B12 in fetal development

Seminars in Cell & Developmental Biology 22 (2011) 619–623

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Review

B12 in fetal development M. Reese Pepper, Maureen M. Black ∗ University of Maryland School of Medicine, Department of Pediatrics, Division of Growth and Nutrition, USA

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Article history: Available online 6 June 2011 Keywords: B12 Fetal development Cognitive development International nutrition Nutrition

a b s t r a c t Vitamin B12 (cobalamin) is necessary for development of the fetus and child. Pregnant women who are vegetarian or vegan, have Crohn’s or celiac disease, or have undergone gastric bypass surgery are at increased risk of B12 deficiency. Low serum levels of B12 have been linked to negative impacts in cognitive, motor, and growth outcomes. Low cobalamin levels also may be related to depression in adults. Some studies indicate that B12 supplementation may improve outcomes in children, although more research is needed in this area. Overall, the mechanisms of B12 action in development remain unclear. Further studies in this area to elucidate the pathways of cobalamin influence on development, as well as to prevent B12 deficiency in pregnant women and children are indicated. © 2011 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intrauterine vitamin B12 deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Low birth weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Neural tube defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Longitudinal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pediatric B12 deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of B12 deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Depression and B12 function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Deficiency levels of key nutrients have been indicated as causing poor child development in the antenatal period, affecting all areas of development from brain to bone [1]. One of the most prominent examples linking vitamins to development is the finding that prenatal folate deficiency causes neural tube defects [2]. Widespread acknowledgement of the negative effects of folate deficiency has led to worldwide fortification of foods with folate to prevent deficiency in pregnant women [3]. Vitamin B12, or cobalamin, has also been identified as a crucial nutrient for fetal development [4]. Folate metabolism for the prevention of macrocytic anemia was once thought to be the only role of B12. However, cobalamin’s role may be more complex (Fig. 1).

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B12 functions as an enzyme to catalyze mitochondrial conversion of methylmalonic acid to succinyl-CoA, essential for synthesis of hemoglobin as well as metabolism of fat and protein. Vitamin B12 also functions as a cofactor, with folic acid, for generation of methionine from homocysteine in the cytosol. Methionine, with adenosine triphosphate, forms S-adenosyl methionine (SAM), which donates its methyl group for DNA methylation and functions in epinephrine synthesis (Fig. 2) [5]. Serum B12 values below 200 pg/mL are frequently considered deficient [6], although the lower limit defined by the Institute of Medicine is 120–180 pmol/L (170–250 pg/mL) [5]. When B12 levels are low, the resultant decrease in methylation activity is thought to account for some of the deleterious effects of B12 deficiency on fetal development. 2. Intrauterine vitamin B12 deficiency

∗ Corresponding author at: 737 W Lombard St Rm 163, Baltimore, MD 21201, USA. Tel.: +1 410 706 0213; fax: +1 410 706 5090. E-mail address: [email protected] (M.M. Black). 1084-9521/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcdb.2011.05.005

Recommended intake of B12 for pregnant women is increased to 2.6 ␮g, versus 2.4 ␮g/day for adults, to meet the needs of the

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2.1. Low birth weight

Fig. 1. Negative consequences of intra-uterine and childhood B12 deficiency.

fetus [7]. During pregnancy the fetus absorbs B12 through the placenta. Among pregnant women with B12 deficiency, the levels of B12 transported to the fetus decline. As B12 is found primarily in animal products, women who are vegetarian or vegan are at risk for B12 deficiency [8]. Women with decreased B12 absorption due to intestinal diseases, such as Crohn’s or celiac disease, are also at risk [9]. Pernicious anemia, a disease caused by atrophic gastritis or gastric autoimmune disorders resulting in low levels of intrinsic factor, causes malabsorption of B12 resulting in deficiency. Evidence suggests that maternal short gut syndrome and gastric bypass surgery could also result in fetal B12 deficiency [10–13]. Case reports of vegetarian and vegan mothers with low B12 status have long indicated that infants of B12 deficient mothers may manifest failure-to-thrive, irritability, and reduced cerebral growth [14]. Case studies of the impact of B12 deficiency on neurological development have been reported as early as 1962 in India [15]. Pooled analysis of 46 case studies of maternal B12 deficiency, including 18 mothers with pernicious anemia and 30 vegans, revealed a variety of clinical pathologies [16]. All reports indentified megaloblastic anemia in the infants, and most children also refused complementary foods and had hypotonia, developmental delay, lethargy, and birth weight <10th percentile.

Vegetarians in India frequently manifest B12 deficiency, although folate deficiency is rare [17]. Therefore, Yajnik et al. postulate that high homocysteinemia in this population can be attributed primarily to B12 deficiency [18]. Two studies from India examined the relation between plasma homocysteine or B12 in pregnancy and infant birth weight. One enrolled 80 pregnant women from Pune and found that elevated plasma homocysteine in pregnancy was a significant negative predictor of birth weight [18]. The other enrolled 478 pregnant women in Bangalore and measured serum B12 levels during each trimester [19]. Infants whose mothers were in the low tertile of serum B12 concentration in the second trimester had over nine times higher odds of being born <10th percentile of weight for gestational age, compared to the highest tertile, even after adjusting for maternal age, education, parity, and baseline weight. Maternal folate levels during pregnancy were not related to low birth weight in this sample. 2.2. Type 2 diabetes Infants with intrauterine growth restriction are at increased risk of type 2 diabetes later in life [20]. The mechanisms of this prenatal programming are unclear [21], but B12 deficiency may be involved. Yajnik et al. followed 653 pregnancies, measuring the mothers and their children from gestation through age 6 [22]. B12 deficiency was observed in 60% of the women in the second trimester, although only one had low folate levels, and plasma homocysteine levels were negatively related to plasma B12 (p < 0.001). Levels of plasma B12 at 18 weeks gestation were significantly related to insulin resistance at age 6, even after controlling for child’s age, sex, birth weight, skinfold thickness at birth, gestational age at delivery, socioeconomic status, and mother’s protein intake during pregnancy (p < 0.05). Maternal folate was also a significant predictor of homeostatic model assessment of insulin resistance (HOMA-R), although the interaction between folate and B12 was non-significant. This study indicates that fetal B12 deficiency may

Fig. 2. B12 functions as a cofactor in enzymatic activities of methionine synthase for synthesis of methionine and tetrahydrofolate.

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be related to risk for type 2 diabetes; more work is needed in this area. 2.3. Neural tube defects Although folate deficiency is primarily responsible for neural tube defects (NTDs) in countries with high intake of animal-based foods, B12 insufficiency may also increase risk of NTDs. In a casecontrol study, cobalamin levels in amniotic fluid of children born with NTDs were significantly lower than in age-matched controls (150 pg/mL vs. 540 pg/mL, p < 0.05) [23]. There was no difference in amniotic folate levels between children with NTDs and controls. Small studies in Egyptian and Chinese mothers (NTD groups N = 35 and 84, respectively), have evaluated folate and B12 status of children born with NTDs versus control groups. In Egypt, serum folate concentration did not differ in women whose children had a NTD compared to the control group [24]. However, average B12 levels were lower and fasting plasma homocysteine higher in women with an affected child. The Chinese study indicated that lower maternal levels of both folate and B12 significantly increased the odds of having a child with a NTD. NTDs are a global problem, although rates are lower in countries where foods are supplemented with folate and meat intake supplies adequate B12. A nested, case-control study of 95 Irish women who bore a child with a NTD found that a 1 ng/L increase in B12 concentration was related to a 0.3% decrease in risk of NTD, independent of red cell folate levels [25]. Mothers with <250 ng/L plasma B12 had more than a 2.5-fold higher risk of bearing a child with an NTD, even after controlling for folate. 2.4. Longitudinal studies Longitudinal studies have provided evidence of long-term cognitive effects of intrauterine B12 deficiency. A prospective study in Mexico evaluated the relationship between first trimester maternal dietary B12 and child development at 12 months of age in 253 children [26]. The Bayley Scales of Infant Development were used to compare children of mothers who consumed <2 ␮g/day B12 vs. children whose mothers consumed at least 2 ␮g. There were no significant differences in psychomotor development, but children of mothers in the low B12 group had mental scores 1.6 points lower than children of mothers with adequate intake on the Bayley Mental Development Scale at 12 months. The study examined the effect of a single nucleotide polymorphism in the folate pathway on susceptibility to neurodevelopmental consequences of B12 and folate deficiencies. The relationship between B12 intake and cognitive development was independent of maternal allele status, while the effects of low folate intake were significant only in children with the homozygous genotype. Researchers from the Pune Maternal Nutrition Study in India evaluated 9-year-old children of mothers who had low (<77 pM) versus high (>224 pM) B12 status at 28 weeks gestation [27]. Maternal B12 levels during pregnancy significantly predicted children’s B12 status at age 6. Tests of frontal lobe (perceptual tracking and simple sequencing tasks) and temporal lobe function (short term memory) showed significant differences favoring children of mothers in the high B12 group, even after controlling for the child’s age, gender, socioeconomic status, head circumference, weight, and B12 status at age 6. Maternal prenatal B12 and homocysteine concentration were examined in the Mysore Parthenon Study in India and children were followed through 9 years of age [28]. This prospective birth cohort found that prenatal homocysteine concentration was significantly associated with birth weight, as others have reported [18,19]. No associations were found between prenatal maternal B12 quartile and children’s scores on six of the cognitive measures

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evaluated at age 9. However, mothers with B12 <150 pmol/L had children who scored significantly lower on a verbal fluency test than mothers with normal B12, after adjusting for child’s sex, age, gestational age, SES, birth weight, head circumference at birth and 9 years, BMI, education, and folate level. 3. Pediatric B12 deficiency B12 deficiency among children has also been a focus of investigation, particularly among children raised on diets low on animal source foods. A study of 48 adolescents 9–14 years old in the Netherlands, who followed meat-free macrobiotic diets until age 6, had significantly lower cobalamin levels compared to omnivorous controls [29]. Scores on the Raven’s Progressive Matrixes [30], a measure of reasoning ability, in the combined sample of macrobiotic-exposed and control subjects were significantly related to cobalamin concentration after controlling for age. Cobalamin concentration in the macrobiotic group was positively related to scores on a test of divergent thinking. Inclusion of ferritin status in the model did not affect significance, suggesting that the iron content of meat may not be related to the effect of B12 deficiency on cognition. A study of 598 6- to 10-year-old children in Bangalore evaluated plasma B12 and cognitive performance [31]. The children had B12 concentrations similar to the cobalamin-deficient macrobiotic group from the Netherlands (151 and 266 vs. 136 and 227 pmol/L for the 25th and 75th percentiles, in Bangalore and Netherlands, respectively) [29]. Measures of short term memory, retrieval, and mental processing were inversely associated with levels of B12 after adjustment for age, height-for-age, sex, school, hemoglobin, folate status, and maternal education. This unexpected negative relationship does not have a clear explanation, although it is noteworthy that the entire sample had low B12 levels. Future studies might consider inclusion of plasma homocysteine levels. In studies of geriatric populations, elevated homocysteine has been related to B12 status, and may have a direct impact on cognitive function [32]. Research on plasma B12 levels of Guatemalan children has found poor motor functioning in children with inadequate B12 levels. The Bayley Scales of Infant Development were administered at 12 and 21 months of age. At 12 months, infants with low plasma B12 had lower scores on secure walking motor skills, compared to children with adequate B12 stores [33]. Children with daily dietary B12 intake under 1.44 ␮g had significantly lower psychomotor scores than children who consumed adequate B12 from complementary foods. At 21 months, children who had marginal or lower plasma B12 levels were smaller by weight and length and achieved lower scores on the psychomotor scale than children with adequate B12 levels [34]. 4. Treatment of B12 deficiency Supplementation of pregnant women may improve B12 status, although this area requires further study. In a small observational analysis in Pune, India, 163 women were interviewed at 17 weeks gestation to determine whether they were receiving supplements (none, folic acid only, or B12 with folic acid) [35]. Women who were not given a vitamin supplement had stable levels of B12, but homocysteine levels rose significantly by 34 weeks compared to supplemented women. Among women who received B12 and folic acid, plasma homocysteine at 34 weeks was significantly associated with B12 dose, but not related to folate supplement level. Evaluation of the children born to women who vary in the dose and frequency of supplement received during pregnancy could give insight into the long-term impact of varying levels of prenatal B12 supplementation in this population.

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Dietary B12 intervention may be related to cognitive ability in older children. A food supplementation trial in Kenyan children from 12 schools randomized to receive a daily snack of meat, milk, or oil, or control and measured cognitive performance on the Raven’s Progressive Matrices test of problem-solving after 21 months [36]. Children in schools randomized to receive meat improved their scores more than children in non-meat schools. When diet recalls of the children were evaluated for B12 intake, overall dietary B12 was not related to performance on Raven’s Progressive Matrices [37]. However, higher B12 intake was predictive of improvement in the digit span forward test, a measure of short-term memory (monthly increase in test score 0.11). When the lowest and highest deciles of B12 intake were compared, higher intake was associated with a 0.24 point higher increase in digit span forward test score or 20% improvement compared to the lowest B12 level. 5. Depression and B12 function Deficiencies in several nutrients have been associated with risk of depression [38]. B12 has been implicated in depression due to its role in synthesis of S-adenosyl methionine, an important methyl donor for production of monoamine transmitters such as norepinephrine. In a sample of over 500 elderly subjects from the Netherlands, B12 levels <258 pmol/L were associated with a 63% higher odds of depressive disorder, even after controlling for socioeconomic and health factors [39]. A Japanese study of postpartum women found no association between quartile of B12 intake and risk of depression at 4 months postpartum [40]. However, even the lowest quartile of subjects consumed an average of 3.3 ␮g/day, well above the Dietary Reference Intake of 2.8 ␮g/day for lactating women [5]. Evaluation of the relationship between B12 and depressive symptoms in children could be a focus for future study. 6. Future areas In high income countries, vitamin B12 deficiency due to low dietary intake is relatively uncommon due to high availability and consumption of animal-based foods [10]. Women who limit their animal source intake during pregnancy (e.g., vegetarians and vegans) are often advised to take a B12 supplement. Cases of reduced intestinal absorption of B12 have been associated with Crohn’s and Celiac diseases. There is emerging evidence suggesting that gastric bypass surgery may interfere with intestinal absorption of B12, potentially jeopardizing infants of women who have had a gastric bypass. Obesity reduction following gastric bypass surgery has been shown to result in a “fertility rebound”, thus the numbers of pregnant women who have previously undergone weight loss surgery is growing [41]. At least one study has reported that infants of women who underwent Roux-en-Y gastric bypass surgery prior to pregnancy had significantly lower birth weight than normal weight or BMI-matched mothers [42]. A recent case study reported severe B12 deficiency (serum B12 84 pg/mL) in a woman at 4 months postpartum who had undergone bariatric surgery 6 years prior [43]. The infant was also B12 deficient, and was diagnosed with pancytopenia and developmental delay, including brain atrophy in the cortical and sub-cortical regions. Following B12 treatment, the child evidenced improved neurological status with delays in development of motor and speech function. Longitudinal studies of macronutrient status in pregnant women following surgery for obesity are warranted. 7. Summary Although much of the evidence of the importance of B12 during development comes from countries characterized by vegetarianism

and low intake of animal source food, infant B12 deficiency can be found globally. The increasing popularity of bariatric surgery, incidence of Crohn’s and celiac diseases, pernicious anemia, and vegetarianism together contribute to the rate of 0.88/100,000 newborns in the US being identified as B12 deficient [10]. In recent years, prospective studies have provided some evidence that prenatal and postnatal vitamin B12 deficiency may be negatively related to child development. B12 may play a role in fetal development of the brain or later cognitive functioning, and may be related to increased risk for type 2 diabetes later in life. However, the biological mechanisms of B12 action in development remain unclear. There do not seem to be universal effects of B12 deficiency, indicating that the effects of B12 deficiency may be indirect, impacting vulnerability or altering developmental processes. For example, in the elderly, elevated homocysteine levels have been suggested as a better indicator of cognitive decline than B12 concentration [44]. Although B12 is necessary for metabolism of homocysteine into methionine, the pathway also requires folate, methionine synthase, and S-adenosyl methionine. As shown in the Pune Maternal Nutrition Study, a B12 concentration <150 pmol/L accounted for only 24% of the population attributable risk of elevated homocysteine [22]. Maternal vitamin B12 status seems to play a role in intrauterine development, which may impact birth weight, risk of diabetes, and cognitive functioning. Longitudinal supplementation trials are needed to isolate the effects of B12, and allow inference of causation. Pregnancy among women post-bariatric surgery poses risks, although little is known about the long term effects of B12 deficiency in this population. Furthermore, biochemical analyses into the functions of B12 are needed to elucidate the mechanisms influencing fetal development. The impact of B12 on children remains unclear, highlighting the need for further research in this area. From a public health perspective, there is suggestive evidence that in some cases, B12 deficiency during pregnancy poses risks to fetal development with long-lasting health and developmental consequences, and B12 deficiency during childhood may compromise children’s cognitive and motor development. However, the strength of the evidence varies, suggesting an indirect relationship. The few supplementation trials have not yielded consistent findings, again suggesting that mechanisms linking B12 deficiency to children’s development are indirect. Although research is needed to clarify the mechanisms linking B12 deficiency to child development, research is also needed on strategies to prevent B12 deficiency among pregnant women and young children. References [1] Benton D, ILSI Europe A.I.S.B.L. Micronutrient status, cognition and behavioral problems in childhood. Eur J Nutr 2008;(August (47 Suppl 3)):38–50. [2] Vitamin Study Research Group. Prevention of neural tube defects: results of the medical research council vitamin study. MRC vitamin study research group. Lancet 1991;338(July (8760)):131–7. [3] Berry RJ, Bailey L, Mulinare J, Bower C, Folic Acid Working Group. Fortification of flour with folic acid. Food Nutr Bull 2010;31(March (1 Suppl)):S22–35. [4] Black MM. Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr Bull 2008;29(June (2 Suppl)):S126–31. [5] Institute of Medicine, Food and Nutrition Board. Dietary reference intakes: thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998. [6] Gropper SS, Smith JL, Groff JL. Advanced nutrition and human metabolism. Wadsworth Cengage Learning; 2009. [7] Dietary Supplement Fact Sheet: Vitamin B12 [Internet]; c2010 [cited 2011 03/01]. Available from: http://ods.od.nih.gov/factsheets/VitaminB12Consumer/. [8] Allen LH, Rosenberg IH, Oakley GP, Omenn GS. Considering the case for vitamin B12 fortification of flour. Food Nutr Bull 2010;31(March (1 Suppl)):S36–46. [9] Yakut M, Ustun Y, Kabacam G, Soykan I. Serum vitamin B12 and folate status in patients with inflammatory bowel diseases. Eur J Intern Med 2010;21(August (4)):320–3. [10] Hinton CF, Ojodu JA, Fernhoff PM, Rasmussen SA, Scanlon KS, Hannon WH. Maternal and neonatal vitamin B12 deficiency detected through expanded newborn screening – United States, 2003–2007. J Pediatr 2010;157(July (1)):162–3.

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