Metabolic Changes in the Infant of the Diabetic Mother

Metabolic Changes in the Infant of the Diabetic Mother r

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JAMES W. FARQUHAR, M.D.

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Facts about metabolic changes in the infant of the diabetic mother are hard to establish for two very good reasons. Such babies are relatively uncommon, so that effective studies are likely only in those centres which concentrate care of diabetic mothers in the hands of one team. In the second place the high foetal mortality rate, the frequency of neonatal morbidity, and the desire to protect live-born infants from all further harm impart to each birth a sense of high drama, so that those who have at heart the welfare of mother and child must pick a delicate path between good practice and good research. Blood, urine, faeces, lung gases and function, electrocardiography, cardiac catheterisation and intravenous therapy are difficult to secure or perform when a team of competitive research fellows with their equipment surround one immature infant in an Isolette. For these reasons the centres concerned tend to concentrate on one aspect of the foetal problem and try not to get its importance out of perspective. The greater proportion of deaths occur in utero,H so that those babies who survive birth may have been in prenatal difficulty, and a wide range of metabolic abnormalities is to be expected. Although recent research has confirmed this, and though it has shed a little light on foetal morphology, it has done little to clarify the mysteries of mortality. Single abnormal biochemical observations must not be viewed in isolation. The appearance of a known convict on the scene of a new crime does not constitute proof of his involvement, and direct evidence or much that is indirect but reliable is necessary to establish guilt. The range of abnormalities and suspects is now reviewed, although not all the evidence is of equal value, and the leader of the ring almost certainly escapes detection.

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BODY WATER

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Everyone knows that the diabetic mother bears excessively large I

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babies not only when she is diabetic, but also sometimes for many years beforehand. The flushed, podgy face and corpulent contour of this bon vivant and the alternating postures of abandonment and of twittering irritability are well recognised in any obstetric hospital. Less well known, however, are the constitution of the foetal giant and the proportion of such babies who look undernourished rather than obese. The limbs of the common, plump variety can sometimes be made to pit on pressure, and large babies tend to lose more grams in weight in the first week of life than do those in the normal weight range. In less critical days pitting oedema was interpreted as water retention rather than as its intercompartmental movement. The imagined greater weight loss which was absolute, and not relative to the weight at birth, was thought to represent the renal elimination of excessive water. An attempt to establish these facts 46 provided the surprise result that, when compared with infants who were fed similarly and who had been born by the same route to normal women, babies of diabetic mothers lost no more weight. This shook the theory that excessive birth weight was due in part to water retention, and it demanded an alternative explanation. The careful studies of Osler93- 97 on living newborn babies, rather than on the highly selected group of cadavers which had been for years the only source of information, showed that those of diabetic women have less extracellular water and less total water than is normal. This finding was interpreted as consistent with an increased amount of body fat and has been substantiated in independent observations by Cheek, Maddison, Malinek and Coldbeck19 and by Clapp, Butterfield and O'Brien. 22 Most babies studied by Cheek et al. were about three days old and showed an appreciable shift of water from the extracellular to the intracellular phase, while Clapp et al. found no change in the ratio of intracellular to extracellular water on the first day, but had some data to suggest that the ratio increases in babies of diabetic mothers during the first three days of life, either because of a disproportionate loss of extracellular water in the urine or of migration of water into the cell. Although few figures are available, 25 , 38, 98 personal enquiry in other centres suggests that infants of diabetic mothers pass rather more urine than is normal during the first few days of life and that the volume depends to some extent on maternal hydration.

BODY FAT

The larger series described by morbid anatomists say little about the subcutaneous fat of such babies,15, 33, 135 but then the mortality rate is greatest among the smaller ones,39-41 and those in the autopsied group may have lost weight for some days before death. Yet measurement of the fat layer, both by skin fold thickness and by X-ray, shows that it is increased in infants of diabetic mothers by about 40 per cent over that

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of the normal newborn and by 50 per cent over normal infants of comparable maturity.94 The direct analysis of one cadaver by Fee and Weil48 showed that fat was moderately increased for a baby of comparable size and much increased in relation to maturity. Their findings have since been confirmed in a larger series. 49

HYPOGLYCAEMIA

These babies become more hypoglycaemic more quickly during the first few hours of life than do infants of normal women. The earlier literature has been extensively reviewed by Pedersen,lOl Komrower 74 and Farquhar,37.39 who regarded this often asymptomatic finding with less concern than did Hartmann and Jaudon 62 and John. 70 The first three authors held that hypo glycaemia is common and that it is frequently unproductive of symptoms or of future disability. They claimed that its coexistence with abnormal neonatal behaviour is an indication less for giving glucose than for seeking an alternative diagnosis. Babies of both diabetic and normal women can, in my experience, be both asymptomatic and undamaged at blood glucose levels below 20 mg. or even 10 mg. per 100 mI., and yet every paediatrician must be concerned about the group of symptomatic infants who present later with cerebral damage and who have been described by Cornblath, Odell and Levin,27 Brown and Wallis 12 and Neligan, Robson and Watson. 90 When glucose was given soon after birth to these babies in an effort to prevent hypo glycaemia, 40 it often failed to raise the blood glucose level as much as might have been expected. In a later study Baird and Farquhar3 showed that infants of diabetic mothers remove a glucose load from the blood much more quickly than do infants of normal women, although the results, when judged by adult standards, suggest that the difference is due to the poorer tolerance shown by normal newborn babies. These findings have been confirmed by Schwartz, Bowie and Mulligan,117 Mulligan and Schwartz,87 Larsson (personal communication) and Cornblath (personal communication). The glucose tolerance of normal newborns, however, can be made to conform to that of newborn infants of diabetic women and of normal adults if 0.13 unit of soluble insulin per kilogram of body weight is added to the intravenous glucose load. 44 The way in which the glucose level in heel-prick capillary blood rises immediately after the injection of a glucose load and the steady rate at which it usually falls over the next 60 to 90 minutes suggest that in most cases blood from this site may be taken to represent what is happening elsewhere in the body. This is important in view of Stur's128 concern that hypo glycaemia in heel-prick blood may represent an entirely local condition or an attempt at glucose conservation on the part of the body by reduction in skin flow. Babies of diabetic mothers can break down glycogen when given an injection of

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glucagon in appropriate dosage,26 and indeed most of them can restore their blood sugar level to normal without this aid37 in a few hours after birth.

ACID-BASE BALANCE

Lowrey, Graham and Tsao 79 found that babies of diabetic women, when compared with the normal newborn, tended towards an uncompensated acidosis with lowered plasma pH and raised pC02 values, as well as some reduction in protein, chloride and total base. This opinion was shared by Reardon et al.,112 Segal et al. 118 and Reardon.n 1 A similar situation was described in babies of prediabetic women who had little or no metabolic disturbanceP Simultaneous observations made on diabetic mothers and on their babies before the latter had taken their first breath confirmed a lowered pH and a raised pC02 which did not correlate with maternal values.71 Seligman 119 has found that the range of values in such babies at 20 minutes and three hours for pH, pC02 and buffer base is greater than in the normal newborn, but may relate to maturity. Infants who suffer the idiopathic respiratory distress syndrome have both a nonrespiratory and a respiratory acidosis. According to Goodlin,58 a degree of foetal metabolic acidosis similar to that found at birth in infants of diabetic mothers can be induced in the foetus of the nondiabetic mother by giving her ammonium chloride, and yet the acidotic newborn is asymptomatic. More recently Prod'hom et al. 107 have made further studies of respiratory function and acid-base balance on such infants. They conclude that apart from a slight persistent respiratory acidosis at the ages of one and four hours, the acid-base balance in cord and arterial blood of well, undistressed babies delivered by caesarean section to diabetic women a few weeks before term differs little from the normal. They thought it reasonable to assume that in the parameters measured (ventilation, gaseous metabolism, functional residual capacity, intrapulmonary gas exchange and acid-base balance) well babies of diabetic and normal women differed little from one another. These observations do not extend to the abnormal infant, on whom further studies are required. An attempt has been made to do this by examination of amniotic fluid obtained without disturbance of the pregnancy through a transabdominal paracentesis. 116 Only seven cases are described, and of these, two showed metabolic acidosis associated quite simply with diabetic ketoacidosis of the mother.

OXYGENATION OF THE FOETUS

The earlier observation by Berglund and Zetterstrom5 that the

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peripheral blood of babies of diabetic mothers contains abnormal numbers of nucleated red cells suggested possible prenatal anoxia. MacKay88 and Prystowskylo8 found some evidence for this by oximetry of foetal and maternal blood, but Prystowsky later qualified this.lo9 Although the normal myometrial blood flow late in diabetic pregnancy described by Brudenell, Miles and Colemanl3 does not exclude foetal anoxia, Peello5 has recently restated that further studies have failed to confirm reduced oxygen saturation in the newborn, and the small number of amniotic fluid studies by Schreiner, Biihlman and Gubler,116 whatever the value of this technique may prove to be eventually, have not revealed diminished oxygen supply to the foetus in the last 10 weeks of pregnancy.

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PROTEIN, FAT AND GLYCOGEN

According to Fee and Weil,49 the fat-free bodies of babies of diabetic and nondiabetic women differ little so far as other constituents are concerned. Although earlier reports suggested increased myocardial glycogen, they may need to be reviewed in the light of Shelley'sl20 more recent studies of neonatal glycogen reserves in which the heart was much the most richly endowed and where glycogen persisted when it had been largely exhausted in liver and striated muscle. Villee U13 found no difference in the glycogen levels of foetal tissues obtained before the twenty-second week of diabetic and nondiabetic pregnancy. Although Cardelll5 reckoned myocardial glycogen to be significantly increased in six of 10 hearts examined, Warren and LeComptel35 were impressed by only two ouf of five, and they were later quoted by Driscoll et al. 33 as having found normal amounts of glycogen in only three out of four hearts in their series. There is even less in the liver,l5 but autopsy material is an unsatisfactory basis on which to judge a substance which is the source of quick energy for an infant fighting a losing battle for his life. The nitrogen excretion of such babies during the first few days of life is greater than normal, according to Nicolopoulos and Smith,91 and this is further increased in the presence of the idiopathic respiratory distress syndrome. This has also been the experience of Osler and Pedersen,98 who found that though urinary nitrogen excretion during the first few days was similarly increased in babies of diabetics and in premature babies of nondiabetics, the urine volume of the diabetic group was twice that of the other, and this they attribute to glycogenolysis. The oxidation of available fat may also contribute, but Osler95 does not favour such an explanation. So far as the plasma protein fractions are concerned, a significant increase in beta lipoprotein and in alpha-2 glycoprotein during the last trimester has been described by Ditzel and Moinat. 32 The pre-beta-lipid

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fraction has been found by Vernet and Smith132 to behave differently in successful and unsuccessful diabetic pregnancy, increasing in the former from the twenty-fifth week and falling abruptly after delivery, while in the latter it rises earlier, reaches higher levels and persists for some time after the baby's birth. The electrophoretic pattern of the serum proteins has also been found to differ significantly from normal by Sirek and Sirek,122 the diabetic grouping having a larger number of distinct arcs, in particular that which is in continuation with the orosomucoid and that in the siderophilin region. In a short study of otherwise normal newborns of diabetic women Lloyd 77 found little abnormal in the cord levels of cholesterol, phospholipid and alpha-, beta- and gamma-lipoprotein, but some variations were found in the subsequent week and could not be correlated with anything of apparent clinical significance. According to Pantelakis et al. 99a and Mortimer,85a the serum total lipid, total cholesterol and phospholipid levels in the cord blood of infants of diabetic mothers are significantly higher than normal. Sirek, Sirek and Leibel123 found that the hexose, hexosamine and sialic acid contents of the glycoproteins were significantly raised in babies whose mothers had uncomplicated diabetes.

ELECTROLYTES The electrolytic state of infants of diabetic mothers has been studied from the viewpoints both of elimination and of plasma or tissue levels. They were thought by Cook et al.24 to behave with regard to urinary elimination of electrolytes very like normal babies of comparable gestational age. Zetterstrom and Aberg 145 were largely in agreement with this, but believed that they might excrete less potassium during the first few days than do other prematures with oedema. No difference from the normal could be found by Stapleton126 which could not be accounted for in terms of maturity. In a re-examination of the problem, however, Cook et al,25 found that infants of diabetic mothers excreted proportionately more sodium, chloride and potassium than control babies of comparable weight and slightly more than infants of comparable gestation. The mean electrolyte excretion, however, in infants of diabetic mothers studied by Osler and Pedersen98 was higher or at the upper limit of what has been described as normal for gestational age. In all these studies, only Zetterstrom and Aberg 145 have suggested a limited difference in the excretion of potassium and sodium. The total body sodium and chloride of infants of diabetic mothers was calculated by Fee and Weil49 to be reduced in comparison to normal control babies, while potassium levels were unchanged. Low plasma potassium levels were reported by Bjorklund6 of an order which was thought to be responsible for changes in the electro-

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cardiogram. 7 Brief mention of a possible need to use potassium in treatment was made by Peel,I°4 and from their studies Fee and Weil49 believe that an occasional death, even an occasional intrauterine death, may result from potassium depletion. Normal levels have, however, been reported by Lowrey et al.,79 Zetterstrom and Aberg,145 Clayton23 and Gellis and Hsia,54 while changes suggestive of potassium abnormality were not a feature of electrocardiograms studied in my own series,39 nor in the larger series studied by Page, Garland, Stephens and Hare. 99 On the other hand, Rose1l 3 found that though sodium and chloride levels were normal, serum potassium concentration could be raised in infants of diabetic mothers, and this was, of course, more striking in the presence of idiopathic respiratory distress syndrome. Such concern over high serum potassium levels is felt by LaSelve et al,76 that they have conducted exchange transfusions for the correction of levels as high as 12 mEq. per litre. In a study of sodium and potassium levels in the wall of the umbilical artery Goodlin 58 found potassium levels to be significantly raised. I have recognised only one case in which death took place suddenly on the second day of life in a baby who was previously asymptomatic. His serum potassium level was 12 mEq. per litre. 44 The cause of this hyperpotassaemia was unknown, and autopsy was entirely unrevealing. Calcium levels may also be abnormal, and though the two cases of idiopathic hypoparathyroidism reported by Kunstadter et al. 75 must surely be most unusual, temporary hypocalcaemia as a common feature has been reported by Zetterstrom and Arnhold,146 Craig,28 Craig and Buchanan29 and Gittleman et aJ.56 Raised serum phosphate levels have been reported by Zetterstrom and Arnhold,146 Gittleman et a1. 56 and Rose.l1 3 Whatever the importance of hypocalcaemia per se, the combined effect on myocardial function of low calcium and raised potassium levels should be remembered. 47

BILIRUBIN

The tendency to deep jaundice40 relates to the late introduction of feeding.l1 5 Apart from this, the cause remains obscure, and Taylor et al,130 present evidence against its being due to either a failure in prenatal placental clearance of pigment or to increased postnatal haemolysis. They suggest that the fault lies in glucuronyl transferase inadequacy, and this, combined with hypoglycaemia,147 at least seems to be the obvious explanation. Olsen, Osler and Pedersen92 found that the curve of the average daily bilirubin concentration of infants of diabetic mothers corresponds closely to that for infants of nondiabetic women having a birth weight of less than 2000 gm. Higher bilirubin levels were recorded in babies born by Caesarean section.

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INSULIN

The most significant histological finding is the hypertrophy of pancreatic islet tissue, the literature of which has been fully reviewed by Pedersen 101 and Farquhar. 39 In recent years first Cardell16 and then Woolf and Jackson140 measured the fourfold difference in islet tissue between the babies of diabetic and of normal women, and Cardell found that the increase consisted largely of beta cell hyperplasia. D' Agostino and Bahn30 have also reported both a relative and an absolute increase in islet tissue with features which suggest increased insulin production. The rapid development of hypo glycaemia and the increased glucose tolerance of these babies fit the suggestion that they produce more insulin than normal. This has been difficult to prove, because doubt exists about the permeability of the human placenta to maternal insulin, although Spellacy et al. 125 have recently examined the problem and believe that insulin does not pass freely from mother to child. Evidence in favour of increased insulin secretion by infants of diabetic mothers has been provided, however, by Baird and Farquhar,3 who have shown that they have significantly greater insulin activity in their plasma than do normal babies at the same time-interval after a standard intravenous glucose load. Although this almost certainly reflects a truly greater capacity to secrete insulin, the limitations of the experiment should be remembered, and repetition of the assay at various timeintervals after glucose injection might have shown that normal babies are capable of as much insulin activity later in the test. This would not fit, however, with the glucose tolerance of the two groups. Stimmler, Branzie and O'Brien 127 conclude from their studies that infants of diabetic mothers do have higher circulating insulin levels than normal at birth, that this cannot be correlated with the maternal blood glucose level at delivery, and that excessive insulin activity continues for at least two hours after birth in response to an unknown factor.

ADRENAL CORTICOSTEROIDS

Fifteen years ago, in a medical world which was fast becoming more familiar with the clinical and biochemical effects of corticosteroid activity, suspicion that steroids might be implicated in the aetiology of diabetes mellitus, in the shaping of these curious babies, and in the high perinatal mortality rate is not now surprising. The case was reviewed at that time by Farquhar. 3s I no longer believe that the many strange things which may be found in, and which happen to, infants of diabetic mothers can be explained in terms of a general increase in adrenocortical activity, but the conflicting reports of those who have further pursued this aspect are intriguing. Increased urinary excretion of corticosteroids was first described by

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Bjorklund 8 and by Bjorklund and Jensen 9 and was thought to relate to the hypopotassaemia described by Bjorklund. a. 7 Corticosteroids were detected by Hoet 64 in the amniotic fluid of diabetic but not of nondiabetic pregnancies. This is not the experience, however, of Baird and Bush,2 who found no difference. Similar negative results in blood or urine have been reported by Rose,113 Tolstoi et aI.,131 Migeon, Nicolopoulos and Cornblath83 and more recently by Aarskog. 1 The last two publications in particular are authoritative, although Cathro18 points out that in Aarskog's series the infants of diabetic mothers were about 24 hours older than the controls, and this could make a clear difference to the result. Further evidence in favour of increased adrenocortical activity has been provided by Farquhar,38 Klein and Taylor,73 Forsyth and Cathro,51 Lloyd 77 and Cathro.18 Field, Smith and Reardon 50 found that infants of diabetic mothers with respiratory distress excrete twice the amount of corticosteroid that stressed premature infants do. In further work Smith, Reardon and Field 124 found that the excretion of PorterSilber chromogens during the first week of life in normal babies is rather greater than that in immature infants and is only half that of infants of diabetic mothers who were comparable in clinical state and treatment. This held true even when the figures were expressed per kilogram, per square metre of surface area, per millilitre of urine volume or per milligram of creatinine excreted. Of even greater interest perhaps are the very careful studies of Grossman, Crigler and Gold 60 and of Cathro,18 who have found not only a quantitative increase above the normal in infants of diabetic mothers, but also similar and significant qualitative differences in the existing metabolites.

GROWTH HORMONE

The role of pituitary growth hormone in causing what seem to be giant babies necessarily attracts interest in view of the earlier experimental work of Houssay and Biasotti65 and of Young141- 143 on animals and the observations of Luft et aI.,81 Raben l1° and Hernberg 63 on hypophysectomised human diabetics given injections of purified human pituitary growth hormone. Increased growth hormone activity may be demonstrable in some human diabetics. 34 Some earlier pathological studies suggested that the eosinophilic cells of the anterior pituitary in infants of diabetic mothers might be hypertrophied or hyperplastic, but the evidence was unconvincing. They were considered normal by Warren and LeCompte 135 and were not mentioned by Driscoll, Benirschke and Curtis. 33 Gaunt, Bahn and Hayles 53 found no significant increase in the number of cells, but thought they might be appreciably larger than cells examined in a control series. This would seem to be an unlikely response to a maternal stimulus, and Chesley20 has reported that no significant difference exists in the serum

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pituitary growth hormone levels of diabetic and nondiabetic women in pregnancy. OESTROGENS

A great deal of interest has surrounded the possible relation of oestrogen deficiency and foetal morbidity or death since the publications by the Smiths and the therapeutic approach of White. 138 The establishment of biochemical methods has produced a series of studies, but all have concerned the mother, and I am unaware of any measurements in the child. Maternal oestrogen levels in the peripheral blood of pregnant diabetics were not judged to lie outside the normal range by Roy and Kerr. ll4 Although very low levels were found in association with intrauterine death and with very small babies, these were associated with some other abnormality such as pregnancy toxaemia. The work is judged to support the opinion of Taylor et al.1 29 that no need exists for oestrogen-replacement therapy in diabetes. A correlation between maternal oestrogen excretion and poor foetal growth was previously reported in nondiabetic pregnancy by Kellar et al,72 and confirmed recently by Martin and Hahnel. 82 So far as the baby is concerned, Diczfalusy and Troen,31 Mikhail, Wiqvist and Diczfalusy84 and Booth et al.1° refer to the important foetal role of conjugating oestrogen.

GONADOTROPIllNS

As with oestrogens, chorionic gonadotrophin studies have been confined to the pregnant diabetic, and I have no record of levels in the urine of the newborn. High levels in maternal urine are reported by White l38 and in the serum or blood of one third of the patients studied by Loraine and Matthew. 78 No close correlation with foetal progress was apparent.

COMMENTARY

Infants of diabetic mothers are interesting because of the altered structure and the altered risks that are created by development in the diabetic environment. Yet the two features, nutritional abnormality and higher mortality rate, are not intimately linked.41 Some women can produce very large babies without loss or even deviation from normal neonatal behaviour, while others will produce large or small babies with a high mortality rate in utero or as newborn. The paediatrician must not forget that the intrauterine loss is at least as great as the neonatal one, and that his problems are but the later and visible signs of earlier

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metabolic problems which defy investigation other than by measurements of maternal function or, in a limited way so far, by amniocentesis. As the foetus who most demands investigation is denied to the investigator, he must try to draw imaginary regression lines backward from postnatal studies and guess at earlier disturbance. This is still rather unsuccessful. The size of the baby is influenced by control of hyperglycaemia, by the coexistence of maternal nephropathy, and possibly by a genetic factor. Some have had difficulty in accepting the role of the mother's blood sugar level because the large babies of prediabetic women have developed in an environment where glucose has not exceeded the mother's renal threshold. But a constant feed into the foetus at, say, 150 mg. per 100 ml. without insulin treatment of the mother may be as effective as the same level with insulin or at a higher level with ketosis. Diabetic women who are maintained normoglycaemic throughout the day produce babies which are more normal in size.102, 103 An inverse relation has been established between birth weight and the lowest postnatal blood glucose level,101 and a direct relation exists between birth weight and pancreatic islet hypertrophy. This is in striking contrast with experience in the syndrome of temporary neonatal diabetes mellitus, in which the baby is often poorly nourished at birth and hyperglycaemic67 and in which Gerrard and Chin55 have suggested the very reverse mechanism of production, i.e. low prenatal glucose levels in the foetus leading to underdevelopment of pancreatic beta cells and hypoinsulinism. And both contrast with the idiopathic hypoglycaemia of the newborn12, 89, 90 which are undernourished and hypoglycaemic. This latter group has more in keeping with the proportion of infants of diabetic mothers who are similarly malnourished, suffer hypoglycaemia and have a high morbidity and mortality rate. The evidence in favour of foetal hyperinsulinism in infants of diabetic mothers is now strong, and increased glucose and insulin are thought to lead to obesity. Newer microtechniques of determining insulin activity will facilitate further studies. These should compare the insulin response to both oral and intravenous glucose loads, since the former is said to promote a more significant and sustained rise and to permit the calculation of an index for purposes of comparison.35 In relation to foetal obesity Mueller, Solomon and Brown86 found that the artificial maintenance of a high concentration of free fatty acid in the maternal plasma in pregnant rats led to an abnormal accumulation of fat in the foetus. Diabetes mellitus is, of course, accompanied by a rise in the plasma concentration of nonesterified fatty acid, and this is corrected by insulin. Other stimulants to foetal insulin production exist and, as already mentioned, are relevant to diabetes. Pituitary growth hormone can increase insulin production, although it may also act as an antagonist,21 can be diabetogenic and could promote foetal beta cell hyperplasia

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either directly or by causing hyperglycaemia. Although Pedersen and Osler in various publications have rejected the possible role of pituitary growth hormone because they believe it to be incompatible with foetal obesity, Ehrlich and Randle 34 declare that the hormone does not cause fat mobilisation if the subject has free access to glucose and food, and this the infant of a diabetic mother has, except perhaps when he suffers from what is called "placental insufficiency," and then he is lean enough. High levels of chorionic gonadotrophin may be found too inconsistently to explain foetal obesity, although the increased subcutaneous fat and rounded contour of the pubescent girl are said to occur with the appearance of gonadotrophins rather than of oestrogens. lOO Synalbumin insulin antagonist has been the subject of many publications by Vallance-Owen and his colleagues, and its possible relevance to infants of diabetic mothers has been reviewed. 42 This agent exists in the albumin fraction of plasma, seems dependent upon the integrity of the pituitary-adrenal axis and opposes the use of glucose in muscle, while opposing little the conversion of glucose to fat. Ensinck, Mahler and Vallance-Owen36 have evidence that the antagonist is the B-chain of the insulin molecule which, by occupying its appropriate locus on the cell membrane, competes with and so blocks the insulin molecule itself. Should the antagonist cross the placenta, and it is smaller than insulin in molecular size, then it could promote obesity of the kind seen. As the activity or level of antagonist seems to be less when exogenous insulin dosage is adequate, then foetal size would also be less when diabetes is well controlled, and this is so. The antagonist would seem not to oppose liver glycogenesis, but could limit glycogen formation in skeletal muscle or possibly in the heart. The small number of published observations about cardiac glycogen provide no conclusive answer, and there is certainly no consistent or obvious increase to be found in autopsy material, although Shelley found considerable amounts in the hearts of babies of nondiabetic women. This point certainly merits closer study in view of the susceptibility of the infant of a diabetic mother to sudden and unexpected prenatal and intranatal death, cyanotic attacks and respiratory distress. If the infant is simply the product of a long-term infusion with glucose and a high level of foetal insulin, surely the glycogen reserve should be apparent at least in those who have died suddenly from some such cause as intracranial haemorrhage. The presence of the antagonist is probably compatible with the more rapid clearance from the blood of a glucose load in infants of diabetic mothers. While not for a moment suggesting that symptomatic hypoglycaemia does not exist. I want to re-emphasise43 that such a diagnosis must be made only with the greatest care, and even "responses to glucose" can be unrelated to the correction of hypoglycaemia. The foetal heart suddenly became inaudible in a 32-year-old primiparous diabetic, and intrauterine death of the foetus was assumed. She went into

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labour almost at once, the baby's head was rotated, and she was delivered with Keilland's forceps. The infant proved to be alive (weight 2835 gm.) and apparently well until four hours, when minimal respiratory distress was observed. The blood glucose level (oxidase method) was 216 mg. per 100 ml. at birth, and successive hourly readings of 88, 10, 6, 7, 9 and 5 mg. were obtained. At 11 hours it was still only 4 mg. per 100 mI., and respiratory distress was more obvious. After glucagon, 0.5 mg., the blood glucose level was 46 and 37 mg. at 12 and 15 hours respectively, but the baby still had distressed but less rapid respiration. The chest radiogram was normal. At 24 hours the blood glucose level was again 8 mg. per 100 ml., the infant was noted to be twitching in a hypoglycaemic way, and a slow glucose infusion was begun. She had received only 2 gm. of glucose in two hours when the blood level was found to be 307 mg., and her condition, including the twitching, became so bad that intermittent positive pressure respiration was required. An electrocardiogram taken just before death at 36 hours was interpreted as representative of a severe electrolyte disturbance, probably very severe hyperpotassaemia. The serum calcium level was 8 mg. per 100 mI. Autopsy revealed a massive subdural haemorrhage causing severe cerebral compression to which the paediatric pathologist had no hesitation in attributing death. There was no pulmonary hyaline membrane, and in life there had been no clinical indication of increased intracranial pressure. Hypoglycaemia and its treatment had quite overshadowed the need for further investigation. But what were the relationships of cerebral injury to hypoglycaemia and hyper glycaemia, and does an infant who can respond to glucagon become first profoundly hypoglycaemic and then hyperglycaemic on a dose of glucose which could not achieve half this figure even in a normal and less tolerant newborn?

Whatever the influence of antagonist may be on glycogen reserve, enough of the latter exists to make possible a response to glucagon or epinephrine, and most babies can correct the hypo glycaemia spontaneously in a few hours. Grollman, McCaleb and White 59 have recently reported on three patients who were judged to have hyperinsulinism, but in whom no adenoma was found. Histology showed that each had a deficiency of pancreatic alpha cells, and on this evidence the hypo glycaemia was judged to represent glucagon deficiency. Infants of diabetic mothers certainly respond in minutes to injected glucagon, and yet they may take hours to raise their blood glucose spontaneously from hypoglycaemic levels. Perhaps this results not only from hyperinsulinism, but also from hypoglucagonism? There is much circumstantial evidence to support the theory that foetal beta cell development relates to prenatal blood glucose levels. Perhaps the hyperglycaemia which promotes an exaggerated response on the part of the beta cells retards development of alpha cells, and the disproportionate content of beta and alpha cells in the pancreatic islets represents not only hyperplasia of the one, but also hypoplasia of the other. Nor are the catecholamines likely to be as helpful in the correction of hypo glycaemia as in later life, for at this age they consist largely of norepinephrine,66, 136, 137 and this is less effective than epinephrine in promoting glycogenolysis.

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Increased production of adrenal corticosteroids is stimulated by and assists in the correction of hypoglycaemia. Now that these steroids seem much less likely to be the cause of foetal morphology, their increased levels in blood or urine in some series could be explained in this way. This would infer that those who find steroid values to be increased are dealing with mothers whose diabetes is less well controlled, so that they produce large infants with relatively greater beta cell hyperplasia and hypoglycaemia. This may be unacceptable. The explanation of hypocalcaemia is just as difficult, especially as it may appear before the infant has had much by mouth. Pituitary growth hormone can increase the urinary excretion of calcium, according to Ikkos, Luft and Gemzell,68 Raben,llo Shepard, Nielsen, Johnson and Bernstein,121 Hanna, Harrison, MacIntyre and Fraser61 and Luft,80 but it has also been shown to produce a positive calcium balance. Should pituitary growth hormone be the cause of the foetal morphology, then it must be active throughout foetal development, and yet neither clinical examination nor direct analysis of the cadaver provides evidence of calcium, magnesium or phosphate depletion. This same argument makes placental insufficiency, which could cause failure of the active transport of calcium from mother to child,139 an equally unlikely cause. The two cases of hypoparathyroidism to which reference has been made are interesting. The literature on hyperparathyroidism and pregnancy has been recently reviewed by Wagner, Transbpl and Melchior,134 and though the foetus has a raised serum calcium level at birth, this quickly gives place to symptomatic hypocalcaemia toward the end of the first week. The associated high intrauterine and neonatal mortality and low birth weight for maturity have something in common with the "bad risk-small foetus" diabetic pregnancies, but the hypocalcaemia is rather late in developing and, when the mother has hyperparathyroidism, intrauterine deaths do not happen in the absence of maternal bone disease. Hypercalciuria can be caused in rats by the intravenous infusion of epinephrine and norepinephrine. 85 The same may be true of man,69 but the short-term release of norepinephrine is an inconceivable cause per se of hypocalcaemia within days of birth. The same holds true of the increased production of adrenal corticosteroids. Because of the likely role of the pituitary-adrenal axis in the aetiology of diabetes mellitus, the work of Friesen52 is of interest. Friesen has shown that a number of extracts of the anterior pituitary can, when injected into rabbits, cause a fall in serum calcium for two hours followed by a return to normal in four hours. There is an associated increase in serum free fatty acids, an effect which is opposite to that of insulin and which is shared not only with pituitary growth hormone, but also with other pituitary polypeptides. ll Lastly, in addition to such possible hormonal explanations, of

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course, there is a possible association between calcium and carbohydrate metabolism, and in some cases of hypernatraemic dehydration in infancy I have seen not only coexisting hypocalcaemia, but also hypoglycaemia. Hypocalcaemia can occur similarly in babies of nondiabetic women who have had a complicated pregnancy and/or delivery,1I7 and this may suggest a disturbance of central control. Indeed it is possible that hypoglycaemia, hypocalcaemia and other metabolic disturbances stem from abnormalities in the central nervous system. The case quoted above is an example, but there are others in which hypoglycaemia and hypocalcaemia found soon after birth have been associated with evidence of intracranial bleeding or a high protein content in the cerebrospinal fluid. Similarly, hypernatraemia may follow head injury and cause cerebral damage. The pre-existence of neurological damage could explain why severe mental defect is found after some cases of hypoglycaemia and yet not after others, and could dictate why hypoglycaeInia is prolonged in one and brief in the other. Much remains to be done in this complex field. Hypopotassaemia and metabolic acidosis at birth are understandable when maternal ketoacidosis exists, but such a correlation has not been reported in all cases, and the acidosis may exist where maternal care has been excellent. Acidosis induced by ammonium chloride is unproductive of symptoms, and the acid-base balance of babies who are well at birth is now reported from Boston to be little different from normal. The nature of the acidosis which is associated with babies who are ill before idiopathic respiratory distress syndrome develops has still to be discovered. Hyperpotassaemia and increased nitrogen loss are understandable when the idiopathic respiratory distress syndrome exists, and lesser degrees, like the increased urinary excretion of corticosteroids in some series, may only represent a response to inapparent stress. Severe prenatal stress or prolonged, severe hypoglycaemia, as in the case recorded above, may be important, and hyperpotassaemia in such babies must be remembered, anticipated and treated. Earlier feeding with more adequate formula 411 may help prevent both tissue breakdown and hyperpotassaemia. Osler's finding of reduced total body and extracellular water is comprehensible, but the reports of intracellular water being increased in relation to extracellular fluid by the third day are more difficult to grasp, since pitting oedema may appear and may still be present at this time. Such findings may relate to local therapeutic practice of both mother and child. I have said nothing about the idiopathic respiratory distress syndrome because I doubt whether this has an explanation any different from that which will be found to explain this condition in immature infants of nondiabetic women. We have been thinking up to now of the typical plump infant, whether he is well or in some way symptom a-

i~r

.1

II

I

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tic. The runtlike infant which may be produced consistently by a few diabetic women and sporadically by others is different largely in terms of nutrition and prognosis. He is subject to all the changes mentioned above, but is more susceptible to intrauterine death or to respiratory distress. The cause is unknown, and though women with nephropathy produce smaller babies, they are not necessarily like this, although such infants are born to women without clinical nephropathy. Although placental insufficiency or isoimmunisation has been suggested, no proof of either exists. Previous studies of the diabetic placenta have been briefly reviewed. 41 • 44 More recently Burstein, Berns, Hirata and Blumenthal14 have claimed the demonstration of placental abnormality in relation to basement membrane structures. This has been criticised by Behrman.4 Nevertheless neither light nor electron microscope studies of chorionic villi by Zacks and Blazar144 revealed any difference in the placentas of diabetic and nondiabetic women. Nor has Pinkerton106 found any evidence of histological changes peculiar to diabetes. A very high standard of control of the maternal diabetes and skiHul anaesthesia and Caesarean section, probably before term, for all primiparae will help reduce abnormality, metabolic disorder and mortality. It will not yet prevent them in more than 90 per cent at the very best, and this figure will be unobtainable for many. With regard to management of the newborn, skilled resuscitation should be available, and whatever means of dealing with the idiopathic respiratory distress syndrome the paediatrician may judge most appropriate. The bulky and often pulsatile cord requires careful occlusion and observation. Where facilities exist the blood glucose and potassium levels should be followed, and symptomatic hypo glycaemia should be treated at once. Asymptomatic hypoglycaemia with figures below 30 mg. per 100 ml. may require treatment if it persists beyond 24 hours. Glucagon should be given by injection in a dose of 300 micrograms per kilogram of body weight, and if this is inadequate, it may be followed with glucose by nasogastric tube or infusion to maintain the glucose value of 40 mg. per 100 mI. This figure is chosen because it is detectable by Dextrostix (Ames) and forms a convenient way of monitoring glucose at the cotside. When early feeding is desirable, the infant must be most carefully observed for four or five days, since cyanotic attacks are often associated with feeding.

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