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Diabetes mellitus in pregnancy: Have all the problems been solved?
Diabetes Mellitus in Pregnancy: Have all the Problems Been Solved?
STEVEN G. GABBE, M.D. Philadelphia, Pennsylvania
From the Department of Obstetrics and Gynecology, Jerrold R. Gelding Division of Fetal Medicine, University of Pennsylvania, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Dr. Steven G. Gabbc. University of Pennsylvania, Woman’s Hospital Division, 3400 Spruce Street, Philadelphia, PA 19104.
The past decade has seen a remarkable improvement in the prognosis for the pregnancy complicated by diabetes mellitus. Perinatal survival has become as common in these pregnancies as in normal ones. This improved outcome has been achieved through a better understanding of maternal metabolism and the needs to regulate maternal glycemia carefully as well as through reliable techniques for the surveillance of fetal well-being and advances in neonatal care. Significant perinatal morbidity still occurs, and congenital malformations-the leading cause of perinatal mortality today-remain an unresolved problem. Maternal outcome must also be considered. Uncertainty remains regarding the course of retinopathy in pregnancy, and the small group of diabetic women with coronary artery disease do appear to be at increased risk for mortality during gestation. A systematic screening program for gestational diabetes must now be adopted. In the past decade we have seen a remarkable improvement in the prognosis for pregnancy complicated by diabetes mellitus. Maternal survival was assured many decades ago, but only within the recent past has perinatal survival become as common in these pregnancies as in normal ones. This improved outcome is the result of a better understanding of the metabolism of the mother to be and the needs to carefully regulate her glycemia as well as through reliable techniques for fetal surveillance and advances in neonatal care. Significant perinatal mortality and morbidity do frequently occur in those women who receive less than optimal care during pregnancy. Furthermore, congenital malformations-the leading cause of perinatal mortality todayremain an unsolved problem. Carbohydrate Metabolism in Pregnancy. During gestation, significant metabolic changes occur which must be appreciated for the successful management of the pregnancy complicated by diabetes [l]. The maternal compartment supplies the fetus with an uninterrupted supply of fuels. Adaptations to meet this demand include hyperinsulinemia, insulin resistance and an increased likelihood of ketosis developing in the mother to be during food deprivation or “accelerated starvation.” Hyperinsulinemia and insulin resistance in the mother are most marked during the third trimester when fetal anabolism predominates. These changes are due to increased levels of human placental lactogen, a growth hormone-like material produced by the placenta which increases maternal lipolysis and maternal utilization of fats for energy. Glucose is then spared for fetal consumption. Other hormones, which also contribute to the insulin resistance noted at this time of pregnancy, include free cortisol and prolactin. Estrogen and progesterone may directly alter maternal islet cell function, producing P-cellchyperplasia and the resulting hyperinsulinemia.
March 1961
The American Journal of Medicine
Volume 79
613
DIABETES
TABLE I
MELLITLJS
IN PREGNANCY--GABBE
Detection of Diabetes in Pregnancy (Upper Limits of Normal)
Screening test 50 g, 1 hour Oral glucose tolerance test Fasting 1 hour 2 hours 3 hours
Whole Blood (m9ldU
Plasma (mW
130
140
90 165 145 125
105 190 165 145
l
Diagnosis of gestational diabetes is made when any two values are exceeded. l
Insulin does not cross the placenta. Therefore, although the fetus receives a continuous supply of maternal glucose, it will not be effected by maternal insulin. During the diabetic pregnancy, the hypoinsulinemic mother may become hyperglycemic. Maternal hyperglycemia would be associated with fetal hyperglycemia, leading to stimulation of the fetal pancreas with fetal P-cell hyperplasia and fetal hyperinsulinemia. It is this combination of fetal hyperglycemia and hyperinsulinemia which leads to much of the morbidity and mortality seen in the infant of the diabetic mother. Freinkel and Metzger [2] emphasized that, in the pregnant woman with insulin-dependent diabetes, underutilization of glucose as well as overproduction of other metabolic fuels may alter fetal development. Maternal Morbidity and Mortality. At the present time, maternal mortality is rare in the pregnancy complicated by diabetes mellitus. There is no evidence that pregnancy shortens the life expectancy of women with diabetes nor is there any evidence that the deterioration in renal function in women with diabetic nephropathy will be permanent. The small group of diabetic women who have coronary artery disease do appear to be at an increased risk for mortality during gestation [3]. There is still uncertainty regarding the course of retinopathy [4]. Early diabetic retinopathy may progress in pregnancy, but regress after delivery. There is concern that those patients who demonstrate neovascularization on the disc may experience rapid progression of their disease during gestation, and it has been suggested that this group be considered for therapeutic termination of pregnancy. Changes in maternal metabolism may lead to a deterioration of glycemic control. Ketoacidosis is more common and may occur at relatively low blood sugar levels. Hypoglycemia is often encountered in the first trimester, as estrogen increases the sensitivity of adipose tissue and skeletal muscle to insulin. After delivery, with removal of the placenta, the contra-insulin effects of human placental lactogen are terminated, and hypoglycemia may again result.
614
March 1961
The American Journal of Medicine
Perinatal Morbidity and Mortality. Fetal hyperglycemia and fetal hyperinsulinemia will have great impact on the outcome of pregnancy in the diabetic mother [5]. This combination of excess substrate and insulin, an important fetal growth hormone, can lead to fetal macrosomia. Such overgrown infants frequently suffer traumatic complications at the time of vaginal delivery. It has been well recognized that after 36 weeks’ gestation, the infant of the diabetic mother is much more likely to die in utero. Although the etiology of this mortality remains unknown, it may be linked to fetal hyperglycemia and hyperinsulinemia. In an effort to avoid intrauterine deaths, physicians have electively terminated the pregnancy of the diabetic woman between 35 and 36 weeks’ gestation. This approach has been associated with increased mortality from the respiratory distress syndrome, for at any gestational age, hyaline membrane disease is more likely to develop in the infant of the diabetic mother. Fetal hyperinsulinemia and hyperglycemia have been found to alter fetal lung development and surfactant synthesis in experimental animals. During the past decade, fetal deaths and perinatal mortalities arising from trauma and respiratory distress syndrome have been markedly reduced. At the present time, the most frequent cause of perinatal loss in pregnancies complicated by insulin-dependent diabetes is the congenital malformation. The frequency of severe malformations involving many organ systems is two to threefold greater in the infant of the diabetic mother. Such malformations must occur during the first seven weeks of embryonic development, long before most diabetic women seek prenatal care. There is increasing evidence that these malformations, which now account for 30 to 50 percent of all deaths in infants of the diabetic mother, may be attributed to hyperglycemia and poor metabolic regulation during the early weeks of pregnancy [6]. After delivery, the infant of the diabetic mother often experiences hypoglycemia, hypocalcemia and hyperbilirubinemia as well as the respiratory distress syndrome. Several recently recognized neonatal complications include cardiomyopathy, polycythemia and hyperviscosity, and small left colon syndrome. Thus, maternal diabetes may have a significant impact on both the structure and function of these infants. Although most Detection of Diabetes in Pregnancy. attention has been directed to the management of the insulin-dependent diabetic patient, it must be recognized that 90 percent of all diabetes in pregnancy occurs in those patients with gestational diabetes. This disorder has been characterized as one restricted to women in whom the onset or recognition of diabetes or impaired glucose tolerance occurs during pregnancy. It is the result of inadequate pancreatic reserve in response to the diabetogenic stress of pregnancy, and it is most often encountered during the third trimester of pregnancy. Although the diagnosis in these patients is made using
Volume 70
DIABETES
TABLE II
Class A B C D F R H
IN PREGNANCY--GABBE
White Classification of Diabetes in Pregnancy Age of Onset W
Pregnancy Any20 lo-19 or lo-19 20 Any Any Anv
Vascular Disease
Duration (Yr)
Any Any Anv
a 100 g oral glucose tolerance test, a well-organized screening program must be established (Table I). O’Sullivan et al. [7] have emphasized that screening patients by historic or clinical means is inadequate, as many women who go on to have gestational diabetes fail to manifest these clues. They have recommended that all pregnant patients be screened using a 50 g oral glucose load followed by a blood glucose determination 1 hour later. This test has a sensitivity of 79 percent and a specificity of 87 percent when compared to subsequent glucose tolerance test results. It should be noted that since the over-all prevalence of gestational diabetes is 2 to 3 percent, the yield of any screening program will also be low. However, the diagnosis is an extremely important one as macrosomia as well as other neonatal morbidity may develop in infants of women with gestational diabetes. Furthermore, from 10 to 15 percent of all women with gestational diabetes will demonstrate significant fasting and postprandial hyperglycemia and require treatment with insulin. As many as 50 percent of the patients who exhibit gestational diabetes will show further deterioration of carbohydrate metabolism during the next 15 years of life [8]. These patients should not be given oral contraceptive agents as these hormones may reproduce the derangement in carbohydrate homeostasis seen during gestation.
PATIENT
MELLITLJS
MANAGEMENT
Risk Assessment. In determining the optimal course of patient care, it is essential that the risks encountered by the pregnant patient with diabetes be considered. The most widely applied risk assessment system has been that of Dr. Priscilla White [9], who stressed that the age at onset of diabetes, its duration and the presence of maternal vascular disease could have an important impact on the outcome of the pregnancy (Table II). These factors may all be determined in the prepregnant state. Pedersen et al. [lo] noted that certain prognostitally bad signs of pregnancy, specifically ketoacidosis, pyelonephritis, pregnancy-induced hypertension and poor clinic attendance, were often associated with an unfavorable outcome. Patients with diabetes in pregnancy may be more simply divided into three functional groups: Group
0 0 0 Benign retinopathy Nephropathy Proliferative retinopathy Heart disease
Insulin 0 + -I+ + + +
l-Those women with gestational diabetes who manifest an abnormal glucose tolerance test but in whom a normal fasting glucose level is maintained. An intrauterine death is an extremely rare occurrence in such gravidas. Group Z-Insulin-dependent di’abetic women, including the obese patient, whose diabetes is easily regulated as well as the juvenile or insulin-dependent woman whose condition is more difficult to control. Group 3-Insulin-dependent diabetic patients with vascular disease including nephropathy and proliferative retinopathy. Management of the Patient with Insulin-Dependent Diabetes. Ideally, care of these women should begin prior to gestation. The patient and her family should be well aware of the risks and financial demands of pregnancy. Control of maternal glycemia within normal physiologic limits is the most important therapeutic goal for the physician. In normal pregnancies, maternal plasma glucose levels rarely exceed 100 mg/dl except for brief periods after meals. Fasting levels range from 60 to 80 mg/dl [ll]. The benefits of careful control are clear. Karlsson and Kjellmer [12] demonstrated a perinatal mortality rate of 38 per 1,000 if mean maternal blood glucose levels were maintained below 100 mg/dl during the third trimester. If mean glucose levels exceeded 150 mg/dl, perinatal mortality rose almost sixfold. In several series in which maternal fasting plasma glucose levels have been maintained between 100 and 150 mg/dl, perinatal mortality rates of 30 to 50 per 1,000 were reported [13,14]. However, at these glucose levels, considerable macrosomia and neonatal hypoglycemia may still be encountered. In those treatment programs in which physiologic glucose levels are sought, macrosomia is reduced and neonatal morbidity is less [15]. Increasing evidence also suggests that congenital malformations are related to poor control during early embryogenesis. Therefore, the insulin-dependent diabetic woman should be in optimal control at the time of conception and throughout the first trimester of pregnancy. Adequate control of the pregnant insulin-dependent diabetic woman usually requires two injections of insulin daily, as well as careful adjustment of caloric in-
March 1981
The American Journal of Medicine
Volume 70
615
UIAWTES
MELLlTlJS
IN PKIKNAKCY-(;AARF.
take. Patients usually receive a mixture of NPH and regular insulin in the morning with the amount of NPH insulin exceeding that of regular insulin by a z to 1 ratio. In the evening, equal amounts of NPH and regular insulin are employed. Jovanovic et al. [16] have demonstrated that the administration of regular insulin at dinner time and NPH insulin at bedtime may reduce the occurrence of nocturnal hypoglycemia. For those patients receiving twice daily injections of insulin, a dietary program containing three meals and three snacks should be considered. This diet contains 30 to 35 kcal/kg ideal body weight with approximately 40 to 50 percent of total calories as carbohydrate, 30 to 35 percent as fat and 20 to 25 percent as protein. Diabetic control may be assessed at home through the use of a glucose reflectance meter. If this approach cannot be utilized, patients should obtain a weekly profile of glucose values determined throughout the day. Hemoglobin A,, values have not proved to be extremely useful in the management of the pregnant, insulindependent patient, although this determination may be made at the first encounter with the patient to provide a rapid assessment of the patient’s prior diabetic regulation. Early in pregnancy, hospitalization may be required to evaluate and educate the pregnant, diabetic patient. At this time, the patient may be taught to use the glucose reflectance meter. Monitoring urinary glucose excretion is often inadequate in pregnancy as renal glycosuria, a consequence of an increase in glomerular filtration rate, is quite common. This initial hospitalization also provides an opportunity to assess the patient’s vascular condition with an ophthalmologic consultation, determination of baseline creatinine clearance and protein excretion, and an electrocardiogram. A urine culture may be obtained and should be repeated every four to six weeks. After the patient’s initial hospitalization, care is continued at one to two week intervals so that control may be assessed and uterine growth evaluated. Pregnancyinduced hypertension is more common in the pregnant diabetic patient and, as the second trimester progresses, evidence of hypertension, rapid weight gain and proteinuria should be sought. In the third trimester, the concern for fetal well-being becomes paramount. Fetal surveillance is begun at this time using both biophysical and biochemical methods. Urinary or plasma levels of estriol, a hormone which is dependent upon both fetal and placental contributions for its synthesis, must be determined on a daily basis. Rising estriol levels or values within the expected normal range are rarely associated with an intrauterine death. However, estriol determination, like other antepartum tests of fetal status, may have significant false-positive results [17]. Weekly antepartum monitoring of the heart rate has become the key biophysical technique for fetal assess-
816
March 1961
The American Journal of Medicine
ment. The nonstress test monitors the activity of the fetus and its associated fetal heart rate accelerations. A tracing showing both fetal activity and simultaneous heart rate accelerations, the so-called reactive pattern, is very rarely associated with an intrauterine death. However, a nonreactive test, one without fetal activity and/or accelerations, may herald fetal compromise and should be investigated with a contraction stress test or oxytocin challenge test. This evaluation examines the response of the fetal heart rate to uterine contractions. Slowing of the fetal heart rate after contractions or late decelerations suggests fetal jeopardy. In the past, much emphasis was placed on a decreasing insulin requirement as an indication of fetal distress. It is presumed that reduced insulin needs reflected placental failure and a decrease in production of the contra-insulin hormones of pregnancy. However, recent evidence has indicated that decreasing insulin requirements may not only be a very late indication of fetal compromise, but that they are also often misleading
b81. Fetal growth should be followed at four to six week intervals using ultrasound scanning. This technique can detect hydramnios, intrauterine growth retardation and macrosomia. The timing of delivery for the insulin-dependent diabetic patient is a critical one. On one hand, the physician hopes to obtain adequate fetal maturation to avoid the respiratory distress syndrome and neonatal morbidity. On the other hand, the threat of intrauterine death must be considered. The clinician ideally seeks a gestational age of 38 weeks’ with evidence of completed pulmonary maturation. The lecithin to sphingomyelin ratio (L:S) of amniotic fluid has proved to be a most useful tool in assessing the production of surfactant by the fetal lung. An L:S of 2 or greater has rarely been associated with the respiratory distress syndrome. A final marker of fetal pulmonary maturation is the production of the acidic phospholipid phosphatidylglycerol (191. Elective delivery may be accomplished either by induction of labor or caesarean section. The latter is selected when fetal macrosomia is suspected. When antepartum testing suggests fetal jeopardy, earlier delivery must be considered. An amniocentesis is first performed, and fetal pulmonary maturation evaluated. In such circumstances, a mature L:S ratio would prompt elective termination of the pregnancy. Premature delivery is undertaken only when all signs of fetal monitoring indicate fetal jeopardy or worsening maternal hypertension or retinopathy. There is rarely a need for corticosteroid therapy to accelerate fetal lung maturation in insulin-dependent diabetic patients. Such treatment may lead to rapid decompensation of maternal control. During delivery, maternal glucose levels must be carefully regulated. It has been demonstrated that ma-
Volume 70
DIABETES
ternal hyperglycemia during labor and delivery will be associated with a greater frequency of neonatal hypoglycemia [zO]. In women undergoing elective caesarean section the morning insulin dose may be withheld on the day of delivery, and they should be hydrated with saline solution. After the operative procedure, the patient’s glucose levels must be followed and insulin administered as needed. While in labor, the patient’s labor may be easily controlled with a glucose-insulin infusion [21]. Much of the management of the pregnant, insulindependent, diabetic patient may be achieved as an outpatient. However, several centers have found that hospitalization in late pregnancy is an important part of the treatment program for indigent women as well as for those who have neglected their diabetes throughout pregnancy. Antenatal care and delivery must occur’at a perinatal center with adequate neonatal support. In recent years, the specialist in maternal-fetal medicine has assumed an increasingly independent role in the management of the diabetic patient. Such persons have become comfortable in managing both the obstetrical aspects of the patient’s pregnancy and her diabetes. Ideally, however, the pregnant woman should be seen not only by a person skilled in maternal-fetal medicine, but also by an internist. This combined approach will smooth the transition through the pregnant and postpartum states. Management of the Patient with Gestational Diabetes. Women with gestational diabetes will usually be identified late in pregnancy. Once this diagnosis has been made, a dietary program of approximately 2,000 to 2,500 calories daily, with the exclusion of simple sugars is instituted [22]. Patients should be followed at two week
MELLITUS
IN PREGNANCY--GABBE
intervals and their fasting and postprandial glucose levels should be determined at each visit. If fasting plasma glucose levels reach 105 mg/dl and postprandial glucose values exceed 120 mg/dl, insulin treatment must be considered [23].However, at the present time, routine insulin therapy in cases of gestational diabetes cannot be advocated. Patients with gestational diabetes may be safely followed to 40 weeks’ gestation before fetal surveillance is begun [22]. At this point, fetal monitoring with estriol determinations and heart rate monitoring should be started. The risk of intrauterine death is greater in those patients with gestational diabetes who have had a prior stillbirth or in whom pregnancy induced-hypertension develops. In such patients, a program of surveillance should be initiated at 34 weeks’ gestation. CONCLUSION At the present time, the prognosis for both the pregnant woman with diabetes and her infant is excellent. The perinatal mortality for women with gestational diabetes is no higher than that of the normal pregnant woman. Women with insulin-dependent diabetes may expect an over-all perinatal survival of 90 to 95 percent [6].The excess mortality in this group of patients is largely due to fatal, congenital malformations. The management of the pregnant diabetic patient has reached an important crossroads. It has become apparent that further advances will depend upon better techniques for regulating diabetes throughout pregnancy, as well as, perhaps, the period immediately preceding conception. This can only be achieved through the collaborative efforts of both the internist and the obstetrician.
REFERENCES 1. Kalkhoff RK, Kissebah AH, Kim HJ: Carbohydrate
2.
3. 4.
5. 6.
7.
8.
and lipid metabolism during normal pregnancy: relationship to gestational hormone action. Semin Perinatol 1978; 2: 291. Metzger BE, Freinkel N: Effects of diabetes mellitus on endocrinologic and metabolic adaptations of gestation. Semin Perinatol 1978;2:309. Silfen SL, Wapner RJ, Gabbe SG: Maternal outcome in class H diabetes mellitus. Obstct Gynecol 1980; 55: 749. Singerman LJ, Aiello LM. Rodman HM: Diabetic retinopathy: effects of pregnancy and laser therapy. Diabetes 1980: 21: 1A. Gellis SS, Hsia DY: The infant of the diabetic mother. Am l Dis Child 1959; 97: 1. Gabbe SC: Application of scientific rationale in the management of the pregnant diabetic patient. Semin Perinatol 1978; 2: 361. O’Sullivan JB. Mahan CM, Charles D. Dandrow RV: Screening criteria for high-risk gestational diabetic patients. Am J Obstet Gynccol 1973; ?IS: 905. O’Sullivan JB: Prospective study of gestational diabetes and its treatment. Sutherland HW, Stowers JM eds. Carbohy-
9. 10.
11.
12.
13.
14.
15.
March 1981
drate metabolism in pregnancy and the newborn. Edinburgh: Churchill Livingstone, 1975; 195. White P: Pregnancy complicating diabetes. Am J Mcd 1949; 7. , lxla ““II. Pedersen J, Pedersen LM, Anderson B: Assessors of fetal perinatal mortality in diabetic pregnancy. Diabetes 1974: 23: 302. Gillmer MDG, Beard RW, Brookc FM, ct al.: Carbohydrate metabolism in pregnancy. I. Diurnal plasma glucose profile in normal and diabetic women. Br Med J 1975; 3: 399. Karlsson K, Kjellmer I: The outcome of diabetic pregnancies in relation to the mother’s blood.sugar level. Am J Obstet Gvnecoll972: 112: 213. Gabbe SG. Mestman JH. Freeman RK. ct al.: Management and outcome of diabetes mellitus. Classes B-R. Am I Obstet Gynecoll977; 129: 723. Kitzmiller JL, Cloherty JP, Younger MD, et al.: Diabetic pregnancy and perinatal morbidity. Am J Obstet Gynecol 1978; 131: 560. Roversi GD. Gargiulo M, Nicolini U, et al.: A new approach to the treatment of diabetic pregnant women. Am J Obstct Gynecoll979; 135: 567.
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DIABETES MELLITUS IN PREGNANCY-GABBE
16.
Jovanovic L, Peterson CM, Saxena BB, Dawood MJ, Saudck CD: Feasibility of maintaining normal glucose profiles in insulinldependcnt pregnant diabetic women. Am J Med 1980: 68: 105. 17. Whittle MJ. Anderson D, Lowcnsohn RI, Mestman JH, Paul RH, Goebelsmann U: Estriol in pregnancy. VI. Experience with unconjugated plasma cstriol assays and antcpartum fetal heart rate testing in diabetic pregnancies. Am J Obstct GynecolI979: 135: 674. 18. Gabbe SG; Dizercga GS, Mestmnn JH: Remission of diabetes mellitus during pregnancy. Am J Obstct Gynccoll976; 125: 264.
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19. 20. 21. 22. 23.
Kulovich MV, Gluck L: The lung profile. II. Complicated pregnancy. Am J Obstct Gynccol1979: 135: 64. Soler NG. Soler SM. Malins JM Neonatal morbidity among infants of diabetic mothers. Diabctcs Care 1978; 1: 340. Yeast JD, Porreco RP, Ginsberg HA: The USCof continuous insulin infusion for the peripartum management of the diabetic pregnancy. Am J Obstct Gynecol 1978; 131: 861. Gabbe SG, Mestman JH, Freeman RK, Anderson GV, Lowensohn RI: Management and outcome of Class A diabetes mellitus. Am J Obstct Gynccol 1977; 127: 465. Workshop-conference on gestational diabctcs. Diabetes Care 1980: 3: 501.
Volume 70
STEVEN G. GABBE, M.D. Philadelphia, Pennsylvania
From the Department of Obstetrics and Gynecology, Jerrold R. Gelding Division of Fetal Medicine, University of Pennsylvania, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Dr. Steven G. Gabbc. University of Pennsylvania, Woman’s Hospital Division, 3400 Spruce Street, Philadelphia, PA 19104.
The past decade has seen a remarkable improvement in the prognosis for the pregnancy complicated by diabetes mellitus. Perinatal survival has become as common in these pregnancies as in normal ones. This improved outcome has been achieved through a better understanding of maternal metabolism and the needs to regulate maternal glycemia carefully as well as through reliable techniques for the surveillance of fetal well-being and advances in neonatal care. Significant perinatal morbidity still occurs, and congenital malformations-the leading cause of perinatal mortality today-remain an unresolved problem. Maternal outcome must also be considered. Uncertainty remains regarding the course of retinopathy in pregnancy, and the small group of diabetic women with coronary artery disease do appear to be at increased risk for mortality during gestation. A systematic screening program for gestational diabetes must now be adopted. In the past decade we have seen a remarkable improvement in the prognosis for pregnancy complicated by diabetes mellitus. Maternal survival was assured many decades ago, but only within the recent past has perinatal survival become as common in these pregnancies as in normal ones. This improved outcome is the result of a better understanding of the metabolism of the mother to be and the needs to carefully regulate her glycemia as well as through reliable techniques for fetal surveillance and advances in neonatal care. Significant perinatal mortality and morbidity do frequently occur in those women who receive less than optimal care during pregnancy. Furthermore, congenital malformations-the leading cause of perinatal mortality todayremain an unsolved problem. Carbohydrate Metabolism in Pregnancy. During gestation, significant metabolic changes occur which must be appreciated for the successful management of the pregnancy complicated by diabetes [l]. The maternal compartment supplies the fetus with an uninterrupted supply of fuels. Adaptations to meet this demand include hyperinsulinemia, insulin resistance and an increased likelihood of ketosis developing in the mother to be during food deprivation or “accelerated starvation.” Hyperinsulinemia and insulin resistance in the mother are most marked during the third trimester when fetal anabolism predominates. These changes are due to increased levels of human placental lactogen, a growth hormone-like material produced by the placenta which increases maternal lipolysis and maternal utilization of fats for energy. Glucose is then spared for fetal consumption. Other hormones, which also contribute to the insulin resistance noted at this time of pregnancy, include free cortisol and prolactin. Estrogen and progesterone may directly alter maternal islet cell function, producing P-cellchyperplasia and the resulting hyperinsulinemia.
March 1961
The American Journal of Medicine
Volume 79
613
DIABETES
TABLE I
MELLITLJS
IN PREGNANCY--GABBE
Detection of Diabetes in Pregnancy (Upper Limits of Normal)
Screening test 50 g, 1 hour Oral glucose tolerance test Fasting 1 hour 2 hours 3 hours
Whole Blood (m9ldU
Plasma (mW
130
140
90 165 145 125
105 190 165 145
l
Diagnosis of gestational diabetes is made when any two values are exceeded. l
Insulin does not cross the placenta. Therefore, although the fetus receives a continuous supply of maternal glucose, it will not be effected by maternal insulin. During the diabetic pregnancy, the hypoinsulinemic mother may become hyperglycemic. Maternal hyperglycemia would be associated with fetal hyperglycemia, leading to stimulation of the fetal pancreas with fetal P-cell hyperplasia and fetal hyperinsulinemia. It is this combination of fetal hyperglycemia and hyperinsulinemia which leads to much of the morbidity and mortality seen in the infant of the diabetic mother. Freinkel and Metzger [2] emphasized that, in the pregnant woman with insulin-dependent diabetes, underutilization of glucose as well as overproduction of other metabolic fuels may alter fetal development. Maternal Morbidity and Mortality. At the present time, maternal mortality is rare in the pregnancy complicated by diabetes mellitus. There is no evidence that pregnancy shortens the life expectancy of women with diabetes nor is there any evidence that the deterioration in renal function in women with diabetic nephropathy will be permanent. The small group of diabetic women who have coronary artery disease do appear to be at an increased risk for mortality during gestation [3]. There is still uncertainty regarding the course of retinopathy [4]. Early diabetic retinopathy may progress in pregnancy, but regress after delivery. There is concern that those patients who demonstrate neovascularization on the disc may experience rapid progression of their disease during gestation, and it has been suggested that this group be considered for therapeutic termination of pregnancy. Changes in maternal metabolism may lead to a deterioration of glycemic control. Ketoacidosis is more common and may occur at relatively low blood sugar levels. Hypoglycemia is often encountered in the first trimester, as estrogen increases the sensitivity of adipose tissue and skeletal muscle to insulin. After delivery, with removal of the placenta, the contra-insulin effects of human placental lactogen are terminated, and hypoglycemia may again result.
614
March 1961
The American Journal of Medicine
Perinatal Morbidity and Mortality. Fetal hyperglycemia and fetal hyperinsulinemia will have great impact on the outcome of pregnancy in the diabetic mother [5]. This combination of excess substrate and insulin, an important fetal growth hormone, can lead to fetal macrosomia. Such overgrown infants frequently suffer traumatic complications at the time of vaginal delivery. It has been well recognized that after 36 weeks’ gestation, the infant of the diabetic mother is much more likely to die in utero. Although the etiology of this mortality remains unknown, it may be linked to fetal hyperglycemia and hyperinsulinemia. In an effort to avoid intrauterine deaths, physicians have electively terminated the pregnancy of the diabetic woman between 35 and 36 weeks’ gestation. This approach has been associated with increased mortality from the respiratory distress syndrome, for at any gestational age, hyaline membrane disease is more likely to develop in the infant of the diabetic mother. Fetal hyperinsulinemia and hyperglycemia have been found to alter fetal lung development and surfactant synthesis in experimental animals. During the past decade, fetal deaths and perinatal mortalities arising from trauma and respiratory distress syndrome have been markedly reduced. At the present time, the most frequent cause of perinatal loss in pregnancies complicated by insulin-dependent diabetes is the congenital malformation. The frequency of severe malformations involving many organ systems is two to threefold greater in the infant of the diabetic mother. Such malformations must occur during the first seven weeks of embryonic development, long before most diabetic women seek prenatal care. There is increasing evidence that these malformations, which now account for 30 to 50 percent of all deaths in infants of the diabetic mother, may be attributed to hyperglycemia and poor metabolic regulation during the early weeks of pregnancy [6]. After delivery, the infant of the diabetic mother often experiences hypoglycemia, hypocalcemia and hyperbilirubinemia as well as the respiratory distress syndrome. Several recently recognized neonatal complications include cardiomyopathy, polycythemia and hyperviscosity, and small left colon syndrome. Thus, maternal diabetes may have a significant impact on both the structure and function of these infants. Although most Detection of Diabetes in Pregnancy. attention has been directed to the management of the insulin-dependent diabetic patient, it must be recognized that 90 percent of all diabetes in pregnancy occurs in those patients with gestational diabetes. This disorder has been characterized as one restricted to women in whom the onset or recognition of diabetes or impaired glucose tolerance occurs during pregnancy. It is the result of inadequate pancreatic reserve in response to the diabetogenic stress of pregnancy, and it is most often encountered during the third trimester of pregnancy. Although the diagnosis in these patients is made using
Volume 70
DIABETES
TABLE II
Class A B C D F R H
IN PREGNANCY--GABBE
White Classification of Diabetes in Pregnancy Age of Onset W
Pregnancy Any
Vascular Disease
Duration (Yr)
Any Any Anv
a 100 g oral glucose tolerance test, a well-organized screening program must be established (Table I). O’Sullivan et al. [7] have emphasized that screening patients by historic or clinical means is inadequate, as many women who go on to have gestational diabetes fail to manifest these clues. They have recommended that all pregnant patients be screened using a 50 g oral glucose load followed by a blood glucose determination 1 hour later. This test has a sensitivity of 79 percent and a specificity of 87 percent when compared to subsequent glucose tolerance test results. It should be noted that since the over-all prevalence of gestational diabetes is 2 to 3 percent, the yield of any screening program will also be low. However, the diagnosis is an extremely important one as macrosomia as well as other neonatal morbidity may develop in infants of women with gestational diabetes. Furthermore, from 10 to 15 percent of all women with gestational diabetes will demonstrate significant fasting and postprandial hyperglycemia and require treatment with insulin. As many as 50 percent of the patients who exhibit gestational diabetes will show further deterioration of carbohydrate metabolism during the next 15 years of life [8]. These patients should not be given oral contraceptive agents as these hormones may reproduce the derangement in carbohydrate homeostasis seen during gestation.
PATIENT
MELLITLJS
MANAGEMENT
Risk Assessment. In determining the optimal course of patient care, it is essential that the risks encountered by the pregnant patient with diabetes be considered. The most widely applied risk assessment system has been that of Dr. Priscilla White [9], who stressed that the age at onset of diabetes, its duration and the presence of maternal vascular disease could have an important impact on the outcome of the pregnancy (Table II). These factors may all be determined in the prepregnant state. Pedersen et al. [lo] noted that certain prognostitally bad signs of pregnancy, specifically ketoacidosis, pyelonephritis, pregnancy-induced hypertension and poor clinic attendance, were often associated with an unfavorable outcome. Patients with diabetes in pregnancy may be more simply divided into three functional groups: Group
0 0 0 Benign retinopathy Nephropathy Proliferative retinopathy Heart disease
Insulin 0 + -I+ + + +
l-Those women with gestational diabetes who manifest an abnormal glucose tolerance test but in whom a normal fasting glucose level is maintained. An intrauterine death is an extremely rare occurrence in such gravidas. Group Z-Insulin-dependent di’abetic women, including the obese patient, whose diabetes is easily regulated as well as the juvenile or insulin-dependent woman whose condition is more difficult to control. Group 3-Insulin-dependent diabetic patients with vascular disease including nephropathy and proliferative retinopathy. Management of the Patient with Insulin-Dependent Diabetes. Ideally, care of these women should begin prior to gestation. The patient and her family should be well aware of the risks and financial demands of pregnancy. Control of maternal glycemia within normal physiologic limits is the most important therapeutic goal for the physician. In normal pregnancies, maternal plasma glucose levels rarely exceed 100 mg/dl except for brief periods after meals. Fasting levels range from 60 to 80 mg/dl [ll]. The benefits of careful control are clear. Karlsson and Kjellmer [12] demonstrated a perinatal mortality rate of 38 per 1,000 if mean maternal blood glucose levels were maintained below 100 mg/dl during the third trimester. If mean glucose levels exceeded 150 mg/dl, perinatal mortality rose almost sixfold. In several series in which maternal fasting plasma glucose levels have been maintained between 100 and 150 mg/dl, perinatal mortality rates of 30 to 50 per 1,000 were reported [13,14]. However, at these glucose levels, considerable macrosomia and neonatal hypoglycemia may still be encountered. In those treatment programs in which physiologic glucose levels are sought, macrosomia is reduced and neonatal morbidity is less [15]. Increasing evidence also suggests that congenital malformations are related to poor control during early embryogenesis. Therefore, the insulin-dependent diabetic woman should be in optimal control at the time of conception and throughout the first trimester of pregnancy. Adequate control of the pregnant insulin-dependent diabetic woman usually requires two injections of insulin daily, as well as careful adjustment of caloric in-
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take. Patients usually receive a mixture of NPH and regular insulin in the morning with the amount of NPH insulin exceeding that of regular insulin by a z to 1 ratio. In the evening, equal amounts of NPH and regular insulin are employed. Jovanovic et al. [16] have demonstrated that the administration of regular insulin at dinner time and NPH insulin at bedtime may reduce the occurrence of nocturnal hypoglycemia. For those patients receiving twice daily injections of insulin, a dietary program containing three meals and three snacks should be considered. This diet contains 30 to 35 kcal/kg ideal body weight with approximately 40 to 50 percent of total calories as carbohydrate, 30 to 35 percent as fat and 20 to 25 percent as protein. Diabetic control may be assessed at home through the use of a glucose reflectance meter. If this approach cannot be utilized, patients should obtain a weekly profile of glucose values determined throughout the day. Hemoglobin A,, values have not proved to be extremely useful in the management of the pregnant, insulindependent patient, although this determination may be made at the first encounter with the patient to provide a rapid assessment of the patient’s prior diabetic regulation. Early in pregnancy, hospitalization may be required to evaluate and educate the pregnant, diabetic patient. At this time, the patient may be taught to use the glucose reflectance meter. Monitoring urinary glucose excretion is often inadequate in pregnancy as renal glycosuria, a consequence of an increase in glomerular filtration rate, is quite common. This initial hospitalization also provides an opportunity to assess the patient’s vascular condition with an ophthalmologic consultation, determination of baseline creatinine clearance and protein excretion, and an electrocardiogram. A urine culture may be obtained and should be repeated every four to six weeks. After the patient’s initial hospitalization, care is continued at one to two week intervals so that control may be assessed and uterine growth evaluated. Pregnancyinduced hypertension is more common in the pregnant diabetic patient and, as the second trimester progresses, evidence of hypertension, rapid weight gain and proteinuria should be sought. In the third trimester, the concern for fetal well-being becomes paramount. Fetal surveillance is begun at this time using both biophysical and biochemical methods. Urinary or plasma levels of estriol, a hormone which is dependent upon both fetal and placental contributions for its synthesis, must be determined on a daily basis. Rising estriol levels or values within the expected normal range are rarely associated with an intrauterine death. However, estriol determination, like other antepartum tests of fetal status, may have significant false-positive results [17]. Weekly antepartum monitoring of the heart rate has become the key biophysical technique for fetal assess-
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ment. The nonstress test monitors the activity of the fetus and its associated fetal heart rate accelerations. A tracing showing both fetal activity and simultaneous heart rate accelerations, the so-called reactive pattern, is very rarely associated with an intrauterine death. However, a nonreactive test, one without fetal activity and/or accelerations, may herald fetal compromise and should be investigated with a contraction stress test or oxytocin challenge test. This evaluation examines the response of the fetal heart rate to uterine contractions. Slowing of the fetal heart rate after contractions or late decelerations suggests fetal jeopardy. In the past, much emphasis was placed on a decreasing insulin requirement as an indication of fetal distress. It is presumed that reduced insulin needs reflected placental failure and a decrease in production of the contra-insulin hormones of pregnancy. However, recent evidence has indicated that decreasing insulin requirements may not only be a very late indication of fetal compromise, but that they are also often misleading
b81. Fetal growth should be followed at four to six week intervals using ultrasound scanning. This technique can detect hydramnios, intrauterine growth retardation and macrosomia. The timing of delivery for the insulin-dependent diabetic patient is a critical one. On one hand, the physician hopes to obtain adequate fetal maturation to avoid the respiratory distress syndrome and neonatal morbidity. On the other hand, the threat of intrauterine death must be considered. The clinician ideally seeks a gestational age of 38 weeks’ with evidence of completed pulmonary maturation. The lecithin to sphingomyelin ratio (L:S) of amniotic fluid has proved to be a most useful tool in assessing the production of surfactant by the fetal lung. An L:S of 2 or greater has rarely been associated with the respiratory distress syndrome. A final marker of fetal pulmonary maturation is the production of the acidic phospholipid phosphatidylglycerol (191. Elective delivery may be accomplished either by induction of labor or caesarean section. The latter is selected when fetal macrosomia is suspected. When antepartum testing suggests fetal jeopardy, earlier delivery must be considered. An amniocentesis is first performed, and fetal pulmonary maturation evaluated. In such circumstances, a mature L:S ratio would prompt elective termination of the pregnancy. Premature delivery is undertaken only when all signs of fetal monitoring indicate fetal jeopardy or worsening maternal hypertension or retinopathy. There is rarely a need for corticosteroid therapy to accelerate fetal lung maturation in insulin-dependent diabetic patients. Such treatment may lead to rapid decompensation of maternal control. During delivery, maternal glucose levels must be carefully regulated. It has been demonstrated that ma-
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ternal hyperglycemia during labor and delivery will be associated with a greater frequency of neonatal hypoglycemia [zO]. In women undergoing elective caesarean section the morning insulin dose may be withheld on the day of delivery, and they should be hydrated with saline solution. After the operative procedure, the patient’s glucose levels must be followed and insulin administered as needed. While in labor, the patient’s labor may be easily controlled with a glucose-insulin infusion [21]. Much of the management of the pregnant, insulindependent, diabetic patient may be achieved as an outpatient. However, several centers have found that hospitalization in late pregnancy is an important part of the treatment program for indigent women as well as for those who have neglected their diabetes throughout pregnancy. Antenatal care and delivery must occur’at a perinatal center with adequate neonatal support. In recent years, the specialist in maternal-fetal medicine has assumed an increasingly independent role in the management of the diabetic patient. Such persons have become comfortable in managing both the obstetrical aspects of the patient’s pregnancy and her diabetes. Ideally, however, the pregnant woman should be seen not only by a person skilled in maternal-fetal medicine, but also by an internist. This combined approach will smooth the transition through the pregnant and postpartum states. Management of the Patient with Gestational Diabetes. Women with gestational diabetes will usually be identified late in pregnancy. Once this diagnosis has been made, a dietary program of approximately 2,000 to 2,500 calories daily, with the exclusion of simple sugars is instituted [22]. Patients should be followed at two week
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intervals and their fasting and postprandial glucose levels should be determined at each visit. If fasting plasma glucose levels reach 105 mg/dl and postprandial glucose values exceed 120 mg/dl, insulin treatment must be considered [23].However, at the present time, routine insulin therapy in cases of gestational diabetes cannot be advocated. Patients with gestational diabetes may be safely followed to 40 weeks’ gestation before fetal surveillance is begun [22]. At this point, fetal monitoring with estriol determinations and heart rate monitoring should be started. The risk of intrauterine death is greater in those patients with gestational diabetes who have had a prior stillbirth or in whom pregnancy induced-hypertension develops. In such patients, a program of surveillance should be initiated at 34 weeks’ gestation. CONCLUSION At the present time, the prognosis for both the pregnant woman with diabetes and her infant is excellent. The perinatal mortality for women with gestational diabetes is no higher than that of the normal pregnant woman. Women with insulin-dependent diabetes may expect an over-all perinatal survival of 90 to 95 percent [6].The excess mortality in this group of patients is largely due to fatal, congenital malformations. The management of the pregnant diabetic patient has reached an important crossroads. It has become apparent that further advances will depend upon better techniques for regulating diabetes throughout pregnancy, as well as, perhaps, the period immediately preceding conception. This can only be achieved through the collaborative efforts of both the internist and the obstetrician.
REFERENCES 1. Kalkhoff RK, Kissebah AH, Kim HJ: Carbohydrate
2.
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7.
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and lipid metabolism during normal pregnancy: relationship to gestational hormone action. Semin Perinatol 1978; 2: 291. Metzger BE, Freinkel N: Effects of diabetes mellitus on endocrinologic and metabolic adaptations of gestation. Semin Perinatol 1978;2:309. Silfen SL, Wapner RJ, Gabbe SG: Maternal outcome in class H diabetes mellitus. Obstct Gynecol 1980; 55: 749. Singerman LJ, Aiello LM. Rodman HM: Diabetic retinopathy: effects of pregnancy and laser therapy. Diabetes 1980: 21: 1A. Gellis SS, Hsia DY: The infant of the diabetic mother. Am l Dis Child 1959; 97: 1. Gabbe SC: Application of scientific rationale in the management of the pregnant diabetic patient. Semin Perinatol 1978; 2: 361. O’Sullivan JB. Mahan CM, Charles D. Dandrow RV: Screening criteria for high-risk gestational diabetic patients. Am J Obstet Gynccol 1973; ?IS: 905. O’Sullivan JB: Prospective study of gestational diabetes and its treatment. Sutherland HW, Stowers JM eds. Carbohy-
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drate metabolism in pregnancy and the newborn. Edinburgh: Churchill Livingstone, 1975; 195. White P: Pregnancy complicating diabetes. Am J Mcd 1949; 7. , lxla ““II. Pedersen J, Pedersen LM, Anderson B: Assessors of fetal perinatal mortality in diabetic pregnancy. Diabetes 1974: 23: 302. Gillmer MDG, Beard RW, Brookc FM, ct al.: Carbohydrate metabolism in pregnancy. I. Diurnal plasma glucose profile in normal and diabetic women. Br Med J 1975; 3: 399. Karlsson K, Kjellmer I: The outcome of diabetic pregnancies in relation to the mother’s blood.sugar level. Am J Obstet Gvnecoll972: 112: 213. Gabbe SG. Mestman JH. Freeman RK. ct al.: Management and outcome of diabetes mellitus. Classes B-R. Am I Obstet Gynecoll977; 129: 723. Kitzmiller JL, Cloherty JP, Younger MD, et al.: Diabetic pregnancy and perinatal morbidity. Am J Obstet Gynecol 1978; 131: 560. Roversi GD. Gargiulo M, Nicolini U, et al.: A new approach to the treatment of diabetic pregnant women. Am J Obstct Gynecoll979; 135: 567.
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16.
Jovanovic L, Peterson CM, Saxena BB, Dawood MJ, Saudck CD: Feasibility of maintaining normal glucose profiles in insulinldependcnt pregnant diabetic women. Am J Med 1980: 68: 105. 17. Whittle MJ. Anderson D, Lowcnsohn RI, Mestman JH, Paul RH, Goebelsmann U: Estriol in pregnancy. VI. Experience with unconjugated plasma cstriol assays and antcpartum fetal heart rate testing in diabetic pregnancies. Am J Obstct GynecolI979: 135: 674. 18. Gabbe SG; Dizercga GS, Mestmnn JH: Remission of diabetes mellitus during pregnancy. Am J Obstct Gynccoll976; 125: 264.
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19. 20. 21. 22. 23.
Kulovich MV, Gluck L: The lung profile. II. Complicated pregnancy. Am J Obstct Gynccol1979: 135: 64. Soler NG. Soler SM. Malins JM Neonatal morbidity among infants of diabetic mothers. Diabctcs Care 1978; 1: 340. Yeast JD, Porreco RP, Ginsberg HA: The USCof continuous insulin infusion for the peripartum management of the diabetic pregnancy. Am J Obstct Gynecol 1978; 131: 861. Gabbe SG, Mestman JH, Freeman RK, Anderson GV, Lowensohn RI: Management and outcome of Class A diabetes mellitus. Am J Obstct Gynccol 1977; 127: 465. Workshop-conference on gestational diabctcs. Diabetes Care 1980: 3: 501.
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