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.