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Diabetic pregnancy and perinatal morbidity
CURRENT DEVELOPMENTS
Diabetic pregnancy and perinatal morbidity JOHN
L. KITZMILLER,
JOHN
P. CLOHERTY,
M.
DONNA
ASHRAF SUZANNE ILENE
M.D. M.D.
YOUNGER,
M.D.
TABATABAII, B.
M.D.
ROTHCHILD,
SOSENKO,
MICHAEL
F. EPSTEIN,
SHAILINI
SINGH,
RAYMOND
K.
M.D.
M.D.
NEFF,
M.D.
M.D. Sc.D.
Boston, Massachusrtts Pregnancy outcome was analyzed in 147 diabetic women, 71 per cent of whom were dependent on insulin for more than 10 years. Ambulatory management of diabetes was carried out with weekly clinic visits until hospitalization at 36 to 37 weeks’ gestation. Modern methods of fetal assessment were applied, and the timing and route of delivery were individualized. Of these patients, 35 per cent were delivered at or beyond 38 weeks’ gestation. The primary cesarean section rate was 55 per cent. Polyhydramnios was a frequent maternal complication and was associated with premature labor and neonatal death in two cases. Poiyhydramnios was least common in women with the lowest mean outpatient blood glucose. The perinatal survival rate was 96.6 per cent, and there were no instances of unexpected intrauterine fetal death. The incidence of respiratory distress syndrome (RDS) in the newborn infant was 7.6 per cent. No severe RDS was seen when the lecithinisphingomyelin (L/S) ratio was greater than 3.0, but three of 24 infants delivered with an L/S ratio of 2.1 to 3.0 developed severe RDS. Other forms of neonatal morbidity noted in this population were 9 per cent major congenital anomalies; 7 per cent transient tachypnea of the newborn, 22 per cent hypocalcemia, 19 per cent hyperbilirubinemia, and 47 per cent hypoglycemia. The latter was more common in macrosomic infants, defined as greater than the ninetieth percentile of birth weight for gestational age (LGA), who represented 36 per cent of the neonates. Mean outpatient postprandial blood glucose was higher in patients delivered of LGA infants and was correlated with birth weight in White Classes 6 to D. (AM. J. OBSTET. GYNEWL. 131: 560, 1978.)
From the Departments of Obstetrics and Gynecology, Pediatrics, and Medicine, Boston Hospitalfor Women and the Jo&n Clinic, Haruard Medical School, and the Health Sciences Computing Facility, Harvard School of Public Health. Reprint requests: Dr. John L. Kitzmilier, Boston Hospital for Women, See&y G. Madd Bldg., 250 Longwood Ave., Boston, Massachusetts 02115.
560
DIABETES MELLITUS antedating pregnancy is recognized as an important cause of maternal morbidity, birth defects, intrauterine fetal death, and neonatal morbidity and death. An increased incidence of these complications has been associated with duration of diabetes, the presence of vascular lesions, and the degree of control of the diabetic state during pregnancy. OOOZ-937&I/78/05131-0560$02.10/O
0 1978 The C. V. Mosby Co.
Diabetic
Patients with poor control of diabetes have a higher risk of fetal or neonatal death, and the occurrence of ketoacidosis. in particular, carries an excessive rate of fetal ,oss.s:~.87. 103* n addition, Pedersen and associates 74 pointed our that patients who are noncompliant (neglectors) and do not cooperate with the treatment plan have an increased risk of pregnancy loss. The importance of diabetic control during pregnancy received impetus from Karlsson and Kjellmer’s”’ study of 95 gravid patients well distributed throughout the White classifications in the years 1966 to 1970. They measured blood glucose several times a day in hospitalized patients after 30 to 32 weeks’ gestation. The group with the lowest mean preprandial glucose values (
Background Maternal morbidity. In the first half of pregnancy there is often an improvement of carbohydrate tolerance in the insulin-dependent diabetic woman.73 The cause may be related to fetal-placental utilization of glucose.“” The improvement in tolerance is manifested clinically by increased frequency and severity of hypoglycemic reactions, which may appear in the absence of warning signs. lo3 Later in pregnancy decreased carbo-
pregnancy
and perinatal
morbtdity
561
hydrate tolerance is the rule, with an inc rc;~secl dosage of insulin demanded, and there is a strotlg tendenc\ to the rapid development of ketoacidosis.“’ l%csc diahetogenic effects of pregnancy are related IO ,intagonisni of the peripheral effects of insulin anti rt~h;~ncrd lipolysis and ketogenesis in the tasting stat<‘. i’rogressivc placental secretion of human placental lac-togen is ;I major factor in the altered metabolism (bt gestatioll.“’ Vascular complications, sur11 its prollti,rating retinopathy and glomerular nephropathv, JIXI thr tragic hallmark of many cases of diabetes 01’ ll,ng duration. Information on the effect of pregnanc’v OII the vascular complications of diabetes is limited SPIKY no svstemati( studies of the effect of pregnancv OII the irdrnte OIcourse of benign or proliferating rctinclpathv have been performed. Contrasting opinions th,tt pt-qnatw induces rapid progression, has no t+fGci on diabetic retinopathy, and has a beneficial ettcc I OII diabetic, retinopathy and that remissions occur followi~lg complytion of pregnancy have been advanced.‘, x In ;I series of 2.147 diabetic pregnant patients rep0rtc.d tn White,‘03 the incidence of malignant pr~Jlftrating retinopathy was 0.5 per cent and the incidertc c of benign retinopathy was 2.9 per cent. These wmrn devrloprd lesions during pregnancy, and the much larger group of women in whom retinal disease precrded pregnant.! was not taken into account. It has keen buggcasted that proliferating diabetic retinopathk, in colbtrast IO the benign form, has a greater bur unpredictable tendency to progress during pregnancy, cspeciall~ if the proliferating phase is. noted during the first trimester? This was the basis for the recommendaGor1 i.or termination of pregnancy in diabetic patients developing proliferating retinopathy.“g However. irr I CYCnt ycarh many cases of proliferating retinopathv tlul-ing prepnancy have been controlled b), laser photr~coagt~iation therapy. Since the effect of this therapy on the natural histo,? of retinopathy during and after prt’~nancy has not been systematically studied, 2 the quctiott of longterm consequences remains. Determination of the incidence and prognosis of diby thr abetic nephropathy in pregnancx ,’ is clouiieti tendency of the diabetic pregnant woman to dej,elop pyelonephritis or pre-eclampsia.“’ The t’e:v ‘tvailablt studies reviewed by Pedersen79 suggest that L linical and laboratory parameters of diabetic nephropathy usuali! return toward the prepregnancy level after delivcsr\ .i’t In a series from 1959 to 1963, Pedersen and Pedersen” found urinary tract infection to be present in I6 pet cent and clinical pyelonephritis to be present in 6 per cent of 283 pregnant women with diabctcbs. An increased perinatal mortality rate was assoc~iated with pyelonephritis and with pre-eclampsia711~~ thr above
562
Kitzmiller
et al.
series Pedersen and Pedersen7j classified 23 per cent of patients as having pre-eclampsia on the basis of acute hypertension, proteinuria, edema, or weight increase. In a review of the literature published in 1963, Kyle”” reported an average incidence of toxemia of 25 per cent (range: 8 to 45 per cent). The superimposed preeclamptic syndrome is perhaps most common, devastating, and difficult to diagnose in patients with White Class F diabetes.” Polyhydramnios is a common maternal complication of diabetic pregnancy. For the years 1959 to 1964, Pedersen and Pedersen?” reported a 25 per cent incidence. The cause of polyhydramnios remains uncertain in most cases. It is not usually related to congenital malformations of the fetus. In addition, there is no relationship between amniotic fluid volume and the expected elevation in glucose and other solutes in the amniotic fluid9 A recent study did not find increased fetal output of urine (as measured by ultrasound) in patients with increased volumes of amniotic fluid.gg Pedersen73 found a lower incidence of polyhydramnios in hospitalized as compared to ambulatory patients in the latter part of pregnancy. However, the relative contribution of bed rest in the hospital as compared to tighter diabetic control in that study remains uncertain. Antepartum fetal distress. The actual cause of intrauterine fetal distress and death during diabetic pregnancy remains unknown in most cases. As noted above, there are clinical associations with severe maternal hyperglycemia and ketosis, hypertensive syndromes, and pyelonephritis.7” The risk increases later in pregnancy. lo3 Whether or not the risk of fetal death is increased during episodes of maternal (thus fetal) hypoglycemia remains controversiaLz7s Ia3 Fetal monitoring tests of various types have been widely applied in the last decade in the presumption that fetal distress can be diagnosed and stillbirth prevented by prompt delivery. One reflection of the fetal condition is obtained by measuring the concentration of estriol in maternal blood or urine. Since the fetal adrenal and liver provide the precursor (16a-hydroxydehydroepiandrosterone) for placental aromatization to estriol, the accumulation of this estrogen in maternal fluids is often representative of fetal-placental function. The pattern of serial values in a given woman is important since there is wide variation in amount of estriol from one diabetic patient to another. Many have reported higher mean urinary estriol values in diabetic pregnant women, usually in association with fetal macrosomia and placentomegaly.s2 It is clear that estriol levels must be measured daily in order to detect the rather sudden onset of fetal distress observed in some pregnancies of diabetic women.38, jZ,78 Low urinary es-
July I. 1978 Am. J. Ohet. Gynecd.
trio1 values may be found in diabetic women with vascular or renal complications, and this may be indicative of’ intrauterine fetal growth retardation. Antepartum fetal heart rate monitoring has also been applied as a measure of fetal well-being in diabetic pregnancies. This tool is based on extensive studies of fetal cardiovascular responses to hypoxia carried out in the last decade. Experimentally, in pregnant sheep and monkeys, maternal hypoxia or impaired placental perfusion generally leads to fetal hypoxia with resultant decelerations of the fetal heart rate and decreased beat-to-beat variability. Similar heart rate patterns are observed in some human fetuses in response to the transient hypoxia of uterine contractions, cord compression, and maternal vascular disease or from unknown causes. When delivered, a higher percentage of such fetuses as compared to control fetuses have low Apgar scores, hypoxia, and acidosis. The high-risk fetus of the diabetic pregnant woman has an increased incidence of such distress during antepartum fetal heart rate monitoring tests and during labor.“‘, gfi Fetal macrosomia, liyperinsulinism, and neonatal hypoglycemia. The infant of the diabetic mother (IDM) is particularly prone to macrosomia (largebirth-weight syndrome). Mean birth weight in the IDM was 550 grams more and mean length was 1.5 cm greater than that in a group of control infants (mean gestational age of 260 days and matched for various maternal data).‘” Osler and Pedersen7’ concluded that the macrosomic IDM contains less total body water and that the increase in weight is due to increased fat, postulated to be deposited as the result of excessive insulin secretion. It is plausible to consider the large size of the organs of the IDM and the excessive accumulation of’ fat and glycogen in these organs to be due to the excess quantities of nutrients (glucose, amino acids, and free fatty acids) available to the fetus of the pregnant woman with diabetes. Such nutrients alone without insulin to facilitate their transport into cells would not be sufficient to explain the enlargement of muscle tissues (including heart) and adipose tissue. Evidence to date suggests that the fetus of the diabetic mother is hyperinsulinemic. Pedersen’” explained the origin of the fetal hyperinsulinism as follows: Maternal diabetes is associated with maternal hyperglycemia which leads to fetal hyperglycemia and excessive stimulation of the fetal pancreas to produce insulin. There is a strong correlation of glucose levels in maternal and fetal bloodstreams. Crawford’” demonstrated a maternalto-fetal glucose difference of 13 mg. per 100 ml. and concluded that the gradient of maternal-fetal glucose concentrations is maintained in a minute-to-minute
Diabetic
fashion, even in the presence of a rapidly changing glucose concentration in maternal blood. Spellacy and associate?” described a direct relationship between the blood glucose of mother and infant across the placenta; they also found that the infant’s umbilical vein glucose was always lower than the maternal venous glucose. In the pregnant rhesus monkey, Chez and colleagues” found a close correlation of fetal glucose levels with maternal ones, with no evidence of an upper limit of placental glucose transfer. The regulation of insulin release during fetal life has attracted a great deal of attention. The results of studies in this field indicate that glucose is a less efficient stimulus to insulin release in the fetus than in the adult.” However, a sustained increase of the fetal blood glucose concentrarion in utero may induce a significant rise of the fetal plasma insulin level. Arginine or leucine in the presence of glucose can markedly enhance the fetal insulin release. Therefore, the fetus of the pregnant woman with diabetes exposed to high levels of glucose and amino acids in the blood has the potential for early maturation of the pancreatic beta cell. Steinke and Driscoll”’ found that the content of insulin per gram of pancreas in the IDM was significantly higher than in control infants. They also showed microscopically that the pancreas of the IDM had hypertrophy and hyperplasia of the pancreatic islets as a result of proliferation of the beta cells. Shima and associates”” found a strong correlation between birthweight in overgrown infants and the infants’ serum insulin levels, indicating that the excessive size of certain newborns may be the result of hyperinsulinism. Cardell’ found a correlation between the quantity of islet tissue at autopsy and the birth weight of the IDM. A large number of studies have shown more rapid attainment of a higher peak plasma insulin level, resulting in a more rapid disposal of glucose in IDM as compared to control infants when both groups were exposed to glucose infusions.‘. J”. 64,69 The insulin assayed in the infants was of fetal rather than maternal origin, as demonstrated in the studies of Adam and associates’ and Spellacy and associates,gl who concluded that maternal insulin does not cross the placenta. Measurement of C-peptide has provided an alternative means of monitoring beta-cell function in the presence of maternally derived insulin antibodies, which cross the placenta and interfere with the usual radioimmunoassays for insulin in fetal and newborn blood. C-peptide immunoreactivity was examined by Block and coworkers” in IDM’s and compared to infants of mothers with gestational diabetes and control infants6 The) found that cord C-peptide immunoreactivity levels were significanth higher in infants of diabetic mothers
pregnancy
and oertt:ata!
morbidity
563
as compared with those of normal O>~III-O~ inlants: therefore, a slightly different approa.il ~\‘;t+ ~tsed IO confirm hyperinsulinism in the 111x1. A common problem in the IDM is cal-ly postnatal hypoglycemia, secondary to exe essivca insulin secretion after division of the umbilical cxjrd and rhe termination of placental transfer of glucose. Hww\cr. the association of severe neonatal hypoglycemia with cord insulirt levels has not been demonstratrd in :111 studies.“” Johnston and Bloom’g suggested thar the neonatal pancreatic glucagon response to Ihc* postnatal fall in glucose is inappropriately small irl rhc LD>l. especialI) in cases with sustained hypoglycemia. 1ncreased Fetal glucose and insulin concentrations have been shown to inhibit basal and alanine-stimulated glut ;~gon secretion in the normal newborn infant.“‘. 62 ~~ur~w~t studies ot hepatic glucose output in normal infants and IDM’s should increase our understanding of nronat;~l hvpcvglycemia. Neonatal pulmonary complications. [‘he nujw cause of mortality in the IDM in the past has been RDS. This was the conclusion of Driscoll and aqsoc’iates”‘. x0 in their review of 55 autopsies of IDM’s. all
564
Kitzmiller et al.
and physiologic development has led to the use of animal models of diabetic pregnancy and in vitro examination of the fetal lung. Epstein and co-workers23 used the rhesus monkey fetus from mothers rendered hyperglycemic by the injection of streptozotocin, a specific pancreatic beta-cell cytotoxin. They observed marked differences between the normal and hyperglycemic fetuses in the ability of the lung to synthesize, store, and release lecithin, the principal component of the surface-active material in the lung. Sosenko and co-worker?’ have reported preliminary observations in another animal model of diabetic pregnancy, the alloxan-treated rabbit. At 27% days’ gestation, the hyperglycemic rabbit fetuses showed less surface-active material in pulmonary lavage fluid and demonstrated less deflation stability in pressure-volume measurements when compared with control fetuses. These studies indicate that the maternal diabetic state affects fetal lung development; the exact mechanism of this interaction has been examined in a cell culture system by Smith and associates.88 They utilized a monolayer cell culture system of the fetal rabbit lung and examined the effect on lecithin synthesis when insulin was added to the culture system. They found that, although insulin alone results in a small but significant increase in lecithin synthesis, the addition of both insulin and cdrtisol to cell culture results in a marked diminution of the stimulatory effect observed when cortisol alone was added. Since cortisol is thought to be the physiologic stimulus for the increased synthesis of lecithin in the fetal lung seen at approximately 90 per cent of term gestation, they hypothesized that insulin might interfere with this normal increase in lecithin synthesis. This increase in lecithin synthesis is responsible for the normal functioning of the neonatal lung at term; therefore, the elevated insulin concentration in fetal plasma in IDM’s may interfere with this normal maturational sequence and lead to the increased incidence of RDS seen in IDM’s. Although there have been no controlled studies examining this hypothesis, improved control of the maternal-fetal hyperglycemia may minimize the abnormalities in fetal lung maturation and lead to a decreased incidence of RDS. Neonatal hypexbilirubinemia and hypocalcemia. Hyperbilirubinemia and hypocalcemia are commonly found in the early life of the IDM. Hyperbilirubinemia was noted in 38 per cent of the newborn infants studied by Pedersen73 and in 27 per cent of those studied by Essex and co-workers,24 but these authors used a low limit of normal (10 mg. per deciliter). The cause of the hyperbilirubinemia is presumed to be related to func-
July I. 1978 Am. J. Obstet. Gynecd.
tional prematurity of hepatic enzymes necessary for the conjugation of bilirubin.70 hypocalcernia Tsang and colleagues sfi demonstrated in six of 10 infants of mothers with White Classes B, C, and D. The incidence of hypocalcemia was increased over that in a matched control group even when gestational age and perinatal complications were considered. Pedersen73 found hypocalcemia in 10 per cent of IDM’s in a recent series. Hypomagnesemia wasnot observed. The cause of neonatal hypocalcemia is unknown but may be related to persistent functional hyperparathyroidism in these infants.“” Congenital anomalies. Almost all investigators have found an increased incidence of major birth defects in offspring of diabetic mothers compared to those of control populations. Studies of the incidence and pathogenesis of congenital anomalies in IDM’s have been reviewed recently by Gabbe.“” Varied types of anomalies, including anencephaly-meningocele,2j transposition of the great vessels, ventricular septal defect, coarctation of the aorta,“’ caudal regression syndrome and vertebral dysplasia,3s ** ureteral duplication, renal agenesis,” and anal atresia.R7 are observed. In a retrospective review, Naeve 68 found no increase in malformations in infants born to diabetic fathers and nondiabetic mothers as compared to normal fathers. Pedersen,73 Koller,“3 and Naeve6” all reported an increased risk of congenital anomalies in infants born to mothers with White Classes D, F, and R diabetes, suggesting associations with duration of maternal disease and vascular complications. It is probable that there are multiple etiologic factors in the increased incidence of anomalies in IDM’s. The role of genetic factors has not been substant.iated.3”, 6H Molsted-Pederson and associates69 speculated that fetal hypoxia could play a role in diabetic pregnancies complicated by vascular disease, but they later concluded that better metabolic control in the same group of patients reduced the risk of birth defects.73 Similarly, Karlsson and Kjellmer”’ observed a low incidence of anomalies in offspring of the subgroup of pregnant women with diabetes easiest to control later in pregnancy. Hypoglycemia may be associated with an increased risk of fetal malformations. Insulin injected into chick and rodent embryos produced vertebral and bony anomalies.40~ 47, 56 The anomalies were decreased when hypoglycemia was prevented by adding glucose to the preparationsjo Hyperglycemia may also be a cause of fetal anomalies. Litters born to diabetic mice have an increased incidence of limb malformations and cleft palate. When the mothers are treated with insulin, this
Diabetic pregnancy and perinatal morbidity
increased incidence is eliminated.“j While the mechanism of the effect of hyperglycemia is uncertain, it may involve the role of collagen in inducing embryogenesis.‘” Fibroblasts grown in medium containing a high level of glucose secrete more collagen as compared with fibroblasts in medium containing physiologic amounts of glucose. Ino -4 large amount of this collagen mav be converted to glycosyl and one can speculate that alteration of the collagen molecule in terms of carbohydrate moieties might affect the induction process. Since fetal hyperinsulinism in the IDM should not occur until the fetal pancreas is functional, well after the major period of morphogenesis, endogenous insulin should not be a cause of malformations.
Clinical study The dilemma of traditional management of pregnancy in the diabetic patient has been to time delivery to balance the risk of stillbirth late in gestation with that of neonatal death from pulmonary immaturity earlier in gestation. Recent conceptual and technologic advances in the realm of fetal assessment have offered the opportunity of individualized management for each diabetic pregnant woman. This is our initial report on the application of these techniques to a large population of pregnant women with insulin-dependent diabetes in an attempt to reduce perinatal deaths to a minimum. Diabetic pregnancy is both a mode1 for the team approach to perinatal medicine and a test of the utility of our diagnostic measures.
Subjects and methods Patient population. During 1975 to 1978, 175 women registered at the pregnancy clinic of the Joslin Diabetes Foundation. Twenty-eight women aborted, 21 spontaneously (12 per cent) and seven electively ‘(4 per cent). Th,is includes three women (2 per cent) who underwent late abortions after the ultrasonographic diagnosis of fetal anencephaly. This report analyzes our experience with the remaining 147 women whose pregnancies attained 24 weeks’ gestation. Table I describes the White classification and the parity of this group of women. Chemical diabetes was diagnosed during pregnancy in 9 per cent of the patients (by a 100 Gm. oral glucose tolerance test), with the diagnostic criteria of O’Sullivan and associates.72 Class B includes three subjects with newly diagnosed diabetes who were hyperglycemic despite dietary therapy and who were begun on a regimen of insulin therapy during the pregnancy. Among the 37 patients with Class D diabetes, 23 were so characterized on the basis of onset of diabetes under age 10 or duration of diabetes for more
8 9
565
-‘x .9B*b CONFIDENCE LIMITS FOR NORMAL PREGNANCY
50
I
FASTING
I HOURS AFTER
2
x
BREAKFAST
Fig. 1. Solid line indicates the upper limit established by O’Sullivan and co-workers72 for normal random blood glucose values in pregnant women. The difference from normal was calculated for each clinic visit of our diabetic subjects and expressed as A0.B.G. Mean A0.B.C;. was computed for each pregnancy. Broken lines divide distribution of mean A0.B.C.. values for 134 insulin-dependent subjects into thirds. than 20 years, and 14 were classified on the basis of (Class F) benign re tinopathy. lo3 Diabetic nephropathy is presumed when proteinuria greater than 400 mg. per 24 hours is found in early pregnancy, in the ahsence of infection. Renal biopsies were not perfc>rmed. The two patients with Class R diabetes received laser photocoagulation therapy for proliferativc~ retinopath) during pregnancy. Outpatient management. Patients we9~ seen weekly in a combined medical and obstetric. clinic. Dietary adherence and symptoms of hypoglycemia were reviewed. The therapeutic diet averaged X? calories per kilogram of body weight during pregnancy with the following caloric distribution: breakfast, ‘/a; lunch. ‘/5; and supper, z/3, with allowance for thlec-hour postprandial snacks. Sufficient carbohydrate, was given to minimize ketonuria (usually 190 to 200 Gm. per da) during the first and second trimesters, often 200 to 240 Cm. per day in the third trimester); l..> ttr 2.0 Cm. of protein per kilogram of body weight during pregnant) was given, and the caloric prescription was completed with fat. Insulin dosage was ad-justed weekly by the physician on the basis of home urine texts for glucose and acetone (second voided specimen bef’ore meals and at bedtime, Clinitest* two-drop method), level of exercise, hypoglycemic reactions, and the glucose concentration in whole blood at the time of the c-linic visit. By the second half of pregnancy most patients received a 1: 2 mixture of regular: NPHS or lente insulin, with an appropriate fraction of the dose given before supper. The goal of therapy was to maintain blood glucose levels as close to normal as possible without incapacitating the patients with hypoglycemic reaction\ *Ames Co., Inc., Elkhan, Indiana. tE. R. Squibb, Princeton, New Jerset,.
566
Kitzmiller et al.
The 98 per cent confidence limits for random blood glucose levels in normal pregnant women, published by O’Sullivan and co-workers,‘2 were used to establish a nomogram for outpatient blood glucose (O.B.G.). The difference from normal blood glucose for each clinic visit was calculated (A0.B.G.; Fig. l), and the average A0.B.G. for each pregnancy was determined. Estrogen-progesterone injections were given to only 21 per cent of the subjects, since this practice was discontinued in 1975. Ultrasound p-scans were obtained routinely at 18 to 20 weeks’ gestation to confirm the length of gestation and to rule out gross fetal anomaly. Urine samples over a 24 liour period were collected weekly for estriol and creatinine measurement after 30 weeks’ gestation. Low estriol levels were defined as below the 95 per cent confidence limits for total urinary estrogen for gestational age in normal pregnancy. Oxytocin challenge tests (OCT’s) were performed weekly after 33 weeks’ gestation by the following method: oxytocin was administered by intravenous infusion pump in a graduated manner until three contractions occurred in a 10 minute period. A test was considered positive when more than 50 per cent of all contractions were associated with late decelerations of the fetal heart rate. A test was considered suggestive when any late decelerations were observed. Patients with low or declining urinary estriol, suggestive or positive OCT. poor control of diabetes, or complications such as severe pregnancy headache, polyhydramnios diagnosed by clinical examination, pre-eclampsia, or severe renal disease were admitted to the hospital for intensive monitoring. Patients without complications were routinely admitted at 36 to 37 weeks’ gestation. Inpatient management. In the antepartum special care unit the insulin regimen and diet were modified on the basis of the reduced level of exercise and the concentration of glucose in venous plasma or capillary blood measured two to four times daily. Monitoring for antepartum fetal distress consisted of daily measurement of urinary estriol and creatinine levels over 24 hours and a weekly OCT. An acute fall in estriol was defined as greater than 40 per cent decrease from the mean of the previous three days. The OCT was performed more often if there was a previously inadequate or suggestive test or a low estriol level or when hypertension was present. Amniocentesis was performed (when possible) prior to consideration of delivery to predict fetal pulmonary maturity, usually at 36 to 37 weeks’ gestation. Amniocentesis was frequently performed in the ultrasound laboratory to select the best tap site. The L/S ratio was measured according to the method of Gluck and col-
July
1, 1978
Am. J. Obstet. Gynecoi.
leagues36 by densitometry. Total amniotic fluid cortisol (conjugated and unconjugated) was determined by- a modification of the radioimmunoassay for plasma cortisol.2R Once an L/S ratio judged to be mature was obtained, patients with a previous cesarean section were delivered by repeat operation. Prior to 1976. 2.0 was thought to indicate fetal lung maturity. After 1976, an L/S ratio of 3.5 was used. Patients who were candidates for vaginal delivery were observed until the cervix was believed to be ready for induction of labor, unless maternal or fetal distress supervened, or unless the attending obstetrician and patient decided on a primary cesarean delivery on the basis of- a large fetus (eight cases). In this way the timing and route of delivery were individualized. On the morning of a scheduled repeat cesarean section no insulin was given until the patient was in the recovery room. When labor ensued or was induced or a cesarean section was scheduled later in the day, insulin was cut to half of the prepregnancy level for the day of delivery and intravenous dextrose was administered. During labor. the fetal heart rate was monitored with an internal scalp electrode, and scalp pH was measured when indicated. Intrapartum fetal distress was defined as persistent late decelerations and a scalp pH less than 7.25. Epidural anesthesia was used frequently during labor and regional block or balanced general anesthesia (thiopental sodium, nitrous oxide, and succinylcholine) was used for cesarean delivery.16 Neonatal management. All IDM’s were initially observed in the Special Care Nursery. The plan of management has been published.” Length of gestation was determined by usual obstetric criteria, including ultrasound, and was confirmed by clinical or Dubowitz assessment of the neonate.’ ” The following laboratory studies were routinely done: blood glucose at one, two, three, six, 12, 24, 36, and 48 hours of age; total serum calcium at six, 12, 24, and 48 hours: direct and indirect serum bilirubin at 24 and 48 hours. We began early feedings of “well” infants with bottle or gavage of 5 ml. of 10 per cent dextrose per kilogram by one hour of age. Hourly feedings were continued until the blood glucose was stable; thereafter infants were fed every two hours and then every three hours with increasing volume. By 12 hours of age most infants received 20 calories per ounce of formula with dextrose as needed. Infants were transferred to breast-feeding as soon as possible, when desired by the mother. Neonatal hypoglycemia was defined as a blood glucose level below 30 mg. per deciliter in any infant, regardless of gestational age and whether or not they were symptomatic. If feedings were not tolerated (large volumes retained in the stomach) or hypoglycemia
Diabetic pregnancy and perinatai morbidity 567
Table
I. White’s classification,parity, and degree
of hyperglycemia
in diabetic
subjects (mean
z s.D.)
Menn (i S.I).J Parity No.
1
2
23
5 10 28 'Lo 5 -! 69
4 9 18 12 1 1 4'3
4 11 11 5 2 0 33
clar.<
13 30 57 37 H L' 147
A B C I) F R
No. of clinic visits
A0.B.G. * (mg. ldl.)
Days HI hospi&l pmr to &l&q
17 -c 6 19 f 7 i9+-7 20 f 5 18 k 7 27, 17
-132 14 +66 f 30 +65-+28 +67 rt33 +69? 57 +40,+78
10 5 7 10 17 13 jI 7 21 I 16 28,27
*A.O.B.G. = Mean blood glucose difference from normal for all outpatient Table 1Y 0. 13 30 57 37 8
II. Maternal Cl4.SS A B c II F
piasma, glwosr in hospital (mg. idl. i
Perinfltal .sunlival rate( %)
9 1' II
7,4..!4. 106 " 34 111243 113-c-41 1212 36 105, 94
137 It ‘.!9 14 1 2 214 k47 + 52 139 t ‘14 16O. I.17
100 93.3 IO0 94.6 87.5 100 96.6
visits.
complications
Pregnancy headache
Keto-
acidosis
Pyelonephritis
Genml edema
Pobhydramnias
P?v?mture labor
Preeclampsia
T~0?lSit%nt
hypertension
C’hronir
hypertaszon
I-hyroid disease
I 2
1 2
1
1
I 1
(2%)
(3%)
(1%)
2 4 2 5
8 19 15 4
3 3 2 1
1 3 3
4 1
(9%)
(31%)
(6%)
(5%)
(4%)
persisted. treatment with intravenous dextrose was instituted. Infants weighing <2,000 grams or in distress were not fed but were given 10 per cent dextrose by intravenous infusion. Hypocalcemia was defined as a total serum calcium level klow 7 mg. per deciliter and was treated by oral or intravenous therapy. Hyperbilirubinemia was defined as an indirectly reacting bilirubin level greater than 15 mg. per deciliter. Early treatment with phototherapy or exchange transfusion was instituted to prevent any rise in unconjugated biliruhin that might have resulted in free bilirubin (unbound to albumin) in the plasma.” The presence of free bilirubin was detected with the Kernlute assay. A positive test led to immediate exchange transfusion. Criteria for the diagnosis of RDS in the neonate were clinical signs (grunting, retractions, respiratory rate >60 per minute), typical findings at roentgenography (diffuse reticulogranular pattern and air bronchograms”‘“), and an increased oxygen requirement (to maintain the Pao, at 50 to 70 torr) for >48 hours with no other identified cause of respiratory difficulty (i.e., heart disease, infection). For classification of severity of RDS see Table IX. Criteria for the diagnosis of transient tachypnea of the neonate (TTN) were the presence of grunting, retractions, and a respiratory rate ~30 per minute for more than six hours after birth in a near-term infant with minimal cyanosis (FIN% < 0.4).4 The chest roentgenogram of TTN shows prominent
3 ti .).. 4
(5s)
(6%)
vascular markings, edematous interlobar septa, and pleural effusions. TTN has a benign course, and infants are usually in room air by 24 hours of age. The chest roentgenogram begins to clear by 24 hours, and the findings are resolved in three to five days. RDS was managed as previously described.‘” In this study one of us 0. P. C.) reviewed charts and roentgenograms of all infants with any respiratory difficulty to assure uniformity of diagnosis. All possible congenital anomalies were also reviewed. Major defects were considered to be those responsible for death and those that would cause a significant handicap in the future or require major surgery to correct. Minor anomalies made up the rest. Since this u’as a retrospective review, many minor malformations not of clinical significance may not have been recordcrl in the chart and thus were missed. Analysis of data. Standard two-sample t tests and two-way contingency tables with chi-square tests were used to assess the statistical significance of group differences. Multiple linear-regression analysis was used to assess the correlation of a set of independent variables with a dependent variable where appropriate.
Results Control of diabetes. Of our subjects, 7 I per cent had diabetes longer than 10 years, and only 0 per cent had gestational diabetes not requiring insulin. As seen in
566
Kitzmiller et al.
Table No. 13 30 57 31 8
2 147
III. Antepartum class A B C D F R
*Negative OCT one-minute
Apgar
fetal monitoring
Serial estriol measurements
Chronically low estriol
2 28 57 35 8 132 (:O%, and one-minute score 2, one.
Apgar
Acute fall in estriol
Positive OCT (%i
A bnomal e&01(%)
: 3 4 3
2 (7%) 4 (7%) 5 (14%j 6 (75%1 ___
4 20 46 30 7
3 4 5
2 1 1 1
12* (9%)
5t (4%)
score > 5, nine;
OCT performed
positive
109 (?4%) OCT
and
(5%) (7%) (13%) 143%)
~
12$ (11%)
one-minute
Apgar
17 (13%)
score
2. two;
Both abnormal (%)
1 (5%) 1 (3%) 3 (43%) 5 (5%) no OCT
and
tNegative OCT with no intrapartum fetal distress and one-minute Apgar score 8, one; positive OCT and one-minute Apgar score < 5, three; no OCT with intrapartum fetal distress and one-minute Apgar score 2, one, *Normal estriol level and one-minute Apgar fetal distress): abnormal estriol and _- score > 5. seven (two with intrapartum one-minute Apgar score > 5, five. Table I, there is little difference between Classes B, C, and D in the mean number of weekly clinic visits or the difference from normal in the mean blood glucose level. The population of insulin-dependent diabetic patients can be grouped into thirds on the basis of low, medium, or high average values of outpatient blood glucose (Fig. 1). The distribution of numbers of patients in these groupings was similar throughout Classes B, C, D, and F. Average length of stay in the hospital prior to delivery was 13 days, but this was significantly longer in the patients with diabetic nephropathy and the two patients who had been treated for proliferative retinopathy during pregnancy. The average concentrations of plasma glucose while in the hospital are also given in Table I. There was little difference between Classes B, C, and D. Plasma glucose concentration (inpatient) should be reduced by -14 per cent for comparison with the outpatient glucose measurements in whole blood. Maternal complications. Maternal complications are given in Table II. Clinically apparent polyhydramnios occurred in nearly one third of our patients. Six of the subjects with polyhydramnios went into premature labor (prior to 36 weeks’ gestation) (13 per cent), and in two cases neonatal death was primarily caused by prematurity. In contrast, the incidence of premature delivery (~36 weeks’ gestation) in our total hospital population (live-born infants) was 4 per cent in the same time period as this study. Polyhydramnios was associated with congenital anomalies in only two cases: one infant with combined spina bifida, clubfoot, and cleft palate and one infant with bilateral clubfeet. Polyhydramnios was less common in the group with the lowest outpatient blood glucose level as compared with groups 2 and 3 (Fig. 1) (chi-square value was 3.84 with one degree of freedom; p = 0.05). There was a tendency for the group with polyhydramnios to have higher average plasma glucose concentrations in the hospital
but the differences were only significant at the sampling time of 3:OO P.M. (138.2 i: 29.6 versus 152.9 2 42.2 mg. per deciliter; p < 0.05). Hypertensive disorders were noted in 14 per cent of the diabetic pregnant patients under study. The incidence of pre-eclampsia (5 per cent) was only slightly higher than that of our entire hospital population during the same time period (3.8 per cent). Two of the 13 cases of generalized edema were associated with preeclampsia and five with diabetic nephropathy. The coexistence of thyroid disorders with juvenile diabetes in women of childbearing age has been reported separately41 and was seen in 6 per cent of our patients. Antepartum fetal monitoring. The results of estriol measurements and OCT’s are shown in Table 111. Estrio1 excretion was chronically low in 12 of 132 patients in whom estriol was measured. Infant birth weight was below the tenth percentile for gestational age (SGA) in only three of these 12 pregnancies (one Class D, two Class F). Birth weight was appropriate for gestationa age (AGA) in the other nine infants. Maternal creatinine clearance was not decreased in patients with Class C to D diabetes with low estriol levels and AGA infants compared to subjects with normal urinary estriol levels. Of the 12 women with chronically low estriols, OCT’s were negative in nine, and the one-minute Apgar scores of these neonates were 6 to 8 (eight cesarean sections, one vaginal delivery). Two patients with Class F diabetes developed positive OCT’s in addition to chronically low urinary estriol levels, and their neonates had one-minute Apgar scores of 2 at cesarean delivery. One patient with Class C diabetes with low estriol did not have an OCT performed because of premature rupture of the membranes, but her infant’s one-minute Apgar score was 2 at cesarean section performed for failure to progress in labor at 34 weeks’ gestation. Five patients exhibited a fall in estriol level greater
Diabetic
Table
IV. Gestational
length
and birth weight
pregnancy
and perrnat,:!l
class
533
13 30 57 37 8 J 3 147
A B c I:, F R
0 3 I 1 4 t (6%)
Table
34-35
36-?7
; 7 5 2 0 21 (14%)
1 9 31 24 0 1 ?4!&
569
(mean t S.D.)
Weeks’ gestation ‘VO.
morbfdity
--T---Lagth oj gestation (wk.)
??8 12 11 18 7 2 -L
39.8 36.3 36.9 36.7 33.9
+ c k 2 2
Birth weight (grump)
1.8 3.0 1.4 1.6 3.1
3501 3461 3407 3120 1872 3610.
-
I&,4
SGA
-c 500 It 853 k 654 t 65Q it 759 39.55
0 0 0 3 2 II.
(355:)
" Ir, z' :' I3 0 i zj (3fzll;)
(3.Z%,
/
-;ZE 2 6 7 2 0 0 i7 (1 I..i%)
V. Route of delivery Cesarean
NO.
iFi 57 37 8
Class
Vaginal delivery
Labor not inducible*
AB c 1) ii
1; (36.7%) 17 (29.8%) 9 (24.3%) 1
8 (26.7%) 9 (15.8%) 7 (18.9%) 4
24 (6.7%) 9 (15.8%) 7 (18.9%) 1
75 (31.3%)
28 (19.0%)
23 (15.6%)
2 147
Dystocia
section Intrapatium fetal distress
t
: (6.7%) 2 (3.5%) 3 (8.1%)
i(6.1Pj
Repe&
7 (23.3%) 20 (35.1%) I I (29.7%.) L” 0
4: (27.9%:)
*Ruptured membranes, two; placenta previa, one; pre-eclampsia, turn fetal distress, four; presumed antepartum fetal distress, eight; L/S ratio. eight. Total = 28. ?Breech-no labor, six: cephalopelvic disproportion, five; failure
two; renal failure polyhydramnios,
than 40 per cent of the mean value for the preceding three days. The OCT was negative in one woman, and her infant’s one-minute Apgar score was 8 when delivered vaginally after a labor without signs of intraparturn fetal distress. Three women with falling estriol levels also had positive OCT’s, and one-minute Apgar scores were 2, 4, and 4, respectively, after delivery by primary cesarean section. One woman with an acute fall in estriol level did not have an OCT because of premature labor, and the one-minute Apgar score was 2 after cesarean section performed for intrapartum fetal distress. The OCT was positive in 12 of 109 diabetic women in whom the test was performed. Seven patients had normal urinary estriol levels, and their babies’ oneminute Apgar scores were 6 to 8 (four primary cesarean sections. one cesarean section for intrapartum fetal distress, and two vaginal deliveries, one after signs of late intrapartum fetal distress). Three women with positive OCT’s had an acute fall in estriol and LWO had
during labor. Nine women had an OCT suggestive of abnormality, but the test was not repeated. In Iive of these nine, there was no other evidence of fetal distress, but in four of them the one-minute Apgar scores were below 6 when their infants were delivered bv primary cesarean section. Length of gestation and birth weight. Mean length of gestation and birth weight for each White class are given in Table IV. Pregnant women with gestational diabetes not requiring insulin (i.e., normoglycemic on diet) were allowed to go into spontaneous labor up to 40 weeks’ gestation. Five of 13 patients with Class .4 diabetes, who had not been delivered by 40 weeks, were admitted to the hospital for antepartum fetal monitoring, and labor was induced at 41 to 43 weeks’ gestation. Of the 124 patients in Classes B, C, and D. 19 per cent were delivered prior to 36 weeks and 29 per cent were delivered at term (2 38 weeks). Mean length of gestation and birth weight were significantly lower in patients with diabetic nephropathy. 'The difference in mean birth weight between Class D and Class B or C did not reach statistical significance (t = 1.84; p > 0.05). There were three SGA infants delivered of 37 patients with Class D diabetes and two in eight patients with Class F diabetes. Slightly more than one third of all neonates were large for gestational age
chronically scores
low were
estriol
2 to 4 when
levels. their
The
one-minute
babies
were
Apgar delivered
promptly by primary cesarean section. OCT’s suggestive of abnormality were recorded in I5 women. Six had a repeat test, which was negative. Only one of these fetuses exhibited signs of distress
to progress
and fetal distress, one; confirmed antepartwo; elective at 37 to 41 weeks with mature
in labor,
12. Total
= 23.
570
July I, 1.9% Am. J. Obstet. C$mol.
Kitzmiller et al.
Table
~ 4oooI cn 3000
VI. Birth
$+7&42)
Patient
Fractured clavicle Erb’s palsy Shoulder dystocia Shoulder dystocia
N. G.
14’
D. J.
s. L.
‘Ooo; 34
35
36
37
30
39
4500
-
Table
GESTATION
++
+++
-
+
+
pc .Ol
+ +
+ 0
39* 3fi* 361 39s
8 9 4 9
Intrapartum
fetal distress One-minute
Route of delivery
Apgar
scwe
I-3
4-6
7-9
Total
2 3 5
6 :2 9
1 3 4
9 s 18*
*Of 72 women in labor (25 per cent).
+
2000
VII.
Vaginal Cesarean section
+ +
2500
3,544 3,118 3,67 1 4,139
One-minule Apgar score
40
Fig. 2. Mean birth weight of infants of women with Class B to D diabetes delivered at 34 to 40 weeks’ gestation. -
Length
of gesta-
“AGA. tLGA.
WEEKS
5000
delivery
(grams) I tia (wk.)
Type
D. E. -
or difficult Birth weight
2 2000
trauma
25
50
I 75
100
125
IS0
I 175
A 0. B.C.
Fig. 3. Correlation of birth weight of 119 live-born infants with mean ( ?S.D.) maternal A0.B.G. values for women with Class B to D diabetes; infants were delivered at 36 to 38 weeks’ gestation. r* = 0.12. (LGA), that is, they were above the ninetieth percentile of weight for gestational age of -8,000 consecutive infants who were delivered at BHW in the same time period as this study. Macrosomic infants were primarily found in Class B (50 per cent), Class C (39 per cent), and Class D (35 per cent) diabetes. Of all infants in the series, 11 per cent weighed more than 4,000 grams at delivery. The average outpatient blood glucose level was significantly higher in 50 women in Classes B to D with LGA infants (mean & SD. A0.B.G. was 70.8 “_ 29.1 mg. per deciliter), as compared to 7 1 women in Classes B to D who were delivered of infants with birth weights appropriate for their gestational age (A0.B.G. was 59.2 r 31.7 mg. per deciliter, t = 2.03; p < .05). Mean birth weight did not increase appreciably in infants delivered beyond 36 weeks’ gestation (Fig. 2). For women
in Classes B to D delivered at 36. to 38 weeks’, birth weight was somewhat related to maternal outpatient blood glucose (Fig. 3). Correlation and multiple linear-regression analyses were applied to w&men in Classes B to D delivered at all grstutional uge.r. The simple (zero-order) correlation coefficients between birth weight and the following variables were found to be 0.15 for maternal weight, 0.43 for gestational age, and 0.23 for A0.B.G. The multiple regression of birth weight on maternal weight, gestational age, and A0.B.G. revealed significant contributions from each of the three explanatory variables: t statistics for each variable were 2.20 (p < 0.05). 5.62 (p < O.OOl), and 3.45 (p < O.OOl), respectively, for the three variables. Labor and delivery. The route of delivery of om subjects is given in Table V. Seventy-five women (51 per cent) underwent primary or repeat cesarean section without attempting labor (28, labor not inducible: six, breech presentation; 41, repeat cesarean sections). Of the remaining 72 women who began spontaneous or induced labor, 46 (64 per cent) were delivered vaginally, 17 (24 per cent) were delivered by cesarean section because of dystocia, and nine (12.5 per cent) were delivered by cesarean section for intrapartum fetal distress. Of the 46 vaginal deliveries, four were classified as difficult or traumatic (8.7 per cent). Clinical details are given in Table VI. Two of the infants were macrosomic but only one had a low one-minute Apgal score. All of these infants did well in the nursery. Intrapartum fetal distress was diagnosed in 25 per cent of the women who had spontaneous or induced labor. This diagnosis was made on the basis of late de-
Diabetic pregnancy and perinatal morbidity
Table VIII. Delivery Classes B to D
Vaginal
outcome
in term versus 35 to 37 week pregnancies
deliveries?
Dystocia, cesarean sectiont Breech, cesarean section Birth trauma or difficult delivery Intrapartum fetal distress+ Labor not inducible, cesarean sectiong Repeat
cesarean
35-37 wk. (No. = 79)
>38 wk. (No. = 36)
22135 (63%) 9135 (26%) 4
12117 (71%) 3117 (lS%) 1
9135 (4:)
sectiong
24179 44/79
number
of women
number
of pregnancies.
(30%) (56%)
versus LGA
.4GA (No.
infatrts.
= 639
LG.4 (,Vo. = JY}
19129 (66%) 4/29 (14%) 2
5/17 (2;) (29%) 5136 (14%) 13/36 (36%) 16136 (44%)
16/79 (20%)
Neonatal hypoglycemias *Three SCA in Class D. tDenominator represents SCesarean sections. §Denominator represents
(26%)
and AGA
571
IN3 tie3
Y/29 (3:) (3 1%) 12163 (19%) 22163 (35%) 28/63 (44%)
‘l/23
(65%) (26%) ,)
(2:)
(17%)
9!49 (18%) 151-N (31%) 33i49 (67%)/i
in labor.
j/p < 0.05. Table
IX. Neonatal
pulmonary
complications RDSf
hio.
class
I3 29 57 37 7
A B c D F
TTN and pneumothorax
-TTN”
Indeterminatet
Mild
Severe
1+/2+ 1 1
3 4 1
Total
I 1
: 9 4 3
3+/4+
1
1 3 2 3
1 1
s
Apnea
i (17.2%J 6.9’5
7.6%
*Transient tachypnea of the neonate. SUpon review of chart and roentgenograms TTN and mild RDS could not be differentiated. $.RDS: I+: requiring Fro, < 0.5; 2+; requiring FIO, 7 0.5; 3+: requiring positive end-expiratory respiratory therapy. $Excludes one stillbirth and one immediate neonatal death celerations and a scalp pH below 7.25. The distribution of one-minute Apgar scores is given in Table VII. Eight cases of intrapartum fetal distress occurred late in labor and vaginal deliveries were performed.* With one exception the one-minute Apgar scores were below t. One of the infants with a one-minute Apgar score of 1 died immediately* and the infant with a one-minute Apgar score of 2 had a neonatal course complicated only by TTN and hypoglycemia. There were nine cases of fetal distress earlier in labor, and immediate cesarean section was performed. Of the three with very low Apgar scores at one minute, one infant died of congenital anomalies, one infant had severe RDS, and another, delivered at 31 weeks, had apneic spells but no RDS. One infant with a one-minute Apgar score of 5 developed TTN: the remaining five infants had un*See Table XVI for clinical details of the other vaginal delivery (Patient S. P.).
pressure; 4+: requiring
complicated neonatal courses. It is important to note that of 18 patients with intrapartum fetal distress only three had evidence of antepartum fetal distress as shown by low or falling estriol excretion and/or positive or suggestive OCT. The percentages of patients with intrapartum fetal distress during labor were 25 per cent for Class B, 14 per cent for Class C. and 30 pet cent for Class D. There was no apparent relationship between outpatient blood glucose and the development of antepartum or intrapartum fetal distress. Delivery outcome was not significantly different in a comparison of pregnancies delivered at term with those delivered at 35 to 37 weeks’ gestation in Classes B to D (Table VIII). In this population the delivery outcomeofLGA infants was similartothatof AG.4 infants. Neonatal pulmonary complications. Neonatal pulmonary complications were related to diabetic class, length of gestation, and the route of delivery and are
572
Kitzmiller
et
al.
July 1, 1958 Am. J. Obstrt. Gyneco.
Table X. Length of gestation, route of delivery, and neonatal pulmonary complications (number with cesarean sections in italics)
Weeks
28 29 30 31 32 33 34 35 36 37 38 39 40
No.
None
iTN
Indeterminate to
Severe
mild RDS
RDS
1
1 4
1* 1*
2
lS.li
1
4 17 22 43 28 8 2 131$
? 4,ll
I
10,lO 9,x5 519 4.14 1, 34,74
2
1
?
3 I
3
2,8
2,:
-23
*Died. tApneic spells. $Excludes 13 with Class A diabetes, one stillbirth, one infant who died immediately of severe birth asphyxia, and 1 infant who died of severe congenital anomalies incompatible with life. given in Tables IX and X. Upon review of clinical records and roentgenograms, two cases could not be differentiated between TTN or mild RDS, and the diagnoses are listed as indeterminate. Transient tachypnea of the neonate was observed in 7 per cent of the subjects. The majority of these babies were deliver&l at or beyond 36 weeks’ gestation with a mature L/S ratio. The incidence of severe RDS was also 7 per cent with cases distributed from 28 to 39 weeks of gestation. Four of the 10 cases of severe RDS occurred in infants delivered at 37 to 39 weeks’ gestation, reprdenting 5 per cent of neonates delivered at 237 weeks. The only deaths from RDS, however, occurred in two infants delivered at 28 and 30 weeks. As seen in Table X, a greater proportion of infants delivered by cesarean section developed TTN or RDS, but the tendency did not reach statistical significance (x2 = 1.83; p < 0.25). The occurrence of TTN was not associated with higher levels of maternal outpatient blood glucose or with fetal macrosomia. Of 24 infants delivered with an L/S ratio between 2 and 3, three developed severe RDS (12 per cent); this contrasts with only one infant with mild RDS (plus two indeterminate cases) in 76 infants where the L/S ratio was greater than 3 (Table XI). Thirteen infants were delivered with an L/S ratio less than 2, and six developed RDS. Serial L/S ratios were obtained in 24 patients. The ratio declined more than 0.5 units in only three cases and rose in all others. The L/S ratio did not
rise earlier in gestation in Class D compared with Class B or C. Severe RDS was observed in four IDM’s when the concentration of total cortisol in amniotic fluid was >60 ng. per milliliter (Table XII). This contrasts with a recent report on a small series of pregnancies in nondiabetic pregnancy from our hospital where RDS was not seen with an amniotic fluid cortisol level was >60 ng. per milliliter.*’ Neonatal morbidity. Other forms of neonatal morbidity are given in Tables XIII and XIV. Neonatal complications were unusual in offspring of women with Class A diabetes but were otherwise distributed throughout the White Classes. Hypoglycemia was the most common complication, occurring in nearly half of the neonates despite their being on a regimen of early feeding. I2 As seen in Table VIII, hypoglycemia was more frequent in LGA infants of Classes B, C. and D (x2 = 5.83; p < 0.05). Hypoglycemia was unusual in premature infants, possibly because of the early administration of intravenous glucose to these babies soon after delivery. Hypocalcemia, observed in 22 per cent of infants, was not associated with neonatal hypoglycemia (x2 = 1.05; p > 0.05) or with LGA infants (x2 = 0.12: p > 0.05). Neonatal serum calcium concentration showed a weak correlation with maternal serum levels (r = 0.23; p C= 0.05). Neonatal hypocalcemia was not more frequent in winter months. Hyperbilirubinemia (bilirubin over 15 mg. per deciliter) was present in 19 per cent of neonates, but the natural history was affected by early intervention with phototherapy in many other infants. Poor feeding was present in 37 per cent of the infants and often prolonged their stay in the Special Care Nursery. Individual congenital anomalies are listed in Table xv. Perinatal mortality rate. The over-all perinatal survival rate was 96.6 per cent for 147 diabetic subjects whose pregnancies attained 24 weeks. The clinical details of the five perinatal deaths in this series of patients are summarized in Table XVI. We consider that three of these deaths possibly could have been prevented with different obstetric management at the time of delivery. Two of these deaths occurred early in the study period when cesarean section delivery for fetal indications was not always utilized at 28 to 30 weeks’ gestation. Seventy-eight of the patients had prior pregnancies, some of which terminated in other hospitals. Of 124 prior pregnancies in this group of patients, there were 15 stillborn infants (12 per cent) and 10 neonatal
Diabetic
Table
XI. L/S and neonatal
respiratory
L./s
No
ratio
distress
b3.0 2. I-3.0 I.52.0 11.5
66 21 4 _I 92
pregnancy
and perinatili
morbidity
573
distress TTN 7 2 Yt
*Gestations in which L/S ratio was determined. IL/S values were 2.7, 2.8, and 2.9. $Excludes one patient who did not have L/S ratio determined deaths (8 per cent). This 80 per cent perin& survival rate in the prior pregnancies of our multiparous pregnant women is comparable to the perinatal survival rate of 96 per cent for this group during the study period reported here.
Comment Control of diabetes. The importance of “tight control” of diabetes during pregnancy has been emphasized in recent years. 3y,“’ W. SoA key feature of our protocol is the weekly office visit, so that the internist and obstetrician can anticipate and avoid complications. Further, our patients are taught to adjust their insulin dose at home, depending on urinary and capillary blood glucose estimations. If questions arise, they are encouraged to contact the medical staff by telephone. We do not, however, usually reach the level of normoglycemia proposed by the Scandinavians as necessary to achieve a good outcome (Fig. l).” The majority of our patients have no endogenous insulin, and it is difficult to achieve physiologic control of the blood glucose with the present methods of administering exogenous insulin. In Europe, prolonged hospitalization has been used to achieve better metabolic control in the third trimester of the diabetic pregnancy. Economics of health care in the United States has prevented us from applying this measure on a routine basis, and our patients are usually admitted only at 36 to 37 weeks’ gestation; however, our perinatal survival rates are good, and others have also demonstrated the efficacy of ambulatory management.J7, ‘” Cost-benefit analyses of several procedures designed to normalize the blood glucose level and of prolonged hospitalization remain to be performed in large numbers of diabetic pregnant women. Measures of metabolic control during diabetic pregnancy also need to be evaluated. A weekly blood glucose determination gives only limited information, and there may be substantial variability in the measurement
Table XII. pulmonary Concentration (ng. /ml.) >90 80-89
70-79 60-69 50-59 <50
Amniotic status
fluid cortisol
Normal
T-TN
30 6 14 14 5
1 2 I 1 I
1
1
and neonatal
Ind&-rnuna& 60 miki RDS
1 it
Severe RDS 1 I 1 1 1
1
of urinary or capillary blood glucose at home. We arc currently investigating the role of monthly hemoglobin A,C measurements.:“, lo5 in assessing hyperglycemia and its relationship to pregnancy outcome. Metabolic substrates other than glucose may also be important in the pathology of diabetic gestation, and \ue need much more detailed knowledge of the role of’ amino acids, fatty acids, ketone bodies, and lactic acid. Mateinal complications. Polyhydramnios is the most common maternal complication of diabetic pregnant) in our series, occurring in one third of cases. The cause of polyhydramnios remains unknown in the vast majority. The relationship of the degree of hyperglJ,cemia to the incidence of polyhydramnios is uncertain. Pedersen73 did not demonstrate a close connection between the volume of amniotic fluid and the level ot maternal blood glucose. Others, however. have stated that better control of blood glucose results in less polyhydramnios. X” In this series, polvhvdramnios was less , I common in the group of patients with the lowest outpatient blood glucose levels. It has been demonstrated that hospitalization in the last eight weeks crf pregnancy is associated with a lower volume of arnnicjtic fluid.7:’ It is unclear whether bed rest or better metabolic control is responsible for the difference observed We have a low incidence of pyelonephriris compared to the frequency of 6 per cent reported bv Pedersen”’ in 293 diabetic pregnancies. The diagnosts of asymptomatic bacteriuria by serial urine cultures during
574
Kitzmiller et al.
Table
XIII.
No.
July I. 1978 Am. J. Obstet. Gynccol.
Neonatal
morbidity
Ch.SS
13
A
30 57 37 8 2 147
B C D F R
Hypoglycemia
Hyperbilirubinemiu
Hypocalcemiu
Poor ,feeding
Birth defects* (majorlminw)
10 (33%) 23 (40%‘) 13 (35%) 8
012 (017%) 614 (11%/7%) S/2 (16%/5%) 110
54 (37%)
1318 (9%/5%)
010 1: (37%) 35 (61%)
18 (49%) 1
A (30%)
7 (23%)
10 (18%) 9 (24%)
15 (26%) 5 (14%) 1
3
-.A
6f (47%)
33 (22%)
o/o
*Includes three with anencephaly excluded from total of 147. Table
XIV. Weeks
Neonatal
morbidity
No.
and length None
28 29 i:
:
32 33 34 35 36 37 38 39
4 15 22 41 25 7
2 (13%) 5 (23%) 7 (17%) 11(44%) 2
40
2120
2: (23%)
of gestation Hypeglycemia
(White
Classes B to D) Hyperbilirubinaiu
HYPo-
cakemia
1
Poor feeding 1
1
2 7 11 25 11 4
1
k (47%) (50%) (61%) (44%)
pregnancy and treatment of positive cases with appropriate antibiotics may be responsible for our low incidence. The pre-eclamptic syndrome is much less common now than in past series from Joslin Clinic.lo3 One reason may be our exclusion of the diagnosis of superimposed pre-eclampsia in our eight patients with Class F diabetes, four of whom had chronic hypertension. The diagnosis of superimposed pre-eclampsia is almost impossible to make with assurance, since the nephrotic syndrome frequently worsens during late gestation. A detailed analysis of our continuing experience with diabetic nephropathy in pregnancy will be reported separately. It is obvious that the low level of preeclampsia was not associated with parenteral sex steroid therapy, since we abandoned this therapy early in 1975. We would like to think that encouragement of modified bed rest at home is at least in part responsible for the decline in pre-eclampsia in this high-risk patient population. Most of the subjects of this study were not treated with diuretics for any reason. The term “pregnancy headache” describes the unusual occurrence of severe, deep midline headache lasting two to four days in the second or third trimester of pregnancy, which requires hospitalization and treatment with narcotic analgesics for relief. In our experience this characteristic headache is much more com-
21
(33%) 9 (41%) 11 (27%) 5 (20%) 1
3 6 (40%) 5 (23%) 11(27%) 2 (8%) 2
4 12 12 13 10
32 (27%)
31 (26%)
55 (46%)
(80%) (55%) (32%) (40%)
monly diagnosed during pregnancy than at other times during the lives of insulin-dependent diabetic women. The severe headache may be related to small infarctions of the pituitary gland, which in more severe cases have presumably caused a syndrome of ante- and post-partum pituitary insufficiency in diabetic women, in the absence of precipitating metabolic or circulatory disturbances.83 Brennan and co-workers’ found that the incidence of small pituitary infarctions was l/50 in an autopsy study of diabetic subjects compared to l/550 in nondiabetic subjects.’ None of our patients demonstrated signs of pituitary insufficiency during or after pregnancy. Antepartum fetal monitoring. Assays of fetal wellbeing are necessary in order to carry pregnancies in diabetic women safely to a stage of fetal pulmonary maturity. The measurement of urinary estriol on a daily basis and the OCT have proved useful in our study series. In cases of chronically low or mildly falling estriol excretion, the OCT gives reassurance as to which fetuses are not in acute distress, and the pregnancies should be continued if the L/S ratio is not mature. On the other hand, approximately 50 per cent of our patients with a positive OCT showed no other evidence of fetal or neonatal distress on the basis of estriol excretion, course in labor, or immediate neonatal con-
Volume ; ?J1 Number i
Table
XV. Birth
Diabetic
pregnancy
and perinatal
defects
morbidity
575
-
h’ct.
class
13 30
A B
None None
.5!)
c;
2 anencephaly 1 spina bifida, clubfeet, and cleft palate 1 clubfeet 1 terminal transverse hemimeliat 1 ventricular septal defect and hemivertebrae 1 anencephaly 1 hypoplastic lungs, severe cardiac anomaly, absent kidney, and clubfeet 2 ventricular septal defect 2 patent ductus arteriosus (persistent) 1 caudal regression syndrome None
Major*
.Mzmrf None 1 epiaastric and umbilical hernia 1 $o&dact$>:
3x
8 2 1508
F R
1 congenital dislocation of hip 1 dermoid of skull 2 preauricular skin tags
2 pigmented
nevus
None None
*Major: Causing death or significant handicap or requiring major surgerv. Total = I3 (9 percent) with four deaths !?.6 per cent). tTota1 = eight (5 per cent). ICongenital absence of arm, 2 cm. below elbow. DTotal = 147 plus three anencephalic fetuses aborted at 20 to 24 weeks’ gestation. dition. Thus, we believe strongly that the combination of estriol measurements and antepartum fetal heart rate monitoring will improve the specificity of the diagnosis of suspected fetal distress. In our experience, cases of true fetal jeopardy on retrospective analysis exhibited both low or falling estriol excretion and a positive OCT. Gabbe and co-workers32 recently reported similar results. However, a few unpublished anecdotal reports of isolated fetal deaths in the presence of negative or suspicious OCT’s or normal estriol excretion have been communicated to us. Some cases were associated with pre-eclampsia or severe maternal hyperglycemia. We plan to continue our prospective evaluation of the role of antepartum fetal monitoring in the management of diabetic pregnancy. Serial measurement of unconjugated estriol in plasma may increase diagnostic specificity and eliminate the delay attendant upon the use of 24 hour urinary assays.17 Length of gestation and birth weight. Premature labor remains a major problem in obstetrics, and it had a large effect on the perinatal mortality rate in this series. being associated with three of the five losses (Table XVI). In the presence of impending premature delivery, the use of corticosteroids has been advocated to reduce the risk of RDS. We have recently confirmed the beneficial effect in pregnancies of’ nondiabetic women in a randomized clinical trial of dexamethasone.” Four of the present series of diabetic pregnant women were included in that study. This number is far too small to evaluate whether the therapy has been beneficial for them, but these pregnant women who received corticosteroids did exhibit marked loss of di-
Table Patient
XVI.
Perinatal
Class
L. P.
B
M. K.
B
D. R.
D
N. W.
D
s. P.
F
deaths (I 975 to lY76) Cmnmal
Premature labor at 28 wk., vaginal delivery as breech, Apgar score 2-5, 1,030 grams, severe RDS Ketoacidosis at 27 weeks, feral death by time of admission to hospital Premature labor at 30 wk., vaginal delivery, Apgar score 2-7, 1,049 grams, severe RDS, intracranial hemorrhage Neonatal death at term due Lo bypoplastic lungs, severe cardiac anomalies Premature labor at 29 wk., partial abruptio placental, epidural anesthetic, late decelelxtions, vaginal deliver, 1,670 grams, Apgar score 1, died immedtately
There were three induced abortions at 20 to 24 weeks for anencephaly. abetic control during the treatment period, with plasma glucose climbing to 400 mg. per deciliter at times, despite intermittent injections of regular insulin. Although there was no measurable fetal distressduring treatment in our few cases, corticosteroids may pose a potential hazard to fetal well-being during the course of treatment. Many more diabetic pregnant women and their fetuses will need to be studied in a controlled manner to determine the benefit and safety ofcorticosteroid administration to these patients. The relationship of maternal hyperglycemia to infant birth weight has been unclear, despite general acceptance of the fetal hyperglycemia-hyperinsulinismmacrosomia hypothesis. 73 Neither Karlsson and K.jellmerS’ nor Persson7” could demonstrate a significant re-
576
Kitzmiller et al.
lationship between mean blood glucose and excessive birth weight in pregnant women hospitalized during the last weeks of pregnancy. Metzger and colleagues63 found that maternal branched-chain amino acids such as leucine were related to birth weight in gestational diabetes while mean blyd glucose concentration was not. These amino acids cross the placenta by active transport and are insulinogenic. Szabo and Szabos3 and others have speculated that free fatty acids may be involved with macrosomia in pregnancies of diabetic women. In our study, the A0.B.G. throughout pregnancy correlated with infant birth weight in White Classes B to D, and this correlation remained when we controlled for length of gestation and maternal weight with the use of a multiple linear-regression analysis (Fig. 3). The mean A0.B.G. was also significantly higher in women delivered of LGA infants as opposed to AGA infants. Since neonatal hypoglycemia was more common in our macrosomic infants, these findings support the concept of “tight control” of maternal blood glucose during pregnancy to reduce neonatal morbidity. Labor and delivery. Are labor and vaginal delivery safe for diabetic parturients? The issues of concern are the development of intrapartum fetal distress and the possibility of birth trauma. Our series demonstrates that fetal monitoring of heart rate and scalp pH is essential, since consistent signs of fetal distress developed in 25 per cent of the women in labor. In only three of the 18 cases had there been any indication of anteparturn fetal distress on the basis of estriol levels or OCT. When decelerations and low scalp pH developed in the second stage of labor and vaginal delivery was performed, all but one newborn infant did well despite low one-minute Apgar scores. Long-term follow-up of the children is necessary, of course, to be sure no deleterious effects of such management occur. The “unripe cervix” remains a practical problem in the management of high-risk pregnancies; it resulted in the performance of cesarean sections in 24 per cent of our candidates for vaginal delivery. Since 16 (15 per cent) of our cases were classified as semielective for induction of labor or as having a false presumption of fetal distress, we can perhaps expect the numbers of cases in the category of “uninducible cervix” to decline as physicians become more experienced in following pregnancies in diabetic women to term. However, in many cases there was general agreement on the need to terminate pregnancy, and the only recourse was primary cesarean section. We need to learn more about the factors influencing ripening of the cervix and to apply better techniques for the safe induction of labor. In changing our protocol so that we could allow
July 1. 1978 Am. J. Obstet. Gunecctl.
pregnancies to proceed to term, we were concerned that the frequency of macrosomiti and other complicatioqs would increase. This does not seem to have been the case. For a number of reasons, only half of our patients in Classes B to D were delivered at 38 weeks or beyond as compared with 35 to 37 weeks’ gestation in the remainder. The percentages of vaginal delivery, dystocia leading to cesarean section, birth trauma. and intrapartum fetal distress were not significantly differentbetween the two groups (35 to 37 versus 38-t weeks’ gestation). These same statistics from 49 pregnancies with LGA infants were compared with those from 63 pregnancies whose infants were AGA and were found to be similar. We conclude that any diabetic pregnant woman can have a complicated labor or a difficult delivery, but that judgment as to the need to perform a cesarean delivery should be individualized. Maternal recovery and maternal-infant bonding are more difficult with cesarean deliveries, and the risk of RDS in the neonate is greater.7” Proper metabolic control is difficult at the time of parturition. This results from the use of intravenous fluids containing glucose and from the reluctance to use large doses of long-acting insulin in view of the marked postpartum insulin sensitivity that diabetic women exhibit. The relationship of hyper- or hypoglycemia to fetal distress during labor is unknown, but studies in animals relating fetal damage to hyperglycemia and lactic acidosis may lead to the clarification of this relationship.67, ” We need to develop well-controlled methods of nearly instantaneous insulin delivery to diabetic women in labor or during cesarean delivery to determine if normalization of blood glucose and possibly other metabolic substrates will reduce fetal distress, birth asphyxia, and neonatal complications such as hypoglycemia and poor feeding.“‘, lo’ Neonatal pulmonary complications. The studies of Hubbell and associates* and Robert and associates7s at BHW showed incidences of RDS of 27 and 23 per cent, respectively, in IDM’s delivered from 1958 to 1968. In those years, pregnancies in diabetic women were terminated according to a schedule based on the White classification, without benefit of tests of fetal well-being or the L/S ratio to predict pulmonary maturity. In the present study, the incidence of RDS was only 7.6 per cent compared with 5 and 9 per cent in recent reports of Gabbe and colleague? and Persson and co-workers,” respectively. Diagnostic criteria for RDS have not changed. The proportion of infants delivered by cesarean section is not different from that in the population studied by Robert and associatesTY However, the proportion of infants of insulin-dependent pregnant women delivered at 38+ weeks is greater in the current
Diabetic
study (29 versus 2 per cent), and the proportion of infants delivered at ~36.5 weeks is smaller (21 versus 6 1 per cent). We conclude that the ability to carry safely most diabetic pregnancies to the time of fetal pulmonary maturity (as determined by the L/S ratio) has dramatically decreased the incidence of RDS. The L/S ratio has been a useful predictor of pulmonary maturity in normal pregnancies with less than 1 per cent of infants having RDS with an L/S ratio >2.“7 There have been many reports of IDM’s who developed RDS with L/S ratios >2.11a 13* “3 *‘. 26 The incidence of RDS with “mature” L/S ratios in these cases ranged from 8 to 27 per cent. Gabbe and colleagues3* reported on 200 pregnancies in diabetic women in 1977 and reported only a 3 per cent incidence of RDS in IDM’s with an L/S ratio of 2 or more. This incidence was the same in his normal population. In our study an L/S ratio in excess of 3.5 was considered to be a reliable predictor of fetal pulmonary maturity. With an L/S ratio between 2 and 3, three of 24 infants (12 per cent) had severe RDS. When the L/S ratio was less than 2, half of the infants had severe RDS. The phenomenon of RDS in IDM’s with L/S ratios over 2: 1 is thought to be due to the presence of lecithin with low surface activity.“6 A more specific assay for surface-active material is obviously required, and we are currently evaluating the concentration of disaturated phosphatidylcholine”” in amniotic fluid, which may be :I more specific indicator of pulmonary maturity,“‘. ‘IR Mueller-Heubach and co-workers66 recently analyzed the reliability of the L/S ratio in pregnancies of diabetic women, with results similar to ours. As in their series all of our infants who developed severe RDS late in gestation with an L/S >2 were delivered by cesarean section without birth asphyxia. Their data indicate that the L/S ratio rises later in gestations of diabetic women compared with nondiabetic women. The peculiarities of fetal lung maturation, phospholipid production and secretion. and clinical development of RDS coexistent with pregnancy in diabetic women remain to be elucidated. Gluck and Kulovich3” reported delayed maturation of the L/S ratio in White’s Class A, B, and C diabetes and accelerated maturation in Classes D, E, and F. Others”‘. lo4 suggest a fall in L/S ratio as term approaches in IDM’s. Our series did not show an earlier rise in L/S ratio in pregnant patients with Class D as compared with Class B or C diabetes; of 24 cases with serial L/S ratios only three cases showed a decline. Neonatal morbidity. In a prospective study of 18,159 infants including IDM’s at the BHW from February, 1972, to February. 1975. Holmes ahd col-
pregnancy
and permatal
morbidity
577
leagues 44 found a 2 per cent incidence 01‘ ma.jor malformations. They found a 5 per cent incidence of‘ serious malformations in the IDM’s of this group (14/290). The infants in our study had a 9 per cent incidence of major anomalies. This increase in serious birth defects found in IDM’s is similar to the 8 per cr’nt incidence reported by Gabbe and associates”* and !hr incidence of 6 per cent reported by Pedersen.“’ Determination of the causes of the increased risk of birth defects in offspring of diabetic WOIIIPII is lacking, and this is an important area for research. Review of the course of early pregnancy in our pattents who were delivered of infants with congenital malformations did not reveal any striking features. Sincr we g-ive insulin to the tolerance level, almost all of’ oul- patients experience hypoglycemic reactions, especially in the first trimester. Much more detailed metabolic, monitoring will be necessary, however, if we are to learn what perturbations of the pregnant woman and ff*tr~s are associated with birth defects in the neonate. The study of Holmes and co-cr;orkt:rs”” showed an incidence of anencephaly in Caucasian Infants of 1.4/1,000 (anencephaly is rare in blacks ill Boston and the diabetic population studied here I almost all Caucasian). In a study of 664 pregnancies in diabetic women at BHW from January, 1965. to hqust, 1975, Zimble and associates lo7 found an incidence of anencephaly in IDM’s of 7.5/1,000. In the two-year period of the present study fetal anencephal!occurred in three of 150 pregnancies (20/1,000~. ;\nencephaly seems to occur more often than cspected in infants delivered of diabetic mothers as c-ompared with nondiabetic mothers in Massachusetts. The improvement in perinatal survival indicates that other end points must be used to gauge advances or changes in the management of pregnancy in diabetic women. The majority of the neonates m this series had significant neonatal morbidity. Gabbe and colleagues3’. :j2 reported neonatal morbidit\ in 65 per cent of 169 IDM’s. Nearly half of our infants were hypoglycemic despite a regimen of early feeding. I’he IDM, if symptomatic from hypoglycemia, usually is quiet and lethargic rather than jittery. Other symptoms such as apnea, tachypnea, respiratory distress, shock, cyanosis, and seizures may occur. If symptoms are present. the infant is probably at greater risk for sequelae than if asymptomatic. a2 The significance of’ II) poglycemia without symptoms is unclear, but conservative management to maintain the blood glucose level in the normal range appears to be indicated. A definitive study is needed to determine if rigid corm-c>1 of maternal blood glucose during labor and delivery will prevent neonatal hypoglycemia.““, I”* The concrntration of’
578
Kitzmiller et al.
free C-peptide was measured in a proportion of the infants of this study and was found to be significantly higher in IDM’s with hypoglycemia in the first six hours of life.8s This supports the role of hyperinsulinism in neonatal hypoglycemia in IDM but does not exclude the roles of glucagon deficiency and decreased glycogenolysis and gluconeogenesis. The other common forms of neonatal morbidity in this and other series are hypocalcemia, hyperbilirubinemia, hypotonia, and poor feeding. Their causes remain unknown, and their occurrence prolongs the observation and treatment of the IDM without respiratory distress in our Special Care Nursery. The relationship of fetal and neonatal morbidity to long-term development of these children should be investigated. Such studies will be difficult, because the possible perinatal influences may be difficult to differentiate from effects of subsequent biological and psychosocial conditions. The difficulties of parent-infant bonding in the intensive medical environment surrounding parturition of diabetic women need to be recognized and evaluated. Perinatal mortality rate. The perinatal mortality rate in this series (3411,000) is among the best reported to date for large groups of women with severe diabetes.‘*. “‘3 ‘X ‘lg. 73.X* SoThe rate approaches that of our general hospital population in the same time period (22/ l,OOO), although it is achieved at a high cost in effort and finances expended.
REFERENCES 1. Adam, P. A. J., Teramo, K., Raiha, N:, et al.: Human fetal insulin metabolism early in gestation: Response to acute elevation of the fetal glucose concentration and placental transfer of human insulin ‘131, Diabetes. 18: 409, 1969. L. M.: Report of the National Commission on 2. Aiello, Diabetes, SCOPE *Workshop on Pregnancy, Department of Health. Education. and Welfare Publication No. (NIH) 76-1023. 3. Assemany, S. R., Muzzo, S., and Gardner, L. I.: Syndrome of phocomelic diabetic embryopathy (caudal dysplasia), Am. J. Dis. Child. 123: 489, 1972. 4. Avery, M. E., Galewood, 0. B., and Brumley, G.: Transient tachypnea of the newborn, Am. J. Dis. Child. 111: 380, 1966. 5. Baird, J., and Farquhar, J. W.: Insulin secreting capacity in newborn infants of normal and diabetic mothers, Lancet 1: 71, 1962. M. B.. Pildes. R. S.. Mossabhov. N. A., et al.: 6. Block. C-peptide immunoreactivity’ (CPR): A new method for studying infants of insulin-treated diabetic mothers, Pediatrics 53: 923, 1974. 7. Brennan, C. F., Malone, R. G. S., and Weaver, J. A.: Pituitary necrosis in diabetes mellitus, Lancet 2: 12, 1956. 8. Cardell. B. S.: Hvnertronhv and hvperplasia of the pan creatic islets in newborn infants, J. Fathbl. 66: 335, 1953. 9. Cassady, G.: Amniocentesis, Clin. Perinatol. 1 (1): 87. 1974.
July I, 197x Am. J. Obster. Gynec~l.
Many factors undoubtedly play a role in the success of our approach to management. Because of the strengths of the educational programs of the Joslin Clinic early in the lives of our diabetic pregnant women, we have a very low proportion of “neglecters.” as described by Pedersen and colleagues.74 The incidence of pyelonephritis and pre-eclampsia is low in our current series. The availability of the cu-fetoprotein assay and ultrasonography has allowed the early diagnosis of anencephaly so that pregnancies may be terminated. Application of measures which can assess fetal well-being, such as daily urinary estriol determinations and the OCT, has allowed pregnancies to be carried closer to term and has prevented the occurrence of sudden, unexpected fetal death late in gestation. Individualization of the timing of delivery on the basis of the LIS ratio and advances in neonatal care have dramatically reduced the incidence and mortality rate of RDS. We are grateful to Drs. Priscilla White, Luke Gillespie, and John Hubbell for the inspiration of their pioneering efforts in the care of diabetic pregnant women and their babies and to Drs. Charles Graham, John Hare, I. John Davies, Fredric Frigoletto, Philip Stubblefield, Dan Tulchinsky, and the staff of the Joint Program in Neonatology for expert assistance with ciinical management of these patients.
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Chez, R. A., Mintz, D. H., Reynolds, W. A., et al.: Maternal-fetal plasma glucose relationships in late monkey pregnancy, AM. J. OBSTET. GYNECOL. 121: 938, 1975. Chez, R. A., Mintz, D. H., and Epstein, M. F.: Fetal hormonal mechanisms for plasma glucose homeostasis in normal and glucose intolerant pregnancy, in CameriniDavalos. R. A.. and Cole. H. S.. editors: Earlv Diabetes in Early Life, New York, l975, Academic Press, Inc.. pp. 141-163. Cloherty, J. P., and Epstein, M. F.: Infants born to diabetic mothers, in Willis, S. S., and Kagan, B., editors: Current Pediatric Therapy, Philadelphia, 1978, W. B. Saunders Co., pp. 325-330. Crawford, J. S.: Maternal and cord blood at delivery. IV. Glucose, sodium, Potassium, calcium, chloride, Bill. Neonate. 8: 222, 1965. Cruz, A. C., Buhi, W. C., Birk, S. A., et al.: Respiratory distress syndrome with mature lecithinisphingomyelin ratios: Diabetes mellitus and low Apgar scores, AM. J. OBSTET. GYNECOL. 126: 78, 1976. Dahlenburg, G. W., Martin, F. I. R., Jeffrey, P. R., et al.: Amniotic fluid lecithin/sphingomyelin ratio in pregnancy complicated by diabetes, Br. J. Obstet. Gynaecol. 84: 294, 1977. Datta, S., and Brown, W. U.: Acid-base status in diabetic mothers and their infants following general or spinal anesthesia for cesarean section, Anesthesiology 47: 272, 1977.
Volume Number
131 5
17.
Diabetic
Distler, W., Gabbe, S., Freeman, R. G., et al.: Estriol in pregnancy. V. Unconjugated and total plasma estriol in the management of diabetic pregnancy, AM. J. OBSTET. GYNECOL. 130: 424, 1978. 18. Donald, I. R., Freeman, R. K., Goebelsmann, U., et al.: Clinical experience with the amniotic fluid lecithin/ ;$~gomyelin ratio, AM. J. OBSTET. GYNECOL. 115: 547,
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Driscoll, S. G.: The pathology of pregnancy complicated by diabetes mellitus, Med. Clin. North Am. 49: 1053, 1965. Driscoll, S. G., Benirschke, K., and Curtis, G. W.: Neonatal deaths among infants of diabetic mothers. Postmortem findings in ninety-five infants, Am. J. Dis. Child. 100: 818, 1960. Dubowitz. I,.: Clinical assessment of gestational age in the newborn infant. 1. Pediatr. 77: 1, 1970. Duhring, J. I,., &id Thompson, S. A.: Amniotic fluid phospholipid analysis in normal and complicated pregnancies, AM. J. OBSTET. GYNECOL. 121: 218, 1975. Epstein, M. F., Farrell, P. M., and Chez, R. A.: Fetal lung lecithin metabolism in the glucose-intolerant rhesus monkey pregnancy, Pediatrics 57: 722, 1976. Essex, N. L., Pyke, D. A., Watkins, P. J., et al.: Diabetic pregnancy, Br. Med. J. 4: 89, 1973. Farquhar. J. W.: Prognosis for babies born to diabetic mothers in Edinburg, Arch, Dis. Child. 44: 36, 1969. Farrell, P. M., and Avery, M. E.: Hyaline membrane disease, .4m. Rev. Respir. Dis. 111: 657, 1975. Felig. P.: Body fuel metabolism and diabetes mellitus in pregnancy, Med. Clin. North Am. 61: 43, 1977. Fencl, M. D., and Tulchinsky, D.: Total cortisol in amniotir fluid and fetal lung maturation, N. Engl. J. Med. 29P: 133, 1975. Fiser. R. H., Williams, P. R., Fisher, D. A., et al.: The effect of oral alanine on blood glucose and glucagon in the human newborn infant, Pediatrics 56: 78, 1975. Gabbay, K. H., Hasty, K., Breslow, J. L., et al.: Glycosylated hemoglobins and long term blood glucose control in diabetes mellitus, J. Clin. Endocrinol. Metab. 44: 859, 1977. Gabbe. S. G., Mestman, J. H., Freeman, R. K., et al.: Management and outcome of class A diabetes melhtus, AM. J. OBSTET. GYNECOL. 127: 465, 1977. Gabbe, S. G., Mestman, J. H., Freeman, R. K., et al.: Management and outcome of pregnancy in diabetes mellitus, classes B to R. AM. I. OBSTET. GYNECOL. 129: 723. 1977. Gabbe. S. G.:‘Congenital malformations in infants of diabetic mothers, Obstet. Gynecol. Surv. 32: 125, 1977. Gabbe, S. G.. Lowensohn, R. I., Mestman, J. H., et al.: Lecithin/sphingomyelin ratio in pregnancies complicated by diabetes mellitus. AM. J. OBSTET. GYNECOL. 128: 757, 1977. Gluck. L., and Kulovich, M. V.: Lecithin/sphingomyelin ratios in amniotic fluid in normal and abnormal pregnancy, AM. J. OBSTET. GYNECOL. 115: 539, 1973. Gluck, L., Kulovich, M. V., Borer, R. C., et al.: The interpretation and the significance of the lecithin/ sphingomyelin ratio in amniotic fluid, AM. J. OBSTET. GYNECOL. 120: 142, 1974. Gluck, L., Kulovich, M. V., Borer, R. L., et al.: Diagnosis of the respiratory distress syndrome by amniocentesis, AM. J. OBSTET. GYNECOL. 109: 440, 1971. Goebelsmann, U., Freeman, R. K.. Mestman, J. H., et al.: Estriol in pregnancy. II. Daily urinary estriol assays in the management of the pregnant diabetic woman, AM. J. OBSTET. GYNECOL. 115: 795, 1973. Gugliucci, C. L., O’Sullivan, M. J., Opperman, W., et al.: Intensive care of the pregnant diabetic, AM. J. OBSTET. G~NECOI. 125: 435, 1976.
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Milner, R. D. G., and Hales, C. N.: Effect of intravenous glucose on concentration of insulin in maternal and umbilical cord plasma, Br. Med. J. 1: 284, 1965. Molsted-Pederson, L., Tygshrap, I., and Pedersen, J.: Congenital malformations in newborn infants of diabetic women. Correlation with maternal diabetic vascular complications, Lancet 1: 1124, 1964. Mueller-Heubach, E., Caritis, S. N., Edelstone, D. I., et al.: Lecithinlsphingomyelin ratio in amniotic fluid and its value for the prediction of neonatal respiratory distress syndrome in pregnant diabetic women, AM. J. OBSTET. GYNECOL. 130: 28, 1978. Myers, R. E.: Lactic acid accumulation as cause of brain edema and cerebral necrosis resulting from oxygen deprivation, Adv. Perinatol. Neurol. in press. Naeve, C.: Congenital malformations in offspring of diabetics, Ph. D. thesis, Harvard University School of Public Health, 1967. Obenshain, S. S., Adam, P. A., King, K. C., et al.: Human fetal insulin response to sustained maternal hyperglycemia, N. Engl. J. Med. 283: 566, 1970. Olsen, B. R., Osler, M., and Pedersen, J.: Neonatal jaundice in infants born to diabetic mothers, Dan. Med. Bull. lo: 18, 1963. Osler, M., and Pedersen, J.: The body composition of newborn infants of diabetic mothers, Pediatrics 26: 985, 1960. O’Sullivan, J. B., Mahan, C. M., Charles, D., et al.: Medical treatment of the gestational diabetic, Obstet. Gynecol. 43: 817, 1974. Pedersen, J.: The Pregnant Diabetic and Her Newborn, 2nd Ed., Baltimore, 1977, Williams and Wilkins. Pedersen, J., Molstead-Pederson, L., and Pedersen, B.: Assessors of fetal perinatal mortality in pregnancy, Diabetes 23: 302, 1974. Pedersen, J., and Pedersen, L. M.: Prognosis of the outcome of pregnancies in diabetics. A new classification, Acta Endocrinol. 50: 70, 1965. Persson, B.: Treatment of diabetic pregnancy, Hr. J. Med. Sci. 11: 609, 1975. Persson, B., Feychtung, H., and Gentz, J.: Management of the infant of the diabetic mother, in Sutherland, H. W., and Stowers, J. M., editors: Carbohydrate Metabolism in Pregnancy and the Newborn, Edinburgh, London, and New York, 1975, Churchill Livingstone, pp. 232-248. Rivlin, M. E., Mestman, J. H., Hall, T. D., et al.: Value of estriol estimations in the management of diabetic pregnancy, AM. J. OBSTET. GYNECOL. 106: 875, 1970. Robert, M. F., Neff, R. K., Hubbell, J. P., et al.: Association between maternal diabetes and the respiratory distress syndrome in the newborn, N. Engl. J. Med. 294: 357, 1976. Roversi, G. D., Canussio, V., Gargiulo, M., et al.: The intensive care of perinatal risk in pregnant diabetics: A new therapeutic scheme for the best control of maternal disease, J. Perinat. Med. 1: 114, 1973. Rowland, T. W., Hubbell, J. P., and Nadas, A. S.: Congenital heart disease in IDM, J. Pediatr. 83: 815, 1973. Rusnak, S. L., and Driscoll, S. G.: Congenital spinal anomalies in infants of diabetic mothers, Pediatrics 35: 989, 1965. Schalch, D. S., and Burday, S. Z.: Antepartum pituitary insufficiency in diabetes mellitus, Ann. Intern. Med. 74: 357, 1971. Shelley, H. J., Bassett, J. M., and Milner, R. D.: Control of carbohydrate metabolism in the fetus and newborn, Br. Med. Bull. 31: 37, 1975. Shima, K. C., Price, S., and Foa, P. P.: Serum insulin concentration and birthweight in human infants, Proc. Sot. Exp. Biol. Med. 121: 55, 1966.
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Skjaeraasen, J., and Lindback, T.: Phospholipid concentrations in amniotic fluid from diabetic pregnant women, Acta Obstet. Gynecol. Stand. 55: 225, 1976. Smith, D. W.: Recognizable Patterns of Human Malformation: Genetic, Embryologic and Clinical Aspects, Philadelphia, 1970, W. B. Saunders Co. Smith, B. T., Giroud, L. J. P., Robert, M. F., et al.: Insulin antagonism of cortisol action on lecithin synthesis by cultured fetal lung cells, J. Pediatr. 87: 953, 1975. Sosenko, I. R., Kitzmiller, J. L., Loo, S., et al.: Free C-peptide: Relationship to hypoglycemia, macrosomia, and hyaline membrane disease in the infant of the diabetic mother, Pediatr. Res. (in press). Sosenko, I. R., Lawson, E. E., Demottaz, V., et al.: Delayed lung maturation in fetuses of alloxan diabetic rabbits, Pediatr. Res. (in press). Spellacy, W. N., Goetz, F. C., Greenberg, B. Z., et al.: Human placental gradient for plasma insulin and blood glucose, AM. J. OBSTET. GYNECOL. 90: 753, 1964. Steinke, J., and Driscoll, S. G.: The extractable insulin content of pancreas from fetuses and infants of diabetic and control mothers, Diabetes 14: 573, 1965. Szabo, H. A., and Szabo, 0.: Placental free fatty acid transfer and fetal adipose tissue development: An explanation of fetal adiposity in infants of diabetic mothers, Lancet 2: 498, 1974. Taeusch, H. W., Frigoletto, F., Kitzmiller, J. L., et al.: Risk of respiratory distress syndrome and maternal infection after prenatal dexamethasone treatment, Submitted for publication. Torday, J. S., Lawson, E. E., and Carson, L.: Rapid measurement of surface active lecithin, AM. J. OBSTET. GYNECOL. Submitted for publication. Tsang, R. C., Kleinman, L. I., Sutherland, J. M., et al.: Hypocalcemia in infants of diabetic mothers, J. Pediatr. 80: 384, 1972. Tyson, J. E., and Felig, P.: Medical aspects of diabetes in pregnancy and the diabetogenic effects of oral contraception, Med. Clin. North Am. 55: 947, 1971. Tyson, J. E., and Hock, R. A.: Gestational and pregestational diabetes: An approach to therapy, AM. J. OBSTET. GYNECOL. 125: 1009, 1976. van Otterlo, L. C., Wladimiroff, J. W., and Wallenburg, H. C.: Relationship between fetal urine production and amniotic fluid volume in normal pregnancy and pregnancy complicated by diabetes, Br. J. Obstet. Gynaecol. 84: 205, 1977. Villee, D., and Powers, M. L.: The effect of glucose and insulin on collagen secretion by human skin fibroblasts in vitro, Nature 268: 156, 1977. Warren, S., and LeCompte, P. M.: Pathology of Diabetes Mellitus, Philadelphia, 1966, Lea & Febinger. West, T. E., and Lowy, C.: Control of blood glucose during labor in diabetic women with combined glucose and low dose insulin infusion, Br. Med. I. 1 (6071): 1252, 1977. White, P.: Diabetes mellitus in pregnancy, Clin. Perinatol. 1: 331, 1974. Whitfield, C. R., Sproule, W. B., and BrudeneIl. M.: The amniotic fluid lccithin/sphingomyelin area ratio (LSAR) in pregnancies complicated by diabetes, Br. J. Obstet. Gynaecol. 80: 918, 1973. Widness, 1. A., Schwartz, H. C., Thompson, D., et al.: Glycohemoglobin (HbA,C): A predictor of birthweight in infants of diabetic mothers, 1. Pediatr. 92: 8, 1978. Zackman, R. D.: Hyaline membrane disease and the immature lung, in Wesenberg, R. L., editor: The Newborn Chest, Haeerstown. Md., 1973, Harper and Row. Zimble, N., Mirray, J., and Feingold, ‘M.: Personal Communication. .n
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Diabetic pregnancy and perinatal morbidity JOHN
L. KITZMILLER,
JOHN
P. CLOHERTY,
M.
DONNA
ASHRAF SUZANNE ILENE
M.D. M.D.
YOUNGER,
M.D.
TABATABAII, B.
M.D.
ROTHCHILD,
SOSENKO,
MICHAEL
F. EPSTEIN,
SHAILINI
SINGH,
RAYMOND
K.
M.D.
M.D.
NEFF,
M.D.
M.D. Sc.D.
Boston, Massachusrtts Pregnancy outcome was analyzed in 147 diabetic women, 71 per cent of whom were dependent on insulin for more than 10 years. Ambulatory management of diabetes was carried out with weekly clinic visits until hospitalization at 36 to 37 weeks’ gestation. Modern methods of fetal assessment were applied, and the timing and route of delivery were individualized. Of these patients, 35 per cent were delivered at or beyond 38 weeks’ gestation. The primary cesarean section rate was 55 per cent. Polyhydramnios was a frequent maternal complication and was associated with premature labor and neonatal death in two cases. Poiyhydramnios was least common in women with the lowest mean outpatient blood glucose. The perinatal survival rate was 96.6 per cent, and there were no instances of unexpected intrauterine fetal death. The incidence of respiratory distress syndrome (RDS) in the newborn infant was 7.6 per cent. No severe RDS was seen when the lecithinisphingomyelin (L/S) ratio was greater than 3.0, but three of 24 infants delivered with an L/S ratio of 2.1 to 3.0 developed severe RDS. Other forms of neonatal morbidity noted in this population were 9 per cent major congenital anomalies; 7 per cent transient tachypnea of the newborn, 22 per cent hypocalcemia, 19 per cent hyperbilirubinemia, and 47 per cent hypoglycemia. The latter was more common in macrosomic infants, defined as greater than the ninetieth percentile of birth weight for gestational age (LGA), who represented 36 per cent of the neonates. Mean outpatient postprandial blood glucose was higher in patients delivered of LGA infants and was correlated with birth weight in White Classes 6 to D. (AM. J. OBSTET. GYNEWL. 131: 560, 1978.)
From the Departments of Obstetrics and Gynecology, Pediatrics, and Medicine, Boston Hospitalfor Women and the Jo&n Clinic, Haruard Medical School, and the Health Sciences Computing Facility, Harvard School of Public Health. Reprint requests: Dr. John L. Kitzmilier, Boston Hospital for Women, See&y G. Madd Bldg., 250 Longwood Ave., Boston, Massachusetts 02115.
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DIABETES MELLITUS antedating pregnancy is recognized as an important cause of maternal morbidity, birth defects, intrauterine fetal death, and neonatal morbidity and death. An increased incidence of these complications has been associated with duration of diabetes, the presence of vascular lesions, and the degree of control of the diabetic state during pregnancy. OOOZ-937&I/78/05131-0560$02.10/O
0 1978 The C. V. Mosby Co.
Diabetic
Patients with poor control of diabetes have a higher risk of fetal or neonatal death, and the occurrence of ketoacidosis. in particular, carries an excessive rate of fetal ,oss.s:~.87. 103* n addition, Pedersen and associates 74 pointed our that patients who are noncompliant (neglectors) and do not cooperate with the treatment plan have an increased risk of pregnancy loss. The importance of diabetic control during pregnancy received impetus from Karlsson and Kjellmer’s”’ study of 95 gravid patients well distributed throughout the White classifications in the years 1966 to 1970. They measured blood glucose several times a day in hospitalized patients after 30 to 32 weeks’ gestation. The group with the lowest mean preprandial glucose values (
Background Maternal morbidity. In the first half of pregnancy there is often an improvement of carbohydrate tolerance in the insulin-dependent diabetic woman.73 The cause may be related to fetal-placental utilization of glucose.“” The improvement in tolerance is manifested clinically by increased frequency and severity of hypoglycemic reactions, which may appear in the absence of warning signs. lo3 Later in pregnancy decreased carbo-
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hydrate tolerance is the rule, with an inc rc;~secl dosage of insulin demanded, and there is a strotlg tendenc\ to the rapid development of ketoacidosis.“’ l%csc diahetogenic effects of pregnancy are related IO ,intagonisni of the peripheral effects of insulin anti rt~h;~ncrd lipolysis and ketogenesis in the tasting stat<‘. i’rogressivc placental secretion of human placental lac-togen is ;I major factor in the altered metabolism (bt gestatioll.“’ Vascular complications, sur11 its prollti,rating retinopathy and glomerular nephropathv, JIXI thr tragic hallmark of many cases of diabetes 01’ ll,ng duration. Information on the effect of pregnanc’v OII the vascular complications of diabetes is limited SPIKY no svstemati( studies of the effect of pregnancv OII the irdrnte OIcourse of benign or proliferating rctinclpathv have been performed. Contrasting opinions th,tt pt-qnatw induces rapid progression, has no t+fGci on diabetic retinopathy, and has a beneficial ettcc I OII diabetic, retinopathy and that remissions occur followi~lg complytion of pregnancy have been advanced.‘, x In ;I series of 2.147 diabetic pregnant patients rep0rtc.d tn White,‘03 the incidence of malignant pr~Jlftrating retinopathy was 0.5 per cent and the incidertc c of benign retinopathy was 2.9 per cent. These wmrn devrloprd lesions during pregnancy, and the much larger group of women in whom retinal disease precrded pregnant.! was not taken into account. It has keen buggcasted that proliferating diabetic retinopathk, in colbtrast IO the benign form, has a greater bur unpredictable tendency to progress during pregnancy, cspeciall~ if the proliferating phase is. noted during the first trimester? This was the basis for the recommendaGor1 i.or termination of pregnancy in diabetic patients developing proliferating retinopathy.“g However. irr I CYCnt ycarh many cases of proliferating retinopathv tlul-ing prepnancy have been controlled b), laser photr~coagt~iation therapy. Since the effect of this therapy on the natural histo,? of retinopathy during and after prt’~nancy has not been systematically studied, 2 the quctiott of longterm consequences remains. Determination of the incidence and prognosis of diby thr abetic nephropathy in pregnancx ,’ is clouiieti tendency of the diabetic pregnant woman to dej,elop pyelonephritis or pre-eclampsia.“’ The t’e:v ‘tvailablt studies reviewed by Pedersen79 suggest that L linical and laboratory parameters of diabetic nephropathy usuali! return toward the prepregnancy level after delivcsr\ .i’t In a series from 1959 to 1963, Pedersen and Pedersen” found urinary tract infection to be present in I6 pet cent and clinical pyelonephritis to be present in 6 per cent of 283 pregnant women with diabctcbs. An increased perinatal mortality rate was assoc~iated with pyelonephritis and with pre-eclampsia711~~ thr above
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series Pedersen and Pedersen7j classified 23 per cent of patients as having pre-eclampsia on the basis of acute hypertension, proteinuria, edema, or weight increase. In a review of the literature published in 1963, Kyle”” reported an average incidence of toxemia of 25 per cent (range: 8 to 45 per cent). The superimposed preeclamptic syndrome is perhaps most common, devastating, and difficult to diagnose in patients with White Class F diabetes.” Polyhydramnios is a common maternal complication of diabetic pregnancy. For the years 1959 to 1964, Pedersen and Pedersen?” reported a 25 per cent incidence. The cause of polyhydramnios remains uncertain in most cases. It is not usually related to congenital malformations of the fetus. In addition, there is no relationship between amniotic fluid volume and the expected elevation in glucose and other solutes in the amniotic fluid9 A recent study did not find increased fetal output of urine (as measured by ultrasound) in patients with increased volumes of amniotic fluid.gg Pedersen73 found a lower incidence of polyhydramnios in hospitalized as compared to ambulatory patients in the latter part of pregnancy. However, the relative contribution of bed rest in the hospital as compared to tighter diabetic control in that study remains uncertain. Antepartum fetal distress. The actual cause of intrauterine fetal distress and death during diabetic pregnancy remains unknown in most cases. As noted above, there are clinical associations with severe maternal hyperglycemia and ketosis, hypertensive syndromes, and pyelonephritis.7” The risk increases later in pregnancy. lo3 Whether or not the risk of fetal death is increased during episodes of maternal (thus fetal) hypoglycemia remains controversiaLz7s Ia3 Fetal monitoring tests of various types have been widely applied in the last decade in the presumption that fetal distress can be diagnosed and stillbirth prevented by prompt delivery. One reflection of the fetal condition is obtained by measuring the concentration of estriol in maternal blood or urine. Since the fetal adrenal and liver provide the precursor (16a-hydroxydehydroepiandrosterone) for placental aromatization to estriol, the accumulation of this estrogen in maternal fluids is often representative of fetal-placental function. The pattern of serial values in a given woman is important since there is wide variation in amount of estriol from one diabetic patient to another. Many have reported higher mean urinary estriol values in diabetic pregnant women, usually in association with fetal macrosomia and placentomegaly.s2 It is clear that estriol levels must be measured daily in order to detect the rather sudden onset of fetal distress observed in some pregnancies of diabetic women.38, jZ,78 Low urinary es-
July I. 1978 Am. J. Ohet. Gynecd.
trio1 values may be found in diabetic women with vascular or renal complications, and this may be indicative of’ intrauterine fetal growth retardation. Antepartum fetal heart rate monitoring has also been applied as a measure of fetal well-being in diabetic pregnancies. This tool is based on extensive studies of fetal cardiovascular responses to hypoxia carried out in the last decade. Experimentally, in pregnant sheep and monkeys, maternal hypoxia or impaired placental perfusion generally leads to fetal hypoxia with resultant decelerations of the fetal heart rate and decreased beat-to-beat variability. Similar heart rate patterns are observed in some human fetuses in response to the transient hypoxia of uterine contractions, cord compression, and maternal vascular disease or from unknown causes. When delivered, a higher percentage of such fetuses as compared to control fetuses have low Apgar scores, hypoxia, and acidosis. The high-risk fetus of the diabetic pregnant woman has an increased incidence of such distress during antepartum fetal heart rate monitoring tests and during labor.“‘, gfi Fetal macrosomia, liyperinsulinism, and neonatal hypoglycemia. The infant of the diabetic mother (IDM) is particularly prone to macrosomia (largebirth-weight syndrome). Mean birth weight in the IDM was 550 grams more and mean length was 1.5 cm greater than that in a group of control infants (mean gestational age of 260 days and matched for various maternal data).‘” Osler and Pedersen7’ concluded that the macrosomic IDM contains less total body water and that the increase in weight is due to increased fat, postulated to be deposited as the result of excessive insulin secretion. It is plausible to consider the large size of the organs of the IDM and the excessive accumulation of’ fat and glycogen in these organs to be due to the excess quantities of nutrients (glucose, amino acids, and free fatty acids) available to the fetus of the pregnant woman with diabetes. Such nutrients alone without insulin to facilitate their transport into cells would not be sufficient to explain the enlargement of muscle tissues (including heart) and adipose tissue. Evidence to date suggests that the fetus of the diabetic mother is hyperinsulinemic. Pedersen’” explained the origin of the fetal hyperinsulinism as follows: Maternal diabetes is associated with maternal hyperglycemia which leads to fetal hyperglycemia and excessive stimulation of the fetal pancreas to produce insulin. There is a strong correlation of glucose levels in maternal and fetal bloodstreams. Crawford’” demonstrated a maternalto-fetal glucose difference of 13 mg. per 100 ml. and concluded that the gradient of maternal-fetal glucose concentrations is maintained in a minute-to-minute
Diabetic
fashion, even in the presence of a rapidly changing glucose concentration in maternal blood. Spellacy and associate?” described a direct relationship between the blood glucose of mother and infant across the placenta; they also found that the infant’s umbilical vein glucose was always lower than the maternal venous glucose. In the pregnant rhesus monkey, Chez and colleagues” found a close correlation of fetal glucose levels with maternal ones, with no evidence of an upper limit of placental glucose transfer. The regulation of insulin release during fetal life has attracted a great deal of attention. The results of studies in this field indicate that glucose is a less efficient stimulus to insulin release in the fetus than in the adult.” However, a sustained increase of the fetal blood glucose concentrarion in utero may induce a significant rise of the fetal plasma insulin level. Arginine or leucine in the presence of glucose can markedly enhance the fetal insulin release. Therefore, the fetus of the pregnant woman with diabetes exposed to high levels of glucose and amino acids in the blood has the potential for early maturation of the pancreatic beta cell. Steinke and Driscoll”’ found that the content of insulin per gram of pancreas in the IDM was significantly higher than in control infants. They also showed microscopically that the pancreas of the IDM had hypertrophy and hyperplasia of the pancreatic islets as a result of proliferation of the beta cells. Shima and associates”” found a strong correlation between birthweight in overgrown infants and the infants’ serum insulin levels, indicating that the excessive size of certain newborns may be the result of hyperinsulinism. Cardell’ found a correlation between the quantity of islet tissue at autopsy and the birth weight of the IDM. A large number of studies have shown more rapid attainment of a higher peak plasma insulin level, resulting in a more rapid disposal of glucose in IDM as compared to control infants when both groups were exposed to glucose infusions.‘. J”. 64,69 The insulin assayed in the infants was of fetal rather than maternal origin, as demonstrated in the studies of Adam and associates’ and Spellacy and associates,gl who concluded that maternal insulin does not cross the placenta. Measurement of C-peptide has provided an alternative means of monitoring beta-cell function in the presence of maternally derived insulin antibodies, which cross the placenta and interfere with the usual radioimmunoassays for insulin in fetal and newborn blood. C-peptide immunoreactivity was examined by Block and coworkers” in IDM’s and compared to infants of mothers with gestational diabetes and control infants6 The) found that cord C-peptide immunoreactivity levels were significanth higher in infants of diabetic mothers
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as compared with those of normal O>~III-O~ inlants: therefore, a slightly different approa.il ~\‘;t+ ~tsed IO confirm hyperinsulinism in the 111x1. A common problem in the IDM is cal-ly postnatal hypoglycemia, secondary to exe essivca insulin secretion after division of the umbilical cxjrd and rhe termination of placental transfer of glucose. Hww\cr. the association of severe neonatal hypoglycemia with cord insulirt levels has not been demonstratrd in :111 studies.“” Johnston and Bloom’g suggested thar the neonatal pancreatic glucagon response to Ihc* postnatal fall in glucose is inappropriately small irl rhc LD>l. especialI) in cases with sustained hypoglycemia. 1ncreased Fetal glucose and insulin concentrations have been shown to inhibit basal and alanine-stimulated glut ;~gon secretion in the normal newborn infant.“‘. 62 ~~ur~w~t studies ot hepatic glucose output in normal infants and IDM’s should increase our understanding of nronat;~l hvpcvglycemia. Neonatal pulmonary complications. [‘he nujw cause of mortality in the IDM in the past has been RDS. This was the conclusion of Driscoll and aqsoc’iates”‘. x0 in their review of 55 autopsies of IDM’s. all
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and physiologic development has led to the use of animal models of diabetic pregnancy and in vitro examination of the fetal lung. Epstein and co-workers23 used the rhesus monkey fetus from mothers rendered hyperglycemic by the injection of streptozotocin, a specific pancreatic beta-cell cytotoxin. They observed marked differences between the normal and hyperglycemic fetuses in the ability of the lung to synthesize, store, and release lecithin, the principal component of the surface-active material in the lung. Sosenko and co-worker?’ have reported preliminary observations in another animal model of diabetic pregnancy, the alloxan-treated rabbit. At 27% days’ gestation, the hyperglycemic rabbit fetuses showed less surface-active material in pulmonary lavage fluid and demonstrated less deflation stability in pressure-volume measurements when compared with control fetuses. These studies indicate that the maternal diabetic state affects fetal lung development; the exact mechanism of this interaction has been examined in a cell culture system by Smith and associates.88 They utilized a monolayer cell culture system of the fetal rabbit lung and examined the effect on lecithin synthesis when insulin was added to the culture system. They found that, although insulin alone results in a small but significant increase in lecithin synthesis, the addition of both insulin and cdrtisol to cell culture results in a marked diminution of the stimulatory effect observed when cortisol alone was added. Since cortisol is thought to be the physiologic stimulus for the increased synthesis of lecithin in the fetal lung seen at approximately 90 per cent of term gestation, they hypothesized that insulin might interfere with this normal increase in lecithin synthesis. This increase in lecithin synthesis is responsible for the normal functioning of the neonatal lung at term; therefore, the elevated insulin concentration in fetal plasma in IDM’s may interfere with this normal maturational sequence and lead to the increased incidence of RDS seen in IDM’s. Although there have been no controlled studies examining this hypothesis, improved control of the maternal-fetal hyperglycemia may minimize the abnormalities in fetal lung maturation and lead to a decreased incidence of RDS. Neonatal hypexbilirubinemia and hypocalcemia. Hyperbilirubinemia and hypocalcemia are commonly found in the early life of the IDM. Hyperbilirubinemia was noted in 38 per cent of the newborn infants studied by Pedersen73 and in 27 per cent of those studied by Essex and co-workers,24 but these authors used a low limit of normal (10 mg. per deciliter). The cause of the hyperbilirubinemia is presumed to be related to func-
July I. 1978 Am. J. Obstet. Gynecd.
tional prematurity of hepatic enzymes necessary for the conjugation of bilirubin.70 hypocalcernia Tsang and colleagues sfi demonstrated in six of 10 infants of mothers with White Classes B, C, and D. The incidence of hypocalcemia was increased over that in a matched control group even when gestational age and perinatal complications were considered. Pedersen73 found hypocalcemia in 10 per cent of IDM’s in a recent series. Hypomagnesemia wasnot observed. The cause of neonatal hypocalcemia is unknown but may be related to persistent functional hyperparathyroidism in these infants.“” Congenital anomalies. Almost all investigators have found an increased incidence of major birth defects in offspring of diabetic mothers compared to those of control populations. Studies of the incidence and pathogenesis of congenital anomalies in IDM’s have been reviewed recently by Gabbe.“” Varied types of anomalies, including anencephaly-meningocele,2j transposition of the great vessels, ventricular septal defect, coarctation of the aorta,“’ caudal regression syndrome and vertebral dysplasia,3s ** ureteral duplication, renal agenesis,” and anal atresia.R7 are observed. In a retrospective review, Naeve 68 found no increase in malformations in infants born to diabetic fathers and nondiabetic mothers as compared to normal fathers. Pedersen,73 Koller,“3 and Naeve6” all reported an increased risk of congenital anomalies in infants born to mothers with White Classes D, F, and R diabetes, suggesting associations with duration of maternal disease and vascular complications. It is probable that there are multiple etiologic factors in the increased incidence of anomalies in IDM’s. The role of genetic factors has not been substant.iated.3”, 6H Molsted-Pederson and associates69 speculated that fetal hypoxia could play a role in diabetic pregnancies complicated by vascular disease, but they later concluded that better metabolic control in the same group of patients reduced the risk of birth defects.73 Similarly, Karlsson and Kjellmer”’ observed a low incidence of anomalies in offspring of the subgroup of pregnant women with diabetes easiest to control later in pregnancy. Hypoglycemia may be associated with an increased risk of fetal malformations. Insulin injected into chick and rodent embryos produced vertebral and bony anomalies.40~ 47, 56 The anomalies were decreased when hypoglycemia was prevented by adding glucose to the preparationsjo Hyperglycemia may also be a cause of fetal anomalies. Litters born to diabetic mice have an increased incidence of limb malformations and cleft palate. When the mothers are treated with insulin, this
Diabetic pregnancy and perinatal morbidity
increased incidence is eliminated.“j While the mechanism of the effect of hyperglycemia is uncertain, it may involve the role of collagen in inducing embryogenesis.‘” Fibroblasts grown in medium containing a high level of glucose secrete more collagen as compared with fibroblasts in medium containing physiologic amounts of glucose. Ino -4 large amount of this collagen mav be converted to glycosyl and one can speculate that alteration of the collagen molecule in terms of carbohydrate moieties might affect the induction process. Since fetal hyperinsulinism in the IDM should not occur until the fetal pancreas is functional, well after the major period of morphogenesis, endogenous insulin should not be a cause of malformations.
Clinical study The dilemma of traditional management of pregnancy in the diabetic patient has been to time delivery to balance the risk of stillbirth late in gestation with that of neonatal death from pulmonary immaturity earlier in gestation. Recent conceptual and technologic advances in the realm of fetal assessment have offered the opportunity of individualized management for each diabetic pregnant woman. This is our initial report on the application of these techniques to a large population of pregnant women with insulin-dependent diabetes in an attempt to reduce perinatal deaths to a minimum. Diabetic pregnancy is both a mode1 for the team approach to perinatal medicine and a test of the utility of our diagnostic measures.
Subjects and methods Patient population. During 1975 to 1978, 175 women registered at the pregnancy clinic of the Joslin Diabetes Foundation. Twenty-eight women aborted, 21 spontaneously (12 per cent) and seven electively ‘(4 per cent). Th,is includes three women (2 per cent) who underwent late abortions after the ultrasonographic diagnosis of fetal anencephaly. This report analyzes our experience with the remaining 147 women whose pregnancies attained 24 weeks’ gestation. Table I describes the White classification and the parity of this group of women. Chemical diabetes was diagnosed during pregnancy in 9 per cent of the patients (by a 100 Gm. oral glucose tolerance test), with the diagnostic criteria of O’Sullivan and associates.72 Class B includes three subjects with newly diagnosed diabetes who were hyperglycemic despite dietary therapy and who were begun on a regimen of insulin therapy during the pregnancy. Among the 37 patients with Class D diabetes, 23 were so characterized on the basis of onset of diabetes under age 10 or duration of diabetes for more
8 9
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-‘x .9B*b CONFIDENCE LIMITS FOR NORMAL PREGNANCY
50
I
FASTING
I HOURS AFTER
2
x
BREAKFAST
Fig. 1. Solid line indicates the upper limit established by O’Sullivan and co-workers72 for normal random blood glucose values in pregnant women. The difference from normal was calculated for each clinic visit of our diabetic subjects and expressed as A0.B.G. Mean A0.B.C;. was computed for each pregnancy. Broken lines divide distribution of mean A0.B.C.. values for 134 insulin-dependent subjects into thirds. than 20 years, and 14 were classified on the basis of (Class F) benign re tinopathy. lo3 Diabetic nephropathy is presumed when proteinuria greater than 400 mg. per 24 hours is found in early pregnancy, in the ahsence of infection. Renal biopsies were not perfc>rmed. The two patients with Class R diabetes received laser photocoagulation therapy for proliferativc~ retinopath) during pregnancy. Outpatient management. Patients we9~ seen weekly in a combined medical and obstetric. clinic. Dietary adherence and symptoms of hypoglycemia were reviewed. The therapeutic diet averaged X? calories per kilogram of body weight during pregnancy with the following caloric distribution: breakfast, ‘/a; lunch. ‘/5; and supper, z/3, with allowance for thlec-hour postprandial snacks. Sufficient carbohydrate, was given to minimize ketonuria (usually 190 to 200 Gm. per da) during the first and second trimesters, often 200 to 240 Cm. per day in the third trimester); l..> ttr 2.0 Cm. of protein per kilogram of body weight during pregnant) was given, and the caloric prescription was completed with fat. Insulin dosage was ad-justed weekly by the physician on the basis of home urine texts for glucose and acetone (second voided specimen bef’ore meals and at bedtime, Clinitest* two-drop method), level of exercise, hypoglycemic reactions, and the glucose concentration in whole blood at the time of the c-linic visit. By the second half of pregnancy most patients received a 1: 2 mixture of regular: NPHS or lente insulin, with an appropriate fraction of the dose given before supper. The goal of therapy was to maintain blood glucose levels as close to normal as possible without incapacitating the patients with hypoglycemic reaction\ *Ames Co., Inc., Elkhan, Indiana. tE. R. Squibb, Princeton, New Jerset,.
566
Kitzmiller et al.
The 98 per cent confidence limits for random blood glucose levels in normal pregnant women, published by O’Sullivan and co-workers,‘2 were used to establish a nomogram for outpatient blood glucose (O.B.G.). The difference from normal blood glucose for each clinic visit was calculated (A0.B.G.; Fig. l), and the average A0.B.G. for each pregnancy was determined. Estrogen-progesterone injections were given to only 21 per cent of the subjects, since this practice was discontinued in 1975. Ultrasound p-scans were obtained routinely at 18 to 20 weeks’ gestation to confirm the length of gestation and to rule out gross fetal anomaly. Urine samples over a 24 liour period were collected weekly for estriol and creatinine measurement after 30 weeks’ gestation. Low estriol levels were defined as below the 95 per cent confidence limits for total urinary estrogen for gestational age in normal pregnancy. Oxytocin challenge tests (OCT’s) were performed weekly after 33 weeks’ gestation by the following method: oxytocin was administered by intravenous infusion pump in a graduated manner until three contractions occurred in a 10 minute period. A test was considered positive when more than 50 per cent of all contractions were associated with late decelerations of the fetal heart rate. A test was considered suggestive when any late decelerations were observed. Patients with low or declining urinary estriol, suggestive or positive OCT. poor control of diabetes, or complications such as severe pregnancy headache, polyhydramnios diagnosed by clinical examination, pre-eclampsia, or severe renal disease were admitted to the hospital for intensive monitoring. Patients without complications were routinely admitted at 36 to 37 weeks’ gestation. Inpatient management. In the antepartum special care unit the insulin regimen and diet were modified on the basis of the reduced level of exercise and the concentration of glucose in venous plasma or capillary blood measured two to four times daily. Monitoring for antepartum fetal distress consisted of daily measurement of urinary estriol and creatinine levels over 24 hours and a weekly OCT. An acute fall in estriol was defined as greater than 40 per cent decrease from the mean of the previous three days. The OCT was performed more often if there was a previously inadequate or suggestive test or a low estriol level or when hypertension was present. Amniocentesis was performed (when possible) prior to consideration of delivery to predict fetal pulmonary maturity, usually at 36 to 37 weeks’ gestation. Amniocentesis was frequently performed in the ultrasound laboratory to select the best tap site. The L/S ratio was measured according to the method of Gluck and col-
July
1, 1978
Am. J. Obstet. Gynecoi.
leagues36 by densitometry. Total amniotic fluid cortisol (conjugated and unconjugated) was determined by- a modification of the radioimmunoassay for plasma cortisol.2R Once an L/S ratio judged to be mature was obtained, patients with a previous cesarean section were delivered by repeat operation. Prior to 1976. 2.0 was thought to indicate fetal lung maturity. After 1976, an L/S ratio of 3.5 was used. Patients who were candidates for vaginal delivery were observed until the cervix was believed to be ready for induction of labor, unless maternal or fetal distress supervened, or unless the attending obstetrician and patient decided on a primary cesarean delivery on the basis of- a large fetus (eight cases). In this way the timing and route of delivery were individualized. On the morning of a scheduled repeat cesarean section no insulin was given until the patient was in the recovery room. When labor ensued or was induced or a cesarean section was scheduled later in the day, insulin was cut to half of the prepregnancy level for the day of delivery and intravenous dextrose was administered. During labor. the fetal heart rate was monitored with an internal scalp electrode, and scalp pH was measured when indicated. Intrapartum fetal distress was defined as persistent late decelerations and a scalp pH less than 7.25. Epidural anesthesia was used frequently during labor and regional block or balanced general anesthesia (thiopental sodium, nitrous oxide, and succinylcholine) was used for cesarean delivery.16 Neonatal management. All IDM’s were initially observed in the Special Care Nursery. The plan of management has been published.” Length of gestation was determined by usual obstetric criteria, including ultrasound, and was confirmed by clinical or Dubowitz assessment of the neonate.’ ” The following laboratory studies were routinely done: blood glucose at one, two, three, six, 12, 24, 36, and 48 hours of age; total serum calcium at six, 12, 24, and 48 hours: direct and indirect serum bilirubin at 24 and 48 hours. We began early feedings of “well” infants with bottle or gavage of 5 ml. of 10 per cent dextrose per kilogram by one hour of age. Hourly feedings were continued until the blood glucose was stable; thereafter infants were fed every two hours and then every three hours with increasing volume. By 12 hours of age most infants received 20 calories per ounce of formula with dextrose as needed. Infants were transferred to breast-feeding as soon as possible, when desired by the mother. Neonatal hypoglycemia was defined as a blood glucose level below 30 mg. per deciliter in any infant, regardless of gestational age and whether or not they were symptomatic. If feedings were not tolerated (large volumes retained in the stomach) or hypoglycemia
Diabetic pregnancy and perinatai morbidity 567
Table
I. White’s classification,parity, and degree
of hyperglycemia
in diabetic
subjects (mean
z s.D.)
Menn (i S.I).J Parity No.
1
2
23
5 10 28 'Lo 5 -! 69
4 9 18 12 1 1 4'3
4 11 11 5 2 0 33
clar.<
13 30 57 37 H L' 147
A B C I) F R
No. of clinic visits
A0.B.G. * (mg. ldl.)
Days HI hospi&l pmr to &l&q
17 -c 6 19 f 7 i9+-7 20 f 5 18 k 7 27, 17
-132 14 +66 f 30 +65-+28 +67 rt33 +69? 57 +40,+78
10 5 7 10 17 13 jI 7 21 I 16 28,27
*A.O.B.G. = Mean blood glucose difference from normal for all outpatient Table 1Y 0. 13 30 57 37 8
II. Maternal Cl4.SS A B c II F
piasma, glwosr in hospital (mg. idl. i
Perinfltal .sunlival rate( %)
9 1' II
7,4..!4. 106 " 34 111243 113-c-41 1212 36 105, 94
137 It ‘.!9 14 1 2 214 k47 + 52 139 t ‘14 16O. I.17
100 93.3 IO0 94.6 87.5 100 96.6
visits.
complications
Pregnancy headache
Keto-
acidosis
Pyelonephritis
Genml edema
Pobhydramnias
P?v?mture labor
Preeclampsia
T~0?lSit%nt
hypertension
C’hronir
hypertaszon
I-hyroid disease
I 2
1 2
1
1
I 1
(2%)
(3%)
(1%)
2 4 2 5
8 19 15 4
3 3 2 1
1 3 3
4 1
(9%)
(31%)
(6%)
(5%)
(4%)
persisted. treatment with intravenous dextrose was instituted. Infants weighing <2,000 grams or in distress were not fed but were given 10 per cent dextrose by intravenous infusion. Hypocalcemia was defined as a total serum calcium level klow 7 mg. per deciliter and was treated by oral or intravenous therapy. Hyperbilirubinemia was defined as an indirectly reacting bilirubin level greater than 15 mg. per deciliter. Early treatment with phototherapy or exchange transfusion was instituted to prevent any rise in unconjugated biliruhin that might have resulted in free bilirubin (unbound to albumin) in the plasma.” The presence of free bilirubin was detected with the Kernlute assay. A positive test led to immediate exchange transfusion. Criteria for the diagnosis of RDS in the neonate were clinical signs (grunting, retractions, respiratory rate >60 per minute), typical findings at roentgenography (diffuse reticulogranular pattern and air bronchograms”‘“), and an increased oxygen requirement (to maintain the Pao, at 50 to 70 torr) for >48 hours with no other identified cause of respiratory difficulty (i.e., heart disease, infection). For classification of severity of RDS see Table IX. Criteria for the diagnosis of transient tachypnea of the neonate (TTN) were the presence of grunting, retractions, and a respiratory rate ~30 per minute for more than six hours after birth in a near-term infant with minimal cyanosis (FIN% < 0.4).4 The chest roentgenogram of TTN shows prominent
3 ti .).. 4
(5s)
(6%)
vascular markings, edematous interlobar septa, and pleural effusions. TTN has a benign course, and infants are usually in room air by 24 hours of age. The chest roentgenogram begins to clear by 24 hours, and the findings are resolved in three to five days. RDS was managed as previously described.‘” In this study one of us 0. P. C.) reviewed charts and roentgenograms of all infants with any respiratory difficulty to assure uniformity of diagnosis. All possible congenital anomalies were also reviewed. Major defects were considered to be those responsible for death and those that would cause a significant handicap in the future or require major surgery to correct. Minor anomalies made up the rest. Since this u’as a retrospective review, many minor malformations not of clinical significance may not have been recordcrl in the chart and thus were missed. Analysis of data. Standard two-sample t tests and two-way contingency tables with chi-square tests were used to assess the statistical significance of group differences. Multiple linear-regression analysis was used to assess the correlation of a set of independent variables with a dependent variable where appropriate.
Results Control of diabetes. Of our subjects, 7 I per cent had diabetes longer than 10 years, and only 0 per cent had gestational diabetes not requiring insulin. As seen in
566
Kitzmiller et al.
Table No. 13 30 57 31 8
2 147
III. Antepartum class A B C D F R
*Negative OCT one-minute
Apgar
fetal monitoring
Serial estriol measurements
Chronically low estriol
2 28 57 35 8 132 (:O%, and one-minute score 2, one.
Apgar
Acute fall in estriol
Positive OCT (%i
A bnomal e&01(%)
: 3 4 3
2 (7%) 4 (7%) 5 (14%j 6 (75%1 ___
4 20 46 30 7
3 4 5
2 1 1 1
12* (9%)
5t (4%)
score > 5, nine;
OCT performed
positive
109 (?4%) OCT
and
(5%) (7%) (13%) 143%)
~
12$ (11%)
one-minute
Apgar
17 (13%)
score
2. two;
Both abnormal (%)
1 (5%) 1 (3%) 3 (43%) 5 (5%) no OCT
and
tNegative OCT with no intrapartum fetal distress and one-minute Apgar score 8, one; positive OCT and one-minute Apgar score < 5, three; no OCT with intrapartum fetal distress and one-minute Apgar score 2, one, *Normal estriol level and one-minute Apgar fetal distress): abnormal estriol and _- score > 5. seven (two with intrapartum one-minute Apgar score > 5, five. Table I, there is little difference between Classes B, C, and D in the mean number of weekly clinic visits or the difference from normal in the mean blood glucose level. The population of insulin-dependent diabetic patients can be grouped into thirds on the basis of low, medium, or high average values of outpatient blood glucose (Fig. 1). The distribution of numbers of patients in these groupings was similar throughout Classes B, C, D, and F. Average length of stay in the hospital prior to delivery was 13 days, but this was significantly longer in the patients with diabetic nephropathy and the two patients who had been treated for proliferative retinopathy during pregnancy. The average concentrations of plasma glucose while in the hospital are also given in Table I. There was little difference between Classes B, C, and D. Plasma glucose concentration (inpatient) should be reduced by -14 per cent for comparison with the outpatient glucose measurements in whole blood. Maternal complications. Maternal complications are given in Table II. Clinically apparent polyhydramnios occurred in nearly one third of our patients. Six of the subjects with polyhydramnios went into premature labor (prior to 36 weeks’ gestation) (13 per cent), and in two cases neonatal death was primarily caused by prematurity. In contrast, the incidence of premature delivery (~36 weeks’ gestation) in our total hospital population (live-born infants) was 4 per cent in the same time period as this study. Polyhydramnios was associated with congenital anomalies in only two cases: one infant with combined spina bifida, clubfoot, and cleft palate and one infant with bilateral clubfeet. Polyhydramnios was less common in the group with the lowest outpatient blood glucose level as compared with groups 2 and 3 (Fig. 1) (chi-square value was 3.84 with one degree of freedom; p = 0.05). There was a tendency for the group with polyhydramnios to have higher average plasma glucose concentrations in the hospital
but the differences were only significant at the sampling time of 3:OO P.M. (138.2 i: 29.6 versus 152.9 2 42.2 mg. per deciliter; p < 0.05). Hypertensive disorders were noted in 14 per cent of the diabetic pregnant patients under study. The incidence of pre-eclampsia (5 per cent) was only slightly higher than that of our entire hospital population during the same time period (3.8 per cent). Two of the 13 cases of generalized edema were associated with preeclampsia and five with diabetic nephropathy. The coexistence of thyroid disorders with juvenile diabetes in women of childbearing age has been reported separately41 and was seen in 6 per cent of our patients. Antepartum fetal monitoring. The results of estriol measurements and OCT’s are shown in Table 111. Estrio1 excretion was chronically low in 12 of 132 patients in whom estriol was measured. Infant birth weight was below the tenth percentile for gestational age (SGA) in only three of these 12 pregnancies (one Class D, two Class F). Birth weight was appropriate for gestationa age (AGA) in the other nine infants. Maternal creatinine clearance was not decreased in patients with Class C to D diabetes with low estriol levels and AGA infants compared to subjects with normal urinary estriol levels. Of the 12 women with chronically low estriols, OCT’s were negative in nine, and the one-minute Apgar scores of these neonates were 6 to 8 (eight cesarean sections, one vaginal delivery). Two patients with Class F diabetes developed positive OCT’s in addition to chronically low urinary estriol levels, and their neonates had one-minute Apgar scores of 2 at cesarean delivery. One patient with Class C diabetes with low estriol did not have an OCT performed because of premature rupture of the membranes, but her infant’s one-minute Apgar score was 2 at cesarean section performed for failure to progress in labor at 34 weeks’ gestation. Five patients exhibited a fall in estriol level greater
Diabetic
Table
IV. Gestational
length
and birth weight
pregnancy
and perrnat,:!l
class
533
13 30 57 37 8 J 3 147
A B c I:, F R
0 3 I 1 4 t (6%)
Table
34-35
36-?7
; 7 5 2 0 21 (14%)
1 9 31 24 0 1 ?4!&
569
(mean t S.D.)
Weeks’ gestation ‘VO.
morbfdity
--T---Lagth oj gestation (wk.)
??8 12 11 18 7 2 -L
39.8 36.3 36.9 36.7 33.9
+ c k 2 2
Birth weight (grump)
1.8 3.0 1.4 1.6 3.1
3501 3461 3407 3120 1872 3610.
-
I&,4
SGA
-c 500 It 853 k 654 t 65Q it 759 39.55
0 0 0 3 2 II.
(355:)
" Ir, z' :' I3 0 i zj (3fzll;)
(3.Z%,
/
-;ZE 2 6 7 2 0 0 i7 (1 I..i%)
V. Route of delivery Cesarean
NO.
iFi 57 37 8
Class
Vaginal delivery
Labor not inducible*
AB c 1) ii
1; (36.7%) 17 (29.8%) 9 (24.3%) 1
8 (26.7%) 9 (15.8%) 7 (18.9%) 4
24 (6.7%) 9 (15.8%) 7 (18.9%) 1
75 (31.3%)
28 (19.0%)
23 (15.6%)
2 147
Dystocia
section Intrapatium fetal distress
t
: (6.7%) 2 (3.5%) 3 (8.1%)
i(6.1Pj
Repe&
7 (23.3%) 20 (35.1%) I I (29.7%.) L” 0
4: (27.9%:)
*Ruptured membranes, two; placenta previa, one; pre-eclampsia, turn fetal distress, four; presumed antepartum fetal distress, eight; L/S ratio. eight. Total = 28. ?Breech-no labor, six: cephalopelvic disproportion, five; failure
two; renal failure polyhydramnios,
than 40 per cent of the mean value for the preceding three days. The OCT was negative in one woman, and her infant’s one-minute Apgar score was 8 when delivered vaginally after a labor without signs of intraparturn fetal distress. Three women with falling estriol levels also had positive OCT’s, and one-minute Apgar scores were 2, 4, and 4, respectively, after delivery by primary cesarean section. One woman with an acute fall in estriol level did not have an OCT because of premature labor, and the one-minute Apgar score was 2 after cesarean section performed for intrapartum fetal distress. The OCT was positive in 12 of 109 diabetic women in whom the test was performed. Seven patients had normal urinary estriol levels, and their babies’ oneminute Apgar scores were 6 to 8 (four primary cesarean sections. one cesarean section for intrapartum fetal distress, and two vaginal deliveries, one after signs of late intrapartum fetal distress). Three women with positive OCT’s had an acute fall in estriol and LWO had
during labor. Nine women had an OCT suggestive of abnormality, but the test was not repeated. In Iive of these nine, there was no other evidence of fetal distress, but in four of them the one-minute Apgar scores were below 6 when their infants were delivered bv primary cesarean section. Length of gestation and birth weight. Mean length of gestation and birth weight for each White class are given in Table IV. Pregnant women with gestational diabetes not requiring insulin (i.e., normoglycemic on diet) were allowed to go into spontaneous labor up to 40 weeks’ gestation. Five of 13 patients with Class .4 diabetes, who had not been delivered by 40 weeks, were admitted to the hospital for antepartum fetal monitoring, and labor was induced at 41 to 43 weeks’ gestation. Of the 124 patients in Classes B, C, and D. 19 per cent were delivered prior to 36 weeks and 29 per cent were delivered at term (2 38 weeks). Mean length of gestation and birth weight were significantly lower in patients with diabetic nephropathy. 'The difference in mean birth weight between Class D and Class B or C did not reach statistical significance (t = 1.84; p > 0.05). There were three SGA infants delivered of 37 patients with Class D diabetes and two in eight patients with Class F diabetes. Slightly more than one third of all neonates were large for gestational age
chronically scores
low were
estriol
2 to 4 when
levels. their
The
one-minute
babies
were
Apgar delivered
promptly by primary cesarean section. OCT’s suggestive of abnormality were recorded in I5 women. Six had a repeat test, which was negative. Only one of these fetuses exhibited signs of distress
to progress
and fetal distress, one; confirmed antepartwo; elective at 37 to 41 weeks with mature
in labor,
12. Total
= 23.
570
July I, 1.9% Am. J. Obstet. C$mol.
Kitzmiller et al.
Table
~ 4oooI cn 3000
VI. Birth
$+7&42)
Patient
Fractured clavicle Erb’s palsy Shoulder dystocia Shoulder dystocia
N. G.
14’
D. J.
s. L.
‘Ooo; 34
35
36
37
30
39
4500
-
Table
GESTATION
++
+++
-
+
+
pc .Ol
+ +
+ 0
39* 3fi* 361 39s
8 9 4 9
Intrapartum
fetal distress One-minute
Route of delivery
Apgar
scwe
I-3
4-6
7-9
Total
2 3 5
6 :2 9
1 3 4
9 s 18*
*Of 72 women in labor (25 per cent).
+
2000
VII.
Vaginal Cesarean section
+ +
2500
3,544 3,118 3,67 1 4,139
One-minule Apgar score
40
Fig. 2. Mean birth weight of infants of women with Class B to D diabetes delivered at 34 to 40 weeks’ gestation. -
Length
of gesta-
“AGA. tLGA.
WEEKS
5000
delivery
(grams) I tia (wk.)
Type
D. E. -
or difficult Birth weight
2 2000
trauma
25
50
I 75
100
125
IS0
I 175
A 0. B.C.
Fig. 3. Correlation of birth weight of 119 live-born infants with mean ( ?S.D.) maternal A0.B.G. values for women with Class B to D diabetes; infants were delivered at 36 to 38 weeks’ gestation. r* = 0.12. (LGA), that is, they were above the ninetieth percentile of weight for gestational age of -8,000 consecutive infants who were delivered at BHW in the same time period as this study. Macrosomic infants were primarily found in Class B (50 per cent), Class C (39 per cent), and Class D (35 per cent) diabetes. Of all infants in the series, 11 per cent weighed more than 4,000 grams at delivery. The average outpatient blood glucose level was significantly higher in 50 women in Classes B to D with LGA infants (mean & SD. A0.B.G. was 70.8 “_ 29.1 mg. per deciliter), as compared to 7 1 women in Classes B to D who were delivered of infants with birth weights appropriate for their gestational age (A0.B.G. was 59.2 r 31.7 mg. per deciliter, t = 2.03; p < .05). Mean birth weight did not increase appreciably in infants delivered beyond 36 weeks’ gestation (Fig. 2). For women
in Classes B to D delivered at 36. to 38 weeks’, birth weight was somewhat related to maternal outpatient blood glucose (Fig. 3). Correlation and multiple linear-regression analyses were applied to w&men in Classes B to D delivered at all grstutional uge.r. The simple (zero-order) correlation coefficients between birth weight and the following variables were found to be 0.15 for maternal weight, 0.43 for gestational age, and 0.23 for A0.B.G. The multiple regression of birth weight on maternal weight, gestational age, and A0.B.G. revealed significant contributions from each of the three explanatory variables: t statistics for each variable were 2.20 (p < 0.05). 5.62 (p < O.OOl), and 3.45 (p < O.OOl), respectively, for the three variables. Labor and delivery. The route of delivery of om subjects is given in Table V. Seventy-five women (51 per cent) underwent primary or repeat cesarean section without attempting labor (28, labor not inducible: six, breech presentation; 41, repeat cesarean sections). Of the remaining 72 women who began spontaneous or induced labor, 46 (64 per cent) were delivered vaginally, 17 (24 per cent) were delivered by cesarean section because of dystocia, and nine (12.5 per cent) were delivered by cesarean section for intrapartum fetal distress. Of the 46 vaginal deliveries, four were classified as difficult or traumatic (8.7 per cent). Clinical details are given in Table VI. Two of the infants were macrosomic but only one had a low one-minute Apgal score. All of these infants did well in the nursery. Intrapartum fetal distress was diagnosed in 25 per cent of the women who had spontaneous or induced labor. This diagnosis was made on the basis of late de-
Diabetic pregnancy and perinatal morbidity
Table VIII. Delivery Classes B to D
Vaginal
outcome
in term versus 35 to 37 week pregnancies
deliveries?
Dystocia, cesarean sectiont Breech, cesarean section Birth trauma or difficult delivery Intrapartum fetal distress+ Labor not inducible, cesarean sectiong Repeat
cesarean
35-37 wk. (No. = 79)
>38 wk. (No. = 36)
22135 (63%) 9135 (26%) 4
12117 (71%) 3117 (lS%) 1
9135 (4:)
sectiong
24179 44/79
number
of women
number
of pregnancies.
(30%) (56%)
versus LGA
.4GA (No.
infatrts.
= 639
LG.4 (,Vo. = JY}
19129 (66%) 4/29 (14%) 2
5/17 (2;) (29%) 5136 (14%) 13/36 (36%) 16136 (44%)
16/79 (20%)
Neonatal hypoglycemias *Three SCA in Class D. tDenominator represents SCesarean sections. §Denominator represents
(26%)
and AGA
571
IN3 tie3
Y/29 (3:) (3 1%) 12163 (19%) 22163 (35%) 28/63 (44%)
‘l/23
(65%) (26%) ,)
(2:)
(17%)
9!49 (18%) 151-N (31%) 33i49 (67%)/i
in labor.
j/p < 0.05. Table
IX. Neonatal
pulmonary
complications RDSf
hio.
class
I3 29 57 37 7
A B c D F
TTN and pneumothorax
-TTN”
Indeterminatet
Mild
Severe
1+/2+ 1 1
3 4 1
Total
I 1
: 9 4 3
3+/4+
1
1 3 2 3
1 1
s
Apnea
i (17.2%J 6.9’5
7.6%
*Transient tachypnea of the neonate. SUpon review of chart and roentgenograms TTN and mild RDS could not be differentiated. $.RDS: I+: requiring Fro, < 0.5; 2+; requiring FIO, 7 0.5; 3+: requiring positive end-expiratory respiratory therapy. $Excludes one stillbirth and one immediate neonatal death celerations and a scalp pH below 7.25. The distribution of one-minute Apgar scores is given in Table VII. Eight cases of intrapartum fetal distress occurred late in labor and vaginal deliveries were performed.* With one exception the one-minute Apgar scores were below t. One of the infants with a one-minute Apgar score of 1 died immediately* and the infant with a one-minute Apgar score of 2 had a neonatal course complicated only by TTN and hypoglycemia. There were nine cases of fetal distress earlier in labor, and immediate cesarean section was performed. Of the three with very low Apgar scores at one minute, one infant died of congenital anomalies, one infant had severe RDS, and another, delivered at 31 weeks, had apneic spells but no RDS. One infant with a one-minute Apgar score of 5 developed TTN: the remaining five infants had un*See Table XVI for clinical details of the other vaginal delivery (Patient S. P.).
pressure; 4+: requiring
complicated neonatal courses. It is important to note that of 18 patients with intrapartum fetal distress only three had evidence of antepartum fetal distress as shown by low or falling estriol excretion and/or positive or suggestive OCT. The percentages of patients with intrapartum fetal distress during labor were 25 per cent for Class B, 14 per cent for Class C. and 30 pet cent for Class D. There was no apparent relationship between outpatient blood glucose and the development of antepartum or intrapartum fetal distress. Delivery outcome was not significantly different in a comparison of pregnancies delivered at term with those delivered at 35 to 37 weeks’ gestation in Classes B to D (Table VIII). In this population the delivery outcomeofLGA infants was similartothatof AG.4 infants. Neonatal pulmonary complications. Neonatal pulmonary complications were related to diabetic class, length of gestation, and the route of delivery and are
572
Kitzmiller
et
al.
July 1, 1958 Am. J. Obstrt. Gyneco.
Table X. Length of gestation, route of delivery, and neonatal pulmonary complications (number with cesarean sections in italics)
Weeks
28 29 30 31 32 33 34 35 36 37 38 39 40
No.
None
iTN
Indeterminate to
Severe
mild RDS
RDS
1
1 4
1* 1*
2
lS.li
1
4 17 22 43 28 8 2 131$
? 4,ll
I
10,lO 9,x5 519 4.14 1, 34,74
2
1
?
3 I
3
2,8
2,:
-23
*Died. tApneic spells. $Excludes 13 with Class A diabetes, one stillbirth, one infant who died immediately of severe birth asphyxia, and 1 infant who died of severe congenital anomalies incompatible with life. given in Tables IX and X. Upon review of clinical records and roentgenograms, two cases could not be differentiated between TTN or mild RDS, and the diagnoses are listed as indeterminate. Transient tachypnea of the neonate was observed in 7 per cent of the subjects. The majority of these babies were deliver&l at or beyond 36 weeks’ gestation with a mature L/S ratio. The incidence of severe RDS was also 7 per cent with cases distributed from 28 to 39 weeks of gestation. Four of the 10 cases of severe RDS occurred in infants delivered at 37 to 39 weeks’ gestation, reprdenting 5 per cent of neonates delivered at 237 weeks. The only deaths from RDS, however, occurred in two infants delivered at 28 and 30 weeks. As seen in Table X, a greater proportion of infants delivered by cesarean section developed TTN or RDS, but the tendency did not reach statistical significance (x2 = 1.83; p < 0.25). The occurrence of TTN was not associated with higher levels of maternal outpatient blood glucose or with fetal macrosomia. Of 24 infants delivered with an L/S ratio between 2 and 3, three developed severe RDS (12 per cent); this contrasts with only one infant with mild RDS (plus two indeterminate cases) in 76 infants where the L/S ratio was greater than 3 (Table XI). Thirteen infants were delivered with an L/S ratio less than 2, and six developed RDS. Serial L/S ratios were obtained in 24 patients. The ratio declined more than 0.5 units in only three cases and rose in all others. The L/S ratio did not
rise earlier in gestation in Class D compared with Class B or C. Severe RDS was observed in four IDM’s when the concentration of total cortisol in amniotic fluid was >60 ng. per milliliter (Table XII). This contrasts with a recent report on a small series of pregnancies in nondiabetic pregnancy from our hospital where RDS was not seen with an amniotic fluid cortisol level was >60 ng. per milliliter.*’ Neonatal morbidity. Other forms of neonatal morbidity are given in Tables XIII and XIV. Neonatal complications were unusual in offspring of women with Class A diabetes but were otherwise distributed throughout the White Classes. Hypoglycemia was the most common complication, occurring in nearly half of the neonates despite their being on a regimen of early feeding. I2 As seen in Table VIII, hypoglycemia was more frequent in LGA infants of Classes B, C. and D (x2 = 5.83; p < 0.05). Hypoglycemia was unusual in premature infants, possibly because of the early administration of intravenous glucose to these babies soon after delivery. Hypocalcemia, observed in 22 per cent of infants, was not associated with neonatal hypoglycemia (x2 = 1.05; p > 0.05) or with LGA infants (x2 = 0.12: p > 0.05). Neonatal serum calcium concentration showed a weak correlation with maternal serum levels (r = 0.23; p C= 0.05). Neonatal hypocalcemia was not more frequent in winter months. Hyperbilirubinemia (bilirubin over 15 mg. per deciliter) was present in 19 per cent of neonates, but the natural history was affected by early intervention with phototherapy in many other infants. Poor feeding was present in 37 per cent of the infants and often prolonged their stay in the Special Care Nursery. Individual congenital anomalies are listed in Table xv. Perinatal mortality rate. The over-all perinatal survival rate was 96.6 per cent for 147 diabetic subjects whose pregnancies attained 24 weeks. The clinical details of the five perinatal deaths in this series of patients are summarized in Table XVI. We consider that three of these deaths possibly could have been prevented with different obstetric management at the time of delivery. Two of these deaths occurred early in the study period when cesarean section delivery for fetal indications was not always utilized at 28 to 30 weeks’ gestation. Seventy-eight of the patients had prior pregnancies, some of which terminated in other hospitals. Of 124 prior pregnancies in this group of patients, there were 15 stillborn infants (12 per cent) and 10 neonatal
Diabetic
Table
XI. L/S and neonatal
respiratory
L./s
No
ratio
distress
b3.0 2. I-3.0 I.52.0 11.5
66 21 4 _I 92
pregnancy
and perinatili
morbidity
573
distress TTN 7 2 Yt
*Gestations in which L/S ratio was determined. IL/S values were 2.7, 2.8, and 2.9. $Excludes one patient who did not have L/S ratio determined deaths (8 per cent). This 80 per cent perin& survival rate in the prior pregnancies of our multiparous pregnant women is comparable to the perinatal survival rate of 96 per cent for this group during the study period reported here.
Comment Control of diabetes. The importance of “tight control” of diabetes during pregnancy has been emphasized in recent years. 3y,“’ W. SoA key feature of our protocol is the weekly office visit, so that the internist and obstetrician can anticipate and avoid complications. Further, our patients are taught to adjust their insulin dose at home, depending on urinary and capillary blood glucose estimations. If questions arise, they are encouraged to contact the medical staff by telephone. We do not, however, usually reach the level of normoglycemia proposed by the Scandinavians as necessary to achieve a good outcome (Fig. l).” The majority of our patients have no endogenous insulin, and it is difficult to achieve physiologic control of the blood glucose with the present methods of administering exogenous insulin. In Europe, prolonged hospitalization has been used to achieve better metabolic control in the third trimester of the diabetic pregnancy. Economics of health care in the United States has prevented us from applying this measure on a routine basis, and our patients are usually admitted only at 36 to 37 weeks’ gestation; however, our perinatal survival rates are good, and others have also demonstrated the efficacy of ambulatory management.J7, ‘” Cost-benefit analyses of several procedures designed to normalize the blood glucose level and of prolonged hospitalization remain to be performed in large numbers of diabetic pregnant women. Measures of metabolic control during diabetic pregnancy also need to be evaluated. A weekly blood glucose determination gives only limited information, and there may be substantial variability in the measurement
Table XII. pulmonary Concentration (ng. /ml.) >90 80-89
70-79 60-69 50-59 <50
Amniotic status
fluid cortisol
Normal
T-TN
30 6 14 14 5
1 2 I 1 I
1
1
and neonatal
Ind&-rnuna& 60 miki RDS
1 it
Severe RDS 1 I 1 1 1
1
of urinary or capillary blood glucose at home. We arc currently investigating the role of monthly hemoglobin A,C measurements.:“, lo5 in assessing hyperglycemia and its relationship to pregnancy outcome. Metabolic substrates other than glucose may also be important in the pathology of diabetic gestation, and \ue need much more detailed knowledge of the role of’ amino acids, fatty acids, ketone bodies, and lactic acid. Mateinal complications. Polyhydramnios is the most common maternal complication of diabetic pregnant) in our series, occurring in one third of cases. The cause of polyhydramnios remains unknown in the vast majority. The relationship of the degree of hyperglJ,cemia to the incidence of polyhydramnios is uncertain. Pedersen73 did not demonstrate a close connection between the volume of amniotic fluid and the level ot maternal blood glucose. Others, however. have stated that better control of blood glucose results in less polyhydramnios. X” In this series, polvhvdramnios was less , I common in the group of patients with the lowest outpatient blood glucose levels. It has been demonstrated that hospitalization in the last eight weeks crf pregnancy is associated with a lower volume of arnnicjtic fluid.7:’ It is unclear whether bed rest or better metabolic control is responsible for the difference observed We have a low incidence of pyelonephriris compared to the frequency of 6 per cent reported bv Pedersen”’ in 293 diabetic pregnancies. The diagnosts of asymptomatic bacteriuria by serial urine cultures during
574
Kitzmiller et al.
Table
XIII.
No.
July I. 1978 Am. J. Obstet. Gynccol.
Neonatal
morbidity
Ch.SS
13
A
30 57 37 8 2 147
B C D F R
Hypoglycemia
Hyperbilirubinemiu
Hypocalcemiu
Poor ,feeding
Birth defects* (majorlminw)
10 (33%) 23 (40%‘) 13 (35%) 8
012 (017%) 614 (11%/7%) S/2 (16%/5%) 110
54 (37%)
1318 (9%/5%)
010 1: (37%) 35 (61%)
18 (49%) 1
A (30%)
7 (23%)
10 (18%) 9 (24%)
15 (26%) 5 (14%) 1
3
-.A
6f (47%)
33 (22%)
o/o
*Includes three with anencephaly excluded from total of 147. Table
XIV. Weeks
Neonatal
morbidity
No.
and length None
28 29 i:
:
32 33 34 35 36 37 38 39
4 15 22 41 25 7
2 (13%) 5 (23%) 7 (17%) 11(44%) 2
40
2120
2: (23%)
of gestation Hypeglycemia
(White
Classes B to D) Hyperbilirubinaiu
HYPo-
cakemia
1
Poor feeding 1
1
2 7 11 25 11 4
1
k (47%) (50%) (61%) (44%)
pregnancy and treatment of positive cases with appropriate antibiotics may be responsible for our low incidence. The pre-eclamptic syndrome is much less common now than in past series from Joslin Clinic.lo3 One reason may be our exclusion of the diagnosis of superimposed pre-eclampsia in our eight patients with Class F diabetes, four of whom had chronic hypertension. The diagnosis of superimposed pre-eclampsia is almost impossible to make with assurance, since the nephrotic syndrome frequently worsens during late gestation. A detailed analysis of our continuing experience with diabetic nephropathy in pregnancy will be reported separately. It is obvious that the low level of preeclampsia was not associated with parenteral sex steroid therapy, since we abandoned this therapy early in 1975. We would like to think that encouragement of modified bed rest at home is at least in part responsible for the decline in pre-eclampsia in this high-risk patient population. Most of the subjects of this study were not treated with diuretics for any reason. The term “pregnancy headache” describes the unusual occurrence of severe, deep midline headache lasting two to four days in the second or third trimester of pregnancy, which requires hospitalization and treatment with narcotic analgesics for relief. In our experience this characteristic headache is much more com-
21
(33%) 9 (41%) 11 (27%) 5 (20%) 1
3 6 (40%) 5 (23%) 11(27%) 2 (8%) 2
4 12 12 13 10
32 (27%)
31 (26%)
55 (46%)
(80%) (55%) (32%) (40%)
monly diagnosed during pregnancy than at other times during the lives of insulin-dependent diabetic women. The severe headache may be related to small infarctions of the pituitary gland, which in more severe cases have presumably caused a syndrome of ante- and post-partum pituitary insufficiency in diabetic women, in the absence of precipitating metabolic or circulatory disturbances.83 Brennan and co-workers’ found that the incidence of small pituitary infarctions was l/50 in an autopsy study of diabetic subjects compared to l/550 in nondiabetic subjects.’ None of our patients demonstrated signs of pituitary insufficiency during or after pregnancy. Antepartum fetal monitoring. Assays of fetal wellbeing are necessary in order to carry pregnancies in diabetic women safely to a stage of fetal pulmonary maturity. The measurement of urinary estriol on a daily basis and the OCT have proved useful in our study series. In cases of chronically low or mildly falling estriol excretion, the OCT gives reassurance as to which fetuses are not in acute distress, and the pregnancies should be continued if the L/S ratio is not mature. On the other hand, approximately 50 per cent of our patients with a positive OCT showed no other evidence of fetal or neonatal distress on the basis of estriol excretion, course in labor, or immediate neonatal con-
Volume ; ?J1 Number i
Table
XV. Birth
Diabetic
pregnancy
and perinatal
defects
morbidity
575
-
h’ct.
class
13 30
A B
None None
.5!)
c;
2 anencephaly 1 spina bifida, clubfeet, and cleft palate 1 clubfeet 1 terminal transverse hemimeliat 1 ventricular septal defect and hemivertebrae 1 anencephaly 1 hypoplastic lungs, severe cardiac anomaly, absent kidney, and clubfeet 2 ventricular septal defect 2 patent ductus arteriosus (persistent) 1 caudal regression syndrome None
Major*
.Mzmrf None 1 epiaastric and umbilical hernia 1 $o&dact$>:
3x
8 2 1508
F R
1 congenital dislocation of hip 1 dermoid of skull 2 preauricular skin tags
2 pigmented
nevus
None None
*Major: Causing death or significant handicap or requiring major surgerv. Total = I3 (9 percent) with four deaths !?.6 per cent). tTota1 = eight (5 per cent). ICongenital absence of arm, 2 cm. below elbow. DTotal = 147 plus three anencephalic fetuses aborted at 20 to 24 weeks’ gestation. dition. Thus, we believe strongly that the combination of estriol measurements and antepartum fetal heart rate monitoring will improve the specificity of the diagnosis of suspected fetal distress. In our experience, cases of true fetal jeopardy on retrospective analysis exhibited both low or falling estriol excretion and a positive OCT. Gabbe and co-workers32 recently reported similar results. However, a few unpublished anecdotal reports of isolated fetal deaths in the presence of negative or suspicious OCT’s or normal estriol excretion have been communicated to us. Some cases were associated with pre-eclampsia or severe maternal hyperglycemia. We plan to continue our prospective evaluation of the role of antepartum fetal monitoring in the management of diabetic pregnancy. Serial measurement of unconjugated estriol in plasma may increase diagnostic specificity and eliminate the delay attendant upon the use of 24 hour urinary assays.17 Length of gestation and birth weight. Premature labor remains a major problem in obstetrics, and it had a large effect on the perinatal mortality rate in this series. being associated with three of the five losses (Table XVI). In the presence of impending premature delivery, the use of corticosteroids has been advocated to reduce the risk of RDS. We have recently confirmed the beneficial effect in pregnancies of’ nondiabetic women in a randomized clinical trial of dexamethasone.” Four of the present series of diabetic pregnant women were included in that study. This number is far too small to evaluate whether the therapy has been beneficial for them, but these pregnant women who received corticosteroids did exhibit marked loss of di-
Table Patient
XVI.
Perinatal
Class
L. P.
B
M. K.
B
D. R.
D
N. W.
D
s. P.
F
deaths (I 975 to lY76) Cmnmal
Premature labor at 28 wk., vaginal delivery as breech, Apgar score 2-5, 1,030 grams, severe RDS Ketoacidosis at 27 weeks, feral death by time of admission to hospital Premature labor at 30 wk., vaginal delivery, Apgar score 2-7, 1,049 grams, severe RDS, intracranial hemorrhage Neonatal death at term due Lo bypoplastic lungs, severe cardiac anomalies Premature labor at 29 wk., partial abruptio placental, epidural anesthetic, late decelelxtions, vaginal deliver, 1,670 grams, Apgar score 1, died immedtately
There were three induced abortions at 20 to 24 weeks for anencephaly. abetic control during the treatment period, with plasma glucose climbing to 400 mg. per deciliter at times, despite intermittent injections of regular insulin. Although there was no measurable fetal distressduring treatment in our few cases, corticosteroids may pose a potential hazard to fetal well-being during the course of treatment. Many more diabetic pregnant women and their fetuses will need to be studied in a controlled manner to determine the benefit and safety ofcorticosteroid administration to these patients. The relationship of maternal hyperglycemia to infant birth weight has been unclear, despite general acceptance of the fetal hyperglycemia-hyperinsulinismmacrosomia hypothesis. 73 Neither Karlsson and K.jellmerS’ nor Persson7” could demonstrate a significant re-
576
Kitzmiller et al.
lationship between mean blood glucose and excessive birth weight in pregnant women hospitalized during the last weeks of pregnancy. Metzger and colleagues63 found that maternal branched-chain amino acids such as leucine were related to birth weight in gestational diabetes while mean blyd glucose concentration was not. These amino acids cross the placenta by active transport and are insulinogenic. Szabo and Szabos3 and others have speculated that free fatty acids may be involved with macrosomia in pregnancies of diabetic women. In our study, the A0.B.G. throughout pregnancy correlated with infant birth weight in White Classes B to D, and this correlation remained when we controlled for length of gestation and maternal weight with the use of a multiple linear-regression analysis (Fig. 3). The mean A0.B.G. was also significantly higher in women delivered of LGA infants as opposed to AGA infants. Since neonatal hypoglycemia was more common in our macrosomic infants, these findings support the concept of “tight control” of maternal blood glucose during pregnancy to reduce neonatal morbidity. Labor and delivery. Are labor and vaginal delivery safe for diabetic parturients? The issues of concern are the development of intrapartum fetal distress and the possibility of birth trauma. Our series demonstrates that fetal monitoring of heart rate and scalp pH is essential, since consistent signs of fetal distress developed in 25 per cent of the women in labor. In only three of the 18 cases had there been any indication of anteparturn fetal distress on the basis of estriol levels or OCT. When decelerations and low scalp pH developed in the second stage of labor and vaginal delivery was performed, all but one newborn infant did well despite low one-minute Apgar scores. Long-term follow-up of the children is necessary, of course, to be sure no deleterious effects of such management occur. The “unripe cervix” remains a practical problem in the management of high-risk pregnancies; it resulted in the performance of cesarean sections in 24 per cent of our candidates for vaginal delivery. Since 16 (15 per cent) of our cases were classified as semielective for induction of labor or as having a false presumption of fetal distress, we can perhaps expect the numbers of cases in the category of “uninducible cervix” to decline as physicians become more experienced in following pregnancies in diabetic women to term. However, in many cases there was general agreement on the need to terminate pregnancy, and the only recourse was primary cesarean section. We need to learn more about the factors influencing ripening of the cervix and to apply better techniques for the safe induction of labor. In changing our protocol so that we could allow
July 1. 1978 Am. J. Obstet. Gunecctl.
pregnancies to proceed to term, we were concerned that the frequency of macrosomiti and other complicatioqs would increase. This does not seem to have been the case. For a number of reasons, only half of our patients in Classes B to D were delivered at 38 weeks or beyond as compared with 35 to 37 weeks’ gestation in the remainder. The percentages of vaginal delivery, dystocia leading to cesarean section, birth trauma. and intrapartum fetal distress were not significantly differentbetween the two groups (35 to 37 versus 38-t weeks’ gestation). These same statistics from 49 pregnancies with LGA infants were compared with those from 63 pregnancies whose infants were AGA and were found to be similar. We conclude that any diabetic pregnant woman can have a complicated labor or a difficult delivery, but that judgment as to the need to perform a cesarean delivery should be individualized. Maternal recovery and maternal-infant bonding are more difficult with cesarean deliveries, and the risk of RDS in the neonate is greater.7” Proper metabolic control is difficult at the time of parturition. This results from the use of intravenous fluids containing glucose and from the reluctance to use large doses of long-acting insulin in view of the marked postpartum insulin sensitivity that diabetic women exhibit. The relationship of hyper- or hypoglycemia to fetal distress during labor is unknown, but studies in animals relating fetal damage to hyperglycemia and lactic acidosis may lead to the clarification of this relationship.67, ” We need to develop well-controlled methods of nearly instantaneous insulin delivery to diabetic women in labor or during cesarean delivery to determine if normalization of blood glucose and possibly other metabolic substrates will reduce fetal distress, birth asphyxia, and neonatal complications such as hypoglycemia and poor feeding.“‘, lo’ Neonatal pulmonary complications. The studies of Hubbell and associates* and Robert and associates7s at BHW showed incidences of RDS of 27 and 23 per cent, respectively, in IDM’s delivered from 1958 to 1968. In those years, pregnancies in diabetic women were terminated according to a schedule based on the White classification, without benefit of tests of fetal well-being or the L/S ratio to predict pulmonary maturity. In the present study, the incidence of RDS was only 7.6 per cent compared with 5 and 9 per cent in recent reports of Gabbe and colleague? and Persson and co-workers,” respectively. Diagnostic criteria for RDS have not changed. The proportion of infants delivered by cesarean section is not different from that in the population studied by Robert and associatesTY However, the proportion of infants of insulin-dependent pregnant women delivered at 38+ weeks is greater in the current
Diabetic
study (29 versus 2 per cent), and the proportion of infants delivered at ~36.5 weeks is smaller (21 versus 6 1 per cent). We conclude that the ability to carry safely most diabetic pregnancies to the time of fetal pulmonary maturity (as determined by the L/S ratio) has dramatically decreased the incidence of RDS. The L/S ratio has been a useful predictor of pulmonary maturity in normal pregnancies with less than 1 per cent of infants having RDS with an L/S ratio >2.“7 There have been many reports of IDM’s who developed RDS with L/S ratios >2.11a 13* “3 *‘. 26 The incidence of RDS with “mature” L/S ratios in these cases ranged from 8 to 27 per cent. Gabbe and colleagues3* reported on 200 pregnancies in diabetic women in 1977 and reported only a 3 per cent incidence of RDS in IDM’s with an L/S ratio of 2 or more. This incidence was the same in his normal population. In our study an L/S ratio in excess of 3.5 was considered to be a reliable predictor of fetal pulmonary maturity. With an L/S ratio between 2 and 3, three of 24 infants (12 per cent) had severe RDS. When the L/S ratio was less than 2, half of the infants had severe RDS. The phenomenon of RDS in IDM’s with L/S ratios over 2: 1 is thought to be due to the presence of lecithin with low surface activity.“6 A more specific assay for surface-active material is obviously required, and we are currently evaluating the concentration of disaturated phosphatidylcholine”” in amniotic fluid, which may be :I more specific indicator of pulmonary maturity,“‘. ‘IR Mueller-Heubach and co-workers66 recently analyzed the reliability of the L/S ratio in pregnancies of diabetic women, with results similar to ours. As in their series all of our infants who developed severe RDS late in gestation with an L/S >2 were delivered by cesarean section without birth asphyxia. Their data indicate that the L/S ratio rises later in gestations of diabetic women compared with nondiabetic women. The peculiarities of fetal lung maturation, phospholipid production and secretion. and clinical development of RDS coexistent with pregnancy in diabetic women remain to be elucidated. Gluck and Kulovich3” reported delayed maturation of the L/S ratio in White’s Class A, B, and C diabetes and accelerated maturation in Classes D, E, and F. Others”‘. lo4 suggest a fall in L/S ratio as term approaches in IDM’s. Our series did not show an earlier rise in L/S ratio in pregnant patients with Class D as compared with Class B or C diabetes; of 24 cases with serial L/S ratios only three cases showed a decline. Neonatal morbidity. In a prospective study of 18,159 infants including IDM’s at the BHW from February, 1972, to February. 1975. Holmes ahd col-
pregnancy
and permatal
morbidity
577
leagues 44 found a 2 per cent incidence 01‘ ma.jor malformations. They found a 5 per cent incidence of‘ serious malformations in the IDM’s of this group (14/290). The infants in our study had a 9 per cent incidence of major anomalies. This increase in serious birth defects found in IDM’s is similar to the 8 per cr’nt incidence reported by Gabbe and associates”* and !hr incidence of 6 per cent reported by Pedersen.“’ Determination of the causes of the increased risk of birth defects in offspring of diabetic WOIIIPII is lacking, and this is an important area for research. Review of the course of early pregnancy in our pattents who were delivered of infants with congenital malformations did not reveal any striking features. Sincr we g-ive insulin to the tolerance level, almost all of’ oul- patients experience hypoglycemic reactions, especially in the first trimester. Much more detailed metabolic, monitoring will be necessary, however, if we are to learn what perturbations of the pregnant woman and ff*tr~s are associated with birth defects in the neonate. The study of Holmes and co-cr;orkt:rs”” showed an incidence of anencephaly in Caucasian Infants of 1.4/1,000 (anencephaly is rare in blacks ill Boston and the diabetic population studied here I almost all Caucasian). In a study of 664 pregnancies in diabetic women at BHW from January, 1965. to hqust, 1975, Zimble and associates lo7 found an incidence of anencephaly in IDM’s of 7.5/1,000. In the two-year period of the present study fetal anencephal!occurred in three of 150 pregnancies (20/1,000~. ;\nencephaly seems to occur more often than cspected in infants delivered of diabetic mothers as c-ompared with nondiabetic mothers in Massachusetts. The improvement in perinatal survival indicates that other end points must be used to gauge advances or changes in the management of pregnancy in diabetic women. The majority of the neonates m this series had significant neonatal morbidity. Gabbe and colleagues3’. :j2 reported neonatal morbidit\ in 65 per cent of 169 IDM’s. Nearly half of our infants were hypoglycemic despite a regimen of early feeding. I’he IDM, if symptomatic from hypoglycemia, usually is quiet and lethargic rather than jittery. Other symptoms such as apnea, tachypnea, respiratory distress, shock, cyanosis, and seizures may occur. If symptoms are present. the infant is probably at greater risk for sequelae than if asymptomatic. a2 The significance of’ II) poglycemia without symptoms is unclear, but conservative management to maintain the blood glucose level in the normal range appears to be indicated. A definitive study is needed to determine if rigid corm-c>1 of maternal blood glucose during labor and delivery will prevent neonatal hypoglycemia.““, I”* The concrntration of’
578
Kitzmiller et al.
free C-peptide was measured in a proportion of the infants of this study and was found to be significantly higher in IDM’s with hypoglycemia in the first six hours of life.8s This supports the role of hyperinsulinism in neonatal hypoglycemia in IDM but does not exclude the roles of glucagon deficiency and decreased glycogenolysis and gluconeogenesis. The other common forms of neonatal morbidity in this and other series are hypocalcemia, hyperbilirubinemia, hypotonia, and poor feeding. Their causes remain unknown, and their occurrence prolongs the observation and treatment of the IDM without respiratory distress in our Special Care Nursery. The relationship of fetal and neonatal morbidity to long-term development of these children should be investigated. Such studies will be difficult, because the possible perinatal influences may be difficult to differentiate from effects of subsequent biological and psychosocial conditions. The difficulties of parent-infant bonding in the intensive medical environment surrounding parturition of diabetic women need to be recognized and evaluated. Perinatal mortality rate. The perinatal mortality rate in this series (3411,000) is among the best reported to date for large groups of women with severe diabetes.‘*. “‘3 ‘X ‘lg. 73.X* SoThe rate approaches that of our general hospital population in the same time period (22/ l,OOO), although it is achieved at a high cost in effort and finances expended.
REFERENCES 1. Adam, P. A. J., Teramo, K., Raiha, N:, et al.: Human fetal insulin metabolism early in gestation: Response to acute elevation of the fetal glucose concentration and placental transfer of human insulin ‘131, Diabetes. 18: 409, 1969. L. M.: Report of the National Commission on 2. Aiello, Diabetes, SCOPE *Workshop on Pregnancy, Department of Health. Education. and Welfare Publication No. (NIH) 76-1023. 3. Assemany, S. R., Muzzo, S., and Gardner, L. I.: Syndrome of phocomelic diabetic embryopathy (caudal dysplasia), Am. J. Dis. Child. 123: 489, 1972. 4. Avery, M. E., Galewood, 0. B., and Brumley, G.: Transient tachypnea of the newborn, Am. J. Dis. Child. 111: 380, 1966. 5. Baird, J., and Farquhar, J. W.: Insulin secreting capacity in newborn infants of normal and diabetic mothers, Lancet 1: 71, 1962. M. B.. Pildes. R. S.. Mossabhov. N. A., et al.: 6. Block. C-peptide immunoreactivity’ (CPR): A new method for studying infants of insulin-treated diabetic mothers, Pediatrics 53: 923, 1974. 7. Brennan, C. F., Malone, R. G. S., and Weaver, J. A.: Pituitary necrosis in diabetes mellitus, Lancet 2: 12, 1956. 8. Cardell. B. S.: Hvnertronhv and hvperplasia of the pan creatic islets in newborn infants, J. Fathbl. 66: 335, 1953. 9. Cassady, G.: Amniocentesis, Clin. Perinatol. 1 (1): 87. 1974.
July I, 197x Am. J. Obster. Gynec~l.
Many factors undoubtedly play a role in the success of our approach to management. Because of the strengths of the educational programs of the Joslin Clinic early in the lives of our diabetic pregnant women, we have a very low proportion of “neglecters.” as described by Pedersen and colleagues.74 The incidence of pyelonephritis and pre-eclampsia is low in our current series. The availability of the cu-fetoprotein assay and ultrasonography has allowed the early diagnosis of anencephaly so that pregnancies may be terminated. Application of measures which can assess fetal well-being, such as daily urinary estriol determinations and the OCT, has allowed pregnancies to be carried closer to term and has prevented the occurrence of sudden, unexpected fetal death late in gestation. Individualization of the timing of delivery on the basis of the LIS ratio and advances in neonatal care have dramatically reduced the incidence and mortality rate of RDS. We are grateful to Drs. Priscilla White, Luke Gillespie, and John Hubbell for the inspiration of their pioneering efforts in the care of diabetic pregnant women and their babies and to Drs. Charles Graham, John Hare, I. John Davies, Fredric Frigoletto, Philip Stubblefield, Dan Tulchinsky, and the staff of the Joint Program in Neonatology for expert assistance with ciinical management of these patients.
10.
11.
12.
13.
14.
15.
16.
Chez, R. A., Mintz, D. H., Reynolds, W. A., et al.: Maternal-fetal plasma glucose relationships in late monkey pregnancy, AM. J. OBSTET. GYNECOL. 121: 938, 1975. Chez, R. A., Mintz, D. H., and Epstein, M. F.: Fetal hormonal mechanisms for plasma glucose homeostasis in normal and glucose intolerant pregnancy, in CameriniDavalos. R. A.. and Cole. H. S.. editors: Earlv Diabetes in Early Life, New York, l975, Academic Press, Inc.. pp. 141-163. Cloherty, J. P., and Epstein, M. F.: Infants born to diabetic mothers, in Willis, S. S., and Kagan, B., editors: Current Pediatric Therapy, Philadelphia, 1978, W. B. Saunders Co., pp. 325-330. Crawford, J. S.: Maternal and cord blood at delivery. IV. Glucose, sodium, Potassium, calcium, chloride, Bill. Neonate. 8: 222, 1965. Cruz, A. C., Buhi, W. C., Birk, S. A., et al.: Respiratory distress syndrome with mature lecithinisphingomyelin ratios: Diabetes mellitus and low Apgar scores, AM. J. OBSTET. GYNECOL. 126: 78, 1976. Dahlenburg, G. W., Martin, F. I. R., Jeffrey, P. R., et al.: Amniotic fluid lecithin/sphingomyelin ratio in pregnancy complicated by diabetes, Br. J. Obstet. Gynaecol. 84: 294, 1977. Datta, S., and Brown, W. U.: Acid-base status in diabetic mothers and their infants following general or spinal anesthesia for cesarean section, Anesthesiology 47: 272, 1977.
Volume Number
131 5
17.
Diabetic
Distler, W., Gabbe, S., Freeman, R. G., et al.: Estriol in pregnancy. V. Unconjugated and total plasma estriol in the management of diabetic pregnancy, AM. J. OBSTET. GYNECOL. 130: 424, 1978. 18. Donald, I. R., Freeman, R. K., Goebelsmann, U., et al.: Clinical experience with the amniotic fluid lecithin/ ;$~gomyelin ratio, AM. J. OBSTET. GYNECOL. 115: 547,
40.
19.
43.
20.
21. 22.
23.
24. 25. 26. 27. 28.
29.
30.
31.
32.
33. 34.
35
36.
37.
38.
39.
Driscoll, S. G.: The pathology of pregnancy complicated by diabetes mellitus, Med. Clin. North Am. 49: 1053, 1965. Driscoll, S. G., Benirschke, K., and Curtis, G. W.: Neonatal deaths among infants of diabetic mothers. Postmortem findings in ninety-five infants, Am. J. Dis. Child. 100: 818, 1960. Dubowitz. I,.: Clinical assessment of gestational age in the newborn infant. 1. Pediatr. 77: 1, 1970. Duhring, J. I,., &id Thompson, S. A.: Amniotic fluid phospholipid analysis in normal and complicated pregnancies, AM. J. OBSTET. GYNECOL. 121: 218, 1975. Epstein, M. F., Farrell, P. M., and Chez, R. A.: Fetal lung lecithin metabolism in the glucose-intolerant rhesus monkey pregnancy, Pediatrics 57: 722, 1976. Essex, N. L., Pyke, D. A., Watkins, P. J., et al.: Diabetic pregnancy, Br. Med. J. 4: 89, 1973. Farquhar. J. W.: Prognosis for babies born to diabetic mothers in Edinburg, Arch, Dis. Child. 44: 36, 1969. Farrell, P. M., and Avery, M. E.: Hyaline membrane disease, .4m. Rev. Respir. Dis. 111: 657, 1975. Felig. P.: Body fuel metabolism and diabetes mellitus in pregnancy, Med. Clin. North Am. 61: 43, 1977. Fencl, M. D., and Tulchinsky, D.: Total cortisol in amniotir fluid and fetal lung maturation, N. Engl. J. Med. 29P: 133, 1975. Fiser. R. H., Williams, P. R., Fisher, D. A., et al.: The effect of oral alanine on blood glucose and glucagon in the human newborn infant, Pediatrics 56: 78, 1975. Gabbay, K. H., Hasty, K., Breslow, J. L., et al.: Glycosylated hemoglobins and long term blood glucose control in diabetes mellitus, J. Clin. Endocrinol. Metab. 44: 859, 1977. Gabbe. S. G., Mestman, J. H., Freeman, R. K., et al.: Management and outcome of class A diabetes melhtus, AM. J. OBSTET. GYNECOL. 127: 465, 1977. Gabbe, S. G., Mestman, J. H., Freeman, R. K., et al.: Management and outcome of pregnancy in diabetes mellitus, classes B to R. AM. I. OBSTET. GYNECOL. 129: 723. 1977. Gabbe. S. G.:‘Congenital malformations in infants of diabetic mothers, Obstet. Gynecol. Surv. 32: 125, 1977. Gabbe, S. G.. Lowensohn, R. I., Mestman, J. H., et al.: Lecithin/sphingomyelin ratio in pregnancies complicated by diabetes mellitus. AM. J. OBSTET. GYNECOL. 128: 757, 1977. Gluck. L., and Kulovich, M. V.: Lecithin/sphingomyelin ratios in amniotic fluid in normal and abnormal pregnancy, AM. J. OBSTET. GYNECOL. 115: 539, 1973. Gluck, L., Kulovich, M. V., Borer, R. C., et al.: The interpretation and the significance of the lecithin/ sphingomyelin ratio in amniotic fluid, AM. J. OBSTET. GYNECOL. 120: 142, 1974. Gluck, L., Kulovich, M. V., Borer, R. L., et al.: Diagnosis of the respiratory distress syndrome by amniocentesis, AM. J. OBSTET. GYNECOL. 109: 440, 1971. Goebelsmann, U., Freeman, R. K.. Mestman, J. H., et al.: Estriol in pregnancy. II. Daily urinary estriol assays in the management of the pregnant diabetic woman, AM. J. OBSTET. GYNECOL. 115: 795, 1973. Gugliucci, C. L., O’Sullivan, M. J., Opperman, W., et al.: Intensive care of the pregnant diabetic, AM. J. OBSTET. G~NECOI. 125: 435, 1976.
41. 42.
44.
45.
46.
47. 48.
49.
50.
51.
52.
53. 54 55. 56. 57.
58.
59.
60.
61.
62.
63.
pregnancy
and perinatal
morbidity
579
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