9 The infant of the diabetic mother

9 The infant of the diabetic mother KENNETH

R. MOUNTAIN

As medical syndromes go, the infant of the diabetic mother (IDM) is a relatively recent phenomenon. Before 1930 it was well recognized that diabetes upset pregnancy so much, and vice versa, that most diabetic pregnancies ended up with either a fetal death in utero or a neonatal death soon after birth, usually from a fulminating form of respiratory distress. Often the mother, too, did not survive because of the disastrous effect on the control of her diabetes caused by the pregnancy. Indeed, if an obstetrician brought a diabetic pregnancy through to a successful conclusion with both a live mother and baby he would usually celebrate his success with an article in the journals and then be invited to speak at various conferences around the country as a keynote speaker, so rare was this phenomenon. Then, with the discovery of insulin by Banting and Best in 1921, with its increasing use in diabetic pregnancies and with the resultant improvement in diabetic control in the 1930s, these interesting infants began to survive. In the 1940s they began to survive in sufficient numbers for it to become evident that these babies were different. They not only looked different but they had a number of different problems peculiar to the IDM, and so began research into this fascinating group of babies. PERINATAL M O R T A L I T Y Very few groups of babies (except perhaps for the very low birth weight extremely premature babies) have had such a spectacular fall in perinatal mortality as has occurred with IDMs over the past 25 years. In 1966 at the Royal Women's Hospital, Melbourne, soon after the Diabetes in Pregnancy (DIP) Programme was first established by Dr Robert R o m e and his colleagues, the perinatal mortality was 26%. Since then, as shown in Figure 1, the perinatal mortality has fallen quite dramatically, so that in 1990 it is now between 2% and 3%, and this is not withstanding a change in the definition of stillbirth during that time to include all fetal deaths after 20 weeks' gestation, whereas in the 1960s only those that died after 28 weeks were considered to be stillbirths and thus could be included in the perinatal mortality figures. Elsewhere around the world similar improvements have been reported. Over 30 years ago Gellis and Hsia (1959) analysed the Boston lying-in Bailli~re' s Clinical Obstetrics and Gynaecology--

Vol. 5, No. 2, June 1991 ISBN 0-7020-1534-2

413 Copyright© 1991,by Bailli~reTindall All rights of reproductionin any form reserved

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experience (the then Mecca of diabetes in pregnancy management, mainly because of the influence of Priscilla White) with 934 pregnancies from 1940 to 1956. They reported the fetal mortality after 28 weeks' gestation to be 23% for the decade 1940-1950, whilst for the next 6 years, 1950-1956, it had fallen to 16.5%. They reported a combined stillbirth and neonatal death rate of 19% for viable pregnancies over 28 weeks' gestation. The commonest cause of neonatal death in their study was hyaline membrane disease (HMD), which was found in 33% of all live-born IDMs. They also reported that lethal congenital abnormalities were found in 1.8% of infants, a figure which was about twice that of the normal population. More recently Pedersen (1977) noted a decline in the perinatal mortality in IDMs in Denmark from 22.1% to 7.4% during the period between 1960 and 1972, and even more recently Gabbe (1987), in a series which summarized the recent world literature (777 pregnancies during 1983-1985), noted only four stillbirths and no neonatal deaths if congenital abnormalities and poor attenders were excluded. The cause of this remarkable fall in perinatal mortality is obviously multifactorial. Some of the important changes as they have occurred at the Royal Women's Hospital, Melbourne, are shown in Figure 1. There is no doubt that one of the most important reasons is the advent of neonatal intensive care (in about 1970 at the Royal Women's Hospital). With the ability to ventilate babies it meant that they were no longer likely to die from the severe form of HMD which used to cause most of the neonatal deaths prior to 1970. The impact of neonatal intensive care is shown in Figure 2, which breaks perinatal mortality up into stillbirths and neonatal deaths. From 1970-1975 the neonatal death rate was reduced by a factor of 4 from 9.9% down to 2.4%, whereas over the same period stillbirths were only reduced to approximately half that of the 1970 figure (10.3% to 5.5%). Since

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Figure 2. Fetal and neonatal deaths at the Royal Women's Hospital, Melbourne, 1970-1990, emphasizing the improvement in the neonatal death rate (1970 figures are the average for the previous 5 years). 1975 there has been a m o r e gradual lowering of both the stillbirth rate and the neonatal death rate, and overall the perinatal mortality has plateaued out at between 2.0 and 3.0%. which is still about three times the national figure for all babies. There is still a hard core of unexplained fetal deaths in utero in spite of m o d e r n methods of fetal monitoring and, if we exclude gestational diabetics, the perinatal mortality in those with insulin dependent diabetes ( I D D M ) at the Royal W o m e n ' s Hospital is still around 7.2% (Table 1), which is far from satisfactory. However, many of these are very high-risk patients with chronic renal disease, severe pre-eclampsia and intrauterine growth retardation. The perinata| mortality in gestational diabetics in our p r o g r a m m e is now similar to that for the general nondiabetic population. However, there is no place for complacency in this group because these are diagnosed and treated gestational diabetics; the actual perinatal mortality for undiagnosed gestational diabetics is, of course, unknown. Table 1. Perinatal mortality at the Royal Women's Hospital, Melbourne, 1986-1990, showing the difference between gestational diabetics and insulin dependent diabetics. The overall perinatal mortality rate was 3.1%.

Number Fetal deaths Neonatal deaths Perinatal loss

Gestational diabetes

Insulin dependent diabetes

217 1 0 0.28%

138 6 4 7.2%

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Table 2. Causes of neonatal death in IDMs at the Royal Women's Hospital, Melbourne, 1966-1990, showing the virtual disappearance of HMD and birth trauma but the persistence of congenital malformations as causes of neonatal death.

Number

of babies

HMD Congenital

malformations

Birth trauma Infection Asphyxia Necrotizing enterocolitis

1966-1970

1971-1977

1978-1984

1985-1990

195

257

375

355

12 3

1 2

1 3

-3

3 1

1 1

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-1

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1 --

---

The impact of modern neonatal intensive care becomes more obvious when one studies the causes of neonatal deaths at the Royal Women's Hospital, Melbourne, from 1966 to 1990 (Table 2). In this period 12 babies died of H M D (out of 19 neonatal deaths), whereas in the 20 years since then we have only lost two babies due to this problem. Birth trauma, too, has been eradicated as a cause of neonatal death, but deaths due to congenital malformations remain, and are now the most common cause of death in the neonatal period. However, there is no doubt that the most important single factor in the improvement of perinatal mortality in IDMs over the past 25 years is the improvement in diabetic control during pregnancy. Physicians and obstetricians now realize that what might be acceptable control in the nonpregnant state is not acceptable when the diabetic is pregnant, and much more rigid control is necessary to ensure that the fetus and the neonate survive. Obviously if further inroads into lowering the perinatal mortality even further are to be made, the problem of deaths due to congenital malformations and unexplained stillbirths need to be addressed even more vigorously.

PRENATAL PROBLEMS Congenital malformations As mentioned above, with the marked reduction in neonatal deaths due to H M D and the virtual obliteration of deaths due to birth trauma, congenital malformations have now emerged as the most common cause of neonatal death. Indeed, in some centres it has overtaken sudden fetal death in utero as the most c o m m o n contributor to the overall perinatal mortality. Most studies have demonstrated a three- to four-fold increase in major congenital malformations in infants of I D D M mothers (Table 3) (Soler et al, 1976; Pedersen, 1977; Freinkel, 1980; Mills, 1982). During 1977 to 1981 at the North-Western University Medical Center, USA, Simpson et al (1983) reported that birth defects were encountered in 4.9% of their gestational diabetics and 10.9% of those with pregestational diabetes compared with

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THE INFANT OF THE DIABETIC MOTHER Table 3. Congenital malformations in I D M s and their relative risk ratios compared with the non-diabetic population. F r o m Mills (1987) with permission. Malformation

Sacral dysgenesis Situs inversus Renal agenesis Cardiac anomalies Anencephalus Holoprosencephaly

Risk ratio

200-600 84 6 4-5 3 40-400

2.4% of their normal non-diabetic gravida population. This indicates that not even the offspring of gestational diabetics are immune to this problem, although most of these would probably have had unrecognized pre-existing diabetes. Although no organ systems are exempt and almost any congenital defect can occur, the malformation thought to be most characteristic of diabetic embryopathy is sacral agenesis, or 'the caudal regression syndrome', which is found 200 to 600 times more commonly in IDMs (Mills et al, 1979). Central nervous system (CNS) malformations, particularly anencephaly and spina bifida, are ten times more common in IDMs than in the rest of the population (Reece and Hobbins, 1986), and a recent study found that holoprosencephaly is 40 to 400 times more common (Barr et al, 1983). Cardiac defects, particularly ventricular septal defects and complex lesions such as transposition of the great vessels, are four to five times more common; since the normal population has a 0.6-0.7% risk of having a congenital heart lesion, this means that IDMs have a 2.4-3.5% risk of being born with a heart defect. If diabetes is teratogenic, and the teratogenic factor or factors is some metabolic derangement during the first trimester, then it would seem logical to presume that the poorer the diabetic control during the first 2 months after conception, the greater the risk. This in fact was borne out by two separate haemoglobin A l c (HbAlc) studies in the early 1980s in two different parts of the world. Miller et al (1981) showed that if the HbAlc at the 14th week (reflective of diabetic control for the previous 4-6 weeks) was less than 6.9%, then there was no greater risk of congenital malformations. If the HbAlc was 7.0-8.5%, thus indicating fair control, the incidence of congenital malformations was 5.1%, and if it was more than 8.6% the incidence of congenital malformations was a massive 22.4%. Leslie et al (1978) in the UK came to the same conclusion, and later Ylinen et al (1984) and Reid et al (1984) confirmed these findings. Thus it seems that faulty maternal metabolism in the first 7 weeks after conception, possibly in association with increased genetic susceptibility, is at the basis of the increased risk of congenital malformations in diabetic pregnancies, but the specific teratogenic factor or factors have yet to be elucidated. However, many have been implicated by animal studies and

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there is good supportive scientific evidence. In 1977 Cockcroft and Coppola followed by Sadler (1980) and Freinkel et al (1983a) demonstrated that whole rat embryos cultured in high concentrations of D-glucose during days 9.5 to 11.5 showed growth retardation, abnormalities of fusion of the neural folds, microcephaly, and malformations of the eyes, v asculature, heart, etc. Later Freinkel et al (1984) showed that this did not happen when other hexoses such as fructose, inositol, sorbitol or galactose were substituted, thus indicating the specificity of glucose. Moreover, the teratogenic effect of glucose in this situation was dose dependent--the higher the concentration the greater the incidence of birth defects. Sadler and Horton (1986), however, showed that insulin had no teratogenic effects in mouse embryos exposed to insulin concentrations 500 times normal. Therefore it seems that, at least as far as congenital malformations are concerned, insulin is blameless, if glucose is not. Other 'fuels' which may be disturbed in diabetes, such as ketones, have also been implicated. Several workers (Horton and Sadler, 1983; Horton et al, 1985; Lewis et al, 1983; Freinkel et al, 1986) showed that exposure of whole rat embryos to D,L-[3-hydroxybutyrate can retard growth, delay neural tube closure and cause other malformations. Freinkel et al (1986) and Lewis et al (1983) showed that ketones and glucose together can be synergistic in their teratogenic effects--so-called 'fuel-mediated organ teratogenesis'--so that if used together in smaller doses they could cause an increased incidence of malformations than if used singly in larger doses. The teratogenic effects of 'high glucose' concentrations has also been shown by Baker et al (1981), who demonstrated lumbar and sacral malformations in the rat fetus when diabetes was induced in the mother with streptozotocin (streptozocin) before day 6. Furthermore, Baker et al (1981) was able to reduce significantly the incidence of these lumbosacral defects when insulin therapy was used in these diabetic pregnant rats to produce normoglycaemia. Just how these derangements in metabolic fuels cause malformations is not clearly understood, but Freinkel et al (1983b, 1984) suggested that they might do so by inhibition of glycolysis at a critical stage of embryogenesis when the developing fetal rat is totally dependent on glycolytic pathways. This stage proved to be up to day 10.8, because similar insults after day 11 did not produce defects. He was able to produce growth retardation and defects in neural tube closure by adding o-mannose, which inhibits glycolysis, to the culture medium of whole rat embryos up to day 10.8. Freinkel et al (1985) further supported his hypothesis that interruption of glycolysis was a possible mechanism for causing the teratogenic effects of hyperglycaemia and/or ketones by suggesting that hypoglycaernia might also exert similar teratogenic effects. Hypoglycaemia was caused in pregnant rats (Buchanan et al, 1986) with insulin infusions on day 9.5 to 9.75, and they were able to demonstrate significant increases in the incidence of growth retardation and malformations compared with a control group similarly infused with insulin but kept euglycaemic with simultaneous infusions of glucose. These findings have been reproduced by others (Akazawa et al, 1987; Ellington, 1987; Sadler and Hunter, 1987), and so Freinkel (1989)

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sounded a warning about attempting 'too tight' control of diabetes at or around conception because hypoglycaemia might be just as teratogenic as hyperglycaemia and/or ketones. Thus he recommended the 'near normalization' of glucose control rather than'full normalization' during the first 8 weeks after conception. Although this warning is heeded, most workers would encourage energetic control of diabetes at conception and for the first 8 weeks of gestation. However, conception is rather unpredictable, so Fuhrmann et al (1983) and others recommended 'pre-conception clinics' to try to attain euglycaemia before conception and to maintain this for the first trimester. In a prospective study in East Germany Fuhrmann et al (1984) was able to demonstrate a significant reduction in major malformations if his diabetic women received pre-conceptional care. Fuhrmann et al (1984) found a major malformation rate of only 1.1% in pre-conceptional registrants compared with a rate of 4.7% in those attending for the first time after 8 weeks gestation. This was demonstrated even more emphatically by Steel (1985), who found a rate of 3.3% in those attending her pre-pregnancy clinic compared with 12.7% in those coming late. These studies strongly suggest the beneficial effect of 'tight control' during organogenesis in reducing t h e rate of congenital malformations. However, even with good control during the first trimester, or even before conception, most recent studies (apart from that by Fuhrmann et al, 1984) have quoted an incidence of around 3.0-3.5% for major malformations which, although much reduced, is still approximately double that for the non-diabetic population. Finally, there has been an association demonstrated between early intrauterine growth retardation and congenital malformations. Pedersen and MOlsted-Pedersen (1981) followed a series of 99 diabetic women with ultrasounds performed between 7 and 14 weeks' gestation: 38 of these fetuses were shown to be small for gestational age and these 38 had seven of the nine major malformations seen in the entire series. This study has yet to be confirmed, but the questions posed concerning the predictability of congenital malformations needs to be addressed as soon as possible so that appropriate counselling of diabetic women in the first trimester can be given. Thus the approximate three-fold increase in the risk of IDDM women of having a malformed baby is well established. Animal studies have suggested a link between derangements in various metabolites known to occur in poorly controlled diabetes such as hyperglycaemia, ketones and hypoglycaemia, but whether these can be extrapolated to humans has yet to be established. Also exactly how they cause the teratogenic effects is not understood. In the meantime there seems little doubt that if we are to reduce the incidence of these birth defects, optimal control of diabetes before, during and for 8 weeks after conception has to be energetically pursued, ideally through pre-conceptional clinics, although in practice attendance at these clinics has been found to be difficult to achieve and maintain. Fetal death In the past, unexplained stillbirth has been a very important contributor to the

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high perinatal mortality in diabetic pregnancies. In a large series from Copenhagen, Pedersen and Brandstrup (1956) reported a 27% fetal mortality from 1946 to 1952, but this fell to 15% in the ensuing 3 years, 1953 to 1955. In our series at the Royal Women's Hospital, Melbourne, from 1966 to 1969 the stillbirth rate was 10.3%, whereas it fell to 2.4% in the years 1986 to 1989. Thus, these unexplained sudden fetal deaths have become much less common in recent years, due presumably to a combination of stricter diabetic control during the pregnancy and more sophisticated, intense fetal monitoring. However, they still occur at approximately four times the rate in non-diabetic pregnancies, and they can happen with alarming swiftness in spite of a normal fetal cardiotocograph the previous day. There is no doubt they are more likely to occur in patients who receive less than optimal care. Other factors known to be associated with sudden fetal death are more than 36 weeks' gestation, patients with long-term diabetes and vascular disease, poor diabetic control, polyhydramnios, macrosomic infants, pre-eclampsia and ketoacidosis. In the 1960s, in an effort to try to reduce the incidence of sudden unexplained stillbirth, a policy of premature delivery was developed so that it became routine to deliver IDMs, often by elective caesarean section, at 36 weeks' gestation. This reduced the number of stillbirths but increased the number of neonatal deaths due to HMD, as frequently these babies were born more prematurely than expected because of errors in estimating fetal size and gestation. The precise cause of this excessive stillbirth rate in pregnancies complicated by diabetes is unknown. However, acute on chronic intrauterine hypoxia is a likely suspect. One of the reasons for this suspicion is that IDMs are often born polycythaemic, with increased numbers of nucleated red cells in the peripheral blood (Mimouni et al, 1986a). This increase in haemoglobin, red blood cells and red cell precursors is probably due to erythropoietin stimulation of the reticuloendothelial system--Widness et al (1981) found that 33% of IDMs had increased cord blood erythropoietin levels compared with controls. This stimulation of erythropoietin release in turn is presumably due to intrauterine hypoxia. Miller (1946) found increased extramedullary haemopoiesis in macrosomic IDMs at post-mortem, with increased numbers of normoblasts and 'erythroblastosis as seen in rhesus disease but in the absence of haemolysis'. Later Naeye (1965) found macrosomic IDMs had livers which weighed 199% more than controls due to a three-fold increase in haematopoietic tissue and an increase in hepatocyte cytoplasm. That chronic intrauterine hypoxia can be present in pregnancies complicated by diabetes is rather paradoxical, considering how well the placenta must be functioning in transferring nourishment to these macrosomic infants. How could they be chronically hypoxic and yet chronically overnourished? Again there is good support for this premise from animal studies. There is evidence that maternal diabetes may produce alterations in red cell oxygen release and placental blood flow. Madsen (1986) showed that in poorly controlled diabetes a shift to the left may occur in the oxyhaemoglobin dissociation curve, thus causing increased haemoglobin oxygen affinity and therefore reduced red cell oxygen delivery at the tissue

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level. He also showed that this may not occur in well-controlled diabetes and is most noticeable when patients are recovering from diabetic ketoacidosis. Reduced uterine blood flow certainly contributes to intrauterine growth retardation in pregnancies complicated by diabetic vasculopathy, and it is well accepted that these growth retarded fetuses are much more likely to suffer sudden fetal death. There is also a relationship between poor maternal metabolic control and reduced uterine blood flow as measured by the injection of radioactive traces (Nyland et al, 1982). Ketoacidosis and pre-eclampsia, two conditions known to be associated with an increased risk of fetal death in utero, may further decrease uterine blood flow. In ketoacidosis, hypovolaemia and hypotension occur as a result of dehydration, thus causing reduced blood flow through the intervillous spaces. Preeclampsia may cause reduced uterine blood flow by narrowing and spasm of the spiral arterioles. Carson et al (1980) found that hyperinsulinaemia caused in fetal lambs by an insulin infusion for 1-4 days was associated with a significant fall in arterial oxygen tension as well as a lowering of blood glucose. Milley et al (1984) confirmed these findings, but was able to produce fetal hypoxia with lower levels of hyperinsulinaemia and with n o hypoglycaemia. Phillipps et al (1982) infused chronically catheterized fetal lambs with intravenous glucose, causing hyperglycaemia for 3-11 days, and found that whole blood oxygen content fell by one third, and that plasma erythropoietin levels as well as insulin levels rose. Finally, Teramo et al (1987) in Helsinki found that amniotic fluid and umbilical vein erythropoietin levels were significantly raised in diabetic pregnancies. He also demonstrated that there is a strong relationship between maternal HbAlc levels (twice weekly) and the log-transformed amniotic fluid erythropoietin and umbilical vein erythropoietin levels. Thus, poor diabetic control caused increased amniotic fluid and umbilical vein erythropoietin. Presumably, therefore, poor control increases the risk for fetal hypoxia. Thus it seems quite probable that hyperglycaemia, either in its own right or via hyperinsulinaemia, can cause chronic fetal hypoxia, and that this, perhaps together with some precipitating factor such as ketoacidosis or worsening pre-eclampsia, is the basis of the sudden fetal death which has puzzled and distressed workers with diabetes in pregnancy for over half a century. It is also possible that severe hypoglycaemia may be implicated in some fetal deaths. Thus it behoves clinicians who manage diabetic pregnancies to maintain strict diabetic control, especially during the last trimester, in order to minimize the risk of this, one of the most serious and distressing of all problems associated with diabetes in pregnancy.

Macrosomia

Macrosomia has been one of the hallmarks of the effects of diabetes on the fetus ever since it was first recognized over 150 years ago. It is discussed in detail in Chapter 5.

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NATAL PROBLEMS Asphyxia

As already discussed, IDMs are more prone to intrauterine hypoxia during the pregnancy and therefore more prone to developing fetal distress in labour. Thus fetal heart monitoring with a scalp electrode during labour is mandatory with or without fetal scalp pH back-up. The decision to proceed to caesarean section with early signs of fetal distress is perhaps more readily taken, especially with a macrosomic fetus, because nothing is more guaranteed to produce a very depressed baby at birth than a difficult forceps, possibly with shoulder dystocia as well, at the end of a labour complicated by intrauterine hypoxia. A paediatrician should always be present at all deliveries of IDMs, whether they are born by the vaginal route or by caesarean section, as the risk of low Apgar scores is much higher than in non-diabetic labours and so expert resuscitation is more likely to be needed. Intravenous sodium bicarbonate may be necessary and should be kept at hand if there are signs of fetal distress. Dextrose given as a bolus intravenous dose is very unlikely to be necessary as part of the resuscitation process and will only enhance the risk of neonatal hypoglycaemia during the first few hours after birth by further stimulation of hyperinsulinaemia, thus it should be avoided if possible.

Birth trauma

Because of macrosomia, birth injuries are much more common in IDMs. Fractured clavicles, Erb's palsy and other brachial plexus injuries (BPIs), fractured humerus, cephalhaematoma and excessive bruising have all been reported to be more common in IDMs born vaginally. Even being born by caesarean section does not completely rule out the risk of birth trauma in very macrosomic infants. In the past birth trauma was not an uncommon cause of neonatal death (see Table 2) and this was one of the reasons it became policy in many DIP programmes during the 1960s to deliver all IDMs at 36 weeks' gestation (mostly by elective caesarean section), not only to reduce the risk of stillbirth but also the risk of birth trauma. The commonest cause of birth trauma in IDMs is shoulder dystocia. This can cause fractured clavicles and, more importantly, BPI, which has the potential to cause permanent disability. The incidence of shoulder dystocia in the general gravida population is reported to be between 2 and 4 per 1000 deliveries, although more recently Acker et al (1985) found the incidence in his series in Boston to be approximately one in 50 deliveries, and Benedetti (1987) in Seattle, in a review of 10000 births, found the incidence to be slightly less than one in 100. However, as Benedetti pointed out, the definition of shoulder dystocia is rather loose and is usually 'in the eye of the beholder'. The incidence of shoulder dystocia is, as expected, strongly related to birth weight (Benedetti and Gabbe, 1978), but the prediction of

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those that might suffer this complication is rather elusive. This is discussed further in Chapter 8. The most serious after-effect, apart from perinatal asphyxia, of shoulder dystocia is BPI, and, as one would expect, it too is strongly related to birth weight (McFarland et al, 1986). McFarland et al (1986) also found a strong relationship to the method of delivery, the risk being much greater in mid-forceps and vacuum extraction deliveries. Although most Erb's palsies recover completely within 6 to 8 weeks, the risk of permanent disability was reported as ranging from 22 to 44% depending on the severity of the initial injury and the duration of follow-up (Benedetti, 1987), although infants with transient BPI may not have been considered in this study. At any rate the risk of permanent disability following BPI is much more significant than was originally thought--all the more reason to consider caesarean section if the risk of shoulder dystocia is high. With the newer microsurgical techniques neurosurgeons are attempting surgical repair of severe BPIs with some encouraging initial results. Hence, early surgical referral of the more severe BPIs that are not showing early and continued signs of recovery would seem prudent.

Caesarean section

The incidence of caesarean section deliveries in pregnant diabetics is, for obvious reasons, very high, ranging from 30 to 70% in most DIP programmes. In the DIP clinic at the Royal Women's Hospital, Melbourne, the caesarean section rate is currently running at 37.5%. However, although caesarean section may reduce the risk to the fetus of perinatal asphyxia and birth trauma, it is not without cost. There is no doubt that caesarean section increases the risk of respiratory distress, both from 'wet lung syndrome' (WLS) and, in those babies less than 37 weeks' gestation, from HMD, and this may represent a significant increase in risk to the baby's survival in a group of babies already at high risk from respiratory distress because of biochemical lung immaturity. How caesarean section does this is not clear, but lack of thoracic compression during vaginal delivery may be a factor and depression at birth from anaesthetic agents may be another. However, the principal cause is thought to be lack of the stimulation of lung fluid absorption that is brought about by the secretion of catecholamines by the mother during labour (Brown et al, 1983). Whatever the reason, the increased risk of respiratory distress, and therefore of survival, is real and therefore always has to be taken into account when the decision to proceed to caesarean section is taken, especially elective caesarean section. There is some evidence that the risk of respiratory distress is less if the baby is born with good Apgar scores; thus, where possible, an epidural anaesthetic would be preferred. If a general anaesthetic is unavoidable a short inductiondelivery time is important as there is no doubt that the longer the inductiondelivery time, the more depressed the baby is at birth, which may increase the risk of respiratory distress.

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POSTNATAL PROBLEMS Clinical features 'These infants are remarkable not only because, like foetal versionsof Shadrach, Meshach and Abednego, they emerge at least alive from within the fiery metabolic furnace of diabetes mellitus, but because they resemble one another so closely that they might well be related. They are plump, sleek, liberally coated with vernix caseosa, full faced and plethoric. The umbilical cord and the placenta share in the gigantism. During the first 24 extra-uterine hours they lie on their backs, bloated and flushed, their legs flexed and abducted, their lightly closed hands on either side of their head, the abdomenprominent and their respirations sighing. They convey the distinct impression of having had such a surfeit of both food and fluid pressed upon them by an insistent hostess that they desire only peace so that they may recover from their excesses. And on the second day their resentment of the slightest noise improves the analogy while their trembling anxiety seems to speak of intra-uterine indiscretions of which we know nothing.' J. W. Farquhar, 1951

This classic description of the I D M by Farquhar, one of the leading workers in the field in the 1950s and 1960s, is as true today as it was then, except perhaps we now know a little more about the 'intra-uterine indiscretions' of diabetes mellitus. As everyone knows, the typical I D M is big and fat and, as most people now describe them, 'macrosomic'. This term is an unfortunate one because it technically purports only to the size of the baby and yet recently it has come to include all the other clinical features typical of the IDM. Many E u r o p e a n centres use the term 'diabetic fetopathy', which is probably more appropriate. What then are the other clinical features of these fascinating babies? Their heads are relatively small compared with their 'macrosomic' bodies, although when transposed on to growth charts the head circumference is usually found to be well within the normal range. Their length is usually in proportion to their weight, although often the length is not as far above the 90th centile as the weight. Certainly their 'macrosomia' is not only due to fat; their bony frames are also large and many of their viscera are over-sized, particularly the liver, spleen and heart, presumably from excess glycogen stores and extramedullary haemopoiesis. Their faces are the most typical feature. Their cheeks are enormously enlarged so that on side view they almost completely hide their tiny noses. The polycythaemia which often accompanies IDMs gives the cheeks that rosy hue which has been labelled 'the tomato face of the I D M ' . With all this extra fat the face is wide and the neck short, almost obliterated by the wide double chin which invariably rests on the upper chest, the eyes are small and buried in pads of fat, and there is often a crease across the bridge of the nose because of overhanging fat from the forehead. All the facial features, the nose, the mouth, the eyes and the chin appear tiny in stark contrast to the wideness and obesity of the face itself. The ears too are often small, with excessive hair extending down the lateral edge of the outer helix (the so-called 'hairy ears' of the IDM) and the ear lobes are often up-tilted, presumably from intrauterine pressure of the fat shoulders and the short neck. The breast tissue is usually underdeveloped for their gestation and the

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abdomen prominent, although not obviously distended. The liver can usually be palpated 2-3 cm under the right costal margin and often a tip of spleen is palpable. The umbilical cord is usually thick with Wharton's jelly so that several cord clamps are often needed to be sure of safe closure. It leads to a massive placenta which can often weigh over 1000 g. It seems strange that this luxurious organ can function so well as far as nourishment of the fetus is concerned and yet so poorly for oxygen transport. The genitalia are relatively small and underdeveloped, although this is probably just a reflection of the true maturity of the baby. The skin is tight and shiny and often 'liberally coated with vernix', and lanugo is also often in generous supply. They are plethoric with marked acrocyanosis, their ruddy complexions often belying an inadequate blood oxygen saturation. They 'lie on their backs, bloated and flushed . . . their lightly closed hands on either side of their head'--this is extraordinarily typical. The legs are fully abducted in a frog-like posture, and thus the posture is that of an overgrown premature baby. Indeed their behaviour during the first week or two of life is usually much more immature than their true clinical gestation, so that they are sleepy, floppy and poor feeders, suggesting that something about the maternal diabetes has caused a delay in the development of the CNS. On the other hand, they are extremely irritable, jittery and screechy when disturbed for the first 2-3 days, suggesting that some external factor is irritating their CNS such as hypoglycaemia, polycythaemia, hypocalcaemia or hypomagnesaemia, or maybe this CNS irritability is the result of acute on chronic intrauterine hypoxia or even birth trauma. They often have a transient 'tachypnoea'; in our experience between 40 and 50% have this. Although it usually settles quickly within the first 12-24"h, oxygen therapy is necessary until it does. Because of this and the polycythaemia they are prone to cyanotic episodes, which may also be due to hypoglycaemia. The first inkling that they may have a cardiomyopathy is a tachypnoea combined with an overactive precordium as well as poor peripheral pulses. Thus these macrosomic, so-called 'sugar babies' have an appearance and behaviour during the first few days of life which is extraordinarily similar and predictable--as Farquhar said 'they resemble one another so closely that they might well be related'. But not all IDMs appear and behave this way. At least half to three-quarters of them (perhaps depending on diabetic control) appear and behave completely normally, although, even if not typical in appearance, they can still become hypoglycaemic, develop respiratory distress and all the other well-known neonatal complications, although these are far less likely to occur in 'non-macrosomic' babies (see below). About 5-10% of IDMs are the opposite of this picture--small, undernourished and growth retarded. These are often born to mothers who have had diabetes for 20 years or more and have complications of diabetes such as retinopathy and renal disease (White's classes D, F and R).

Neonatal complications If the IDM escapes sudden fetal death in utero, escapes perinatal asphyxia

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and birth t r a u m a , and is born alive, there are still m a n y hurdles to o v e r c o m e . T h e r e are a significant n u m b e r of complications k n o w n to be associated with the n e o n a t a l p e r i o d of the I D M - - s o m e of t h e m life-threatening and m o s t of t h e m m a y be associated with long-term morbidity if not l o o k e d for, diagnosed and treated. T h e n e o n a t a l complications which have b e e n associated with I D M s are given in Table 4; not an insignificant list. Table 5 gives the incidence of each of the m o r e c o m m o n complications as they o c c u r r e d in a g r o u p of 106 babies born in our D I P unit b e t w e e n 1979 and 1981. It also shows that almost all of the complications are less c o m m o n in the infants of gestational diabetics (apart f r o m h y p o m a g n e s a e m i a and h y p o c a l c a e m i a ) . Nevertheless, all of these n e o n a t a l problems can still occur in the infants of gestational diabetic m o t h e r s and can be just as severe; they are just less likely to occur. H e n c e m o n i t o r i n g of infants of gestational diabetic m o t h e r s should still be just as vigilant. O f course since that study, o v e r the past 10 years, there has b e e n a policy to deliver I D M s m u c h m o r e towards term if p o s s i b l e - - w e aim for t e r m delivery in gestational diabetics and at least 38 weeks in m o t h e r s with I D D M - - s o most of the complications listed a b o v e would be m u c h less c o m m o n t o d a y because, Table 4. Complications that have been associated with the neonatal period in IDMs. Macrosomia Respiratory distress Hypoglycaemia Hypocalcaemia Hypomagnesaemia Jaundice Congenital malformations Polycythaemia Cardiomyopathy Birth trauma Thrombosis Congenital microcolon Intrauterine growth retardation Table 5. Incidence of neonatal complications at the Royal Women's Hospital, Melbourne, 1979-1981, showing how almost all complications are more common in infants of those with IDDM compared with infants of those with gestational diabetes (GDM). Complication Macrosomia (> 90th centile) Respiratory distress (including TTNB) Hypoglycaemia (< 2.0 mmol/1) Hypocalcaemia (< 1.7 mmol/l) Hypomagnesaemia (< 0.7 mmol/l) Jaundice (> 200 mmol/1) Polycythaemia (haematocrit > 0.6 l) Cardiomyopathy (clinical CCF) Congenital malformation (major)

Overall incidence

IDDM (n = 66)

GDM (n = 40)

45.6% 38.4% 55.2% 31.1% 75.7% 53.8% 44.1% 4.8% 6.6%

54.4% 46.9% 61.0% 32.4% 73.0% 65.6% 48.5 % 7.3% 7.4%

24.7% 23.6% 421.2% 28.5% 80.5% 35.1% 33.3% Nil 5.4%

TTNB = transient tachypnoea of the newborn.

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except perhaps for polycythaemia, cardiomyopathy and congenital malformations, they are all more common with prematurity. We are in the process of reassessing the incidence of neonatal complications in the light of more mature gestation, but there is no doubt that neonatal morbidity can be greatly decreased by delaying delivery more towards 40 weeks' gestation if possible (Hanson and Persson, 1986). If an IDM is born macrosomic there is no doubt that he or she is more likely to develop most of the neonatal complications, except perhaps hypomagnesaemia and congenital malformations; Table 6 compares the incidence of the more common complications in macrosomic babies with those in non-macrosomic infants. Thus, if an IDM is born macrosomic in size and has most of the typical clinical features, he or she should be monitored much more carefully, particularly with reference to respiratory distress, hypoglycaemia and cardiomyopathy, because these have the potential to cause so much more serious harm. Table 6. Incidence of neonatal complications at the Royal W o m e n ' s Hospital, Melbourne, 1979-1981 (n = 106), showing that most complications are significantly m o r e c o m m o n in macrosomic IDMs. Complication

Macrosomic

Non-macrosomic

44.8% 64.5% 34.0% 77.1% 50.0% 70.8% 8.3% 6.25%

35.1% 46.0% 28.6% 74.5% 37.9% 47.9% 1.75% 7.0%

Respiratory distress (including TTNB) Hypoglycaemia (< 2.0 mmol/l) Hypocalcaemia (< 1.7 mmol/l) Hypomagnesaemia (< 0.7 mmol/l) Polycythaemia (haematocrit > 0.61) Jaundice (> 200 mmol/l) Cardiomyopathy (clinical CCF) Congenital malformations (major) T T N B = transient tachypnoea of the newborn.

Respiratory distress It has been known for several decades that IDMs have an increased risk .of respiratory distress syndrome (Gellis and Hsia, 1959; Driscoll et al, 1960). Indeed, prior to the introduction of neonatal intensive care in the 1950s and 1960s, respiratory distress was the commonest cause of neonatal death. In 1976 Robert et al found that the corrected risk of respiratory distress in IDMs was nearly six times that of babies born to mothers without diabetes. Since then, however, with the emphasis on improvement in diabetic control and prolongation of the pregnancy beyond 38 weeks' gestation, respiratory distress has become much less common. Several studies agree that in wellcontrolled diabetics delivered at term, the risk of respiratory distress is no higher than that in the general population (Gabbe et al, 1977; Jovanovic et al, 1981; Dudley and Black, 1985). However, diabetes cannot always be perfectly controlled and delivery before term is often necessary, hence respiratory distress can still be a major worry; the risk of its development must always be balanced against the risk of prolonging the pregnancy, since no other neonatal complication, apart from lethal congenital malformations, has such potential to cause death.

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Clinical causes of respiratory distress. Whereas there seems no doubt that the increased risk of respiratory distress in IDMs is related directly to the biochemical immaturity of lung function, not all respiratory distress in these babies is due to HMD. Indeed, it is probable that most is due to WLS, especially if the babies are over 36 weeks' gestation. In a series of 75 IDMs from the Royal Women's Hospital, Melbourne (unpublished data) born between 1976 and 1978, of the 35 (46.6%) who suffered some degree of clinical respiratory distress only three had HMD on X-ray (Table 7). The Table 7. Radiological diagnosis of 31 babies with respiratory distress in a series of 75 IDMs studied at the Royal Women's Hospital, Melbourne, 1975-1977. Respiratory distress

X-ray diagnosis

Mild (n = 16) (02 30% or less for 6-36h)

Normal (n = 10) Aspiration syndrome (n = 2) WLS (n = 4)

Moderate (n = 13) (02 50% or less for 36-120 h)

WLS (n = 12) H M D (n = 1)

Severe (n = 2) (IPPV necessary)

H M D (n = 2)

IPPV = intermittent positive-pressure ventilation.

three that had HMD radiologically were clinically the most severe (two needing intermittent positive-pressure ventilation); the rest had either WLS (n= 16), aspiration syndrome (n=2) or their X-rays appeared normal (n = 10). All three with HMD were less than 36 weeks' gestation, whereas 12 of those with WLS (75%) were more than 36 weeks' gestation. There were seven babies in this series less than 36 weeks' gestation (10%) and three (42%) of these had HMD, while the remaining four all developed WLS. Thus IDMs less than 36 weeks' gestation are very likely indeed to get respiratory distress in some form. It seems that IDMs are very likely to get respiratory distress in the first hours of life but, whereas they are more likely to get HMD than infants of non-diabetic mothers of equivalent gestation, the most common form of respiratory distress in IDMs in our study is WLS in those babies more than 36 weeks' gestation. The pathogenesis of WLS is not clearly understood, but it seems that it too is related in some way to the biochemical immaturity of lung function which occurs in these babies because WLS (or transient tachypnoea of the newborn) is much less common when the gestation is over 38 weeks. Hence there is a need to get IDMs (both infants of insulin dependent diabetics as well as infants of gestational diabetics) as close to term as possible to minimize all forms of respiratory distress, although WLS is usually benign and easily treated.

Hypoglycaemia Along with respiratory distress, neonatal hypoglycaemia is perhaps the other very important complication of IDMs because of its frequency and its

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potential to cause long-term handicap. If less than 2.0 mmol/1 is considered abnormal, then in our experience approximately 50% of IDMs will develop hypoglycaemia within the first 12 h of life. It is due, mainly, to hyperinsulinism secondary to beta cell hyperplasia brought about by the passive transfer of excess amounts of glucose (and possibly amino acids or other substrates) across the placenta. Raised amounts of C-peptide and free insulin have been demonstrated in cord blood by many workers (Phelps et al, 1978; Sosenko et al, 1979; Kuhl et al, 1982). Once the maternal supply of glucose is cut off by clamping the cord, this excess insulin circulating in the baby's system quickly rids the plasma of the remaining glucose, and so blood glucose levels may drop precipitously and alarmingly during the first hour or two of life. Neonatal hypoglycaemia may be added to, or aggravated by, three other factors: polycythaemia, hypoglucagonism and increased maternal plasma glucose levels during labour if the mother is given too much intravenous glucose. Polycythaemia causes hypoglycaemia by the increased number of red blood cells directly absorbing glucose from the serum, glucose of course being their main metabolic nutrient. Johnston and Bloom (1975) demonstrated that IDMs are unable to respond to hypoglycaemia by releasing adequate amounts of glucagon from the alpha cells of the pancreas to mobilize glycogen. Not only does glucagon promote hepatic glycogenolysis but it both stimulates and induces the rate-limiting enzymes of gluconeogenesis. In addition, IDMs are relatively glucagon resistant, requiring approximately ten times the usual amount of glucagon to cause glycogen to be released and broken down into glucose. Thus we have the paradoxical situation that, although the IDM has enormous amounts of glycogen laid down in just about every tissue, particularly the liver, spleen, lungs, heart and skeletal muscle, it is unavailable to counteract the rapid falls in glucose that these babies experience during the first few hours of life due to hyperinsulinism. Finally it has been shown by several workers that inadequate maternal glycaemic control during labour and delivery can aggravate neonatal hypoglycaemia, presumably by even further stimulating insulin release from the fetal/neonatal pancreas (Soler et al, 1978). Thus it is important to keep the maternal blood glucose below 5.5 mmol/1 during labour. Thus, these babies are extraordinarily prone, for a number of reasons, to rapid fails in blood glucose soon after birth and so it is essential to monitor their blood glucose frequently before feeds during the first 24 h and, in an effort to avoid hypoglycaemia, to feed them early with frequent, highcarbohydrate, high-calorie feeds. This is one reason for these babies to be admitted to a special care nursery for the first 24--48h so that reliable Dextrossix (or glucometer) measurements can be done by experienced nursing staff.

Hypocalcaemia and hypomagnesaemia Hypocalcaemia (less than 1.7 mmol/1) occurs in approximately 25-50% of all IDMs and, even when factors such as prematurity and birth asphyxia are controlled for, the incidence of hypocalcaemia is still very significant (Tsang

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et al, 1972). Furthermore, the incidence of hypocalcaemia is directly related to the severity of the diabetes. Hypomagnesaemia occurs in 70-80% of IDMs and, strangely enough, in our experience seems to be just as common in gestational diabetics as in insulin dependent diabetics and in nonmacrosomic infants as in macrosomic infants, and seems to be unrelated to diabetic control. The hypocalcaemia appears to be due to a transient functional hypoparathyroidism which is present during the first 2-4 days of life. There is therefore an inadequate parathormone response to the normal fall in serum calcium wh'~ch occurs during the first few days after the maternal supply via the placenta is cut off and oral intake is inadequate. Hypocalcaemia (and hypomagnesaemia) may be aggravated by perinatal asphyxia and prematurity, both of which are more common in this group of infants. Decreased serum calcium levels in IDMs correlate with hypomagnesaemia and decreased parathormone secretion (Tsang et al, 1975; Schedewie et al, 1979; Noguchi et al, 1980). This hypoparathyroidism may be due to a direct enzyme depressant effect of fetal insulin, but recent studies by Mimouni et al (1987a,b) suggest that it may be due to an overall lack of total body magnesium. It appears that in IDDM there is an increased loss of magnesium in the urine and for this reason most patients with IDDM are hypomagnesaemic. This causes decreased excretion of parathormone, most likely through an alteration in the calcium-sensitive, magnesium-dependent adenylate cyclase involved in parathormone secretion (Levine and Coburn, 1984). Cruikshank et al (1983) also showed that pregnant diabetic women have lower serum magnesium levels than controls and do not exhibit the normal increase in parathormone secretion during gestation. Mimouni et al (1987a) demonstrated that amniotic fluid magnesium was decreased in diabetic pregnancies, which probably reflects decreased fetal urinary magnesium excretion, supporting the hypothesis that the fetus in diabetic pregnancies is magnesium deficient. Shaul et al (1986) also showed that in situations of magnesium deficiency, an infusion of magnesium intravenously causes an increase in parathormone secretion, but the parathormone secretion decreased with intravenous magnesium when the pre-infusion serum magnesium level was normal or high. Thus she postulated that in states of magnesium deficiency (which is present in most IDMs) there is'a functional hypoparathyroidism which is then responsible for hypocalcaemia, also seen in many IDMs. Furthermore, this hypocalcaemia may be refractory to normal calcium treatment unless the hypomagnesaemia is also corrected. Thus IDMs exhibit transient functional hypoparathyroidism at birth, leading, in some, to neonatal hypocalcaemia. This functional hypoparathyroidism may be due to a state of magnesium deficiency, which in itself is secondary to maternal hypomagnesaemia created by the increase in urinary magnesium excretion that exists in diabetes mellitus. The hypomagnesaemia, which is very frequently seen in IDMs (see Tables 5 and 6), is a reflection of an overall magnesium deficiency but may in turn be perpetuated by the lack of parathormone response. This hypocalcaemia and hypomagnesaemia seems to reach its lowest level on the second and third days, and so we recommend that all IDMs ought to have serum calcium and magnesium levels measured

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on the second and third days whether symptomatic or not. Usually if the levels are mildly decreased they are easily corrected with oral calcium gluconate and a single injection of magnesium sulphate. If the calcium level is very low, or symptoms are pronounced, then an intravenous infusion of calcium may be indicated.

Polycythaemia Polycythaemia, defined as a haematocrit of more than 0.651, is common in IDMs. In normal infants of non-diabetic mothers the incidence is approximately 3% of babies born at sea level, but in a recent prospective study by Mimouni et al (1986b) an incidence of 12% was found in IDMs. In our study at the Royal Women's Hospital, Melbourne in 1981 (Mountain, unpublished data) we found an incidence of 44.1%, but this was retrospective and we used a haematocrit of 0.61 or more. Nevertheless we did find that polycythaemia is more common in macrosomic babies compared with nonmacrosomic babies and also in infants of mothers with I D D M compared with infants of gestational diabetic mothers. The principal mechanism of this polycythaemia seems to be that it is secondary to chronic intrauterine hypoxia which in turn is due to fetal hyperglycaemia, hyperinsulinaemia, or both, as already detailed in the section on fetal death. Chronic fetal hypoxaemia causes increased serum erythropoietin levels, which stimulates the reticuloendothelial system of the fetus, thus producing increased erythropoiesis and increased red cell mass together with an increase in blood volume. There is no doubt that cord erythropoietin levels in IDMs are raised (Widness et al, 1981), and fetal lambs made hyperglycaemic and hyperinsulinaemic with intravenous glucose infusions also have lowered blood oxygen content and raised cord erythropoietin levels (Phillips et al, 1982). However, acute transfer of blood from the placenta to the baby may also be a factor. This may occur at birth due to delayed clamping of the cord and positioning of the baby, but it may also occur in utero as a result of acute asphyxia. Studies by Oh et al (1975) and confirmed by Yao and Lind (1972) demonstrated that in chronically catheterized fetal lambs made hypoxic by their mothers breathing 10% oxygen there was a transfusion of 25% of the placental blood volume to the fetus. If there is an acute expansion of blood volume in the perinatal period, the neonate has to make circulatory compensation by haemoconcentration. This involves transudation of fluid from the blood into the extravascular compartment during the first 6-12 h of life, causing increased fluid in the interstitial spaces of various organs, a reduction in blood volume and a corresponding rise in haematocrit and blood viscosity (Oh et al, 1966a,b). This so-called 'hyperviscosity syndrome', together with increased interstitial fluid, has various clinical manifestations. It acts on the CNS, causing jitteriness and irritability and in extreme cases cyanotic episodes, apnoea and convulsions. It may cause or aggravate respiratory distress by its effect on the pulmonary circulation and it may also affect the gastrointestinal system, causing food intolerance or even necrotizing enterocolitis. It may

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cause hypoglycaemia by virtue of the increased numbers of red blood cells 'using up' plasma glucose, oliguria because of sluggish circulation through the glomeruli and, of course, it often causes jaundice because of the increased numbers of red blood cells that need to be broken down. Thus polycythaemia in IDMs is not an insignificant problem, and it is essential that the cord is clamped immediately on delivery of the baby to stop any placental transfusion thereafter. In our unit we also advise partial exchange transfusion with plasma (25 ml kg) if the haematocrit is more than 0.71 and if the baby is symptomatic, e.g. with severe respiratory distress, refractory hypoglycaemia or extreme CNS excitation. Jaundice

Pathological hyperbilirubinaemia (i.e. serum bilirubin above 200 ~mol/l) is frequent in IDMs. In our series we noted 53.8% of all IDMs developed serum bilirubins above 200 ~mol/1, with the incidence being 65.6% in infants of mothers with IDDM compared with 35.1% in infants of gestational diabetics. Several other studies have quoted similar if not quite so dramatic incidences (Ylinen et al, 1981; Widness et al, 1985). The incidence of hyperbilirubinaemia is also related to macrosomia. We found 70.8% of macrosomic IDMs had serum bilirubins above 200 p~mol/1, whereas only 47.4% of the non-macrosomic IDMs developed pathological jaundice. Of the 53.8% of IDMs in our series that developed hyperbilirubinaemia about half required phototherapy, but exchange transfusion was rarely necessary. Thus jaundice in IDMs, although common, does not rise extremely rapidly and is usually easily controlled with phototherapy as long as this is begun early enough. Therefore, about 25-30% of IDMs will require phototherapy with the resultant parental anxiety that this brings, and so parents need to be warned that phototherapy is often necessary. The actual cause of this hyperbilirubinaemia is unclear, but many possibilities have been put forward. There is no doubt that a major contributing factor is increased bilirubin production, and Stevenson et al (1979) showed that bilirubin production is significantly increased in IDMs compared with control term infants. This increased bilirubin production is probably due mainly to the polycythaemia commonly seen in IDMs, and polycythaemic IDMs are more likely to have a serum bilirubin above 170 ~mol/1 than non-polycythaemic IDMs (Gamsu, 1978). However, this has been thrown into doubt by several more recent studies that failed to show an association between jaundice and polycythaemia (Stevenson et al, 1979; Widness et al, 1981; Black et al, 1982; Bucalo et al, 1984), and Stevenson et al (1979) postulated that ineffective erythropoiesis or increased haemolysis is the main cause of jaundice in IDMs. There may indeed be a small element of increased red cell breakdown as there is some laboratory evidence that the red blood cells of IDMs have a shorter life span (Goldberg et al, 1982). The increased bruising and trauma which is commonly associated with macrosomic IDMs doubtless also contributes to the increased bilirubin production and therefore to the jaundice. As well as this, prematurity is still

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a factor as, no matter how much we may try to get these babies to term, a great number of them still need to be born prematurely and therefore will have less mature liver function. Other factors that may be involved include the increased use of oxytocin, as there is certainly a much higher incidence of induction of labour in these babies, and hypoglycaemia may also decrease uridyldiphosphogluconic acid, the substrate for bilirubin conjugation. As well as this there may be increased resorption of deconjugated bilirubin from the large bowel. Stevenson et al (1981) has found, however, a difference in the pre-phototherapy bilirubin concentrations in IDMs compared with normal infants that cannot be explained by increased bilirubin production alone. Their findings were consistent with a relative delay in the clearance of bilirubin in IDMs, thus implicating impairment of either uptake of bilirubin into the hepatocyte, conjugation or excretion, or all three. Thus it would seem that immaturity of liver function in its ability to conjugate and/or excrete bilirubin may also be a factor, and perhaps insulin, which seems to have a propensity to delay maturation of enzyme systems in many fetal organs, may again be the culprit. Extramedullary haemopoiesis may also be a factor in delaying excretion, but the serum bilirubin in jaundiced IDMs is nearly always unconjugated, thus implicating immaturity of uptake or conjugation rather than excretion of the conjugated bilirubin. Thereby the actual cause of hyperbilirubinaemia in IDMs is still unclear, but, whatever the cause, it remains a common problem and strict control of diabetes during pregnancy may be the best way to reduce its incidence. At any rate the essence of management is to frequently monitor serum bilirubin levels with the onset of clinical jaundice (the plethoric appearance of these babies can sometimes hide a surprisingly high level of jaundice), to start phototherapy early, to correct hypoglycaemia and to make sure of an adequate fluid intake so that dehydration does not exaggerate the problem.

Cardiomyopathy IDMs have for many years been known to be at risk for cardiac enlargement and congestive cardiac failure (CCF) in the neonatal period. In 1943 Miller and Wilson drew attention to the cardiomegaly on chest X-rays in macrosomic babies with cyanosis, respiratory distress and clinical CCF. Then in 1960 Driscoll et al demonstrated an increased cardiac weight in IDMs dying postnatally. They reported that 37% of IDMs' hearts weighed more than two standard deviations above the normal and many were three standard deviations above the mean cardiac weight for a particular gestation. However, it was Gutgesell et al (1976), with the advent of cardiac ultrasonography, who first described a transient form of hypertrophic subaortic stenosis in IDMs. They emphasized the significant hypertrophy of the interventricular septum that leads to outflow tract obstruction of the left ventricle very similar to that found in adults with idiopathic hypertrophic subaortic stenosis. The incidence of cardiomyopathy in IDMs presenting with symptoms of CCF is about 5%, but more recently, with cardiac ultrasound being performed more often, it has been shown to be much more common than originally thought, although most cardiomyopathies thus detected are

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asymptomatic. No single pathogenic mechanism for this cardiomyopathy in IDMs has been clearly defined, but some possible causes have been suggested, such as a direct effect of hyperinsulinaemia, excess glycogen stores in heart muscle, or that it is secondary to hypoglycaemia, hypocalcaemia or chronic intrauterine asphyxia. However, most workers have concentrated on the effects of hyperinsulinaemia on cardiac muscle and some studies have reported elevated serum insulin levels in fetuses with macrosomia (Strink and Driscotl, 1965) and cardiomegaly (Cowett and Schwartz, 1982). Insulin appears to act as an anabolic hormone in the fetus, producing not only macrosomia but visceromegaly, particularly of the heart, liver, spleen and placenta (Neufeld et al, 1978). Animal studies have also demonstrated that hyperinsulinaemia produced artificially in the fetus by insulin infusions (Susa et al, 1979) or by inducing diabetes in the animal mother with streptozotocin (Mintz et al, 1972) results in macrosomic fetuses with cardiac hypertrophy and cardiomegaly. In addition, many studies have related retrospectively the severity of cardiomegaly and cardiac septal hypertrophy with diabetic control--the poorer the control the greater the septal hypertrophy (Mace et al, 1979; Gutgesell et al, 1980). Breitweser et al (1980) found the most severe septal hypertrophy in those with the most profound hypoglycaemia--further evidence of the link with hyperinsulinaemia. Microscopically, the increased cardiac glycogen that was thought to be at the basis of the problem has not been substantiated, but hypertrophy and hyperplasia with a peculiar disruption of the normal myofibrillar pattern has been demonstrated similar to that seen in adults with hypertrophic cardiomyopathy (Buckley et al, 1977; Sheehan et al, 1986). Several retrospective studies have shown an increased risk of cardiomyopathy in IDMs whose mothers have shown poor diabetic control during the pregnancy (Mace et al, 1979; Gutgesell et al, 1980; Holliday, 1981), and other workers have shown that the risk is greatly increased with macrosomic infants (Miller and Wilson, 1943), there being a strong relationship between cardiac hypertrophy and fetal weight. A prospective study by Reller et al (1985) failed to show a difference in interventricular septal thickness between an early presentation group (8-10 weeks) and a group that presented late (15-32 weeks), although both groups had significantly thicker interventricular septums than a non-diabetic control group, and both groups were subjected to the same regimen of strict diabetic control over the last one third of the pregnancy. The CCF appears to be due to outflow tract obstruction secondary to gross hypertrophy of the interventricular septum which bulges into and narrows the subaortic canal (Mace et al, 1979; Gutgesell et al, 1980). Reduced stroke volume has been demonstrated in Doppler studies (Walther et al, 1 9 8 5 ) the greater the septal hypertrophy, the lower the stroke volume. Certainly the CCF is not due to diminished systolic contractile function of the left ventricle. This has been shown to be normal (Gutgesell et al, 1980; Holliday, 1981) or above normal (Mace et al, 1979; Leslie et al, 1982) in Doppler flow studies. The electrocardiogram is either normal or shows evidence of right ventricular hypertrophy or biventricular hypertrophy.

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Clinical features. Clinically, it is often initially difficult to distinguish between CCF and respiratory distress, and of course IDMs may have both. Indeed, the unexpected persistence of what appears to be mild to moderate WLS for many days is probably due to an element of CCF as well. The cardiomyopathy may present soon after birth with cyanosis, mottling, tachypnoea and tachycardia, with or without signs of frank CCF such as cardiomegaly, a gallop rhythm and liver enlargement. The diagnostic dilemma of such an IDM, who is usually very macrosomic, can be quite difficult. Does the baby just have severe respiratory distress, congenital heart disease, a cardiomyopathy, or all three? An overactive precordial impulse with poor pulses may give a clue to a heart problem, as does a systolic murmur, although this usually is absent in cardiomyopathy. A chest X-ray usually shows a combination of an enlarged heart with WLS with or without interstitial oedema, but the only way to make a definitive diagnosis is with cardiac ultrasound and Doppler flow studies, and any institution which delivers a significant number of IDMs should have this facility at its disposal. Indeed, at our institution this is now done routinely on all IDMs within the first 24 h of life whether in respiratory distress or not; we are finding a surprising incidence of approximately 30-40% of mild to moderate interventricular septal hypertrophy (over 5 ram), mostly without symptoms, but the presence of which alerts the clinician to the possible development of CCF, which may take a day or two to become evident. Treatment. The vast majority of IDMs with cardiomyopathy need no treatment at all except for initial oxygen therapy for the transient tachypnoea which often accompanies cardiomyopathy. If CCF becomes evident on clinical grounds, and cardiac ultrasound has confirmed the presence of cardiomyopathy and ruled out a structural cardiac defect, most cases respond to supportive treatment with fluid restriction, oxygen, diuretics and the correction of metabolic disturbances such as hypoglycaemia, hypocalcaemia, hypomagnesaemia and acidosis, as well as polycythaemia. If CCF persists or worsens in spite of these measures, propranolol is the drug of choice (Gutgesell et al, 1976; Holliday, 1981; Cowett and Schwartz, 1982; Walther et al, 1985). Digitalis and other positive inotropic agents are contraindicated as these, by virtue of their enhancement of contractility, may exacerbate the outflow tract obstruction. Most of the symptoms and signs of CCF secondary to cardiomyopathyin IDMs have resolved by 2-4 weeks of age and they can be weaned off the therapy. The natural history of this condition is benign, most hearts being back to normal by 6-12 months of life with no long-term sequelae. M A N A G E M E N T OF IDMs

The management of the IDM in our unit begins during pregnancy with an explanation to all mothers (with fathers if possible) during a 20-min talk in small groups from the consultant paediatrician of what can happen to their baby in the neonatal period and why it will be necessary for the baby to be

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admitted to the special care nursery for intensive monitoring for the first 24-48h. The increased risk of caesarean section is explained and it is emphasized that their babies are normal but prone to a number of problems which, if carefully watched for and treated early, are usually benign and have no after effects, except, of course, for respiratory distress which can on occasions require admission to the intensive care nursery. Mothers/parents are encouraged, of course, to visit and be with their babies at any time of the day for as long as they like. The importance of diabetic control, particularly for the baby's sake, is reinforced. Since we have been having these rather informal talks with parents over the past 2-3 years, we have found much better acceptance of the neonatal management and possibly better compliance with diabetic control. Because of the increased risk of intrauterine asphyxia during labour, and of traumatic delivery, a paediatrician is always present at the birth of IDMs. After a rather foreshortened but reasonable bonding period with the parents in the labour ward, the baby is then transferred to the special care nursery and observed in an incubator. If there is any sign of respiratory distress generous oxygen therapy is begun immediately, an X-ray of the chest organized and arterial blood gases measured by an arterial stab. Any metabolic acidosis (a base excess of more than - 5 ) is corrected and oxygen therapy is adjusted according to a transcutaneous oxygen monitor. If the chest X-ray shows only WLS, which is usually the case in babies more than 36 weeks' gestation, and the baby is needing no more than 30% oxygen, oral feeds are begun as soon as possible. If the baby needs more than 30% oxygen and/or the X-ray chest shows HMD, an intravenous infusion is set up with 10% dextrose and oral feeds withheld. If the respiratory distress worsens and moderate to severe HMD is present on the X-ray the baby is transferred to the intensive care unit for arterial catheterization and possible mechanical ventilatory support. The baby is fed with his or her first feed soon after admission consisting of a high carbohydrate containing formula, and is then fed 2-hourly, beginning at 60 ml/kg and increasing to 90ml/kg over the first 24h. We use a 20 Calorie/30 ml sweetened condensed milk formula because it contains almost 50% of its calories in the form of sucrose which, in contrast to lactose, is well tolerated during the first 48 h of life and, in our experience, rapidly corrects mild hypoglycaemia. Blood glucose levels are monitored immediately on admission by a glucometer (or Dextrostix), then hourly for 6h, then 2-hourly before feeds for the next 8h and then 4-hourly before feeds thenceforth until 48 h of age, if blood glucose measurements have stabilized. If any of the initial measurements are less than 1.0 mmol/l then an intravenous infusion of 10% dextrose is set up. If, however, the hypoglycaemia is less severe (1.0-2.0 mmol/1) then an intramuscular injection of glucagon is given (300 ~g/kg--approximate total dose of 1.0-1.5iu), which usually brings about a response within 30 min and lasts often for 6-8 h. If the blood glucose falls again a second injection may be tried, but if this effect is not lasting or if there is unsatisfactory response to the first injection then an intravenous dextrose infusion is begun. If this does not control the blood glucose then 15% dextrose may be used, and if this is unsuccessful then

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intravenous glucagon is added in a dose of 1 iu/20 ml at 1 ml/h via a Y piece attachment. If this in turn fails to keep the blood glucose above 2.0 mmol/1 then hydrocortisone is administered (10mg/kg per 24 h in 8-hourly doses intravenously or intramuscularly). Even the most refractory of hypoglycaemias will respond to this and, in our experience, we have never had to resort to diazoxide, which directly antagonizes the action of insulin and which may be necessary in extremely severe cases of hypoglycaemia. The haemoglobin and haematocrit are measured during the first 12 h and, if the haematocrit is above 0.7 1 and the baby is symptomatic, an exchange transfusion with plasma may be necessary, especially if there is severe respiratory distress, CCF, refractory hypoglycaemia, or severe CNS signs. A cardiac ultrasound is undertaken during the first 24 h on all IDMs in our unit both to exclude structural cardiac lesions and cardiomyopathy. Serum calcium and magnesium levels are measured on day 2 and day 3, or sooner if symptomatic. The hypoglycaemia which occurs in our experience in approximately 50% of cases (i.e. under 2.0 mmol/l) has usually stabilized on 3-hourly feeds during the second or third day of life and so the baby can then be transferred back to the mother in the postnatal ward (if stable in air) and breast feeding begun. Complementary feeds together with blood glucose measurements may need to be continued for the next day or two. Serum bilirubin levels are monitored, unless the jaundice is very mild, and phototherapy begun early rather than later. Most babies are discharged home (especially if born at 38 weeks' gestation or more) fully established on breast feeding by the end of the first week. All babies at our institution are followed up for the first 4 years or longer if necessary. CONCLUSION In no other group of babies, except perhaps for the extremely low birth weight/under 30 weeks' gestation group, has the perinatal mortality improved so dramatically over the past 25 years. There has also been considerable improvement in morbidity, as demonstrated by the improvement in long-term follow-up studies over recent years. There are many reasons for this improvement, but I believe that the two most important have been the more intensive, aggressive care of the newborn baby during the first 48 h of life and, perhaps most important of all, the understanding that diabetic control is much more important in the pregnant state than when the diabetic is not pregnant. There seems little doubt that most, if not all, of the perinatal problems associated with IDMs are due to either fetal hyperglycaemia (with or without some other transplacental substrate) or hyperinsulinaemia, both of which, of course, are strongly related to diabetic control. Thus the closer one gets to normoglycaemia during every day of the pregnancy, the better the baby's chances of firstly being born alive, secondly of having a complication-flee neonatal period and finally of being a normal citizen in the future. However, the perinatal mortality is still approximately two to three times that of the non-diabetic population (possibly double this

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in I D D M ) , a n d if w e a r e to m a k e f u r t h e r i n r o a d s i n t o t h e s u r v i v a l o f I D M s m o r e n e e d s to b e u n d e r s t o o d a b o u t t h e c a u s e s o f s u d d e n f e t a l d e a t h , m a c r o s o m i a a n d c o n g e n i t a l m a l f o r m a t i o n s , so t h a t steps c a n b e t a k e n t o reduce the incidence of these three remaining major problems.

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