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Influence of mineral and vitamin supplements on pregnancy outcome
European Journal of Obstetrics & Gynecology and Reproductive Biology, Volume 164, Issue 2, October 2012, Pages 127 - 132
The literature was searched for publications on minerals and vitamins during pregnancy and the possible influence of supplements on pregnancy outcome. Maternal iron (Fe) deficiency has a direct impact on neonatal Fe stores and birth weight, and may cause cognitive and behavioural problems in childhood. Fe supplementation is recommended to low-income pregnant women, to pregnant women in developing countries, and in documented deficiency, but overtreatment should be avoided. Calcium (Ca) deficiency is associated with pre-eclampsia and intra-uterine growth restriction. Supplementation may reduce both the risk of low birth weight and the severity of pre-eclampsia. Gestational magnesium (Mg) deficiency may cause hematological and teratogenic damage. A Cochrane review showed a significant low birth weight risk reduction in Mg supplemented individuals. Intake of cereal-based diets rich in phytate, high intakes of supplemental Fe, or any gastrointestinal disease, may interfere with zinc (Zn) absorption. Zn deficiency in pregnant animals may limit fetal growth. Supplemental Zn may be prudent for women with poor gastrointestinal function, and in Zn deficient women, increasing birth weight and head circumference, but no evidence was found for beneficial effects of general Zn supplementation during pregnancy. Selenium (Se) is an antioxidant supporting humoral and cell-mediated immunity. Low Se status is associated with recurrent abortion, pre-eclampsia and IUGR, and although beneficial effects are suggested there is no evidence-based recommendation for supplementation.
An average of 20–30% of pregnant women suffer from any vitamin deficiency, and without prophylaxis, about 75% of these would show a deficit of at least one vitamin. Vitamin B6 deficiency is associated with pre-eclampsia, gestational carbohydrate intolerance, hyperemesis gravidarum, and neurologic disease of infants. About 25% of pregnant women in India are folate deficient. Folate deficiency may lead to congenital malformations (neural tube damage, orofacial clefts, cardiac anomalies), anaemia and spontaneous abortions, and pre-eclampsia, IUGR and abruption placentae. Pregestational supplementation of folate prevents neural tube defects. A daily supplemental dose of 400 μg/day of folate is recommended when planning pregnancy. In developing countries diets are generally low in animal products and consequently in vitamin B12 content. An insufficient supply may cause reduced fetal growth. In vegetarian women, supplementation of vitamin B12 may be needed. Vitamin A deficiency is prevalent in the developing world, impairing Fe status and resistance to infections. The recommended upper limit for retinol supplements is 3000 IU/day. Vitamin A supplementation enhances birth weight and growth in infants born to HIV-infected women. Overdosing should be avoided. Low concentrations of vitamin C seem to increase the development of pre-eclampsia, and supplementation may be beneficial. Supplementation with vitamin D in the third trimester in vitamin D deficient women seems to be beneficial. The use of vitamins E, although generally considered “healthy”, may be harmful to the pregnancy outcome by disrupting a physiologic oxidative gestational state and is consequently not recommended to prevent pre-eclampsia. Further studies on specific substances are needed as the basis for stratified, placebo-controlled analyses.
Keywords: Minerals, Vitamins, Deficiency, Adverse effects, Pregnancy, Pre-eclampsia, Eclampsia.
During pregnancy a series of continuous, physiological adjustments affect nutrient metabolism and energy requirements, the pre-pregnancy nutritional status constituting a critical factor for fetal growth and maternal health. The most important determinants of restricted fetal growth in the Western world are a low pre-pregnancy body mass index and a low gestational weight gain. Malnourished women more likely bear growth-restricted babies. Nutrition and supplementation of minerals and vitamins are likely key factors in the prophylaxis and management.
Pre-eclampsia–eclampsia is a multiorgan disease and a major cause of morbidity and mortality in mother, fetus, and offspring, most devastating in developing countries. Pre-eclampsia is associated with low levels of certain vitamins and minerals . Its causes and pathogenesis are still uncertain, and many controversies exist concerning occurrence and management. Our aim is to focus on pregnancy outcome in relation to nutritional deficiencies in minerals and vitamins, and to study the indications for nutritional support.
A non-systematic literature search in PubMed and the Cochrane Databases was undertaken using search words “minerals” or “vitamins” associated with “pregnancy” or “supplementation”. In addition, in-house literature databases were screened. Journals dedicated to nutrition were screened specifically. Observational studies, randomised controlled trials, and meta-analyses, and reviews were selected. The referred studies were chosen on an estimation of clinical and global importance.
Iron (Fe) is a micronutritient essential for haemoglobin synthesis and several organ functions. Fe deficiency is the most widespread nutrient deficiency in the world, affecting more than 50% of all pregnant women in developing countries and being prevalent also in the industrialised parts of the world. It may lead to anaemia, intrauterine growth retardation (IUGR), and neonates small for gestational age (SGA). The prevalence of moderate to severe sideropenic anaemia varies among pregnant women, being 4–5 times greater in Nepal (21%) than in Java (6%) and Peru (4%), and approximately 20% in industrialised countries  and . Fe deficiency induces maternal and fetal stress, increasing cortiocotropin-releasing hormone (CRH), cortisol production, and oxidative damage to fetal erythrocytes. This may inhibit fetal growth. Maternal Fe status has a direct impact on neonatal Fe stores, and birth weight seems dependent on the mother's Fe status . Maternal Fe deficiency during pregnancy may have long-term effects and may cause cognitive and behavioural problems in childhood. A controlled study of Fe supplements to 513 low-income pregnant women, 48% of whom had low ferritin and haemoglobin, showed a significantly higher mean birth weight, a lower incidence of low birth weight (LBW) and a significantly improved birth weight in the supplemented group . Conflicting results are presented on the routine iron supplementation during pregnancy, however. Low haemoglobin and plasma ferritin are good indicators for supplementation. Overtreatment should be avoided as it may increase risks (preterm delivery, gestational diabetes mellitus, IUGR) when maternal iron stores are normal or overloaded .
Calcium (Ca) has important roles in mediating muscle function, blood vessel dynamics, nerve impulse transmission, secretion of hormones, blood coagulation, cell membrane functions, and skeletal development. Ca is required for normal blood coagulation, cell membrane functions, optimal Ca absorption and development of the skeleton. During pregnancy, a substantially increased demand for Ca occurs. This is met by a doubling of intestinal absorption and mobilisation from the skeleton . Deficiency is rare in pregnancy, but is associated with pre-eclampsia, and may induce IUGR. An overall significant 17% risk reduction for LBW and significantly increased birth weight occur after Ca supplementation, probably due to prolonged gestation. An association of low birth weight and low intake of milk and vitamin D during pregnancy was demonstrated . However, in a recent Cochrane report of 21 randomised, controlled studies, including 16,602 women, no statistically significant improvement in terms of preterm births and low birth weight, was demonstrated . Results from a large, multinational, randomised, non-stratified, placebo-controlled study showed that supplementation did not prevent pre-eclampsia, but reduced its severity, the maternal morbidity, and the neonatal morbidity and mortality . Thus, present data are conflicting; making evidence-based general recommendations uncertain.
Magnesium (Mg) is a widespread enzyme cofactor and activator. Hypomagnesemia in diabetic women may lead to both maternal and fetal hypoparathyreoidism with secondary hypomagnesaemia and hypocalcemia. Gestational Mg deficiency may interfere with fetal growth and development and may cause a range of morbidity from hematological to teratogenic damage . A Cochrane review including seven trials of Mg supplementation in pregnancy, most of them uncontrolled, showed a significant overall LBW risk reduction in supplemented individuals. Too few controlled data are available for general recommendations .
Zinc (Zn) is essential for the activity of approximately 100 enzymes. In addition to antioxidant functions, Zn supports the immune system. It is essential for embryogenesis and important for normal fetal growth and growth during childhood and adolescence. Zn deficiency in pregnant experimental animals limits fetal growth and is, if severe, teratogenic. General physiological adjustments in intestinal Zn absorption meet fetal demands, but transfer of sufficient Zn to the fetus is dependent on maintenance of normal maternal serum Zn concentrations. Intake of cereal-based diets rich in phytate, high intakes of supplemental Fe, or any gastrointestinal dysfunction, may interfere with Zn absorption. Supplemental Zn may be prudent in any of these conditions during pregnancy . Zn supplementation was associated with significantly higher birth weight and head circumference in a 1995 randomised study of 580 African-American pregnant women with low plasma Zn levels . However, a review of 17 randomised controlled trials, involving 9000 women showed no evidence for beneficial effects of general Zn supplementation during pregnancy. Most randomised, controlled trials were too small and not uniformly designed to detect effects on pregnancy outcome .
Selenium (Se) is an antioxidant supporting humoral and cell mediated immunity, important for reproduction. Low Se status is associated with recurrent abortions, pre-eclampsia and IUGR  and . A study suggested beneficial effects of Se supplementation in the development of pre-eclampsia in Iranian women . Presently, however, no evidence-based recommendations can be given as to supplementation. Prospective trials are awaited.
Vitamins are fat- or water-soluble organic compounds, essential in small amounts for support of normal physiologic functions, that cannot generally be biosynthesised quickly enough to meet the needs of the body. An average 20–30% of pregnant women suffer from a vitamin deficiency; and without prophylaxis, about 75% would show a deficit of at least one vitamin. In a study it was observed that despite vitamin supplementation, a high percent of vitamin A, B6, niacin, thiamin and B12 hypovitaminemia was noted during all pregnancy trimesters. An especially high percentage of niacin deficiency was seen during the 1st trimester, and it worsened in later trimesters; B-12 deficits increased during the late trimester .
4.1. Vitamin A
Vitamin A (retinoids) is a fat-soluble vitamin essential for gene regulation, cell differentiation, proliferation and growth, innate and adaptive immune system, maintenance of mucosal surfaces, intestinal iron uptake, hematopoiesis, vision and reproduction. While vitamin A deficiency is prevalent in the developing world, overdose rather than deficiency is common in developed countries, reflecting richness in food resources and modern emphasis on antioxidants and “healthy eating”. Vitamin A is considered teratogenic in high concentrations. The recommended upper limit for retinol supplements is 5000 IU/day , but high doses (8000–10,000 IU/day) have not been associated with increased risk of malformations. Vitamin A supplementation has been shown to improve birth weight and growth among infants born to HIV-infected pregnant women, possibly due to the enhancement of immunity . Vitamin A supplementation may thus be beneficial in high-risk pregnancies, but otherwise pregnant women should avoid excess supplementation with vitamin A .
4.2. Vitamin B complex: B1 (thiamine), B6 (pyridoxine) and folate
4.2.1. Vitamin B1
Vitamin B1 (thiamine) is a water-soluble vitamin acting as a coenzyme, being essential in energy metabolism, and lipid and nucleotide synthesis enzymes, especially in the developing brain. Deficiency may impair brain development. Specific active placental transport systems for vitamin B1 and riboflavin cause higher concentrations in the fetus than in maternal blood. Vitamin B1 deficiency is common in developing countries, especially during pregnancy, and may impair fetal growth. There is, however, a paucity of articles on the role of vitamin B1 supplementation in pregnancy.
4.2.2. Vitamin B6
Vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine) is a water-soluble vitamin, important as co-enzymes in protein metabolism in development of the central nervous system. Poultry, fish, pork, eggs, liver, kidney, soya beans, peanuts and walnuts are rich sources. Vitamin B6 deficiency rarely occurs alone, but is often associated with deficiencies in several B-complex vitamins. Vitamin B6 deficiency is associated with pre-eclampsia, gestational carbohydrate intolerance, hyperemesis gravidarum, and neurologic disease of infants. There is, however, no appropriate evidence to detect clinical benefits of vitamin B6 supplementation in pregnancy and/or labour other than one trial suggesting protection against dental decay .
Folate is a water-soluble B vitamin that plays a major co-enzymatic role in carbon metabolism and in the synthesis of DNA, RNA and certain amino acids. Dietary folate deficiency is prevalent in developing countries, about 25% of pregnant women in India being folate deficient. Deficiency may lead to congenital malformations (neural tube damage, orofacial clefts, cardial anomalies), anaemia and certain complications during pregnancy (spontaneous abortions, bleeding, pre-eclampsia, IUGR and abruptio placentae) . Low folate status may also cause hyperhomocystemia, hypercoagulability and venous thrombosis.
To reduce risk of congenital malformations and pregnancy complications a daily supplemental dose of 400 μg/day of folate is recommended when planning pregnancy . Increased risk of fetal neural tube defects is seen in several conditions: obesity, personal or family history of neural tube defects, pregestational diabetes, and epilepsy. A higher dose (5 mg) is recommended in these situations .
A systematic review and a meta-analysis (92 studies identified, 41 evaluated) concluded that maternal consumption of folic acid-containing prenatal multivitamins is associated with decreased risk of several congenital anomalies, not only neural tube defects . A large randomised controlled trial including 2928 women, demonstrated no difference in mean birth weight, placental weight or gestational age. Folic acid in high doses, however, was associated with significantly reduced risk of LBW . The effect of folic acid taken throughout pregnancy is still unclear, but evidence may support a beneficial effect on fetal growth.
4.4. Vitamin B12
Vitamin B12 (cobalamin) is a member of the vitamin B complex, an important support for erythropoiesis, found primarily in meat, eggs and dairy products. There is a global increased prevalence of low plasma vitamin B12 concentrations during pregnancy. In developing countries diets are generally low in animal products and consequently in vitamin B12 content. Pregnant women consuming a long-term, predominantly vegetarian diet, have an increased risk of vitamin B12 deficiency .
A decline in plasma cobalamin is common also in pregnant women consuming an adequate diet, explained by alterations in haptocorrin-bound cobalamin, while intestinal absorption is unimpaired . The significance of low plasma cobalamin is uncertain, although a negative fetal outcome has been reported . A strong association between maternal and infant plasma vitamin B12 concentrations at delivery has been demonstrated, indicating that maternal B12 status affects the fetal vitamin status at birth. Low maternal concentrations are associated with multiple clinical symptoms and reduced fetal growth . Sanchez et al.  found no evidence of an increased risk of pre-eclampsia. Vitamin B12 deficiency may cause defective DNA synthesis, megaloblastic anaemia and neurological abnormalities. The role of vitamin B12 supplementation in pregnancy is uncertain. Special care should be noted. Supplementation may be especially needed in women at nutritional risk, by vegetarian women, in malabsorption disorders and in communities or countries where under-nutrition is prevalent.
4.5. Vitamins C and E
Oxidative stress is an important pathogenic factor for development of pre-eclampsia. Plasma oxidative stress markers are elevated in women with pre-eclampsia . Recently, much interest has been focused on the water-soluble vitamin C (ascorbic acid) and the fat-soluble vitamin E (alpha-tocopherol being the most active form), which are powerful antioxidants for the prevention and treatment of pre-eclampsia. Supplementation treatment would appear a logical approach. Both vitamin C and vitamin E concentrations are reduced in pre-eclampsia, parallel with an increase in oxidative stress markers . Zhang et al. observed an increased risk of pre-eclampsia among women with an intake below 85 mg vitamin C . Oxidative stress was proposed as a key factor involved in the development of pre-eclampsia. Supplementing women with antioxidants during pregnancy seemed feasible to counteract oxidative stress and thereby prevent or delay the onset of pre-eclampsia. Biochemical indices of pre-eclampsia were normalised in a placebo-controlled study in high-risk women receiving combined vitamin C and E . A Cochrane report (7 trials; 6082 women) on the preventive use of antioxidants (any antioxidant) versus placebo during pregnancy showed a significant 39% reduction in the risk of pre-eclampsia. The effect on other outcomes was modest . Two similar studies showed no effect of vitamin C  and vitamin E, respectively , and a meta-analysis concluded that combined vitamin C and E supplementation during pregnancy does not reduce the risk of pre-eclampsia, fetal or neonatal loss, small for gestational age infant, or preterm birth .
Results from vitamin C supplementation are conflicting, however. Even given in high doses, the vitamin may not achieve sustained serum levels to provide effective antioxidant activity. Further clinical trials are therefore suggested to be postponed until “further rigorous research is undertaken” .
The safety of vitamin E prophylaxis against pre-eclampsia has been questioned. A prospective Danish cohort study reported an increased incidence of severe pre-eclampsia/eclampsia and HELLP syndrome in women consuming high amounts of vitamin E. For vitamin E intake aggregated from diet and supplementation (n = 49,373), with an intake of 10.5–13.5 mg/day as a reference, the “severe pre-eclampsia/eclampsia/HELLP” odds ratio (OR) was 1.46 (95% confidence interval (CI) 1.02–209) . Other studies have also given rise to some concern about vitamin C and E supplementation because of risk of gestational hypertension and LBW. Combined vitamin C and E supplementation not only have no potential benefit in improvement of maternal and neonatal outcome but increase the risk of gestational hypertension in women at risk of pre-eclampsia and low birth weight  and .
During pregnancy, a physiologic placental inflammation of type 1 is dominant, with production of pro-inflammatory Th1 cytokines, while type 2 (Th2) cytokines, which are anti-inflammatory, are suppressed. In pre-eclampsia, type 1 inflammation is dominant . The formation of reactive oxygen species (ROS) in macrophages in the placenta may damage endothelial cells, causing placental ischemia, eventually insufficiency and consequently IUGR  as part of down-regulated immunoregulatory system where the T-cell function is reduced . The prime antioxidant component of vitamin E (α-tocopherol) might enhance the Th1 induction and prevent the early-to-late Th1 to Th2 switch in normal human pregnancy . In addition to its antioxidative properties vitamin E also has a variety of non-antioxidative pleiotropic effects on redox-regulated transcription , cell cycle , and cytokine signalling . Vitamin E could also be a potential interferon-gamma (IFN-gamma) mimic, facilitating persistent proinflammatory reactions at the fetal–maternal interface . The clinical significance of these actions is unclear. It follows that supplementation of vitamin C may be advantageous and that vitamin E in pregnancy is possibly dangerous, and may not be recommended.
4.6. Vitamin D
Vitamin D is a fat-soluble vitamin which plays an important role in immune function, cell differentiation, bone growth and the reduction of inflammation. Vitamin D is essential for Ca homeostasis and in reducing the risk of chronic diseases. It is biologically inactive and must be metabolized to its biologically active forms. It enters the circulation from the gut or skin and is transported to the liver, where it is hydroxylated to 25-hydroxyvitamin D 25(OH)D, the major circulating form of vitamin D.
Vitamin D deficiency is variable in adolescents. About 40% of African American and 4% of Caucasian-non-Hispanic women have low plasma concentrations. Vitamin D status in pregnant women should be of concern even in industrialised countries. Even moderately decreased levels of 25-hydroxyvitamin D at the end of winter were associated with poor fetal and infant skeletal growth and tooth mineralisation .
Vitamin D deficiency is a risk factor in fetal growth, bone metabolism, and fetal immune system development. Increased availability of 1,25-dihydroxyvitamin D may improve immune regulation, after correction of inadequate Ca intake, contributing to the observed benefit .
Osteomalacia is a well-recognised pregnancy complication in Asians living in the United Kingdom. Asian immigrants to Europe are at particular risk of vitamin D deficiency during pregnancy, with dietary inadequacy being an important factor. A higher incidence of severe deficiency in vegetarians indicates that oral intake is important. Recently the role of vitamin D in the prevention of pre-eclampsia has been debated, but associations between maternal vitamin D levels and fetal growth were not demonstrated in a Norwegian study, where supplementation in the third trimester in subjects on a vitamin D deficient diet significantly increased birth weights and crown-heel-lengths . Other studies showed only slight or no effects of vitamin D supplementation. Overall, vitamin D supplementation in at-risk populations leads to improved neonatal handling of Ca. There is no evidence of benefit of general supplementation during pregnancy beyond the amounts routinely required to prevent vitamin D deficiency .
5. Multiple micronutrients
Micronutrient deficiencies often appear in combination, especially in developing countries, due to a range of causes, such as insufficient availability of adequate food quality, cultural differences, seasonal variations, poverty, and infections in the population. This is often the case in developing countries . Results from several randomised, controlled studies show significant improvements in pregnancy outcomes (increase in birth weight; reduction in low birth weight) after introduction of multiple micronutrient (MMN) supplementation  and . Availability of large scale blood tests in these communities is scarce, and little is therefore known about the range and extent of nutrient deficiencies, and no data exist on the optimal composition of MMN. Overall, however, there is evidence that outcomes are better when providing a minimum of three components . The most prevalent deficiencies in developing countries are iron, Ca, vitamin D, vitamin A, Zn, and folate. Even in developed countries selected groups are micronutrient deficient, e.g. pregnant adolescents, possibly calling for MMN treatment .
MMN can be implemented in a large-scale programme and should be well suited for developing countries, where medical and economic resources are limited. Production and distribution are not very costly, and the application fairly simple. In addition, and rather a sine qua non, improvements in ante-natal health services and securing of adequate food supplies must have priority.
For many decades vitamin supplements have been regarded as solely health-promoting. Deficiencies may result in significant morbidity, where vitamin treatment is curative. Increased demands may ensue during pregnancy, with negative consequences to the fetus and child health. However, the effect of vitamin supplements in non-deficient pregnant individuals is poorly understood.
Considerable problems arise in the interpretation of dietary studies and in determining the consequences on pregnancy and fetal growth. There is a paucity of well designed, controlled studies. Isolated deficiencies of dietary components rarely appear, and the quantification of individual food components, e.g. vitamins, as well as the estimation of food intake, are difficult and unreliable. Furthermore, the populations studied are often non-homogenous and poorly defined. The inclusion of large numbers of individuals is necessary to allow statistically reliable analyses. These studies are usually not stratified in terms of defined deficiencies, demographic background, etc. In intervention studies from populations where under-nutrition is prevalent the diets are usually deficient in several food components. Supplementation of single components may therefore be insufficient to obtain a clinical response, and a multiple micronutrient supplementation may contain unnecessary and even harmful overdoses. In addition, nutrient interactions are numerous. However, valuable data emerge from non-interventional, population studies. Although not stratified, these studies usually recruit patients from areas and cultures with generally known dietary shortcomings. Findings from these studies may be applied in controlled interventional studies where corresponding deficiencies can be objectively detected, e.g. vitamin B12 in vegetarians .
Pre-eclampsia is an important cause of impaired fetal health and development, and naturally, much of the literature on pregnancy outcome relates to this condition. New insights in the immunology of pregnancy have shed some light on the basis of treatment and prophylaxis of pre-eclampsia. As reported, placental oxidative stress has been demonstrated, and up to now, antioxidant agents have been advocated as a logical approach to both prophylaxis and treatment. Several vitamins have antioxidative properties. During the early stages of placental development an oxidative drive may, however, be a physiological phenomenon governing the further maturation of the placenta. An immunological switch from the pro-inflammatory type Th1 cytokine response towards the anti-inflammatory Th2 occurs towards the later part of the pregnancy. This switch may be of importance, both for fetal development and neonatal and child health. Supplementation with vitamins C and E may negatively affect this switch, resulting in complications.
Normal mineral and vitamin metabolism is important for successful pregnancies, but when it comes to practical implications, very few evidence-based, general recommendations on prophylactic measures can be derived from the literature. Micronutritients of particular importance for prevention of adverse pregnancy outcomes are folic acid, Zn, and Fe . Pre-pregnancy and early pregnancy folate supplementation is now firmly established. Fe treatment in iron deficiency seems to have a beneficial effect on pregnancy outcome. Most other intervention studies large enough to allow statistically reliable analysis, however, include mixed populations which are not stratified according to single or multiple deficiencies. Therefore, numbers needed to treat are unknown and unnecessary treatment may carry risks. Studies from areas with high prevalence of specific nutrient defects are important, however, showing that supplementation prophylaxis works. The ideal prospective trial is therefore awaited, including individuals with a pre-gestational, biochemically and physiologically defined nutritional status as the basis for a stratified, placebo-controlled analysis. In the meantime, individual evaluation is necessary if feasible.
In conclusion, substitution therapy and supplementation may be beneficial during pregnancy, but specific deficiencies should be sought. Pre-pregnancy and early pregnancy folate supplementation is now firmly established, and iron treatment in iron deficiency seems to have a beneficial effect on pregnancy outcome. Pregnant women consuming a long-term, predominantly vegetarian diet, have an increased risk of vitamin B12 deficiency and supplementation with B12 may be needed. Asian immigrants to Europe are at particular risk of vitamin D deficiency during pregnancy, with dietary inadequacy being an important factor. Vitamin D may be beneficial against development of pre-eclampsia. Supplementation with vitamins C may be beneficial. Supplementation with vitamin E is not presently recommended, and may even be hampered by untoward effects.
Both authors were equally involved in literature studies and writing.
Conflict of interest statement
Approval by the Medical Ethics Committee was not considered necessary. The Committee was not contacted.
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