Open Med.

2015; 10: 163-175

Review Article Open Access

Agata Kawalec*, Kamil Nelke, Krystyna Pawlas, Hanna Gerber

Risk factors involved in orofacial cleft

predisposition – review

Abstract: Clefts that occur in children are a special topic. 1 Introduction

Avoiding risk factors, and also an early diagnosis of cleft
possibility can result in minimizing or avoiding them. According to Mayo Health Book, several factors can be
If on the other hand when clefts occur they require a involved with orofacial cleft (OFC) predispositions: geo-
long-term, multistage specialized treatment. Etiology of graphic factors, race, family history, sex, exposure to risk
clefts seems to be related to many factors. Factors such factors in pregnancy, such as alcohol consumption and
as genetic, environmental, geographic and even race tobacco smoking, poor nutrition, viral infections, drugs
factors are important. Identification of risk factors can and also teratogens in the workplace and home. Recent
lead to prevention and prophylactic behaviors in order studies show that even obesity during pregnancy may be
to minimize its occurrence. Exposure to environmental related with cleft lip and palate [1].
factors at home and work that lead to cleft predisposition Orofacial clefts are very common world-wide with an inci-
should not be disregarded. It seems that before planning dence of 1.7 per 1000 babies being diagnosed with OFC [2].
a family it would be wise to consult with doctors of differ- Different factors are related with its occurrence. It seems
ent specializations, especially in high-risk families with that geographic and climatic factors are also quite import-
cleft history in order to analyze previous lifestyle. Clefts ant. In different part of the world, thanks to mass com-
are very common in hereditary facial malformations and munication, people traveling and migration, geographic
are causing a lot of other irregularities in the head and borders can be moved and cleft occurrence in different
neck region. In this paper after a brief papers review part of the world might change.
authors present socio-geographic, environmental and Asia has an incidence of 17/1000, American Indians
also work place related factors that are influencing preg- 3,6/1000, African Americans 0,4/1000. Gender ratio is also
nant women condition and should be taken under serious higher in boys. Cleft palate is more frequent in males, but
consideration. females more often have only cleft palate (about 0,5:1000).
According to the Mayo Health Book authors, isolated cleft
Keywords: Clefts; risk factors; lifestyle; predisposing palate and cleft lip with or without cleft palate are present
factors; environmental factors in 1,7 children per 1000 live births, but ethnic and geo-
graphic variations greatly influence this issue [3-5].

DOI 10.1515/med-2015-0027

Received: September 9, 2013; accepted: December 11, 2014

2 Facial morphogenesis and related
diseases
In order to fully understand the etiology of OFC it is very
important to know how facial embryogenesis and morpho-
genesis takes place. After activity of various risk factors in
*Corresponding author: Agata Kawalec, Wroclaw Medical Universi- different stages of facial morphogenesis OFC clefts might
ty, Wrocław, Poland, E-mail: [email protected] occur with characteristic intensity.
Agata Kawalec, Krystyna Pawlas, Department of Hygiene, Silesian Face morphogenesis consists of five processes. The
Piast’s Medical University, Poland
frontonasal process and two maxillary and mandibu-
Kamil Nelke, Hanna Gerber, Department of Maxillo-Facial Surgery,
Silesian Piast’s Medical University, Poland lar processes made from mesenchyme surrounded with

© 2015 Agata Kawalec et al. licensee De Gruyter Open

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164   Agata Kawalec et al.

epithelium lining that also surrounds and covers entire 3 Factors related with orofacial
oral cavity. It is well known that the human skull consists
of desmocranium, chondrocranium and viscerocranium.
clefts
All parts have a great effect on proper growth [6]. During
Many factors are related with clefts; however they are
embryogenesis various factors might interrupt or change
depend on the time, place and moment of morphogenesis
the proper course in facial development at any moment
and proper facial formation [16,17]. We present the most
during pregnancy. Facial processes have their own growth
important eisk factors such as: geographic, family history
outline. The frontal process grows out from medial nasal
and genetics, alcohol and tobacco, diet, medicament
and lateral nasal processes which surround the bilateral
intake during pregnancy, infections, and occupational
nasal pits. The next stage is a fusion of processes anteri-
hazards influencing orofacial cleft occurrence.
orly with the maxillary processes to form upper lip, alveo-
lus and primary palate [7]. For example oral clefts, such as
cleft lip and cleft palate have different congenital failure
episodes and occurrence. Cleft lip is related to a failure
in the fusion of maxillary and median nasal processes.
4 Geographic-related factors
Cleft palate is related with a failure of the palate to fuse
It is quite important to notice that prevalence of OFC
proprely. Moved posteriorly the maxillary processes fuse
world-wide and its relation with geographic, climate,
to form the secondary palate. Because of the multifactor
and socio-epidemiological factors is still a focus of many
etiology of orofacial clefts and impact of cleft inducing
studies. Maybe perhaps because of those findings OFC
factors, clefts can be unilateral, bilateral, have different
could be more predictable.
sides and consist of various types [8,9].
Predisposition to oral clefts is also different in geo-
In many cases orofacial clefts can also occur with
graphic regions. Many different studies were performed
various syndromes and have also other manifestations.
world-wide in various geographic regions, climates and
Also genetic disorders have a great influence on cleft
continents. Because of those results authors describe a
occurrence. Many different gene mutations and diseases
very important ethnic and social dependence. Asians
are the cause of facial defects.
have the highest risk marked at 14:10000 births but a
It is also very important to notice that clefts can be
special geographic occurrence in regions such as Japan,
related to various syndromes and defects. Most common
Korea and China should be more carefully evaluated.
one is Pierre-Robin sequence. Other Syndromes related
Other races followed by caucasian have 10:10000 births,
with clefts, are: van der Wounde’s, Opitz, Stickler,
followed by African Americans 4:10000 births.
Apert’s, DiGeorge’s, CHARGE syndrome (Coloboma, Heart
Studies shows that African children are least likely to
defect,  Atresia choanae,  Retarded growth and devel-
have clefts, however cleft lip and palate is most common
opment,  Genital hypoplasia,  Ear anomalies/deafness’)
in American Indian and Asian children. Geographic loca-
Waardenburg’s, Hedgehog’s, trisomy 13 Patau’s syndrome,
tion of Africa, its history, different cultural and ethnical
Trisomy 18  Edwards’ syndrome, amniotic band anom-
factors makes it a very special place for evaluation and
alad, Fryn’s, Meckel’s Treacher Collins, velo-cardio-fa-
describing orofacial cleft occurrence and predisposition.
cial syndrome (VCF), oculo-auriculo-vertebral spectrum
Butali review study performed in Africa suggest that it is
(OAV, Goldenhar syndrome, hemifacial microstomia) and
necessary to set up a diagnostic system in order to fully
other syndromes [10,11]. Many studies also conclude that
measure cleft occurrence in different regions in Africa and
females have a higher risk of breast cancer, primary brain
more studies and researches need to be performed to fully
malignancy while males have a higher risk of primary lung
evaluate this issue [18]. Adetayo et al performed survey
cancer [12]. Also Quality of Life (QOL) of patients suffering
questionnaires in West Africa in 2007, and conclude that
from clefts is different, because of behavioral problems,
geographic situation of Africa, its geographic and social
anxiety, depression, lack of self-esteem and others [13].
status has a great effect on cleft patient’s life [19,20]. For
Also dental, facial or combined abnormalities might
example not only funding, infrastructural, education and
occur with clefts. Cleft occurrence with or without any
care are important.
other orodental abnormalities or syndromes is less
Both in Japan and in western Asia regional occur-
common [14,15].
rences and cleft predisposition is different. Elahi et
al conclude that many geographic and epidemiologic
studies were carried out worldwide. Therefore authors

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  Risk factors involved in orofacial cleft predisposition   165

performed a study in northern Pakistan based on birth newborns, born in metropolitan and non-metropolitan
registry [21]. 117 cases from 61156 live births were found. areas have greater rage difference of occurrence [27].
Those results seem to confirm that cleft lip and/or palate Socioeconomic risk factors have to be carefully eval-
was 1.91 per 1000 births, however boys had more cleft clip uated. Acuña-González et al study performed in Mexico
and lip with palate and girls had more often isolated cleft marks that the following factors have a and are related
palates. This study can not only mark the prevalence of with OFC: low socioeconomic status, birth in southern
clefts in Pakistan, but also can show special geographic Mexico region, home delivery or public hospital delivery,
and cultural differences in clefts. On the other hand Dai familial history, other siblings or family malformations,
et al study made in China between 1996 and 2000, con- and infections during pregnancy [28].
cludes that cleft palate (CP) was identified in 499 perina- According to study performed by Rodrigues et al
tals among 2218616 births and was quite different in rural that consisted of evaluation of data gathered between
and urban areas [22]. The highest rate of 2.84 per 10000 1998 to 2002, on 15786107 live births 5764 newborns had
live births was found in maternal age group more than 35 OFC Study also shows that cleft occurrence in Brazil was
years, and also geographic variation between provinces 0.36per 1000 live births. Ratio of OFC prevalence was more
is different. Authors also conclude that because of poor common in 1.6 men for 1 female with greater prevalence in
birth quality, perinatals diagnosed with syndromic CP had southern and midwest regions with a very low rate in the
a poor prognosis. northern region of Mexico. It seems that geographic and
Studies performed by Pradubwong et al in Thailand climatic variances have a great effect on OFC occurrence
with usage of special Geographic Information System [29]. Study performed in 10 South America countries per-
(GIS) indicate that most patients with clefts lived in central formed by Poletta et al also concludes that not only geo-
and northern Northeast Thailand, and most in Khon Kaen graphic region of South America has a great influnce, but
province [23]. Thanks to usage of such systems not only also familial history and family members living and trav-
surgeries and treatments can be planned but also routine eling in different countries and continents is very import-
patient check-ups and improvement of patient’s life can ant [30].
be achieved. Ulucan et al conclude that regional differences in
It is also worthy to note , that not only geographic nutritional habits and life style have various effects in
factors are very important in cleft occurrence, but also non-syndromic cleft lip with/without palate occurrence
in opioid administration in children. A study performed in Turkey [31]. This might be related with Europe-Asian
by Rabbitts et al concludes that operated cleft children ethnics and habits.
in Central and South America received less opioid intra- According to Silberstein et al, in the Negev region in
operatively than African and Indian children and more Israel their study among Bedouin and Jewish in a well-de-
research are need to take place to evaluate this extraor- fined geographic area describes that Bedouin population
dinary finding [24]. Root describes a special neighbor- has a greater decrease of facial clefts than the Jewish pop-
hood-level socioeconomic status (SES) conditions and ulation [32]. In some cases natural and traditional habits
factors that influence health outcomes [25]. Border cross- related with geographic regions might decreased greatly
ing, illegal residency, refugees and a great amount of amount of clefts.
influx of peoples to the USA has a great effect on orofacial Studies made in Europe conclude some very important
cleft predisposition. Because of presence or lack or social facts. For example refugees and the opening of borders of
insurance that affects socio-epidemiological status, peo- United Europe might be related with migration of peoples
ple’s treatment and detection of clefts is varying. with different predisposition to clefts and familial history
North, Central and South Americas have a greater dif- of its occurrence. Even studies made by Dai et al, confirm
ferences in their orofacial cleft predisposition, occurrence that in order to fully describe and measure orofacial cleft
and treatment. Salemi et al indicate that FBDR (Florida occurrence in the borders of countries, a special surveil-
Birth Defects Registry), which is used to collect data at lance system is required [33].
geographic area in Florida is very accurate and helpful to Durning et al studies performed in Wales between
describe and mark every 9 from 10 born infants. In conclu- 1982 and 2003 indicate that 831 babies were born with oro-
sion a special tool to set up geographic regions and borders facial cleft, equating to 109 clefts per 100,000 live births.
is very important [26]. Study performed in Colorado, USA, Authors conclude that serious association between mate-
between 1982–1988 performed by Amidei et al marks rial deprivation and orofacial clefts is essential and more
out that country of residence, Hispanic or non-Hispanic studies are needed to take place in order to fully evaluate
this problem [34].

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166   Agata Kawalec et al.

Croatian study consisted of the analysis of 525298 live- complete diagnosis, familial history and geographic
births since 1988 to 1998, and marked out that OFC inci- region assessment [39].
dence grown slowly and was different in some geograph- Males have cleft lip with or without cleft palatealmost
ical areas [35]. twicw as often, and females have cleft palate without cleft lip.
On the other hand, habitants of Australia and Oceania Many different factors are involved in cleft predispo-
have different rates of orofacial cleft occurrence. Australian sition. Parent’s age, especially mother’s age. Studies per-
findings from a study on a group of newborns from 1980 formed by Shaw, Baird, Vieira, DeRoo seem to confirm that
to 2009 conclude that within occurrence of cleft lip with/ maternal age is related to oral cleft risk; however not in all
without cleft palate and cleft and palate was 1.9 and 1.3 older studied maternal groups clefts occur [40,41,42,43].
times higher respectively, for Aboriginal Australians. This
finding may conclude that geographic and ethnic factors
are very important [36].
Geographic factors have a great meaning in orofacial 6 Alcohol and tobacco
cleft predisposition, occurrence and treatment methods.
Because habits, social conditions, access to drugs and Exposure to risk factors in pregnancy such as alcohol may
tobacco, alcohol, its consumption in different geographic induce cleft lip and palate. When alcohol is combined
regions during pregnancy is highly related with heredi- with other factors, such as tobacco, drugs, and also other
tary disease occurrence and predisposition. If more risk socio-geographic factors cleft risk is greatly higher.
factors accumulate it is more possible for many diseases It seems that both combined factors are increasing
to appear. risk of OFC. Miller et al study performed in Russian region
Murmansk in baby homes and orphanages suggest that
geographic region of Murmansk and its greater expres-
sion of prenatal exposure to alcohol. Because of that chil-
5 Family history and genetic factors dren’s growth, maturation and even occurring symptoms
are more common [44].
Family history involving any present or past members of Environmental factors in study made by Molina-
family can induce a higher risk of having baby with a cleft. Solana indicates that in cleft lip and/or palate main
Therefore genetic counselling should be offered. factors are: tobacco 1.48 , alcohol 1.28 , folic acid intake
On the other hand Lace et al conclude that different 0.77 , obesity 1.26 , stressful events 1.41 , low blood zinc
population predisposition to OFC is related with several levels 1.82 and fever during pregnancy1.30 [45]. Tobacco
genes, for example European gene might be related with intake seems to have the most serious influence on OFC
mitochondrial DNA (mtDNA) haplotypes. As a result according to Lebby et al, 1.66 ratio [46]. On the other hand,
authors conclude that it is unlike that mtDNA has a direct study performed by Leite et al concludes that mother’s
role in cleft lip and palate predisposition [37]. Therefore all smoking in first trimester of pregnancy was not statisti-
newborns and their parents should be closely evaluated, cally significant, but increased alcohol use increases the
examined and had special data gathered, which might be risk of cleft lip with or without cleft palate and cleft palate
very useful in diagnosis and prevention of orofacial clefts. alone to 3.41 and 8.30 and within the higher dose of drugs
It seems that genetic consults have a great impact of early ratio of OFC seems to increase [47].
hereditary disease findings. Tobacco and alcohol are well known factors involved
It is very important to routinely gather data about in OFC occurrence. Honein et al study describes associa-
newborn’s, OFC and other hereditary diseases occurrence. tion between periconceptional maternal smoking, envi-
Another study made in US by Johnson et al, suggests that ronmental tobacco smoke and cleft lip with or without
the number of prenatally diagnosed orofacial clefts is cleft palate and cleft palate only in infants born between
very low, and this tendency should be changed in order to 1997 and 2001. The authors conclude that periconcep-
decrease number of its occurrence [38]. tional smoking was associated with bilateral cleft lip
Cousley et al study made after evaluating Yorkshire and palate. Smoking more than 25 cigarettes per day was
regional cleft database seems to confirm that a special related with higher amounts of bilateral CLP and even
diagnostic system should be used to clarify and evaluate Pierre Robin sequence [48].
local occurrence of clefts. Author indicates that a special Diaz Casado et al, confirm that orofacial clefts have
program should be used to identify OFC newborns, their many factors that might induce clefts and also studies
explaining their origin seems to have few theories. Low

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  Risk factors involved in orofacial cleft predisposition   167

social status with abuse of tobacco, alcohol and/or drug Shaw et al investigated whether a woman’s peri-
addiction have a great effect on predisposition to orofacial conceptional use of multivitamins containing folic acid
clefts, and also use during pregnancy is causing not only was associated with a reduced risk of orofacial clefts.
OFC but also other congenital syndromes and malforma- Authors found that a reduced risk of orofacial clefts is
tions [49]. Genetic factors involved in orofacial clefts are more common in mothers that had used multivitamins
still being considered inserious studies being performed containing folic acid during the period from one month
world-wide [50]. before through two months after conception. In this study
When orofacial clefts occur they have a great impact woman using multivitamins containing folic acid pericon-
on infant feeding, speech, language and voice forma- ceptionally had a 25-50% reduction in risk for offspring
tion, breathing, oral functions, bite, teeth formation and with orofacial clefts compared to women who did not use
other related topics. Because of that newborns with OFC such vitamins [53].
should be carefully treated by many specialists. Studies According to O’Neill and a national population-based
made in the USA indicate that more cleft surgeries are case-control study performed in Norway folic acid sup-
made in teaching hospitals than in nonteaching hospi- plements during early pregnancy (400 microgram per
tals which have some positive effects on OFC treatment day) seem to reduce the risk of isolated cleft lip (with or
(decreased number of complications), for both patients without  cleft palate) by about one third. Moreover the
and parents [51]. author claims that other vitamins and dietary factors
such as a diet rich in fruits, vegetables and other high-fo-
liate-containing foods may provide additional benefit.
According to this study the lowest risk of  cleft  lip was
7 Diet among women who ate foliate-rich diets and also took
folic acid supplements and multivitamins. Folic acid did
Factors such as diet including folic acid, vitamins, zinc not provide protection against cleft palate alone [54].
and other microelements have a great effect on preg- Moreover the population-based infant study cohort
nancy. Some authors also point out that drinking cola and of the national Growing Up in Ireland performed by
tea might have some influence on pregnancy. Drugs, med- Kelly et al which was focused on 11,134 9-month-old
icine, corticosteroids, antibiotics and local and general infants also suggests that taking folic acid may partially
agents used in pregnancy have a great effect on OFC pre- prevent  cleft  lip and palate occurrence  [55]. Wilcox et al
disposition. Other quite important matters are health also claim that folic acid supplements during early preg-
statue and infections present in pregnant women. Viral nancy seem to reduce the  risk  of isolated  cleft  lip (with
infections and diseases related with elevated body tem- or without  cleft  palate) by about one third. According
peratures also have a great effect on hereditary disease to them other  vitamins  and dietary factors may provide
occurrence. Work and factors related with work, such additional benefit [56]. It seems that folic acid intake is
as radiation, high temperatures, chemical agents, light, the most important factor, but combined with other ratio-
electromagnetic field and others are influencing women’s nal health food intake might cumulate positive effects on
health in early stages of pregnancy when in some cases pregnancy.
pregnant women don’t even know about their condition. On the other hand Little et al in a U.K.-based
One of the most important factors related to OFC is case-control study focused on determination of the asso-
diet, because the diet of pregnant women influence the ciations between non-syndromic cleft lip with or without
infant growth. cleft palate and cleft palate only and maternal intake of
In a case-control study of 203 mothers of children with dietary  foliate  and supplemental  folic acid, in an area
a  cleft  lip or  cleft palate  and 178 mothers with non-mal- where the prevalence at birth of neural tube defects has
formed offspring Vujkovic et al proved that the use of the been high and flour is not fortified with folic acid. There
maternal Western diet–high in meat, pizza, legumes, and was no overall association between CL-P and CP and either
potatoes, and low in fruits–increases the risk of offspring energy-adjusted total foliate intake or supplemental folic
with a  cleft  lip or  cleft palate  approximately two fold. acid  use, irrespective of dosage. Also the same authors
That means that dietary and lifestyle profiles should be concluded that overall, higher intakes of total  foliate  do
included in preconception screening programs [52]. Other not appear to prevent oral  clefts  in this population [57].
studies performed world-wide also seem to confirm those Perhaps genetic predisposition and familial history has a
findings. greater influence on OFC occurrence than folic acid intake.

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Badovinac et al meta-analysis undertook to test the It is very important to point out that in different geo-
hypothesis that non-syndromic oral cleft birth prevalence graphic regions of the world vitamin intake may differ.
is different for those whose mothers took  folic acid-con- This finding is essential for proper diet planning in differ-
taining supplements and for those whose mothers did ent part of the world.
not. The results support the hypothesis of a protective Hozyasz et al suggest that also microelements can play
effect of  folic acid-containing supplement intake during role in the pathoetiology of clefts, especially low levels of
pregnancy on the risk for oral clefts [58]. zinc, and elevated level of cooper in mother’s serum [65].
It seems that improving our knowledge of the role Authors investigated the relation between concentrations
of nutrition in the pathogenesis of orofacial clefts may of maternal zinc and copper and the risk of an infant being
stimulate the development of nutritional interventions born with an orofacial cleft. The results suggest that asso-
for orofacial clefts prevention in the future. Folic acid ciation between concentrations of maternal zinc and the
fortification in the United States became mandatory risk of orofacial clefts in offspring are noticeable [66].
from January 1st 1998 in order to reduce the occurrence Munger et al reported that poor maternal zinc status
of neural tube defects (NTDs). Yazdy et al evaluated the was a risk factor for OCs in the Philippines, where OC prev-
impact of folic acid fortification on orofacial clefts using alence is high and maternal plasma zinc concentration
United States birth certificate data for 45 states and the (PZc) is low. No such association was found in Utah, what
District of Columbia. Authors compared orofacial cleft suggest that poor maternal zinc status may become a risk
prevalence among births prefortification and postfortifi- factor only when zinc status is highly compromised [67].
cation. According to this study folic acid fortification in According to Tamura et al higher plasma zinc concen-
the United States was associated with a small decrease trations in Filipino women in reproductive age were asso-
in orofacial cleft prevalence, but the decline was much ciated with a lower risk for oral clefts in their children [68].
smaller than that observed for NTDs [59]. Also results Krapels et al in their study demonstrate that zinc and
of Canfield et al study indicated statistically significant myo-inositol are important in the etiology of CL/P, because
decrease in the birth prevalence for cleft  palate, which a low maternal serum myo-inositol concentration (<13.5
suggest some modest benefit from the folic acid fortifica- mmol/L) and a low red blood cell zinc concentration (<189
tion on the prevalence of cleft palate [60]. mmol/L) increased cleft lip palate risk. The cleft lip and
On the other hand it appears that folic acid fortifica- palate children and their mothers had significantly lower
tion had very little or no effect on the prevalence of oral red blood cell zinc concentrations than controls [69].
clefts in infants born in Texas [61]. Maybe geographic According to Huber et al oral clefts did not appear to
factor is related to these findings. be significantly associated with estimated dietary intake
Levels of vitamin intake during pregnancy are also of nitrate, nitrite, and nitrosamines [70].
related with fetus formation, however in some geo- Consumption of drinks such as tea, caffeine, coke
graphic regions normal diet is better than vitamin and other drinks is related in some cases with OFC occur-
supplementation. rence. There are also evidence that tea consumption is
Wong et al suggest that elevated mean serum concen- associated with a reduced odds ratio of both cleft lip with
trations of homocysteine may be a risk factor for having or without cleft palate and cleft palate only. There is also
non-syndromic orofacial cleft offspring [62]. little evidence of an association between caffeine expo-
Munger et al suggest that poor maternal vitamin B-6 sures to clefts when all sources of caffeine are present in
status is associated with an increased risk of cleft lip/ diet [71]. On the other hand Collier et al didn’t suggest an
palate at two sites in the Philippines. They also suggest association between maternal dietary caffeine intake and
that associations between foliate status and CL/P risk orofacial  clefts. The authors claim that caffeine-contain-
appear to be a result of statistical interaction between ing medications require further additional study [72].
foliate, vitamin B-6, and case-control status that produced Bille et al study is focused on the association between
different results in study areas of higher versus lower prev- oral  clefts  and first trimester maternal lifestyle factors
alence of vitamin B-6 deficiency [63]. based on prospective data from the Danish National Birth
For example according to a population-based Cohort (approximately 100,000 pregnancies). Results of
case-control study in Norway between 1996 and 2001 per- this study did not find statistically significant associa-
formed by Johansen et al maternal intake of vitamin A is tions with drinking more than 1 l of cola per week and oral
associated with reduced risk of cleft palate only, and there clefts [73].
is no evidence of increased risk of clefts among women
with the highest 5% of vitamin A intake [64].

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  Risk factors involved in orofacial cleft predisposition   169

8 Medicaments intake during That means the infant exposed in the first trimester of

pregnancy pregnancy to the anticonvulsant drug lamotrigine has an

increased risk to have an isolated cleft palate or cleft lip
deformity [76].
Not only are diet and nutritional factors important for OFC
Puhó et al evaluated the possible association between
predisposition, but also medicament intake is related with
all kinds of drug treatments during pregnancy and iso-
significant OFC risk.
lated cleft lip with or without cleft palate and posterior
In some clinical situations it is necessary for woman
cleft palate in the offspring. Authors confirmed the oro-
to take medicaments during pregnancy. According to FDA
facial cleft inducing effect of phenytoin, carbamazepine,
(Food and Drug Administration) drugs are classified into
oxytetracycline, and thiethylperazine and suggested a
five categories (category A, B, C, D, X), which describe
possible association between orofacial clefts and oxpren-
the potential benefits and risks of use of the drug in preg-
olol and amoxicillin. However authors pay attention to the
nant women. The use of medicaments during pregnancy
fact those drugs may have only a limited role in the origin
requires careful consideration. Some epidemiological
of isolated OFC [77].
studies have explored that relationship between orofacial
To examine whether maternal corticosteroid use
clefts and medicaments during pregnancy is very import-
during pregnancy is associated with delivering an infant
ant. Because of that also additional educational cam-
with an orofacial cleft Carmichael et al performed a study,
paigns are need to take place, for example for reducing
which results suggest a moderately increased risk of cleft
OTC (over the counter) accessible drugs.
lip/palate among women who use corticosteroids during
Bronchodilatators are most often prescribed for the
early pregnancy stages [78].
treatment and control of symptoms of obstructive lung
Park-Wyllie et al suggest that prednisone does not
diseases such as asthma and chronic obstructive pulmo-
represent a major teratogenic risk in humans at therapeu-
nary disease.
tic doses [79]. Corticosteroids are used to treat many dis-
Munsie et al assessed whether mothers who used
eases during pregnancy, such as inflammatory diseases.
bronchodilators during early pregnancy were at an
The association between the risk of orofacial clefts in
increased risk of delivering infants with orofacial clefts,
infants and the use of corticosteroids during pregnancy
and observed a statistically significant association
is still unclear from the available evidence. The results of
between maternal bronchodilator use during the pericon-
the study of Hviid et al did not show an increased risk of
ceptional period and the risk of CLO after controlling for
orofacial clefts after usage of corticosteroids during preg-
other risk factors. However authors pay attention to the
nancy. Investigation of the pattern of association between
fact that it is still unclear whether the increased odds ratio
orofacial clefts and the use of dermatologic corticoste-
observed in this study are due to the bronchodilators,
roids during pregnancy indicated that this result did not
the severity of asthma, or both, or are not related to each
statistically mark out a causal connection and more likely
other [74].
arose from multiple statistical comparisons [80].
Also anticonvulsant drugs were considered to cause
Park-Wyllie et al collected prospectively and followed
an increased risk of clefts, however still other studies are
up 184 women exposed to prednisone in pregnancy and
taking place to fully explain this risk. Data confirming the
188 pregnant women who were counseled for non-tera-
association between diazepam and orofacial clefts risk are
togenic exposure. In study there was no statistical dif-
divergent. Marinucci et al in their review analyze acces-
ference in the rate of major anomalies between the cor-
sible data from international studies investigating the
ticosteroid-exposed and control groups. Authors suggest
combined genetic and environmental causes of cleft lip
a marginally increased risk of major malformations after
with or without cleft palate and describe successes and
first-trimester exposure to corticosteroids. In addition,
limitations in identifying underlying genetic and envi-
summary odds ratio for case-control studies after exam-
ronmental factors. Authors suggest that more studies are
ining oral clefts was significant (3.35 [95% CI 1.97, 5.69]).
needed to characterize the effects of diazepam during
Although prednisone does not represent a major terato-
gestation on the child’s development, particularly on
genic risk in humans at therapeutic doses, it does increase
orofacial clefts [75].
risk of OFC studies performed on animals [81].
Association of another anticonvulsant drug – lam-
On the other hand Bay Bjørn et al performed a preva-
otrigine – with oral clefts was a subject of Holmes et al
lence study of 83,043 primiparous women who gave birth
study who noticed increased frequency of isolated cleft
to a single live-born in northern Denmark, in 1999-2009.
palate in infants exposed to lamotrigine during pregnancy.
Authors did not find evidence of an association between

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170   Agata Kawalec et al.

use of corticosteroids in early pregnancy and risk of con- 10 Occupational factors

genital malformations in offspring [82].
Another group of drugs which is used during preg- Occupational factors related with job and job-related
nancy are antibiotics. According to the study of Mølgaard- factors have a great influence on OFC predisposition.
Nielsen et al who investigated the association between Social factors do not allow every woman not to work
antibiotic use in early pregnancy and the risk of isolated during pregnancy. The environment of working place can
orofacial clefts in a Danish nation-wide cohort study, anti- be a place, where the women are exposed to many factors
biotic use in early pregnancy is not a major risk factor for which can potentially increase risk of oral clefts.
isolated orofacial clefts [83]. On the other hand results of Maternal occupations, which have been reported to
the study performed by Lin et al suggests that maternal use increase risk of oral clefts, are services such as hairdress-
of amoxicillin in early pregnancy may be associated with ing,  agriculture, and leather or shoe manufacturing  as
an increased risk of cleft lip with or without cleft palate for well as exposure to pesticides, lead, and aliphatic acids.
third-gestational-month use [84]. Studies made by Bianchi et al, Garcia et al, Lorente et al,
Wyszynski et al seem to confirm those findings [87, 88, 89,
90].
Bianchi et al in their study performed on data derived
9 Infections from the Florence Eurocat registry surveillance program,
indicates a notable, significant relation between mater-
Viral infections such as HSV are very common and have a nal occupation as a pelt or leather worker and orofacial
great influence in any hereditary disease occurrence. clefts in offspring [91].  The results of a study presented by
Infections of HIV and AIDS in which pregnant women Garcia et al suggest that the mothers who were involved in
require antiretroviral prophylaxis additional approaches agricultural activities during the month before conception
are necessary. The aim of these drugs is to prevent vertical and the first trimester of pregnancy have increased risk
HIV transmission to the offspring from infected mothers. for oral clefts in offspring. The authors consider possible
Association between antiretroviral prophylaxis and risk of association between exposures to pesticides during agri-
oral clefts was investigated. Albano et al and Vassiliki et culture activities [92].
al did not find evidence for increased risk of cleft lip or Romitti et al in meta-analysis consisted of review-
cleft palate among infants exposed to antiretroviral drugs ing 230 studies on pesticides and orofacial clefts confirm
during pregnancy. Vassiliki additionally analyzed 5 years some findings. The results of this meta-analysis suggest
of available data from the Food and Drug Administration’s that maternal exposure to pesticides is associated with a
Adverse Events Reporting System (Medwatch program) modest but marginally significant risk of cleft. The authors
and calculated reporting odds ratios (RORs) and their claim that in order to better understand the relationship
associated 95% confidence intervals. The results suggest between  pesticide  exposure and orofacial  clefts, future
there were infants exposed to antiretroviral drugs (such studies should consider evaluation of multiple routes
as lamivudine, the combination abacavir sulfate/lamivu- of parental exposure, etiologically homogenous pheno-
dine/zidovudine, and nelfinavir, followed by nevirapine, types, and individual genetic susceptibility [93].
lopinavir/ritonavir, and lamivudine/zidovudine) during Organic solvents and other chemicals are often
pregnancy in the Antiretroviral Pregnancy Registry (APR) present in women’s occupational and domestic environ-
and haven’t been born with increased risk of cleft lip or ment. This presence is quite dangerous. Those agents can
cleft palate [85, 86]. be found in both work and in home. That means that iden-
Antineoplastic drugs during pregnancy are associated tification of the agent responsible for specific reproductive
with increased risk of oral clefts. According to this data outcome is difficult. Maybe carefully performed question-
there are evidences regarding the association of medica- naires could be useful.
ments use in pregnancy and congenital malformations in The association between organic solvents and risk
offspring. This subject requires additional researches. of oral clefts was the subject of the study performed by
Chevrier et al. The authors investigated the role of mater-
nal occupational exposure to organic solvents at the
beginning of pregnancy in the risk of non-syndromic oral
clefts. Authors collected data from a case-control study
conducted in France between 1998 and 2001 at seven
hospitals. The results suggest that the risk of oral clefts

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  Risk factors involved in orofacial cleft predisposition   171

increases linearly with level of exposure within the three 11 Conclusion

subgroups of oxygenated solvents–aliphatic alcohols,
glycol ethers, and other oxygenated solvents (including We conclude that there are many factors, which can be
esters, ketones, and aliphatic aldehydes) [94]. involved in OFC predispositions. Many of them require
Laumon et al in their case-control study conducted in additional research to confirm their significance in etiol-
the Rhône-Alpes region of France during the years 1985 to ogy of these orofacial malformations. Also a quite import-
1989 compared maternal exposure to any organic solvent ant matter in OFC is an adequate and precise measuring
between 200 infants with cleft lip and/or cleft palate and device of etiology and occurrence of OFC while using a
400 controls. Both groups were compared to exposures special data base performed just after delivery of new-
to nine subgroups of  solvents. They found association borns would be highly useful. In many cases lack of doc-
between halogenated aliphatic  solvents and oral clefts umentation and proper medical examinations leads to
[95]. misinformation and misdiagnosis , both very important
Pregnant women working during pregnancy might factors in OFC management.
be potentially exposed to different risk factors. During Improving our knowledge about the risk factors and
years and civilization expansion and advancement more potential risk factors leading to oral clefts can be very
risk factors had occurred. The study of Lorente et al was useful in their prevention Education of future mothers
performed to investigate the role of maternal exposures about behaviors before and during pregnancy, which can
at work during pregnancy and the occurrence of oral increase the risk of oral clefts is very important. It might
clefts. The authors examined occupational exposures of cause decrease in the OFC occurrence and improve local
851 women (100 mothers of babies with oral clefts and health systems, however lack of information and people’s
751 mothers of healthy referents) who worked during the lack of education might have a great impact on OFC.
first trimester of pregnancy. All data was analyzed. The The parent’s attitude in OFC patients and their
women were part of a multicenter European case-referent response to prognosis and treatment is very important.
study conducted using 6 congenital malformation regis- Most parents do not perceive oral clefts as a severe con-
ters between 1989 and 1992. Analysis suggests that occu- dition and they didn’t consider the termination of preg-
pational exposures such as aliphatic aldehydes, glycol nancy because of OFC in the offspring. Because of a great
ethers, lead compounds, biocides, antineoplastic drugs, but long term treatment of OFC the patient’s quality of life
trichloroethylene, and aliphatic acids are associated with can be greatly improved if treatment takes place just after
orofacial clefts [96]. childbirth and lasts almost their entire life.
Although results of many studies suggest that mater- On the other hand the real vision of future life of the
nal occupational exposure to organic solvents during child with OFC is not so optimistic. The children require
pregnancy may lead to increased risk of oral clefts, these a multidisciplinary approach. Also complications are
results should be interpreted cautiously, because of multi- common. Among complications which are connected with
ple exposures during pregnancy. OFC are: chronic glue ear, hearing loss, soft palate muscle
Environmental factors considered to be risk factors of malformation which influence hearing, speaking and
orofacial clefts are electromagnetic fields and also other swallowing, dental cavities with displaced teeth or lack of
light and electric sources that after long exposure might teeth, poor speech and quite often the value of problems
be dangerous. related with OFC are not related to the size of the defect.
Shaw et al investigated whether the periconcep- Nasal breathing, articulation, rehabilitation of occlusion
tional use of electric blankets, bed warmers, or electri- often require treatment until the end of maturation.
cally heated waterbeds increases the risk of women to It is also important for physicians to educate the
deliver infants or fetuses with orofacial clefts. The results patients and prescribe medicaments if necessary with low
suggest that women, who reported more frequent use of teratogenic risk. Without proper drug administration and
a bed-heating device, or longer duration of use, did not not referring to physician recommendations, some com-
appear to have a higher risk for delivering offspring with plications connected with OFC might occur.
anomalies than were women who reported less frequent The results of many studies are divergent. Further
or shorter-duration use [97]. understanding of environmental risk factors in different
geographic and ethnic regions requires more study.
Next challenges are related with continuation of
European and national programs not only helping

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172   Agata Kawalec et al.

Inherited Craniofacial Skeletal Morphology. The Cleft Palate-

patients with OFC but also gathering socio-geographical
Craniofacial Journal. 2004; 11, 41; 613-621
data and their evaluation. [16] Wang W, Guan P, Xu W, Zhou B. Risk factors for oral clefts: a
Patients suffering from orofacial clefts have decreased population-based case-control study in Shenyang, China.
functioning levels because of malocclusion, biting prob- Paediatr Perinat Epidemiol. 2009; 7; 23(4):310-320
lems, hipodontia and other co-existing problems. Facial [17] Bille C, Skytthe A, Vach W, Knudsen LB, Andersen AM, Murray
JC, Christensen K. Parent’s age and the risk of oral clefts.
aesthetics, social acceptance and well-being are related
Epidemiology. Am J Hum Genet. 2007; 1; 80(1): 76-90
with their quality of life, self-acceptance and contacts [18] Butali A, Mossey P. Epidemiology of orofacial clefts in Africa:
with others. Multidisciplinary approachs with long-term Methodological challenges in ascertainment. Pan Afr Med J.
treatment are very important to improve health and life. 2009; 2:5
[19] Adetayo O, Ford R, Martin M. Africa has unique and urgent
Conflict of interest statement: Authors state no conflict barriers to cleft care: lessons from practitioners at the
pan-african congress on cleft lip and palate. Pan Afr Med
of interest
J. 2012; 12: 15
[20] Adetayo OA, Martin MC. Demographics of cleft care providers
in Africa and reported experience in training and practice:

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