10,000 live births

Thus, among newborns with a CL, approximately one-third had CL alone and two-thirds had CL with CP.

In a report of 22 population- and hospital-based surveillance programs affiliated with the International Clearinghouse for Birth Defects Surveillance and Research in 18 countries, the pooled prevalence of CL with CP for 1974 to 2014 was 6.4 per 10,000 live births plus stillbirths, but prevalence varied widely among programs [2]. 

EPIDEMIOLOGY

Race/ethnicity affects the prevalence of CL:

The First Nations population of British Columbia, Canada, has the highest reported birth prevalence of CL/P in the world: nearly 30 per 10,000 births [3].

In the United States, the prevalence of CL alone and CL with CP is highest in American Indian or Alaska Natives (4.2 and 10.1 in 10,000 live births), lowest in Black Americans (2.1 and 3.7 in 10,000 live births), and at an intermediate level in other groups (White, Hispanic, Asian or Pacific Islander Americans) [1]. By contrast, the prevalence of CP is relatively constant across races and ethnicities.

The male to female ratio of CL/P is 2:1, while the male to female ratio of CP is 1:2 [1].

Maternal age ≥35 years has been associated with an increased risk for oral clefts in offspring in several different populations [1].

EMBRYOLOGY — Craniofacial development represents a complex interaction of cell patterning, migration, proliferation, and differentiation. Much of the facial tissue originates by cell migration from the embryonic neural crest, which is governed by regulatory, structural, and positional genes.

Cleft lip – Normally, complete closure of the lip is accomplished by 35 days postconception as the lateral nasal, median nasal, and maxillary mesodermal processes merge. Failure of closure of any one of the three normal sites of fusion can produce unilateral (most common), bilateral (less common), or median (rare) lip clefting (figure 1).

CL is considered incomplete when only the upper lip is affected and complete when the defect extends to the nose.

Cleft palate – CP occurs when midline fusion of the palatal shelves fails to occur. Abnormalities in programmed cell death may contribute to lack of palatal fusion, although this mechanism remains debated. CP can occur with CL or alone; the latter is possible because palatal closure is not completed until 56 to 58 days postconception, well after closure of the lip, and because the etiology may differ.

ETIOLOGY — Most oral clefts are nonsyndromic. Syndromes account for approximately 30 percent of cases of CL/P and 50 percent of cases of CP [4].

Nonsyndromic cases — Nonsyndromic clefting is a genetically complex event with gene-gene and gene-environment interactions.

Genetic factors — The process of midface development involves genes that control cell patterning, cell proliferation, extracellular communication, and differentiation. Gene variants in any of these developmental processes crucial to midface development have been associated with development of clefts [5-7]. Over 30 candidate genes have been identified, although as a group they contribute to a relatively small percentage of nonsyndromic cases. Variants in genes associated with syndromic clefting are found in approximately 10 percent of individuals with apparently nonsyndromic oral clefts, suggesting genetic overlap between nonsyndromic and syndromic etiologies [8].

While many genes have been associated with oral clefting in animal models, findings in humans are more limited [9]. Some genes that have been implicated include SATB2 (transcription factor), SHH (Sonic hedgehog; also associated with holoprosencephaly), genes causing Loeys-Dietz syndrome, and IRF6 (associated with van der Woude syndrome, but there are many rare syndromic causes of clefting; see below).

Environmental factors — While animal studies have associated clefting with in utero exposure to several medications and other environmental agents, an association in humans is possible but far less clear. It is possible that teratogen exposure contributes to clefting in genetically at-risk fetuses but not others.

Some of the environmental agents that have been implicated include:

Drugs

Antiseizure agents, such as phenytoin, sodium valproate, and topiramate [10,11], and the folic acid antagonist methotrexate are examples of commonly administered drugs probably associated with oral clefts. While the relative risk of an oral clefting abnormality is increased, the absolute risk of clefting after drug exposure remains small. However, patients taking these drugs should work with their clinicians to discontinue use, if possible and particularly during the period of organogenesis.

Ondansetron is sometimes used for treatment of nausea and vomiting of pregnancy. Evidence of a possible small absolute increase in oral clefts with first-trimester ondansetron exposure (risk difference 2.7 per 10,000 births, 95% CI 0.2-5.2 [12]) is reviewed separately. (See "Nausea and vomiting of pregnancy: Treatment and outcome", section on 'Ondansetron'.)

Diazepam increases the incidence of CP in mice, but the best evidence from human studies does not show an increase in oral clefts [13].

Nitrofurantoins were associated with CL/P (adjusted OR 2.1, 95% CI 1.2-3.9) in NBDPS [14] but not in two other studies [15,16]. The limitations of the NBDPS data are reviewed separately. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Antibiotics'.)

Corticosteroids – An association between oral clefts and corticosteroid use [17] has not been upheld by recent studies; for example, the National Birth Defects Prevention Study (NBDPS) database found no association (odds ratio [OR] 1.0, 95% CI 0.7-1.4) [17]. The risk of oral clefts with any systemic corticosteroid use during the entire period from 1997 to 2009 was also not increased (CL/P: OR 1.6, 95% CI 0.9-2.8; CP: OR 0.8, 95% CI 0.3-2.1).

Cigarette smoking Smoking cessation is routinely recommended for its pregnancy-related and general health benefits. (See "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options".)

In a meta-analysis that pooled individual participant data from studies that used similar methods in European populations, maternal smoking increased the risk for CL/P (OR 1.62, 95% CI 1.35-1.95) and CP (OR 1.38, 95% CI 1.04-1.83) [18]. Teratogenesis has been attributed to hypoxia, as well as a component of tobacco (cadmium).

In case-control studies of risk factors for oral clefts, the joint risk of cigarette smoking and a rare fetal allele at the TGF-alpha gene locus was greater than for either risk factor alone [19,20]. Periconceptional smoking among females with an MSX1 allele was associated with a threefold risk of having a child with CL/P in one study [21]. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate".)

An international population-based study reported an association between passive smoke exposure and oral clefts (OR 1.14, 95% CI 1.02-1.27) [22].

Folate deficiency – The role of folate in the etiology of orofacial clefts is controversial. For most females of reproductive potential, one multivitamin containing at least 0.4 mg of folic acid once per day beginning at least one month prior to conception and continuing through the first trimester is recommended to reduce the risk of neural tube defects and possibly other congenital anomalies. A higher dose (1 mg per day) may be recommended to patients with a family history of CL/P. (See "Preconception and prenatal folic acid supplementation", section on 'Congenital anomalies other than NTDs (possibly effective)'.)

An association between folate deficiency with CL/P is apparent in studies of specific medications that increase the risk of having a fetus with CL/P. Several of the antiseizure medications are folate antagonists, suggesting a causal link between these agents and the higher risk of CL/P among exposed fetuses.

By comparison, maternal use of folic acid (folic acid supplements or in a multivitamin at any time during the three months before pregnancy to the end of pregnancy and/or dietary folate intake) was associated with a reduction in CL/P (OR 0.60, 95% CI 0.49-0.73) and a nonsignificant reduction in CP (OR 0.87, 95% CI 0.74-1.03) in a meta-analysis of mostly observational studies [23]. The lack of statistically significant reduction among fetuses with CP further supports the recognized etiologic and epidemiologic differences between CL/P and CP. However, data from observational studies raise concerns of potential bias and confounding.

Maternal obesity – Maternal obesity has been associated with a small, but statistically significant, increase in several congenital anomalies, including oral clefts [24]. (See "Obesity in pregnancy: Complications and maternal management", section on 'Congenital anomalies'.)

Achieving a body mass index in the normal range preconception is desirable for both pregnancy-related and general health benefits. (See "Obesity in pregnancy: Complications and maternal management".)

Amniotic band sequence – Typically, amniotic band sequence describes a range of congenital anomalies often exemplified by extremity amputations and constriction rings. Abdominal wall defects, such as limb-body wall complex, can also be seen. Facial clefting may be significant and include CL or CL/P but not CP. The clefting is often atypical in position, reflecting a disruption of orofacial development.

Debate continues as to the underlying etiology of this deformation spectrum with both intrinsic and extrinsic models. While the presence of fibrous bands is considered suggestive of extrinsic deformation and disruption, other investigators have favored an intrinsic model and possibly a single gene etiology for some cases. (See "Amniotic band sequence".)

Other – Exposure to other agents, such as viral infection, radiation, and significant metabolic perturbation (eg, poorly managed diabetes), has also been associated with clefting. Evidence supporting and refuting these associations is conflicting.

Syndromic cases — Syndromes account for approximately 30 percent of cases of CL/P and 50 percent of cases of CP [4]. Variants in a single gene or deletion or duplication of a genomic region (copy number variant [CNV]) can be associated with syndromic clefting. The CP associated with 22q11-deletion syndrome is an example of a CNV associated with clefting.

Although oral clefting is noted in over 100 syndromes, six deserve specific comments due to their frequency, variable presentations, and modes of inheritance.

Van der Woude syndrome – Van der Woude syndrome is an autosomal dominant disorder and the most common form of syndromic clefting, accounting for 1 to 2 percent of cases [25]. The phenotypic expression can range from lower lip pits that are often combined with CL/P or CP or, rarely, clefts without pits [26]. Hypodontia, bifid uvula, and submucosal CP have also been described. This syndrome should be considered if either parent or a family member has these subtle findings identified on examination or by history. (See "Syndromes with craniofacial abnormalities", section on 'Van der Woude syndrome'.)

Stickler syndrome – Hereditary arthro-ophthalmopathy or Stickler syndrome is typically an autosomal dominant disorder, but rarely autosomal recessive, characterized by flat facies, myopia, hearing loss, and spondyloepiphyseal dysplasia. Clefts of the hard and/or soft palate and uvula may occur. This syndrome should be considered in infants with CP, especially when there is a family history of deafness or ocular complications. (See "Syndromes with craniofacial abnormalities", section on 'Stickler and Marshall syndromes'.)

Deletion of chromosome 22q11 – Submicroscopic loss of chromosomal material from chromosome 22q11 within the DiGeorge syndrome region is associated with a spectrum of findings in addition to CP: conotruncal cardiac anomalies, thymic hypoplasia, and velopharyngeal webs. While the majority of cases represent a de novo microdeletion, in up to 15 percent, a similar deletion is identified in a parent with variable, and often subtle, manifestations [27]. Thus, this syndrome should be considered in patients with CP and a family history of other anomalies, especially cardiac. (See "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis".)

Oral-facial-digital (OFD) syndrome, type I – OFD type I is an example of a rare, X-linked dominant syndrome. Lethality in males is suggested by a skewed female to male ratio in affected individuals and by an increase in early pregnancy loss in families with affected females. Manifestations in affected females are variable and subtle, including hyperplastic frenula, cleft tongue, median CL, CP, and digital anomalies. It is caused by mutations within a specific gene on the X chromosome (OFD1), which encodes a protein that is a core component of the centrosome [28]. This syndrome should be considered based on the fetal sex and maternal reproductive history. (See "Kidney cystic diseases in children" and "Kidney cystic diseases in children", section on 'Genetic disorders'.)

Treacher Collins syndrome – This is an autosomal dominant disorder with characteristic facial features including downward slanting palpebral fissures, micrognathia, dysplastic ears, and deafness. Mental development is normal. Affected individuals have varied phenotypes. The gene most commonly mutated in this syndrome is TCOF1. Rarely, Treacher Collins syndrome is caused by heterozygous mutations in POLR1D or biallelic mutations in POLR1C [29]. This syndrome should be considered in the fetus with additional atypical facial features, including micrognathia and dysplastic or malpositioned auricles. (See "Syndromes with craniofacial abnormalities", section on 'Treacher Collins syndrome'.)

PRENATAL DIAGNOSIS

Benefits — Prenatal diagnosis of an oral cleft can increase the chance of identifying some syndromes prenatally and provides time for the parent(s) to become informed about and adjust to the facial abnormality; prepare for the needs of their offspring; and make arrangements to transfer to a center with prenatal, delivery, and/or neonatal care commensurate with maternal and/or neonatal needs. It also allows them the option of terminating the pregnancy.

Ultrasound evaluation and findings

Gestational age – CL/P cannot be diagnosed reliably until the soft tissues of the fetal face can be clearly visualized sonographically, which is at 13 to 14 weeks of gestation by transabdominal ultrasound and slightly earlier by transvaginal ultrasound.

Diagnosis of CL – Assessment of the upper lip is a component of the standard obstetric examination. In the second trimester, fetal ultrasound images in the coronal view and axial planes are optimal for visualization of the lip and palate, respectively (image 1).

Unilateral CL is diagnosed when discontinuity is seen in the soft tissues of the upper lip unilaterally; bilateral CL is diagnosed when the discontinuity is bilateral.

CL is complete when it fully divides the lip and extends to the base of the nose. CL is partial when only a portion of the lip is involved. Partial CL is the most mild form of CL and not associated with underlying bony defects.

Median CL is rare, diagnosed when the midline upper lip is absent (image 2), and is often associated with holoprosencephaly [30].

Assessment for CP – When CL is detected, the palate should be carefully imaged as the majority of infants with CL also have palatal involvement: 85 percent of bilateral CL and 70 percent of unilateral CL cases are associated with CP [31].

The palate is assessed by imaging the alveolar ridge and assessing for discontinuity. When bilateral CL/P is complete, the nose appears elevated, and a premaxillary protrusion (seen as a paranasal echogenic mass) may be more conspicuous than the cleft itself (image 3) [32].

CP alone is not commonly detected prenatally [33]. It should be suspected in fetuses with micrognathia and polyhydramnios; fetal magnetic resonance imaging (MRI) can be helpful in assessment (image 4) [34].

Diagnostic performance — A 2010 systematic review reported a wide range of sensitivities for prenatal diagnosis in low-risk populations: prenatal detection rates for CL/P ranged from 9 to 100 percent and 0 to 22 percent for CP [33]. Higher sensitivity has been reported in high-risk populations, with use of three-dimensional (3D) ultrasound (image 5A-B) and MRI (sensitivity 97 percent, specificity 94 percent for CP [34]) in fetuses with additional malformations, in research studies, and in the era of the routine second-trimester fetal anatomic survey [34-40]. For example:

In the 2010 systematic review, 3D ultrasound in high-risk patients resulted in a detection rate of 100 percent for CL and 86 to 90 percent for CL with CP [33].

A European registry (1996 to 1998) reported the following frequencies of correct prenatal diagnosis: CL/P alone, 18 percent; CL/P with multiple other malformations, 34 percent; CL/P with a chromosomal abnormality, 52 percent; and CL/P as part of a syndrome, 58 percent [39].

In the Netherlands, the introduction of a routine 20-week fetal anomaly scan in 2007 was associated with a high rate of prenatal detection of CL/P: 82 percent (42 of 51 cases) of CL/P alone identified at birth [40].

Associated abnormalities — Fetuses with oral clefts should undergo careful full body assessment for additional structural abnormalities, which are common and vary by type and location of the oral cleft. For example, associated anomalies have been detected in 28 percent of fetuses with both CL and CP, 8 percent of those with CL alone, and 22 percent of those with CP alone [41]. Associated anomalies are very common with midline CL and more common with bilateral CL/P than unilateral CL/P (100, 25, and 10 percent, respectively, in one study [42]). Clefts in atypical positions may be associated with amniotic bands.

Associated anomalies typically involve the central nervous system/skeletal system (33 percent) and cardiovascular system (24 percent), which are sites of tissues with neural ectodermal origin. Sometimes, the associated anomaly is detected before the lip and palate are examined and prompt careful examination of these structures. As an example, midline forebrain abnormalities (eg, holoprosencephaly) are associated with malformation of midline facial structures such as median CL and CP.

Polyhydramnios was noted in 15 out of 230 (6.5 percent) pregnancies with CL/P alone in one study, and the palate was involved in 13 of these cases [43]. It may not develop until the second half of pregnancy, well after the time of routine anatomic survey, and likely results from impaired fetal swallowing.

OBSTETRIC MANAGEMENT

Genetic evaluation — We offer genetic testing to all patients with fetal oral clefts. This information can be used for decision-making around pregnancy termination versus continuation and with neonatal care planning after birth.

Clinical assessment to determine whether CL/P has occurred in the context of a multisystem syndromic disorder or positive family history versus an isolated sporadic event is an important consideration and will determine the approach to genetic testing.

In all cases, noninvasive prenatal testing may be used to screen for common trisomies, while amniocentesis for microarray is diagnostic. Chromosomal abnormalities (eg, trisomy 13) are found in 40 to 60 percent of fetuses with CL/P plus associated anomalies [44]. Although fetuses with CL/P without associated abnormalities are likely to be euploid [42], we offer microarray to these patients as well because of the possibility that prenatal sonographic diagnosis missed associated malformations [45]. (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers".)

Gene panels are available to sequence over a dozen clefting-associated genes, including those present in the Stickler and van der Woude syndromes, which are among the more common syndromic causes of oral clefts (see 'Syndromic cases' above). As with gene panels in numerous other disorders, some caveats should be considered. For example, not all genes for syndromes associated with oral clefts are on available panels or even known, and sequencing candidate genes can reveal pathogenic variants as well as variants of unknown significance. Given the range of possible genes involved in oral clefts, some consider exome sequencing a preferable approach to targeted sequencing panels [8]. (See 'Counseling and referrals' below.)

If gene panel or exome sequencing is considered, appropriate pre- and posttest genetic counseling by a provider experienced in the complexities of genomic sequencing is recommended.

Counseling and referrals

Patients with an ultrasound diagnosis of presumed CL/P alone or CP alone should understand that prenatal evaluation for additional anomalies may not detect all anomalies and is generally unable to detect cognitive deficits or sensory deficits affecting vision or hearing. As an example, in one series of fetuses presumed to have CL/P alone after detailed ultrasound examination, approximately one-fifth were found to have additional anomalies at birth [46].

Referral to a provider with expertise in genetics can be helpful for discussion of results and implications of any genetic testing that has been performed, the chances of a syndromic versus nonsyndromic etiology, and options for and utility of additional prenatal or postnatal genetic testing.

Referral to the neonatology service that will attend the birth is also desirable. They can counsel parent(s) about newborn management issues; begin a discussion about planning surgical repair; and initiate a referral to a multidisciplinary cleft or craniofacial management team, which may include pediatrics, genetics, nursing, nutrition, oral surgery, dentistry, orthodontics, otolaryngology, plastic and reconstructive surgery, psychology, social work, speech pathology, and audiology. Postnatal care by an experienced multidisciplinary team is necessary because affected infants/children may have problems with feeding/chewing, breathing, speech intelligibility, sleep, ear infections and hearing, and social integration, which can be mitigated by surgery, dental treatment, speech therapy, and psychosocial interventions. The multidisciplinary team can give parents information on the medical and psychosocial issues that these children and their families face [47], as well as the timing, risks and benefits, and costs of treatment options to assist them in making informed decisions on their child's behalf. (See "Overview of craniofacial clefts and holoprosencephaly", section on 'Treatment' and "Neonatal oral feeding difficulties due to sucking and swallowing disorders", section on 'Management approach'.)

Fetal surgery — Repair of oral clefts in surgically created animal models has been successfully performed and resulted in scar-free fetal healing and normal development of the face and skull. Whether this will also be possible in humans in whom the clefts have not been surgically created is unknown. Given the excellent results achieved with postnatal surgical techniques for CL/P repair, there is little current benefit to in utero correction.

Prenatal care and delivery — In most cases, the identification of a fetus with an oral cleft does not alter antepartum or intrapartum maternal care. In the minority of cases with impaired fetal swallowing (eg, CL/P with micrognathia), polyhydramnios can develop and may be severe, leading to preterm labor and maternal discomfort. (See "Polyhydramnios: Etiology, diagnosis, and management in singleton gestations".)

Birth should occur at a hospital that can provide care commensurate with neonatal needs, and mode of birth should be based on usual obstetric considerations.

NEWBORN MANAGEMENT — The initial focus of postdelivery newborn care is assessment of the infant's airway and sucking ability. Infants with severe Pierre Robin sequence (CP in association with micrognathia) may need expert support after birth to maintain a safe airway. Infants with a palatal cleft generally cannot generate sufficient negative intraoral pressure to suck milk effectively from bottle or breast but often can be bottle fed with formula or expressed breast milk with use of adaptive feeding equipment (eg, squeezable bottle, modified nipple, spoon) [48]. By contrast, infants with CL and no palatal abnormality often can feed from bottle or breast without special devices [49,50]. Consultation with an infant feeding/lactation specialist with expertise in this area is suggested. (See "Infant benefits of breastfeeding" and "Breastfeeding: Parental education and support".)

Primary lip repairs can often be undertaken at three months of age with palatal repairs around six months. Additional surgeries, as well as speech and orthodontic therapies, are often needed [51]. The American Cleft Palate-Craniofacial Association emphasizes coordinated care with proper sequencing of evaluations and treatments within the framework of the patient's overall developmental, medical, and psychological needs and provides important support and information for parents (acpa-cpf.org).

RECURRENCE RISKS — The pattern of inheritance of nonsyndromic oral clefts without additional anomalies does not typically follow Mendelian genetics; rather, this is a multifactorial disorder with multigene and environmental contributions [52]. The presence of an oral cleft in a parent, a prior offspring, or in the family history requires the following assessments to predict risk of recurrence:

Determination of a possible familial microform (ie, an incomplete or minor expression of a trait or illness) – A comprehensive family history and physical examination of the oral cavities of both biologic parents are essential prior to assigning a recurrence risk. Familial forms of both CL/P and CP with both autosomal dominant and sex-linked recessive inheritance have been reported.

Most notable of these is van der Woude syndrome, a very rare autosomal dominant lip pit syndrome, where the microform may manifest as "healed" cleft lip, bifid or grooved uvula, or submucous cleft palate [53]. The healed cleft lip appears as a single ridge or groove from the vermillion to the nostril. Nasal asymmetry and dental/alveolar abnormalities are also considered microforms of oral clefts. (See 'Syndromic cases' above.)

Delineation of CL/P from CP – While CL/P and CP both represent oral clefts, the recurrence risk of each differs, especially in the setting of a previously affected child. In general, the risk of recurrent CP is higher than the risk of recurrent CL/P [54], anatomic severity affects recurrence risk in first-degree relatives, and the type of cleft is predictive of the recurrence type [52]. A relatively large Danish study of live born children with CL/P or CP with no recognized syndrome or non-cleft major malformation determined the frequency of oral clefts in relatives based on the proband's phenotype, as shown in the table (table 1) [52]. The frequency increases if more than one first-degree family member is affected.

Presence of a possible syndrome – Consultation with a clinical geneticist is useful to obtain a detailed medical and family history, perform a dysmorphology examination, and suggest appropriate diagnostic testing, all of which may be necessary to make a diagnosis of a syndromic versus nonsyndromic oral cleft and to identify the specific syndrome.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Syndromes with craniofacial anomalies".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Cleft lip and cleft palate (The Basics)")

SUMMARY AND RECOMMENDATIONS

Terminology – The oral cleft is the most common craniofacial malformation in the newborn. It may consist of cleft lip alone, cleft lip with cleft palate, or cleft palate alone (figure 1). Cleft lip with or without a cleft palate (CL/P) and cleft palate alone (CP) differ with respect to embryology, etiology, candidate genes, associated abnormalities, and recurrence risk. (See 'Introduction' above and 'Embryology' above.)

Epidemiology – In the United States, the estimated prevalence of oral clefts (CL/P and CP) was reported to be 14.5/10,000 live births. The prevalence of CL alone, CL with CP, and CP alone has been reported to be 3.1, 5.6, and 5.9 per 10,000 live births, respectively. (See 'Prevalence' above.)

Race/ethnicity affects the prevalence of CL. By contrast, the prevalence of CP is relatively constant across races and ethnicities. The male to female ratio of CL/P is 2:1, while the male to female ratio of CP is 1:2. (See 'Epidemiology' above.)

Risk factors/etiology – Both genetic and environmental factors influence the development of oral clefts. Most oral clefts are nonsyndromic (a genetically complex event with gene-gene and gene-environment interactions); syndromes account for approximately 30 percent of cases of CL/P and 50 percent of cases of CP.

Females planning pregnancy can reduce their risk of having a child with nonsyndromic oral cleft by working with their clinician to discontinue drugs associated with this malformation (eg, certain antiseizure medications) and following routine preconception advice, such as smoking cessation, avoidance of alcoholic beverages, and supplementation with folic acid. (See 'Nonsyndromic cases' above.)

Syndromic cases may be caused by variants in a single gene or deletion or duplication of a genomic region (copy number variant [CNV]). Oral clefting is noted in over 100 syndromes. Van der Woude syndrome is an autosomal dominant disorder and the most common form of syndromic clefting, accounting for 1 to 2 percent of cases. (See 'Syndromic cases' above.)

Prenatal diagnosis – Oral clefts are diagnosed prenatally beginning after 12 weeks of gestation when the soft tissues of the fetal face can be clearly visualized sonographically and developmental separation of the lip and palate should no longer be present. The sensitivity of fetal ultrasound for facial clefting is highest when CL/P is associated with other structural anomalies. In other situations, such as CL/P alone in a low-risk population, the sensitivity may only reach 50 percent. CP alone is the most difficult oral malformation to diagnose prenatally, with a very low detection rate. Three-dimensional ultrasound and magnetic resonance imaging, where available, can provide a clear image of the malformation and may enhance detection, especially of CP alone. (See 'Prenatal diagnosis' above.)

Postdiagnostic evaluation – Fetuses found to have oral clefts should undergo careful assessment for additional structural abnormalities as these defects are noted in 50 percent of newborns with CP, 20 percent of those with CL and CP, and 8 percent for those with CL. (See 'Prenatal diagnosis' above.)

Chorionic villus sampling or amniocentesis for chromosome microarray should be offered to patients with ultrasound findings of fetal oral clefts; if associated anomalies are present, there is a high rate of chromosomal abnormalities. Further genetic analysis by specific panels or exome sequencing may be considered on a case-by-case basis, taking into consideration family history and any associated anomalies. (See 'Obstetric management' above.)

Recurrence risk – The recurrence risk of CL/P and CP depend on the setting, and can be as high as 50 percent in the setting of a dominant disorder with a minimally affected parent, emphasizing the need for thorough multidisciplinary care. (See 'Recurrence risks' above.)

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Topic 6769 Version 43.0

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