Lorna Kemble Pregnancy and Birth

Diabetes and pregnancy 19401980

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In 1946 it was decided, with Professor Brandstrup at the Rigshospital, University of Copenhagen, to centralize the management and study of diabetes and pregnancy to the Obstetrical Department of Professor Brandstrup, who previously had interest in the problems involved.1,2

The first study from the Copenhagen Centre was designed to find possible characteristics of the course of diabetes during pregnancy, to contribute to a quantitative elucidation of the incidence of alterations occurring and to set up rules for the supervision of pregnant diabetics.3 Two typical periods in diabetic alterations took place, reaching a peak at about the second to third month and at about the seventh month. During the former period, an improvement in tolerance, lasting for an average of 2-3 months, was commonly observed. The manifestation of this improvement was insulin coma, or other insulin reactions, or an improvement in the degree of compensation. During the latter period there is often a decreased tolerance, manifesting itself as a diabetic precoma, acute acidosis or a necessity for raising the insulin dosage. The duration of this reduction in tolerance averaged 2 months.3

A treatment policy was described as follows:3,4 referral to a diabetes center as early as possible in pregnancy; outpatient control every 2-3 weeks until the fifth gestational month and weekly thereafter. About 8 weeks before calculated term the patient was hospitalized for prophylactic purposes and remained as an inpatient until delivery, which was usually induced c. 3 weeks before term. This applied to uncomplicated cases. On the whole, the patients were hospitalized in the presence of any complications that failed to yield immediately to ambulatory measures. Perinatal mortality fell from c. 40 to 25% in the period from 1946 to 1952 and for the group with long-term control perinatal mortality was as low as 12%. However, in the period from 1956 to 1965 the total perinatal mortality was still as high as 18.5% and the focus was now on the high incidence of severe congenital malformations (CM), a subject which was still under debate in the 1950s and 1960s. In a paper from 1964, M0lsted-Pedersen et al.5 showed in a convincing way that the incidence of severe CM was significantly higher in newborns of diabetic mothers and, furthermore, that fatal and multiple CM were five times higher in this group, and there was a significant correlation to the severity of the maternal diabetes. Based on these results, it was proposed that CM in infants of diabetic mothers were due in particular to the presence of maternal vascular complications with an insufficient blood supply to the uterus and placenta.

During the 1970s this view was changed in favor of the metabolic hypothesis, i.e. incomplete metabolic compensation at nidation and during the first trimester might be important. In a study from the late 1970s, a series comprising 949 newborn infants of diabetic mothers were treated at the Copenhagen Centre during pregnancy and delivery in the period from 1966 to 1977. The malformation rate was 8.2%.6 By analyzing the series it was found that the rate of CM in White classes B—F was significantly reduced from 14.1 to 7.4% in infants whose mothers preconceptionally attended two hospitals which specialized in the treatment and ambulatory control of diabetes. The observation demonstrated the importance of procuring constant care for diabetic women outside pregnancy in order to decrease the malformation rate.

During the first half of the 1980s the rate of severe CM decreased significantly at the Copenhagen Centre. The explanation for this significant decline is not a simple one and the cause may be non-specific, but some points of possible relevance were reported.7 Firstly, from c. 1980, diabetologists in Denmark had intensified their treatment of diabetics, especially that of the young. Secondly, in 1976 an outpatient clinic for instructions in contraception and planning for future pregnancies in diabetic women was organized at the Copenhagen Centre. A few years after the opening of this clinic a significant increase - from 35 to 70% - in the frequency of planned pregnancies was seen. Thirdly, some induced abortions were performed due to elevated levels of alpha-fetoprotein (ultrasound examination verified severe neural tube defects) and in a few diabetic women from classes D and F who had poorly regulated diabetic metabolism during conception and during the first gestational weeks, and moreover whose fetuses had a significant ultrasound-verified growth delay in early pregnancy, thereby having a significantly increased risk of severe CM (see below).8

The impact of preconceptional care has been strongly underlined by the Copenhagen Centre's later clinical experience (Table 3.1).9 In unplanned pregnancies in Type 1 diabetic women, the rate of pregnancy complications and preterm deliveries are doubled compared to insulin-dependent diabetes mellitus (IDDM) women who preconceptionally planned their pregnancy. Furthermore, the incidence of severe CM and the perinatal mortality were markedly increased in the unplanned group.

In his thesis from 1952, J0rgen Pedersen10 mentioned the hyperglycemia (maternal) - hyperinsulinism (fetal) hypothesis, but at that time direct measurements of plasma insulin were not possible. In the second edition of his book The Pregnant Diabetic and Her Newborn,11 the hypothesis ran as follows: maternal hyperglycemia results in fetal hyperglycemia and, hence, in hypertrophy of fetal islet tissue with insulin hypersecretion. The hyperinsulinism in the presence of more than adequate supplies of glucose, abruptly eliminated at birth, explains several of the characteristic features observed in the offspring. Over the years the theory, its consequences and explanatory powers have been intensively discussed, especially in papers from the Copenhagen Centre.12-15 The results of many pathoanatomical, clinical, physiological and biochemical investigations have adducted a nearly common agreement of the theory, which is now, more than 20 years after Pedersen's death, simply called the Pedersen theory.

White's16 widely used classification of pregnant diabetes is based on factors present in the mother before pregnancy, particularly with regard to the severity of her diabetes and vascular complications. This classification indicates groups of pregnant women with a different basic fetal mortality risk and a different proneness to complications, and hence fetal mortality. However, a more individual prognosis was required.

In order to improve the possibilities of predicting the outcome of pregnancies in diabetics, a consecutive series of

Summary on early growth delay 1 7

304 pregnancies from the Copenhagen Centre in the 5-year period from 1959 to 1963 was analyzed. Patients with a poor prognosis were divided into four groups: pregnant women who developed (1) hyperpyretic pyelitis, (2) precoma or severe acidosis, (3) toxaemia or (4) could be designated as 'neglec-tors.'17 These four groups are designated as PBSP (prognosti-cally bad signs during pregnancy) and concern complications which become evident during the actual pregnancy. Although the classification may not be perfect, the inherent concept of the White classification, i.e. that the chance of a successful pregnancy is not the same for all pregnant diabetics, is fundamentally correct.18 The simultaneous combined use of the two complementary classifications is recommended until more precise classifications are available.