Micronutrients for Fetal Reprogramming
For many years, adult lifestyle factors have been believed to be the primary cause of major health problems. Obesity, heart disease and diabetes are known to stem from a sedentary lifestyle associated with a fat- and salt-rich diet is a risk factor for this chronic disease.
Micronutrients for Fetal Reprogramming
For many years, adult lifestylefactors have been believed to be the primary cause of major health problems.Obesity, heart disease and diabetes are known to stem from a sedentarylifestyle associated with a fat- and salt-rich diet is a risk factor for thischronic disease.
British epidemiologist, Dr. DavidBarker’s keen observations have been popularized as the “Barker hypothesis” or“Fetal Origins of Adult Disease” (FOAD). The critical period coincides with thetiming of rapid cell differentiation. Essentially, programming refers to theprocess of sustaining or affecting a stimulus or impairment that occurs at acrucial point in its development.
Low birth weight affects largenumbers of infants in developing countries. Premature delivery makes a majorcontribution, but unlike the situation in developed countries, intrauterinegrowth retardation (IUGR) is the predominant cause. IUGR carries both short-and long-term disadvantages for the infant. Short-term consequences of IUGR includean increased risk of fetal, neonatal, infant death and impaired postnatalgrowth, immune function and intellectual development. Long term consequencesinclude an increased risk of adult chronic disease (cardiovascular disease andtype 2 diabetes). This increased risk has been attributed to permanent changein structure and metabolism resulting from undernutrition during criticalperiods of early development (the fetal origins of adult disease hypothesis).An inadequate supply of nutrients forces the fetus to adapt, down-regulategrowth and prioritize the development of essential tissues. Adaptations includepreferential blood flow to the brain and reduced flow to the abdominal viscera,altered body composition (reduced muscle mass) and reduced secretion andsensitivity to the fetal growth hormones (insulin-like growth hormone andinsulin).
Maternal Nutrition and FetalGrowth
Fetal growth depends on theuptake of nutrients, which occurs at the end of a complex maternal supply linethat begins with the mother’s intake (appetite, diet, absorption). Thenutritional status of the mother, which is an important factor that affects theprogramming of the body, involves factors such as maternal body composition,maternal dietary intake, fetal genes, blood flow to the uterus and placenta.
Nutrients arriving at theplacenta depend on the mother’s intermediary metabolism and endocrine status;her partitioning of nutrients among storage, use and circulation; the capacityof circulating transport proteins; and cardiovascular adaptations to pregnancy,such as plasma volume expansion, which determine uterine blood flow. These areinfluenced by her nutritional status and infection load in ways that are poorlyunderstood.
The fetus adapts to maternal malnutritionthrough changes in the production of fetal and placental hormones that regulatemetabolism, redistribute blood flow and control growth. The immediate metabolicresponse of the fetus to malnutrition is to consume its substrate to produceenergy through catabolism. Undernourishment of the fetus causes metabolicdependence on glucose to both decrease and increase the oxidation of othersubstrates, such as amino acids and lactic acid. Extended malnutrition resultsin delayed growth, reducing substrate use and lowering the metabolic rate, to interferefetal viability.
If fetus is exposed toundernutrition or malnutrition during rapid cell differentiation of thepancreatic beta cells due to maternal and placental abnormalities, it will tryto overcome these limitations through metabolic programming. This process willcause impaired development of the endocrine pancreas, which results in poorinsulin secretion.
Epidemiological Observations
A study traced 16.000 men andwomen born in Hertfordshire, England, from 1911 to 1930 from birth and showedthat the mortality rate from coronary heart disease was twice as high in thosewith low birth weights that it was in the high birth weight group. Birth weightand adult blood pressure also showed an inverse correlation. Prominentalterations associated with fetal programming included insulin resistance,hypertension and increased serum low-density lipoprotein (LDL) cholesterol andfibrogen concentrations, which are all characteristics of metabolic syndrome.
According to PUSDATIN (PusatData dan Informasi Kementrian Kesehatan Republik Indonesia) 2019, thenumber of diabetes patients in Indonesia reached 10,7 million and was ranked 7thwith the most diabetes patients in the world. And from Riskesdas, data showsthe prevalence of cardiovascular diseases such as hypertension, coronary heartdisease, chronic kidney failure, and stroke increased.
Mechanism of Fetal Programming
Within this framework, the fetalgenome determines the intrauterine growth potential, but actual growth isprimarily determined by environmental effects, such as fetal nutrition and thehormonal environment.
Fetal programming can affectindividual gene expression at any stage, from changes in molecular biologicalfunctions, such as receptor cell density or sensitivity, to permanent hormonalchanges or even alterations in metabolism or responses to physiologicalstressor.
1. Gene-imprinting (DNA methylation/chromatinremodeling)
2. Cell-alterations in the receptordensity/metabolic breakdown of messengers
3. Organ-structural changes/alterations in organvolume/tissue composition
4. System-resseting of hormonal axes/altered stressresponses
Nutrition delivered through the placenta is an especially importantdeterminant of fetal growth because it allows the fetus to meet the growthpotential determined by the underlying genotype. Recent reports have emphasizedthe impact of interactions between genotypes and the uterine environment.
The Placenta’s Role in Fetal Programming
Several epidemiological studies have reported on therelationship between placental weight and the placental weight/birth weightratio in fetal programming, and there are ongoing animal dan human studies onthe overall role of the placenta in fetal programming. The placenta regulatesmaternal-to-fetal nutritional composition and supply. It is also the source ofhormonal signals that affect maternal and fetal metabolism. Proper developmentof the placenta is critical to normal fetal development and plays and activerole in programming the in utero fetal experience, which influences diseasesthat may apperar in adulthood. The function of the placenta develops graduallyin a series of closely organized developmental stages of pregnancy. The timingof any abnormalities in development will be crucial to the resulting placentalfunction and thus to fetal programming. This damage, which alters placentaldevelopment, includes hypoxia and abnormal maternal nutrition.
Hypoxia, oxidation, and nitrification stress all alterplacental development, and the associated changes in placental function may bethe general fundamental mechanism underlying fetal programming.
Maternal MicronutrientDeficiency
Maternal micronutrient status hasbeen posited to influence hormonal regulatory pathways in the developing fetus andneonate. Vitamins and minerals are essential for human health and development.It has been estimated that 2 billion people worldwide suffer from at least 1form of micronutrient deficiency.
For a number of reasons, it isplausible to hypothesize that deficiency of vitamins and minerals duringcritical stages of development will have long lasting health consequences.
1. Cardiovascular - Kidney Function
Cardiac and vascular morphogenesis is guided by acomplex series of events in early gestation. An alteration in the maternalenvironment may result in irreversible nephron deficits determined beforebirth. Risk factors for cardiovascular disease, including endothelialdysfunction, intima-media thickness, microvascular density, and arterialcompliance, have been studied in relation to their association with size atbirth. Some research have examined that vitamins A and D, folate, iron, andzinc is correlated to cardiovascular function.
Vitamin A: There is strong evidence thatmaternal vitamin A status during embryonic and fetal periods is important fornormal cardiac development. RA, the biologically active form of vitamin A, isan important signaling molecule during fetal cardiovascular development. Astate of both deficiency and excess has been associated with congenitalmalformations in both human and animal studies.
Folate / 5-MTHF: Maternal folate status mayattenuate some of the adverse effects of protein restriction. Folatesupplementation restored vasodilatation response to VEGF (vascularendothelial growth factor) and reduce SBP (systolic blood pressure)but did not affect NO synthase mRNA levels. It has also been postulated thatfolate levels in human pregnancies are associated with endothelial function inthe neonate, maybe through oxidative inactivation and reduced synthesis of NO.
Zinc: Severe zinc deficiency can causedevelopmental impairments to the heart, among other organs. Women with moderatezinc deficiency were supplemented during pregnancy and their fetuses weremonitored. The zinc-supplemented group had a lower mean heart rate at 20 weekof gestation.
Maternal iron or zinc deficiency results in anincrease in the relative weight of the kidneys and reduction in nephron numberin the offspring. Greater sodium sensitivity may explain some of the effects onblood pressure among offspring of iron-restricted dams, who had a 2-foldgreater response to sodium intake on mean arterial pressure at 36 week of age.
Iron / Fe: Hypoxia as a result of maternal irondeficiency increases cardiac size and decreases the number of cardiomyocytesand capillaries. Iron deficiency during the embryonic period resulted inreduced embryonic growth, increased heart size, and delayed vasculardevelopment. Embryonic hypertension, with an increase in vascular resistancedue to decreased angiogenesis, may also partially explain the observed increasein heart size.
2. Pancreas dan β-cells
There is limited evidence that deficiencies in vitaminA, folate, zinc, and iron may have an effect on pancreatic development or thepathogenesis of insulin resistance.
Folate and Vitamin B12: Gestational folate orvitamin B12 status may be predictors of insulin resistance via epigeneticmechanisms. One observational study found lower maternal erythrocyte folateconcentration at 28 week and low vitamin B12 status at 18 weeks gestation to beassociated with higher adiposity and insulin resistance, measured by thehomeostasis model assessment, among children at 6 years of age.
Zinc and Iron: Zinc is essential for theactivities of pancreatic β-cells, especially insulin storage and secretion. Insulinsecretion leads to co-release of zinc contributes the paracrine communicationin the pancreatic islets. In particular, Zinc is needed for the correct storageof insulin in secretory vesicles by ensuring that insulin forms crystallinestructures. Furthermore, Zinc is co-secreted with insulin and is involved inparacrine and autocrine communications within the pancreas. Higher serum zincconcentration is associated with increased insulin sensitivity.
Iron is an essential element involved in a variety ofphysiological functions. In the pancreatic beta-cells, being part of Fe-Scluster proteins, it is necessary for the correct insulin synthesis andprocessing. The link between iron and diabetes first emerged consideringpathological conditions as hemochromatosis and beta thalassemia.
3. Body Composition and Adiposity
Developmental programming may influence bodycomposition through appetite regulation, a propensity for increased sedentarybehaviour, epigenetic modification of key regulatory genes, and altered fatdeposition and adipocyte metabolism.
Maternal dietary restriction in iron, zinc, calcium,and magnesium, individually or in combination, was found to result in increasedpercent body fat and some varying effects on insulin resistance in theoffspring. Maternal supplementation during pregnancy with iron + folate + zinc,resulted in slight increase in height and decreased adiposity as reflected bylower skinfold thickness in children at 6-8 years of age relative to controls.
4. The Lung
Many respiratory pathologies in adulthood appear tohave their origins in impaired growth and maturation of the lung in utero.
Vitamin A: The lungs are sensitive to maternalvitamin A deficiency. In particular, deficiency results in immature lungs withreduced bronchial branching and reduced elastin (important for maturation ofalveoli both in the number and size, which in turn influences lung capacity inthe neonate). Retinoids are critical in lung development and maturation duringthe early postnatal period when lung structures are rapidly developing.
Vitamin D: It is well known that vitamin Dplays an important role in bone health and the immune system, evidence isemerging, which shows that vitamin D levels are associated with better lung function,suggesting it plays an important role in maintaining good respiratory health.It is believed that vitamin D has an impact on lung structure, respiratorymuscle strength and immune response to respiratory pathogens.
Vitamin E: Vitamin E has anti-oxidantproperties whose primary function is as a chain-breaking anti-oxidant,preventing peroxidation of lipid molecules. Because oxidative stress andinflammation are features of many lung diseases, nutrients with anti-oxidantand anti-inflammatory properties could be a useful tool in prevention ortreatment.
5. Cerebrovascular
5-MTHF: Cerebral folate deficiency (CFD) is amedical condition in which the 5-MTHF in the brain is depleted. Insufficient5-MTHF in the brain can cause developmental delay, developmental deterioration,epileptic seizures, psychiatric symptoms, and leukoencephalopathy. Periferal5-MTHF deficiency is caused by nutritional folate deficiency, reduced folateabsorption from the intestine, and inborn errors of folate metabolism affecting5-MTHF biosynthesis including methylenetetrahydrofolate reductase (MTHFR)deficiency.
Vitamin B12: Vitamin B12, along with otherB-vitamins, acts as co-factors by specific enzymes to carry out metabolicfunction in the body. A vitamin B12 deficiency can be caused by a reduceddietary intake, frequently in the case of a vegetarian diet, and or changes inabsorption. Study found that poor vitamin B12 status was significantlyassociated with greater severity of white matter lesions in the brain, whichmay be a result of reduced myelin integrity.
DHA: DHA has also been shown to have a number ofneuroprotective effects including suppressing pro-inflammatory pathways andupregulating pro-resolving mediators such as neuroprotection D1, modulatingmitochondrial function and reducing oxidative stress. Dietary DHA is also knowto modulate a number of neurotransmitter systems including the cholinergicsystem, which is known to play a key role in memory and learning and thedegradation of which is associated with the typical cognitive deficits observedin normal and pathological aging.
PT. SIMEXPHARMACEUTICAL INDONESIA as one of the pharmaceutical companies inIndonesia presents MAXMIL® products as a pregnancysupplement containing 18 critical micronutrients for pregnancy andbreastfeeding. MAXMIL® has a rolein preventing the occurrence of micronutrient deficiencies in pregnant women. MAXMIL® containsmultivitamin and mineral, such as: 4th Generation Folate (as(6S)-5-Methyltetrahydrofolic acid glucosamine salt), Coral calcium, Vitamin K2,Fe, Vitamin C, DHA, Vitamin B12, Magnesium, Vitamin E, Vitamin D3, Vitamin B6,Zinc, Potassium Iodide, Vitamin B1, Vitamin B2, Nicotinamide, and Biotin.
Sumber
Calkins K., Devaskar SU. 2015.Fetal Origins of Adults Disease. Curr Probl Pediatr Adolesc Health 2011 July;41(6): 158 – 176.
Kwon EJ., Kim YJ. 2017. What is fetal programming?: alifetime health is under the control of in utero health. Obstet Gynecol Sci2017; 60(6): 506-519
Marku A., Galli A., Marciani P., et.al. 2021. IronMetabolism in Pancreatic Beta-Cell Function and Dysfunction. MDPI: Cells 2021,10, 2841.
Nygaard SB., Larsen A., et.al. 2014. Effects of zincsupplementation and zinc chelation on in vitro β-cell function in INS-IEcells. BMC Research Notes 2014, 7:84
Akiyama T., Kuki I., Kim K.,et.al. 2022. Folic acid inhibits 5-methyltetrahydrofolate transport across theblood-cerebrospinal fluid barrier: Clinical biochemical data from two cases.JMID Reports. 2022;63:529-535
Yahn GB., Abato JE., Jadavji NM.2020. Role of vitamin B12 deficiency in ischemic stroke risk and outcome.Neural Regeneration Research, Vol. 16, No.3., March 2021
Jackson PA., Forster JS., BellJG., et.al. 2016. DHA Supplementation Alone in Combination with Other NutrientsDoes not Modulate Cerebral Hemodynamics or Cognitive Function in Healthy OlderAdults. MDPI: Nutrients 2016, 8, 86.