**7. Risk factors**

The role of environmental factors in the etiology of OFC has been extensively studied. Known and suspected risk factors for CL/P and CP include family history, maternal nutrition, and exposure to teratogenic agents. The upper lip and palate are developed by 7 and 9 weeks after conception, respectively. Therefore, risk factors must be present before these times to influence the risk of CL/P and CPO.

#### **7.1. Heredity**

Family history is one of the strongest risk factors for both CL/P and CP. The risk of CL/P and CP has been reported to be increased in the first-, second-, and third-degree relatives and the identical twins of individuals with CL/P and CP, with even nonsyndromic cases of CL/P exhibiting evidence of genetic components [58–61]. However, few cases demonstrate true Mendelian inheritance patterns [62]. Moreover, CL/P and CP are known to be influenced by environmental risk factors. Specifically, there is growing evidence of gene-environment interactions that may influence the risk of these conditions.

#### **7.2. Maternal drug use**

Maternal drug use seems to play only a small role for the origin of orofacial clefts, but studies have shown that maternal use of folate antagonists (valproic acid and carbamazepine), dihydrofolate reductase inhibitors (trimethoprim, triamterene, and sulfasalazine), benzodiazepines, nonsteroidal anti-inflammatory drugs, retinoids, and corticosteroids is associated with a marked increase of cleft lip and palate [63–67].

#### **7.3. Maternal diseases**

The increased risk of having a child with CL/P or CP in women with nongestational diabetes or maternal hyperthermia is well-characterized [68, 69]. Additionally, a study conducted in Hungary found an increased risk of CL/P for children born to mothers with influenza, common cold, orofacial herpes, and gastroenteritis during pregnancy, posterior CP in mothers with influenza, sinusitis, and bronchitis, and OFC in mothers with epilepsy or angina pectoris [70].

#### **7.4. Nutrition**

The role of maternal nutrient intake in the development of congenital malformations in the child has long been studied with the aim of elucidating the etiologies of specific birth defects and informing effective prevention strategies. Evidence indicates that maternal nutrient intake affects the risk of giving birth to a child with CL/P or CP. In particular, a lack of vitamin B9, more commonly known as folate (or its synthetic form, folic acid), in the mother's diet has long been linked to the risk of congenital malformations. An association between maternal folate intake and reduced risk of having a child with CL/P or CP has previously been demonstrated [71]. However, studies have not consistently linked folic acid with OFC as they have with neural tube defects [72, 73].

Previous reports have shown maternal intake of vitamins other than folate, such as other B vitamins (e.g. riboflavin), iron, zinc, and the amino acids choline, methionine, and cysteine, to be associated with reduced risk of having a child with CL/P or CP [72, 74, 75].

Vitamin A is known to play a crucial role in fetal development. Deficient and excessive intakes of vitamin A increase the risk of birth defects, including OFC, in animals as well as humans [76–79], but exact daily intake numbers have not been established [80].

#### **7.5. Maternal exogenous exposures**

**7. Risk factors**

**7.1. Heredity**

**7.2. Maternal drug use**

**7.3. Maternal diseases**

pectoris [70].

**7.4. Nutrition**

ence the risk of CL/P and CPO.

12 Designing Strategies for Cleft Lip and Palate Care

interactions that may influence the risk of these conditions.

with a marked increase of cleft lip and palate [63–67].

The role of environmental factors in the etiology of OFC has been extensively studied. Known and suspected risk factors for CL/P and CP include family history, maternal nutrition, and exposure to teratogenic agents. The upper lip and palate are developed by 7 and 9 weeks after conception, respectively. Therefore, risk factors must be present before these times to influ-

Family history is one of the strongest risk factors for both CL/P and CP. The risk of CL/P and CP has been reported to be increased in the first-, second-, and third-degree relatives and the identical twins of individuals with CL/P and CP, with even nonsyndromic cases of CL/P exhibiting evidence of genetic components [58–61]. However, few cases demonstrate true Mendelian inheritance patterns [62]. Moreover, CL/P and CP are known to be influenced by environmental risk factors. Specifically, there is growing evidence of gene-environment

Maternal drug use seems to play only a small role for the origin of orofacial clefts, but studies have shown that maternal use of folate antagonists (valproic acid and carbamazepine), dihydrofolate reductase inhibitors (trimethoprim, triamterene, and sulfasalazine), benzodiazepines, nonsteroidal anti-inflammatory drugs, retinoids, and corticosteroids is associated

The increased risk of having a child with CL/P or CP in women with nongestational diabetes or maternal hyperthermia is well-characterized [68, 69]. Additionally, a study conducted in Hungary found an increased risk of CL/P for children born to mothers with influenza, common cold, orofacial herpes, and gastroenteritis during pregnancy, posterior CP in mothers with influenza, sinusitis, and bronchitis, and OFC in mothers with epilepsy or angina

The role of maternal nutrient intake in the development of congenital malformations in the child has long been studied with the aim of elucidating the etiologies of specific birth defects and informing effective prevention strategies. Evidence indicates that maternal nutrient intake affects the risk of giving birth to a child with CL/P or CP. In particular, a lack of vitamin B9, more commonly known as folate (or its synthetic form, folic acid), in the mother's diet has long been linked to the risk of congenital malformations. An association between maternal Most of the CL/P and CPO epidemiologic studies support a role for environmental factors in the etiology of clefting. The most common risk factors reported were maternal exposure to tobacco products [81, 82], alcohols [83], some viral infections [70], pesticides [84], and teratogens in the workplace or at home in early pregnancy [85–87]. Recognized teratogens included rare exposures such as phenytoin, valproic acid, thalidomide, and herbicides such as dioxin. As mentioned previously, risk of CL/P or CPO conferred by these exposures—in particular tobacco—may be modulated by the presence or absence of certain genetic factors [19, 88, 89].
