CURRENT DEVELOPMENTS

Gestational and pregestational diabetes: An approach to therapy JOHN R.

E. ALAN

Baltimore,

TYSON, HOCK,

M.D B.S.

MaTland

The objective of management in the pregnant diabetic patient ti to achieve physiologic glucose homeostasis through the use of diet and insulin. As outlined, the numerous ancillary tests developed during the past 15 years to assist the clinician in determining impending fetal death have left much to be desired, especially where metabolic homeostasis has not been achieved prior to the thirty-sixth week of gestation. The statistics from this institutiorz indicate that the maintenance of the plasma glucose concentration belou 100 mg. per cent throughout gestation, regardless of the severity of the diabetes, all but removes the risk of maternal-fetal complications due to diabetes. The management is uniform for all patients exhibiting an abnormality of carbohydrate metabolism, and, although it is rather dajjjcult to accept, there have been minimal neonatal complications when the protocol outlined in this presentation has been followed.

DIABETES IN pregnancy would appear ubiquitous since pregnancy itself is acknowledged to be diabetogenic.‘-” Thus, the diagnosis and treatment of truly abnormal gestational carbohydrate metabolism are difficult. The clinician, whether obstetrician or internist, must display a substantial understanding of the physiology of normal gestation as it pertains to metabolism in order to provide effective therapy. This communication presents an overview of recent scientific observations regarding the physiology of gestational metabolism and its application to the management of diabetes in pregnancy. Our system of management has successfully reduced the perinatal mortality rate for the combined classes of diabetes in

From the Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine. Presented in part at the Jubilee Congress Association of South Africa, July, 1975.

pregnancy cent.*

at The Johns Hopkins

Hospital

to 2.3 per

Preamble Traditionally, the successful management of the gestational diabetic patient has been equated with the delivery of a live infant who survives until at least the sixth postpartum week. We are concerned that this may be an inappropriate end point for assessing the efficacy of prenatal management since we support Churchill and associates4 who contended that persistent maternal metabolic derangement, measured as ketonuria and hyperglycemia, may be detrimental to the subsequent cerebral development of the child. In more recent studies, Yssing confirmed this impression by observing a positive correlation between subnormal estriol levels in pregnant diabetic patients and subsequent evidence of cerebral damage during a 10 year follow-up. Fifty-

The

of the Medical

Reprint requests: Dr. John E. Tyson, Associate Professor, Department of Gynecology and Obstetrics, The Johns Hopkins Hospital, Baltimore, MaTland 21205.

*Based upon a five-year 1974, of 315 patients.

1009

study,

July

1, 1969

to June

30,

1010

Tyson

Table

I. Classification Joslin

White ClU.SS A B C D E F R

one

per

pregnancies

and Hock

Clinic

of pregnant

diabetic

patients

Rigshospitald Owet

Duration

Pregnancy Over 19 yr. of age IO-19 yr. of age Under 10 yr. of age Under 10 yr. of age Under 10 yr. of age Under 10 yr. of age

Gestation Less than 10 yr. 10-19 yr.

cent

More More

low

than than

20 yr. More 20 More ?O

24 hour

than yr. than vr.

of

(Copenhagen): in pregnancy

progno~hcally (PBSP)

bad signs

Clinical pyrlonephdis: urinary tract infection with an acute elevation of temperature exceeding 39” C., confirmed by culture of the urine Precoma: diabetic acidosis with a venous standard bicarbonate below 10 mEq./L. Srr~re acidosis: venous standard bicarbonate lo-17 mEq./L. SCIVIP toxemia: two of the following three signs present: (1) blood pressure > 150/100 for at least five days before delivery, (2) more than 0.1% albuminuria for at least 24 hr. before delivery, (3) severe edema or a weight gain > 20 Kg. Mild toxemia: two of the following signs present: (1) blood pressure 140/90 for at least three days before delivery, (2) more than 0.05% albuminuria for at least 24 hr. before delivery, (3) moderate edema or weight gain > 15 Kg. Neglect: Failure to follow the recommended regimen, irrespective of the cause, e.g., “psychopathy,” low intelligence, first attendance late in pregnancy (at delivery), poor social circumstances. and lack of proper information

20 yr.

of the progeny with

---

(Boston)

complicated

urinary

estriol

diabetic determi-

nations had considerable cerebral impairment compared to only 22.4 per cent for the group with normal estriol levels (p < 0.01). The disorders ranged from cerebral palsy to severe behavioral problems. We believe that as physicians we must recognize the significance of the maternal plasma glucose concentration in diabetic pregnancy and initiate programs of’ care designed to restore physiologic glucose homeostasis in the pregnant diabetic patient. Such management virtually eliminates fetal macrosomia and neonatal hypoglycemia, both of which contribute to an increased perinatal mortality rate.

The disbetogenic effect of pregnancy In normal gestation, the diabetogenic effect of pregnancy is associated with an alteration in the peripheral utilization of glucose’ and hyperlipidemia,6 both of which appear secondary to increasing insulin resistance.3* ’ Such resistance is brought about by contrainsulin factors including estrogen,‘, ’ human growth hormone (HGH),“, IL placental lactogen (HPL),=s I3 and two distinct insulin-degrading enzyme systems in the placenta. l4 That the metabolism ot maternal insulin is enhanced by a degradative system was proposed by Freinkel and Goodner’” as early as 1960. In the intervening years, this sytem has been shown to be maternal in origin in that it resides on the

,]ohlw Hopkin.\

(Baltwww)

I. &stationai ctirsbutr.~ A. Dietary control B. Exogenous insulin and dietary control II. Pregestatiod &b&r A. Without related complications B. With related corncations 1. Renovasc.ular 2. Retinal

maternal side of the placenta. Gitlin and &leagues showed that insulin fails to cross the placenta in tither direction.16 Thus, the degradation is unilateral. It is most attractive to propose that the development of gestational diabetes is predicated solely on the pancreatic beta cell inability to maintain suitable insulin secretion in order to support g-r~tationn(glucose homeostasis.3 Such a hypothesis must also acknowledge the many predisposing factors known to influence insulin secretion,17, lx not the least of which is maternal agei and obesity. *’ However, it should be noted thaL appropriate insulin therapy in the pregnant diabetic patient has a favorable effect on pregnancy outcome.‘“, ” It should be emphasized that those investigators reporting a favorable lowering of perinatal mortality rates in diabetic pregnancy of 3.8” and 4.7 per cent”” have guarded closely glucose homeostatic mechanisms by strict dietary and insulin management.

The classification of

8 in ~rwmcy

The two most generally accepted classifications of diabetes in pregnancy are those of White23 and Pedersen and colleagues, “3 ” shown in Table-l. Each is of a predictive value based upon the accumulation of a~ vast amount of retrospective data. Unfortunately, dif.ferences in treatment regimens between the two centers have produced somewhat disparate results in terms of over-all perinatal deaths.* By the White classification. Class A diaberrs repre-

Volume Number

Gestational

125 7

sents an abnormality of carbohydrate metabolism appearing during pregnancy and “is treatable” with diet alone. The need for insulin administration in such patients changes the classification immediately. Classes C through F display diverse symptomatology. All such complications adversely influence fetal outcome presumably due to the lack of pregestational diabetic control. The Pedersen classification evaluates the outcome of diabetic pregnancy under the heading PBSP (prognostically bad signs in pregnancy).‘* Included are those events expected to adversely influence fetal outcome. Through the application of basic physiologic principles, a more simplified classification has been devised where gestational diabetes is defined as a state of abnormal maternal carbohydrate metabolism beginning at aq stage of gestation and totally absent by the sixth postpartum week. Gestational diabetes may be controlled by diet or, in the presence of two consecutive basal fasting plasma glucose concentrations in excess of 100 mg. per 100 ml., the addition of exogenous insulin therapy. The term “pregestational diabetes” defines a state of altered carbohydrate metabolism which always antedates the pregnancy. In such cases, the physician must assume the role of surrogate pancreas, providing exogenous insulin according to the patient’s metabolic needs as determined by basal and two-hour postprandial glucose concentrations. The route of delivery under optimal conditions is vaginal: however, the detection of fetal macrosomia increases the likelihood of cesarean section. Cesarean section in such cases has reduced the number of birth canal-related trauma which normally increases the rate of infant morbidity and death 25-28

Physiology of gestational metabolism Physiologic alterations in pregnancy metabolism include fasting hypoglycemia and hypoinsulinemia, enhanced ketogenesis,” and increased amino acid turnover.‘“. 3o Traditionally, such alterations have been ascribed to the decreased peripheral utilization of glucose com.pensated for by increased glucose transfer to the developing fetoplacental unit3i Fasting nonketotic hypoglycemia can be found throughout normal gestation and the immediate puerperium.32 Fig. 1 demonstrates such basal hypoglycemia and depicts the further decline in the basal plasma glucose concentration as pregnancy progresses. Measurement of the basal plasma glucose concentration prior to breakfast appears to be the single most important factor in terms of identifying alterations in carbohydrate metabolism. Further discussion on this will follow. Normal basal plasma glucose concentrations lie

and pregestational

diabetes

1011

1_ u 56

IRST HALF kCONTROL--t---GESTATION,+

Fig. I. between

32

19

SECOND HALF

46

I5

: 72 96 HOURS POSTPARTUM-

Fasting plasma glucose concentrations obtained 7:00 and 8:00 A.M. in healthy, normal pregnant and

nonpregnant women. Numbers within the bars represent the total number of patients sampled. A minimum of two basal samples derived

were from

obtained these.

from

each

patient

and

a mean

was

between 65 and 75 mg. per 100 ml. throughout pregnancy and are somewhat lower (55 to 70 mg. per 100 ml.) in the immediate puerperium.32S 33 When the glucose/insulin ratio of Perley and Kipni? was applied to our data, a positive rank correlation between the glucose/insulin values in nonpregnant and pregnant women in the first half of gestation was observed (p < O.OOl), indicating the basal plasma insulin concentration is directly proportional to the basal glucose concentration. Between the twenty-fourth and twenty-eighth weeks of gestation, placental contrainsulin factors increasingly modify carbohydrate metabolism. This is interpreted as a net antagonism to the action of circulating insulin. The pancreatic response is one of augmented insulin secretion. For reasons established by screening criteria,“, 3’ pancreatic reserve may be diminished or exhausted, leading to abnormal carbohydrate metabolism (gestational diabetes), the net result of ir~~Gquatr insulin secretion. The etiology of maternal hypoglycemia during the first half of gestation remains at least partially obscure but may be related to maternal glucose accretion and storage as fat in addition to increased utilization of glucose by the fetoplacental unit.3’ Table II presents the approximate maternal weight increment distribution attributed to pregnancy-related body compartments calculated for isocaloric diets. In the first three months of gestation, the estimated maternal metabolic contribution to fetoplacental growth is minute, yet maternal hypoglycemia and hypoinsulinemia is observed. A possible explanation for this would be the enhancement of maternal glucose utilization by es-

1012

Tyson and Hock

40-

1 Ar9imtw

Estrogen

1

tion

may

actually

through

hypothalamus,“~ rate

placental

gestation,

Fig. 2. Plasma HGH

responses to the intravenous administration of crystalline insulin (0.1 U. per kilogram of body weight) or the infusion of 30 Gm. of arginine monochloride over a 30 minute interval. Note the significant correlation between HGH responses to both stimuli and the significant difference between control and postpartum patients. X-X, Control insulin; O---O, control after arginine; A-----A, arginine; A---A, insulin. (Previously published in AM. J. OBSTET. GYNFXOL. 103: 313, 1969.) gain

in

gain (Kg.) each trimester

First

Total

gain accounted

*From

Pitkin,

at end of

1.0

3.4 0.6 1.0 (5.0) 1.0 0.5 1.5 1.5 (4.5)

0.3 0.4 (1.7) 0.8 0.3 1.3 0.0 (2.4)

0.3 0.1 0.3 0.0 (0.7)

36 and

the

0.7

4.1 Gynecol.

progesterone.’

When

are

with

compared

50

per

of

gestation

cent

changes, volume

of

the

augmentation

40: 773,

of insulin’s

the statistics those total

of for

of Hytten

Pitkin

weight

is accounted

and

gain by

including an increase and increases in maternal

A definite reported may during

be

sex difference

exists

to

glucose

loading

and

in

Leitch

in

the

first

the plasma breast and

half

by

Merimee

and

mediated

via

in the

plasma

fasting

is observed

as pituitary

HGH

Fineberg.

This

and it Estrogen

is

Routine

has

of pituitary HGH for this difference’”

and

have

utilized

Gm.

load

somatomedin

(sulfation

the

sensitivit! of pregcsta-

the

next

four

to six

glucose

associates”

oral

glucose

tolerance

such

glucose,

observed

insulin

response

such

distinguishing

not

accurate

accuracy

tests various

has emphasized ingestion are

that related

an overnight

fast:

(2)

secretion

as glucagon

gestation,

and

increasingly

the insulin to: (1) the the

insulili

to the to measure along with

importam

diabetes.“’ responses insulin level

insulin

increment

(orrelate

in

Williams5”

to

glucose following

withiu

glucose ingestion; hours after glucose lcvrls

gastrin

chaltetrge.“’

beerr possible concentrations of

gastric

glucose.“‘, “’ plasma glucose

glucose

forms

to the

b)

proportional

first few minutes following the insulin ievel two to three normal

information

to a given

are

test. glucose

is related

is directly

always insulin

results

oral

are released in response to oral ultimate peripheral maternal

While it has immunoreactive

In

of the

insulin

factors

consistent

in terms

more Such

additional

with

50

hours.5”

two

proved

ot Lests

an oral

ad

three-hour

test has provided

use

Ofal

rests thr

integrity.

”

including

have

of such

the

loads.‘“at one

three-hour

of

carbohydrate with

of regimens

however,

pancreatic

which The

abnormal

sampling

value

provocation and

oral

blood

and

accuracy

glucose

factor).‘”

the from

returns.

accomplished

a variely with

O’Sullivan

plasma

is thought and may

by the HPL.. insulin

insulin

over

for

been

intravenous”-‘”

concentration

difference

lessened

restoration

secretion

screening

metabolism

blood uterine

more marked antagonism to

the-

Plasma glucose measurements in the identification of gestational diabetes

related

as recently

in

L’. Since

Vnforturiatelv. HPI. is absent

since

of

hvpoglycemia in HGH Fig.

and

metabolism

tolerance

co-workers,“’

half Likewise,

is not

A gradual

weeks

19’72. by

in

hypoglycemia

tional

Traditionally,

action

gestationally

and

estrogen-related,3Y prolonged fasting.40

the hyperglycemic effect to be partially responsible be

gestation.‘” clear-cut

markedly.

9.5

weight.3R response

cross-reactivity second

attenuated.

shown

in

an increase

placental factors. specifically and continue to antagoni/.c

maternal

on pancreatic trogen”,

of

the

of pregnancy

HGH. HGH

of a subsequent

R. M., et al.: Obstet.

basis is

increased

Such

maternal plasma within the first six postpartum hours, while HGH secretion remains attenuated. During this

Third

Second

Negligible Negligible Negligible

for

is ”

In

as

during is not

hyporhesis

increase

pregnancy*

Fetus Placenta Amniotic fluid (fetal subtotal) Increased uterine size Increased breast size Increased blood volume Increased extracellular fluid (maternal subtotal)

the

secretion

effect

secrelion

and

an i&cased

gestation

stimirli.““~

women,

diabetogenic

time, of weight

Cumulative

earlv on

HGH

absence of mav replace

secrr-

pitut.iarv

encourage

lactogen.‘”

postpartum

components

HGH

the

amino acid infusion and insulin-induced fail to provoke significant increments

MINUTES

II. Average

in

be rationalized

with

Table

it may

to provocative

cannot

on

disappearancr.“”

secretion

response

enhanced

action

sy yet

of glucose HGH

provoke

a direct

the

and (3) intake. with

the

Volume Number

Gestational and pregestational diabetes

125 7

1013

125 100 75 50 25

second

0 150

c

half gestation

(n=20)

0

0

2

I

0

3

HOURS

-E g 125 T-

4. Plasma glucose concentrations in 84 women with gestational diabetes after the oral ingestion of 100 Cm. of glucose. These values are compared to the mean glucose concentrations observed in 50 normal pregnant women who underwent an oral glucose tolerance test between the twentieth and twenty-fourth weeks of gestation, The shaded area represents the difference between the norma values and the upper limits of normal commonly used to define the range of normal glucose tolerance.”

Fig.

p 100 I 8 73

75

d

50

$ ::

25

first

0 I50

,

half

gestation

(n=21)

2

125 100 75 50 25 0

control

0

(n=lO)

60

120

180

MINUTES 3. Plasma glucose concentrations in healthy women following the ingestion of 100 Cm. of glucose. The shaded areas represent two standard deviations from the mean.

Fig.

basal plasma glucose concentration and are lower in earlier gestation than at term.“’ The maintenance of normal glucose tolerance during gestation occurs at the expense of exaggerated insulin secretion. Yen and colleague? have suggested that the retardation of glucose deposition in pregnancy is associated with an increased glucose pool as well as a defect in the timing, quantity, and quality of the insulin response to intravenous glucose. These physiologic observations incriminate the effect of contrainsulin

factors (see below). Since the maintenance of gestational euglycemia occurs at the expense of altered insulin secretion, the physician must develop strict standards for evaluating carbohydrate metabolism in pregnancy as well as new objectives for management. Plasma glucose concentrations following the ingestion of 100 Gm. of oral glucose are shown for normal women in the first and second halves of gestation (Fig. 3). The mean glucose concentration in the first half of gestation at one hour was 103.1 2 5.2 mg. per 100 ml. compared to a one-hour plasma glucose concentration of 128.3 + 4.4 mg. per 100 ml. in the second half of gestation. These values compare favorably with those of studies reported by others’? and are consistent with findings in our prepregnant control subjects. The standard error of the mean of such values was unusually small. Nevertheless, each point was calculated to include two standard deviations from the mean to establish 95 per cent confidence limits for the testing procedure. ” As an indication of the abnormality in carbohydrate metabolism observed in women in our clinic, Fig. 4 presents the mean curve for abnormal glucose tolerance in 84 women with gestational diabetes. Mean maternal weight was 165 & 13 pounds or ~20 per cent of ideal body weight.* While the abnormality was grossly apparent in these women, care should be taken to evaluate the glucose curve obtained *Metropolitan

Life Tables, 1959.

1014

Tyson

and t-lock

in 50 normal healthy pregnant women between the twentieth and twenty-fourth weeks of gestation. The single middle line demarcates what traditionally has been the upper limit of normal for glucose testing.17 Since the physiologic response to oral glucose is much lower, women with such abnormalities may escape detection on testing but are usually identified post partum, having been delivered of infants weighing >4,000 gram.G2-6” In our clinic, 9 per cent of’all women screened for diabetes on the basis of existing criteria have negative glucose tolerance tests yet deliver infants weighing >4.000 grams.” Since the maximal diabetogenic effect of pregnancy is observed beyond the twenty-fourth week of gestation. it has been customary to retest all women with prior negative glucose tolerance tests between the twenty-eighth and thirty-second weeks of gestation. Eighty per cent of such repeat tests are positive.

Diabetic management based upon the plasma glucose concentration Our screening criteria of the potential gestational diabetic patient have been reported elsewhere.31 The three-hour oral glucose tolerance test is used as a matter of preferance, although the 50 Gm. test is both practical and accurate.‘7* .i2 Tests are performed on all women fulfilling two or more of the criteria at the time of registration for prenatal care. Routine screening of all pregnant women has been suggested but is currently impractical in our clinic due to staff limitations. The identification of an abnormal glucose tolerance test is followed by the use of the g/ucosc~finrwl or profile which consists of regular blood sampling every two hours over a 14 hour period in order to evaluate not only the &~tw of’ abnormality but also the timing of the abnormal glucose values. Diurnal fluctuations are also recorded. Interpretation of the results is made with allowance for the normal diurnal fluctuation in the plasma glucose concentration.““’ ” The patient’s diet, activity. and/or insulin requirement are now adjusted separately according to the glucose panel. Subsequent profiles are obtained at appropriate intervals to confirm the degree of control. To avoid the need for persistent blood letting, an alternate method of plasma glucose testing has been sought. It is our belief that, to be managed correctly. pregnant diabetic patients must have determination of basal glucose levels. This was accomplished through the use of glucose oxidase-impregnated paper sticks* where capillary blood glucose concentrations were *Dextrostix, Mch’aughton

Ames Cu., Ave., Elkhart.

Inc., Div. Miles Indiana 46514.

Labs.,

Inc..

819

obtained each morning. Women were instructed LCJ obtain blood from the lateral aspect 01 .I ter-rninal digital phalanx with a sharp stylet. Samples ~WI-C obtained each morning prior to breakfast or insulin administration. The calorimetric reading thought to be most sensitive to the naked eye lies between 45 and 90 mg. per 100 ml. or well within the range consitlercd 10 represent “adequat.e chemical contwl.” -I’\\ elw ~~~~11~~ have successfullv complctctl pregnancies whew Aik glucose values were obtained hy this mcthc~rl. 1%;. economy associated with the determination 01’ 111~ blood glucose concenwation b\ this method apprars to justify its use. In each insrance, an infant lvhc)se ~eighr was within the range of infants born to normal rncbthcl-s at the comparable stage of gestation was deliwretl. The accuracy of Dextrostix has t)ern studied h? Spellacy and co-workers” utilizing a reflcctancr nwte~~. The addition of t.his instrument greatly cwhawes the accuracy of our results. Due to subtle color r-hangcs between varying concentrations of‘ blood glut occ. the glucose oxiclase-impregnawi stick is 01 little V;&N dl the extremes of blood sugar determination. tl~t is, helow 25 mg. per 100 ml. and above 175 mg. pu- 100 ml. Since the objective of ou1- Inanagcnlent was to maintaiu

the

blood

glucose

concentration

and 90 mg. per 100 ml., the ef‘ficicnc~ was adequate.

twtwren

-I3

trl the nwthod

Daily caloric management Marked differences in dietary intake rxist between women of various socioeconomic classes. ‘l‘he normal clinic population at Johns Hopkins is 20 per cent OVCI ideal body weight due to a dietary intake rich ill carbohydrate. Women of a higher Focioeconomic class. on the other hand. are usually 250 >250 1250 175 130 90 45-90 90 90 45 45

375 342 333 295 265 183 138 98 79 64 86 42 58

insulin requirement during the first 24 hours is usually less than 30 C. Blood glucose is measured every 30 minutes during the first hour post partum and hourly thereafter for up to 12 hours. Since the rapid loss of HPL from the plasma is accompanied by increasing insulin sensitivcan be anticipated between 5 and 7 'ty, 31 hypoglycemia hours post partum. Thus, close observation of the patient by recovery room nursing personnel will avoid any catastrophe associated with a sudden fall in the plasma glucose concentration. When blood is drawn for laboratory analysis, a glucose oxidase-impregnated stick is used to estimate the blood glucose immediately at the bedside. Table III shows the remarkable accuracy of the “stick” method compared to AutoAnalyzer values. Hypoglycemia is simply managed by temporarily discontinuing the insulin infusion and advancing the glucose infusion. The administration of highly concentrated glucose solutions is not necessary. Hyperglycemia is controlled by increasing the insulin infusion and monitoring the blood glucose concentration more frequently in the opposite arm. In our experience, the blood glucose concentration stabilizes in the first 12 to 18 postpartum hours, a time when oral liquid feeding may be instituted. Within 24 hours of delivery, one may resume the administration of the daily insulin requirement by subcutaneous injection. At this time, however, the daily insulin requirement should be reduced to an amount equal to 60 per cent of the prepregnant dose. insulin management in the later puerperium The release of HGH in response to insulin-induced hypoglycemia is a physiologic attempt to maintain

maternal

glucose

homeostasis

through ~‘1lll;inwc.i diabetic patient, Illi, phenomenon is absent due to HGH suppression at~tl must he considered when providing for adequate puerperal diet and insulin therapy. During the first four to six postpartum weeks, HGH srcrrtiolr Kradually returns. and with it there is a gradual increasr it1 the daily insulin requirement.

lipolysis.““. 12i In the parturient

Nursing

in the puerperal

diabetic

patient

n’ursing may be beneficial to the postpartum diabetic patient. Unfortunately, scientific data are lacking to support this observation in terms of the metabolic, energv/ cost relationship between mother and child. Maternal caloric- expenditure for marnmar\; milk production ih between 600 and 900 calories per day. of which 2.50 calories may he taken from maternal stores. Milk production occurs de nova from substrates obtailletl from the maternal vasculature sequestered by tlte breast and synthesized into specific nutrition;d ccnnpc)nents. As far back as 1935. wide flu