Etiology, prenatal diagnosis, obstetrical management, and recurrence of orofacial clefts

Author:
Louise Wilkins-Haug, MD, PhD
Section Editors:
Deborah Levine, MD
Helen V Firth, DM, FRCP, DCH
Deputy Editor:
Vanessa A Barss, MD, FACOG

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Nov 2016. | This topic last updated: May 25, 2016.

INTRODUCTION The most common craniofacial malformation identified in the newborn is

the orofacial cleft, which consists of cleft lip with or without cleft palate (CL/P) or isolated cleft
palate (CP) [1]. They can occur as part of a syndrome involving multiple other organs or as an
isolated malformation. Most studies suggest that about 70 percent of cases of CL/P and 50
percent of CP are nonsyndromic [2]. Although both congenital anomalies result in malformation
of the midface, CL/P and CP differ with respect to embryology, etiology, candidate genes,
associated abnormalities, and recurrence risk.

PREVALENCE AND EPIDEMIOLOGY The reported prevalence of orofacial clefts varies by

country, method of ascertainment, and classification. In the United States, the National Birth
Defects Prevention Network for 2007 to 2011 reported the estimated prevalence of orofacial
clefts (CL alone, CP alone, and CL with CP) was 14.5/10,000 live births (1 in 690 births): the
prevalence of CL alone was 3.1/10,000 live births, the prevalence of CL with CP was 5.6 per
10,000 live births, and the prevalence of CP alone was 5.9 per 10,000 live births [3]. Thus,
among newborns with a CL, approximately one-third had CL alone and two-thirds had CL with
CP.

Race/ethnicity also affects the prevalence of orofacial clefts. Prevalence was lowest in American
blacks (10.2/10,000 live births), highest in American Indian or Alaska Natives (20.5/10,000 live
births), and at an intermediate level in other groups (whites, Hispanics, Asians, Pacific Islander)
[3]. The First Nations population of British Columbia, Canada, has the highest reported birth
prevalence of orofacial clefts in the world, nearly 30/10,000 births [4].

In contrast, the prevalence of isolated CP appears to be constant across races and ethnicities.
CP likely has a different etiology than CL, and environmental and genetic factors (discussed
below) likely affect risk of development of CL more than development of CP.

Sex also affects prevalence. The prevalence of CL alone and CL with CP is higher in males than
females, but the prevalence of CP alone is higher in females than males [3].

Prevalence increases modestly with maternal age 35 years [3].

EMBRYOLOGY Craniofacial development represents a complex interaction of cell
patterning, migration, proliferation, and differentiation. Much of facial tissue originates by cell
migration from the embryonic neural crest. Underlying this development are regulatory,
structural, and positional genes that govern the required cell-cell interactions.

Cleft lip Complete closure of the lip is usually 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, bilateral, or (rarely) median
lip clefting (figure 1). Lack of fusion of the facial elements can be mild, involving only the upper
lip, or can extend into the palate or the midface, thereby affecting the nose, forehead, eyes, and
brain.

CL can be unilateral or bilateral; unilateral CL on the left side is the most common presentation.

Cleft palate Isolated CP occurs when there is primary lack of fusion of the palatal shelves.
Abnormalities in programmed cell death may contribute to lack of palatal fusion, although this
mechanism remains debated. Isolated disruption of palate shelves can occur after closure of the
lip because palatal closure is not completed until 56 to 58 days postconception.

ETIOLOGY The detection and study of fetal midfacial anomalies have led to important
information regarding the candidate genes and environmental factors influencing fetal
development.

Genes The process of midface development involves genes which control cell patterning,
cell proliferation, extracellular communication, and differentiation. Gene defects in each of these
developmental processes crucial to midface development are associated with cleft
malformations [5]. Clefting usually represents a genetically complex event; single Mendelian
disorders associated with clefting are less common. While at least one major gene may be
operative in one-half of patients, in most cases, 2 to 20 genes are thought to interact to result in
facial clefting [6].

There are several major categories of genetic defects:

Proliferation defects, eg, sonic hedgehog gene

Extracellular matrix defects, eg, TGF-alpha variant
Differentiation defects, eg, TGF-beta gene
Interferon regulatory factors, eg, IRF-6
Cell adhesion molecules

Most of the above genes have been implicated in animal models as responsible for orofacial
clefting; similar findings in humans are more limited.

Sonic hedgehog gene Interactions between the ectoderm and the mesoderm are important
in facial development. The secreted protein sonic Hedgehog (shh) mediates ectodermal
functions, and mutations of this gene classically produce holoprosencephaly. Several lines of
evidence support shh as an ectodermal signal that regulates the outgrowth and fusion of the
facial domains [5,7].

TGF-alpha variants Transforming growth factor (TGF)-alpha is a receptor ligand made in the
epithelia. In humans, CL/P has been associated with a rare variant of TGF-alpha called Tagl.
This variant has been found mostly among individuals with family histories of cleft defects [8].
The magnitude of CL/P risk varies among different Tagl alleles (C2, C1, RasI) [9]

TGF-beta-3 gene TGF-beta-3 is expressed just prior to palatal fusion. In newborns, the lack
of this factor results in isolated CP. Its role likely relates to its ability to cause degradation of the
midline epithelial seam, thus allowing complete fusion of the palatal shelves. In humans, a rare
allele of this gene has been associated with CL/P, particularly among familial cases [10].

IRF 6 As one of a family of transcription factors, the specific function of IRF 6 (interferon
regulatory factor 6) is unknown. Most IRFs code for DNA binding motifs and as such would be
expected to have a wide range of effects. Mutation in IRF 6 has been identified in autosomal
dominant van der Woude syndrome of CL/P and lip pits. Several investigators speculate that
other alterations of IRF 6 are responsible for a portion of nonsyndromic CL/P [11].

Environmental agents Epidemiological extension of the knowledge gained from animal

teratogen studies to humans has identified several agents that are associated with an increased
frequency of midfacial malformation after in-utero exposure. In addition, teratogen exposure
may be a contributing factor in the genetically at-risk fetus.

Medications Several medications sometimes prescribed for reproductive age females are
recognized as teratogens with specificity for midfacial development. Antiseizure agents, such
as phenytoin, sodium valproate, and topiramate [12,13], and the folic
acid antagonist methotrexate are examples of commonly administered drugs associated with
orofacial clefts. While the relative risk of orofacial abnormality is increased, the absolute risk of
clefting after drug exposure remains small.

An association between orofacial clefts and corticosteroid use is less clear as some
epidemiologic data suggest a possible association with CL/P [14-16]. Although 1997 to 2002
data from the National Birth Defect Prevention Study (NBDPS) reported a statistical association
between maternal corticosteroid use (all routes of administration) and CL/P in offspring (OR 1.7,
95% CI 1.1-2.6) [16], analysis of a more recent (2003 to 2009) and larger NBDPS database
found no association (OR 1.0 95% CI 0.7-1.4) [17]. The risk or orofacial clefts with any systemic
corticosteroid use during the entire period 1997-2009 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).

Diazepam increases the incidence of CP in mice, but the best evidence from human studies
does not show an increase in orofacial clefts [18]. (See "Risks associated with epilepsy and
pregnancy" and "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases
during pregnancy and lactation".)
Ondansetron is sometimes used for treatment of nausea and vomiting of pregnancy
unresponsive to other drugs. Studies have been conflicting with regard to birth defects
associated with this medication [19,20]. An association with cleft palate warrants continued
evaluation [21].

Cigarette smoking In a 2013 meta-analysis that pooled individual participant data from
studies that used similar methods in European populations, maternal smoking significantly
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)
[22]. Teratogenesis has been attributed to hypoxia, as well as a component of tobacco
(cadmium). Gene-environment interactions are also under investigation [2]. The joint risk of
cigarette smoking and a rare fetal allele at the TGF-alpha gene locus was greater than either
alone in case/control studies of risk factors for orofacial clefts [23,24]. (See "Cigarette smoking:
Impact on pregnancy and the neonate".)

An international population-based study also found an association between passive smoke

exposure and oral clefts (OR 1.14, 95% CI 1.02-1.27) [25].

Alcohol Maternal alcohol consumption also appears to be associated with an increased risk
of facial clefting [26]. As an example, a large case/control study of 731 infants and fetuses with
orofacial clefts found that women with weekly binge drinking (greater than five drinks consumed
in one session) were more likely to have a child with isolated CL/P, CL/P with other
malformations, and syndromic CL/P [27]. Animal studies suggest the underlying impact of
maternal ethanol may be either alterations in cell membrane fluidity or reduced activity of
specific enzymes such as superoxide dismutase [28]. (See "Overview of substance misuse in
pregnant women" and "Alcohol intake and pregnancy".)

Folate deficiency Folate is an essential component in the process of DNA methylation, and
its deficiency contributes to a range of birth defects. While the most notable associations are
with neural tube defects and cardiac malformations, some evidence emerged a few years ago
for a possible association with the development of CL/P, although this remains controversial.
Indeed, despite extensive study, the evidence is not converging and there is no strong evidence
of an association between oral clefts and folic acid intake alone. Multivitamin use in early
pregnancy, however, may protect against oral clefts, especially CL/P, although this association
may be confounded by other lifestyle factors associated with multivitamin use [29].

The contribution of folate deficiency to development of CL/P can be viewed from several
perspectives. First, mice models using gene knockouts for folate receptors result in fetal
malformations including CL/P. Delivery of folate by alternative pathways in these mice models
prevents an increase in CL/P, as well as other malformations [30]. In other mouse models, the
absence of folic acid binding protein alone resulted in malformations including CL/P. In these
deficient mice, genes of neurocrest differentiation were also altered, reinforcing the concept that
folate plays a role in the control of a wide range of genes [31].
In human populations, folate deficiency and the risk of a child with CL/P has been studied by
various approaches. In the 2013 meta-analysis described above that pooled individual
participant data from studies that used similar methods in European populations, maternal use
of folic acid (folic acid supplements and/or dietary folate intake) in the periconceptional period
was associated with a reduction in CL/P (OR 0.70, 95% CI 0.65-0.94), but no significant
reduction in isolated CP (OR 1.2, 95% CI 0.89-1.57) [22]. The lack of significant reduction
among fetuses with CP further supports the recognized etiologic and epidemiologic differences
between CL/P and isolated CP. In contrast, a 2015 Cochrane review found no evidence of a
preventive or negative effect on CP (RR 0.73, 95% CI 0.05-10.89; three studies; 5612 births;
low quality evidence) or CL (RR 0.79, 95% CI 0.14-4.36; three studies; 5612 births; low quality
evidence) [32].

Additionally, several genetic epidemiologic studies have focused on gene polymorphisms of the
enzymes of the folate pathway. These studies also support an association of folate deficiency
and CL/P. In particular, among fetuses who are homozygous for a polymorphism of acetyl-N-
transferase (NAT-1), and in whom maternal multivitamins were not taken in early pregnancy, the
risk for CL/P was two-fold higher [33].

Polymorphisms of methyl tetrahydrofolate reductase (MTHFR), an important enzyme in the

pathway of folate metabolism, have also been implicated in individual studies [34-36]; however,
the 2013 meta-analysis described above [22] did not observe an association between CL/P and
either the infant or maternal CT and TT genotype. These gene-environment interactions require
further study.

Lastly, the association of folate deficiency with CL/P is apparent in studies of specific
medications which increase the risk of having a fetus with CL/P. Several of the antiepileptic
medications are folate antagonists suggesting a causal link between these agents and the
higher risk of CL/P among exposed fetuses. In animal studies, induction of CL/P through
exposure to procarbazine could be partially ameliorated through concurrent folate
supplementation [37]. Extension of this concept to human studies, however, has not established
a lowered risk of CL/P among mothers who received multivitamins early in pregnancy and were
also taking antiepileptic drugs, many of which are folate antagonists [38].

Other Maternal obesity has been associated with a small, but statistically significant,
increase in several anomalies, including orofacial clefts [39]. (See "Obesity in pregnancy:
Complications and maternal management", section on 'Congenital anomalies'.)

Orofacial clefts are a component of many syndromes. (See 'Presence of a syndrome' below.)

PRENATAL DIAGNOSIS Prenatal diagnosis of orofacial clefts may increase the chance of
identifying some syndromes prenatally, provides time for parents to learn about and adjust to
the facial abnormality, provides parents an opportunity to prepare for the needs of the infant (eg,
feeding issues surgical repair), and allows them the option of terminating the pregnancy.
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 by transabdominal ultrasound, but somewhat earlier
by transvaginal ultrasound. Fetal ultrasound images in the coronal view and axial planes are
optimal for visualization of the fetal lip and palate, respectively (image 1). Orientation and
development of other facial structures can provide useful information for distinguishing
unilateral, bilateral, and midline malformations. As an example, midline forebrain abnormalities
(eg, holoprosencephaly) suggest malformation of midline facial structures may also be present.
The majority of infants with CL also have palatal involvement: 85 percent of bilateral CL and 70
percent of unilateral CL are associated with CP [40]. CP with an intact lip comprises 27 percent
of isolated CL/P.

A 2010 systematic review reported a wide range of sensitivities (9 to 100 percent) for prenatal
diagnosis of CL/P in low risk populations [41]. Better data were provided by the National Birth
Defects Prevention Study (1998-2004), an ongoing population based case-control study in the
United States [42]. Live births, stillbirths, and abortuses are included if medical record review by
a clinical geneticist ascertains eligibility criteria are met. Infants with chromosomal abnormalities
and single gene disorders, as well as those with orofacial clefts secondary to another defect (eg,
holoprosencephaly, amniotic band sequence), are excluded. For the years 1998 to 2004,
prenatal diagnosis was made in 33.3 percent of the 978 cases of CL/P, 20.3 percent of the 522
cases of CL only, and 0.3 percent of the 798 cases of CP only [42]. The sensitivity of fetal
ultrasound for detecting facial clefting was slightly higher when the orofacial cleft was
associated with other unrelated structural anomalies (33.5 versus 28.2 percent with no other
anomalies).

Higher sensitivities have been observed in research studies and studies that included orofacial
clefts related to other defects (eg, syndrome associated with a chromosomal abnormality,
holoprosencephaly). A European registry (1996-98) reported the following frequencies of correct
prenatal diagnosis: isolated CL/P, 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 [43]. Higher sensitivity has also been reported in recent studies. In The Netherlands, the
introduction of a routine 20 week anomaly scan in 2007 was associated with prenatal detection
of 82 percent (42 of 51 cases) of isolated CL/P identified at birth [44].

Three-dimensional ultrasound (image 2A-B) [45-48] and magnetic resonance imaging (image 3)
[49,50], when available, can provide a clear image of the malformation and may enhance
detection of isolated cleft palate.

Associated abnormalities Fetuses found to have orofacial clefts should undergo careful
assessment for additional structural abnormalities, as these defects were noted in 22 percent of
newborns with CP, 28 percent of those with CL and CP, and 8 percent for those with CL in one
study [51]. The variation in rate of associated anomalies emphasizes the underlying differences
in the development of CL/P versus CP. The location of the cleft also appears to affect the
incidence of anomalies: in another study, the incidence of anomalies was 9.8 percent for
unilateral CL/P, 25 percent for bilateral CL/P, and 100 percent for midline CL/P [52]. These
anomalies typically involve the central nervous system/skeletal system (33 percent) and
cardiovascular system (24 percent), all sites of tissues with neural ectodermal origin.

Among fetuses with a presumed isolated CL/P visualized by ultrasound, even careful
surveillance for additional anomalies may not be revealing. As an example, in one series of
fetuses presumed to have "isolated" CL/P after detailed ultrasound, nearly a quarter (21.6
percent) were found to have additional anomalies at birth [53].

Chromosomal abnormalities are rare in fetuses with isolated clefts [52], but are found in 40 to 60
percent of those with both orofacial clefts and other anomalies [54]. The prevalence of
associated anomalies is higher in fetuses with orofacial clefts than in liveborn infants with
orofacial clefts; this likely reflects the high rate of pregnancy termination and stillbirth among
fetuses with multiple anomalies and abnormal karyotype.

OBSTETRICAL MANAGEMENT Amniocentesis for karyotype should be offered to women

with ultrasound findings of fetal orofacial clefts and associated anomalies because of the high
rate of chromosomal defects. Orofacial clefts in the absence of associated congenital
abnormalities are unlikely to be associated with a chromosomal abnormality [52]; however, the
difficulty in prenatal sonographic diagnosis of some of the associated malformations supports
the offer of chromosomal evaluation in all fetuses with prenatally diagnosed facial clefts [55].

The identification of a fetus with a craniofacial cleft will not alter antepartum or intrapartum care
of the mother. Repair of orofacial 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. "In utero" correction of a human fetal cleft has been attempted;
the child delivered prematurely and died at two months of life [56].

Antenatal management of the woman with an ultrasound diagnosis of a fetal craniofacial cleft
should include referral to a comprehensive management team. The neonatology service that will
attend the delivery should be notified in advance, and can counsel the parents about newborn
management issues and planning surgical repair.

POSTNATAL MANAGEMENT Care of the newborn will entail attention, not only to surgical
repair, but also to more immediate needs, such as feeding and airway problems. 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 [57]. The
Cleft Lip and Palate Association (www.clapa.com) provides important support and information
for parents.

RECURRENCE RISKS The presence of CL/P or CP in a parent, a prior child born to the
couple, or in the family history requires further investigation if appropriate risk assessment is to
be provided. Such assessment entails three important considerations:

Delineation of CL/P from isolated CP

 Determination of a possible microform in the family
Presence of a possible syndrome

Delineation of cleft lip/palate from cleft palate While CL/P and CP both represent
craniofacial clefting, the recurrence of each differs, especially in the setting of a previously
affected child. In general, the risk of recurrent isolated CP is higher than the risk of
recurrent CL/P [58]. The severity of recurrent defects cannot be predicted by the severity of the
defect in the index case.

The frequency of oral clefts in relatives based on the proband's phenotype is shown in the table
(table 1) [59]

Presence of a microform in the family A careful family history, as well as physical

examination of the oral cavities of both parents, is essential prior to assigning a recurrence risk.
Familial forms of both CL/P and CP exist with both autosomal dominant and sex-linked
recessive inheritance reported. Most notable of these is the autosomal dominant lip pit
syndrome (Van der Woude syndrome). Expression can range from lip pits to CL/P or
CP. CL/P occurs due to a dominantly inherited Van der Woude syndrome in 1 to 2 percent of
individuals with what appears to be isolated CL. Other microforms can include submucosal CP
or bifid uvula; both suggest a higher recurrence rate than that given for the multifactorial
inheritance of isolated CL/P or CP.

Presence of a syndrome A thorough examination of the newborn or stillborn infant is always

warranted. Although orofacial clefting is noted in over 300 syndromes, four deserve additional
comment due to their frequency, variable presentations, and modes of inheritance
(see "Syndromes with craniofacial abnormalities"):

Deletion of chromosome 22q11 (CP) Microscopic 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 defects, thymic hypoplasia, and velopharyngeal
webs. While the majority of cases represent a new microdeletion, in up to 15 percent, a similar
deletion is identified in a parent with variable, and often subtle, manifestations [60]. In families
with scattered individuals with conotruncal malformations and/or cleft palate, further evaluation
for microdeletion of 22q- is appropriate. (See "DiGeorge (22q11.2 deletion) syndrome:
Management and prognosis".)

Oral-facial-digital syndrome, type I (CL/P) This is one of the few X-linked dominant
syndromes. Lethality in males is suggested by a skewed female to male ratio in affected
individuals and by an increase in miscarriage rate in families with affected females.
Manifestations in affected females are variable and subtle, including hyperplastic frenula, cleft
tongue, median cleft lip, cleft palate, and digital anomalies. Mutations within a specific gene on
the X chromosome (OFD1), which encodes a protein that is a core component of the
centrosome [61], are variable without specific patterns unique in either the sporadic or familial
cases [62].
Treacher-Collins syndrome (CP) 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 may have varied expression.
The gene most commonly mutated in this syndrome is known (TCOF1) and mutations appear to
increase cell death in the prefusion neural folds [63]. A family history of additional members with
deafness, ear abnormalities, or CP should prompt further consideration of this syndrome,
although many cases occur de novo. Rarely, heterozygous mutations in the gene POLR1D
cause Treacher-Collins syndrome or biallelic mutations in the gene POLR1C [64].

Amniotic band sequence (CL/P) Typically, amniotic band sequence (ABS) is applied to a
range of birth defects 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 isolated 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 are considered suggestive of extrinsic deformation and disruption,
other investigators have favored an intrinsic model, and possibly a single gene etiology for some
cases. There may be a subset of ABS patients in whom additional minor malformations, such as
polydactyly, in the same setting as traditional ABS deformations suggest an underlying intrinsic
model. A human homolog of the Ds (disorganization gene) in mice has been proposed for such
individuals [65]. (See "Amniotic band sequence".)

Stickler syndrome (CP) Hereditary arthro-ophthalmopathy or Stickler syndrome is an

autosomal dominant disorder characterized by flat facies, myopia, 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 CP.

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

The most common craniofacial malformation identified in the newborn is the orofacial
cleft, which consists of cleft lip with or without cleft palate (CL/P) or isolated cleft palate
(CP). About 70 percent of cases of CL/P and 50 percent of CP are nonsyndromic.
Conversely, about 30 percent of cases of CL/P and 50 percent of CP are syndromic and
specialist genetic advice should be sought in these cases. (See 'Introduction' above.)
CL/P is more common than CP alone. The prevalence of CL/P varies
with race/ethnicity and gender. (See 'Prevalence and epidemiology' above.)
Both genetic and environmental factors influence the development of orofacial clefts.
Women planning pregnancy can reduce their risk of having a child with an orofacial cleft by
working with their doctor to discontinue drugs associated with this malformation. Advice on
smoking cessation and not consuming alcoholic beverages should be given. Avoiding
folate deficiency by diet or supplements may also be useful. (See 'Etiology' above.)
Orofacial clefts are diagnosed 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 isolated CL/P in a low risk population, the sensitivity may only reach 50
percent. Isolated CP is the most difficult orofacial malformation to diagnose prenatally with
a low detection rate of <7 percent. Three-dimensional ultrasound and magnetic resonance
imaging, where available, can provide a clear image of the malformation and may enhance
detection, especially of isolated CP. (See 'Prenatal diagnosis' above.)
Fetuses found to have orofacial clefts should undergo careful assessment for additional
structural abnormalities, as these defects are noted in 50 percent of newborns with isolated
CP, 20 percent of those with CL and CP, and 8 percent for those with isolated CL.
(See 'Prenatal diagnosis' above.)
Amniocentesis for karyotype should be offered to women with ultrasound findings of fetal
orofacial clefts and associated anomalies because of the high rate of chromosomal
defects. (See 'Obstetrical management' above.)
The recurrence risk of cleft lip/palate depends on the setting. (See 'Recurrence
risks' above.)