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.
British epidemiologist, Dr. David Barker’s keen observations have been popularized as the “Barker hypothesis” or “Fetal Origins of Adult Disease” (FOAD). The critical period coincides with the timing of rapid cell differentiation. Essentially, programming refers to the process of sustaining or affecting a stimulus or impairment that occurs at a crucial point in its development.
Low birth weight affects large numbers of infants in developing countries. Premature delivery makes a major contribution, but unlike the situation in developed countries, intrauterine growth retardation (IUGR) is the predominant cause. IUGR carries both short- and long-term disadvantages for the infant. Short-term consequences of IUGR include an increased risk of fetal, neonatal, infant death and impaired postnatal growth, immune function and intellectual development. Long term consequences include an increased risk of adult chronic disease (cardiovascular disease and type 2 diabetes). This increased risk has been attributed to permanent change in structure and metabolism resulting from undernutrition during critical periods of early development (the fetal origins of adult disease hypothesis). An inadequate supply of nutrients forces the fetus to adapt, down-regulate growth and prioritize the development of essential tissues. Adaptations include preferential blood flow to the brain and reduced flow to the abdominal viscera, altered body composition (reduced muscle mass) and reduced secretion and sensitivity to the fetal growth hormones (insulin-like growth hormone and insulin).
Maternal Nutrition and Fetal Growth
Fetal growth depends on the uptake of nutrients, which occurs at the end of a complex maternal supply line that begins with the mother’s intake (appetite, diet, absorption). The nutritional status of the mother, which is an important factor that affects the programming 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 the placenta depend on the mother’s intermediary metabolism and endocrine status; her partitioning of nutrients among storage, use and circulation; the capacity of circulating transport proteins; and cardiovascular adaptations to pregnancy, such as plasma volume expansion, which determine uterine blood flow. These are influenced by her nutritional status and infection load in ways that are poorly understood.
The fetus adapts to maternal malnutrition through changes in the production of fetal and placental hormones that regulate metabolism, redistribute blood flow and control growth. The immediate metabolic response of the fetus to malnutrition is to consume its substrate to produce energy through catabolism. Undernourishment of the fetus causes metabolic dependence on glucose to both decrease and increase the oxidation of other substrates, such as amino acids and lactic acid. Extended malnutrition results in delayed growth, reducing substrate use and lowering the metabolic rate, to interfere fetal viability.
If fetus is exposed to undernutrition or malnutrition during rapid cell differentiation of the pancreatic beta cells due to maternal and placental abnormalities, it will try to overcome these limitations through metabolic programming. This process will cause impaired development of the endocrine pancreas, which results in poor insulin secretion.
Epidemiological Observations
A study traced 16.000 men and women born in Hertfordshire, England, from 1911 to 1930 from birth and showed that the mortality rate from coronary heart disease was twice as high in those with low birth weights that it was in the high birth weight group. Birth weight and adult blood pressure also showed an inverse correlation. Prominent alterations associated with fetal programming included insulin resistance, hypertension and increased serum low-density lipoprotein (LDL) cholesterol and fibrogen concentrations, which are all characteristics of metabolic syndrome.
According to PUSDATIN (Pusat Data dan Informasi Kementrian Kesehatan Republik Indonesia) 2019, the number of diabetes patients in Indonesia reached 10,7 million and was ranked 7th with the most diabetes patients in the world. And from Riskesdas, data shows the prevalence of cardiovascular diseases such as hypertension, coronary heart disease, chronic kidney failure, and stroke increased.
Within this framework, the fetal genome determines the intrauterine growth potential, but actual growth is primarily determined by environmental effects, such as fetal nutrition and the hormonal environment.
Fetal programming can affect individual gene expression at any stage, from changes in molecular biological functions, such as receptor cell density or sensitivity, to permanent hormonal changes or even alterations in metabolism or responses to physiological stressor.
Nutrition delivered through the placenta is an especially important determinant of fetal growth because it allows the fetus to meet the growth potential determined by the underlying genotype. Recent reports have emphasized the impact of interactions between genotypes and the uterine environment.
The Placenta’s Role in Fetal Programming
Several epidemiological studies have reported on the relationship between placental weight and the placental weight/birth weight ratio in fetal programming, and there are ongoing animal dan human studies on the overall role of the placenta in fetal programming. The placenta regulates maternal-to-fetal nutritional composition and supply. It is also the source of hormonal signals that affect maternal and fetal metabolism. Proper development of the placenta is critical to normal fetal development and plays and active role in programming the in utero fetal experience, which influences diseases that may apperar in adulthood. The function of the placenta develops gradually in a series of closely organized developmental stages of pregnancy. The timing of any abnormalities in development will be crucial to the resulting placental function and thus to fetal programming. This damage, which alters placental development, includes hypoxia and abnormal maternal nutrition.
Hypoxia, oxidation, and nitrification stress all alter placental development, and the associated changes in placental function may be the general fundamental mechanism underlying fetal programming.
Maternal micronutrient status has been posited to influence hormonal regulatory pathways in the developing fetus and neonate. Vitamins and minerals are essential for human health and development. It has been estimated that 2 billion people worldwide suffer from at least 1 form of micronutrient deficiency.
For a number of reasons, it is plausible to hypothesize that deficiency of vitamins and minerals during critical stages of development will have long lasting health consequences.
1. Cardiovascular - Kidney Function
Cardiac and vascular morphogenesis is guided by a complex series of events in early gestation. An alteration in the maternal environment may result in irreversible nephron deficits determined before birth. Risk factors for cardiovascular disease, including endothelial dysfunction, intima-media thickness, microvascular density, and arterial compliance, have been studied in relation to their association with size at birth. Some research have examined that vitamins A and D, folate, iron, and zinc is correlated to cardiovascular function.
Vitamin A: There is strong evidence that maternal vitamin A status during embryonic and fetal periods is important for normal cardiac development. RA, the biologically active form of vitamin A, is an important signaling molecule during fetal cardiovascular development. A state of both deficiency and excess has been associated with congenital malformations in both human and animal studies.
Folate / 5-MTHF: Maternal folate status may attenuate some of the adverse effects of protein restriction. Folate supplementation restored vasodilatation response to VEGF (vascular endothelial growth factor) and reduce SBP (systolic blood pressure) but did not affect NO synthase mRNA levels. It has also been postulated that folate levels in human pregnancies are associated with endothelial function in the neonate, maybe through oxidative inactivation and reduced synthesis of NO.
Zinc: Severe zinc deficiency can cause developmental impairments to the heart, among other organs. Women with moderate zinc deficiency were supplemented during pregnancy and their fetuses were monitored. The zinc-supplemented group had a lower mean heart rate at 20 week of gestation.
Maternal iron or zinc deficiency results in an increase in the relative weight of the kidneys and reduction in nephron number in the offspring. Greater sodium sensitivity may explain some of the effects on blood pressure among offspring of iron-restricted dams, who had a 2-fold greater response to sodium intake on mean arterial pressure at 36 week of age.
Iron / Fe: Hypoxia as a result of maternal iron deficiency increases cardiac size and decreases the number of cardiomyocytes and capillaries. Iron deficiency during the embryonic period resulted in reduced embryonic growth, increased heart size, and delayed vascular development. Embryonic hypertension, with an increase in vascular resistance due to decreased angiogenesis, may also partially explain the observed increase in heart size.
2. Pancreas dan β-cells
There is limited evidence that deficiencies in vitamin A, folate, zinc, and iron may have an effect on pancreatic development or the pathogenesis of insulin resistance.
Folate and Vitamin B12: Gestational folate or vitamin B12 status may be predictors of insulin resistance via epigenetic mechanisms. One observational study found lower maternal erythrocyte folate concentration at 28 week and low vitamin B12 status at 18 weeks gestation to be associated with higher adiposity and insulin resistance, measured by the homeostasis model assessment, among children at 6 years of age.
Zinc and Iron: Zinc is essential for the activities of pancreatic β-cells, especially insulin storage and secretion. Insulin secretion leads to co-release of zinc contributes the paracrine communication in the pancreatic islets. In particular, Zinc is needed for the correct storage of insulin in secretory vesicles by ensuring that insulin forms crystalline structures. Furthermore, Zinc is co-secreted with insulin and is involved in paracrine and autocrine communications within the pancreas. Higher serum zinc concentration is associated with increased insulin sensitivity.
Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. The link between iron and diabetes first emerged considering pathological conditions as hemochromatosis and beta thalassemia.
3. Body Composition and Adiposity
Developmental programming may influence body composition through appetite regulation, a propensity for increased sedentary behaviour, epigenetic modification of key regulatory genes, and altered fat deposition and adipocyte metabolism.
Maternal dietary restriction in iron, zinc, calcium, and magnesium, individually or in combination, was found to result in increased percent body fat and some varying effects on insulin resistance in the offspring. Maternal supplementation during pregnancy with iron + folate + zinc, resulted in slight increase in height and decreased adiposity as reflected by lower skinfold thickness in children at 6-8 years of age relative to controls.
4. The Lung
Many respiratory pathologies in adulthood appear to have their origins in impaired growth and maturation of the lung in utero.
Vitamin A: The lungs are sensitive to maternal vitamin A deficiency. In particular, deficiency results in immature lungs with reduced bronchial branching and reduced elastin (important for maturation of alveoli both in the number and size, which in turn influences lung capacity in the neonate). Retinoids are critical in lung development and maturation during the early postnatal period when lung structures are rapidly developing.
Vitamin D: It is well known that vitamin D plays an important role in bone health and the immune system, evidence is emerging, 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, respiratory muscle strength and immune response to respiratory pathogens.
Vitamin E: Vitamin E has anti-oxidant properties whose primary function is as a chain-breaking anti-oxidant, preventing peroxidation of lipid molecules. Because oxidative stress and inflammation are features of many lung diseases, nutrients with anti-oxidant and anti-inflammatory properties could be a useful tool in prevention or treatment.
5. Cerebrovascular
5-MTHF: Cerebral folate deficiency (CFD) is a medical condition in which the 5-MTHF in the brain is depleted. Insufficient 5-MTHF in the brain can cause developmental delay, developmental deterioration, epileptic seizures, psychiatric symptoms, and leukoencephalopathy. Periferal 5-MTHF deficiency is caused by nutritional folate deficiency, reduced folate absorption from the intestine, and inborn errors of folate metabolism affecting 5-MTHF biosynthesis including methylenetetrahydrofolate reductase (MTHFR) deficiency.
Vitamin B12: Vitamin B12, along with other B-vitamins, acts as co-factors by specific enzymes to carry out metabolic function in the body. A vitamin B12 deficiency can be caused by a reduced dietary intake, frequently in the case of a vegetarian diet, and or changes in absorption. Study found that poor vitamin B12 status was significantly associated with greater severity of white matter lesions in the brain, which may be a result of reduced myelin integrity.
DHA: DHA has also been shown to have a number of neuroprotective effects including suppressing pro-inflammatory pathways and upregulating pro-resolving mediators such as neuroprotection D1, modulating mitochondrial function and reducing oxidative stress. Dietary DHA is also know to modulate a number of neurotransmitter systems including the cholinergic system, which is known to play a key role in memory and learning and the degradation of which is associated with the typical cognitive deficits observed in normal and pathological aging.
PT. SIMEX PHARMACEUTICAL INDONESIA as one of the pharmaceutical companies in Indonesia presents MAXMIL® products as a pregnancy supplement containing 18 critical micronutrients for pregnancy and breastfeeding. MAXMIL® has a role in preventing the occurrence of micronutrient deficiencies in pregnant women. MAXMIL® contains multivitamin 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?: a lifetime health is under the control of in utero health. Obstet Gynecol Sci 2017; 60(6): 506-519
Marku A., Galli A., Marciani P., et.al. 2021. Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction. MDPI: Cells 2021, 10, 2841.
Nygaard SB., Larsen A., et.al. 2014. Effects of zinc supplementation and zinc chelation on in vitro β-cell function in INS-IE cells. BMC Research Notes 2014, 7:84
Akiyama T., Kuki I., Kim K., et.al. 2022. Folic acid inhibits 5-methyltetrahydrofolate transport across the blood-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., Bell JG., et.al. 2016. DHA Supplementation Alone in Combination with Other Nutrients Does not Modulate Cerebral Hemodynamics or Cognitive Function in Healthy Older Adults. MDPI: Nutrients 2016, 8, 86.
