New data on the importance of gestational Mg deficiency

ARTICLE

Auteur(s) : Jean Durlach¹, Nicole Pagès², Pierre Bac³, Michel Bara⁴, Andrée Guiet-Bara⁴

¹ President of the international Society for the Development of Research on Magnesium (SDRM). Pierre et Marie Curie University (UPMC) F-75252 Paris Cédex 05 France;
² Laboratoire de Toxicologie, Faculté de Pharmacie, Strasbourg, 67400 Illkirch-Graffenstanden, France;
³ Laboratoire de Pharmacologie, Faculté de Pharmacie, Paris XI, 92290 Chatenay-Malabry, France;
⁴ Laboratoire de Physiologie et de Pathologie, UPMC, 75252 Paris Cedex 05, France

Introduction

Chronic magnesium deficiency in human beings is frequent. On all the continents a large part of the population has a dietary intake lower than the recommended dietary allowances (RDAs) for magnesium [1].

The nutritional adequacy for magnesium is based on major traditional indicators, balance studies mainly. American RDAs are 420mg/day for adult men and 320 mg/day for adult women [2].

The expression of RDAs for magnesium in terms of the daily magnesium intake for each age and sex group corresponds to 22 items [2].

Whereas Ca kinetics essentially depend on age, the best expression of RDA for Ca is related to various life stage groups [1, 2], but magnesium kinetics rely on body weight independently of age and sex [1, 2].

The best expression of RDA for magnesium is the daily value per Kg body weight [1, 3-7].

A large proportion of the population has a dietary intake lower than RDA for magnesium. For example 23% of women of the SUVIMAX cohort consume less than two thirds of the RDA for magnesium [2]. Marginal or moderate chronic primary magnesium deficiency may frequently occur in fertile women.

Experimental and general clinical consequences of gestational magnesium deficiency

Well documented experimental studies in rats of gestational magnesium deficiency during pregnancy show that magnesium deficiency may have marked effects on the processes of parturition and post-uterine involution and on fetal growth and development: either teratogenic effects or morbidity (i.e. hematological disorders, disturbances in thermoregulation [8-14].

The consequences of maternal primary magnesium deficiency in women have been insufficiently investigated. Gestational magnesium deficiency is able to induce maternal, fetal, neonatal and pediatric consequences which might last throughout life. To check the validity of the importance of maternal primary chronic magnesium deficiency, the protocol of a long term multicentric placebo controlled study on the effects of a maternal nutritional oral magnesium supplementation on morbidity and lethality in foetus, neonates, infants, children and adults should be carried out, not only during pregnancy and during the first year but throughout life. This type of intervention trial appears as the only means to assess the importance of the clinical consequences of gestational chronic magnesium deficiency in human beings [1, 5, 7, 15].

Two clinical forms of chronic gestational magnesium deficiency in women have been stressed:

– Premature labor or spontaneous abortion when chronic maternal magnesium deficiency is involved in uterine hyperexcitability [16];

Preterm birth and magnesium

Preterm birth is the major cause for perinatal morbidity and mortality in the developed world. The aim of tocolysis is to prolong pregnancy.

Long term tocolysis has now been given up. It has not been demonstrated that it improved perinatal or neonatal outcomes. But it increases maternal and fetal adverse effects. There is no evidence for continuing tocolytic treatment after an effective tocolysis of 48h.

Short term tocolysis enables the obstetrician and neonatalogist to optimise the handling of a premature baby through the administration of antepartum corticoids which reduces hyaline membrane disease and the possibility of arranging an in utero transfer to a center with neonatal intensive care facilities [16-24].

Beta-2 mimetics are the principal agents used for myometrial relaxation [17]. They are the reference tocolytic drugs in most countries [20]. There is good evidence that beta-2 mimetics prolong pregnancy, but there is no proof for their beneficial effects on perinatal or neonatal outcomes. There is however good evidence that they are associated with a high level of maternal, fetal and neonatal side-effects which may be more or less severe [16-23, 25-35]. Besides rare sudden maternal death and pulmonary oedema, other side-effects are frequent. They concern the cardiovascular apparatus and metabolic balance: chest pain, dyspnea, cardiac arrhythmias, palpitations, tachycardia, hypotension, headache, nasal stuffiness, nausea, vomiting, tremor, dizziness, hyperglycemia, hypokalemia and hypomagnesemia.

These side-effects may require the discontinuation of treatment. Two mechanisms may be involved in these side-effects: beta-1 receptor stimulation and excessive doses of beta-2 mimetics (see for example lipolytic effects causing hypomagnesemia) [16]. Because of the large incidence of side-effects the use of high doses of beta-2 mimetics for suppression of premature labor have been either stopped or limited to short treatments (48h) with the lowest possible doses (inducing heart rate < 120) [16].

Magnesium therapies and tocolysis

Two types of magnesium therapy may be used for tocolysis: pharmacological magnesium therapy and nutritional magnesium therapy [16].

Pharmacological magnesium therapy for tocolysis (most often intravenous high doses of MgSO4) may be used whatever the magnesium status. Despite the lack of clear tocolytic effects, intravenous high doses of MgSO4 are one of the most popular tocolytics in North-America [18, 21], but they may induce toxicity.

Nutritional magnesium therapy is meant to balance magnesium deficiency. If gestational magnesium deficiency is the cause for uterine overactivity, nutritional magnesium supplementation constitutes the etiopathogenic atoxic tocolytic treatment: it is devoid of any toxicity since it restores a physiological magnesium balance [16]. Premature births and repeated miscarriages may be observed during experimental magnesium deficiency. Chronic primary magnesium deficiency is highly frequent and particularly during gestation since, for exemple, 23% of women in France have dietary magnesium intakes lower than two-thirds of RDA for magnesium [1, 16]. When gestational magnesium deficiency is involved in uterine overactivity, nutritional magnesium supplementation significantly reduces the incidence of spontaneous abortion, prolongs the period of gestation and favors the appearance of factors that indicate a better outcome for the newborn (weight, height, head circumference). It improves the impaired development of the neonate [16, 36]. To identify pregnant women with gestational magnesium deficiency, the most appropriate way is to evaluate their magnesium intake. If the diet history is not easily available, the coexistence of other clinical manifestations of magnesium deficiency such as neuromuscular hyperexcitability ought to be investigated: Chvosteck sign particularly (which appears to be correlated with magnesium intake, but not with the serum magnesium concentration), click, iterative EMG tracings, « idiopathic » mitral valve prolapse. But the dynamic oral physiological magnesium load test (5mg/kg/day) constitutes the best evidence of magnesium deficiency [1, 15, 16].

L. Spätling recommends for all pregnancies an oral atoxic magnesium supplementation with 2 or 3 single doses of 5 mMol magnesium per day. A randomized placebo-controlled double blind crossover study has indicated that this magnesium supplementation results in an efficient well tolerated magnesium therapy [36, 37].

Nutritional magnesium therapy is also a useful accessory treatment for tocolysis, devoid of toxicity, which increases the effectiveness and safety of the associated tocolytic drugs such as beta-2 mimetics. Their efficiency and tolerance are considerably improved by physiological oral magnesium supplementation both for the mother (neural, pulmonary and cardiovascular protection) and for the fetus (normal birthweight instead of underdevelopment). The dose of the beta-2 adrenergic receptor agonists used for tocolysis may be reduced by the synergic myorelaxant effects of beta-2 mimetics and of magnesium on myometrium [16, 25, 36, 38-40].

Pharmacological magnesium therapy for tocolysis

Regarding tocolytic pharmacological magnesium treatment, the usual route is parenteral [28-33], but large doses have been given orally, although rarely [41, 42]. Intravenous high doses of MgSO4 is the most commonly used first line tocolytic agent among obstetricians in the United States [20, 43].

The mechanism according to pharmacological magnesium therapy used for tocolysis is the inhibition of myometrial activity due to modulation of Ca uptake, binding and distribution in smooth muscle cells. But intravenous MgSO4 lacks any specificity with regard to its relaxing action on uterine or other smooth muscle: for example it is able to induce not only myometrial relaxation but also vasodilator effects [15, 16, 23, 25, 44, 45].

Efficacy of intravenous MgSO4 for tocolysis has not been evaluated rigorously. Several randomized trials did not bring evidence of tocolytic effectiveness. Intravenous MgSO4 cannot be recommended as a tocolytic agent for women in preterm labor [16, 18-20, 45, 66]. Efficacy of intravenous MgSO4 for tocolysis is dubious and its safety has not been demonstrated: tocolytic doses of intravenous MgSO4 may induce many side-effects.

Maternal side-effects

Several maternal side-effects are frequent and most often of mild importance. They may be related to dosage and speed of infusion: flushing, sweating and a sensation of warmth, weakness, headache, palpitations, chest pain, shortness of breath, nausea, vomiting.

Pulmonary edema is rare and made more likely by concomitant corticotherapy.

Administration of the highest doses can lead to depression, hypothermia, respiratory and cardiac arrest due to an iatrogenic magnesium excess.

Long term MgSO4 tocolysis may induce local adverse events (such as injection site pain, itching, erythema, swelling, induration and palpable venous cord), deficits in information processing ability, an increased rate of clinical chorioamnionitis and osteoporosis [5, 15, 16, 23, 25, 44-51].

Fetal and pediatric side-effects

Magnesium crosses the placental barrier and the fetal kidney does not excrete magnesium with the same efficiency as the mature kidney. Maternal treatment with high intravenous tocolytic MgSO4 doses exposes the newborn to a hypermagnesemia that is correlated with the duration of the pharmacological magnesium therapy. The neonate hypermagnesemia can lead to hyporeflexia, poor suckling and, rarely, respiratory depression. This neonatal magnesium overload can affect intracardial and peripheral circulation, the APGAR score, the calcium metabolism and induce meconial discharge. Other forms of neonatal magnesium overload with normal magnesemia may be observed. Only the myoelectric tracings reveal inhibition of neuromuscular transmissions which contraindicates any prescription that may enhance such latent curariform effects [5, 15, 16, 45, 52-54].

In contrast several retrospective observational studies describe an association between maternal tocolytic high intravenous MgSO4 treatment and a reduction in cerebral palsy in low birthweight infants. In order to check whether antenatal exposure to maternal pharmacological magnesium supplementation has neuroprotection effects on premature children, several prospective trials were conducted [55-58]. But there was profound disappointment when a scheduled interim data safety analysis of the American trial MAGNET revealed a strong association between MgSO4 maternal treatment and total (fetal + neonatal + post neonatal) pediatric mortalities. Contrary to the original hypotheses the data have shown that maternal pharmacological magnesium exposure was not associated with a lower risk of cerebral palsy but a statistically significant increase in the risk of neonatal intraventricular hemorrhage as well as total adverse paediatric outcomes [16, 59, 60]. But other research has shown that prenatal exposure to intravenous MgSO4 was not associated with increased neonatal morbidity or mortality [51].

Differences between the effects of antenatal pharmacological maternal therapy might be due to the dosage of MgSO4 since in an animal model the fetal mortality was dose related [61], but the nature of the anion ought to be discussed. Pharmacological doses of magnesium salts may induce toxicity which differs according to the nature of anions: MgSO4 seems to be the worst magnesium salt toxicologically and pharmacologically. Strangely enough in all these important trials it was the only one which was routinely used although nowhere can be found any sort of justification for that choice. It seems therefore necessary to determine the therapeutic ratio (LD50 / ED50) of the various available magnesium salts before pharmacological use. The higher its value, the greater the safety margin [16, 44, 59, 62-65].

To sum up: high doses of intravenous MgSO4 for tocolysis are less efficient and unsafe. Because of its maternal and pediatric side-effects, maternal pharmacological magnesium therapy should be abandoned for tocolysis. Anions other than sulfate could have a better effect on health outcome in the neonate: it seems necessary to determine the therapeutic ratio of various magnesium salts before their clinical use.

Sudden Infant Death Syndrome (SIDS) and magnesium

SIDS and magnesium deficiency

The hypothesis that magnesium deficit may play a role in the pathogenesis of SIDS was taken into consideration for the first time in the seminal paper published in 1972 by Caddell. She highlighted the analogy between an anaphylactoid shock due to histamine release induced by mild stress in a magnesium deficient weanling rat and the final SIDS event: SIDS would be due to magnesium deficiency shock [66]. In 1988, she reported the results of a retrospective study in 200 premature neonates with apnea neonatorum. Some of these infants had been treated with magnesium salts and in the magnesium treated group zero SIDS was observed [67]. However this hypothesis raises several methodological problems:

– analogy does not mean causality;

– no allergen was detected before the anaphylactoid shock of SIDS.

The study of 200 premature neonates was retrospective, not blinded and the criteria applied to the infants treated with magnesium are not known.

A superacute lethal anaphylactoid magnesium deficiency shock is inexplicable as a mechanism of SIDS [68-70]. Although Caddell did not refute these various criticisms, she still maintains the same hypothesis for SIDS being caused by a magnesium deficiency shock [71] and describes a corresponding experimental risk model [72].

Instead of this unlikely superacute severe infant magnesium deficiency as a cause for SIDS, our theory [69] which stresses the possible link between gestational chronic magnesium deficiency and some forms of SIDS is consistent with all the epidemiological and pathological prerequisites characterizing SIDS: the curve of age at death, the stigmata of early maternal intrauterine injury, the seasonal predominance in winter, the absence of an adequate cause of death at autopsy, the risk factors subgroups (low socioeconomic level, environmental factors and mistakes in the baby care) and the importance of dysthermic forms. SIDS may be the result of an impaired control of brown adipose tissue (BAT) thermoregulatory mechanisms leading to a modified temperature set point: hypothermic forms may be induced by functional failure of BAT and hyperthermic forms by inappropriate functional excess of chemical thermogenesis. Among the morphological features of SIDS, BAT alterations have been largely described [69, 70], but nevertheless may be omitted in recent reviews [71, 73].

Some SIDS may result from offspring chronic magnesium deficiency due to chronic maternal magnesium deficiency, possibly through dysthermias due to a magnesium dependent disorder - a modified temperature set point- of the transition from chemical to physical infant thermoregulation [69, 70]. A possible prevention of these SIDS due to the fetal consequence of maternal magnesium deficiency could rely on simple maternal nutritional magnesium supplementation [69-70]. The levels of magnesium in traditional diets of selected ethnic groups with either the highest or the lowest rates of SIDS appear to confirm the importance of maternal magnesium intake in protecting the offspring from SIDS [74].

SIDS and magnesium depletion

It is always important to discriminate between the two types of magnesium deficit: magnesium deficiency due to insufficient intake which merely requires oral physiological nutritional magnesium supplement and magnesium depletion related to a dysregulation of magnesium status which is not controlled by oral nutritional magnesium intake, but requires more or less specific correction of its causal dysregulation [15, 70, 75]. Among the various forms of magnesium depletion, experimental and clinical data highlight the importance of the forms caused by the association of a low magnesium intake (that is to say a magnesium deficiency) with various types of a stress.

For example, several stresses may be associated with gestational magnesium deficiency which may induce SIDS due to various subgroups of magnesium depletion. These stresses concern baby care and environment [70].

Stress in baby care may involve sleeping position, bedding, wrapping, ambiant temperature and feeding.

– A recent decline in the rate of SIDS is attributed to putting the infant to bed in a non-prone sleeping position [69, 70, 73].

– Wrapping and room temperature, neither excessive nor insufficient, to avoid thermal stress [69-70].

– Breast feeding is less common than bottle feeding among cases of SIDS than among controls [70].

Besides the environmental factors concerning baby care such as thermal stress by ambiant temperature, high altitude and exposure to various toxic substances may constitute diverse noxious environmental stressors.

– High altitude exposure may increase the risk of SIDS but is not commonly found in SIDS cases [69, 70].

– Drugs such as phenobarbital and phenothiazines, pesticides (and lindane particularly), ambiant pollutants (either contributing factors to hypoxia such as carbon monoxide, sulphur dioxide and hydrocarbons or metal pollutants: Cd and Pb mainly [69, 70, 73] may constitute other risk factors for SIDS.

– The role of chronopathological stress [76] appears as most often neglected: SIDS may be induced by a primary chronopathological form of magnesium depletion with hypofunction of the biological clock, the main marker for which is a decrease in melatonin production [75,76].

The first data are anatomic.

The pineal gland of SIDS infants is smaller and less responsive to photoperiod stimulatory effects than those of normal infants.

The epochal papers from the lab of Wurtman [78, 79] directly stress the links between SIDS and pineal dysfunction. Samples of whole blood, ventricular cerebrospinal fluid (CSF) and/or vitreous humour were obtained at autopsy from 68 infants whose deaths were attributed to either SIDS or other causes. The melatonin (MT) concentrations were measured by radioimmunoassay. A significant correlation was observed for MT levels in different body fluids from the same individual. After adjusting for age difference, CSF melatonin levels were significantly lower among the SIDS infants than among those dying of other causes [78]. Post mortem blood levels of MT were lower by about 50 per cent in infants who died from SIDS [79].

Following SIDS research has focused on infants who have experienced an Apparent Life-Threatening Event (ALTE). Sivan et al. [80] compared the urinary excretion of the main melatonin metabolite: 6 sulfatoxy-melatonin (6 SMT) in 80 infants who had (and had not) experienced an ALTE. On a double blind basis, the total of 6 SMT excreted over 24 h and the diurnal rhythm in the rate of 6 SMT excretion were assessed using urine samples taken from disposable diapers. The mean daily excretion of 6 SMT was significantly lower in the group having experienced ALTE [80].

The deleterious effects of this pineal deficit in SIDS may be due to the decrease of the direct stimulating action of MT on BAT [69, 70, 81] and to the effects of the multiple other mechanisms of action of the hypofunction of the biological clock [2, 70, 77]. In the cases of SIDS due to magnesium depletion with hypofunction of the biological clock, this dysfunction of the timing oscillator appears as a primary disorder without the stigmata of the secondary forms of hypofunction of the biological clock: light hypersensitivity, reactive photophobia, diurnal, spring and summer prevalence [70].

The mechanism of the primary hypofunction of the biological clock in SIDS seems ontogenic.

SIDS might be linked to an impaired maturation of photoneuroendocrine system [70, 80-82] and of BAT [69]. For example, the follow-up of the ALTE infants, performed 6 to 8 weeks later (59 to 66 weeks of post conceptional age) revealed that urinary 6 SMT excretion increased in all of them, suggesting a delayed ontogeny rather than a permanent deficit of melatonin (MT) production [80].

– It is necessary to insure in all maternal diets a magnesium intake corresponding to the RDA for magnesium (6 mg/kg/day) [1, 15, 16, 69, 70]. Practically, a magnesium supplementation lower or equal to 300 mg per day provides a magnesium supplement under the tolerable upper intake level (UL) for magnesium, unlikely to pose toxical risks of adverse health effects, that is to say an atoxic nutritional supplement [1, 2]. The palliative treatment of chronic gestational magnesium deficiency may constitute the only preventive treatment of SIDS due to maternal magnesium deficiency [69, 70]. But when SIDS is due to magnesium depletion which is caused by the association of a low magnesium intake with diverse types of stress, either in baby care or environmental, it is necessary to add to the nutritional magnesium palliative treatment of the maternal magnesium deficient diet, various baby care and environment controls: non-prone sleeping position for the baby, discontinuation of parental smoking particularly [70] and chronopathological treatments: darkness therapy per se: total light deprivation at night for the infant, possibly with an eye mask [70, 76, 83]. The place in the prevention of SIDS of magnesium therapy for the infant (choice and doses of the magnesium salts used oral or parenteral route and indications) and of the use of other darkness mimicking agents such as melatonin, L tryptophan and taurine is not yet clear [70, 76].

Conclusion

– In the various consequences of chronic gestational magnesium deficiency in women, in premature labor and SIDS particularly, nutritional magnesium therapy is efficient and atoxic.

– On the contrary pharmacological magnesium therapy used to cause a therapeutic magnesium overload may induce magnesium toxicity, especially through high doses and the nature of the anion. It seems necessary to determine the therapeutic ratio (LD50 / ED50) of the various available magnesium salts before their pharmacological use [5, 15, 44, 62, 70].

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