Normal and abnormal calcium, phosphorus and magnesium metabolism in the perinatal period

6 Normal and Abnormal Calcium, Phosphorus and Magnesium Metabolism in the Perinatal Period J. O. F O R F A R

NORMAL CALCIUM, PHOSPHORUS AND MAGNESIUM METABOLISM IN THE PERINATAL PERIOD Quantitatively and qualitatively calcium, phosphorus and magnesium are minerals of great importance in the newborn infant affecting as they do the structure of bone, muscle contraction, nerve impulse transmission, blood coagulation, a wide range of enzymatic reactions, protein synthesis, permeability of capillaries and cellular membranes, antibody--antigen reactions, leucocyte phagocytosis, etc. In maintaining health, too, the distribution and compartmentation within the body are of great importance.

Maternal Requirements A joint committee of the Food and Agricultural Organization of the United Nations and the World Health Organization has suggested that special demands in the third trimester of pregnancy and during lactation necessitate a maternal intake of 1000 to 1200 g calcium daily. This is in accordance with Leitch's (1959) earlier calculations of requirements. It has also been suggested that 2000 g per day are desirable (Duggin et al, 1974), but intakes of this order lead to strongly positive calcium balances and may give rise to hypercalcaemia (Kerr et al, 1962), and hypercalciuria (Duggin et al, 1974). Such an intake is probably excessive (Hytten, Lind and Thomson, 1974). Nursing mothers contribute 0.1 to 0.5 g of calcium per day to their offspring. The daily requirement of magnesium during later pregnancy has been estimated as 400 to 600 mg per day (Seelig, 1971). The vitamin D requirement of pregnant mothers is not accurately known but is probably of the order of at least 700 iu per day (Pitkin et al, 1972).

Calcium, Phosphorus and Magnesium Concentrations in the Mother Blood Plasma calcium concentration is usually lower in the pregnant woman than in the non-pregnant, falling until about the 30th week and tending to rise thereClinics in Endocrinology and Metabolism--Vol. 5, No. 1, March 1976.

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after until delivery. Average values on first booking at, say, 10 weeks, at 30 weeks and at delivery would be 2.4 (9.6), 2.3 (9.2) and 2.4 (9.6) retool/1 (mg/100 ml) (Watney et al, 197~ ; Watney and Rudd, 1974). Maternal plasma calcium concentrations tend to be lower in successive pregnancies. The lower calcium concentrations in pregnancy are largely accounted for by a fall in protein-bound calcium related to the hypoalbuminaemia of pregnancy. The concentration of unbound (diffusible) calcium remains unaltered (Kerr et al, 1962) and is of the order of 1.3 to 1.5 mmol/l (5.2 to 5.8 rag/100 ml) or 57 per cent of total calcium, compared with the normal adult percentage of 53 per cent (Cantarow, Montgomery and Bolton, 1930; Andersch and Oberst, 1936; Delivoria-Papadopoulos et al, 1967; Bergman, 1972). It is usually assumed that, for practical purposes, diffusible calcium consists almost entirely of ionised calcium and represents the filterable calcium obtained by ultrafiltration. More recently, based on the use of a calcium electrode to determine ionised calcium, it has been reported that there is a fall in ionised calcium during the third trimester and that the concentration may be of the order of 1.1 mmol/l (4.4 rag/100 ml) (Tan, Raman and Sinnathray, 1972). In toxaemia of pregnancy there is a fall in the ratio of diffusible calcium to non-diffusible calcium due to increase in the latter (Cantarow et al, 1930). Plasma phosphorus concentrations are probably lower in the pregnant woman (average 1.0 retool/1 or 3.1 rag/100 ml) than in the non-pregnant woman (average 1.15 mmol/1 or 3.5 mg/100 ml) (Kerr et al, 1962; Khattab and Forfar, 1970; Watney et al, 1971). Plasma magnesium concentrations in the pregnant woman (average 0.7 mmol/1 or 1.7 mg/100 ml at the end of pregnancy) are somewhat lower than in the non-pregnant woman (0.85 mmol/1 or 2.1 mg/100 ml) and show a steady fall throughout pregnancy (de Jorge et al, 1965). Placenta

The calcium content of the placenta has been reported as 0.3 mg/g wet weight, or 4 mg/g dry weight, during the first 36 weeks of pregnancy increasing two to three-fold to 0.5 to 0.9 mg/g wet weight or 8 to 10 mg/g dry weight at term. Others have reported significantly higher calcium concentrations (20 to 70 mg/kg dry weight) with a falling content during pregnancy (McKay et al, 1958). Higher concentrations are seen in severe toxaemia if delivery takes place between the 28th and 36th week of pregnancy, but in toxaemic pregnancies going to term the placental calcium concentration may not be higher than normal (Masters and Clayton, 1940; Widdowson and Spray, 1951; Jeacock, 1963). In toxaemic placentae the concentration of magnesium is above normal (Dawson et al, 1969). Alkaline phosphatase concentration in the placenta increases throughout pregnancy, particularly during the last trimester (McKay et al, 1958). There is a positive correlation between placental weight and cord blood plasma calcium concentration over the first four days of life when placentae of subnormal weight are included (Khattab and Forfar, 1971).

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Amniotic fluid The concentrations of calcium, phosphorus and magnesium in the amniotic fluid at term average 1.7 (1.40 to 1.95), 0.85 (0.10 to 1.58), 0.30 (0 to 0.72) mmol/1 or 6.7 (5.6 to 7.8), 2.6 (0.3 to 4.9) and 0.78 (0 to 1.74) rag/100 ml respectively. At the end of the first trimester the concentration of calcium is 0.25 mmot/1 (1 mg/100 ml) lower while the concentrations of magnesium and phosphorus are nearly twice as high as at term (Economou-Mavrou and McCance, 1958; Widdowson et al, 1962). Transplacental Movement of Calcium, Phosphorus and Magnesium During fetal life calcium ions are transferred from maternal to fetal circulation although the concentration of ionised calcium is higher in the fetus than in the mother suggesting an active transport mechanism or the concept of the 'calcium pump' (Bawden, Wolkoff and Flowers, 1965; Twardock and Austin, 1970; Radde, Parkinson and Hoffken, 1971). Differences in electrical potential across the placenta may also play a part in the transport of calcium ions (Widdas, 1961). Based on experimental evidence in rhesus monkeys transfer of calcium from mother to fetus is accompanied by some transfer of calcium back from fetus to mother. After injection of labelled calcium into the mother the half-life for disappearance from maternal blood (to fetal blood) is two to six minutes followed by a much slower decline (half-life 87 to 160 minutes). These disappearances are matched by corresponding rises in fetal concentration. Labelled calcium injected into the fetus shows a half-life of 1.6 to 5 minutes and there is a corresponding rise in maternal blood calcium. The net balance of calcium transported across the placenta to the fetus is 6 to 10 times that required for fetal growth (MacDonald et al, 1965). Phosphorus is also transferred across the placenta against a gradient, again on a two-way basis, 25 per cent of the phosphorus entering the fetus finding its way back to the mother and the net balance to the fetus meeting the requirement of fetal growth (Fuchs and Fuchs, 1956). Wilde, Cowie and Flexner (1946), on the other hand, found no movement of phosphorus from fetus to mother, the maternal to fetal transport just meeting fetal requirements. Magnesium also appears to be transferred rapidly across the placenta (Aikawa and Bruns, 1960). Hypermagnesaemia may be induced in the newborn infant when the mother has been given magnesium sulphate therapeutically, especially parenterally, for pre-eclampsia or eclampsia. Concentrations similar to those in the mother and up to 2 or 2.5 mmol/1 (4.9 to 6.1 rag/100 ml) may be found in cord blood, implying effective placental transfer (Lipsitz and English, 1967; Stone and Pritchard, 1970). Calcium, Phosphorus and Magnesium Content of the Fetus and Newborn Infant Total content The full-term newborn infant weighing 3.5 kg contains approximately 28 g of calcium, 16 g of phosphorus and 0.75 g of magnesium, 98, 80 and 60 per cent

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respectively of these amounts being present in the skeleton. The soft tissues contain 0.5 g of.calcium, 3.0 g of phosphorus and 0.3 g of magnesium and the extracellular fluid 0.11, 0.06 and 0.025 g respectively of the same elements. The percentage calcium content of the fetus at 14 weeks (total weight 100 g), 28 weeks (1500 g), 35 weeks (2500 g) and 40 weeks (3500 g) is 0.3, 0.7, 0.75 and 0.8 respectively, deposition showing a steep rise in the last trimester and ranging from 140 to 400 mg on average per day or approximately 100 mg/kg/day. The percentage phosphorus content of the fetus at 14, 28, 35 and 40 weeks is 0.2, 0.4, 0.45 and 0.45 respectively, deposition in the last trimester ranging from 100 to 200 mg on average per day or approximately 75 mg/kg/day. The fetal Ca/P ratio thus changes from 1.5 at 12 weeks to 1.8 at term. The percentage magnesium content of the fetus at 14, 28, 35 and 40 weeks is 0.01, 0.02, 0.025 and 0.02 respectively, deposition in the last trimester ranging on average from 5 to 11 mg per day or 3 m g / k g / d a y (Givens and Macy, 1933; McCance and Widdowson, 1951; Widdowson and Spray, 1951; Widdowson and McCance, 1965). Blood

It has been known for over 40 years that the plasma calcium concentration in cord blood is approximately 0.5 mmol/l (2 mg/100 ml) higher than the concentration in maternal blood at the time of delivery (Mull and Bill, 1932; Kerr et al, 1962; Khattab and Forfar, 1970). Most of the difference is accounted for by ionised calcium which in fetal plasma amounts to 64 per cent of the total calcium as opposed to 57 per cent in maternal plasma (Delivoria-Papadopoulos et al, 1967). A more recent report states that the difference between ionised calcium concentrations in mother and fetus is not nearly so marked as this and that, due to lower total calcium in the mother, the percentage of ionised calcium in maternal blood exceeds that of fetal blood (Samaan, Wigoda and Castillo, 1973). Calcium binding in maternal and fetal plasma is similar per gram of protein. After delivery plasma calcium concentrations fall until the third or fourth day and then rise, concentrations in breast-fed infants remaining significantly higher than in bottle-fed infants. The mean values and ranges from a wide range of reports are shown in Figure 1. Both ionised and protein-bound calcium participate in this postnatal fall and subsequent rise (Bergman and Isaksson, 1971; Bergman, 1972). A more marked lowering of plasma calcium concentration occurs from birth until at least the fourth day where the mother suffers from severe pre-eclampsia or where gestation is prolonged in association with an undersized fetus (Khattab and Forfar, 1971). The plasma calcium concentration is kept within very narrow limits despite the free movement of calcium in and out of blood: only onethousandth of the total body calcium is in blood and five times the total amount of calcium in blood passes through the blood every day as calcium moves from gut to blood to tissues to stools and urine. Umbilical venous blood has a somewhat higher calcium content than umbilical arterial blood, of the order of 0.23 mmol/1 (1.0 mg/100 ml) (Hallman and Salmi, 1954).

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Of the commonly used methods for estimating calcium the EDTA method gives results which are of the order of 0.18 to 21 mmol/1 (0.70 to 0.85 mg/100 ml) lower than the oxalate method (Wilkinson, 1957). Although there is some general relationship between the plasma total calcium and total protein in the newborn infant the Maclean--Hastings nomogram is not an accurate indicator of the concentration of ionised calcium in newborn infants (Brown, Boen and Bernstein, 1971; Sorell and Rosen, 1975). Values calculated in this way tend to be higher than real values (Andersch and Oberst, 1936). - - - - BREAST FED BOTTLE FED

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As with calcium the concentration of phosphorus in cord blood - - of the order of 0.48 to 0.81 mmol/1 (1.5 to 2.5 mg/100 ml) - - is higher than in maternal blood at delivery (Todd, Chuinard and Wood, 1939; Bruck and Weintraub, 1955; Khattab and Forfar, 1970). Plasma phosphorus concentrations derived from a wide range of reports in the literature are shown in Figure 2. Different methods tend to give different results but even with the same method a considerable range is reported. Unlike calcium, phosphorus concentrations rise during the postnatal period. Infants fed on cow's milk show a greater rise than those fed on human milk, as do those in whom

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feeding is delayed, presumably due to tissue catabolism. Where gestation is prolonged and the infant is of low birth weight, or if the mother suffers from severe pre-eclampsia, the infant's plasma phosphorus concentration is significantly higher than normal immediately after birth. The cord blood magnesium is generally higher than in the mother's blood by about 0.04 mmol/1 (0.10 mg/100 ml) (Watney et al, 1971). There is said to be no difference in magnesium concentration between umbilical venous and arterial blood but umbilical venous blood has been reported to show a lower magnesium concentration than capillary blood (Jukarainen, 1971), and not to do so (Bajpai et al, 1966). Postmaturity and primiparity tend to be associatedwith subnormal concentrations (Tsang and Oh, 1970b; Jukarainen, 1971).

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3BD U V O I 2 3 4 $ 6 7 Wks. I I DAYSOF LIFE Figure 2. Phosphorus concentrations in plasma during late pregnancy, delivery and the first seven days of life (mean + 2 s.d.).

Estimates of plasma magnesium concentration in the infant in the postnatal period show considerable variation even where the more reliable method of atomic absorption spectrophotometry has been used. Representative concentrations are shown in Figure 3. The average plasma magnesium concentration remains fairly constant in the first week of life. Among breast-fed infants half show a rise in magnesium during the first week and the majority of the remainder show no change; among bottle-fed infants half show a fall during the first week and the majority of the remainder show no change (Anast, 1964).

129

CALCIUM, PHOSPHORUS AND MAGNESIUM METABOLISM CORRELATIONS: CALCIUM, PHOSPHORUS AND MAGNESIUM. In

the full-term infant there is probably no correlation between period of gestation or birth weight and calcium, phosphorus and magnesium concentrations in cord blood or blood taken during the first week of life. Where a mother suffers from severe pre-eclamptic toxaemia or postmaturity, some correlation between period of gestation and cord blood calcium is evident (Khattab and Forfar, 1971). The concentrations of calcium in maternal blood at delivery and the baby's blood at birth show a significant positive correlation, and the same is true for phosphorus (Khattab and Forfar, 1970) and probably magnesium.

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In the infant calcium and phosphorus concentrations in cord blood and over the first few days of life do not correlate (Khattab and Forfar, 1970; Brown, Boen and Bernstein, 1971), but they do correlate inversely from days 6 to 8 (Snodgrass et al, 1973). Plasma calcium concentrations have been reported to correlate inversely with plasma magnesium over the first five days of life (Jukarainen, 1971), and positively over days 6 to 8 (Snodgrass et al, 1973). Negative correlation has been shown between magnesium and phosphorus from birth to the eighth day of life (Jukarainen, 1971; Snodgrass

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et al, 1973). Plasma ionised calcium correlates positively with total plasma calcium in the first few days of life, even though this is said not to occur later in infancy and childhood (Sorrell and Rosen, 1975). Changes in calcium concentration between the first and seventh days of life show a positive correlation with changes in magnesium concentration but an inverse correlation with changes in phosphorus concentration (Snodgrass et al, 1973); there is no correlation between changes in phosphorus and changes in magnesium over the same period. These correlations have been studied with a view to determining the nature of the relationship of maternal to fetal and neonatal mineral metabolism, and the inter-relationship of calcium, phosphorus and magnesium regulation in the fetus and infant. They show that control of mineral metabolism in the mother exerts a specific effect on that in the fetus and that within the fetus there is some inter-relationship between these mechanisms controlling calcium, phosphorus and magnesium even though the mechanisms operate at times in apparently diverse ways.

Cerebrospinal fluid The calcium concentration in cerebrospinal fluid is normally lower than that in plasma ranging between 2.4 and 2.6 mmol/1 (9.5 to 10.5 mg/100 ml) while the magnesium concentration is higher, 1.07 to 1.15 mmol/1 (2.6 to 2.8 rag/100 ml) (Cockburn et al, 1973). Muscle In fetal muscle at 20 weeks gestation the concentration of calcium is higher and phosphorus and magnesium lower than in term infants or adults: calcium -- fetus 3.6 mmol/kg (144 mg/kg), term infant 2.2 mmol/kg (88 mg/kg), adult 1.3 mmol/kg (52 mg/kg); phosphorus -fetus 40 mmol/kg (1239 mg/kg), term infant 47 mmol/kg (1456 mg/kg), adult 59 mmol/kg (1828 mg/kg); magnesium -- fetus 5.3 mmol/kg (129 mg/kg), term infant 7.4 mmol/kg (180 mg/kg), adult 8.4 mmol/kg (204 mg/kg), all in salt-free tissue (Widdowson and Dickerson, 1964). Excreta During the first 24 hours after birth the excretion of calcium in meconium per kilogram body weight is 160 (50 to 264)/~mol/kg or 6.4 (2.0 to 10.6) mg/kg, of phosphorus 74 (23 to 126) /~mol/kg or 2.3 (0.7 to 3.9) mg/kg and of magnesium 288 (107 to 469) gmol/kg or 7.0 (2.6 to 11.4) mg/kg; the urinary excretion of calcium is 9 (4 to 14) /~mol/kg or 0.39 (0.19 to 0.59) mg/kg, of phosphorus 3 (2 to 6) ~mol/kg or 0.10 (0.05 to 0.195) mg/kg and of magnesium 2(0.4 to 4.0) /2mol/kg or 0.05 (0.01 to 0.09) mg/kg (Widdowson et al, 1962). In a situation where the plasma phosphorus concentration is influenced by tissue catabolism and possibly by a high exogenous load from cow's milk feeding the poor renal excretion during the first few days of life is important. By the end of the first week excretion of phosphorus in the urine has risen to 222 gmol/kg (6.9 mg/kg) in breast-fed infants and 732 gmol/kg (22 mg/kg) in cow's milk-fed infants i.e. 70 to 200-fold, while the excretion of calcium has diminished (Williams et al, 1970).

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Neonatal Requirements of Calcium, Phosphorus and Magnesium: Type of Milk Feeding The daily intakes of calcium, phosphorus and magnesium in breast-fed infants at one week of age are of the order of 160 mg, 90 mg and 18 mg (Widdowson et al, 1963). Recommendations on requirements relative to bottle feeding tend to suggest the need for double these amounts at least (100 ml of human milk contains 40 mg calcium, 18 mg phosphorus and 5 mg magnesium, and of cow's milk 125 mg, 90 mg and 13 mg respectively). Widdowson and McCance (1965) have suggested that the supply of phosphorus may lililit the development of the newborn infant for a time after birth (Widdowson et al, 1963). The type of milk fed to an infant can affect the calcium, phosphorus and magnesium concentrations. In breast-fed infants calcium and magnesium are higher and phosphorus lower on the sixth day of life than in infants fed cow's milk preparations including evaporated milk or milk reconstituted from dried milk powder. Adapted (humanised) milks give plasma concentrations in the baby closer to those found in breast milk (Gittleman and Pincus, 1951; Bruck and Weintraub, 1955; Opp6 and Redstone, 1968). The calcium content of cow's milk is higher than that of human milk but relatively the phosphorus content is higher still. Thus the calcium/phosphorus ratios for human and cow's milk are 2.2 and 1.4 respectively. Most artificial milks derived from cow's milk retain the latter ratio, even adapted milks (Shaw, Jones and Gunther, 1973; Widdowson, Southgate and Schutz, 1974). The lower serum calcium concentrations found in newborn infants fed adapted milks are probabl~ associated with absolute lowering of the phosphorus (and calcium) content, not to significant alteration in the calcium/phosphorus ratio.

Parathyroid Hormone (PTH) The concentration of plasma parathyroid hormone (PTH) remains within normal limits (units designated according to the method of assay, e.g. 10 to 60 ~lEq/ml or <70 to 330 pg/ml) during the first 28 weeks of pregnancy but within these limits shows a significant decrease until the 28th week rising thereafter until the 40th week when the average concentration is significantly above that found in the normal non-pregnant woman - - reaching 60 to 100 ~lEq/ml. Beyond the 40th week of pregnancy the concentration falls (Cushard et al, 1972). PTH concentrations during pregnancy thus follow a pattern somewhat similar to that of plasma calcium. Further, mothers with lower plasma calcium levels tend to have higher PTH levels (Watney and Rudd, 1974). Although plasma total and ionised calcium fall during pregnancy and then rise, as does PTH, there is no specific correlation between plasma calcium and PTH concentrations. 'Hyperparathyroidism' thus occurs during normal pregnancy as a physiological response to the demands of the growing fetus upon maternal calcium stores. PTH concentrations in maternal blood at delivery and in cord blood have been reported to be similar (Tsang et al, 1973b; Watney and Rudd, 1974), or higher in maternal blood (Samaan, Wigoda and Castillo, 1973).

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Phosphate clearance is poor at birth but increases 30 to 60-fold by the third day of life. A similar trend with a three to four-fold increase has been observed in the daily rates of urinary excretion of cyclic AMP (urinary cyclic AMP rises in response to PTH), third day excretion being compatible with a state of significantly increased parathyroid activity (Linarelli, 1972). Thus the immediate postnatal fall in calcium in the newborn infant appears to be associated with hypo-activity of the parathyroid at birth and the rise which commences at the fourth day appears to be due to increased activity. Fairney, Jackson and Clayton (1973) found that the plasma PTH rose from 97 pg/ml in cord blood to 217 pg/ml on the sixth day. Coincidentally with this increased parathyroid activity there is also an increased renal proximal tubular responsiveness to PTH (Linarelli, 1972). Premature infants given PTH (5 units/kg i.m.) at 24 and 48 hours after delivery show a transitory calcaemic (and less marked magnesaemic) response lasting for several hours: the lower the infant's plasma calcium the greater the response. The post-treatment 24-hour excretion of calcium, phosphorus and magnesium is not significantly increased, however, compared with a control group (Tsang et al, 1973b). Based on the PTH response to citrate-induced hypocalcaemia during exchange transfusion the greater the postnatal age the greater the capacity for parathyroid response (see page 231).

Alkaline Phosphatase The concentration of plasma alkaline phosphatase rises steadily throughout pregnancy from an average of 5.2 King--Armstrong units per 100 ml at 10 to 20 weeks to 7.5 KA units at 36 weeks gestation, and much greater rises are found in Asian mothers living in Britain. The immediate postnatal concentration averages 9.9 KA units per 100 ml. The average concentration in cord blood (17.8 KA units per 100 ml) is nearly twice that in the mother postnatally (Watney and Rudd, 1974). The increased serum alkaline phosphatase concentrations late in pregnancy may be associated with increasing mobitisation of calcium from bones due to increasing PTH action. Diminished absorption from the gut due to lack of vitamin D is likely to accentuate this.

Vitamin D Although it is well over half a century since the anti-rachitic vitamin D was first isolated from cod liver oil, it is only in the past few years that much has come to be understood of its intermediary metabolism. The D group of vitamins are steroid compounds, the human variety, cholecalciferol (vitamin Dz) being formed in the skin from 7-dehydrocholesterol by ultraviolet light irradiation. Synthetic preparations with anti-rachitic activity are calciferol (ergocalciferol or vitamin D2) and dihydrotachysterol (DHT or AT10). One microgram of either calciferol or cholecalciferol is the equivalent of 40 international units of vitamin D. DHT cannot be quoted in units; it is less effective than the other compounds in curing classical rickets but acts more quickly in raising the plasma calcium level although its effects wear off sooner. It is little used in the neonatal field.

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The range and specificity of function of vitamin D are not yet fully understood. The most certain role is the maintenance of normal blood calcium and phosphorus concentrations. Increase in the concentrations of these two minerals is the most discernible response to vitamin D and appears to result from two effects of the vitamin: firstly, stimulation of calcium (and possibly phosphorus) absorption from the gut, and secondly, mobilisation of calcium and phosphorus from bone in the presence of PTH (DeLuca, 1974). Vitamin D3 is produced in the skin. Dietary vitamin D (mostly D2) is absorbed from the small intestine, provided bile salts are present. Seven years ago the first of the major steps in discovering the intermediate metabolites of vitamin D was taken when it was found that vitamin D3 is hydroxylated in the liver (at carbon-25) under the influence of a microsomal enzyme (25-hydroxylase) to form 25-hydroxycholecalciferol (25-HCC or 25-OH-D3) (Blunt, DeLuca and Schnoes, 1968). Vitamin D2 is likewise converted into 25-hydroxyergocalciferol (25-OH-D~). 25-HCC (25-OH-D) then circulates in plasma apparently bound to a specific carrier protein (Belsey et al, 1974). The next stage of metabolism occurs in the kidney where 25-HCC is converted by further hydroxylation (1-hydroxylase) to 1,25dihydroxycholecalciferol (1,25-DHCC or 1,25-(OH)2-D3) which is the biologically active form of cholecalciferol (Fraser and Kodicek, 1970). This hydroxylation appears to be effected by a mitochondrial enzyme. If animals are given small amounts of vitamin D and a low calcium diet there is marked stimulation of the production of 1,25-DHCC whereas if given high calcium diets the production of 1,25-DHCC is 'turned off' and another metabolite, 24,25-DHCC (24,25-(OH2)-D3), which is probably much less active than 1,25-DHCC, is produced (DeLuca, 1974). The inter-relationship between PTH and vitamin D metabolism remains a matter of some controversy. DeLuca and his co-workers and Kodicek (1974) believe that PTH is a primary factor in the stimulation of 1,25-DHCC production under conditions of normocalcaemia to hypocalaemia and that hypophosphataemia induced by dietary phosphate restriction also stimulates the synthesis of 1,25-DHCC. PTH, in addition to stimulating the formation of 1,25-DHCC, also acts on bone by mobilising calcium but can only do this effectively in the presence of vitamin D (1,25-DHCC). The 1,25-DHCC produced in the kidney also has the effect of increasing calcium absorption from the gut (it does not require PTH for this action). Both mobilisation of calcium from bone and absorption from the alimentary tract raise the concentration of calcium in the blood which inhibits PTH activity and therefore 'switches off' mobilisation of calcium from bone and absorption from the alimentary tract (the raised calcium will 'switch on' calcitonin -- see below). It is possible that when plasma calcium is raised and PTH reduced 25-HCC is converted preferentially to the less active 24,25-DHCC. On the other hand Galante et al (1972, 1973) while not rejecting the suggestion that PTH may increase the production of 1,25-DHCC in some circumstances, consider that PTH normally suppresses the conversion of 25-HCC to 1,25-DHCC and that the major determinant of the type of metabolite produced in the kidney is the intracellular calcium concentration in the renal cells. Thus in this theory a low plasma calcium, with low

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concentration in renal cells, would itself stimulate the formation of 1,25DHCC and it is postulated that PTH, by producing an influx of calcium into the renal cells, would inhibit the formation of 1,25-DHCC while stimulating the formation of 24,25-DHCC. Under this theory the effect of PTH on increasing intestinal calcium absorption cannot be due to an effect on vitamin D metabolism (as PTH suppresses 1,25-DHCC production) and Galante et al (1972) postulate that PTH itself is the main agent of calcium absorption from the gut. The question as to whether 1,25-DHCC is necessary for the action of PTH (if it is not necessary for this, its function under the propositions put forward by Galante et al is not clear) is left open, but it is recognised that if it is, the action of PTH in diminishing the production of 1,25-DHCC may represent a self-limiting effect of the hormone. These views hardly accord with the statement by Wills (1973) that PTH is unlikely to play a major part in calcium absorption. Identification of the metabolic products involved in vitamin D activity has led to the synthesis of analogues and one of these, 1 alpha-hydroxycholecalciferol (la-HCC or la-OH-D2) has a biological activity comparable to that of 1,25-DHCC. Thus while 25-HCC would be suitable for treatment in conditions in which hepatic disturbance is present, la-HCC would be of value in chronic renal disease, hypoparathyroidism and vitamin D dependency disease, i.e. where kidney disease or PTH or enzyme deficiency prevents the conversion of 25-HCC to 1,25-DHCC. In mothers the concentration of 25-HCC during pregnancy shows considerable variation. This variation is not related to the length of gestation. Concentrations in maternal blood at delivery show a significant correlation with cord blood concentrations of 25-HCC. At normal (6.4 to 12.0 nmol/1 or 16 to 30 ng/ml) maternal plasma concentrations of 25-HCC the infant concentration averages 80 per cent of the maternal concentration, at high ( 1 2 + nmol/1 or 3 0 + ng/ml) maternal concentrations, 68 per cent of the maternal concentration, and at low (0.8 to 6.0 nmol/1 or 2 to 15 ng/ml) maternal concentration 108 per cent (Hillman and Haddad, 1974). This happens irrespective of whether the infant is born at term, is premature or is a twin. These data are in keeping with the likelihood that there is passive or facilitated transfer of 25-HCC across the placenta, and animal experiments show that such passage takes place (Haddad, Boisseau and Avioli, 1971). Maternal 25-HCC status is thus clearly an important determinant of the 25-HCC status of the newborn infant. In those living in temperate countries 25-HCC concentration tends to be significantly higher in the summer months compared with the winter months even though there are no corresponding changes in plasma calcium concentration (Haddad and Stamp, 1974; McLaughlin et al, 1974). In mothers receiving large quantities of vitamin D a proportion is excreted as 25-HCC in breast milk (Goldberg, 1972). Calcitonin A hypocalcaemic principle in blood - - given the n a m e of calcitonin - - was first recognised over 10 years ago (Copp, Davidson and Cheney, 1961).

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Calcitonin is elaborated by distinctive cells in the thyroid and parathyroid glands designated 'C' cells. These are derived from the ultimobranchial body of the embryo which, as the embryo develops in mammals, merges with the thyroid and parathyroid glands. Activity is expressed in MRC units or milliunits, as determined by the hypocalcaemic effect produced in young rats, or as nanograms of synthetic calcitonin. The normal adult mean is 0.5 ng/ml (s.d. = 0.25). The primary effect of calcitonin is to inhibit bone resorption and release of calcium from the skeleton. It is an important part of the negative feedback control of hypercalcaemia whether this results from increased absorption of calcium from the gut, the injection of calcium salts or increased parathyroid hormone activity. The effect of calcitonin on vitamin D metabolism is to enhance the production of 1,25-DHCC by the kidney. Whether it does this by increasing PTH secretion or by lowering the calcium concentration in kidney cells (see above) is not clear. Plasma calcitonin is reported to be significantly higher in the pregnant mother (mean 1.3 ng/ml) at term than the non-pregnant mother and higher in venous cord blood (4ng/ml) than in the mother. It is still higher (by 2 ng/ ml) in blood from the umbilical artery than from the vein (Samaan, Wigoda and Castillo, 1973), suggesting a fetal rather than a maternal origin. Calcitonin concentration remains high (5 ng/ml) during the first 24 hours of life, falling to half this level by the end of the first month (Samaan, Anderson and Adam-Mayne, 1975). Salmon and porcine calcitonin also have a very significant natriuretic effect (Keeler, Walker and Copp, 1970).

ABNORMAL CALCIUM, PHOSPHORUS AND MAGNESIUM METABOLISM IN THE PERINATAL PERIOD Clinical Management of Disturbed Calcium, Phosphorus and Magnesium Metabolism Due to the limited symptomatic responses of which the newborn infant is capable the range of clinical features in calcium, phosphorus and magnesium disturbance is a restricted one, largely dictated by variations in plasma calcium and magnesium. Plasma phosphorus concentrations can range much more widely without symptomatic effect. Hypocalcaemia and hypomagnesaemia occurring in a 'primary' way present in the neonatal period, usually after the third day, with neuromuscular irritability which can include jitteriness, hyperalertness, increased muscle tone particularly extensor tone, increased deep reflexes, clonus, Chvostek's sign, transient hemisyndrome and a high-pitched cry. These may culminate in convulsions or convulsions may occur without much evidence of such premonitory symptoms. The convulsions associated with hypocalcaemia and hypomagnesaemia per se involve rhythmical myoclonicjerks at a rate of one to three per second. They may be focal, multifocal or generalised, remaining of one pattern or changing to another (Cockburn et al, 1973). Provided they are not prolonged and generalised, when cyanosis and deterioration in feeding

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behaviour can occur, these convulsions usually produce little generalised disturbance and an infant may continue to feed in the presence of a focal convulsion. 'Sunsetting' of the eyes and spreading of the intracranial sutures may occur with hypocalcaemia. This raised intracranial pressure is presumably due to cerebral oedema resulting from loss of fluid from poorly supported vessels whose permeability has been reduced. There may be generalised oedema also and in such cases it has been suggested that secondary aldosteronism is a contributory factor (Chiswick, 1971). Hypocalcaemia (seldom hypomagnesaemia) can occur secondarily as part of a more profound underlying disease usually during, but not confined to, the first three days of life. The basic disturbance is usually asphyxia or birth injury, or both, and the predominating symptoms are those resulting from these two disorders not from the hypocalcaemia. Tonic fits (uncommon in 'primary' hypocalcaemia) with apnoea, hypotonia, apathy, loss of primitive reflexes, feeding difficulties and persisting paresis are likely symptoms (Brown, Cockburn and Forfar, 1972). Hypercalcaemia and hypermagnesaemia are much less likely to occur spontaneously in the neonatal period but may result from therapeutic administration of calcium and magnesium to the infant or of magnesium to the mother antenatally. Symptoms include apathy, flaccidity, muscular hypotonia and vomiting. In severe cases of hypermagnesaemia there may be a curare-like state with respiratory paralysis.

Classification of Disturbed Calcium, Phosphorus and Magnesium Metabolism in the Perinatal Period Calcium, phosphorus and magnesium metabolism in the perinatal period can be disturbed through a number of mechanisms. 1. Inherent (genetic) defects in the parents transmitted to the offspring. 2. Congenital absence or hypoplasia of the parathyroids. 3. Disturbance of the maternal (intrauterine) mineral status with 'reciprocal' disturbance of fetal mineral metabolism. 4. Nutritional deficiency. 5. Impaired placental function with disturbed transmission. 6. Prematurity and intrauterine growth retardation. 7. Perinatal asphyxia and birth injury. 8. Increased phosphorus load on feeding. Several of these factors may operate together: in the asphyxiated and then bottle-fed premature infant born to a vitamin D-deficient Asian mother with severe pre-eclamptic toxaemia at least half of these mechanisms could operate.

Inherent (Genetic) Defects in Parents Hypoparathyroidism Barr et al (1971) have described cases of inherited hypoparathyroidism and reviewed the literature. Inherited hypoparathyroidism may present with hypocalcaemic symptoms, usually convulsions, in the neonatal period.

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Sometimes the significance of these symptoms is only recognised in retrospect when the child is later investigated for 'epilepsy' or psychomotor retardation. About 20 cases have been recognised in which the disease has apparently occurred as an autosomal dominant affecting two generations, and there are occasional cases where inheritance is seemingly sex-linked recessive (Peden, 1960), or autosomal recessive (Niklasson, 1970). Hypomagnesaemia may also be a feature of the autosomal-recessive type and there may be associated adrenal insufficiency and skin moniliasis (Whitaker et al, 1956).

Hyperparathyroidism Familial cases of this have been reported, presumably transmitted as autosomal recessives (Hillman et al, 1964), and a kindred in which there were 11 cases has been described (Culter, Reiss and Ackerman, 1964). It is possible that single 'sporadic' cases could be similarly derived (Fretheim and Gardborg, 1965). Histologically cases of neonatal hyperparathyroidism are associated with characteristic 'chief' cells in the parathyroids.

Congenital Absence or Hypoplasia of the Parathyroids Third and fourth pharyngeal pouch (D| George) syndrome The main glandular structures derived from the third and fourth pharyngeal pouches are the parathyroid glands and the thymus. Both may be congenitally absent or hypoplastic resulting in severe hypocalcaemia often associated with intractable diarrhoea, failure to thrive, lymphopenia and immunological deficiency (Taitz, Zarate-Salvador and Schwartz, 1966). Mortality in such cases is high.

Congenital (idiopathic) hypoparathyroldism Idiopathic hypoparathyroidism does not usually develop in the neonatal period but four per cent of such cases do and can be considered to be due to congenital parathyroid hypoplasia (Kunstadter et al, 1963). At least two cases have been associated with diabetes in the mother, and one has had associated glaucoma (Rhyne and Carriker, 1956).

Absence of calcitonin-secreting 'C' cells (in the thyroid and parathyroid glands) which are derived from the neural crest and ultimobranchial body which, if it occurred, would presumably cause hypercalcaemia does not appear to have been described.

Disturbance of Maternal (Intrauterine) Mineral Status with 'Reciprocal' Disturbance of Fetal Mineral Metabolism Due to the free passage of calcium across the placenta the fetus reflects maternal plasma calcium concentrations. There is some controversy regarding placental passage of PTH in man and little knowledge about the

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placental transfer of calcitonin. In those disorders in which the 'reciprocal' effect is evident a high calcium concentration in the mother induces a low concentration in the fetus (presumably the high maternal levels are transmitted to the fetus and cause suppression of parathyroid function) and low maternal levels cause fetal hyperplasia (presumably the low maternal levels transmitted to the fetus stimulate parathyroid function).

Maternal hyperparathyroidism associated with neonatal hypoparathyroidism Wagner, Transb¢l and Melchior (1964) collected data from the literature regarding 23 women with hyperparathyroidism who during the course of their disease had at least 34 pregnancies. Of the 25 surviving live-born infants 11 were stated to have had tetany, three were stated not to have had tetany, and in 11 no statement was made regarding tetany. Usually such neonatal tetany has been transitory (Hartenstein and Gardner, 1966), but rarely it has been chronic (Bruce and Strong, 1955). Plasma magnesium concentrations may be lowered along with calcium, and in some cases there is more significant lowering of magnesium than calcium (Ertel, Reiss and Spergel, 1969). Not infrequently the clue to the mother's disease has been the occurrence of tetany in her offspring.

Maternal hypoparathyroidism associated with neonatal hyperparathyroidism Landing and Kamoshita (1970) reported twins with hypercalcaemia where the mother was suffering from hypoparathyroidism following earlier thyroidectomy and referred to other cases in the literature. These cases died and were proved to have parathyroid hyperplasia.

Nutritional Deficiency 'Idiopathic' neonatal tetany In the newborn infants of mothers who have no recognisable disease th~ occurrence of transitory spasmophilia and tetanic convulsions, usually after the third day of life and in response to feeding with cow's milk, is now one of the commonest neonatal disorders with an incidence which may exceed one per cent of live births. These symptoms are very prone to occur in infants of diabetic mothers. Nearly 40 years ago Bakwin (1937) suggested that the primary cause of neonatal tetanus was temporary hypofunction of the newborn infant's parathyroid gland aggravated by the calcium-lowering effect of the high phosphate content of cow's milk feeding. About the same time Friderichsen (1939) suggested that hypofunction of the neonatal parathyroids was the result of 'abundance of maternal parathyroid hormone reaching the fetus' and inducing hypoplasia (passage of PTH across the placenta was implied). The concept of temporary parathyroid insufficiency has been widely accepted as a cause of idiopathic neonatal tetany (Fanconi and Prader, 1967), and it has been shown that PTH levels are significantly lower in tetanic infants than in non-tetanic (David and Anast, 1974). Further observations on idiopathic neonatal tetany have not detracted from the view that the direct cause of the hypocalcaemia is parathyroid insufficiency in the affected infant but have extended the relationship of this with other hormone

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disturbances. The parathyroid insufficiency is accompanied by the high levels of calcitonin which are present in the first few days of life. In tetanic infants these calcitonin levels are not different from those in non-tetanic infants -- at least in tetanic infants of diabetic mothers (Bergman, Kjellmer and Selstrum, 1974). The infant may be more sensitive to these high calcitonin levels, however, because of the low PTH activity. Purvis et al (1973) have shown that neonatal tetany is seasonal in incidence and related to pregnancy in the winter months. Adults in general show lower 25-HCC concentrations in the winter months (Haddad and Stamp, 1974; Gupta, Round and Stamp, 1974). Purvis et al also showed that enamel hypoplasia in the primary dentition occurred frequently in infants who had suffered from neonatal tetany. Histological studies of the affected teeth indicated that the enamel defect had been determined antenatally in the last trimester of pregnancy. Similar defects are seen in infants with congenital hypoparathyroidism (Riley, 1969) and in infants born to mothers with severe nutritional osteomalacia (Maxwell, 1934). Further it has been shown that few mothers, at least in certain parts of the country, take vitamin D supplements in pregnancy (Forfar and Nelson, 1973). These findings suggest that maternal vitamin D deficiency is the underlying factor in neonatal tetany. Such a deficiency would result in secondary hyperparathyroid hyperplasia in the mother which, mediated through the placenta either by direct transfer of PTH or by a less direct way, results in suppression of parathyroid function in the fetus. This parathyroid insufficiency is 'carried over' into the early days of postnatal life and in conjunction with the high CT levels now unopposed by PTH and aggravated by high phosphate feeding in cow's milk-fed infants is likely to create a state of hypocalcaemia. Other relevant factors are an older age in the mother, high parity and lower social class (Roberts, Cohen and Forfar, 1973). Further support for the view that 'idiopathic' neonatal tetany is due primarily to vitamin D deficiency in the mother has been obtained by Rosen et al (1974) who found that in mothers of infants with neonatal tetany and their infants plasma 25-HCC levels were very low. Belton et al (1975) showed that small vitamin D supplements (400 units/day) given to the pregnant mother raise the 25-HCC concentrations in both mother and infant. Vitamin D given to infants with tetany also produces a marked elevation of the plasma calcium concentration when an oral loading dose of calcium is given eoincidentally (Barr and Forfar, 1969). Another therapeutic consideration is the possible effect of uncorrected hypomagnesaemia in inhibiting the release of calcium from bone. Unless hypomagnesaemia is corrected calcium may be ineffective in treating neonatal tetany (Cockburn et al, 1973). In 'idiopathic' neonatal tetany hypocalcaemia is associated with hyperphosphataemia in 60 per cent of cases and with hypomagnesaemia in 50 per cent of cases. Isolated hypomagnesaemia occurs in seven per cent of cases (Cockburn et al, 1973). Fetal rickets

Moderate vitamin D deficiency would appear to result in 'idiopathic' neonatal tetany and the specific biochemical disturbances which go with it.

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Where there is severe calcium and vitamin D deficiency resulting in osteomalacia in the mother a somewhat different picture presents. Not only is there hypocalcaemia in the infant (which is usually of a lesser degree than that present in the mother) but there are also rachitic changes in bone (both in mother and infant) recognisable radiologically. Maternal osteomalacia has always been common in many of the less developed countries (Maxwell, 1934), but has been reported with considerable frequency recently in Britain in Asian immigrants (Swan and Cooke, 1971; Clark, Simpson and Young, 1972; Moncrieff and Fadahunsi, 1974). On the basis of animal experiments, magnesium deprivation in the mother will result in magnesium deficiency in the fetus. Nutritional deficiency in a mother with long-standing untreated coeliac disease associated with hypomagnesaemia has been reported to result in hypomagnesaemic tetany in her newborn infant (Davis, Harvey and Yu, 1966). Impairment of Placental Function with Disturbed Mineral Transmission Conditions such as severe pre-eclamptic toxaemia and postmaturity with an undersized fetus which are likely to be associated with placental insufficiency may result in neonatal hypocalcaemia (Khattab and Forfar, 1970). Likewise, subnormal magnesium levels have been reported in infants born to toxaemic mothers and in infants small for gestational age (Tsang and Oh, 1970b; Forfar, Cockburn and Brown, 1973). Intrauterine growth retardation per se is not necessarily associated with hypocalcaemia (Tsang et al, 1975), suggesting that where intrauterine growth retardation is associated with placental malfunction hypocalcaemia and hypomagnesaemia may occur but that where it occurs for other reasons the calcium status of the fetus may not be significantly affected. Prematurity and Intrauterine Growth Retardation In the premature infant concentrations of calcium tend to be lower than in the full-term infant (Bruck and Weintraub, 1955; Yu et al, 1965), although this is not so in respect of cord blood (Forfar, Cockburn and Brown, 1973). Thirty to 35 per cent of preterm infants show hypocalcaemia (plasma calcium <1.8 mmol/1 or <7 mg/100 ml) and 12 per cent show hypomagnesaemia (plasma magnesium <0.62 mmol/1 or <1.5 mg/100 ml) (Tsang et al, 1973a). The lower the birth weight of premature infants, the lower does the plasma calcium tend to be and the more widely does it fluctuate. When premature infants are included there is a positive correlation between gestational age and plasma calcium (Tsang et al, 1973a). No significant correlation, has been found between birth weight and plasma calcium (Khattab and Forfar, 1970, 1971). Fewer preterm infants who are small for gestational age show subnormal plasma calcium levels than preterm infants who are of appropriate weight for gestational age (Tsang and Oh, 1970a). 'Healthy' premature infants fed human milk show only a slight fall or no postnatal fall in plasma calcium concentration: cow's mild-fed premature

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infants or fasted premature infants tend to show a fall in plasma calcium for three days then a rise, a pattern similar to that of the full-term infant (Bruck and Weintraub, 1955). In infants under 1500 g plasma calcium concentrations of 1.6 to 1.7 mmol/1 (6.4 to 7.0 mg/100 ml) may be unassociated with symptoms (Yu et al, 1965). Cord blood phosphorus concentrations fluctuate widely and the range remains wide throughout the first week of life. Concentrations tend to be higher in premature infants compared with full-term infants, particularly with cow's milk feeding or fasting, and the concentration rises during the first week (Bruck and Weintraub, 1955; Yu et al, 1965). In low birth weight infants and in those of short gestation period (particularly <35 weeks) plasma magnesium tends to be higher than normal (Jukarainen, 1971), with the exception of low birth weight infants of toxaemic mothers who tend to have subnormal concentrations within the first day (Jukarainen, 1971). Premature infants who are small for gestational age tend to have lower plasma magnesium concentrations than those whose weight is appropriate for gestational age (Tsang and Oh, 1970; Forfar, Cockburn and Brown, 1973), i.e. the opposite situation to that which pertains with calcium. Hillman and Haddad (1975) have produced evidence that hydroxylation of vitamin D to 25-HCC in the liver is impaired in the premature infant. This is likely to play some part in rickets of prematurity and could result in failure to utilise exogenously administered vitamin D. Perinatal Asphyxia and Birth Injury

Perinatal asphyxia and birth injury are often associated with hypocalcaemia, particularly during the first three days of life (Brown, Cockburn and Forfar, 1973; Tsang et al, 1974). Magnesium may also be lowered in asphyxia but is very much less likely to be affected than calcium. In cord blood magnesium levels are higher than normal in asphyxiated infants and show a significant negative correlation with the Apgar score and positive correlation with the use of resuscitative processes and time until onset of the first breath (Engel and Ertil, 1970). This elevation of magnesium may well be due to the fact that magnesium is predominantly an intracellular ion and can be released from cells damaged by asphyxia and trauma during the processes of labour and delivery. Hypocalcaemia (and hypomagnesaemia) associated with asphyxia and birth injury does not usually present as tetany but rather as the symptom pattern dictated by the asphyxia and birth injury. ' Increased Phosphorus Load on Feeding

'Idiopathic' neonatal tetany can occur in breast-fed infants but the large majority of cases occur in infants who are fed cow's milk with its higher phosphorus content. The apparent increase in neonatal tetany in recent years in association with cow's milk feeding seems likely to have been related to a reduction of the intake of vitamin D by pregnant mothers to a subnormal level and not to any increased use of cow's milk. This may have resulted from

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the concern regarding over-medication with vitamin D which arose about 20 years ago when idiopathic hypercalcaemia of infancy reached almost epidemic proportions in Britain and was considered to be related to excessive vitamin D intake. The problem of neonatal tetany induced by cow's milk feeding can be approached in two ways, either by modifying cow's milk used for infant feeding in such a way as to reduce its phosphorus content or to reduce the infant's sensitivity to phosphate loading by ensuring that mothers during pregnancy have an adequate intake of vitamin D. The latter would appear to be the more logical approach although both approaches may be adopted. 'Adapted' milks containing vegetable fat may aggravate hyperbilirubinaemia by virtue of their fatty acid content (see page 116), and the higher linoleic acid content of such milks may result in anaemia in the presence of the vitamin E deficiency which is frequently present in such infants when iron is given to prevent anaemia.

Other Disturbances of Calcium, Phosphorus and Magnesium Metabolism The infant of the diabetic mother appears to be more prone to neonatal tetany than infants born to mothers without diabetes (see page 246) (ZetterstrSm and Arnhold, 1958). Both hypoealcaemia and hypomagnesaemia may occur (Clark and Carr6, 1967; Keipert, 1969). Diabetes in the mother appears to exaggerate the factors which cause 'idiopathic' neonatal tetany. Perhaps greater demands on maternal vitamin D stores by the large fetus contribute and, as it has been shown that there is a positive correlation between blood glucose in the mother and plasma calcium in the infant in states of 'placental insufficiency', insulin-induced hypoglycaemia in the mother might play some part (Khattab and Forfar, 1971). Glueagon stimulates calcitonin secretion in animals (Care et al, 1970) so that a glucagon response to the hypoglycaemia from which the infant of the diabetic mother frequently suffers could be an important factor. This is more likely where there are stress factors such as asphyxia operating (Johnston and Bloom, 1973). Hypercalcaemia has been reported along with subcutaneous fat necrosis (Barltrop, 1963) with the suggestion that with resolution calcium is released from the calcium-rich necrotic tissue causing temporary hypercalcaemia. Hypomagnesaemia may occur in neonatal hepatitis and congenital biliary atresia (Kobayashi and Shiraki, 1967) and may also occur as a result of exchange transfusion.

Treatment The treatment of hypocalcaemic and hypomagnesaemic states is primarily that of the prevention and treatment of the conditions which cause them. Neonatal hypocalcaemia can be relieved by calcium gluconate given intravenously (5 ml/kg/24 hours of a 10 per cent solution) and hypomagnesaemia by intramuscular magnesium sulphate (0.2 ml/kg of a 50 per cent solution per dose). As the release of calcium from the calcium pool may be inhibited in the presence of hypomagnesaemia, correction of this may be necessary

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before administered calcium proves effective. In 'idiopathic' neonatal tetany magnesium alone has been shown to be a more effective form of treatment than calcium alone (Turner et al, 1975). The need for an adequate calcium intake in pregnancy and for vitamin D supplements has been emphasised by the occurrence of rickets among Asian populations in Britain and the increased incidence of neonatal tetany over the past few years. Vitamin D given to the newborn infant may act too slowly to prevent hypocalcaemia and hypomagnesaemia and in the premature infant may not be converted adequately to 25-HCC. The role of substances such as la-DHCC in neonatal therapy has not yet been explored. CONCLUSION Calcium, phosphorus and magnesium concentrations can be measured easily in the blood of mother and newborn infant. On the basis of such measurements short-term remedial action can be taken in most instances. Hypocalcaemia and hypomagnesaemia per se, although they can produce dramatic clinical effects and although they can clearly damage the primary dentition, do not appear to result in serious long-term damage if they are recognised and treated (although severe magnesium deprivation in rats can inhibit normal cerebral development). Calcium, phosphorus and magnesium are now recognised to be involved in many disease processes which affect the fetus and newborn infant, however, and may well play a significant but more indirect part in disorders such as asphyxia, bleeding, oedema, infection and abnormal bone formation. Their exact role in these has yet to be determined.

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Aikawa, J. K. & Bruns, P. D. (1960) Placental transfer and fetal tissue uptake of Mg in the rabbit. Proceedings of the Society for Experimental Biology and Medicine, 105, 95-98. Anast, C. (1964) Serum magnesium levels in the newborn. Pediatrics, 33, 969-974. Andersch, M. & Oberst, F. W. (1936) Filterable serum calcium in late pregnant and parturient women, and in newborn. Journal of Clinical Investigation, 15, 131-153. Bajpai, P. C., Sugden, D., Ramos, A. & Stern, L. (1966) Serum magnesium levels in the newborn and older child. Archives of Disease in Childhood, 41, 424-427. Bakwin, H. (1937) Pathogenesis of tetany of the newborn. American Journal of Diseases of Children, 54, 1211-1266. Barltrop, D. (1963) Hypercalcaemia associated with neonatal fat necrosis. Archives of Disease in Childhood, 38, 516-518. Barr, D. G. D. & Forfar, J. O. (1969) Oral calcium-loading test in rickets and in neonatal tetany: effect of vitamin D. British Medical Journal, ill, 150-152. Barr, D. G. D., Prader, A., Esper, U., Rampini, S., Marrian, V. & Forfar, J. O. (1971) Chronic hypoparathyroidism in two generations. Helvetica Paediatrica Acta, 26, 507-521. Bawden, J. W., Wolkoff, A. S. & Flowers, C. E. (1965) Maternal--fetal blood calcium relationship in sheep. Obstetrics and Gynecology, 25, 548-552. Belsey, R., Clark, M. B., Bernat, M., Glowacki, J., Holick, M. F., DeLuca, H. F. & Potts, J. T. (1974) The physiologic significance of plasma transport of vitamin D and metabolites. American Journal of Medicine, 57, 50-56. Belton, N. R., Cockburn, F., Forfar, J. O., Giles, M. M. & Stephen, R. (1975) Neonatal hypocalcaemia and its relationship to vitamin D and mineral metabolism in the pregnant mother. 9th International Congress on Clinical Chemistry, Toronto.

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Societies, 4~ 17. Culter, R. E., Reiss, E. & Ackerman, L. V. (1964) Familial hyperparathyroidism. A kindred involving 11 cases with a discussion of chief cell hyperplasia. New Engiand Journal of Medicine, 270, 859-865. Cushard, W. G., Crediton, M. A., Canterbury, J. M. & Reiss, E. (1972) Physiologic hyperparathyroidism in pregnancy. Journal of Clinical Endocrinology and Metabolism, 34, 767771. Dancis, J., Springer, D. & Cohlan, S. Q. (1971) Fetal homeostasis in maternal malnutrition. 11. Magnesium deprivation. Pediatric Research, 5, 131-136. David, L. & Anast, C. S. (1974) Calcium metabolism in newborn infants. The interrelationship of parathyroid function and calcium, magnesium and phosphorus metabolism in normal, "sick" and hypocalcaemic newborns. Journal of Clinical Investigation, 54, 287-296. Davis, J. A., Harvey, D. R. & Yu, J. S. (1965) Neonatal fits associated with hypomagnesaemia. Archives of Disease in Childhood, 40, 286-290. Dawson, E. B., Croft, H. A., Clark, R. R. & McGarrity, W. J. (1969) Study of nine cation levels in term placentas. American Journal of Obstetrics and Gynecology, 103, 1144-1147. de Jorge, B., Delasco, D., Barros de Ulhoa, C. A. & Antimes, M. (1965) Magnesium concentration in the blood serum of normal pregnant women. Obstetrics and Gynecology, 25, 253-254. Delivoria-Papadopoulos, M., Battaglia, F. C., Bruns, P. D. & Meschia, G. (1967) Totarproteinbound and ultrafilterable calcium in maternal and fetal plasmas. American Journal of Physiology, 213, 363-366. DeLuca, H. F. (1974) Vitamin D--1973. American Journal of Medicine, 57, 1-12.

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