|Year : 2016 | Volume
| Issue : 1 | Page : 23-31
Prevalent risk factors for nonsyndromic cleft lip and palate in a South-Western Nigerian population
Oginni Fadekemi Olufunmilayo1, Makinde Olufemiwa Niyi2, Adenekan Anthony Taiwo3, Oladele Ayodeji Olarewaju4
1 Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
2 Department of Obstetrics, Gynaecology and Perinatology, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
3 Department of Anaesthesia, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
4 Plastic Surgery Unit, Department of Surgery, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
|Date of Web Publication||9-Feb-2016|
Oginni Fadekemi Olufunmilayo
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, College of Health Sciences, Obafemi Awolowo University, Ile-Ife 220005, Osun State
Source of Support: None, Conflict of Interest: None
Objective: Various risk factors (RFs) have been associated with cleft lip and/or cleft palate (CL/P) in many populations, but none has been identified in a South-Western Nigerian population. We sought to identify the prevailing RFs for nonsyndromic CL/P in the South-Western Nigerian population. Study Design: We conducted a case-control study at Obafemi Awolowo University Teaching Hospital (OAUTH) Ile-Ife. Patients with nonsyndromic CL/P presenting at the OAUTH and randomly selected infants conceived and delivered in the same zone as the patients were studied. We elicited information on RFs for CL/P around subjects' conceptions. Results: 157 patients aged 1 day to 4 months and 157 controls were reviewed. A female preponderance was observed (F:M= 1.24:1). Chi-square tests reveal that mother's age, gravidity at the birth of index child, pregnancy illnesses, child's birth rank, maternal medication use in the first trimester (FT), the absence of antenatal care (ANC), positive family history; and parent's occupational exposure differed significantly between these groups. A logistic regression revealed increased odds of having a child with CL/P with paternal age ≥40 years, maternal age ≤20 years, pregnancy illness, febrile illness in FT, attempted abortion, and birth rank ≥4 th . Furthermore, primigravid status at birth of index child, the absence of ANC, history of neonatal death, medication use in the FT, as well as parent's occupation demonstrated varying increased odds that attained statistical significance. Conclusion: Multiple interrelated factors may be implicated in the etiology of CL/P in the studied population. We advocate prompt health education and public enlightenment directed at addressing and eliminating these RFs.
Keywords: Cleft lip, cleft palate, risk factors
|How to cite this article:|
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
|How to cite this URL:|
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 [serial online] 2016 [cited 2019 Oct 18];3:23-31. Available from: http://www.jclpca.org/text.asp?2016/3/1/23/176001
| Introduction|| |
The contribution of birth defects, including cleft lip and/or palate [CL/P] to neonatal and infant mortality and morbidity worldwide is substantial.  It is estimated that about 8,000,000 children worldwide are born with a serious birth defect of genetic origin annually.  A substantial part of this burden rests in the low-income countries, where its toll has been underestimated for a variety of reasons.  Available data suggests that CL/P is least prevalent in the black African population and most prevalent in Asians and Amerindians. 
Although its etiology remains poorly understood, the multifactorial concept implicating environmental and genetic factors in isolation or in combination is widely accepted.  While the endogenous factors are largely inborn and relatively unpreventable, exogenous factors are influenced mostly by the sequel of human activities, available natural resources, as well as general lifestyles of individuals. Consequently, a number of risk factors (RFs) for CL/P and cleft palate only (CPO) have been proposed over time. The roles of some of these factors are fairly established, but others still relatively contentious.
Previous studies have implicated a variety of RFs in the etiology of congenital malformations generally. ,, Maternal RFs reported for CL/P include the history of fever or cold, use of analgesics, antipyretic drugs, and poor ventilation during heating.  The environmental factors had a stronger association with risk for CL/P, but CPO was influenced more by the history of cleft, maternal smoking,  and folic acid deficiency.  Other implicated factors are higher birth order  and advanced maternal age. 
Donkor et al.  reported low socioeconomic class and relatively young maternal age among Ghanaians while environmental factors were implicated in a Congolese population. 
Previous studies in South-Eastern Nigerian population implicated advanced parents' ages, positive family history, low socioeconomic class, alcohol use, and herbal medication use inconsistently. ,
Since prevailing RFs are bound to vary from place to place, it is paramount to investigate them at various locations. South-Western Nigeria has a population of about 30 million, land mass of 79,665 km 2 , and average population density 685.8/km 2 .  The zone is inhabited predominantly by the Yoruba-speaking Nigerian tribes. Farming is a predominant occupation among the Yorubas with Cocoa being the major cash crop produced. It is one of the most urbanized and economically developed parts of Nigeria, housing most of the nation's first generation higher institutions and their allied healthcare facilities.  To the best of our knowledge, there is no case-control study designed to examine the RFs for CL/P among South-Western Nigerians.
Our goal was to examine some environmental factors identified as RF for CL/P in previous studies among our patients. Based on the previous studies, we hypothesized that maternal febrile illnesses, exposure to tobacco smoke, alcohol use, medication use, advanced maternal/paternal age, and previous neonatal death or stillbirth could be positively associated with having a child with CL/P. Our observations suggest a hypothesis that maternal concoction use, absence of antenatal care (ANC), teenage pregnancy, and attempted abortion could be positively associated with having a child with CL/P. Furthermore, we hope to provide information on preventive strategies relevant to the studied group.
| Study design|| |
A case-control study of the RFs associated with conception and births of patients with nonsyndromic CL/P presenting at the Obafemi Awolowo University Teaching Hospital (OAUTH) over a 7-year period (January 2007 to December 2013) was undertaken. Based on their association with specific malformative patterns or their presence as isolated defects, CL/P were classified as syndromic and nonsyndromic.  We obtained human subjects research review and approval and conducted the research in accordance with the ethics standard of 1964 Declaration of Helsinki and its later amendment. We obtained verbal consent for participation in the study from parents; where mothers were aged <18 years we obtained consent from grandparent(s).
Cases and controls eligibility criteria include age ≤4 months, and conception and birth in South-Western Nigeria. Cases were determined by the presence of CL/P with no specific malformative pattern in patients presenting between January 2007 and December 2013. They were reviewed for information on listed RF, through interviews of the parent(s).
Controls comprising of infants with no birth defects, attending OAUTH well-baby clinics, matched for age and sex as cases were selected randomly. Controls were selected within 2-4 weeks of collecting case data. The mode of data collection and time from birth to interview was similar to that of the cases.
We collected data through an oral interview which usually lasted 10-15 min depending on respondent's comprehension of questions asked and need for clarifications. This was for all an interviewer-administered questionnaire, asking similar questions from the cases and controls; except exemption of CL/P related questions from the controls. Mothers of all cases and controls were interviewed but where present, both parents participated.
We obtained data on parents' and patients' demographic details including parents' ages, occupation, and mother's gravidity at the birth of the index child (patient or subject). Moreover, we inquired about the use of alcohol, orthodox medications, and exposures to tobacco smoke (active or passive) from conception through the end of the first trimester (FT). Responses were obtained in the form of yes or no but additionally, we asked about content(s) of native concoctions taken. We examined other factors like pregnancy illness(es) (classified as febrile and nonfebrile illnesses) during the FT, appraised ANC received, family history of CL/P or CPO, attempted termination of index pregnancy, the birth rank of index child, and gravidity at the birth of index child. Furthermore, we elicited histories of prior stillbirth, neonatal death, and multiple pregnancies.
Maternal age at conception was categorized as ≤20, 21-34 and ≥35 years while paternal age was categorized as ≤25, 26-39 and age ≥40 years.
Parents' occupations served as markers for exposure to chemical agents. Blinded to the case or control status, parents' occupations were dichotomized, modeled as a categorical nominal variable, and graded on a scale of 1-3 based on the risk and possibility of exposure to implicated chemical agents. Categories 1, 2, and 3, respectively were allotted to parents to connote no/low, moderate, and high risks of exposure to toxins, respectively, based on documentations in existing literature. ,, Occupations like office clerk, classroom teacher, homemaker, clergy were grouped into category 1, whereas tailoring, auto mechanic, driving, cloth weaving, produce buying, etc., were grouped into category 2, and large scale/cash crop farming, furniture making, painting, hairdressing, panel beating, soap making, etc., were classified into category 3. Traders were categorized based on what they sold. Where parents engaged in more than one occupation, the one with the higher risk was assumed. Individual parent score of 3 qualifies him or her for high occupational exposure while scores 1 and 2 were classified as absent, low, or moderate level exposure.
Data obtained were entered into a computer system and analyzed using SPSS version 16.0 (SPSS Inc., Chicago, IL). Findings in the cases and controls were compared descriptively and with the Chi-square test. Multivariate analysis was employed to estimate the effect of RFs on CL/P in the studied groups. Statistical significance was inferred at p < 0.05.
| Results|| |
157 patients aged 1 day to 4 months were recruited into the study. A female preponderance was observed (M:F = 1:1.24). [Table 1] illustrates the distribution of sex, age, birth rank, and parents' background characteristics of cases and controls. Mother's age and gravidity at conception differed significantly between the cases and controls (p < 0.05).
|Table 1: Distribution of cases and controls by sociodemographic variables South-Western Nigeria 2007-2013|
Click here to view
[Table 2] demonstrates the parents' occupational exposure and maternal illnesses. A statistically significantly higher proportion of parents in the control group had no or low occupational exposure risks (p < 0.0001). The predominant maternal occupations among cases were trading, farming, hairdressing, and tailoring while fathers were usually farmers, carpenters/furniture makers, and battery charger. Fathers of controls were principally civil servants (mostly teachers, clerks) while mothers were mostly students, teachers, and traders. Similarly, the occurrence of febrile illness in mothers was significantly higher (p < 0.001) among the cases compared with controls.
|Table 2: Distribution of cases and controls by parents' occupational exposure and maternal illnesses South-Western Nigeria 2007-2013|
Click here to view
[Table 3] shows the distribution of some RFs among the controls and cases. A statistically significant difference in maternal medication use, the absence of ANC, positive family history of CL/P, maternal and paternal occupational risk exposures was found between cases and controls.
|Table 3: RFs by all clefts, cleft lip, and cleft lip and palate against control, South-Western Nigeria 2007-2013|
Click here to view
[Table 4] summarizes the results of multivariate analysis estimating the odds ratios (ORs) of the association between the outcome and the independent variables or RF in the study. The effect of maternal age was significant as the odds of having a child with CL/P was much higher for maternal age ≤20 years (OR = 5.86). Moreover, paternal age ≥40 years, (OR = 2.43), birth rank ≥4 th (OR = 2.24), pregnancy illness at FT (OR = 2.03), and febrile illnesses at FT (OR = 1.83) of pregnancy doubled the risk of having a child with CL/P. These did not attain statistical significance (p > 0.05).
|Table 4: Multivariate analysis of RFs for cleft abnormality South-Western Nigeria 2007-2013|
Click here to view
A primigravid maternal status at birth of index child increased the odds of having a baby with CL/P by 5 times (OR = 5.12) than in multigravid mother. The association was statically significant (p = 0.000) [Table 4].
Similarly, the absence of ANC, previous history of neonatal death, medication use within the FT, and parent's involvement in occupation adjudged to expose them to RF increased the probability of having children with CL/P significantly (OR = 4.22-18.58) (p = 0.000-0.045).
| Discussion|| |
Although a series of case reports, observational, and epidemiological studies have generated a long list of implicated RFs,  it is impracticable to examine all the RFs for CL/P in a single study; hence, we examined our patients for some RFs. Our choice of RFs was informed basically by findings of previous studies, personal observations, prevailing sociocultural practices, and ease of recall.
This case-control study found a female preponderance among CL/P patients studied. This finding is at variance with previous studies that have found slight male preponderance  or an equal ratio.
Selecting controls matched for age, sex, and place of birth was aimed at controlling confounders that could not be assessed easily (such as environmental hazards, socioeconomic status, or access to healthcare). That was the best we could do given the prevailing circumstances.
Advanced parental ages have been implicated in the risk for having children with CL/P by many studies;  the suggested mechanism being the presence of a single gene mutation. Although the debate on "how old is too old" is ongoing, the majority have set the limit at ≥35 years.  Despite the fact that societal changes have led to beginning families relatively later,  this has had no influence on the set age limits. Rather it has been associated with the advances in reproductive technology. Our findings support the implication of advanced age,  and also agrees with an association between young maternal age and presence of congenital malformations.  The very young mothers demonstrated related RFs like attempted illegal abortion and failure to receive ANC.
Being primigravid at the birth of index child appears to be a statistically significant risk for having a child with CL/P. This finding is in agreement with studies that have found the first birth rank as the most prevalent associated with CL/P.  Based on anecdotal reports, we may deduce that primigravid women are usually relatively inexperienced and uninformed about ANC. Similarly, compared with the control, a higher proportion of mothers had gravidity ≥4 at the birth of index patient [Table 1]. This finding agrees with previous reports that have implicated increased maternal/paternal ages and associated gene mutation with increasing age. 
A significantly greater proportion of cases reported a history of illness (febrile more than nonfebrile-illness) during pregnancy compared to controls. While this was strongly significant at the bivariate level (p < 0.001) [Table 2], the observed association appeared to have been due to confounding bias as it was not significant in a multivariate analysis. Most febrile illnesses in cases were identified as malaria fever by mothers (25/41 = 61.0%) and self-managed with regular antimalaria drugs (chloroquine sulfate or amodiaquine) purchased over the counter (OTC) and or native concoction. On rare occasions, they were typhoid fever (4 cases = 9.8%).
Although febrile illnesses are common in the tropics, and South-Western Nigeria is holoendemic for malaria, cases of febrile illnesses are often but not always malaria.  Among controls, maternal illnesses were described predominantly as "morning sickness" (11/14 = 78.6%), which was often self-limiting. Febrile illnesses were rarer among controls, (7.0%) and were managed in hospitals in all cases except one.
A review of chemoprophylaxis and curative treatment of malaria in pregnancy in orthodox healthcare practice; paying particular attention to possible passage of teratogens, from the mother to the embryo/fetus between the 4 th and 9 th week of intrauterine life was undertaken. Medications employed at the relevant period are rated safe (nonteratogenic) when administered in approved therapeutic dosages. Additionally, prolonged continuous daily or weekly administration of antimalarials was avoided because of existing "holoendemicity" and "herd immunity." The period under review witnessed increased resistance of Plasmodium falciparum to most antimalarials, and the emergence of a new national treatment guideline, (intermittent preventive therapy [IPT]) for prophylaxis.  The IPT is not prescribed in the FT because of possible teratogenic effects; hence, it is unlikely that antimalarials prescribed and administered in standard orthodox healthcare facilities will be harmful to the mother-fetus pair; except on the rare occasion of inaccurate menstrual history.
While it is difficult to conclude that all reported illnesses had a direct significance to the outcome of pregnancy (especially among the cases), we consider it crucial to establish (through longitudinal studies) the exact link between maternal febrile illnesses and CL/P in our population. Possibly some of the illnesses tagged malaria were other types of febrile illnesses possessing inherent tendencies to induce the formation of congenital anomalies. ,
In this study, the absence of proper ANC increased the risk of having a child with CL/P by four-fold. While it is known that a substantial proportion (about 60%) of babies in South-Western Nigeria are delivered outside the hospital setting  predominant delivery locations in our study group, include homes, religious mission houses, and traditional birth attendants' places, etc. Avoidance of ANC in hospitals may be attributed to poverty, cultural beliefs, religious inclinations, perceived attitude of hospital personnel to clients, anticipated delay/prolonged hospital stay, and avoidance of caesarean section. Absent or inadequate ANC is a possibly a marker for low socioeconomic/educational status, poverty, malnutrition and attendant tendencies to engage in self-medication, OTC medication use, native doctor patronage, and other unhealthy practices. Although some of the religious homes that engage in ANC have some orthodox presence, this could be regulated and extended to other similar settings. Introducing incentives for early antenatal booking and regular clinic attendance may encourage mothers' participation and avoidance of some RF.
In this study, medication use in the FT increased the risk of having a child with CL/P by six-fold. The most common medications used were various brands of antimalarials and acetaminophen. Widespread and indiscriminate use of antimalarials (and other medications) by pregnant women due to the ease of accessing and procuring such drugs OTC is common in our environment. A pharmacokinetic study has revealed an increased metabolism of antimalarials (e.g., chloroquine) with increased concentration of metabolites like desmethyl chloroquine (potentially teratogenic) in the third trimester.  It is opined that an increased metabolism may also occur in the FT thus increasing the probability of teratogenicity.  Acetaminophen was the most common of the orthodox medications taken among the mothers studied, like in an Ethiopian study. 
Attempted abortion as a RF for CL/P is sparsely reported in literature. We found this predominantly in young unmarried mothers (not statistically significant). A disquieting side to this is availability prescription medication OTC, serving abortifacients in mothers with unwanted pregnancies. A mother employed high-dose IM Gentamycin (180 mg daily for 7 days). We presume that some/most of such attempts may not have been disclosed to us; since abortion is illegal in Nigeria.
Unintentional continuous use of oral contraceptives was reported occasionally among cases. This observation could be suggestive of an ill-defined association between oral contraceptive use and birth defects. 
Folk medicine is knowledge of the mode of treatment or traditional beliefs common to a group of rural people.  Use of native concoction or herbal preparations is a part of Nigeria's cultural life and was reported across cases and controls. Despite widespread orthodox medical practice, their uses appear to be enduring as shown by this study. They are taken voluntarily or enforced as part of family rites and tradition, acclaimed to be essential for the health of mother-fetus pair. Avoidance of orthodox medications has also been attributed to unpleasant adverse reactions (e.g., pruritus with chloroquine), exorbitant costs, and traditional/cultural beliefs.
Interestingly, respondents knew the names but not always the content of the preparations they took. These preparations are usually made locally, untailored, with no standardization of content, and concentration or recommended doses. Regular content includes seeds, roots, herbs, fruits, spices, animal parts, etc., with water or alcohol as solvents.
The occupational risks in both parents demonstrated a significant association with having a child with CL/P. Among cases, father's occupation was predominantly farming, carpentry, and furniture making, but controls were mostly civil servants (predominantly teachers and clerks). The exposure of farmers to pesticides, fertilizers, etc., and furniture/woodworkers to a variety of chemical solvents, wood preservatives, etc., have been identified as possible RF.  In concordance with previous reports, history of exposure to such agents was less among control.  We elicited instances where chemicals were stored in respondents' homes/bedrooms.
Mothers of children with CL/P, on the other hand, were mostly traders (usually in cloth related wares and cosmetic agents) and tailors/fashion designers. This concurs with an earlier report of an association between textile workers and orofacial anomalies in their offsprings.  The likelihood of contact with residual dye on the fabrics and threads cannot be ruled out. 9.6% of mothers among cases were hairdressers, a profession that brings them into regular contact with agents implicated in the risk of abortion  and birth defect.  Contrariwise, mothers of controls were usually civil servants, class teachers, and students in higher institutions. We believe that public enlightenment on occupational health hazards and birth defects should be given serious attention. Moreover, research efforts, directed at examining specific occupation, and determining their exposure risks longitudinally should be in place.
We found no association between maternal alcohol use and CL/P in the studied group. Culturally, alcoholism is not fashionable among women of childbearing age in South-Western Nigeria. Thus, it is not a popular open practice in the study location. Consequently, the possibility of concealing the practice in mothers may be high. Nevertheless, (12 = 7.6% and 8 = 5.2%) of mothers of cases and controls, respectively, had a positive history of alcohol use in pregnancy. Interestingly, alcohol was a component of native concoction taken in over half (11/20) of them. Alcohol use (alone or as solvents in concoctions) among mothers of childbearing age should be discouraged.
Previous studies have identified previous neonatal deaths as a predictor of the presence of CL/P; in this series this subset demonstrated 185% increased the risk of having a child with CL/P though not statistically significant. The prevalent cultural inclination prohibits recounting unpleasant circumstances like neonatal deaths, stillbirths or births of children with defects for fear of stigmatization, recurrence, and keeping a memory that remains a hurt. Regrettably our registry systems are not capable of helping to verify informants' submissions.
We found no association between exposure to tobacco smoke, history of stillbirth, attempted abortion, multiple pregnancy, and positive family history. Like alcohol use, smoking is not admired in women of childbearing age, although more common among cases, all mothers admitted to passive smoking only.
Some studies have linked multiple pregnancies with a risk of birth defects, but ours has shown that spontaneous multiple pregnancies were, in fact, more common among controls. We attribute this to the relatively high incidence of spontaneous twinning (one of the highest globally) in South-Western Nigeria. 
The cases, however, had greater representation in the high birth order. This concurs with the inconclusive findings of a meta-analysis. 
We identified some limitations of this study. Despite the age restriction in subjects studied, there is a possibility of recall bias. Deliberate underreporting of sensitive occasions like an attempted abortion, alcohol use, etc., are likely, because of guilt or shame.
We relied on occupational titles rather than onsite assessment in evaluating the risk of exposure. Pregnancy illness as described by mothers may have limited reliability. Though classified as febrile and nonfebrile, it excludes severity and are not perfectly defined. Likewise, it was difficult to assess the exact dosages of medication used. While creating an index for occupational exposures might bias association, we find this style of presentation appropriate for the diversity of occupation represented in the study group.
| Conclusion|| |
Our findings suggest that possible predictors of CL/P in an offspring include maternal age ≤20 years, primigravid status at birth of index child, medication use, the absence of ANC, paternal occupation exposure, and previous neonatal death.
Overall, we see a picture of interrelated or network effect of related RF at play and these may be grouped in triads or quadruples. These conditions that tend to propagate each other include young motherhood (teenage pregnancy), failed attempted abortion, self-medication, and default from ANC.
We advocate prompt health education and public enlightenment programs directed at curbing poor health seeking behaviors particularly associated with teenage pregnancy, protection from occupational hazards, and encouraging comprehensive ANC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hunt O, Burden D, Hepper P, Johnston C. The psychosocial effects of cleft lip and palate: A systematic review. Eur J Orthod 2005;27:274-85.
UNICEF Information Fact Sheet on Birth Registrations in Nigeria; July, 2007.
Laura EM. Epidemiology of cleft lip and palate. In: Comprehensive Cleft Care. New York: McGraw-Hill Medical Inc.; 2009. p. 35-42.
Krost B, Schubert J. Influence of season on prevalence of cleft lip and palate. Int J Oral Maxillofac Surg 2006;35:215-8.
Varela MM, Nohr EA, Llopis-González A, Andersen AM, Olsen J. Socio-occupational status and congenital anomalies. Eur J Public Health 2009;19:161-7.
Meadow SR. Congenital abnormalities and anticonvulsant drugs. Proc R Soc Med 1970;63:48-9.
Hooiveld M, Haveman W, Roskes K, Bretveld R, Burstyn I, Roeleveld N. Adverse reproductive outcomes among male painters with occupational exposure to organic solvents. Occup Environ Med 2006;63:538-44.
Wang W, Guan P, Xu W, Zhou B. Risk factors for oral clefts: A population-based case-control study in Shenyang, China. Paediatr Perinat Epidemiol 2009;23:310-20.
Chung KC, Kowalski CP, Kim HM, Buchman SR. Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate. Plast Reconstr Surg 2000;105:485-91.
Shaw GM, Lammer EJ, Wasserman CR, O′Malley CD, Tolarova MM. Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet 1995;346:393-6.
Hollier LM, Leveno KJ, Kelly MA, MCIntire DD, Cunningham FG. Maternal age and malformations in singleton births. Obstet Gynecol 2000;96(5 Pt 1):701-6.
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.
Longombe AO, Tshimbila Kabangu JM. The epidemiological approach of clefts lip and palate in the eastern of Democratic Republic of Congo. Ann Chir Plast Esthet 2012;57:245-9.
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. Available from: http://www.intermedcentral.hk/
. [Last accessed on 2014 Jul 10].
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.
Stuppia L, Capogreco M, Marzo G, La Rovere D, Antonucci I, Gatta V, et al.
Genetics of syndromic and nonsyndromic cleft lip and palate. J Craniofac Surg 2011;22:1722-6.
Chia SE, Shi LM. Review of recent epidemiological studies on paternal occupations and birth defects. Occup Environ Med 2002;59:149-55.
Herdt-Losavio ML, Lin S, Chapman BR, Hooiveld M, Olshan A, Liu X, et al.
Maternal occupation and the risk of birth defects: An overview from the National Birth Defects Prevention Study. Occup Environ Med 2010;67:58-66.
Iregbulem LM. The incidence of cleft lip and palate in Nigeria. Cleft Palate J 1982;19:201-5.
Bille C, Skytthe A, Vach W, Knudsen LB, Andersen AM, Murray JC, et al.
Parent′s age and the risk of oral clefts. Epidemiology 2005;16:311-6.
Bianchi F, Hemminki K, Kyyronen P, Vaittinen P. Parental age as a risk factor of childhood leukaemia and brain cancer in offspring. Epidemiology 1999;10:271-5.
Blickstein I. Motherhood at or beyond the edge of reproductive age. Int J Fertil Womens Med 2003;48:17-24.
Croen LA, Shaw GM. Young maternal age and congenital malformations: A population-based study. Am J Public Health 1995;85:710-3.
Nwosu J, Odubanjo MO, Osinusi BO, editors. The Nigerian Academy of Science 2009 Reducing Maternal and Infant Mortality in Nigeria (Workshop Summary). Lagos, Nigeria: West African Book Publishers; 2009. p. 35-43.
Acs N, Bánhidy F, Puhó E, Czeizel AE. Maternal influenza during pregnancy and risk of congenital abnormalities in offspring. Birth Defects Res A Clin Mol Teratol 2005;73:989-96.
Orimadegun AE, Akinbami FO, Tongo OO, Okereke JO. Comparison of neonates born outside and inside hospitals in a children emergency unit, southwest of Nigeria. Pediatr Emerg Care 2008;24:354-8.
Chukwuani MC, Bolaji OO, Onyeji CO, Makinde ON, Ogunbona FA. Evidence for increased metabolism of chloroquine during the early third trimester of human pregnancy. Trop Med Int Health 2004;9:601-5.
Kassaw C, Wabe NT. Pregnant women and non-steroidal anti-inflammatory drugs: Knowledge, perception and drug consumption pattern during pregnancy in ethiopia. N Am J Med Sci 2012;4:72-6.
Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980;112:73-9.
Sofowora EA. Medicinal Plants and Traditional Medicine in Africa. Chichester: John Willy & Sons Limited; 1982. p. 1-256.
John EM, Savitz DA, Shy CM. Spontaneous abortions among cosmetologists. Epidemiology 1994;5:147-55.
Akinboro A, Azeez MA, Bakare AA. Frequency of twinning in southwest Nigeria. Indian J Hum Genet 2008;14:41-7.
Vieira AR, Orioli IM. Birth order and oral clefts: A meta-analysis. Teratology 2002;66:209-16.
[Table 1], [Table 2], [Table 3], [Table 4]