环境因素对非综合征性唇腭裂发生的影响

非综合征性唇腭裂是常见的先天发育畸形,其发病与遗传和环境因素的协同作用有关。本文对孕妇叶酸补充、饮酒、吸烟等环境因素对患儿非综合征性唇腭裂发生的影响及其可能的机制作一综述。     

环境因素对非综合征性唇腭裂发生的影响

非综合征性唇腭裂是常见的先天发育畸形，其发病与遗传和环境因素的协同作用有关。本文对孕妇叶酸补充、饮酒、吸烟等环境因素对患儿非综合征性唇腭裂发生的影响及其可能的机制作一综述。     

维生素A族与唇腭裂发生关系的研究进展

维生素A族与唇腭裂发病的关系一直受到唇腭裂病因研究学者的高度关注,近年来更是对过量维生素A族致唇腭裂发病的机制进行了深入的研究。本文就与唇腭裂发病相关的维生素A族种类,维生素A族在唇腭裂发病中作用的流行病学研究,以及过量维生素A族,特别是视黄酸致唇腭裂发生的机制作一综述。     

96例非综合征性唇腭裂发病因素的统计分析

目的：了解现阶段唇腭裂发病的流行病学特点,寻找环境危险因素,为降低本地唇腭裂的发生提供依据。方法：采用病例一对照设计,运用流行病学问卷调查,进行统计学分析。结果：父亲学历（P=00．008）、复合维生素补充（P=00．039）,母亲孕期感染（P=0．015）、情绪问题（P=0．000）及被动吸烟（P=0．009）与唇腭裂发病有相关性,进入回归方程。结论：环境因素对唇腭裂的发生有重要影响,父亲高学历及母亲补充复合维生素能减少唇腭裂的发生,母亲孕期感染,情绪问题及被动吸烟等能增加唇腭裂的发病风险。     

汉族人转化生长因子-α基因多态性与环境因素和非综合征性唇腭裂的关系

目的研究汉族人转化生长因子- α（TGF- α）基因多态性与环境因素和非综合征性唇腭裂（NSCL/P）的关系。方法通过问卷调查获得所有研究对象母亲孕早期感染史、孕期服药史及叶酸补充等资料。应用多聚酶链反应（PCR）结合限制性酶切方法，确定199例NSCL/P患者与203例正常人的基因型。将基因型与孕早期感染史、孕期服药史及叶酸补充因素进行分析。结果NSCL/P患者的C2等位基因频率比正常对照组明显增高，其差异有统计学意义（P<0.05）。孕早期感染、孕期服药及不补充叶酸的孕妇发生NSCL/P增多。C1C2基因型与孕早期感染、孕期服药和叶酸补充3个因素有交互作用。结论TGF- α基因的突变与汉族人NSCL/P的发生有相关性，孕早期感染史、孕期服药史及叶酸补充等环境因素与NSCL/P的发生有关。含有C2等位基因的个体对孕早期感染、孕期服药和叶酸缺乏3个危险因素更为敏感。     

孕期吸烟与先天性唇腭裂畸形发生的研究进展

唇腭裂的病因复杂,与很多遗传及环境因素有关。环境影响因素如药物苯妥英钠,二噁英,营养摄入不足,孕期吸烟,饮酒等均与唇腭裂的发生存在较密切的相关性。其中孕妇孕期吸烟的致畸作用是颅面畸形及流行病学专家研究的较多且最为明确的因素之一。本文就孕期吸烟与先天性唇腭裂畸形关系的研究进展综述如下。     

叶酸拮抗亚甲基四氢叶酸还原酶基因沉默的实验研究

目的:探讨叶酸补充拮抗5,10-亚甲基四氢叶酸还原酶(MTHFR)基因下调的作用机制.方法:MTT法检测叶酸梯度补充后拮抗MTHFR基因功能下调对细胞增殖的影响;流式细胞仪分析MTHFR基因功能下调补充叶酸前后细胞周期的改变.结果:MTHFR基因功能下调后,不同剂量叶酸补充可以逆转MTHFR基因功能下调对EPM细胞的不良影响,影响程度与补充叶酸的浓度在一定范围内具有剂量依赖性.结论:MTHFR基因是重要的先天性唇腭裂候选基因,叶酸补充可以拮抗MTHFR基因功能下调对胚胎腭突发育的不良影响.     

邯郸地区非综合征唇腭裂患儿发生率及其与环境因素和IRF6基因多态性的相关性研究

目的分析邯郸地区非综合征唇腭裂(non-syndromic cleft lip with or without cleft palate,NSCL/P)患儿发生率及其与环境因素和IRF6基因多态性的相关性。方法对2016年3月-2018年4月产科新生儿22460例临床资料进行回顾性分析,统计唇腭裂发生情况。并采用单因素分析和多因素Logistic回归分析影响新生儿发生唇腭裂的影响因素。结果①在22460例新生儿中,NSCL/P有48例,占比2.13‰,其中,单纯性唇裂15例,占比31.25%,腭裂12例,占比25.00%,唇腭裂21例,占比33.33%。;②所有患儿及其父母与健康组基因型频率分布经检验均符合HW平衡,NSCL/P组中单纯性唇裂与唇腭裂rs642961位点的AA基因频率明显高于健康组,数据间差异具有统计学意义(P<0.05);③父亲吸烟、母亲吸烟、母亲被动吸烟、母亲孕期具有疾病史与服药史、未补充维生素与叶酸等环境因素中新生儿NSCL/P的发病率明显增高(P<0.05);④母亲吸烟、母亲被动吸烟、母亲孕期具有疾病史与服药史、未补充维生素与叶酸等环境因素是影响新生儿发生NSCL/P的独立危险因素(P<0.05)。结论 IRF6基因rs642961位点的变异可诱发NSCL/P的发生,同时,母亲吸烟与被动吸烟、母亲孕期具有疾病史与服药史、未补充维生素与叶酸等环境因素可增加NSCL/P发病的风险。     

妊娠期母亲吸烟与婴幼儿患唇腭裂的关系

有流行病学资料显示,妊娠期母亲吸烟是婴儿患唇腭裂的一个危险因素,然而由于很多这类研究涉及的样本很少,使得两者之间的因果关系并未确立。为了揭示妊娠期母亲吸烟与婴儿患唇腭裂的关系,作者作了以下调查研究。     

非综合征型唇腭裂发病危险因素的病例对照研究

目的了解现阶段本地区非综合征型唇腭裂的流行病学特点,探究其发病相关的危险因素,为早期预防提供依据。方法采用病例-对照研究设计,选择来自江苏、安徽及其周边地区的非综合征型唇腭裂患者以及健康对照,利用调查问卷的形式对非综合征型唇腭裂发病相关的一些危险因素进行调查研究(包括唇腭裂家族遗传史、父母的文化程度、生育年龄、妊娠反应、胎次、孕期用药、感染、孕期主动吸烟、孕期被动吸烟、孕期饮酒情况、营养状况等共计14项),分别利用卡方检验和Logistic回归作单因素和多因素分析。结果最终共有352例非综合征型唇腭裂患者以及602例健康对照纳入本研究。单因素分析发现与非综合征型唇腭裂发生相关的危险因素有:妊娠反应、孕期被动吸烟、父亲文化程度以及唇腭裂家族遗传史。而多因素分析模型进一步发现孕期维生素摄入、母亲文化程度也可以影响非综合征型唇腭裂的发病风险。结论妊娠反应、孕期被动吸烟、父母亲文化程度、维生素摄入以及唇腭裂家族遗传史是本地区非综合征型唇腭裂的发病相关因素。     

Oral clefts and vitamin supplementation.

OBJECTIVES: The evidence linking low levels of folic acid and orofacial clefting (OFC) is presently equivocal. There is stronger evidence for the role of folic acid supplementation in protection against the occurrence and recurrence of neural tube defects. The present investigation tested the hypotheses that cleft lip, cleft palate, or both are inversely associated with maternal intake of dietary and supplemental vitamins during the periconceptional period and first 4 months of pregnancy in a Brazilian population. DESIGN: A population-based, case-control study of cleft lip with or without cleft palate (CL(P)) and isolated cleft palate (CP) in a Brazilian population. In structured interviews, case histories were taken from the mothers of a consecutive sample of 450 infants born with nonsyndromic OFC. RESULTS: Mothers who had children with CL(P) were less likely to have been supplemented during the periconceptional period. The statistical significance of the difference in prevalence of the use of supplements between mothers of patients and of controls was greater for the CL(P) group: p < .05 for CP and p < .001 for CL(P). Multivariate analysis confirmed this finding of a protective effect for both types of orofacial cleft. CONCLUSIONS: The use of vitamin supplements in the first 4 months of pregnancy was suggestive of a protective effect against the occurrence of CP and CL(P) in this population. The significance of an association between multivitamin supplementation and OFC and the possible role of gene/environment interaction are discussed.     

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.     

Folate and clefts of the lip and palate--a U.K.-based case-control study: Part I: Dietary and supplemental folate

OBJECTIVES: We sought to determine the associations between nonsyndromic cleft lip with or without cleft palate (CL-P) and cleft palate only (CP) and maternal intake of dietary folate and supplemental folic acid, in an area where the prevalence at birth of neural tube defects has been high and flour is not fortified with folic acid. METHODS: Interviews regarding periconceptional dietary intake and supplement use were completed with the mothers of 112 CL-P cases, 78 CP cases, and 248 unaffected infants. The data were analyzed by logistic regression methods. RESULTS: There was no overall association between CL-P and CP and either energy-adjusted total folate intake or supplemental folic acid use, irrespective of dosage. CONCLUSION: Overall, higher intakes of total folate do not appear to prevent oral clefts in this population.     

Non-syndromic orofacial clefts in Southern Italy: pattern analysis according to gender, history of maternal smoking, folic acid intake and familial diabetes.

BACKGROUND: Genetic studies have demonstrated that non-syndromic clefts of the lip, alveolus and palate have an heterogeneous genetic background, and that environmental factors contribute to the onset of this malformation. Therefore studies on different and homogeneous populations can be useful in detecting potentially related environmental and genetic factors. PURPOSE: The aim of the present study was to evaluate whether gender, folic acid intake, family history of diabetes and/or smoking during pregnancy were associated with a specific type of cleft in a group of patients affected by non-syndromic clefts, collected from Southern Italy. MATERIAL AND METHODS: Data from one hundred and twenty-six patients were evaluated retrospectively. Each cleft was described as composed by separate antomical entities such as lip, alveolus, primary and secondary palate. None had an isolated alveolar cleft and this was used as internal control. Pattern analysis was used to detect differences in the frequencies of any possible combination of 7 types of clefting stratified according to the studied variables. Data were analysed by comparing observed proportions. RESULTS: Isolated cleft palate as well as right-sided clefts of lip, alveolus and palate were more frequent in females (p = 0.0014 and 0.0281, respectively), while left sided clefts were more frequent in males (p = 0.0359). A lack of consumption of folic acid was associated with an higher incidence of clefts of the left lip (p = 0.018), while familial diabetes was associated more often with isolated cleft palate (p = 0.0014). CONCLUSIONS: Gender-related results were comparable with those found in Northern Italy and other countries. Environmentally related results disclosed specific subclasses of clefting associated with lack of folic acid consumption and familial diabetes.     

Changing lifestyles and oral clefts occurrence in Denmark.

OBJECTIVE: The aim of this project was to assess whether any changes in the birth prevalence of cleft lip with/without cleft palate (CL[P]) occurred in Denmark during the period 1988 through 2001. In this period an official recommendation of a supplementation of folic acid to pregnant women was introduced; furthermore, smoking among pregnant women decreased considerably. DESIGN AND SETTINGS: There are few places in which ecological studies of oral clefts are possible. Denmark provides a particularly good setting for this kind of study because of a high ascertainment and a centralized registration of subjects with cleft over the last 65 years. PARTICIPANTS: Cleft occurrence in Denmark from 1936 to 1987 has previously been reported. Here we extend the study to include all live-born children with oral clefts born in Denmark in 1988 through 2001. Among a total of 992,727 live births, 1332 children with CL(P) were born during this period. RESULTS AND CONCLUSIONS: The birth prevalence of CL(P) in Denmark has previously been found to be constant in the period 1962 through 1987, with a frequency of 1.4 to 1.5 per 1000 live births. This study showed a similar occurrence in 1988 through 2001 (birth prevalence = 1.44 per 1000 live births, 95% confidence interval = 1.37 to 1.52). The introduction of folic acid and the decrease in smoking prevalence among pregnant women do not seem to have reduced the birth prevalence. This may be due to noncompliance with the folic acid recommendation and/or only a weak causal association between folic acid and smoking and occurrence of CL(P).     

Unraveling human cleft lip and palate research

The focus of this work is to highlight the most recent advances in the understanding of cleft lip and palate occurrence. Information regarding research on long-term outcomes, genes and their interactions with other genes, and gene-environment interactions is compiled to provide the reader with a critical and up-to-date overview on the current knowledge of the etiology of cleft lip and palate. Recent epidemiological evidence strongly suggests that individuals born with clefts have a shorter lifespan and may have a higher incidence of cancer and psychological disorders. IRF6 has been shown to be an important contributor to cleft lip and palate, but the functional variant leading to the defect has not yet been defined. Inactivation of MSX1 and genes in the FGF family has also been shown to lead to cleft lip and palate. In addition, missense mutations in several candidate genes may cause cleft lip and palate, but definitive evidence regarding the biological consequences of these mutations is yet to be unraveled. Maternal cigarette smoking increases the risk of a baby born with clefts, in particular when the mother carries the GSTT1-null variants. The latest approaches in cleft research include the analysis of several additional phenotypical features of the population, with the goal of increasing the statistical power of genetics studies.     

Smoking and orofacial clefts: a United Kingdom-based case-control study.

OBJECTIVE: To investigate the association between smoking and orofacial clefts in the United Kingdom. DESIGN: Case-control study in which the mother's exposure to tobacco smoke was assessed by a structured interview. SETTING: Scotland and the Manchester and Merseyside regions of England. PARTICIPANTS: One hundred ninety children born with oral cleft between September 1, 1997, and January 31, 2000, and 248 population controls, matched with the cases on sex, date of birth, and region. MAIN OUTCOME MEASURE: Cleft lip with or without cleft palate and cleft palate. RESULTS: There was a positive association between maternal smoking during the first trimester of pregnancy and both cleft lip with or without cleft palate (odds ratio 1.9, 95% confidence interval 1.1 to 3.1) and cleft palate (odds ratio 2.3, 95% confidence interval 1.3 to 4.1). There was evidence of a dose-response relationship for both types of cleft. An effect of passive smoking could not be excluded in mothers who did not smoke themselves. CONCLUSION: The small increased risk for cleft lip with or without cleft palate in the offspring of women who smoke during pregnancy observed in this study is in line with previous evidence. In contrast to some previous studies, an increased risk was also apparent for cleft palate. In these U.K. data, there was evidence of a dose-response effect of maternal smoking for both types of cleft. The data were compatible with a modest effect of maternal passive smoking, but the study lacked statistical power to detect or exclude such an effect with confidence. It may be useful to incorporate information on the effects of maternal smoking on oral clefts into public health campaigns on the consequences of maternal smoking.