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Micronutrient formulations for prevention of complications of pregnancy

RB Singh1,Sanjay Mishra2,*,Shailesh Kumar3,Amit Mani Tiwari2,Fabien De Meester4,Ramesh K Goyal5,Kumar Kartikey1,Meenakshi Singh6
1
Halberg Hospital and Research Institute, Moradabad 244 001, U.P., India
2
School of Biotechnology, IFTM University, Delhi Road (NH 24), Moradabad 244 102, U.P., India
3
Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur India
4
Columbus Paradigm Institute, Waterloo, Belgium
5
Department of Pharmacology, L.M. College of Pharmacy, Navrangpura, Ahmedabad 380 009, Gujrat
6
Council of Scientific Research, New Delhi, India
DOI: 10.2741/S507 Volume 10 Issue 1, pp.175-184
Published: 01 January 2018
(This article belongs to the Special Issue Current trends in biotechnology)
*Corresponding Author(s):  
Sanjay Mishra
E-mail:  
sanjaymishra@iftmuniversity.ac.in
Abstract

According to a relatively recent UNICEF report, 15 percent of the infant population of the world is of low birth weight with India accounting for one third of all the world’s low-weight newborns. Twenty percent of all low birth weight infants die within a month. This mortality figure is higher in developing countries due to inadequate nutritional intake by pregnant women. Development of a new package of nutrient-rich food based on egg or milk or soy bean proteins, containing multiple micronutrient supplements, available at affordable cost, may protect against morbidity and mortality among pregnant women as well as low birth weight in newborns. These benefits may continue to decrease morbidity and mortality during infancy and childhood and might reduce the risk of chronic diseases in later adult life.

Key words

Eclampsia, Epigenetic Inheritance, Low Birth Weight Infants, Micronutrient Supplementation, Ovolipids, Pregnancy, Review

2. Introduction

According to the 2013 UNICEF report entitled ‘Improving Child Nutrition (1), the achievable imperative for global progress, over 20 million children, including 15percent of infants, was observed to be born with low birth weight throughout the world in the 2011 assessment year with India representing one third of the world’s low birth weight population. Every year more than c20 million infants world-wide are born weighing less than 2500 g (2-3). World Health Organization (WHO) has defined low birth weight as the weight at birth being less than 2,500 g or 5.5 pounds (4). This standard cut-off of low birth weight for global comparison is based on observations and reflects that low birth infants are 20 times more susceptible to death as compared to heavier babies of same age (5). High mortality is commonly found in developing nations when compared with developed ones. An underweight birth leads to poor health outcome and the individual is more prone to being infected by various diseases in later stages of life. Adequate nutrition supply during pregnancy is very essential for both child and maternal health. Pregnant women are vulnerable to inadequate nutritional status because of the high nutrient demands during pregnancy (6). Deficiency of micronutrients such as iron, folate, zinc and various vitamins such as A, B6, B12, C, E and riboflavin is very common in people of developing nations and highly represented in pregnant women (7). Micronutrient deficiency is due to inadequate intake of nutritional food such as meat, fruits, and vegetables and in some cases it is pertinent to note that infections may also lead to nutritional deficiency. Multiple micronutrient supplementations to pregnant women have been observed to be very helpful in preventing adverse outcomes of pregnancy by fulfilling the maternal demand, also improving immune status of child and mother (8-16). The WHO strongly recommends food supplementation of folic acid and iron to minimize the risk of iron deficiency anemia among pregnant women. These recommendations are being implemented by some developing countries. In a 'step ahead' programme, supplementation of micronutrients can be provided at very nominal cost (12, 13).

Certain studies accomplished in the last few decades indicate that multiple micronutrient deficiency is becoming a public health issue in developing nations due to its association with various metabolic disorders such as cardiovascular diseases (CVDs) and type 2 diabetes in later adult life (6,7,14). Maternal under-nutrition and micronutrient deficiency have also been demonstrated to be an important underlying cause of complications of pregnancy and low birth weight in neonatal and infancy (9, 12,13, 15-16). WHO and UNICEF have suggested that under-nutrition and maternal micronutrient deficiencies are likely to be responsible for major complications in pregnancy in mothers as well as morbidity and mortality in the fetus (13, 17). Micronutrient supplements during pregnancy can act as a precautionary measure for reducing the morbidity and mortality in infants, as well as in treating maternal complications during pregnancy. Hence supplement recommendations by UNICEF/WHO/UNU (United Nations University) for pregnant women are to include 15 micronutrients as follows: 400 μg folic acid, 30 mg iron, 800 μg vitamin A, 200 IU vitamin D, 10 mg vitamin E, 70 mg vitamin C, 1.4 mg vitamin B1, 1.4 mg vitamin B2, 18 mg niacin, 1.9 mg vitamin B6, 2.6 μg vitamin B12, 15 mg zinc, 2 mg copper, 65 micrograms of selenium and 150 micrograms of iodine, to be administered during the antenatal period. The comparative needs of micronutrients in three different conditions, viz. non-pregnant, pregnant and lactating women are shown in Table 1. The Expert Group of the International College of Nutrition proposed that this regimen needs further modification by adding chromium to prevent diabetes as well as omega-3 fatty acids, flavones and amino acids to enhance brain development and immunity among infants so as to prevent eclampsia, stroke, postpartum psychosis, hypertension, diabetes, dementia and depression in women in the next few months of follow up (18-19). These strategies can protect against nutritional problems related to under-nutrition and chronic diseases; cardiovascular diseases, diabetes, cancer, obesity, osteoporosis, chronic lung diseases and neurodegenerative diseases that occur in later life (Figure 1).

Table 1. List of some essential micronutrients required in nonpregnant, pregnant and lactating women according to the recommendations of UNICEF and WHO
MicronutrientsNon-pregnant womenPregnancyLactation
Iron15mg3015
Zinc8mg11mg12mg
Calcium1000µmg10001000
Iodine150µg220 µg290 µg
Selenium55 µg60 µg70 µg
Vitamin A700 µg770 µg1300 µg
Vitamin B1.1. mg1.4. mg1.4. mg
  -Thiamin(B1)1.1. mg1.4. mg1.6. mg
  -Riboflavin(B2)14 mg18 mg17 mg
  -Niacin1.2.-1.5.1.9.2.0. mg
  -Vitamin B62.4. µg2.6. µg2.8. µg
  -Vitamin B120.4. mg0.6. mg0.5. mg
Folate75 mg85 mg120 mg
Vitamin D5 µg5 µg5 µg
Vitamin E15 mg15 mg19 mg

Figure 1. Data representation of low weight births in the developing world

3. Mechanisms of micronutrient deficiency in pregnancy

Since micronutrient deficiency is highly prevalent in the general population, it may worsen concurrently among pregnant women due to increased demand because of oxidative stress and complications (14). Micronutrients such as folate, iron, zinc, copper, selenium, iodine, and vitamins (20) A, B6, B12, C, E and riboflavin are highly desirable during pregnancy due to their increased demand to serve the needs of fetus and mother (6,7,14). Iron is required for normal functioning of a large number of biological processes. Naturally, in pregnancy, the mother depletes her iron stores, one of the most essential micronutrients, in order to fulfill demands of baby by an adequate amount. The transfer of iron from mother to fetus takes place through a complex mechanism. In the process of trans-placental transfer of iron (21), the first step involves binding of transferrin (Tf)-bound iron to the transferrin receptor. Thereafter, the uptake of this iron bound complex is by an endosome, followed by acidification, and then release of iron by a divalent metal transporter 1. The efflux of iron across the basolateral membrane is carried out through ferroportin and oxidation of Fe (II) by zyklopen (22). Iodine, an essential micronutrient, works as a key component of the thyroid hormone metabolic processes, which are critically associated with fetal growth, development and metabolism. There are various consequences of iodine deficiency, resulting in inadequate thyroid hormone formation. This deficiency can affect individuals of any age, gender, and physiological conditions. Iodine deficiency during pregnancy may show an effect on fetal development, leading to mild intellectual blunting and to cretinism in children. Endemic cretinism, said to be the most serious iodine deficiency disorder, is represented by symptoms of permanently stunted physical and mental development, caused by an untreated congenital deficiency of thyroid hormones as a consequence of severe maternal iodine deficiency (23). There is some information about deficiency of antioxidant flavonoids, omega-3 fatty acids and amino acids influencing immunity, neuronal function and cardiovascular risk as well as epigenetic inheritance of non-communicable diseases (NCDs), which may also influence outcome of pregnancy (4,8, 13,14). In respect of vitamin C, a study was accomplished indicating vitamin C deficiency during pregnancy was found to be positively correlated with development of ‘ever wheeze’ and eczema during the children’s second year (24). The greater need for certain nutrients during pregnancy may be because of red blood cell mass being expanded during pregnancy. This RBC mass is proportionally less than that of plasma, hence some biochemical levels for minerals and trace elements fall in plasma, for example, hemoglobin fall is parallel to red blood cell volume (8,14). Zinc and magnesium are also important during pregnancy but their concentration fluctuates at various stages of same. The zinc concentration declines progressively with pregnancy, whereas magnesium shows no gestational dependence until late pregnancy where it declines continuously. The essentiality of zinc as a micro nutrient is highly desirable in pregnancy because many fundamental processes are dependent on Zn. In addition to adequate intake during pregnancy and lactation, Zn is studied in number of researches that have a wide range of pathological outcomes which are associated with deficiency of zinc including birth defects, impaired immune function, and growth retardation, increased susceptibility to infection, skin disorders and central nervous system dysfunction (25). The selenium element is incorporated into various proteins to make selenoproteins, including the antioxidant enzyme, selenoprotein-P, glutathione peroxidase, and thioredoxin reductases. Also, selenium is essential for thyroid hormones formation and thus for normal functioning of the thyroid gland. Overall maternal selenium concentrations and glutathione peroxidase activity decline during pregnancy (25, 26). Copper plays a significant role in the human body. It is mainly involved in the formation of a wide range of enzymes and catalyzes various metabolic processes in mother during pregnancy and the developing fetus. During pregnancy, many changes may occur in copper levels, due to transport in both mother and fetus. The serum copper increases in early pregnancy and continues to rise to reaching levels at full term approximately twice those found in non-pregnant women (25). Copper concentration increases in pregnancy but phosphorus remains constant because of maternal adaptation. The primary bone-forming minerals calcium, phosphorus, magnesium and zinc are also contributing essential micronutrients. At the time of birth, an infant contains approximately 20–30 g calcium, 16 g phosphorus, 750 mg magnesium and 50 mg zinc, of which approximately 98, 80, 60 and 30percent, respectively, are found in the skeleton of fetus (27). Calcium absorption increases initially in pregnancy, while the gradual decline is observed in protein-bound fraction in serum throughout the pregnancy, though the free ionic concentration remains relatively constant. The homeostatic control of ionic calcium is maintained by a complex interaction of vitamin D, parathyroid hormone and calcitonin. Enormous oxidative stress during pregnancy and eclampsia requires considerable doses of antioxidants to neutralize the free radicals, which may be damaging to both fetus and mother (8,14).

4. Can micronutrient modulate epigenetic mechanisms?

It is possible that multiple micronutrient supplementations have a beneficial effect on molecular epigenetic markers of diseases in newborn, infants and on adult diseases that develop later in life (19, 28-30). Methylation of DNA, RNA and chromatids are common biochemical epigenetic mechanisms, which occur at regions of certain genes (19, 28-31). Nutrient deficiencies or excesses, pollutants and radiation can predispose cellular stress leading to DNA methylation. Cellular stress during replication induces many minor deletions and duplications in the genome, adding fuel for human diversity and disease (28-31). Replication stress is known to be hazardous for the cell and is thought to contribute to ageing and cancer. DNA methylation is crucial for cell development and for stabilizing cell function, though the extent of methylation may be a determinant of dysfunction. There are multiple factors involved in epigenetic mechanisms, viz.; specific nutrients and nutrient deficiency, exposure to other environmental factors, tobacco, western diet, pollutants and inherited genetic polymorphisms that can alter DNA methylation. The yellow Agouti mouse with obesity and yellow coat colour variation is the best example of epigenetic inheritance due to nutrient deficiency in pregnant mice caused by hypomethylation of the Agouti gene (31). This finding poses the possibility that nutrient supplementation to pregnant women might substitute the methyl group to repair the abnormal methylation of the Agouti gene and help in the prevention of obesity and metabolic syndrome (32, 33). Removal of the methyl group from normally methylated Agouti gene by increased supplementation of certain nutrients, namely, choline, betaine, folic acid and vitamin B12, may be helpful in repairing the deficit leading to normal methylation of genes, resulting in decreased risk of obesity and diabetes (32, 33). In one experimental study, Waterland and Jirtle (2003) altered the nutrient intake to serve as methyl group donors in mouse mothers, to cause methylation or demethylation of the Agouti gene by epigenetic modification (32). In this developing mouse fetus, if the above modification occurs shortly after fertilization, the baby mouse may exhibit the yellow fur and obese phenotype with greater risk of developing cancer and diabetes (17). However, the genetic code remains unchanged from normal mice. These nutrients; choline, betaine, folic acid and vitamin B12, in the diet of pregnant yellow Agouti mice may reduce the deleterious phenotypes in offspring, by donating methyl groups and allowing for the remethylation of the Agouti gene. If these mice be born with the Agouti phenotype, they can pass that deleterious epigenetic trait to their offspring, regardless of their diet during pregnancy. This landmark study indicates that nutrients can cause phenotypic changes, which can pass on through cell division and mating to the offspring due to their possible influence on natural selection (32). There is a need to examine the effects of low omega-6:omega-3 ratio diet, flavones, arginine, taurine, cysteine, coenzyme Q10 on remethylation of the Agouti gene and their effects on phenotypic variations. Any of these nutrients or nutraceuticals can provide the methyl group, which is added to DNA via folate and methionine pathways. The packaging and function of the human genome are controlled by epigenetic mechanisms. However, it is not yet clear which methyl mark accounts for ageing or the development of diseases and how a nutrient deficiency or pollutant causes DNA damage. It is possible that the epigenome of a mother may be altered due to hormonal changes during pregnancy, which may interact with nutrients or nutraceuticals, mental stress, tobacco and or alcohol consumption and environmental pollutants resulting in expression of disease phenotypes (32, 33). The mechanisms may involve proteins that interpret cytosine methylation signals, and thus epigenetic changes may precede genetic changes in the arterial and vascular cells due to different biochemical factors, such as glycemia, hyperinsulinemia and pro-inflammatory cytokines, which may be responsible for development of chronic diseases in adult life. The DNA hypomethylation activates the relevant genes, for example, oncogenes in cancer, and initiates chromosomal instability. However, DNA hypermethylation may also initiate silencing of protective genes resulting in cancers. These methylation patterns can develop molecular epigenetic markers for a variety of cancers, CVD and diabetes. The DNA sequence of humans appears to be under a strong influence of the genome and packed chromatin, which facilitates the differential expression of genes. Trans-generational response to nutrition, early life circumstances, development of adult diseases and longevity (28) as well as mechanisms of trans-generational epigenetic inheritance and their implications for the study of heredity and evolution, are underway (33,34).

5. Effects of micronutrient on complications of pregnancy

There is evidence that the repair of micronutrient deficiency among pregnant women immediately after 8 weeks of conception can reduce the prevalence of low birth weight babies and morbidity and mortality of mothers, new born and infants (35-42). In the case of low birth weight, supplementation of calcium, vitamin A, vitamin D, and beta carotene has been found to be protective against risk of subsequent type 2 diabetes, hypertension, heart disease, schizophrenia, and depression in later life (35-42). The Tromso heart study proposed that poor nutrition during childhood, and the Bogalusa Heart Study revealed that obesity during infancy, could be one of the risk factors for adult cardiovascular diseases (43,44). It has been proposed that human adaptations occur in epigenetics, early in life, which may be before conception, to conserve nutrients and energy during deficient supply that becomes a risk factor for adequate food supply (45-48). In 1996, one author (first), while discussing with the late Dr David Barker and Dr Caroline Fall, proposed that deficiency of magnesium, zinc, chromium and omega-3 fatty acids during pregnancy appear to be important in the pathogenesis of CVDs and type2 diabetes among offspring in later adult life. Caroline Fall is an international expert on micronutrient supplements among pregnant women (49-50) and David Barker was an eminent epidemiologist in health and nutrition at Southampton University. Several expert groups on knowledge synthesis about determinants of low birth weight and preterm births, and stillbirth, reported that micronutrient supplementation during antenatal period can prevent; complications of pregnancy among mothers, morbidity and mortality among newborn and infants, and risk of chronic diseases in later adult life (16, 47-52). Of all these studies, in a recent randomized trial, women were provided supplements containing 15 micronutrients or iron–folic acid alone, taken daily from early pregnancy to 12 weeks postpartum, during a follow-up of 180 days (51). These findings revealed that among the 22,405 pregnant women in the multiple micronutrient group and the 22,162 pregnant women in the iron-folic acid group there were 14,374 and 14,142 live-born infants, respectively. There were 764 deaths (54.0. per 1000 live births) in the iron–folic acid group and 741 deaths (51.6. per 1000 live births) in the multiple micronutrient group (relative risk (RR), 0.95; 95percent CI, 0.86-1.06). Multiple micronutrient supplementation resulted in a non–statistically significant reduction in stillbirths (43.1 vs. 48.2 per 1000 births; RR, 0.89; 95percent CI, 0.81-0.99; P less than 0.02) and significant reductions in preterm births (18.6 vs. 21.8 per 100 live births; RR, 0.85; 95percent CI, 0.80-0.91; Pless than 0.0.01) and low birth weight (40.2 vs. 45.7 per 100 live births; RR, 0.88; 95percent CI, 0.85-0.91; Pless than 0.0.01). Despite no reduction in all-cause infant mortality up to age 6 months, this trial is a land mark (51). Because of multiple micronutrient therapy, resulting in a non–statistically significant reduction in stillbirths and significant reductions in preterm births and low birth weight, these babies would be less susceptible to develop CVDs and type2 diabetes in later adult life. Thus, antenatal multiple micronutrients compared with iron–folic acid supplementation is superior and further trials adding other micronutrients; magnesium, omega-3 fatty acids, amino acids can provide further benefits, particularly in vegetarian populations where people are rapidly adopting Western diet (46, 52). In developed countries, antioxidant vitamin supplementations have not been reported to be protective (46). In a more recent clinical trial among 20 infants, ovolipids supplementation rich in amino acids and omega-3 fatty acids has been found to be protective against metabolic syndrome (53). Folic acid or folate is a B vitamin, which is water soluble necessary for the healthy growth of the neural tube in the fetus which develops into the central nervous system constituted by brain and spinal cord. Without folic acid, the neural tube may not close correctly that may lead to spina bifida, a condition in which the spinal cord and or a sac filled with spinal fluid which protrudes through an opening at the back, or anencephaly. Folic acid supplementation can reduce the incidence of neural tube defects by 70%, according to the CDC (Centers for Disease Control and Prevention). The National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation funded study concluded that antenatal iron and folic acid supplementation should be encouraged in low- and middle-income countries and also at global level. Iron in addition to folate is one of the major trace elements required during pregnancy. Deficiency of iron in pregnancy can result in preterm delivery and maternal anemia. Adequate iron is required from conception, throughout the pregnancy and during lactation. Its deficiency during lactation may be associated with mental retardation (10, 14).

6. Developments of food supplements for pregnant women

In developing countries, major efforts are made to study the role of protein-energy malnutrition, and deficiencies of micronutrients, mainly, iron, iodine, and folic acid because of diets being deficient in proteins-calories causing low-birth weight babies while micronutrient deficiencies are related to anemia (iron, folic acid, and vitamin B 12), hypothyroidism (iodine), and neural tube defects (folic acid) (6, 12, 13, 18, 19). However, it is now clearer that micronutrient appear to be responsible for overall health of the mothers and infants and hence dietary supplements should be developed by the food industry for pregnant mothers, even men, planning to have children. Apart from 15 micronutrients proposed by WHO/UNICEF/UNU (54), which have been proven to be beneficial (51), further new additions and dose increases of nutrients in the existing formulation appear to be a new strategy to achieve further benefit in morbidity and mortality of mothers and the newborn (16, 18, 53). It is possible that adding micronutrients to ovolipids can make it a superfood for mothers as well as babies, for overall health and prevention of low birth weight. The infant milk formulation (Ovolipids IF) was based on guidelines of the ESPGHAN (4) and contained 2.4 g P/100Cal (10percent), 5.2g F/100Cal (45 percent), 11.5 g C/ 100Cal (45percent), based on duck egg, whey proteins and glucose syrups (54-55). This approach including egg as a base, along with 25 micronutrients may be a new package of nutrient rich superfood for mothers as well as babies for health benefits. For vegetarians, milk or soy bean proteins along with 25 micronutrients could be an alternative approach. Both the approaches can provide superfood supplements for prevention of morbidity and mortality among mothers and newborn and chronic diseases of these babies in later adult life.

WHO/UNICEF/UNU proposed 15 micronutrients; 30 mg iron, 400 micrograms folic acid, 800 micrograms RE vitamin A, 200 IU vitamin D, 10 mg vitamin E, 70 mg vitamin C, 1.4 mg vitamin B1, 1.4 mg vitamin B2, 18 mg niacin, 1.9 mg vitamin B6, 2.6 μg vitamin B12, 15 mg zinc, 2 mg copper, 65 micrograms selenium and 150 μg iodine, to be administered during the antenatal period. The Expert Group of the International College of Nutrition has proposed further modification by adding chromium and magnesium as well as omega-3 fatty acids, flavones, choline, betaine and amino acids, probiotics (approximately 25 nutrients) for further improvement in overall benefits (32, 56-62). Choline, betaine, folic acid and vitamin B12 are known to prevent methylation of the DNA and chromatids, which is known to predispose metabolic syndrome in the offspring (32-34).The quantity of some of the nutrients may also be enhanced for further benefits. Since cardiovascular diseases and type 1 and type 2 diabetes have emerged in epidemic proportions, this approach may be protective against these diseases (63).

In brief, multiple micronutrient supplementations during pregnancy appear to be protective against morbidity and mortality in mothers and low birth weight among newborn. These superfood supplements may be developed for both vegetarians as well as non-vegetarians by using either egg, or milk with soybean and protein, along with 25 other micronutrients for health benefits. These benefits may decrease morbidity and mortality in the babies during infancy and childhood and thus possibly reducing the risk of chronic diseases in later adult life.

7. Acknowledgments

This piece of work is an outcome from collaborative efforts of: (a) Halberg Hospital and Research Institute, Moradabad 244 001, U.P., India; (b) School of Biotechnology, IFTM University, Delhi Road (NH 24), Moradabad 244 102, U.P., India; (c) Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur India; (d) Columbus Paradigm Institute, Waterloo, Belgium; (e) Department of Pharmacology, L.M. College of Pharmacy, Navrangpura, Ahmedabad 380 009, Gujarat, India; (f) Council of Scientific Research, New Delhi, India. Douglas Wilson contributed to the evaluation of the science and proofing of the manuscript..

Authors declare no other conflict of interest with the exception that ovolipids for infants were developed by Fabien De Meester.

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    32. F. Jablonka and G. Raz: Transgenerational epigenetic inheritance: prevalence, mechanisms and implications for the study of heredity and evolution. Q Rev Biol 84, 131-176 (2009)
    DOI: 10.1086/598822
    PMid:19606595

    33. Shaan E. Alam, R. B. Singh, Siddharth Gupta, ParinitaDherange, Fabien De Meester, AgnieszkaWilczynska, SunitiDharwadkar, Douglas Wilson, Pali Hungind: Nutritional aspects of epigenetic inheritance. Canad J Physiol Pharmacol 90, 889-894 (2012)
    DOI: 10.1139/y2012-105
    PMid:22803604

    34. T. Harder, E. Rodekamp, K. Schellong, J. W.Dudenhausen and A. Plagemann: Birth weight and subsequent risk of type 2 diabetes: A meta-analysis. Am J Epidemiol 165, 849–57 (2007)
    DOI: 10.1093/aje/kwk071
    PMid:17215379

    35. L. A. van Mierlo, L. R. Arends, M. T. Streppel, M. P. Zeegers, F. J. Kok, D. E. Grobbee, and J. M. Geleijnse. Blood pressure response to calcium supplementation: A meta-analysis of randomized controlled trials. J Hum Hypertens 20, 571–80 (2006)
    DOI: 10.1038/sj.jhh.1002038
    PMid:16673011

    36. Jing Pan , and Kenneth M. Baker: Retinoic acid and the heart. Vitam Horm 75, 257–83 (2007)
    DOI: 10.1016/S0083-6729(06)75010-5

    37. J. McGrath, K.Saari, H. Hakko, J. Jokelainen, P. Jones, M. Jarvelin, David Chant, and MattiIsohanni. Vitamin D supplementation during the first year of life and risk of schizophrenia: A Finnish birth cohort study. Schizophr Res 67, 237–45 (2004)
    DOI: 10.1016/j.schres.2003.08.005
    PMid:14984883

    38. R. G. Ross, S. K. Hunter, L. McCarthy, J Beuler, A. K. Hutchison, B. D. Wagner, Sherry Leonard, Karen E. Stevens, and Robert Freedman: Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. Am J Psychiatry 170, 290–8 (2013)
    DOI: 10.1176/appi.ajp.2012.12070940
    PMid:23318559 PMCid:PMC3640283

    39. B. M. Y. Leung, B. J. Kaplan, C. J. Field, S. Tough, M. Eliasziw, Mariel Fajer Gomez, Linda J. McCargar, and Lisa Gagnon : Prenatal micronutrient supplementation and postpartum depressive symptoms in a pregnancy cohort.BMC Pregnancy and Childbirth 13(2), (2013)

    40. Cindy T. McEvoy, Diane Schilling, Nakia Clay, Keith Jackson, Mitzi D. Go, Patricia Spitale, Carol Bunten, Maria Leiva, David Gonzales, Julie Hollister-Smith, Manuel Durand, Balz Frei, A. Sonia Buist, Dawn Peters, Cynthia D. Morris and Eliot R. Spindel: "Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial." JAMA 311, 2074-2082 (2014)
    DOI: 10.1001/jama.2014.5217
    PMid:24838476 PMCid:PMC4296045

    41. T. Pfab, T. Slowinski, M. Godes, H. Halle, F. Priem and B. Hocher: Low birth weight, a risk factor for cardiovascular diseases in later life, is already associated with elevated fetal glycosylated hemoglobin at birth. Circulation 114, 1687-92 (2006)
    DOI: 10.1161/CIRCULATIONAHA.106.625848
    PMid:17030683

    42. E. Arnesenand A. Forsdahl: The Tromsø heart study: coronary risk factors and their association with living conditions during childhood. J Epidemiol Community Health 39, 210-4 (1985)
    DOI: 10.1136/jech.39.3.210
    PMid:4045360

    43. S. David, D. S. Freedman, L. K. Khan, W. H. Dietz, S. R. Srinivasan and G. S. Berenson: Relationship of childhood obesity to coronary heart disease risk factors in adulthood: The Bogalusa Heart Study. Pediatrics 108, 712 -718 (2001)
    DOI: 10.1542/peds.108.3.712

    44. R. L. Jirtle and M. K. Skinner: Environmental epigenomics and disease susceptibility. Nature Rev Gen 8, 253-262 (2007)
    DOI: 10.1038/nrg2045
    PMid:17363974

    45. T. Handjieva-Darlenska, K. Hristova, and R. B. Singh: Antioxidant vitamins and the heart. World Heart J 6, 179-184 (2014)

    46. B. A. Haider and Z. A. Bhutta: Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst Rev 4, 4–18 (2006)
    DOI: 10.1002/14651858.CD004905.pub2

    47. P. S. Shah and A. Ohlsson: Knowledge synthesis group on determinants of low birth weight and preterm births. Effects of prenatal MMN supplementation on pregnancy outcomes: a meta-analysis. CMAJ 180, E99–E108 (2009)

    48. C. Ronsmans, D. J. Fisher, C. Osmond, B. M. Margetts and C. H. Fall: Maternal Micronutrient Supplementation Study Group: Multiple micronutrient supplementation during pregnancy in low-income countries: a meta-analysis of effects on stillbirths and on early and late neonatal mortality. Food Nutr Bull 30, S547–S557 (2009)

    49. C. H. Fall, D. J. Fisher, C. Osmond and B. M. Margetts: Maternal Micronutrient Supplementation Study Group: Multiple micronutrient supplementation during pregnancy in low-income countries: a meta-analysis of effects on birth size and length of gestation. Food Nutr Bull 30, S533–S546 (2009)

    50. Keith P. West Jr, A. A. Shamim, S. Mehra, A. B. Labrique, H. Ali, S. Shaikh, R. D. Klemm, L. S. Wu, M. Mitra, R. Haque, A. A. Hanif, A. B. Massie, R. D. Merrill, K. J. Schulze, P. Christian: Effect of maternal multiple micronutrient vs iron–folic acid supplementation on infant mortality and adverse birth outcomes in rural Bangladesh The JiVitA-3 Randomized Trial. JAMA 312(24), 2649-2658 (2014)
    DOI: 10.1001/jama.2014.16819
    PMid:25536256

    51. R. B. Singh, P. Visen, D. Sharma, S. Sharma, R Mondal and J.P. Sharma: Study of functional foods consumption patterns among decedents dying due to various causes of death. The Open Nutra J 8, 16-28 (2015)
    DOI: 10.2174/1876396001508010016

    52. R. B. Singh, R. Kumar, G. Cornelissen, T. Takahashi, F. De Meester and S. Baathallah: Obesity is a brain disease? A tribute to prof. Franz halberg. 18th World Congress of Clinical Nutrition, Abstract Book, Ubon Ratchithani, Thailand. Feb 1-3, (2014)

    53. UNICEF/WHO/UNU. Composition of multiple micronutrient supplements to be used in pilot programme among pregnant women in developing countries. New York: NY:UNICEF, (1999)

    54. R. B. Singh, M. A. Niaz, V. Rastogi, R. Beegum and N. K. Singh: Diet, antioxidants and risk of cancer; a case control study. J Nutr Environ Med 7, 267-274 (1997)
    DOI: 10.1080/13590849762385

    55. R. B. Singh, V. Rastogi, R. Singh, M. A. Niaz, S. Srivastav, M. Aslam and N. K. Singh: Magnesium and antioxidant vitamins status and risk of complications of ageing in an elderly urban population. Mag Res 9, 299-306 (1996)

    56. K. Hristova, T. Nakaoka, K. Otsuka, J. Fedacko, R. Singh, R. B. Singh, F. De Meester, A. Wilczynska and D. W. Wilson: Perspectives on Chocolate Consumption and Risk of Cardiovascular Dis-eases and Cognitive Function. The Open Nutraceuticals J 5, 207-212 (2012)
    DOI: 10.2174/1876396001205010207

    57. D. Barraud, P. E. Bollaert and S. Gibot: Impact of the Administration of probiotics on mortality in critically ill adult patients: A meta-analysis of randomized controlled trials. Chest 143, 646-55 (2013)
    DOI: 10.1378/chest.12-1745
    PMid:23460153

    58. M. Loef and H. Walach: The omega-6/omega-3 ratio and dementia or cognitive decline: a systematic review on human studies and biological evidence. J Nutr Gerontol Geriatr, 32, 1-23 (2013)
    DOI: 10.1080/21551197.2012.752335
    PMid:23451843

    59. M. R. Skilton, O. T. Raitakari and D. S. Celermajer: High intake of dietary long-chain?-3 fatty acids is associated with lower blood pressure in children born with low birth weight: NHANES 2003-2008. Hypertension (2013) (Epub ahead of print)PMID: 23460284.

    60. Robert E. Black, Lindsay H. Allen, Zulfiqar A. Bhutta, Laura E. Caulfield, Mercedes De Onis, MajidEzzati, Colin Mathers, Juan Rivera, and Maternal and Child Undernutrition Study Group: Maternal and child undernutrition. The Lancet 371, 243–260 (2008)
    DOI: 10.1016/S0140-6736(07)61690-0

    61. A. Shehab, G. Elkilany, R.B. Singh, K. Hristova, H. Chaves, G Cornelissen, K. Otsuka. Coronary risk factors in southwest Asia. World Heart Journal 7, 21-30 (2015)

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    33. Shaan E. Alam, R. B. Singh, Siddharth Gupta, ParinitaDherange, Fabien De Meester, AgnieszkaWilczynska, SunitiDharwadkar, Douglas Wilson, Pali Hungind: Nutritional aspects of epigenetic inheritance. Canad J Physiol Pharmacol 90, 889-894 (2012)
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    PMid:22803604

    34. T. Harder, E. Rodekamp, K. Schellong, J. W.Dudenhausen and A. Plagemann: Birth weight and subsequent risk of type 2 diabetes: A meta-analysis. Am J Epidemiol 165, 849–57 (2007)
    DOI: 10.1093/aje/kwk071
    PMid:17215379

    35. L. A. van Mierlo, L. R. Arends, M. T. Streppel, M. P. Zeegers, F. J. Kok, D. E. Grobbee, and J. M. Geleijnse. Blood pressure response to calcium supplementation: A meta-analysis of randomized controlled trials. J Hum Hypertens 20, 571–80 (2006)
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    PMid:16673011

    36. Jing Pan , and Kenneth M. Baker: Retinoic acid and the heart. Vitam Horm 75, 257–83 (2007)
    DOI: 10.1016/S0083-6729(06)75010-5

    37. J. McGrath, K.Saari, H. Hakko, J. Jokelainen, P. Jones, M. Jarvelin, David Chant, and MattiIsohanni. Vitamin D supplementation during the first year of life and risk of schizophrenia: A Finnish birth cohort study. Schizophr Res 67, 237–45 (2004)
    DOI: 10.1016/j.schres.2003.08.005
    PMid:14984883

    38. R. G. Ross, S. K. Hunter, L. McCarthy, J Beuler, A. K. Hutchison, B. D. Wagner, Sherry Leonard, Karen E. Stevens, and Robert Freedman: Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. Am J Psychiatry 170, 290–8 (2013)
    DOI: 10.1176/appi.ajp.2012.12070940
    PMid:23318559 PMCid:PMC3640283

    39. B. M. Y. Leung, B. J. Kaplan, C. J. Field, S. Tough, M. Eliasziw, Mariel Fajer Gomez, Linda J. McCargar, and Lisa Gagnon : Prenatal micronutrient supplementation and postpartum depressive symptoms in a pregnancy cohort.BMC Pregnancy and Childbirth 13(2), (2013)

    40. Cindy T. McEvoy, Diane Schilling, Nakia Clay, Keith Jackson, Mitzi D. Go, Patricia Spitale, Carol Bunten, Maria Leiva, David Gonzales, Julie Hollister-Smith, Manuel Durand, Balz Frei, A. Sonia Buist, Dawn Peters, Cynthia D. Morris and Eliot R. Spindel: "Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial." JAMA 311, 2074-2082 (2014)
    DOI: 10.1001/jama.2014.5217
    PMid:24838476 PMCid:PMC4296045

    41. T. Pfab, T. Slowinski, M. Godes, H. Halle, F. Priem and B. Hocher: Low birth weight, a risk factor for cardiovascular diseases in later life, is already associated with elevated fetal glycosylated hemoglobin at birth. Circulation 114, 1687-92 (2006)
    DOI: 10.1161/CIRCULATIONAHA.106.625848
    PMid:17030683

    42. E. Arnesenand A. Forsdahl: The Tromsø heart study: coronary risk factors and their association with living conditions during childhood. J Epidemiol Community Health 39, 210-4 (1985)
    DOI: 10.1136/jech.39.3.210
    PMid:4045360

    43. S. David, D. S. Freedman, L. K. Khan, W. H. Dietz, S. R. Srinivasan and G. S. Berenson: Relationship of childhood obesity to coronary heart disease risk factors in adulthood: The Bogalusa Heart Study. Pediatrics 108, 712 -718 (2001)
    DOI: 10.1542/peds.108.3.712

    44. R. L. Jirtle and M. K. Skinner: Environmental epigenomics and disease susceptibility. Nature Rev Gen 8, 253-262 (2007)
    DOI: 10.1038/nrg2045
    PMid:17363974

    45. T. Handjieva-Darlenska, K. Hristova, and R. B. Singh: Antioxidant vitamins and the heart. World Heart J 6, 179-184 (2014)

    46. B. A. Haider and Z. A. Bhutta: Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst Rev 4, 4–18 (2006)
    DOI: 10.1002/14651858.CD004905.pub2

    47. P. S. Shah and A. Ohlsson: Knowledge synthesis group on determinants of low birth weight and preterm births. Effects of prenatal MMN supplementation on pregnancy outcomes: a meta-analysis. CMAJ 180, E99–E108 (2009)

    48. C. Ronsmans, D. J. Fisher, C. Osmond, B. M. Margetts and C. H. Fall: Maternal Micronutrient Supplementation Study Group: Multiple micronutrient supplementation during pregnancy in low-income countries: a meta-analysis of effects on stillbirths and on early and late neonatal mortality. Food Nutr Bull 30, S547–S557 (2009)

    49. C. H. Fall, D. J. Fisher, C. Osmond and B. M. Margetts: Maternal Micronutrient Supplementation Study Group: Multiple micronutrient supplementation during pregnancy in low-income countries: a meta-analysis of effects on birth size and length of gestation. Food Nutr Bull 30, S533–S546 (2009)

    50. Keith P. West Jr, A. A. Shamim, S. Mehra, A. B. Labrique, H. Ali, S. Shaikh, R. D. Klemm, L. S. Wu, M. Mitra, R. Haque, A. A. Hanif, A. B. Massie, R. D. Merrill, K. J. Schulze, P. Christian: Effect of maternal multiple micronutrient vs iron–folic acid supplementation on infant mortality and adverse birth outcomes in rural Bangladesh The JiVitA-3 Randomized Trial. JAMA 312(24), 2649-2658 (2014)
    DOI: 10.1001/jama.2014.16819
    PMid:25536256

    51. R. B. Singh, P. Visen, D. Sharma, S. Sharma, R Mondal and J.P. Sharma: Study of functional foods consumption patterns among decedents dying due to various causes of death. The Open Nutra J 8, 16-28 (2015)
    DOI: 10.2174/1876396001508010016

    52. R. B. Singh, R. Kumar, G. Cornelissen, T. Takahashi, F. De Meester and S. Baathallah: Obesity is a brain disease? A tribute to prof. Franz halberg. 18th World Congress of Clinical Nutrition, Abstract Book, Ubon Ratchithani, Thailand. Feb 1-3, (2014)

    53. UNICEF/WHO/UNU. Composition of multiple micronutrient supplements to be used in pilot programme among pregnant women in developing countries. New York: NY:UNICEF, (1999)

    54. R. B. Singh, M. A. Niaz, V. Rastogi, R. Beegum and N. K. Singh: Diet, antioxidants and risk of cancer; a case control study. J Nutr Environ Med 7, 267-274 (1997)
    DOI: 10.1080/13590849762385

    55. R. B. Singh, V. Rastogi, R. Singh, M. A. Niaz, S. Srivastav, M. Aslam and N. K. Singh: Magnesium and antioxidant vitamins status and risk of complications of ageing in an elderly urban population. Mag Res 9, 299-306 (1996)

    56. K. Hristova, T. Nakaoka, K. Otsuka, J. Fedacko, R. Singh, R. B. Singh, F. De Meester, A. Wilczynska and D. W. Wilson: Perspectives on Chocolate Consumption and Risk of Cardiovascular Dis-eases and Cognitive Function. The Open Nutraceuticals J 5, 207-212 (2012)
    DOI: 10.2174/1876396001205010207

    57. D. Barraud, P. E. Bollaert and S. Gibot: Impact of the Administration of probiotics on mortality in critically ill adult patients: A meta-analysis of randomized controlled trials. Chest 143, 646-55 (2013)
    DOI: 10.1378/chest.12-1745
    PMid:23460153

    58. M. Loef and H. Walach: The omega-6/omega-3 ratio and dementia or cognitive decline: a systematic review on human studies and biological evidence. J Nutr Gerontol Geriatr, 32, 1-23 (2013)
    DOI: 10.1080/21551197.2012.752335
    PMid:23451843

    59. M. R. Skilton, O. T. Raitakari and D. S. Celermajer: High intake of dietary long-chain?-3 fatty acids is associated with lower blood pressure in children born with low birth weight: NHANES 2003-2008. Hypertension (2013) (Epub ahead of print)PMID: 23460284.

    60. Robert E. Black, Lindsay H. Allen, Zulfiqar A. Bhutta, Laura E. Caulfield, Mercedes De Onis, MajidEzzati, Colin Mathers, Juan Rivera, and Maternal and Child Undernutrition Study Group: Maternal and child undernutrition. The Lancet 371, 243–260 (2008)
    DOI: 10.1016/S0140-6736(07)61690-0

    61. A. Shehab, G. Elkilany, R.B. Singh, K. Hristova, H. Chaves, G Cornelissen, K. Otsuka. Coronary risk factors in southwest Asia. World Heart Journal 7, 21-30 (2015)

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RB Singh, Sanjay Mishra, Shailesh Kumar, Amit Mani Tiwari, Fabien De Meester, Ramesh K Goyal, Kumar Kartikey, Meenakshi Singh. Micronutrient formulations for prevention of complications of pregnancy. Frontiers in Bioscience-Scholar. 2018. 10(1); 175-184.