The Whitehall-Robins Report - Centrum · 2020-02-26 · Micronutrients and pregnancy (birth)...
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Micronutrients and pregnancy (birth) outcome October 2006 - Volume 15, Number 3 John M Scott School of Biochemistry and Immunology, Trinity College Dublin, Ireland Recommended Dietary Allowance (RDA) and Adequate Intake (AI) for micronutrients during pregnancy The Table in this report summarizes all of the nutrient levels relevant to pregnancy and lactation and compares these to those for non-pregnant women, as recommended by the National Academy of Science, Institute of Medicine 1,2,4,6 . Please refer to two past issues of the Whitehall- Robins Reports, for definitions and terms used in the Dietary Reference Intakes reports for minerals 7 and vitamins 8 . Folic Acid/Folates The folate cofactors of which there are seven different forms in human cells are involved in two metabolic cycles 9 . The DNA cycle and the methylation cycle. The various forms act as coenzymes to some of the enzymes involved in de novo purine and pyrimidine biosynthesis and as such, they are necessary for the synthesis of DNA and for cell division. In folate defi- ciency, the arrest of DNA biosynthesis and with it cell division is seen as a very clear macrocyotic anaemia, characterized by the occurrence of abnormal red cell precursors in the bone marrow called megaloblasts. The function of the methylation cycle is to provide methyl (-CH 3 ) groups to several methyltransferases that methylate a wide range of compounds such as proteins, lipids, DNA, and hormones . The effects of reduction in these methylations are hard to predict, but it appears that at least one is involved in nerve synthesis. Severe folate deficiency is also associated with a neuropathy similar to that seen in B12 deficiency, albeit of a less severe nature. Severe folate deficiency manifested as anemia is rare nowadays in developed countries. This anemia was frequently encountered during the second and the third trimester of pregnancy, however, dietary improvements now make it a rare condition. During pregnancy there are reductions in serum folate levels, due to increased catabolism, fetal requirements and haemodilution. If left unsupplemented these may lead into a deficiency state manifested as an overt anaemia. However, the avoidance of maternal anaemia may not really be the issue. Clearly there is a need to maintain optimal levels to sustain the very rapid growth rates of the developing embryo/fetus. For such growth, the folate cofactors are essential and any reduction in their status may pose a risk to the fetus. In this context reduced folate status and elevated homocysteine during pregnancy have been associated with increased risk of abruption placentae 10 and unexplained pregnancy loss 11 , probably due to some genetic variants that involve folate metabolism. In addition, it may result in impaired inter-uterine growth with lower birth weight 12 . Elevation of the biomarker for poor folate status, namely maternal plasma homocysteine has also been shown to be a possible risk for pre-eclampsia 13 . It has been shown that folic acid supplementation in late pregnancy increases maternal folate status and reduces plasma homocysteine 14 . This suggests that continued supplementation with folic acid throughout pregnancy seems to be prudent although it is not currently part of obstetrical practice in many countries. It would also recognize the reality that without the use of supplements (or foods fortified with folic acid) only a minority of pregnant women would meet the pregnancy RDA for folic acid/folate of 600 μg/d. Neural Tube Defects (NTDs) prevention by folic acid is important. For effective NTDs prevention, folic acid must be taken periconceptionally. The critical event of the closure of the neural plate to make the neural tube and the eventual spinal column takes place between days 21 and 27 post conception. Additional folic acid after day 27 would be expected to be of little benefit, since the neural tube may either be closed properly at that stage or is left with an aperture causing spina bifida. This event happens so early in pregnancy that the vast majority of women do not realize that they are pregnant until after the critical closure event at day 27. The recommendation from CDC 15 is that “all women of child-bearing age in the United States who are capable of becoming pregnant should consume 0.4 mg (400 μg) of folic acid per day for the purpose of reducing their risk of having a pregnancy affected with spina bifida or other NTDs.” Because a previous occurrence of an NTD birth puts women at a high risk of a further such birth (recurrence) the recommendation to prevent recurrence is 4.0mg/d. This “because their risk of having an NTD affected pregnancy may outweigh any risk that may occur as a result of the use of 4.0 mg of folic acid.” Since 1998 flour has been fortified with folic acid in the US and Canada with a resultant 30 to 70% drop in NTDs prevalence 16 . It should of course be emphasised that to avoid over exposure to the general public the level of flour fortified is not sufficient to optimally lower NTDs. Thus, a folic acid supplement (400 μg/d) is still needed periconceptionally 15 . Iron The most important function of iron is the biosynthesis of haemoglobin. It is thus clear why the most apparent outcome of iron deficiency is a very characteristic hypochromic microcytic anaemia. However, iron is also a cofactor for many enzymes and processes in cells and it appears that deficiency may also effect several other functions 2 . One such function that may have implications for intrauterine deficiency is impairment of cognitive development and intellectual performance 2 . In pregnancy, even moderate iron deficiency is associated with increased risk of maternal death, premature delivery, low birth weight and increased perinatal infant mortality. Extra demands for iron exist in pregnancy due to transfer of iron to the placenta/fetus and increased erythrocyte mass. These are offset a little by increased intestinal absorption. However, there is an extra requirement in pregnancy from the usual RDA for women of childbearing age of 18 mg/d to 27 mg/d 2 . The Whitehall-Robins Report Requirements for individual micronutrients vary widely from nutrient to nutrient; hence the efficiency with which various diets fulfil these requirements is as variable. For example, biotin, which is an essential vitamin has never been found to be deficient in humans because of its abundance in our diet 1 . By contrast, iron deficiency/inadequacy is highly prevalent among women with supposedly “normal” dietary intakes 2 . The requirements for several nutrients are increased during pregnancy. Thus women’s current diets, even in developed countries, may be inadequate to meet several nutrient requirements during pregnancy. Even apparently good diets may fall short for some nutrients. There are some specific nutrients where optimal levels are in practice not achievable. While such intakes may not result in overt deficiency, it is becoming increasingly obvious that substantial numbers of the general population have suboptimal status for several nutrients. One might argue philosophically that this should not have happened during human evolution and that diets should be capable of achieving optimal intakes. While everyone should strive to meet their nutrient requirements through diet, many are failing to do so 3 . Therefore, it is prudent to complement the diet with rational supplementation to guard against nutrient inadequacies. During pregnancy, several nutrient requirements are increased markedly and the emphasis in this report is on these nutrients, namely folate/folic acid, iron, vitamin D 4 , and vitamin A. In determining whether pregnant women are at risk of deficiency or inadequacy, one is frequently analyzing biochemical makers of such under-nutrition in pregnancy. Although protection of the woman through optimizing her nutritional status is important, it is as important for the developing embryo/fetus. This is because except in extreme circumstances , it could be assumed that the mother will regain her nutritional and health status post delivery. By contrast the effect on the developing embryo and fetus may be irreversible. Such effects may be manifested as increased risk of any of the following birth defects: abrupto placenta; spontaneous abortion; miscarriage; impaired intrauterine growth; and reduced birth weight. In addition, the well-known Barker hypothesis suggests that impaired status in utero is a risk factor for the subsequent development of chronic diseases such as heart disease, stroke, type II diabetes etc. 5 . It would seem prudent to ensure that both maternal and, consequently, embryo/fetal status is optimized before and during pregnancy.
Transcript of The Whitehall-Robins Report - Centrum · 2020-02-26 · Micronutrients and pregnancy (birth)...
Micronutrients and pregnancy (birth) outcome
October 2006 - Volume 15, Number 3
John M ScottSchool of Biochemistry and Immunology, Trinity College Dublin, Ireland
Recommended Dietary Allowance (RDA) and AdequateIntake (AI) for micronutrients during pregnancyThe Table in this report summarizes all of the nutrientlevels relevant to pregnancy and lactation and comparesthese to those for non-pregnant women, as recommendedby the National Academy of Science, Institute ofMedicine1,2,4,6.
Please refer to two past issues of the Whitehall-Robins Reports, for definitions and terms used in theDietary Reference Intakes reports for minerals7 andvitamins8 .
Folic Acid/FolatesThe folate cofactors of which there are seven differentforms in human cells are involved in two metaboliccycles9. The DNA cycle and the methylation cycle. The various forms act as coenzymes to some of theenzymes involved in de novo purine and pyrimidinebiosynthesis and as such, they are necessary for thesynthesis of DNA and for cell division. In folate defi-ciency, the arrest of DNA biosynthesis and with it celldivision is seen as a very clear macrocyotic anaemia,characterized by the occurrence of abnormal red cellprecursors in the bone marrow called megaloblasts.The function of the methylation cycle is to providemethyl (-CH3) groups to several methyltransferasesthat methylate a wide range of compounds such asproteins, lipids, DNA, and hormones . The effects ofreduction in these methylations are hard to predict, butit appears that at least one is involved in nerve synthesis.Severe folate deficiency is also associated with a neuropathy similar to that seen in B12 deficiency,albeit of a less severe nature. Severe folate deficiencymanifested as anemia is rare nowadays in developedcountries. This anemia was frequently encounteredduring the second and the third trimester of pregnancy,however, dietary improvements now make it a rarecondition. During pregnancy there are reductions inserum folate levels, due to increased catabolism, fetal
requirements and haemodilution. If left unsupplementedthese may lead into a deficiency state manifested asan overt anaemia. However, the avoidance of maternalanaemia may not really be the issue. Clearly there is aneed to maintain optimal levels to sustain the veryrapid growth rates of the developing embryo/fetus. For such growth, the folate cofactors are essential andany reduction in their status may pose a risk to thefetus. In this context reduced folate status and elevatedhomocysteine during pregnancy have been associated withincreased risk of abruption placentae10 and unexplainedpregnancy loss11, probably due to some genetic variantsthat involve folate metabolism. In addition, it may resultin impaired inter-uterine growth with lower birthweight12. Elevation of the biomarker for poor folate status, namely maternal plasma homocysteine has alsobeen shown to be a possible risk for pre-eclampsia13.It has been shown that folic acid supplementation inlate pregnancy increases maternal folate status andreduces plasma homocysteine14. This suggests thatcontinued supplementation with folic acid throughoutpregnancy seems to be prudent although it is not currently part of obstetrical practice in many countries.It would also recognize the reality that without the useof supplements (or foods fortified with folic acid) only aminority of pregnant women would meet the pregnancyRDA for folic acid/folate of 600 µg/d.
Neural Tube Defects (NTDs) prevention by folic acid isimportant. For effective NTDs prevention, folic acidmust be taken periconceptionally. The critical event ofthe closure of the neural plate to make the neural tubeand the eventual spinal column takes place betweendays 21 and 27 post conception. Additional folic acidafter day 27 would be expected to be of little benefit,since the neural tube may either be closed properly atthat stage or is left with an aperture causing spina bifida.This event happens so early in pregnancy that the vastmajority of women do not realize that they are pregnantuntil after the critical closure event at day 27. The
recommendation from CDC15 is that “all women ofchild-bearing age in the United States who are capableof becoming pregnant should consume 0.4 mg (400 µg)of folic acid per day for the purpose of reducing theirrisk of having a pregnancy affected with spina bifida orother NTDs.” Because a previous occurrence of anNTD birth puts women at a high risk of a further suchbirth (recurrence) the recommendation to preventrecurrence is 4.0mg/d. This “because their risk of havingan NTD affected pregnancy may outweigh any risk thatmay occur as a result of the use of 4.0 mg of folic acid.”
Since 1998 flour has been fortified with folic acid in theUS and Canada with a resultant 30 to 70% drop inNTDs prevalence16.
It should of course be emphasised that to avoid overexposure to the general public the level of flour fortifiedis not sufficient to optimally lower NTDs. Thus, a folic acidsupplement (400 µg/d) is still needed periconceptionally15.
IronThe most important function of iron is the biosynthesisof haemoglobin. It is thus clear why the most apparentoutcome of iron deficiency is a very characteristichypochromic microcytic anaemia. However, iron is alsoa cofactor for many enzymes and processes in cellsand it appears that deficiency may also effect severalother functions2. One such function that may haveimplications for intrauterine deficiency is impairment ofcognitive development and intellectual performance2.In pregnancy, even moderate iron deficiency is associatedwith increased risk of maternal death, premature delivery,low birth weight and increased perinatal infant mortality.Extra demands for iron exist in pregnancy due to transferof iron to the placenta/fetus and increased erythrocytemass. These are offset a little by increased intestinalabsorption. However, there is an extra requirement inpregnancy from the usual RDA for women of childbearingage of 18 mg/d to 27 mg/d2.
The Whitehall-Robins Report
Requirements for individual micronutrients vary widely from nutrient to nutrient; hence the efficiency with which various diets fulfil these requirements is asvariable. For example, biotin, which is an essential vitamin has never been found to be deficient in humans because of its abundance in our diet1. By contrast,iron deficiency/inadequacy is highly prevalent among women with supposedly “normal” dietary intakes2. The requirements for several nutrients areincreased during pregnancy. Thus women’s current diets, even in developed countries, may be inadequate to meet several nutrient requirements during pregnancy. Even apparently good diets may fall short for some nutrients. There are some specific nutrients where optimal levels are in practice not achievable.While such intakes may not result in overt deficiency, it is becoming increasingly obvious that substantial numbers of the general population have suboptimalstatus for several nutrients. One might argue philosophically that this should not have happened during human evolution and that diets should be capable ofachieving optimal intakes. While everyone should strive to meet their nutrient requirements through diet, many are failing to do so3. Therefore, it is prudentto complement the diet with rational supplementation to guard against nutrient inadequacies. During pregnancy, several nutrient requirements are increased markedly and the emphasis in this report is on these nutrients, namely folate/folic acid, iron,vitamin D4, and vitamin A. In determining whether pregnant women are at risk of deficiency or inadequacy, one is frequently analyzing biochemical makers of such under-nutrition inpregnancy. Although protection of the woman through optimizing her nutritional status is important, it is as important for the developing embryo/fetus. This is because except in extreme circumstances , it could be assumed that the mother will regain her nutritional and health status post delivery. By contrastthe effect on the developing embryo and fetus may be irreversible. Such effects may be manifested as increased risk of any of the following birth defects:abrupto placenta; spontaneous abortion; miscarriage; impaired intrauterine growth; and reduced birth weight. In addition, the well-known Barker hypothesissuggests that impaired status in utero is a risk factor for the subsequent development of chronic diseases such as heart disease, stroke, type II diabetes etc. 5.It would seem prudent to ensure that both maternal and, consequently, embryo/fetal status is optimized before and during pregnancy.
Micronutrients and pregnancy (birth) outcome October 2006 - Volume 15, Number 3
References 1. Institute of Medicine, “Dietary Reference Intakes for thiamine, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin and choline”, Washington DC: National Academy Press, 1998. Available online at:http://www.nap.edu/catalog/6015.html. 2. Institute of Medicine, “Dietary Reference Intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium and zinc”, Washington DC: NationalAcademy Press, 2001. Available online at: http://www.nap.edu/catalog/10026.html 3. Cuskelly C.J., McNulty H., Scott J.M. “Effect of increasing dietary Folate on red-cell Folate: implications for prevention of neural tube defects”, Lancet, 347, 657-659 (1996).4. Institute of Medicine, “Dietary Reference Intakes for calcium, phosphorus, magnesium, vitamin D and fluoride”, Washington DC: National Academy Press, 1997. Available online at: http://www.nap.edu/catalog/5776.html. 5. Paneth, N., Susser, M., “Earlyorigin of coronary heart disease (the “Barker hypothesis”)”, British Medical Journal, 310, 411-412 (1995). 6. Institute of Medicine, “Dietary Reference Intakes for vitamin C, vitamin E, selenium and carotenoids”, Washington DC: National Academy Press,2000. Available online at: http://www.nap.edu/catalog/9810.html. 7. Barr, S.I., “Dietary reference intakes: minerals”, Whitehall-Robins Report, 2003: volume 12, No. 1. 8. Barr, S.I., “Dietary reference intakes: vitamins”, Whitehall-Robbins Report, 2003, volume12, No. 2. 9. Scott J.M., Weir D.G. “The role of folic acid/Folate in pregnancy: prevention is better than cure”, Recent Advances in Obstetrics and Gynaecology, 20, 1-20 (1998) 10. Parle-McDermott A., Mills J.L., Kirke P.N., Cox C., Signore C.C., Kirke S., MolloyA.M., O’Leary V.B., Pangilinan F.J., O’Herlihy C., Brody L.C., Scott J.M. “MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae”, American Journal of Medical Genetics , 132A(4): 365-368, (2005) 11. Parle-McDermott, A,Pangilinan, F., Mills, J.L., Signore, C.C., Molloy, A.Mm., Cotter, A., Conley, M., Cox, C., Kirke, P.N., Scott, J.M., Brody, L.C., “A polymorphism in the MTHFD1 gene increases a mother’s risk of having an unexplained second trimester pregnancy loss”. Mol. HumReprod. 2005 July; 111 (7): 477-80. 12. Murphy M.M., Scott J.M., Arija V., Molloy A.M., Fernandez-Ballart J.D. “Maternal Homocysteine and Birth Weight Are Affected by Maternal Homocysteine before Conception and throughout Pregnancy” ClinicalChemistry, 50 (5), 1406-1412 (2004) 13. Cotter A.M., Molloy A.M., Scott J.M., Daly S.F. “Elevated plasma homocysteine in early pregnancy: a risk factor for the development of nonsevere preeclampsia” American Journal of Obstetrics and Gynaecology, 189(2), 391-394 (2003) 14. Holmes V.A., Wallace J.M.W., Alexander H.D., Gilmore W.S., Bradbury I., Ward M., Scott J.M., McFaul P., McNulty H. “Homocysteine is lower in the third trimester of pregnancy in women with enhanced folate status from continuedfolic acid supplementation”, Clinical Chemistry,51: 629-634 (2005) 15. Centers for Disease Control, “Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects”, MMWR 1992; 41 (No. RR-14): 1-7.16. Ray, J.G., Meier, C., Vermeulen, M.J., Boss, S., Wyatt, P.R., and Cole, D.E., “NTD reduction post fortification”, The Lancet, 2002, 28; (360): 2047-8.
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Vitamin DExposure to sunlight is the main contributor to the levelsof circulating vitamin D rather than dietary intake. Thepregnant and non-pregnant AI for vitamin D is currentlyset at 5.0 µg/d (200 IU). However, this value assumesnot only sunlight exposure but also latitudes where UVrays penetrate. This has led the Institute of Medicine(IOM) recommendation to state “there is no need toincrease vitamin D age-related AI during pregnancyabove that required for non-pregnant women”4.However, because of its concern about effective sunlight exposure it adds “an intake of 10 µg (400 IU)/daywhich is supplied by prenatal vitamin supplements,would not be excessive”4.
Vitamin AThe non-pregnant RDA for vitamin A of 700 µg is slightlyincreased to 770 µg in pregnancy2. Because this vitaminis a known teratogen, high daily intake above the RDAshould be avoided. Levels should be kept well belowthe ULs for pregnancy, of 2,000 µg, for women between14-18 years or 3,000 µg for women 19 years and older2.
β-CaroteneAs quoted by the IOM6 there is “a large body of observational epidemiological evidence that suggeststhat higher blood concentrations of β-Carotene isassociated with lower risk of severe chronic disease.”It goes on to say that no evidence suggested that acertain percentage of vitamin A needed should comefrom such provitamin A carotenoides. It went on to addhowever, that the known health benefits of five servingsof fruit or vegetables per day would be expected toprovide 5.2 to 6.0 mg/d of provitamin A. This would contribute approximately 50 to 65 per cent of the RDAfor vitamin A2. The above considerations have promptedsome multivitamin manufacturers to include β-Carotenein their formulae to achieve the overall RDA of 770 µg/d.
Vitamins and minerals where either a small or noincrease is necessary (1,2,4,6)
Biotin, Pantothemic Acid, Niacin, Vitamin C, Vitamin E(α Tocopherol), Thiamin (Vitamin B1), Riboflavin(Vitamin B2), Vitamin B12, Vitamin K, Calcium*,Magnesium, Molybdenum, Manganese, Iodine,Fluoride, Copper, Chromium, Zinc, Selenium,Phosphorus, Arsenic, Boron, Chromium, Nickel, Silicon, Vanadium.
*It is accepted that the growing fetus is supplied with considerablequantities of calcium by the mother. However, there is good evidencethat the latter shows no reduced status during pregnancy. It appearsthat fetal requirements are met by maternal hormonal changes thatenhance her intestinal absorption of calcium.
RDA1 or (AI)2 UL3
Nutrients Females Pregnant Lactating Pre/LacVitamin A µg 700 <19y
4 750 <19y4 1,200 <19y
4 2,000>19y
5 720 >19y5 1,300 >19y
5 3,000β-Carotene None established (N/E) (N/E) (N/E) (N/E)Vitamin E mg 15 15 16 1,000Vitamin K µg (90) <19y
4 (75) <19y4 (75) No UL6
>19y5 (90) >19y
5 (90)Vitamin C mg 75 85 < 19 115 2,000
> 19 120Vitamin D µg (5) (200 IU) (5) (5) 50Folate µg 400 600 500 1,000Vitamin B12 µg 2.4 2.6 2.8 No ULThiamin mg 1.1 1.4 1.5 No ULRiboflavin mg 1.0 1.4 1.6 No ULVitamin B6 mg 1.3 1.9 2.0 100Biotin µg (30) (30) (35) No ULPanthothenate mg (5) (6) (7) No ULNiacin mg 14 18 17 35Choline mg (425) (450) (550) 3,500Iron mg 18 27 <19y
4 10 45>19y
5 9Calcium mg (1,000) <19y
4 (1,300) <19y4 (1,300) 2,500
>19y5 (1000) >19y
5 (1,000)Iodine µg 150 220 290 <19y
4 900>19y
5 1,100Manganese mg (1.8) (2.0) (2.6) <19y
4 9>19y
5 11Copper µg 900 1,000 1,300 <19y
4 8,000>19y
5 10,000Molybdenum µg 45 50 50 1,000Selenium µg 55 60 70 400Zinc mg 8 <19y
4 12 <19y4 13 40
>19y5 11 >19y
5 12Chromium µg (25) <19y
4 29 <19y4 44 No UL
>19y5 30 >19y
5 45Fluoride mg (3.0) (3.0) (3.0) 10Phosphorous mg 700 <19y
4 1,250 <19y4 1,250 3,500 preg
>19y5 700 >19y
5 700 4,000 lact.Magnesium mg 14-18y 360 14-18y 400 14-18y 300 350
19-30y 310 19-30y 350 19-30y 31031-50y 320 31-50y 360 31-50y 320
1 RDA = Recommended Dietary Allowance 2 AI = Adequate Intake values given in brackets ( )3 UL = Tolerable Upper Intake Level for pregnancy or lactation4 < = under 19 years of age5 > = over 19 years of age6 No UL = no reliable data on adverse effects
