These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.ORIGINAL ARTICLE How to Improve Prognosis in Type 1 Diabetic Pregnancy Old problems, new concepts David R. Hadden, MD OBJECTIVE— To improve the prognosis of pregnancy in type 1 diabetes. RESEARCH DESIGN AND METHODS— This study is an epidemiological analysis of pregnancy outcome in type 1 diabetic mothers attending the combined diabetic antenatal clinic at the Royal Maternity Hospital, Belfast, from 1940 to 1990. Short-term measurement of maternal insulin sensitivity and of intrauterine fetal habituation was taken in selected pregnancies. The article also assesses the European and U.K. recommendations for diabetes in pregnancy, with a goal "to achieve pregnancy outcome in the diabetic woman that approximates that of the non-diabetic woman." RESULTS— Outcomes from 1985 to 1995 in >800 pregnancies, of which about 60% were delivered at the Regional Centre, suggested that the perinatal mortality was lower for those managed throughout at the center. The highest obstetric risk was in those pregnancies referred to the center at some point later in the pregnancy from a peripheral obstetric clinic. Studies of insulin sensitivity in normal and preeclamptic pregnancy by minimal-model analysis of a frequently sampled intravenous glucose tolerance test and of glycosylated hemoglobin in a large survey of nondiabetic pregnancy indicate that the pregnant state may unmask an increase in insulin resistance, causing both pregnancy-induced hyperglycemia and pregnancy-induced hypertension. Fetal habituation, studied by responses to a variable sound stimulus, was less effective in diabetic pregnancy, which may indicate changes in fetal brain function. CONCLUSIONS— Pregnancy in a type 1 diabetic mother remains a high-risk obstetrical situation, even with presently available intensive diabetic supervision. Diabetes Care 22 (Suppl. 2):B104–B108, 1999 The first description of diabetes in pregnancy was by H.G. Bennewitz (1). In that pregnancy, the mother survived, having had symptoms of diabetes for at least 1 year previously, but the baby died due to obstructed labor because of severe macrosomia. J.W. Williams, the Professor of Obstetrics at Johns Hopkins University, Baltimore, Maryland, noted in 1909 (2) that the prognosis for diabetes in pregnancy was not as alarming as was frequently stated and that many patients did perfectly well. Only a small proportion of patients actually died in coma or collapse at the end of pregnancy. E.P. Joslin in Boston, Massachusetts, in 1915 (3) also felt that with severe dietary restriction, pregnancy could take place in diabetic patients far more readily than had been supposed. However, it is true that before the advent of insulin, very few diabetic women conceived and that the perinatal mortality ranged between 40 and 60% (4). In the first 50 years of insulin use in diabetic pregnancy, considerable advances were made, and a number of centers developed close cooperation between specialists. A pioneer in this field was Priscilla White in Boston, Massachusetts (5). Other centers with a large number of patients were Karlsberg in what became East Germany, the Rigshospital in Copenhagen, and King's College Hospital in London. Two important obstetrical factors that have been recognized more recently in type 1 diabetic pregnancy are the concept of early growth delay, first recognized by ultrasound measurement, and the increased incidence of congenital malformations (6). There is now good evidence that poor metabolic control in early pregnancy contributes to an increased risk of both spontaneous abortion and fetal malformations (7–9). The first suggestion that prepregnancy counseling as a logical prelude to the management of the pregnant diabetic woman would reduce these problems (10) has now been amply confirmed (11,12). The fetal outcomes in the 180 women who became pregnant during the prospective multicenter Diabetes Control and Complications Trial confirmed that timely institution of intensive therapy is associated with rates of spontaneous abortion and congenital malformation similar to those in the nondiabetic population (13). Pre-conception intensive care, although more expensive to provide, will still result in cost savings if the incidence of adverse outcomes is reduced (14). Even today, however, there is still need for improvement in achieving the aim of a successfully planned pregnancy as a health care goal for every diabetic woman (15). THE BELFAST EXPERIENCE—A combined diabetic antenatal clinic has been at the Royal Maternity Hospital in Belfast for >40 years and has accumulated considerable experience in both the obstetrical and diabetic management of these pregnancies. The simple expression of perinatal mortality shows a fall from >30 to 4% during the 50 years between 1940 and 1990 (Fig. 1). This major fall must be due to a number of interlinked factors, not simply to the use of insulin. It is important to note that the perinatal mortality for the hospital as a whole fell from approximately 10 to 2% during the same time and there is therefore still a doubling of risk for the diabetic pregnancy.
One of the major problems observed in the 1980s was that of congenital fetal abnormalities. There were 30 such abnormalities in the Belfast experience over the 10-year period (Fig. 2). The most frequent was congenital heart disease. Increased concentration by both mothers and staff on prepregnancy control of blood glucose has probably been associated with a fall in the number of congenital malformations from 17 to 13 in successive 5-year periods, but it is unclear whether this risk can be totally abolished (16,17) (Table 1).
A number of scientific investigations of embryo development in hyperglycemic surroundings indicated that a unifying concept for the mechanism of diabetic teratogenesis may be embryonic excess of free oxygen radicals (18). Initial studies with a clinical focus in this field have not shown any deficiency of free radical scavengers in the food intake of type 1 diabetic mothers (19), but the actual relationship between dietary intake of these substances and their action at a cellular level remains unclear. RECOMMENDATIONS— In Europe, the St. Vincent Declaration has provided a 5-year target "to implement effective measures for the prevention of costly diabetic complications." In particular, it set a goal "to achieve pregnancy outcome in the diabetic woman that approximates that of the non-diabetic woman." It is recognized that European countries still vary widely in the provision of antenatal care, but special attention to the pregnant diabetic woman has clear advantages. An interdisciplinary team should intensify the health and diabetic care of the diabetic woman before conception and maintain it during the pregnancy. A set of recommendations have been identified for the U.K., and these are likely to be relevant to all European countries, although there will be slight differences from one to another (20). Pre-conception counseling remains a most important goal and must be undertaken by the diabetes nurse and diabetes physician at a point well before the onset of pregnancy. This requires a prepregnancy management structure within the diabetes care team and the identification of potential pregnancies. The reason it is now possible for these management protocols to function is the ability of patients to accurately self-monitor their own blood glucose. The routine use of ultrasound to measure fetal size during diabetic pregnancy has also made a major difference to obstetrical management. It is recommended that ultrasound should be carried out at least three times in pregnancy: early at first booking to recognize possible early growth delay or congenital malformations; later at about 28 weeks to determine fetal size, hydramnios, and further possible malformations; and last, at about 36 weeks to identify the presence of macrosomia. During delivery, fetal heart-rate monitoring should be continued, and a well-tried protocol for intravenous glucose and insulin is necessary to maintain the maternal plasma glucose between 4 and 6 mmol/l (21). Postpartum, there will be a rapid reduction of insulin requirement. Breast-feeding is important and adjustment of the mother's food intake to accommodate this must be recognized. The same need for strict blood glucose control is not necessary postpartum, and it is very important to avoid the risk of hypoglycemia in the mother while feeding the baby. Postnatally, contraceptive advice and return to regular diabetes clinic supervision should occur. Good communication between obstetrician, family doctor, and diabetes clinic is not always achieved, and it is at this stage that a careful outcome assessment for both mother and baby must take place. THE CASE FOR CENTRALIZED CARE— The evidence that centralized hospital care in this obstetrical environment was beneficial for all pregnant type 1 diabetic mothers was established in 1987 (22). Earlier studies of centralization at a national level in East Germany by Bibergeil and Fuhrman showed the possibility of an extremely rigid protocol and raised fears of an excessively authoritarian regimen (23). Further analysis of the Belfast data from 1985 to 1995 shows that of >800 pregnancies—of which 60% were delivered in the Royal Maternity Hospital in Belfast, which is the regional center—there was a consistently better outcome for those who were managed throughout at the joint antenatal clinic. The perinatal mortality was 25.9 per 1,000 for those mothers managed throughout at this joint clinic but rose to 75 per 1,000 for those mothers who were referred at some point later in the pregnancy from an obstetrical clinic peripheral to the Royal Maternity Hospital. Even when those higher-risk pregnancies had been referred, the outcome in these other obstetrical units still showed a perinatal mortality of 33.5 per 1,000. There is also evidence that the congenital malformation rate was significantly lower in the mothers cared for at the central unit. The cesarean section rate, however, was not greatly different between the three groups. The overall perinatal mortality rate for the whole population of Northern Ireland (1.5 million) during this decade was 9.3 per 1,000 total births, so even in the centralized clinic the mortality risk for a diabetic pregnancy was about threefold the normal risk (Table 2).
The concept of shared care, which is now widespread for the management of type 1 diabetic patients, has led to the risk of fragmentation of such a centralized service. It is important that the special risk of diabetic pregnancy is recognized both obstetrically and in family practice and that suitable facilities are established to ensure that specialist care is available for these pregnancies without undue traveling or too-frequent clinical attendance. There is certainly scope for organization of such a service at a regional level (24). PRENATAL PSYCHOLOGY— The possibility of behavioral changes as a potential long-term effect of maternal hyperglycemia on the fetal brain has concerned a number of workers in this field. Freinkel (25) drew attention to this possibility in his Banting Memorial Lecture "Of Pregnancy and Progeny." Mulder and Visser (26) used real-time ultrasound to study fetal movement patterns in women with type 1 diabetes and showed that there was evidence of a specific diabetes-related influence on the functional development of the embryonic and fetal nervous system. Studies of fetal habituation, which is the decrement in response after repeated stimulation with the same sound stimulus, have allowed further progress in this area (27). Using a small ultrasound sensor and a series of acoustic stimuli of 2 s duration and a 5 s inter-stimulus interval, there is a difference in the habituation and dishabituation performance of diabetic and control fetuses. Diabetic fetuses at 28 and 32 weeks' gestational age perform more poorly (they take more trials to habituate) and are less likely to show true habituation, which indicates that the decrement in response is due to neuronal fatigue rather than learning to ignore the stimulus. Whether these changes in fetal brain function antenatally are related to subsequent psychological measures of brain function remains to be shown (28). HYPERTENSION IN DIABETIC PREGNANCY—Pregnancy and essential hypertension are both associated with insulin resistance, and hypertensive disorders of pregnancy continue to be leading causes of both maternal and fetal problems. The association of hypertension in pregnancy with diabetes is well recognized as an obstetrical risk but has not been studied from an etiological point of view until recently. Some of the studies in this field have suggested that pregnancy-induced hypertension is associated with an increase in insulin resistance. A careful study by Roberts et al. (29) using minimal-model analysis of a frequently sampled intravenous glucose tolerance test showed that in matched preeclamptic and normotensive pregnancies, there was actually an increase in insulin sensitivity (reduced insulin resistance) in the preeclamptic group compared with the normotensive women. This unexpected result may be explained by the fact that previous studies failed to distinguish between the two forms of pregnancy-induced hypertension, nonproteinuric gestational hypertension or proteinuric preeclampsia. Roberts (30) has suggested an analogy between the concepts of gestational hypertension and gestational diabetes, which may both be characterized by an increase in insulin resistance in pregnancy. Further support for this concept comes from comparison of glycosylated hemoglobin measurements in a large epidemiological survey of nondiabetic women where those who subsequently developed gestational hypertension had higher glycosylated hemoglobin values at 28 weeks than did those who subsequently developed true preeclampsia (31). Studies in Sweden and in Finland show that hypertension in women with gestational diabetes has a significant deleterious effect on the neonatal morbidity. In Finland, there was a higher incidence of chronic hypertension in women with gestational diabetes (32). In Sweden, in women with gestational diabetes, there was a higher incidence of chronic hypertension if the gestational diabetes was diagnosed before 24 weeks' gestation (33). GEOGRAPHICAL DIFFERENCES— Finland has been shown to have the highest incidence in Europe of type 1 diabetes in girls aged 0–14 years (34). This means that the prevalence of type 1 diabetes in pregnancy will also be high. The World Health Report for 1997, Conquering Suffering, Enriching Humanity (35), suggests that there will be an increase of 120% in the total number of cases of diabetes worldwide by 2025. The increase will be four times greater in the developing world and will be greater in women than in men, although the actual increase in type 1 diabetic mothers becoming pregnant will depend as much on family size and demographics as on a rising incidence of type 1 diabetes. The challenge will increase to prevent the actual onset of type 1 diabetes, and the interaction of pregnancy with various possible preventive strategies remains unknown. In the meantime, the management of pregnancy in the type 1 diabetic mother remains a high-risk strategy, although the outcome should be good (36). References 2. Williams JW: The clinical significance of glycosuria in pregnant women. Am J Med Sci 137:1–26, 1909 3. Joslin EP: Pregnancy and diabetes mellitus. Boston Med Surg J 173:841–849, 1915 4. Pedersen J: The Pregnant Diabetic and Her Newborn. 2nd ed. Copenhagen, Munksgaard, 1977, p. 15 5. White P: Pregnancy and diabetes: medical aspects. Med Clin North Am 49:1015–1030, 1965 6. Pedersen JF, Mølsted-Pedersen L: Early growth retardation in diabetic pregnancy. Br Med J i:18–19, 1979 7. Hanson U, Persson B, Thunell S: Relationship between haemoglobin A1c in early type 1 (insulin-dependent) diabetic pregnancy and the occurrence of spontaneous abortion and fetal malformation in Sweden. Diabetologia 33:100–104, 1990 8. Landon MB, Gabbe SG, Piana R, Mennuti MT, Main EK: Neonatal morbidity in pregnancy complicated by diabetes mellitus: predictive value of maternal glycaemic profiles. Am J Obstet Gynecol 156:1089–1095, 1987 9. 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Eriksson UJ: Embryo development in diabetic pregnancy. In Diabetes and Pregnancy: An International Approach to Diagnosis and Management. Dornhorst A, Hadden DR, Eds. Chichester, U.K., Wiley, 1996, p. 63–76 19. Bates JH, Young IS, Galway L, Traub AI, Hadden DR: Antioxidant status and lipid peroxidation in diabetic pregnancy. Br J Nutr 78:523–532, 1997 20. Brown CJ, Dawson A, Dodds R, Gamsu H, Gillmer M, Hall M, Hounsome B, Knopfler A, Ostler J, Peacock I, Rothman D, Steel J: Report of the Pregnancy and Neonatal Care Group. Diabet Med 13:S43–S53, 1996 21. Hadden DR: The management of diabetes in pregnancy. Postgrad Med J 72:525–531, 1996 22. Traub AI, Hegarty JM, Cooper TK, Maginnis S, Hadden DR: Is centralized hospital care necessary for all insulin-dependent pregnant diabetics? Br J Obst Gynaecol 94:957–962, 1987 23. Fuhrmann K, Reiher H, Semmler K, Fischer F, Fischer M, Glöckues E: Prevention of congenital malformations in infants of insulin-dependent diabetic mothers. Diabetes Care 6:219–223, 1983 24. Hadden DR: Diabetes in pregnancy: past, present and future. In Diabetes and Pregnancy: An International Approach to Diagnosis and Management. Dornhorst A, Hadden DR, Eds. Chichester, U.K., Wiley, 1996, p. 3–21 25. Freinkel N: Of pregnancy and progeny. Diabetes 27:1023–1035, 1980 26. Mulder EJH, Visser GHA: Growth and motor development in fetuses of women with type 1 diabetes. Early Hum Dev 25:91–115, 1991 27. Hepper PG, Leader LR: Fetal habituation. Fetal Maternal Med Rev 8:109–123, 1996 28. Doherty NN, Hepper PG, Hadden DR: Examining CNS functioning in fetuses of diabetic mothers (Abstract). Diabet Med 15 (Suppl. 1):S47, 1998 29. Roberts RN, Henriksen JE, Hadden DR: Insulin sensitivity in pre-eclampsia. Br J Obst Gynaecol. 105:1095–1100, 1998 30. Roberts RN: Hypertension in women with gestational diabetes. Diabetes Care 21 (Suppl. 2):B27–B32, 1998 31. Roberts RN, Traub AI, Kennedy AL, Hadden DR: Glycosylated haemoglobin and hypertension arising in pregnancy. Br J Obst Gynaecol. 105:1122–1124, 1998 32. Suhonen L, Teramo K: Hypertension and pre-eclampsia in women with gestational diabetes mellitus. Acta Obstet Gynae Scand 72:269–272, 1993 33. Nordlander E, Hanson U, Persson B: Factors influencing neonatal morbidity in gestational diabetic pregnancy. Br J Obstet Gynaecol 96:671–678, 1989 34. Green A, Gale EAM, Patterson CC, for the Eurodiab ACE Study Group: Incidence of childhood-onset insulin-dependent diabetes mellitus: the Eurodiab ACE Study. Lancet 339:905–909, 1992 35. World Health Organization: The World Health Report 1997: Conquering Suffering, Enriching Humanity. Geneva, World Health Org., 1997 36. Simmons D: Persistently poor pregnancy outcomes in women with insulin dependent diabetes (Editorial). BMJ 315:263–264, 1997 From the Sir George E. Clark Metabolic Unit, Royal Victoria Hospital; and the Diabetes Antenatal Clinic, Royal Maternity Hospital, Belfast, Northern Ireland, U.K. Address correspondence and reprint requests to Professor David R. Hadden, Royal Victoria Hospital, Metabolic Unit, Grosvenor Rd., Belfast BT12 6BA, Northern Ireland, U.K. E-mail: davidhadden@general.rght.n-i.nhs.uk. Received for publication 27 May 1998 and accepted in revised form 21 September 1998. This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG. Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
