Impairment of counterregulatory hormone responses to hypoglycemia in pregnant women with insulin-dependent diabetes mellitus

Impairment of counterregulatory hormone responses to hypoglycemia in pregnant women with insulin-dependent diabetes mellitus Michael P. Diamond, MD,. E. Albert Reece, MD: Sonia Caprio, MD,c Timothy W. Jones, MD, Stephanie Amiel, MD, Nancy DeGennaro, RN,b Andrea Laudano, RN,. Mario Addabbo, Robert S. Sherwin, MD, and William V. Tamborlane, MDd C

New Haven, Connecticut

Intensive Insulin therapy directed at elimination of hyperglycemia is advocated during pregnancy in women with insulin-dependent diabetes mellitus. Because such treatment is complicated by frequent hypoglycemic episodes, we evaluated maternal and fetal responses in nine intensively treated pregnant women with insulin-dependent diabetes mellitus during an insulin-induced, gradual, controlled fall in plasma glucose levels. In contrast to values in nonpregnant control women, reductions in glucose to 44 ± 2 mg/dl in pregnant diabetic patients failed to elicit an increase in glucagon levels. Epinephrine release during hypoglycemia was also markedly suppressed In the pregnant diabetic subjects (106 ± 32 vs 327 ± 52 pg/ml in controls, p < 0.001). Furthermore, the plasma glucose level at which epinephrine and growth hormone were released was 5 to 10 mg / dllower In the pregnant women with insulin-dependent diabetes mellitus (p < 0.05). The basal fetal heart rate remained unchanged and continued to manifest accelerations during the hypoglycemic state. We conclude that the high frequency of hypoglycemia In intensively treated pregnant women With insulin-dependent diabetes mellitus may be due in part to impaired counterregulatory hormonal responses. (AM J DBSlEl GVNECOL 1992;166:70-7.)

Key words: Hypoglycemia, pregnancy, diabetes mellitus, counterregulation, insulin Infants of mothers with insulin-dependent diabetes mellitus are at increased risk for fetal and neonatal complications, including congenital malformations, stillbirths, macrosomia, and birth injuries. ' Initiation of intensive insulin therapy aimed at achieving strict glycemic control after conception has resulted in a decreased incide nce of all these complications, with the notable exception of congenital malformations!' J Unfortunately, the methods used to achieve tight regulation of glucose levels have been accompanied by frequent episodes of maternal hypoglycemia .. In one report from our center: more than one sixth of blood glucose measurements were <50 mg/ dl, all women had hypoglycemic symptoms, and eight of 22 experienced severe hypoglycemia. This frequency of severe hypo-

From the DiVISIOns of ReproductIVe Endocrinology" and MaternalFetal MediCine/ Department of Obstetncs and Gynecology, the Department of M ediCine,' and the Department of P edzatrz cs.' Yale University School of MediCIne. Recewedfor pubhcation February' 7, 1991; revised June 5,1991; accepted June 17,1991. R epnnt )'equests: Michael P . Dzamond. MD. Yale Umve fSlty School ofMedicine, 333 CedarSt., P .O. Box 3333, New H aven, CT0651O. Supported by a Diabetes Treatment Center of America Research Grant and Nattonal InstItutes of H ealth Grants Nos. DK20495 and RR00125. M.P.D. is a Clinical ASSOCIate Physicwn of the General Chmcal Research Center.

6/1/31813 70

glycemic episodes is higher than that reported in nonpregnant patients with insulin-dependent diabetes mellitus receiving either intensive or conventional insulin treatment. 5 Although the mechanisms responsible for the high frequency of hypoglycemia in intensively treated mothers are unknown, this phenomenon may reflect more stringent target glucose goals during pregnancy. Previous studies in nonpregnant patients receiving intensive insulin therapy suggest that such therapy is associated with the development of suppressed counterregulatory responses to h ypoglycemia 6. 7 that appear to be due to a lowering of the plasma glucose level triggering counterregulatory hormone responses." Whether similar adaptations occur in pregnant women with tightly controlled insulin-dependent diabetes mellitus has not been determined . The current study was consequently undertaken to examine maternal homeostatic responses and fetal well-being during a controlled hypoglycemic stimulus with the hypoglycemic clamp technique in pregnant women with tightly controlled insulin-dependent diabetes mellitus. Material and methods Nine pregnant patients with insulin-dependent diabetes mellitus (27 ± 2 years old) were recruited from the Yale Diabetes Faculty Practice in the Division of

Response to hypoglycemia dUring pregnancy

Volume 166 Number I, Pan I

71

Insulin Infusion (2.0 mUIkg°min) Variable Glucose Infusion

120

• Insulin Dependent Diabetic, Pregnant o Non-Diabetic, Non-Pregnant

100 ~

~

80

Q)

60

§. f/)

8:l

(5

40

20 0

-20

0

40

80

120

160

200

240

Time (minutes) Fig. L Plasma glucose levels during hypoglycemic clamp studies in pregnant, intensively treated insulin-dependent diabetic women, and nonpregnant, nondiabetic control women .

Maternal-Fetal Medicine, Department of Obstetrics and Gynecology. To be eligible for study, they had to have had insulin-dependent diabetes mellitus for > 1 year before pregnancy, ha\ e been treated intensively in the Diabetes in Pregnancy Program for :::::8 weeks, and have been able LO achieve glycosylated hemoglobin levels <8.5% (mean ± 3 SD of nondiabetic controls). Patients were excluded if they had other hormone deficiencies or clinical evidence of autonomic neuropathy that might predispose to problems with hypogl ycemia_Clinical characteristics of these women, including White's classification, are summarized in Table 1. Estimated gestational age at the time of study ranged from 21 to 37 weeks (by last menstrual period and ultrasonographic assessment) . The duration of diabetes mellitus in these women ranged from 3 to 22 years (average 16 ± 2 years, median 17 years). Clinical management of diabetes during pregnancy has been previously described} Briefly, pregnant diabetic women measured blood glucose levels at home approximately se\'en times per day (before and after each meal and at bedtime) with a reflectance meter. Accuracy of these home measurements was confirmed by weekly laboratory measurements. Insulin doses were continuously adjusted on the basis of the home glucose profiles, with the goal of fasting and preprandiallevels <100 mg / dl and 2-hour postprandial levels <120 mg/dl. Rapid-or intermediate-acting insulin was administered as three or more daily injections (n = 8) or by a continuous subcutaneous insulin infusion with a portable pump (1/ = 1). Hypoglycemic episodes were recorded and subjectively graded as mild (responded to self-administered snack), moderate (required another person's assistance), or severe (required glucagon

or intravenous glucose, usually in an emergency room setting). Obstetric management has also been previously described 4 and included antepartum biophysical and biochemical monitoring, serial ultrasonographic examinations, assessment of fetal lung maturity before elective intervention , and a policy of vaginal delivery unless intervening events necessitated cesarean section. Seven healthy, age-matched, nonobese, nonpregnant, nondiabetic women served as controls. The mean age of these women was 27 ± 2 (range 20 to 35) and their glycosylated hemoglobin value averaged 6.5 ± 0.4. These nondiabetic women received the same hypoglycemic clamp study as the pregnant diabetics, except that the last step lowering the plasma glucose level to 45 mg / dl was omitted (because of symptoms in the nondiabetic subjects). Written informed consent was obtained from all subjects before the study. The study protocol was approved by the Human Investigation Committee of Yale University School of Medicine. Procedures. Studies were performed after a 10-hour overnight fast. Diabetic subjects were admitted LO the Yale General Clinical Research Center on the evening before the study. Their evening dose of intermediateacting insulin was omitted. An indwelling intravenous catheter was placed in an antecubital vein for moniLOring plasma glucose, and basal insulin replacement was provided by a low-dose intravenous infusion of insulin that was adjusted every 30 to 60 minutes to achieve plasma glucose levels of -100 mgl dl, without nocturnal hypoglycemia, as previously described." On the morning of study a second catheter was inserted into a dorsal hand vein, and that hand was then placed in a heated box (65 0 to 70 0 C) to arterialize ve-

72

Diamond at al.

January 1992 Am J Obstet Gynecol

Table I. Maternal characteristics of pregnant insulin-dependent diabetic women undergoing hypoglycemic clamp testing Subject No.

Age (yr)

I

24 35 29 34 28 24 31 20 22

2 3 4 5 6 7 8 9

Gravidity

Parity

3 3

0 2 0

I

2

1 I

3 2 1

Estzmated gestational age (wk)

Whzte's classification

Initial viszt

10

FR D R FR B FR FR D C

I

0 0 0 0 0

I

Study

27 31 33 36 32 21 28 37 27

PC

10 9 22 9 9 13 14

*Required another person's assistance. tRequired glucagon or intravenous glucose.

Table II. Characteristics of infants of insulin-dependent diabetic mothers who underwent hypoglycemic clamp testing during gestation Estimated gestatzonal age at delwery (wh)

Interval between study and delwery (days)

39

80

2 3

40 36

59 21

4 5 6

39 39 38

22 50 114

7

39

77

8

39 39

12 91

Subject No.

9

Apgar scores

Method of delwery

Indication for cesarean sectzon

Cesarean section Vaginal Cesarean section Vagmal Vaginal Cesarean section Cesarean section Vaginal Cesarean section

Cephalopelvic disproportion Cephalopelvic disproportion Cephalopelvic disproportion Cephalopelvic disproportion Cephalopelvic disproportion

nous blood." This line was used for blood sampling during the clamp study. After a 30-minute rest period, two blood samples were obtained at 20 minute intervals for measurement of baseline glucose and hormone levels. A primed continuous infusion of rapid-acting human insulin (Novolin R, Squibb-Novo, Princeton, N.].) was then begun; the continuous rate was 2 mU/kg/min, preceded by priming of 8 mU/kg/min for 5 minutes and 4 mU Ikg/min for 5 minutes. Plasma glucose levels were determined every 5 minutes during the insulin infusion with a Beckman Glucose Analyzer II (Beckman, Fullerton, Calif.), and a variable infusion of 20% dextrose was adjusted to maintain the desired glycemic plateau. The plasma glucose level was brought to -90 mgl dl by the end of the first 40 minutes of the study. Thereafter, plasma glucose was reduced by 10 mg/dl every 40 minutes until a plateau of 50 mg/dl was achieved. In the pregnant diabetic women the study

I min

5 min

Wezght (gm)

Neonatal complications

9

9

2892

None

8 9

9 9

3950 2970

H yperbiliru binemia None

9 9 9

9 9

9

3420 3870 2660

None None None

9

9

3720

None

9 9

9 9

3460 3520

None None

was extended for an additional 40 minutes to allow plasma glucose to fall to 45 mg/dl. In all pregnancies in which the estimated gestational age of the fetus was ~30 weeks, a reactive nonstress test was obtained before the study was begun. In those fetuses <30 weeks estimated gestational age or with a nonreactive nonstress test, fetal well-being was established by a biophysical profile score of at least 8 out of 10. Fetal heart rate (FHR) monitoring was performed to assess fetal well-being during each 40-minute plateau. At the completion of the study, the FHR was monitored during reestablishment of a normal glucose level and again after lunch. Determinations. Plasma glucose was measured in duplicate at the patient'S bedside with a glucose analyzer (Beckman). The calibration of the analyzer was checked at 30-minute intervals; the coefficient of variation for the assay was <2%. Catecholamines were measured

Response to hypoglycemia during pregnancy 73

Volume 166 Number 1, Part 1

Glycosylated hemoglobzn (%) I nztial VISit

5.7 4.7 7.6 10.8 6.2 8.5 5.9 6.8 10.9

I

Hypoglycemic episodes

Study

Mean glucose (mg/dl) in week befor e study

Moderate* (No. /wk)

5.9 5.6 6.0 8.3 7.0 7.6 4.8 5.8 7.5

129 135 85 97 132 138 128 122 139

2.4 3.9 4.9 2.5 2.3 1.5 2.3 1.2 1.8

with a radioenzymatic assay (Amersham, Arlington Heights, Ill.). Growth hormone (Kallestad Diagnostics, Austin, Tex.), cortisol (Clinical Assays, Cambridge, Mass.), and glucagon (ICN Biomedicals, Inc., Carson, Calif.) were determined by radioimmunoassay. Human chorionic gonadotropin and prolactin were measured by immunoradiometric techniques (Serono Diagnostics, Woking, Surrey, England). Human placental lactogen (hPL) levels were determined by Smith Kline Clinical Laboratories, King of Prussia, Pa. Glycosylated hemoglobin was measured chromatographically after saline solution washing to remove the labile fraction with a microcolumn kit (Isolab, Akron, Ohio). Analyses. The weekly mean glucose value (see Table I) represents the average of every preprandial and postprandial glucose measurement for a I-week period before the study and comprises at least four measurements each day of the week. The plasma glucose threshold for hormone release determined during the clamp procedure was defined as the glucose level at which an unequivocal sustained increment in circulating hormone concentrations above basal levels was first observed: 75 pg/ml for epinephrine, 50 pg/ml for norepinephrine, 7 ng/ml for growth hormone, and 7 fLg / dl for cortisol. fi In each subject the mean of all control hormone values was used as the basal hormone level from which significant change was measured. To avoid the confounding effects of spontaneous growth hormone peaks, we used the mean of the four nadir values during the euglycemic phase as the baseline for defining growth hormone thresholds. The incremental value for epinephrine was chosen as one likely to be of clinical relevance,9 and the values for growth hormone and cortisol were chosen from published definitions of normal responses to the insulin tolerance test of pituitary-adrenal axis function as previously described. lO These definitions were used to avoid errors caused by small spontaneous fluctuations in hormone levels during the study. Because of differences in basal values during pregnancy for growth hormone and cortisol,

I

Severd (No./wk)

0 0 1 0 0 2 2 1 2

these data are presented as the increment above basal values. Data are presented as mean ::t SEM. Comparisons between the diabetic and nondiabetic groups were made by analysis of variance with a repeated-measures design and by the Student t test. Comparisons within each group were performed by analysis of varia'nce and paired t test. A p value <0.05 is reported as significant. Results

Diabetes control. As shown in Table I, there was a modest variation in weekly mean glucose levels (range 85 to 139 mg/dl) in the patients during intensive treatment. At the time of the clamp study, all but one of the subjects had glycosylated hemoglobin levels in the normal range (i.e., 4% to 8.5%). As expected! achievement of stringent treatment goals was associated with the common occurrence of moderate and severe hypoglycemic episodes (Table I). Counterregulatory hormone responses. As shown in Fig. 1, basal glucose levels after the overnight fast were higher in the pregnant women with insulin-dependent diabetes mellitus than in control women (lOS ± 8 vs 85 ± 2 mg/dl, p < 0.05). However, plasma glucose levels were virtually identical in the two groups after the initial 40 minutes of the study (Fig. 1). As shown in Fig. 2, basal glucagon, epinephrine, and norepinephrine levels were similar in the pregnant diabetics and healthy nonpregnant control subjects. After induction of hypoglycemia, glucagon levels (109 ± 11 pg/ml, basal) in the pregnant subjects with insulin-dependent diabetes mellitus declined slightly to 91 ± 12 pg/ml (p = not significant) by the end of the study (plasma glucose 44 ± 2 mg/dl). In contrast, in the nonpregnant, nondiabetic control group glucagon initially declined but then rose from a plateau level of 75 ± 12 pg/ml to 115 ± 21 pg/ml (p < 0.01) when plasma glucose fell to 48 mg / dl. In the nondiabetic women, plasma epinephrine rose from 41 ± 11 to 327 ± 52 pg/ml (p < 0.001) at the

74

Diamond et al.

January 1992 Am J Obstet Gynecol

Insulin Infusion (2.0 mU/kgomin) Variable Glucose Infusion

400

E

~

300

c ·c .c Q.

200

c '0.

100

Q)

Q)

w

Insulin Infusion (2.0 mUlkgomin)

• Insulin-Dependent Diabetic, Pregnant o Non-Diabetic, Non-Pregnant

0.:::> c_

.g.s

~ Q)

t5

e 111E.g :::J III

:rC: 0 Cl

-E C:'Q

B :I.

III

'1:

g.

200

l

100

c: 0

Z

1118' EU :fj

0 01

a

50 I I 0 -20 0

,

40

,

I

I

80 120 160 Time (minutes)

I

200

,

240

Fig. 2. Epinephrine, norepinephrine, and glucagon responses to hypoglycemia in pregnant, intensively treated insulin-dependent diabetic women, and nonpregnant, nondiabetic control women.

Variable Glucose Infusion • Insulin-Dependent Diabetic, Pregnant o Non-Diabetic, Non-Pregnant

16

c 0

12 E 0:::r E 8 .co, ~.s

e

4


0 -2 30

Cl

'0 U)

001

U,:,
o

20 :::::-

."0 t::_

10

2

0 -10

I

I

9

6

!

ft!

!

1-!

,

,

t

1

3

, , 0 -20 0

,

40

,

80 120 160 Time (minutes)

,

200

,

240

Basal~

,

40

,

!

!

80 120 160 Time (minutes)

,

200

Table III. Glucose threshold for counterregulatory hormone secretion

Epinephrine Norepinephrine Growth hormone

Nonpregnant, nondiabetIc controls (mgldl)

Pregnant diabetic subjects (mg I dl)

55 ± 3 57 ± 5 50 ± 1

49 ± 4 44 ± 2t

46 ± 2*

*p < 0.05 versus controls. tp < 0.01 versus controls.

Insulin Infusion (2.0 mu/kgomin)

Q)

t t f

Fig. 4. Human chorionic gonadotropin and hPL levels in pregnant, intensively treated insulin-dependent diabetic women during hypoglycemic clamp studies.

100

c:

g

ttH f--1

0 12

~

a::c: c Q)

0 150

I

20000

(ij::::-

300

C

.c

60000

o c: '0. 40000 c:

0 400

E

Variable Glucose Infusion

E 80000

240

Fig. 3. Changes in growth hormone and cortisol levels from basal concentrations during hypoglycemic clamp studies in pregnant, mtensively treated insulin-dependent diabetic women, and nonpregnant, nondiabetic control women.

end of the study when the plasma glucose level was 50 mgl dl. In contrast, in spite of equivalent hypoglycemia, the rise in the plasma epinephrine level in the pregnant diabetic women was blunted and delayed. When the plasma glucose level was lowered to 50 mg/dl in the pregnant women with insulin-dependent diabetes mellitus the rise in plasma epinephrine level was only one third (106 ± 32 pg/ml) of that seen in control women (P < 0.001). Even when the glucose level was lowered to 44 ± 2 mgl dl, the epinephrine level was still lower than that observed in controls (Fig. 2). Furthermore, the plasma glucose threshold triggering release of epinephrine was 46 ± 2 mg/dl, a value significantly less than that in control subjects (55 ± 3, P < 0.05) (Table II). There was no significant difference in the rise of norepinephrine in the two groups during hypoglycemia. Basal immunoreactive growth hormone levels were elevated in the pregnant diabetic women (11.0 ± 0.7

Response to hypoglycemia during pregnancy

Volume 166 Number 1, Part 1

75

Fig. 5. FHRs from pregnant, intensively treated insulin-dependent diabetic pregnancies during hypoglycemic clamp studies.

Table IV. Glucose and hormone levels during hypoglycemic clamps in previously described nonpregnant subjects and pregnant subjects in current study with insulin-dependent diabetes mellitus Nonpregnant dwbetlc subjects IntenSIVe tleatment

Pregnant dwbetlc subjects (thiS study): Intensive treatment

92 ± 1 53 ± 1 48 ± 2

90 ± I 50 ± 1 42 ± 1

105 ± 8 50 ± 1 44 ± 2

55 ± 10 477 ± 75 690 ± 123

41 ± 9 138 ± 27 320 ± 64

26 ± 4 96 ± 29 194 ± 46

13.2 ± 2.1 19.9 ± 2.3 21.2 ± 3.5

9.7 ± 1.4 17.4 ± 4.6 30.3 ± 6.3

1.0 ± 0.7 15.8 ± 1.5 19.6 ± 2.5

ConventIOnal treatment Glucose (mg/dl) Basal 180-200 min 220-240 min Epinephrine (pg/ml) Basal 180-200 min 220-240 min Growth hormone (ng/ml) Basal 180-200 min 220-240 min

ng/ml) as compared with controls (2.7 ± 0.4 ng/ml;

p < 0.001, Fig. 3). Nevertheless, the increase in growth hormone in the final 80 minutes in the nonpregnant, nondiabetic controls was greater than that in the pregnant diabetics. Additionally, the plasma glucose threshold for release of growth hormone was significantly suppressed in the pregnant diabetics (44 ± 2 vs 50 ± 1 in controls, p < 0.01) (Table II). Basal cortisol levels were also significantly higher in the pregnant diabetic individuals than the control women (26.3 ± 31 vs 12.9 ± 2.5 f,Lg/dl P < 0.01, Fig. 3). Cortisol levels rose slightly, but insignificantly above baseline, in both groups during the study. There was no significant change in plasma human chorionic gonadotropin, hPL (Fig. 4), or prolactin during hypoglycemia. Fetus. The baseline FHR of the eight fetuses "2:.27 weeks' estimated gestational age during the control pe-

I

riod ranged from 128 to 150 beats/min, with a mean of 138 ± 3 beats/min. Reduction in the glucose level to 45 ng/dl was associated with no significant change in the mean FHR (Fig. 5) and continued identification of FHR accelerations. Neonatal outcome. As shown in Table III, delivery of infants occurred at an average of 38.2 ± 0.6 weeks' gestation (range 34 to 40 weeks) and followed the conclusion of the study by 63.2 ± 11.5 days (range 12 to 114 days). Five of the infants were delivered vaginally and four by cesarean section; indications for cesarean section were cephalopelvic disproportion in all four women. Average Apgar scores at 1 minute and 5 minutes were 8.7 ± 0.2 and 8.8 ± 0.2, respectively. The average fetal weight was 3385 ± 151 gm. The only neonatal complication was hyperbilirubinemia in one infant (Table III).

76

Diamond et al.

Comment

The detrimental effects of poor maternal glycemic control on the fetus throughout gestation Jl , 12 have led to the common use of intensive insulin therapy in women with insulin-dependent diabetes mellitus in an attempt to maintain normal glucose profiles. Although improvements in metabolic control clearly diminish the incidence of fetal complications!' 3 it is uncertain whether the more stringent goals of achieving normal blood glucose profiles in pregnancy offers additional benefits outweighing the risk of increased fetal and maternal hypoglycemia. Coustan et aJ.4 have previously reported a very high frequency of hypoglycemic events with strict glycemic control. In part, this may be due to the large doses of insulin that are required to meet target plasma glucose goals, especially in the later stages of pregnancy. Alterations in counterregulatory mechanisms may contribute as well. Nonpregnant6,7 patients with long-standing insulin-dependent diabetes mellitus lose the ability to secrete glucagon in response to hypoglycemia. I ', 14 Although adrenomedullary and other counterregulatory responses are sufficient to compensate for the loss of glucagon in many patients, recent studies in nonpregnant subjects with insulin-dependent diabetes mellitus 6,7 suggest that intensive insulin therapy itself may adversely effect the magnitude and timing of the release of other counterregulatory hormones (e.g., epinephrine. growth hormone, and cortisol). Such acquired deficits in counterregulation might be an additional factor contributing to the frequent occurrence of severe hypoglycemia during diabetic pregnancies where vigorous attempts at restoring normoglycemia have been commonplace. In this study we evaluated pregnant patients with insulin-dependent diabetes mellitus receiving intensive insulin therapy and experiencing frequent hypoglycemic episodes and demonstrated deficient secretion of glucagon and retarded and reduced release of epinephrine and growth hormone in response to a standardized hypoglycemic stimulus compared with nonpregnant, nondiabetic women. Furthermore, there was no increase in secretion of hPL during hypoglycemia in our patients. It is noteworthy that hPL levels have been shown to rise in nondiabetic pregnant subjects during hypoglycemia in some I 5 , 16 but not all reports. 17 Thus deficient hPL response to hypoglycemia in insulin-dependent diabetics may reflect an additional impairment attributable to diabetes or its control, adefect that represents a derangement in the fetal-placental unit rather than being solely of maternal origin. The mechanism underlying the impaired response to hypoglycemia in pregnant women with insulin-dependent diabetes mellitus is unclear. The defect might be a result of pregnancy, the diabetic state, or the institution of strict metabolic control. An effect of preg-

J anuary 1992 Am J Obstet Gyneco1

nancy per se cannot be excluded because of our inability to perform hypoglycemic clamp studies in nondiabetic pregnancies for ethical reasons. Of the counterregulatory hormones examined, prior reports using insulin tolerance testing suggest that the growth hormone response to hypoglycemia in pregnancy may be impaired. 1 ~·20 Additionally, as already described , long-standing diabetes is associated with loss of the ability to secrete glucagon in response to hypoglycemia, and in some cases a reduction in the magnitude of epinephrine responses as well. 13, 14 With regard to glycemic control, institution of intensive insulin therapy is associated with impairment in counterregulatory hormone response in individuals with insulin-dependent diabetes mellitus,6, 7 aneffect associated with a reduction in the plasma glucose threshold for initiating counterregulatory responses. If we compare the epinephrine and growth hormone rise in pregnant women with insulin-dependent diabetes mellitus reported here with intensively managed nonpregnant patients with insulin-dependent diabetes mellitus reported previously," a trend to greater impairment in counterregulatory hormone secretion is seen during pregnancy (Table IV). It is noteworthy that these pregnant women with insulin-dependent diabetes mellitus had lower glycosylated hemoglobin levels than in the nonpregnant subjects in the previous report, perhaps indicating better metabolic control. Alternatively, the lower glycosylated hemoglobin may be due to younger red blood cell age. As assessed by electronic FHR monitoring, the fetuses tolerated hypoglycemia without significant changes in FHR. These findings allow some degree of reassurance for the pregnant diabetic experiencing hypoglycemic episodes, particularly in view of the clinical report of persistent severe fetal bradycardia attributed to a similar degree of maternal hypoglycemia in two patients. 21 However, the rise in maternal epinephrine levels associated with hypoglycemia (and perhaps fetal elevations of epineprhine in association with fetal hypoglycemia) did not elicit a rise in the basal FHR. It is possible insufficient amounts of maternal epinephrine crossed the placenta, that the fetus (at the estimated gestational age studied) does not respond to hypoglycemia by increasing catecholamine secretion, or that the fetus is not able to respond to epinephrine by acceleration of the FHR. More in-depth assessment of fetal well-being is required before definitive conclusions can be drawn about the impact of hypoglycemia on the fetus. In summary, while the relative contributions of intensive insulin therapy, diabetes mellitus, and pregnancy per se is not fully delineated, this report clearly demonstrates that counterregulatory hormone response to hypoglycemia is impaired in pregnant insu-

Volume 166 Number I, Part I

lin-dependent diabetic women. Thus intensive metabolic regulation of such subjects is associated with frequent hypoglycemic episodes, not only because of the effect of insulin per se but also because of derangement of compensatory hormonal secretion. Importantly, the fetus tolerated this temporary hypoglycemic challenge without alteration of the FHR. REFERENCES l. Diamond MP, Salyer SL, Vaughn WK, Cotton R, Boehm FH. Reassessment of White's classification and Pedersen's prognostically bad signs of diabetic pregnancies in insulindependent diabetic pregnancies. AM ] OBSTET GYNECOL 1987; 156:599-604. 2. Gabbe SG, Mestman]H, Freeman RK, et al. Management and outcome of pregnancy in diabetes mellitus, classes B to R. AM] OBSTET GYNECOL 1977;129:723-32. 3. Soler NG, Soler SM, Malins ]M. Neonatal morbidity among infants of diabetic mothers. Diabetes Care 1978; 1:340-50. 4. Coustan DR, Reece EA, Sherwin RS, et al. A randomized clinical trial of the insulin pump vs intensive conventional therapy in diabetic pregnancies. ]AMA 1986;255:631-6. 5. DCCT Research Group. Diabetes control and complications trial (DCCT). Results of feasibility study. Diabetes Care 1987;10:1-19. 6. Amiel SA, Sherwin RS, Simonson DC, Tamborlane wv. Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 1988;37:901-7. 7. Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin RS. Intensive insulin therapy reduces counterregulatory hormone responses to hypoglycemia in patients with type I diabetes. Ann Intern Med 1985;103:184-90. 8. Abumrad NN, Rabin D, Diamond MP, Lacy WW. Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man. Metabolism 1981;30:936-40.

Response to hypoglycemia during pregnancy

77

9. Clutter WE, Bier DM, Shah SD, Cryer PE. Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. ] Clin Invest 1980;66:94-1Ol. 10. Cryer PE. DIagnostic endocrinology. ed 2. New York: Oxford University Press, 1979. 11. Fuhrmann K, Reiher H. Semmler K, et al. Prevention of congenital malformations in infants of insulin-dependent diabetic mothers. Diabetes Care 1983;6:219-23. 12. Mills ]L, Knopp RH, Simpson ]L, et al. Lack of relation of increased malformation rates in infants of diabetic mothers to glucose control during organogenesis. N Engl ] Med 1988;318:671-6. 13. Gerich ]E, Langloisd M, Noacco C, Karam ]H, Forsham PH. Lack of a glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha-cell defect. Science 1973;182:171-3. 14. Bolli G, DeFeo P, Compagnucci P, et al. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Diabetes 1983;32:134. 15. Spellacy WN, Buhi WC, Birk SA. Human growth hormone and placental lactogen levels in mid pregnancy and late postpartum. Obstet Gynecol 1970;36:238-43. 16. Spellacy WN, Buhi WC, Schram ]D, Birk SA, McCreary SA. Control of human chorionic somatomammotropin levels during pregnancy. Obstet Gynecol 1971;37 :567 -73. 17. Samaan N, Yen SSC, Friesen H, Pearson OH. Serum placental lactogen levels during pregnancy and in trophoblastic disease.] Clin Endocnnol 1966;26:1303. 18. Yen SSC, Samaan N, Pearson OH. Growth hormone levels in pregnancy.] Clin Endocrinol 1967;27:1341-7. 19. Mintz DH, Stock R, Finster ]L, Taylor AL. The effect of normal and diabetic pregnancies on growth hormone responses to hypoglycemia. Metabolism 1968;17:54-6l. 20. Spellacy WN, Buhi WC. Pituitary growth hormone and placental lactogen levels measured in normal term pregnancy and at the early and late postpartum periods. AM ] OBSTET GYNECOL 1969;105:888-96. 2l. Langer 0, Cohen WR. Persistent fetal bradycardia during maternal hypoglycemia. AM ] OBSTET GYNIcCOL 1984; 149:688-90.