hyperglycaemia foetal hyperinsulinism in diabetic

POSTGRAD. MED. J. (I962), 38, 6IZ

MATERNAL HYPERGLYCAEMIA AND FOETALHYPERINSULINISM IN DIABETIC PREGNANCY

JAMES W. FARQUHAR, M.D., F.R.C.P.(Edin.)Department of Child Life and Health, University of Edinburgh;

Simpson Memorial Maternity Pavilion, Royal Infirmary, Edinburgh

THE babies born to diabetic women, and to thosewomen whose diabetes declares itself only in laterlife, are usually heavier than average for theirgestational age, and their overall length may begreater. They have a pronounced tendency todevelop brief neonatal hypoglycxmia and a con-siderable increase both in pancreatic islet cell areaand in the insulin-secreting response to injectedglucose. Under ideal conditions and in largeseries they have a perinatal mortality rate whichmay be four times that for babies of normalwomen, and which even in good hospitals may besix or seven times greater than normal (Farquhar,I958a).This paper summarizes the evidence for the

existence of these physical abnormalities andspeculates on their cause.

The Physical AbnormalitiesWeight

Since Bennewitz (I828) first recorded theenormous still-born feetus of a woman who wasrecognizably diabetic only in pregnancy, in-disputable evidence for the excessive birth weightof such infants has been presented. It wasdescribed by Fischer (I935), and in the experienceof White and Hunt (I943) the average weight ofnormal babies at any gestational age is exceeded byfour-fifths of these infants. Similar findings havebeen reported from large series studied by Miller,Hurwitz and Kuder (I944), Peel and Oakley(1950), Warren and Le Compte (1952), Cardell(I953), Pedersen (I954), Farquhar (I959) andGellis and Hsia (I959). The increased weight isclearly a function of the diabetic environment inwhich the foetus develops, as the babies of diabeticfathers do not differ discernibly at birth from thoseof non-diabetic men (Babbott, Rubin and Gins-burg, I958).The infants have often been described as

cedematous (Miller, Johnson and Durlacher, I944;Given, Douglas and Tolstoi, 1950; White, I952;and Gellis, 1954). Many authors believed that this

Paper read at a course on 'Growing Points inPeediatrics' held by the' University of Cambridge Schoolof Clinical Research, Postgraduate Medical Teaching,April I962.

implied such retention of water that it made asignificant contribution to the excessive birthweight, and that in shedding it as urine the infantslost much more than the usual amount of weightduring the first week of life. The fact that Cardell(I953a) found little cedema in his autopsy seriescould be explained by the infants having shedtheir fluid before death, and the first real challengeto the popular ' waterlogged baby ' story camewhen we surprised ourselves by finding that inthe Edinburgh series the babies had not lost sig-nificantly more weight than control infants duringthe first week of life when they were matched asclosely as possible for several relevant factors,including the route of delivery (Farquhar andSklaroff, I958). Osler, in Copenhagen, studied thetotal body water and the extracellular water ofsuch babies and of a normal group. He was ableto show that the infants of diabetic mothers havesignificantly less total and extracellular water,although they have no reduction in intracellularwater, and he suggested that these findings are inkeeping with foetal obesity and the possible bindingof water in cells by increased glycogen formation(Osler, 1960a). He then compared the sub-cutaneous fat layer of such babies with that ofnormal full-term infants and with control babiesof the same maturity born to non-diabetic women,using measurement of skin-fold thickness andradiological measurement of the subcutaneoustissue of the lower leg and chest. He showed thatsubcutaneous fat was increased in the diabeticseries by from 38 to 46% compared with normalinfants and by 50% compared with controls (Osler,i96ob).Only one direct chemical analysis of the cadaver

of a typical infant of a diabetic woman has beenpublished so far (Fee and Weil, I960). This babysuffered from idiopathic respiratory distress anddied at 2i hours. Fat was found to be moderatelyincreased for an infant of comparable size andmarkedly increased on the basis of gestation whencompared with figures given by Widdowson andSpray (I95I). Similarly the body water-to-proteinratio corresponded more with gestational age thanwith body size and the relationship betweensodium, chloride and potassium suggested that

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November I962 FARQUHAR: Maternal Hyperglyccemia and Foetal Hyperinsulinism 613

there was no increase in extracellular fluid, but aslight increase in intracellular water. Theseauthors have now completed the direct examinationof eight further cadavers and of a number of babiesof non-diabetic mothers. Their results will bepublished later, but, although their calculations areas yet incomplete, they are likely to confirm theiroriginal finding, and the body fat of infants ofdiabetic women seems to be increased certainlyfrom the 34th week of gestation (Fee and Weil,I962).The recent development of commercial tech-

niques for finding the lean meat content of animaland bird carcases by determining their naturalradioactive potassium-40 content (Kulwich, Fein-stein, Golumbic, Hiner, Seymour and Kaufman,I96I) opens up a possible new way of calculatingthe muscle mass contribution to total weight inlive infants of diabetic and non-diabetic women.

LengthLength is a one-dimensional measurement and

any variation from the normal is likely to be lessimpressive than in the case of body weight, but theearlier reporters of fcetal gigantism in diabeticpregnancy suspected an increase in body length aswell as in weight, a fact of considerable interest inview of experimental work on the production ofanimal diabetes with pituitary growth hormone.Actual length was said by Warren and Le Compte

(1952) to exceed that calculated in more thanhalf the babies in their series, and Cardell (1953a)confirmed that the infants in his were longer thannormal controls of the same gestational age, andthat this increase was proportionate to weight. Nocomment was passed on length by Driscoll,Benirschke and Curtis (I960), but in any case theirobservations, as well as those of Warren and LeCompte and of Cardell, refer to autopsy examina-tions, and the birth weight, and so possibly alsothe birth length, of perinatal deaths may not berepresentative of these characteristics for the groupas a whole (Farquhar, I962).

In Pedersen's series (1954) the infants ofdiabetic mothers were found as a group to exceedin total length by an average of I.5 cm. the babies ofnon-diabetic 36- to 38-week pregnancies. Routinebut rather inexact measurements of crown-heellength in the earlier Edinburgh series indicatedat least this order of difference (Farquhar, I958b).Gellis and Hsia (I959) did not discuss length.Osler and Pedersen (I960), however, confirmedPedersen's earlier observation and stated that theinfants were no longer than babies of comparableweight or, as Cardell had said, the infants werelarge but proportionate. They also showed thatthe radiological bone age of infants of diabeticmothers does not correspond to their length and

60

C.-H. IMINBLRGH

LENGTH55

IN

CM. - *50 , . x- Ex / E FORGCUVFOR

NON-DABETICx PREGNANCIEScx(FROIMELLI9S,tO)

45-

32 33 34 35 36 37 38 39 40 41GESTATIONAL AGE IN WEEKS

FIG. i.-Crown-heel lengths of babies born to diabeticmothers in Boston (Mass.) and Edinburgh.

weight, but to their gestational age or even less.Radiological measurements of bone, muscle andfat widths are feasible from quite early in childhood(Stuart, Hill and Shaw, 1940; Maresh, I96I), butpersonal attempts at such in newborn infants inBoston were so full of possible error that they wereabandoned. Careful measurements of crown-heellengths were made by measuring-board on a furtherseries of infants of diabetic mothers at the BostonLying-in Hospital, Massachusetts, and the Simp-son Memorial Maternity Pavilion, Edinburgh.(Crown-heel length was used rather than crown-rump to allow comparison with previous studies.)The calculation of gestational age according to thedate of onset of the woman's last menstrual periodis notoriously imperfect, but is probably as goodas any other method available. The results aregiven in Fig. i, where the normal mean curve hasbeen calculated from Ellis (I95i) and is probablyacceptable for both cities. The vertical lines inter-secting the curve indicate ± i cm. from the mean,and the graph very strongly suggests that infantsof diabetic mothers in Boston and Edinburgh areas a group appreciably longer than controls. Eachinfant of a diabetic woman was carefully re-measured about the fifth day of life when weightloss was greatest, and it may be seen from Fig. 2that increases and decreases in measurement weresmall and that they were probably the result ofpositional change. Thus there is evidence thatnewborn infants of diabetic mothers are not onlyobese, but they are longer than controls, and thisprobably results in part from increased skeletalgrowth.

HypoglycamiaThe fact that the newborn infants of most

diabetic women develop a brief period of hypo-



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614 POSTGRADUATE MEDICAL JOURNAL November I962

- o0

II .I

1.0 0-s 0 0.5 1.0CENTIMETRES CHANGE

FIG. 2.-Frequency distribution of changes in crown-heel lengths of infants born to diabetic mothers(Boston, Mass., and Edinburgh).

loo s

o-80

a60 .

D . ,D 40-0O NORMAL20 DIABETIC

BIRTH 2 4 6 2 4 6 8 10HOURS DAYS

FIG. 3.-Arithmetic means of the blood sugar levelsin a group of normal infants and in a group ofinfants of diabetic women.

glycamia during the first few hours of life and thaton average this is more pronounced than in babiesof non-diabetic women has probably been provedbeyond all reasonable doubt and is illustrated inFig. 3 (Farquhar, I956a). Later work, particu-larly that of Hallman, Furuhjelm, Harri andPuranen (1956), who used a so-called 'true glu-cose ' method, has shown that the neonatal bloodglucose level may be even lower than was previouslysuggested by older techniques, but this probablyholds true equally for infants of diabetic and non-diabetic mothers. This is certainly the personalimpression gained from current, as yet unpub-lished, work using a modification of the glucose-oxidase technique of Huggett and Nixon (1957).Pancreatic Islet Area

Unusual size of the pancreatic islets of Langer-hans in babies of diabetic mothers has beenrecognized by many histologists since the earlydescriptions of Dubreuil and Anderodias (I920)and Wiener (1924). Many of these referencesare given by Pedersen (1952) and Farquhar (1958a).The islets vary in size appreciably, not only fromone pancreas to another, but from field to fieldwithin the same pancreas, and doubt has existedamong pathologists as to whether the total isletcell volume of such glands would prove abnormal if

I. N.M.

LsD.M.

FIG. 4.-Relative areas of pancreatic islets in newbornsof normal and diabetic mothers.

they were matched properly for duration of preg-nancy. Ogilvie (1958) is in no doubt about thequite remarkable size of such islets, and if theextensive experimental observations of Tejning(I947) be applied to such a belief, then an increasedislet cell volume may be assumed from his con-clusion that ' if in a section of pancreas we find anumber of islets which is relatively greater thannormal we can-in spite of the fact that the verylarge and the largest islets are only a relatively smallpart of the islet tissue-draw the conclusion thatthe total volume of islet tissue is larger thannormal '. But there are also two separate studiesof actual islet area. Cardell (I953b) found that theislets of infants of diabetic mothers formed fromi.8 to 9.9% of total pancreatic tissue comparedwith a normal neonatal range of from 0.7 to 2.6%,while Woolf and Jackson (I957) found the meansof the two groups to be 6.5 and 1.3% respectively.Thus, in relation to the size of the pancreas,the dead newborn infants of diabetic women seemto have roughly four times more islet tissue thanthe normal (Fig. 4), although another really large,careful study may be desirable. Unfortunately, theBoston group have gone no further so far than tostate that 8i% of 57 infants examined by themshowed appreciable islet hyperplasia (Driscoll andothers, I960).

Although histological knowledge of the islets offretus and newborn is fairly recent (Ferner, 1952;Robb, I96I), several careful studies report that inbabies of diabetic mothers the beta cells commonlyform much more than the normal 50% of totalneonatal islet cells, so that islet hypertrophy is



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November io62 FARQUHAR: Maternal Hyperglyca,fmia and Fcetal Hyperinsulinism 615

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FIG. 5.-The position of the catheter in relation tothe venous drainage of the pancreas.

achieved by beta cell hyperplasia (Hultquist,Lindgren and Dalgaard, 1946; Cardell, I953b;Woolf and Jackson, 1957; Driscoll and others,I960). This finding implies an increased capacityto secrete insulin (Farquhar, 1959).

Insulin-secreting CapacityThe capacity of the islet beta cells of the new-

born infant of the diabetic woman to respond tothe normal physiological stimulus (i.e. a rise in thelevel of blood glucose) has been tested recentlyby determining both the speed with which anintravenous glucose load is removed from circula-tion and the plasma-insulin activity of venousblood collected close to the point of insulin dis-charge (Fig. 5) immediately before and again fiveminutes after the injection of glucose (Baird andFarquhar, I962).The experiment can be criticized on such

grounds as the admitted inability to provide anentirely satisfactory control group or even on therat-diaphragm technique of assay, but the resultsare quite clear and they suggest that the pancreasof these babies during the first few hours of liferesponds more actively to a rise in blood glucosethan does the pancreas of the normal infant. Theexperiment also excludes the possibility that thehigh plasma-insulin activity produced in the babyis accounted for by the transfer of exogenous orendogenous insulin from the mother.

Possible Causes of Increased InsulinSecretion

Pedersen believes that the maternal blood sugarlevel determines the foetal one, that there is littlelag between the two, and that at birth the baby'sblood glucose falls to a point decided by theaverage prenatal glycoemia. He suggests that thehyperglycemia of maternal diabetes, or pre-diabetes, promotes faetal hyperglycemia, and thatthis so stimulates the ftetal pancreatic beta cellsthat abnormal amounts of insulin are secretedwhich, in the presence of copious glucose, pro-motes foetal obesity. The positive correlation ofislet cell area and birth weight (Cardell, I953b) isin keeping with this thesis.

Fcetal obesity is also accompanied by increasedfretal length, and animal experiment strongly sug-gests that this may also result from increasedinsulin in the presence of abundant food (Far-quhar, I956b), so that the phenomenon of thesleek, fat and proportionately long baby of adiabetic mother may be explicable on hyper-glycmmia and increased insulin activity alone.Among the possible known causes of hyperinsulin-ism which require consideration, the most im-portant are maternal hyperglyceemia, pituitarygrowth hormone, hyperadrenocorticism and theinsulin antagonist which has been so intensivelyinvestigated by Vallance-Owen.

HyperglyceemiaIslet cell hyperplasia has been produced by

maintaining hyperglycxemia in guinea-pigs (Woer-ner, 1938), dogs (Houssay, Foglia, Smyth, Riettiand Houssay, 1942), cats (Dohan and Lukens,1948) and rats (Tejning, I947; Hultquist, I948;Wissler, Findley and Frazier, I949). In Hult-quist's experiments the tissue was taken from theoffspring of rats who had been pancreatectomizedin pregnancy. Hyperglycemia has been doubtedas the cause of increased fcetal weight because ofthe well-known gigantism of babies born to womenwho only became frankly diabetic many yearsafterward and who were not recorded to haveglycosuria in pregnancy. Both Hagbard (1958) andHagen (I96I) have claimed, however, that womenwho bear large infants have higher than normalfasting blood sugars and some decrease in glucosetolerance. This finding may not be shared byeveryone, but such decreased glucose tolerance asthe prediabetic woman may have in pregnancycan be balanced by the increased feetal use ofglucose, so that the maternal level may not riseto the renal threshold unless the glucose load is sosuddenly imposed that her level rises faster thanthe mechanism for maternal-fcetal equilibrationpermits.The ' hyperglycaemia hypothesis' is borne out



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6i6 POSTGRADUATE MEDICAL JOURNAL November I962

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5000 -8 8

4500° r 1334000-

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DIABETES

FIG. 6.-Patterns of family birth weight in prediabeticand diabetic pregnancy.

within certain limits by the experiences first ofPedersen (I952) and Pedersen and Brandstrup(1956), and later of Oakley (I96I), who claimedthat the average birth weight of such infants couldbe reduced to within the normal range by pro-longed very strict control of the maternal glycamiathroughout each 24 hours for much of the preg-nancy.Many people believe that during the pre-

diabetic years maternal glucose tolerance may beprogressively impaired with each pregnancy untilclinical diabetes appears. Were this so, then agradually mounting mean maternal blood sugar ineach pregnancy could be expected, with the con-sequent birth of heavier and heavier babies up tothe point where diabetes is recognized and thematernal hyperglycemia is controlled. But inpractice there are important exceptions to thispattern.Some examples of prediabetic family birth

weights may be seen in Fig. 6. Some women bearinfants of steadily increasing weight, others areremarkably consistent over many years, while withsome the trend is steadily downward, and with yetothers there is no trend at all (Farquhar, I962).Were no other changing factor involved than these,then differing patterns could be explained only bysuch variables as appetite and activity or, lessconspicuously perhaps, on a genetic basis (Pyke,1960).

Pituitary Growth HormoneThe experiments of Young (1953, I96I) suggest

that pituitary growth hormone (PGH) may play apart in causing diabetes mellitus. The administra-tion of purified PGH to pancreatectomized andhypophysectomized baboons causes a rise in bloodsugar and the appearance of ketosis (Gillman,

Gilbert, Epstein and Allan, 1958). Similarly,hypophysectomized human diabetics develop apronounced rise in blood glucose and ketosis whengiven purified human growth hormone (Luft,Ikkos, Gemzell and Olivecrona, 1958; Raben,1959; Hernberg, I960).Using an immunological method for measuring

this hormone, Ehrlich and Randle (I96I) found itincreased in the majority of obese diabetics and indiabetics with retinopathy, but less so or not at allin other diabetics. They suggest that increasedmaternal PGH may be responsible for the largesize of the fcetus in diabetic pregnancy. This possi-bility was discussed by Osler and Pedersen (I960)because they believed fcetal obesity to be incon-sistent with it, the hormone having fat-mobilizingand protein-sparing effects. But Ehrlich andRandle point out that fat mobilization can be sup-pressed if the animal or human has free access toliberal amounts of glucose or food (Salter andBest, 1953; Raben and Hollenberg, I960).Of some interest are the observations that PGH

is strongly lactogenic (Chadwick, Folley and Gem-zell, I96I; Lyons, Li and Johnson, I96I), becauseas a group diabetic women lactate rather poorly(Farquhar, I959). There are individual exceptionsto this rule, and a variety of discouraging factorsexist, among which the physician or obstetricianmay sometimes be numbered. Excessive lactationin prediabetic pregnancy has been suspected byJackson (1952), in whose experience lactationfailed as overt diabetes appeared. But if excessivePGH is directly responsible for fcetal overgrowthin diabetic pregnancy, and if it is truly lactogenic,then failures of maternal lactation would surely beless usual, and there might be feetal breast enlarge-ment and secretion even in the immature new-born, a development which is rare.

Adrenal GlucocorticoidsThe puffy features, plethora and cedematous

appearance of the babies at birth led to their beingdescribed as ' Cushingoid' by Jackson (I955)among others. Unusual hirsutism has been notedby Eklund, Hjelt and Lumme (I960) and Driscolland others (I960). Adrenal glucocorticoids can bediabetogenic to normal human subjects, may ex-aggerate the carbohydrate disorder of diabetic ones,have been reported as increased in diabetes mel-litus, have caused foetal gigantism and intra-uterine death when given to pregnant animals, andcan promote pancreatic islet hypertrophy (Far-quhar, I956b). Increased corticosteroids have beendescribed in the amniotic fluid, the blood or theurine of babies of diabetic mothers by Hoet andLukens (1954), Bjorklund and Jensen (I955),Farquhar (i956b), Klein and Taylor (ig60) and



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FARQUHAR: Maternal Hyperglycemia and Fwetal Hyperinsulinism

Lloyd (I96I), but not in the careful blood studymade by Migeon, Nicolopoulos and Cornblath(I960), nor in the amniotic fluid study by Baird andBush (I960).The recently established findings that such in-

fants are obese and are without increased totalbody water, extracellular water or salt indicate thatany increase in corticosteroids (maternal or foetal)which they possess is unlikely to be great or pro-longed and is not the principal cause of their beta-cell hyperplasia and obesity. This does not excludethe possibility that corticosteroids are active insome other way.

Insulin AntagonistThe existence of an insulin antagonist in normal

human subjects was described by Vallance-Owenand Hurlock (1954). Such an excess of thisantagonist was found in the plasma of hyper-glycoemic diabetics that it could inhibit the actionof added insulin (Vallance-Owen, Hurlock andPlease, I955). It opposes insulin activity in muscle,but not lipogenesis (Pyke and Please, I957). It isfound in the albumin fraction of plasma (Vallance-Owen, Dennes and Campbell, 1958a), is probablyof low molecular weight and may be a polypeptide(Vallance-Owen and Lilley, Ig6Ia). Its action isbelieved by Vallance-Owen, Dennes and Campbell(I958b) to depend upon the pituitary, but Lowy,Blanshard and Phear (I96I) think it may be in-dependent of it. It would seem to be dependentupon adrenal corticosteroids (Vallance-Owen andLilley, I96Ia). High levels of antagonist have beenfound in the plasma of obese diabetics and pre-diabetics (Vallance-Owen and Lilley, ig6ib), andit has been found in the plasma of young untreatedketotic diabetics (Steinke, Taylor and Renold,I96I).Such findings are in keeping with those of

Maclean and Ogilvie (I959) that diabetes in theyoung may be accompanied by initial islet hyper-plasia, and that it may occur in some patients whohave a normal quantity of islet tissue. Thus theantagonist may result in increased secretion ofinsulin which is unblocked or at least less restrictedin lipogenesis than it is in glucose utilization inmuscle. The child or adult becomes obese andlater may develop diabetes, even although islettissue may not decline for some years. The lowmolecular weight of the antagonist makes possibleits transfer across the placenta from prediabeticor diabetic mother to the baby (Vallance-Owenand Lilley, ig6ib), where it would oppose thesecretion of fcetal beta cells, so causing fietalobesity and possibly a true acceleration of lineargrowth if the action of insulin on skeletal growthis uninfluenced by it.

Variable Activity of PGH and the Antagonist inRelation to Fctal Morphology

Both human growth hormone, as a pituitaryproduct, and the antagonist, whose action isdependent upon the pituitary and adrenal cortex,-are probably subject to variations in their amountand activity, and this could explain not onlyspontaneous changes in diabetic control, but aIlothe variable pattern of foetal weight in prediabeticor diabetic pregnancy (Fig. 6).

If increased length for gestational age resultsdirectly from the action of PGH (unmediated byinsulin), then the maintenance of maternal normo-glycamia by strict control in pregnancy shouldresult in the birth of long babies of normal birthweight, whereas if increased length results fromincreased insulin secretion promoted by hyper-glycamia or the antagonist, then such strict controlmay be followed by the birth of infants whoseweight and length are normal for gestation.Further comparison of accurately measured foetallengths and weights is required and the resultsshould be related to the standard of carbohydratecontrol in individual patients.

Perinatal MortalityThe experiences of Pedersen (1952) and of

Oakley (I96I) show that strict control of the preg-nant diabetic's blood glucose, and all t-he extra carethat goes with that, results not only in babies ofmore normal appearance and birth weight, butalso in significant reduction of perinatal mortalityin viable pregnancies. This may suggest that the' hyperglycamia hypothesis' may also explain thehigh incidence of foetal death.

The Time of DeathUntil now appreciably more than half the feetal

deaths which have been reported in most largeseries have occurred in utero, and it is importantthat the pxdiatrician, who may never see themacerated still-births, recognizes this when con-sidering the possible causes of neonatal disturbanceor death. Thus intrauterine death may be in-dependent of the jungle of abnormal findingsdescribed in the live newborn, among which arecongenital malformation, hypoglycewmia, hypo-potassamia, hyperpotasswmia, hypocalcamia,hypoadrenocorticism, hyperadrenocorticism, hypo-tension, pulmonary hyaline membrane, metabolicand respiratory acidosis and hyperbilirubinemia.One or other of these may be productive of symp-toms or even of death, but the fundamental abnor-mality predates their development.

Autopsy FindingsThe post-mortem examination of still-born

infants of diabetic women seldom reveals any ex-

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6i8 POSTGRADUATE MEDICAL JOURNAL November I962

*=SURVIVOR X= DEATH

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4500 Is ~ -II 9

4000 2 - 153500-

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FIG. 7.-Examples of high foetal survival rate at highbirth weight in prediabetic and diabetic pregnancy.

planation for death other than signs of intrauterineanoxia. Neonatal deaths may show similar changes,and pulmonary hyaline membrane is commonlypresent. Congenital malformations have not con-tributed to neonatal mortality in the Edinburghseries, and Cardell (1953a) found significant mal-formations just as commonly in babies of non-diabetic women. In this respect these two studiesare quite different from the Boston one, where anincreased incidence of serious congenital abnor-malities is reported (White, I952; Driscoll andothers, I960). Personal experience of the Bostonseries, however, suggested that, even with thisincreased incidence, less than 20% of the deathscould be explained by lethal malformations.Similarly, although the occurrence of renal veinthrombosis (Takeuchi and Benirschke, I96I) isinteresting, it is extremely rare.

The Role of ObesityOsler and Pedersen (I960) have suggested that

obesity may restrict neonatal respiration and thatbreakdown of excessive glycogen may so releasewater that circulatory difficulty results. This maypossibly contribute to the embarrassment of analready abnormal infant, but experience in thisseries suggests that, if the safe birth of the largerbabies can be assured, then they may make entirelysatisfactory progress. In Fig. 7 examples are givenof several families of such larger babies, only onemember of whom died, and all the others werequite normal in all respects. Indeed, the process ofgrowing heavier and longer because of the stimulusof extra glucose and insulin seems so physiologicalthat it provides a poor explanation for death, andthe babies seem to conform to the principle soclearly enunciated by McCance (I959) and

McCance and Widdowson (I96I) that growth hasprotective properties.

Mortality and Birth WeightIn the large Boston series, perinatal fetal mor-

tality is higher among those diabetic mothers whosuffer from nephropathy, and their babies are sig-nificantly smaller than are those of women whosediabetes is unassociated with such a gross renallesion (Oppe, Hsia and Gellis, I957). But irres-pective of whether the mothers in the Edinburghseries suffered from this complication or not, still-birth, idiopathic respiratory distress and neonataldeath (Fig. 8) have all been much commoneramong babies of less than 3 kg. birth weight thanin heavier infants, even when consideration isgiven only to those of 36 weeks' gestation or more(Farquhar, I959, I962). The perinatal mortalityis also greater in the smaller babies in the Bir-mingham series (Malins, I962). Thus this ex-perience accords with that of Brandstrup, Oslerand Pedersen (I96I), who found a 'middle-cut'of babies within their series who were of a gesta-tional age and birth weight in which mortality waslow. The Edinburgh series suggests further thatit is much safer to be above this optimum weightrange than it is to be below it, and this conflictswith the notion that simple intrauterine over-nutrition is the harmful factor.

Mortality in FamiliesA study of the mortality pattern of families

born to diabetic women varies widely (Fig. 9)from those in which all the babies survive to thosein which all die, and in the io8 families of thisseries 57 mothers have produced i85 babies with-out loss, whereas the other 51 mothers have pro-duced 203 babies with a mortality of 38%(Farquhar, I962).

The Influence of ControlAlthough the standard of both diabetic control

and obstetrical supervision very materially affectsthe prognosis for faetal survival (Farquhar, I959,I962), just as the strictness of carbohydrate controlalone may alter the prognosis for circulatory healthin pure pancreatic diabetes (Duncan, MacFarlaneand Robson, 1958), it is equally clear from thisstudy that some women without nephropathy andwith optimal care may have a dism-al record offoetal loss and that others may be entirely success-ful, although their supervision and co-operationdo not differ. Furthermore, even if diabetic controlis of the very high, almost unique, standardachieved by Pedersen and his colleagues in Copen-hagen, where the mothers are maintained virtuallynormoglycaemic for many weeks until delivery,the viable faetal mortality over a number of years



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~itns*6gFIG. 8.-Maturity, birth weight and survival of infants of diabetic women.

does not fall below 120 per i,ooo (Brandstrup andothers, I96I). This figure is three or four timesgreater than that for non-diabetic pregnancies.Thus it would seem certain that some factor otherthan control of the blood glucose level contributestoward intrauterine death and to those biochemicalor clinical abnormalities which may appear in thelive-born.

Idiopathic Respiratory Distress SyndromeThe idiopathic respiratory distress syndrome

(IRDS) is seen commonly in newborn infants ofdiabetic mothers, and pulmonary hyaline mem-brane is found in from 25 to 75% of the neonataldeaths. In the 95 neonatal deaths described byDriscoll and others (I960), membrane formation ofsome degree was recognized in 75%, it was diffuselypresent in the lungs of 57%, it was the majorautopsy lesion in 5i%, and it existed presumably

in other distressed infants who survived. Theauthors found the lesion to be identical with thatseen in babies of non-diabetic women.The extensive literature about this very im-

portant neonatal problem has been comprehen-sively reviewed by James (I959) and by Gregg andBernstein (I96I). Whatever may be the oetiologicalimportance of such deficiencies as those of thesurface-active mucopolysaccharide material de-scribed by Avery and Mead (I959), which facili-tates lung expansion, or of the plasminogen-plasmin system (Quie and Wannamaker, I960)which promotes the lysis of exuded fibrin, all thatis known of clinical factors common to the twosusceptible groups (prematurely born babies andinfants of diabetic mothers) is that both areimmature, that both are likely to have experiencedintrauterine oxygen-lack of dangerous duration,and that Casarean section may have a provocative



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|xzN.N.D.|177

a 143

-K 141

89M -

0----044

9

8,

20 15 10 5 5 10 15 20 25 30PREDIABETIC 0 DIABETIC

YEARS

FIG. 9.-Patterns of viable foetal mortality in thefamilies of diabetic women.

effect. Infants who are more mature may survivehypoxia and neonatal asphyxia without developingdistress, and those who are less mature may surviveundistressed if the cause of their premature de-livery does not involve intrauterine hypoxia. Aperiod of insufficient placental exchange beforebirth seems to form the foundation upon whichimmaturity of such enzyme systems as these justquoted and the normal post-natal adjustments ofcirculation and of fluid compartments build furthermechanical and metabolic abnormalities with re-sultant hyaline membrane formation. Progressivedegrees of placental disruption were accompaniedby diminishing concentrations of hexosamine(mucopolysaccharide) in the lungs of faetuses andnewborns in the study by Crawford and Mitchell(I962). This may reflect falling concentrations ofthe surface-active material of Avery and Mead(I959), but no correlation was established betweenconcentrations and the occurrence of neonatalrespiratory distress. The authors indicate, how-ever, that the series may be too small and thatautopsy analyses do not necessarily mirror the'live ' situation. It is also interesting to recall inthis connection that the incidence both of IRDSand of neonatal death in this series is higher ininfants of less than 3,000 g. birth weight, and thatGruenwald (I960) has shown that the surface-active material in lung is uniformly present inbabies who weigh 3,000 g. or more. This is againinconsistent with the belief that babies who havebeen fattened and forced in growth with glucoseand insulin should have an increased incidence ofrespiratory distress and neonatal death.

The present evidence fits the hypothesis thatneonatal disturbance and mortality result from pre-natal under-nutrition and impaired exchange ofoxygen and carbon dioxide caused by placental in-sufficiency and that their rarer occurrence in obeseinfants may be due either to difficult and thereforeanoxic birth or to late failure of a placenta uponthe efficient performance of which a macrosomaticinfant depends. Once respiratory distress hasdeveloped, however, the conditions which prevailin babies of diabetic women may increase the diffi-culty. A study of the various large autopsy seriesalready quoted will show that there is no goodevidence for the existence of increased glycogenin these infants. They are known to raise theirblood sugars at an unstated time after birth inresponse to adrenalin (Reardon, 1958), but thebetter documented study of Cornblath, Nicolo-poulos, Ganzon, Levin, Gordon and Gordon(i96I) has shown not only that spontaneously borninfants of diabetic mothers have a hyperglycammicresponse to glucagon which is similar to that pro-voked in those born by the same route to non-diabetic women, but that those delivered byCasarean section require a ten-fold increase inglucagon dosage to achieve the same result, whileCornblath gained the impression that infants withdistress were less responsive to the hormone thanwere asymptomatic babies. Although the histo-logical studies may imply simply that the excessiveglycogen was used before the infants died, it couldbe a point against the simple maternal-hyper-glycaemia-fetal hyperinsulinism hypothesis and infavour of activity of the maternal insulin antagonistwithin the fietus. Furthermore, the need of thesedistressed infants to use their fat, of which theyhave more than their share, for energy may requirethat they obtain more oxygen than the metabolismof glycogen would need at a time when pulmonaryexchange is inadequate and releases more waterthan would glycogen at a time when the circulationis already embarrassed.

The Placenta and Micro-circulation in DiabetesAlthough the ratio of faetal to placental weight

is similar in deaths and survivors and does notdiffer from that in non-diabetic pregnancy, pla-cental structure and function have attracted muchinterest in diabetes, and the possibility of pre-mature placental ageing and consequent insuf-ficiency resulting in foetal starvation and anoxia,often slowly but sometimes abruptly, has been dis-cussed (Farquhar, 1959).The hormonal replacement therapy used by the

Joslin Clinic to correct a suspected imbalancearising out of placental insufficiency has failed tomeet with universal acclaim and it certainly fails toprevent faetal death or idiopathic respiratory



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FARQUHAR: Maternal Hyperglyceemia and Fcetal Hyperinsulinism

distress. Calcification of the maternal pelvicvessels, reported in Boston (White, 1952), is rarelyfound in Edinburgh and so provides no explana-tion for the foetal mortality in this series.* Theextensive extra-medullary erythropoiesis whichexists at birth, the considerable normoblastaemiaand raised hemoglobin have been ascribed to intra-uterine hypoxia (Miller, Johnson and Durlacher,I944; Given and others, 1950; Berglund andZetterstrom, 1954). Reduced availability of oxygento the fietus was demonstrated in diabetic preg-nancy by MacKay (1957) and the normal myo-metrial blood flow found by Brudenell, Miles andColeman (i96i) cannot exclude possible poortransfer of oxygen and nutrients across theplacenta.

Earlier histological studies of the placenta indiabetes were unrevealing except for an un-confirmed suggestion of abnormal stromal cedemamade by MacKay (I952). More recently Burstein,Soule and Blumenthal (I957) have found that,unlike those of either normal or hypertensive-toxacmic groups, the placentae of about one-thirdof diabetic women show marked endarteriticlesions of vessels which may progress to vascularobliteration or thrombosis and true infarct forma-tion. But whatever the larger vessels of maternalorigin may show, general recognition is now givento the early widespread involvement of the venules,capillaries and arterioles throughout the body inthis condition (Colwell, I960). This may be seenin the small vessels of the bulbar conjunctiva ifgood equipment is used (Ditzel, White andDuckers, 1954; Ditzel, 1956; Ditzel and Moinat,1957; Bech, Hansen, Lorentzen and Lundbaek,I960; Ditzel, Beaven and Renold, I960; Landauand Davis, I960; Farquhar, I962). Electronmicroscope studies of diabetic kidney have shownthat thickening of the basement membrane up toten times normal may exist in all glomeruli(Farquhar, Hopper and Moon, I959). Earlierlesions take the form of small deposits of hyalinein close relation to the basement membrane andbetween the cell membranes of adjacent endo-thelial cells. These deposits expand and isolateendothelial cytoplasm until the capillary lumen isobliterated. Sabour (I96I), Sabour, Nagy ElMahallawy and Abou-El-Naga (I96I) and Mac-Donald (I962) have confirmed these findings inrenal biopsy material from young Edinburghpatients with recent onset diabetes and have shownthat the abnormalities are probably almost orentirely coincidental with the onset of the metabolicdisturbance. Simultaneous studies of conjunctival

* Such differences between various centres are prob-ably real. The Joslin Clinic must attract previously un-successful cases from all over the United States.

and nail-bed vessels by Landau and Davis (I960)have revealed what has been called the basicdiabetic lesion, capillary congestion on the venousside, severe capillary narrowing and conjunctivalmicropools. Light- and electron-microscopestudies of toe and finger pulp capillaries fromdiabetics by Aagenaes and Moe (I96I) revealed aperi-endothelial PAS-positive material in manyspecimens. This abnormality was particularlypronounced in those patients whose disease hadbegun before the age of 40 and where retinopathyand nephropathy were present. In the worst casesthe PAS-positive layer was more than ten timesthicker than the normal basement membrane.The delicate micro-vessels in the fuetal placental

villi by means of which supply and excretion aremaintained are exposed to a continuous high-pressure flow of diabetic blood. It seems reasonableto expect that as part of an organ which may ageprematurely even in apparently normal pregnancy,and more commonly in toxamia, these micro-vessels may undergo the same sort of subtle changewhich electron-microscopy has revealed in capil-laries elsewhere, and which could interfere withfcetal nutrition and excretion and even withsurvival.

Plasma Protein Abnormalities(a) In the Diabetic Mother. The literature on

protein, lipoprotein and protein-bound carbo-hydrate abnormalities in the serum of diabeticpatients has been extensively reviewed by ljarque,Marble and Tuller (1959), and they make it clearthat these protein fractions can be abnormal beforeclinical evidence of vascular complications appears.In their own study of sera from young diabeticsthey have found decreased albumin, increaseda2-globulin, raised p- and reduced oc-lipoproteinsand increased x2-glycoproteins, particularly inthe presence of vascular complications. Ditzeland Moinat (I957) have shown that in diabeticpregnancy great increases in maternal 5-lipoproteinand oX2-glycoprotein fractions are also possibleduring the last trimester in association withchanges in the small vessels of the bulbar con-junctiva, but they were unable to relate thesefindings to the outcome of pregnancy.The abnormal serum lipoprotein component,

pre-3-lipid (p-P-l), which is known to occur inpatients with clinical coronary artery disease, hasbeen studied in diabetic pregnancy by Vernet andSmith (I96I). Whatever its relationship to thedevelopment of vascular complications, it wasfound to increase in successful diabetic pregnanciesfrom the 25th week, to be considerably elevatedat term and to fall rapidly after delivery. In un-successful diabetic pregnancies, however, thep-r-l was found to be slightly raised even before

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250- CHOLESrEROL 250- PHOSPHOLIPID

INFANTS OF

--_~JAA~DL4ABTIC MOTHERS0 - " | 6 i,NORMAL INFANTS

~100, O

50 50

O C ' ' C , ., *,,Ub5 1 2 3 4 5 6 7 DAY5 1 2 3 4 5 6 7

30 -LOPROTEIN UPID 300- -UPOPROTEIN LIPID

250

-2O- 0-200 ~'-LIPOPR0TEiN LFIO

w,... c a e -

5110 150 -so50

Y1 2 34 5 67 DAYS12 3 4567 DAYS S1234 5 67

FIG. io.-Changes in serum lipid and lipoprotein lipid concentrations during the first week oflife in infants of diabetic mothers and in normal infants.

the z5th week and to increase through the lasttrimester to a very high level in the first two weeks'post-partum. This abnormality is not associatedwith poor diabetic control and, although the studyfailed to establish a relationship between p-3-llevels and recognizable vascular lesions, this doesnot exclude the existence of subtle but importantchanges in the placenta.

(b) In the Newborn Infants of Diabetic Women.We have been unable to distinguish much variationof cholesterol, phospholipid, cx-, P- or y-lipo-protein levels from normal values in cord blood in aseries of i i asymptomatic babies of diabeticmothers (Fig. io), although the mean pattern invenous blood varied from the normal (as deter-mined by Rafstedt and Swahn, I954) during thefirst week (Lloyd, I96I).

Elevation of certain glycoprotein fractions hasbeen recognized in adults with clinical signs ofdegenerative vascular disease, and the serum ofnewborn infants of diabetic women has beenstudied by Sirek, Sirek and Liebel (I96I), whodetermined the hexose, hexosamine and sialic acidcontents of the carbohydrate moiety conjugatedwith serum proteins (glycoproteins). All theseconstituents were found to be significantly elevated

in infants whose mothers had no signs of degenera-tive vascular disease, had uneventful pregnanciesuncomplicated by ketoacidosis or hypoglycemiaand had glycoprotein values similar to the pregnantnon-diabetic woman at term. As in our own series,the babies who were studied ran normal neonatalcourses and the raised levels were attributed torapid tissue growth in macrosomic infants.

Possible Inherited Abnormality of Fcetal TissueThe PAS-positive material found in intimate

relationship with capillary endothelium in diabetesmay be the extracellular product of neighbouringcells which are inherently abnormal in this con-dition or else the response of normal cells to anabnormal milieu. Thus fcetal and fcetal placentaltissue affected by an inherited metabolic disorder,probably in mucopolysaccharide metabolism,could respond to some diabetogenic factor in thematernal blood with lesions capable of interferingwith placental function. In this respect it is worthnoting that, although the work of Ditzel and others(I954) has not yet been confirmed, they describeda variety of 'diabetic' changes in the micro-circulation of the bulbar conjunctiva in from one-quarter to almost one-half of young asymptomatic



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children of diabetic mothers and established apositive correlation between the degree of thesevascular changes and prediabetic glucose tolerancetests. Although purely speculative, this hypothesisthat ftetal tissue which is inherently abnormal itselfmay respond in a dangerous way to the diabeticmilieu has the merit of explaining the inconsis-tencies of fcetal mortality in a population most ofwhom are presumably diabetic for a similar if notidentical cause, whether this be the existence of theinsulin antagonist or an excess of human growthhormone with or without the participation ofadrenal corticosteroids. And as all these factorsmay cross the placenta, perhaps we should submitthe capillaries of these infants to electron-micro-scopy if the placental villi present too great a prob-lem for this technique.

ManagementIn the light of these factual and speculative con-

siderations brief comment may be made onmanagement of the diabetic woman and her new-born child.

Diabetic ControlThe diabetic should be maintained as nearly

normoglycamic as possible and ketone-free duringthe last two months of pregnancy. Pedersen (1952)aimed at very careful supervision for about 20weeks prior to delivery and during the latter halfof this time the woman was in hospital. Insulin isadjusted by him according to blood sugar deter-minations carried out four times daily. Thisstandard of control is exceptional elsewhere, butthe evidence strongly suggests that it should beour aim. And with this the fcetal mortality can bereduced to a figure below which it seems impossibleto lower it by carbohydrate control alone

Avoidance of Drugs Toxic to the FaetusThe great majority of diabetic women must have

dietary control and insulin during pregnancy. Buta woman may also have drugs which affect carbo-hydrate metabolism, which relieve anxiety, whichdeal with urinary infection, which effect diuresisor lower blood pressure, which are designed tocorrect anaemia, and so forth. The possible terato-genic effects of tolbutamide and its relatives (DeMeyer, I96I) are currently under discussion, butthere are many other harmful things which thepregnant diabetic may be given (Lancet, I96I,I962), and nowhere does a greater need exist forthe closest co-operation between general prac-titioner, consultant physician, obstetrician, pwdia-trician and others on prescribing and record-keeping.

Obstetric CareAnte-natal care must be regular and for the

last six weeks or more will be in hospital. Toxoemia,hypertension, hydramnios and other complicationsof pregnancy which significantly alter diabeticperinatal mortality must be recognized early anddealt with suitably.The time and method of delivery will be in-

fluenced by parity, by past obstetric history, bythe existence of pregnancy complications and bythe growth of the fretus. Where history and ex-amination indicate maternal good health, excellentcontrol and successful fletal growth as estimatedroughly by size and possibly by X-ray, then thenearer the obstetrician may approach towardplanning vaginal delivery at term. The majority ofclinics are likely to permit this only where the pastobstetric history is excellent, and they are likelyto undertake premature induction of labour orabdominal delivery at about 37 weeks for allothers. On the other hand, a poor past obstetrichistory, the presence either of factors likely toimpair placental function or of such an indicationof placental insufficiency as failure of foetal growth,are all indications for early delivery by meanswhich will avoid as far as is possible intra-partumanoxia. The exact timing of this between 35 and 37weeks is a skill developed by long obstetrical ex-perience. The practice of permitting placentaltransfusion of the infant by delaying clamping ofthe cord should be observed with care. Personalexperience no more than suggests that someinfants of diabetic mothers, possibly those whohave been hypoxic and who have a raised hamato-crit, may be distressed by this extra load.

Care of the NewbornThe principles of management are those for all

newborn infants and include gentle warm handling,the assurance of a clear airway and the earlyoxygenation of the baby, using such modernmethods as are indicated. We have not found thatany advantage follows emptying the baby's stomachat birth (Farquhar, I959), but experience suggeststhat the average volume of gastric contents at birthmay vary widely in different hospitals and possiblywith control and the technique of delivery.*The baby should then be kept under very close

observation for some days. The Edinburgh prac-tice is to place the nude infant in an ' Isolette ' atan environmental temperature of from 85 to go°F.,

* I should like to say in passing that we can never bequite certain that personal observations and practicesare applicable everywhere else, e.g. the urine volume ofinfants of diabetic mothers in Edinburgh during thefirst 24 hours is only a fraction of what it is in twoAmerican centres, and this seems to depend upon thevolumes of intravenous fluid given to mothers in thehours befcre delivery.

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depending on birth weight, where he is watchedcontinuously by a personal nurse for about fourdays and certainly until 24 to 48 hours of feedinghave been accomplished without incident. En-vironmental temperature may be reduced graduallyif the baby is well established or showing signs ofbeing too hot, and after four days he is transferredto a cot. Oxygen is not given as a routine exceptin the minutes following delivery.

HypoglyccemiaAn earlier study, in which the literature up

until that time was reviewed, failed to show that thesubnormal blood sugar levels achieved by theseinfants were productive of symptoms, and on thisevidence the common practice of giving glucosefrom birth by one or other route was discontinued(Farquhar, 1956a). Although the evidence onwhich this policy was based has been criticizedby Cornblath and others (I96I) largely on thegrounds of the blood sugar method then available,we have not as yet altered the practice of allowingthe hypoglycamia to correct itself spontaneouslyduring the first few hours. Thus we give neitherglucose nor a glycogenolytic agent, such asglucagon. During the recent study by Baird andFarquhar (I962) very low levels of blood glucose,determined by an enzyme technique, were foundin quite asymptomatic babies, and an extensivepersonal series being conducted at present by thesame method has shown that asymptomatic levelsbelow 20 mg./ioo ml. are common and that theycan be unproductive of symptoms below I0mg./ioo ml. Experience, however, has also con-firmed the finding of Cornblath, Odell and Levin(I959) that occasionally the newborn babies ofnon-diabetic mothers car' be symptomatic as aresult of prolonged hypog]ycormia and that theycan be relieved by raising the blood glucose. Thisis a complicated problem which requires furtherclarification, but perhaps the very low levelsachieved by infants of diabetic mothers in thisseries may be too brief to provoke a clinicalresponse. And yet the possible need of these babiesto burn fat and protein in the presence of poorpulmonary exchange may indicate a need forglucose even where a normal blood glucose exists.

Idiopathic Respiratory Distress SyndromeWater and detergent aerosols were shown by

Hsia, Peterson and Gellis (1957) not to influencethe respiratory distress of these babies. There arecertainly other measures now available, and timeis likely to show that one or other of them is muchmore effective. The intravenous correction ofacidosis by sodium and of tissue breakdown andrising potassium levels by glucose (monitored bystudies of blood pH, Pco2 and oxygen saturation)

is now being practised by many people in additionto Usher (1959), and opinion varies from con-servatism to enthusiasm, with the latter gainingground.

FeedingPractice during the past I5 years with regard to

feeding has swung from starting within minutes ofdelivery to delaying until the fourth or fifth day.The evidence now suggests that there is merit instarting careful oral feeding at from 24 to 48 hoursof age, dependent upon the baby's condition.Some may practise intravenous feeding withinhours of the baby's birth if they are convinced bythe findings of Carrington, Shuman and Reardon(I957) and Reardon (1958). The Boston Lying-inHospital study published by Rudolph, Hubbell,Drorbaugh, Cherry, Auld and Smith (I959) andby Hubbell, Drorbaugh, Rudolph, Auld, Cherryand Smith (I96I), in which cases were allocated atrandom to early and late feeding groups, has failedto confirm Reardon's claim that early feedingreduces mortality and, indeed, more deathsoccurred in the ' early feeders ' than in the ' late ',although this result did not achieve statistical sig-nificance in view of the relatively small number ofdeaths involved. The principal difference betweenthe two groups lay in the significantly higher levelof unconjugated bilirubin in the ' late feeders ',but exchange transfusion for an idiopathic rise ofunconjugated bilirubin of 20 mg./ioo ml. has beennecessary only once in the Edinburgh series. Whenfeeding is introduced early the baby must be undercontinuous observation so that inhalational in-cidents may be treated with immediate efficiency.

InfectionThe incidence of staphylococcal infection has

been variable in this series over the years. Theymay be a little more susceptible, but then they haveoften been handled a great deal, exposed to a highenvironmental temperature and submitted to de-hydration. They should be examined carefully atleast once daily for any abnormality and particu-larly for infection at all sites, including the lungs,whether or not there has been so-called idiopathicrespiratory distress.

Summary(i) Babies of diabetic mothers are fatter, longer

and more likely to become hypoglycemic thanthose of normal mothers. Their pancreatic hist-ology suggests increased beta-cell activity anddirect evidence exists of increased capacity tosecrete insulin.

(2) These findings are in keeping with thematernal hyperglycaemia-faetal hyperinsulinismhypothesis.

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(3) Possible reasons for maternal hyperglycemiaare reviewed, including abnormal Human GrowthHormone and corticosteroid activity and also theexistence of an Insulin Antagonist.

(4) The hypothesis does not explain easily thehigh perinatal mortality.

(5) Placental function may become inadequatein some pregnancies, possibly because the organ'sshort-lived micro-circulation becomes involved inthe general small vessel changes of diabetesmellitus. This might be more likely where placentalcells inherit the basic diabetic abnormality.

(6) The management of diabetic pregnancy andthe newborn infant is briefly reviewed.

I should like to thank the Postgraduate Board of theUniversity of Cambridge for the invitation to read thispaper, Professor Richard Ellis for his continued supportof this study, and Dr. Robertson F. Ogilvie for hisadvice on fcetal pancreatic histology. I am grateful toDr. John Hubbell, Jr., of the Boston Lying-in Hospital,for making available to me further length measurements,to Drs. Beverley Fee and William Weil for giving mefurther information about their direct analyses of infantsof diabetic mothers, and to my colleague, Mrs. AnnLloyd, for permission to quote figures from her work.I am indebted to Miss Elizabeth Meiklejohn for muchsecretarial help, and to the editors of the Lancet and ofthe Archives of Disease in Childhood for permission toreproduce Fig. 5 and Figs. 3 and 8 respectively.

REFERENCESAAGENAES, O., and MOE, H. (I96I): Light- and Electron-Microscopic Study of Skin Capillaries of Diabetics, Diabetes,

1O, 253.AVERY, M. E., and MEAD, J. (1959): Surface Properties in Relation to Atelectasis and Hyaline Membrane Disease,

Amer. 3. Dis. Child., 97, 517.BABBOTT, D., RUBIN, A., and GINSBURG, J. (1958): The Reproductive Characteristics of Diabetic Men, Diabetes, 7, 33.BAIRD, C. W., and BUSH, I. E. (I960): Cortisol and Cortisone Content of Amniotic Fluid from Diabetic and Non -

Diabetic Women, Acta endocr. (Kbh.), 34, 97.BAIRD, J. D., and FARQUHAR, J. W. (I962): Insulin-Secreting Capacity in Newborn Infants of Normal and Diabetic

Women, Lancet, i, 71.BECH, K., HANSEN, E., LORENTZEN, S. E., and LUNDBAEK, K. (I960): The V/A Ratio of the Smaller Vessels of the

Bulbar Conjunctiva in Diabetes Mellitus, Diabetes, 9, 44I.BENNEWITZ, H. G. (I828): Symptomatic Diabetes Mellitus: Report of a case described by Bennewitz in Osann's

'I2ter Jahresbericht des Poliklinischen Institutes zu Berlin', p. 23, Edinb. med. 3., 30, 217.BERGLUND, G., and ZETTERSTROM, R. (1954): Infants of Diabetic Mothers: I. Faetal Hypoxia in Maternal Diabetes,

Acta peediat. (Uppsala), 43, 368.BJORKLUND, S. I., and JENSEN, C. C. (I955): Infants of Diabetic Mothers, with Special Reference to Neonatal Adreno-

cortical Function as Assessed by Urinary Excretion of I7-Ketosteroids, Acta endocr. (Kbh.), I8, I33.BRANDSTRUP, E., OSLER, M., and PEDERSEN, J. (196I): Perinatal Mortality in Diabetic Pregnancy: The Relationship

to Management during Pregnancy and to Faetal Age and Weight, Ibid., 37, 434.BRUDENELL, J. M., MILES, J. M., and COLEMAN, A. (I96I): The Clearance of Radioactive Sodium from the Myometrium

of the Pregnant Diabetic, Y. Obstet. Gynaec. Brit. Comm., 68, 238.BURSTEIN, R., SOULE, S. D., and BLUMENTHAL, H. T. (1957): Histogenesis of Pathological Processes in Placentas of

Metabolic Disease in Pregnancy: II: The Diabetic State, Amer. 3. Obstet. Gynec., 74, 96.CARDELL, B. S. (I953a): The Infants of Diabetic Mothers: A Morphological Study,3. Obstet. Gynaec. Brit. Emp., 60, 834.

(I953b): Hypertrophy and Hyperplasia of the Pancreatic Islets in Newborn Infants, Y. Path. Bact., 66, 335.CARRINGTON, E. R., SHUMAN, C. R., and REARDON, H. S. (1957): Evaluation of the Prediabetic State during Pregnancy,

Obstet. and Gynec., 9, 664.CHADWICK, A., FOLLEY, S. J., and GEMZELL, C. A. (I96I): Lactogenic Activity of Human Pituitary Growth Hormone,

Lancet, ii, 24I.COLWELL, A. R. (I960): Histology of Small Blood Vessel Disease in Diabetes, Diabetes, 9, 503.CORNBLATH, M., NICOLOPOULOS, D., GANZON, A. F., LEvIN, E. Y., GORDON, M. H., and GORDON, H. H. (1I96I):

Studies of Carbohydrate Metabolism in the Newborn Infant: IV. The Effect of Glucagon on the Capillary BloodSugar in Infants of Diabetic Mothers, Pediatrics, 28, 592., ODELL, G. B., and LEVIN, E. Y. (1959): Symptomatic Neonatal Hypoglycemia Associated with Toxemia ofPregnancy, 3. Pediat., 55, 545.

CRAWFORD, J. S., and MITCHELL, P. E. G. (I962): Hexosamine Concentration in the Lungs of Foetuses and Neonates,Lancet, i, 250.

DE MEYER, R. (I96I): E'tude Experimentale de la Glycoregulation Gravidique et de L'Action Teratogene des Per-turbations du Metabolisme Glucidique. Bruxelles: Editions Arscia S.A.

DITZEL, J. (1956): Angioscopic Changes in the Smaller Blood Vessels in Diabetes Mellitus and their Relationship toAgeing, Circulation, 14, 386.BEAVEN, D. W., and RENOLD, A. E. (I960): Early Vascular Changes in Diabetes Mellitus, Metabolism, 9, 4oo.and MOINAT, P. (1957): The Responses of the Smaller Blood Vessels and Serum Proteins in Pregnant DiabeticSubjects, Diabetes, 6, 307.WHITE, P., and DUCKERS, J. (1954): Changes in the Pattern of the Smaller Blood Vessels in the Bulbar Conjunctiva

in Children of Diabetic Mothers, Ibid., 3, 99.DOHAN, F. C., and LUKENS, F. D. W. (1948): Experimental Diabetes Produced by the Administration of Glucose,

Endocrinology, 42, 244.DRISCOLL, S. G., BENIRSCHKE, K., and CURTIS, G. W. (I960): Neonatal Deaths Among Infants of Diabetic Mothers,

Amer. 3. Dis. Child., IOO, 8 I 8.



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DUBREUIL, G., and ANDERODIAS, J. (1920): Ilots de Langerhans Geants Chez un Nouveau-ne de Mere Glycosurique,C.R. Soc. Biol. (Paris), 83, I490.

DUNCAN, L. J. P., MACFARLANE, A., and ROBSON, J. S. (958) Diabetic Retinopathy and Nephropathy in PancreaticDiabetes, Lancet, i, 822.

EHRLICH, R. M., and RANDLE, P. J. (I96I): Serum Growth Hormone Concentrations in Diabetes Mellitus, Ibid., ii, 233.EJARQUE, P., MARBLE, A., and TULLER, E. F. (1959): Proteins, Lipoproteins and Protein-bound Carbohydrates in the

Serums of Diabetic Patients, Amer. 3r. Med., 27, 221.EKLUND, J., HJELT, L., and LUMME, T. (I960): Hirsutism in the Children of Diabetic Mothers, Ann. Padiat. Fenn.,

6, 233.ELLIS, R. W. B. (I95): Assessment of Prematurity by Birth Weight, Crown-Rump Length and Head Circumference,

Arch. Dis. Childh., 26, 411.FARQUHAR, J. W. (I956a): The Significance of Hypoglycemia in the Newborn Infant of the Diabetic Woman, Ibid.,

31, 203.(I956b): The Possible Influence of Hyperadrenocorticism on the Fcetus of the Diabetic Woman, Ibid., 31, 483.(I958a): The Child of the Diabetic Woman, M.D. Thesis, University of Edinburgh.(I958b): Unpublished data.(1959): The Child of the Diabetic Woman, Arch. Dis. Childh., 34, 76.(I962): Birth Weight and Survival of Babies of Diabetic Women, Ibid., 37, 321.and SKLAROFF, S. (I958): Post-natal WVeight Loss of Babies Born to Diabetic and Non-Diabetic Womren, Ibid.,

33, 323.FARQUHAR, M. G., HOPPER, J., and MOON, H. (1959): Diabetic Glomerulosclerosis: Electron and Light Microscopic

Studies, Amer. Y. Path., 35, 721.FEE, B., and WEIL., W. B. (I960): Body Composition of a Diabetic Offspring by Direct Analysis, Amer. Y. Dis. Child.

100, 7i8.(I962): Personal communication.

FERNER, H. (1952): ' Das Inselsystem des Pankreas '. Stuttgart: Gcorg Thieme.FISCHER, L. (1935): Riesenkinder bei miitterlichem Diabetes, Zbl. Gynak., 59, 249.GELLIS, S. S. (1954): in' Textbook of Pediatrics ' by W. E. Nelson, 6th edition. London: Saunders.

, and HsIA, D. Y.-Y. (1959): The Infant of the Diabetic Mother, Amer. Y. Dis. Child., 97, I.GILLMAN, J., GILBERT, C., EPSTEIN, E., and ALLAN, J. C. (1958): Endocrine Control of Blood Sugar, Lipamia, and

Ketonaemia in Diabetic Baboons, Brit. med. 5., ii, 1260.GIVEN, W. P., DOUGLAS, R. G., and TOLSTOI, E. (I950): Pregnancy and Diabetes, Amer. Y. Obstet. Gynec., 59, 729.GREGG, R. H., and BERNSTEIN, J. (I96I): Pulmonary Hyaline Membranes and the Respiratory Distress Syndrome,

Amer. Y. Dis. Child., 102, 871.GRUENWALD, P. (I960): Prenatal Origin of the Respiratory Distress (Hyaline-Membrane) Syndrome of Premature

Infants, Lancet, i, 230.HAGBARD, L. (1958): The ' Prediabetic ' Period from an Obstetric Point of View, Acta obstet. gynec. scand., 37, 497.HAGEN, A. (I96I): Blood Sugar Findings during Pregnancy in Normals and Possible Prediabetics, Diabetes, 1O, 438.HALLMAN, N., FURUHJELM, U., HARRI, J., and PURANEN, J. (1956): Blood Sugar and Other Reducing Substances in

Children of Diabetic Mothers, Ann. Paediat. Fenn., 2, 249.HERNBERG, C. A. (I960): The Effect of Human Growth Hormone on Severe Juvenile Diabetes after Hypophvsectomy,

Acta endocr. (Kbh.), 33, 559.HOET, J. P., and LUKENS, F. D. W. (1954): Carbohydrate Metabolism during Pregnancv, Diabetes, 3, I.HOUSSAY, B. A., FOGLIA, V. G., SMYTH, F. S., RIETTI, C. T., and HOUSSAY, A. B. (i942): Hypophysis and Secretion

of Insulin, 5. exp. Med., 75, 547.HsIA, D. Y.-Y., PETERSON, H. G., and GELLIS, S. S. (1957): Controlled Clinical Trials on the Effect of Water Vapour

Mist on Respiratory Distress in Infants of Diabetic Mothers, Pediatrics, 20, 234.HUBBELL, J. P., DRORBAUGH, J. E., RUDOLPH, A. J., AULD, P. A., CHERRY, R. B., and SMITH, C. A. (I96I): 'Early'

versus ' Late' Feeding of Infants of Diabetic Mothers, New Engl. 5'. Med., 265, 835.HUGGETT, A. ST. G., and NIXON, D. A. (I957): Use of Glucose Oxidase, Peroxidase and O-Dianisidine in Determination

of Blood and Urinary Glucose, Lancet, ii, 368.HULTQUIST, G. T. (1948): An Investigation on Pregnancy in Diabetic Animals, Acta path. microbiol. scand., 25, 131.

LINDGREN, I., and DALGAARD, J. B. (1946): Congenital Hyperplasia of Islands of Langerhans with Increase in5 Cells in Fretuses of Diabetic Mothers, Nord. Med., 31, I841.

JACKSON, W. P. U. (1952): Studies in Pre-diabetes, Brit. med. 5'., ii, 69o.(1955): A Concept of Diabetes, Lancet, ii, 625.

JAMES, L. S. (1959): Physiology of Respiration in Newborn Infants and in the Respiratory Distress Syndrome, Pediatrics,24, IO69.

KLEIN, R., and TAYLOR, P. (I960): 17-HYdroxycorticosteroids in Blood of Diabetic Mothers and their Offspring,Ibid., 26, 333.

KULWICH, R., FEINSTEIN, L., GOLUMBIC, C., HINER, R. L., SEYMOUR, W. R., and KAUFMAN, W. R. (I961): Relationshipof Gamma-ray Measurements to the Lean Content of Hams, 5. Animal Sci., 20, 497.

Lancet Editorial (I96I): latrogenic Diseases of the Newborn, Lancet, ii, 753.(I962): Thalidomide and Congenital Malformations, Ibid., i, 307.

LANDAU, J., and DAVIS, E. (I960): The Small Blood-vessels of the Conjunctiva and Nail-bed in Diabetes Mellitus, Ibid.,ii, 73I.

LEE, M. O., and SCHAFFER, N. K. (1934): Anterior Pituitary Growth Hormone and Composition of Growth, 5. Nutr.,7, 337.

LLOYD, A. V. (I96I): Unpublished data.Lowy, C., BLANSHARD, G., and PHEAR, D. (I96I): Antagonism of Insulin by Albumin, Lancet, i, 802.LUFT, R., IKKOS, D., GEMZELL, C. A., and OLIVECRONA, H. (1958): Effect of Human Growth Hormone in Hypophysec-

tomized Diabetic Subjects, Ibid., i, 721.



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November I962 FARQUHAR: Maternal Hyperglycemia and Fcetal Hyperinsulinism 627

LYONS, W. R., Li, C. H., and JOHNSON, R. E. (I96I): Proc. 43rd Meeting Endocr. Soc. N. Y.MCCANCE, R. A. (1959): The Maintenance of Stability in the Newly Born: I. Chemical Exchange, Arch. Dis. Childh.,

34,36I.and WIDDOWSON, E. M. (I96I): Mineral Metabolism of the Fcetus and Newborn, Brit. med. Bull., 17, 132.

MAcDONALD, M. (i962): Conference on Disorders of Carbohydrate Metabolism, Royal College of Physicians, Lancet,i, 794.

MACKAY, D. G. (1952): Reported by P. White in 'Treatment of Diabetes Mellitus' by E. P. Joslin, gth editionLondon: Kimpton.

MACKAY, R. B. (I957): Observations on the Oxygenation of the Fcetus in Normal and Abnormal Pregnancy, J. Obstet.Gynec. Brit. Emp., 64, I85.

MACLEAN, N., and OGILVIE, R. F. (1959): Observations on the Pancreatic Islet Tissue of Young Diabetic Subjects,Diabetes, 8, 83.

MALINS, J. M. (I 962): Conference on Disorders of Carbohydrate Metabolism, Royal College ofPhysicians, Lancet, i, 794.MARESH, M. M. (I96I): Bone, Muscle and Fat Measurements, Pediatrics, 28, 971.MIGEON, C. J., NICOLOPOULOS, D., and CORNBLATH, M. (I960): Concentrations of I7-Hydroxycorticosteroids in the

Blood of Diabetic Mothers and in Blood from the Umbilical Cords of their Offspring at the Time of Delivery,Ibid., 25, 605.

MILLER, H. C., HURWITZ, D., and KUDER, K. (1944): Fetal and Neonatal Mortality in Pregnancies Complicated byDiabetes Mellitus, J. Amer. med. Ass., 124, 271., JOHNSON, R. D., and DURLACHER, S. H. (1944): A Comparison of Newborn Infants with Erythroblastosis Fetaliswith those Born to Diabetic Mothers, J. Pediat., 24, 603.

OAKLEY, W. G. (I961): Panel Discussion on Diabetes during Gestation and its Influence on Fcetal Pathology andNeonatal Behaviour, IVth Congress of the International Diabetes Federation, Geneva.

OGILVIE, R. F. (1958): Personal communication.OppE, T. E., HsIA, D. Y.-Y., and GELLIS, S. S. (1957): Pregnancy in the Diabetic Mother with Nephritis, Lancet, i, 353.OSLER, M. (ig6oa): Body Water of Newborn Infants of Diabetic Mothers, Acta endocr. (Kbh.), 34, 26I.

(ig6ob): Body Fat of Newborn Infants of Diabetic Mothers, Ibid., 34, 277.and PEDERSEN, J. (I960): The Body Composition of Newborn Infants of Diabetic Mothers, Pediatrics, 26, 985.

PEDERSEN, J. (1952): ' Diabetes and Pregnancy: Blood Sugar of Newborn Infants'. Copenhagen: Danish SciencePress.(1954): Weight and Length at Birth of Infants of Diabetic Mothers, Acta endocr. (Kbh.), I6, 330.and BRANDSTRUP, E. (1956): Faetal Mortality in Pregnant Diabetics, Lancet, i, 607.

PEEL, J. H., and OAKLEY, W. G. (1950): The Management of Pregnancy in Diabetics, Trans. I2th Brit. Congr. ObstetGynaec., London, p. i6i.

PYKE, D. A. (I960): The Genetics of Heavy Babies. Meeting of the Scientific Section of the British Diabetic Association,Glasgow., and PLEASE, N. W. (I957): Obesity, Parity and Diabetes, 5'. Endocr., 15, 26.

QuIE, P. G., and WANNAMAKER, L. W. (I960): The Plasminogen-Plasmin System of Newborn Infants, Amer. Y. Dis.Child., IOO, 836.

RABEN, M. S. (1959): Human Growth Hormone, Diabetes, 8, 232., and HOLLENBERG, C. H. (I960): Growth Hormone and the Mobilization of Fatty Acids, Ciba Found. Coll. Endocr.,13, 89.

RAFSTEDT, S., and SWAHN, B. (1954): Studies on Lipids, Proteins and Lipoproteins in Serum from Newborn Infants,Acta peediat. (Uppsala), 43, 221.

REARDON, H. S. (1958): Adaptation to Extra-uterine Life, Report of the 3Ist Ross Conference on Pediatric Research,p. 82.

ROBB, P. (I96I): The Development of the Islets of Langerhans in the Human Fcetus, Quart. Y. exp. Physiol., 46, 335.RUDOLPH, A. J., HUBBELL, J. P., DRORBAUGH, J. E., CHERRY, R. B., AULD, P. A. M., and SMITH, C. A. (1959): Early

versus Late Feeding of Infants of Diabetic Mothers: A Controlled Study, Amer. 5. Dis. Child., 98, 496.SABOUR, M. (I96I): IVth Congress of the International Diabetes Federation, Geneva.

, NAGY EL MAHALLAWY, M., ABOU-EL-NAGA, I. (I96I): Clinical and Diagnostic Aspects of Diabetic Nephro-pathy, Scot. med. 5'., 6, 495.

SALTER, J., and BEST, C. H. (1953): Insulin as a Growth Hormone, Brit. med. 5., ii, 353.SIREK, 0. V., SIREK, A., and LIEBEL, B. S. (i96i): Serum Glycoproteins in Newborn Infants of Diabetic Mothers,

Diabetes, 10, 375.STEINKE, J., TAYLOR, K. W., and RENOLD, A. E. (I96I): Insulin and Insulin Antagonists in the Serum of Untreated

Juvenile Diabetes: Studies with Isolated Rat Diaphragm and Rat Adipose Tissue, Lancet, i, 30.STUART, H. C., HILL, P., and SHAW, C. (1940): The Growth of Bone, Muscle and Overlying Tissue as Revealed by

Studies of Roentgenograms of the Leg Area, Monogr. Soc. Res. Child Develop., 5 (No. 3).TAKEUCHI, A., and BENIRSCHKE, K. (I96I): Renal Venous Thrombosis of the Newborn and its Relation to Maternal

Diabetes, Biol. Neonat. (Basel), 3, 237.TEJNING, S. (1947): Dietary Factors and Quantitative Morphology of the Islets of Langerhans, Acta med. scand.,

suppl. I 98.USHER, R. (1959): The Respiratory Distress Syndrome of Prematurity: I. Changes in Potassium in the Serum and the

Electrocardiogram and Effects of Therapy, Pediatrics, 24, 562.VALLANCE-OWEN, J., DENNES, E., and CAMPBELL, P. N. (I958a): Insulin Antagonism in Plasma of Diabetic Patients and

Normal Subjects, Lancet, ii, 336.(1958b): The Nature of the Insulin Antagonist Associated with Plasma Albumin. Ibid. ii, 696.

and HURLOCK, B. (1954): Estimation of Plasma Insulin by the Rat Diaphragm, Ibid., i, 68.and PLEASE, N. W. (1955): Plasma Insulin Activity in Diabetes Mellitus Measured by the Rat Diaphragm

Technique, Ibid., ii, 583., and LILLEY, M. D. (Ig6Ia): An Insulin-Antagonist Associated with Plasma Albumin, Ibid., i, 804.



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-(I196 ib): Insulin Antagonism in the Plasma of Obese Diabetics and Prediabetics, Ibid., i, 8o6.VERNET, A., and SMITH, E. B. (I96I): Lipoprotein Patterns in Diabetes and the Changes Occurring during Pregnancy,

Diabetes, 1O, 345.WARREN, S., and LE COMPTE, P. M. (I952): 'The Pathology of Diabetes ', 3rd edition.' Philadelphia.WHITE, P. (1952): in ' Treatment of Diabetes Mellitus' by E. P. Joslin, gth edition. London: Kimpton.

, and HUNT, H. (I943): Pregnancy Complicating Diabetes, J. clin. Endocr., 3, 500.WIDDOWSON, E. M., and SPRAY, C. M. (I95I): Chemical Development in utero, Arch. Dis. Childh., 26, 205.WIENER, H. J. (I924): Diabetes Mellitus in Pregnancy, Amer. Jt. Obstet. Gynec., 7, 710.WISSLER, R. W., FINDLEY, J. W., and FRAZIER, L. E. (1949): Pancreatic Islet Hyperplasia in Rats Force Fed High

Carbohydrate Diets, Proc. Soc. exp. Biol. (N. Y.), 71, 308.WOERNER, C. A. (1938): Studies of the Islands of Langerhans after Continuous Intravenous Injection of Dextrose,

Anat. Rec., 71, 33.WOOLF, N., and JACKSON, WV. P. U. (1957): Maternal Prediabetes and the Fcetal Pancreas, J. Path. Bact., 74, 223.YOUNG, F. G. (1953): The Growth Hormone and Diabetes, Recent Progr. Hormone Res., 8, 471.

(I96I): Experimental Research on Diabetes Mellitus, Brit. med. J., ii, 1449.



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