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Possible relationship between low birth weight and magnesium status: from the standpoint of “fetal origin” hypothesis

Magnesium Research. Volume 19, Numéro 1, 63-9, March 2006, Review article

Summary

Auteur(s) : Junji Takaya, Fumiko Yamato, Kazunari Kaneko , Department of Pediatrics, Kansai Medical University, Moriguchi, Osaka, Japan.

Illustrations

ARTICLE

Auteur(s) : Junji Takaya, Fumiko Yamato, Kazunari Kaneko

Department of Pediatrics, Kansai Medical University, Moriguchi, Osaka, Japan

Several studies have shown the association of size at birth or indications of poor fetal growth with later development of metabolic syndromes and insulin resistance [1]. Hales et al. [2] proposed that impaired glucose tolerance and type 2 diabetes may arise as a result of programming, a term used to describe persistent changes in organ structure and function caused by exposure to adverse environmental influences during critical periods of development [3]. Because size at birth is determined largely by non-genetic factors, these findings have led to the “fetal origin” hypothesis, which proposes that fetal adaptation to an adverse intrauterine environment affecting fetal growth may program lifelong physiological changes [4].Magnesium (Mg) is an important cofactor for the enzymes involved in carbohydrate metabolism: an important role of Mg in insulin action has been reported [5]; in adults and in children, low serum and intracellular Mg ([Mg²⁺]_i) concentrations are associated with insulin resistance, impaired glucose tolerance, and decreased insulin secretion [6, 7]. Furthermore, lower dietary Mg intake could cause insulin resistance both in children and adults [8, 9]. Based on these findings, we studied whether low [Mg²⁺]_i in the fetus may be one of the critical abnormalities associated with low birth weight infants.In this review, we hypothesize that intrauterine magnesium deficiency may induce metabolic syndromes in later life. We discuss the potential contribution of aberrant Mg regulation to low birth weight and to the pathogenesis of metabolic syndromes.

Magnesium deficiency

It is reported that the amount of maternal Mg intake is not only associated with pregnancy outcome but also with infant health [10]. From a cohort study consisting of 912 people, aged 50 years, born as term singletons around the time of the 1944-1945 Dutch famine, coronary heart disease, raised lipids, altered clotting and obesity were more frequently observed after exposure to famine in early gestation compared to those not exposed to famine, and decreased glucose tolerance was more frequently found in people exposed to famine in later gestation [12]. These findings show that maternal undernutrition during gestation has serious effects on health in later life. Another study demonstrated that the risk of having very low birth weight infants (less than 1,500 g birth weight) is reduced if the mother’s drinking water contains higher amounts of Mg [11]. By the end of normal pregnancy, the fetus is believed to acquire approximately 28 g of calcium, 16 g of phosphorous and 0.7 g of Mg, mostly during the third trimester: 80% of fetal accretion of Mg occurs during the third trimester [13]. Barker speculated that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmed later metabolic disease [4].

From these findings, maternal undernutrition, including Mg deficiency during gestation, obviously affects the health of the fetus in adult life, while the timing of the nutritional insult on the mother is an important determinate.

Placental transport

The levels of total calcium, ionized calcium, and Mg are higher in fetal circulation compared to those in the maternal blood [14]. Copper and selenium share the same transport pathway in the placental membrane along a concentration gradient in maternal-fetal direction, while an active transport plays a predominant role for Mg and iron [15]. In fact, the existence of an active transport mechanism for Mg in the placenta was recently suggested by using cultured trophoblast cells, i.e. a functional Na⁺/Mg²⁺ exchanger that functions to maintain low [Mg²⁺]_i in the cells [16]. The activity of this exchanger might be influenced by maternal plasma sodium concentration because acute maternal hyponatremia in experimental rats reduced the maternal-fetal transfer of Mg via placenta [17], while there may be other pathways of Mg transport in the placenta. Whereas mean levels of ionized calcium do not change during labor, the mean maternal serum levels of ionized Mg and total Mg fall at delivery, which suggests the presence of homeostatic mechanisms in the fetus and placenta, indicating that free Mg in umbilical venous blood may enhance Mg transport to the fetus [18].

In mammals, the nutrient exchange process takes place across the placenta, a highly developed organ with numerous functions throughout the most of gestational period, and maternal-fetal homeostasis depends on a properly functioning placenta. Maternal Mg deficiency obviously affects health of the fetus.

Placental vascular flow and magnesium

Calcium and Mg are co-factors in the synthetic activity of a variety of enzymes. A variety of hormones, cytokines and growth factors produced by fetal membranes and placenta can act locally on the myometrium [19]. The ability of the uterine artery to dilate during pregnancy may be specifically related to upregulation of multiple pathways for production of nitric oxide (NO) [20]. The activity of constitutive NO synthase is dependent on calcium and is inhibited by a reduction in the concentration of Mg [21]. Markedly reduced permeability to calcium and Mg of fetal membranes in preterm labor suggests that this abnormality could be an important factor for the activation of the myometrium in preterm labor [22]. Placental insufficiency as well as maternal malnutrition is also an important cause for IUGR (( figure 1 )). Model experiments of IUGR have been conducted by the reduced uterine blood flow. One of these IUGR models was prepared by uterine artery ligation in pregnant dams and their offspring were studied: Jansson & Lambert reported that this IUGR model was associated with impaired glucose tolerance in adult life, only in female rats [23].

Mg has an immediate effect on placental vascular flow as well as Ca and NO. Reduced placental vascular flow is at least, in part, responsible for placental insufficiency and IUGR.

Mg sulfate and pre-eclampsia

Mg is widely used in obstetric practice to treat pre-eclampsia. Therapeutic levels of Mg have also been found to produce specific placental effects such as vasodilation [24]. From the study of human umbilical artery resistance in vitro [25], Mg sulfate exerts a relaxant effect on umbilical arterial tone, attenuating the vasoconstrictor effect of angiotensin II and endothelin-1 in the fetal-placental vasculature. It did not affect, however, the activity of thromboxane mimetic. In addition, angiotensin II and thromboxane mimetic were shown to induce interleukin (IL)-1β secretion by placental tissue, and this effect was completely reduced by perfusion of Mg sulfate. These results suggest the inhibition of local production of IL-1β could be one of the mechanisms; i.e. Mg sulfate reduces the vasoconstrictory effect of angiotensin II in human placenta.

Mg sulfate used for the treatment of pre-eclampsia or hypertensive disease in pregnancy may have beneficial effects on the feto-placental circulation.

Mg supplement and pregnancy outcome

It is well known that plasma Mg falls in pregnancy because of the accumulation of iron in the placenta and fetus. Many women, especially those from disadvantaged backgrounds, have lower Mg intakes than recommended doses [26]. Mg is therefore widely given as a supplement during pregnancy, particularly in cases of preterm labor. There are several reports that oral Mg supplementation in pregnancy is safe and that it has a positive effect on the fetal morbidity [27]. Patients in preterm labor have significantly depressed serum Mg levels, while in patients with pre-eclampsia Mg levels were not significantly different from controls [28]. Several papers reported that Mg supplementation during pregnancy could reduce fetal growth retardation and pre-eclampsia and increase birth weight. Mg therapy decreased the rate of IUGR, premature rupture of membranes and premature delivery in risk pregnancies treated with betamimetics [29]. Oral Mg treatment from before the 25^th week of gestation was associated with a lower frequency of preterm birth, a lower frequency of low birth weight and fewer small for gestational age infants compared with a placebo [30]. Mg intake of 513 women towards the end of the first trimester of pregnancy was calculated from a record of food consumption. Mg intake was correlated with weight, length, and head circumference at birth as well as length of gestation up to a threshold of around 3,200 g birth weight [31]. In addition, the supplement of Mg (100 mg/d) during the second and third trimesters had no effect on the outcome of pregnancy.

Mg supplementation is beneficial in the management of pregnancy-induced hypertension. The effect of Mg was compared with that of placebo in a randomized double-blind controlled study of patients with pregnancy-induced hypertension [32]. Mg supplementation reduced maternal mean arterial blood pressure. The gestational age at delivery was the same in both groups, whereas the relative fetal birth weight among nulliparas was reduced in the placebo group [32]. On the other hand, some papers reported that Mg supplementation during pregnancy did not improve pregnancy outcome. Between 13 and 24 weeks’ gestation, 400 young normotensive primigravid women randomly received oral Mg (365 mg/d) or a placebo. The Mg-supplemented group had significantly higher Mg levels at delivery. However, between the groups there were no differences in either systolic or diastolic blood pressure, incidence of pre-eclampsia, fetal growth retardation, preterm labor, birth weight, gestational age at delivery, or number of infants admitted to the special care unit [10].

Any influence of Mg is confined to the first trimester or before. However, the timing and dose of Mg supplementation may alter the pregnancy outcome.

Neural protective effect of magnesium

Mg deficiency increases the susceptibility of cells and tissues to peroxidation, worsens the inflammatory reaction, reduces the immune response, exaggerates catecholamine release in stress, and diminishes energy metabolism [33, 34]. Mg has multiple catalytic roles in cellular enzyme systems and neuronal functioning [35] and can block the N-methyl-D-aspartate receptor and thus prevent excitatory amino acids, commonly released during episodes of hypoxia and ischemia, from producing neuronal damage [36].

Apoptosis has been shown to occur within normal placental tissues during early pregnancy (5 and 7 weeks) and during the third trimester [37], and fetal growth restriction has been shown to be associated with increased levels of placental apoptosis [38]. Both hypoxia and extracellular Mg are postulated to stimulate this placental apoptosis in vitro [39], and hypoxia-stimulated placental apoptosis may be further advanced by increasing the extracellular Mg concentration.

Although Mg is also used in obstetric practice to attempt to arrest the progress of premature labor, there is controversy regarding the advantageous effect of Mg sulfate for reducing the risk of neonatal brain damage or cerebral palsy in low birth infants: in one study this concept is not currently supported [40], but in another case-control study in infants weighing less than 1,500 g at birth a substantial reduction in cerebral palsy was demonstrated in children whose mothers received Mg sulfate in labor [41].

Fetal/early childhood antecedents and adult chronic diseases

Epidemiological studies in humans have shown that impaired intrauterine growth is associated with an increased incidence of cardiovascular, metabolic, and other diseases in later life [42]. The first indication that fetal and early development could be involved in adult susceptibility to type 2 diabetes came from studies of men in the United Kingdom [2]. The odds ratio of the lightest compared with the heaviest at birth exhibiting the features of the metabolic syndrome was 18 [1]. Subsequently thinness at birth was found to increase the risk of insulin resistance in later life [43]. These types of relationship have been described in a wide variety of populations worldwide, in females as well as males [44]. Low birth weight is often followed by accelerated postnatal growth, and this may be important for risk of metabolic syndromes in adult life. People who had low birth weight or who subsequently showed catch-up growth have higher susceptibility for central obesity, type 2 diabetes, and cardiovascular disease in later life [45]. The nature of this link between catch-up growth and risks for such chronic diseases remains obscure, although several lines of evidence point to the phase of catch-up growth as a state of hyperinsulinemia [46].

Fetal programming

Fetal programming is the phenomenon whereby alteration in fetal growth and development in response to the prenatal environment has long-term or permanent effects. The mechanisms are supposed to be as a direct effect on cell number, altered stem cell function and resetting of regulatory hormonal axes (( figure 1 )).

There are several candidates for explaining gestational programming as follows: 1) a potential role for the hypothalamic-pituitary-adrenal (HPA) axis has been suggested, as the mediators of the fetal response to nutrient stress, i.e. maternal low protein diet, were profoundly suppressed [47, 48]; 2) fetal programming of the growth hormone insulin-like growth factor (GH-IGF) axis also has been proposed to serve as a link between fetal growth and adult-onset disease [49]. Glutamate decarboxylase 2 promoter variant is associated with childhood obesity in the French population and influenced fetal growth, feeding behavior, and possibly insulin secretion [50]. The potential effects of the maternal low protein diet on fetal growth and programming of hypertension and dysregulation of glucose metabolism are thought to be mediated by inhibition of placental 11β-hydroxysteroid dehydrogenase 2 activity [51, 52].

Furthermore, there is strong evidence regarding the association between low birth weight and insulin resistance in later life. The “thrifty phenotype hypothesis”, which postulates that fetal programming for adaptation to an adverse intrauterine environment results in lower insulin sensitivity in utero, is one of the hypotheses to explain this association.

Recently, we reported that [Mg²⁺]_i of cord blood platelets correlated well with birth weight and that infants born small for gestational age (SGA) showed lower [Mg²⁺]_i compared to those born with appropriate weight for gestational age [53]. We also previously reported that [Mg²⁺]_i is lower in children with diabetes mellitus and obesity [54].

Taking these findings together, we believe that decreased [Mg²⁺]_i in infants with SGA can be the initial pathophysiologic event leading to one of these events. In fact, a recent animal study supported our data demonstrating that the maternal Mg restriction irreversibly increases body fat and induces insulin resistance in pups by 6 months of age [55].

Although low birth weight and poor prenatal nutrition are strongly associated with metabolic syndromes in later life [56], postnatal catch-up growth was recently considered also to be a pivotal element associated with developing various pathological conditions [57]: Desai et al. reported that if catch-up growth is controlled by continuing maternal food restriction during the period of suckling, individuals born with low birth weights are not different from controls in adulthood, with respect to body weight, fat, or leptin in experimental rats [58]. Thus the degree of newborn nutrient enhancement and timing of catch-up growth of IUGR newborns may determine the programming of orexigenic hormones and offspring obesity.

It is intriguing in clinical practice that the concept of a sensitive or crucial period may operate to cause long-term changes in development and adverse outcomes in later life.

Conclusion

The fetal origin hypothesis by Barker et al. states that fetal undernutrition in middle to late gestation leading to disproportionate fetal growth programs later metabolic diseases. As low [Mg²⁺]_i is an intrinsic abnormality seen in infants with low birth weight, it is considered that the fetal Mg deficiency is an important determinant of insulin resistance in later life. Further exploration is, however, obviously needed to investigate the pathophysiological mechanisms underlying the development of metabolic syndromes in the light of the unknown developmental abnormalities during the fetal period.

Acknowledgements

Authors would like to express their sincere gratitude to Dr. Yohnosuke Kobayashi, Professor emeritus, for fruitful discussion. A part of this study was supported by the Mami Mizutani foundation and by Grant-in-Aid for Scientific research (C) from the Japan Society for the Promotion of Science (No. 17591123).

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