RESEARCH ARTICLE Open Access

Epidemiological characteristic of Orofacialclefts and its associated congenitalanomalies: retrospective studyA. Impellizzeri1, I. Giannantoni2, A. Polimeni3, E. Barbato4 and G. Galluccio5*

Abstract

Background: To evaluate the relationship between gender, ethnicity/citizenship, clinical phenotype, totalprevalence, and the various congenital malformations associated with oral clefts (OC) in Italy across the period2001–2014.

Methods: A retrospective analysis (2001–2014) was conducted based on the National Congenital MalformationRegistries network of Italy (Emilia-Romagna Registry of Birth Defects [IMER] and Registro Toscano Difetti Congeniti[RTDC]), which were analyzed to investigate time trends, geographical/ethnic clusters, topography, sex ratio, andassociated congenital anomalies of OC phenotypes.

Results: Among 739 registered cases, 29.8% were syndromic or had multi-malformed associated anomalies,compared with 70.2% having isolated orofacial cleft. Cleft lip (CL) was observed in 22%, cleft palate (CP) in 40%, andcleft lip and palate (CLP) in 38% of live births, stillbirths, and terminations of pregnancy for fetal anomaly cases.Other associated conditions were major anomalies of cardiovascular defects (39%), followed by defects of the limbs(28%), neuroectodermal defects (23%), and urogenital malformations (10%).Male-to-female sex ratio was 1:1.14 in CP, 1.22:1 in CL, and 1.9:1 in CLP. Foreigners were represented by 29% fromSoutheast Asia, 25% from Balkans, 25% from North-Central Africa, 9% from the East, 7% from Western Europe, and5% from South America. Total prevalence of OC cases ranged from 0.9 (RTDC) to 1.1 (IMER) of 1000 births.

Conclusions: This retrospective study provides a population-based, clinical-epidemiological description of theorofacial cleft phenomenon. As a relatively frequent congenital malformation, its social and economic impact isworthy of further study. These abnormalities can cause significant problems that may be solved or minimized byearly diagnosis and treatment.

Keywords: Cleft lip, Cleft palate, Epidemiology, Ethnicity, Gender, Prevalence, Longitudinal register study

BackgroundIn Europe, according to significant studies, the combinedbirth prevalence of cleft palate (CP) and cleft lip (CL) withor without CP is approximately 1 per 700 live births, withethnic and geographic variation [1]. Orofacial cleft is oneof the most frequent congenital anomalies, with a higherbirth prevalence than neural tube defects, but lower thancardiovascular malformation [2]. Based on the dataavailable in Italian registries of congenital malformation

anomalies, the aim of the present study was to evaluatethe relationship among gender, ethnicity, and citizenshipand to delineate a topographic and more specific pheno-typical distribution of oral cleft (OC) and the variouscongenital malformations associated with it. Therefore, inaddition to the results deriving from European Surveil-lance of Congenital Anomalies (EUROCAT), the examdata are provided by the two abovementioned registries,ranging from 2001 to 2014. The choice to analyze datafrom only two regional malformation registries existing inItaly originates from the need to analyze in detail andprovide a complete overview of the anomalies detected inthe population. Both the Italian regions evaluated in the

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

* Correspondence: gabriella.galluccio@uniroma1.it5Department of Oral and Maxillofacial Sciences, “Sapienza” University ofRome, Rome, ItalyFull list of author information is available at the end of the article

Impellizzeri et al. BMC Oral Health (2019) 19:290 https://doi.org/10.1186/s12903-019-0980-5

http://crossmark.crossref.org/dialog/?doi=10.1186/s12903-019-0980-5&domain=pdfhttp://orcid.org/0000-0002-6876-8839http://creativecommons.org/licenses/by/4.0/http://creativecommons.org/publicdomain/zero/1.0/mailto:gabriella.galluccio@uniroma1.it

registers are located in the central area of the country andcover about 17% of the total of the Italian population, fora total of 9.5 million of people.Our data may provide references for appropriate re-

sources to establish and direct counseling and primarypreventive projects, given the social and economic publichealth care burden represented by OCs, based onspecific national data.Currently, Italy does not have a structured national

Congenital Malformations (CM) surveillance system,which is limited to some Italian Regions that employdifferent methodological aspects and gather Epidemio-logical data related to CM in a number of regionalregistries, therein the difficulty to obtain a nationalprevalence rate. The data set does not permit to observeprevalence trends and the impact of specific preventiveactions and the quality of epidemiological data needs tobe implemented. However, such registries permit tofollow the monitoring of about 400.000 newborns/year(70% out of all newborns in Italy However, given thepossibility of variations in the detection systems, the datareported in the national registers should be analyzedwith caution.In order to increase the sharing of data between the

different existing databases, within the National Centerfor Rare Diseases (CNMR) a central coordination unit(CM) is present, whose duty is to achieve methodo-logical uniformity, cooperation and control of the qualityof the data collected.The CM is composed of the leaders of the various reg-

isters, representatives of the Italian Ministry of Healthand the Italian National Institute of Statistics and has asits ultimate goal the creation of a national data collec-tion center. A single center of National collection wouldgreatly improve the quality of epidemiological surveil-lance of the Congenital Malformations. The latter repre-sent 5% of the living born, when you consider that themiscarriage involves the 10–25% of pregnancies, andtherefore are of great interest from an economic andsocial point of view. The mortality rate pursuant to MCis high, and so are the consequences related to clinicalseverity and complications.Furthermore, since chemicals, environmental pollution

and drugs can be linked to teratogenicity, the import-ance of epidemiological surveillance is linked to the pos-sibility of using the MC as early biological markers forenvironmental and pharmacological toxicity. The MCsurveillance, in fact, provides an evaluation of the effectof the alleged etiological factor to which the populationhas been exposed 6–8 months before the event. It, there-fore, follows that the CM of surveillance is essential tocontrol the frequency and temporal trends of the condi-tions, with the ultimate aim to evaluate etiological fac-tors and related risk.

The definition of Congenital Malformations is that ofthose defects characterized by a functional, structural,morphological, positional anomaly of a single organ orpart of it, or even of a large section of an anatomicaldistrict, mainly macroscopic, that has happened beforebirth. Structural and functional defects generally occurduring the prenatal development and can usually berecognized at birth; however, in a minority of cases, thedefects are seen and diagnosed clearly afterwards, even ayear after birth. Therefore, since the follow up a yearafter is not mandatory, several cases can be misclassifiedor undiscovered and consequently not included in thecongenital register’s annual report.The CM, if taken singularly, represent rare events, but

the entire category from the mild to the severe formsaffects about the 3–5% of the live births, depending on themodality and capacity of the diagnostic ascertainment, theinclusive/exclusive operative criteria of the cases or theextension range of surveillance time. The prevalence ofthe structural defects that alone are evident within the firstweek of life after birth is assessed at 2%. The prevalence atbirth of all the congenital defects has a merely indicativevalue: in fact, it has to be considered that not all the casesare reported due to the spontaneous fetal abortion orinterrupted pregnancies. The latter ones represent a rele-vant portion of more severe malfomative cases such as thedefects of the neural tube, that nevertheless can be diag-nosed very precisely in advance. The same can be said ofpostnatal diagnosis, since some of the congenital malfor-mations that cannot be outlined at birth are oftendiagnosed during puberty or in adult age, such as cardio-vascular and genital malformations. The CM are respon-sible of 20–25% of deaths at birth, 45% of perinatal deaths,and 3–4% of infant deaths: namely, in the first case thedeath occurred after the 28° week of childbearing; the sec-ond case consists in the sum up of the tardy fetal deathand early neonatal death within the first week of life; andlastly the third case concerns the sum of the early neonataldeath (within 7 days of life), tardy neonatal death (from8°to 28°day) and post-neonatal death (from 29° to 365° dayof life). In the last decades, overall prevalence and fre-quency trends have decreased, but they have raised interms of infant morbidity and severe handicap.The aim of the present study was to evaluate the rela-

tionship among gender, ethnicity, and citizenship and todelineate a topographic and more specific phenotypicaldistribution of oral cleft (OC) and the various congenitalmalformations associated with it. It was also an oppor-tunity to investigate the structure and coordination ofnational regional congenital malformation registers.

MethodsA population-based retrospective study was carried outon data drawn from the Emilia-Romagna Registry of

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 2 of 14

Birth Defects (IMER; Azienda Ospedaliera-Universitariadi Ferrara) and the Registro Toscano Difetti Congeniti(RTDC) that reported to EUROCAT between 2001 and2014.The research has been conducted in full accordance

with the ethical principles of the World Medical Associ-ation Declaration of Helsinki. The data have been takenby different operators from the RTDC and IMER be-cause these regional registries have a common epidemio-logical methodology in collecting malformation cases;their data are well structured and organized, assuring alarge number of information on each individual usefulfor statistical analysis, thus providing reliable and high-quality statistical projections. The study covered theperiod between 2001 and 2014 because of the accessibil-ity of the surveys of the two registries, which were madepublic after 3 years. Epidemiological evaluation of OCswas drafted according to the following selected denomi-nators (registers of provenance):

� Type of event (live birth, stillbirth, or termination ofpregnancy for fetal anomaly [TOPFA])

� Citizenship of the mother,� Clinical diagnosis and other associated multiple

congenital anomalies (MCAs)� Descriptive clinical phenotype of each case� International Classifications of Disease (ICD) 9 or

ICD10 code� Sex

The ICD Codes is a free medical coding resource fea-turing a powerful search tool, code converters, brows-able indexes and coding references. The numbers 9 or10 indicate the update revision number.All data were standardized to the current ICD10BPA

code system embraced by the International Clearing-house for Birth Defects, as all data inserted with the pre-vious ICD9 code have been converted to the new onesaccording to specific tables; those data lacking a morespecific code have been reassigned according to the clin-ical phenotype described by the single collector-clinicianand fed into the ICD10BPA code system and its subclas-sifications, as illustrated in Table 1 and 2.

The data were interpolated and processed by statisticalsurvey and analysis according to the previous parame-ters, producing:

1. sex ratio and cleft phenotype distribution,2. Type of event subset and time-trends prevalence of

OCs,3. Laterality of CLP and Anatomical topography of OCs4. Isolated /Multiple Congenital Anomalies (MCAs)5. Citizenship/Ethnic group rates in OCs

The definition of citizenship is related to the actual stateof attribution of the Italian nationality, which is only givento people born from Italian parents. (iure sanguinis).

ResultsThis retrospective, population-based study was con-ducted from the RTDC and IMER between 2001 and2014. The research identified a total amount of 739cases out of 709.068 total births. All 739 collected caseswere so provided: 506 OC cases, including live birthsand stillbirths out of 404,360 total births surveyed fromIMER and 277 OC cases including live births and still-births out of 304,708 births surveyed from the RTDCdatabase of all syndromic and non-syndromic cases ofOC observed between 2001 and 2014. The analyzed pa-rameters and interpolated data produced the subsequentresults and graphic reports, here reported in the orderindicated in the material and methods section.

Sex ratio and cleft phenotype distributionEvaluating the distribution of OCs, we noted an unex-pected 40% prevalence of CP cases over 38% of CLPcases and 22% of CLs (as displayed in Table 3), whichassessed and confirmed the female prevalence in CP (1:1,14) in spite of the male predominance in the CL (1,22:1) and CLP (1,9,1) groups (Fig. 1).

Type of event subset and time-trends prevalence of OCsOccurrence prevalence rates of OCs in live births, still-births, and TOPFA are reported in Figs. 2 and 3.The proportional-rates diagram of ascertained events

regarding both registers outlines the low percentage of

Table 1 ICD10BPA code system for Birth Defects, and its sub classifications

ICD10BPA code system

Orofacial cleft 749,000–749,090 Q35 - Q37

749,100–749,190

749,200–749,290

CL with or without palate 749,100–749,190 Q36, Q37

749,200–749,290

CP 749,000–749,090 Q35 excluding CL association[Q36-Q37] 749100–749,290

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 3 of 14

stillbirths despite the number of live births and TOPFAcases. Overall, the CL + CLP and CP proportional ratesfound in the casuistry (data recording by our study)amounted to 87.7% of the ascertained cases for livebirths, 0.88% of stillbirths (5 out of 739), and 11.12% ofTOPFA (specifically, a total of 49 over 506 cases werereported from IMER, whereas 29 over 277 cases ofTOPFA were brought in by the RTDC data report).Prevalence rates of single OC categories were thus

derived: ‰.

– 0.9 × 1.000 live births, 0.014 × 1.000 stillbirths and0.13 × 1.000 TOPFA for IMER.

– 0.8 × 1.000 live births, 0.003 × 1.000 stillbirths and0.09 × 1.000 TOPFA for RTDC.

Total prevalence of OC cases ranged from 0.9 (RTDC)to 1.1 (IMER) × 1.000 total births.

Laterality of CLP and Anatomical topography of OCsExamining the anatomical distribution of CLP cases in termsof side or site affected, we have calculated an average of thisvalues and we found that 13% of the CLP cases were bilateral,compared to 87% unilateral, with a right-to-left ratio of 1:3.The anatomical topography of congenital malformation

was noted as follows: CL was observed in 22% of cases, CPin 40%, CL and palate (CLP) in 38% of live births, still-births, and TOPFA. The degree of involvement withregard to CP may vary and be subtle, from a sub-mucouscleft to a cleft of the hard or/and soft palate to a cleftextending to the incisive foramen. In our study, CP wasfound in 38% of all the employed OC datasets, topograph-ically subdivided as shown in Fig. 4. The anatomical distri-bution of the observed phenotypes of CP (Q.35) includesthe following subgroup: Cleft of the hard palate identifiedby Q.35.1 in 41% of cases; cleft of the soft palate Q.35.3, in28% of cases; cleft of the uvula Q.35.7, in 2% of cases; cleftof both hard and soft palates (complete) Q.35.5, in 9% ofcases; and CP NOS Q.35.9 in 20% of cases. Prevalence ofthe latter category is due to an NOS diagnosis of theclinical phenotype by the single clinician who reported thecase having impinged data quality (Table 4).

Isolated/Multiple Congenital Anomalies (MCAs)As shown in Table 5, the overall collected data weredivided into 29.8% syndromic and multi-malformed

Table 2 Q.35; Q.36; Q.37. ICD10BPA code system of OCs

Q.35 CP (including palatal fissure)

Q.35.1 Cleft Of Hard Palate

Q.35.3 Cleft Of Soft Palate

Q.35.5 Cleft Of Hard And Soft Palates

Q.35.7 Cleft Of Uvula

Q.35.9 Cleft Of Palate, Nos (Not Otherwise Specified)

Q.36 Cl (Incl. Harelip, Congenital Fissure)

Q36.0 Cleft Lip, Bilateral

Q.36.1 Cleft Lip, Unilateral

Q.36.9 Cleft Lip, Nos

Q.37 CL And Palate (CLP)

Q.37.0 Cleft Hard Palate With Bilateral Cleft Lip

Q37.1 Cleft Hard Palate With Unilateral CL (Incl. Cleft Hard Palate With CL NOS)

Q.37.2 Cleft Soft Palate With Bilateral Cleft Lip

Q.37.3 Cleft Soft Palate With Unilateral CL (Incl. Cleft Soft Palate With CL NOS)

Q.37.4 Cleft Hard And Soft Palates With Bilateral Cleft Lip

Q.37.5 Cleft Hard And Soft Palates With Unilateral CL (Incl. Cleft Hard AndSoft Palates With CL (NOS)

Q.37.8 Unspecified CP With Bilateral CL

Q.37.9 Unspecified Cleft Palate With Unilateral CL (Incl. CP With CL NOS)

Table 3 Sex and topographic distribution

Sex CL CP CLP

Males 82 125 171

Females 67 143 90

Total (678) 149 (22%) 268 (40%) 261 (38%)

Sex ratio (M:F) 1.22:1 1:1.14 1.9:1

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 4 of 14

anomalies associated with OC, compared with 70.2% iso-lated OCs.The highest birth prevalence among isolated OCs was

found to be CP - not including Pierre Robin (PR) se-quence - which might be considered a syndromic com-plex because of its high association (59.6%) withobstructive sleep apnea respiratory problems [3]. Evenconsidering CP to be isolated, it would still represent thesecond most frequent isolated cleft type of OC (afterCL/P), followed by CLP and CL taken separately. Amongall multi-malformed, chromosomal, and syndromicforms, CLP had the highest rates (50%), followed by CP(35%), and CL as the lowest (15%).Among multi-malformed Infants with OC (CP, CL,

and CLP) and others - recognized as having congeni-tal or specific syndromic pathology - we have tracedthose who presented various associated major anomal-ies and sorted out subgroups of malformations in-cluding limbs, eyes, ears, nose, skin, and the followingsystems: cardiovascular, urogenital, respiratory, gastro-intestinal, musculoskeletal, and CNS (Table 6). Thefour major, and most represented, statistical categor-ies were cardiovascular defects, urogenital malforma-tions, defects of the upper and lower limbs, andneuroectodermal defects. As shown in Fig. 5, the firstgroup represents 39% of all malformations and in-cludes intra-atrial and intraventricular septum defects,transposition of great vessels, permeable foramenovale, Fallot’s tetrology, and single umbilical artery.The second group, representing 10% of the overallanomalies, involves such malformations as crypt-orchidism, hypospadias, and anorectal atresia. The

third group, with 28% of the anomalies, includes poly-dactyly, clinodactyly, syndactyly, congenital club foot,and agenesis or aplasia of the limbs. The fourth, andfinal, group (23%) includes other associated anomaliesof specific syndromic forms and subsumes ventriculo-megaly, holoprosencephaly and anencephaly, partialagenesis of the corpus callosum or cerebellum, thusexcluding minor or less statistically relevant systemdefects. Table 6 analyzes each parameter in detail.Note that if an infant had more than one defect in the

same organ system, the infant would be counted separ-ately for each system affected. Overall organ systems arenot mutually exclusive.The most common additional major defects found

among infants with CL, counting once for each case ifthere were multiple malformations in the same category,were CNS and limb defects - almost equally propor-tioned (25%) - followed by congenital heart malforma-tions (21.4%), defects of the face and ears (10.7%),urogenital and gastrointestinal defects (7.1% each), andeyes and musculoskeletal defects (3.6%).On the other hand, CP patients had a cardiovascular

defects rate of 28.1%, followed by limbs (18.7%), urogeni-tal (13.5%), and CNS (12.5%) defects. The rest are sharedby the eyes (10.4%), face and ears (8.3%), respiratory(5.2%), and musculoskeletal (3.1%) defects.CLP patients showed a prevalence of cardiovascular

defects (27.3%) and limbs and CNS defects equally pro-portioned (21%), followed by relevant urogenital malfor-mations (10.9%), and other minor organ-system defectssuch as ear (7%), eye (5.5%), gastrointestinal(4%), muscu-loskeletal (2.3%), and respiratory (0.78%).

Fig. 1 OC sex ratio

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 5 of 14

Therefore, almost 43% of the specified MCAs werecardiovascular defects, followed by limb defects (28%),CNS malformations (27%), and urogenital defects (25%),the remainder distributed among the remaining categor-ies: ear-face defects, eye defects, gastrointestinal anomal-ies, and integumental defects. Those rates were ignoredbecause all the categories are not mutually exclusive andcan be variously combined in single cases.A further consideration pertains MCAs and chromosome-

related and unrelated syndromes.Indeed, the last group taken into consideration in-

cludes all the specified syndromes, chromosome abnor-malities and single-gene disorders, in addition to aheterogeneous group of associated single and multiplecongenital malformations.Table 7 shows the distribution of the syndromic and

the congenital- and multi-malformed associated anomal-ies of the OCs; the remaining non-isolated cases thatexhibited minor or mild congenital features such as

hypertelorism, auricular annex, and microphthalmiawere counted together as MCAs.As already seen in Table 6, it has to be underlined that

CLP was the most frequent cleft type found in infantswith chromosomal abnormalities (27 of 40 cases), whileCP prevails slightly over CLP in non-chromosomal syn-dromes/sequels, among which MCA (first) and PierreRobin sequence/syndrome (PR) (second) were the mostcommonly observed. It must be emphasized that theremaining associated anomalies (112) could still presentundetected chromosomal defects not yet ruled out. Theinclusion of PR syndrome in the CP group increased thechances of having additional malformations. PR syn-drome is a set of abnormalities affecting the head andface, consisting of a small lower jaw (micrognathia), atongue that is placed further back than normal (glossop-tosis), and blockage (obstruction) of the airways. Thiscondition is described as a “sequence” because one of itsfeatures, underdevelopment of the lower jaw (mandible),

Fig. 2 Occurrence prevalence rates of OCs in live births, stillbirths, and TOPFA

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 6 of 14

Fig. 3 Cleft lip with/without palate for 10.000 births

Fig. 4 CP clinical patterns

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 7 of 14

sets off a sequence of events before birth that cause theother signs and symptoms.Considering the relationship between MCA and OC

phenotypes, CL/P represented 63% compared with the37% found in CP cases. The MCA group was the largest:112 cases, of which 52% were non-isolated OCs; 15.19%of the overall OCs. Among OCs with MCAs, four casesof MCA have been specifically recognized as being con-sequent to maternal diabetes (not identifying whethertype 1 or 2 or gestational diabetes). Even though ourcase sample was too small to assess the odds ratio, it stillsupports the premise that maternal diabetes should beincluded as a risk factor for MC [5];.

Citizenship/Ethnic group rates in OCsInsofar as the mother’s citizenship in the single cases ofOC was concerned, 501 of the 739 global cases wereItalian, 155 were foreign, and 83 did not declare theircitizenship (respecting the privacy policy of each insti-tute) (Fig. 6).Foreigners were represented as follows: 29% from South-

east Asia (including China, The Philippines, India, Bhutan,Pakistan), 25% from the Balkan Peninsula (Serbia, Albania,Bosnia-Herzegovina, Macedonia, Romania, Bulgaria, andHungary), 25% from north and central Africa (Morocco,Nigeria, Congo, Benin, Egypt, Tunisia, Senegal, and BurkinaFaso), 9% from eastern Europe (Poland, Ukraine, Russia,Belarus, Lithuania, and Moldavia), 7% from western Europe(Germany, Spain, France, Republic of San Marino, and TheNetherlands), and 5% from Latin America (Cuba, Brazil,Peru, Ecuador, and Colombia) (Fig. 7).

DiscussionThe current study gathered population data pooledfrom two of the National Congenital MalformationRegistries networks, IMER and RTDC, to evaluate theepidemiological characteristics of OC and its associatedcongenital anomalies in 739 collected cases in terms ofprevalence, topography, sex ratio, and ethnic clusters.Considering the OC phenotype distribution assessed inthis study, most authors have found a similar predom-inance of CLP over CL [6–11]. The prevalence of CPcases may vary, probably due to methodological differ-ences, such as referral sources and age of patientexamined, as reported by Genisca in 2009 [12]. CP phe-notypes, such as submucous CP, are usually less fre-quently detected by clinicians in infants than in olderpatients, as it was found in 43% of the CP cases in aprevious study [13].Females predominated in CP (M:F, 0.8:1) and males

predominated in CL/P (1.5: 1); these are characteristicand consistent features reported in European and world-wide datasets [14] . The same gender prevalence for OCcategories, as illustrated in Fig. 3, was found in Genisca’sstudy [12], whose results are consistent with those ofother studies showing that CL and CLP were moreprevalent among males, while CP was more prevalentamong females; this tendency was also demonstrated byother authors [15–18]. The latter gender difference isparticularly remarkable in PR syndrome (CP, glossopto-sis, and micrognathia) patients, where it was found, inaccordance with other international studies, that females(71%) significantly prevailed over males (29%) [19, 20].Suspecting a genetic basis, researchers investigated agenomic region regarding PR etiology: SOX 9 gene(17q23), which is indeed involved in determining sexregion SRY [21]. Since this gender dissimilarity is wellconfirmed, with the sex ratio in the previously quotedliterature ranging from 1.3 to 1.5 for CL/P and 0.8 forCP, it was suggested that different etiopathogeneticmechanisms concerning CL/P and CP be hence sub-tended. The frequency of diagnosed PR cases was re-ported to be 13% of all CP cases, which was a lowervalue than those found by Genisca (23%) and Doray(21%) [12, 22].

Table 4 Percentage of Associated congenital anomalies in OCs, MCA NOS: Multiple Congenital Anomalies Not Other Specified

Clinical phenotype Isolated Syndromes Multi-malformed Chromosomal

Relative percentage

Cleft lip (CL) 118 (84%) 3 (2%) 15 (10.7%) 4 (3%)

Cleft palate (CP) 192 (68%) 46 (16%) 38 (13%) 7 (3%)

CL and palate (CLP) 166 (64.5%) 14 (5.5%) 50 (20%) 25 (10%)

Subtotal (over 678) 476 (70%) 63* 103* 36*(tot 29.8%)

*represent the relevant value in the table

Table 5 Percentage of Syndrome patterns in OCs

Clinical phenoptype Isolated Syndromes Chromosomal

Relative percentage

Cleft lip (CL) 129 (25%) 4 (2%) 5 (2.3%)

Cleft palate (CP) 209 (40%) 49 (22%) 8 (3.7%)

CL and palate (CLP) 181 (35%) 15 (7%) 27 (13%)

Subtotal (over 739) 519 68* 40*

(70,2%) (tot 29.8%)

*represent the relevant value in the table

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 8 of 14

Table 6 Major anomalies associated with Oral Clefts taken using the Statistical Monitoring Protocol 2012 -link EUROCAT DataManagement Program (EDMP)

Major associated anomalies CL21

CP63

n n

Anencephaly 2 1

Spina bifida – –

Microcephalus/Hydrocephalus – –

Absence of corpus callosum – 1

Defects of the central nervous system (CNS) Other brain defects (ventriculomegaly, encephalocele.etc.) 3 4

Defects of eyes

Anophthalmia/microphthalmia 1 4

Hypertelorism 1 2

Coloboma – 3

Others 2

Defects of ear/nose (Low ear attachment, microtia, etc.) 4 3

Defects of the respiratory system (Laryngomalacia, pulmonary artery ectasia, etc.) – 3

Ventricular septal defects – 16

Cardiovascular defects Atrioventricular septal defects – 2

Other cardiovascular defects 8 8

Defects of the digestive system Atresia, microgastria, omphalocele 4 –

Defects of the urogenital system Polycystic kidney – –

Hypospadias (2nd or 3rd degree) – 2

Cryptorchidism – 5

Anorectal atresia/stenosis – 4

Other urogenital defects 1 6

Defects of the limbs Polydactyly/syndactyly/agenesis 3 14

Clubfoot 4 7

Other congenital defects of the limbs 4 4

Musculoskeletal defects (Vertebral / rib defects,craniosynostosis, dysplasia, etc.) 1 5

Defects of the integument Cystic hygroma, hypoplasia cutis – 1

Fig. 5 Distribution of associated system anomalies

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 9 of 14

Table 7 The distribution of the syndromic and the congenital- and multi-malformed associated anomalies of the OCs

Diagnostic groups Diagnosis CL CP CLP

Chromosome anomaly Syndromes (Tot. 40) Trisomy 13 (Patau) – 5 11

Trisomy 18 (Edwards) 2 1 1

Trisomy 21 1 – 2

Deletion 22q (DiGeorge) – – 1

Deletion 4p16 1 – –

47xxy – 1 2

46xxr – 1 –

Other subtelomeric rearrangments – – 4

Syndromes without chromosome anomalies (Tot. 68) Syndrome with arthrogryposis – 2 + 1 1

Moebius, Beals

Meckel-Gruber – – 1

Van der Woude – 2 –

Binder 1 – –

Holoprosencephaly 1 3 10

Fraser 1– – –

Goldenhar 2 2 3

Kabuki – – –

Treacher-Collins 3 –

Syndrome Sequence with genetic anomalies Pierre Robin – 35 –

Malformation/complex (Tot. 112) MCA 16 39 53

MCA–related maternal diabetes 3 1

Totals 26 98 90

Fig. 6 Mothers’ citizenship distribution

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 10 of 14

As often seen in other descriptive studies [7, 23, 24],among infants with CLP, if cleft was specified as unilateral,about two-thirds were left-sided. One possible explanationis that the blood vessels supplying the right side of thefetal head leave the aortic arch closer to the heart and thusthe right-sided structures are better nourished than thoseon the left, as proposed by Johnston [25].Non-syndromic, isolated OCs represented about 70%

of cases; this prevalence was also observed by Stoll andGenisca [12, 26]. Overall, the frequency of associatedanomalies to OCs prevailed in the CL/P phenotypegroup (21.6%), in line with a similar study by Croen(2007) showing that most CL/P cases (56% over 44% ofCP-MCA; mainly CLP rather than CL), were associatedwith congenital multi-malformations, but in minor pro-portion to the 34% found by Calzolari [11] in an analysisof 21 years of EUROCAT and the 28% referred byMilerad [27] . Others investigating the chromosomalabnormality and syndromic rates for CL/P and CP con-firmed the results [5, 9, 13, 28, 29].The small sample of stillbirths was found to have a

high association with other congenital malformations[3], related to CL/P in 67% of cases, but contrasting withthe findings of Shaw [9], who observed similar patternsfor both CP and CL/P. In fact, only 21.4% of stillbirthcases were confirmed as isolated and 9.5% were purelychromosomal anomalies, whereas the remaining 69.1%were associated with at least one other congenital mal-formation, thus emphasizing the fact that monitoringMCA- and OC-affected infants is important, especiallysince they are the most sensitive and reliable indicatorsof teratogenic environmental risk. Not surprisingly, re-searchers have for many years recognized that many ofthe known human teratogens induce MCA phenotypes ra-ther than isolated phenotypes [30]. Previous observershave suggested that infants with two or more congenitalanomalies are worthy of study because multiple

malformations in a child are “the most sensitive indicatorsof environmental teratogenic agents and such anomaliesare responsible for a considerable part of infant mortality,”according to Czeizel [10]. In our study, the most commondefects associated with CL were those of the limbs, heart,and other musculoskeletal sites, which is similar tocorresponding descriptive, epidemiological studies of OC[11, 31, 32], whereas defects of the heart, limbs, urogenitalsystem, and CNS were most often observed among infantswith CP. These findings are in contrast to CLP patientswho showed higher rates for these systems, resembling re-sults found by Genisca [12]. The close association betweenOCs and congenital cardiovascular defects is not surpris-ing considering the contiguity of the pericardial area (aor-tic arches of the primitive heart) and the facial processes(pharyngeal arches) of the embryological sites. Therefore,clinicians who take care of such patients should be awareof these observations and carefully screen OC infants todetect these conditions early, especially for cardiovasculardefects, which are the most frequently associated defectsfound at older ages [33]. In fact, Rittler revealed that 7.2%of OC infants were reclassified as having MCAs (especiallycardiovascular defects) at 1-year follow-up [13].Jamilian et al. found that 38% of cleft lip and/or palate

patients suffered from congenital heart disease but only2% of control groups had congenital heart disease andthe majority CL/P patients were born with congenitalabnormalities and physical anomalies. Furthermore,42.2% of the 187 patients suffering from oral clefts in-cluded in their study were subjects with blood group A[34]. This finding corresponds with the findings ofChzhan and Khen who found that congenital clefts ofthe upper lip and palate are most frequent in subjectswith blood group A. Therefore, Blood group A may beconsidered as a factor of risk of developing this condi-tion [35]. Other factors such as history of clefts, folicacid consumption and consanguineous marriage were

Fig. 7 Maternal citizenship distribution

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 11 of 14

strongly associated with increased risk of CL/P. Prenatalscreening and genetic tests are strongly recommended inthese high-risk groups. Therefore, echocardiographyshould be a proposed examination in the evaluation ofchildren with cleft palate before surgical correction [36].Among nine specific detected chromosomal anomalies,

36 cases were found globally (5.5% of all OC clinical re-cords), whereas Trisomy 13 (14 cases) prevailed over Tri-somy 18 (10 cases) and Trisomy 21 (3 cases) and theabove prevailed over all the others of the category. CL/Pcases were by far the most represented in this diagnosticgroup (80%). In fact, compared with Trisomy 18 and Tri-somy 21, Trisomy 13 was found to be highly associatedwith craniomaxillofacial malformations. This was con-firmed, through prenatal sonographic imaging, by Ettema[37], as particularly evident in cleft deformities (76.9%).Similarly, Tolarova, Shaw and Genisca [9, 12, 22], reporteda congruous higher rate of clefts, mostly CL/P, in infantswith Trisomy 13. This is in contrast with Vallino [31],who found Trisomy 18 to be more frequent than theothers. Infants with CP and micrognathia were classifiedas having PR syndrome and included in the analyzedgroup, even though PR is not properly considered asyndromic pattern [4]; however, since it is commonly as-sociated with relevant respiratory distress problems suchas obstructive sleep apnea syndrome (due to subsequentreduction of the upper posterior pharyngeal airway), it isso considered.Interesting information, useful for the Health Services

assistance programs and planning, came from the ana-lysis of the citizenship distribution of OC.Investigating ethnic clusters in OCs through the

maternal citizenship data is limited in that it does notprovide or relate to any data on the genetic subset of thebiological father, who, considering the rising number ofmixed marriages, could be of a different race. Nor doescitizenship always correspond to race, although it is theclosest parameter to it; nevertheless, the mother’s coun-try of origin reveals the role of environmental and gen-etic factors. Specifically, it was estimated - ISTAT 2011– [38] that the percentage of children born of an Italianfather and foreign mother, foreign father and Italianmother, and both parents foreign were 5.2, 1.5, and23.9%, respectively, for the Emilia-Romagna region and4.8, 1.1, and 18.6%, respectively, for the Tuscany region.The three major ethnic groups represented by females

living in the areas in question were from Romania

(14.3%), Morocco (12.5%), and Albania (10.8%) amongalmost 257,900 foreign female residents in the Emilia-Romagna region and by females from Albania (23.4%),Romania (16.2%), and China (7.9%) among almost 192,100 foreign female residents in the Tuscany region. Aslightly different ethnic/citizenship predominance, forthe first three groups, was found among the IMER for-eign mothers, who were found to come mainly fromMorocco, closely followed by Albania and Romania,whereas in the Tuscany registry (RTDC), Chinesemothers were by far the most represented, followed byRomanians and north Africans.The increasing presence of foreign patients can be

related to the increase in immigration over the pastdecade, especially from the new east-central and Balkancountries annexed to the European Union whose influxhas recently increased compared with the North Africanmigration. A time trend figure illustrating the annualnumber of OC infants born to foreign mothers in eachregional registry shows a steady increase in foreign OCcases; this is in line with the data provided by the decen-nial Italian censuses completed on January 1, 2001, andJanuary 1, 2011 (covering the period examined in thepresent study). These registries covering the Tuscany(RTDC) and Emilia-Romagna (IMER) regions supplyreliable and realistic national data; they have a largeforeign population in their territory (Tuscany, 9.7%) and(Emilia-Romagna, 11.3%) compared with the nationalmean of 7.5%.Overall, the prevalence of OCs (CL/P and CP groups;

0.9–1.1/1000 births) is comparable to the congruousEuropean mean of 1.52/1000 during the investigatedperiod (Table 8), thus confirming an apparent correl-ation between the European latitude and the OC preva-lence rate, [11].The OC prevalence rate has consistently risen in the

IMER and decreased in the RTDC, suggesting an overlapwith the foreign presence over the study year. Thisobservation illustrates how migration fluctuates and howthe various ethnic-genetic clusters, with their specific ra-cial prevalence, affect the OC national prevalence rates.Indeed, in the past 5 years, an increasing number of for-eigners has been recorded (with a prevalence of Balkans,east-central Europeans, Asians, and South Americansover those from southern Europe and northern Africa),which might explain the increasing prevalence of OCsover the same years. In fact, the literature has reported

Table 8 Mean values of European prevalence of OCs, 2001–2014 (data from EUROCAT)

Austria France Italy Poland UK Belgium Germany Malta Portugual

1.54/1000 1.63/1000 1.03/1000 1.61/1000 1.63/1000 1.71/1000 2.11/1000 2.03/1000 0.70 /1000

Croatia Hungary Spain Denmark Ireland Norway Ukraine Netherlands Switzerland

1.38/1000 1.30/1000 0.10/1000 2.4 /1000 1.54/1000 1.87/1000 1.51/1000 2.08/ 1000 1.89 /1000

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 12 of 14

the highest incidence of orofacial clefts among NativeAmericans (3.6/1.000), followed by Asians (2–1.82/1.000), Caucasians (1/1.000), and Africans (0.3/1.000)[39, 40]. Racial differences affect more CL/P phenotypesthan they do CPs, as other researchers suggested, report-ing a higher number of CL cases in a sample of patientsbelonging to a population with high consanguinity ratesand thus suggesting that CL/P has a greater genetic in-fluence in its etiology [2, 21, 22] . CL/P prevalence rateshave different racial values despite a generally concord-ant assessed prevalence of 0.6–0.9/1.000 for CP, as notedin the literature. Thus, more specific, demonstrativestudies are needed to support the enhanced hypothesisof descriptive epidemiology alone and therefore to pro-duce evidence of causality. The modern approach is toselect additional and controlled, reliable information onpresumed relationships. Given the limited power toexamine this interconnection, we consider these resultsmerely hypothetical.

ConclusionsThe present study provides a population-based, descrip-tive epidemiological reference for OCs in Italy in ourattempt to assemble a national surveillance of this rela-tively frequent congenital malformation due to its socialand economic impact on health care and welfare, espe-cially in anticipation of a different composition of theoverall population for the future pursuant to the increaseof migration phenomena. The investigation of timetrends, geographical/ethnic clusters, topography, sex ra-tios, and the congenital anomalies associated with OCphenotypes also provides clues about how to test andcorroborate the efficiency of primary preventive projectsand where to direct supplemental resources based onspecific regional requirements. Even though full cover-age of the entire national territory was not achieved, ourefforts have provided enough data to delineate an accur-ate picture of the phenomenon as it has existed in Italyacross the decade. Although other data, such as com-bined racial/ethnic and genetic subsets of both motherand father as related to migration influxes, would havebeen interesting to evaluate and interpolate, even goingso far as to include all national data—such an ambitiousundertaking is best left to future research. However, wehope to have established sufficient data to increase theawareness of the public health sector as to the preva-lence of this distressful deformity.

AbbreviationCL: Cleft lip; CLP: cleft lip and palate; CM: Congenital Malformations; CP: cleftpalate; EUROCAT: European Surveillance of Congenital Anomalies;IMER: Emilia-Romagna Registry of Birth Defects; MCAs: multiple congenitalanomalies; OC: oral clefts; PR: Pierre Robin sequence/syndrome;RTDC: Registro Toscano Difetti Congeniti; TOPFA: termination of pregnancyfor fetal anomaly

AcknowledgmentsThe authors declare that no acknowledgment to other persons is due.

Authors’ contributionsAll authors read and approved the final manuscript. AI Conception anddesign of the work, drafted the work; IG Acquisition and analysis of data; APInterpretation of data; EB Interpretation of data; GG Conception and designof the work, substantively revised the work;

FundingThe authors declare that no institutional funding is provided for thepublication of this article. The authors also accept the funding policies of thejournal.

Availability of data and materialsTo obtain access to the raw data, contact Dr. Alessandra Impellizzeri,Italy- Email address: ale.impellizzeri@gmail.com/, alessandra.impellizzeri@uniroma1.it.The datasets supporting the conclusions of this article are available at thefollowing web addresses:http://web.unife.it/progetti/imer/imernew/elab.htmhttp://web.unife.it/progetti/imer/imernew/tabelle.htmhttp://www.malattierare.toscana.it/dati-statistici/

Ethics approval and consent to participateThe authors declare that the Ethics approval and participant consent was notnecessary as this study involved the use of a previously-published de-identified database according to national legislation. The Ethics Approval isnot applicable.

Consent for publicationNot applicable.

Competing interestsAll the authors declare the absence of any conflict of interest.

Author details1Unit of Orthodontics, Department of Oral and Maxillofacial Sciences,“Sapienza” University of Rome, Rome, Italy. 2Private Practice, Rome, Italy.3Department of Oral and Maxillo-facial Sciences, Pediatric Dentistry Unit,“Sapienza” University of Rome, Rome, Italy. 4Sapienza” University of Rome,Rome, Italy. 5Department of Oral and Maxillofacial Sciences, “Sapienza”University of Rome, Rome, Italy.

Received: 10 November 2017 Accepted: 29 November 2019

References1. Leslie EJ, Carlson JC, Shaffer JR, Feingold E, Wehby G, et al. A multi-ethnic

genome-wide association study identifies novel loci for non-syndromic cleftlip with or without cleft palate on 2p24.2, 17q23 and 19q13. Hum MolGenet. 2016a;

2. Bianchi F, Calzolari E, Ciulli L, Cordier S, Gualandi F, Pierini A, Mossey P.Environment and genetics in the etiology of cleft lip and cleft palate withreference to the role of folic acid. Epidemiol Prev. 2000 Jan–Feb;24(1):21–7.

3. Murray JC, Dixon MJ, Marazita ML, Beaty TH. Cleft lip and palate:understanding genetic and environmental influences. Nat Rev Genet. 2011Mar;12(3):167–78.

4. Tinanoff N. Syndromes with oral manifestations. In: Kliegman RM, StantonBF, St Geme III JW, Schor NF, editors. Nelson textbook of pediatrics. 20th ed.Philadelphia, PA: Elsevier; 2016.

5. Shaw GM, Carmichael SL, Nelson V, Wasserman CR, Croen LA. Socio-economic status and risk of conotruncal heart defects and orofacial clefts.Paed Perinat Epidemiol. 2003 Jul;17(3):264–71.

6. Ericson A, Källen B, Westerholm P. Cigarette smoking as an etiologic factorin cleft lip and palate. Am J Obstet Gynecol. 1979;135:348–53.

7. Jensen BL, Kreiborg S, Dahl E, Fogh-Andersen PI. Cleft lip and palate inDenmark, 1976-1981: epidemiology, variability, and early somaticdevelopment. Cleft Palate J. 1988 Jul;25(3):258–69.

8. Owens JR, Jones JW. Epidemiology of facial clefting. Cleft Palate J. 1988 Jul;25(3):258–69.

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 13 of 14

mailto:ale.impellizzeri@gmail.commailto:alessandra.impellizzeri@uniroma1.itmailto:alessandra.impellizzeri@uniroma1.ithttp://web.unife.it/progetti/imer/imernew/elab.htmhttp://web.unife.it/progetti/imer/imernew/tabelle.htmhttp://www.malattierare.toscana.it/dati-statistici/

9. Shaw GM, Carmichael SL, Yang W, Harris JA, Lammer EJ. Congenitalmalformations in births with orofacial clefts among 3.6 million Californiabirths, 1983-1997. Am J Med Genet A. 2004 Mar 15;125A(3):250–6.

10. Czeizel AE, Sárközi A, Wyszynski DF. Oral clefts with associated anomalies:findings in the Hungarian congenital abnormality registry. BMC Oral Health.2005 Jun 28;5:4.

11. Calzolari E, Pierini A, Astolfi G, Bianchi F, Neville AJ, Rivieri F. Associatedanomalies in multi-malformed infants with cleft lip and palate: anepidemiologic study of nearly 6 million births in 23 EUROCAT registries. AmJ Med Genet A. 2007 Mar 15;143(6):528–37.

12. Genisca AE, Frías JL, Broussard CS, Honein MA, Lammer EJ, Moore CA, et al.Orofacial clefts in the national birth defects prevention study. Am J MedGenet A. 2009 Jun;149A(6):1149–58.

13. Rittler M, Cosentino V, López-Camelo JS, Murray JC, Wehby G, Castilla EE.Associated anomalies among infants with oral clefts at birth and during a 1-year follow-up. Am J Med Genet A. 2011 Jul;155A(7):1588–96.

14. Wyszynski DF, Sárközi A, Czeizel AE. Oral clefts with associated anomalies:methodological issues. Cleft Palate Craniofac J. 2006 Jan;43(1):1–6.

15. Stoll C, Alembik Y, Dott B, Roth MP. Epidemiological and genetic study in207 cases of oral clefts in Alsace, north-East France. J Med Genet. 1991 May;28(5):325–9.

16. Milan M, Astolfi G, Volpato S, Garani GP, Clementi M, Tenconi R, et al. 766cases of oral cleft in Italy. Data from Emilia Romagna (IMER) and NortheastItaly (NEI) registers. Eur J Epidemiol. 1994 Jun;10(3):317–24.

17. Croen LA, Shaw GM, Wasserman CR, Tolarová MM. Racial and ethnicvariations in the prevalence of orofacial clefts in California, 1983–1992. Am JMed Genet. 1998 Aug 27;79(1):42–7.

18. Croen LA, Stoll C, Alembik Y, Dott B, Roth MP. Associatedmalformations in patients with oral clefts. Am J Med Genet A. 2007 Oct15;143A(20):2463–5.

19. Tolarová M. A study of the incidence, sex-ratio, laterality and clinical severityin 3,660 probands with facial clefts in Czechoslovakia. Acta Chir Plast. 1987;29(2):77–87.

20. Spilson SV, Kim HJ, Chung KC. Association between maternal diabetesmellitus and newborn oral cleft. Department of Surgery, the University ofMichigan medical center, Ann Arbor 48109-0340, USA [2001].

21. Leslie EJ, Liu H, Carlson JC, Shaffer JR, et al. A genome-wide associationstudy of Nonsyndromic cleft palate identifies an etiologic missense variantin GRHL3. Am J Hum Genet. 2016b;98:744–54.

22. Doray B, Badila-Timbolschi D, Schaefer E, Fattori D, Monga B, Dott B, et al.Epidemiology of orofacial clefts (1995-2006) in France (congenitalmalformations of Alsace registry). Arch Pediatr. 2012 Oct;19(10):1021–9.

23. Clementi M, Tenconi R, Collins A, Calzolari E, Milan M. Complex segregationanalysis in a sample of consecutive newborns with cleft lip with or withoutcleft palate in Italy. Hum Hered. 1995 May–Jun;45(3):157–64.

24. Bernheim N, Georges M, Malevez C, De Mey A, Mansbach A. Embryologyand epidemiology of cleft lip and palate. B-ENT. 2006;2(Suppl 4):11–9.

25. Stoll C, Alembik Y, Dott B, Roth MP. Associated malformations in patientswith oral clefts. Am J Med Genet A. 2007 Oct 15;143A(20):2463–5.

26. Johnston MC, Bronsky PT. Animal models for human craniofacialmalformations. J Craniofac Genet Dev Biol. 1991 Oct–Dec;11(4):277–91.Embryonic craniofacial development. Prog Clin Biol Res 1991; 373: 99–115

27. Milerad J, Larson OD, Hagberg C, Ideberg M. Associated malformations ininfants with cleft lip and palate: a prospective, population-based study.Pediatrics. 1997 Aug;100(2 Pt 1):180–6.

28. DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleft malformations:associations with maternal and infant characteristics in Washington state.Terat. 2003 Sep;67(9):637–42.

29. Hashmi SS, Waller DK, Langlois P, Canfield M, Hecht JT. Prevalence ofnonsyndromic oral clefts in Texas: 1995–1999. Am J Med Genet A. 2005 May1;134(4):368–72.

30. Mossey PA, Little J, Munger RG, Dixon MJ, Shaw WC. Lancet. 2009 Nov 21;374(9703):1773–85.

31. Vallino-Napoli LD, Riley MM, Halliday JL. An epidemiologic study of orofacialclefts with other birth defects in Victoria. Australia Cleft Palate Craniofac J.2006 Sep;43(5):571–6.

32. Al-Balkhi KM. The distribution and classification of clefts in patientsattending a cleft lip and palate clinic in Riyadh. Saudi Arabia Saudi Med J.2008 May;29(5):739–42.

33. Grech V, Lia A, Mifsud A. Congenital heart disease in a patient withmicroform cleft lip. Cleft Palate Craniofac J. 2000 Nov;37(6):596–7.

34. Jamilian A, Sarkarat F, Mehrdad J, Neshandar M, Amini E, Khosravi S,Ghassemi A. Family history and risk factors for cleft lip and palate patientsand their associated anomalies. Stomatologija Baltic Den and Maxill Fac J.2017;19(3):78–83.

35. Chzhan S, Khen DF. The incidence of the development of congenital cleftsof the upper lip and palate in relation to blood group among theinhabitants of the provinces of the People's Republic of China.Stomatologiia. 1990;69:71–2.

36. Sun T, Tian H, Wang C, Yin P, Zhu Y, Chen X, et al. Asurvey of congenitalheart disease and other organic malformations associated with differenttypes of orofacial clefts in Eastern China. PLoS One. 2013;8:e54726.

37. Ettema AM, Wenghoefer M, Hansmann M, Carels CE, Borstlap WA, Bergé SJ.Prenatal diagnosis of craniomaxillofacial malformations: a characterization ofphenotypes in trisomies 13, 18, and 21 by ultrasound and pathology. CleftPalate Craniofac J. 2010 Mar;47(2):189–96.

38. ISTAT. Statistical report. La popolazione straniera residente in Italia. RapportoOversalute 2014

39. Mossey PA, Shaw WC, Munger RG, Murray JC, Murthy J, Little J. Globaloral health inequalities: challenges in the prevention and managementof orofacial clefts and potential solutions. Ann Plast Surg. 2001 Nov;47(5):477–8.

40. Forrester MB, Merz RD. Descriptive epidemiology of oral clefts in amultiethnic population, Hawaii, 1986-2000. Cleft Palate Craniofac J. 2004Nov;41(6):622.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Impellizzeri et al. BMC Oral Health (2019) 19:290 Page 14 of 14

AbstractBackgroundMethodsResultsConclusions

BackgroundMethodsResultsSex ratio and cleft phenotype distributionType of event subset and time-trends prevalence of OCsLaterality of CLP and Anatomical topography of OCsIsolated/Multiple Congenital Anomalies (MCAs)Citizenship/Ethnic group rates in OCs

DiscussionConclusionsAbbreviationAcknowledgmentsAuthors’ contributionsFundingAvailability of data and materialsEthics approval and consent to participateConsent for publicationCompeting interestsAuthor detailsReferencesPublisher’s Note