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Original Research Communications |
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: We assessed the effects of dietary and supplemental folate intakes during extended lactation.
Design: Lactating women (n = 42) were enrolled in a double-blind, randomized, longitudinal supplementation trial and received either 0 or 1 mg folic acid/d. At 3 and 6 mo postpartum, maternal folate status was assessed by measuring erythrocyte, plasma, milk, and dietary folate concentrations; plasma homocysteine; and hematologic indexes. Infant anthropometric measures of growth, milk intake, and folate intake were also assessed.
Results: In supplemented women, values at 6 mo for erythrocyte and milk folate concentrations and for plasma homocysteine were not significantly different from those at 3 mo. In supplemented women compared with unsupplemented women at 6 mo, values for erythrocyte folate (840 compared with 667 nmol/L; P < 0.05), hemoglobin (140 compared with 134 g/L; P < 0.02), and hematocrit (0.41 compared with 0.39; P < 0.02) were higher and values for reticulocytes were lower. In unsupplemented women, milk folate declined from 224 to 187 nmol/L (99 to 82 ng/mL), whereas plasma homocysteine increased from 6.7 to 7.4 µmol/L. Dietary folate intake was not significantly different between groups (380 ± 19 µg/d) and at 6 mo was correlated with plasma homocysteine in unsupplemented women (r = -0.53, P < 0.01) and with plasma folate in supplemented women (r = 0.49, P < 0.02).
Conclusions: A dietary folate intake of 
380 µg/d may not be sufficient to prevent mobilization of maternal folate stores during lactation.
Key Words: Lactation • plasma folate • erythrocyte folate • milk folate • dietary folate intake • plasma homocysteine • women
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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15% of women show signs of suboptimal folate status as evidenced by low serum and erythrocyte folate concentrations (<6.8 and <340 nmol/L, respectively) (2).
Substantial evidence now exists establishing a relation between enhanced folate intake during the periconceptual period and the prevention of neural tube defects (3, 4). Neural tube defects are among the most common birth defects in the United States and affect 1 in 1000 infants (5). Compromised maternal folate status during pregnancy is also linked to low birth weight (6) and abruptio placentae (7) and to disorders that affect maternal health. Low folate status is associated with cellular dysplasia, often the predecessor of cancerous lesions in the epithelial layer of the cervix and colon (8), and elevated plasma homocysteine, a functional index of diminished folate status that is an independent risk factor for cardiovascular disease (9).
Although the requirement for folate during pregnancy has been studied extensively (10), folate needs for sustaining lactation are less well established (11). Most of our knowledge of the folate requirement of lactating women has been obtained indirectly from measurements of the amount of folate secreted in milk and from estimated maintenance requirements of the mother, which are assumed to be similar to those of nonreproducing women. Functional or health outcomes of various folate intakes during lactation are rarely examined (12).
A review of the literature indicates that apparently healthy women can become folate depleted in the early postpartum period (13). Milk folate content can be maintained at a level that prevents the development of folate inadequacy in exclusively breast-fed infants, but often at the expense of maternal folate stores. During lactation, folate is preferentially taken up by actively secreting mammary glands, and only in the case of frank maternal folate deficiency is milk folate reported to decline to critically low concentrations (14).
The incremental folate need for milk secretion was previously based on the assumption that the folate content of human milk averages 113 nmol/L (15); recent evidence from our laboratory indicates that this value was underestimated (16). After trienzyme treatment, typical folate concentrations of human milk range from 159 to 227 nmol/L (70–100 ng/mL) and average 195 nmol/L (86 ng/mL).
In this investigation, we studied women longitudinally during extended lactation and provided 0 or 1 mg folic acid (pteroylglutamic acid) daily in a double-blind, randomized fashion. Maternal folate status was assessed by using dietary, hematologic, and biochemical indexes. Measures of milk intake and infant growth were used as indexes of lactational performance.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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6 mo, no unusual dietary practices, not using oral contraceptives, and willing to comply with the experimental protocol. The use of human subjects in this investigation was approved and reviewed annually by the Institutional Review Board, Office of Regulatory Compliance, Pennsylvania State University. Informed, written consent was obtained from all women.
Preliminary study
Because we were unaware of any reported values for plasma homocysteine concentrations of lactating women, before the start of the double-blind study, 10 women were recruited to establish normative values for plasma homocysteine under conditions of nutritional adequacy. These subjects were given a multivitamin and mineral supplement (Materna; Lederle Laboratories, Pearl River, NY) providing 12 µg vitamin B-12, 10 mg vitamin B-6, and 1 mg folic acid/d starting at 3 mo postpartum for 3 mo. A multivitamin supplement was chosen because, in addition to folate, vitamins B-6 and B-12 are known to influence plasma homocysteine concentrations (17).
Experimental design
A double-blind, randomized, longitudinal supplementation trial with 42 lactating women was conducted. Assignment of subjects to groups was balanced for parity. All subjects received a multivitamin and mineral supplement (Liquid Centrum; Lederle Laboratories) and either 1 mg folic acid/d or a placebo tablet containing 0 mg folic acid/d (West-ward Pharmaceutical Corporation, Eatontown, NJ). The multivitamin and mineral supplement provided 2500 IU vitamin A as retinyl palmitate, 60 mg vitamin C, 400 IU vitamin D as ergocalciferol, 30 IU vitamin E as all-rac-
tocopheryl acetate, 1.5 mg thiamine, 1.7 mg riboflavin, 20 mg niacinamide, 2 mg vitamin B-6, 6 µg vitamin B-12, 300 µg biotin, 10 mg pantothenic acid, 9 mg Fe, 150 µg I, 3 mg Zn, 2.5 mg Mn, 25 µg Cr, and 25 µg Mo. Folic acid tablets were indistinguishable from placebo tablets. Multivitamin and mineral and folic acid or placebo preparations were provided in monthly allotments for the purpose of monitoring subject compliance. Compliance was defined as successfully taking 80% of the monthly allotment.
At 3 mo postpartum (baseline, before the start of supplementation) and at 6 mo postpartum (after 3 mo of supplementation), samples of breast milk and blood were collected and maternal diets were assessed. Measures of infant growth (weight, recumbent length, and head circumference) and milk intake were collected concurrently at 3 and 6 mo postpartum. All biological samples were handled under gold light to prevent photooxidization of folate and were stored at -70°C until analyzed.
Methods
Blood analyses
About 4 mL blood was drawn into tubes containing EDTA. A complete blood count and a differential smear were performed by using an electronic hematology analyzer (Max M model; Coulter Corporation, Miami). Measurements of hemoglobin, hematocrit, mean corpuscular volume, neutrophil hypersegmentation, and reticulocytes were included in the hematologic assessment. Neutrophil hypersegmentation was defined as a neutrophil lobe count >3.5. Hypersegmentation of neutrophils is a functional measure of abnormal folate metabolism (18). Portions of whole blood were frozen with 0.1 mol phosphate buffer/L containing 0.05 mol ascorbate/L for erythrocyte folate analysis. Plasma was separated from the remaining blood and frozen for folate and homocysteine analyses. Plasma and erythrocyte folate were measured by a microbiological assay with Lactobacillus casei (ATCC 7469) as the test organism (19). Plasma homocysteine was measured by HPLC according to the method of Araki and Sako (20), with some modifications. To measure non-protein-bound homocysteine, samples were mixed with 0.6 mol perchloric acid/L and then centrifuged at 1000 x g for 10 min at room temperature to precipitate plasma proteins.
Milk folate analysis
Complete breast expression was used to collect milk samples (15–30 mL) by manual means or with the assistance of a mechanical pump (Marshall Baby Care Products, Lincolnshire, IL; Ross Laboratories, Columbus, OH; or Evenflo Products, Ravenna, OH). Samples were stored with ascorbate to achieve a final concentration of 0.05 mol ascorbate/L. Data from our laboratory showed an 85% increase in measurable human milk folate after samples are treated with -amylase (EC 3.2.1.1) and mycolysin (EC 3.4.24.31) in addition to folate conjugase (
-Glu-X carboxypeptidase, EC 3.4.19.9) (16). Trienzymatic treatment is now recognized for its merit in enhancing the measurement of folate in foods (21–23), but had not been previously applied to human milk samples. Before microbiological assays were performed, milk samples were incubated with -amylase (type X-A; Sigma Chemical Co, St Louis), mycolysin (type XIV), and rat serum folate conjugase (Harlan Bioproducts, Indianapolis) at 37°C in a stepwise procedure for 4, 8, and 3 h, respectively. Milk samples were heat-treated in 0.1 mol phosphate buffer/L containing 0.05 mol ascorbate/L, pH 4.1, by boiling at 100°C for 5 min. The milk folate content was measured in a microbiological assay with L. casei as the test organism (19).
Dietary folate intake
Before 2-d food records were collected, subjects received instruction in accurately describing and quantifying their usual intake. Participants were instructed to use a 2-dimensional Food Portion Visual (Nutrition Consulting Enterprises, Framingham, MA) to aid in estimations of portion sizes. Dietary data were analyzed at the Diet Assessment Center at the Department of Nutrition, Pennsylvania State University. Nutrient intakes were tabulated by using NUTRITION DATA SYSTEM software (nutrient database version 24, food database version 9A; Nutrition Coordinating Center, University of Minnesota, Minneapolis). Folate intake was expressed as a 2-d average of recorded dietary intake at 3 and 6 mo postpartum. Complete nutrient profiles are reported elsewhere (24); folate intakes are reported here according to group assignment.
Anthropometry
Weight, recumbent length, and head circumference of infants were measured by using an electronic balance (Detecto Scale Company, Webb City, MO), a pediatric length-measuring board (Ellard Instrumentation Ltd, Seattle), and measuring tape (Ross Laboratories), respectively. Measures of infant growth were used as objective indexes of successful lactation. Self-reported heights and weights of mothers were obtained at entry to the study.
Infant milk and folate intakes
The daily milk intake of infants was measured by 24-h test weighing. Mothers were provided with an electronic balance (Detecto Scale Company) and instructed in proper weighing procedures. Infants were weighed before and after each feeding for 3 consecutive days. Milk intake was expressed as a 3-d average. With the introduction of foods other than breast milk, food records were used to assess infant nutrient intakes. By using data on milk intake and corresponding folate content, infant folate intakes were calculated.
Statistical analyses
SAS for WINDOWS (version 6.12, 1996; SAS Institute Inc, Cary, NC) was used for data tabulation and statistical analyses (25). Group differences were analyzed by analysis of variance (ANOVA) and covariance (ANCOVA) with repeated measures. Group (plus or minus folic acid) and time (3 and 6 mo) were treated as main effects, with a group by time interaction. Prenatal supplementation and parity were entered as covariates. One-way ANOVA was used to assess changes in biochemical and hematologic indexes and dietary folate intake within groups over time and between groups at one time point. Correlation analyses were used to determine associations among maternal indexes of folate status, dietary folate, supplemental folic acid, parity, and prenatal supplementation. A P value <0.05 was chosen as the level of significance. All values in the text, tables, and figures are presented as means ± SEMs.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The subjects' ages ranged from 26 to 42 y (
: 34 y). Mean maternal weight (67 ± 3 kg), body mass index (BMI; in kg/m2: 25 ± 1), and parity (parity = 2) were not significantly different between groups, nor was folate intake from prenatal supplements, which averaged 0.9 mg/d. Of the 42 women studied, all were white and only 11 did not take prenatal supplements during pregnancy and in the early postpartum period before enrollment. Prenatal supplements used by women included Prenatal Plus (Rugby, Norcross, GA), Zenate (Solvay Pharmaceuticals, Marietta, GA), StuartNatal (Stuart, Atlanta), and Prenate-90 (Bock Pharmacal, St Louis), all of which provided 1 mg folic acid/d, and a variety of generic preparations that provided between 0.4 and 0.8 mg folic acid/d. Women enrolled were fairly well educated (16 ± 0.5 y of education) and were from middle- to high-income households as indicated by a mean socioeconomic score of 72 (26).
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Maternal measures
All measures used to assess the effect of enhanced folate intake during lactation are presented in Table 2. Baseline measures were made at 3 mo postpartum and after 3 mo of supplementation with folate (6 mo postpartum). No significant differences were noted between groups for any measure at 3 mo, with the exception of milk folate. Higher milk folate values were observed in unsupplemented women than in supplemented women. Neither parity nor prenatal supplementation was a significant variable for any of the outcomes measured in this investigation.
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). Dietary folate intakes were not significantly different between groups at either 3 or 6 mo. Folate intake at 6 mo was positively correlated with intakes at 3 mo (r = 0.69, P < 0.001).
Biochemical indexes
Supplemental folate had no significant effect on plasma folate values. Even though differences were not significantly different, mean plasma folate concentrations in the supplemented group (47.6 ± 6.5 nmol/L) were 10.8 nmol/L higher than those in the unsupplemented group (36.8 ± 4.2 nmol/L; Table 2). However, mean erythrocyte folate concentrations did respond significantly to folate supplementation. Values were higher at 6 mo in women receiving 1 mg supplemental folate/d than in unsupplemented women (P < 0.05). Both plasma and erythrocyte folate at 6 mo were positively associated with values at 3 mo (r = 0.35, P < 0.02, and r = 0.45, P < 0.01, respectively). Plasma folate was not associated with dietary folate at 3 mo but was at 6 mo (r = 0.38, P < 0.01).
In all but 2 women, values for plasma homocysteine (Table 2) were similar to values found in the preliminary study and well below the cutoff for hyperhomocysteinemia [<15 µmol/L (28)]. The 2 elevated values for plasma homocysteine (15.5 and 18.5 µmol/L) were noted at 6 mo in women who were receiving supplemental folate. Because all women also received 2 mg vitamin B-6 and 6 µg vitamin B-12, these elevated values were unrelated to vitamin intake. A time effect was noted for plasma homocysteine (P < 0.05). Within-group analysis showed that the increase in plasma homocysteine from 3 to 6 mo was significant in the unsupplemented group (P < 0.05), but not in the folate-supplemented group. Plasma homocysteine values at 6 mo were associated with values at 3 mo in both groups (r = 0.52, P < 0.01). In folate-supplemented women only, plasma homocysteine was inversely related to plasma folate at 6 mo (r = -0.53, P < 0.01). There also was an inverse relation between plasma homocysteine and dietary folate intake at 6 mo in women not receiving supplemental folate (r = -0.53, P < 0.01; Figure 1).
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). At 6 mo, hemoglobin was significantly higher in folate-supplemented women than in unsupplemented women (P < 0.02). Repeated-measures ANOVA suggested a nonsignificant group by time interaction (P < 0.09) for reticulocytes and a nonsignificant group effect (P < 0.07) for hematocrit. The value for reticulocytes in both groups of women was within the normal range (0.005–0.015), but decreased in folate-supplemented women at 6 mo (P < 0.05) (29). Additionally, hematocrit values were higher in folate-supplemented women than in unsupplemented women at 6 mo (P < 0.02). No abnormal neutrophil lobe counts were noted at either 3 or 6 mo postpartum.
Milk folate
A time effect for milk folate concentrations was noted (P < 0.03; Table 2). In women not supplemented with folate, milk folate decreased significantly from 3 to 6 mo (P < 0.02). Folate supplementation, however, prevented a decline in milk folate from 3 to 6 mo postpartum. In folate-supplemented women only, milk folate was positively correlated with plasma homocysteine (r = 0.71, P < 0.01) and negatively correlated with plasma folate (r = -0.52, P < 0.01) at 6 mo.
Infant outcome measures
Anthropometry
Anthropometric indexes of growth (weight, length, and head circumference) indicated that all infants were growing normally (Table 3). All measures of infant growth increased significantly from 3 to 6 mo (P < 0.001) and there were no significant differences between groups. All infants were within the 5th and 95th National Center for Health Statistics (30) percentiles for weight and head circumference at both 3 and 6 mo. Nine infants were just above the 95th percentile and 1 was just below the 5th percentile for length at 3 mo; 4 infants were above the 95th percentile for length at 6 mo.
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The mean calculated folate intake of infants at 3 mo was 62 µg/d. At 6 mo, folate intake from breast milk alone was 55 µg/d and that from foods other than breast milk was 14 ± 3 µg/d. No group differences were noted in folate intakes of infants. Calculated intakes indicated that infants in this study were receiving on average the current recommended daily intake for folate (65 µg) at 3 mo and 80% of the recommended intake (80 µg) at 6 mo (31).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Estimated average folate needs during lactation can be calculated by using data from the present study in conjunction with published data. The previous recommended dietary allowance for folate during lactation was based on the estimated requirement of nonpregnant, nonlactating women (180 µg/d), with an additional 100 µg/d to cover losses due to milk secretion (15). That increment was based on the assumptions of a human milk folate content of 113 nmol/L (50 ng/mL) and an average daily milk production of 800 mL/d during established lactation. It is now fairly well established that folate needs for nonreproducing women are similarly greater than estimated previously. Both Sauberlich et al (32) and O'Keefe et al (33) investigated folate requirements of nonreproducing women consuming diets with defined folate contents. These investigations estimated folate requirements to be 200–400 µg/d as assessed from changes in biochemical and functional indexes of folate status. Data from the present study show that the average folate content of human milk (195 nmol/L, or 86 ng/mL) is 72% greater than the value used previously and that corresponding folate losses due to milk secretion are also greater. From these data and by using the same assumptions used by the Food and Nutrition Board for food folate bioavailability (50%) and milk volume transferred to infants (780 mL) (31), we estimate the average requirement for folate during lactation to be 455 µg/d. This estimate assumes an average folate requirement for nonreproducing women of 320 µg/d and includes an increment of 135 µg/d for milk synthesis (780 mL/d x 86 µg/1000 mL x 100/50 = 135 µg/d). The recommended dietary allowance for folate during lactation was recently increased from 280 to 500 µg/d (31).
We observed a decline in mean milk folate content (from 224 to 187 nmol/L) from 3 to 6 mo in women ingesting 380 µg folate/d without supplemental folate, whereas women receiving supplemental folate maintained similar values at 3 and 6 mo (186 and 182 nmol/L). Folate in human milk is reported to remain stable or to increase as lactation progresses (34–37) and there is considerable variability in reported mean values for folate in human milk (50–319 nmol/L) (13). It is now well established that methodologic difficulties rather than differences among individuals are responsible for the wide range in values reported for milk folate (16, 38, 39). Previously, our laboratory reported that in the analysis of human milk folate, it is essential to preserve labile folates with ascorbate or another antioxidant, to heat samples to denature folate-binding proteins, and to treat samples with folate conjugase to cleave glutamyl residues (38). We also applied 2 other enzymatic treatments [-amylase and mycolysin, which were recently shown to enhance measurable folate in other biological samples (21–23)] to our milk samples before they were analyzed by microbiological assays. Using this improved method, we observed an 85% increase in measurable human milk folate compared with that observed with treatment with folate conjugase alone (16).
Plasma homocysteine values for nearly all of the lactating women in this study were within the normal range reported for nonreproducing women (27). Nonetheless, plasma homocysteine increased significantly from 3 to 6 mo postpartum in women not receiving supplemental folate but remained stable in women receiving supplemental folate. There is general agreement in the literature that plasma homocysteine is negatively associated with dietary folate intake and plasma folate (33, 40–42). Plasma homocysteine was negatively associated with plasma folate only in the folate-supplemented group and with dietary folate only in the unsupplemented group at 6 mo.
Plasma folate concentrations did not change significantly from 3 to 6 mo postpartum in either supplemented or unsupplemented women. This may reflect the fact that all participants in this study had relatively high plasma folate concentrations at baseline (16–70 nmol/L). Ek (35) reported that length of lactation is inversely related to plasma folate concentrations. Folate supplementation during lactation is reported to have differing effects on plasma folate. Tamura et al (43) reported plasma folate concentrations to be 7 times greater than at baseline after 4 wk of supplementation with 1 mg folate/d. Women in that study, however, were at different stages of lactation and had an average plasma folate concentration of 13 nmol/L before supplementation. Conversely, Thomas et al (44) reported that plasma folate was similar between folate-supplemented (with 0.8 mg/d) and unsupplemented lactating women at 6 mo postpartum (29.5 nmol/L). In Finnish women receiving 0.1 mg folate/d, plasma folate increased from 16 to 20 nmol/L, yet up to 10% of those presumably well-nourished lactating women exhibited signs of folate inadequacy (plasma folate 
7 nmol/L) from 1 to 6 mo postpartum (45).
All women in this study had erythrocyte folate values well above the value indicative of deficiency, <340 nmol/L (46). Erythrocyte folate concentrations were not significantly different between groups at 3 mo, but were elevated in supplemented compared with unsupplemented women at 6 mo. Erythrocyte folate is reported to decline during both pregnancy (47) and lactation in the early postpartum period (36, 47, 48). Because erythrocyte folate concentrations are thought to parallel liver folate stores, the diminished values observed in unsupplemented women indicate that liver folate stores were mobilized to meet the nutritional demands of lactation. The extent to which maternal folate stores can continue to compensate for dietary deficits during lactation is not known. The importance of such information is stressed considering that current recommendations are for continued breast-feeding for 12 mo (49) and that nutrition supplementation is not necessary during lactation (50).
Most unexpected were our findings of elevated hemoglobin and hematocrit concentrations in the folate-supplemented group at 6 mo. Consistent with these findings was a decline in reticulocytes in supplemented but not unsupplemented women from 3 to 6 mo. These patterns of change in hematologic indexes suggest that some degree of ineffective erythropoiesis was evident in women not receiving supplemental folate. The hematologic responses can be ascribed to folate because all women received a multivitamin and mineral supplement providing ample quantities of iron and vitamins B-6 and B-12.
With use of traditional assessment methods for lactational performance (infant anthropometric indexes, volume of milk ingested, and milk folate content), we judged women in the present investigation to be lactating successfully. All infants displayed weight gain within the 5th and 95th percentiles of the National Center for Health Statistics standards and showed no signs of growth faltering. Average milk intake of infants in the present study (675 mL/d) was well within the expected range (51). Infants in this study received milk that furnished on average 80–100% of the current recommended dietary allowance for folate (65 µg/d at 3 mo and 80 µg/d at 6 mo). Although infants received apparently adequate amounts of folate and were growing within expected ranges, maternal folate status was deteriorating. Other investigations reported that maternal folate stores can be depleted to maintain milk folate content and that folate deficiency is precipitated by lactation (14).
In January 1998, mandatory folic acid grain-enrichment policies were initiated (52). Cereal grains fortified with 140 µg folic acid/100 g are predicted to increase dietary folate intakes by 100 µg/d for women of reproductive age (53). In the present study, lactating women obtained 30% of their total daily dietary folate from fortified, ready-to-eat cereals (54), which are folate sources of high bioavailability (55). However, current enrichment policies do not alter the amount of folate added to ready-to-eat cereals, so it is not certain whether and to what extent such policies will affect the folate intakes of lactating women. National data on distribution patterns of foods contributing folate to diets of lactating women are needed.
In summary, results from the present study showed that folate status diminished in lactating women consuming 380 µg dietary folate/d but that maternal folate status was preserved with 1 mg supplemental folate. Despite the reduction in folate status in lactating women, average milk folate contents were maintained at levels furnishing 100% and 80% of the current recommended dietary allowances for infants at 3 and 6 mo, respectively (31). These findings stress the importance of including maternal indexes of nutritional adequacy in addition to infant indexes when assessing lactational performance.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Presented in part at Experimental Biology '97, April 1997, New Orleans [Mackey AD, Lim HS, Picciano MF, Smiciklas-Wright H. Biochemical indices of folate adequacy diminish in women in extended lactation. FASEB J 1997;11:A1037 (abstr)].
3 Supported in part by US Department of Agriculture grant 93-0-1059.
4 Address reprint requests to MF Picciano, The Pennsylvania State University, Department of Nutrition, S129C Henderson Building, University Park, PA 16802. E-mail: mfp4{at}psu.edu.
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REFERENCES |
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-amylase and protease in addition to folate conjugase. Food Chem 1998; 63:401–7.
-amylase, and folate conjugase treatments. J Agric Food Chem 1997;45:135–9.
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