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1
To,
The Ethical committee
The Children’s Hospital & The ICH Lahore
Sir,
I am doing Masters in Public Health from PGMI Lahore. I am on deputation from The Children’s
Hospital & ICH Lahore where I was working as Deputy Medical Superintendent. I am planning for
research on Factors predisposing to cleft lip and palate in children as a part of fulfillment of my
Masters thesis. I need ethical approval for my research proposal.
Thanking you
Dr. Asad Zain
DMS CH & ICH
Dated: 6.9.2017
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FACTORS PREDISPOSING TO CLEFT LIP AND PALATE IN CHILDREN
Dr. Asad Zain
BACKGROUND:
The greatest asset of any country is the new generation of healthy intelligent and wise
children. This asset is made inefficient if the children are born with congenital malformations.
1
A
significant component of human birth defects comprises of craniofacial anomalies.
Second most
common entity in this group are Oral clefts.
2
Clefts of the lip and palate represent a heterogeneous
group of disorders affecting the lips and oral cavity and are generally divided into two groups,
isolated cleft palate and cleft lip with or without cleft palate. Orofacial clefts may involve the lip,
the roof of the mouth (hard palate), or the soft tissue in the back of the mouth (soft palate).
Oral, facial, and craniofacial deformity occur when there is involvement of these structures.
3
These defects arise in about 1.7 per 1000 live-born babies, with ethnic and geographic
variation.
4
The incidence varies by race, sex and geographic location.
Asians are at higher risk than
whites or blacks.
1
A research from Pakistan showed that out of total 61,156 births 117 children were
born with oral clefts with the incidence to be 1.91/1000 live births.
5
A review article revealed that
the prevalence of cleft lip and cleft palate was from 0.78 to 2.14 in Iranian children.
1
An environmental and complex multi-faceted genetic etiology is involved in oral clefts.
Oral cleft often occurs as a part of well- recognized syndromes but numerous risk factors are also
involved in the disease causal pathway. Maternal factors like smoking, anti-epileptic drugs usage,
congenital toxoplasmosis, rubella, cytomegalovirus, herpes simplex (TORCH) infections, nutritional
deficiencies of folic acid during pregnancy are the common risk factor along with consanguinity.
1
In
recent years very significant progress has been made with respect to genetic determinants and
a range of environmental risk factors for cleft lip and palate.
6
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3
Cleft lip (CL) alone was observed more often than combined cleft lip and cleft palate
(CLP) or isolated cleft palate (CP).
2
A study from India showed that the commonest
malformation was CLP followed by CP without cleft lip and isolated CL was seen least
common.
7
A research done by Daniella and a study published in BMC Pediatrics also showed
similar results with majority of the defects were CLP.
8.9
Another study
from Malaysia also
showed CLP as the most common malformation.
10
There is high morbidity and mortality in children with oral clefts as compared to the
unaffected children. Their speech and hearing capabilities may also be affected in addition to
impairment of facial appearance. Hearing impairment was documented to be 63% in patients with
cleft lip and cleft palate in an Indian study.
7
Patients with OFCs have additional risks of
malnutrition and anemia due to feeding problems. Respiratory infections are the most
frequent infections. Children with OFC develop respiratory infections because they are
exposed to false food routes.
9
Effects on psychology can lead to long-lasting adverse outcomes for
health and social integration. Typically, children with these disorders need multidisciplinary care
from birth to adulthood. The multi-disciplinary approach required include primary surgical repair
hearing assessment and speech therapy.
A research from Agha Khan University Pakistan showed a slight preponderance of males
53%, majority presented in first few months of life.
2
A study done by Hiroshi and an Indian study
showed much higher incidence in males as compared to females with male to female ration of 2:1.
7,11,
Isolated CL or CP was present in 57.5% and there was syndromic association in 2.7%.
2,9
A much
higher percentage of malformations associated with cleft lip and cleft palate occurred in 41.3%
of all patients in a research from Japan. Congenital heart disease was the most common
disease category found in these children with cleft lip and cleft palate.
9
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4
Consanguinity was found in 17% of cases in AKU research.
2
Similarly another study
from Pakistan also showed a relatively higher incidence of consanguineous marriages in the parents
of children with oral clefts in comparison with matched controls (32% versus 18%). This study also
showed a higher mean age of parents of these children as compared to their age matched controls.
5
A
study from Northern Pakistan also showed 61% consanguinity in children who presented with
orofacial cleft.
12
Similarly a review article from Iran also showed a significant high consanguineous
marriages in parents of these children.
1
A case control study by Betty showed that the
consanguinity was statistically significant in cleft group, and in the control group the
consanguineous relation of parents was very low.
13
Consanguinity among the parents was found
to be the most common risk factor in a study published in JPMA.
2
A number of factors determine the risk of recurrence of cleft lip or cleft palate including
malformation present in a particular family, the number of family members with clefts, how closely
related these people are, the race and sex of the affected individuals. Once parents have a child with a
cleft. the risk that the next child will be affected is 25%. If there is more than one person in the
immediate family with a cleft, the risk rises to 1012%. An individual who is the only one in his or
her family with a cleft has 25% chances that his or her child will have a cleft. If the individual with
the cleft also has a close relative with a cleft, the risk increases to 1012% that a child will have a
cleft. Finally, the unaffected siblings of an individual with a cleft have a roughly 1% risk of having a
baby with a cleft. If a syndrome is involved, the risk for recurrence within the family could be as high
as 50%.
3
A research done by showed 21% had a positive family history of cleft deformities.
12
With regards to audit, research, and the provision of services maintaining a
register of children born with orofacial clefts is recognized as important component of health
care system.
6
The greatest impact in advancing our understanding of orofacial clefts is the
exploration of demographic variables in different populations throughout the world. Significant
differences exist, however, across and within ethnic, racial and national boundaries that underscore
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5
the importance of obtaining this important data in different regions of the world. There is lack of
proper knowledge of factors predisposing to cleft lip and palate in children in the developing
countries and researches on this topic from Pakistan are scarce. We therefore planned this study with
the aim to determine the predisposing environmental and genetic risk factors for cleft lip and palate
in children, their association with other congenital malformations and presence of other associated
risk factors in these patients. Although access to care has increased in recent years, but quality of
care still varies substantially in developing countries, Prevention is the ultimate objective for clefts of
the lip and palate and a prerequisite of this aim is to elucidate causes of the disorders.
RESEARCH HYPOTHESIS:
Cleft lip and palate has an association with young parental (both father and mother) age and
consanguinity in parents with equal distribution in both genders.
RESEARCH QUESTION:
Are young parental age, consanguinity of parents and male gender a risk factor for cleft lip and cleft
palate in children.
AIMS AND OBJECTIVES:
To determine the predisposing risk factor to cleft lip and cleft palate in children.
MATERIALS AND METHODS:
Inclusion Criteria:
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6
All those children from birth to any age having congenital cleft lip or cleft palate who will visit The
Children’s Hospital Lahore, Surgery or Plastic Surgery Out-patient department or admitted in these
wards for surgical treatment purposes will be included in the study.
Same age and sex matched children without cleft lip or cleft palate visiting the outpatient department
with minor ailments or for routine vaccination purposes will be included as controls.
Exclusion Criteria:
Children having traumatic cleft lip or palate were excluded.
Place of Study:
The Children’s Hospital & ICH Lahore.
Sample Size:
Sample size is calculated by using Open-epi statistical calculator with 95% CI and 5% margin of
error is 50 children with cleft lip and cleft palate. (incidence of cleft lip and cleft palate is 1.7%).
4
Fifty children not having orofacial clefts will be included as controls.
Study Design:
Case control study
Study Procedure:
The present study will be conducted among children under two children presenting to the Out-patient
department of Plastic surgery of General Surgery or admitted in these wards for surgical treatment
purposes will be included in the study. After informed consent children of both genders with age
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7
range of birth to 2 years old were included. All the mothers will be interviewed using pre-designed
questionnaire. Each patient will undergo a detailed history and thorough clinical examination. Their
clinical features were noted focusing mainly age, sex, weight, syndromic facies, any other associated
congenital anomaly like talipes equinovarus or presence of congenital heart defect. The presence of
congenital cleft lip or cleft palate in siblings or any other relative, and number of child (first born or
having elder siblings) in the family was noted in the history. History related to maternal age, father’s
age and consanguinity will also be taken. Same history and examination was done for age matched
and sex matched controls without having oral clefts.
Data Analysis:
The data will be analyzed using Statistical Package for Social Sciences (SPSS) version 20 software.
Variables will be analyzed by calculating frequency, mean, standard deviation and percentages. Chi
sq test with p value of < 0.05 will be taken as significant.
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8
REFERENCES:
1. Jafari A, Zarea K, Mehregan N. The Prevalence of Cleft Lip and Cleft Palate and Related
Risk Factors among Iranian Children from 2000 to 2016 : a Literature Review. Int J
Pediatr. 2017;5(40):468797.
2. Raheel M, Jajja N, Ghani A, Cawasji ZF, Imran S, Khan MS. Oral Clefts : A review of the
cases and our experience at a single institution.JPMA. 2011; 63(9):1098102.
3. Agbenorku P. Orofacial Clefts : A Worldwide Review of the Problem. Plastic Surgery
2013;1-7.
4. Mossey P a, Little J, Munger RG, Dixon MJ, Shaw WC. Cleft lip and palate. Lancet.
2009;374(9703):177385.
5. Plastic A, June RS, Elahi M, Elahi MM, Sc M, Jackson IT, et al. Epidemiology of Cleft
Lip and Cleft Palate in Epidemiology of Cleft Lip and Cleft Palate in Pakistan. Plastic And
Reconstructive Surgery. 2004; 113(6): 1548-55.
6. Carroll K, Mossey PA. Anatomical Variations in Clefts of the Lip with or without Cleft
Palate. Plastic Surgery International. 2012;1-6.
7. Subramaniam V, Manuprasad S, Kallikkadan HH, K VK. Otological and audiological
manifestations in cleft lip and cleft palate children : a clinical study. Int J Otorhinolaryngol
Head Neck Surg. 2015;1(1):710.
8. Reis D, Martelli B, Machado RA, Rodrigues M, Aquino SN De. Non sindromic cleft lip
and palate: relationship between sex and clinical extension. 2012;78(5):11620.
9. Nagalo K, Ouédraogo I, Laberge J, Caouette-laberge L, Turgeon J. Congenital
malformations and medical conditions associated with orofacial clefts in children in
Burkina Faso. BMC Pediatrics. 2017;16.
10. Ariff Z, Rahman A. Demographic data on the characterization of oral clefts in Malaysia.
Pakistan Oral & Dental Journal. 2015; 35(1):10810.
11. Koga H, Iida K, Maeda T, Takahashi M, Fukushima N. Epidemiologic Research on
Malformations Associated with Cleft Lip and Cleft Palate in. 2016;110.
12. Patterns of Cleft Lip and Cleft Palate in Northern Pakistan. Arch Clin Exp Surg.2012;
1(2):63-70.
13. Jose BA, Subramani SA, Mokhasi V, Jayan M. Consanguinity and clefts in the
craniofacial region : A retrospective case-control study. J Cleft Lip Palate Craniofacial
Anomalies. 2015;2(2):1137.
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9
PROFORMA
CLEFT LIP AND CLEFT PALATE IN CHILDREN
Cases Sr. No: Control Sr. No:
Name: Age:
Sex: M/ F Date:
Length: Weight: z score:
Syndromic facies: Y/No
Presence of other congenital anomalies: Y/No
Congenital Heart Disease: Y/No
Talipes equino varus: Y/No
Consanguinity: Y/No
Mother’s Age:
Father’s age:
Number in siblings: 1
st
born 2 3 4 5 7
Any relative with cleft lip: Y/No
Sibling with cleft lip and cleft palate: Y/No

Unformatted Attachment Preview

1 To, The Ethical committee The Children’s Hospital & The ICH Lahore Sir, I am doing Masters in Public Health from PGMI Lahore. I am on deputation from The Children’s Hospital & ICH Lahore where I was working as Deputy Medical Superintendent. I am planning for research on “Factors predisposing to cleft lip and palate in children” as a part of fulfillment of my Masters thesis. I need ethical approval for my research proposal. Thanking you Dr. Asad Zain DMS CH & ICH Dated: 6.9.2017 2 FACTORS PREDISPOSING TO CLEFT LIP AND PALATE IN CHILDREN Dr. Asad Zain BACKGROUND: The greatest asset of any country is the new generation of healthy intelligent and wise children. This asset is made inefficient if the children are born with congenital malformations.1 A significant component of human birth defects comprises of craniofacial anomalies. Second most common entity in this group are Oral clefts.2 Clefts of the lip and palate represent a heterogeneous group of disorders affecting the lips and oral cavity and are generally divided into two groups, isolated cleft palate and cleft lip with or without cleft palate. Orofacial clefts may involve the lip, the roof of the mouth (hard palate), or the soft tissue in the back of the mouth (soft palate). Oral, facial, and craniofacial deformity occur when there is involvement of these structures.3 These defects arise in about 1.7 per 1000 live-born babies, with ethnic and geographic variation.4 The incidence varies by race, sex and geographic location. Asians are at higher risk than whites or blacks.1 A research from Pakistan showed that out of total 61,156 births 117 children were 5 born with oral clefts with the incidence to be 1.91/1000 live births. A review article revealed that the prevalence of cleft lip and cleft palate was from 0.78 to 2.14 in Iranian children.1 An environmental and complex multi-faceted genetic etiology is involved in oral clefts. Oral cleft often occurs as a part of well- recognized syndromes but numerous risk factors are also involved in the disease causal pathway. Maternal factors like smoking, anti-epileptic drugs usage, congenital toxoplasmosis, rubella, cytomegalovirus, herpes simplex (TORCH) infections, nutritional deficiencies of folic acid during pregnancy are the common risk factor along with consanguinity.1 In recent years very significant progress has been made with respect to genetic determinants and a range of environmental risk factors for cleft lip and palate.6 3 Cleft lip (CL) alone was observed more often than combined cleft lip and cleft palate (CLP) or isolated cleft palate (CP).2 A study from India showed that the commonest malformation was CLP followed by CP without cleft lip and isolated CL was seen least common.7 A research done by Daniella and a study published in BMC Pediatrics also showed similar results with majority of the defects were CLP.8.9 Another study from Malaysia also showed CLP as the most common malformation.10 There is high morbidity and mortality in children with oral clefts as compared to the unaffected children. Their speech and hearing capabilities may also be affected in addition to impairment of facial appearance. Hearing impairment was documented to be 63% in patients with cleft lip and cleft palate in an Indian study.7 Patients with OFCs have additional risks of malnutrition and anemia due to feeding problems. Respiratory infections are the most frequent infections. Children with OFC develop respiratory infections because they are exposed to false food routes.9 Effects on psychology can lead to long-lasting adverse outcomes for health and social integration. Typically, children with these disorders need multidisciplinary care from birth to adulthood. The multi-disciplinary approach required include primary surgical repair hearing assessment and speech therapy. A research from Agha Khan University Pakistan showed a slight preponderance of males 53%, majority presented in first few months of life. 2 A study done by Hiroshi and an Indian study showed much higher incidence in males as compared to females with male to female ration of 2:1.7,11, Isolated CL or CP was present in 57.5% and there was syndromic association in 2.7%.2,9 A much higher percentage of malformations associated with cleft lip and cleft palate occurred in 41.3% of all patients in a research from Japan. Congenital heart disease was the most common disease category found in these children with cleft lip and cleft palate.9 4 Consanguinity was found in 17% of cases in AKU research.2 Similarly another study from Pakistan also showed a relatively higher incidence of consanguineous marriages in the parents of children with oral clefts in comparison with matched controls (32% versus 18%). This study also showed a higher mean age of parents of these children as compared to their age matched controls.5 A study from Northern Pakistan also showed 61% consanguinity in children who presented with orofacial cleft.12 Similarly a review article from Iran also showed a significant high consanguineous marriages in parents of these children.1 A case control study by Betty showed that the consanguinity was statistically significant in cleft group, and in the control group the consanguineous relation of parents was very low.13 Consanguinity among the parents was found to be the most common risk factor in a study published in JPMA.2 A number of factors determine the risk of recurrence of cleft lip or cleft palate including malformation present in a particular family, the number of family members with clefts, how closely related these people are, the race and sex of the affected individuals. Once parents have a child with a cleft. the risk that the next child will be affected is 2–5%. If there is more than one person in the immediate family with a cleft, the risk rises to 10–12%. An individual who is the only one in his or her family with a cleft has 2–5% chances that his or her child will have a cleft. If the individual with the cleft also has a close relative with a cleft, the risk increases to 10–12% that a child will have a cleft. Finally, the unaffected siblings of an individual with a cleft have a roughly 1% risk of having a baby with a cleft. If a syndrome is involved, the risk for recurrence within the family could be as high as 50%.3 A research done by showed 21% had a positive family history of cleft deformities.12 With regards to audit, research, and the provision of services maintaining a register of children born with orofacial clefts is recognized as important component of health care system.6 The greatest impact in advancing our understanding of orofacial clefts is the exploration of demographic variables in different populations throughout the world. Significant differences exist, however, across and within ethnic, racial and national boundaries that underscore 5 the importance of obtaining this important data in different regions of the world. There is lack of proper knowledge of factors predisposing to cleft lip and palate in children in the developing countries and researches on this topic from Pakistan are scarce. We therefore planned this study with the aim to determine the predisposing environmental and genetic risk factors for cleft lip and palate in children, their association with other congenital malformations and presence of other associated risk factors in these patients. Although access to care has increased in recent years, but quality of care still varies substantially in developing countries, Prevention is the ultimate objective for clefts of the lip and palate and a prerequisite of this aim is to elucidate causes of the disorders. RESEARCH HYPOTHESIS: Cleft lip and palate has an association with young parental (both father and mother) age and consanguinity in parents with equal distribution in both genders. RESEARCH QUESTION: Are young parental age, consanguinity of parents and male gender a risk factor for cleft lip and cleft palate in children. AIMS AND OBJECTIVES: To determine the predisposing risk factor to cleft lip and cleft palate in children. MATERIALS AND METHODS: Inclusion Criteria: 6 All those children from birth to any age having congenital cleft lip or cleft palate who will visit The Children’s Hospital Lahore, Surgery or Plastic Surgery Out-patient department or admitted in these wards for surgical treatment purposes will be included in the study. Same age and sex matched children without cleft lip or cleft palate visiting the outpatient department with minor ailments or for routine vaccination purposes will be included as controls. Exclusion Criteria: Children having traumatic cleft lip or palate were excluded. Place of Study: The Children’s Hospital & ICH Lahore. Sample Size: Sample size is calculated by using Open-epi statistical calculator with 95% CI and 5% margin of error is 50 children with cleft lip and cleft palate. (incidence of cleft lip and cleft palate is 1.7%).4 Fifty children not having orofacial clefts will be included as controls. Study Design: Case control study Study Procedure: The present study will be conducted among children under two children presenting to the Out-patient department of Plastic surgery of General Surgery or admitted in these wards for surgical treatment purposes will be included in the study. After informed consent children of both genders with age 7 range of birth to ≤ 2 years old were included. All the mothers will be interviewed using pre-designed questionnaire. Each patient will undergo a detailed history and thorough clinical examination. Their clinical features were noted focusing mainly age, sex, weight, syndromic facies, any other associated congenital anomaly like talipes equinovarus or presence of congenital heart defect. The presence of congenital cleft lip or cleft palate in siblings or any other relative, and number of child (first born or having elder siblings) in the family was noted in the history. History related to maternal age, father’s age and consanguinity will also be taken. Same history and examination was done for age matched and sex matched controls without having oral clefts. Data Analysis: The data will be analyzed using Statistical Package for Social Sciences (SPSS) version 20 software. Variables will be analyzed by calculating frequency, mean, standard deviation and percentages. Chi sq test with p value of < 0.05 will be taken as significant. 8 REFERENCES: 1. Jafari A, Zarea K, Mehregan N. The Prevalence of Cleft Lip and Cleft Palate and Related Risk Factors among Iranian Children from 2000 to 2016 : a Literature Review. Int J Pediatr. 2017;5(40):4687–97. 2. Raheel M, Jajja N, Ghani A, Cawasji ZF, Imran S, Khan MS. Oral Clefts : A review of the cases and our experience at a single institution.JPMA. 2011; 63(9):1098–102. 3. Agbenorku P. Orofacial Clefts : A Worldwide Review of the Problem. Plastic Surgery 2013;1-7. 4. Mossey P a, Little J, Munger RG, Dixon MJ, Shaw WC. Cleft lip and palate. Lancet. 2009;374(9703):1773–85. 5. Plastic A, June RS, Elahi M, Elahi MM, Sc M, Jackson IT, et al. Epidemiology of Cleft Lip and Cleft Palate in Epidemiology of Cleft Lip and Cleft Palate in Pakistan. Plastic And Reconstructive Surgery. 2004; 113(6): 1548-55. 6. Carroll K, Mossey PA. Anatomical Variations in Clefts of the Lip with or without Cleft Palate. Plastic Surgery International. 2012;1-6. 7. Subramaniam V, Manuprasad S, Kallikkadan HH, K VK. Otological and audiological manifestations in cleft lip and cleft palate children : a clinical study. Int J Otorhinolaryngol Head Neck Surg. 2015;1(1):7–10. 8. Reis D, Martelli B, Machado RA, Rodrigues M, Aquino SN De. Non sindromic cleft lip and palate: relationship between sex and clinical extension. 2012;78(5):116–20. 9. Nagalo K, Ouédraogo I, Laberge J, Caouette-laberge L, Turgeon J. Congenital malformations and medical conditions associated with orofacial clefts in children in Burkina Faso. BMC Pediatrics. 2017;1–6. 10. Ariff Z, Rahman A. Demographic data on the characterization of oral clefts in Malaysia. Pakistan Oral & Dental Journal. 2015; 35(1):108–10. 11. Koga H, Iida K, Maeda T, Takahashi M, Fukushima N. Epidemiologic Research on Malformations Associated with Cleft Lip and Cleft Palate in. 2016;1–10. 12. Patterns of Cleft Lip and Cleft Palate in Northern Pakistan. Arch Clin Exp Surg.2012; 1(2):63-70. 13. Jose BA, Subramani SA, Mokhasi V, Jayan M. Consanguinity and clefts in the craniofacial region : A retrospective case-control study. J Cleft Lip Palate Craniofacial Anomalies. 2015;2(2):113–7. 9 PROFORMA CLEFT LIP AND CLEFT PALATE IN CHILDREN Cases Sr. No: Control Sr. No: Name: Age: Sex: M/ F Date: Length: Weight: z score: Syndromic facies: Y/No Presence of other congenital anomalies: Y/No Congenital Heart Disease: Y/No Talipes equino varus: Consanguinity: Y/No Y/No Mother’s Age: Father’s age: Number in siblings: 1st born 2 3 Any relative with cleft lip: Y/No Sibling with cleft lip and cleft palate: Y/No 4 5 7 Name: Description: ...
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