Diabetes in pregnancy

CURRENT OPINION Pertinent comments

Diabetes in pregnancy With special

reference

RICHARD

C.

THOMAS

W.

to prediabetes

BORONOW, McELIN,

and chemical

diabetes

M.D.* M.D.,

M.S.

Eoanston, Illinois

D I A B E T E s mellitus in pregnancy has long been recognized as an obstetrical complication of great importance. A prodigious amount of literature has accumulated regarding this subject and, in recent years, certain basic principles of attitude and management have evolved which have virtually eliminated maternal deaths and offer prospects of improved fetal survival. However, fetal wastage is still high and an unceasing effort to reduce this loss is mandatory. One group of patients in which improved fetal salvage might be obtained is the gravidas with mild metabolic defects-more difficult to detect, easier to control, but nonetheless potentially lethal. Early detection of mild aberrations in carbohydrate metabolism and enlightened management could become critical. Allen1 in 1939, reported that among all infants born to a group of known dia-

betics prior to the diagnosis of diabetes, there was a 15.3 per cent incidence of stillbirth (in contrast to an expected rate of about 14 per 1,000 births”* ‘+ 55). In 1944, Miller, Hurwitz, and KudeP* focused attention on “prediabetes” as an entity of clinical significance in terms of fetal survival. Subsequently, others have reviewed the weights and perinatal mortality of babies born to mothers in the years prior to the onset of frank clinical diabetes mellitus and have confirmed the reality of the hazards to the fetus in these years, Jackson and co-workers?‘, ” have studied the morbid anatomy of these infants and have described pathologic changes which they feel to be characteristic. Recently,22 he has re-emphasized his earlier observations that the pathologic findings in infants of diabetic and “prediabetic” mothers are the same. Case

From the Department of Obstetrics and GynecoEogy, Northwestern University Medical School, Ckicayo, Illinois, and The Evanston Hospital Association.

reports

Illustrative of these instances of subclinical diabetes are the following 3 cases recently discovered within a brief period of time. The blood sugar determinations were made by the Somogyi-Nelson technique and indicate true glucose values.

Presented before the Chicago Gynecological Society, Nov. 15, 1963. *Present address: M. D. Anderson Hospital, Houston, Texas.

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Volume Number

91 I

Case 1. A 234 pound, 18-year-old gravida ii, para i, Negro woman completed spontaneous labor in the thirty-seventh week of gestation and was delivered by low forceps of an 11 pound, 15 ounce male. This pregnancy was complicated by excessive weight gain and minimal edema. There was no hypertension, albuminuria, or glycosuria. Past history indicated the prior birth of an 8 pound, 4 ounce male infant at term. There was no family history of diabetes. On the third postpartum day, the fasting blood sugar determination was 80 mg. per cent. A standard oral glucose tolerance test was performed, and the results were as follows: 1 hour, 210 mg. per cent; 2 hours, 208 mg. per cent; and 3 hours, 149 mg. per cent. We used the following commonly accepted limiting values; fasting, 110 mg. per cent; 1 hour, 170 mg. per cent; 2 hour, 120 mg. per cent; 3 hour, 110 mg. per cent (true glucose). To be regarded as diabetes, 3 consecutive values must be abnorma13a Case 2. This 35-year-old gravida v, para ii, Negro woman had first trimester abortions in 1947 and 1959. There were term pregnancies in 1947 and 1948, and the weights of the babies were 10 pounds, 7 ounces, and 9 pounds, 7 ounces, respectively. There was no glycosuria or toxemia. Because of the prior delivery of large babies and the knowledge that a sister had diabetes, a fasting blood sugar determination was performed early in the last trimester, and a level of 83 mg. per cent was obtained. The glucose tolerance test revealed the following blood sugar values: 1 hour, 190 mg. per cent; 2 hour, 166 mg. per cent; and 3 hour, 149 mg. per cent. Labor was induced one week prior to term. A 9 pound, 14 ounce male was delivered by midforceps after forceps rotation from the occipitotransverse position. Case 3. A 26-year-old gravida vi, para v, was admitted 12 days prior to term for elective repeat cesarean section. She weighed 140 pounds, the blood pressure was 124/70 mm. Hg, and the admission urinaIysis was negative. There was no family history of diabetes. Her obstetrical history included vaginal deliveries of 8 pound, 8 pound, 9 ounce, and 9 pound, 4 ounce infants in 1955, 1957, and 1958. In 1959, a 9 pound, 12 ounce infant in breech position was delivered abdominally after trial labor. With repeat cesarean section in 1960, 2 weeks prior to term, a 5 pound, 6 ounce infant was delivered. All five babies survived. An uneventful repeat cesarean section was performed during this hospitalization and an 8 pound. 6 ounce infant was delivered.

Diabetes

in

pregnancy

1023

The baby, observed to be slightly edematous, became tachypneic several hours after delivery and died of clinical “respiratory distress syndrome” on the third day of life. Autopsy revealed hyaline membrane disease. On the seventh postoperative day a glucose tolerance curve was performed, realizing, nonetheless, that it might be too late to reflect the true diabetogenic influence of pregnancy. A slightly elevated curve was obtained. The values were: fasting blood sugar, 76 mg. per cent; 1 hour, 191 mg. per cent; 2 hour, 120 mg. per cent; and 3 hour, 113 mg. per cent. These cases represented chemical (synonyms: glucose tolerance curve or subclinical) diabetes as opposed to frank clinical diabetes. How should one regard an abnormal glucose tolerance curve? What is the maternal and fetal significance of this finding? Are there varying degrees of severity of the “diabetic state”? The concepts of “frank diabetes,” “chem” “gestational diabetes,” “latent ical diabetes, “prediabetes,” diabetes,” and their various synonyms are beclouded by lack of semantic and variable overlapping clarity. Vague exists, The varying subdivisions within the total spectrum of the “diabetic state” have been considered chiefly in the literature of internal medicine and endocrinolog+ 9* ‘3 despite the very significant obstetrical implications. Obstetrical management of these cases provoked wide discussion among our staff, and counsel concerning management ranged from nihilism to insulin administration with early cesarean section. This “therapeutic” debate has encouraged us to: 1. Survey the variants of the diabetic state in pregnancy and to classify them. This classification is presented in Table I. 2. Evaluate the contemporary usage of the and the varying interpreterm “prediabetes” tations of its clinical significance. 3. Delineate a program for the diagnosis and management of subclinical diabetes. Frank

diabetes

II-Al

We must briefly survey the definition and management of frank diabetes mellitus in

1024

Boronow

and

Table I. Classification

April 1, 1965 .Am. J. Obst. & Gynrc.

McElin

of the variants

I. Diabetes A. Frank diabetes Synonyms Clinical diabetes Overt diabetes Both the fasting blood sugar and glucose tolerance curves are abnormally elevated B. Chemical diabetes Synonyms “Mild” diabetes Unsuspected diabetes Subclinical diabetes Class A diabetes40 Normal fasting blood sugar but abnormally elevated glucose tolerance curve C. Latent diabetes Synonyms Incipient diabetes definition Prediabetesea I8 (see correct below) Gestational diabetes6. w Other synonyms listed under chemical diabetes Normal fasting blood sugar but abnormally elevated glucose tolerance curve under the diabetogenic stimulus of pregnancy, steroid stimulation test, and other drugs ( thiazides3?) II. Prediabetes This is a period of time prior to the onset of diabetes (either frank diabetes, chemical diabetes or latent diabetes) when no detectable defect in carbohydrate metabolism is evident under any circumstances. It is an era, diagnosed in retrospect, after a metabolic error is detected. It is not, therefore, a clinical entity

pregnancy before we can evaluate its apparent precursor state. This discussion will serve as a departure point for comment. The frank diabetic (I-A, Table I) is commonly considered the “clinical diabetic.” This patient has both an elevated fasting blood sugar and an elevated glucose tolerance curve. The hyperglycemic glycosuria, the deficient glycogen synthesis, and the resultant symptoms all reflect a subnormal capacity for glucose utilization; that is, a basic chemical defect. In the patient with “frank” diabetes, therefore, the chemical defect is severe enough to be manifest clinically. On the contrary, with the “glucose tolerance curve” diabetic patients (I-B), this metabolic defect is not severe enough to cause clinical symptoms ; thus, the diabetic state is purely chemical.

At present, most authorities urge early delivery in almost all instances. Jones,‘” to the contrary, rejects the concept of early delivery, insisting that these babies need “all the maturity they can get,” and advises abdominal delivery only for breech presentation, poor diabetic control, pre-eclampsia, and hydramnios. Eastman and Hellman’” emphasize individualized management with more frequent use of delivery before the thirty-eighth week. Current thinking is best summarized in the review article by Gellis and Hsials (262 references). They concluded that maternal age, parity, insulin requirement, age of onset and duration of the diabetes, toxemia, hydramnios, and hormone imbalance were not related to fetal loss. Their analysis demonstrated

two

maternal

factors

to be of defi-

The first is severity of the disease, according to the Nelson-GillespieWhite classification4” which emphasizes longterm vascular effects. The second factor is diabetic control which is regarded by Gellis and Hsia as highly significant. They feel the type of anesthesia for delivery and the modality of delivery (spontaneous versus induced labor and vaginal versus abdominal delivery) are not of s$gnificance in fetal outcome. Their studies indicate that the respiratory distress syndrome is not influenced by the route of delivery, contention to the contrary notwithstanding. The time of delivery appears to be the most significant obstetrical factor. A gestational age of 35 to 36 weeks seems to be optimal. Recently, we tend to permit an additional week beyond this limit in uncomplicated cases where such an extension is considered clinically sound.l”t 2i nite

significance.

Chemical

diabetes

(I-B)

It has been mentioned that all the symptoms of the frank diabetic are manifestations of a pronounced aberration in carbohydrate metabolism. When this basic chemical defect is very slight, it may be without clinical manifestation. This condition is pure chemical diabetes (I-B, Table 11. It is diagnosed by biochemical means : the characteristic glucose tolerance curve.

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Diabetes

Colwel17 lists three criteria by which frank and chemical diabetes mellitus may be diagnosed and differentiated. These criteria, in order of their importance, are: ( 1) failure of the glucose tolerance curve to return to normal in three hours; (2) an elevated fasting blood sugar; and (3) the height of the peak blood sugar level. In frank diabetes, all levels of the curve are abnormal. In chemical diabetes, the glucose tolerance curve is abnormal but the patient is asymptomatic. Our criteria for glucose tolerance curve “normals” have been specified earlier. latent

diabetes

(1-C)

Latent diabetes or incipient diabetes (I-C, Table I) is also chemical diabetes, but qualified in that it is unmasked only by the stress of a “diabetogenic” stimulus. Burt3 is one of the many who emphasize that pregnancy is diabetogenic. He postulates two possible mechanisms : ( 1) decreases in peripheral utilization of carbohydrate, and (2) insulin antagonism. Recently, Freinkel and Goodner13 have presented a strong case for a different mechanism. Their “degradation theory” postulates breakdown of maternal insulin by the products of conception. Whatever the mechanism, the diabetogenesis of pregnancy is well recognized. In the sense of challenging pancreatic reserve, it is, perhaps, analogous to the steroid stimulation test. Prediabetes

(II)

Prediabetes, as it is called in many studies based on obstetrical histories, is not a clinical entity because it cannot be diagnosed. It is a retrospective diagnosis. As Futcher and LongI state, prediabetic patients are those “destined to become diabetic but manifesting no abnormality in carbohydrate metabolism at the time of the pregnancy in question.” Conn and Fajans agree.** s They call the prediabetic period the time from conception until one can demonstrate diminished insulin activity. They too emphasize that, at this time, there is no biochemical test that can identify a prediabetic individual with

in pregnancy

1025

Table II. Reported retrospective

Author

perinatal mortality studies of prediabetes

1 i$$ijj

Allen1 Miller*s Herzsteinll Barnes2 Gilbert16 MO,+’ Paton31 Patterson32 White40

Stiyb$hs

in

1 pez

15.3 5 5 5

35 15.4 35 15 16.7 21 32 30

5 5 5 10

Table III. retrospective

Reported studies

perinatal mortality in of chemical diabetes

Stillbirths (%) 14.6 14

Author Millers3 Jackson21 Dolgerll Pedowitzss

Neonatal deaths (%)

Perinatal

8.7

22.9

1OSS

f%)

14.9 20.5

certainty. Some41 lg, 21 have used the label, prediabetes, for that state with an abnormal glucose tolerance curve but with a normal fasting blood sugar during pregnancy. Some call these women gestational diabetics. Since “pre” means “before,” we should use prediabetes to mean “that period of time prior to the onset of diabetes” as above, and we reject the use of the term “prediabetes” for anything other than a retrospective analysis. Chemical or glucose tolerance curve diabetes (I-B) is diabetes. Gestational diabetes (I-C) or chemical diabetes of pregnancy (normal after pregnancy) must be regarded in the same light as a steroid stimulation test and interpreted as latent or incipient diabetes; that is, diabetes in its earliest phase. Obstetrical chemical and

significance diabetes,

of latent

diabetes,

prediabetes

Having outlined the semantics of these terms, we must then ask what is the clinical significance of each of these conditions to

1026

Boronow

and

McElin

the fetus. Tables II and III list previously reported perinatal mortality in these states, assembled into the categories of diabetes proposed herein, rather-in some casesthan the telms which were used in the original articles. It is clear that in chemical diabetes (I-B) the perinatal losses are significant. When chemical diabetes is diagnosed in pregnancy, one cannot tell if it is chemical (I-B) or latent (I-C) at that time. The significance to the fetus is the same at that time and whether the diabetic state is to be ultimately classified as chemical or latent may be determined only in the postpartum period. It is equally true, at face value in most retrospective studies, that perinatal losses are significant in the prediabetic period. In the Herzstein and Dolger” series, with a 15.4 per cent perinatal loss, the suggestion is made that the 5 year period of “prediabetes” might include some patients actually diabetic because of the inability to determine the exact date of onset. This, to us, seems a most significant reservation. Most data regarding the period before frank diabetes was discovered, and which suggest that this time period was hazardous to the fetus, were obtained by studying the obstetrical histories of frankIy diabetic women. It then follows that some of the perinatal losses during these “prediabetic” years may represent perinatal loss in women who, at that time, were chemically diabetic (I-B) ; more, perhaps. were latent diabetics (I-C) ; a few, perhaps, were frank, but undiagnosed, diabetics (I-A). Similarly, data have been recorded confirming the relationship of both the prediabetic period and abnormal carbohydrate metabolism to the large baby.‘“, ?I, x Thus, fetal environment is clearly affected in chemical diabetes. Whether or not this environment is deleterious to the fetus in the actual prediabetic period is more difficult to ascertain. One may decide between two basic alternatives: (1) That prediabetic patients do, indeed, have some metabolic defect and this defect is not yet marked enough to alter the glucose tolerance curve; but is detrimental to the

Aplil 1, 1965 Am. J. Obst. & Cynec.

fetal environment and does account for some perinatal loss, or (2) that the prediabetic period (as defined herein) has no lethal clinical significance for the fetus in utero. This hypothesis assumes that actual prediabetes is merely an era in the life history of a woman who ultimately becomes diabetic, before even the latent diabetic state can be unmasked by steroids or pregnancy. If the latter (alternative 2) is correct, the alleged clinical significance of true prediabetes may well, as Herzstein and Dolger suggest, have been misstated, falsely derived from the losses due to undiagnosed diabetes of all types: (I-A) mild, frank diabetes, (I-B) chemical diabetes, or (I-C) latent diabetes. O’Sullivan”” has established the chronological relationship of these conditions. By means of the life table technique, he has demonstrated the natural progression of the diabetic state, starting with gestational diabetes (latent diabetes-the earliest detectable state). After .5vz years, statistical interpolation suggests 67 per cent of these patients will have frank clinical diabetes. Certainly, the retrospective studies recorded in Tables II and III, notwithstanding their value in focusing attention on subtle alterations in carbohydrate metabolism, nonetheless, have not provided any clear data permitting a choice between the two proposed viewpoints. At our private hospital where, attended by specialists, an enlightened public makes early diagnosis the rule rather than the exception, we have encountered no fetal losses in the prediabetic years, but we have had significant macrosomia. This observation was derived from a careful review of the antenatal records of all diabetic women deIivered at this hospital in the last 20 years. It is our impression, particularly with regard to lethal effects, that “alternative 2” (above) is more likely correct, i.e., that the prediabetic period has no lethal clinical significance for the fetus. As mentioned, the increased perinatal loss in the chemical diabetic (I-B) and of the latent diabetic (I-C) is well established. Additional support is derived from numerous

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Diabetes

articles49 11, ls* 21* 26, 2* usually this entity as prediabetes. Chemical

(I-B) and latent

referring

to

(I-Cl diabetes

Diagnosis. To reduce the significant chemical diabetic perinatal wastage, it is essential that both early and precise diagnoses be made. Certain indications for specialized study may be listed which demand further investigation. These are: (1) glycosuria; (2) family history of diabetes; (3) previous unexplained stillbirth or neonatal death; (4) previous delivery of a large baby (over 9 pounds) ; (5) history of repeated abortion, hydramnios, or congenital anomalies; and (6) marked obesity. A fasting blood sugar determination alone represents a grossly inadequate screening procedure. If a screening procedure is desired, the 2 hour postprandial determination should be selected. A level of 110 mg. per cent makes glucose tolerance testing mandat0ry.l’ Glucose tolerance testing should be repeated in the third trimester when the carbohydrate utilization mechanism is under greatest Because many pregnant stress. women may be receiving a thiazide derivative during late pregnancy, it should be borne in mind that these drugs have been shown 37 Furthermore, any gestato be diabetogenic. tional diabetic tolerance curve which reverts to normal in the postpartum period should be re-evaluated with the standard steroid stimulation test; and with the standard oral glucose tolerance test in each trimester of subsequent pregnancies. Management. There is no unanimity of opinion regarding management of chemical or latent diabetes in the pregnant woman. White’O manages the hyperglycemia by diet alone. The Mt. Sinail’ group controls hyperglycemia by diet and advocates delivery after 36 weeks’ gestation if the baby appears to be in excess of 4,000 grams. Carrington and coworker+ ‘, 6 insist on careful dietary control. They induced labor at 36 to 37 weeks in the past; more recently they often delay induction’ for several weeks. They do not regard uncomplicated chemical diabetes as an indication for cesarean section. Pedowitz and

in pregnancy

1027

Shlevin33 strongly urge dietary control with prenatal care just as for the frank diabetic patient. They further recommend delivery at 37 weeks by the most appropriate method. Hoetlss I9 postulates that management of the hyperglycemia of the chemical diabetic might decrease fetal loss and possibly prevent or delay frank diabetes in the mothers by relieving the stress on the maternal pancreatic islet cells. He report?* 30 patients with a history of stillbirth or neonatal loss who had abnormal glucose tolerance curves. He controlled the hyperglycemia with insulin and then performed abdominal delivery at 35 to 36 weeks without perinatal mortality. Wilkerson and Remein381 3s are now evaluating insulin treatment in chemical diabetes in a controlled study. Thus far, among patients with abnormal glucose tolerance curves who received no special management (and who serve as controls), there have been three times as many 9 pound babies as in the patients with abnormal glucose tolerance curves treated with insulin. Their large, continuing study should do much to clarify present understanding of subclinical diabetes and pregnancy. It is our opinion that careful diabetic control should be maintained by diet. We advise vaginal delivery 14 days prior to term. If conditions are not favorable for amniotomy, stimulation with oxytocin or sparteine sulfate may be of benefit. It should be emphasized that whenever elective preterm delivery is selected, all of the safeguarding criteria for vaginal delivery must be fulfilled. These have recently been enumerated by one of us,27 If a reasonable trial of induction is unsuccessful, delivery is effected abdominally. Delivery may be indicated 21 days prior to term if the infant appears to be very large, if the diabetic state deteriorates, or if other complications ensue. Conclusions 1. We have presented 3 cases illustrating the clinical implications of chemical diabetes. 2. A classification of diabetes of obstetrical significance is presented and discussed. In particular, the semantic differences between

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Boronow

April 1, 1965 Am. J. Obst. & Gym.

and McElin

prediabetes and chemical and latent diabetes are discussed and shown to be clinically realistic, We reject the use of the term “prediabetes” for anything other than a retrospective analysis. 3. The high fetal losses associated with the so-called “prediabetic period” and with chemical diabetes, in particular, are cited. We agree with others who feel that fetal loss in the prediabetic period has been overstated; that these losses more likely reflect undiagnosed diabetes of all types; and that, very probably, the prediabetic period has no lethal clinical significance for the fetus.

4. The situations that demand suspicion of chemical diabetes are listed, and the appropriate tests and criteria for diagnostic evaluation are reviewed. 5. Various principles of management of the pregnant chemical diabetic are discussed. We favor: (a) careful dietary control, (b) delivery 14 days prior to term, and (c) earlier delivery (21 days prior to term) if clinically indicated. 6. It is suggested that perinatal survival will improve as an awareness of the significance of chemical diabetes prompts early diagnosis and enlightened management.

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1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11.

12.

13. 14. 15. 16. 17. 18.

19.

Allen, E.: AM. J. OBST. & GYNEC. 38: 982, 1939. Barnes, H. H. F., and Morgan, M. E.: J. Obst. & Gynaec. Brit. Emp. 55: 449, 1948. Burt, R. L.: Clin. Obst. & Gynec. 3: 310, 1960. Carrington, E. R.: Clin. Obst. & Gynec. 3: 911, 1960. Cariington, E. R., and Messick, R. R.: AM. 1. OBST. & GYNEC. 85: 669. 1963. Barrington, E. R., Reardon,’ H. S., and Shuman, C. R.: J. A. M. A. 166: 245, 1958. Colwell, A. R.: Types of diabetes mellitus and their treatment, Springfield, Illinois, 1950. Charles C Thomas. Publisher. Con;, J. W., and Fajans,‘S. S.: Am. J. Med. 31: 839, 1961. Conn, J. W., and Fajans, S. S.: Diabetes 11: 335, 1962. Danforth, D. N., and Boronow, R. C.: Clin. Obst. & Gynec. 5: 409, 1962. Dolger, H., Bookman, J. J., Joelson, R. H., and Fischer, A. E.: Diabetes mellitus, In Guttmacher, A., and Rovinsky, J. J., editors: Medical, surgical and gynecological complications of pregnancy, Baltimore, 1960, Williams & Wilkins Company. Eastman, N. J., and Hellman, L. M.: Williams obstetrics ed. 12, New York, 1961. Appleton-Century-Crofts, Inc. Freinkel, N., and Goodner, C. J.: Arch. Int. Med. 109: 235, 1962. Futcher, P. H., and Long, W. N.: Bull. Johns Hopkins Hosp. 94: 128, 1954. Geilis, S. S.,‘and Hsia; D. Y. Y.: A. M. 4. 1. Dis. Child. 97: 1. 1959. ?Xlbert, J. A. L., ind Dunlop, D. M.: Brit. M. J. 1: 48, 1949. He&stein, J., and Dolger, H.: Am. J. Obst. & Gvnec. 51: 420. 1946. Hoet, J. P.: Diabktes and pregnancy, Extrait des Acquisitions Medicales Recentes 1953, Editions Medicales Flamarian. Quoted by Wilkerson.38, 39 Hoet, J. P.: Diabetes 3: 1, 1954.

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Illinois Department of Public Health, Maternal Activities Report, 1926, Springfield. Jackson, W. P. 0.: &it. M. j. 2:. 690, 1952. Tackson. W. P. U.: Diabetes 9: 373. 1960. jackson; W. P. U.: Diabetes 11: 3341 1962. Jackson, W. P. U., and Woolf, N.: Diabetes 7: 446, 1958. Jones, W. S.: Diabetes 7: 439, 1958. Lund, C. J., and Weese, W. H.: AM. J. OBST. 8-z GYNEC. 65: 815. 1953. McElin, T. W.: Clin. Obst. & Gynec. 5: 426, 1962. Miller, H. C., Hurwitz, D., and Kuder, K.: T. A. M. A. 124: 271. 1944. Moss, J. M., and h;lulholland, H. B.: Ann. Int. Med. 34: 678, 1951. O’Sullivan, J. B.: New England J. Med. 264: 1082, 1961. Paton, D. M.: AM. J. OBST. & GYNEC. 56: 558, 1948. Patterson, M., and Burnstein, N.: Arch. Int. Med. 34: 678, 1951. Pedowitz, P., and Shlevin, E. L.: Obst. & Gynec. 9: 524, 1957. Potter. E. L.: Patholoev of the fetus and infant, id. 2, Chicago, IbSl, Year Book Medical Publishers, Inc. Reid, D. E.: A textbook of obstetrics, Philadelphia and London, 1962, W. B. Saunders Company. Remein. Q._ R., and Wilkerson, H. L. C.: J. Chron. Dis. 13: 6, 1961. Shauiro. A. P.. Benedek. T. G.. and Small. J. i.: Gew England J. hied. 2651 1028, 1961: Wilkerson, H. L. C.: Am. J. Pub. Health 49: 1032, 1959. Wilkerson, H. L. C., and Remein, Q .R.: Diabetes 6: 324, 1957. White, P.: Pregnancy complicating diabetes, In Joslin, E. P., Root, H. F., White, P., and Marble, A., editors: Trreatment of diabetes, ed. 10, Philadelphia, 1959, Lea & Febiger. 636 Church Street Euanston, lllinois 60201