**Strategies for Prevention of Neural Tube Defects**

Hiroko Watanabe1 and Tomoyuki Takano2 *1Department of Clinical Nursing, 2Department of Pediatrics, Shiga University of Medical Science Japan* 

#### **1. Introduction**

30 Neural Tube Defects – Role of Folate, Prevention Strategies and Genetics

Wilcox, A.J., Lie, R.T., Solvoll, K., Taylor, J., McConnaughey, D.R., Abyholm, F., Vindenes, H.,

Wilson, A., Platt, R., Wu, Q., Leclerc, D., Christensen, B., Yang, H., Gravel, R.A., & Rozen, R.

Wong, L.Y. & Paulozzi, L.J. (2001). Survival of infants with spina bifida: a population study,

1979-94. *Paediatr Perinat Epidemiol,* Vol. 15, No. 4, pp. 374-378.

pp. 763-766.

*Genet,* Vol. 8, pp. 2009-2016.

No. 4, pp. 317-323.

methylenetetrahydrofolate reductase in neural tube defects. *Q J M,* Vol. 88, No. 11,

Vollset, S.E., & Drevon, C.A. (2007). Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ, Vol. 334, No. 7591, pp. 464. Wilson, A., Leclerc, D., Rosenblatt, D.S., & Gravel, R.A. (1999a). Molecular basis for

methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism. *Hum Molec* 

(1999b). A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. *Molec Genet Metab,* Vol. 67,

> Neural tube defects (NTDs) are congenital malformations of the brain and spinal cord caused by the failure of neural tubes to close between 21 and 28 days after conception (Sadler, 2005). Any disruption of neurulation during or prior to this time may result in a defect or failure of neural tube closure. Non-invasive prenatal diagnostic testing by ultrasound and maternal serum screening, which should be offered at 16 to 20 weeks gestation and 15 to 20 weeks gestation, respectively, will identify 95% of spina bifida and 100% of anencephaly cases. After 15 weeks of pregnancy, invasive prenatal diagnostic testing with ultrasound-guided amniocentesis can evaluate the fetal karyotype and measure amniotic fluid alpha-fetoprotein and acetylcholinesterase, to assist in differentiating between open or closed lesions (Chodirker et.al., 2001). The majority of cases can be categorized as either anencephaly (lack of closure in the region of the head) or spina bifida (lack of closure below the head).

> Folate deficiency before conception and during early pregnancy is one potential cause of NTDs. Folate is the general term for water soluble B vitamin predominantly found in green leafy vegetables. Adequate folate intake is required for normal metabolism, cell division, neural function and growth. Humans are unable to synthesize folate and depend on an adequate and constant intake. Both observational and interventional studies, including randomized, controlled trials, have demonstrated that adequate consumption of folic acid periconceptionally can prevent 50-70% of NTDs (Czeizel & Dudas, 1992).

> Currently, 57 countries have regulations for mandatory fortification of wheat flour with folic acid, (Flour Fortification Initiative, 2009) and health agencies in many countries have officially recommended the periconceptional consumption of folic acid in the range of 400 to 500 μg in young women of reproductive age who are capable of conceiving or planning to conceive (Centers for Disease Control and Prevention [CDC], 1992; Bower et al., 1995). The prevalence of spina bifida and anencephaly in the United States has declined significantly since the onset of fortification of enriched grain products with folic acid. The latest prevalence of spina bifida and anencephaly rates in the United States, reported in 2006, was 3.05 and 1.56 per 10,000 live births, respectively (Neural tube defect ascertainment project, 2010). On the other hand, the incidence of spina bifida in countries in which the fortification

Strategies for Prevention of Neural Tube Defects 33

 *Lipomeningocele:* The dysraphic spinal cord is accompanied by fatty tissue deposits. *Spina bifida occulta:* This is defined as a defect in the posterior bony components of the

Fig. 1. A coronal section of the spinal cord in a patient with a meningomyelocele. Note the overdistended and deformed central canal showing hydromyelia. Hematoxylin and eosin

These malformations are incompatible with survival beyond birth and today are observed

Myelomeningoceles involve all of the underlying layers, including the spinal cord, nerve roots, meninges, vertebral bodies and skin. The spinal cord may be exposed because of a complete failure of neural closure, or may be covered by a membrane. Although myelomeningocele may be situated at any longitudinal level of the neuroaxis, lumbosacral involvement is the most common (Fig. 2). Varying degrees of paresis of the legs, usually profound, and sphincter dysfunction are the major clinical manifestations. Fifty to seventy percent of neural tube defects can be prevented if a woman consumes sufficient folic acid daily before conception and throughout the first trimester of her pregnancy (Gleeson et al., 2006). Maternal serum alpha-fetoprotein determination and ultrasound examination are now routinely used to identify fetuses that have or are likely to have spina bifida or anencephaly (Drugan et al., 2001). Alpha-fetoprotein is a component of the fetal cerebrospinal fluid, and it may leak into the amniotic fluid from the open neural tube. Closed lesions often do not lead to increased alpha-fetoprotein concentrations. The management of a child with a myelomeningocele requires the concerted efforts of a multidisciplinary team involving many specialists. Treatment includes surgical reduction of the myelomeningocele and other associated defects, prevention of infection, covering of the myelomeningocele, control of hydrocephalus, management of urinary dysfunction, and treatment of the paralysis and abnormalities of the hips and feet (Gleeson et al., 2006).

vertebral column without involvement of the cord or meninges.

Source; Modified from Takano, T. & Becker, L.E. (1997).

**3. Clinical features and management** 

**3.1 Craniorachischisis, excencephaly and anencephaly** 

almost exclusively on ultrasound examination during pregnancy.

staining.

**3.2 Myelomeningocele** 

of enriched grain product with folate is not compulsory or endorsed officially, was 5.32 per 10,000 live births (Annual report 2007 with data 2005, 2009). The primary objective of this review article is to discuss the strategies for prevention of NTDs.

#### **2. Definition and classification**

NTDs are common and severe congenital malformations of the central nervous system occurring secondary to a lack of closure of the neural tube. The following three groups are categorized based on the severity of the defects (Copp & Harding, 2004).

#### **2.1 Severe form**

The severe form of the NTD spectrum includes open defects resulting from the failure of neural tube closure, in which the interior of the brain or spinal cord communicates directly with outside, and includes the following:


#### **2.2 Moderate form**

The moderate form of NTD includes *encephaloceles* and *meningoceles*. These defects result from herniation of the brain or meninges through an opening in the skull or vertebral column, respectively. These defects appear to be primary abnormalities of skeletal development, not neural tube closure, as the brain and spinal cord appear to have closed normally prior to herniation.

#### **2.3 Mild form**

The mild end of the NTD spectrum is represented by a third group of dysraphic defects in which there are closed abnormalities of the spinal cord, usually in the low lumbar and sacral regions. The following types are included:


of enriched grain product with folate is not compulsory or endorsed officially, was 5.32 per 10,000 live births (Annual report 2007 with data 2005, 2009). The primary objective of this

NTDs are common and severe congenital malformations of the central nervous system occurring secondary to a lack of closure of the neural tube. The following three groups are

The severe form of the NTD spectrum includes open defects resulting from the failure of neural tube closure, in which the interior of the brain or spinal cord communicates directly

 *Craniorachischisis:* There is an almost complete absence of neural tube closure, affecting both the brain and spine. This malformation results from a failure of the initiating event

 *Excencephaly:* This is a brain defect resulting from a failure of cranial neural tube closure. Although this appearance is seen only in embryos and early fetuses, the

 *Anencephaly:* Exposed cranial neural folds may degenerate with advancing gestation. This is a catastrophic malformation in which the brain is severely degeneratd and the

 *Myelomeningocele:* This results from a failure of the closure of the spinal neural tube, most often in the lumbosacral region. In *spina bifida cystica*, a meningeal sac containing the open spinal cord herniates through a vertebral defect. In *myeloceles*, the open spinal

The moderate form of NTD includes *encephaloceles* and *meningoceles*. These defects result from herniation of the brain or meninges through an opening in the skull or vertebral column, respectively. These defects appear to be primary abnormalities of skeletal development, not neural tube closure, as the brain and spinal cord appear to have closed

The mild end of the NTD spectrum is represented by a third group of dysraphic defects in which there are closed abnormalities of the spinal cord, usually in the low lumbar and sacral

 *Diplomyelia:* This is a side-by-side or anteroposterior duplication of the spinal cord. *Diastematomyelia:* A midline septum divides the spinal cord longitudinally into two

usually unequal portions extending up to 10 thoracolumbar segments.

*Hydromyelia:* The central canal is overdistended (Fig. 1).

review article is to discuss the strategies for prevention of NTDs.

categorized based on the severity of the defects (Copp & Harding, 2004).

persistently open cranial neural folds have an everted appearance.

**2. Definition and classification** 

with outside, and includes the following:

of neurulation in the early embryo.

cord is directly exposed as a flat open lesion.

skull vault is absent.

normally prior to herniation.

regions. The following types are included:

**2.2 Moderate form** 

**2.3 Mild form** 

**2.1 Severe form** 


Source; Modified from Takano, T. & Becker, L.E. (1997).

Fig. 1. A coronal section of the spinal cord in a patient with a meningomyelocele. Note the overdistended and deformed central canal showing hydromyelia. Hematoxylin and eosin staining.

#### **3. Clinical features and management**

#### **3.1 Craniorachischisis, excencephaly and anencephaly**

These malformations are incompatible with survival beyond birth and today are observed almost exclusively on ultrasound examination during pregnancy.

#### **3.2 Myelomeningocele**

Myelomeningoceles involve all of the underlying layers, including the spinal cord, nerve roots, meninges, vertebral bodies and skin. The spinal cord may be exposed because of a complete failure of neural closure, or may be covered by a membrane. Although myelomeningocele may be situated at any longitudinal level of the neuroaxis, lumbosacral involvement is the most common (Fig. 2). Varying degrees of paresis of the legs, usually profound, and sphincter dysfunction are the major clinical manifestations. Fifty to seventy percent of neural tube defects can be prevented if a woman consumes sufficient folic acid daily before conception and throughout the first trimester of her pregnancy (Gleeson et al., 2006). Maternal serum alpha-fetoprotein determination and ultrasound examination are now routinely used to identify fetuses that have or are likely to have spina bifida or anencephaly (Drugan et al., 2001). Alpha-fetoprotein is a component of the fetal cerebrospinal fluid, and it may leak into the amniotic fluid from the open neural tube. Closed lesions often do not lead to increased alpha-fetoprotein concentrations. The management of a child with a myelomeningocele requires the concerted efforts of a multidisciplinary team involving many specialists. Treatment includes surgical reduction of the myelomeningocele and other associated defects, prevention of infection, covering of the myelomeningocele, control of hydrocephalus, management of urinary dysfunction, and treatment of the paralysis and abnormalities of the hips and feet (Gleeson et al., 2006).

Strategies for Prevention of Neural Tube Defects 35

association with microcephaly. A prenatal diagnosis of encephaloceles may be established by the determination of an increased amniotic alpha-fetoprotein content and ultrasound studies (Graham et al., 1982). Surgical corrections of all but the smallest encephaloceles are necessary.

This malformation is compatible with normal spinal function, and neurological

Patients with diastematomyelia present with congenital scoliosis, hydrocephalus, or cutaneous lesions such as hairy patch, dimple, hemangioma, subcutaneous mass, or teratoma (Kothari & Bauer, 1997). A progressive myelopathy, with deformities of the feet, scoliosis, kyphosis, or discrepancy in leg length, also may develop. Resection of the spur in

This occurs in at least 5% of the population, but most often is asymptomatic. This defect is often found incidentally on radiographic studies or is diagnosed because of a subtle clinical finding, such as a tuft of hair or a cutaneous angioma or lipoma in the midline of the back

In 1976, Smithells et al. (1976) suggested that folate deficiency was a cause of NTDs because women with NTDs infants had low blood folate levels. Later, they reported that periconceptional vitamin supplementation, including folic acid, reduced the recurrence of NTDs (Smithells et al., 1983). Further studies provided a growing body of evidence. Folic acid exists as polyglutamates in green leafy vegetables and other natural sources. It consists of a pteridine ring, p-aminobenzoic acid, and glutamine acid. Although folate deficiency is

Beaudin and Storver (2007) showed the pathway linking alterations in folate status with NTDs (Fig. 4). They summarized that disruption of folate metabolism could result in homocysteine accumulation, impaired nucleotide biosynthesis, and impaired cellular methylation. These metabolic impairments evoke genomic responses such as alterations in gene expression, genomic instability, reduced mitotic rates, and impaired DNA repair. Impairments in metabolism and/or genomic responses may influence cellular responses critical to proper neural tube closure, including cell proliferation, survival, differentiation, and migration. SNPs in folate-related genes can influence both maternal and infant folate status, or alternatively, Aminopterin (4-aminopteroic acid; APN) can also directly disrupt metabolism. APN is an antineoplastic drug with immunosuppressive properties used in chemotherapy and a synthetic derivative of pterin, and works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase. Its binding affinity for dihydrofolate reductase effectively blocks tetrahydrofolate synthesis. This results in the depletion of

deterioration suggests the presence of diastematomyelia or tethering.

diastematomyelia frequently does not result in any clinical improvement.

marking the location of the defect (Guggisberg et al., 2004).

**4. The mechanism of folate deficiency and NTDs** 

an established risk factor for NTDs, the exact mechanism is not clear.

nucleotide precursors and inhibition of DNA, RNA, and protein synthesis.

**3.5 Diplomyelia** 

**3.6 Diastematomyelia** 

**3.7 Spina bifida occulta** 

Fig. 2. A lumbar myelomeningocele in a newborn, showing a large meningeal sac (asterisk). The midline sagittal view from a computed tomography study.

#### **3.3 Meningocele**

A meningocele is a protrusion of the meninges without accompanying nervous tissue, and it is not associated with neurological deficits. The mass usually is evident as a fluid-filled protrusion covered by skin or a membrane in the midline. When careful examination of patients with a suspected meningocele reveals significant neurological abnormalities such as the equinovarus deformity, gait disturbance or abnormal bladder function, the diagnosis of a meningomyelocele is appropriate. A meningocele can be found in the cranial (Fig. 3) or high cervical area.

Fig. 3. A cranial meningocele in a newborn. Note the meningeal herniation through a small opening of the frontal skull (arrow) into the nasal cavity. The midline sagittal view from a magnetic resonance imaging study.

#### **3.4 Encephalocele**

An encephalocele is a herniation of the intracranial contents through a midline skull defect. The cranial meningoceles contain only leptomeninges and cerebrospinal fluid, whereas encephaloceles also contain brain parenchyma. The amount of compromised and deformed neural tissue and the degree of resultant microcephaly determine the extent of cerebral dysfunction (Gleeson et al., 2006). Severe intellectual and motor delays typically occur in association with microcephaly. A prenatal diagnosis of encephaloceles may be established by the determination of an increased amniotic alpha-fetoprotein content and ultrasound studies (Graham et al., 1982). Surgical corrections of all but the smallest encephaloceles are necessary.

#### **3.5 Diplomyelia**

34 Neural Tube Defects – Role of Folate, Prevention Strategies and Genetics

Fig. 2. A lumbar myelomeningocele in a newborn, showing a large meningeal sac (asterisk).

A meningocele is a protrusion of the meninges without accompanying nervous tissue, and it is not associated with neurological deficits. The mass usually is evident as a fluid-filled protrusion covered by skin or a membrane in the midline. When careful examination of patients with a suspected meningocele reveals significant neurological abnormalities such as the equinovarus deformity, gait disturbance or abnormal bladder function, the diagnosis of a meningomyelocele is appropriate. A meningocele can be found in the cranial (Fig. 3) or

Fig. 3. A cranial meningocele in a newborn. Note the meningeal herniation through a small opening of the frontal skull (arrow) into the nasal cavity. The midline sagittal view from a

An encephalocele is a herniation of the intracranial contents through a midline skull defect. The cranial meningoceles contain only leptomeninges and cerebrospinal fluid, whereas encephaloceles also contain brain parenchyma. The amount of compromised and deformed neural tissue and the degree of resultant microcephaly determine the extent of cerebral dysfunction (Gleeson et al., 2006). Severe intellectual and motor delays typically occur in

The midline sagittal view from a computed tomography study.

**3.3 Meningocele** 

high cervical area.

magnetic resonance imaging study.

**3.4 Encephalocele** 

This malformation is compatible with normal spinal function, and neurological deterioration suggests the presence of diastematomyelia or tethering.

#### **3.6 Diastematomyelia**

Patients with diastematomyelia present with congenital scoliosis, hydrocephalus, or cutaneous lesions such as hairy patch, dimple, hemangioma, subcutaneous mass, or teratoma (Kothari & Bauer, 1997). A progressive myelopathy, with deformities of the feet, scoliosis, kyphosis, or discrepancy in leg length, also may develop. Resection of the spur in diastematomyelia frequently does not result in any clinical improvement.

#### **3.7 Spina bifida occulta**

This occurs in at least 5% of the population, but most often is asymptomatic. This defect is often found incidentally on radiographic studies or is diagnosed because of a subtle clinical finding, such as a tuft of hair or a cutaneous angioma or lipoma in the midline of the back marking the location of the defect (Guggisberg et al., 2004).

#### **4. The mechanism of folate deficiency and NTDs**

In 1976, Smithells et al. (1976) suggested that folate deficiency was a cause of NTDs because women with NTDs infants had low blood folate levels. Later, they reported that periconceptional vitamin supplementation, including folic acid, reduced the recurrence of NTDs (Smithells et al., 1983). Further studies provided a growing body of evidence. Folic acid exists as polyglutamates in green leafy vegetables and other natural sources. It consists of a pteridine ring, p-aminobenzoic acid, and glutamine acid. Although folate deficiency is an established risk factor for NTDs, the exact mechanism is not clear.

Beaudin and Storver (2007) showed the pathway linking alterations in folate status with NTDs (Fig. 4). They summarized that disruption of folate metabolism could result in homocysteine accumulation, impaired nucleotide biosynthesis, and impaired cellular methylation. These metabolic impairments evoke genomic responses such as alterations in gene expression, genomic instability, reduced mitotic rates, and impaired DNA repair. Impairments in metabolism and/or genomic responses may influence cellular responses critical to proper neural tube closure, including cell proliferation, survival, differentiation, and migration. SNPs in folate-related genes can influence both maternal and infant folate status, or alternatively, Aminopterin (4-aminopteroic acid; APN) can also directly disrupt metabolism. APN is an antineoplastic drug with immunosuppressive properties used in chemotherapy and a synthetic derivative of pterin, and works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase. Its binding affinity for dihydrofolate reductase effectively blocks tetrahydrofolate synthesis. This results in the depletion of nucleotide precursors and inhibition of DNA, RNA, and protein synthesis.

Strategies for Prevention of Neural Tube Defects 37

1994). In June 2007, the Australian Food Regulatory Ministerial Council agreed to mandatory fortification of bread-making flour with folic acid. The standard, September 2009, requires the mandatory addition of 200-300 μg folic acid per 100 grams of bread-

The percentage of the world's wheat flour produced in large roller mills that is fortified has increased from 18% to 30%. By 2015, the target date of the World Health Organization millennium Development Goals, the Flour Fortification Initiative goal is for 80% of the

According to the Morbidity and Mortality Weekly Report, if 50%-70% of NTDs can be prevented through daily consumption of 400 μg of folic acid, assuming an annual prevalence of 300,000 NTDs, worldwide folic acid fortification could lead to the prevention

Numerous studies have evaluated the effect of folic acid fortification on primary prevention of NTDs. A significant, worldwide decline in the prevalence of NTDs was noted in the period following folic acid fortification. In the United States, during 1995-1996, an NTD affected approximately 4,000 pregnancies. The number declined to 3,000 pregnancies in 1999-2000, following the mandated fortification of enriched cereal grain products with folic acid (CDC, 2004). From the prefortification period of 1996-1996 to the early postfortification of 1999-2000, the prevalence of spina bifida and anencephaly decreased dramatically (CDC, 2008). The latest prevalence of spina bifida and anencephaly rates in the United States, reported in 2006, was 3.05 and 1.56 per 10,000 live births, respectively, based on birth defects

Source by neural tube defect ascertainment project of the National Birth Defects Prevention Network at

Australia presented similar findings. The prevalence of NTDs dramatically declined from 20 per 10,000 births in the prefortification period to 5 per 10,000 births in the postfortification

Fig. 5. Prevalence of spina bifida and anencephaly in the United States, 1995-2006

surveillance data (Neural tube defect ascertainment project, 2010) (Fig. 5).

making flour (Food Liaison, 2007).

**5.1.2 The effect of fortification** 

world's roller-mill wheat flour to be fortified (CDC, 2010).

of 150,000 - 210,000 NTDs per year (CDC, 2010).

Centers for Disease Control and Prevention. \*NTDs: Spina bifida + Anencephaly

Source: Beaudin, A.E. & Stover, P.J. (2007)

Fig. 4. Pathway linking alterations in folate status with NTDs

#### **5. Strategies for prevention of NTDs**

The prevalence of NTDs has declined considerably during the past three decades, due to advances in the refined resolution of ultrasonography for fetal examination, the clinical availability of serum alpha-fetoprotein measurements, termination of affected pregnancies, and the consumption of folic acid supplements among reproductive-aged women. Included in these factors, successful mandatory fortification programs have been documented in several countries, including the United States, Canada, and Australia (Abeywardana et al., 2010; De Wals et al., 2008; Pfeiffer et al., 2008).

#### **5.1 Countries of fortification of enriched grain product with folate**

#### **5.1.1 Mandated folic acid fortification programs**

In 1992, the U.S. Public Health Service recommended that all women of reproductive age in the United States who were capable of becoming pregnant should consume 400 μg of synthetic folic acid daily from fortified foods and/or supplements and that they should consume a balanced, healthy diet of folate-rich food in order to reduce the risk of NTDs (CDC, 1992). The Food and Drug Administration mandated the addition of folic acid to all enriched cereal grain products by January 1998 (Food and Drug Administration, 1996). In 2009, the U.S. Preventive Services Task Force (2009) published updated guidelines reinforcing these recommendations.

Canada introduced a fortification program in 1998, mandating the folic acid fortification of enriched white flour, as well as some corn and rice products, with ranges from 95 to 309 μg/100 g for different products (Ray et al., 2002). In Australia, the Australian National Health and Medical Research Council recommended a periconceptional daily supplement intake of 500 μg folic acid for women of childbearing age in 1993, and voluntary folic acid fortification of certain foods was permitted (National Health and Medical Research Council,

The prevalence of NTDs has declined considerably during the past three decades, due to advances in the refined resolution of ultrasonography for fetal examination, the clinical availability of serum alpha-fetoprotein measurements, termination of affected pregnancies, and the consumption of folic acid supplements among reproductive-aged women. Included in these factors, successful mandatory fortification programs have been documented in several countries, including the United States, Canada, and Australia (Abeywardana et al.,

In 1992, the U.S. Public Health Service recommended that all women of reproductive age in the United States who were capable of becoming pregnant should consume 400 μg of synthetic folic acid daily from fortified foods and/or supplements and that they should consume a balanced, healthy diet of folate-rich food in order to reduce the risk of NTDs (CDC, 1992). The Food and Drug Administration mandated the addition of folic acid to all enriched cereal grain products by January 1998 (Food and Drug Administration, 1996). In 2009, the U.S. Preventive Services Task Force (2009) published updated guidelines reinforcing these recommendations. Canada introduced a fortification program in 1998, mandating the folic acid fortification of enriched white flour, as well as some corn and rice products, with ranges from 95 to 309 μg/100 g for different products (Ray et al., 2002). In Australia, the Australian National Health and Medical Research Council recommended a periconceptional daily supplement intake of 500 μg folic acid for women of childbearing age in 1993, and voluntary folic acid fortification of certain foods was permitted (National Health and Medical Research Council,

Source: Beaudin, A.E. & Stover, P.J. (2007)

**5. Strategies for prevention of NTDs** 

2010; De Wals et al., 2008; Pfeiffer et al., 2008).

**5.1.1 Mandated folic acid fortification programs** 

Fig. 4. Pathway linking alterations in folate status with NTDs

**5.1 Countries of fortification of enriched grain product with folate** 

1994). In June 2007, the Australian Food Regulatory Ministerial Council agreed to mandatory fortification of bread-making flour with folic acid. The standard, September 2009, requires the mandatory addition of 200-300 μg folic acid per 100 grams of breadmaking flour (Food Liaison, 2007).

The percentage of the world's wheat flour produced in large roller mills that is fortified has increased from 18% to 30%. By 2015, the target date of the World Health Organization millennium Development Goals, the Flour Fortification Initiative goal is for 80% of the world's roller-mill wheat flour to be fortified (CDC, 2010).

#### **5.1.2 The effect of fortification**

According to the Morbidity and Mortality Weekly Report, if 50%-70% of NTDs can be prevented through daily consumption of 400 μg of folic acid, assuming an annual prevalence of 300,000 NTDs, worldwide folic acid fortification could lead to the prevention of 150,000 - 210,000 NTDs per year (CDC, 2010).

Numerous studies have evaluated the effect of folic acid fortification on primary prevention of NTDs. A significant, worldwide decline in the prevalence of NTDs was noted in the period following folic acid fortification. In the United States, during 1995-1996, an NTD affected approximately 4,000 pregnancies. The number declined to 3,000 pregnancies in 1999-2000, following the mandated fortification of enriched cereal grain products with folic acid (CDC, 2004). From the prefortification period of 1996-1996 to the early postfortification of 1999-2000, the prevalence of spina bifida and anencephaly decreased dramatically (CDC, 2008). The latest prevalence of spina bifida and anencephaly rates in the United States, reported in 2006, was 3.05 and 1.56 per 10,000 live births, respectively, based on birth defects surveillance data (Neural tube defect ascertainment project, 2010) (Fig. 5).

Source by neural tube defect ascertainment project of the National Birth Defects Prevention Network at Centers for Disease Control and Prevention. \*NTDs: Spina bifida + Anencephaly

Fig. 5. Prevalence of spina bifida and anencephaly in the United States, 1995-2006

Australia presented similar findings. The prevalence of NTDs dramatically declined from 20 per 10,000 births in the prefortification period to 5 per 10,000 births in the postfortification

Strategies for Prevention of Neural Tube Defects 39

incidences of NTDs. Japan is one such country, although 440 μg of dietary folate with balanced meals was recommended to all Japanese women of reproductive age by the Ministry of Health (2000) to prevent birth defects. In 2008, the National Nutrition Survey in Japan reported that the mean dietary intake of folate, vitamin B6, and vitamin B12 of nonpregnant women aged 18-29 years was less than the recommended dietary allowance (RDA) (Ministry of Health, Labour and Welfare, 2008). Another study showed (Mito et al., 2007) that more than 80% of Japanese women aged between 17 and 41 had inadequate (i.e., less than the RDA of 240 μg/d) folate intake in 2002. This failure of women to meet the RDA for folate intake may have lead to the increase in the prevalence of spina bifida from1.96 per 10,000 live births (1974-1980) to 5.32 (2001-2005) (Annual report 2007 with data 2005, 2009). In China, women who are planning marriage or pregnancy are advised to take 400 μg of supplemental folic acid every day, starting before conception, through to the end of the first trimester of pregnancy, but this is not mandatory (Ren et al., 2006). Northern China has one of the highest reported NTD birth prevalence rates in the world. The prevalence of NTDs was 4.5 per 1,000 in 2002 (Zhang & Wang, 2004), and only 35.8% of the affected population was aware of folic acid; fewer than 15% of women reported taking folic acid periconceptionally, with the percentage being significantly lower than the average among rural farming women with less education (Ren et al., 2006). The low level of awareness as well as the low reported rate of

periconceptional supplementation may explain the high prevalence of NTDs.

known environmental factor (Waller et al., 1994; Werler et al., 1996).

levels of women, and to prevent the occurrence of NTDs.

There have been three main approaches to reduce the incidence of NTDs: health promotion to improve the knowledge and awareness of folic acid, ensuring the use of fortified folic acid and folic acid supplements, and reducing the number of obese women, which is also a

The USA, Canada, and Australia have implemented food fortification programs successfully with resultant improvement in serum folate levels and reduction in incidences of NTDs. Education campaigns can be effective and public health campaigns aimed at informing and influencing behavioral change in all individuals. Rofail et al. (2011) examined pre- and postcampaign awareness, knowledge, and consumption data for women of reproductive-age in Australia. Awareness of folic acid improved post-campaign, with the percentage improvement between pre- and post-campaigns ranging from 6 to 41%. Women's knowledge of the association between folate and spina bifida increased from 8% before the program began to 67% two-and-a-half years later. The proportion of women taking periconceptional folic acid supplements increased from 13% to 30% over the same period (Bower et al., 1997). Since the introduction of this promotion, the prevalence of NTDs in Western Australia, which was about two per 1,000 births from 1980 until 1995, fell by 30% in 1996 (Bower et al., 2002). The estimated increase in mean serum folate concentration was 19% after educational campaigns to increase periconceptional folic acid use (Metz et al., 2002). The ultimate goal of any folic acid awareness campaign is to promote use of folic acid supplements, to increase the blood folate

**6.1 Health promotion to improve knowledge and awareness regarding folic acid** 

**6. Feature approaches** 

period. A declining trend of 26% was seen during this period (Abeywardana et al., 2010). Chan et al. (2008) reported a decline in the total prevalence of NTDs from 2.06 per 1,000 births in the prefortification period to 1.23 per 1,000 births in the mandatory fortification period (RR: 0.60, 95% confidence interval (CI): 0.48-0.74; p<0.001). Sayed et al. (2008) showed that the prevalence of spina bifida decreased from 1.41 per 1,000 births in the prefortification period to 0.98 per 1,000 births in the mandatory fortification period (RR: 0.69, 95% CI: 0.49-0.98). Ten studies suggested that food fortification could reduce the incidence of NTDs by 20 to 50%.

The effect of folic acid fortification on the incidence of NTDs has also reported in Jordan. Seventy-eight NTDs were recorded among 61,447 births between 2000 and 2006 at a Jordan hospital. Of the cases, spina bifida was the most common type of anomaly (87.2%), followed by encephalocele (11.5%), and anencephaly (1.3%). The incidence of NTDs decreased from 1.85 (95% CI; 1.2-2.4)per 1000 births before fortification (2000-2001) to 1.07 (95% CI; 0.7-1.5) during the fortification period (2002-2004), and to 0.95 (95% CI; 0.5-1.5) after full fortification (2005-2006), a 49% reduction (Amarin & Obeidat, 2011). Thus, the folic acid fortification strategy was clearly successful in some countries.

#### **5.1.3 Blood folate levels after fortification**

The mandatory fortification of standardized enriched cereal grain products in the United States has resulted in a substantial increase in blood folate concentrations. The percentage of the population with low serum folate (<3 ng/mL) declined from 21% in the period before fortification (1988-1994) to <1% of the total population in the period immediately following fortification (1999-2000) (Pfeiffer et al., 2008). In a study based on data from the National Health and Nutrition Examination Survey (NHANES), the mean serum folate concentration for women aged 15-44 years who did not use supplements increased from 10.7 nmol/L to 28.6 nmol/L shortly after the initiation of fortification in the United States, representing an almost threefold increase (CDC, 2000). In the most recent analysis of NHANES data, the CDC reported a 16% decline in serum folate concentrations among women aged 15-44 years from 1999-2000 to 2003-2004; red blood cell folate concentrations decreased 8% over the same time periods (CDC, 2007). The reason of these different decreased rate may that red blood cell folate concentrations reflect body stores at the time of red cell synthesis and are considered a better measure of long-term folate status (>3 months) than serum folate concentrations, which reflect recent dietary intake (Scientific Advisory Committee on Nutrition, 2006).

In Australia, researchers examined the impact of mandatory fortification of flour with folic acid on the blood folate levels in 20,592 Australians, including in women of childbearing age between 2009 and 2010. In 2010, there was a 31% increase in mean serum folate levels (from 17.7 nmol/L to 23.1 nmol/L), and a 22% increase in mean red blood cell (RBC) folate levels (from 881 nmol/L to 1071 nmol/L) after mandatory fortification with folic acid of wheat flour used in bread making among women of childbearing age (Brown et al., 2011). The introduction of mandatory fortification with folic acid has significantly reduced the prevalence of folate deficiency.

#### **5.2 Countries with voluntary fortification of enriched grain products with folate**

Countries where the fortification of enriched grain products with folate is not compulsory or officially endorsed report low folate status among reproductive-aged women and high

period. A declining trend of 26% was seen during this period (Abeywardana et al., 2010). Chan et al. (2008) reported a decline in the total prevalence of NTDs from 2.06 per 1,000 births in the prefortification period to 1.23 per 1,000 births in the mandatory fortification period (RR: 0.60, 95% confidence interval (CI): 0.48-0.74; p<0.001). Sayed et al. (2008) showed that the prevalence of spina bifida decreased from 1.41 per 1,000 births in the prefortification period to 0.98 per 1,000 births in the mandatory fortification period (RR: 0.69, 95% CI: 0.49-0.98). Ten studies

The effect of folic acid fortification on the incidence of NTDs has also reported in Jordan. Seventy-eight NTDs were recorded among 61,447 births between 2000 and 2006 at a Jordan hospital. Of the cases, spina bifida was the most common type of anomaly (87.2%), followed by encephalocele (11.5%), and anencephaly (1.3%). The incidence of NTDs decreased from 1.85 (95% CI; 1.2-2.4)per 1000 births before fortification (2000-2001) to 1.07 (95% CI; 0.7-1.5) during the fortification period (2002-2004), and to 0.95 (95% CI; 0.5-1.5) after full fortification (2005-2006), a 49% reduction (Amarin & Obeidat, 2011). Thus, the folic acid fortification

The mandatory fortification of standardized enriched cereal grain products in the United States has resulted in a substantial increase in blood folate concentrations. The percentage of the population with low serum folate (<3 ng/mL) declined from 21% in the period before fortification (1988-1994) to <1% of the total population in the period immediately following fortification (1999-2000) (Pfeiffer et al., 2008). In a study based on data from the National Health and Nutrition Examination Survey (NHANES), the mean serum folate concentration for women aged 15-44 years who did not use supplements increased from 10.7 nmol/L to 28.6 nmol/L shortly after the initiation of fortification in the United States, representing an almost threefold increase (CDC, 2000). In the most recent analysis of NHANES data, the CDC reported a 16% decline in serum folate concentrations among women aged 15-44 years from 1999-2000 to 2003-2004; red blood cell folate concentrations decreased 8% over the same time periods (CDC, 2007). The reason of these different decreased rate may that red blood cell folate concentrations reflect body stores at the time of red cell synthesis and are considered a better measure of long-term folate status (>3 months) than serum folate concentrations, which reflect

In Australia, researchers examined the impact of mandatory fortification of flour with folic acid on the blood folate levels in 20,592 Australians, including in women of childbearing age between 2009 and 2010. In 2010, there was a 31% increase in mean serum folate levels (from 17.7 nmol/L to 23.1 nmol/L), and a 22% increase in mean red blood cell (RBC) folate levels (from 881 nmol/L to 1071 nmol/L) after mandatory fortification with folic acid of wheat flour used in bread making among women of childbearing age (Brown et al., 2011). The introduction of mandatory fortification with folic acid has significantly reduced the

**5.2 Countries with voluntary fortification of enriched grain products with folate** 

Countries where the fortification of enriched grain products with folate is not compulsory or officially endorsed report low folate status among reproductive-aged women and high

recent dietary intake (Scientific Advisory Committee on Nutrition, 2006).

suggested that food fortification could reduce the incidence of NTDs by 20 to 50%.

strategy was clearly successful in some countries.

**5.1.3 Blood folate levels after fortification** 

prevalence of folate deficiency.

incidences of NTDs. Japan is one such country, although 440 μg of dietary folate with balanced meals was recommended to all Japanese women of reproductive age by the Ministry of Health (2000) to prevent birth defects. In 2008, the National Nutrition Survey in Japan reported that the mean dietary intake of folate, vitamin B6, and vitamin B12 of nonpregnant women aged 18-29 years was less than the recommended dietary allowance (RDA) (Ministry of Health, Labour and Welfare, 2008). Another study showed (Mito et al., 2007) that more than 80% of Japanese women aged between 17 and 41 had inadequate (i.e., less than the RDA of 240 μg/d) folate intake in 2002. This failure of women to meet the RDA for folate intake may have lead to the increase in the prevalence of spina bifida from1.96 per 10,000 live births (1974-1980) to 5.32 (2001-2005) (Annual report 2007 with data 2005, 2009).

In China, women who are planning marriage or pregnancy are advised to take 400 μg of supplemental folic acid every day, starting before conception, through to the end of the first trimester of pregnancy, but this is not mandatory (Ren et al., 2006). Northern China has one of the highest reported NTD birth prevalence rates in the world. The prevalence of NTDs was 4.5 per 1,000 in 2002 (Zhang & Wang, 2004), and only 35.8% of the affected population was aware of folic acid; fewer than 15% of women reported taking folic acid periconceptionally, with the percentage being significantly lower than the average among rural farming women with less education (Ren et al., 2006). The low level of awareness as well as the low reported rate of periconceptional supplementation may explain the high prevalence of NTDs.

#### **6. Feature approaches**

There have been three main approaches to reduce the incidence of NTDs: health promotion to improve the knowledge and awareness of folic acid, ensuring the use of fortified folic acid and folic acid supplements, and reducing the number of obese women, which is also a known environmental factor (Waller et al., 1994; Werler et al., 1996).

#### **6.1 Health promotion to improve knowledge and awareness regarding folic acid**

The USA, Canada, and Australia have implemented food fortification programs successfully with resultant improvement in serum folate levels and reduction in incidences of NTDs. Education campaigns can be effective and public health campaigns aimed at informing and influencing behavioral change in all individuals. Rofail et al. (2011) examined pre- and postcampaign awareness, knowledge, and consumption data for women of reproductive-age in Australia. Awareness of folic acid improved post-campaign, with the percentage improvement between pre- and post-campaigns ranging from 6 to 41%. Women's knowledge of the association between folate and spina bifida increased from 8% before the program began to 67% two-and-a-half years later. The proportion of women taking periconceptional folic acid supplements increased from 13% to 30% over the same period (Bower et al., 1997). Since the introduction of this promotion, the prevalence of NTDs in Western Australia, which was about two per 1,000 births from 1980 until 1995, fell by 30% in 1996 (Bower et al., 2002). The estimated increase in mean serum folate concentration was 19% after educational campaigns to increase periconceptional folic acid use (Metz et al., 2002). The ultimate goal of any folic acid awareness campaign is to promote use of folic acid supplements, to increase the blood folate levels of women, and to prevent the occurrence of NTDs.

Strategies for Prevention of Neural Tube Defects 41

knowledgeable about folic acid; they are also the least likely to report consuming a supplement containing folic acid. Recent studies have indicated that only 39% of southern Australian subjects (Chan et al., 2008), and 13.5% of Canadian subjects (French et al., 2003), knew they should take folic acid before pregnancy. Fortifying foods with folic acid has been a highly effective and uniform intervention, because fortification makes folic acid accessible

Overweight status and obesity have become serious global public health issues. Nearly two thirds of reproductive-aged women in the United States are currently overweight or obese (≥25 kg/m2). In the NHANES, the prevalence of obesity (BMI ≥30 kg/m2) in women aged 20-49 years continues to be high, exceeding 30% after 1999 (Flegal et al., 2010). In the latest NHANES data from 2007-2008 of 877 women aged 20-39 years, the prevalence of

The worldwide trend of increasing obesity may lead to increasing the incidences of NTDs. A population-based case-control study by Shaw et al. (1996) indicated an increased risk for NTD-affected pregnancies among obese women with BMIs >29 kg/m2, compared to women of normal pre-pregnancy BMIs (OR: 1.9, 95% CI: 1.3-2.9), when adjusted for maternal age, education, gravidity, use of vitamins, and use of alcohol. Rasmussen et al. (2008) conducted a metaanalysis of 12 published reports, including 4 cohort and 8 case-control studies conducted from 2000 through 2007, on the relationship between maternal obesity and the risk of NTDs. Unadjusted odds ratios for an NTD-affected pregnancy were 1.22 (95% CI: 0.99-1.49), 1.70 (95% CI: 1.34-2.15), and 3.11 (95% CI: 1.75-5.46) among overweight, obese, and severely obese women, respectively, compared with normal-weight women. Based on the results of this metaanalyisis, maternal obesity was associated with a 1.7-fold increased risk of NTDs, and severe obesity was associated with a >3-fold increased risk. A possible mechanism may involve problems with glucose metabolism, because obese women are more likely to have pre-pregnancy diabetes mellitus, which is a well-known risk factor for NTDs (Becerra et al., 1990; Werler et al., 1996). However, the reasons for this association are

The risks associated with high BMI are best addressed before conception because weight loss during pregnancy is not recommended. Counseling to support improvements in diet and physical activity is a first-step intervention. All women with a BMI of 25 kg/m2 or greater should be offered specific strategies to improve the balance and quality of their diets,

NTDs are life threatening and cause life-long disabilities. They are a worldwide problem, affecting an estimated 300,000 or more fetuses or infants each year. Experimental and epidemiological evidence has shown that periconceptional dietary supplementation with folic acid can result in an estimated 50-70% decrease in the prevalence of NTDs. To reduce more incidences of NTDs, each reproductive-aged woman must try to consume food fortified with folic acid and folic acid supplements and maintain adequate BMIs before conception. Special attention or renewed educational approaches must target reproductive-

to all women of childbearing age, without requiring substantial behavioral changes.

overweight status (BMI ≥25 kg/m2) and obesity were 59.5% and 34.0%, respectively.

**6.3 Reduce the number or obese or overweight women** 

to decrease caloric intake, and to increase physical activity.

not yet known.

**7. Conclusion** 

An U. S. national survey showed differences in folic acid awareness and knowledge among age groups (CDC, 2008). In 2007, approximately 61% of women aged 18-24 years reported being aware of folic acid, compared to 87% of women aged 25-34 years and 89% of women aged 35-45 years. Women aged 18-24 years were also less knowledgeable about the need for folic acid consumption before pregnancy (6%), compared to women aged 35-45 years (16%). In addition, approximately 33% of women who were aware of folic acid had received the information about folic acid from their health-care providers, followed by finding information in a magazine or newspaper (31%) and receiving it through radio or television (23%). Official health education initiatives have promoted folic acid supplementation and a diet rich in folates through mass media, including TV, newspapers, and magazine articles worldwide (CDC, 2010). Special attention and targeted approaches must concentrate on this age group. Public health campaigns aimed at increasing awareness, knowledge, and periconceptional use of folic acid should concentrate on using appropriate intervention methods worldwide.

#### **6.2 Encouragement to increase women's dietary intake of folic acid and use of folic acid supplements**

Many women of childbearing age in the United States do not maintain a healthy diet prior to, during, or after pregnancy. Numerous studies have reported that women in the United States do not consume the recommended 400 μg of folic acid (Hilton, 2007; Rinsky-Eng & Miller, 2002). In Japan, more than 80% of Japanese women between 17 and 41 years of age had inadequate folate intake - less than the recommended daily allowance of 240 μg/d (Mito et al., 2007; Watanabe et al., 2008). Other studies have also shown that most women of reproductive age in the U.S. are not getting enough vitamin C or B6, in addition to folic acid (Cena et al., 2008 ; Yang et al., 2007).

As previously indicated, consuming folate-rich foods or ingesting folic acid, a synthetic compound available through dietary supplements and through fortified foods, can increase folate levels. Folic acid is approximately 1.7 times more bio-available than folate, and therefore, has a greater efficiency in making an impact on folate levels (Neuhouser & Beresford, 2001).

In the U.S, the percentage of women of childbearing age who took daily supplements containing folic acid increased from 28% in 1995 (prefortification) to 32% in 2003 (postfortification) (Green-Raleigh et al., 2006), and to 40% in 2007 (US Department of Health and Human Services [USDHHS], 2010). One of the Healthy People 2010 objectives was to increase to 80% the proportion of all women of childbearing age who consume 400 μg of folic acid daily to reduce the risk for serious birth defects (USDHHS, 2010). Although a worldwide campaign contributed to progress toward this goal, approximately 60% of childbearing-aged women are still not consuming a daily supplement containing folic acid.

One should note that supplementation alone is not an effective approach because one-third to one-half of all pregnancies in the Unites States is unplanned (Custer et al., 2008). Women often do not know that they are pregnant during the crucial first 4 to 8 weeks of pregnancy. Neural tube development occurs during this time, hence the importance of ensuring adequate folic acid intake. Women aged 18-24 years have the highest rate of unintended pregnancies in the United States (Finer & Henshaw, 2006) but remain the least aware of and

An U. S. national survey showed differences in folic acid awareness and knowledge among age groups (CDC, 2008). In 2007, approximately 61% of women aged 18-24 years reported being aware of folic acid, compared to 87% of women aged 25-34 years and 89% of women aged 35-45 years. Women aged 18-24 years were also less knowledgeable about the need for folic acid consumption before pregnancy (6%), compared to women aged 35-45 years (16%). In addition, approximately 33% of women who were aware of folic acid had received the information about folic acid from their health-care providers, followed by finding information in a magazine or newspaper (31%) and receiving it through radio or television (23%). Official health education initiatives have promoted folic acid supplementation and a diet rich in folates through mass media, including TV, newspapers, and magazine articles worldwide (CDC, 2010). Special attention and targeted approaches must concentrate on this age group. Public health campaigns aimed at increasing awareness, knowledge, and periconceptional use of folic acid should concentrate on using appropriate intervention

**6.2 Encouragement to increase women's dietary intake of folic acid and use of folic** 

Many women of childbearing age in the United States do not maintain a healthy diet prior to, during, or after pregnancy. Numerous studies have reported that women in the United States do not consume the recommended 400 μg of folic acid (Hilton, 2007; Rinsky-Eng & Miller, 2002). In Japan, more than 80% of Japanese women between 17 and 41 years of age had inadequate folate intake - less than the recommended daily allowance of 240 μg/d (Mito et al., 2007; Watanabe et al., 2008). Other studies have also shown that most women of reproductive age in the U.S. are not getting enough vitamin C or B6, in addition to folic acid

As previously indicated, consuming folate-rich foods or ingesting folic acid, a synthetic compound available through dietary supplements and through fortified foods, can increase folate levels. Folic acid is approximately 1.7 times more bio-available than folate, and therefore, has a greater efficiency in making an impact on folate levels (Neuhouser &

In the U.S, the percentage of women of childbearing age who took daily supplements containing folic acid increased from 28% in 1995 (prefortification) to 32% in 2003 (postfortification) (Green-Raleigh et al., 2006), and to 40% in 2007 (US Department of Health and Human Services [USDHHS], 2010). One of the Healthy People 2010 objectives was to increase to 80% the proportion of all women of childbearing age who consume 400 μg of folic acid daily to reduce the risk for serious birth defects (USDHHS, 2010). Although a worldwide campaign contributed to progress toward this goal, approximately 60% of childbearing-aged women are still not consuming a daily supplement containing folic acid. One should note that supplementation alone is not an effective approach because one-third to one-half of all pregnancies in the Unites States is unplanned (Custer et al., 2008). Women often do not know that they are pregnant during the crucial first 4 to 8 weeks of pregnancy. Neural tube development occurs during this time, hence the importance of ensuring adequate folic acid intake. Women aged 18-24 years have the highest rate of unintended pregnancies in the United States (Finer & Henshaw, 2006) but remain the least aware of and

methods worldwide.

**acid supplements** 

Beresford, 2001).

(Cena et al., 2008 ; Yang et al., 2007).

knowledgeable about folic acid; they are also the least likely to report consuming a supplement containing folic acid. Recent studies have indicated that only 39% of southern Australian subjects (Chan et al., 2008), and 13.5% of Canadian subjects (French et al., 2003), knew they should take folic acid before pregnancy. Fortifying foods with folic acid has been a highly effective and uniform intervention, because fortification makes folic acid accessible to all women of childbearing age, without requiring substantial behavioral changes.

#### **6.3 Reduce the number or obese or overweight women**

Overweight status and obesity have become serious global public health issues. Nearly two thirds of reproductive-aged women in the United States are currently overweight or obese (≥25 kg/m2). In the NHANES, the prevalence of obesity (BMI ≥30 kg/m2) in women aged 20-49 years continues to be high, exceeding 30% after 1999 (Flegal et al., 2010). In the latest NHANES data from 2007-2008 of 877 women aged 20-39 years, the prevalence of overweight status (BMI ≥25 kg/m2) and obesity were 59.5% and 34.0%, respectively.

The worldwide trend of increasing obesity may lead to increasing the incidences of NTDs. A population-based case-control study by Shaw et al. (1996) indicated an increased risk for NTD-affected pregnancies among obese women with BMIs >29 kg/m2, compared to women of normal pre-pregnancy BMIs (OR: 1.9, 95% CI: 1.3-2.9), when adjusted for maternal age, education, gravidity, use of vitamins, and use of alcohol. Rasmussen et al. (2008) conducted a metaanalysis of 12 published reports, including 4 cohort and 8 case-control studies conducted from 2000 through 2007, on the relationship between maternal obesity and the risk of NTDs. Unadjusted odds ratios for an NTD-affected pregnancy were 1.22 (95% CI: 0.99-1.49), 1.70 (95% CI: 1.34-2.15), and 3.11 (95% CI: 1.75-5.46) among overweight, obese, and severely obese women, respectively, compared with normal-weight women. Based on the results of this metaanalyisis, maternal obesity was associated with a 1.7-fold increased risk of NTDs, and severe obesity was associated with a >3-fold increased risk. A possible mechanism may involve problems with glucose metabolism, because obese women are more likely to have pre-pregnancy diabetes mellitus, which is a well-known risk factor for NTDs (Becerra et al., 1990; Werler et al., 1996). However, the reasons for this association are not yet known.

The risks associated with high BMI are best addressed before conception because weight loss during pregnancy is not recommended. Counseling to support improvements in diet and physical activity is a first-step intervention. All women with a BMI of 25 kg/m2 or greater should be offered specific strategies to improve the balance and quality of their diets, to decrease caloric intake, and to increase physical activity.

#### **7. Conclusion**

NTDs are life threatening and cause life-long disabilities. They are a worldwide problem, affecting an estimated 300,000 or more fetuses or infants each year. Experimental and epidemiological evidence has shown that periconceptional dietary supplementation with folic acid can result in an estimated 50-70% decrease in the prevalence of NTDs. To reduce more incidences of NTDs, each reproductive-aged woman must try to consume food fortified with folic acid and folic acid supplements and maintain adequate BMIs before conception. Special attention or renewed educational approaches must target reproductive-

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insufficiency among adults following increased folic acid food fortification in 44


Neural tube defects (NTD) are serious birth defects of the brain and spine, occurring when the neural tube doesn't form or close completely. They are among the most frequent congenital malformations, affecting 300,000 pregnancies worldwide. Two forms of NTDs, spina bifida and anencephaly, account for 90% of all cases (Centers for Disease Control,

Studies had proven that supplementation of women of childbearing age with folic acid can prevent up to 70% of all cases of NTDs (Laurence et al 1981, MRC Vitamin Study Research Group 1991). These researches led to international recommendations that all women of childbearing age consume 400 micrograms of folic acid daily for the prevention of neural tube defects at least 1 month before and throughout the first trimester of pregnancy (CDC 1992, Institutes of Medicine 1998, WHO 2002). Three potential approaches were advocated to increase level of folic acid consumption among the general population: fortification of food supply, improvement of dietary habits and use of dietary supplements (CDC, 1992). In some countries such as Canada and the USA, these recommendations led to the fortification of all enriched grain products with folic acid. This action decreased the occurrence of spina bifida by 31% and anencephaly by 16% (CDC 2004) and thus was considered as a partial success. As for the change in eating habits, meeting dietary recommendations for grain intake is an important step to achieving the recommended daily intake for folic acid. Studies have shown that non pregnant women of childbearing age reported an average daily consumption of 128 mcg of folic acid, representing only 32 percent of the daily recommended amount (Yang et al. 2007). These facts imply that most women still need to daily consume a dietary supplement containing folic acid at the recommended dose (400 µg) in order to prevent pregnancies with NTDs. Despite all this, several studies have shown a low consumption of folic acid supplements worldwide: numbers vary from prevalence as low as 7.5% in Lebanon (Nasr Hage et al 2011) to the highest percentage of 40 % in Canada and the USA (Morin et al. 2002; Petrini et al, 2008). These percentages remain far from the "Healthy people 2010" goal aiming that a minimum of 80% of women of childbearing age consume at least 400 mcg of folic acid daily in the periconception period. Levels of awareness and knowledge have been studied extensively in women of childbearing age in order to explain the low prevalence of folic acid intake with variable results in different countries. Although these levels of awareness and knowledge were thought to explain low levels of folic acid consumption, a systematic review of the literature showed that variable interventions on folic acid increased women's awareness from 60% to 72% and knowledge

**1. Introduction** 

CDC, 1989).

Claudine Nasr Hage and Grace Abi Rizk

*Saint Joseph school of medicine* 

*Lebanon* 

Zhang, X. & Wang, L. (2004). Analysis of birth defects surveillance, 1966-2002. *Matern Child Health Care China*, Vol. 19: 93-4 (in Chinese). **3** 

Claudine Nasr Hage and Grace Abi Rizk

*Saint Joseph school of medicine Lebanon* 

#### **1. Introduction**

46 Neural Tube Defects – Role of Folate, Prevention Strategies and Genetics

Zhang, X. & Wang, L. (2004). Analysis of birth defects surveillance, 1966-2002. *Matern Child* 

Neural tube defects (NTD) are serious birth defects of the brain and spine, occurring when the neural tube doesn't form or close completely. They are among the most frequent congenital malformations, affecting 300,000 pregnancies worldwide. Two forms of NTDs, spina bifida and anencephaly, account for 90% of all cases (Centers for Disease Control, CDC, 1989).

Studies had proven that supplementation of women of childbearing age with folic acid can prevent up to 70% of all cases of NTDs (Laurence et al 1981, MRC Vitamin Study Research Group 1991). These researches led to international recommendations that all women of childbearing age consume 400 micrograms of folic acid daily for the prevention of neural tube defects at least 1 month before and throughout the first trimester of pregnancy (CDC 1992, Institutes of Medicine 1998, WHO 2002). Three potential approaches were advocated to increase level of folic acid consumption among the general population: fortification of food supply, improvement of dietary habits and use of dietary supplements (CDC, 1992). In some countries such as Canada and the USA, these recommendations led to the fortification of all enriched grain products with folic acid. This action decreased the occurrence of spina bifida by 31% and anencephaly by 16% (CDC 2004) and thus was considered as a partial success. As for the change in eating habits, meeting dietary recommendations for grain intake is an important step to achieving the recommended daily intake for folic acid. Studies have shown that non pregnant women of childbearing age reported an average daily consumption of 128 mcg of folic acid, representing only 32 percent of the daily recommended amount (Yang et al. 2007). These facts imply that most women still need to daily consume a dietary supplement containing folic acid at the recommended dose (400 µg) in order to prevent pregnancies with NTDs. Despite all this, several studies have shown a low consumption of folic acid supplements worldwide: numbers vary from prevalence as low as 7.5% in Lebanon (Nasr Hage et al 2011) to the highest percentage of 40 % in Canada and the USA (Morin et al. 2002; Petrini et al, 2008). These percentages remain far from the "Healthy people 2010" goal aiming that a minimum of 80% of women of childbearing age consume at least 400 mcg of folic acid daily in the periconception period. Levels of awareness and knowledge have been studied extensively in women of childbearing age in order to explain the low prevalence of folic acid intake with variable results in different countries. Although these levels of awareness and knowledge were thought to explain low levels of folic acid consumption, a systematic review of the literature showed that variable interventions on folic acid increased women's awareness from 60% to 72% and knowledge

genes codifying to enzymes needed for nucleotide biosynthesis such as the polymorphism in methylenetetrahydrofolate dehydrogenase, and the role of the genes codifying proteins involved in the transport, capture and cell retention of folate (DeMarco et al, 2006; Beaudin and Stover, 2009). The role of nutrition in the development of NTDs has been studied. The relationship between folic acid deficiency and NTDs may be linked to lower gene expressions due to alteration in the methylation and synthesis of DNA (Zeisel, 2009). The daily consumption of folic acid reduced the level of homocysteine, a risk factor in the

Early studies in the sixties and seventies suggested a role for diet in NTDS (Hibbard and Smithells 1965; Knox, 1972; Smithells et al 1976). In early eighties, two randomized controlled trials showed a reduction in the recurrence of NTDs with folic acid supplementation but these studies were criticized for their methodological limitations (Laurence et al 1981; Smithells et al, 1980). Further observational studies conducted in the eighties suggested that the consumption of folic acid by women of childbearing age is protective against NTDs in newborns (Bower and Stanley, 1989; Milunsky et al, 1989; Mulinar et al, 1988). This was confirmed by a randomized multicenter controlled trial showing that daily supplementation of women in childbearing age with folic acid reduced by 72% the risk of recurrence of NTDs (MRC Vitamin Study Research Group 1991). The conclusive proof of the preventive effect of folic acid for women with no NTD history came from a randomised controlled study conducted in Hungary that showed no NTD cases occured among 2104 women taking folic acid as compared with six cases among 2052 pregnancies in the group not taking folic acid (Czeizel and Dudas, 1992). A meta-analysis study published in 2010 reviewed all observational and randomized studies evaluating the first occurrence and recurrence of NTDs and related mortalities in pregnancy. It concluded that folic acid intake reduced the recurrence of NTDs by 70% and the first occurrence of

All the data confirming the protective effect of folic acid against NTDs led to international recommendations concerning folic acid consumption in women of childbearing age. The Institutes of Medicine and CDC recommend the maternal consumption of 400 micrograms of synthetic folic acid daily at least 1 month before conception and during the first few months of pregnancy (CDC, 1992; Institute of Medicine, 1998). The Canadian college of medical geneticists recommended that a minimum dose of 0.8 mg/day of folic acid along with a well-balanced diet should be prescribed for women planning a pregnancy, starting before conception and for at least 10-12 weeks of pregnancy (Van Allen et al, 1993). Similar

The EUROCAT published a report about the "prevention of neural tube defects by periconceptional folic acid supplementation in Europe" (EUROCAT special report, updated version December 2009). In most European countries where a policy exists, periconceptional folic acid supplements are recommended at a daily dose of 0.4 to 0.5 mg and the dose of 4 to 5 mg is reserved for women who have had a previous pregnancy

guidelines were issued by the Canadian college of obstetricians and gynecologists.

development of NTDs (Boyles et al, 2005).

NTD by 62% (Blencowe et al, 2010).

**2.4 Recommendations for folic acid consumption in pregnancies** 

**2.3 Evidence for prevention of NTDs with folic acid** 

from 21% to 45%. At the same time, levels of folic acid consumption increased only from 14% to 23% showing a positive but suboptimal impact (Chivu et al. 2007). As Green and Kreuter say "changes in knowledge and awareness alone cannot be assumed to translate into changes in behavior" (Green and Kreuter, 1991). There is still a gap between awareness and behavior on one side and usage of folic acid on the other side. This gap could be explained by determinants of behavioral change such as unplanned pregnancies, perceived barriers for taking folic acid pills, lack of time, level of education, age group and culture.

This chapter will discuss the preventive role of folic acid in the development of neural tube defects and the recommendations concerning its consumption. Factors related to folic acid knowledge, attitude and behavior will be analyzed as well as suggestions made for effective strategies aiming to improve its usage among women of childbearing age.

#### **2. Role of folic acid in the prevention of NTDs**

#### **2.1 Folic acid as a vitamin**

Folate, also known as vitamin B9, is a water-soluble B vitamin that occurs naturally in food. It is an essential nutrient that humans can not synthesize. Folic acid is the synthetic form of folate that is found in supplements and added to fortified foods. Folate is found naturally in a wide variety of foods particularly leafy green vegetables such as spinach, asparagus and lettuce, grains such as beans, peas and lentils, fruits such as orange, cantaloupe and melon, kidney, liver, egg yolk and yeast. Most folates have many molecules of glutamic acid; they have to be converted to monoglutamate to be absorbed in the intestine. The synthetic form has one molecule of glutamic acid making it more bioavailable than the natural form. Folate is critically important for fetal development. It has a role in DNA synthesis, acts as a cofactor for many essential cellular reactions and is implicated in the metabolism of several amino acids especially in the conversion of homocysteine to methionine; thus, the need for folate increases during periods of rapid tissue growth such as in pregnancy. When folate is insufficient, DNA synthesis is impaired and cells are unable to successfully achieve mitosis. In addition, the methylation process of proteins, lipids and myelin is inhibited (Rosenblatt, 1995).

#### **2.2 Mechanism of NTD prevention with folic acid**

The mechanism by which folic acid prevents NTDs remains unknown. Many theories have been proposed. Genetic, nutritional, environmental factors or a combination of these play a role in the development of NTDs. The genetic theory of methylation was proposed by Blom et al (Blom et al, 2006). Problems during embryogenesis in the methylation of DNA, proteins and lipids are related to the development of NTDs. A mutation in the gene coding for the methylenetetrahydrofolate reductase enzyme, responsible of the generation of a methyl group essential for biosynthesis of methionine and nucleotides, is believed to contribute to fetal nervous system malformation such as spina bifida (Mills et al, 1995). This mutation accounts for one-fourth of NTDs suggesting that the protective effect of folate, reaching a 70% reduction in NTDs, involves other environmental factors or gene-environment interactions (Posey et al, 1996). Other genes involved in the methylation cycle through remethylation or transsulfuration of homocysteine were also involved in the development of NTDs (Boyles et al, 2005). Besides the methylation theory, two other theories were proposed as genetic explanations for the relationship between folic acid and NTDs: the role of the

from 21% to 45%. At the same time, levels of folic acid consumption increased only from 14% to 23% showing a positive but suboptimal impact (Chivu et al. 2007). As Green and Kreuter say "changes in knowledge and awareness alone cannot be assumed to translate into changes in behavior" (Green and Kreuter, 1991). There is still a gap between awareness and behavior on one side and usage of folic acid on the other side. This gap could be explained by determinants of behavioral change such as unplanned pregnancies, perceived barriers for taking folic acid pills, lack of time, level of education, age group and culture.

This chapter will discuss the preventive role of folic acid in the development of neural tube defects and the recommendations concerning its consumption. Factors related to folic acid knowledge, attitude and behavior will be analyzed as well as suggestions made for effective

Folate, also known as vitamin B9, is a water-soluble B vitamin that occurs naturally in food. It is an essential nutrient that humans can not synthesize. Folic acid is the synthetic form of folate that is found in supplements and added to fortified foods. Folate is found naturally in a wide variety of foods particularly leafy green vegetables such as spinach, asparagus and lettuce, grains such as beans, peas and lentils, fruits such as orange, cantaloupe and melon, kidney, liver, egg yolk and yeast. Most folates have many molecules of glutamic acid; they have to be converted to monoglutamate to be absorbed in the intestine. The synthetic form has one molecule of glutamic acid making it more bioavailable than the natural form. Folate is critically important for fetal development. It has a role in DNA synthesis, acts as a cofactor for many essential cellular reactions and is implicated in the metabolism of several amino acids especially in the conversion of homocysteine to methionine; thus, the need for folate increases during periods of rapid tissue growth such as in pregnancy. When folate is insufficient, DNA synthesis is impaired and cells are unable to successfully achieve mitosis. In addition, the

strategies aiming to improve its usage among women of childbearing age.

methylation process of proteins, lipids and myelin is inhibited (Rosenblatt, 1995).

The mechanism by which folic acid prevents NTDs remains unknown. Many theories have been proposed. Genetic, nutritional, environmental factors or a combination of these play a role in the development of NTDs. The genetic theory of methylation was proposed by Blom et al (Blom et al, 2006). Problems during embryogenesis in the methylation of DNA, proteins and lipids are related to the development of NTDs. A mutation in the gene coding for the methylenetetrahydrofolate reductase enzyme, responsible of the generation of a methyl group essential for biosynthesis of methionine and nucleotides, is believed to contribute to fetal nervous system malformation such as spina bifida (Mills et al, 1995). This mutation accounts for one-fourth of NTDs suggesting that the protective effect of folate, reaching a 70% reduction in NTDs, involves other environmental factors or gene-environment interactions (Posey et al, 1996). Other genes involved in the methylation cycle through remethylation or transsulfuration of homocysteine were also involved in the development of NTDs (Boyles et al, 2005). Besides the methylation theory, two other theories were proposed as genetic explanations for the relationship between folic acid and NTDs: the role of the

**2. Role of folic acid in the prevention of NTDs** 

**2.2 Mechanism of NTD prevention with folic acid** 

**2.1 Folic acid as a vitamin** 

genes codifying to enzymes needed for nucleotide biosynthesis such as the polymorphism in methylenetetrahydrofolate dehydrogenase, and the role of the genes codifying proteins involved in the transport, capture and cell retention of folate (DeMarco et al, 2006; Beaudin and Stover, 2009). The role of nutrition in the development of NTDs has been studied. The relationship between folic acid deficiency and NTDs may be linked to lower gene expressions due to alteration in the methylation and synthesis of DNA (Zeisel, 2009). The daily consumption of folic acid reduced the level of homocysteine, a risk factor in the development of NTDs (Boyles et al, 2005).

#### **2.3 Evidence for prevention of NTDs with folic acid**

Early studies in the sixties and seventies suggested a role for diet in NTDS (Hibbard and Smithells 1965; Knox, 1972; Smithells et al 1976). In early eighties, two randomized controlled trials showed a reduction in the recurrence of NTDs with folic acid supplementation but these studies were criticized for their methodological limitations (Laurence et al 1981; Smithells et al, 1980). Further observational studies conducted in the eighties suggested that the consumption of folic acid by women of childbearing age is protective against NTDs in newborns (Bower and Stanley, 1989; Milunsky et al, 1989; Mulinar et al, 1988). This was confirmed by a randomized multicenter controlled trial showing that daily supplementation of women in childbearing age with folic acid reduced by 72% the risk of recurrence of NTDs (MRC Vitamin Study Research Group 1991). The conclusive proof of the preventive effect of folic acid for women with no NTD history came from a randomised controlled study conducted in Hungary that showed no NTD cases occured among 2104 women taking folic acid as compared with six cases among 2052 pregnancies in the group not taking folic acid (Czeizel and Dudas, 1992). A meta-analysis study published in 2010 reviewed all observational and randomized studies evaluating the first occurrence and recurrence of NTDs and related mortalities in pregnancy. It concluded that folic acid intake reduced the recurrence of NTDs by 70% and the first occurrence of NTD by 62% (Blencowe et al, 2010).

#### **2.4 Recommendations for folic acid consumption in pregnancies**

All the data confirming the protective effect of folic acid against NTDs led to international recommendations concerning folic acid consumption in women of childbearing age. The Institutes of Medicine and CDC recommend the maternal consumption of 400 micrograms of synthetic folic acid daily at least 1 month before conception and during the first few months of pregnancy (CDC, 1992; Institute of Medicine, 1998). The Canadian college of medical geneticists recommended that a minimum dose of 0.8 mg/day of folic acid along with a well-balanced diet should be prescribed for women planning a pregnancy, starting before conception and for at least 10-12 weeks of pregnancy (Van Allen et al, 1993). Similar guidelines were issued by the Canadian college of obstetricians and gynecologists.

The EUROCAT published a report about the "prevention of neural tube defects by periconceptional folic acid supplementation in Europe" (EUROCAT special report, updated version December 2009). In most European countries where a policy exists, periconceptional folic acid supplements are recommended at a daily dose of 0.4 to 0.5 mg and the dose of 4 to 5 mg is reserved for women who have had a previous pregnancy

USA in 2001-2002. They found that the average daily consumption was 128 µg/day, representing 32% of the daily recommended amount (Yang et al, 2007). Knowing the importance of grain intake in achieving the recommended intake for folic acid, Briefel and Johnson reviewed national data in the USA on grain intake; they found that, in 1999-2000, only 24% of the population met the recommendation for daily servings of grains (Briefel and Johnson, 2004). The German Nutrition Report 2004 stated that the average daily intake of all women in Germany was 215µg/day, still below the reference value of 400µg/day (EUROCAT, 2009). Another study done by Heinz showed that 81% of women 18-40 years of age had a daily folic acid consumption of less than 150µg (Heinz et al, 2001 as in EUROCAT, 2009). In Hungary, a dietary survey conducted in 2003-2004 showed that the average daily folic acid intake is 132.3µg/day (EUROCAT, 2009).The average daily natural folate intake of most women in different European countries ranges from 230 to 280 µg /day (Flynn et al, 2009). A review done by Kumaniyka and his colleagues in 2000 on dietary behavioral changes in relation with nutrients such as fruits, vegetables and grains highlighted the difficulty of sustaining these behavioral modifications (Kumaniyka et al, 2000). These studies show that achieving the recommendations for folic acid consumption by food folates alone requires major dietary modifications unlikely to be achieved by women of childbearing age. Furthermore, one study tried to compare the effectiveness of the 3 suggested interventions for meeting the recommendations on folic acid. A 12-week trial evaluated the changes in red blood cell folate in response to one of the following interventions: folic acid supplementation (400µg/day), natural food folates (400µg/day), fortified food (400µg/day), qualitative dietary advice and control diet. The study showed that the only interventions increasing significantly blood folate were food fortification and folic acid supplements. The increase in natural food folates did not translate into higher levels of blood folate, most probably because of the low bioavailability and stability of

natural folates compared to the synthetic form (Cuskelly et al, 1996).

Regulations for mandatory food fortification with folic acid are currently in place in 53 countries (CDC, 2010). In 1996, the United States Food and Drug Administration (FDA) issued a mandate to fortify all enriched grain products with folic acid, to be fully implemented in 1998. Food items covered by this mandate were mainly flour, corn meal, pasta and rice and they were fortified with 140µg/100g of cereal grains. At this level of fortification, women are expected to consume an average of 100µg daily of folic acid from fortified cereal grain products (FDA, 1996). Folic acid food fortification became mandatory in Canada and Costa Rica in 1998, with the fortification respectively of 150µg and 180µg /100g of enriched flour and uncooked cereal grains (Chen and Rivera, 2004; Ray, 2004). In 2000, the Chilean ministry of health mandated that folic acid should be added at a level of 2.2mg/kg to wheat flour (Hertrampf and Cortés, 2004). In June 2004, the Brazilian government introduced mandatory fortification of wheat and maize flour with 150µg/100 g (Almeida and Cardoso, 2010). A number of Middle Eastern countries, as well as Indonesia now fortify their flour. South Africa issued a mandate on food fortification in 2003 with 150 µg of folic acid added to 100g of cereal grains (Sayed et al, 2008).The Australian government had agreed to fortification of flour and bread with folic acid, starting September 2009. In Europe mandatory fortification of a staple food with folic acid has been seriously considered in 8 countries (Denmark, Germany, Ireland, Northern Netherlands, Norway, Poland,

**3.2 Fortification of food with folic acid** 

complicated with NTDs. Table 1 (adapted from the EUROCAT report) summarizes periconceptional folic acid supplementation policies around Europe.

Because half of all pregnancies in the United States are unplanned (Finer and Henshaw 2006), and because NTDs occur often before a woman knows she is pregnant, the Centers for Disease Control and Prevention (CDC) recommends that all women who can become pregnant consume the recommended amount of folic acid daily, regardless of their pregnancy intentions (CDC, 2004).


Table 1. Folic acid supplementation policy in European countries (until December 2007)

#### **3. Community interventions to increase folate intake**

Three ways were advocated in order to increase folate intake in women of childbearing age: improvement of dietary habits, fortification of food supply with folic acid and the use of folic acid supplements (CDC, 1992)

#### **3.1 Improvement of dietary habits**

Studies have shown that the average consumption of folate by women is not more than 200µg/day (Gregory et al, 1990; Subar et al, 1989). Yang and colleagues calculated the average daily dietary intake of folate and folic acid by women of childbearing age in the

complicated with NTDs. Table 1 (adapted from the EUROCAT report) summarizes

Because half of all pregnancies in the United States are unplanned (Finer and Henshaw 2006), and because NTDs occur often before a woman knows she is pregnant, the Centers for Disease Control and Prevention (CDC) recommends that all women who can become pregnant consume the recommended amount of folic acid daily, regardless of their

Table 1. Folic acid supplementation policy in European countries (until December 2007)

Three ways were advocated in order to increase folate intake in women of childbearing age: improvement of dietary habits, fortification of food supply with folic acid and the use of

Studies have shown that the average consumption of folate by women is not more than 200µg/day (Gregory et al, 1990; Subar et al, 1989). Yang and colleagues calculated the average daily dietary intake of folate and folic acid by women of childbearing age in the

**3. Community interventions to increase folate intake** 

folic acid supplements (CDC, 1992)

**3.1 Improvement of dietary habits** 

Status Year current policy

introduced

periconceptional folic acid supplementation policies around Europe.

Country Folic acid policy

Austria Unofficial 1998 Belgium Unofficial - Croatia Unofficial - Denmark Official 1997 Finland Official 2004 France Official 2000 Germany Unofficial 1994 Hungary Official 1996 Ireland Official 1993 Italy Official 2004 Malta Dietary 1994 Netherlands Official 1993 Norway Official 1998 Poland Official 1997 Portugal Official 1998 Slovenia Official 1998 Spain Official 2001 Sweden Official 1996 Switzerland Official 1996 UK Official 1992 Ukraine Official 2002

pregnancy intentions (CDC, 2004).

USA in 2001-2002. They found that the average daily consumption was 128 µg/day, representing 32% of the daily recommended amount (Yang et al, 2007). Knowing the importance of grain intake in achieving the recommended intake for folic acid, Briefel and Johnson reviewed national data in the USA on grain intake; they found that, in 1999-2000, only 24% of the population met the recommendation for daily servings of grains (Briefel and Johnson, 2004). The German Nutrition Report 2004 stated that the average daily intake of all women in Germany was 215µg/day, still below the reference value of 400µg/day (EUROCAT, 2009). Another study done by Heinz showed that 81% of women 18-40 years of age had a daily folic acid consumption of less than 150µg (Heinz et al, 2001 as in EUROCAT, 2009). In Hungary, a dietary survey conducted in 2003-2004 showed that the average daily folic acid intake is 132.3µg/day (EUROCAT, 2009).The average daily natural folate intake of most women in different European countries ranges from 230 to 280 µg /day (Flynn et al, 2009). A review done by Kumaniyka and his colleagues in 2000 on dietary behavioral changes in relation with nutrients such as fruits, vegetables and grains highlighted the difficulty of sustaining these behavioral modifications (Kumaniyka et al, 2000). These studies show that achieving the recommendations for folic acid consumption by food folates alone requires major dietary modifications unlikely to be achieved by women of childbearing age. Furthermore, one study tried to compare the effectiveness of the 3 suggested interventions for meeting the recommendations on folic acid. A 12-week trial evaluated the changes in red blood cell folate in response to one of the following interventions: folic acid supplementation (400µg/day), natural food folates (400µg/day), fortified food (400µg/day), qualitative dietary advice and control diet. The study showed that the only interventions increasing significantly blood folate were food fortification and folic acid supplements. The increase in natural food folates did not translate into higher levels of blood folate, most probably because of the low bioavailability and stability of natural folates compared to the synthetic form (Cuskelly et al, 1996).

#### **3.2 Fortification of food with folic acid**

Regulations for mandatory food fortification with folic acid are currently in place in 53 countries (CDC, 2010). In 1996, the United States Food and Drug Administration (FDA) issued a mandate to fortify all enriched grain products with folic acid, to be fully implemented in 1998. Food items covered by this mandate were mainly flour, corn meal, pasta and rice and they were fortified with 140µg/100g of cereal grains. At this level of fortification, women are expected to consume an average of 100µg daily of folic acid from fortified cereal grain products (FDA, 1996). Folic acid food fortification became mandatory in Canada and Costa Rica in 1998, with the fortification respectively of 150µg and 180µg /100g of enriched flour and uncooked cereal grains (Chen and Rivera, 2004; Ray, 2004). In 2000, the Chilean ministry of health mandated that folic acid should be added at a level of 2.2mg/kg to wheat flour (Hertrampf and Cortés, 2004). In June 2004, the Brazilian government introduced mandatory fortification of wheat and maize flour with 150µg/100 g (Almeida and Cardoso, 2010). A number of Middle Eastern countries, as well as Indonesia now fortify their flour. South Africa issued a mandate on food fortification in 2003 with 150 µg of folic acid added to 100g of cereal grains (Sayed et al, 2008).The Australian government had agreed to fortification of flour and bread with folic acid, starting September 2009. In Europe mandatory fortification of a staple food with folic acid has been seriously considered in 8 countries (Denmark, Germany, Ireland, Northern Netherlands, Norway, Poland,

before conception. This fact constitutes a limitation for the reliance on supplements as a primary public health program since in many countries, a high level of pregnancies are unplanned such as in the USA where up to 50% of pregnancies are unplanned. International studies have shown a low level of compliance with folic acid supplements intake. In the USA, the percentage of women of childbearing age who consume folic acid supplements is low, slightly increasing from 28% in 1995 to 33% in 2005, up to 40% in 2007 (CDC, 2008). Even in the Netherlands, where the percentage of planned pregnancies is estimated at 85%, only 36% of women take folic acid supplements during the periconceptional period (Meijer and De Walle, 2005). These low levels of intake were seen in different countries with the highest percentage of intake seen in Canada and the USA (40%) and the lowest percentages in Korea (10.3%), Thailand (9.7%) and Lebanon (7.5%) (Kim et al, 2009; Morin et al, 2002; Nasr Hage et al, 2011; Nawapun and Phupong, 2007; CDC, 2008).

Of interest is the relationship between knowledge, awareness and adequate intake of folic acid. Awareness concerning folic acid is usually evaluated in response to the question "have you ever heard or read anything about folic acid?"; levels of awareness reported in the literature are very variable. In the USA, the March of Dimes Birth Defects Foundation reported national levels of awareness of 52% in 1995, increasing to 84% in 2005 (March of Dimes Birth Defects Foundation, 2005). The analysis done by the CDC showed that from 2003 to 2007, levels of awareness were stagnant around 80% (79% in 2003 and 81% in 2007) (CDC, 2008). In Canada, awareness reached a percentage of 95% (French et al, 2003). Even in countries were folic acid intake is very low, women have usually high levels of awareness such as in Lebanon where 60% of women knew about folic acid but only 7.5% of them were using supplements adequately (Nasr Hage et al, 2011). Still in some countries, the number of women who have heard of folic acid is low, reaching 18% in Turkey (Turgul et al, 2009). Even though levels of awareness are acceptable in general with some exceptions, the gap lies in knowledge concerning the benefits of folic acid in NTDs prevention, the nutritional source of natural and synthetic folates and the adequate period of folic acid intake. National percentages in the USA showed that in 1995 only 4% of American women knew that folic acid help reduce the risk of birth defects. These numbers reached 24% in 2004 before decreasing to 19% in 2005. The same report stated that only 2% of American women identified the adequate period for folic acid intake, percentages reaching 12% in 2004 and dropping to 7% in 2005 (March of Dimes Birth Defects Foundation, 2005). A CDC report showed that knowledge concerning the adequate period of intake raise slightly to 12% in 2007 (CDC, 2008). In Canada where the levels of awareness and intake are relatively high, only 25% of women studied in Vancouver knew that folic acid could prevent birth defects (French et al, 2003). As expected, low levels of knowledge were also found in countries with low levels of folic acid intake such as in Thailand where 25% of surveyed women knew that folic acid was something important and in Lebanon where 14% knew about the role of folic acid in NTD prevention and 25% knew about the adequate period for supplementation (Nasr Hage et al, 2011; Nawapun and Phupong, 2007). These numbers show that low intake of folic acid supplements is, at least partially related to lack of knowledge. This relationship was suggested by French and colleagues showing that 78% of the women in their study

**4. Women's knowledge and awareness concerning folic acid** 

Switzerland and the UK), but debates are still going on. Until now, no European country has agreed to mandatory food fortification with folic acid (EUROCAT, 2009). At the same time, food voluntarily fortified with folic acid (such as breakfast cereals) is available in many European countries. These countries do not implement mandatory folic acid supplementation because, according to them, expected additional health benefits are not scientifically proven in clinical trial, because of feared health consequences and because of the issue of freedom of choice (Eichholzer et al, 2006).

Studies have shown a positive impact of food fortification on blood folate concentrations and a reduction in the prevalence of NTDs in the USA (Boulet et al, 2008), in Canada (Godwin et al, 2008) and in Chile (Nazer et al, 2007).

Measuring blood folate concentrations constitutes one way to evaluate the effect of food fortification programs. Folate deficiency is defined as a serum folate concentration <7nmol/l (3ng/ml) or a red blood cell folate concentration <315nmol/l (140ng/ml) (Crider et al, 2011). In The USA, median serum folate increased from 12.6µg/l in 1994 to 18.7 µg/l in 1998 after food fortification (Lawrence et al, 1999). In Canada, a study conducted on 38,000 women in Ontario showed an increase in red blood cell folate from 527nmol/l to 741 nmole/l after food fortification (p<0.001) (Ray et al, 2002). In Chile, the mean serum concentrations and red blood cell folate increased respectively from 9.7 and 290nmol/l to 37.2 and 707nmol/l (p<0.0001) after mandatory fortification (Hertrampf et al, 2003).

The main purpose for folic acid fortification was to reduce the occurence of NTDs and the associated mortality and morbidities. Many studies around the world evaluated the impact of food fortification on the prevalence of NTDs. In the USA, a report published by the CDC in 2004 found a reduction of 27% in spina bifida and anencephaly between 1995-1996 and 1999-2000 (CDC, MMWR 2004). Different studies in the USA with different methodologies showed a decrease in the prevalence of NTDs between 19-32% after mandatory food fortification, reaching 23 to 54% for spina bifida and 11% to 16% for anencephaly (Boulet et al, 2008; Honein et al, 2001; Mathews, 2008; Williams et al, 2002). In Canada, studies have shown an even greater impact of food fortification than the impact shown in the USA. De Wals and collegues examined the NTD trends before and after food fortification in seven of ten Canadian provinces (De Wals et al, 2007, 2008). They showed a 46% reduction of NTDs and the magnitude of the decrease was higher for spina bifida (53%) than for anencephaly (38%) (De walls et al, 2007). Similar results were found in Chile, Argentina and Brazil with a reduction in the prevalence of NTDs by 19 to 55 % (Lopez-Camelo et al, 2010). In South Africa, Sayed and his collegues found a significant decline of 30.5% in the prevalence of NTDs (41.6% for spina bifida and 10.9% for anencephaly) following food fortification in 2003 (Sayed et al, 2008). The differences found in the magnitude of the decline in NTD prevalence after food fortification among different countries depend on many factors such as the initial prevalence of NTDs, the initial folate status of the population, the consumption of fortified food by the population and the presence of birth defects surveillance systems (Crider et al, 2011).

#### **3.3 Folic acid supplements**

The third way suggested for increasing women consumption of folic acid is the use of supplements. In order to be effective, these supplements should be taken at least 1 month

Switzerland and the UK), but debates are still going on. Until now, no European country has agreed to mandatory food fortification with folic acid (EUROCAT, 2009). At the same time, food voluntarily fortified with folic acid (such as breakfast cereals) is available in many European countries. These countries do not implement mandatory folic acid supplementation because, according to them, expected additional health benefits are not scientifically proven in clinical trial, because of feared health consequences and because of

Studies have shown a positive impact of food fortification on blood folate concentrations and a reduction in the prevalence of NTDs in the USA (Boulet et al, 2008), in Canada

Measuring blood folate concentrations constitutes one way to evaluate the effect of food fortification programs. Folate deficiency is defined as a serum folate concentration <7nmol/l (3ng/ml) or a red blood cell folate concentration <315nmol/l (140ng/ml) (Crider et al, 2011). In The USA, median serum folate increased from 12.6µg/l in 1994 to 18.7 µg/l in 1998 after food fortification (Lawrence et al, 1999). In Canada, a study conducted on 38,000 women in Ontario showed an increase in red blood cell folate from 527nmol/l to 741 nmole/l after food fortification (p<0.001) (Ray et al, 2002). In Chile, the mean serum concentrations and red blood cell folate increased respectively from 9.7 and 290nmol/l to 37.2 and 707nmol/l

The main purpose for folic acid fortification was to reduce the occurence of NTDs and the associated mortality and morbidities. Many studies around the world evaluated the impact of food fortification on the prevalence of NTDs. In the USA, a report published by the CDC in 2004 found a reduction of 27% in spina bifida and anencephaly between 1995-1996 and 1999-2000 (CDC, MMWR 2004). Different studies in the USA with different methodologies showed a decrease in the prevalence of NTDs between 19-32% after mandatory food fortification, reaching 23 to 54% for spina bifida and 11% to 16% for anencephaly (Boulet et al, 2008; Honein et al, 2001; Mathews, 2008; Williams et al, 2002). In Canada, studies have shown an even greater impact of food fortification than the impact shown in the USA. De Wals and collegues examined the NTD trends before and after food fortification in seven of ten Canadian provinces (De Wals et al, 2007, 2008). They showed a 46% reduction of NTDs and the magnitude of the decrease was higher for spina bifida (53%) than for anencephaly (38%) (De walls et al, 2007). Similar results were found in Chile, Argentina and Brazil with a reduction in the prevalence of NTDs by 19 to 55 % (Lopez-Camelo et al, 2010). In South Africa, Sayed and his collegues found a significant decline of 30.5% in the prevalence of NTDs (41.6% for spina bifida and 10.9% for anencephaly) following food fortification in 2003 (Sayed et al, 2008). The differences found in the magnitude of the decline in NTD prevalence after food fortification among different countries depend on many factors such as the initial prevalence of NTDs, the initial folate status of the population, the consumption of fortified food by the

population and the presence of birth defects surveillance systems (Crider et al, 2011).

The third way suggested for increasing women consumption of folic acid is the use of supplements. In order to be effective, these supplements should be taken at least 1 month

**3.3 Folic acid supplements** 

the issue of freedom of choice (Eichholzer et al, 2006).

(Godwin et al, 2008) and in Chile (Nazer et al, 2007).

(p<0.0001) after mandatory fortification (Hertrampf et al, 2003).

before conception. This fact constitutes a limitation for the reliance on supplements as a primary public health program since in many countries, a high level of pregnancies are unplanned such as in the USA where up to 50% of pregnancies are unplanned. International studies have shown a low level of compliance with folic acid supplements intake. In the USA, the percentage of women of childbearing age who consume folic acid supplements is low, slightly increasing from 28% in 1995 to 33% in 2005, up to 40% in 2007 (CDC, 2008). Even in the Netherlands, where the percentage of planned pregnancies is estimated at 85%, only 36% of women take folic acid supplements during the periconceptional period (Meijer and De Walle, 2005). These low levels of intake were seen in different countries with the highest percentage of intake seen in Canada and the USA (40%) and the lowest percentages in Korea (10.3%), Thailand (9.7%) and Lebanon (7.5%) (Kim et al, 2009; Morin et al, 2002; Nasr Hage et al, 2011; Nawapun and Phupong, 2007; CDC, 2008).

#### **4. Women's knowledge and awareness concerning folic acid**

Of interest is the relationship between knowledge, awareness and adequate intake of folic acid. Awareness concerning folic acid is usually evaluated in response to the question "have you ever heard or read anything about folic acid?"; levels of awareness reported in the literature are very variable. In the USA, the March of Dimes Birth Defects Foundation reported national levels of awareness of 52% in 1995, increasing to 84% in 2005 (March of Dimes Birth Defects Foundation, 2005). The analysis done by the CDC showed that from 2003 to 2007, levels of awareness were stagnant around 80% (79% in 2003 and 81% in 2007) (CDC, 2008). In Canada, awareness reached a percentage of 95% (French et al, 2003). Even in countries were folic acid intake is very low, women have usually high levels of awareness such as in Lebanon where 60% of women knew about folic acid but only 7.5% of them were using supplements adequately (Nasr Hage et al, 2011). Still in some countries, the number of women who have heard of folic acid is low, reaching 18% in Turkey (Turgul et al, 2009). Even though levels of awareness are acceptable in general with some exceptions, the gap lies in knowledge concerning the benefits of folic acid in NTDs prevention, the nutritional source of natural and synthetic folates and the adequate period of folic acid intake. National percentages in the USA showed that in 1995 only 4% of American women knew that folic acid help reduce the risk of birth defects. These numbers reached 24% in 2004 before decreasing to 19% in 2005. The same report stated that only 2% of American women identified the adequate period for folic acid intake, percentages reaching 12% in 2004 and dropping to 7% in 2005 (March of Dimes Birth Defects Foundation, 2005). A CDC report showed that knowledge concerning the adequate period of intake raise slightly to 12% in 2007 (CDC, 2008). In Canada where the levels of awareness and intake are relatively high, only 25% of women studied in Vancouver knew that folic acid could prevent birth defects (French et al, 2003). As expected, low levels of knowledge were also found in countries with low levels of folic acid intake such as in Thailand where 25% of surveyed women knew that folic acid was something important and in Lebanon where 14% knew about the role of folic acid in NTD prevention and 25% knew about the adequate period for supplementation (Nasr Hage et al, 2011; Nawapun and Phupong, 2007). These numbers show that low intake of folic acid supplements is, at least partially related to lack of knowledge. This relationship was suggested by French and colleagues showing that 78% of the women in their study

Being married was frequently identified as a factor of high folic acid intake. Cleves and colleagues found that married women were almost twice more likely than single women to take a daily supplement (Cleves et al, 2004). In the Netherlands, 42% of married women used folic acid supplement as compared to 10% of single women (p<0.001) (Timmermans et al, 2008). Another factor related to folic acid usage is the planning of pregnancy. Studies have shown that women who intended their pregnancies were 3 times more likely to use adequately folic acid supplements than women with unintended pregnancies (Rosenberg et al, 2003). In Europe, countries such as Norway and Ireland, studies have shown a higher chance of folic acid usage among women with planned pregnancies compared to unplanned pregnancies (McGuire et al, 2010; Nilsen et al, 2006). A planned pregnancy was also a factor related to supplements consumption in non-western countries such as Lebanon and Korea (Kim et al, 2009; Nasr Hage et al, 2011). The impact of this factor increases with the proximity of the planned conception, with women who indicate their desire to become pregnant at some time in the future but with no specific plan, being no more likely to take a daily folic acid supplement than women never wanting to become pregnant (Cleves et al, 2004). The number of pregnancies was also found as a determinant of folic acid intake with women having had anterior pregnancies more likely to take folic acid supplements than women with their first pregnancy (Carmichael et al, 2006; Nasr Hage et al, 2011; Nilsen et al, 2006). Only one study conducted in Australia by Forster and his colleagues showed that having had other pregnancies is correlated with lower levels of folic acid intake (Forster et al, 2009). National studies in the USA showed that the pregnancy status was also a factor

Age is a very important factor in relationship with folic acid for many reasons. In the USA, women in the age of 18-24 years account for one third of all births. At the same time, studies have shown that this age group had the least awareness and knowledge about folic acid and the lowest reported daily use of supplements (Morin et al, 2002; CDC, 2008; Timmermans et al, 2008). Furthermore, women in this age group have multiple risk factors for inadequate folic acid consumption. They have a high rate of unintended pregnancies, reaching 80% of all pregnancies in this age group (Finer and Henshaw, 2006) and they adopt risky sexual behaviors, not using systematically birth controls in about 1 in 5 women (Chandra et al, 2005). In this age group, women have also the lowest median annual household income (DeNavas-Walt et al, 2006) and often haven't completed college. They engage in unhealthy dietary behavior and often fail to meet dietary intake recommendations (Anding et al, 2001). All these behavioral, economical, educational and nutritional factors contribute to the low level of folic acid consumption in this age group and to the increased risk of pregnancies affected by NTDs. One study found that women aged 14-19 years were twice as likely to have a pregnancy with NTD as women 25-29 years of age (Reefhuis and Honein, 2004). It is of noteworthy to highlight the fact that all these studies in this age group were conducted in western countries where sexual activities and pregnancies in young, single women are socially accepted in opposition

An interesting study conducted by Ahluwalia and his collegues showed that certain psychosocial factors as well as advice from a health care provider help women to make decisions about folic acid use (Ahluwalia et al, 2007). In this study, regular use of multivitamins was positively associated with perceived benefits and negatively associated

influencing positively the chance of folic acid intake (CDC, 2008).

to more conservative societies where data on this subject is lacking.

with perceived barriers.

indicated that, with knowledge of the benefits of folate, they would use folic acid supplements to reduce the risk of birth defects (French et al, 2003). Another survey done in 2009 by the Gallup organization showed that when women were told the health benefits of taking a multivitamin with folic acid, 66% stated they were "willing" to buy and take a multivitamin and 22% stated they were "somewhat willing" (North Carolina Folic acid Council, 2009). A systematic review of the literature showed that variable interventions on folic acid increased women's awareness from 60% to 72% and knowledge from 21% to 45%. At the same time, levels of folic acid consumption increased only from 14% to 23% showing a positive but suboptimal impact (Chivu et al. 2007).

#### **5. Folic acid intake**

#### **5.1 Determinants of folic acid intake**

Studies measuring levels of folic acid intake looked for the factors related to behavior in order to explain low levels of usage. Daily folic acid intake is shown to be related to race/ethnicity, income, marital status, a positive attitude toward taking a physician's advice, knowledge about the relationship between folic acid and birth defects, planning for the pregnancy, earlier pregnancies and earlier discussion between the women and her physician about vitamins (Ahluwalia et al, 2007; Carmichael et al, 2006; Cleves et al, 2004; French et al, 2003; Rosenberg et al, 2003). Studies also found that younger age is related to a lower intake of folic acid supplements (Morin et al, 2002; CDC, 2008; Timmermans et al, 2008).

Studies in the USA showed that African-American and Hispanic women were less likely to use folic acid supplements than Caucasian women (Ahluwalia et al, 2007; Carmichael et al, 2006; Cleves et al, 2004). Half of Hispanic women, and one third of African-American women aged 18-24 years, as compared to Caucasian women were taking folic acid supplements. An Irish study showed that women from Asia/Middle East, Eastern Europe, Africa and South America were less likely to use folic acid supplements than those from Western Europe and that the highest intake was among women from North America, Australia and New Zealand (McGuire et al, 2010). Ethnicity was also a factor influencing the uptake of folic acid supplements in the Netherlands, where non-western women were less likely to use supplements than western women (Timmermans et al, 2008).

The relationship between low income and a lower intake of supplements has been highlighted in the literature. In their report published in 2008, Petrini and colleagues showed that the lowest prevalences of folic acid intake were seen in those with an annual household income of <\$25,000 compared to those with >\$50,000; these prevalences varied from 24% to 32% between the years 2003 and 2007 for women with the lowest income, and from 38% to 43% between 2003 and 2007 for women with the highest income (CDC, 2008). In Australia, a low income of less than 30,000\$ was also associated with low levels of supplements intake (Forster et al, 2009). Lower socio-economical status was related to an inadequate behavior concerning folic acid supplements (no intake or less than recommended intake) in 2 studies conducted in Ireland and The Netherlands (McGuire et al, 2010; Timmermans et al, 2008). At the same time, high level of education in women of childbearing age was associated with a high level of folic acid intake (Nasr Hage et al, 2011; Nawapun and Phupong, 2007; CDC, 2008).

indicated that, with knowledge of the benefits of folate, they would use folic acid supplements to reduce the risk of birth defects (French et al, 2003). Another survey done in 2009 by the Gallup organization showed that when women were told the health benefits of taking a multivitamin with folic acid, 66% stated they were "willing" to buy and take a multivitamin and 22% stated they were "somewhat willing" (North Carolina Folic acid Council, 2009). A systematic review of the literature showed that variable interventions on folic acid increased women's awareness from 60% to 72% and knowledge from 21% to 45%. At the same time, levels of folic acid consumption increased only from 14% to 23% showing

Studies measuring levels of folic acid intake looked for the factors related to behavior in order to explain low levels of usage. Daily folic acid intake is shown to be related to race/ethnicity, income, marital status, a positive attitude toward taking a physician's advice, knowledge about the relationship between folic acid and birth defects, planning for the pregnancy, earlier pregnancies and earlier discussion between the women and her physician about vitamins (Ahluwalia et al, 2007; Carmichael et al, 2006; Cleves et al, 2004; French et al, 2003; Rosenberg et al, 2003). Studies also found that younger age is related to a lower intake of folic acid

Studies in the USA showed that African-American and Hispanic women were less likely to use folic acid supplements than Caucasian women (Ahluwalia et al, 2007; Carmichael et al, 2006; Cleves et al, 2004). Half of Hispanic women, and one third of African-American women aged 18-24 years, as compared to Caucasian women were taking folic acid supplements. An Irish study showed that women from Asia/Middle East, Eastern Europe, Africa and South America were less likely to use folic acid supplements than those from Western Europe and that the highest intake was among women from North America, Australia and New Zealand (McGuire et al, 2010). Ethnicity was also a factor influencing the uptake of folic acid supplements in the Netherlands, where non-western women were less

The relationship between low income and a lower intake of supplements has been highlighted in the literature. In their report published in 2008, Petrini and colleagues showed that the lowest prevalences of folic acid intake were seen in those with an annual household income of <\$25,000 compared to those with >\$50,000; these prevalences varied from 24% to 32% between the years 2003 and 2007 for women with the lowest income, and from 38% to 43% between 2003 and 2007 for women with the highest income (CDC, 2008). In Australia, a low income of less than 30,000\$ was also associated with low levels of supplements intake (Forster et al, 2009). Lower socio-economical status was related to an inadequate behavior concerning folic acid supplements (no intake or less than recommended intake) in 2 studies conducted in Ireland and The Netherlands (McGuire et al, 2010; Timmermans et al, 2008). At the same time, high level of education in women of childbearing age was associated with a high level of folic acid intake (Nasr Hage et al, 2011;

a positive but suboptimal impact (Chivu et al. 2007).

supplements (Morin et al, 2002; CDC, 2008; Timmermans et al, 2008).

likely to use supplements than western women (Timmermans et al, 2008).

**5. Folic acid intake** 

**5.1 Determinants of folic acid intake** 

Nawapun and Phupong, 2007; CDC, 2008).

Being married was frequently identified as a factor of high folic acid intake. Cleves and colleagues found that married women were almost twice more likely than single women to take a daily supplement (Cleves et al, 2004). In the Netherlands, 42% of married women used folic acid supplement as compared to 10% of single women (p<0.001) (Timmermans et al, 2008). Another factor related to folic acid usage is the planning of pregnancy. Studies have shown that women who intended their pregnancies were 3 times more likely to use adequately folic acid supplements than women with unintended pregnancies (Rosenberg et al, 2003). In Europe, countries such as Norway and Ireland, studies have shown a higher chance of folic acid usage among women with planned pregnancies compared to unplanned pregnancies (McGuire et al, 2010; Nilsen et al, 2006). A planned pregnancy was also a factor related to supplements consumption in non-western countries such as Lebanon and Korea (Kim et al, 2009; Nasr Hage et al, 2011). The impact of this factor increases with the proximity of the planned conception, with women who indicate their desire to become pregnant at some time in the future but with no specific plan, being no more likely to take a daily folic acid supplement than women never wanting to become pregnant (Cleves et al, 2004). The number of pregnancies was also found as a determinant of folic acid intake with women having had anterior pregnancies more likely to take folic acid supplements than women with their first pregnancy (Carmichael et al, 2006; Nasr Hage et al, 2011; Nilsen et al, 2006). Only one study conducted in Australia by Forster and his colleagues showed that having had other pregnancies is correlated with lower levels of folic acid intake (Forster et al, 2009). National studies in the USA showed that the pregnancy status was also a factor influencing positively the chance of folic acid intake (CDC, 2008).

Age is a very important factor in relationship with folic acid for many reasons. In the USA, women in the age of 18-24 years account for one third of all births. At the same time, studies have shown that this age group had the least awareness and knowledge about folic acid and the lowest reported daily use of supplements (Morin et al, 2002; CDC, 2008; Timmermans et al, 2008). Furthermore, women in this age group have multiple risk factors for inadequate folic acid consumption. They have a high rate of unintended pregnancies, reaching 80% of all pregnancies in this age group (Finer and Henshaw, 2006) and they adopt risky sexual behaviors, not using systematically birth controls in about 1 in 5 women (Chandra et al, 2005). In this age group, women have also the lowest median annual household income (DeNavas-Walt et al, 2006) and often haven't completed college. They engage in unhealthy dietary behavior and often fail to meet dietary intake recommendations (Anding et al, 2001). All these behavioral, economical, educational and nutritional factors contribute to the low level of folic acid consumption in this age group and to the increased risk of pregnancies affected by NTDs. One study found that women aged 14-19 years were twice as likely to have a pregnancy with NTD as women 25-29 years of age (Reefhuis and Honein, 2004). It is of noteworthy to highlight the fact that all these studies in this age group were conducted in western countries where sexual activities and pregnancies in young, single women are socially accepted in opposition to more conservative societies where data on this subject is lacking.

An interesting study conducted by Ahluwalia and his collegues showed that certain psychosocial factors as well as advice from a health care provider help women to make decisions about folic acid use (Ahluwalia et al, 2007). In this study, regular use of multivitamins was positively associated with perceived benefits and negatively associated with perceived barriers.

consumption were excessively low (Egen, 1999 as cited in EUROCAT, 2009). In Ireland, since the recommendations on the consumption of folic acid tablets were issued in 1993, many promotional campaigns were undertaken at the national level through periodic media campaigns. At a more local level, health promotion units and public health departments promoted folic acid through a variety of channels, usually on an on-going basis. Studies evaluating the impact of these campaigns showed that even though women's awareness and knowledge concerning the role of folic acid in NTD prevention have reached high levels (95% and 77% respectively in 2002), the consumption of periconceptional folic acid was very low and not improving , being 21% in 1998 and reaching only 23% in 2002 (Ward et al, 2004). In Sweden, since 2007, the Board of the National Food Administration is sending annual letters to all women 18-45 years of age with information on the link between folic acid and the risk of NTDs, in addition to an offer of free folic acid tablets. No Study was conducted in

Sweden to evaluate the efficacy of this campaign (EUROCAT, 2009).

**6. Health professionals' knowledge and behavior concerning folic acid** 

knowledge did not necessarily translate into counseling patients about its benefits.

Consistent with these results, 2 other studies conducted in the USA showed that even though health care providers were aware of the importance of folic acid in the prevention of NTDs, only half of them discussed folic acid on a regular basis with women of childbearing age (Hauser et al,2004; Power et al, 2000). A pilot study conducted in Ontario, Canada showed that 43% of family physicians did not mention folic acid supplementation as a topic for discussion with women of childbearing age, with women actually planning pregnancies or with women in the first trimester of pregnancy (Pereleman et al, 1996). The same study showed that up to 40% recommended folic acid to an already pregnant woman, and 10%

Some studies found that health professionals play a major role in folic acid usage by women of childbearing age. The survey conducted by the March of the Dimes Foundation showed that 42% of women, aware of folic acid but not consuming it, would take a multivitamin if advised to do so by a health professional (March of the Dimes, 2004). In the 2004 Health Styles Survey, 91% of women 18-45 years of age agreed to take a multivitamin daily to prevent NTDs if their doctor encouraged them (Williams et al, 2006). In order to evaluate health professionals' knowledge and practice, the CDC initiated a national study in USA in 2001 among obstetricians/gynecologists, family/general physicians, nurse practitioners, certified nurse midwives, physician assistants and registered nurses (Williams et al, 2006). The study showed that more than 85% of the health care professionals knew about the adequate time to use folic acid supplements and that these supplements were necessary beyond what is available in diet. At the same time, 42% of the health professionals surveyed did not know the correct folic acid dosage. Nurse practitioners were most likely and family/general doctors were least likely to recommend supplements. The strongest predictor for recommending supplements was the personal intake of multivitamins by the health professional. Since incorporating messages about folic acid into preventive health care messages is critical to increasing folic acid consumption, health professionals were asked if they addressed folic acid intake during well-women visits. More obstetricians/gynecologists than family/general practitioners said they mentioned folic acid regularly to women (65% v/s 50% respectively). The conclusion of this study was that even though knowledge among health professionals concerning folic acid was good, this

#### **5.2 Strategies to improve folic acid use**

In the years following the folic acid recommendations, many educational and promotional campaigns using different means of communication have been used to promote folic acid intake during the periconceptional period with variable results. A systematic review of the literature on interventions designed to improve knowledge, awareness and consumption concerning folic acid was conducted in 2007 (Chivu et al, 2007). Among consumers, the interventions studied were printed and audio-visual media (radio, TV, internet) and printed media with other channels such as counseling, free distribution of folic acid pills, advertisements, magnetized reminders, food labels (folate logo and messages from nutritionists on food packs), slide presentations and reminder phone calls. Among health professionals, the interventions studied consisted of printed materials, training, professional publications, letters, personal communication, incentives (coffee mugs, note pads) and reminder in the patient history form. The review showed that health professionals increased their knowledge about folic acid advised dose from 13 to 58% before intervention to 51% to 70% after intervention and about the recommended period for folic acid usage from 57% to 80% before intervention to 79% to 85% after intervention (p<0.0001). Also, 19% to 62% of health professionals were recommending folic acid to women after the intervention, as compared to 13% to 45% before the intervention. As for women, awareness concerning folic acid increased on average from 60% to 72%, knowledge increased from 21% to 45% and consumption increased from 14% to 23%. Even though variable interventions increased women's knowledge and awareness of folic acid, there were still wide discrepancies between awareness/knowledge and consumption. Studies have shown that, according to social marketing theory, mass media positively influences people's awareness and knowledge, whereas behavior is more influenced by things such as health professionals' counseling and interpersonal communication (Roger, 2003).

Many European countries have launched official educational campaigns on folic acid and its role in the prevention of NTDs. In Belgium, the ONE (Office Of Birth and Childhood) in association with ASBBF (Association Spina Bifida Belge Francophone) ran a campaign including leaflets, a website, information on radio and television and letters to gynecologists and family physicians about the benefits of periconceptional folic acid . After the campaign, a study was conducted in 2006 on 195 women in the first week after delivery. It showed a percentage of folic acid consumption before and during pregnancy of only 12% (EUROCAT, 2009). In Denmark, the Danish Veterinary and Food Administration published leaflets addressing women planning pregnancy and distributed them to clinics, hospitals, pharmacies and drugstores in 1999 and again in 2001.At the same time, a study on compliance with folic acid guidelines was launched in 2000 until 2002 and was able to evaluate the impact of the health education campaign on folic acid usage. This study showed an increase in the proportion of women complying with the recommendation after the campaign. However, even at the end of the period, only 22% of the women with planned pregnancies were following the recommendations on folic acid supplementation (Knudsen et al, 2004). In Germany, there are no official governmental guidelines on periconceptional folic acid and no official health education campaigns. However, in Munich, a non official campaign on folic acid took place from 1996 to 1998. The impact of this campaign was evaluated by measuring periconceptional folic acid intake. This study showed an increase of intake from 2% in 1996 to 5% in 1998. Still, the percentages reached for folic acid

In the years following the folic acid recommendations, many educational and promotional campaigns using different means of communication have been used to promote folic acid intake during the periconceptional period with variable results. A systematic review of the literature on interventions designed to improve knowledge, awareness and consumption concerning folic acid was conducted in 2007 (Chivu et al, 2007). Among consumers, the interventions studied were printed and audio-visual media (radio, TV, internet) and printed media with other channels such as counseling, free distribution of folic acid pills, advertisements, magnetized reminders, food labels (folate logo and messages from nutritionists on food packs), slide presentations and reminder phone calls. Among health professionals, the interventions studied consisted of printed materials, training, professional publications, letters, personal communication, incentives (coffee mugs, note pads) and reminder in the patient history form. The review showed that health professionals increased their knowledge about folic acid advised dose from 13 to 58% before intervention to 51% to 70% after intervention and about the recommended period for folic acid usage from 57% to 80% before intervention to 79% to 85% after intervention (p<0.0001). Also, 19% to 62% of health professionals were recommending folic acid to women after the intervention, as compared to 13% to 45% before the intervention. As for women, awareness concerning folic acid increased on average from 60% to 72%, knowledge increased from 21% to 45% and consumption increased from 14% to 23%. Even though variable interventions increased women's knowledge and awareness of folic acid, there were still wide discrepancies between awareness/knowledge and consumption. Studies have shown that, according to social marketing theory, mass media positively influences people's awareness and knowledge, whereas behavior is more influenced by things such as health professionals'

Many European countries have launched official educational campaigns on folic acid and its role in the prevention of NTDs. In Belgium, the ONE (Office Of Birth and Childhood) in association with ASBBF (Association Spina Bifida Belge Francophone) ran a campaign including leaflets, a website, information on radio and television and letters to gynecologists and family physicians about the benefits of periconceptional folic acid . After the campaign, a study was conducted in 2006 on 195 women in the first week after delivery. It showed a percentage of folic acid consumption before and during pregnancy of only 12% (EUROCAT, 2009). In Denmark, the Danish Veterinary and Food Administration published leaflets addressing women planning pregnancy and distributed them to clinics, hospitals, pharmacies and drugstores in 1999 and again in 2001.At the same time, a study on compliance with folic acid guidelines was launched in 2000 until 2002 and was able to evaluate the impact of the health education campaign on folic acid usage. This study showed an increase in the proportion of women complying with the recommendation after the campaign. However, even at the end of the period, only 22% of the women with planned pregnancies were following the recommendations on folic acid supplementation (Knudsen et al, 2004). In Germany, there are no official governmental guidelines on periconceptional folic acid and no official health education campaigns. However, in Munich, a non official campaign on folic acid took place from 1996 to 1998. The impact of this campaign was evaluated by measuring periconceptional folic acid intake. This study showed an increase of intake from 2% in 1996 to 5% in 1998. Still, the percentages reached for folic acid

**5.2 Strategies to improve folic acid use** 

counseling and interpersonal communication (Roger, 2003).

consumption were excessively low (Egen, 1999 as cited in EUROCAT, 2009). In Ireland, since the recommendations on the consumption of folic acid tablets were issued in 1993, many promotional campaigns were undertaken at the national level through periodic media campaigns. At a more local level, health promotion units and public health departments promoted folic acid through a variety of channels, usually on an on-going basis. Studies evaluating the impact of these campaigns showed that even though women's awareness and knowledge concerning the role of folic acid in NTD prevention have reached high levels (95% and 77% respectively in 2002), the consumption of periconceptional folic acid was very low and not improving , being 21% in 1998 and reaching only 23% in 2002 (Ward et al, 2004). In Sweden, since 2007, the Board of the National Food Administration is sending annual letters to all women 18-45 years of age with information on the link between folic acid and the risk of NTDs, in addition to an offer of free folic acid tablets. No Study was conducted in Sweden to evaluate the efficacy of this campaign (EUROCAT, 2009).

#### **6. Health professionals' knowledge and behavior concerning folic acid**

Some studies found that health professionals play a major role in folic acid usage by women of childbearing age. The survey conducted by the March of the Dimes Foundation showed that 42% of women, aware of folic acid but not consuming it, would take a multivitamin if advised to do so by a health professional (March of the Dimes, 2004). In the 2004 Health Styles Survey, 91% of women 18-45 years of age agreed to take a multivitamin daily to prevent NTDs if their doctor encouraged them (Williams et al, 2006). In order to evaluate health professionals' knowledge and practice, the CDC initiated a national study in USA in 2001 among obstetricians/gynecologists, family/general physicians, nurse practitioners, certified nurse midwives, physician assistants and registered nurses (Williams et al, 2006). The study showed that more than 85% of the health care professionals knew about the adequate time to use folic acid supplements and that these supplements were necessary beyond what is available in diet. At the same time, 42% of the health professionals surveyed did not know the correct folic acid dosage. Nurse practitioners were most likely and family/general doctors were least likely to recommend supplements. The strongest predictor for recommending supplements was the personal intake of multivitamins by the health professional. Since incorporating messages about folic acid into preventive health care messages is critical to increasing folic acid consumption, health professionals were asked if they addressed folic acid intake during well-women visits. More obstetricians/gynecologists than family/general practitioners said they mentioned folic acid regularly to women (65% v/s 50% respectively). The conclusion of this study was that even though knowledge among health professionals concerning folic acid was good, this knowledge did not necessarily translate into counseling patients about its benefits.

Consistent with these results, 2 other studies conducted in the USA showed that even though health care providers were aware of the importance of folic acid in the prevention of NTDs, only half of them discussed folic acid on a regular basis with women of childbearing age (Hauser et al,2004; Power et al, 2000). A pilot study conducted in Ontario, Canada showed that 43% of family physicians did not mention folic acid supplementation as a topic for discussion with women of childbearing age, with women actually planning pregnancies or with women in the first trimester of pregnancy (Pereleman et al, 1996). The same study showed that up to 40% recommended folic acid to an already pregnant woman, and 10%

Ahluwalia, I.B., Lawrence, J.M. and Balluz, L. (2007). Psychosocial factors associated with

Almeida, L.C. and Cardoso, M.A. (2010). Recommendations for folate intake in women:

Anding, J., Suminski, R. and Boss, L. (2001). Dietary intake, body mass index, exercise and

Auriel, E., Biderman, A., Belmaker, I., Freud, T. and Peleg, R. (2011). Knowledge, attitudes,

Beaudin, A.E. and Stover P.J. (2009). Insights into metabolic mechanisms underlying folate-

Blencowe, H., Cousens, S., Modell, B. and lawn, J. (2010). Folic acid to reduce neonatal

Blom, H.J., Shaw, G.M., Den Heijer, M. and Finnell, R.H. (2006) Neural tube defects and folate: case far from closed. *National Review of Neuroscience*; 7: 724-31. Boulet, S.L., Yang, Q., Mai, C., Kirby, R.S., Collins, J.S., Robbins, J.M., Meyer, R., Canfield,

Bower, C. and Stanley, F.J. (1989). Dietary folate as a risk factor for neural tube defects:

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Centers for Disease Control. (1992). Recommendations for the use of folic acid to reduce the

Centers for Disease Control and Prevention. (2004). Spina bifida and anencephaly before and after folic acid mandate--United States, 1995-1996 and 1999-2000. *Morbidity and mortality* 

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recommend it only to pregnant women. Only 14% of physicians in this study had correct knowledge of the appropriate dosages and timing for folate supplements and only 17% of all contacted physicians recommended folate to any women of childbearing age. In Puerto Rico, 88% of primary care physicians demonstrated an inadequate knowledge about folic acid supplements with older physicians and women physicians demonstrating greater knowledge than other physicians in the study (Mirinda et al, 2003). In Israel, 2 studies evaluated physicians' knowledge and practice concerning folic acid. The first study showed that 94% of physicians recommended folic acid to their patients but knowledge in this study was insufficient since only 2% correctly estimated the efficacy of folic acid in decreasing NTDs, 12% knew about the adequate timing and 47% about the correct dosage of folic acid supplements (Abu–Hamad et al, 2008). Another study conducted among women and physicians in Israel showed that 87% of gynecologists recommended preconception folic acid compared to 60% of family physicians (p<0.05) (Auriel et al, 2011). In Germany, a study done in 1996 showed that only 38% of gynecologists in Munich recommended preconceptional folic acid, 8% recommended folic acid at the beginning of pregnancy, 17% recommended folic acid only in cases with family history of NTDS and 37% did not give any recommendation at all. Following an interventional campaign in 1998, 74% of gynecologists recommended preconceptional folic acid. However, there were still 15% of gynecologists who recommended folic acid with the beginning of pregnancy and 11% only in case of a family history (Egen, 2000 as in EUROCAT, 2009).

#### **7. Conclusion**

There is strong evidence that most NTDs are preventable by increasing folate status before conception. Responses to this evidence have been variable around the world. Many governments have issued recommendations regarding the necessity for women to take folic acid, from at least 1 month before conception and during the first 3 months of pregnancy. Up to 53 countries around the world issued regulations for mandatory folic acid fortification of staple food. These countries had the most reduction in NTD prevalence according to registries. Even though this was a success story, it was considered as a partial success since the reduction seen with fortification was less than the reduction seen in studies using folic acid supplements. This was the reason behind the recommendations for folic acid supplements during the periconceptional period, at the dose of 400-500µg/day for women with no history of NTDs and at the dose of 4-5 mg/day in case of family history or previous personal pregnancies with NTDs. Health education campaigns on local and national were launched in many countries with variable results. These campaigns have been mainly effective on increasing the knowledge and awareness of women concerning folic acid. Still, the actual intake of folic acid is quiet low during the periconceptional period. All these facts show that women's behavior is complex and influenced by many determinants. A package of different measures including actions targeting women and health professionals are needed in order to improve intake of folic acid by women of childbearing age.

#### **8. References**

Abu-Hammad, T., Dreiher, J., Vardy, D.A. and Cohen, A.D. (2008). Physicians' knowledge and attitudes regarding periconceptional folic acid supplementation: a survey in Southern Israel. *Med Sci Monit*; 14 95): CR262-7.

recommend it only to pregnant women. Only 14% of physicians in this study had correct knowledge of the appropriate dosages and timing for folate supplements and only 17% of all contacted physicians recommended folate to any women of childbearing age. In Puerto Rico, 88% of primary care physicians demonstrated an inadequate knowledge about folic acid supplements with older physicians and women physicians demonstrating greater knowledge than other physicians in the study (Mirinda et al, 2003). In Israel, 2 studies evaluated physicians' knowledge and practice concerning folic acid. The first study showed that 94% of physicians recommended folic acid to their patients but knowledge in this study was insufficient since only 2% correctly estimated the efficacy of folic acid in decreasing NTDs, 12% knew about the adequate timing and 47% about the correct dosage of folic acid supplements (Abu–Hamad et al, 2008). Another study conducted among women and physicians in Israel showed that 87% of gynecologists recommended preconception folic acid compared to 60% of family physicians (p<0.05) (Auriel et al, 2011). In Germany, a study done in 1996 showed that only 38% of gynecologists in Munich recommended preconceptional folic acid, 8% recommended folic acid at the beginning of pregnancy, 17% recommended folic acid only in cases with family history of NTDS and 37% did not give any recommendation at all. Following an interventional campaign in 1998, 74% of gynecologists recommended preconceptional folic acid. However, there were still 15% of gynecologists who recommended folic acid with the beginning of pregnancy and 11% only in case of a

There is strong evidence that most NTDs are preventable by increasing folate status before conception. Responses to this evidence have been variable around the world. Many governments have issued recommendations regarding the necessity for women to take folic acid, from at least 1 month before conception and during the first 3 months of pregnancy. Up to 53 countries around the world issued regulations for mandatory folic acid fortification of staple food. These countries had the most reduction in NTD prevalence according to registries. Even though this was a success story, it was considered as a partial success since the reduction seen with fortification was less than the reduction seen in studies using folic acid supplements. This was the reason behind the recommendations for folic acid supplements during the periconceptional period, at the dose of 400-500µg/day for women with no history of NTDs and at the dose of 4-5 mg/day in case of family history or previous personal pregnancies with NTDs. Health education campaigns on local and national were launched in many countries with variable results. These campaigns have been mainly effective on increasing the knowledge and awareness of women concerning folic acid. Still, the actual intake of folic acid is quiet low during the periconceptional period. All these facts show that women's behavior is complex and influenced by many determinants. A package of different measures including actions targeting women and health professionals are

needed in order to improve intake of folic acid by women of childbearing age.

Southern Israel. *Med Sci Monit*; 14 95): CR262-7.

Abu-Hammad, T., Dreiher, J., Vardy, D.A. and Cohen, A.D. (2008). Physicians' knowledge

and attitudes regarding periconceptional folic acid supplementation: a survey in

family history (Egen, 2000 as in EUROCAT, 2009).

**7. Conclusion** 

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**4** 

*Germany* 

**Prevention of NTDs** 

*2Institute of Advanced Research, Berlin,* 

 **– Proposal of a New Concept** 

*1Department of Nutrition and Food Science, University of Bonn,* 

Prinz-Langenohl Reinhild1, Pietrzik Klaus1 and Holzgreve Wolfgang2

Neural tube defects (NTDs) are a heterogeneous group of serious congenital structural abnormalities of the brain and spine due to inadequate formation and/or closure of the developing brain and lower spine in the first month of pregnancy. Anencephalus, spina bifida, and encephalocele are the main manifestations of NTDs. The most serious form of NTDs is an anencephalus incompatible with life. Although NTDs can be detected by increased levels of alpha-fetoprotein and especially by ultrasound investigations early in pregnancy (Holzgreve et al., 1994), the prenatal diagnosis is often missed. After prenatal detection of NTDs, careful and comprehensive counseling of the parents is needed. Some parents select to carry the affected child to term, others decide to have a termination of pregnancy within the legal frameworks of their countries. If an anencephaly is recognized only late in gestation or even only at birth, the psychologic shock for the parents is usually prominent, and in their desperation to have at least some positive aspect in an otherwise hopeless situation parents have even requested in these rare situations to have organs transplanted from anencephalic donors (Holzgreve et al. 1987). NTDs have multiple etiologies and the role of folate, other vitamins and various micronutrients as factors in their etiology has been investigated from different angles for a long time now (Holzgreve et al., 1991, Simpson et al., 2010, 2011) A number of observational and interventional studies have demonstrated that folic acid (FA) supplementation before and in early pregnancy reduces the risk of having a NTD-affected offspring (Laurence et al., 1981; Milunsky et al. 1989;

Two intervention trials examining the effect of FA supplementation on NTD occurrence and recurrence, published twenty years ago, supported the evidence of the protective role of FA in NTD prevention (Czeizel et al., 1992; Medical Research Council [MRC], 1991). In these two trials, daily FA supplementation, alone, or in combination with other micronutrients, had started before conception and continued throughout the first trimester of pregnancy. Both studies reported a considerable reduction in NTD prevalence. These results were later confirmed in a public health campaign trial in China. Berry et al. (1999) observed a risk reduction between 40% and 85% in China among women who supplemented 400 µg/day FA. The wide range of decrease depends on the different baseline rates of NTD prevalence

**1. Introduction** 

Smithells et al., 1980; Vergel et al., 1990).

anencephaly during the transition to mandatory folic acid fortification in the United States. *Teratology*; 66: 33-9.

