Effects of diabetic pregnancy on the fetus and newborn

Effects of Diabetic P r e g n a n c y on the Fetus and N e w b o r n Robert Schwartz and Kari A. Teramo

Diabetes in pregnancy is unique because o f the diversity o f problems that can affect the e m b r y o / f e t u s beginning with conception. Considerable effort has been devoted to understanding the basic developmental biology f r o m observing young embryos in vitro or in vivo. Maternal glucose control has been identified as an important event. The preponderance o f evidence indicates that rigid glucose control will minimize the incidence of anomalies incurred before 9 weeks o f pregnancy. Later events are related to fetal hyperinsulinemia. These include fetal macrosomia, respiratory distress syndrome, neonatal hypoglycemia, neonatal hypocalcemia, and neonatal hypomagnesemia. Control o f maternal metabolism can have a significant impact on each o f the above. Finally, the long-term effects o f maternal diabetes are as diverse as the pathogenetic events during pregnancy. Surprisingly, there is a significant transmission rate o f 2% o f type I diabetes if the m o t h e r has insulin-dependent diabetic mother, whereas the rate is 6% for the father. T h e Diabetes in Early Pregnancy Study showed that g o o d maternal control was associated with normal neurodevelopmental outcome. Copyright 9 2 0 0 0 by W.B. Saunders C o m p a n y

he diabetic pregnancy is unique because of diverse systems involved. 1 Thus, diabetic control early in pregnancy can affect organogenesis and control late in pregnancy can affect body composition (ie, macrosomia) and respiratory distress syndrome. Although meticulous control and maintenance of maternal normoglycemia have resulted in improved mortality and ffiorbidity rates, results comparable to a nondiabetic 'population have not yet been achieved consistently.

T the

M e t a b o l i c Effects o f M a t e r n a l D i a b e t e s in the F e t u s a n d t h e N e w b o r n Infant As yet, no single pathogenic mechanism has been clearly defined to explain the diverse problems observed in infants of diabetic mothers (IDMs). Nevertheless, many of the effects can be From the Division o)c Pediatric Endoa~nology amd Metabolism, Brown University at Rhode Island Hospital, Providence, R[; and Department of Obstetrics and Gynecology, University Central Hospital Helsinki, I~Tnland. Supported in part by the National Institutes" of Health (NIH), National Institute of Child Health and Human Development (NICHHD), and the Rhode Island Hospital Research Fund. Address reprint requests to Robert Schwartz, MD, Pediatric Endocrinology and Metabolism, Rhode Island Hospital, 593 Eddy St, Providence, R[ 02903. Copyright 9 2000 by W.B. Saunders Company 0146-0005/00/2402-0005510. 00/0 doi: 10.1053/sp.2000. 636,3

120

attributed to maternal metabolic (glucose) control (Fig 1). Pedersen 1 emphasized the relationship between maternal glucose concentration and neonatal hypoglycemia. His simplified hypothesis recognized that maternal hyperglycemia was paralleled by fetal hyperglycemia, which stimulated the fetal pancreas, resulting in B-cell hypertrophy and hyperplasia with increased insulin content and secretion. Hyperinsulinemia in utero has been shown by cordocentesis and at birth 2,3 (Fig 2). On separation of the fetus from the mother, the f o r m e r no longer is supported by placental glucose transfer, resulting in neonatal hypoglycemia. Hyperinsulinemia in utero affects diverse organ systems including the placenta. 4 Isolated chronic fetal hyperinsulinemia has been p r o d u c e d in normal Rhesus monkeys in the third trimester of pregnancy resulting in fetal macrosomia and organomegaly, except for brain and kidney. 5 Increased body fat was evident and plasma erythropoietin levels were elevated similarly to that found in infants o f diabetic mothers. 6 Insulin acts as the primary anabolic h o r m o n e o f fetal growth and developm e n t resulting in visceromegaly (especially heart and liver) and macrosomia. In the presence of excess substrate (glucose), increased fat synthesis and deposition occur during the third trimester. Fetal macrosomia is reflected by increased body fat, muscle mass, and organomegaly but not in increased size of the brain,

Seminars in Perinatology, Vol 24, No 2 (April), 2000: pp 120-135

12 1

Diabetes in Pregnancy and the Fetus and Newborn

Maternal Diabetes

Fetal [3-Cell Hyperplasia

Fetal Hyperinsulinism

Figure 1. Schema showing hyperglycemia and fetal hyperinsulinemia as related to diverse morbidides.

Oxygen Uptake J"

Delayed Lung

Fetal Substrate Uptake 1"

Maturation Chronic hypoxemia

Krythl'0p0ietio I"

Polycythemia

Fetal ksphyxia

Fetal Maeros0mia

/\

Neonatal Asphyxia

After delivery there is a rapid fall in plasma glucose in the n e o n a t e with persistently low concentrations of plasma free fatty acids (FFA), glycerol, a n d betahydroxybutyrateY In response to an intravenous (IV) glucose stimulus, plasma insulin is increased ( d e t e r m i n e d in the absence of m a t e r n a l insulin antibodies) as is plasma Cpepfide. 8 T h e response to an oral glucose load in infants of diabetic m o t h e r s results in an earlier plasma insulin rise c o m p a r e d with n o r m a l infants, although the area u n d e r the insulin curve is similar. 0 During the initial hours after birth, the response to an acute IV bolus of glucose in IDMs is a rapid rate of glucose disappearance f r o m the plasnm, in contrast to n o r m a l infants who have a delayed response} ~ In contrast, the rise in plasma glucose concentration after stepwise hourly increases in the rate of continuously infused glucose results in elevations even at normal rates, ie, 4 to 6 m g / k g / m i n , n T h e latter may be attributed to a persistence of h e p a d c glucose o u t p u t which differs f r o m the n o r m a l infant. In fact, kinetic studies with D (1-13C) glucose in the initial 2 h o u r after delivery in infants of insulin d e p e n d e n t m o t h e r s indicate a hepatic glucose p r o d u c t i o n of approximately half that observed in n o r m a l infants. ~ Studies with D(u-13C) glucose, however, have revealed a h e t e r o g e n e o u s hepatic response so that suppression of hepatic glucose output in response to e x o g e n o u s glucose is n o t a consistent occurrence. 1~ This effect

;

Stillbirth

Shoulder dystocia

IRDS

Neonatal Hypoglycemia

Birth Weight (SDU)

§

;9

§

9

.

§

9149

o~

e

+§ o

9

L

o 81 9 .~. o 0 ' O ~ . ~ r , O

/r

,

"

9 9 9 ..

_

o ~o ~o.~"

_" o

9

-

9

9 0

I 10

9

00

0

I 100

I 1000

I 10000

Total Insulin (pmol/L) Figure 2. Relationship of infant birth weight (SDUs relative to a large Helsinki reference population) compared with umbilical plasma total insulin (pmol/ L). Open circle, control subjects; close circle, diabetic subjects. The regression line refers to all subjects except the large for gestational age control subjects (+). n = 123; y --- -2.87 + 1.53X; r~ = .41; P = .001; r = .64.

122

Schwartz and Teramo

may reflect the difference in tracer as well as prior maternal metabolic condidon. On the basis o f animal and in vitro studies of the isolated pancreas, the simplified hyperglycemia-hyperinsulinemia hypothesis has been exp a n d e d by Freinke114 and Milner and Hill .5 to include maternal "mixed nutrients" as controlling factors. O f the major maternal nutrients (glucose, fatty acids, ket0nes, and amino acids), it is likely that, in addition to glucose, amino acids are important to maturation o f the fetal B cell and release o f insulin, although the evidence is not definitive. Ketones readily cross the placenta and may provide substrate, but they do not affect insulin secretion. With the exception of essential fatty acids, l o n g chain fatty acids probably do not cross the placenta in sufficient quantities to influence growth and development in utero. 3.Iterations of plasma glucocorticoids a n d growth h o r m o n e s have not been significant in IDMs. The somatomedins (IGF-I, IGF-II) have not been f o u n d to be increased in umbilical cord plasma in diabetic pregnancies n o r in the rhesus fetuses with primary hyperinsulinemia. 5,a6 In contrast, urinary excretion of catecholamines is diminished, especially in infants with low plasma glucose concentrations. In addition, _plasma glucagon levels are less elevated after delivery i n comparison to normal infants. Perinatal Mortality

Perinatal mortality has decreased from over 30% to 2% to 4% in insulin-dependent diabetic m o t h e r (IDDM) pregnancies over the last five decades (Table 1).aa 7 The basis for the decrease in perinatal mortality has been improvement in

the diabetic control both before and during pregnancy as well as improvement in obstetric and neonatal care. However, perinatal mortality is still 3 to 6 times higher than in the general population in centers specializing in the care o f diabetic pregnancies (Table 1) and in smaller hospitals it is even higher. 17 In N o r t h e r n Ireland from 1985 through 1995 perinatal mortality was 2.6% in diabetic pregnancies managed throughout pregnancy at a tertiary care center, but 7.5% in diabetic patients referred from peripheral hospitals during pregnancy to the same tertiary care c e n t e r / 7 Despite the referral o f high-risk diabetics to the tertiary care center, the perinatal mortality remained higher for subjects referred from peripheral hospitals than in the tertiary care center. This gives clear evidence of the advantage of centralized, continuous care o f type 1 diabetic pregnancies. It also shows that centralization of care should start in early pregnancy, preferably before conception. T h e incidence of juvenile type 1 diabetes is increasing worldwide and has m o r e than doubled over the last three decades in Finland. is This is reflected also as a continuous increase in the annual n u m b e r of infants born to IDDM mothers (Table i). Because the perinatal mortality rate has not changed over the last 25 years, the absolute n u m b e r of perinatal deaths is actually increasing (Table 1). Thirty to 40% o f perinatal deaths in IDDM pregnancies are caused by malformations, 20% to 30% by prematurity, and 20% to 30% by intrauterine asphyxia including late gestation fetal death. T h e r e Were 17 (2.4%) perinatal deaths at the D e p a r t m e n t o f Obstetrics and Gynecology, Helsinki University Central Hospital during the 10-year period from 1988 to 1997 (Table 2).

Table 1. Perinatal Mortality Rates in IDDM Pregnancies at the University Central Hospital Helsinki

(1951-1997) Perinatal Mortality Rates ~me

Period

Infants

195i-1960 1959-1968 1970-I97I 197521980 1988:1997

162 23t 52 279 702

Infants/Year

Stillbirths

16 23 26 47 70

* Annual mean. t Reference: Statistical Year Book of Finland 1997.

30 25 3 3 10

First Week Neonatal Deaths

No.

IDDM %

Finland * %

16 23 4 3 7

46 48 7 6 17

28.5 20.8 13.5 2.2 2.4

3.21t 2.32t 2.32t 1.25t 0.68 t

123

Diabetes in Pregnancy and the Fetus and Newborn

Table 2. Seventeen Perinatal Deaths (2.4%) Among 702 Infants Born to IDDM Mothers at the University Central Hospital Helsinki (1988-1997) Case No.

White's Class

Gestation (wk + d)

Birthweight (g)

F/N Death

Comment

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

B C C B C F C D D F F B B B B D D

23 + 5 25 + 1 25 + 1 25 + 2 26 + 3 26 + 4 27 + 6 28 + 4 29 + 2 30 + 1 30 + 1 31 + 1 33 + 6 36 + 1 37 + 3 38 + 1 39 + 2

575 370 500 725 830 785 400 705 1,195 810 1,900 1,380 1,350 2,250 6,500 3,415 5,000

F F N N F N F N F N N F F F F F N

PROM Multiple malformations IRDS IRDS Unexplained IRDS Placental abruption IRDS Placental infarctions IRDS Kidney malformations Umbilical cord complication Placental infarctions Placental abrnption Unexplained Unexplained Left heart hypoplasia

Abbreviations: F, fetal; N, neonatal; PROM, premature rupture of membranes; IRDS, respiratory distress syndrome.

Seven of the 17 perinatal deaths occurred before 28 weeks o f gestation and 13 before 35 weeks of gestation. Five newborn infants delivered at or before 30 weeks of gestation died because of prematurity and severe respiratory distress synd r o m e (RDS). The indication to deliver prematurely was severe preeclampsia with or without fetal distress. Only 3 o f the 17 perinatal deaths resulted from major malformations. However, there were 5 induced abortions because of major fetal malformations during the same time period.~gAt least 3 of the 5 fetuses (1 with a n e n c e p h aly, 1 with severe hydrocephaly, and 1 with multiple malformations) would have resulted in a perinatal death. Thus, perinatal mortality figures will be influenced by the detection of fatal malformations in early pregnancy and by the policy of interrupting such pregnancies. Furthermore, the same definition of perinatal mortality is n o t used universally. Many centers use 28 weeks of gestation as the lower limit. In Tables 1 and 2 perinatal mortality was calculated from pregnancy losses occurring at and after 22 weeks of gestation.

Fetal Asphyxia and Distress The incidence of abnormal fetal heart rate, cord b l o o d acidosis, and low Apgar scores is increased in diabetic pregnancies, z,z~They o c c u r m o r e of-

ten in diabetics with p o o r glycemic control during the last trimester o f pregnancy than in diabetics with g o o d glycemic control. 2t Fetal plasma and amniotic fluid erythropoietin concentrations are frequently elevated in diabetic pregnancies suggesting 9 an increased incidence of chronic fetal hypoxia. 6,22 Accordingly, fetal and neonatal polycythemia and increased reticutocytosis at birth are seen more often in diabetics than in healthy mothers. Depletion o f iron stores in fetal liver, heart, and brain observed at autopsies of new.born infants o f diabetic mothers 23 also suggests that chronic hypoxia precedes fetal death in the majority of diabetic pregnancies. Although the exact pathogenetic mechanisms of fetal asphyxia in diabetic pregnancies is not fully understood, several factors may compromise fetal oxygen supply. Madsen z4 has reviewed maternal, placental, and fetal factors that can cause fetal asphyxia in diabetics. Maternal factors include hyperglycemia and elevated hemoglobin Alc (HbAac) levels. Smoking during pregnancy is especially harmful to the fetus of the diabetic mother. 25 Thickening of the basement m e m b r a n e of the chorionic villi in diabetic pregnancies can increase the diffusion distance of oxygen between the m o t h e r and the fetus. However, the placenta seems to be able to compensate for

124

Schwartz and Teramo

these adverse morphological changes by increasing the total area o f the chorionic villi. 26 Uterine blood flow of the placental bed is decreased especially in diabetics with p o o r glycemic controlY 7 Pathological changes in the spiral arteries of the placental bed have been reported in diabetics with vascular complicationsY 8 Both hyperglycemia and hyperinsulinemia increase oxygen consumption with a simultaneous decrease in oxygen content of arterial blood in the fetal lamb. 29-31 In the human, maternal HbAlc concentrations in the third trimester of diabetic pregnancies correlate highly significantly with fetal plasma erythropoietin levets. 32 Fetal amniotic fluid insulin also correlates significantly with fetal plasma erythropoietin levels independently from maternal glycemia, z2 Thus, both fetal hyperglycemia secondary to maternal hyperglycemia and fetal hyperinsulinemia may cause fetal chronic hypoxemia and eventually fetal death. A direct relationship between the degree of fetal macrosomia and amniotic fluid erythropoietin levels has recently been reported, 3-3 suggesting that the more macrosomic the fetus is, the greater the risk of fetal chronic hypoxia. This agrees with the observation that the stillbirth rate increases when birth weight is more than 4,000 g, especially a m o n g fetuses weighir~g over 5,000 g.34 It is likely that the majority of the "unexplained" stillbirths in diabetic pregnancies result from chronic fetal hypoxia. In the 1950s, the risk of fetal death increased gradually during the last m o n t h of pregnancy to more than 10%. 35 Despite considerable improvement in the perinatal results of diabetic pregnancies, "unexpected" fetal deaths still occur. Strategies to prevent stillbirths in diabetic pregnancies include fetal surveillance by fetal heart rate and ultrasonic monitoring, and by elective delivery of the infant at 37 to 39 weeks of gestation even in wellcontrolled uncomplicated diabetic pregnancies with or without confirmation of fetal lung maturity. We speculate that by intensive fetal surveillance most of the fetal deaths in diabetic pregnancies can be prevented by early detection o f chronic fetal hypoxia. T h e r e is no a g r e e m e n t of the best m e t h o d to monitor fetal well being in diabetic pregnancies. Heart rate variation, Doppler blood flow measurements and biophysical profile differ in fetuses of diabetics from fetuses of healthy moth-

ers, but they have limited clinical value in the diagnosis of fetal distress and acidemia in diabetic pregnancies. 36,37 A twice weekly nonstress testing has been suggested to secure fetal well being in patients with good glycemic control and without pregnancy complications. 3s,39 Kjos et a139 used twice-weekly nonstress testing of fetal heart rate in 1,501 women with diabetes. However, most of the diabetic patients had gestational diabetes and only 111 had IDDM. No controlled studies exist on the use of fetal heart rate monitoring in the detection of fetal distress or in prevention o f fetal death in diabetic pregnancies. It is unclear whether twice-weekly nonstress testing is e n o u g h to secure fetal health in diabetics with p o o r glycemic control or in macrosomic fetuses.

Congenital Malformations The overall incidence of congenital malformations in IDDM pregnancies has been 6% to 13%, which is 2- to 4-fold that of the general population. 4~ However, major structural anomalies, ie, defects that are fatal or require surgery, are 7 to 10 times more frequent in the offspring of diabetic mothers than in the general population. 42 The severity of congenital malformations in diabetic pregnancies influences also the perinatal outcome: 30% to 40% of perinatal deaths in Helsinki are caused by congenital malformations. Typical malformations in the offspring of diabetics are heart, central nervous system and renal and urinary system defects 4z (Fig 3). Limb, rib and spinal defects, especially caudal dysgenesis, are also increased in diabetic pregnancies. These malformations occur before the ninth pregnancy week (seventh week from conception),44 which has important implications in the prevention of malformations in diabetic pregnancies. The exact teratogenic mechanisms of malformations in diabetic pregnancies are unknown. In experimental diabetic models hyperglycemia, hypoglycemia, hyperketonemia, nonenzymatic glycation of proteins and disturbances in arachidonic acid and prostaglandin metabolism have b e e n implicated to cause malformations in the offspring. 45,46Elevated intracellular levels o f free oxygen radicals have been associated with diabetic embryopathy in rats. 47 Recently, hypergly-

Diabetes in Pregnancy and the Fetus and Newborn

125

Figure 3. Severe malformation in an infant of an insulin-dependent (white class F) diabetic whose maternal control was suboptimal in the first trimester: HbA = 9.4%. There were skeletal malformations; sacral agenesis. In normal subjects HbAlc = 5.4 _+ 0.6%.

cemia-induced malformations in mice a n d rat embryos have b e e n shown to correlate with the n u m b e r of genomic DNA mutations. 48 Antioxidants and free radical scavengers seem to r e d u c e the teratogenic risk of hyperglycemia in experim e n t a l models. 49,5~ Maternal hyperglycemia as indicated by elev a t e d glycosylated h e m o g l o b i n Ale (HbAlc) levels at the time o f c o n c e p t i o n or in early p r e g n a n c y correlate directly with increased frequency of congenital malformations in infants of diabetic mothers in several studies. 51-55 O n e study failed to show such a relationship. 56 It has b e e n suggested that the risk of congenital malformations begin to increase only after HbAIr is increased above a certain level, eg, 8 or 12 standard deviations above the nondiabetic m e a n . 55,57 However, in large series of diabetic pregnancies the relationship between m a t e r n a l hyperglycemia in early p r e g n a n c y a n d the frequency of congenital malformations seems to be linear without any threshold level. ~9,58 T o w n e r et a158 showed in pregestational, mainly type II diabetics (non insulin-dependent), that elevated HbAlc in early pregnancy, but not oral hypoglycemic medication, correlated with the increased risk of malformations. Thus, it seems that only diabetics with a n o r m a l HbAlc level in early p r e g n a n c y do n o t have an increased risk o f congenital malformations in their offspring. Unfortunately pregestational diabetics with normal, nondiabetic HbAIr levels in early p r e g n a n c y are

clearly a minority. In the study by S u h o n e n et at m only 7% o f IDDM m o t h e r s had a n o r m a l HbAlc level ( < 2 SD of the nondiabetic m e a n ) in the first trimester of pregnancy. This explains why the frequency of congenital malformations still remains increased in diabetic pregnancies. T h e r e is now clear evidence that prepregnancy i m p r o v e m e n t of glycemic control decreases the frequency of malformations in the offspring of diabetic mothers/9-61 Therefore, the goal should be that every IDDM diabetic should have a p l a n n e d p r e g n a n c y with p r o p e r prepregnancy counseling. T h e highest n u m b e r of p r e p r e g n a n c y a t t e n d a n c e a m o n g IDDM diabetics is reportedly 75%. 62 Usually tbe attendance is m u c h lower, which is partly explained by the fact that 30 to 50% of the diabetic pregnancies are u n p l a n n e d . T h e frequency of congenital malformations in diabetic pregnancies has decreased in some areas during the last two decades probably as a result of the overall i m p r o v e m e n t of the glycemic control. 19,62

Macrosomia Macrosomia and selective o r g a n o m e g a l y are the hallmarks of the diabetic pregnancy, b o t h insulin-dependent and gestational (Fig 4). T h e f o r m e r in large m e a s u r e is due to excessive adipose tissue. 4,63 T h e obstetric and pediatric literature is confusing because of lack of a g r e e m e n t as to the definition o f macrosomia. T h e multi-

126

Schwartz and Teramo

Figure 4. Two infants born at full-term from diabetic mothers. The appropriate-sized infant on the right was born to a white class C mother who was rigidly controlled during pregnancy. The macrosomic infant on the left was born to a woman diagnosed as gestationally diabetic late in pregnancy and whose management was inadequate.

plicity of factors that affect fetal growth is ign o r e d when a birth weight over 4,000 g alone is considered as macrosomia. The problem of definition o f macrosomia has been reviewed recently. 64 The best current definition is two standard deviations above the mean weight for gesrational age corrected for sex in an appropriate standard population. However, this will not characterize the selective organomegaly seen in the infant of the diabetic mother. 4,65 With this definition, a strong relation between fetal weight (standard deviation units) and umbilical plasma insulin or C-peptide has been observed -~,66 (Fig 2). Maternal diabetes increases the risk for shoulder dystocia by 3- to 4-fold c o m p a r e d with re-

tuses of the same weight of nondiabetic mothers. 67,68 Shoulder dystocia results in plexus brachialis injury in 9% when the birth weight is less than 4,000 g and in 26% when the birth weight is over 4,500 g both a m o n g diabetic and nondiabetic mothers. 6s Brachial plexus injuries cause p e r m a n e n t impairment of the function of the arm in 5% to 10% of infants. The identification of fetuses with an increased risk for shoulder dystocia has been problematic. Risk factors for shoulder dystocia include fetal macrosomia in previous or present pregnancy, maternal diabetes, previous shoulder dystocia and excessive maternal weight gain during pregnancy. 69 Estimates of fetal weight by ultrasonography have not been accurate. 7~ The

Diabetes in Pregnancy and the Fetus and Newborn

major problems in using sonography in assessing fetal macrosomia are that fetal body composition and fetal shoulder width c a n n o t be reliably assessed. Abdominal circumference, especially measured serially during the third trimester of pregnancy, is the best single sonographic meas u r e m e n t in the detection o f macrosomic fetuses in diabetic pregnancies. 71 However, clinical prediction o f fetal macrosomia has b e e n r e p o r t e d to equal ultrasound prediction. 72 Fetal weight, s h o u l d e r width, and the pelvic capacity can be measured by magnetic resonance imaging (MRI). 7~-75 Clinical studies for evaluating the value of MRI in prevention of shoulder dystocia of macrosomic fetuses are clearly needed. Recently, a more than 50% decrease in the shoulder dystocia rate (from 2.4% to 1.1%) has b e e n reported when using sonography and elective cesarean section to deliver fetuses with an estimated weight of over 4,250 g in diabetic pregnancies. 76 T h e cesarean section rate increased during t h e same time period by 15% (from 21.7% to 25.1%). A l t h o u g h cardiac hypertrophy apart from congenital heart disease has b e e n recognized in autopsies of IDMs for the past three decades, it has only been in the last 10 years that attention has b e e n directed to a peculiar form of subaortic stenosis similar to the idiopathic hypertrophic subaortic stenosis f o u n d in adults. 77 This particular entity may be associated with symptomatic congestive heart failure. As with the adult variant, therapy with digoxin in these infants is contraindicated since the resultant increased myocardial contractility has b e e n r e p o r t e d to be deleterious. Propranolol appears to be the therapeutic drug of choice, as in the adult. Although the pathogenesis remains controversial at present, fetal hyperinsulinism, and, hence, the degree o f maternal hyperglycemia, may be the major stimulus. Primary fetal hyperinsulinemia in the rhesus fetus has been f o u n d to be associated with significant cardiac muscular hypertrophy and cardiomegaly. 66 Clinically, this disorder resolves spontaneously over a period of weeks to m o n t h s with correction of the echocardiographic features as well.

Respiratory Distress Syndrome The overall risk of respiratory distress, including RDS, has clearly decreased, but it remains a

127

potentially severe complication in the very preterm infant of the diabetic m o t h e r (Table 2). Robert et al TM showed that diabetes per se predisposes to RDS in IDM. They f o u n d a 5.6 times higher risk of RDS in IDM than in infants of nondiabetic mothers when confounding variables were excluded. While the clinical association has been long recognized, recent investigations have increased o u r understanding of the pathophysiological interrelationships. Pulmonary surfactant p r o d u c t i o n increases near term and probably results from the activation of the pathway for dipatmityol lecithin, which in turn may be mediated through increases in fetal plasma cortisol levels.79, 80 Whereas plasma cortisol production rates are normal in the IDM, it has b e e n shown that insulin can interfere with incorporation of choline into lecithin even when cortisol is present. Incorporation of labeled glucose and fatty acid residues into saturated phospholipid phosphatidylglycerol (PG) is r e d u c e d in fetal rabbit lung slices in the presence of insulin, sl Thus fetal hyperinsulinemia may play a role in delaying fetal pulmonary maturation. T h e exact pathogenetic mechanisms of delayed fetal lung maturation in diabetic pregnancies are not fully understood. The synthesis of lecithin, the major c o m p o n e n t of lung surfactant, does not differ between fetuses o f diabetic and nondiabetic mothers. However, the synthesis of the acidic (PG) is clearly delayed in diabetic pregnancies. 82 The presence o f PG in the amniotic fluid eliminates the risk for false positive L / S (locithia/ sphingomyelin) ratios in diabetic pregnancies.8~-84 Surfactant from bovine lungs, h u m a n amniotic fluid, or synthetic surfactant has now b e e n used to treat successfully infants with respiratory distress syndrome. This has b e e n particularly important for very small, p r e t e r m infants. T h e trend to deliver diabetic patients later in gestation rather than earlier is increasing. Previously, early delivery was advised to diminish the i~isk of intrauterine fetal death, but increasing assessment of fetal well-being affords the obstetrician the opportunity of delivering the patient at the optimal time (see Fetal Asphyxia and Distress). RDS must be managed with particular attention to fluid administration, oxygen, correction of acidosis, and ventilator support when necessary.

128

Schwartz and Teramo

I-Iypoglyeemia The frequency o f hypoglycemia in the infant of the diabetic m o t h e r is unclear historically. In a large series (934 pregnancies), Gellis and Hsia s5 concluded that hypoglycemia was not a problem. Unfortunately, they analyzed total reducing substances; hence, true glucose was obscured in the analysis. Later, Farquhar s6 and McCann et al 7 i n d e p e n d e n t l y r e p o r t e d a high frequency o f asymptomatic hypoglycemia immediately (minutes) after delivery (Fig 5). A rapid fall in plasma glucose concentration following delivery is characteristic o f the IDM of the poorly controlled mother. Values less than 30 to 35 m g / d L (1.67 to 1.94 m m o l / L ) in full-term infants and in p r e t e r m infants are abnormal and may occur within 30 minutes after clamping the umbilical vessels. Factors that are known to influence the degree of hypoglycemia include maternal glycemic control during pregnancy and especially

w

o

200- I "~ "n

I z ",, I

o---O 6ESTATiONAL DIABETIGS aO

w e "..t _~ ,20% o

~_~,,

o-o ,.s0L,. 0 PE oE., \

40

~ "..

/

,8

/

11

\~

.................

~"

,o .........

. o ............... .......

.............

HOURS

Figure 5. Mean blood glucose in first hours of life. Serial changes in the concentration of glucose in the blood of infants immediately after delivery. The group from mothers with gestational diabetes had abnormal intravenous glucose tolerance tests during pregnancy but received no insulin therapy. Note the maternal blood glucose at delivery averaged 180 m g / d L Currenfly, rigid control of maternal blood glucose before and during delivery avoids these extreme changes in the newborn.

during labor and delivery. 87 Maternal hyperglycemia results in fetal hyperglycemia, which stimulates the fetal pancreas to synthesize excessive insulin. 14,15 Maternal hyperglycemia (greater than 125 m g / d L [6.94 m m o l / L ] ) during labor will exaggerate the infant's normal post-delivery fall in plasma glucose concentration. In severe cases, neonatal hypoglycemia may persist for 48 hours or longer. It is also important to remember that hypoglycemia may develop later than 24 hours after birth, s7 As n o t e d previously, fetal hyperinsulinemia is associated with suppressed levels of plasma FFA a n d / o r diminished hepatic glucose output. 12,ss O t h e r factors that may contribute to the development of hypoglycemia include defective counter-regulation by catecholamines a n d / o r glucagon, s9 Most infants of diabetic mothers are asymptomatic with very low plasma glucose levels. This may be due to the initial brain stores o f glycogen; however, the exact biochemistry is as yet undefined. Signs and symptoms that may be observed are nonspecific and include tachypnea, apnea, tremulousness, sweating, irritability, and seizures. Asymptomatic infants do not require parenteral treatment unless the glucose concentration is very low (<20 m g / d L ) . Early administration of milk at 3 to 4 hours of age may, however, be beneficial if plasma glucose levels are not markedly depressed. In 1955, Pennoyer and H a r t m a n n 9~ f o u n d that only 16 babies had symptoms a m o n g 38 with blood sugar values less than 30 m g / 1 0 0 mL. O f these, only 5 did not have associated problems which could have contributed to the clinical manifestations. Rigid maternal control of blood glucose levels during pregnancy and delivery minimizes the risk of neonatal hypoglycemia. 91 Plasma glucose values may be obtained at delivery from the umbilical vein. Subsequently, the infant should be screened by a rapid bedside technique at one half hour, 2 hours, and 4 hours and then before feeding until stable. Abnormal glucose values (30 to 35 m g / d L ; 1.67 to 1.94 m m o l / L ) require verification by chemical analysis. When symptoms and hypoglycemia coexist at any age, therapy directed at elevating the concentration of glucose in the blood should be initiated. A p r o m p t response to therapy is evidence that hypoglycemia was indeed the cause

Diabetes in Pregnancy and the Fetus and Newborn

of the symptoms. However, if the hypoglycemia has b e e n o f long duration or if the symptoms are due to o t h e r causes, either a partial or delayed response to therapy may occur. During the first hours of life, glucagon in high dosage (300 /xg/kg IV or intramuscularly to a m a x i m u m of 1 m g total dose) can elevate the b l o o d sugar level for up to 2 hours in m o s t infants. 92 Wu et al 9~ have minimized tile fall in blood glucose in IDMs by the intravenous administration of 300 /xg/kg glucagon within 15 minutes after delivery. Because the majority of infants are asymptomatic, glucagon does not a p p e a r warranted. F u r t h e r m o r e , glucagon may stimulate insulin release, which may exaggerate the tendency to hypoglycemia. However, if the infant is severely ill, glucose administered intravenously is the t r e a t m e n t of choice. I f an IV is unavailable or difficult, glucagon may be helpful until umbilical catheterization. Blood sugar levels can be m e a s u r e d at 2- to 6-hour intervals with either f o r m of therapy. T h e symptomatic infant should be treated IV with 0.25 g / k g o f 25% dextrose as a bolus administered during 2 to 4 minutes, but this also stimulates insulin release. T h e infant m u s t be followed by a continuous infusion at 6 to 8 m g / k g / m i n . Bolus injections alone without subseq u e n t infusion will only exaggerate the hypoglycemia by a r e b o u n d m e c h a n i s m and are contraindicated. Once the plasma glucose stabilizes above 45 m g / d L (2.50 m m o l / L ) , the infusion may be slowly decreased while oral feeds are initiated a n d advanced. If hypoglycemia persists, higher glucose rates of 8 to 12 m g / k g / m i n or m o r e may be necessary (see Glaser; this issue). Recently, neonatal hypoglycemia has b e e n rep o r t e d f r o m the pregnancies of the Diabetes Control a n d Complications Trial24 All patients were transferred to intensive therapy as soon as p r e g n a n c y was diagnosed. During pregnancy, HbAIr was 6.6 -+ 0.8% ( m e a n + SD) in the intensive g r o u p and 6.6 -+ 1.3% for the conventional group. Neonatal hypoglycemia (less t h a n 40 m g / d L m e a s u r e d within 72 hours after birth) o c c u r r e d in 34.5% of the intensive g r o u p a n d in 41.9% of the conventional group, However, the glucose values in the first six hours of life did n o t differ between the groups. No late problems or correlation with perinatal events have b e e n identified. No specific late central nervous system complications have b e e n

129

attributed to neonatal hypoglycemia p e r se in IDMs. W h e t h e r the occasional delayed m o t o r d e v e l o p m e n t or psychological dysfunction observed after 5 years is related to early hypoglycemia is unclear.

Hypocalcemia and Hypomagnesemia Besides hypoglycemia, hypocalcemia ranks as one of the m a j o r metabolic d e r a n g e m e n t s observed in the IDM. 95-97 Normally, serum calcium is elevated after a rise in parathyroid h o r m o n e (PTH) levels by 3 mechanisms: mobilization of b o n e calcium, r e a b s o r p t i o n of calcium in the kidney, and increased absorption of calcium in the intestine t h r o u g h action of vitamin D. 9s In opposition, serum calcium is decreased following a rise in calcitonin, which antagonizes the action of PTH. S e r u m calcium may also be elevated by vitamin D (1,25 dihydroxy vitamin D), which improves b o t h absorption of calcium in the intestine after feeding as well as reabsorption f r o m bone. 99 During pregnancy, calcium is transferred f r o m m o t h e r to fetus, c o n c o m i t a n t with an increasing hyperparathyroid state in the mother. Plasma calcium concentrations are higher in the fetus than in the m o t h e r . This hyperparathyroid state may function as a homeostatic compensation to restore the m a t e r n a l calcium that is diverted to the fetus. Neither calcitonin n o r parathyroid h o r m o n e crosses the placenta. At birth, because of the levels o f calcitonin, PTH, and 1,25 dihydroxy vitamin D, s e r u m calcium falls, subsequent to i n t e r r u p t i o n of maternal-fetal calcium transfer. Elevations in P T H and 1,25 dihydroxy vitamin D as early as 24 hours of age insure correction of the low s e r u m calcium concentration. 99 Tsang et aP 7 have shown that there are a n u m b e r of neonates who are prone to hypocalcemia, particularly the prematurely born, the infant who is asphyxiated, and the infant of the diabetic mother. Approximately 50% o f infants b o r n to insulind e p e n d e n t diabetic w o m e n develop hypocalcemia (7 m g / d L [<1.75 m m o l / L ] ) during the first 3 days of life. Evaluation of the mechanism(s) has failed to establish prematurity or asphyxia per se (both o f which may be present in IDMs) as associated factors. However, the frequency and severity o f s e r u m hypocalcemia is directly related to the severity of the diabetes

130

Schwartz and Teramo

and potentiated if birth asphyxia is superimposed on the clinical state. ~~176 It has been postulated that the mechanism at least partially responsible for hypocalcemia is the physicochemical reaction to hyperphosphatemia, which is present during the initial 48 hours after birth. Hypomagnesemia (less than 1.5 m g / d L [0.02 m m o l / L ] ) has been f o u n d in as many as 33% of IDMs. As with hypocalcemia, the frequency and severity of clinical symptoms is correlated with the maternal status. 1~ Neonatal magnesium concentration has been correlated with that in the mother, as well as with the maternal insulin requirements, and the concentration of IV glucose administered to the infant. Hypomagnesemia may suppress parathyroid activity and thus p r o d u c e hypocatcemia. Hypocalcemia and hypomagnesemia, which have similar clinical manifestations to hypoglycefnia, must be considered and treated appropriately. T h e long-term potential deleterious effects of either hypocalcemia or hypomagnesemia are unknown.

The polycythemia frequently observed in IDMs may well be the most important factor associated with hyperbilirubinemia. 1~176 Venous hematocrits 65% or more have b e e n observed in 20% to 40% of IDMs during the first days of life. Occasionally neonatal polycythemia results in clinical symptoms such as jitteriness, seizures, tachypnea, priapism, and oliguria. Therapy with the use of a partial exchange transfusion (10% to 15% of total blood volume) through the umbilical vein with plasmanate or 5% albumin has been associated with a rapid resolution of symptoms. Careful studies examining the relationshi p of neonatal polycythemia to maternal blood glucose control a n d / o r o t h e r perinatal factors associated with the diabetic pregnancy have not been done as yet. A rare complication, first r e p o r t e d 50 years ago, is renal vein thrombosis. 1~ Although the cause of this problem is undefined, there is speculation that it is related to polycythemia.

Hyperbilirubinemia and Polycythemia

T h e r e is concern not only for the problems f o u n d in the immediate neonatal period, b u t also for the long-term effects of maternal diabetes and neonatal complications on growth and development, on psychosocial intellectual capabilities, and finally o n the risk to the infant of subsequently developing diabetes. O n e of the i m p o r t a n t factors influencing long-term prognosis is the improvement in m a n a g e m e n t of the p r e g n a n t diabetic and her infant. Assuming that many of the deleterious effects of the diabetic pregnancy are being modified by normalization o f metabolic status in both the p r e g n a n t woman and her conceptus, the p o o r prognoses that have been reported in previous retrospective studies should be decreased or even ameliorated in future prospective evaluations. 94,1~176 These studies are in contrast to the Rhesus m o n k e y in utero hyperinsulinemia experiments in which postnatal neonatal hypoglycemia was d o c u m e n t e d for 6 or 10 hours. 11~These animals were assessed behaviorally and developmentally by blinded examiners after eight months. No neurological defects were foun& However, the animals with prolonged hypoglycemia had motivational and adaptability problems, but these were overcome with extra attention. No differences were found between experimental and

Hyperbilirubinemia is observed more frequently in the IDM than in the normal infant. 1~ Alt h o u g h a n u m b e r of hypotheses have been suggested, the pathogenesis remains uncertain. T h e increase in Epo indicates that in utero hypoxemia may be important. 6,22,~1 Prematurity (biochemical immaturity), which is present in many IDMs, was one explanation that was rejected after gestationally age-matched comparisons with non-IDMs showed the IDM to be m o r e jaundiced. T h e r e is no increased incidence of Coombs-positive ABO incompatibility. Red blood cell life span, osmotic fragility, and deformability have not been found to be appreciably different in IDMs compared with normal infants, neither has an increased umbilical cord bilirubin n o r an increased postnatal rate of hemoglobin decline b e e n shown. In one evaluation, only macrosomic IDMs were n o t e d to be at risk for hyperbilirubinemia; increased h e m e turnover was postulated to be a significant factor in the pathogenesis. However, Stevenson 1~ suggested that delayed clearance of the bilirubin load was a factor as measured by pulmonary excretion o f carbon m o n o x i d e as an index of bilirubin production.

Long-term Prognosis and Follow-up

Diabetes in Pregnancy and the Fetus and Newborn

control animals. In particular, measures of cognitive abilities or behavior did not distinguish the groups. T h e r e are a few prospective studies of growth and d e v e l o p m e n t of the IDM. Farquhar's 1~ analysis of 231 of a group of 320 infants is significant in that more children up to 15 years of age fell below the third percentile for height than exceeded the 97th percentile (21 v 5). Weight, in contrast, seemed to be equally divided both above and below the normal range. This was confirmed by evaluating the weight and height index of each child expressed as a percentage of the 50th percentile for age and sex. Evaluation by these parameters suggested that excessive weight is almost 10 times more comm o n than unusually low weight. Farquhar 1~ suggests that this may represent a potential "return to obesity" noted at birth in this group of infants. in a n o t h e r study, Bibergeil et a1111 n o t e d that height was elevated in 16.7% but below normal in 9.3%. Infants with a birth weight of more than 4 kg had significant elevations of height and weight at time of entrance to school. Vohr et a1119 recently reported large for gestationaI age offspring of gestational diabetic mothers at ages 4 to 7 years. They f o u n d increasing body size and adiposity. Maternal diabetes and p r e p r e g n a n t adiposity were significant predictors of their unique growth patterns. In consideration of neuropsychological development, it is important to note that the increased frequency of congenital malformations may be directly or indirectly associated with neuropsychological handicaps. In a large series b o r n from the 1946 to 1966, Yssing n3 f o u n d that 36% (265 children) had evidence of cerebral dysfunction or related conditions. Cerebral palsy and epilepsy were f o u n d to be 3 to 5 times higher in comparison to the normal population, but mental retardation was not noted to be different. W h e n present, the difficulties seemed to be related to extremes of maternal age, severity o f diabetes, low birth weight for gestational age, or complications during pregnancy. They were not related to blood glucose concentration. T h e outcome of children at 1, 3, and 5 years of age was evaluated by Stehbens et al~14 Psychological evaluations suggested that at 3 and 5 years of age the IDM is more vulnerable to intellectual impairment, especially if children were

131

born small for gestational age or if their mother's pregnancy was complicated by acetonuria. T h e Diabetes in Early Pregnancy Study 115 allowed for a 3 year follow-up study of 109 IDMs and 90 control infants. Seventy-one percent of subjects completed the serial follow-up evaluations. N e u r o d e v e l o p m e n t of early entry subjects were similar to that of control subjects; whereas late entry subjects scored less well on language measures. Less optimal intellectual development was associated with r e d u c e d head circumference. The investigators concluded that mothers with insulin-dependent diabetes who maintain good control during pregnancy can expect to have infants who are neurodevelopmentally normal; whereas mothers whose diabetes is less well controlled may have infants with less optimal neurodevelopment. The presence of neonatal hypoglycemia per se has not been related to later neuropsychological defects. Persson and Gentz 116 f o u n d no evidence that asymptomatic hypoglycemia leads to intellectual impairment by 5 years o f age. One study has r e p o r t e d an adverse outcome in infants with asymptomatic neonatal hypoglycemia (<1.5 m m o l / L ) . 117 In a small matched series (28 infants) investigated at age 8 years, significantly more difficulties were f o u n d for minimal brain dysfunction in a validated screening test. In addition, the subjects with a history of neonatal hypoglycemia were m o r e often hyperactive, impulsive and easily distracted. On psychological assessment, these children had a lower total developmental score. No gross neurological abnormalities, including ophthalmologic or hearing impairments were found. These observations r e p o r t e d recently from Sweden are contrary to earlier observations from there. 115 The great improvements in obstetrical managem e n t in the past two decades make comparison of newborn outcomes difficult to interpret. The development of juvenile IDDM is a combination of genetic susceptibility, chronic autoi m m u n e destruction of the pancreatic beta cells and external, mainly unknown triggering factors. The question of whether the IDM has an increased likelihood of b e c o m i n g diabetic is important and has been the subject of a n u m b e r of studies and a recent review. Previous data have indicated that 2% to 6% of siblings of diabetic individuals developed diabetes. Although family aggregates do exist, transmitted both through

132

Schwartz and Teramo

and within generations, a simple mode of inheri t a n c e is i n c o n s i s t e n t w i t h t h e r e p o r t e d d a t a . Some investigators have suggested that a polygenic nmltifactorial model best explains the reported observations. A clear sex difference in the parental transmission rate of IDDM has been observed: if the m o t h e r h a s I D D M t h e t r a n s m i s s i o n r i s k is 2 % b u t , i f t h e f a t h e r h a s I D D M , t h e r i s k is 6%.1~ Several genes associated with increased susceptibility to IDDM have been identified. The H L A - D Q g e n e o n c h r o m o s o m e 6 is o n e o f t h e s t r o n g e s t p r e d i s p o s i n g g e n e s f o r I D D M , 119,12~ but the combination of genes varies in different populations. Also protective genes against IDDM h a v e b e e n i d e n t i f i e d , I t is n o w p o s s i b l e t o d e t e r mine the subsequent risk of IDDM by screening tor genetic markers at birth. This may provide t h e b a s i s f o r i n t e r v e n t i o n trials i n t h e p r e v e n t i o n of,IDDM.120,12~

References 1. Pedersen J: The Pregnant Diabetic and Her Newborn. Baltimore, MD, Williams & Wilkins, 1977 2. Salvesen DR, Freeman J, BrudenellJM, et al: Prediction of fetal acidaemia in pregnancies complicated by maternal diabetes mellitus by biophysical profile scoring and fetal heart rate monitoring. B r J Obstet Gynaecol 10()1227-233, 1093 3. Schwartz R, C,ruppuso PA, Petzold K, et al: Hyperinsulinemia and macrosomia in the fetus of the diabetic mother. Diabetes Care 17:640-648, 1994 4. Naeye RL: Infants of diabetic mothers: A quantitative morphologic study. Pediatrics 35:980-988, 1965 5. SusaJB, WidnessJA, Hintz R, et al: Somatomedins and insulin in diabetic pregnancies: effects on fetal macrosomia in the human and rhesus monkey..] Clin Endocrinol Metab 58:1099-1105, 1984 6. Widness JA, Susa JB, Garcia JF, et al: Increased erythropoiesis and elevated erythropoietin in infants born to diabetic mothers and in hyperinsulinemic rhesus fetuses. J Clin Invest 67:637-642, 1981 7. McCann ML, Chert CH, t(atigbak EB, et al: The effects of fructose on hypoglucosemia in infants of diabetic mothers. N EnglJ Med 275:1-7, 1966 8. Isles PE, Dickson M, FarquharJW: Glucose intolerance and plasma insulin in newborn infants of normal and diabetic mothers. Pediatr Res 1:198-208, 1968 9. Pildes RS, Hart RJ, Warrner R, et al: Plasma insulin response during oral glucose tolerance tests in newborns of normal and gestational diabetic mothers. Pediatrics 44:76-82, 1969 10. Light IJ, Keenan WJ, Sutherland JM: Maternal intravenous glucose administration as a cause of hypoglycemia in the infant of the diabetic mother. Am J Obstet Gynecol 113:345-3~0, 1972

11. King KC, Adam PAJ, Clemente BA, et al: Infants of diabetic mothers: Attenuated glucose uptake without hyperinsulinemia during continuous glucose infusion. Pediatrics 44:381-392, 1969 12. Kalhan SC, Savin SM, Adam PAJ: Attenuated glucose production rate in newborn infants of insulin-dependent diabetic mothers. N EnglJ Med 296:375-376, 1977 13. Cowett RM, SusaJB, Giletti B, et al: Glucose kinetics in infants of diabetic mothers. Am J Obstet Gynecol 146: 781-786, 1983 14. Freinkel N: Diabetic embryopathy and fuel-mediated organ teratogenesis: Lessons from animal models. Horm Metabol Res 20:463-475, 1988 15. Milner liD, Hill DJ: Interaction between endocrine and paracrine peptides in prenatal growth control. EurJ Pediatr 146:113-122, 1987 16. D'ErcoleJA: Insulin-like growth factors and their receptors in growth. Endocrinol Metabol Clin North Am 25:573-590, 1996 17. Hadden DR: How to improve prognosis in type 1 diabetic pregnancy. Diabetes Care 22:B104-B108, 1999 (suppt 2) 18. TuomilehtoJ, Karvonen M, Pitk/iniemiJ, et al: Recordhigh incidence of type I (insulin-dependent) diabetes mellitus in Finnish children. The Finnish Childhood Type I Diabetes Registry Group. Diabetologia 42:655660, 1999 19. Suhonen L, Hiilesmaa V, Teramo KA: Glycemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus. Diabetologia 43: 79-82, 2000 20. Mimouni F, Miodowfik M, Siddiqi TA, et al: Perinatal asphyxia in infants of insulin-dependent diabetic mothers. J Pediatr 113:345-353, 1988 21. Teramo K, ,~anmfil~i P, Ylinen K, et al: PatholOgic fetal heart rate associated with poor metabolic control in diabetic pregnancies. Obstet Gynecol 61:559-565, 1983 22. Teramo KA, Widness JA, Clemons GK, et al: Amniotic fluid erythropoietin correlates with umbilical plasma erythropoietin in normal and abnormal pregnancy. Obstet Gynecol 69:710-716, 1987 23. Petty CD, Eaton MA, WobkenJD, et al: Iron deficiency of liver, heart, and brain in newborn infants of diabetic mothers. J Pediatr 121:109-114, 1992 24, Madsen H: Fetal oxygenation in diabetic pregnancy. Danish Med Bull 33:64-74, 1986 25. Madsen H, Ditzel J: Effect of smoking on red cell oxygen transport and release in diabetic pregnancy. Acta Obstet Gynecol Scand 63:77-80, 1984 26. Bj6rk O, Persson B: ViIlous structure in different parts of the cotyledon in placentas of insulin-dependent diabetic women. Acta Obstet Gynecol Scand 63:37-43, 1984 27. Nylund L, Lunell NO, Lewander R, et al: Uteroplacental blood flow in diabetic pregnancy: measurements with indium 113m and a computer-linked gamma camera. A m J Obstet Gynecol 144:298-302, 1982 28. Bj6rk O, Persson B, Stangenberg M, et al: Spiral artery lesions in relation to metabolic control in diabetes mellitus. Acta Obstet Gynecol Scand 63:123-127, 1984 29. Carson BA, Phillips AF, Simmons MA, et al: The effects of sustained insulin infusion upon glucose uptake and

Diabetes in Pregnancy and the Fetus and Newbozvz

30.

31.

32.

33.

34.

35. 36.

37.

38.

39.

40.

41. 42.

43.

44.

45.

46.

47.

oxygenation of the ovine fetus. Pediatr Res 14:147-150, 1980 MilleyJR, Rosenberg AA, Phillips AF, et al: The effect of insulin on ovine fetal oxygen extraction. Am J Obstet Gynecol 149:673-678, 1984 Phillips AF, WidnessJA, GarciaJF, et al: Erythropoietin elevation in the chronically hyperglycemic fetal lamb. Proc Soc Exp Biol Med 170:42-47, 1982 Widness JA, Teramo IgA, Clemons GK, et ah Direct relationship of antepartum glucose control and fetal erythropoietin in human type 1 (insulin-dependent) diabetic pregnancy. Diabetologia 33:378-383, 1990 Teramo K, Kaaja R, Leinonen P, et ah Fetal macrosomia is associated with chronic fetal hypoxia in IDDM pregnancies. J Soc Gynecol Invest 6:88A, 1999 (suppl; abstr) NOMESKO: Births in the Nordic Countries. Registration and outcome of pregnancy 1979-1983. Reykjavik 1987, p 32 Hagbard L: Pregnancy and diabetes mellitus. Aeta Obstet Gynecol Scand 35:1-180, 1956 (suppl 1) Devoe LD, YoussefAA, Castillo RA, et al: Fetal biophysical activities in third-trimester pregnancies complicated by diabetes mellitus. Am J Obstet Gynecol 171: 298-303, 1994 Tincello DG, el Sapagh KM, Walkinshaw SA: Computerized analysis of fetal heart rate recordings in patients with diabetes mellitus: the Dawes-Redman criteria may not be valid indicators of fetal well-being. J Perinat Med 26:102-106, 1998 C)stlund E, Hanson U: Antenatal nonstress test in complicated and uncomplicated pregnancies in type-l-diabetic women. EurJ Obstet Gynecol Reprod Biol 21:1318, 1991 Kjos SL, Leung A, Henry OA, et al: Antepartum surveillance in diabetic pregnancies: Predictors of fetal distress in labor. Am J Obstet Gynecol 173:1532-1539, 1995 Soler NG, Soler SM, Malins JM: Neonatal morbidity among infants of diabetic mothes. Diabetes Care 1:340350, 1978 Mills JL: Malformations in infants of diabetic mothers. Teratology 25:385-394, 1982 Molsted-Pedersen L, Pedersen JF: Congenital malformations in diabetic pregnancies. Clinical viewpoints. Acta Paediatr Scand 320:79-84, 1985 (suppl) Martinez-Frias ML: Epidemiological analysis of outcomes of pregnancy in diabetic mothers: Identification of the most characteristic and most frequent congenital anomalies. Am J Med Genet 51:108-113, 1994 Mills JL, Baker L, Goldman AS: Malformations in infants of diabetic mothers occur before the seventh gestational week. Implications for treatment. Diabetes 28:292-293, 1979 Cousins L: Etiology and prevention of congenital anomalies among infants of overt diabetic women. Clin Obstet Gynecol 34:481-493, 1991 Eriksson UJ, Borg LAH et al: Can fetal loss be prevented? The biochemical basis of diabetic embryopathy. Diabetes Rev 4:49-69, 1996 Eriksson UJ, Borg LAH: Diabetes and embryonic malformations: Role of substrate-induced free-oxygen rad-

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

133

ical production for dysmorphogenesis in cultured rat embr/os. Diabetes 42:411-419, 1993 Lee AT, Reis D, Eriksson UJ: Hyperglycemia-induced embryonic dysmorphogenesis correlates with genomic DNA mutation frequency in vitro and in vivo. Diabetes 48:371-376, 1999 Hagay ZY, Weiss Y, Zusman I, et al: Prevention of hyperglycenfia-associated embryopathy by embryonic overexpression of the free radical scavenger copper zinc dismutase gene. Am J Obstet Gynecol 173:10361041, 1995 Wentzel P, Thunberg L, Eriksson UJ: Teratogenic effect of diabetic serum prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo. Diabetologia 40:7-14, 1997 Miller E, HareJW, ClohertyJP, et al: Elevated maternal hemoglobin Alc in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med 304:1331-1334, 1981 Ylinen K, Aula P, Stenman U-H, et al: Risk of minor and major fetal malformations in diabetics with high haemoglobin Alc values in early pregnancy. Br Med J 289:345-346, 1984 Key TC, Giuffrida R, Moore TR: Predictive value of early pregnancy glycohemoglobin in the insulin-treated diabetic patient. Am J Obstet Gynecol 161:1096-2000, 1987 Miodovnik M, Mimouni F, Dignan PS, et ah Major malformations in infants of IDDM women. Vasculopathy and early first-trimester poor glycemic control. Diabetes Care 11:713-718, 1988 Greene MF, HareJW, ClohertyJP, et al: First-trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology 39:225-231, 1989 MillsJL, Knopp RH, SimpsonJL, et al: Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis. N EnglJ Med 318:671-676, 1988 Hanson U, Persson B, Thunell S: Relationship between haemoglobin Alc in early type 1 (insulin-dependent) diabetic pregnancy and the occurrence of spontaneous abortion and fetal malformation in Sweden. Diabetologia 33:100-104, 1990 Towner D, Kjos SL, Leung B, et ah Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care 18:1446-1451, 1995 Fuhrman K, Reiher H, Semmler K, et al: Prevention of congenital malfoiwnations in infants of insulin-dependent diabetic mothers. Diabetes Care 6:219-223, 1983 Goldman JA, Dicker D, Feldberg D, et ah Pregnancy outcome in patients with insulin-dependent diabetes mellitus with preconceptional control: a comparative study. Am J Obstet Gynecol 155:293-297, 1986 Kitzmiller JL, Gavin LA, Gin GD, et al: Preconception care of diabetes. Glycemic control prevents congenital anomalies. JAMA 265:731-736, 1991 Datum P, Molsted-Pedersen L: Significant decrease in congenital malformations in newborn infants of an unselected population of diabetic women. AmJ Obstet Gynecol 161:i163-1167, 1989 Miller HC: The effect of diabetic and prediabetic preg-

1340

64. 65. 66.

67. 68.

69.

70. 71.

72.

73.

74.

75.

76.

77.

78.

79.

80. 81.

82.

Schwartz and Teramo

nancies on the fetus and newborn infant. J Pediatr 29:455-461, 1946 Schwartz R, Teramo KA: What is the significance of macrosomia? Diabetes Care 22:1201-1205, 1999 Schwartz R, SusaJB: Fetal macrosomia: Animal models. Diabetes Care 3:430-432, 1980 Susa JB, McCormick, KL, Widness JA, et al: Chronic hyperinsulinemia in the fetal rhesus monkey: effects on fetal growth and composition. Diabetes 28:1058-1063, 1979 Acker DB, Sachs BP, Friedman EA: Risk factors for shoulder dystocia. Obstet Gynecol 66:762-768, 1985 Rouse DJ, Owen J, Godenberg RL, et al: The effectiveness and costs of elective cesarema delivery for fetal macrosomia diagnosed by ultrasound. JAMA 276:14801486, 1996 Lewis DF, Edwards MA, Asrat T, et al: Can shoulder dystocia be predicted? Preconceptive and prenatal factors. J Reprod Med 43:654-658, 1998 Reece EA, Coustan DR: Diabetes Mellitus in Pregnancy (ed 2). New York, NY, Churchill Livingstone, 1995 Landon MB, Mintz MC, Gabbe SG: Sonographic evaluation of fetal abdominal growth: predictor of the large-for-gestational age infant in pregnancies complicated by diabetes mellitus. Am J Obstet Gynecol 160: 115-121, 1989 Johnstone FD, Prescott RJ, Steel JM: Clinical and ultrasound prediction of macrosomia in diabetic pregnancy. B r J Obstet Gynaecol 103:743-754, 1996 Kastler B, Gangi A, Mathelin C, et al: Fetal shoulder measurements with MRI. J Comp Asst Tomog 17:777780, 1993 Baker PN, Johnson IR, Gowland PA, et al: Fetal weight estimation by echo-planar magnetic resonance imaging. Lancet 343:644-645, 1994 Sp6rri S, Hanggi W, Braghetti A, et al: Pelvimetry by magnetic resonance imaging as diagnostic tool to evaluate dystocia. Obstet Gynecol 89:902-908, 1997 Conway DL, Langer O: Elective delivery of infants with macrosomia in diabetic women: Reduced shoulder dystocia versus increased cesarean deliveries. A m J Obstet Gynecol 178:922-925, 1998 Halliday HL: Hypertrophic cardiomyopathy in infants of poorly controlled diabetic mothers. Arch Dis Child 56:2-58-263, 1981 Robert MF, Neff RK, Hubbell JP, et al: Association between maternal diabetes and the respiratoly distress syndrome in the newborn. N Engl J Med 294:35%360, 1976 Gluck L, Kulovich MW: Lecithin/sphingomyelin ratios in amniotic fluid in normal and abnormal pregnancy. Am J Obstet Gynecol 115:539-546, 1973 Liggins GC: Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol 45:515-523, 1969 Warburton D: Chronic hyperglycemia with secondary hyperinsulinemia inhibits the maturational response of fetal lamb lungs to cortisol. J Clin Invest 72:433-440, 1983 Hallman M, Teramo K: Amniotic fluid phospholipid profile as a predictor of fetal maturity in diabetic pregnancies. Obstet Gynecol 54:703-707, 1979

83. Kulovich MV, Gluck L: The lung profile. II. Complicated pregnancy. A m J Obstet Gynecol 135:64-70, 1979 84. Hallman M, Teramo K, Kankaanp/ifi K, et al: Prevention of respiratory distress syndrome: current view of fetal lung maturity studies. Ann Clin Res 12:36-44, 1980 85. Gellis SS, Hsia DYY: The infant of the diabetic mother. A m J Dis Child 97:1-41, 1959 86. Farquhar JW: Hypoglycaemia in newborn infants of normal and diabetic mothers. S Afr M e d J 42:237-245, 1968 87. Francois R, Picaud JJ, Ruitton-Ugliengo A, et al: The newborn of diabetic mothers. Biol Neonate 24:1-31, 1974 88. Chen CH, Adam PAJ, Laskowski DE, et ah The plasma free fatty acid composition and blood glucose of norreal and diabetic pregnant women and of their newborns. Pediatrics 36:843-855, 1965 89. Bloom SR, Johnston DI: Failure of glucagon release in inthnts of gestational diabetic mothers. Br MedJ 4:453454, 1972 90. Pennoyer MM, Hartmann AF Sr: Management of infants born of diabetic mothers. Postgrad Med 18:199206, 1955 91. Persson B, GentzJ, Kellum M: Metabolic obsecvations in infants of strictly controlled diabetic mothers. Acta Paediatr Scand 62:465-473, 1973 92. Cornblath M, Nicolopoulos D, Ganzon AF, et al: Studies of carbohydrate metabolism in the newborn infant. IV. The effect of glucagon on the capillary blood sugar in infants of diabetic mothers. Pediatrics 28:592-601, 1961 93. Wu PYK, Modanlov H, Karelitz M: Effect of glucagon on blood glucose homeostasis in infants of diabetic mothers. Acta Paediatr Scand 64:441-445, 1975 94. DCCT Research Group-Diabetes Control and Complications Trial (DCCT): The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N EnglJ Med 329:977-986, 1993 95. Craig WAS: Clinical signs of neonatal tetany: with especial reference to their occurrence in newborn babies of diabetic mothers. Pediatrics 22:29%308, 1958 96. Bergman L: Studies on early neonatal hypocalcemia. Acta Paediatr Scand 248:1-25, 1974 (suppl) 97. Tsang RC, Kleinman LI, SutherlandJM, et ah Hypocalcemia in infants of diabetic mothers. J Pediatr 80:384395, 1972 98. Tsang RC, Chen IW, Friedman MA: Parathyroid function in infants of diabetic mothers. J Pediatr 86:399404, 1975 99. Mimouni F, Tsang RC, Hertzberg VS, et ah Parathyroid hormone and calcitriol changes' in normal and insulindependent diabetic pregnancies. Obstet GynecoI 74:4954, 1989 100. Mimouni F, Loughead J, Miodovnik M, et al: Early neonatal predictors of neonatal hypocalcemia in infants of diabetic mothers: an epidemiologic study. A m J Perinatol 7:203-206, 1990 101. Mimouni F, Miodovnik M, Tsang RC, et al: Decreased amniotic fluid magnesium concentration in diabetic pregnancy. Obstet Gynecol 69:12-14, 1987 102. Taylor PM, Wolfson JH, Bright NH, et al: Hyperbilirn-

Diabetes in Pregnancy and the Fetus and Newborn

103.

104.

105.

106.

107.

108.

109. 110.

111.

112.

binemia in infants of diabetic mothers. Biol Neonate 5:289-298, 1963 Stevenson DK: Bilirubin metabolism in the infant of the diabetic mother: An overview, in Gabbe SG, Oh W (eds): Infant of the Diabetic Mother. Report of the 93rd Ross Conference on Pediatric Research. Columbus, Ohio 1987, pp 109-117 Mimouni F, Miodovik M, Siddiqi TA, et al: Neonatal polycythemia in infants of insulin dependent diabetic mothers. Obstet Gynecol 68:370-372, 1986 Oh W: Pathophysiology of polycythemia in infants of diabetic mothers, in Gabbe SG, Oh W (eds): Infant of the Diabetic Mother. Report of the 93rd Ross Conference on Pediatric Research. Columbus, Ohio 1987, pp 133-141 Black VD: Polycythemia and the infant of the diabetic mother, in Gabbe SG, Oh W (eds): Infant of the Diabetic Mother. Report of the 93rd Ross Conference on Pediatric Research. Columbus, Ohio 1987, pp 142-148 Avery ME, Oppenheimer EH, Gordon HH: Renal-vein thrombosis in newborn infants of diabetic mothers. N EnglJ Med 256:1134-1138, 1957 Warram JH, Krolewski AS, Kahn CR: Determinants of IDDM and perinatal mortality in children of diabetic mothers. Diabetes 37:1328-1334, 1988 Farqnhar JW: Prognosis for babies born to diabetic mothers in Edinburgh. Arch Dis Child 44:36-47, 1969 Schrier AM, Wilhelm PB, Chttrch RM, et al: Neonatal hypoglycemia in the rhesus monkey: effect on development and behavior. Infant Behav Develop 13:189-207, 1990 Bibergeil H, Bodel E, Amendt P: Diabetes and pregnancy: early and late prognoses of children of diabetic mothers, in Camerini-Davalos RA, Cole HS (eds): Early Diabetes in Early Life. New York, NY; Academic Press 1975, pp 427-434 Vohr BR, McGarvey ST, Tucker R: Effects of maternal gestational diabetes on offspring adiposity at 4 to 7 years of age. Diabetes Care 22:1284-1291, 1999

135

113. Yssing M: Long-term prognosis of children born to mothers diabetic when pregnant, in Camerini-Davalos RA, Cole HS (eds): Early Diabetes in Early Life. New York, NY, Academic Press, 1975, pp 575-586 114. StehhensJA, Baker GL, Kitchell M: Outcome at ages 1, 3 and 5 years of children born to diabetic women. AmJ Obstet Gynecol 127:408-413, 1977 115. Jovanovic-Peterson L, Peterson CM, Reed GF, et al: Maternal postprandial glucose levels and infant birth weight: The diabetes in early pregnancy study. Am J Obstet Gynecol 164:103-111, 1991 116. Persson B, Gentz J: Follow-up of children of insulindependent and gestational diabetic mothers. Neuropsychological outcome. Acta Paediatr Scand 73:349358, 1984 117. Stenninger E, Flink F, Eriksson B, et ah Long-term neurological dysfunction and neonatal hypoglycaemia after diabetic pregnancy. Arch Dis Child, Fetal and Neonatal Edition 79:F174-179, 1998 118. Lorenzen T, Pociot F, Stilgren L, et al: Predictors of IDDM recurrence risk in offspring of Danish IDDM Patients. Danish IDDM Epidemiology and Genetics Group. Diabetologia 41:666-673, 1998 119. Rowe RE, Leech NJ, Nepom GT, et ah High genetic risk for IDDM in the Pacific Northwest. First report from the Washington State Diabetes Prediction Study. Diabetes 43:87-94, 1994 I20. Komulainen J, K_nip M, Sabbah E, et aI: Autoimmune and clinical characteristics of type I diabetes in children with different genetic risk loads defined by HLA-DQB1 alleles. Child Diabetes in Finland Study Group. Clin Sci 94:263-269, 1998 121. etdcerblom HK, Kuip M, Hy6ty H, et ah Interaction of genetic and environmental factors in the pathogenesis of insulin-dependent diabetes mellitus. Clin Chem Acta 257:143-156, 1997