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 Table of Contents  
Year : 2022  |  Volume : 9  |  Issue : 2  |  Page : 145-150

Patterns of orofacial clefts and associated risk factors in Pakistan: An institutional experience

Department of Research and Development, Cleft Hospital Pakistan, Gujrat, Pakistan

Date of Submission20-Jan-2022
Date of Acceptance22-Mar-2022
Date of Web Publication23-Aug-2022

Correspondence Address:
Mrs. Ayisha Ayub
Cleft Hospital Pakistan, Juliyani, G.T. Road, Gujrat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jclpca.jclpca_1_22

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Background: Orofacial clefts (OFCs) are one of the most common congenital anomalies worldwide. The purpose of the present study is to identify the incidence of different types of OFCs and the presence of known risk factors among cleft cases in the Pakistani population. Patients and Methods: A retrospective study was conducted at a comprehensive cleft care center, and data were collected from patient files from December 2018 to July 2021. Only cases of cleft lip and/or cleft palate (CL/P) that presented to center were included. SPSS was used for data analysis, and risk factors associated with OFCs were identified. Results: The study included 1269 patients with CL/P. Of the total, 677 (53.3%) patients had cleft lip with cleft palate, 211 (16.6%) had cleft lip only, and 365 (28.7%) had cleft palate only. Bilateral complete cleft lip and palate (n = 276) was most common among the participants followed by midline incomplete cleft palate (n = 215). One hundred and six (8.3%) of the cases were syndromic, and among the remaining nonsyndromic cases, 240 (18.9%) had other associated anomalies. Chi-square tests revealed the following risk factors for CL/P: consanguinity among the parents (P < 0.001), a complication during pregnancy (P < 0.001), medication use during pregnancy (P < 0.001), maternal smoking or exposure to smoking (P = 0.002), history of miscarriage (P = 0.02), and positive family history (P < 0.001). Logistic regression analysis for these factors showed maternal smoking (odds ratio [OR]: 1.99), consanguineous marriage (OR: 1.89), complication during pregnancy (OR: 1.98), and positive history of cleft (OR: 1.9) to be increasing the odds of cleft development. Conclusion: While previous studies have shown many environmental factors to be associated with development of OFCs in the child, the present study provides a quantitative estimate of the risk posed by each individual factor in the Pakistani population.

Keywords: Cleft, cleft lip and palate, consanguineous marriage, maternal smoking, orofacial cleft, risk factors

How to cite this article:
Sadiq H, Ijaz R, Ayub A. Patterns of orofacial clefts and associated risk factors in Pakistan: An institutional experience. J Cleft Lip Palate Craniofac Anomal 2022;9:145-50

How to cite this URL:
Sadiq H, Ijaz R, Ayub A. Patterns of orofacial clefts and associated risk factors in Pakistan: An institutional experience. J Cleft Lip Palate Craniofac Anomal [serial online] 2022 [cited 2022 Dec 8];9:145-50. Available from: https://www.jclpca.org/text.asp?2022/9/2/145/354286

  Introduction Top

Cleft lip and/or cleft palate (CL/P) is one of the most common congenital deformities, accounting for around one-half of all craniofacial anomalies in children.[1],[2] The incidence of CL/P is different around the world and elevated rates are seen in Asian populations.[3],[4] Historically, CL/P has been classified into two categories: cleft lip with or without cleft palate or cleft palate only. This classification is based on the discrete developmental origin of the lip, primary palate, and the secondary palate in addition to the different cellular and genetic etiologies that have formerly been explained for cleft lip with or without cleft palate in opposition to cleft palate only.[5],[6] In addition, there is evidence suggesting distinct etiologic features for cleft lip and cleft lip with cleft palate.[7],[8]

The pathogenesis of CL/P is still not comprehended completely, but it is admitted that it is multifactorial and involves both genetic and environmental risk factors.[9],[10] Environmental factors like family history,[11],[12] particular maternal diseases,[13],[14],[15] drug usage,[16],[17],[18],[19],[20] nutrition,[21],[22],[23] cousin marriage between parents,[24],[25],[26] and teratogens such as smoking,[27] alcohol utilization,[28] and occupational exposures,[29],[30],[31],[32] have been separately studied for their involvement in the development of CL/P in the child. These findings draft the present counseling guidelines for future mothers on the risk of cleft lip as well as cleft palate in the child, for example, prenatal vitamin use, less alcohol and tobacco consumption, and prevention of some pharmacologic drugs/agents.

Very few studies have been conducted regarding the epidemiology of CL/P in Pakistan. Elahi et al.[33] reported a high cleft incidence rate of 1.91 cases/1000 births, but that study is outdated and recent studies with larger sample sizes are required. The aim of this study was to identify the incidence of different types of clefts among patients with CL/P, its association with other congenital anomalies, and the presence of associated risk factors in these patients along with a quantitative estimate of the risk posed by each factor. It is expected that the study results will add to the existing cleft knowledge and contribute toward a better understanding of the cleft patterns in Pakistan in comparison to other populations and risk factors mostly associated with CL/P; as a result, available resources can be properly devoted toward CL/P prevention and counseling programs in general as well as specifically to Pakistan.

  Patients and Methods Top


A retrospective study was conducted at a comprehensive cleft care center from December 2017 to July 2021. Data collection was started after the study was approved by the ethics committee of the center.


Records of all consecutive cases of cleft lip and/or palate (CL/P) that presented to the center, from December 2018 to July 2021, irrespective of their age and gender were included in the study. All of the patients who were previously operated on for CL/P at another hospital were excluded due to the possibility of bias in the determination of the type of cleft deformity.

Data collection

Patient records were obtained from the patient management department of the hospital. Detailed data of these cases were recorded through a comprehensive questionnaire using the data present in the patient files. The questionnaire had three sections for data collection. The first part included details of the patient such as gender, age, weight, birth order, the type of cleft, and any associated anomaly. The second section collected details about the family history of cleft or any other disease while the third section recorded maternal history and other social information such as parental consanguinity and age, pregnancy-related illnesses and infections, childbirth complications, maternal immunization history, trauma, lifestyle behaviors such as smoking and alcohol consumption, financial status, use of supplements or other medication, and other contributing information.


SPSS® software version was used to analyze the various risk factors and demographic variables related to orofacial clefting. Frequencies and percentages along with means and standard deviation were calculated and recorded. Chi-square test was performed for each risk factor to check for its significance and role in the development of cleft.

  Results Top

A total of 1500 patient files were obtained for data collection from the patient management department. Data were missing for some patients while some others were initially operated at other hospitals. The final number of patients with complete data was 1269. Among these patients, 685 (53.9%) were male, 580 (44.7%) were female, and gender information was not recorded for 4 cases. [Table 1] shows the distribution of cases by gender and type of cleft. Clefts of the lip and cleft lip with associated cleft of the palate were more common in males than in females, while cleft palate alone was more common in females.
Table 1: Distribution of cases according to type of cleft and gender of patients

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In this cohort, cleft lip and cleft palate occurred more frequently together. Bilateral complete cleft lip and palate (n = 276) was most common among the participants followed by midline incomplete cleft palate (n = 215) [Table 2].
Table 2: Distribution of cases according to cleft sides in the three groups

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Age at presentation ranged from birth to 36 years for the CL/P group, and birth to 26 years for those with cleft palate. The most common age of presentation was within the 1st month of life for both groups. The median age at primary lip repair was 4 months while the median age for primary palate repair was 13 months.

Of the 1269 patients with clefts presented in this study, 206 (16.2%) had a positive family history of clefting. Fifty-one of these patients reported a family history of cleft in first-degree relatives, and 81 reported a history of cleft in second-degree relatives. In 75 of these cases, a parent, a sibling, or both had a nonsyndromic cleft condition.

One hundred and six (8.3%) out of these 1269 cases were syndromic and presented with Pierre Robin sequence, van der Woude syndrome, Down syndrome, and Stickler syndrome. Among the nonsyndromic cases, 240 (18.9%) had other associated anomalies including ear problems, hypertelorism, clubfoot, hypodontia, poly, and syndactyly. Seventy-eight (6.14%) cases presented with congenital heart problems, asthma, and diabetes.

The mean age of the case mothers was 27.4 years while the mean age of case fathers was 32.5 years [Table 3]. Families of patients with CL/P were found to be more likely of lower-middle socioeconomic status (SES). 62.2% of parents of cleft patients had a consanguineous marriage, and it was the most common identifiable risk factor. Consanguineous marriages are defined as first- or second-cousin marriages; marriages of more distant relatives were not considered consanguineous for this study. First-cousin marriages were more common in this cohort than second-cousin marriages. 43.8% of mothers of patients with CL/P experienced complications during pregnancy, in particular anemia and hypertension along with miscarriage during previous pregnancies. A complication during pregnancy was the second identifiable risk factor followed by maternal smoking or exposure to smoking, positive family history, and medications used during pregnancy. Medications here refer to medicines other than multivitamins or doctor recommended used by the mother during pregnancy for specific health conditions such as hypertension, diabetes, epilepsy, and infections.
Table 3: Selected demographic and clinical variables in parents of cleft cases

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To confirm if the identified risk factors actually played a significant role in the development of orofacial clefts (OFCs), Chi-square test was performed and P < 0.05 was considered significant [Table 4]. Results revealed that all these risk factors were found to be statistically significant for their role in the development of cleft. These factors were further evaluated through logistic regression for calculation of odds ratio (OR). Maternal tobacco exposure showed the highest odds of increasing cleft in the child by 1.99. Similarly, having a consanguineous marriage between parents was found to increase the odds of OFC development by 1.89 times. Pregnancy complications (OR: 1.98) and a positive cleft history (OR: 1.9) were also associated with increased odds of cleft development.
Table 4: Risk factors for orofacial clefts

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  Discussion Top

OFCs are the most common congenital anomalies, occurring in 1 in every 700 births. The highest prevalence has been reported in Mongols.[34] Asian populations are considered to be at most risk, with OFC rates ranging between 1.20 and 1.18/1000 live births.[35],[36] A study conducted in a different province of Pakistan found the mean incidence of cleft to be 1.46/1000 live births.[33]

The present study is one of the few to date that describe the epidemiologic profile of OFCs as well as the various risk factors that may be involved in its development in Pakistan which sees a high incidence of OFCs yet is scarce in appropriate perinatal counseling programs and clinical services.[33] The study was retrospective in design, and many of the findings from this study are consistent with previous reports on risk factors for development of OFCs in the child.

The etiology of OFCs is complex, involving interactions and interplay of numerous genetic and environmental factors. Our finding that consanguinity among parents of patients as the most common identifiable risk factor matched the results of three more studies from Pakistan.[37],[38],[39] Our result of 62.2% consanguineous marriages among cleft parents was similar to the findings of Khan et al.[39] in a local study conducted in Pakistan. These results were also found to be consistent with other studies from the Kingdom of Saudi Arabia, in which consanguineous relationship was observed in 56.8% and 55% of cleft patients.[40],[41] This study, however, is the first to give a quantitative estimate of the risk posed by consanguinity thereby showing that it increases the odds of cleft development by almost two times. It is known that orofacial morphogenesis is controlled by multiple genes. This emphasizes the role that parental consanguinity and positive family history may play in the pathogenesis of OFCs.[42] Our study also shows that positive family history of cleft has a significant role in the development of OFCs, the results of which are consistent with another study conducted in the subcontinent.[43] The recurrence risk of cleft seems to increase with degree relation and level of anatomical severity in the affected relation.[44]

There has been strong observational evidence associating a number of environmental risk factors such as maternal smoking, alcohol use, malnutrition, viral infections, and teratogen use in the first trimester of pregnancy to the incidence of OFCs.[45],[46],[47] Previous studies done in Pakistan could not elucidate pregnancy complications and tobacco exposure as a risk factor due to lack of sufficient data. Our study is the first in the region to identify and quantify pregnancy complications during the perinatal period as a potent risk factor for the development of cleft. The reasons behind these findings are not clear-cut. A number of studies done in the past have shown that numerous maternal health problems, including nongestational diabetes and high fever, are associated with greater risk of OFCs in the child.[13],[14],[15] The study also underlines and quantifies maternal tobacco exposure as a potent risk factor for the development of OFCs. Literature shows that prevalence of smoking in Pakistan is among the highest when compared worldwide and it continues to increase.[48] Our study also underlines and quantifies maternal tobacco exposure as a potent risk factor which increases the odds of the development of OFCs by almost two times. However, a more comprehensive and detailed understanding of the risk associated with smoking is required which can be more helpful for prenatal specialists and providers counseling future parents.

One noteworthy finding from this study was that maternal history of miscarriage was found to be a statistically significant risk factor in the development of OFCs. This finding is consistent with a previous study that reported maternal miscarriage history to be associated with cleft. The sample size in that study was, however, small compared to our sample size.[49]

Another finding in this study that is worthy of mention is that majority of the patients in the study belonged to lower and middle SES which highlights the decreased risk of a child developing OFCs in families with higher SES. While the details for this are imprecise, families of higher SES may access better perinatal health care and counseling, which in turn could help them avoid risk factors not mentioned or studied in this study. They also travel outside the country for such special conditions more often than other families with limited finances. These associations, however, require further exploration.

In this study, there was an overall male dominance for the cleft lip with or without cleft palate while the isolated cleft palate category showed female dominance, which is consistent with Pavri et al.,[50] Goenjian et al.,[51] and Dai et al.[52] These findings are also in conjunction with a local study in which Elahi et al.[33] reported male dominance in cleft lip with or without cleft palate, while the isolated cleft palate was mainly female predominant.

Syndromic clefts are now considered a separate entity, with 55% of OFC cases being associated with a congenital syndrome.[53] Cleft lip and palate is a known feature of more than 200 syndromes, and cleft palate is associated with more than 400 syndromes.[26] We found 106 syndromic cases in which cleft is a well-known feature. This may probably not be the actual prevalence of the syndromic clefts as a lot of these syndromes end up in stillbirths, neonatal deaths, and infant deaths or remain unidentified.

There are some limitations to this study as well. Multifactorial etiology of OFCs is well accepted, so the presence of certain factors may transform the risk conferred by other factors. As, for example, maternal smoking or exposure to smoking has been known to interact with the risk that various genetic factors present to the development of OFCs, and therefore the interplay of environmental and genetic factors can alter the actual risk posed by each factor alone.[54] While this study was able to provide a breakdown of the different risk factors that may be involved in the development of cleft lip and palate, interaction effects were not looked at between these risk factors. More data would likely be needed in order to conduct these analyses. In addition, as this was a retrospective study, the association between different risk factors and development of OFC in the child found in the study cannot be utilized to establish definitive etiologic connections between them. Furthermore, elaborate studies are required to explain the mechanisms behind these associations.

  Conclusion Top

OFCs affect the male population more than females, with the cleft lip with or without cleft palate being the most common deformity. Females are mainly affected by the isolated cleft palate. These deformities are mainly common in children born to parents with consanguineous marriages. A decrease in consanguinity together with better maternal health may decrease the incidence of orofacial deformities. To conclude, this study provides an insight into several environmental factors which may act as risk factors for development of OFCs in the Pakistani population. These findings emphasize the development of proper perinatal educational and counseling parental programs for this population which may reduce the burden of problems associated with OFCs.


We would like to express our heartfelt gratitude and appreciation to Cleft Hospital Pakistan for all the support the center provided during data collection and analysis and special thanks to Dr. Ijaz Bashir for his expertise and assistance throughout all aspects of the study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3], [Table 4]


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