magnesium ( mg ) is an important cofactor for the enzymes that are involved in carbohydrate metabolism : an important role of mg in insulin action has been reported [ 1 , 2 ] ; low serum and intracellular mg ( [ mg]i ) concentrations are associated with insulin resistance , impaired glucose tolerance , and decreased insulin secretion [ 3 , 4 ] .
furthermore , lower dietary mg intake could cause insulin resistance both in children and adults [ 5 , 6 ] .
based on these findings , we studied whether low [ mg]i in the fetus would be one of the critical abnormalities associated with small for gestational age ( sga ) .  
in addition , several studies have shown the association of size at birth or indices in poor fetal growth with later development of metabolic syndrome and insulin resistance .
proposed that impaired glucose tolerance and type 2 diabetes might arise as a result of programming .
programming is a term used to describe persistent changes in organ structure and function caused by exposure to adverse environmental influences during critical periods of development .
hypothesis , which proposes that fetal adaptation to an adverse intrauterine environment affecting fetal growth may program life - long physiological changes .
it has been proposed that various fetal growth patterns and intrauterine growth retardation ( iugr ) arise as a result of an early stimulus or insult .
since both fetal weight and length gains are closely related , there is much overlap between sga and iugr .
sga is defined as birth weight and/or length at least 2 standard deviations below the mean for gestational age .   in this review
, we discuss the potential contribution of aberrant mg regulation to sga and to the pathogenesis of metabolic syndrome later in life .
it is reported that the amount of maternal mg intake is not only associated with pregnancy outcome but also with infant outcome .
the mean daily intake of mg ( 284.3  mg / day ) during pregnancy was found to be lower than recommended .
for example , mg deficiency is reported to occur in 44% of pregnant indian women .
another study has demonstrated that mothers who drink water containing high amounts of mg have a reduced risk of having very low birth weight infants ( less than 1,500  g of birth weight ) . by the end of a normal pregnancy , the fetus
is believed to have acquired approximately 28  g of calcium , 16  g of phosphorous , and 0.7  g of mg , mostly during the third trimester , also the time when 80% of fetal accretion of mg occurs .  
the fetal circulation contains higher levels of total calcium , ionized calcium , and mg compared to maternal blood . in the placental membrane ,
copper and selenium share the same transport pathway along a concentration gradient in the maternal - fetal direction , while mg and iron use predominantly an active transport pathway .
in fact , evidence for an active transport mechanism for mg in the placenta has been demonstrated in cultured trophoblast cells in which low [ mg]i is maintained by the function of a na / mg exchanger .
mg levels in umbilical cord blood are the lowest in preterm low birth weight babies , followed by term low birth weight babies and are the highest in term controls ( p < .05 ) .
calcium and mg have an immediate effect on placental vascular flow . reduced placental vascular flow is at least , in part , responsible for placental insufficiency and fetal growth retardation ( fgr ) .
a variety of hormones , cytokines , and growth factors produced by fetal membranes and the placenta can act locally on the myometrium .
the ability of the uterine artery to dilate during pregnancy may be specifically related to the upregulation of multiple pathways for the production of nitric oxide .
the activity of constitutive nitric oxide synthase is dependent on calcium and is inhibited by a reduction in the concentration of mg .
blood mg levels were reportedly lower in women with severe pre - eclampsia than in healthy pregnant women ( 1.63    0.05  mg / dl versus 1.87    0.05  mg / dl ; p < .001 ) .
therapeutic levels of mg have also been found to produce specific placental effects such as vasodilation . from an in vitro study of human umbilical artery resistance ,
mg sulfate was found to exert a relaxant effect on umbilical arterial tone attenuating the vasoconstrictor effect of angiotensin ii and endothelin-1 in the fetal - placental vasculature .
mg sulfate used for the treatment of pre - eclampsia or hypertensive disease in pregnancy may have beneficial effects on the fetoplacental circulation . prenatal treatment with mg sulfate may influence calcium homeostasis and nonenzymatic antioxidant reserve in erythrocytes of preterm newborns .
it is well known that plasma mg falls in pregnancy because of accumulation of ion in the placenta and fetus .
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 fetal morbidity .
patients in preterm labor have significantly depressed serum mg levels , while in patients with pre - eclampsia , mg levels are not significantly different from that of the controls .
mg supplementation was found to decrease the rate of fgr , premature rupture of membranes , and premature delivery in risk pregnancies treated with betamimetics .
oral mg supplementation given before the 25th week of gestation is associated with a lower frequency of preterm births , a lower frequency of low birth weight , and fewer sga infants compared with the placebo .
mg intake in 513 women who were near the end of their first trimester of pregnancy was determined from records of food consumption .
mg intake correlated with weight , length , and head circumference at birth as well as length of gestation up to a threshold of around 3,200  g of birth weight . on the other hand , mg supplements ( 100  mg / day ) taken during the second and third trimesters had no effect on the outcome of the pregnancy .
the effect of mg compared with placebo in a randomized double - blind controlled study of patients with pregnancy - induced hypertension was investigated .
mg supplementation was found to be beneficial in the management of pregnancy - induced hypertension . at present
, there is insufficient high - quality evidence to show that dietary mg supplementation during pregnancy is beneficial .
it is important to determine the timing and dose of mg supplementation as both factors may alter the pregnancy outcome .
we have previously reported that intracellular magnesium ( [ mg]i ) is lower in children with diabetes mellitus and in children who are obese . in the type 2 diabetes
mellitus and obese groups , platelets responded well to insulin . under insulin - resistant states ,
[ mg]i decreases before the poor reactivity to insulin occurs in platelets . from these findings
, we hypothesize that [ mg]i is decreased earlier than when poor reactivity to insulin develops in platelets exposed to an insulin resistant environment .
this suggests that low [ mg]i may be an intrinsic abnormality in infants with low birth weight . to test this hypothesis
, we studied the relationship of [ mg]i   in cord blood platelets to birth weight .
we found that mean basal [ mg]i , but not plasma magnesium , is lower in sga than in the appropriate for gestational age ( aga ) groups ( 323    162  mol / l versus 488    132  mol / l , p = .004 ) .
mg]i significantly correlates with birth weight ( p < .0001 ) as well as cord plasma leptin ( p = .031 ) and igf-1 ( p < .001 ) .
[ mg]i as well as leptin and igf-1 reflects the extent of fetal growth . also ,
[ mg]i significantly correlates with the quantitative insulin sensitivity check index ( quicki ) ) ( p < .001 )
. decreased [ mg]i in sga might underlie the initial pathophysiological events that lead to insulin resistance .
for example , hyperglycemia may have an effect on mg transport and induce a decline of [ mg]i .
reported that responses to hyperglycemia in vitro were blunted in adult hypertensive subjects and that these responses were closely linked to basal [ mg]i   levels . in our study , we found no correlation between cord plasma glucose and basal [ mg]i   levels .
in addition , we did not find any significant difference in plasma glucose levels between the sga and aga groups .
intrauterine glucose levels may have less of an effect on inducing sga or low [ mg]i .
as [ mg]i plays a promotive role in fetal growth , low [ mg]i may partly be responsible for sga . as low
[ mg]i is an intrinsic abnormality seen in infants with low birth weight , it is considered that fetal mg deficiency is an important determinant of insulin resistance in later life .
in fact , our data was supported by a recent animal study demonstrating that maternal mg restriction irreversibly increases body fat and induces insulin resistance in pups by 6  months of age .
the fetal origin hypothesis by barker et al . [ 810 ] states that fetal undernutrition in middle to late gestation leads to disproportionate fetal growth programs and later metabolic diseases .
fetal programming is a phenomenon in which alterations in fetal growth and development in response to the prenatal environment have long - term or permanent effects .
this theory was further established in the category of developmental origins of health and disease ( dohad ) .
the mechanisms thought to be responsible for fetal programming include the direct effects on cell number , altered stem cell function , and the resetting of regulatory hormonal axes : hypothalamic - pituitary - adrenal axis [ 39 , 40 ] and growth hormone insulin - like growth factor axis .
one of the underlying mechanisms for the postulated early - life programming is that of epigenetics .
altered epigenetic regulation of genes in phenotype induction could possibly give rise to interventions that modify long - term disease risk associated with unbalanced nutrition in early life .
reported that fasting insulin and homeostasis model assessment - insulin resistance ( homa - ir ) increased in offspring from mg - restricted dams at 6  months of age .
maternal and postnatal mg status is important in the long - term programming of body adiposity and insulin secretion in rat offspring .
although low birth weight and poor prenatal nutrition are strongly associated with metabolic syndrome in later life , postnatal catch - up growth was recently considered to also be a pivotal element associated with the development of various pathological conditions .
the concept of a sensitive or crucial period that operates to cause long - term changes in development and adverse outcomes later in life is an intriguing one and should be the focus of more studies in the future .
birth weight is only a crude index of early growth and indicates nothing about the success of a fetus in achieving its growth potential .
[ mg]i may be a marker of early growth restriction , which may be of future diagnostic use as an early predictor of adult diseases .
low [ mg]i , which may represent the prenatal programming of insulin resistance , has lifelong effects on metabolic regulation .
a biological interpretation of the association between birth size and risk of insulin - resistant diseases should emphasize the possible underlying roles of [ mg]i .
 magnesium deficiency in pregnancy frequently occurs because of inadequate or low intake of magnesium . 
 magnesium deficiency during pregnancy can induce not only maternal and fetal nutritional problems , but also consequences that might last in offspring throughout life . 
 many epidemiological studies have disclosed that small for gestational age ( sga ) is associated with an increased risk of insulin resistance in adult life . 
 we reported that intracellular magnesium of cord blood platelets is lower in sga groups than that in appropriate for gestational age groups , suggesting that intrauterine magnesium deficiency may result in sga . 
 
 taken together , intrauterine magnesium deficiency in the fetus may lead to or at least program insulin resistance after birth . in this review 
 , we propose that intrauterine magnesium deficiency may induce metabolic syndrome in later life . 
 we discuss the potential contribution of aberrant magnesium regulation to sga and to the pathogenesis of metabolic syndrome . 
 
1. Introduction
2. Magnesium Deficiency During Pregnancy
3. Mg Supplements and Pregnancy Outcome
4. The Relation of SGA to Intracellular Magnesium in Cord Blood Platelets
5. Fetal Programming
6. Conclusion