Strict glycemic control in women with pregestational insulin-dependent diabetes mellitus

International

Journal of Gynecology

& Obstetrics

47 (1994) 223-227

Article

Strict glycemic control in women with pregestational insulindependent diabetes mellitus J.A. Miranda, J. Mozas, R. Rojas, G. Esteva, C. MUAOZ,A.J. Herruzo Nalda* Division of Maternal-Fetal

Medicine,

Department

General Hospital,

Received 2 February

of Obstetrics and Gynecology.

Centro Materno

Avenida de la Constitucidn 100, 18014 Granada,

Infantil,

Virgen de /as Nieves

Spain

1994: revision received 8 July 1994; accepted 22 July 1994

Abstract

Objecrive: To determine the efficacy of strict glycemic control in women with pregestational insulin-dependent diabetes mellitus (IDDM). Methods: The records of 62 pregnant women with pregestational IDDM who had attended the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Virgen de las Nieves General Hospital, Granada, Spain, between 1982 and 1992, were reviewed. The women had received several daily doses of a mixture of rapid action (regular) and intermediate action insulin with the aim of keeping preprandial glucose levels lower than 95 mg/dl and postprandial glucose levels lower than 120 mg/dl. Perinatal outcomes were compared with those of a control group consisting of 96 randomly selected, normal, pregnant women who gave birth at approximately the same time. Results: Mean glycemic profile in the first assay at an insulin dose of 33.1 f 15.9 W/day was 153.7 l 52.3 mg/dl and the HbA,, was 7.7 f 2.3%. In the last assay before delivery patients received an insulin dose of 68.2 f 30.7 W/day and had a mean glycemic profile of 94.4 f 18.1 mg/dl and an HbA,, of 5.9 f 1.4% (P < 0.001 for all parameters). The perinatal mortality of newborn infants of the diabetic mothers was 48 per 1000, and 11.3 per 1000 had some congenital malformations. Conclusions: Our results verify that strict glycemic control decreases the elevated perinatal mortality normally suffered by IDDM patients. However, if it is to reduce the number of congenital malformations, it must be initiated before the early gestational stages. Keywords: Pregnancy; Insulin-dependent

diabetes mellitus; Strict glycemic control

1. Introduction

Before the discovery of insulin, the perinatal mortality rate in infants of diabetic mothers (IDMs) almost reached 50% [l]. Today it is well * Corresponding

author,

Tel.: +34 58 241202/241100,

202; Fax: +34 58 292401.

0020-7292/94/%07.00 SSDI

0

0020-7292(94)02204-C

1994 International

Federation

Ext.

known that insulin-dependent diabetes mellitus (IDDM) pregnancies have an improved prognosis when follow-up is by a multidisciplinary team, when there is strict control of glycemic levels and when fetal health and growth are closely monitored [2,3]. Jovanovic et al. [2] showed that with strict glycemic control, the perinatal mortality rate is

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J. Gynecol. Obsiet. 47 (1994)

nearly equivalent to that observed in normal pregnancies. Moreover, when this control is achieved in the preconceptional period or in the early stages of gestation, congenital malformations are also markedly reduced [4,5]. This study presents the outcomes of 62 pregestational IDDM patients under strict glycemic control. 2. Material and methods The clinical history of 62 pregnant women with IDDM (1.12 per 1000 singleton births) attending the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Virgen de las Nieves General Hospital, Granada, Spain, between 1982 and 1992, were reviewed. Pregnancies were grouped according to White’s criteria with 42 corresponding to class B, 11 to class C, six to class D and three to class R [16]. The patients’ diets were altered at the first prenatal test to consist of 35 kcal/kg ideal body weight, divided into 45% carbohydrates, 35% fat and 20% proteins. An endocrinological-metabolic study was carried out, which consisted of vein plasma glucose determination by an enzymatic technique (glucose oxidase), using a Centrifuchen Multianalysis analyzer (Boehringer, Barcelona, Spain) 60 min before and 120 min after the three main meals, tests for glucosuria and ketonuria, and HbA,, and creatinine clearance levels. At the first visit echography, urinalysis and an ophthalmological evaluation were also carried out. Insulin treatment was based on mixtures of rapid action (regular) and intermediate action insulin (neutral protamine Hagedorn, NPH). Twothirds of the dose was given before breakfast and one-third before supper. The insulin dose was modified to achieve preprandial glucose values < 95 mg/dl and postprandial glucose values < 120 mg/dl. In four cases insulin was regularly administered with an infusion pump of rapid action insulin at the three main meals. Once euglycemia was achieved, the patients were sent home and readmitted every l-3 weeks for further tests. The fetus was monitored by echography and after week 32 non-stress tests of fetal heart rate were carried out. Final admittance of IDDM pa-

223-227

tients without complications was delayed until week 37-38 and was followed by weekly ultrasound examinations and non-stress tests every l-2 days. Delivery was carried out as near to term as possible, but was scheduled, after a fetal lung maturity study, in cases of poor metabolic control, serious complications or a history of stillbirth. Newborn status was evaluated by Apgar tests at 1 and 5 min after delivery. Immediately after delivery, infant blood glucose, calcium, bilirubin and hematocrit levels were evaluated. Perinatal outcomes were compared with those of a non-diabetic control group which consisted of 96 randomly selected, normal, pregnant women who gave birth at approximately the same time. Statistical analysis consisted of the comparison of means test (Student’s t-test) and the x2-test. 3. Results The IDDM women had a greater mean age than those in the control group (P c 0.001) and lower parity (P < 0.01) (Table 1). Patients were attended for the first test on day 148 f 9 of pregnancy. They were receiving 33.1 f 15.9 IU/day and their mean glycemic profile was 153.7 f 52.3 mg/dl and HbA,, was 7.7 f 2.3%. In the last test before delivery patients were receiving 68.2 i 30.7 IU/day and had a mean glycemic profile of 94.4 f 18.1 mg/dl and an HbA,, of 5.9 * 1.4% (P < 0.001 for all parameters). Complications most frequently associated with these pregnancies were polyhydramnios (nine patients, 14.5%), hypertensive disease (five patients, 8.1%) and urinary infections (four patients, 6.5%). Five women suffered severe relapsing hypoglycemia. Table I Age and parity of the patients

Age (years) (mean l S.D.) Nulliparous, n (%I) Multiparous, n (%) ‘P

<

0.001;

**p

<

0.01.

Diabetic women

Control group

32.1 f 7.3

21.4 f 5.9.

14 (22.5%) 48 (77.5%)

35 (36.5%)** 61 (63.5%)

J. A. Miranda

et al. /In!.

J. Gynecol. Obster. 47 (1994)

Table 2 Birthweight

and newborn Apgar

Birthweight (mean f

SD.)

Birthweight

scores <7

at 5 min

IDMs

Control

group

3220 zt 791

3364 *

397

(g)

>4000

g

7.30’

17.70

(“/;I) 1.04**

8.00

Apgar scores <7 (at 5 min) (XI)

lP

< 0.01; **p

< 0.001.

Mean duration of stay in hospital for the diabetic patients was 45 * 18.4 days. Delivery occurred at 262 i 11 days in the study group and at 280 f 9 days in the non-diabetic control group (P < 0.001). Before week 37,24.2 and 5.5% of the study and control groups, respectively, were delivered (P c 0.001). Cesarean sections were performed on 48.3% of the study group (76.6% of these were elective) and on 8.3% of the control group (P < 0.001). Mean birthweight in the IDMs was 3220 f 791.1 g and was not significantly different from that of the controls. Birthweights in excess of 4000 g were recorded for 17.7% of the IDMs compared with 7.3% of the controls (P < 0.001). The IDMs had an Apgar score of ~7 at 5 min in live cases (8%). In the control group only one newborn had an Apgar score of ~7 at 5 min (Table 2). Mean hospital duration of IDMs was 8.5 f 3 days. The results of blood tests at delivery are shown in Table 3. Congenital malformations were presented in seven newborns in the study group but in none in the control group. Three of these newborns had persistent ductus arteriosus, one hydrocephaly, one hypoplastic genitals, one renal polycystoma Table 3 Analytical

data of IDMs Range

IDMs (mean f Glycemia

(mg/dl)

Calcemia (mg/dl) Bilirubinemia Hematocrit

(x

S.D.)

46.9 zt 17.1

>40

9.3 zt 0.8

>7

(mg/dl)

10.8 zt 3.4

< I2

100)

52.5 zt 10.4

~60

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225

and one hip dysplasia. None of the IDMs with severe hypoglycemic crises presented congenital malformations. In the first assay patients who delivered fetuses with congenital malformations were receiving 39.3 f 12.4 IU/day, their mean glycemic profile was 167.5 f 62.1 and HbA,, was 8.1 f 3.9. The other pregnant women with IDDM were receiving 32.3 f 16.2 IU/day, their mean glycemic profile was 152.1 f 51.4 and HbAi, was 7.9 i 9.8 (P = NS). Prenatal death occurred in three cases in the study group (48 per 1000) and in no cases in the control group. One fetus died at delivery because of abruptio placentae. The two remaining stillbirths occurred postdelivery. One fetus developed disseminated intravascular coagulation, and the other presenting renal polycystoma developed necrotic enteritis. 4. Discussion Strict glycemic control in pregnant IDDM women, demonstrated by the decrease in glycemic and HbA,, levels and the normality of biochemical parameters of IDMs, brought perinatal mortalities down to acceptable levels (48 per lOOO), which is similar to the incidence reported by other authors [3,7], although higher than that achieved by Jovanovic et al. [2] and Landon et al. [8], who reported a perinatal mortality rate similar to that in normal pregnancies. Maintenance of glycemic levels between 95 and 120 mg/dl increases the frequency of hypoglycemic crises, which decrease with the administration of three snacks according to individuals needs. The hypothesis that hypoglycemia is a teratogenic factor is not completely accepted. Some authors consider that in the first months of gestation hypoglycemia can play a teratogenic role almost as important as hyperglycemia [4,9]. Others have suggested that hypoglycemic episodes during organogenesis do not cause fetal malformations [lo]. In our series, hypoglycemic crises were frequent. In five patients they were severe and repeated, and occurred after week 9 of gestation, but none of these newborns had congenital malformations,

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J. Gynecol. Obsrer. 47 (1994) 223-227

Although home glucose monitoring is becoming more popular by reagent strips and reflectometers [11,12], this was not possible in our study due to the lack of measuring apparatus and the social, economic and cultural circumstances of the patients who would have had difficulty in correctly manipulating the data obtained [ 111. Our patients were thus frequently admitted to hospital and stayed for considerable periods of time in order to achieve strict glycemic control. In spite of strict glycemic control, birthweights in excess of 4000 g were recorded in 17.7% of the study group, which was lower than the value obtained by Jovanovic et al. [2] of more than 22%, but more than twice that of the non-diabetic control group. This supports the hypothesis that hyperglycemia alone is not responsible for macrosomia and that other metabolic factors such as free fatty acids, ketonic bodies, growth factors or immunological factors, for instance antiinsulin antibodies, which pass through the placental barrier and can transport maternal insulin to the fetus, also play an important role [4,7]. Fewer cesarean sections (48.3%) were performed than in other studies [3,7,13], but considerably more than in the population as a whole. In the same way, premature deliveries (24.2%) were similar to those in other studies [1,7] and four times more frequent than those of the normal pregnancies. The greatest risk period for structural defects is before week 7 after conception, thus strict glycemic control to prevent congenital malformations is most important in the preconceptional period [4,5,14]. In our study group 11.3% of infants had congenital malformations compared with l-3% of the whole population. This could be explained however by the patients’ late admittance to hospital (21 weeks). In the first test, mean glucose levels in the study group were 153.7 f 2.3% and HbAi, was 7.7 f 2.5%, showing that patients were receiving insufficient doses of insulin. Although the difference between patients who delivered fetuses with and without malformations did not reach significance - probably because of the small sample size and late admittance - the values were higher in the former group than in the other pregnant women with IDDM.

Bearing in mind these results it is logical to suppose, as suggested by other authors [14], that the only effective way to decrease the frequency of congenital malformations in these patients is to carry out strict preconceptional glycemic control and for pregnancies to be planned. The higher frequency of congenital malformations in IDDM women is not accompanied by a higher frequency of chromosomal defects [15]. In our study no chromosomal defects were detected in any of the newborn. Our results confirm that strict glycemic control decreases the perinatal mortality normally shown by these patients, but that it should be initiated before the Iirst gestational stages if the frequency of congenital malformations is to be reduced. References 111Gabbe SG. A story of two miracles: the impact of the discovery of insulin on pregnancy in women with diabetes mellitus. Obstet Gynecol 1992; 79: 295. 121Jovanovic L, Druzin M, Peterson CM. Effect of euglycemia on the outcome of pregnancy in insulindependent diabetic women as compared with normal control subjects. Am J Med 1981; 71: 921. 131 Gabbe SG, Mestman JH, Freeman RG, Goebelsmann UT, Lowenshon RI, Nochimson D, et al. Management and outcome of pregnancy in diabetes mellitus, classes B to R. Am J Obstet Gynecol 1977; 129: 723. [41 Cousins L. Etiology and prevention of congenital anomalies among infants of overt diabetic women. Clin Obstet Gynecol 1991; 34: 481. PI Damm P, Molsted-Pedersen L. Significant decrease in congenital malformations in newborn infants of an unselected population of diabetic women. Am J Obstet Gynecol 1989; 161: 1163. 161 White P. Classifications of obstetric diabetes. Am J Obstet Gynecol 1978; 130: 228. VI Varner MW. Efficacy of home glucose monitoring in diabetic pregnancy. Am J Med 1983; 75: 592. VI Guivarch A, Poulain P, Leveque J. Allannic H, Giraud JR, Grail JY. La grossesse de la femme diabetique. Incidence de malformations, de la macrosomie, mise a jour sur la conduite obstetricale. J Gynecol Obstet Biol Reprod 1992; 21: 696. 191 Landon MB, Langer 0, Gabbe SG, Schick C, Brustman L. Fetal surveillance in pregnancies complicated by insulin-dependent diabetes mellitus. Am J Obstet Gynecol 1992; 167: 617. [IO1 Freinkel N. Diabetic embryopathy and fuel-mediated organ teratogenesis: lessons from animal models. Horm Metab Res 1988; 20: 463.

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[I I] Steel JM, Johnstone FD, Hepburn DA, Smith AF. Can prepregnancy care of diabetic women reduce the risk of abnormal babies?. Br Med J 1990; 301: 1070. [I21 Hare JW. Insulin management of type I and type II diabetes in pregnancy. Clin Obstet Gynecol 1991; 34: 494. [I31 Landon MB, Gabbe SC. Fetal surveillance in the pregnancy complicated by diabetes mellitus. Clin Obstet Gynecol 1991; 34: 535.

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[I41 Jensen BM, Kiihl C, Molsted-Pedersen L, Saurbrey N, Fog-Pedersen h J. Preconceptional treatment with insulin infusion pumps in insulin-dependent diabetic women with particular reference to prevention of congenital malformations. Acta Endocrinol Suppl 1986; 277: 81. [I51 Ulrik Henriques C, Damm P, Tabor A, Goldstein H, Molsted-Pedersen L. Incidence of fetal chromosome abnormalities in insulin dependent diabetic women. Acta Obstet Gynecol Stand 1991; 70: 296.