Maternal malnutrition, environmental exposure during pregnancy and the risk of non-syndromic orofacial clefts

Oral Diseases (2011) 17 , 584–589 Objective: To explore the risk factors of non‐syndromic orofacial clefts. Subjects and Methods: A case–control study was conducted in China, 537 infants born with non‐syndromic cleft lip with/without cleft palate, 176 infants born with cleft palate (CP), and 221 normal controls were recruited to participate in a questionnaire based study to identify risk factors related to maternal nutrition. Results: Single‐factor Chi‐square analysis identified 12 factors as significantly related to non‐syndromic orofacial clefts (P < 0.05). Multiple logistic regression showed five of these factors were associated with non‐syndromic orofacial clefts, male gender and maternal passive smoking during early pregnancy were risk factors for non‐syndromic orofacial clefts (OR = 1.86 and 11.42; 95%CI: 2.28–2.69 and 6.87–19.00, respectively), whereas maternal weight gain during pregnancy and folic acid supplementation during early pregnancy were protective (OR = 0.15 and 0.67; 95%CI: 0.034–0.63 and 0.44–1.00, respectively). Conclusions: Our data may provide references for cleft lip and CP prevention programs, and counseling programs in China.     

Maternal drug use and infant cleft lip/palate with special reference to corticoids.

OBJECTIVE: To study the association between maternal drug use in early pregnancy and orofacial cleft in the infant. DESIGN: Register analysis based on prospectively collected information.Patients: All delivered women in Sweden July 1, 1995, through December 31, 2001. MAIN OUTCOME MEASURE: Presence of orofacial cleft in infant. RESULTS: Prospective information on maternal drug use during the first trimester, as reported in early pregnancy, was studied in 1142 infants with orofacial clefts, isolated or with other malformations, excluding chromosome anomalies. Any drug use was not associated with clefts (odds ratio [OR] = 0.98, 95% confidence interval [95% CI] = 0.85 to 1.13), with isolated clefts (OR = 0.92) with isolated median cleft palate (OR = 1.03, 95% CI = 0.79 to 1.36) or with isolated cleft lip with or without cleft palate (OR = 0.86, 95% CI = 0.71 to 1.05). Reported use of multivitamins, folic acid, or B(12) was not associated with a decrease in orofacial cleft risk (OR = 1.00, 95% CI = 0.63 to 1.52). ORs above 2 were seen for some drugs: sulfasalazine, naproxen, and anticonvulsants, but only a few exposed cases occurred. An association between glucocorticoid use and infant cleft was indicated and seemed to be strongest for median cleft palate. CONCLUSION: Maternal drug use seems to play only a small role for the origin of orofacial clefts, at least in Sweden.     

New evidence for the role of cystathionine beta-synthase in non-syndromic cleft lip with or without cleft palate

Orofacial clefts have a multifactorial aetiology encompassing both genetic and environmental components. While there is wide agreement on the importance of both genetic and nutritional factors, genetic influence in particular has not been well defined. As genetic variants in folate and homocysteine metabolism have been reported to influence the risk of orofacial clefts, an Italian cleft lip with or without cleft palate (CL/P) data set was enrolled for an analysis based on family association to test betaine-homocysteine methyltransferase (BHMT and BHMT2) and cystathionine beta-synthase (CBS) variants. No significant level of association was found between BHMT and BHMT2 variants, while evidence of an allelic association with CL/P was found for the single nucleotide polymorphism rs4920037, mapping at the CBS gene. A log-linear approach indicated that the best genetic model takes into account both mother and child genotypes. This suggests that human orofacial development is influenced by CBS genotypes that possibly operate through intergenerational fetal-maternal interaction.     

非综合征型唇腭裂与MTHFR基因多态性的相关性研究

目的：研究亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR）基因位点C677T和A1298C与中国江苏地区汉族人群非综合征型唇腭裂（（nonsyndromic cleft lip with or without cleft palate,NSCL/P）发生的相关性。方法：采用聚合酶链反应-限制性片段长度多态性检测法对200例NSCL/P患者和213例健康人进行基因型检测。结果：MTHFR C677T对照组与病例组在基因型分布无统计学差异（P〉0.05）,TT基因型和携带T等位基因儿童罹患NSCL/P的风险分别是CC基因型儿童的1.84倍及1.57倍。进一步分层分析发现TT基因型和CT基因型能分别显著增加儿童唇裂伴或不伴腭裂和单纯性唇裂的发病风险。MTHFR A1298C病例组和对照组在基因型频率和等位基因频率有统计学差异（P〈0.05）,AC基因型和携带C等位基因的儿童罹患NSCL/P的风险分别比AA基因型儿童降低49%及43%。分层分析中,AC基因型和携带C等位基因可降低罹患唇裂伴腭裂及唇裂伴或不伴腭裂的风险。结论：MTHFR C677T可能为中国江苏地区汉族儿童NSCL/P的危险因素,而MTHFR A1298C有可能是NSCL/P发生的保护因素。     

Prevention of orofacial clefts: does pregnancy planning have a role?

OBJECTIVE: To investigate the association between pregnancy planning and orofacial clefts in the United Kingdom. DESIGN: Case-control study. SETTING: Scotland and the Manchester and Merseyside regions of England. PARTICIPANTS: One hundred and ninety-one children born with nonsyndromic orofacial cleft, 1997 to 2000, and 247 controls. MAIN OUTCOME MEASURE: Cleft lip with and without cleft palate, and cleft palate. RESULTS: There was an inverse association between planning for pregnancy and orofacial cleft in the offspring (odds ratio [OR] = 0.51, 95% confidence interval [CI] = 0.33-0.79). An unplanned pregnancy together with smoking in the first trimester of pregnancy resulted in almost treble the risk of a child with an orofacial cleft when compared with those who planned their pregnancy and did not smoke (OR = 2.92, CI = 1.50-5.65). CONCLUSIONS: Planned pregnancies were associated with a lower risk of orofacial clefts. Isolation of the elements of pregnancy planning implicated in these results is difficult. Current preconception advice needs to reach a wider audience; however, for maximum impact, efforts are needed to reduce the numbers of unplanned pregnancies.     

Distribution of orofacial clefts and frequent occurrence of an unusual cleft variant in the Rift Valley of Kenya.

OBJECTIVE: To investigate the pattern and distribution of nonsyndromic orofacial clefts among patients in the Rift Valley region of northwestern Kenya. METHODS: Subjects were categorized anatomically for occurrence of an atypical cleft lip variant (ACL), typical cleft lip (CL), cleft lip and palate (CLP), or cleft palate (CP), and family history of orofacial clefts. Tribal ethnicity data were obtained from both cleft and noncleft clinic attendees. RESULTS: There were 194 patients with CL (52.7%), 153 with CLP (41.6%), and 21 with CP (5.7%). CL constitutes a greater fraction of orofacial clefts in the Rift Valley region than reported elsewhere in Africa, principally due to frequent occurrence of ACL (52.5% of all CL). Among noncleft clinic attendees there was a lower fraction of Bantu and larger fraction of Nilotic-Paranilotic tribal ethnicity than in Kenya overall. In contrast, among patients with orofacial clefts there was significant underrepresentation of Bantu and overrepresentation of Nilotic-Paranilotic tribes, particularly Kalenjin. Patients of Kalenjin origin had a much higher rate of positive family history of orofacial clefts than Bantu patients. CONCLUSIONS: There is an unusual anatomic distribution of orofacial clefts in the Kenya Rift Valley, with frequent occurrence of an atypical CL variant. Our findings indicate that Bantu tribes have lower risk of orofacial clefts than Nilotic-Paranilotic tribes, possibly due to inherited genetic differences, perhaps accounting for the relatively low prevalence of orofacial clefts through much of Africa.     

A descriptive epidemiology study of cleft lip and palate in Northern Finland

Objective. The aim of this study was to determine the incidence of cleft lip and/or cleft palate in a population uniquely from Northern Finland. Materials and methods. The records of a total of 214 cleft patients treated between 1998–2011 at the Oulu Cleft Lip and Palate Center at the University of Oulu were assessed on a retrospective basis. Data regarding cleft type, sex and side of cleft was collected and analyzed. Family history of clefting was investigated. Results. Cleft palate (68.7%) was most frequently found, followed by cleft lip and palate (18.7%) and cleft lip with or without alveolus (12.6%). Cleft palate occurred more frequently in females (63.3%) and cleft lip and palate was more frequently found in males (62.5%). The left side was more frequently affected in both male and female patients. Left-sided clefts were observed in 82% of patients compared to right-sided clefts in 18%. A family history of clefting was detected in 20.1% of patients. Conclusion. The incidence of clefts in Northern Finland is higher than the corresponding incidence in other European countries. Cleft palate was the most frequent cleft type and it was more frequent in females. In males, cleft lip and palate was more frequent. The left side was more frequently affected in both genders. One fifth of the patients had a family history of clefts.     

Access to antenatal healthcare and the prevalence of oral clefts: a spatial analysis

Congenital anomalies are caused by a variety of risk factors, including individual and environmental ones. This study estimated the prevalence of oral clefts and examined their area-level risk indicators using data from The National Congenital Anomaly Survey in South Korea. Disease mapping and ecological regression were used to assess the geographical variation and potential risk indicators for oral clefts, such as living in a rural area, material deprivation, and limited access to antenatal healthcare. In South Korea, 1.15 (95% CI, 1.08–1.23) children out of every 1,000 births were born with oral clefts during 2005 and 2006. The most common oral cleft type was cleft palate, followed by cleft lip, then cleft lip and palate. Disease mapping showed that the proportion of areas with a higher risk than the national average was relatively higher for oral clefts than for all congenital abnormalities among rural and healthcare underserved areas. The relative risk of oral cleft prevalence was higher in rural areas and healthcare underserved areas than in urban areas and areas with better access to healthcare. The findings suggest that access to antenatal healthcare as well as area-level risk indicators should be considered a priority when developing measures to decrease the occurrence of oral clefts.     

Relation between the concentration of zinc in maternal whole blood and the risk of an infant being born with an orofacial cleft

We investigated the relation between concentrations of maternal zinc and copper and the risk of an infant being born with an orofacial cleft. We did a case–control study using 116 mothers of children with isolated cleft lip with or without cleft palate (cleft group), and 64 mothers of unaffected children (control group). Mothers with a whole blood zinc concentration of 47.1 μmol/L or less had a risk 2.5 times higher of having a child with an orofacial cleft than those with a higher concentration (or level) (95% CI 1.03–6.23; p < 0.05). A low zinc concentration combined with a high copper concentration was seen only in the cleft group. This evidence suggests an association between concentrations of maternal zinc and the risk of orofacial clefts in offspring.     

Seasonal variation and regional distribution of cleft lip and palate in zambia

Objective: To assess variations in seasonality and regional distribution of orofacial clefts in babies born in Zambia. Design: A retrospective chart review was done using records of all cleft procedures performed by the only plastic surgeon in Zambia (G.J.). Delivery data from the University Teaching Hospital (UTH) were also examined to estimate the birth prevalence of orofacial clefts (55,108 live births between 2001 and 2005). Patients: All cleft patients operated in Zambia from 2000 to 2006 (413 patients). Results: A low birth prevalence of clefts (1/4239 live births) was found using UTH delivery data. Surgical data showed no difference for the frequency of one gender over another overall (M:F ratio is 1.04; p = .70). More bilateral clefts occurred in cleft lip and palate (CLP) patients than in cleft lip (CL) patients (p < .01), and more unilateral left-sided clefts occurred in CL than in CLP patients (p = .03). The data reflected seasonal variation in month of birth of cleft lip with or without cleft palate (CL+/-P) patients (p < .01), with a peak in April and May and more births in March through August (57.2%) than in September through February (42.8%). There was regional variation in cleft births among the nine Zambian provinces (p < .01). Conclusions: This study shows seasonal variation in clefts that may be explained, at least in part, by environmental factors affecting the development of CL+/-P. Access to treatment is likely the major determinant of regional disparity in clefts. These results provide a basis for further epidemiological studies of orofacial clefts in Zambia.     

Birth prevalence of cleft lip and palate in Colorado by sex distribution, seasonality, race/ethnicity, and geographic variation

An epidemiologic study was designed to describe the association of potential risk factors with the occurrence of cleft lip and palate (CL/P) births in Colorado for the years 1982–1988. There were 307 children out of 381, 175 live births identified, through birth certificate data, with a diagnosis of cleft palate or cleft lip with or without cleft palate. For this period, the birth prevalence was 0.82/1000. Male gender [odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.28, 2.04], white race (OR = 2.87, 95% CI = 1.52, 5.44), and non-metropolitan residence (OR = 1.59, 95% CI = 1.23, 2.05) were each associated with an excess risk of having a cleft abnormality of any type at birth. No differences in the occurrence of cleft lip and palate were observed by month of birth, altitude of county of residence, or in Hispanic compared with non-Hispanic newborns. Using information from the 1989 Colorado Registry for Children with Special Needs, there was little evidence of ascertainment bias on major factors of interest for the birth certificate data. Further studies are required to define the factors associated with excess risk of CL/P in non-metropolitan areas.     

Non-syndromic cleft lip and/or cleft palate: Epidemiology and risk factors in Lubumbashi (DR Congo), a case-control study

Purpose

To determine the incidence and risk factors of occurrence of non-syndromic cleft lip and/or cleft palate (NSCLP) in Lubumbashi.

Genotype and haplotype analysis of WNT genes in non-syndromic cleft lip with or without cleft palate

The wingless-type MMTV integration site family (Wnt) signalling pathway plays a crucial role in craniofacial development. Recently, nucleotide variants in WNT genes have been shown to be associated with oral congenital anomalies, including facial clefts. Therefore, in the current study we decided to assay the association of nucleotide variants in selected WNT genes with the risk of non-syndromic cleft lip with or without cleft palate (NCL/P) in the Polish population. Fourteen polymorphisms in WNT3, WNT3A, WNT5A, WNT8A, WNT9B, and WNT11 were tested in a group of 210 patients with NCL/P and in a properly matched control group. The most significant results were found for the WNT3 rs3809857 variant, which, under the assumption of a recessive model, was associated with a two-fold decrease in the risk of NCL/P (OR(TT vs. GT + GG) = 0.492, 95% CI: 0.276-0.879, P = 0.015). Moreover, haplotype analysis revealed that WNT3 is significantly correlated with NCL/P. The global P-values for haplotypes of rs12452064_rs7207916 and rs3809857_rs12452064_rs7207916 were 0.0034 and 0.0014, respectively, and these results were statistically significant, even after the permutation test correction. In conclusion, our study confirmed the involvement of polymorphisms in the WNT3 gene in NCL/P aetiology in the tested population.     

Genetic and environmental risk factors for submucous cleft palate

A multifactorial aetiology with genetic and environmental factors is assumed for orofacial clefts. Submucous cleft palate (SMCP), a subgroup of cleft palates with insufficient median fusion of the muscles of the soft palate hidden under the mucosa, has a prevalence of 1:1,250-1:5,000. We described the prevalence of risk factors among 103 German patients with the subtype SMCP and genotyped 24 single nucleotide polymorphisms (SNPs) from 12 candidate genes for orofacial clefts. Analysis of risk factors yielded a positive history for maternal cigarette smoking during pregnancy in 25.2% of the patients, and this was significantly more frequent than in the normal population. The group of patients differed in allele frequencies at SNP rs3917192 of the gene TGFB3 (nominal P = 0.053) and at SNP rs5752638 of the gene MN1 (nominal P = 0.075) compared with 279 control individuals. Our results indicate a potential role of maternal smoking during pregnancy for the formation of SMCP. The analysis of genetic variants hints at the contribution of TGFB3 and MN1 in the aetiology of SMCPs.     

Centre-based statistics of cleft lip with/without alveolus and palate as well as cleft palate only patients in Aden,Yemen

ObjectiveThe purpose of the study was to report the types and patterns of cleft lip with/without cleft alveolus and palate as well as cleft palate only as seen in Aden, Yemen.Design and settingRetrospective, centre-based study conducted at the Cleft Lip and Palate Centre, Aden University, Yemen.Material and methodsStatistical evaluation of the data from all cleft patients who were registered at or referred to this centre during the years 2005–2011.ResultsA total of 1110 cleft patients were seen during the period studied (2005–2011). Amongst these there were 183 (16.48%) with a cleft lip and 144 (12.98) with a cleft of lip and alveolus, 228 (20.54%) had a cleft palate, and 555 (50%) had a combination of cleft lip, alveolus, and palate. The clefts were found more often in males than in females (56.5% boys versus 43.5% girls). This difference was statistically significant (p ≤ 0.001). Statistically significant sex differences were also noted when evaluating the various cleft types. Isolated cleft palates were found most often in females. Among the cleft palate cases there were 102 (9.2%) with a cleft soft palate only. The ages of the patients were between one day and 40 years.Two hundred and one children (18%) had a positive family history of clefts. Among the risk factors considered in this study, consanguineous marriages among cousins were found most frequently (in 48% of the cases). In contrast to this, only 10% of the mothers had reported to have been taking medication directly prior to or during the first trimester of their pregnancy. On average the mothers were neither very young nor very old.ConclusionThe prevalence rate of orofacial cleft types among this Yemeni sample was similar to prevalence rates previously reported in white Caucasians. The present study did neither find many cases with medication before, nor during, pregnancy; there were few young or very old mothers; and the incidence of positive family histories was similar to those found in other studies on clefts. However, consanguineous marriages were encountered quite often.     

Differences in the clinical appearances of white versus black patients with facial cleft deformities: a retrospective study of a South African clinic.

OBJECTIVE: The purpose of this study was to determine the difference in prevalence of the different categories of facial cleft deformities between the white and black patients in a database of 2806 cleft cases at the University of Pretoria. No variation of clefts between these two groups has ever been compared previously. For this purpose, the clefts were classified according to the system described by Bütow in 1985. MATERIAL AND METHODS: Records of 2806 patients attending the university's cleft lip and palate clinic, between August 1983 and February 2006, were reviewed. The study group included cleft patients with syndromic and nonsyndromic CL, CLA, CLAP, hP, hPsP, sP, COMBI clefts with or without oblique or transverse facial (or Tessier) clefts. Very few of the cases presented with speech problems only, but with no clefts. The cleft categories of cleft lip, cleft palate and cleft lip and palate, as well as their subdivisions, were analysed. RESULTS: Of these cleft patients, 2003 were white patients and 665 were black patients; the rest were Indian, Coloured and East-Asian patients. In the black and the white population groups (n = 2668), there were more males with cleft in the white group (58.2%), but more females with clefts in the black group (54.9%). The most common cleft type generally was the cleft lip, alveolus and palate cleft (CLAP) with a 434% prevalence of white patients and 296% of black patients. The most common cleft in the black patients was the cleft palate at 435%, which was only recorded in 35.0% of the white patients. The frequency of the other orofacial clefts in decreasing order was: sP 19.4% for white and 21.2% for black; hPsP 15.2% for white and 21.2% for black; CLA 9.7% for white and 19.8% for black; CL 5.9% for white and 4.5% for black and combinations of different orofacial clefts (COMBI), 6.0% for white and 2.6% for black. The isolated hard palate cleft (hP) occurred very rarely (0.4% for white and 1.1% for black). The left side of the face was more often afflicted (left to right 51.6% to 28.5% for white; and 35.0% to 37.9% for black). In 0.5% (white) and 3.9% (black) median clefts were observed. CONCLUSION: A retrospective study was done of 2806 facial black patients (2668 cases). There was a considerable variation between the groups of orofacial clefts occurring in the two groups.     

Screening for maternal coeliac disease as a potential risk factor for orofacial clefts—a pilot study

There is increasing evidence that dietary folic acid deficiency in utero may increase the risk of developing the ‘cleft lip with or without cleft palate’ (CL ± P) variant of orofacial cleft. Coeliac disease is a common cause of folic acid malabsorption, and in the majority of cases remains undiagnosed. This pilot study assessed the seroprevalence of undiagnosed coeliac disease in a cohort of mothers of infants with CL ± P in the Hyderabad area of India. The seroprevalence of coeliac disease of 1.15% (95% confidence interval 0.37–2.66%) was little different from the expected figure based on published population studies, making a clinically significant association unlikely.     

1433例唇腭裂患者临床资料分析

目的：分析先天性唇腭裂的发病情况及特点,为唇腭裂的预防提供临床资料。方法：对1433例先天性唇腭裂患者进行回顾性临床分析。结果：本组病例中,唇裂390例,唇裂伴腭裂794例,单纯腭裂249例;男性明显多于女性（2.35：1）,但在不完全性腭裂中,女性多于男性（1：0.87）;在单侧唇裂伴或不伴腭裂及完全腭裂中,左侧明显多于右侧（3.58：1）;有家族遗传史的病例占总病例的6.35%;母亲妊娠初期经历危险因素316例,占22.05%;85.97%的患者来自农村;唇腭裂伴发其他畸型者42例,占2.93%。结论：多基因遗传与胚胎发育早期的环境因素是唇腭裂发病的重要因素。     

Genes causing clefting syndromes as candidates for non‐syndromic cleft lip with or without cleft palate: a family‐based association study

Clefts of the orofacial region are among the most common congenital defects, caused by abnormal facial development during gestation. Non‐syndromic cleft lip with or without cleft palate (NSCLP) is a complex trait most probably caused by multiple interacting loci, with possible additional environmental factors. As facial clefts form part of more than 300 syndromes, one strategy for identifying the genetic causes of NSCLP could be to study candidate genes responsible for clefting syndromes. Three genes were selected for this investigation: TP63, which codes for the tumour protein p63 and causes Ectrodactyly‐Ectodermal dysplasia‐orofacial Cleft syndrome; JAG2, a downstream gene of TP63; and MID1, which is responsible for Opitz syndrome. A linkage disequilibrium investigation was performed with intragenic single nucleotide polymorphisms on each of these genes in a sample study of 239 patients/parents trios. Evidence which suggests that JAG2 and MID1 may play a role in NSCLP was obtained.     

宁夏地区非综合征型唇腭裂环境因素的研究

目的 探讨宁夏地区非综合征型唇腭裂（NSCL/P）发病相关环境因素。方法 采用病例对照研究方法纳入NSCL/P患者453例,正常新生儿452例。对研究对象进行问卷调查,利用SPSS 16.0统计软件对数据进行卡方检验和Logistic回归分析。结果 NSCL/P患病类型构成比为唇裂︰唇裂合并腭裂︰腭裂=1︰2.02︰1.51。Logistic回归分析显示妊娠期发生异常、妊娠期感染、流产史、孕前孕中服用药物、饮茶、吸烟、饮酒、居住地附近工厂为危险因素（P<0.05）。单胎、早孕反应、食用豆制品食物、水果为保护因素（P<0.05）。结论 加强母亲孕期饮食均衡,避免感染、流产、服用药物以及不良生活习惯对降低NSCL/P的发生具有重要意义。