Draft English 3 Farida Apriani

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The Correlation between Spina Bifida and Folic Acid Deficiency in Pregnant

Women

Author : Farida Apriani

Nim : 030.07.12

Jakarta, January 2012

MEDICAL FACULTY OF TRISAKTI


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Table of Content

Preface .. .3

Abstract ..............................................................................................................................4

Chapter I

Introduction .....5

Chapter II

Definition, Epidemiology, Etiology 6

Patophysiology .....8 Classification ...11

Diagnosis ..13

Treatment ....18 Prevention19

Complication20 Prognosis ..22

Folic acid...25

Chapter III

Discussion .27

Chapter IV

Conclusion 32

Reference 33


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PREFACE

Assalamualaikum Wr Wb

First I would like to thank to Allah SWT, because only with his permit I could finish this

paper. In this opportunity, I would like to thank :

My family and friends for their supportDr. Maskito as my supervisor to help me for make this paper.

I made this paper to complete my duty in English III and I hope this paper will usefull for

all of us. But as a writer, I know that this paper might be not entirely perfect and have many

mistakes, so I need critics from people who read my paper.

Wassalamualaikum Wr Wb

Jakarta, January 2012

Farida Apriani

030.07.089


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ABSTRACT

Spina bifida is the most complex but treatable central nervous system abnormality that

comprises varying degrees of spinal cord malformation. Spina bifida is classified as a defect of

the neural tube (ie, the embryonic structure that develops into the spinal cord and brain).

Recognized 4000 years ago, it is visibly evident at birth.

Neural tube defects have a range of presentations, from stillbirth to incidental radiographic

findings of spina bifida occulta. Spina bifida cystic, or myelomeningocele, is visibly evident at

birth. Patients with myelomeningocele present with a spectrum of impairments, but the primary

functional deficits are lower limb paralysis and sensory loss, bladder and bowel dysfunction, and

cognitive dysfunction.

Laboratory screening tests for neural tube defects can be performed through blood tests,

amniocentesis, or both. These typically are used in combination with fetal ultrasonography.

Treatment advances have allowed an increasing number of patients with neural tube defects to

participate and be productive in mainstream society. However, medical, surgical, and

rehabilitation issues arise in the patient with myelomeningocele from birth through adulthood.

Folic acid fortification has reduced neural tube defect prevalence by 50% to 70%. It is unlikely

that fortification levels will be increased to reduce neural tube defect prevalence further.

Therefore, it is important to identify other modifiable risk factors. Vitamin B12 is metabolically

related to folate; moreover, previous studies have found low B12 status in mothers of children

affected by neural tube defect. Our objective was to quantify the effect of low B12 status on

neural tube defect risk in a high-prevalence, unfortified population.

To improved survival rates in patients with spina bifida can be expected with treatment; quality

of life is at least partially dependent on the speed, efficiency, and comprehensiveness of that

treatment from birth.

Keywords : Spina Bifida, Neural tube defect, folic acid.


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CHAPTER I

INTRODUCTION

Background

Neural tube defects are a group of birth defects that result from improper development of

the spine, spinal cord, or brain during pregnancy.Spina bifida,in which some of the spinal cord

bulges out through an opening in the spine, is most common. Neural tube defects occur in

children of all ethnic backgrounds and in all countries.

Research studies have shown that a woman who takes folic acid supplements prior to and during

pregnancy reduces her risk of having a child born with a neural tube defect. The neural tube isfully developed between 22 and 28 days after conception (3-4 weeks), but many women are not

even aware they are pregnant at that time.

Folic acid has been proven to prevent most cases of spina bifida. It is recommended that women of

child-bearing age consume folic acid fortified grain products and/or supplements prior to pregnancy.

Since 2006, there has been an increase in the number of countries that fortify their flour with folic

acid. Country specific data on fortification of flour with folic acid has been tracked along with

amounts of fortified flour consumed per person. Estimates of spina bifida affected pregnancies and

country-specific birth estimates were also utilized to estimate the amount of folic acid preventable

spina bifida cases. Utilizing a predetermined prevention factor model, it is estimated that 13.81% of

spina bifida cases are currently being prevented with folic acid flour fortification. Since the average

US population consumes between 100 and 200 mcg folic acid from fortified flour, and this is

associated with a significant decrease in the number of cases of spina bifida, an updated prevention

factor model was created. Under these circumstances, it is estimated that 22.38% of spina bifida

cases are globally prevented with folic acid flour fortification. Although these values show an

increase in cases prevented since 2006, there is still a significant amount of work required in order to

increase consumption of folic acid in women of child-bearing age and for countries to regulate and

require flour fortification with folic acid.
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CHAPTER II

Definition of Spina bifida

Spina bifida (cleft spine) is a birth defect affecting the spinal column. Spina

bifida progresses from a cleft, or splitlike opening, in the back part of the backbones (the spinal

vertebrae). In more severe cases, it involves thespinal cord.Spina bifida is the most common of

a group of birth defects known asneural tube defects, which affect the central nervous system

(brain and spinal cord).

Epidemiology of Spina Bifida

Spina bifida is one of the most common birth defects, with an average worldwide incidence of 1

2 cases per 1000 births, but certain populations have a significantly greater risk.

In the United States, the average incidence is 0.7 per 1000 live births. The incidence is higher on

the East Coast than on the West Coast, and higher in whites (1 case per 1000 live births) than in

blacks (0.10.4 case per 1000 live births). Immigrants from Ireland have a higher incidence of

spina bifida than do nonimmigrants.

The highest incidence rates worldwide were found in Ireland and Wales, where 34 cases of

myelomeningocele per 1000 population have been reported during the 1970s, along with more

than six cases of anencephaly (both live births and stillbirths) per 1000 population. The reported

overall incidence of myelomeningocele in the British Isles was 23.5 cases per 1000 births.(1,3)

Etiology

The etiology in most cases of myelomeningocele is multifactorial, involving genetic,

racial, and environmental factors, in which nutrition, particularly folic acid intake, is key.

Cytoplasmic factors, polygenic inheritance, chromosomal aberrations, and environmental
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influences (eg, teratogens) have all been considered as possible causes. A small number of cases

are linked to specific etiologic factors.

Most infants born with myelomeningocele are born to mothers with no previously affected

children. However, other offspring in a family with 1 affected child are at greater risk of neural

tube defect than are children without affected siblings. The risk is 1 in 20-30 for subsequent

pregnancies, and if 2 children are affected, the risk becomes 1 in 2. An increase in the risk of

myelomeningocele has also been reported for second- and third-degree relatives of affected

individuals.

Up to 10% of fetuses with a neural tube defect detected in early gestation have an associated

chromosome abnormality. Associated chromosome abnormalities include trisomies 13 and 18,

triploidy, and single-gene mutations.(4)

In women with pregestational diabetes, the risk of having a child with a CNS malformation,

including myelomeningocele, is 2-10 fold higher than the risk in the general population. The

mechanism underlying this teratogenic effect is not well defined but is related to the degree of

maternal metabolic control. The risk in women who develop gestational diabetes is lower than

the risk of women with pregestational diabetes, but it might not be as low as in the general

population.

(2,5)

Other risk factors for myelomeningocele include maternal obesity, hyperthermia (as the result of

maternal fever or febrile illness or associated with the use of saunas, hot tubs, and tanning beds),

and maternal diarrhea. Intrauterine exposure to antiepileptic drugs, particularly valproate and

carbamazepine, and to drugs to induce ovulation are identified risk factors.

The risk of having a child with myelomeningocele has also possibly been associated with

maternal exposures to fumonisins, electromagnetic fields, hazardous waste sites, disinfection by-

products found in drinking water, and pesticides.

Research in the 1980s showed correction of folic acid deficiency as an effective means of

primary and recurrent prevention.At least half of cases of neural tube defects are related to a


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nutritional deficiency of folic acid or increased requirement and, thus, are potentially

preventable.

In September 1992, the US Public Health Service (USPHS) recommended intake of folic acid at

a dosage of 0.4 mg/d for all women anticipating pregnancy. In February 1996, the USPHS

announced mandatory folic acid fortification of enriched cereal grain, a measure that was

expected to increase the daily intake of folic acid in women of reproductive age by

approximately 100 mcg/day.

After fortification, an estimated 24% decline in myelomeningocele rates was reported to have

occurred between 1996 and 2001, based on data from United States surveillance systems.

Current fortification programs are preventing about 22,000 cases, or 9% of the estimated folic

acid-preventable spina bifida and anencephaly cases.(6)

Pathophysiology of Spina Bifida

Neural tube defects are the result of a teratogenic process that causes failed closure and

abnormal differentiation of the embryonic neural tube. Neural tube defects occur between the

17th and 30th day of gestation, at a time when the mother may not be aware that she is pregnant

and the fetus is estimated to be about the size of a grain of rice.

The most common neural tube defects are anencephaly and myelomeningocele. Anencephaly

results from failed closure of the rostral end of the neural tube, resulting in incomplete formation

of the brain and skull.

Spina bifida cystica causes a problem when the meningeal cyst (meningocele) includes cord

tissue extending into the cyst (in which case, it is a myelomeningocele). The condition is also of

particular concern when the neural tube is completely open and the ependymal layer is exposed

as a myelocele or myeloschisis. Meningocele alone may cause no neurologic problems if the

cord is confined to the vertebral canal.

Myelomeningocele results from failed closure of the caudal end of the neural tube, resulting in

an open lesion or sac that contains dysplastic spinal cord, nerve roots, meninges, vertebral
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bodies, and skin (see the image below). The anatomic level of the myelomeningocele sac roughly

correlates with the patient's neurologic, motor, and sensory deficits.

Myelomeningocele is associated with abnormal development of the cranial neural tube, which

results in several characteristic CNS anomalies. TheChiari type II malformation is characterized

by cerebellar hypoplasia and varying degrees of caudal displacement of the lower brainstem into

the upper cervical canal through the foramen magnum. This deformity impedes the flow and

absorption of cerebrospinal fluid (CSF) and causes hydrocephalus, which occurs in more than

90% of infants with myelomeningocele.

Cerebral cortex dysplasia, including heterotopias, polymicrogyria, abnormal lamination, fused

thalami, and corpus callosum abnormalities, also occurs frequently. Mesodermal structures

surrounding the neural tube, such as the vertebra and ribs, also may be malformed.

Unprotected neural elements are at severe risk during delivery. The sequelae of the neural tube

defect follow directly from this lack of protection, occurring mechanically or resulting from

desiccation, scarring with closure, and/or a lack of vascular support or from other insults to the

delicate neural elements; recent reports of prenatal open intrauterine surgery are discussed later.

The neurologic damage generally results in a neurogenic bowel and bladder, which leads to

incontinence. With a lack of neural input, a contracted bladder causes hydronephrosis along with

infections and renal failure, which may be the prime determinant of longevity in patients with

spina bifida.

As a pattern, neurologic innervation is not symmetrical between lower-limb flexors and

extensors; the corresponding levels are lower (caudal) for the extensors than for the flexors.

Generally, muscular imbalance is present, which results in joint contractures and developmental

problems, such as hip dislocation and spinal deformities.

Normal intelligence can be expected with aggressive shunting for hydrocephalus, although subtle

defects in coordination may be associated with the cerebellar deficiency from the Arnold-Chiari

malformation. Seizure activity secondary to the neural tube defect may be noted.
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Myelomeningocele often occurs along with multiple system congenital anomalies. Commonly

associated anomalies are facial clefts, heart malformations, and genitourinary tract anomalies.

Urinary tract anomalies, such as solitary kidney or malformed ureters, may contribute to

increased morbidity in the presence of neurogenic bladder dysfunction. (7)

Embryology

During prenatal development, neuroectoderm thickens into the neural plate, which then folds into

a neural groove by the time somites appear. The groove deepens to become the neural tube, and

dorsal fusion begins centrally, extending cephalad and caudally, with the cephalad pole fusing at

the 25th day. The ventricle becomes permeable at the 6th to 8th week of gestation but this

apparently does not proceed normally in patients with myelomeningocele.

Some studies suggest that an increased amount of neural crest material in the defect prevents

neural tube closure. Another hypothesis is that an already closed tube ruptures; increased

permeability of the rhombic groove leads to greater cerebrospinal fluid (CSF) secretion and

increased luminal pressure, with the tube then expanding and essentially splitting the neural

element at its weakest areas (ie, the cephalic and caudal ends).

Obesity

Obesity is prevalent in children with myelomeningocele, especially those with high-lumbar and

thoracic-level lesions, because of reduced capacity for caloric expenditure. The decreased muscle

mass of the lower body musculature results in a lower basal metabolic rate. In addition, activity

levels generally are lower than in unaffected children as a direct result of lesion-related mobility

deficits and as an indirect result of decreased opportunities for disabled children to participate in

physical play.

Obesity can exert negative impact on self-image and further perpetuate a cycle of inactivity and

overeating. Excessive weight impedes maximal independence and ambulation.


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Bone involvement

Bone mineral density is decreased in patients with myelomeningocele. Markers of bone

reabsorption were found more frequently in limited ambulators and nonambulators than in

children who ambulated regularly.

Children with myelomeningocele are at higher risk of lower extremity fractures. Reduced muscle

activity in the paralyzed limb and decreased weight-bearing forces result in decreased bone mass.

In addition, many fractures occur after orthopedic interventions, especially after procedures

associated with cast immobilization. Fractures in myelomeningocele tend to heal quickly, and

excessive callus formation often is seen.(6,8)

Classification of Spina Bifida

Neural tube defects are disorders that involve the incomplete development of the brain

and/or spine. One of the most common neural tube defects is Spina Bifida. This condition occurs

when, during the first month of pregnancy, the bones around the spinal cord fail to close properly

allowing nerves to bulge out from the back and become expired. In mild cases, there are no

symptoms or only minor physical disabilities are the result. However, in many patients, this leads

to severe disability. There are three types of Spina Bifida:

Spina bifida occulta

OccultaisLatin for "hidden". This is the mildest form of spina bifida. In occulta, the outer part

of some of the vertebrae are not completely closed.The split in the vertebrae is so small that the

spinal cord does not protrude. The skin at the site of the lesion may be normal, or it may have

some hair growing from it; there may be a dimple in the skin, or abirthmark.

Many people with this type of spina bifida do not even know they have it, as the condition isasymptomatic in most cases. The incidence of spina bifida occulta is approximately 10% of the

population, and most people are diagnosed incidentally from spinal X-rays. A systematic review

of radiographic research studies found no relationship between spina bifida occulta and back

pain. More recent studies not included in the review support the negative findings.
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However, other studies suggest spina bifida occulta is not always harmless. One study found that

among patients with back pain, severity is worse if spina bifida occulta is present.

Meningocele

The least common form of spina bifida is a posterior meningocele (or meningeal cyst). In a

posterior meningocele, the vertebrae develop normally, however the meninges are forced into the

gaps between the vertebrae. As the nervous system remains undamaged, individuals with

meningocele are unlikely to suffer long-term health problems, although there are reports of

tethered cord.Causes of meningocele includeteratoma and othertumors of thesacrococcyx and

of thepresacral space,andCurrarino syndrome.

A meningocele may also form through dehiscences in the base of skull. These may be classified

by their localisation to occipital, frontoethmoidal, or nasal. Endonasal meningoceles lie at the

roof of the nasal cavity and may be mistaken for a nasal polyp. They are treated surgically.

Encephalomeningoceles are classified in the same way and also contain brain tissue.

Myelomeningocele

This type of spina bifida is the most common and often results in the most severe complications.

In individuals with myelomeningocele, the unfused portion of the spinal column allows the

spinal cord to protrude through an opening. The meningeal membranes that cover the spinal cord

form a sac enclosing the spinal elements. Spina bifida with myeloschisis is the most severe form

of myelomeningocele. In this type, the involved area is represented by a flattened, plate-like

mass of nervous tissue with no overlying membrane. The exposure of these nerves and tissues

make the baby more prone to life-threatening infections.

The protruded portion of the spinal cord and the nerves which originate at that level of the cord

are damaged or not properly developed. As a result, there is usually some degree ofparalysis and

loss of sensation below the level of the spinal cord defect. Thus, the higher the level of the

defect, the more severe the associated nerve dysfunction and resultant paralysis. People may

have ambulatory problems, loss of sensation, deformities of the hips, knees or feet and loss of
http://en.wikipedia.org/wiki/Tethered_Spinal_Cord_syndromehttp://en.wikipedia.org/wiki/Teratomahttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Sacrococcygeal_teratomahttp://en.wikipedia.org/wiki/Presacral_spacehttp://en.wikipedia.org/wiki/Currarino_syndromehttp://en.wikipedia.org/wiki/Nasal_cavityhttp://en.wikipedia.org/wiki/Nasal_polyphttp://en.wikipedia.org/wiki/Paralysishttp://en.wikipedia.org/wiki/Paralysishttp://en.wikipedia.org/wiki/Nasal_polyphttp://en.wikipedia.org/wiki/Nasal_cavityhttp://en.wikipedia.org/wiki/Currarino_syndromehttp://en.wikipedia.org/wiki/Presacral_spacehttp://en.wikipedia.org/wiki/Sacrococcygeal_teratomahttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Teratomahttp://en.wikipedia.org/wiki/Tethered_Spinal_Cord_syndrome


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muscle tone. Depending on the location of the lesion, intense pain may occur originating in the

lower back, and continuing down the leg to the back of the knee.(9)

Diagnosis of Spina Bifida

The most obvious finding on physical examination is some degree of motor and sensory

loss.Neurologic impairment is classified by traditional neurosegmental levels based on the

clinically determined strength of specific muscle groups. The functional motor level does not

always correspond to the anatomic level of the lesion.

In addition, it is important to realize that the motor paresis may be asymmetrical, that it may not

correspond to the sensory level, and that it may be combination of upper and lower motor neuron

lesions. Serial measurements and accurate documentation of the functional level of the lesion

allow for early detection of progressive neurologic deterioration related to a variety of associated

CNS problems.

In addition to determining the functional neurosegmental level, it is important to distinguish the

type of paralysis, either spastic or flaccid. Most patients with myelomeningocele have a flaccid

paraparesis below the spinal cord lesion.

An estimated 10-25% of patients have been reported to have a spastic paraparesis. This

presentation is presumably related to an intact but isolated segment of cord distal to the lesion.

Spastic paraparesis has been associated with a poorer prognosis for walking and higher rates of

orthopedic procedures.

For the sake of general functional prognosis and anticipation of specific musculoskeletal

complications, myelomeningocele patients frequently are classified as belonging to one of the

following groups, based on the neurosegmental level of the lesion:

Thoracic High lumbar Low lumbar Sacral


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In the thoracic group, innervation of the upper limb and neck musculature and variable function

of trunk musculature are present, with no volitional lower limb movements. Patients with

thoracic malformations tend to have more involvement of the CNS and associated cognitive

deficits.

In the high-lumbar group, variable hip flexor and hip adductor strength is characteristic. Absence

of hip extension, hip abduction, and all knee and ankle movements are noted.

In the low-lumbar group, hip flexor, adductor, medial hamstring, and quadriceps strength is

present. The strength of the lateral hamstrings, hip abductors, and ankle dorsiflexors is variable;

the strength of the ankle plantar flexors is absent.

In the sacral-level group, strength of all hip and knee groups is present. Ankle plantar flexor

strength is variable.

Involvement of the upper extremities is also common. Spasticity in the upper extremities occurs

in approximately 20% of patients with myelomeningocele. It has been related to the number of

shunts required to control hydrocephalus and has been shown to adversely affect independence

in activities of daily living.

In patients with hydrocephalus, lack of upper extremity coordination is also seen. This lack of

coordination also may be related to Chiari II malformation, motor-learning deficits, and/or

delayed development of hand dominance. Affected children have problems with fine motor

tasks, particularly when timed. New-onset weakness or spasticity in the upper extremities may be

a hallmark of progressive neurologic dysfunction.

Spinal and lower extremity deformities and joint contractures are prevalent in children with

myelomeningocele. Multiple factors may be involved, including intrauterine positioning, other

congenital malformations, muscle imbalances, progressive neurologic dysfunction, poor postural

habits, and reduced or absent joint motion.

Spinal deformities may be congenital or acquired. Vertebrae and rib anomalies are associated

with congenital or early development of severe kyphotic and scoliotic deformities. Acquired


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scoliosis is neuromuscular in origin and is related to muscle imbalances. Increased lumbar

lordosis and kyphosis of the entire spine or localized to the lumbar region are also observed. All

of the spinal deformities occur more frequently in groups with higher spinal lesions.

The lower extremity deformities that occur are related to the functional level of the lesion.

Thoracic and high-lumbar groups tend to have increased prevalences of the following:

Lumbar lordosis Hip abduction and external rotation contractures Knee flexion Equinus contractures of the ankles

Unopposed hip flexion and adduction contractures in the high-lumbar group frequently result in

dislocated hips.

The mid- and low-lumbar groups often have the following deformities:

Hip and knee flexion contractures Increased lumbar lordosis Genu valgus and calcaneal valgus malalignment Overpronated feet

Patients in the sacral group often exhibit mild hip and knee flexion contractures and increased

lumbar lordosis with various ankle and foot positions.

Children with myelomeningocele are often short in stature. This has been related to multiple

factors, including the following:

Structural issues (eg, abnormalities of the spinal column and lower limb contractures)

Functional spinal level, which influences the amount of neurotrophic input from thelower extremities on appendicular skeletal growth

Alteration in the hypothalamic-pituitary axis, with associatedgrowth hormone deficiency
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Weight should be assessed in patients with spina bifida. Because of their decreased linear limb

growth and spine growth, patients should be monitored for weight using arm span measurements,

as opposed to ratios of height versus weight. During growth spurts, patients require close

monitoring for the development of any deformities, from scoliosis to deformities of the lower

extremities.

Ocular muscle palsies, swallowing and eating problems, and abnormal phonation are signs of

cranial nerve dysfunction. These symptoms may be related to the Chiari II malformation,

hydrocephalus, and/or brainstem dysplasia.

Laboratory screening tests for neural tube defects can be performed through blood tests,

amniocentesis, or both. These typically are used in combination with fetal ultrasonography.

Prenatal diagnosis and ultrasound confirmation allow for preparation and parental referral to

appropriate care services.

The fetal presence of an open neural tube defect is marked by an elevated alpha-fetoprotein level

in the amniotic fluid. Peak concentrations of alpha-fetoprotein in the 13th to 15th weeks of

pregnancy permit diagnosis, and ultrasound confirmation with amniocentesis generally is

possible at 15-18 weeks. Encephaloceles or skin-covered myeloceles are unlikely to be detected

by alpha-fetoprotein measurement.

In children with spina bifida, in addition to routine laboratory screening examination, testing

would include levels of anticonvulsants, urine cultures, and perhaps cystometrograms and skin

testing for latex sensitivity. The last can be performed by enzyme-linked immunosorbent assay

(ELISA) or skin prick.(8)

Fetal Ultrasonography

Some centers use fetal ultrasonography as the primary screening tool for neural tube defects,

usually at approximately 18 weeks gestational age. This trend reflects the increasing

sophistication of fetal ultrasonographic technology. The procedure avoids the roughly 1% risk of

abortion following amniocentesis, but accurate diagnosis depends on the skill and experience of

the operator and the quality of the equipment.


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The combination of maternal serum AFP screening with second-trimester ultrasonographic

screening detects over 90% of neural tube defects from 20 weeks' gestation.

With ultrasonography, myelomeningocele may be detected during scanning of the fetal head for

subtle changes in the cranial and cerebellar configurations. The diagnosis of myelomeningocele

is certain when the following 3 classic central findings are present:

Concavity of the frontal bones Ventriculomegaly The Chiari II malformation

Currently, ultrasonography is not sensitive enough to provide reliable and accurate detection of

the level of the defect. Preliminary experience indicates that the use of 3- and 4-dimensional

ultrasonography will improve the accuracy in determining the upper level of the

myelomeningocele lesion.

After confirmation of fetal myelomeningocele, clinicians at most tertiary care centers perform

weekly ultrasonographic examinations to observe the growth and development of the fetus.

Alpha-Fetoprotein and Acetylcholinesterase

Estimation of maternal serum alpha-fetoprotein (AFP) has been used since the late 1970s. Blood

samples are taken early in the second trimester. The AFP level is elevated in 70-75% of cases in

which the fetus has an open spina bifida.

Since many possible reasons exist for false-positive results, a presumptive diagnosis based on

maternal serum AFP is confirmed with amniocentesis and assay of the amniotic fluid for AFP, as

well as for the presence of acetylcholinesterase, a nerve-specific enzyme. Myelomeningocele can

be detected in 99% of affected fetuses through combined use of these tests.

Siblings of patients with spina bifida have an increased incidence of neural tube defects.

Consequently, following the birth of a child with spina bifida, amniocentesis is suggested during

subsequent pregnancies to monitor AFP.


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Radiographs

Radiographs of the vertebrae provide information for early evaluation when an infant is born

with myelomeningocele. After delivery, the criterion standard for determining the level of the

lesion is a plain film radiograph.

Congenital spinal deformities need to be tracked closely. Acquired or neuromuscular spinal

deformities require imaging based on clinical exam; these deformities should be followed

routinely during growth, and more frequently during times of rapid growth.

Plain radiographs are important for the clinical evaluation for scoliosis, dysplasia, and

dislocation of the hip. Radiographs, along with ultrasound evaluation, should be used to assess

any area of pain because of the high risk of pathologic fractures.

(1,8)

Treatment of Spina Bifida

There is no known cure for spina bifida. Treatment primarily focuses on dealing with

symptoms as they arise, since they vary so greatly from person to person.

Surgery to correct the spinal problem in spina bifida cystica is often done. This involves

carefully tucking the spinal contents back into the spinal column, and closing the covering back

up. This often happens shortly following birth to reduce the risk of developing an infection, and

requires some time to heal afterward. Surgery has not been known to allow someone to regain

functions they would not have had otherwise like movement, bowel, or bladder control.

A child with spina bifida is often carefully watched for signs of hydrocephalus. This may be

done by measuring head circumference (which may enlarge) or with periodic head ultrasound or

CT scans. If hydrocephalus is found, a procedure to put in a ventriculoperitoneal (VP) or

ventriculoatrial (VA) shunt may be done. If a shunt is placed, it must be continually monitoredand may need to be adjusted. Some people have their shunts removed later if the hydrocephalus

never returns, and some people have a shunt for their entire lives.


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Medications are widely available to treat those who develop seizures, and these may need

periodic adjustments. Those who have problems with bowel or bladder control may require

surgery, medications, or may never fully have these functions.

Babies and children with clubfoot often need to see an orthopedic surgeon and physiatrist, both

of whom can recommend ways to correct them. Wearing braces on the legs can turn the feet back

to their usual position, and this may be the only thing required. Sometimes surgery is necessary.

Surgery to correct the spinal problem during a pregnancy is experimental and not widely

available. Since 1997, about 200 fetuses have had closure of myelomeningoceles during

pregnancy. Since the surgery is so new, exact success rates, safety and long-term effects of the

procedure are still not known as of early 2004.

The medications used most frequently in myelomeningocele are for treatment of neurogenic bladder

dysfunction. These medications are used in conjunction with some form of bladder emptying technique to

prevent upper urinary tract complications and to facilitate social continence.(8)

Prevention

Since the late 20th century, the incidence of myelomeningocele has undergone a

significant decline in the United States and worldwide. This decline is related to increasing

availability and accuracy of prenatal diagnosis with the option for early pregnancy termination

and the introduction of primary prevention in the form of folic acid therapy in the periconceptual

phase.

Studies demonstrating a reduction in the frequency of spina bifida with folic acid

supplementation during pregnancy are accumulating, with reduction on the order of 50%.

Bell and Oakley reported that current worldwide programs of folic fortification of wheat and

maize flour have resulted in an annual worldwide decrease of about 6,600 folic acid-preventable

spina bifida and anencephaly cases since 2006. They note that the pace of preventing these

serious birth defects can be accelerated if more countries require fortification of both wheat and

maize flour and if regulators set fortification levels high enough to increase a woman's daily


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average consumption of folic acid to 400 mcg. The US Preventive Services Task Force

Recommendation remains 0.4-0.8 mg of folic acid daily.

However, the metabolism of folic acid appears to be abnormal in affected patients, suggesting

that spina bifida may result from an inherited defect rather than strictly a deficiency.

High intake of folic acid may mask the anemia of vitamin B-12 deficiency and allow neurologic

damage to progress untreated, so widespread folic acid supplementation has been recommended

with caution, but in pregnancy it has had gratifying benefits. Better understanding of the genetic

factors involved in spina bifida could allow its prevention.(6,9)

Complication

Neurologic Complications

Neurologic complications in patients with myelomeningocele are related to a variety of CNS and

spinal cord pathologies. Approximately 25-35% or more of children with myelomeningocele are

born with hydrocephalus, and an additional 60-70% of patients with myelomeningocele develop

hydrocephalus after closure of the myelomeningocele lesion. Hydrocephalus can cause

expansion of the ventricles and loss of cerebral cortex and is associated with an increased risk of

cognitive impairment.

Seizures occur in 10-30% of affected children and adolescents. These seizures can be related to

brain malformation, or they may be a sign of shunt malfunction or infection.

The Chiari type II malformation is present anatomically in almost all patients with

myelomeningocele and can result in hindbrain and/or upper cervical spinal cord dysfunction.

Clinical manifestations of the Chiari II malformation are more common during infancy and,

overall, are seen in 20-30% of affected children. However, symptoms can develop at any age and

can manifest acutely or chronically.

While symptoms are often mild, lower brainstem dysfunction is the leading cause of death in

infants with myelomeningocele because of associated stridor, apnea, and aspiration pneumonitis.

Common symptoms of lower brainstem dysfunction in infants include abnormal cry, swallowing


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or feeding difficulties, and frequent vomiting or gastroesophageal reflux. Older children and

adults may present with weakness or spasticity of the upper extremities, headache or neck pain,

cerebellar dysfunction, oculomotor changes, and scoliosis.

A tethered spinal cord is caused by the tendency for the spinal cord to adhere to the meningocele

repair and can prevent the normal cephalad migration of the cord during growth. A tethered cord

is present anatomically in most children with myelomeningocele. However, diagnosis of tethered

cord syndrome is confirmed on the basis of clinical signs and symptoms, which can include pain,

sensory changes, spasticity, and progressive scoliosis. In addition, uncontrolled hydrocephalus

and Chiari II malformation must be excluded as causes.

Symptoms similar to those of tethered cord syndrome can be caused by other intraspinal

pathologies (eg, mass lesions of the cord, diastematomyelia, cord cavitation and narrowing,

adhesions, dural bands).

Syringomyelia is caused by uncontrolled hydrocephalus that results in entry of CSF into the

central canal of the spinal cord, causing dilatation and pressure. While this is a common MRI

finding in patients with myelomeningocele, this condition is symptomatic in only 2-5%.

Symptoms described include progressive scoliosis, spasticity, and increasing weakness of the

extremities.

Urologic Complications

Myelomeningocele is the most common cause of neurogenic bladder dysfunction in children.

The nature of the urinary tract dysfunction in myelomeningocele depends on the level and extent

of the spinal cord lesion.

Disruption of the neural axis between the pons and the sacral spinal cord by the

myelomeningocele may cause uninhibited detrusor contractions or dyssynergia, a lack of

coordination of the external bladder sphincter that causes involuntary sphincter activity during

detrusor contraction. Myelomeningocele in the sacral area can produce a lower motor neuron

lesion, resulting in detrusor areflexia.


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These abnormalities may occur singly or in combination and typically result in incontinence and

impaired bladder emptying that can lead to vesicoureteral reflux and high voiding pressures. If

untreated, this condition can lead to potentially more serious complications, including frequent

infections, upper urinary tract deterioration, and, ultimately, renal failure.

The main determinant of upper urinary tract deterioration is the intravesical pressure in storage

and voiding situations. A high incidence of vesicoureteral reflux and ureteral dilation is found in

patients with myelomeningocele whose leak-point pressures were greater than 40 cm water.

High pressures may result from increased outlet resistance or decreased bladder wall compliance.

Increased outlet resistance may be caused by sphincter dyssynergia or fibrosis of a denervated

sphincter. Decreased bladder wall compliance is associated with areflexia of the detrusor. Any of

these urologic dysfunctions can occur in myelomeningocele, but manifestations may vary over

time because of the changing neurologic status in some of these patients.(7)

Prognosis

Studies of children with prenatally diagnosed myelomeningocele suggest that less severe

ventriculomegaly and a lower anatomic level of lesion on prenatal ultrasonograms predict better

developmental outcomes in childhood.

Aggressive treatment with closure in the neonatal period leads to survival in most cases of spina

bifida, and aggressive shunting of hydrocephalus can permit the retention of near-normal

intelligence in the majority of patients.

Cognitive dysfunction is most strongly correlated with the presence of hydrocephalus, along with

hydrocephalus-related illness parameters (ie, the necessity of shunting, number of shunt

revisions, shunt infections, and additional structural abnormalities of the CNS). Cognitive

function has also been related to the level of the lesion. Upper-level lesions have been associated

with a higher frequency of mental retardation and lower scores on measures of intelligence,

academic skills, and adaptive behavior.

The ability to ambulate depends on, and directly correlates with, the functional sensorimotor

level. Studies have shown that approximately 50-60% of young adult patients ambulate


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household or community distances, with about 20% of these patients using some orthotic or

assistive device. The other 50% of patients use wheelchairs as their primary form of mobility.

Approximately 20% of these individuals ambulate with orthotics and assistive devices as a form

of therapeutic exercise.

Several studies have shown that ambulation in patients with myelomeningocele is related to the

strength of certain key muscles, including the iliopsoas, gluteus medius, hamstrings, and/or

quadriceps. Specifically, a motor neurologic level of L5 or quadriceps strength graded as good (4

out of 5) in the first 3 years of life is predictive of a good prognosis for community ambulation.

Gluteus medius strength was the best predictor of a need for gait aids and orthoses. In a 25-year

follow-up study of young adults with myelomeningocele, no patient with a lesion at L3 or above

ambulated a majority of the time.

Maximal ability to ambulate usually is achieved by the time the child reaches age 8-9 years.

Studies have shown that a majority of preadolescent patients, even those with higher-level

lesions, are community ambulators when they receive aggressive multidisciplinary interventions.

However, after adolescence, community ambulation decreases to approximately 50%.

The ability to ambulate tends to decline in the second decade of life because of increased body

dimensions and higher energy requirements. Lower-extremity muscle deterioration also mayplay a role. Functional decline with aging in patients with myelomeningocele also can be

exacerbated by obesity, decubitus ulcers, and psychological issues.

Except for sphincter control, independence in activities of daily living is likely for children born

with myelomeningocele without hydrocephalus. For those born with myelomeningocele and

hydrocephalus, those with a level of lesion of L4/5 (quadriceps grade of good) or below are

likely to be independent for almost all activities of daily living except sphincter control. Those

with higher-level lesions are at significant risk for dependence in activities of daily living.

The data on continence from the literature is variable, which in part reflects inconsistencies in the

definition of social continence. Studies report 40-85% achievement of bladder continence and

50-85% achievement of bowel continence. Approximately 25% of patients are continent of both

bowel and bladder. The likelihood of social continence improves when training is instituted


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before age 7 years. The psychosocial consequence of bowel and bladder incontinence can have a

dramatic impact on children with myelomeningocele, especially in adolescence.

Studies of adults with myelomeningocele have shown that about 20-30% secure gainful

employment. In one study, employment status was related to lesion level and motor

independence. However, motor independence was not found to be related to self-reported quality

of life or range of life experiences.

Several studies have shown a greater number of shunt revisions are associated with reduced

independence and achievement in adulthood. This suggests that close medical management in

order to minimize episodes of increased intracranial pressure may improve adult employment

and quality of life.

Perceived family environment may explain different levels of participation of patients with

myelomeningocele in employment, community mobility, and social activity as an adult, even

beyond what can be explained by lesion level and intelligence. A positive correlation exists

between perceived family encouragement of independence and outcomes in young adults with

myelomeningocele.

Mortality

In general, survival and degree of neurologic impairment depend on the level of the spinal

segment involved, the severity of the lesion, and the extent of associated abnormalities.

The mortality rate for infants with myelomeningocele is increased over the general population

risk in the first year of the life. Mortality rates reported for untreated infants range from 90-100%

based on several studies dating from the turn of the century through recent years. Most untreated

infants die within the first year of life. Death in the first 2 years of life for those untreated usually

results from hydrocephalus or intracranial infection. The likelihood that a 2-month-old infant

untreated for myelomeningocele lives 7 years is only 28%.

Survival rates for infants born with myelomeningocele have improved dramatically with the

introduction of antibiotics and developments in the neurosurgical treatment of hydrocephalus.


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Early death in treated and untreated patients is associated with advanced hydrocephalus and

multiple system congenital anomalies.

Renal compromise occurs because of problems related to neurogenic bladder. Despite advances

in the management of neurogenic bladder, renal failure is still the leading cause of death in

patients with myelomeningocele after the first year of life.

Longevity may depend on careful, clean, intermittent catheterization; and compliance with a

bowel and bladder regimen. Long-term survival into adulthood and advanced age is now

common with aggressive treatment and an interdisciplinary clinical approach. With proper

urologic management, more than 95% of children with myelomeningocele continue to have

normal renal function.(6,9)

Folic Acid

Folate is a generic term for a water-soluble, B-complex vitamin that serves as an

essential coenzyme in single-carbon transfers in the metabolism of nucleic and amino acids and

thus fills an important function in purine and pyrimidine metabolism. It occurs in certain natural

foods as polyglutamate, a form less absorbed than free folate. Folic acid (a monoglutamic acid)is the oxidized and most active form of the vitamin; found rarely in food, it is the form used in

vitamin preparations and food fortification. The distinction between food folate and folic acid is

important because of differing bioavailability (ie, food folate is only about half as available as

folic acid consumed on an empty stomach).

Since 1998, it has been added to cold cereals, flour, breads, pasta, bakery items, cookies, and

crackers, as required by federal law. Foods that are naturally high in folic acid include leafy

vegetables (such as spinach, broccoli, and lettuce), okra, asparagus, fruits (such as bananas,

melons, and lemons) beans, yeast, mushrooms, meat (such as beefliver andkidney), orange

juice, and tomato juice.

Women who arepregnant or might become pregnant take folic acid to preventmiscarriage and
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neural tube defects,birth defects such asspina bifida that occur when the fetuss spine and

back dont close during development.

Folic acid is needed for the proper development of the human body. It is involved in producing

the genetic material called DNA and in numerous other bodily functions.

Folic acid really effective to prevent neural tube defect.Folic acid is likely safe for most people.

Most adults do not experience any side effects when consuming the recommended amount each

day, which is 400 mcg.

High doses of folic acid might cause abdominal cramps, diarrhea, rash, sleep disorders,

irritability, confusion, nausea, stomach upset, behavior changes, skin reactions, seizures, gas,

excitability, and other side effects.

There is some concern that taking too much folic acid for a long period of time might cause

serious side effects. Some research suggests that taking folic acid in doses of 800-1200 mcg

might increase the risk of heart attack in people who have heart problems. Other research

suggests that taking these high doses might also increase the risk of cancer such as lung or

prostatecancer.(10)
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CHAPTER III

Discussion

Correlation Between Folic acid And Spina Bifida Disease

The congenital defect results from failure of closure ("neurulation") of the embryologic

nervous system very early in pregnancy at 23 to 30 days gestation. The resulting deformity

ranges from a small opening in the spinal cord at the sacral region, to an open skull or even

absent brain. The latter is known as anencephaly and is not compatible with life. The open

deformity of the spine is technically called myelomeningocele and causes a complexion of

problems similar to a permanent spinal cord injury; everything below is affected.

Currently about 2,500 children are born in the United States each year with NTD's; twenty five

of these come from Oregon. Many suffer a life long disability and require multiple surgeries and

complicated equipment. A few suffer a lifetime of discomfort. The cost of care averages $50,000

in the first year of life, $12,000 yearly thereafter, and $250,000 in a patient lifetime.

It is not known how frequently these abnormal formations occur.

The mechanism for this deficient formation of the nervous system so early in pregnancy is

multifactorial. Differing ethnic rates, regional variations, family clustering, and increased risk of

recurrence in later pregnancies all suggest genetic mechanisms. But environmental associations

have long been observed. Birth rates vary with time and location, and there are temporal clusters

particularly following famine and poverty. Frequency also varies with socio-economic status.

These defects are also more common when, during pregnancy, the mother takes certain

medications (Valproate for seizures), has diabetes, or drinks heavily with resulting Fetal Alcohol

Syndrome (FAS).

Years ago it was proposed that there might be a mechanism which could explain these apparently

disparate observations and characteristics. A dietary factor during pregnancy could impact

metabolism in a targeted way, affecting the normal migration of neural crest cells trying to form

the fetal nervous system. Perhaps one metabolic pathway may be side tracked by various

deleterious effects. A genetic variation in a metabolic pathway would explain ethnic, regional,


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familial, and temporal variations. A single pathway might combine potential environmental as

well as genetic patterns in the occurrence of spina bifida and other Neural Tube Defects. The

dietary factor has been found to be one of the B vitamins, folate.

In the late nineteen-fifties it was shown that a chemical called aminopterin which blocks folate,

causes NTD's in laboratory animals when they were also deficient in folate in their diet. Twenty

years later a British researcher found low levels of folate in the serum, especially in the red cells,

of mothers who had borne a pregnancy with NTD.

In the last ten years there have been numerous clinical investigations of the impact of dietary

folate during pregnancy. Early retrospective studies surveyed mothers to report on vitamin usage

during previous pregnancies. History of ingestion could be compared between groups of mothers

of children with NTD's and those without. Four out of five major studies confirmed a 50 to 80%

decline in these birth defects if mothers had taken supplemental folate early in pregnancy, or

better still, prior to conception.

Such retrospective clinical surveys are flawed by recall. Controlled prospective clinical trials

with supplemental folate were finally run in the late '80's and early nineteen-nineties. The

British, who have a much higher prevalence than in the U.S.A., ran a multicenter study in seven

countries, treating mothers who had already borne a child with an NTD. They prescribed 4 mg offolic acid (the synthetic form of folate), ten times the recommended dietary allowance (RDA).

The study was halted early when the statistics revealed a 72% lower chance of bearing another

pregnancy with an NTD in the supplemented mothers.

The definitive study was finally reported in late 1992. A Hungarian group conducted a

randomized, controlled trial of periconceptional multivitamin supplementation, including low

dose folate. The supplemented mothers had no affected fetuses in 2,000 pregnancies, while those

2,000 pregnancies supplemented only with trace elements bore six infants with NTD's. And, the

treated mothers had newborns with lower rates of all forms of birth defects!

The presumed mechanism of folate is as a substrate in DNA synthesis. Deficiency causes an

increase in levels of homocysteine. It is not known how that affects neurulation, but we now

know the causative step in the metabolic pathway.


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Enter the world of molecular biology. The deranged metabolic pathway is described in

simultaneous reports of findings of an abnormally slow enzyme in the DNA synthesis pathways

at the site of function of folate in 15% of children with spina bifida, as well as in their mothers

and/or their fathers. "In some pregnancies, there was an increased requirement for folate to

ensure normal closure of the neural tube." Some women unknowingly have a need for greater

folate intake than the current Recommended Daily Allowances (RDA's). We have thus tied

together our understanding of the environmental, dietary, and genetic aspects of neural tube

defects.

That slow enzyme had already been known. It is a common genetic variant of

methyltetrahydroxy folate reductase (MTHFR), markers of which are found in up to half of the

American public. The homozygous state of the abnormal enzyme in folate metabolism hadalready been associated with elevated levels of homocysteine and well documented increased

risk of cardiovascular disease.

reference.8 5,10 Methylenetetrahydrofolate reductase and other enzymes important inhomocysteine metabolism.


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Where do we get folate to prevent birth defects and lower rates of cardiovascular disease? The

Greek origin of the word folate means "leafy green". Your mother was right: eat your green

vegetables ! There is no known toxicity. Americans tend to get their folate from these food items,

in order of frequency---orange juice, wheat products, beans, salad, non-fortified cereal, eggs, and

liver. But only twenty percent of women of child bearing age get adequate folate in their natural

diet to adequately bathe their ovaries to prevent NTD's. It is presumed that the same dietary

unmet needs occur in the segment of the general population who would have lower rates of

cardiovascular disease if their enzyme needs were covered.

This information, with a few additional facts, can be used to generate public recommendations.

In the U.S., half of all pregnancies are unplanned. Over 90% of NTD's are first sporadic

occurrences. Strategies directed at recurrence to the same mother are therefore insufficient.Strategies directed at the diagnosis of pregnancy are too late; the embryologic defect has already

occurred. Dietary change is a long term goal. With these facts in mind, a more inclusive policy

recommendation has been devised. The Centers for Disease Control therefore recommend that

every woman, "capable of becoming pregnant" (euphemism for having sex) should supplement

her diet with 400 micrograms or 0.4 mg folic acid (the synthetic form of folate) daily throughout

her child bearing years. (4.) That recommendation is easy to carry out because the folic acid

content of many non-prescription daily vitamins is just that--0.4 mg or 400 micrograms.

Women who have already had a pregnancy with an NTD are at risk for a repeat occurrence.

These women are recommended to consult their physician for prescriptions for the higher dose (4

mg) of folic acid to be taken one month prior to conception through the third month of

pregnancy. They would also be wise to supplement at the newly recommend low dose RDA of

0.4 mg when using contraception and not planning pregnancy.

The above universal dietary supplementation would lower the rate of birth defects such as

anencepehally and spina bifida by at least 50%.

Public health has been called "the successful implementation of what is known to be effective."

The knowledge exists to promulgate effective policy to prevent over half of the NTD's born, as

well as cardiovascular events in 30,000 men and 18,000 in women each year. Yet the general


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public cannot be counted on to voluntarily take daily vitamin supplementation. Long term public

health policy should address child bearing age women as well as large segments of the adult

population of America. Many argue that public policy should become universal dietary

fortification, to the levels of the doses shown to be preventive of NTD's. Fortunately folate is

water soluble and could be added to grain products, just as iron and trace elements are added to

white flour. Folic acid is already added to some brands of dry breakfast cereals.

There is a theoretical risk in universal fortification of diet with folic acid. Megaloblastic anemia,

the presenting sign of Pernicious Anemia, would be masked by high level folate

supplementation. Later, irreversible peripheral neuropathy would become the first sign of

Pernicious Anemia. The number of cases which would be hidden by fortification is unknown.

However, it has been proposed that low level folate in combination with B12 might prevent bothdeficiencies.

The Food and Drug administration (FDA) has promulgated new rules requiring that folic acid

"be added to specific flour, breads and other grains. These foods were chosen because they have

a long history of being successful vehicles for improving nutrition to reduce the risk of classic

nutrient deficiency diseases." These rules take effect in 1998, and will include most enriched

breads, flours, corn meals, rice, noodles, macaroni and other grain products. Fortification will

range from 0.43 to 1.4 mg per pound of product. These levels will allow the daily intake from all

sources to remain below the recommended upper limit of 1 mg per day, considered safe for all

population groups.(1,6,8)


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CHAPTER IV

CONCLUSION

Food fortification with folic acid was associated with a significant reduction in the reate

of neural tube defect. For women who may get pregnant, it is really important. When a woman

has enough folic acid in her body before and during pregnancy, it can prevent major birth defects

of her baby's brain or spine. For preventing neural tube defects: at least 400 mcg of folic acid per

day from supplements or fortified food should be taken by women capable of becoming pregnant

and continued through the first month of pregnancy. Foods with folic acid in them include leafy

green vegetables, fruits, dried beans, peas and nuts. Enriched breads, cereals and other grainproducts also contain folic acid.
http://www.nlm.nih.gov/medlineplus/neuraltubedefects.htmlhttp://www.nlm.nih.gov/medlineplus/neuraltubedefects.html


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References

1. 1. Ray, J.G., Singh, G., & Burrows, R.F. (2004). Evidence for suboptimal use ofpericonceptional folic acid supplements globally. BJOG: and International Journal ofObstetrics and Gynaecology, vol. 111, p. 399.

2. Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY. Impact of folic acidfortification of the US food supply on the occurrence of neural tube defects. JAMA.2001;285(23): 29812986.

3. Lopez-Camelo, J.S., et al. (2005). Reduction of birth prevalence rates of neural tubedefects after folic acid fortification in Chile. American Journal of Medical Genetics PartA, published online 4/21/05.

4. Boulet, S. L., Q. Yang, et al. (2008). "Trends in the postfortification prevalence of spinabifida and anencephaly in the United States." Birth Defects Research Part A: Clinical and

Molecular Teratology 82(7): 527-532.5. Christianson, A., Modell, Bernadette, Howson, Christopher (2006). March of Dimes

Global Report on Birth Defects: The Hidden Toll of Dying and Disabled Children. WhitePlains, March of Dimes.

6. Bell KN, Oakley GP Jr. Update on prevention of folic acid-preventable spina bifida andanencephaly.Birth Defects Res A Clin Mol Teratol. Jan 2009;85(1):102-7.

7. Fletcher JM, Copeland K, Frederick JA, et al. Spinal lesion level in spina bifida: a sourceof neural and cognitive heterogeneity.J Neurosurg. Apr 2005;102

8. Kohl T, Gembruch U, Thomas; Thomas Kohl, Ulrich Gembruch (October 3, 2008)."Current status and prospects of fetoscopic surgery for spina bifida in human fetuses".Fetal Diagnosis and Therapy24: 318320.

9. Kim Y.I. (2004). Will mandatory folic acid fortification prevent or promote cancer?American Journal of Clinical Nutrition, vol. 80, pp. 1123-1128.

10. Knudsen, V.K., Mikkelsen, T.B., Michaelsen, K.F., & Olsen, S.F. (2004). Lowcompliance with recommendations on folic acid use in relation to pregnancy: Is there aneed for fortification?Public Health Nutrition, vol. 7, pp. 843-850.
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