42.  Screening for Neural Tube Defects_Including Folic Acid/Folate Prophylaxis



RECOMMENDATION



The offering of screening for neural tube defects by maternal serum a-fetoprotein (MSAFP)

measurement is recommended for all pregnant women who are seen for prenatal care in locations

that have adequate counseling and follow-up services available (see Clinical Intervention).

Screening with MSAFP may be offered as part of multiple-marker screening (see Chapter 41).

There is insufficient evidence to recommend for or against the offering of screening for neural

tube defects by midtrimester ultrasound examination to all pregnant women, but recommendations

against such screening may be made on other grounds (also see Chapter 36). Daily multivitamins

with folic acid to reduce the risk of neural tube defects are recommended for all women who are

planning or capable of pregnancy (see Clinical Intervention).



Burden of Suffering



Neural tube defects, including anencephaly, encephalocele, and spina bifida, account for

substantial morbidity and mortality. Anencephaly is almost always lethal, usually resulting either

in stillbirth or death within hours or days of birth. Spina bifida can range from mild (spina bifida

occulta) to severe (myelomeningocele). The manifestations of severe spina bifida may include

infectious complications, paraplegia, bladder and bowel incontinence, Arnold-Chiari

malformations, hydrocephalus, and, as a complication of hydrocephalus, diminished intelligence.1

Aggressive surgical and medical care is often necessary for severely affected cases, along with

special schooling and rehabilitative services for patients with permanent disabilities. Based on

1988 cross-sectional data, the estimated lifetime cost of spina bifida is $258,000 per case.2



The birth prevalence of neural tube defects has declined substantially over the past 60 years.3,4

Neural tube defects are reported in 3.6-4.6/ 10,000 live births in the United States.3,5 These

rates underestimate true incidence, however, because affected pregnancies may be spontaneously

or electively aborted and because not all cases are detected and reported at birth. Population-based

active surveillance programs that include prenatal diagnoses have reported neural tube defect

rates of 7.2-15.6/10,000 live-born and stillborn infants.6 A personal or family history of a

pregnancy affected by a neural tube defect is associated with an increased risk of having an affected

pregnancy, as is maternal insulin-dependent diabetes, but about 90-95% of cases occur in the

absence of any positive history.7-9 The birth prevalence of neural tube defects in the U.S. is

higher at younger maternal ages and is more than one third higher for whites than blacks.5



Accuracy of Screening Tests



Tests for neural tube defects include ultrasound examination and measurement of maternal serum

a-fetoprotein (MSAFP), amniotic fluid a-fetoprotein (AFAFP), and amniotic fluid

acetylcholinesterase (AFAChE). The latter two are used primarily as confirmatory tests and should

not be regarded as part of routine screening of women at low risk for neural tube defects.

Ultrasound examination is used both as a screening test and as a follow-up test after positive

MSAFP screening.



An elevated MSAFP measured at 16-18 weeks' gestation is a good predictor of neural tube defects.

Depending on the cutoff used to define an elevated level (usually 2-2.5 times the median value for

gestational age, reported as multiples of the median or MoM), screening can detect between 56%

and 91% of affected fetuses.10-17 An elevated MSAFP occurs in about 1-5% of pregnant

women,9,14,15,17-20 but for a number of reasons, the likelihood of a neural tube defect given a

positive screening test result is small. First, about one third of positive tests are not confirmed by

a second MSAFP measurement.9,19 Second, although the reported specificity of MSAFP when

followed by appropriate diagnostic tests (i.e., high-resolution ultrasonography, AFAFP, AFAChE)

approaches 100%,12,18,21 MSAFP assays themselves are relatively nonspecific. About 90-95%

of cases with confirmed elevated MSAFP are caused by conditions other than neural tube defects,

such as an underestimated gestational age, other congenital anomalies, intrauterine growth

retardation, multiple gestations, or fetal demise.7,9,10,18,20,22 An ultrasound examination is

necessary to rule out these explanations for an elevated MSAFP. If ultrasonography does not

provide an explanation for the abnormal result (as occurs in about 50%),10,14,15,17 an

amniocentesis should be offered to measure AFAFP and/or AFAChE levels.8 Less than 10% of these

lead to the discovery of a neural tube or abdominal wall defect; the majority of the fetuses tested

are normal.9 In comparison with the number of women who must be tested, the actual number of

neural tube defects detected through screening the general population is small (0.06-0.16% of

pregnancies).9,10,18,19



Virtually all cases of anencephaly can be detected by ultrasound alone,24 as can many closed

neural tube defects that may escape detection by MSAFP measurement. Current ultrasound

techniques are less sensitive, however, in detecting other neural tube defects such as small

meningomyeloceles.11 In addition, although the published sensitivities and specificities of

sonographic detection of spina bifida are high (79-96% and 90-100%, respectively),24-28

investigators have emphasized that these data were obtained from centers with special

expertise.24 They may overestimate the sensitivity that would be expected when prenatal

ultrasound is conducted with older equipment or is performed by those with less complete

training,28 which has become increasingly common as more physicians perform their own

ultrasound examinations.29 In addition, many of the published studies were of high-risk women

and may not be generalizable to screening in the low-risk population. Nevertheless, recent

improvements in ultrasound diagnosis of neural tube defects, with sensitivity and specificity

approaching 100% when performed by expert sonographers at major screening centers, has

caused some experts to recommend the use of ultrasound instead of MSAFP in pregnancies at low

risk for neural tube defects.30,31 Ultrasound and MSAFP have not been directly compared as

screening tests for neural tube defects.



Effectiveness of Early Detection



The detection of neural tube defects in utero provides as its principal benefit the opportunity to

inform prospective parents of the likelihood of carrying an affected fetus. Parents may be

counseled about the consequences of the malformation and can make more informed decisions about

optimal care for their newborn or about elective abortion. The antenatal diagnosis of a severe

and/or lethal malformation (e.g., anencephaly) may spare parents some of the trauma associated

with delivering such an infant. No controlled trials have been performed to prove that those

screened for neural tube defects have better outcomes compared to those not screened, however.

Therefore, the usefulness of this information depends to a large extent on the personal preferences

and abilities of the parents.32 Whether or not parents choose to use prenatal screening is related

both to their views on the acceptability of induced abortion and their perceived risk of the fetus

being abnormal.33



Induced abortion is sought by the majority of women who choose to be screened and whose

screening tests reveal neural tube defects, thus leading to a decreased birth prevalence of affected

infants among screened women.10,14,15,34-37 Time series from the United Kingdom, where

screening by MSAFP and ultrasound is widespread, have reported a 49-50% decline in the birth

prevalence of anencephaly and a 32-38% decline in the birth prevalence of spina bifida

attributable to elective abortion for suspected central nervous system malformation.38,39 The

effectiveness of screening in reducing the number of infants born with neural tube defects is

decreased by less than universal acceptance of screening, incomplete detection of affected fetuses,

and varying decisions about elective abortion following early detection.35



Several interventional cohort studies have evaluated the effect of MSAFP programs on the birth

incidence of neural tube defects. In one such study, MSAFP screening was offered to all pregnant

women attending antenatal clinics during the study period (n = 15,687), of whom 70% were

actually screened.35 Of 66 total neural tube defects, 54 occurred in the screened group

(4.9/1,000) and 12 occurred in the unscreened population (2.5/1,000). The higher incidence

rate in the screened group suggests that women who elected screening may have been at higher

risk. Offering screening resulted in the elective abortion of 56% (37/66) of all pregnancies with

neural tube defects. In the screened group, 11 (20%) were not detected by screening. Six (11%)

were detected but were not aborted because ultrasonography or tests on amniotic fluid mistakenly

indicated an unaffected pregnancy. Screening resulted in fewer infants being born with neural tube

defects (1.6/1,000 in screened women vs. 2.5/1,000 in unscreened women). In another cohort

study of more than 18,000 women, MSAFP screening was accepted in approximately 85% of

second-trimester pregnancies and detected 80% of open neural tube defects, all of which were

electively aborted.34 Screening in this population reduced the birth prevalence of anencephaly by

90% and of open spina bifida by 72%. In a third study, screening was performed in 72% of clinic

patients and detected 59% of all affected pregnancies, 94% of which were aborted.36 Offering

screening therefore prevented the births of 55% of affected fetuses.



There is limited evidence evaluating ultrasound screening for neural tube defects. One randomized

controlled trial of routine ultrasound examination in low-risk women reported increased prenatal

detection of fetal malformations, but no differences in induced abortion rates, survival rates of

anomalous fetuses, or other perinatal outcomes.28,40 Neural tube defects were included among

the anomalies detected, but the study was not designed to evaluate this outcome specifically and

only 13 such defects occurred in the entire enrolled population. Of eight neural tube defects

occurring in the screened group, seven were detected by screening and electively aborted, reducing

the birth prevalence by 88%, to 0.13/1,000 screened women. In controls, three of five neural

tube defects were detected prenatally, two of which were aborted, reducing the birth prevalence to

0.39/1,000. The numbers of fetuses affected by neural tube defects were too small for valid

statistical comparison. Interventional cohort studies evaluating routine ultrasound examination as

a screening test for detection of neural tube defects have not been published, so there is inadequate

information available on the acceptability and impact of ultrasound screening, confirmatory tests,

and induced abortion in the general population.



Early detection of neural tube defects may also help parents to prepare emotionally, although this

potential benefit has not been evaluated. It may enable clinicians to provide more intensive

obstetric care and to better prepare for the delivery and care of the baby. Studies are limited,

however, regarding the impact of these measures on neonatal morbidity and mortality. In a series

of 208 patients aged 2-18 years with meningomyeloceles, there were no statistically significant

differences in motor or sensory level, or in ambulatory function, between those delivered

vaginally compared to those who had cesarean delivery.41 On the other hand, in a retrospective

population-based study of 160 fetuses with uncomplicated meningomyelocele, cesarean delivery

before the onset of labor resulted in better motor function at age 2 years than vaginal delivery or

cesarean delivery after a period of labor.42 Follow-up to 4 years of age was available for 85% of

the original cohort.43 The pre-labor cesarean group continued to have a significantly greater

difference between the anatomic and motor spinal cord level compared to the vaginally delivered

group. Motor function was not significantly better at 4 years, however. These types of studies have

important design limitations. Controlled trials evaluating early cesarean delivery for neural tube

defects have not yet been published.



Another potential benefit of MSAFP screening for neural tube defects is the discovery during

testing of abnormalities other than the target condition. A raised level of MSAFP, even in the

absence of a congenital defect, is a risk factor for low birth weight, preterm labor, preeclampsia,

and abruptio placentae;20,44,45 early obstetric intervention for these problems may be

beneficial (see also Chapter 37). Reduced levels of MSAFP are associated with Down syndrome and

certain other chromosomal anomalies; MSAFP is one component of multiple-marker screening,

which is recommended for the early detection of Down syndrome (see Chapter 41). The ultrasound

evaluation that follows the detection of raised MSAFP may lead to a diagnosis of twins or a more

accurate assessment of gestational age, and some studies suggest that acting on this information

may improve neonatal outcome (see Chapter 36). Other congenital anomalies, such as

diaphragmatic hernia, gastroschisis, nonimmune fetal hydrops, and obstructive uropathy, may

also be detected. Discovery of a fetus affected by one of these anomalies may be useful for parental

decision making, allowing the options of elective abortion or of antenatal treatment if available,

planning for delivery and appropriate neonatal care. Controlled trials have not proven that early

detection of these anomalies improves outcome, however. Indeed, studies suggest that fetuses with

diaphragmatic hernias detected in utero have poorer outcomes than those detected after

birth,46,47 perhaps in part because larger defects are more likely to be detected prenatally.



The potential benefits of early detection of neural tube defects must be weighed against the

potential risks of screening. The most important risks include those to the fetus from

amniocentesis, the psychological effects on the parents of a positive test, the complications

resulting from induced abortion, and the risk of elective abortion of normal pregnancies due to

false-positive test results. The risks of amniocentesis include miscarriage, puncture of the fetus,

bleeding, infection, and possibly isosensitization.9 The exact rate of fetal loss due to amniocentesis

is uncertain, since women undergoing this procedure are already at increased risk of fetal loss.

The procedure-related rate of fetal loss with current technique appears to be about 0.5-

0.8%.48-50 The best evidence on amniocentesis risks comes from a randomized controlled trial

of screening,48 which reported a procedure-related risk of fetal loss of 0.8% of pregnancies. This

may nevertheless overestimate current rates of loss as techniques have improved. In a more

recent series of patients undergoing amniocentesis as part of a clinical trial, the risk of fetal loss

was 0.04%.51 In a randomized controlled trial, neonatal respiratory distress syndrome and

neonatal pneumonia were more frequent after amniocentesis, independent of birth weight and

gestational age; the additional risk was about 1%.48 A similar trend was seen in the Medical

Research Council study,52 but has not been confirmed in other studies. Infection has not been

identified as a significant problem in any large studies. No clinically important effects on

development, behavior, or physical status were identified in 4-year-old children whose mothers

had undergone midtrimester amniocentesis.53 Although MSAFP screening will increase the

number of women undergoing amniocentesis, in cohort studies of screening programs fewer than

2% of MSAFP-screened women received amniocentesis.10,14,15,17



Another risk of screening is the harmful psychological effect on parents of a positive test result.

This is especially important because the large majority of positive screening tests in low-risk

pregnancies are false positives. There is evidence that expectant parents with normal fetuses who

are informed of an abnormal MSAFP test suffer substantial anxiety during the weeks of diagnostic

testing and waiting for definitive results.54-57 The anxiety level of these women at delivery was

the same as that of women who had normal screening test results, however. No published

controlled trials have evaluated whether counseling and education prior to screening alleviates

these psychological effects. Elective abortion of pregnancy because of a fetal anomaly may also have

important psychological effects. In one small case-control study,58 women who aborted fetuses

with major malformations (including neural tube defects) experienced grief similar to those

experiencing spontaneous perinatal loss, but no comparison was made to women delivering an

infant with a severe anomaly, who may also grieve for the loss of a normal infant. Most women

screened will have normal results, and this may have psychological benefits for the reassured

parents.



The potential complications of induced abortion must also be considered, since this is the outcome

of the majority of positive diagnostic test results. The maternal case-fatality rate from legal

induced abortion is 0.4/100,000 procedures, which is substantially lower than the eight to nine

maternal deaths per 100,000 live births due to pregnancy and childbirth.59-62 Rates of other

major maternal complications are also lower than in pregnancy and childbirth, occurring in an

estimated 0.1% of legal abortions.62 All maternal complication rates are higher with

second-trimester than with first-trimester abortions.



The most serious consequence of false-positive results, the induced abortion of a normal

pregnancy on the basis of erroneous diagnostic test results, appears to be very uncommon with

current diagnostic techniques (i.e., high-resolution ultrasound, AFAFP, and AFAChE).

Investigators have reported false-positive results leading to elective abortion of normal fetuses in

0.006-0.07% of women screened.10,17,18,34,38,63,64



Primary Prevention (Folic Acid/Folate Prophylaxis)



Randomized placebo-controlled trials65,66 and nonrandomized controlled trials67-69 in

pregnant women with a prior pregnancy affected by a neural tube defect have demonstrated that

folic acid supplements substantially  reduce the risk of recurrent neural tube defects. In the

international, multicenter British Medical Research Council (MRC) trial, involving nearly 1,200

high-risk women, 4 mg of folic acid daily at least 1 month before conception through the first

trimester reduced the risk of recurrence of neural tube defects from 3.5% to 1.0%, for a relative

risk of 0.28 (95% confidence interval, 0.12 to 0.71). The MRC and two other trials tested folic

acid doses of 4-5 mg/day, but the 86% risk reduction seen in one nonrandomized trial67 that used

0.36 mg of folic acid plus multivitamins daily suggests that lower doses may also be effective.



Several case-control studies have reported a reduced risk of neural tube defects in women without

a prior affected pregnancy who took daily multivitamins during the periconceptional period (from

1-3 months before conception to 0.5-3 months after conception).70-72 One of these analyzed the

amount of folic acid the multivitamins contained, which was 0.4 mg for most women.71 A similar

study, on the other hand, reported no protective effect of either folic acid alone or multivitamins

with folic acid.73 Stronger evidence for a benefit of periconceptional multivitamins with folic acid

in low-risk pregnant women comes from a cohort study of 22,715 women.74 The risk of neural

tube defects was significantly reduced, from 3.3/1,000 to 0.9/1,000 women, with daily intake of

multivitamins containing 0.1-1.0 mg of folic acid during the first 6 weeks of pregnancy. In an

unadjusted analysis, taking multivitamins with folic acid both in the 3 months before conception

and in the first trimester was also protective against neural tube defects. In a random sample of

the multivitamin users, about two thirds consumed multivitamins containing a daily dose of at

least 0.4 mg of folic acid and 95% consumed at least 0.1 mg of folic acid daily. A randomized

double-blind controlled trial of the efficacy of daily periconceptional multivitamin-multimineral

supplements containing 0.8 mg of folic acid in preventing first occurrences of neural tube defects

was conducted in Hungary, enrolling 4,753 women planning pregnancy.75,76 Full

supplementation was defined as taking them from 28 days before conception to at least the second

missed menstrual period. The average daily consumption of dietary folate was 0.18 mg, which is

similar to the estimated average intake of 0.2 mg/day by women aged 19 to 34 years in the United

States.77 The supplemented group experienced a significantly decreased prevalence of neural tube

defects (0 of 2,104 vs. 6 of 2,052), congenital malformations as a whole (13.3 compared to

22.9/1,000), and major congenital abnormalites other than neural tube defects and genetic

syndromes diagnosed by 8 months of age (14.7 vs. 28.3/1,000). Three observational studies

provide limited evidence for the effectiveness of dietary folate at levels higher than 0.1-0.25

mg/day in preventing the occurrence of neural tube defects.70,71,74 All three studies reported a

protective effect of greater dietary folate intake, although not all results were statistically

significant or adequately reported.



Research on adverse effects from folic acid supplementation is limited. Evidence that folic acid

supplements in daily doses of 1-5 mg can mask the hematologic manifestations of vitamin B12

deficiency, possibly delaying its diagnosis and treatment thereby leading to permanent neurologic

consequences, is limited to uncontrolled intervention studies78-80 and case reports.81-83

Hematologic improvement in pernicious anemia has also been reported in some patients taking

folic acid doses <1 mg, but the response is not consistent, particularly at lower doses.79,84-86

Nevertheless, this has been advanced as one reason to avoid universal supplementation or food

fortification with folic acid. It has also been argued, however, that it is unreasonable to maintain

anemia to make it easier to diagnose B12 deficiency while some neural tube defects occur that are

potentially avoidable by supplementation.87 Limited evidence supports independent associations of

low-normal folate and B12 levels, and high homocysteine levels, with neural tube defects,88,89

suggesting that a causal mechanism for these defects may be an abnormality in methionine

synthase, a folate- and B12-dependent enzyme. If these results are confirmed, supplementation

with both folic acid and B12 may be appropriate to prevent neural tube defects. This could reduce

the potential for adverse effects of folate supplementation in B12-deficient patients.



Folic acid supplementation may also reduce intestinal absorption of zinc.90 A randomized trial in

which 50 women received either 10 mg folic acid or placebo daily showed no effect on plasma zinc

concentrations after 2 and 4 months, however.91 One cross-sectional study found a significant

correlation between pregnancy complications and high folate and low zinc concentrations in the

plasma of 450 pregnant women,92 but confirmation is needed. Patients under therapy with

medications that interfere with folic acid metabolism (e.g., treatments for cancer, asthma,

arthritis, AIDS, and psoriasis) may be adversely affected by folic acid supplementation, but this

risk has not been adequately assessed.93 Folic acid supplementation might theoretically provoke

convulsions in epileptic women by interfering with the activity of certain anticonvulsants; this

potential risk has not been well studied.



None of the trials of healthy pregnant women reported serious adverse effects associated with folic

acid supplementation. In the Hungarian trial,94 infants born to women who received a

multivitamin-multimineral supplement with folic acid did not differ from those born to women

receiving only trace elements in mortality, somatic development, mental and behavioral

development, or total serious or chronic disorders, at 8-21 months (mean 11 months) of age. The

rate of atopic dermatitis, asthma, and wheezy bronchitis was significantly increased in the group

whose mothers received multivitamins (16 vs. 5/1,000), but more affected infants in the

supplemented group also had a positive family history for these disorders. This difference may

also be a chance effect due to the large number of comparisons made. A series of 91 children born

to women who had taken daily multivitamins containing 0.36 mg of folic acid to prevent neural

tube defect recurrences revealed no adverse effects on health, auditory, visual, growth, or

developmental status at age 7-10 years, compared with the general population.95 The study found

significant increases in neurotic traits, but whether this was attributable to folic acid or to other

causes (e.g., increased parental anxiety related to having had a previously affected pregnancy) is

unknown.



Recommendations of Other Groups



The American College of Obstetricians and Gynecologists (ACOG),8 the American Society of Human

Genetics,96,97 the American Academy of Pediatrics (AAP),98 the Canadian Task Force on the

Periodic Health Examination,99 and an international expert consensus conference11 have

recommended that MSAFP screening be offered to all pregnant women at 16-18 weeks' gestation,

provided that it is accompanied by adequate counseling and follow-up and is performed in areas

with qualified diagnostic centers (conventional and high-resolution ultrasound, amniocentesis)

and high-quality standardized laboratories. The Canadian Task Force also recommends that

high-resolution ultrasonography may be adequate for low-risk women.99 The AAP and ACOG

recommend that patients with a personal or family history of neural tube defects be offered

amniocentesis at 15-16 weeks' gestation with AFAFP testing.100 The recommendations of the

American Academy of Family Physicians (AAFP) on screening for neural tube defects are

currently under review.



The AAP,101 Canadian Task Force,99 and U.S. Public Health Service (USPHS)102 recommend

that all women of childbearing age who are capable of becoming pregnant take 0.4 mg of folic acid

daily to reduce the risk of having a pregnancy affected with a neural tube defect. The AAP,101

Canadian Task Force,99 ACOG,103 and the USPHS104 recommend that patients who have had a

previous pregnancy affected by a neural tube defect and who are planning to become pregnant

should be offered treatment with 4 mg of folic acid daily starting 1-3 months prior to planned

conception and continuing through the first 3 months of pregnancy. The recommendations of the

AAFP on folate supplementation for the prevention of neural tube defects are currently under

review.



Discussion



MSAFP is a sensitive screening test for neural tube defects. When positive results are followed by

appropriate diagnostic tests, such as high-resolution ultrasound, AFAFP and AFAChE, MSAFP is

highly specific as well. Early detection leads to a reduced birth prevalence of severely affected

fetuses and may reduce complications due to labor and delivery in affected infants. It can also detect

several other conditions, for some of which effective interventions exist. While MSAFP screening

is a relatively safe procedure, neural tube defects are relatively uncommon, and in certain

low-prevalence populations it is possible for the complication rate from screening and its

follow-up diagnostic tests to equal or exceed the detection rate for the target condition. Some have

expressed concern that the relatively small number of neural tube defects detected through

screening may not justify the potential risks of amniocentesis and parental anxiety for the large

majority of normal fetuses.32 The increased risk may, nevertheless, be acceptable to parents

with strong fears of having an abnormal child.105 Whether or not to receive MSAFP screening

therefore depends on the preferences of the individual patient, who must receive adequate

counseling regarding potential risks and benefits of screening before being screened in order to

make an informed decision. Ultrasonography performed by expert sonographers at major

screening centers also appears to be a sensitive and specific screening tool, but these findings may

not be generalizable to sonographers in other settings. Ultrasound has not yet been adequately

evaluated as a routine screening test for neural tube defects.



Identification and abortion of pregnancies affected by neural tube defects raises important ethical

concerns, a full discussion of which is beyond the scope of this chapter. These concerns include the

implicit message that having a neural tube defect is an undesirable state, the interpretation of

induced abortion in eugenic terms by some persons, and societal and economic pressures that may

stigmatize families with a member who has a neural tube defect. These issues highlight the

importance of offering screening and prenatal diagnosis of neural tube defects in a value-sensitive

fashion with emphasis on reliable information about the defects themselves as well as about the

potential risks and benefits of screening and diagnostic procedures.



For a woman who has had a previous pregnancy affected by a neural tube defect, there is good

evidence that folic acid supplementation begun at least 1 month prior to conception and continued

through the first trimester decreases the risk of recurrence. The only dosage adequately studied is

a daily supplement of 4 mg, although some evidence suggests that lower dosages may be effective.

For low-risk women who are planning pregnancy, a randomized controlled trial and several

observational studies indicate that periconceptional intake of multivitamin-multimineral or

multivitamin preparations containing 0.4-0.8 mg of folic acid can significantly reduce the risk of

first occurrence of neural tube defects. All of these studies indicate the need to start

supplementation at least 1 month before conception and to continue daily supplements through the

first 2 to 3 months of pregnancy. There is limited evidence that dietary folate intake of greater

than 0.1-0.3 mg/day reduces the risk of neural tube defects. No studies have directly compared

the effectiveness of multivitamins with folic acid to increased dietary folate intake for the

primary prevention of neural tube defects, but the evidence supporting use of multivitamins with

folic acid is of higher quality. The current estimated average daily consumption of only 0.2 mg of

dietary folate by American women aged 19-34 years77 suggests that achieving adequate dietary

intake may be more difficult for some women than taking supplements. It is unknown whether

women who already have a diet that meets or exceeds 0.4 mg/day of folate would gain additional

benefit from vitamin supplements. The effort required to assess dietary folate intake adequately

may outweigh the costs and potential harms from routine supplementation.



Since half of pregnancies in the U.S. are unplanned,106 all women capable of becoming pregnant

would need to take multivitamins with folic acid (or increase their dietary folate intake) to

maximize prevention of neural tube defects. It is likely that in the observational studies evaluating

the association between multivitamins with folic acid and reduced risk of neural tube defects,

many of the women evaluated had unplanned pregnancies, providing indirect evidence in support of

this intervention. The ability of clinicians to convince women not contemplating pregnancy that

they should take multivitamins with folic acid in order to prevent neural tube defects is unknown.

Many women of childbearing age who are not planning pregnancy may not take supplements or

pursue diets adequate in folate, particularly those who are poorer and less educated. Some

authorities suggest that food fortification with folate has greater potential to reach the entire

population at risk.101-111



The results of controlled trials indicate that folic acid supplementation will not prevent all neural

tube defects. The Centers for Disease Control and Prevention estimates that low-dose folic acid

supplementation of all women capable of pregnancy would reduce the incidence of neural tube

defects in the U.S. by 50%.102 Therefore, the use of periconceptional folic acid supplements does

not preclude offering screening for neural tube defects, although the cost-effectiveness of such

screening is likely to be reduced given a lower risk of occurrence.



CLINICAL INTERVENTION



The offering of screening for neural tube defects by maternal serum a-fetoprotein (MSAFP)

measurement at 16-18 weeks' gestation is recommended for all pregnant women who are seen for

prenatal care in locations that have adequate counseling and follow-up services, skilled

high-resolution ultrasound and amniocentesis capabilities, and reliable, standardized laboratories

("B" recommendation). Women with elevated MSAFP levels should receive a second confirmatory

test when time allows (i.e., before 18 weeks of gestation), and high-resolution ultrasound

examination by an adequately trained and experienced examiner before amniocentesis is

performed. Screening with MSAFP may be offered as part of multiple-marker screening (see

Chapter 41). There is currently insufficient evidence to recommend for or against the offering of

screening for neural tube defects by routine midtrimester ultrasound examination in pregnant

women ("C" recommendation). Recommendations may be made against such screening, except

when conducted by expert sonographers at major screening centers, based on its unproven

accuracy in other settings, the availability and proven effectiveness of MSAFP screening, and cost.

See Chapter 36 for additional recommendations regarding routine ultrasound examination in

pregnancy. Pregnant women at high risk of neural tube defects (e.g., those with a previous affected

pregnancy) should be referred to specialized centers for appropriate diagnostic evaluation,

including high-resolution ultrasound and amniocentesis.



Folic acid supplementation at a dose of 4 mg/day beginning 1-3 months prior to conception and

continuing through the first trimester is recommended for women planning pregnancy who have

previously had a pregnancy affected by a neural tube defect, to reduce the risk of recurrence ("A"

recommendation). It is also recommended that all women planning pregnancy take a daily

multivitamin or multivitamin-multimineral supplement containing folic acid at a dose of 0.4-0.8

mg, beginning at least 1 month prior to conception and continuing through the first trimester, to

reduce the risk of neural tube defects ("A" recommendation). Taking a daily multivitamin

containing 0.4 mg of folic acid is also recommended for all women capable of becoming pregnant, to

reduce the risk of neural tube defects in unplanned pregnancies ("B" recommendation). Women

taking drugs that interfere with folate metabolism (e.g., methotrexate, pyrimethamine,

trimethoprim, phenytoin), women at increased risk of vitamin B12 deficiency (e.g., vegans or

persons with AIDS), and those with epilepsy whose seizures are controlled by anticonvulsant

therapy, should consult with their clinician regarding potential risks and benefits prior to

considering folic acid supplementation. There is currently insufficient evidence to recommend for

or against counseling women planning or capable of pregnancy to increase their dietary folate

consumption to 0.4 mg/day as an alternative to taking multivitamins with folic acid ("C"

recommendation). Offering counseling to increase dietary folate intake to women who do not wish

to take folic acid supplements may be recommended on other grounds, including low risk, low cost,

and likely benefit.



The use of periconceptional multivitamins with folic acid does not necessarily obviate the need to

offer screening for neural tube defects during pregnancy, since not all defects will be prevented by

prophylaxis.



The draft update of this chapter was prepared for the U.S. Preventive Services Task Force by

Carolyn DiGuiseppi, MD, MPH, based in part on background material prepared by

Marie-Dominique Beaulieu, MD, MSc, and Brenda Beagan, MA, for the Canadian Task Force on the

Periodic Health Examination.



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