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Further reading

Ahmad H, Mehta NJ, et al. Pneumocystis carinii pneumonia in pregnancy. Chest 2001;120(2):666–671.

Anon. Influenza vaccination and treatment during pregnancy. ACOG Committee Opin 2004;305:1125–1126.

Barth W. Asthma in pregnancy. In: Clark SL, Cotton DB, Hankins GDV, Phenlan J, eds.Critical care obstetrics, 3rd edn. Malden, MA: Blackwell Science, 1997.

Benedetti TJ, Valle R, et al. Antepartum pneumonia in pregnancy. Am J Obstet Gynecol1982;144(4):413–417.

Cheek TG, Gutsche BB. Maternal physiologic alterations during pregnancy. In: Shnider SH,Levinson G, eds. Anesthesia for obstetrics. Baltimore: Williams & Wilkins; 1984:3.

Clark SL, Hankins GD, et al. Amniotic fluid embolism: analysis of the national registry. AmJ Obstet Gynecol 1995;172(4 Pt 1):1158–1167; discussion 1167–1169.

Fowler MJ Jr, Thomas CE, et al. Diffuse cerebral air embolism treated with hyperbaric oxygen:a case report. J Neuroimaging 2005;15(1):92–96.

Gardner MO, Doyle NM. Asthma in pregnancy. Obstet Gynecol Clin North Am 2004;31(2):385–413, vii.

Mabie WC, Barton JR, et al. Adult respiratory distress syndrome in pregnancy. Am J ObstetGynecol 1992;167(4 Pt 1):950–957.

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38 Diabetes mellitus in pregnancyCarol J. Homko, Zion Hagay, and E. Albert Reece

Diabetes mellitus is a heterogeneous disorder characterized by hyperglycemia, whichis a result of relative or absolute insulin deficiency. It is estimated that diabetes mel-litus affects approximately 4 million women of childbearing age in the United States.

Classification

Diabetes during pregnancy is still generally classified using the original system proposed by Priscilla White almost 40 years ago. White’s classification relates theonset of diabetes, its duration, and the degree of vasculopathy to the outcome ofpregnancy. Practically speaking, women with pregnancies complicated by diabetesmellitus may be separated into one of two groups:1 Gestational diabetes: women with carbohydrate intolerance of variable severity,

with onset or first recognition during the present pregnancy.2 Pregestational diabetes: women known to have diabetes before pregnancy.

Table 38.1 presents the classifications that include these two groups.

Handbook of Clinical Obstetrics: The Fetus & Mother, Third EditionE. Albert Reece, John C. Hobbins

Copyright © 2007 by Blackwell Publishing Ltd

Epidemiology and etiology

As diabetes mellitus is a heterogeneous disorder rather than a single disease, the dif-ferent types of diabetes should be distinguishable from each other (see Table 38.2).

Ninety percent of all pregnant diabetic patients have gestational diabetes melli-tus (GDM), whereas type 1 (insulin-dependent diabetes) and type 2 (noninsulin-dependent diabetes) account for the remaining 10%. In general, type 1 and type 2

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Table 38.1 Classification of diabetes in pregnancy.

Pregestational diabetes:

Class Age of onset (years) Duration (years) Vascular disease Therapy

A Any Any No Diet onlyB > 20 < 10 No InsulinC 10–19 10–19 No InsulinD Before 10 > 20 Benign retinopathy InsulinF Any Any Nephropathy InsulinR Any Any Proliferative retinopathy InsulinH Any Any Heart disease Insulin

Gestational diabetes:

Class Fasting glucose level Postprandial glucose level

A-1 < 105mg/dL and < 120mg/dLA-2 > 105mg/dL and/or > 120mg/dL

Based on the American College of Obstetricians and Gynecologists (ACOG), TechnicalBulletin no. 92 (Chicago), May 1986, with modifications.

Table 38.2 Classification of glucose intolerance.

Nomenclature Old name(s)

Type I Type 1 diabetes Insulin-dependent diabetesJuvenile-onset diabetes

Type II Type 2 diabetes Noninsulin-dependent diabetesMaturity-onset diabetes

Type III Other specific types Secondary diabetesType IV Gestational diabetes mellitus

From the Report of the Expert Committee on the Diagnosis and Classification of DiabetesMellitus. Diabetes Care 1997;7:1183.

diabetes can be distinguished from each other using clinical criteria and/or islet cellantibody studies (Tables 38.3 and 38.4).

Metabolic changes in normal and diabetic pregnancies

Insulin secretion and insulin resistance in normal pregnancyInsulin is the major hormonal signal regulating metabolic responses to feeding andtissue use of carbohydrates; it is also the major glucose-lowering hormone. It is pro-duced by the B cells of the pancreas and is secreted into the hepatic portal circula-tion, from which it reaches and acts on the liver and other peripheral tissues (i.e.,muscle and fat). Insulin suppresses endogenous glucose production by inhibitinghepatic glycogenolysis and gluconeogenesis. On the other hand, it stimulates glucoseuptake and fuel storage of glycogen and triglyceride in the liver, muscle, and adiposetissue (Table 38.5).

Late pregnancy is characterized by accelerated growth of the fetoplacental unit,rising plasma concentrations of several diabetogenic hormones including human placental lactogen and estrogens, and increasing insulin resistance. Several inves-tigators have demonstrated increased first- and second-phase insulin release duringlate gestation as well as increased plasma insulin/glucose ratios. Buchanan and col-leagues (1990), using the minimal model technique, found that peripheral insulinsensitivity was reduced to approximately one-third of normal during late gestation. Similar findings have been reported by other investigators using the euglycemic–hyperinsulinemic clamp technique. Decreases of 50% and 33% in insulin-stimulatedglucose uptake have been reported, indicating peripheral insulin resistance duringthe third trimester of pregnancy.

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Table 38.3 Predominant characteristics of type 1 and type 2 diabetes.

Characteristic Type 1 Type 2

Prevalence 0.1–0.5% 5–10%*Weight at onset Nonobese Often obeseAge at onset Usually young, < 30 years Usually older, > 40 yearsSeasonal variations Yes NoInsulin level Low or absent VariableKetosis Most often UnusualMHC gene associations HLA-DR4, HLA-DR3, HLA-DQ NoTwin studies 30–50% concordance 80–100% concordanceAnti-islet cell antibodies Positive in 70% of individuals No

with new type 1

HLA, human leukocyte antigen; MHC, major histocompatibility complex.

*Prevalence in Western countries.


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Table 38.4 Empiric risk for offspring of parents with type 1 and type 2 diabetes developingdiabetes.

Affected parent(s) Empiric risk estimate of offspring

Type 1 diabetesMother 1%Father 6%Parents unaffected, sibling affected Overall 5–6%

No. of haplotypes shared:1 haplotype = 5%2 haplotypes = 13%No haplotypes = 2%

Both parents affected 33%

Type 2 diabetesMODY 50%Obese 7%Nonobese 15%Both parents affected 60–75%

MODY, maturity-onset diabetes of youth.

Table 38.5 Summary of the metabolic effects of insulin.

Target tissue Enhances glucose and amino acid uptakeIncreases glycogen synthesisConverts glucose into fatty acidsInhibits glyconeogenesis

Muscle Enhances glucose and amino acid uptakeIncreases glycogen synthesis

Adipose tissue Increases glucose and amino acid transportIncreases fatty acid synthesisInhibits release of fatty acids from fat stores“Fat-sparing effect” is enhanced by glucose utilization in

many tissues

Central nervous system Has little or no effect on uptake or metabolism of glucose

All tissues Increases protein synthesisInhibits protein catabolism

From Brumfield C, Huddleston JF. The management of diabetic ketoacidosis in pregnancy.Clin Obstet Gynecol 1984;27:50.

Gestational diabebes mellitus

Definition and incidenceGDM is defined as carbohydrate intolerance of variable severity with onset or firstrecognition during the present pregnancy. This means that the glucose intolerancemay have antedated the pregnancy but was not recognized by the patient or thephysician. The incidence of GDM varies in different study populations and is esti-mated to occur in 3–5% of pregnant women. The likelihood of developing gesta-tional diabetes is significantly increased among certain subgroups, and these includewomen with a family history of type 2 diabetes, advancing maternal age, obesity,and nonwhite ethnicity.

Screening for gestational diabetesIn the United States, screening for gestational diabetes mellitus consists of a 50-goral glucose load, followed 1h later by a plasma glucose determination. The screenis performed without regard to the time of day or interval since the last meal. It isrecommended that screening be carried out at 24–28 weeks’ gestation in average-risk women not known to have diabetes mellitus. Women deemed to be at high riskfor GDM should be tested as soon as possible. Women possessing all of the fol-lowing characteristics are considered to be a low risk and may not require testing:< 25 years of age, of normal weight, without a history of abnormal glucose metab-olism or poor obstetric outcome, and with no first-degree relative with diabetes.

A value of plasma venous glucose between 130 and 140mg/dL has been recom-mended as a threshold to indicate the need for a full diagnostic oral glucose toler-ance test (OGTT). When the plasma glucose screening test results are > 185mg/dL,patients are gestational diabetics and no further testing is required (Table 38.6).

DiagnosisThe diagnosis of GDM is, in most cases, based on an abnormal result of an OGTTduring pregnancy. The OGTT is administered under standard conditions: 100 g ofglucose is given orally in at least 400mL of water after an overnight fast of 8–14h.

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Table 38.6 Incidence of a positive glucose tolerance test among 96 gravidas with 50-g, 1-hscreening test values > 134mg/dL (plasma, glucose oxidase).

Screening test result (mg/dL) Incidence of gestational diabetes (%)

135–144 14.6145–154 17.4155–164 28.6165–174 20.0175–184 50.0> 185 100.0

From Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. AmJ Obstet Gynecol 1982;144:768.

The patient should have at least 3 days of unrestricted diet with more than 150 gof carbohydrates and should be at rest during the study. Diagnosis requires that atleast two out of four glucose levels of the OGTT meet or exceed the upper limitsof normal values. Whole blood and plasma glucose criteria of the OGTT used forthe diagnosis of GDM are presented in Table 38.7.

Pregestational diabetes mellitus

Congenital anomalies in infants of diabetic mothersThe frequency of major congenital anomalies among infants of diabetic mothers hasbeen estimated at 6–10%, which represents a two- to fivefold increase over the fre-quency observed in the general population. Congenital malformations in fetuses ofdiabetic patients are now responsible for approximately 40% of all perinatal deaths,replacing respiratory distress syndrome (RDS) as the leading cause of infant death.These malformations usually involve multiple organ systems (Table 38.8), withcardiac anomalies being the most common, followed by central nervous system andskeletal malformations.

Prevention of fetal anomaliesClinical studies suggest that euglycemia during organogenesis is critical in the prevention of congenital anomalies. Several investigators have recruited diabeticwomen before pregnancy and attempted to place them under tight glycemic controlbefore conception. These studies are summarized in Table 38.9.

Periconceptional careManagement of the pregnant diabetic woman is a complex task that ideally beginsbefore conception. Prepregnancy clinics for diabetics were initiated in Edinburgh in1976. In such clinics, physicians have the opportunity to explain to the patient andher partner the practice of diabetes care during pregnancy, in particular the need


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Table 38.7 Oral glucose tolerance test (100-g) values for the diagnosis of gestationaldiabetes (mg/dL).

Study:O’Sullivan* NDDG† Carpenter and Coustan‡

Fasting 90 105 951-h 165 190 1802-h 145 165 1553-h 125 145 140

*From O’Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy.Diabetes 1964;13:278.†From the National Diabetes Data Group. Classification and diagnosis of diabetes mellitusand other categories of glucose intolerance. Diabetes 1979;28:1039.‡From Carpenter and Coustan (1982).

for stringent glycemic control. At the initial visit, the patient’s general medical statusis assessed, and signs of retinopathy, nephropathy, hypertension, and ischemic heartdisease are looked for. The patient undergoes ophthalmologic evaluation, electro-cardiography, and kidney function tests. Optimization of blood glucose controlshould be achieved before a woman is advised to become pregnant. It is generallyrecommended that women achieve a glycosylated hemoglobin level that is less than 1% above the upper limit of normal. Women should receive appropriate contraceptive therapy while preparing for pregnancy. For women who are notalready following an intensive diabetes regimen, an extensive period of educationand the institution of self blood glucose monitoring is also necessary.

Diabetes management during pregnancy

Diabetes during pregnancy has been associated with increased perinatal mortality,an increased rate of Cesarean sections, significant risk of macrosomia, and otherneonatal morbidities, including serious birth trauma, hypoglycemia, hypocalcemia,polycythemia, and hyperbilirubinemia. Management is therefore directed towardreducing perinatal mortality and morbidity, a goal that may be achieved by main-taining close surveillance of the mother and fetus and stringent glucose control.

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Table 38.8 Congenital anomalies of infants of diabetic mothers.

Skeletal and central nervous systemCaudal regression syndromeNeural tube defects excluding anencephalyAnencephaly with or without herniation of neural elementsMicrocephaly

CardiacTransposition of the great vessels with or without ventricular septal defectVentricular septal defectsCoarctation of the aorta with or without ventricular septal defect or patent ductus

arteriosusAtrial septal defectsCardiomegaly

RenalHydronephrosis

Renal agenesisUreteral duplicationGastrointestinalDuodenal atresiaAnorectal atresiaSmall left colon syndrome

OtherSingle umbilical artery

From Reece EA, Hobbins IC. Diabetes embryopathy, pathogenesis, prenatal diagnosis andprevention. Obstet Gynecol Surv 1986;41:325.


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Table 38.9 Summary of selected clinical studies using a program of preconceptionalmetabolic control to prevent diabetes-associated birth defects.

Investigator No. of Malformation Glucose No. of Malformation Glucose (year) patients rate (%) control patients rate (%) control

Controlachieved

Studyachieved

group group

Pedersen et 284 14.1 Inadequate 363 7.4 Improvedal. (1979)

Miller et 58 22.4 HbA1c > 58 3.4 HbA1c ≤al. (1981) 8.5% 8.5%

Fuhrmann 292 7.5 Mean daily 128 0.8 Mean daily et al. plasma plasma (1983) glucose glucose

≥110mg/dL ≥110mg/dLin 88.3% in 20.7% of patients of patients

Steel 65 9.2 – 78 3.9 –(1988)

Goldman 31 9.6 MBG = 44 0 MBG = 110et al. 163 ± ± 6.5mg/dL(1986) 10.2mg/dL HbA1c =

HbA1c = 7.39 ±10.42 ± 0.34%0.47%

Kitzmiller 53 15.1 HbA1c < 46 2.2 HbA1c <et al. 9.0% in 9.0% in (1986) 47% of 87% of

patients patients

Mills et al. 279 9.0 – 397 4.9 –(1988)

Damm et 61 8.2 Mean 193 1.0 Mean al. (1989) HbA1c HbA1c

7.3 ± 1.5% 7.1 ± 1.2%

Steel et al. 143 10.4 96 1.4(1990)

Kitzmiller 110 25 HbA1c > 84 1.7 HbA1c <et al. 10.6% 7.9%(1991)

Wilhoite et 123 6.5 – 62 1.6 –al. (1993)

HbA1c, hemoglobin A1c; MBG, mean blood glucose.

From Reece EA, Friedman AM, Copel J, Kleinman CS. Prenatal diagnosis and managementof deviant fetal growth and congenital malformations. In: Diabetes mellitus in pregnancy,2nd edn. New York: Churchill Livingstone, 1995.

DietDiet therapy is considered a standard treatment for diabetes mellitus. The goals ofdiet therapy are to provide adequate maternal and fetal nutrition, appropriate ges-tational weight gain, and to minimize glucose excursions. For women with preges-tational diabetes, guidelines suggest that diet composition should be based on anindividualized nutrition assessment. In GDM, it is generally accepted that carbo-hydrate levels should not exceed 40–45% of total calories. Restricted saturated fats and cholesterol and increased dietary fiber are suggested. Most patients areinstructed on how to maintain a diet that consists of three meals and one to threesnacks, the last snack usually being taken at bedtime. The bedtime snack should becomposed of complex carbohydrates with proteins to maintain adequate bloodglucose levels during the night, thereby avoiding nocturnal hypoglycemia.

Patient weight gains are assessed at each visit to the clinic, and caloric intake isadjusted accordingly. The aim is to prevent weight reduction and its associated keto-genic risk while ensuring optimal weight gain. It is desirable to increase weight by 2–4 lb (0.9–1.7kg) in the first trimester and 0.5–1.0 lb (200–450g) per weekthereafter until term. A total weight gain of 22–30 lb (10–13kg) during normal anddiabetic pregnancy is recommended.

It is generally agreed that pregnancy is not the time for weight reduction; however,excessive weight gain should be firmly discouraged. Dietary advice to the obese preg-nant diabetic patient is a matter of controversy. Several authors have indicated thatcaloric restriction in obese pregnant patients is contraindicated. However, there are data to show that modest caloric restriction (25–30kcal/day), especially for themorbidly obese patient, is not associated with ketonuria or elevated plasma ketoneconcentrations.

Insulin administrationInsulin is the only pharmacologic therapy currently recommended to treat diabetesduring pregnancy. The goal of insulin therapy is to achieve blood glucose levels thatare nearly identical to those observed in healthy pregnant women. Therefore, mul-tiple injections of insulin are usually required in women with pre-existing diabetes.Human insulin is the least immunogenic of all insulins and is exclusively recom-mended in pregnancy. The rapid-acting insulin analogs with peak hypoglycemicaction 1–2h after injection offer the potential for improved postprandial glucosecontrol. Studies support their safety during pregnancy and their ability to improveblood glucose control. Insulin requirements may change dramatically throughoutthe various stages of gestation. In the first trimester, the maternal insulin require-ment is approximately 0.7U/kg of body weight/day. This is increased in the thirdtrimester to 1.0U/kg/day. There are several different approaches to insulin admin-istration, as outlined in Table 38.10. We prefer to use the three-injection scheme,which permits better control of the fasting blood glucose levels while minimizingthe risk of middle-of-the-night hypoglycemia.

In addition, continuous subcutaneous insulin infusion pumps have also beenshown to be effective during pregnancy. Insulin therapy delivered by a subcutaneous

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infusion pump more closely resembles that of physiologic insulin release. Insulinpumps deliver a continuous basal rate of insulin infusion with pulse-dose incrementsbefore meals.

Insulin therapy should be initiated in all women with GDM who fail to maintaineuglycemia with diet. We start women on a daily insulin dose of 20U of neutral pro-tamine Hagedorn (NPH) and 10U of regular insulin daily. Insulin doses are adjustedaccording to blood glucose levels, and an evening injection is added if fasting hyper-glycemia persist. Some investigators have advocated the use of prophylactic insulin in


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Table 38.10 General guidelines for insulin administration.

Regimen Prebreakfast Prelunch Predinner Bedtime Commentsno. insulin insulin insulin insulin

I. Two- NPH + – NPH + – Give two-thirds of the totalinjection regular or regular or dose as prebreakfast dose scheme rapid-acting rapid-acting and one-third as predinner

analog; 2:1 analog doseDisadvantage: predinnerNPH may cause nocturnalhypoglycemia (1–3am) andmay not be effective in controlling the early morning glucose level

II. Three- NPH + – Regular or NPH This regimen may be moreinjection regular or rapid-acting effective than regimen I. Byscheme rapid-acting analog changing the administration

analog; 2:1 of NPH to bedtime, nocturnal hypoglycemia may be prevented and earlymorning glucose control may be achieved

III. Four- NPH + Regular or Regular or NPH This is the most effective injection regular or rapid-acting rapid-acting regimen. We use it as an scheme rapid-acting analog analog alternative to regimen II.

analog Here the dose of insulin given at bedtime replaces basal daily insulin requirements. This regimen(with a rapid-acting analog)works especially well for patients with morning sickness or erratic schedules

NPH, neutral protamine Hagedorn.

GDM to reduce the risk of macrosomia. However, the advantages of this therapy mustbe weighed against the disadvantages of no treatment.

Although the current data demonstrate a relationship between metabolic controland neonatal complications, maternal glycemia may not be the sole parameter ofoptimal control. In women with gestational diabetes, Buchanan and colleagues(1990) have suggested the use of fetal ultrasound to identify pregnancies at risk offetal macrosomia and related morbidity. They have found that a fetal abdominalcircumference < 75th percentile for gestational age obtained in the late secondtrimester or early third trimester can distinguish pregnancies at low risk from thoseat high risk of producing large for gestational age (LGA) infants. Their data suggestthat maternal glucose concentrations alone may not accurately predict which fetusesare at high risk of excessive fetal growth and support the use of fetal criteria todirect metabolic therapies in GDM.

Self-monitoring of blood glucoseSelf blood glucose monitoring has become the mainstay of management for preg-nancies complicated by diabetes mellitus. Blood glucose measurements should be obtained at least four times a day (fasting and 1–2h after meals) in women with gestational diabetes and five to seven times a day in women with pre-existingdiabetes. In addition to this regular monitoring, patients should also test wheneverthey feel symptoms of either hyperglycemia or hypoglycemia. Detailed recordkeeping is useful to help identify glucose patterns. Daily urine ketone testing should be performed to insure early identification of the development of starvationketosis or ketoacidosis. Ketone testing should also be performed any time the blood glucose level exceeds 200mg/dL, during illness, or when the patient is unableto eat.

Antepartum assessment

Maternal assessmentOphthalmologic and renal function tests, including creatinine clearance and total urinary protein excretion, are performed in each trimester, or more often ifindicated. In patients with vasculopathy, an electrocardiogram is performed at theinitial visit and repeated, if clinically indicated. In patients in White’s class H, theelectrocardiogram is performed routinely in each trimester. The echocardiogram isperformed at enrollment and repeated in the pregnancy, depending on the initialfindings. It is extremely important to detect early signs of pregnancy-induced hyper-tension; therefore, an assessment of blood pressure and the signs of proteinuria andedema formation is essential. It is estimated that approximately 25% of all diabet-ics develop preeclampsia during pregnancy. The highest incidence is seen amongpatients with vasculopathy.

Fetal surveillanceAll pregnancies complicated by diabetes require extra assessment. The use of ultra-

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sonography provides essential information about the fetus. A first-trimester scan isused to date the pregnancy and to establish viability and fluid volume status. Asecond-trimester scan is repeated at 18–20 weeks’ gestation to rule out fetal anom-alies. Subsequent ultrasound evaluations are then performed at 4- to 6-week inter-vals to assess fluid volume and fetal growth. Because diabetic patients are at risk ofgrowth aberrations (intrauterine growth restriction and macrosomia), this frequencyis recommended to identify states of altered growth.

Antepartum fetal testingIn pregnant diabetic patients, stillbirth occurs with increased frequency, particularlyin the third trimester. Therefore, a program of fetal monitoring should be initiated,usually at 32–33 weeks. Currently, in most medical centers, outpatient protocolsfor antepartum fetal surveillance include either once- or twice-weekly nonstress tests(NSTs), once-weekly oxytocin challenge tests (OCTs), or biophysical profiles. Whichis the best test remains controversial because controlled, prospective randomizedstudies comparing the various methods of antepartum fetal assessment are lacking.Many investigators have concluded that the NST is simple, inexpensive, and rea-sonably reliable. Therefore, the NST is most widely used for pregnancies compli-cated by diabetes mellitus.

Timing and mode of deliveryIn recent years, there has been a significant change in the attitude of obstetriciansand perinatologists toward the mode and timing of delivery of type 1 and type 2pregnant patients. It is now recognized worldwide that, if the pregnant diabeticpatient and her fetus are under stringent metabolic control and antepartum sur-veillance, delivery may be safely delayed in most cases until term or the onset ofspontaneous labor. During labor and delivery, it is necessary to maintain maternaleuglycemia to avoid neonatal hypoglycemia.

Maternal complicationsDiabetic women have a markedly higher risk of a number of pregnancy compli-cations. Because of a paucity of data on maternal complications during diabeticpregnancy, the exact relative risk for each complication is not known. Complica-tions that have been reported to be more frequent in diabetic pregnancy includespontaneous abortion, preterm labor, pyelonephritis, polyhydramnios, and hyper-tensive disorders. Also directly related to metabolic control are hypoglycemia and diabetic ketoacidosis (DKA; Fig. 38.1). These complications, together with the vas-cular alterations and the higher Cesarean section rate, contribute to the highermaternal morbidity and mortality among diabetic pregnant patients.

Morbidity of the infant of the diabetic mother

In the last decade, the perinatal morbidity rate in pregnancies complicated by diabetesmellitus has been remarkably reduced. However, severe neonatal morbidity in infants


303

of diabetic mothers is still a problem that may affect even infants delivered at term.The following sections briefly discuss the most common neonatal morbidities.

HypoglycemiaHypoglycemia is diagnosed when plasma glucose levels are less than 35mg/dL and25mg/dL in term and preterm infants respectively. Infants of diabetic mothers inunsatisfactory glycemic control often develop hypoglycemia during the first fewhours of life. The reported incidence ranges from 25% to 40% of infants of dia-betic mothers. Poor glycemic control during pregnancy and high maternal plasmaglucose levels at the time of delivery increase the risk of occurrence, particularly if the patients have been delivered by Cesarean section. The most efficient means of therapy for hypoglycemia is continuous dextrose infusion at a rate of4–6mg/kg/min. The use of a bolus of a hypertonic glucose infusion should beavoided to prevent later rebound hypoglycemia. Occasionally, hypoglycemia maypersist beyond the second day of life and may require the use of glucocorticoids.

Hypocalcemia and hypomagnesemiaThere is a significant increase in the incidence of hypocalcemia and hypomagne-

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Relative insulin deficiency

Hyperglycemia

Glucosuria

Osmoticdiuresis

Dehydration

Serumhyperosmolarity

↑Secretion of:

glucagoncatecholaminecortisolgrowth hormone

Urinaryloss of:Na+

K+

Cl–

HCO3–

Urinarywaterloss

Proteincatabolism

Hepaticgluconeogenesis

Acidosis(PH↓)

Ketonemia

Hepaticoxidationof FFA

Free fatty acid(FAA)

↑ Lipolysis

Figure 38.1 Metabolic alterations in diabetic ketoacidosis.

semia in infants of diabetic mothers. The incidence of neonatal hypocalcemia,defined as calcium levels at or below 7mg/dL, has been reported to approach 20%in a group of infants with a mean gestational age at delivery of 38 ± 0.2 weeks.

PolycythemiaPolycythemia is diagnosed when the venous hematocrit exceeds 65%. This condi-tion has been reported to affect one-third of neonates of diabetic mothers in thefirst few hours of life. The mechanism responsible for polycythemia in these babiesmay be related to chronic intrauterine hypoxia that leads to an increase in ery-thropoietin and a consequent increase in red blood cell production.

Respiratory distress syndrome (RDS)RDS was considered a common neonatal morbidity in the infants of diabeticmothers in the past. However, the incidence has decreased dramatically with the ini-tiation of strict glycemic control. Factors contributing to the development of RDSin these infants are preterm deliveries, delayed fetal lung maturation, and a highrate of elective Cesarean section.

HyperbilirubinemiaInfants of diabetic mothers have a higher incidence of hyperbilirubinemia than doinfants of nondiabetic mothers matched for gestational age. The mechanism of thisincreased risk of jaundice is not clear. Early treatment of polycythemia may furtherreduce the risk of hyperbilirubinemia.

CardiomyopathyInfants of diabetic mothers have a higher risk of hypertrophic types of cardiomy-opathy and congestive heart failure. The characteristic findings in echocardio-graphy are generalized myocardial hypertrophy with disproportionate hypertrophyof the interventricular septum. Infants of diabetic mothers with severe cardiomyo-pathy may develop left ventricular outflow tract obstruction with reduced cardiacoutput and congestive heart failure. The natural history of cardiomyopathy ininfants of diabetic mothers is different from other types of cardiomyopathy in thatthere is a complete regression of hypertrophic changes to normal after severalmonths.

Conclusion

The diagnosis of diabetes mellitus during pregnancy has certain implications for thewell-being of both the mother and the fetus. Advances in medical and obstetric carehave dramatically improved the outlook for women with diabetes and their off-spring. However, both mother and child remain at increased risk for a number ofcomplications. Research indicates that the majority of these complications are asso-ciated with hyperglycemia. The achievement and maintenance of euglycemia hastherefore become the major focus of management.


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Further reading

American College of Obstetricians and Gynecologists. Management of diabetes in pregnancy.ACOG Tech Bull 1994;200:1–8.

Buchanan TA, Metzger BE, Freinkel N, et al. Insulin sensitivity and B-cell responsiveness toglucose during late pregnancy in lean and moderately obese women with normal glucosetolerance or mild gestational diabetes. Am J Obstet Gynecol 1990;162:1008–1014.

Engelgau MM, Herman WH, Smith PJ, et al. The epidemiology of diabetes and pregnancy inthe US, 1998. Diabetes Care 1995;18:1029–1033.

Homko CJ, Sivan E, Reece EA, Boden G. Fuel metabolism during pregnancy. Semin ReprodEndocrinol 199;17:119–125.

Jovanovic-Peterson L, Peterson CM. Exercise and the nutritional management of diabetesduring pregnancy. Obstet Gynecol Clin North Am 1996;23:75–86.

Kjos SL, Schaefer-Graf U, Sardesi S, et al. A randomized controlled trial using glycemic plusfetal ultrasound parameters versus glycemic parameters to determine insulin therapy in ges-tational diabetes with fasting hyperglycemia. Diabetes Care 2001;24:1904–1910.

Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Work-shop Conference on Gestational Diabetes Mellitus. Diabetes Care 1998;21(Suppl. 2):B161–167.

Reece EA, Homko CJ. Why do diabetic women deliver malformed infants? Obstet GynecolClin 2000;43:32–45.

Reece EA, Coustan DR, Gabbe SG, eds. Diabetes in women: adolescence, pregnancy andmenopause, 3rd edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2004.

Weintrob N, Karp M, Hod M. Short and long-range complications in offspring of diabeticmothers. J Diabetes Complic 1996;10:294–301.

White P. Pregnancy complicating diabetes. Am J Med 1949;7:609.

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39 Endocrine disorders in pregnancyFred Faas

Significant endocrine changes occur during normal pregnancy (see Table 39.1). Pro-lactin levels rise progressively to 100–300ng/mL by late pregnancy (Fig. 39.1).Twenty-four-hour urine free cortisol, plasma cortisol, and adrenocorticotrophichormone (ACTH) levels all rise normally during pregnancy as a result of large risesin corticotrophic-releasing hormone (CRH), derived from the fetal–placental unit(Table 39.2). Salt and water metabolism changes during pregnancy with a decreasein plasma osmolality to a level of about 10 mOsmol/kg below normal. Renin andaldosterone levels rise progressively to more than twice the levels in the nonpreg-nant state (Fig. 39.2). A placental growth hormone variant is secreted into the cir-culation during pregnancy rising to mean levels of > 20 ng/mL, which results in thedoubling of insulin-like growth factor (IGF)-1 levels (Fig. 39.3). Total calcium levelsfall during pregnancy as a result of hemodilution, but ionized calcium levels, serum25(OH)vitamin D, and parathyroid hormone levels are typically normal.

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