Severe Hypoglycemia Incidence and Predisposing ... - Diabetes Care

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Severe Hypoglycemia Incidence and Predisposing Factors in 85 Pregnancies of Type I Diabetic Women RENATE KIMMERLE, MD LUTZ HEINEMANN, D1PL B1OL, D1PL ING ALEXANDER DELECKI MICHAEL BERGER, MD

OBJECTIVE— To evaluate the incidence and predisposing factors of severe hypoglycemia (SH) in pregnant women with insulin-dependent (type I) diabetes mellitus. RESEARCH DESIGN AND METHODS— SH (impairment of consciousness due to hypoglycemia subsequently treated with glucagon or i.v. glucose) was recorded in all pregnant type I diabetic women (n = 77) who attended our pregnancy clinic during 85 pregnancies from 1986 to 1990. RESULTS— Ninety-four SHs were reported during 35 pregnancies. Of 94 SHs, 84% occurred before the 20th gestational wk (median 12th wk) and 77% during sleep. In the group with SH, there was no permanent maternal sequelae, and there was a favorable fetal outcome (no perinatal death and no congenital malformation). Mean HbAlc values were not different between the group with and without SH for the first half (6.4 ± 1.1 vs. 6.3 ± 0.9%) and 2nd half (5.4 ± 0.6 vs. 5.5 ± 0.7%) of pregnancy. The percentage of women with SH before pregnancy (51 vs. 28%, P < 0.05) and the incidence of SH patients before pregnancy (0.49 vs. 0.08 SH/ patient/yr) was different between the group with and without SH. CONCLUSIONS— SH is frequent during pregnancies of type 1 diabetic women with near normoglycemia. The risk for SH is particularly pronounced during the first half of pregnancy and in women with a history of SH.

N

ear normalization of glycemia throughout pregnancy can prevent most of the fetal problems related

to diabetes occurring in pregnancies of insulin-dependent (type I) diabetic women (1,2). Near normalization of

FROM THE DEPARTMENT OF NUTRITION AND METABOLIC DISEASES, WORLD HEALTH ORGANIZATION COLLABORATING CENTER FOR DIABETES, HEINRICH-HEINE-UNIVERSITY, DUSSELDORF, GERMANY. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO DR. RENATE KIMMERLE, ABT. FUR ERNAHRUNG u.

STOFFWECHSEL, HEINRICH-HEINE-UNIVERSITAT, DUSSELDORF, MOORENSTR. 5,

4 DUSSELDORF

1,

GERMANY. RECEIVED FOR PUBLICATION 23 JULY 1991

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AND ACCEPTED IN REVISED FORM 20 DECEMBER

1991.

blood glucose can be readily achieved by most women cared for in specialized centers with intensified insulin treatment and frequent self-monitoring of blood glucose (2). However, few larger studies investigating the effect of strict metabolic control on the outcome of pregnancy have commented on the problem of severe hypoglycemia (SH) (2,3). Based on animal studies, concern has been raised about the harmful effect of hypoglycemia on organogenesis (4). However, in pregnancies of type I diabetic women, a negative association between hypoglycemia during early pregnancy and congenital malformations has been consistently reported (1,2,5). Therefore, the ongoing debate about how tight metabolic control should be in the first trimester is mainly out of concern for the mothers (3). We evaluated the incidence and circumstances of SH during pregnancies of type I diabetic women who consecutively attended our pregnancy clinic from 1986 to 1990. We compared characteristics of women with and without SH to elucidate specific factors that might help identify women at risk. RESEARCH DESIGN AND METHODS— SH was defined as an impairment of consciousness, which led to the injection of glucagon by another person or to the intravenous administration of glucose by an emergency physician (6). To ascertain SH before and during pregnancy, all pregnant women were asked at the first and at every subsequent visit to our pregnancy clinic whether, how, and when SH had occurred and how they were treated. Additionally, all women were again asked in the spring of 1991, in a structured telephone interview, about the health and development of their child or children. SH was recorded and analyzed from each of the 77 women with pregestational type I diabetes who attended our pregnancy clinic from 1986 to 1990 during 85 pregnancies and who delivered between January 1987 and December 1990 (87 babies, 2 sets of twins, and 2

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24 spontaneous abortions in the first trimes21 ter). Sixty patients had participated in our structured 5-day diabetes treatment and teaching program within 5 yr before their pregnancy (7). This program used 10 intensified insulin treatment based on di6 5 abetes self-management, emphasizing . 2 1 adjustment of insulin doses by the pa1 tients themselves. 12 16 20 24 28 32 36 40 gestational age (weeks) After their first visit to the pregnancy clinic, patients who had not undergone our treatment program before or Figure 1—Frequency of episodes of severe hypatients who were in poor glycemic con- poglycemia during 35 pregnancies according to trol (n = 5) were admitted to our inpa- 4-wk periods of gestational age. Shaded bars, tient treatment program. They were seen severe hypoglycemia that occurred before the every 2 - 4 wk in the pregnancy clinic first visit to the pregnancy clinic. Open bars, where their diary was reviewed, insulin severe hypoglycemia that occurred after the first dose adjustments discussed, venous visit. blood was drawn for HbA lc (highperformance liquid chromatography; Diamat, Bio-Rad, Munich, Germany; normal range 4.2-5.5%, intra- and in- RESULTS— Ninety-four SHs were reterassay coefficients of variation 5 SHs in 5 pregnancies. One Fisher's exact test. woman reported 20 SHs, all of which

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occurred before her first visit to the pregnancy clinic. Three women crashed their cars, without injuries, because they became hypoglycemic and confused while driving in the 8th, 12th, and 13th gestational wk, respectively. Women with and without SH did not differ significantly in most parameters evaluated (Table 1). In both groups, glycemic control was equally good as indicated by similar average HbAlc values during the first and second halves of pregnancy, respectively. The average insulin dose during the gestational week of the episode (14 ± 3 wk) used by the 22 women who had their first SH after their initial visit to the pregnancy clinic did not differ from the average insulin dose of women without SH during a comparable gestational period (0.74 ± 0.2 vs. 0.73 ± 0.21 U • kg-May" 1 ). The ratio of short-acting to basal insulin (NPH and regular insulin [pump-treated patients]) used during the end of the first trimester was not different between women with and without SH (0.9 [0.5-3.5] vs. 1.1 [0.5-2.0]). Among patients with SH during pregnancy, the incidence of SH before pregnancy (0.49 vs. 0.08 SH/patient/yr) and the percentage of women who had had one or multiple SH before pregnancy (51 vs. 28%) was higher compared with women without SH (P < 0.05). Of the seven women with two pregnancies in the study period, three had SH in both pregnancies and three had no SH in both pregnancies. There were no perinatal deaths in either group. Gestational week at delivery, birth weight, and percentage of babies >90th percentile for birth weight were not different for the women with and without SH (Table 1). One woman without SH in pregnancy had a child with a congenital malformation (omphalocele). This woman had been treated with steroids during the first 7 wk of pregnancy, and her HbAu. in the 7th gestational wk was 10.2%. One baby of a woman with one SH in the 16th wk died suddenly at home on the 21st day postpartum. At the time of the telephone

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Table 1—Characteristics of women with and without severe hypoglycemia during pregnancy and outcome of pregnancies SEVERE HYPOGLYCEMIA PARAMETER PREGNANCIES (N) MATERNAL AGE (YR) DURATION OF DIABETES (YR) WHITE'S CLASSIFICATION

PLANNED PREGNANCIES ( N ) GESTATIONS (N) PRIMIPARI (N) INTENSIFIED INSULIN THERAPY BEFORE PREGNANCY (N) INSULIN THERAPY DURING PREGNANCY (1C1T/CS1I; N) BODY MASS INDEX BEFORE PREGNANCY (KG/M 2 ) WOMEN WITH SEVERE HYPOGLYCEMIA BEFORE PREGNANCY (N) INITIAL VISIT TO PREGNANCY CLINIC (GESTATIONAL AGE; WK) HBAU

PRESENT

ABSENT

35 29 ± 5 14 ± 7 B9, C7, D9, R3, F7 24 (69%) 1.8 ± 1.0 21 (60%) 23 (66%) 31 (89%)/4(ll%) 22.2 ±2.9 18 (51%) 8 (6-33)t

50 29 ± 4 13 ± 8 B19, C9, D16, R2, F2, H/Fl, Tl 37 (74%) 1.9 ± 2 . 1 32 (64%) 37 (74%) 42 (84%)/8 (16%) 23.2 ± 2.6 14 (28%)* 9 (1-36)

6.9 ± 1.4 6.4 ± 1.1 5.4 ± 0.6 39 (32-41)t 15.3 ± 5.0 3291 ± 709 7 (20%) 0 0

6.8 ± 1.2 6.3 ± 0.9 5.5 ± 0.7 39 (29-41)t 15.0 ± 5.1 3388 ± 10201= 18 (38%)f 1 0

(%)

INITIAL GESTATIONAL WK 1 - 2 0 GESTATIONAL WK 2 1 - 4 0 GESTATIONAL AGE AT DELIVERY (WK) MATERNAL WEIGHT GAIN DURING PREGNANCY (KG) BIRTH WEIGHT (G) BABIES LARGE FOR GESTATIONAL AGE ( > 9 0 T H PERCENTILE; N) FETAL MALFORMATIONS (N) PERINATAL DEATHS (N)

Data are means ± SD or medians with percentages in parentheses. ICIT, intensified conventional insulin therapy; CSII, continuous subcutaneous insulin infusion. *P < 0.05, all other parameters were not significantly different. tValues in parentheses are ranges, twin pairs were not included.

interview (median age of the children 25 mo [range 2-51 mo]) all other children were alive and well without any developmental problems. CONCLUSIONS— In this study of 85 pregnancies of type 1 diabetic women, one or more episodes of SH were reported during 41% of pregnancies. No physical injury or neurological sequelae beyond the acute impairment of consciousness were reported by the mothers but some of the episodes caused substantial disruptions for the mothers' life. Rayburn et al. (3) reported one death due to SH in a pregnant woman who had taken a large dose of NPH in the morning and did not eat because of morning sickness. In the women of this study, who all used

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intensified insulin therapy, frequent but relatively small doses of insulin and the experience with self-management of insulin therapy before pregnancy was instrumental in limiting the duration and severity of hypoglycemia (6). Although not quite comparable because of differences in definition and ascertainment of SH, similar high frequencies of SH were also reported from other series of pregnancies in type I diabetic women (2,3). When compared with poor glycemic control, near normoglycemia per se might be a predisposing factor for frequent SH in pregnancy (2,3), in analogy to the nonpregnant state (8). However, in this study, in which most women were in good control, lower levels of glycemia were not specifically associated with SH.

Decreased perception of hypoglycemia during pregnancy was reported by many of our patients and could be one mechanism whereby sustained low blood glucose levels could have lead to an increased frequency of SH (9). For the pregnant near-normoglycemic women, the incidence of SH and the percentage of patients with SH was greater than that reported for nonpregnant type I diabetic patients with near normoglycemia (6,8). This might be due to metabolic factors specific for pregnancy (10). For example, in our patients, most of the SH (80%) occurred in the first half of pregnancy, although HbAlc values were even lower in the second half. A clustering of SH during the first half of pregnancy was also reported by others (2,5) and might


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be partly related to a transitionally increased insulin sensitivity in the first 16 wk of pregnancy (10). In contrast, the increasing insulin resistance of the second half of pregnancy might convey some protection against SH in analogy to the scarcity of SH in insulin-treated women with gestational diabetes (3). Our study was too small to exclude adverse effects of SH on fetal outcome with certainty. However, if they exist at all, adverse effects should be extremely rare because in ours and all previous series, near normoglycemia was associated with a fetal outcome resembling that of normal pregnancies despite episodes of SH (1,2,5). Therefore, we do not advocate less-tight glycemic control during pregnancy. Rather, women at special risk should be identified and preventive measures intensified, especially the training in self-adjustment of insulin dose. We found that the only predisposing factor specific for women with SH in pregnancy was frequent SH before pregnancy. This is in accordance with large studies of intensified insulin treatment in nonpregnant type I patients, which also found a history of previous SH to be the principal predisposing factor for SH during the study period (8). Other factors that, in theory, could be associated with an increased risk of SH during pregnancy, e.g., duration of diabetes, White class, not planning of pregnancy, low body mass index, and first pregnancy, did not prove to be associated with SH in our study population. We cannot rule out that women of White class F are at an

increased risk of SH because they were overrepresented in our group with SH, although not significantly. In summary, near normalization of glycemic control in pregnant type I diabetic women is associated with an increased risk of SH even in women who are experienced in intensified insulin therapy. Because the outcome of pregnancy is excellent, near normalization of blood glucose throughout pregnancy should remain the treatment goal, with the patients' self-management skills intensified, ideally before pregnancy. Precautions during the first half of pregnancy, during sleep, and while driving, particularly for women with a history of SH, should reduce the risk for SH.

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during organogenesis in rat embryo culture. Diabetes 38:1573-78, 1989 5. Mills JL, Knopp RH, Simpson JL, Jovanovic-Peterson L, Metzger BE, Holmes LB, Aarons JH, Brown Z, Reed GF, Bicber FR, Van Allen M, Holzman I, Ober C, Peterson CM, Withiam MJ, Duckies A, Muller-Heubach E, Polk BF, National Institute of Child Health and Human Development, Diabetes in Early Pregnancy Study: Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis. N EnglJ Med 318:671-76, 1988 6. Miihlhauser 1, Santiago JV, Bolli GB: The frequency of severe hypoglycemia during intensive insulin therapy. Diabetes Nutr Metab 1:77-88, 1988 7. Muhlhauser I, Bruckner I, Berger M, Cheta D, Jorgens V, Ionescu-Tirgoviste C, Scholz V, Mincu I: Evaluation of an intensified insulin treatment and teaching program as routine management of type I (insulin-dependent) diabetes: the Bucharest-Dusseldorf Study. DiabetologLti 30:681-90, 1987 8. The DCCT Research Group: Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Am J Med 90:450-59, 1991 9. Amiel SA, Pottinger RC, Archibald HR, Chusny G, Cunnah DT, Prior PF, Gale EA: Effect of antecedent glucose control on cerebral function during hypoglycemia. Diabetes Care 14:109-18, 1991 10. Kalkhoff RK, Kissebah AH, Kim HJ: Carbohydrate and lipid metabolism during normal pregnancy: relationship to gestational hormone action. Semin Pctinatol 2:291-307, 1978

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