HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

Report as inappropriate Your report has been received

Shared by: joasiamimi

Similar articles in PubMed

Alert me to new issues of the journal

Download to citation manager

Citing Articles

Citing Articles via HighWire

Citing Articles via Google Scholar

Google Scholar
Articles by Neuhouser, M. L.

Articles by Monsen, E. R.

Search for Related Content

PubMed

PubMed Citation

Articles by Neuhouser, M. L.

Articles by Monsen, E. R.

Journal of the American College of Nutrition, Vol. 17, No. 6, 625-630 (1998)

Published by the American College of Nutrition

Absorption of Dietary and Supplemental Folate in Women with Prior Pregnancies with Neural Tube
Defects and Controls

Marian L. Neuhouser, PhD, RD, Shirley A.A. Beresford, PhD,, Durlin E. Hickok, MD, MPH, and Elaine R.
Monsen, PhD, RD

Interdisciplinary Graduate Program in Nutritional Sciences (M.L.N.), University of Washington,
Seattle

Fred Hutchinson Cancer Research Center (S.A.A.B.), University of Washington, Seattle

Departments of Epidemiology (S.A.A.B., D.E.H.), University of Washington, Seattle

Department of Obstetrics and Gynecology (D.E.H.), University of Washington, Seattle

Department of Health Services and Interdisciplinary Graduate Program in Nutritional Sciences
(E.R.M.), University of Washington, Seattle

Address reprint requests to: Marian L. Neuhouser, PhD, RD, Fred Hutchinson Cancer Research
Center, 1100 Fairview Ave. North, MP-702, PO Box 19024, Seattle, WA 98109-1024.
ABSTRACT

TOP

ABSTRACT

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION

REFERENCES

Background: The Public Health Service of the United States recommends that all women capable of
childbearing consume .4 mg (400 µg) folic acid per day to decrease the risk of having a pregnancy
affected by a neural tube defect such as spina bifida or anencephaly. Three strategies are available
to women to achieve this goal: use of dietary supplements; use of fortified foods; and/or increased
intake of naturally occurring folate from foods. Identification of the most effective vehicle for
delivery of folate to all women is critical in order to prevent these devastating congenital defects.

Objective: To investigate the difference in response to an oral load of folate both from naturally
occurring food sources and synthetic supplements among women with prior pregnancies affected by
neural tube defects and controls.

Methods: We compared the absorption of test doses of 400 µg pteroylglutamic acid (unconjugated
or synthetic folic acid found in supplements) and 400 µg pteroylpolyglutamic acid (conjugated or
food folate) in 10 women with a history of neural tube defect affected pregnancies and eight
controls with normal birth outcomes. The folate test dose was given as either 32 fluid ounces of
orange juice or a folic acid single supplement pill. All participants received each test dose at separate
clinic visits. The response to each test dose was measured by constructing an area under the curve
(AUC) from the serum folate levels at 1, 2 and 3 hours post dose and applying a t-test to compare
within and between cases and controls. We also compared red cell folate, vitamin B12, zinc and
homocysteine between cases and controls.
Results: Within group comparisons showed that the area under the curve was significantly greater
for the pteroylglutamic acid dose compared to the pteroylpolyglutamic acid dose for both cases and
controls (p=0.02 and p=0.03, respectively). In a between group comparison, control women had a
greater serum folate response to both forms of the vitamin compared to the case women, but the
difference reached statistical significance only for the pteroylglutamic acid dose (p=0.02). Other
measured nutrients differed between cases and controls, but did not reach statistical significance.

Conclusion: We conclude that for all women synthetic folic acid as supplements or fortified foods
may be the best way to increase acute folate levels in the blood, and thus delivery to the developing
embryo. Further, since case women had a diminished response to both forms of the vitamin, and
some case women had almost no response, we speculate that women with prior affected
pregnancies may need a larger dose of folate to elicit a plasma response equivalent to the general
population.

Key words: neural tube defects, folic acid, pregnancy, anencephaly, spina bifida, vitamins

INTRODUCTION

TOP

ABSTRACT

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION

REFERENCES

There is substantial epidemiological evidence that the vitamin folic acid helps to prevent the
occurrence and recurrence of neural tube defects such as spina bifida and anencephaly [1–6]. The
Public Health Service of the United States suggests that all women capable of childbearing consume
.4 mg (400 µg) folic acid per day in order to reduce the risk of a pregnancy complicated by a neural
tube defect [7]. Three strategies have been suggested to achieve this goal: 1) increase intake of
dietary folate from naturally occurring sources; 2) fortification of the food supply with folic acid; and
3) use of dietary supplements [7]. The second strategy, fortification of the food supply began on
January 1, 1998; cereal grains sold in the United States are now fortified with 140 µg of folic acid (as
pteroylglutamic acid) per 100 g of grain [8]. At this level of fortification, it has been estimated that
the average woman will increase her folic acid intake by approximately 100 µg per day, but total
folate intake will still be less than the recommended 400 µg/day [9]. Whether the balance of total
folate above that received through fortification should be derived from naturally occurring sources
(as pteroylpolyglutamic acid) or from supplements (as pteroylglutamic acid) is of much scientific and
public health interest. Availability of folate from food varies widely; for instance, an anti-folate factor
in beans and pulses may inhibit absorption of folate [10]. Additionally, exposure to heat and light
during cooking and storage can cause losses of folate from food [11,12]. The synthetic form of the
vitamin found in supplements, on the other hand, is relatively stable, and easily absorbed from the
gastrointestinal tract. With this in mind, individual folate status may depend on the source of folate
in the diet, not just on absolute amounts consumed. Brown and colleagues [13] found that women
who used vitamin supplement pills containing folic acid were able to increase their red cell folate to
levels associated with a decreased risk of neural tube defects [14]. The same outcome was not
achieved for women in the study who simply increased their dietary intake of folate [13]. This finding
concurs with the randomized trial results published by Cuskelly, showing that women who received
either folic acid supplements or folic acid fortified foods were able to significantly increase their red
cell folate levels, but those who received folate rich foods and dietary advice were not able to do so
[15]. In sum, these studies have shown that supplemental folic acid as pteroylglutamic acid is more
effective at increasing red cell folate levels than naturally occurring food sources of folate.

While red cell folate levels may be useful for predicting long-term folate status, nutrient delivery to
the embryo occurs via the mother’s plasma, and as such, acute maternal plasma levels may have a
more profound impact on neural tube closure. Indeed, in animal models, short-term folate
deficiency results in congenital malformations in the offspring [16]. Therefore, we sought to
determine if there was a difference in plasma response to folate from food with that from
supplements, among cases and controls, that may impact availability of the vitamin to the embryo.

MATERIALS AND METHODS

TOP

ABSTRACT

INTRODUCTION

MATERIALS AND METHODS

RESULTS
DISCUSSION

CONCLUSION

REFERENCES

Ten women who had a pregnancy resulting in either anencephaly or spina bifida during the years
1991–1993, and who resided in either King or Snohomish County, Washington at the time of the
pregnancy were cases in this study, recruited using population-based methods described below. The
mean age of case women was 30 years (SD=5.5). Women with liveborn or stillborn infants, or
terminated pregnancies were eligible and participated. However, only isolated neural tube defects
were considered; women whose fetuses or infants had multiple congenital anomalies, or abnormal
karyotypes were excluded.

There is no active birth defects registry in the state of Washington. Population-based recruitment of
cases, therefore, required that several strategies be used. We asked obstetrician/gynecologists at
the two major tertiary referral hospitals in Seattle to identify all cases of isolated neural tube defects
during the years 1991–1993. In addition, we asked the Chief of Birth Defects at Children’s Hospital
and Medical Center in Seattle to identify all new cases of spina bifida between 1991–1993. Finally,
we placed an article describing the study and asking for volunteers in the bi-monthly newsletter of
the Spina Bifida Association of Puget Sound. We believe that by using all of these sources we
identified greater than 95% of all cases of neural tube defects in King and Snohomish Counties,
Washington in the years of interest; we estimated this number to be 34 distinct cases. We verified
these estimates from medical records with a count of neural tube defect cases from Washington
state birth certificate tapes and hospital admissions records.

Eight women from King and Snohomish counties with normal birth outcomes between 1991–1993
and no prior pregnancies affected by a neural tube defect participated as controls. The mean age of
the control women was 36 years (SD=3.0). Controls were recruited using a combination of
population-based methods [17] and word of mouth invitation to employees of the University of
Washington and the Fred Hutchinson Cancer Research Center.

Women were excluded if they were pregnant, or planning a pregnancy within 3 months of study
enrollment, had a diagnosed disease thought to interfere with folate absorption or metabolism such
as Crohn’s disease or Diabetes Mellitus [18], or used medication that could interfere with folate
absorption or metabolism such as sulfasalazine or valproate [19]. Additionally, participants were
asked to refrain from all multivitamin use for 4 weeks prior to enrollment, and throughout the
duration of the investigation.
This study was approved by the University of Washington Human Subjects Review Committee, and
by the Institutional Review Boards of Children’s Hospital and Medical Center, Fred Hutchinson
Cancer Research Center, and Swedish Medical Center. Written informed consent was obtained from
all study participants.

All enrolled women came to the General Clinical Research Center at the University of Washington for
the oral folate challenges; once for a challenge with orange juice (32 fluid ounces Minute Maid®,
prepared in the research kitchen as reconstituted from frozen), and once for a challenge with the
supplement pill (Nature’s Made® single supplement taken with 8 fluid ounces of water). We
randomized participants for their test order, and each test was approximately 4 weeks apart.

Participants arrived fasting at the Clinical Research Center, and a registered nurse immediately drew
blood to measure red blood cell folate and serum vitamin B12 (on the first clinic visit), and serum
folate and serum zinc (on both clinic visits). We also measured total plasma homocysteine in a
subsample of women. Then, we gave each participant her test dose of 400 µg folic acid. No other
food or beverages were permitted during the testing period.

Blood was again drawn at 1, 2 and 3 hours post test dose to measure the change in serum folate,
and as an assessment of absorption, an area under the curve was calculated [20]. Additionally, each
participant completed a previously validated food frequency questionnaire [21] to assess dietary
intake of folate and other nutrients over the previous 3 months, and a medical history form which
included questions on current smoking practices, alcohol use and reproductive history.

Red blood cell folate, serum folate and serum vitamin B12 were all assayed with the Bio-Rad
Radioimmunoassay kit (Bio-Rad Quantaphase, Bio-Rad Laboratories Diagnostics Group, Hercules,
CA), and the Packard RIASTAR gamma counting system. The homocysteine assay was a modification
of the monobromobimane derivitization method and high performance liquid chromatography
(HPLC). Zinc was measured by atomic absorption spectrophotometry.

We used the University of Minnesota’s Nutrition Coding Center nutrient database to analyze the
food frequency questionnaires [21], and SPSS® (version 7.5 for Windows©, Chicago, 1997) for all
statistical analyses [22]. We used the natural logarithmic transformation of the fasting red cell folate,
serum folate and vitamin B12 to normalize the distributions, and then back transformed the logged
values to obtain geometric means. The logged values were compared using the t-test for
independent samples. Since log transformation did not improve the distribution of zinc, we used the
Mann Whitney U test to compare zinc between cases and controls. The principal outcome measure
was the response to the oral folate challenges; an area under the curve beyond the fasting values
was calculated for each type of challenge (food and supplement) using the equation:
AUC=[T0+T1+T2+T3]-(3T0), where T0=fasting serum folate, T1=serum folate one hour post-
challenge, T2=serum folate two hours post challenge, and T3=serum folate three hours post
challenge. Any missing values for the serum folates challenges were replaced by the calculation of
linear trend at point method. The SPSS® program replaces the missing values with their predicted
values [22]. We used this methodology with three participants who had one missing value each due
to hemolysed specimens. There was one participant with two missing values for the challenge with
the pteroylpolyglutamic acid; she was not included in the analysis for this test.

Each area under the curve was log transformed, and compared by the t-test for independent
samples for between group comparisons, and by the t-test for paired samples for within group
comparisons. Values in tables are back transformed and presented in original units.

RESULTS

TOP

ABSTRACT

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION

REFERENCES

All eighteen women recruited for the study completed the entire protocol; there were no dropouts.

Demographic characteristics of the study sample are in Table 1. There was a significant difference in
age (p=0.01) and education (p=0.03) between cases and controls. In spite of these differences,
neither age nor education were considered to be confounders in the analysis for the following
reasons. Previous studies have not shown a consistent association between maternal age and risk
for neural tube defects. Some investigations, for instance, have suggested that a U-shaped
relationship exists between maternal age and NTD risk [23], while others have shown there is no
increased risk with age after controlling for parity [24]. Further, in consideration of the outcome of
interest in this study, absorption of pteroylglutamic acid and pteroylpolyglutamic acid, Bailey
showed in 1984 that intestinal absorption of folate does not vary by age in adults [25]. While the
controls had significantly more education than the cases, all study subjects had at least 12 years of
education, and none were of low-socioeconomic status. All other demographic variables were
similar between the two groups.

View this table:

[in this window]

[in a new window]

Table 1. Demographic Characteristics of 10 Women with a History of Neural Tube Defect Affected
Pregnancies and Eight Controls

Table 2 shows that for fasting blood nutrient determinations, case women had somewhat lower
levels than control women for both red cell folate (206±67 ng/ml vs. 284±127 ng/ml; p=0.09) and
serum folate (6.5±3 ng/ml vs. 10.2±5 ng/ml; p=0.06). The serum folate levels presented are the
mean of the fasting serum folate measurements taken at each visit for each participant. Vitamin B12
was also lower among cases than controls (433±145 pg/ml vs. 511±126 pg/ml), although the
difference was not statistically significant (p>0.10), perhaps because of small sample size. Zinc is
necessary for proper absorption of food folate, but there was no difference in serum zinc (mean of
the serum zinc levels at each visit for each participant) between cases and controls (82±15 µg/dl vs.
83±8 µg/dl; p>0.10). Our dietary analysis also showed no significant differences between cases and
controls with regard to usual dietary intake of folate, but interestingly, both groups on average
consumed far less than the US Public Health Service’s Recommendation of 400 µg per day (219±118
µg day for the cases and 257±96 µg day for the controls). Finally, there was no apparent difference
in homocysteine between cases and controls among the subset of women for whom we tested
(results not shown).
View this table:

[in this window]

[in a new window]

Table 2. Comparison Between Fasting Blood Levels of Nutrients in 10 Women with a History of
Neural Tube Defect Affected Pregnancies and Eight Controls

Using the area under the curve (minus the fasting serum folate level) as a measure of response to
the folate test doses, the controls had a somewhat larger but non-significant response to the oral
challenge with the pteroylpolyglutamic acid (orange juice) compared to the cases; 6.9±2.6 ng/ml for
the cases and 9.6±4.2 ng/ml for the controls; p=0.10. On the other hand, the response area under
the curve for the pteroylglutamic acid (supplement pill) for the controls was 15.3±5.6 ng/ml, and for
the cases it was 9.1±4.4 ng/ml, a difference which reached statistical significance (p=0.02). These
results are shown in Table 3 and displayed graphically in Fig. 1.

View this table:

[in this window]

[in a new window]

Table 3. Serum Folate Response to an Oral Challenge of Folic Acid in 10 Women with a History of
Neural Tube Defect Affected Pregnancies and Eight Controls (Between Group Response)
View larger version (68K):

[in this window]

[in a new window]

Fig. 1. ean serum response to oral challenges of pteroylglutamic acid and pteroylpolyglutamic acid
among cases and controls.

In a within group comparison presented in Table 4, both cases and controls had a significantly larger
response to pteroylglutamic acid (supplement pill) compared to pteroylpolyglutamic acid (orange
juice) using a paired t-test (p=0.02 for cases and p=0.03 for controls). Of interest is that the response
(AUC) of the cases to the supplemental folic acid±4.4 ng/ml) was similar to the response of the
controls to the food folate (9.6±4.2 ng/ml).

View this table:

[in this window]

[in a new window]

Table 4. Serum Folate Response to an Oral Challenge of Supplemental Folic Acid vs. Dietary Folate
in Ten Women with a History of Neural Tube Defect Affected Pregnancies and Seven Controlsa
(Within Group Response)

We found no differences in the response to the tests when we separated our controls into two
groups (those recruited through population based methods, and those who were either University of
Washington or Fred Hutchinson Cancer Research Center employees), as numbers were not
sufficiently large to test differences between recruitment methods.

DISCUSSION

TOP

ABSTRACT

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION

REFERENCES

This is the first study known to compare the absorption of pteroylglutamic acid to
pteroylpolyglutamic acid in women with a history of neural tube defect affected pregnancies vs.
controls. Previous absorption studies have evaluated only the absorption of pteroylpolyglutamic acid
between cases and controls with inconsistent results [26,27]. On the other hand, the observational
and experimental studies demonstrating the protective effect of folic acid against the formation of
neural tube defects have focused mainly on supplemental folic acid [1–6]. Case-control studies of
neural tube defects examining the protective effect of food folate have found weak associations
[27,28].

We have shown that women generally have a larger serum response to folic acid from supplements
compared to food folate. The finding we did not expect was that control women with normal birth
outcomes had a greater response to both forms of the vitamin, and a statistically significant greater
response to the oral challenge with the supplement pill compared to the case women with a history
of neural tube defect affected pregnancies (p=0.02). Fig. 1 shows the response curves for both cases
and controls for each form of the vitamin. We note that the shape of the response curve of the cases
to the pteroylglutamic acid, which is presumably absorbed more easily, is similar to the response
curve of the controls to naturally occurring food folate. In addition, among the case women in our
study, there were four (40%) who had no appreciable plasma response to either form of the vitamin
at the 400 µg dose level. This suggests that some women with a history of neural tube defect
affected pregnancies have a compromised ability to access both naturally occurring folate as well as
synthetic folate.
There are several limitations to our study. There is likely some selection bias in the recruitment of
our study participants, both cases and controls. We had a limited pool of women who were able to
participate in this study, thus restricting our ability to generalize the results. Similarly, our small
sample size of 18 participants may have prevented our finding clear statistically significant
differences between cases and controls for red cell folate, fasting serum folate and vitamin B12 in
spite of apparent differences. Finally, our study did not measure any metabolic variables that may
influence folate response, such as 5,10-methylenetetrahydrofolate reductase genotype.

CONCLUSION

TOP

ABSTRACT

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION

REFERENCES

While we are uncertain of the clinical and public health implications of our study findings, we can
only speculate regarding the importance of a differential response to an oral load of folate among
case and control women. For instance, is there a critical plasma folate level that must be reached in
the mother for optimal delivery to the embryo? Is the smaller area under the curve seen among the
cases in our study below this critical value? Further, would the response of the cases be different
with a larger dose of folate? Several studies have demonstrated that low serum folate and/or
elevated homocysteine can be corrected with pharmacological doses of synthetic folic acid [29–31].
Additional research with our study participants, and with other women who have had neural tube
defect affected pregnancies would help to answer these questions.

In conclusion, since folic acid as pteroylglutamic acid elicits a larger serum response in all the women
in our study, we recommend that this form of the vitamin (as supplements) be used by women of
childbearing potential in conjunction with fortified foods to reach the 400 µg/day goal. There may be
subgroups in the population who require additional folate. This position is consistent with the
publication, "Dietary Reference Intakes for Thiamin, Riboflavin, Niacin Vitamin B6, Folate Vitamin
B12, Pantothenic Acid Biotin and Choline" [32], in which the National Academy of Sciences
recommends that all women capable of childbearing consume 400 µg folic acid per day (as
pteroylglutamic acid from supplements and fortified foods) in addition to naturally occurring sources
of folate. Given that most women currently consume less than 400 µg folate per day from all
sources, education programs are necessary to teach women about the most effective sources of the
vitamin (supplements and fortified foods) and how to increase total folate intake. Additionally, an
increase in the level of folic acid fortification of enriched flour and grain products may be
considered.

ACKNOWLEDGMENTS

This research was supported by the University of Washington’s Royalty Research Fund Grant #608.
The authors also wish to thank the General Clinical Research Center at the University of Washington
Medical Center; the Clinical Nutrition Research Unit Core Laboratory (supported by NIH Grant
#DK35816); the University of Washington Department of Hematology; David B. Shurtleff, MD,
William Graf, MD, David Luthy, MD, Edith Cheng, MD, Bob Resta; the Spina Bifida Association of
Puget Sound, Bill O’Brien and Don Martin.

FOOTNOTES

M.L. Neuhouser, PhD, RD is currently a Post Doctoral Fellow at Fred Hutchinson Cancer Research
Center.

Received October 1, 1997. Accepted May 1, 1998.

REFERENCES

TOP
ABSTRACT

INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION

REFERENCES

MRC Vitamin Study Research Group: Prevention of neural tube defects: results of the medical
research council vitamin study. Lancet 338: 131–137, 1991.[Medline]

Czeizel AE, Dudas I: Prevention of the first occurrence of neural tube defects by periconceptional
vitamin supplementation. N Engl J Med 327: 1832–1835, 1992.[Medline]

Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, Willett W: Multivitamin/folic acid
supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 262:
2847–2852, 1989.[Abstract/Free Full Text]

Mulinare J, Cordero JF, Erikson JD, Berry RJ: Periconceptional use of multivitamins and the
occurrences of neural tube defects. JAMA 260: 3141–3145, 1988.[Abstract/Free Full Text]
Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA: Preconceptional vitamin use, dietary folate
and the occurrence of neural tube defects. Epidemiology 6: 219–226, 1995.[Medline]

Werler MM, Shapiro S, Mitchell AA: Periconceptional folic acid exposure and risk of occurrent neural
tube defects. JAMA 269: 1257–1261, 1993.[Abstract/Free Full Text]

Centers for Disease Control: Recommendations for the use of folic acid to reduce the number of
cases of spina bifida and neural tube defects. MMWR 41(No. RR-14): 1, 1992.

Food Standards: Amendment of standards of identity for enriched grain products to require addition
of folic acid. Federal Register 61(44) 8797, 1996.

Oakley GP, Adams MJ, Dickinson CM: More folic acid for everyone, now. J Nutr 126: 751S–755S,
1996.

Krumdieck CL, Neman AJ, Butterworth R: A naturally occurring inhibitor of folic acid conjugase
(pteroyl-polyglutamate hydrolase) in beans and other pulses. Am J Clin Nutr 26: 460–461, 1973.

Hawkes JG, Villota R: Folates in foods: reactivity stability during processing, and nutritional
implications. Crit Rev Food Sci Nutr 28: 439–538, 1989.[Medline]

Ristow KA, Gregory JF 3rd, Damron BI: Thermal processing on folacin bioavailability in liquid model
food systems, liver and cabbage. J Agric Food Chem 30: 801–806, 1982.[Medline]
Brown JE, Jacobs DR Jr, Hartman TJ, Barosso GM, Stang JS, Gross MD, Zeuske MA: Predictors of red
cell folate level in women attempting pregnancy. JAMA 277: 548–552, 1997.[Abstract/Free Full Text]

Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM: Folate levels and neural tube defects. Implications
for Prevention. JAMA 27: 1698–1702, 1995.

Cuskelly GJ, McNulty H, Scott JM: Effect of increasing dietary folate on red cell folate: implications
for prevention of neural tube defects. Lancet 347: 657–659, 1996.[Medline]

Nelson MM, Wright HW, Asling CW, Evans HM: Multiple congenital abnormalities resulting from
transitory deficiency of pteroylglutamic acid during gestation in the rat. J Nutr 56: 349–369, 1955.

Schlesselman JJ: "Case Control Studies: Design, Conduct and Analysis." New York: Oxford University
Press, 1982.

Lashner BA, Provencher KS, Seidner DL: The effect of folic acid supplementation on the risk for
cancer or dysplasia in ulcerative colitis. Gastroenterology 112: 255–259, 1997.[Medline]

Anonymous: Valproate spina bifida and birth defect registries. Lancet 2: 1404, 1988.[Medline]
Matthews JNS, Altman DG, Campbell MJ, Royston P: Analysis of serial measurements in medical
research. BMJ 300: 230–235, 1990.

Kristal AR, Shattuck AL, Williams A: Food frequency questionnaires for diet intervention research.
Proceedings of the 17th National Nutrient Databank Conference. 1992 June 7–10; Baltimore, MD.
Washington, DC: International Life Sciences Institute, pp 110–125, 1994.

Little J, Elwood JM: Epidemiology of neural tube defects. In Kiely M (ed): "Reproductive and Perinatal
Epidemiology." Boca Raton: CRC Press, 1991.

Fedrick J: Anencephalus: variation with maternal age, parity, social class and region in England,
Scotland and Wales. Ann Hum Genet 34: 31–38, 1970.[Medline]

Bailey LB, Cerda JJ, Bloch BS, Busby MJ, Vargas L, Chandler CJ, Halsted CH: Effect of age on poly and
monogluatamate folacin absorption in human subjects. J Nutr 114: 1770–1776, 1984.

Bower C, Stanley FJ, Croft M, DeKlerk NH: Absorption of pteroylpolyglutamates in mothers of infants
with neural tube defects. Br J Nutr 69: 827–834, 1993.[Medline]

Schorah CJ, Habibzadeh N, Wild J, Smithells RW, Seller MJ: Possible abnormalities of folate and
vitamin B12 metabolism associated with neural tube defects. Ann NY Acad Sci 678: 81–91,
1993.[Medline]
Bower C, Stanley FJ: Dietary folate as a risk factor for neural tube defects: evidence from a case-
control study in Western Australia. Med J Aust 150: 613–619, 1989.[Medline]

Brattstrom LE, Israelsson B, Jeppsson JO, Hultberg BL: Folic acid: an innocuous means to reduce
plasma homocysteine. Scand J Clin Lab Invest 48: 215–221, 1988.[Medline]

Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ, Delport R, Potgieter H: Vitamin requirements
for the treatment of hyperhomocysteinemia in humans. J Nutr 124: 1927–1933, 1994.

Ubbink JB, van der Merwe A, Vermaak WJH, Delport R: Hyperhomocysteinemia and the response to
vitamin supplementation. Clin Invest 71: 993–998, 1993.

"Food and Nutrition Board," Dietary Reference Intakes or Thiamin, Riboflavin, Niacin, Vitamin B6,
Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. Washington DC: National Academy of
Sciences, 1998 (In press).

This article has been cited by other articles:
C. A. M. Anderson, S. H. Jee, J. Charleston, M. Narrett, and L. J. Appel

Effects of Folic Acid Supplementation on Serum Folate and Plasma Homocysteine Concentrations in
Older Adults: A Dose-Response Trial

Am. J. Epidemiol., October 15, 2010; 172(8): 932 - 941.

[Abstract] [Full Text] [PDF]

--------------------------------------------------------------------------------

T. G.K. Bentley, W. C. Willett, M. C. Weinstein, and K. M. Kuntz

Population-Level Changes in Folate Intake by Age, Gender, and Race/Ethnicity after Folic Acid
Fortification

Am J Public Health, November 1, 2006; 96(11): 2040 - 2047.

[Abstract] [Full Text] [PDF]

--------------------------------------------------------------------------------

A. M Molloy

Is impaired folate absorption a factor in neural tube defects?

Am J Clin Nutr, July 1, 2000; 72(1): 3 - 4.
[Full Text] [PDF]

--------------------------------------------------------------------------------

A. M Boddie, E R. Dedlow, J. A Nackashi, F J. Opalko, G. P. Kauwell, J. F Gregory III, and L. B Bailey

Folate absorption in women with a history of neural tube defect-affected pregnancy

Am J Clin Nutr, July 1, 2000; 72(1): 154 - 158.

[Abstract] [Full Text] [PDF]

--------------------------------------------------------------------------------

This Article

Abstract

Figures Only

Full Text (PDF)

Services