|ORIGINAL ARTICLE - RETROSPECTIVE STUDY
|Ahead of print publication
Parental age and the risk of cleft lip and palate in a Nigerian population: A case–control study
Olutayo James1, Olufemi A Erinoso2, Ajoke O Ogunlewe3, Wasiu L Adeyemo1, Akinola L Ladeinde1, Mobolanle O Ogunlewe1
1 Department of Oral and Maxillofacial Surgery, Lagos University Teaching Hospital, Idi Araba; College of Medicine, University of Lagos, Lagos, Nigeria
2 Department of Oral and Maxillofacial Surgery, Lagos University Teaching Hospital, Idi Araba, Nigeria
3 Department of Paediatrics, Lagos University Teaching Hospital, Idi Araba, Lagos, Nigeria
|Date of Submission||21-Apr-2020|
|Date of Acceptance||13-May-2020|
|Date of Web Publication||24-Aug-2020|
C/O Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos
Source of Support: None, Conflict of Interest: None
Background: Orofacial clefts are one of the most common congenital malformations in the facial region. Hypothesis: Older maternal or paternal age presents higher odds of a child with an orofacial cleft. Objective: The objective of the study was to assess the association between parental age and risk of orofacial cleft. Materials and Methods: This was a case–control study among 110 parents of children with orofacial cleft (case group) and 110 parents of children without orofacial cleft (control group). Information on maternal age, paternal age, and type of orofacial cleft in the children were obtained. The results were analyzed using descriptive statistics, Chi-square analysis, and bivariate logistic regressions to measure the association between parental age and orofacial cleft. The value of P was <0.05, with a 95% confidence interval (CI). Results: Information on 219 children (109 cases and 110 controls) was analyzed, of which 52% were females. One respondent from the case group withdrew from the study. The odds of a child with orofacial cleft was statistically significantly lower in mothers aged 26–35 years compared to mothers aged 25 years and less (odds ratio [OR]: 0.32; 95% CI: 0.16, 0.79). Similarly, fathers aged above 35 years had statistically significantly lower odds of children with orofacial cleft than those 25 years and less (OR: 0.18; 95% CI: 0.02, 0.99). Conclusion: Our findings suggest that mothers aged 26-35 years may have lower odds of giving birth to babies with orofacial clefts, compared to younger mothers. Similarly, fathers aged above 35 years may have lower odds of giving birth to a child with orofacial cleft compared to fathers aged 25 years and less.
Keywords: Cleft lip, cleft palate, maternal age, paternal age
|How to cite this URL:|
James O, Erinoso OA, Ogunlewe AO, Adeyemo WL, Ladeinde AL, Ogunlewe MO. Parental age and the risk of cleft lip and palate in a Nigerian population: A case–control study. Ann Maxillofac Surg [Epub ahead of print] [cited 2020 Dec 4]. Available from: https://www.amsjournal.com/preprintarticle.asp?id=293313
| Introduction|| |
Orofacial clefts are one of the most common congenital malformations in the skull and facial area.,, The global incidence of cleft lip and palate (CLP) is reported to be 1 in 700 among Asians, 3.6/1000 live births in the American Indians, and 1/1000 live births among Caucasians. Reports of prevalence from the African populations vary widely, from 0.5/1000 reported in Nigeria to 0.2/1000 reported in Ethiopia. Globally, the prevalence is highest in oriental populations and lowest in Africans.
Orofacial clefts can present clinically as an isolated defect or as part of a syndrome when associated with (usually two or more) malformations in recognizable patterns., The etiology of orofacial cleft is generally believed to be as a result of an interaction between genetic and environmental factors. With advances in genetics and molecular biology, more studies identifying the combined genetics and environmental risk factors responsible for CLP are emerging., Genes such as those encoding transcription factors (MSX1) and growth factors (TGFA and TGFB3) have been implicated in the etiology of CLP,, while environmental risk factors such as maternal exposure to tobacco smoke,, alcohol,, folic acid deficiency,, birth order, and maternal diseases such as diabetes have been reported to play a role.
The relative uncertainty surrounding the effect of parental age presents a gap in our understanding of risk factors for orofacial cleft. There is no consensus on whether or not it is a risk factor for CLP., Investigating the relationship with parental age will expound on the etiology and support a biologic and a public health perspective on preventive measures for orofacial clefts.
A few studies have been conducted according to the recommendation of the International Consortium for oral clefts genetics investigating the relationship between parental age and the incidence of orofacial clefts., In the United States, a population-based study carried out in California showed that women older than 39 years had twice the risk of having a child with CLP when compared to mothers between 25 and 29 years. Similarly, DeRoo et al. found an association between cleft palate (CP) and women below 20 years. These findings support other studies, which found various associations between parental age and orofacial cleft. On the contrary, several studies,, have found no such association between orofacial cleft and parental age. Further, meta-analytic studies by Vieira et al. and Herkrath et al. have given conflicting reports on the relationship between orofacial clefts and parental age. In Africa, the relationship between orofacial cleft and parental age remains unclear, with several studies detailing increased risk with advanced parental age, and others the opposite.,
The aim of this study is to assess the relationship between parental age and the risk of orofacial clefts in our population. Findings from this study will enable us to test the hypothesis that older maternal or paternal age results in a higher risk of giving birth to babies with orofacial clefts.
| Materials and Methods|| |
We conducted a case–control study among 110 parents of children with orofacial cleft (case group) and 110 parents of children without CL/P (control group). One respondent from the case group withdrew from the study.
Study population and settings
Participants in this study consisted of patients from the orofacial cleft and pediatric outpatient clinics at a university teaching hospital in Lagos, Nigeria. Approval was obtained from the Health Research Ethics Committee of the Hospital.
The case–control study recruited patients from two clinical sites at the hospital – cases from the orofacial cleft clinic and controls from the pediatric outpatient clinics. The period of the study was between January 2017 and January 2019. The parents of the selected cohort of patients for this study had been attending either the orofacial cleft or pediatric clinic for at least 6 months before the beginning of the study. Diagnoses of orofacial cleft were coded according to the International Classification of Diseases (ICD), and the 10th ICD revision was used for this study (ICD 10. Q35–37 code).
Findings of a previous study conducted by Mbuyi-Musanzayi et al. were used to estimate the least extreme odds ratio (OR) to be detected at 3.5 for maternal age. Ninety-five children were required in each group (orofacial cleft vs. controls) after accounting for 10% attrition rate. Hence, an orofacial cleft to control ratio was 1:1, requiring 95 children with orofacial cleft and 95 controls. This was increased to 110 in each group for better representation as well as to account for nonresponse.
The inclusion criteria were all children born with CL/P aged between 0 and 12 years for cases (syndromic and nonsyndromic) and children born without CL/P aged between 0 and 12 years for controls (with and without other congenital anomalies). The exclusion criteria were cases with Tessier clefts, individuals from whom we were unable to obtain parental/guardian consent to participate in the study, as well as parents of children who could not ascertain their age.
The primary outcome was the presence or absence of orofacial cleft in a child patient. In this study, the term orofacial cleft is subsequently defined as cleft lip with or without palate (CL/P). The exposure we investigated was parental age at birth of the child. Parental age as defined in this study referred to the independently measured age of the mother (maternal age) and father (paternal age) of a child with CL/P at birth.
Data collection tool
A pro forma questionnaire that contained information about the parents and children was developed. It was interviewer administered and filled for every individual. Data obtained included bio data of parents and children, the age of the father at the birth of the child, the age of the mother at the birth of the child, and the date of birth of the child patient. Parental age was unmatched. However, to reduce confounding from age, the lower limit and upper limits of parental age were placed at 18 and 60 years, respectively. Maternal age was categorized as 25 years and less, 26–35 years, and above 35 years. Paternal age was categorized similarly. The categorization of maternal and paternal age was adapted from prior studies.,,
Ascertainment of cleft
The presence or absence of CL/P was determined by both active and passive ascertainment methods. First, the patient records were screened for patients who fit the case and control eligibility at the cleft and pediatric outpatient clinics, respectively. After passive ascertainment using patient records, all participants were interviewed and examined during clinic visits by two trained research assistants at the respective clinics. During the clinical examination, a pro forma questionnaire was filled, and information from the patient's records was confirmed before entry.
The primary objective of the study was to examine the association between parental age (age of the mother and father independently) and orofacial cleft. Frequencies, percentages (approximated to nearest decimal unit), and Chi-square and logistic regressions were used to compare groups as appropriate. The data were analyzed with the OR for each variable with a 95% confidence interval (CI). Statistical significance was inferred at P < 0.05. The analysis was carried out using the STATA 15.0 software (StataCorp LLC Lakeway Drive, College Station, Texas).
| Results|| |
This was a case–control study among 109 (49.8%) parents of children with orofacial cleft (case group) and 110 (50.2%) parents of children without the orofacial cleft (control group). One respondent from the case group withdrew from the study [Table 1].
The mean maternal age in cases was 29.7 years (range: 16–45 years), while the mean age for controls was 31.3 years (range: 20–48 years). The mean paternal age in cases was 35.8 years (range: 22–55 years), and for controls, it was 37.2 years (range: 23–52 years) [Table 1].
[Table 2] demonstrates a significant association between maternal age and orofacial cleft (<0.05). In the case group, there is a higher proportion (77.3%) of orofacial clefts in mothers aged 25 years and less. The proportion of orofacial cleft decreases with increasing age in cases and inversely in the control group. Bivariate analysis on [Table 3] demonstrates that the maternal age of 26–35 years had statistically significantly reduced odds of orofacial cleft compared to ≤25 years (OR: 0.32; 95% CI: 0.16, 0.79; P: 0.007). Similarly, the maternal age >35 years had reduced odds of orofacial cleft compared to ≤25 years (OR: 0.21; 95% CI: 0.06, 0.66; P: 0.003).
|Table 2: Chi-square analysis of maternal and paternal age in cases and controls|
Click here to view
|Table 3: Bivariate analysis of the maternal and paternal age in the “case” and “control” groups|
Click here to view
On assessing the association between paternal age and orofacial cleft, there was an inverse relationship between paternal age and orofacial cleft [Table 2]. Chi-square analysis demonstrates that as paternal age increases, the proportion of orofacial cleft reduces and inversely for controls (P < 0.05).
[Table 3] displays a bivariate analysis which shows reduced odds of orofacial cleft in the age group 26–35 years compared to ≤25 years (OR: 0.32; 95% CI: 0.03, 1.75; P: 0.15), however, not statistically significant. On the other hand, the age group >35 years had statistically significantly reduced odds of orofacial cleft compared to ≤25 years (OR: 0.18; 95% CI: 0.02, 0.99; P: 0.02) [Table 3].
| Discussion|| |
Our findings reject the hypothesis that increasing maternal age is associated with a higher risk of orofacial cleft in a child. The findings from our study suggest that younger mothers aged 25 years and less have a higher risk of having a child with orofacial cleft compared to mothers above 25 years. Our findings are supported by Olufunmilayo et al. who reported a higher risk of orofacial in the children of mothers younger than 20 years of age. Similarly, Martelli et al., reported an increased risk for CP in mothers <25 years, compared to mothers above 26 years. Other studies have reported the same association between maternal age and the risk of orofacial cleft.,
Multiple studies,, have also reported a higher risk of orofacial cleft with increasing maternal age. In a meta-analysis conducted by Herkrath et al., older maternal age was reported to increase the risk of having a child with nonsyndromic orofacial cleft. In this study, mothers aged between 35 and 39 years had a 20% higher odds of having a child with nonsyndromic orofacial clefts compared to mothers aged between 20 and 29 years. A possible explanation for this relationship may be accumulating environmental exposures as well as chromosomal mutations in aging mothers. Further, a number of studies have reported no relationship between maternal age and the occurrence of oral cleft lip with or without palate.,,,,,, Vieira et al. in a review of eight population-based studies found no association between increasing maternal age and the occurrence of orofacial cleft in children. However, limitations such as the nonadjustment for the presence of syndromes and other risk factors pose a challenge in the interpretation of these findings.
A possible explanation for the increased occurrence of orofacial cleft in younger mothers aged 25 years and less may be a lack of physical maturity and deficiency in vitamins, notably folic acid, which has been associated with congenital disabilities. In addition, teenage pregnancies are more common in low-income families in Nigeria, and the latter may contribute to nutritional deficiencies resulting in the prevalence of orofacial cleft in this segment of the population.
Our findings on paternal age were less conclusive, as paternal age of 25 years and less was not significantly associated with a higher risk of orofacial cleft compared to older paternal age (26–35 years). A significantly lower risk was however found with paternal age above 35 years compared to paternal age of 25 years and less. Contrary to our finding, Mbuyi-Musanzayi et al. reported a higher risk of orofacial cleft when the paternal age is above 35 years compared to between 26 and 35 years. Similar to the suggested origin of increased risk with older maternal age, the increased risk associated with advanced paternal age may be based on a higher rate of de novo mutation in sperm with older age in fathers., Further, in assessing the combined association of both parental ages with orofacial cleft in 2,449,218 births from a Norwegian birth registry between 1967 and 2010, Berg and colleagues reported that the risk of having a child with orofacial cleft increased only when the age of both parents was advanced.
We identify a limitation in this study. Our case and control populations were not age and sex matched. Nonetheless, a key strength of the present study is that it presents accurate data on selected cases and controls in assessing the association of parental age on the occurrence of CL/P.
| Conclusion|| |
The findings from our study suggest that maternal age of 25 years and less may pose a higher risk for orofacial cleft than above 25 years. Similarly, paternal age below of 25 years and less demonstrated a significantly higher risk of orofacial cleft than above 35 years. Future studies could consider the relationship between parental age and different patterns of cleft lip with and without palate, as well as in strictly syndromic or nonsyndromic populations. Further, studies could investigate the interaction of factors such as a parental tobacco smoking, alcohol consumption, the use of folic acid during pregnancy, and with parental age on the risk of orofacial cleft. Epidemiologic studies of orofacial cleft remain relevant to clinical and public health research, as it provides evidence for counseling parents as societal changes are trending towards millennials beginning families relatively later.
The authors would like to thank the clinical and non-clinical staff of the cleft and pediatric community health clinics at Lagos University Teaching Hospital, Lagos State, Nigeria.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Martelli DR, Cruz KW, Barros LM, Silveira MF, Swerts MS, Martineli-Júnior HM. Maternal and paternal age, birth order and inter-pregnancy interval evaluation for cleft lip palate. Braz J Otorhinolaryngol 2010;76:107-12.
Aquino SN, Paranaíba LM, Martelli DR, Swerts MS, Barros LM, Bonan PR, et al
. Study of patients with cleft lip and palate with consanguineous parents. Braz J Otorhinolaryngol 2011;77:19-23.
Impellizzeri A, Giannantoni I, Polimeni A, Barbato E, Gallucio E. Epidemiological characteristic of Orofacial clefts and its associated congenital anomalies: Retrospective study. BMC Oral Health 2019;19:290. https://doi.org/10.1186/s12903-019-0980-5
Omo-Aghoja VW, Omo-Aghoja LO, Ugboko VI, Obuekwe ON, Saheeb BD, Feyi-Waboso P, et al.
Antenatal determinants of oro-facial clefts in Southern Nigeria. Afr Health Sci 2010;10:31-9.
Butali A, Mossey PA. Epidemiology of orofacial clefts in Africa: Methodological challenges in ascertainment. Pan Afr Med J 2009;2:5.
Butali A, Adeyemo WL, Mossey PA, Olasoji HO, Onah II, Adebola A, et al
. The Nigeria CRAN collaboration. Cleft Palate Craniofac J 2014;51:320-5.
Eshete M, Butali A, Deressa W, Pagan-Rivera K, Hailu T, Abate F, et al
. Descriptive epidemiology of orofacial clefts in ethiopia. J Craniofac Surg 2017;28:334-7.
Eshete M, Butali A, Abate F, Hailu T, Hailu A, Degu S, et al
. The role of environmental factors in the etiology of nonsyndromic orofacial clefts. J Craniofac Surg 2020;31:113-6.
Marazita ML, Field LL, Cooper ME, Tobias R, Maher BS, Peanchitlertkajorn S, et al
. Nonsyndromic cleft lip with or without cleft palate in China: Assessment of candidate regions. Cleft Palate Craniofac J 2002;39:149-56.
Vieira AR. Unraveling human cleft lip and palate research. J Dent Res 2008;87:119-25.
Junaid M, Narayanan MB, Jayanthi D, Kumar SG, Selvamary AL. Association between maternal exposure to tobacco, presence of TGFA gene, and the occurrence of oral clefts. A case control study. Clin Oral Investig 2018;22:217-23.
Bille C, Skytthe A, Vach W, Knudsen LB, Andersen AM, Murray JC, et al
. Parent's age and the risk of oral cleft. Epidemiology 2005;16:311-6.
Mitchell LE, Beaty TH, Lidral AC, Munger RG, Murray JC, Saal HM, et al
. Guidelines for the design and analysis of studies on nonsyndromic cleft lip and cleft palate in humans: Summary report from a Workshop of the International Consortium for Oral Clefts Genetics. Cleft Palate Craniofac J 2002;39:93-100.
Shaw GM, Croen LA, Cury CJ. Isolated oral cleft malformations: Associations with maternal age and infant characteristics in a California population. Teratology 1991;43:225-8.
DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleft malformations: Associations with maternal and infant characteristics in Washington State. Birth Defects Res A Clin Mol Teratol 2003;67:637-42.
Baird PA, Sadovnick AD, Yee IM. Maternal age and oral cleft malformations: Data from a population-based series of 576,815 consecutive livebirths. Teratology 1994;49:448-51.
Vieira AR, Orioli IM, Murray JC. Maternal age and oral clefts: A reappraisal. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:530-5.
Herkrath AP, Herkrath FJ, Rebelo MA, Vettore MV. Parental age as a risk factor for non-syndromic oral clefts: A meta-analysis. J Dent 2012;40:3-14.
Mbuyi-Musanzayi S, Kayembe TJ, Kashal MK, Lukusa PT, Kalenga PM, Tshilombo FK, et al
. Non-syndromic cleft lip and/or cleft palate: Epidemiology and risk factors in Lubumbashi (DR Congo), a case-control study. J Craniomaxillofac Surg 2018;46:1051-8.
Figueiredo JC, Ly S, Magee KS, Ihenacho U, Baurley JW, Sanchez-Lara PA, et al
. Parental risk factors for oral clefts among Central Africans, Southeast Asians, and Central Americans. Birth Defects Res A Clin Mol Teratol 2015;103:863-79.
Olufunmilayo OF, Niyi MO, Taiwo AA, Olarewaju OA. Prevalent risk factors for nonsyndromic cleft lip and palate in a South-Western Nigerian population. J Cleft Lip Palate Craniofac Anomal 2016;3:23-31. [Full text]
Donkor P, Plange-Rhule G, Amponsah EK. A prospective survey of patients with cleft lip and palate in Kumasi. West Afr J Med 2007;26:14-6.
Carvalho PH, Machado RA, Almeida Reis SR, Martelli DR, Dias VO, Martelli-Júnior H. Parental age is related to the occurrence of cleft lip and palate in Brazilian populations. Braz J Oral Sci 2016;15:167-70.
Eigbogbo JO, Ututu C, Akadiri OA, Akinbami BO. Parental demography and antenatal events associated with cleft lip and palate deformities in Nigerian population. J Symptoms Signs 2012;1:1-6.
Baird PA, Sadovnick AD, Yee IM. Maternal age and birth defects: A population study. Lancet 1991;337:527-30.
Rajabian MH, Sherkat M. An epidemiologic study of oral clefts in Iran: Analysis of 1,669 cases. Cleft Palate Craniofac J 2000;37:191-6.
Menegotto BG, Salzano FM. Epidemiology of oral clefts in a large South American sample. Cleft Palate Craniofac J 1991;28:373-6.
Amoran OE. A comparative analysis of predictors of teenage pregnancy and its prevention in a rural town in Western Nigeria. Int J Equity Health 2012;11:37.
Oldereid NB, Wennerholm UB, Pinborg A, Loft A, Laivuori H, Petzold M, et al
. The effect of paternal factors on perinatal and paediatric outcomes: A systematic review and meta-analysis. Hum Reprod Update 2018;24:320-89.
Bergh C, Pinborg A, Wennerholm UB. Parental age and child outcomes. Fertil Steril 2019;111:1036-46.
Berg E, Lie RT, Sivertsen A, Haaland OA. Parental age and the risk of isolated cleft lip: A registry-based study. Ann Epidemiol 2015;25:942-7.e941.
[Table 1], [Table 2], [Table 3]