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Chapter 46Diabetes in Pregnancy Thomas R. Moore, MD, and Patrick Catalano, MD tripled, and the incidence of newborn intensive care unit admission is quadrupled.6Global and National Before the 20th century, pregnancy in the diabetic woman por-Prevalence of Diabetes tended death of mother or child, or both. In the 21st century, centers providing meticulous metabolic and obstetric surveillance report peri-Worldwide Perspective on Diabetes natal loss rates approaching but still higher than those seen in theAn epidemic of diabetes and obesity is sweeping the globe, largely nondiabetic population.7,8 Nevertheless, major problems with fetal andbecause of marked shifts in dietary practices and physical activity. In maternal management persist. Stillbirth rates have fallen dramatically2000, 171 million persons on the planet were known to have diabetes, but remain threefold or fourfold greater than rates for the normogly-and by 2030, this ﬁgure is expected to increase to 366 million. More cemic population. Congenital fetal anomalies, many of them lifethan 80% of people with diabetes worldwide live in low- and middle- threatening and debilitating, remain three to four times more commonincome countries. During the next 2 decades, the world population is in diabetic pregnancies than in nondiabetic pregnancies.9 Macrosomiaexpected to increase by 37%, but the prevalence of diabetes will increase and birth injury occur 10 times more frequently in diabetic fetuses.by 114%. In India, sub-Saharan Africa, and Latin America, diabetes Studies indicate that the magnitude of such risks is proportional to theprevalence is projected to increase by 150% to 160%.1 degree of maternal hyperglycemia.10,11 To a great extent, the excessive In the United States and other developed economies, the rise in fetal and neonatal morbidity of diabetes in pregnancy is preventablediabetes prevalence is projected to be higher than 50%. As shown in or at least reducible by meticulous prenatal and intrapartum care. ThisFigure 46-1, in 2005, 20.8 million people (7% of the population) have chapter reviews the pathophysiology of this complex group of disordersbeen diagnosed with some form of diabetes. Another 6.2 million with and identiﬁes the obstetric interventions that can improve outcome.diabetes are undiagnosed. Of women 20 years or older, 8.8% haveovert diabetes, but there is a strong predilection for this disease amongethnic groups. Higher-than-expected rates of pregestational diabetesin women of childbearing age have been reported for 13.3% of non- Classiﬁcation andHispanic blacks, 9.5% of Hispanic and Latino Americans, and 12.8%of Native Americans.2 Pathobiology of Diabetes MellitusEpidemiology of Diabetes in Diagnostic and classiﬁcation criteria for diabetes were issued by theU.S. Women American Diabetes Association (ADA) in 1997.12 These criteria were further modiﬁed in 2003 regarding the diagnosis of impaired fastingStudies suggest that the prevalence of diabetes among women of child- glucose.13 This nomenclature is useful because it categorizes patientsbearing age is increasing in the United States.3,4 Continued immigra- according to the underlying pathophysiology, although we recognizetion among populations with high rates of type 2 diabetes and the that the criteria are not as mutually exclusive as once thought. Theimpact of changes in diet (i.e., increased calories and fat content) and classiﬁcation includes four clinical types:lifestyle (i.e., sedentary) have brought marked increases in the percent-age of patients with preexisting diabetes who will become pregnant in 1. Type 1 diabetes, formerly referred to as insulin-dependent or juve-the future. A virtual epidemic of childhood obesity is occurring in the nile-onset diabetes.United States, bringing with it a sharp rise in childhood and adolescent 2. Type 2 diabetes, formerly referred to as non–insulin-dependent ordiabetes. This trend will have a profound impact on obstetrics and adult-onset diabetespediatrics in the next 2 decades and beyond.5 Increased outreach 3. Other speciﬁc types of diabetes related to a variety of genetic-,efforts to provide care to the populations experiencing rising rates of drug-, or chemical-induced diabetespregestational diabetes will be necessary if a signiﬁcant increase in 4. Gestational diabetes mellitusmaternal and newborn morbidity is to be avoided. When offspring ofdiabetic mothers are compared with weight-matched controls, the risk An alternative classiﬁcation that is commonly used in obstetrics wasof serious birth injury is doubled, the likelihood of cesarean section is proposed by Priscilla White when she was at the Joslin Clinic in Boston
CHAPTER 46 Diabetes in Pregnancy 955 TABLE 46-2 CRITERIA FOR THE DIAGNOSIS ity with advancing gestation. About 2% to 13% of women diagnosed OF DIABETES as having GDM have detectable antibodies directed against speciﬁc beta cell antigens.21,22 Some of these deﬁciencies are population depen- Symptoms of diabetes and a casual plasma glucose level dent. Other patients diagnosed with GDM have genetic variants that 200 mg/dL (11.1 mmol/L). Casual is deﬁned as any time of day without regard to time since the last meal. The classic have been identiﬁed as causes of diabetes in the general population, symptoms of diabetes include polyuria, polydipsia, and including autosomal dominant (discussed later) and maternal or mito- unexplained weight loss. chondrial inheritance patterns.23,24 or It is estimated that as many as 3% to 9% of the population of Fasting plasma glucose level 126 mg/dL (7.0 mmol/L). Fasting is pregnant women will be diagnosed with GDM.15 This translates into deﬁned as no caloric intake for at least 8 hours. approximately 135,000 cases of GDM per year in the United States or alone. This is not surprising, because in many respects, GDM is the Two-hour plasma glucose 200 mg/dL (11.1 mmol/L) during an harbinger of type 2 diabetes for many women, based on the underlying oral glucose tolerance test. The test should be performed as pathophysiology of GDM and the increase in obesity in women of described by the World Health Organization, using a glucose reproductive age. Similarly, there is an increase in the incidence of load containing the equivalent of 75-g anhydrous glucose dissolved in water. GDM in women immigrating to the United States, presumably because of changes in diet and lifestyle. Clinical recognition of GDM is impor- Adapted from American Diabetes Association: Clinical practice tant because therapy can reduce pregnancy complications and poten- recommendations: Standards of medical care for diabetes—2007. tially reduce long-term sequelae in the offspring. Diabetes Care 30:S4-S41, 2007. Genetic and Other Causes of Diabeteswas formerly believed that type 2 diabetes was primarily a disorder of The ADA’s fourth classiﬁcation of diabetes includes speciﬁc types ofolder individuals (accounting for its being called adult-onset diabetes), diabetes attributed to “other causes.” These causes include geneticthere has been a signiﬁcant increase in the prevalence of type 2 diabetes defects in insulin action, diseases of the exocrine pancreas (e.g., cysticsince 1990. At the turn of the 21st century, an estimated 13.8 million ﬁbrosis), and drug- or chemical-induced diabetes, such as in the treat-people had a diagnosis of diabetes, 5 million people had undiagnosed ment of human immunodeﬁciency virus (HIV) infection or afterdiabetes, and 41 million people had prediabetes.17 organ transplantation.19 One of the well-characterized genetic defects Although it is not in the scope of this chapter to review the spec- is often included under the heading of maturity-onset diabetes oftrum of possible causes of type 2 diabetes, the increase in obesity in the young (MODY) (i.e., the glucokinase [GK] mutation). In 1998,the general population is a contributing factor; it is estimated that Hattersley and colleagues25 described the various phenotypic per-approximately two thirds of the population in the United States are mutations associated with the mutations of the glucokinase gene.overweight or obese.18 Obesity, particularly central obesity, which is Glucokinase phosphorylates glucose to glucose-6 phosphate in theestimated by waist circumference, is a well-described risk factor. This pancreas and liver. A heterozygous glucokinase mutation results inincrease in visceral obesity affects hepatic metabolic function and is a hyperglycemia, usually with a mildly elevated fasting glucose andrich source of cytokines and inﬂammatory factors, which are recog- abnormal OGTT result. This occurs because of a defect in the sensingnized as contributing to increasing insulin resistance. of glucose by the beta cell, resulting in decreased insulin release, and Criteria for the diagnosis of diabetes in nonpregnant adults are to a lesser degree because of reduced hepatic glycogen synthesis. Inshown in Table 46-2. Although the 75-g, 2-hour oral glucose tolerance pregnancy, it is estimated that 3% of women with GDM and an ele-test (OGTT) is the most sensitive and speciﬁc diagnostic test for type vated fasting glucose level greater than 110 mg/dL have this mutation.2 diabetes, because of the ease of administration and reproducibility, If the heterozygous mutation is present in the fetus, then the alteredthe fasting glucose test is often used as a ﬁrst-line diagnostic test,19 glucose sensing by the fetal pancreas will result in a decrease in insulinparticularly in the nongravid population. Because the onset of type 2 secretion. In the fetus, insulin is a primary stimulus for growth, anddiabetes is usually insidious, hyperglycemia not sufﬁcient to make the any defect in fetal insulin secretion results in decreased fetal growthdiagnostic criteria for type 2 diabetes is often categorized as impaired and possible growth restriction. Depending on whether the mother orfasting glucose (IFG) (100 mg/dL to 125 mg/dL) or, if the 75-g OGTT fetus, or both, have a defect in the glucokinase gene, the phenotype ofis employed, as impaired glucose tolerance (IGT) (2-hour glucose level the infant can vary from intrauterine growth restriction (IUGR)of 140 mg/dL to 199 mg/dL). The IFG and IGT have been ofﬁcially through normal fetal growth and to macrosomia.designated prediabetes, and prediabetic individuals are at high risk forthe development of type 2 diabetes.19 Maternal-Fetal MetabolismGestational Diabetes MellitusGestational diabetes mellitus (GDM) as deﬁned by the Fourth Inter- in Normal and Diabeticnational Workshop-Conference on Gestational Diabetes as “carbohy-drate intolerance of various degrees of severity, with onset or ﬁrst Pregnancyrecognition during pregnancy.”20 This deﬁnition does not preclude the There are signiﬁcant changes in maternal metabolism in normal preg-possibility that glucose intolerance might have predated the pregnancy nancy. These include changes in maternal nutrient metabolism (i.e.,or that medications might be needed for optimal glucose control. The carbohydrate, lipid, and protein metabolism) and changes in factorsunderlying pathophysiology of GDM in most instances is similar to such as energy expenditure. The overall goal of these maternal meta-that observed for type 2 diabetes: an inability to maintain an adequate bolic adaptations is to prepare the pregnant woman to meet theinsulin response because of the signiﬁcant decreases in insulin sensitiv- increased energy needs of the mother and growth of the fetus in the
956 CHAPTER 46 Diabetes in Pregnancylatter third of pregnancy, when approximately 70% of fetal growth lesser degree in adipose tissue. Various methods are used to assesstakes place.26 The alterations in maternal metabolism are relatively insulin sensitivity in vivo, including mathematical models of fastinguniform during pregnancy unless there are major perturbations such glucose and insulin modeling (e.g., homeostasis model assessmentas starvation conditions. The metabolic changes during pregnancy [HOMA],29 OGTT30), the intravenous glucose tolerance test (i.e.,therefore take place on the background of a woman’s pregestational Bergman minimal model),31 and what many consider to be the goldmetabolic status. For example, if a woman is healthy and lean before standard: the hyperinsulinemic-euglycemic clamp.32 Most of theseconception, there is an increased need to store adipose tissue in early measures have identiﬁed a signiﬁcant 50% to 60% decrease in insulinpregnancy to meet the increased energy demands of late gestation and sensitivity in late gestation.33 The changes in insulin sensitivity duringto develop insulin resistance in late gestation to provide nutrients for gestation are a reﬂection of a woman’s pregravid insulin sensitivitythe growing fetus. If a woman is obese before conception, there is little status. Lean women usually have greater pregravid insulin sensitivityneed to gain additional adipose tissue, but there is the requirement to compared with overweight or obese women. These differences mani-provide nutrients for the fetus in late gestation. fest before pregnancy, and when evaluated against the metabolic back- ground of pregnancy, the relationships are similar in late pregnancy, albeit reduced by approximately 50% to 60% (Fig. 46-3). The decreasesNormal Glucose-Tolerant Pregnancy in insulin sensitivity in late pregnancy are accompanied by an increaseGlucose homeostasis is primarily a balance between insulin resistance in insulin response. The increased insulin response to a glucose loadand insulin secretion. The alterations in insulin resistance affect endog- increases approximately threefold compared with pregravid measuresenous glucose production (primarily hepatic glucose metabolism) and (Fig. 46-4).peripheral glucose metabolism, which takes place in skeletal muscle.In the lean pregnant woman with normal glucose tolerance, there is asigniﬁcant 30% increase in basal hepatic glucose production by the Diabetic Pregnancythird trimester of pregnancy (Fig. 46-2). This is associated with a sig- Alterations in glucose metabolism in women with diabetes have beenniﬁcant increase in basal or fasting insulin concentrations.27 The most extensively examined in women with GDM, although the altera-decrease in fasting glucose concentrations most likely is the result of tions in glucose metabolism in women with type 2 diabetes are mostincreasing plasma volumes in early gestation and increased fetoplacen- likely very similar but with increased insulin resistance and furthertal use in late pregnancy. In the postprandial state, the increasing decompensation of beta cell function. In lean and obese women withinsulin concentrations enhance glucose uptake into skeletal muscle GDM with mildly elevated fasting glucose levels, there is a similarand adipose tissue, and they almost completely suppress hepatic increase in basal endogenous glucose production, as was observed inglucose production. Although this is the case in lean women, obese subjects with normal glucose tolerance, although fasting insulin con-women with normal glucose tolerance have a decreased ability for centrations, particularly in late gestation, are greater than observed ininsulin to completely suppress hepatic glucose production in late preg- normal glucose-tolerant women.28,34 However, during insulin infusionnancy.28 These data support the concept of decreased insulin sensitivity during euglycemic clamps, the ability of insulin to suppress endoge-in late gestation that is more severe in obese women compared with nous glucose production is decreased (approximately 80% versus 95%)non-obese counterparts. in GDM compared with a matched control group. There is also a sig- Peripheral insulin resistance is deﬁned as the decreased ability ofinsulin to affect glucose uptake primarily in skeletal muscle and to a 14 *P .0003 Glucose infusion rate (mg/kg.min) 190 P .0005 12 180 170 P .04 10 160 150 8 mg/min P .005 140 6 130 120 4 110 100 2 Pregravid Early Late 90 Pregravid Early Late pregnancy pregnancy pregnancy pregnancy FIGURE 46-3 Alterations in insulin resistance. LongitudinalFIGURE 46-2 Alterations in glucose production. Longitudinal changes in glucose infusion rate (i.e., insulin sensitivity) in leanchanges in total basal endogenous (primarily hepatic) glucose women from pregravid through early (12 to 14 weeks) and late (34production (mean ± SD) from pregravid through early gestation (12 to 36 weeks) pregnancy during hyperinsulinemic-euglycemic clampto 14 weeks) and late gestation (34 to 36 weeks). (Adapted from (mean ± SD). The asterisk indicates change over time from pregravidCatalano PM, Tyzbir ED, Wolfe RR, et al: Longitudinal changes in status through late pregnancy (ANOVA). (Adapted from Catalano PM,basal hepatic glucose production and suppression during insulin Tyzbir ED, Roman NM, et al: Longitudinal changes in insulin releaseinfusion in normal pregnant women. Am J Obstet Gynecol 167:913- and insulin resistance in non-obese pregnant women. Am J Obstet919, 1992.) Gynecol 165:1667-1672, 1991.)
CHAPTER 46 Diabetes in Pregnancy 957 1st Phase insulin response (μU/mL) 0.3 800 Control *P .0001 GDM 700 600 Pt 0.0001 P .025 500 Pg 0.03 0.2 400 P .025 300 200 100 0.1 0 Pregravid Early Late A pregnancy pregnancy 0 2nd Phase insulin response (μU/mL) Pregravid Early pregnancy Late pregnancy 5000 *P .0001 FIGURE 46-5 Alterations in insulin sensitivity. Longitudinal 4000 changes in insulin sensitivity during clamp 40 mU·m−2·min−1 insulin P 001 infusion in obese women (mean ± SD). GDM, gestational diabetes 3000 mellitus; Pg, difference between groups; Pt, individual longitudinal changes with time. (Adapted from Catalano PM, Huston L, Amini SB, 2000 Kalhan SC: Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and 1000 gestational diabetes. Am J Obstet Gynecol 180:903-916, 1999.) 0 Pregravid Early Late B pregnancy pregnancy 3rd Trimester Postpartum 1000FIGURE 46-4 Increased insulin response. Changes in ﬁrst (A) and Insulin secretion rate (ISR)second (B) phase pregravid through early (12 to 14 weeks) and late 800(34 to 36 weeks) pregnancy insulin response during an intravenous Normalglucose tolerance test (mean ± SD). The asterisk indicates changeover time from pregravid status through late pregnancy (ANOVA). 600(Adapted from Catalano PM, Tyzbir ED, Roman NM, et al:Longitudinal changes in insulin release and insulin resistance in non- 400obese pregnant women. Am J Obstet Gynecol 165:1667-1672, 1991.) 200 GDMniﬁcant decrease in insulin sensitivity in women who go on to develop 0GDM, when estimated before conception or after delivery,35 compared 0.0 0.1 0.2 0.3 0.4with a matched control group. During pregnancy, the percent decrease Insulin sensitivity index (ISI)in insulin sensitivity is approximately the same as the percent changein a matched control group (i.e., approximately 50% to 60%). The FIGURE 46-6 Insulin sensitivity and secretion relationshipsdecreased insulin sensitivity observed during pregnancy in the in normal women and women with gestational diabeteswoman who develops GDM is a function of her pregravid metabolic mellitus. Prehepatic insulin secretion was assessed duringstatus, and clinically, the increased glucose concentrations represent steady-state hyperglycemia using plasma insulin and C-peptidethe inability of pancreatic beta cells to normalize glucose levels concentrations and C-peptide kinetics in individual patients. (Printed(Fig. 46-5). with permission from Buchanan TA: Pancreatic β-cell defects in The relationship between insulin sensitivity and insulin response gestational diabetes: Implications for the pathogenesis and prevention of type 2 diabetes. J Clin Endocrinol Metab 86:989-993, 2001.)has been characterized by Bergman and colleagues16 as a hyperboliccurve or, when multiplied, as the disposition index. A curve that is“shifted to the left” can be plotted for individuals who go on to developGDM (Fig. 46-6). Whether the insulin resistance precedes the beta The data on the changes on glucose metabolism in women withcell defect or they occur concomitantly is not known with certainty. type 1 diabetes are not as well examined. Schmitz and coworkers37However, Buchanan36 proposed that insulin resistance caused the beta evaluated the longitudinal changes in insulin sensitivity in women withcell dysfunction in susceptible individuals. The increased risk of type type 1 diabetes in early and late pregnancy and after delivery. There2 diabetes in women who formerly had GDM may be a function of was a 50% decrease in insulin sensitivity in late gestation. There wasdecreasing insulin sensitivity (i.e., worsening insulin resistance) exac- no signiﬁcant difference in insulin sensitivity in these women in earlyerbated by increasing age, adiposity, and the inability of the beta cells pregnancy or within 1 week of delivery compared with nonpregnantto fully compensate. women with type 1 diabetes. Based on the available data, women with
958 CHAPTER 46 Diabetes in Pregnancytype 1 diabetes have similar alterations in insulin sensitivity compared pregnancies followed prospectively in the Netherlands.46 Glycemicwith women with normal glucose tolerance. control was excellent (Hb A1c ≤7.0% in 75%), but the rates of pre- eclampsia (12.7%), preterm delivery (32%), cesarean section (44%), and maternal mortality (60 deaths per 100,000 pregnancies) were con-Mechanism of Insulin Resistance siderably higher than in the nondiabetic population.The mechanisms related to the changes in insulin resistance duringpregnancy are better characterized because of research in the past Retinopathydecade. The insulin resistance of pregnancy is almost completely Diabetic retinopathy is the leading cause of blindness between the agesreversed shortly after delivery,38 consistent with the clinically marked of 24 and 64 years.47 Some form of retinopathy is present in virtuallydecrease in insulin requirements. The placenta has long been suspected 100% of women who have had type 1 diabetes for 25 years or more;of producing hormonal factors related to these alterations in metabo- approximately 20% of these women are legally blind. The topic oflism. The placental mediators of insulin resistance in late pregnancy diabetic retinopathy has been reviewed elsewhere.48have been ascribed to alterations in maternal cortisol concentrations The pattern of progression of diabetic retinopathy is predictable,and placenta-derived hormones such as human placental lactogen proceeding from mild nonproliferative abnormalities, which are asso-(HPL), progesterone, and estrogen.39-41 Kirwan and associates42 re- ciated with increased vascular permeability, to moderate and severeported that circulating tumor necrosis factor-α (TNF-α) concentra- nonproliferative diabetic retinopathy, which is characterized by vascu-tions had an inverse correlation with insulin sensitivity as estimated lar closure, to proliferative diabetic retinopathy, which is characterizedfrom clamp studies. Among leptin, HPL, cortisol, human chorionic by the growth of new blood vessels on the retina and posterior surfacegonadotropin, estradiol, progesterone, and prolactin, TNF-α was the of the vitreous. It has been proposed that pregnancy acceleratesonly signiﬁcant predictor of the changes in insulin sensitivity from the these changes, although the mechanism is controversial.49 Trials havepregravid period through late gestation. TNF-α and other cytokines not shown any acceleration in microvascular complications whenare produced by the placenta, and 95% of these molecules are trans- pregnant and nonpregnant diabetic subjects were closely followed andported to maternal rather than fetal circulations.42 Other factors, such compared.50as circulating free fatty acids, may contribute to the insulin resistance Vision loss resulting from diabetic retinopathy results from severalof pregnancy.43 mechanisms. First, central vision may be impaired by macular edema Studies in human skeletal muscle and adipose tissue have demon- or capillary nonperfusion. Second, the new blood vessels of prolifera-strated defects in the post-receptor insulin-signaling cascade during tive diabetic retinopathy and contraction of the accompanying ﬁbrouspregnancy. Friedman and colleagues showed that women in late tissue can distort the retina and lead to tractional retinal detachment,pregnancy have reduced insulin receptor substrate-1 (IRS-1) concen- producing severe and often irreversible vision loss. Third, the newtrations compared with those of matched nonpregnant women.44 blood vessels may bleed, adding the further complication of preretinalDownregulation of the IRS-1 protein closely parallels insulin’s or vitreous hemorrhage.decreased ability to induce additional steps in the insulin signalingcascade that result in the transporter (GLUT-4) arriving at the cell FACTORS AFFECTING PROGRESSION OFsurface to allow glucose to enter the cell. Downregulation of IRS-1 RETINOPATHY DURING PREGNANCYclosely parallels the decreased ability of insulin to stimulate 2- Although past studies suggested that rapid induction of glycemicdeoxyglucose uptake in vitro in pregnant skeletal muscle. During late control in early pregnancy stimulated retinal vascular proliferation,51pregnancy in women with GDM, in addition to decreased IRS-1 con- later investigations indicate that the severity and duration of diabetescentrations, the insulin receptor-β (i.e., component of the insulin before pregnancy have a greater effect. Temple and colleagues52 studiedreceptor within the cell rather than on the cell surface) has a decreased 179 women with pregestational type 1 diabetes, performing dilatedability to undergo tyrosine phosphorylation.44 This is an important fundal examination at the ﬁrst prenatal visit, 24 weeks, and 34 weeks.step in the action of insulin after it has bound to the insulin receptor Progression to proliferative diabetic retinopathy occurred in onlyon the cell surface. This additional defect in the insulin-signaling 2.2%, and moderate progression occurred in 2.8%. However, progres-cascade is not found in pregnant or nonpregnant women with sion was signiﬁcantly greater in women who had had diabetes for morenormal glucose tolerance and results in a 25% lower glucose transport than 10 years (10% versus 0%; P = .007) and in women with moderateactivity. TNF-α also acts by means of a serine/threonine kinase, to severe background retinopathy before pregnancy (30% versus 3.7%;thereby inhibiting IRS-1 and tyrosine phosphorylation of the insulin P = .01). In the European Diabetes (EURODIAB) Prospective Compli-receptor.45 These post-receptor defects may contribute in part to the cations Study, 793 potentially childbearing women at baseline com-pathogenesis of GDM and an increased risk for type 2 diabetes in later pleted the follow-up, and 21% gave birth. Duration of diabetes andlife. high HbA1c levels at recruitment were signiﬁcant risk factors for reti- nopathy progression, whereas giving birth was not.50 OPHTHALMOLOGIC MANAGEMENTComplications of Diabetes DURING PREGNANCY Screening for retinopathy by a qualiﬁed ophthalmologist is recom-during Pregnancy mended before pregnancy and again during the ﬁrst trimester for patients with pregestational diabetes because of the demonstratedMaternal Morbidity effectiveness of laser photocoagulation therapy in arresting progres-Women with pregestational diabetes are at risk for a number of obstet- sion. Patients with minimal disease should be re-examined onceric and medical complications. The relative risk of these problems is or twice during the pregnancy and at 3 and 6 months after delivery.proportional to the duration and severity of disease. Evers and cowork- Those with signiﬁcant retinal pathology may require monthlyers reported the maternal morbidity of a cohort of 323 type 1 diabetic follow-up.53
CHAPTER 46 Diabetes in Pregnancy 959Nephropathy rioration can be expected. A study of renal function for 4 years beforeDiabetes is the most common cause of end-stage renal disease in the and 4 years after pregnancy in 11 patients with diabetic nephropathy56United States and Europe. In the United States, diabetic nephropathy showed that the gradual rise in serum creatinine over that periodaccounts for about 45% of new cases of this condition. In 2003, the was unaffected by the intervening pregnancy. Imbasciati and co-cost for treatment of diabetic patients with end-stage renal disease was workers57 performed a longitudinal study of 58 women with chronicin excess of $55,000 annually per person and more than $5 billion in renal disease, following each through pregnancy. The mean serumaggregate.54 About 20% to 40% of patients with type 1 or type 2 dia- creatinine level was 6 mg/dL at the start of the study and 6 mg/dL afterbetes develop evidence of nephropathy over time, but the rate and delivery. Although they found that women with glomerular ﬁltrationextent of progression are highly individual.53 rates less than 40 mL/min and with proteinuria greater than 1 g/day The pathophysiology of diabetic renal disease is incompletely had increased risk of delivering a child with a birth weight less thanunderstood, but several factors play a role, including genetic suscepti- 2500 g (odds ratio [OR] = 5.1; 95% conﬁdence interval [CI], 1.03 tobility, control of hyperglycemia, and the duration and severity of coex- 25.6), the association was not related to renal disease, hypertension,isting hypertension. Additional insults, such as repeated urinary tract and maternal age. When the cohort was taken as a whole, even thoseinfections, excessive glycogen deposition, and papillary necrosis, all with lower glomerular ﬁltration rates and higher levels of proteinuriahasten deterioration of renal function. The kidney is normal at the had similarly modest changes in renal function when after- and before-onset of diabetes, but within a few years, glomerular basement mem- pregnancy indices were compared.57brane thickening can be identiﬁed. By 5 years, there is expansion of the Rossing and colleagues58 evaluated the effect of pregnancy on dete-glomerular mesangium, resulting in diffuse diabetic glomerulosclero- rioration of renal function in 93 women older than 20 years. Theysis. All patients with marked mesangial expansion exhibit proteinuria compared groups of never-pregnant and ever-pregnant women whoexceeding 400 mg in 24 hours. The peak incidence of nephropathy received similar medical therapy and who had similar degrees of renaloccurs after about 16 years of diabetes. function at the start of the study. The results are shown in Figure 46-7. Based on this excellent prospective study, it is evident that pregnancy CATEGORIES OF DIABETIC NEPHROPATHY neither alters the time course of renal disease nor increases the likeli- Categories of diabetic nephropathy are distinguished by the level hood of transition to end-stage renal disease.of urinary protein excretion. Table 46-3 shows normal values andthe current clinical criteria for microalbuminuria and nephropathy. COURSE OF DIABETIC NEPHROPATHYScreening for microalbuminuria can be performed by three methods: DURING PREGNANCYmeasurement of the albumin-to-creatinine ratio in a random spot In general, patients with underlying renal disease before pregnancycollection; 24-hour collection with creatinine, allowing the simultane- can be expected to experience various degrees of deterioration duringous measurement of creatinine clearance; and timed (e.g., 4-hour or pregnancy. The physiologic changes associated with normal pregnancyovernight) collection. The ﬁrst method is preferred because it is the increase renal blood ﬂow and glomerular ﬁltration by 30% to 50%.easiest to carry out in an ambulatory setting, and it provides adequately Most women with preexisting diabetic nephropathy experience thisaccurate information. The other methods are rarely used.55 improvement in renal function, especially during the second trimes- ter.59 During the third trimester, however, when mean arterial pressure EFFECT OF PREGNANCY ON PROGRESSION and peripheral vascular resistance typically increase, women withOF NEPHROPATHY diabetic microvascular disease may experience marked diminution of Although some clinicians discourage pregnancy in women with renal function, an exacerbation in hypertension, and in many cases,diabetic renal disease because of concerns of permanent renal deterio- preeclampsia. The third-trimester increase in maternal blood pressureration as a result of the pregnancy, recent data consistently indicate and serum creatinine concentration are among the most commonthat pregnancy does not measurably alter the time course of diabeticrenal disease. Progression of diabetic nephropathy is closely related to the degreeof glycemic control. To the extent that most women have better glyce-mic control during pregnancy, delay or slowing of renal function dete- TABLE 46-3 CATEGORIES OF DIABETIC RENAL DISEASE Category* Albumin-to-Creatinine Ratio (mg/mg)† Normal <30 Microalbuminuria 30-299 Nephropathy ≥300 *Categories of diabetic nephropathy are distinguished by the level of urinary protein excretion. Two of three collections in a 3- to 6-month period should be abnormal for a diagnosis of microalbuminuria or FIGURE 46-7 End-stage renal disease. Cumulative incidence of nephropathy. † The ratio of albumin to creatinine was determined by random spot end-stage renal disease (ESRD) in ever-pregnant (triangles) and never- collection. pregnant (circles) groups. (From Rossing K, Jacobsen P, Hommel E, Adapted from American Diabetes Association. Standards of medical et al: Pregnancy and progression of diabetic nephropathy. care in diabetes. Diabetes Care 28(Suppl 1):S4-S36, 2005. Diabetologia 45:36, 2002.)
CHAPTER 46 Diabetes in Pregnancy 961transplantation than in those with end-stage renal disease who are on PREECLAMPSIAdialysis. Preeclampsia is more common among women with diabetes, occur- ring four times as frequently in women with pregestational diabetes asCardiovascular Complications in those without diabetes.72 The risk of developing preeclampsia isCardiovascular complications experienced by pregnant women with proportional to the duration of diabetes before pregnancy and thediabetes include chronic hypertension, pregnancy-induced hyperten- existence of nephropathy and hypertension; more than one third ofsion, and rarely, atherosclerotic heart disease. In composite studies pregnant women who have had diabetes for more than 20 years developof all types of diabetic pregnancies, the incidence of hypertensive this condition. As is shown in Figure 46-9, patients with White class Bdisorders during pregnancy varies from 15% to 30%,70,71 with the rate diabetes have a risk proﬁle similar to that of nondiabetic patients, butof hypertension increased fourfold over that for the nondiabetic women with evidence of renal or retinal vasculopathy (classes D, F, orpopulation.72 R) have a 50% excess risk of hypertensive complications over the rate observed for those with no hypertension. Women with diabetic CHRONIC HYPERTENSION nephropathy have similar rates of preeclampsia. Chronic hypertension (i.e., blood pressure at or above 140/90 Renal function assessments should be performed in each trimestermm Hg before 20 weeks’ gestation)73 complicates 10% to 20% of preg- in women with overt diabetic vascular disease and in those who havenancies in diabetic women and up to 40% of those in diabetic women had diabetes for more than 10 years. Signiﬁcant proteinuria, plasmawith preexisting renal or retinal vascular disease.74 The perinatal prob- uric acid levels above 6 mg/dL, or evidence of HELLP syndromelems encountered with chronic hypertension include IUGR, maternal (hemolysis, elevated liver enzymes, and low platelets) should prompt astroke, preeclampsia, and abruptio placentae. In pregestational diabe- workup for preeclampsia.tes, the prevalence of chronic hypertension increases with duration ofdiabetes and is closely associated with nephropathy.72,75 HEART DISEASE The Diabetes in Early Pregnancy (DIEP) study reported that women Although coronary heart disease is rarely encountered in preg-with type 1 diabetes have higher mean blood pressures throughout nant women with diabetes, a study by Airaksinen and colleagues77pregnancy than do normal controls.76 In a signiﬁcant proportion suggests that such women may have preclinical cardiomyopathy andof patients, this difference is probably evidence of underlying renal autonomic neuropathy. The diabetic women studied had less than thecompromise. Preexisting chronic hypertension should be suspected expected increase in left ventricular size and stroke volume in preg-when the diabetic patient’s systolic blood pressure exceeds nancy, lower heart rate increases, and smaller increments in cardiac130/80 mm Hg before the third trimester. The diagnosis is strength- output.ened by ﬁnding a failure of mean blood pressure to decline normally Although uncommon, atherosclerotic heart disease (White class H)in the late second trimester, elevation in the blood urea nitrogen level may afﬂict diabetic patients in the later reproductive years. Patientsabove 10 mg/dL, serum creatinine concentration above 1 mg/dL, cre- with this complication have a mean age of 34 years and exhibit otheratinine clearance less than 100 mL/min, or a combination of these evidence of diabetic vascular involvement (White class D or R).78 Forfactors. diabetic women with cardiac involvement, pregnancy outcome is 40% 35% 30% Percent preeclampsia 25% 20% 15% 10% 5% 0% No Hypertension Hypertension Class B Class C Class D Class F/R hypertension and proteinuria FIGURE 46-9 Likelihood of preeclampsia in diabetic pregnancy by White’s class and preexisting hypertension. The risk of developing preeclampsia is proportional to the duration of diabetes before pregnancy and the existence of nephropathy and hypertension. (From Sibai BM, Caritis S, Hauth J, et al: Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 182:364, 2000.)
962 CHAPTER 46 Diabetes in Pregnancydismal, with a maternal mortality rate of 50% or higher and perinatal of stress hormones (i.e., catecholamines, glucagon, growth hormone,loss rates approaching 30%.79 Recognition of cardiac compromise in and cortisol) further impairs insulin action and contributes to insulinpregnant women with diabetes may be difﬁcult because of the decrease resistance. Left unchecked, this cycle of dehydration, tissue hypoglyce-in exercise tolerance that occurs during normal pregnancy. Compro- mia, and electrolyte depletion can lead to multisystem collapse, coma,mised cardiac function may also be difﬁcult to detect in patients and death.restricted to bed rest for hypertension or poor fetal growth. It is Early in the illness, hyperglycemia and ketosis are moderate. Ifprudent to obtain a detailed cardiovascular history in all diabetic hyperglycemia is not corrected, diuresis, dehydration, and hyperosmo-patients and to consider electrocardiography and maternal echocar- lality follow. Pregnant women in the early stages of ketoacidosisdiography in patients who have type 1 diabetes and are older than 30 respond quickly to appropriate treatment of the initiating cause (e.g.,years or in patients who have had diabetes for 10 years or more. With broad-spectrum antibiotics), additional doses of regular insulin, andintensive monitoring, successful pregnancy is possible, albeit hazard- volume replacement.ous for women with signiﬁcant cardiac disease.80 Patients with advanced DKA usually present with typical ﬁndings, including hyperventilation, normal or obtunded mental state (depend-Diabetic Ketoacidosis ing on severity of the acidosis), dehydration, hypotension, and a fruityDiabetic ketoacidosis (DKA) during pregnancy is a medical emergency odor to the breath. Abdominal pain and vomiting may be prominentfor the mother and fetus. Pregnant women with type 1 diabetes are at symptoms. The diagnosis of DKA is conﬁrmed by the presence ofincreased risk for DKA, although the incidence and morbidity of this hyperglycemia (glucose >200 mg/100 mL) with positive test results forcomplication have decreased from 20% or more in the older literature serum ketones at a level of 1 : 4 or greater.to approximately 2% in later reports.81 The rate of intrauterine fetal As many as one third of patients in the early or very late stages ofdeath, formerly as high as 35% with DKA during pregnancy, has DKA may have initial blood glucose levels less than 200 mg/dL.82 Adropped to 10% or less. pregnant diabetic patient with a history of poor food intake or vomit- Precipitating factors for ketoacidosis include pulmonary, urinary, ing for more than 12 to 16 hours should have a thorough workup foror soft tissue infections; poor compliance; and unrecognized new onset DKA, including a complete blood cell count and electrolyte determina-of diabetes. Because severe DKA threatens the life of the mother and tions. A serum bicarbonate level below 18 mg/dL should prompt per-fetus, prompt treatment is essential. Fetal well-being in particular is in formance of an arterial blood gas analysis. In all cases of DKA, thejeopardy until maternal metabolic homeostasis is reestablished. High diagnosis is conﬁrmed by arterial blood gases demonstrating a meta-levels of plasma glucose and ketones are readily transported to the bolic acidemia (i.e., base excess of −4 or lower).83fetus, which may be unable to secrete sufﬁcient quantities of insulin to Table 46-4 contains a protocol for treatment of DKA. The impor-prevent DKA in utero. tant steps in management should include the following: DKA evolves from inadequate insulin action and functional hypo-glycemia at the target tissue level. This leads to increased hepatic Search for and treat the precipitating cause. Typical initiatorsglucose release but decreased or absent tissue disposal of glucose. include pyelonephritis and pulmonary or gastrointestinal viralGlucose-lacking tissues release ketone bodies, and vascular hypergly- infections.cemia promotes osmotic diuresis. Over time, the diuresis causes pro- Perform vigorous and sustained volume resuscitation. Thefound vascular volume depletion and loss of electrolytes. The release patient will continue to generate vascular volume deﬁcits TABLE 46-4 TREATMENT PROTOCOL FOR DIABETIC KETOACIDOSIS* Measures Initial Phase (6-24 hr) Recovery Phase General Search for initiating cause of ketoacidosis. Continue treatment of initiating cause. Insert bladder catheter. Remove bladder catheter when vascular volume is replaced. If patient is unconscious, establish nasogastric tube. Fluids Administer 0.9% NaCl at 1000 mL/hr × 2 hr and then Continue 0.9% NaCl at 100 mL/hr for at least 48 hours to avoid 500 mL/hr until 5-8 L infused. return of ketoacidosis. Insulin Administer 20 U of insulin by IV bolus and then 5-10 U/hr When acidosis is resolved and plasma glucose <160 mg/dL, by IV infusion. reduce insulin infusion to 0.7-2.0 U/hr. Return to patient’s prior SC insulin dosing after plasma glucose is stable for at least 12 hr. Glucose When plasma glucose is <250 mg/dL, add 5% dextrose to 0.9% NaCl. Potassium If serum K+ level is normal or low, infuse KCl at 20 mEq/hr. Use oral potassium supplementation for 1 week. If serum K+ level is high, wait until K+ is normal, then KCl at 20 mEq/hr. Measure serum K+ level every 2-4 hr. Bicarbonate If pH is <7.1, add one ampule of bicarbonate (50 mEq) to IV; repeat until pH >7.1. *These are general guidelines. Because there may be wide variation in individual patient needs, there is no substitute for careful monitoring of each patient, particularly in the initial phase of therapy. IM, intramuscular; IV, intravenous; KCl, potassium chloride; NaCl, sodium chloride; SC, subcutaneous. Adapted from American College of Obstetricians and Gynecologists (ACOG): Clinical management guidelines for obstetrician-gynecologists. ACOG practice bulletin no. 60, March 2005. Pregestational diabetes mellitus. Obstet Gynecol 105:675-685, 2005.
CHAPTER 46 Diabetes in Pregnancy 963 until her glucose levels and acidosis are largely resolved. A Miscarriage physiologic ﬂuid such as 0.9% NaCl with 20 mEq/L of Studies of miscarriage rates from a decade ago indicated an increased potassium should be used and continued until the acidosis is incidence of spontaneous abortion among women with pregestational substantially corrected (base excess of −2 or less). This usually diabetes, especially those with poor glucose control during the peri- requires an infusion at 1 to 2 L/hr for the ﬁrst 1 to 2 hours, conceptional period. Given the well-documented association between followed by reduced rates (150 to 200 mL/hr) until the base congenital anomalies and hyperglycemia, such a ﬁnding is not surpris- deﬁcit approaches a normal level. ing. Sutherland and Pritchard84 reported the outcomes of 164 diabetic Place a bladder catheter to monitor urine output. pregnancies managed with relaxed glycemic control and found a spon- Use insulin to correct hyperglycemia. Although intermittent taneous abortion rate of almost double the expected rate. Miodovnik injections can be used, a continuous infusion of regular or and coworkers85 studied spontaneous abortion in diabetic pregnancy short-acting insulin (i.e., lispro or aspart) allows frequent prospectively and found an increasing rate among patients with more adjustments. When giving insulin as a continuous infusion, advanced classes of diabetes (rates for classes C, D, and F were 25%, 1 to 2 units/hr gradually corrects the patient’s glucose 44%, and 22%, respectively). Later studies of populations with better abnormality over 4 to 8 hours. Attempts to normalize plasma glycemic control report miscarriage rates similar to those in the non- glucose levels rapidly (i.e., in less than 2 to 3 hours) may result diabetic population,86,87 indicating that diabetic women with excellent in hypoglycemia and further physiologic counterregulatory glycemic control have a risk of miscarriage equivalent to those without responses. diabetes. Monitor serum bicarbonate levels and arterial blood gas base These studies can be used to encourage patients who have not yet deﬁcits every 1 to 3 hours to guide management. Even when conceived to achieve excellent glycemic control. Patients presenting in the plasma glucose level is normalized, acidemia may persist, early pregnancy with normal glycohemoglobin values can be reassured as evidenced by continuing abnormalities in the patient’s that the overall elevation in risk of miscarriage is modest. However, for electrolyte concentrations. Unless volume therapy is patients with glycohemoglobin values 2 to 3 standard deviations above continued until the patient’s electrolyte stores and plasma the norm, intense early pregnancy surveillance is indicated. concentrations have substantially returned to normal, DKA may reappear, and the cycle of metabolic derangement will Congenital Anomalies be renewed. Among women with overt diabetes before conception, the risk of a structural anomaly in the fetus is increased fourfold to eightfold,88 When DKA occurs after 24 weeks’ gestation, fetal status should be compared with the 1% to 2% risk for the general population. In acontinuously monitored by fetal heart rate monitoring or a biophysical cohort study of 2359 pregnancies in women with pregestational dia-proﬁle, or both. However, even when fetal status is questionable during betes, the major congenital anomaly rate was 4.6% overall, with 4.8%the phase of therapeutic volume and plasma glucose correction, emer- for type 1 diabetes and 4.3% for type 2 diabetes, more than double thegency cesarean section should be avoided. Usually, correction of the expected rate. Neural tube defects were increased 4.2-fold and congeni-maternal metabolic disorder is effective in normalizing fetal status. tal heart disease by 3.4-fold. Of all anomalies conﬁrmed in the neonate,Nevertheless, if a reasonable effort has been expended in correcting the only 65% were diagnosed antenatally.9 The typical congenital anoma-maternal metabolic disorder and the fetal status remains a concern, lies observed in diabetic pregnancies and their frequency of occurrencedelivery should not be delayed. are listed in Table 46-6. There is no increase in birth defects among offspring of diabetic fathers and nondiabetic women and women who develop gestationalFetal Morbidity and Mortality diabetes after the ﬁrst trimester, indicating that glycemic control duringPerinatal mortality in diabetic pregnancy has decreased 30-fold since embryogenesis is the main factor in the genesis of diabetes-associatedthe discovery of insulin in 1922 and the institution of intensive birth defects. A classic report by Miller and coauthors89 compared theobstetric and infant care in the 1970s. Improved techniques of main- frequency of congenital anomalies in patients with normal or hightaining maternal euglycemia have led to later timing of delivery and ﬁrst-trimester maternal glycohemoglobin levels and found only a 3.4%reduced iatrogenic respiratory distress syndrome. Nevertheless, the rate of anomalies with an Hb A1c value less than 8.5%, whereas the rateperinatal mortality rates reported for diabetic women remain appro-ximately twice those observed in the nondiabetic population (Table46-5). Congenital malformations, respiratory distress syndrome, andextreme prematurity account for most perinatal deaths in diabetic TABLE 46-6 CONGENITAL MALFORMATIONSpregnancies. IN INFANTS OF INSULIN- DEPENDENT DIABETIC MOTHERS TABLE 46-5 PERINATAL MORTALITY RATES IN Approximate Percent DIABETIC PREGNANCY* Anomaly Relative Risk Risk (%) All cardiac defects 18 8.5 Group Gestational Overt Normal† All central nervous system anomalies 16 5.3 Fetal mortality rate (%)* 4.7 10.4 5.7 Anencephaly 13 Neonatal mortality rate (%)* 3.3 12.2 4.7 Spina biﬁda 20 Perinatal mortality rate (%)* 8.0 22.6 10.4 All congenital anomalies 8 18.4 *Mortality rates = deaths per 1000 live births. Adapted from Becerra JE, Khoury MJ, Cordero JF, et al: Diabetes † Normal was determined from California data from 1986; ﬁgures were mellitus during pregnancy and the risks for speciﬁc birth defects: corrected for birth weight, sex, and race. A population based case-control study. Pediatrics 85:1, 1990.
964 CHAPTER 46 Diabetes in Pregnancyof malformations in patients with poorer glycemic control in the peri- Using autopsy data and chemical analysis of 169 stillbirths, Sparks101conceptional period (Hb A1c above 8.5) was 22.4%. Lucas and cowork- described a relatively comparable rate of accretion of lean body massers90 reported an overall malformation rate of 13.3% in 105 diabetic in fetuses that were small for gestational age (SGA), average for gesta-patients. However, the risk of delivering a malformed infant was zero tional age (AGA), and large for gestational age (LGA), but he foundwith an Hb A1 value less than 7%, 14% with Hb A1 between 7.2% and considerable variation in the accretion of fetal fat in utero. The human9.1%, 23% with Hb A1 between 9.2% and 11.1%, and 25% with Hb A1 fetus at term has the greatest percent of body fat (approximately 10%greater than 11.2%. to 12%) compared with other mammals.102 PATHOGENESIS GROWTH DYNAMICS The mechanism by which hyperglycemia disturbs embryonic devel- The increased growth of the mother is composed primarily of totalopment is multifactorial. The potential teratologic role of disturbances body water and adipose tissue in early gestation.26 Relative to the feto-in the metabolism of inositol, prostaglandins, and reactive oxygen placental unit, the human placenta attains most of its growth by thespecies has been established.91 Embryonic hyperglycemia may promote middle of the second trimester. In contrast, approximately 70% of fetalexcessive formation of oxygen radicals in susceptible fetal tissues, growth occurs over the last third of gestation (1000 g at 28 weeks towhich are inhibitors of prostacyclin.92 The resulting overabundance of 3500 g at term). Yang and associates6 reported that IDMs with diabetesthromboxanes and other prostaglandins may then disrupt the vascu- still have an increased relative risk (RR) of being LGA (RR = 3.59;larization of developing tissues. In support of this theory, addition of 95% conﬁdence interval [CI], 1.55 to 5.84) compared with the infantsprostaglandin inhibitors to mouse embryos in culture medium pre- of women with normal glucose tolerance.100 Ogata and colleagues,103vented glucose-induced embryopathy.93 The pathogenic role of free using serial ultrasound measures of the fetus of women with diabetes,radical species in teratogenesis with diabetes has been underscored by described an increase in the rate of abdominal circumference growthdemonstrating the effect of dietary antioxidants experimentally. High after 24 weeks’ gestation. The increase in growth appears to affect pri-doses of vitamins C and E decreased fetal dysmorphogenesis to non- marily insulin-sensitive tissues such as the subcutaneous fat includeddiabetic levels in rat pregnancy and rat embryo culture.94,95 in measures of abdominal circumference.104 Ninety-ﬁve percent of the variance in fetal abdominal circumference can be accounted for by PREVENTION subcutaneous fat rather than intra-abdominal measures such as liver Because the critical time for teratogenesis is during the period 3 to size. This is consistent with the inability of the fetal liver to store much6 weeks after conception, nutritional and metabolic intervention must glycogen in early third trimester. Reece and coworkers105 showed thatbe instituted preconceptionally to be effective. Several clinical trials of fetuses of diabetic mothers have normal growth of lean body mass suchpreconceptional metabolic care have demonstrated that malformation as head and skeletal growth, even when there is marked hyperglycemia.rates equivalent to those in the general population can be achieved In longitudinal ultrasound studies, Bernstein and associates106 reportedwith meticulous glycemic control.96 Although studies of dietary folate that fetal fat and lean body mass demonstrate unique growth proﬁles.and vitamin C supplementation have demonstrated success in reduc- These unique ultrasound proﬁles potentially provide a more sensitiveing the incidence of congenital anomalies in experimental diabetes in marker of abnormal fetal growth, particularly in infants of womenrats,97 the efﬁcacy of a high-antioxidant diet in preventing diabetes- with diabetes based on the increased fat mass rather than lean mass ofinduced structural anomalies in humans has not been adequately these neonates.106 At delivery, body composition studies by Catalanoexplored. Preconceptional management of pregestational diabetics is and colleagues107 have shown that birth weight alone, even when AGA,discussed in the following sections. may not be a sensitive enough measure of fetal growth in the infant of the diabetic mother. They reported that although there were no sig-Intrauterine Growth Restriction niﬁcant differences in birth weight or lean body mass, the infants ofAlthough the weights of infants of diabetic mothers (IDMs) usually women with GDM had increased fat mass and percent body fat com-are skewed into the upper range, IUGR occurs with signiﬁcant fre- pared with a normoglycemic control group (Table 46-7).quency in diabetic pregnancies, especially in women with underlyingvascular disease. Additional factors that increase the risk for IUGR in PATHOPHYSIOLOGY OF FETAL OVERGROWTHa diabetic pregnancy include the higher incidence of structural anoma- Maternal Glucose Concentrations. Because glucose is the mostlies and maternal hypertension. easily measured nutrient and marker of diabetes, most studies evaluat- Asymmetrical IUGR is encountered most frequently in diabetic ing the effect of diabetes on fetal growth have used measures of glucosepatients with vasculopathy (i.e., retinal, renal, or chronic hyperten- as a reference. Findings from the DIEP indicate that birth weight cor-sion).88 This association suggests that uteroplacental vasculopathy may related best with second- and third-trimester postprandial glucosepromote restricted fetal growth in these patients.98 Patients with poor measures. When 2-hour postmeal glucose measures averaged 120 mg/glycemic control and frequent episodes of ketosis and hypoglycemia dL or less, approximately 20% of infants were macrosomic. In contrast,are also prone to preeclampsia and poor fetal growth. Whether fetal when 2-hour postprandial glucose measures averaged up to 160 mg/growth restriction results from poor maternal-placental blood ﬂow or dL, the rate of macrosomia reached 35%.108 Similarly, Combs andintrinsically poor placental function is unresolved.99 coworkers109 reported that macrosomia was signiﬁcantly associated with postprandial glucose levels between 29 and 32 weeks’ gestation.109Fetal Obesity In contrast, Persson and associates110 showed that fasting glucoseMacrosomia has been deﬁned using various criteria, which include concentrations account for 12% of the variance in birth weight andbirth weight greater than the 90th percentile, birth weight greater than correlated best with estimates of neonatal fat. Uvena and colleagues1114000 g, and estimates of neonatal adiposity based on body composi- found the strongest correlation was between fasting glucose and neo-tion measures. As early as 1923, research by Moulton100 described vari- natal adiposity, rather than postprandial measures.ability in weight among various mammalian species that was attributed Fetal Insulin Concentrations. Based on the early work of Ped-to the amount of adipose tissue or fat mass rather than lean body mass. ersen,112 fetal insulin has long been considered a principal driving
CHAPTER 46 Diabetes in Pregnancy 965 TABLE 46-7 NEONATAL ANTHROPOMETRICS knockout models. Baker and coworkers119 reported that null mutations OF NEWBORNS OF WOMEN WITH for the IGF1 or IGF2 gene decreases neonatal weight by 40% in mice. The effect of both genes is additive.119 Liu and associates120 previously GESTATIONAL DIABETES reported that IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP-3) MELLITUS AND NORMAL were signiﬁcantly elevated in women with type 1 and 2 diabetes com- GLUCOSE TOLERANCE pared with a control group. These data are consistent with the ﬁndings GDM NGT of other investigators, including data for women with type 1 and 2 Feature Measured* (n = 195) (n = 220) P Value diabetes.121,122 Roth and colleagues123 reported that cord levels of IGF-1 were signiﬁcantly greater in macrosomic IDMs than in nonmacroso- Weight (g) 3398 ± 550 3337 ± 549 .26 mic infants of glucose-tolerant or diabetic mothers. Radaelli and Fat free mass (g) 2962 ± 405 2975 ± 408 .74 coworkers124 showed that there was a strong negative correlation Fat mass (g) 436 ± 206 362 ± 198 .0002 between maternal circulating IGFBP-1 and lean body mass in the Body fat (%) 2.4 ± 4.6 10.4 ± 4.6 .0001 Skinfold infants. The study authors speculated that IGFBP-1 might inﬂuence Triceps 4.7 ± 1.1 4.2 ± 1.0 .0001 fetal growth by affecting IGF mediated placental nutrient transport, Subscapular 5.4 ± 1.4 4.6 ± 1.2 .0001 particularly of glucose or amino acids rather than lipids. Decreased Flank 4.2 ± 1.2 3.8 ± 1.0 .0001 IGFBP-1 levels are in keeping with a potential negative transcriptional Thigh 6.0 ± 1.4 5.4 ± 1.5 .0001 regulation of the IGFBP1 gene by insulin.124 Abdominal wall 3.5 ± 0.9 3.0 ± 0.8 .0001 Maternal Obesity. Obesity is an epidemic in developed countries and the developing world.125 In the United States, the prevalence of *Data are presented as the mean ± SD. GDM, gestational diabetes mellitus; NGT, normal glucose tolerance. obesity, deﬁned as a body mass index (BMI = weight/height2) greater Adapted from Catalano PM, Thomas A, Huston-Presley L, Amini SB: than 30 rose to 30.5% in 2000, compared with 22.9% from 1994 Increased fetal adiposity: A very sensitive marker of abnormal in utero through 1998. The proportion of the population meeting the deﬁni- development. Am J Obstet Gynecol 189:1698-1704, 2003. tion of overweight (BMI > 25) increased from 55.9% to 64.5% during the same period.18 The risk of obesity is disproportionate among the races, increasing most among African Americans and Hispanics, thefactor of in utero fetal growth. Experimental data gathered from non- same populations at risk for type 2 diabetes. Several studies suggesthuman primates by Susa and coworkers113 showed that in the rhesus that maternal obesity before conception has an independent effect onmonkey when implanted with an Alzet pump, which delivered con- fetal macrosomia. Vohr and associates126 analyzed various risk factorstinuous, increasing insulin concentrations to the fetus independent of for neonatal macrosomia in women with overt and GDM comparedthe mother’s metabolic condition, there was evidence of fetal over- with obese and normal weight controls.126 Multiple regression analysesgrowth.111 In contrast, when genetic mutations such as glucokinase revealed the pre-pregnancy weight and weight gain were signiﬁcantdeﬁciencies existed only in the fetus, the inability of the beta cell to predictors for infants of GDM and control mothers. In an effort torespond to increasing glucose concentrations results in fetal growth better understand the potential independent effect of maternal obesityrestriction.25 Many studies have conﬁrmed the correspondence of on growth of infants of GDM and normoglycemic women, Catalanoincreased cord insulin concentrations with fetal macrosomia. Schwartz and colleagues127 performed a stepwise logistic regression analysis onand associates114 found that umbilical cord insulin concentrations at data for 220 infants of mothers with normal glucose tolerance and 195delivery correlated with the degree of macrosomia. Cordocentesis infants of GDM (Table 46-8). Gestational age at term had the strongeststudies in late third trimester showed that the ratio of fetal plasma correlation with birth weight and lean body mass. In contrast, maternalinsulin to glucose and the degree of macrosomia were strongly corre- pregravid BMI had the strongest correlation (approximately 7%) withlated.115 Krew and colleagues116 reported that amniotic ﬂuid C-peptide fat mass and percent body fat. Although almost 50% of the subjectsmeasures at term had a strong correlation with fetal adiposity but not had GDM, only 2% fraction of the variance was correlated to fatlean body mass. mass.127 These data support an independent effect of maternal pre- The relationship between elevated insulin concentrations and fetal gravid obesity on fetal growth, particularly fat mass, independent ofmacrosomia exists in late pregnancy, and there is evidence of altered GDM.metabolic function in early gestation. Carpenter and colleagues117 Other Fuels. Many factors are related to fetal overgrowth of thereported that elevated amniotic ﬂuid insulin concentrations obtained infant of a woman with diabetes. The signiﬁcant decreases in insulinfrom normoglycemic patients at 14 to 20 weeks’ gestation and adjusted sensitivity in late gestation affect glucose and lipid and amino acidfor maternal age and weight correlated with the likelihood of subse- metabolism. Although we clinically concentrate on glucose, otherquently diagnosed GDM (OR = 1.9; CI, 1.3 to 2.4). Each increase in nutrients most probably contribute to fetal overgrowth. This conceptamniotic ﬂuid insulin multiple of the median (MOM) was associated is consistent with the hypothesis of fuel-mediated teratogenesis ﬁrstwith a threefold increase in fetal macrosomia.117 These data support proposed by Freinkel in 1980.128 Circulating amino acid concentrationsthe concept that the underlying pathophysiology of GDM and fetal reﬂect the balance between protein breakdown and synthesis. Dug-macrosomia may exist earlier in gestation than is routinely screened gleby and Jackson129 estimated that there is a 15% increase in proteinfor and that it is consistent with subclinical pregravid maternal meta- synthesis during the second trimester and a further 25% increase inbolic disturbances. the third trimester compared with levels in nonpregnant women. Growth Factors. There has been considerable interest in the role These differences appear to have a strong relationship to fetal growth,of insulin-like growth factors (IGFs) and fetal growth. Members of the particularly lean body mass. Butte and coworkers130 and Metzger andIGF family have been implicated in abnormalities of increased and associates131 independently reported higher amino acid concentrationsdecreased fetal growth in humans. IGF-1 and the ratio of IGF-2 to in women with GDM compared with a normoglycemic control group.the IGF-2 soluble receptor have been positively correlated with the Zimmer and colleagues132 reported no signiﬁcant difference in aminoPonderal index.118 However, there is also direct evidence using rodent acid turnover in women with GDM and a control group. However, the
966 CHAPTER 46 Diabetes in Pregnancy TABLE 46-8 STEPWISE REGRESSION 400 ANALYSIS OF FACTORS RELATING Assisted, DM Shoulder dystocia incidence per 1000 TO FETAL GROWTH AND BODY 350 Unassisted, DM Assisted, no DM COMPOSITION IN INFANTS OF Unassisted, no DM 300 WOMEN WITH GESTATIONAL DIABETES MELLITUS (n = 195) 250 AND NORMAL GLUCOSE TOLERANCE (n = 220) 200 Factor r2 Dr 2 P value 150 Birth Weight 100 Estimated gestational age 0.114 — Pregravid weight 0.162 0.048 50 Weight gain 0.210 0.048 Smoking (−) 0.227 0.017 0 Parity 0.239 0.012 .0001 3500–3750 4000–4250 4500–4750 Lean Body Mass 3750–4000 4250–4500 4750–5000 Estimated gestational age 0.122 — Birth weight (grams) Smoking (−) 0.153 0.031 Pregravid weight 0.179 0.026 FIGURE 46-10 Risk of shoulder dystocia by diabetes status and Weight gain 0.212 0.033 instrumental delivery. Shoulder dystocia occurred more often in Parity 0.225 0.013 diabetic deliveries requiring operative vaginal assistance and in Maternal height 0.241 0.016 fetuses above the 90th percentile of birth weight for age. DM, Paternal weight 0.250 0.009 .0001 diabetes mellitus. (From Nesbitt TS, Gilbert WM, Herrchen B: Shoulder dystocia and associated risk factors with macrosomic Fat Mass* infants born in California. Am J Obstet Gynecol 179:476, 1998.) Pregravid BMI 0.066 — Estimated gestational age 0.136 0.070 Weight gain 0.171 0.035 mester triglyceride concentrations were a better predictor of macroso- Group (GDM) 0.187 0.016 .0001 mia than glucose values during the glucose tolerance test. Similarly, Kitajima and colleagues138 examined lipid proﬁles in women with an Percent Body Fat* Pregravid BMI 0.072 — abnormal glucose challenge test in pregnancy and reported that the Estimated gestational age 0.116 0.044 triglycerides had a signiﬁcant correlation with birth weight, even after Weight gain 0.147 0.031 adjusting for signiﬁcant covariables. Although lipid transport from the Group (GDM) 0.166 0.019 .0001 mother to fetus is not well understood, maternal lipid metabolism may play a signiﬁcant role in fetal growth, particularly in accrual of adipose *Pregravid maternal obesity has the strongest correlation with tissue. neonatal measures of fat mass/% body fat in contrast to lean body mass. BMI, body mass index; GDM, gestational diabetes mellitus. Birth Injury Adapted from Catalano PM, Ehrenberg HM: The short and long term Birth injury is more common among the offspring of diabetic mothers, implications of maternal obesity on the mother and her offspring. and macrosomic fetuses are at the highest risk.139 The most common BJOG 113:1126-1133, 2006. birth injuries associated with diabetes are brachial plexus palsy, facial nerve injury, humerus or clavicle fracture, and cephalhematoma. Athu- korala and associates140 studied women with gestational diabetes andinvestigators found that hyperinsulinemia was required to maintain found a positive relationship between the severity of maternal fastingnormal amino acid turnover in the GDM women.132 Kalhan and hyperglycemia and the incidence of shoulder dystocia, with a doublingcoworkers133 reported that leucine turnover and oxidation were greater of risk with each 1-mmol increase in the fasting plasma glucose valuein the obese woman with GDM compared with less obese control on the OGTT. Shoulder dystocia occurred more often in diabetic deliv-subjects. The increased insulin concentrations required to maintain eries requiring operative vaginal assistance (RR = 9.58; CI, 3.70 toappropriate amino acid levels in the woman with diabetes may be 24.81: P < .001) and in fetuses above the 90th percentile of birth weightanother manifestation of the increased insulin resistance in pregnant for age (RR = 4.57; CI, 1.74 to 12.01; P < .005) (Fig. 46-10).women with GDM. Most of the birth injuries occurring in infants of diabetic pregnancy Knopp and associates134 found that there is a twofold to fourfold are associated with difﬁcult vaginal delivery and shoulder dystocia.increase in triglyceride concentrations and a 25% to 50% increase in Although shoulder dystocia occurs in 0.3% to 0.5% of vaginal deliver-cholesterol during gestation. This group also reported a further increase ies among normal pregnant women, the incidence is twofold to four-in triglyceride and high-density lipoprotein cholesterol concentrations fold higher for women with diabetes because the excessive fetal fatin type 2 and GDM patients.135 Similarly, Xiang and colleagues43 deposition associated with hyperglycemia in poorly controlled diabeticdescribed increased basal free fatty acid concentrations in Hispanic pregnancy causes the fetal shoulder and abdominal widths to becomewomen with GDM in the third trimester compared with a matched massive.140 Although one half of shoulder dystocias occur in infants ofcontrol group.136 Knopp and coworkers137 also reported that mid-tri- normal birth weight (2500 to 4000 g), the incidence of shoulder dys-
CHAPTER 46 Diabetes in Pregnancy 967tocia rises 10-fold to 5% to 7% among infants weighing 4000 g or IDMs who manifest cardiac dysfunction in the neonatal periodmore. However, if maternal diabetes is present, the risk at each birth- may have congestive or hypertrophic cardiomyopathy. This conditionweight class is increased ﬁvefold.141 These risks are further magniﬁed is often asymptomatic and unrecognized. Echocardiograms show aif a forceps or vacuum delivery is performed.142 hypercontractile, thickened myocardium, often with septal hypertro- The level of glycemic control is strongly correlated with the risk of phy disproportionate to the ventricular free walls.152 The ventricularshoulder dystocia and birth injury, presumably because increasing chambers are often smaller than normal, and there may be anteriorlevels of hyperglycemia are associated with greater fetal fat deposition. systolic motion of the mitral valve, producing left ventricular outﬂowAthukorola and colleagues140 reported a positive correlation between tract obstruction.the severity of maternal fasting hyperglycemia and the risk of shoulder Neonatal septal hypertrophy may be a response to chronic hyper-dystocia, with each 1-mmol increase in the fasting value in the OGTT glycemia. The maternal level of IGF-1, which is elevated in subopti-associated with an increasing relative risk of 2.09 (CI, 1.03 to 4.25). mally controlled diabetic pregnancy, is signiﬁcantly elevated in neonates Although it would be desirable to predict shoulder dystocia on with asymmetrical septal hypertrophy. Because IGF-1 does not crossthe basis of warning signs during labor such as labor protraction, a the placenta, it may exert its action through binding to the IGF-1suspected macrosomic infant, or the need for midpelvic forceps receptor on the placenta.153 Halse and coworkers154 found that the leveldelivery, less than 30% of these events can be predicted from clinical of B-type natriuretic protein (BNP), a marker for congestive cardiacfactors.143 failure, is elevated in neonates whose mothers had poor glycemic control during the third trimester. Septal hypertrophy can be identiﬁed with sonography in the pre-Neonatal Morbidity and Mortality natal period. Cooper and coworkers155 performed serial fetal echocar- diography on 61 pregnant, diabetic women, demonstrating excessivePolycythemia and Hyperviscosity ventricular septal thickness in the fetuses that were diagnosed postna-Polycythemia (i.e., central venous hemoglobin concentration >20 g/dL tally with asymmetrical septal hypertrophy. When the newborns withor hematocrit >65%) occurs in 5% to 10% of IDMs and is apparently asymmetrical septal hypertrophy were compared with normal infants,related to glycemic control. Hyperglycemia is a powerful stimulus for birth weights (4009 versus 3457 g; P < .01) and maternal glycosylatedfetal erythropoietin production, which is probably mediated by hemoglobin levels (6.7% versus 5.7%) were higher in infants withdecreased fetal oxygen tension.144 Untreated, neonatal polycythemia cardiomyopathy.may promote vascular sludging, ischemia, and infarction of vitaltissues, including the kidneys and central nervous system. Respiratory Distress Syndrome Until recently, respiratory distress syndrome was the most commonNeonatal Hypoglycemia and most serious disease in IDMs. In the 1970s, improved prenatalApproximately 15% to 25% of neonates delivered from women with maternal management for diabetes and new techniques in obstetricsdiabetes during gestation develop hypoglycemia during the immediate for timing and mode of delivery resulted in a dramatic decline in itsnewborn period.145 Neonatal hypoglycemia is less common when tight incidence, from 31% to 3%.156 However, even when matched by gesta-glycemic control is maintained during pregnancy146 and in labor. tional week of pregnancy, IDMs are more than 20 times as likely as A detailed study by Taylor and associates147 found no correlation infants from normal pregnancies to develop respiratory distressbetween the likelihood of neonatal hypoglycemia and Hb A1c, whereas syndrome.157mean maternal glucose levels during labor were strongly predictive. The increased susceptibility to respiratory distress may result fromBecause unrecognized postnatal hypoglycemia may lead to neonatal altered production of alveolar surfactant or abnormal pulmonaryseizures, coma, and brain damage, it is imperative that the neonatal function. Kulovich and Gluck158 reported delayed timing of phospho-team caring for the neonate follow a protocol of frequent postnatal lipid production in diabetic pregnancy, as indicated by a delay in theglucose monitoring until metabolic stability is ensured. appearance of phosphatidylglycerol in the amniotic ﬂuid. In their study, maturational delay occurred only in gestational diabetes (WhiteNeonatal Hypocalcemia and Hyperbilirubinemia class A patients); fetuses of women with other forms of diabetes showedLow levels of serum calcium (<7 mg/100 mL) have been reported in normal or accelerated maturation of pulmonary phospholipid proﬁles.up to 50% of IDMs during the ﬁrst 3 days of life, although later series Although some investigators have failed to demonstrate a delay inrecord an incidence of 5% or less with better-managed pregnancies.148 lung maturation in diabetic pregnancy,159,160 most reports in the litera-Neonatal hyperbilirubinemia occurs in approximately 25% of IDMs, ture indicate a signiﬁcant biochemical and physiologic delay in IDMs.a rate approximately double that for normal infants, with prematurity Tyden and colleagues161 and Landon and coworkers162 reported thatand polycythemia being the primary contributing factors. Close moni- fetal lung maturity occurred later in pregnancies with poor glycemictoring of the newborn of diabetic pregnancy is necessary to avoid the control (mean plasma glucose level >110 mg/dL), regardless of class offurther morbidity of kernicterus, seizures, and neurologic damage. diabetes, when the infants were stratiﬁed by maternal plasma glucose levels. These ﬁndings were conﬁrmed by Moore,163 who demonstratedHypertrophic and Congestive Cardiomyopathy no differences in the rate of rise of the amniotic ﬂuid lecithin-to-In some macrosomic, plethoric infants of mothers with poorly con- sphingomyelin ratio among types of diabetes or degree of glucosetrolled diabetes, a thickened myocardium and signiﬁcant asymmetrical control but found that amniotic ﬂuid phosphatidylglycerol was delayedseptal hypertrophy has been described.149 The prevalence of clinical approximately 1.5 weeks in women with pregestational or GDM dia-and subclinical asymmetrical septal hypertrophy in IDMs has been betes compared with controls (Fig. 46-11). The delay in phosphatidyl-estimated to be as high as 30% at birth, with resolution by 1 year of glycerol was associated with an earlier and higher peak in the level ofage.150 Kjos and colleagues151 found that cardiac dysfunction associated phosphatidyl inositol, suggesting that elevated maternal plasma levelswith this entity often leads to respiratory distress, which may be mis- of myoinositol in diabetic women may inhibit or delay the productiontaken for hyaline membrane disease. of phosphatidylglycerol in the fetus.
968 CHAPTER 46 Diabetes in Pregnancy cohort studies such as the Nurses Health Study165 and the Health Pro- 100 fessional Follow-up Study166 report a J-shaped curve (i.e., a slightly greater BMI among subjects born small but a much greater prevalence of overweight and obesity in those born large).167 The increased preva- 80 Controls lence of adolescent obesity is related to an increased risk of the meta- Overt DM bolic syndrome. The increased incidence of obesity accounts for much 3% GDM of the 33% increase in type 2 diabetes, particularly among the young. 60 Between 50% and 90% of adolescents with type 2 diabetes have a BMI Cumulative % PG greater than 27,168 and 25% of obese children between 4 and 10 years old have impaired glucose tolerance.169 The epidemic of obesity and subsequent risk for diabetes and components of the metabolic syn- 40 drome may begin in utero with fetal overgrowth and adiposity, rather than undergrowth. A retrospective cohort study by Whitaker170 enrolling more than 20 8400 children in the United States in the early 1990s reported that children who were born to obese mothers (based on BMI in the ﬁrst trimester) were twice as likely to be obese when they were 2 years old. If a woman had a BMI of 30 or more in the ﬁrst trimester, the preva- 0 lences of childhood obesity (BMI > 95th percentile based on criteria 29 31 33 35 37 39 41 43 Gestational week at amniocentesis of the Centers for Disease Control and Prevention [CDC]) at ages 2, 3, and 4 years were 15.1%, 20.6%, and 24.1%, respectively. This wasFIGURE 46-11 Delay in fetal pulmonary phosphatidyl between 2.4 and 2.7 times the prevalence of obesity observed inglycerol. The delay in fetal pulmonary phosphatidyl glycerol was children of mothers whose BMI values were in the normal range (18.5associated with a sustained peak in phosphatidyl inositol in diabetic to 24.9). This effect was only slightly modiﬁed by birth weight.pregnancy, suggesting that elevated maternal plasma levels of There is an independent effect of maternal pregravid weight andmyoinositol in a diabetic woman may inhibit or delay the production diabetes on birth weight and on the adolescent risk of obesity. Langerof phosphatidyl glycerol in the fetus. DM, diabetes mellitus; GDM, and colleagues171 reported that in obese women with GDM whosegestational diabetes mellitus; PG, phosphatidyl glycerol. (From Moore glucose was well controlled on diet alone, the odds of fetal macrosomiaTR: A comparison of amniotic ﬂuid fetal pulmonary phospholipids in (birth weight >4000 g) were signiﬁcantly increased (OR = 2.12) com-normal and diabetic pregnancy. Am J Obstet Gynecol 186:641, 2002.) pared with women with well-controlled (diet only) GDM and normal BMIs. Similar results were reported for women with GDM who were poorly controlled with diet or with insulin. In well-controlled, insulin- It is possible that poor neonatal respiratory performance in the requiring women with GDM, there was no signiﬁcant increased riskIDM may have a histologic basis in addition to a biochemical of macrosomia with increasing pregravid BMI. Dabelea and associ-cause. Kjos and coauthors151 identiﬁed respiratory distress in 3.4% of ates172 reported that the mean adolescent BMI was 2.6 kg/m2 greater ininfants delivered of diabetic women, but surfactant-deﬁcient airway sibling offspring of diabetic pregnancies compared with the indexdisease accounted for less than one third of cases, with transient tachy- siblings born when the mothers previously had normal glucose toler-pnea, hypertrophic cardiomyopathy, and pneumonia responsible for ance. Both maternal pregravid obesity and the presence of maternalmost. diabetes may independently affect the risk of adolescent obesity in the The near-term infant of a mother with poorly controlled diabetes offspring.is more likely to have neonatal respiratory dysfunction than is the This risk of developing the metabolic syndrome in adolescents wasinfant of a nondiabetic mother. The observations of Moore163 indicate addressed by Boney and colleagues173 in longitudinal cohort study ofthat the average nondiabetic fetus achieves pulmonary maturity at 34 AGA and LGA infants of women with normal glucose tolerance andto 35 weeks’ gestation, with more than 99% of normal newborns GDM. The metabolic syndrome was deﬁned as the presence of two orhaving a mature phospholipid proﬁle by 37 weeks. In diabetic preg- more of the following components: obesity, hypertension, glucosenancy, however, it cannot be assumed that lung maturity exists until intolerance, and dyslipidemia. Maternal obesity was deﬁned as a pre-approximately 10 days after the nondiabetic time (38.5 gestational gravid BMI higher than 27.3. Children who were LGA at birth had anweeks). Any delivery contemplated before 38.5 weeks’ gestation for increased hazard ratio (HR) for metabolic syndrome (HR = 2.19; CI,other than the most urgent fetal and maternal indications should be 1.25 to 3.82; P = .01) by age 11 years, as did children of obese womenpreceded by documentation of pulmonary maturity by amniocentesis. (HR = 1.81; CI, 1.03 to 3.19; P = .04). The presence of maternal GDMThe neonatal complications of the offspring of diabetic pregnancy is was not independently signiﬁcant, but the risk for developing meta-discussed further in Chapter 58. bolic syndrome was signiﬁcantly different between LGA and AGA off- spring of GDM by age 11 years (RR = 3.6).Long-Term Risks for the Fetus of theObese MotherAlthough much has been written about the increased risk of the meta- Childhood Neurologic Abnormalitiesbolic syndrome (i.e., obesity, hypertension, insulin resistance, and dys- Several reports have suggested childhood neurodevelopmental abnor-lipidemia) in infants born SGA, evidence points toward an increase in malities in offspring of diabetic mothers. Rizzo and colleagues174 com-adolescent and adult obesity in infants born LGA or macrosomic. pared the offspring of 201 mothers with diabetes with 83 children ofThere has been abundant evidence linking higher birth weights to normal mothers and correlated subsequent childhood obesity in theincreased obesity of adolescents and adults for at least 25 years.164 Large offspring of diabetic mothers with internalizing behavior problems,
CHAPTER 46 Diabetes in Pregnancy 969somatic complaints, anxiety or depression, and social problems. Ornoy For patients who have had diabetes for 10 years or longer, anand associates175 assessed IQ scores on the Wechsler Intelligence Scale electrocardiogram, an echocardiogram, and microalbuminuriafor Children–Revised (WISC-R) and Bender tests of the children born and serum creatinine studies should be performed.to diabetic mothers. No differences were found between the study Because retinopathy can progress during pregnancy, the patientgroups in various sensorimotor functions compared with controls, but should establish a relationship with a qualiﬁed ophthalmologicthe children of diabetic mothers performed less well than controls in provider. A baseline retinal evaluation should be completedﬁne and gross motor functions, and they scored lower on the Pollack within the year before conception, with laser photocoagulationtaper test, which is designed to detect inattention and hyperactivity. performed if needed. Previous laser treatment is not aThese investigators also found a negative correlation between the contraindication to pregnancy and may avoid signiﬁcantseverity of maternal hyperglycemia, as assessed by glycosylated hemo- hemorrhage during pregnancy.globin levels in the third trimester, and performance on neurodevel- Thyroid function (i.e., thyroid-stimulating hormone and freeopmental and behavioral tests. thyroxine) should be evaluated and corrected as necessary in all patients with pregestational diabetes because of the frequent coincidence of autoimmune thyroid disease and diabetes. A daily prenatal vitamin that provides 1 mg of folic acid shouldPreconceptional be prescribed for a minimum of 3 months before conception, because folate supplementation signiﬁcantly reduces the risk ofManagement of Women with congenital neural tube defects.Pregestational Diabetes The patient’s occupational, ﬁnancial, and personal situation should be reviewed, because job and family pressures canAlthough widely underused,176 preconceptional care programs have become barriers to achieving and maintaining excellentconsistently been associated with decreased morbidity and mortality.177 glycemic control. In patients with pre-pregnancy hypertensionPatients enrolled in preconceptional diabetes-management programs or proteinuria, particular emphasis should be given to deﬁningobtain earlier prenatal care and have lower Hb A1c values in the ﬁrst support systems that permit extended bed rest in the thirdtrimester.178 A comparison of outcomes among women participating trimester, if it becomes necessary.in a intensive preconceptional program with outcomes among women The patient’s preconception medications should be reviewedreceiving standard care demonstrated lower perinatal mortality (0% and altered to avoid teratogenicity and potential embryonicversus 7%) and reduced congenital anomalies (2% versus 14%). When toxicity. Statins are pregnancy category X drugs and shouldthe preconceptional program was discontinued because of a lack of be discontinued before conception. Angiotensin-convertingfunds, the congenital anomaly rate increased by more than 50%.7 enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) should be discontinued before conception because of ﬁrst trimester teratogenicity and fetal renal toxicity in theRisk Assessment second half of pregnancy. Among oral antidiabetic agents usedSeveral factors should be considered in preconceptional diabetes risk by reproductive-aged women, metformin and acarbose areassessment (Table 46-9): classiﬁed as pregnancy category B drugs, although systematic data on safety are lacking. All other agents are category C Glycemic control should be assessed directly from glucose logs drugs, and unless the potential risks and beneﬁts of oral and by glycosylated hemoglobin levels. antidiabetic agents in the preconception period have been TABLE 46-9 PRECONCEPTIONAL EVALUATION OF THE DIABETIC PATIENT Procedure Tests Recommendations Medical history, family history, review of Selected patients: fasting and postprandial Avoid pregnancy until Hb A1c value is in the symptoms C-peptide determinations to clarify type normal, nonpregnant range of diabetes Physical examination ﬁndings Hypertension ECG, cardiac, renal evaluation Antihypertensive medications Retinopathy Retinal evaluation Ophthalmology consultation Goiter T4, thyroid-stimulating hormones, antibodies Neuropathy Vascular, podiatric evaluations Obesity Exercise, weight loss Proteinuria 24-hr urine for protein, creatinine Nephrology consultation if renal function abnormal Diabetes assessment Hb A1c Glycemic control Home glucose monitoring Stable glycemic proﬁle Nutrition Dietitian consultation Occupational and family life assessment Help prepare patient for lifestyle commitments necessary for tight glycemic control ECG, electrocardiogram; Hb, hemoglobin; T4, thyroxine.
970 CHAPTER 46 Diabetes in Pregnancy carefully weighed, they usually should be discontinued in available studies. The malformation rate in the disease-matched control pregnancy. group was approximately 7.2%, statistically signiﬁcantly higher than the rate found in the metformin group (1.7%). After adjustment for confounders, ﬁrst-trimester metformin treatment was associated withMetabolic Management a statistically signiﬁcant 57% reduction in birth defects.186The goal of preconceptional metabolic management is to achieve an In a study of women with type 2 diabetes mellitus, 93 of whomHb A1c level within the normal range before conception using a safe took metformin (61 in the ﬁrst trimester and 32 throughout theand reliable medication regimen that permits a smooth transition pregnancy) and 121 of whom did not take metformin, there was nothrough the ﬁrst trimester. The patient should be skilled in managing difference between the metformin and control groups in the rate ofher glucose levels in a narrow range well before pregnancy begins, so preeclampsia (13% versus 14%; P = .84), perinatal loss (3% versus 2%;that the inevitable insulin adjustments necessitated by the appetite, P = .65), or neonatal morbidity, including rate of prematurity (23%metabolic, and activity changes of early pregnancy can be accom- versus 22%; P = .7), admission to the neonatal unit (40% versus 48%;plished smoothly. P = .27), respiratory distress (9% versus 18%; P = .07), and neonatal A regimen of regular monitoring of preprandial and postprandial hypoglycemia (20% versus 31%; P = .08).187capillary glucose levels should be instituted. Although there are no data The concentrations of metformin in breast milk are generally low,indicating that postprandial glucose monitoring is required before and the mean infant exposure to metformin has been reported in thepregnancy to achieve adequate control, monitoring these levels range of 0.28% to 1.08% of the weight-normalized maternal dose. Noincreases the preconceptional woman’s awareness of the interaction of adverse effects on blood glucose of nursing infants have beendietary content and quality with postprandial glycemic excursions.179 reported.188The insulin regimen should result in a smooth glucose proﬁle through-out the day, with no hypoglycemic reactions between meals or atnight. Antihypertensive Medications Hypertension is a common comorbidity of diabetes and is found in 20% to 30% of women who have had diabetes for longer than 10 years.Oral Hypoglycemic Agents Although treatment of modest degrees of hypertension (<160 mm HgA longitudinal trial in the United Kingdom of intensiﬁed metabolic systolic) during pregnancy has not been shown to be beneﬁcial intherapy in nonpregnant women with type 2 diabetes180 demonstrated improving perinatal outcome,74 treatment in nonpregnant diabeticthat oral agents were more effective than insulin in lowering Hb A1c women is recommended when blood pressure is consistently higherlevels. This effect was attributed to improved compliance and fewer than 130/80 mm Hg.19 The U.K. Prospective Diabetes Study and thehypoglycemic reactions. For this and other reasons, most women with Hypertension Optimal Treatment trial demonstrated improved out-type 2 diabetes use one or more oral agents for glycemic control—typi- comes, especially in preventing stroke, in patients assigned to lowercally metformin and a sulfonylurea or thiazolidinediones. Details of blood pressure targets. Patients frequently enter the preconceptionalthe mechanism of action and pharmacology of these oral hypoglyce- period taking one or more antihypertensive medications.189 In precon-mic agents are discussed later. Despite the absence of evidence of tera- ceptional and pregnant patients with diabetes and chronic hyperten-togenicity for most of these compounds, none is recommended for use sion, blood pressure target goals of 110/65 to 129/79 mm Hg arein pregnancy. Standard practice is to transition these patients to insulin recommended in the interest of long-term maternal health and mini-management preconceptionally. mizing impaired fetal growth.19 A possible exception is the use of metformin in infertile patients None of the commonly used antihypertensive medications (e.g.,with polycystic ovary syndrome who are otherwise oligo-ovulatory. calcium channel blockers, β-blockers, methyldopa) is teratogenic. ACEThese patients have higher conception and lower miscarriage rates inhibitors deserve special mention because in nonpregnant subjectswith metformin treatment.181 Although two small series documenting with diabetic nephropathy, they have been shown to ameliorate pro-the apparent safety of continuing metformin during pregnancy have teinuria and delay progression to end-stage renal disease. These medi-been published,182,183 discontinuing metformin after pregnancy is cations are therefore considered ﬁrst-line agents for diabetic womenestablished is recommended. with signiﬁcant proteinuria.180 Many women with type 1 diabetes Metformin readily crosses the placenta, exposing the fetus to con- present for consultation preconceptionally or even in early pregnancycentrations approaching those in the maternal circulation. The sequelae while taking these medications. It is not clear whether these medica-of such exposure (i.e., effects on neonatal obesity and insulin resis- tions have teratogenic effects when used in the ﬁrst trimester, but usetance) remain unknown. A study of perfused human placental lobules in the second trimester and beyond can cause a marked reduction infrom gestational diabetic and normoglycemic women demonstrated fetal renal blood ﬂow, resulting in oligohydramnios and even frankthat metformin was readily transferred from the maternal to the fetal fetal renal failure.190 These medications should not be used duringcirculation.184 pregnancy, especially after the ﬁrst trimester. Similar concerns exist for A more direct assessment of maternal and fetal pharmacodynamics other agents in this family (i.e., ARBs and angiotensin receptorwas performed by Charles and coworkers185 by obtaining maternal antagonists).191blood in the third trimester from metformin takers with gestationalor type 2 diabetes. Cord blood also was obtained. Mean metforminconcentrations in cord and maternal plasma were 0.81 and 1.2 mg/L,respectively. The maternal plasma half-life is 5.1 hours. Because these Diagnosing Diabetespharmacokinetics are similar to those in nonpregnant patients, nodosage adjustment is warranted.185 Overt Diabetes With regard to teratogenicity associated with metformin use in Patients with type 1 diabetes are typically diagnosed during an episodepregnancy, Gilbert and associates performed a meta-analysis of eight of hyperglycemia, ketosis, and dehydration. Type 1 diabetes is rarely
CHAPTER 46 Diabetes in Pregnancy 971diagnosed during pregnancy. The diagnosis of type 2 diabetes cannot TABLE 46-10 LOW-RISK CRITERIA FORbe accomplished during pregnancy because of the overlap with early- GESTATIONAL DIABETESonset gestational diabetes. Although the ﬁnding of an elevated Hb A1c SCREENINGlevel in early pregnancy may be suggestive, deﬁnitive diagnosis of type2 diabetes must be made after pregnancy. The diagnostic criteria rec-ommended by the ADA for diabetes are listed in Table 46-2. Hyperglycemia not sufﬁcient to meet the diagnostic criteria fordiabetes is categorized as IFG or IGT, depending on whether it isidentiﬁed through a fasting plasma glucose level or a 75-g, 2-hourOGTT19: IFG: fasting plasma glucose level of 100 to 125 mg/dL (5.5 to 6.9 mmol/L) American Diabetes Association: Gestational diabetes mellitus: A IGT: 2-hour plasma glucose level of 140 to 199 mg/dL (7.8 to position statement. Diabetes Care 27(Suppl 1):S88, 2004. 11 mmol/L) Patients with IFG or IGT before pregnancy should be consideredat extremely high risk for developing GDM. GDM patients whose TABLE 46-11 THREE-HOUR 100-GRAM ORALpostpartum testing results in the diagnosis of IFG or IGT are at sig- GLUCOSE TOLERANCE TEST FORniﬁcant risk for the disease evolving into frank diabetes within 5 to 10 GESTATIONAL DIABETESyears. Test Prerequisites Patients with IFG or IGT should be counseled regarding weight loss 1-hr, 50-g glucose challenge result ≥135 mg/dLand provided instruction for increasing physical activity. Monitoring Overnight fast of 8-14 hrfor the development of diabetes in those with prediabetes should be Carbohydrate loading for 3 days, including ≥150 g of carbohydrateperformed every 1 to 2 years. Screening for and appropriate treatment Seated, not smoking during the testfor other cardiovascular risk factors (e.g., tobacco use, hypertension, Two or more values must be met or exceeded for a diagnosis ofdyslipidemia) is important. There is insufﬁcient evidence to support GDMthe use of drug therapy in women with IFG or IGT. Plasma Glucose Level after a Assessment for Gestational 100-g Glucose Load mg/dL Diabetes Mellitus (mmol/L)Gestational Diabetes Fasting 95 (5.3) 1 hr 180 (10.0)Risk Factor Screening 2 hr 155 (8.6)Risk factor assessment for GDM should be performed at the ﬁrst pre- 3 hr 140 (7.8)natal visit. High-risk clinical characteristics include the following: Age older than 35 to 40 years Obesity (BMI > 30) History of GDM cologists (ACOG)196 recommend the use of the Carpenter and Coustan Delivery of a previous LGA infant diagnostic criteria for the 3-hour, 100-g glucose OGTT (Table 46-11). Polycystic ovary syndrome However, these expert bodies also acknowledge the alternative use of A strong family history of diabetes a single-step, 2-hour, 75-g glucose OGTT. Patients with these risk factors should receive plasma glucose ONE-STEP OPTIONscreening without delay. High-risk women not found to have GDM at The one-step, 75-g glucose, 2-hour OGTT, which is commonly usedthe initial screening should be tested again between 24 and 28 weeks’ outside the United States, is no longer recommended because of itsgestation. inferior detection rate of GDM. Mello and colleagues197 compared the Previously, screening of all pregnant women for GDM was recom- diagnostic efﬁciency of the 75-g, 2-hour OGTT with the 3-hour, 100 g-mended, but the ADA192 modiﬁed this recommendation such that OGTT and found that the 2-hour test was less than one half as sensitivescreening can be omitted for low-risk women meeting all of the criteria in diagnosing GDM (5% versus 12%).listed in Table 46-10. This policy is based on the ﬁndings of Naylor and The current one-step option involves direct administration of thecolleagues,193 who reported that women with one or no risk factors had 3-hour, 100-g glucose OGTT. Two or more values must be met ora 0.9% risk of GDM, whereas 4% to 7% of those with two to ﬁve risk exceeded for the diagnosis of GDM. The critical cutoff values for thefactors were diagnosed with GDM, resulting in a sensitivity of approxi- 3-hour OGTT are listed in Table 46-11. Direct, one-step administra-mately 80% with a false-positive rate of 13%. tion of the 3-hour, 100-g OGTT test should be considered in women with prior GDM, especially those with additional risk factors such asOne- or Two-Step Screening obesity.The diagnosis of GDM is based on a positive OGTT result. Guidelinesissued by the Fourth International Workshop-Conference on Gesta- TWO-STEP OPTIONtional Diabetes Mellitus194 and reafﬁrmed by the Fifth International In the two-step approach, a screening glucose challenge test (GCT)Conference195 and the American College of Obstetricians and Gyne- is administered using 50 g of glucose in the fasting or nonfasting state.
972 CHAPTER 46 Diabetes in Pregnancy TABLE 46-12 SENSITIVITY AND COST SINGLE ABNORMAL VALUE ON THE 3-HOUR ASSOCIATED WITH UNIVERSAL ORAL GLUCOSE TOLERANCE TEST A fasting plasma glucose level exceeding 126 mg/dL should be con- AND SELECTIVE SCREENING sidered highly suspicious for diabetes in pregnant and nonpregnant WITH VARIOUS GLUCOSE patients. Individuals with fasting plasma glucose levels above 126 mg/ CHALLENGE THRESHOLDS dL should have another fasting test; if the result of the second test is Threshold Value for 1-hr, 50-g high, GDM is conﬁrmed. Glucose Challenge Patients with a single abnormal OGTT value are at increased risk for infants with macrosomia and neonatal morbidity. Berkus and col- Factor 130 mg/dL 140 mg/dL leagues201 followed 764 patients with GDM, stratiﬁed by the number Sensitivity (%) 100 79 of abnormal values on their OGTTs. Patients with one or more Percent of population (%) 22 13 abnormal OGTT values had double the incidence of macrosomic requiring OGTT infants (23% to 27% versus 13%; P < .01). When Langer and cowork- Threshold ers202 compared perinatal outcomes in patients with a single abnormal Value (mg/dL) Sensitivity (%) OGTT value with normal women and with aggressively managed GDM patients, they found the incidence of macrosomia to be more Universal 140 90 130 100 than threefold higher in the single abnormal value group than in the Risk factors + age ≥25 yr 140 85 normal (34% versus 9%) and GDM (34% versus 12%) groups. Neo- 130 95 natal morbidity was ﬁvefold higher in the single abnormal OGTT value group (15%) compared with the control and GDM groups (3%). OGTT, oral glucose tolerance test. McLaughlin and colleagues203 reviewed the perinatal outcomes of Adapted from Coustan DR, Nelson C, Carpenter MW, et al: Maternal 14,036 women who had normal 1-hour or 3-hour glucose levels using age and screening for gestational diabetes: A population based study. Obstet Gynecol 73:557, 1989. standard criteria (i.e., 1-hour GCT cutoff of 140 mg/dL and 3-hour OGTT [see Table 46-11]). Of these, 3% had a single elevated value on the 3-hour test. Comparing the single elevated value group to those with all normal values, higher rates of cesarean delivery, preeclampsia, chorioamnionitis, birth weights higher than 4000 g and 4500 g, andFor those whose plasma glucose value obtained after 1 hour exceeds a neonatal intensive care unit admission were recorded (adjustedcritical threshold value, a 100-g, 3-hour OGTT is administered, using OR = 1.6, 1.5, 1.5, 1.7, 2.2, and 1.5, respectively; P < .03).203the diagnostic criteria listed in Table 46-11. These results underscore the problems associated with the methods used to identify patients with GDM. The relationships among carbo- THRESHOLD VALUE FOR THE GLUCOSE hydrate metabolism, macrosomia, and neonatal morbidity create aCHALLENGE TEST continuum that deﬁes a single, clear-cut criterion for diagnosis in all The sensitivity of the GDM testing regimen depends on the thresh- populations. The recommended schemes identify at most 90% of preg-old value used for the 50-g GCT. Recommendations from the ADA19 nancies susceptible to hyperglycemia and fetal macrosomia. The astuteand ACOG196 explain that using a threshold value of 140 mg/dL results clinician should approach women with several GDM risk factors andin approximately 80% detection of GDM, whereas using a threshold a single abnormal OGTT value with caution. When in doubt, a trial ofof 130 mg/dL results in 90% detection. A potential disadvantage of capillary glucose testing may help to clarify the patient’s metabolicusing the lower value of 130 mg/dL is an approximate doubling in the status.number of OGTTs performed. The Canadian study,193 based onreceiver-operator curve analysis, calculated that diagnostic efﬁciency Other Tests for Gestational Diabeteswas optimized when a GCT threshold of 130 mg/dL was used for Several investigators have searched for a single, nonglucose blood testintermediate-risk women (i.e., two to four risk factors) and 128 mg/dL that can accurately predict the results of the OGTT. Because of thefor higher-risk women. These issues are summarized in Table 46-12. proportional relationship of glycated proteins and long-term plasma A threshold plasma glucose value of 130 mg/dL is recommended glucose concentrations, fructosamine and Hb A1c screening have beenfor use in practices with a signiﬁcant proportion of higher-risk gravi- evaluated. Roberts and colleagues204 suggested that fructosaminedas (e.g., multiracial, obese). This approach provides excellent test screening for GDM could produce a sensitivity of 85% with a speciﬁc-sensitivity for GDM (>90%) with acceptable cost. Deﬁnitive random- ity of 95%. A positive relationship between fructosamine levels andized trials regarding cost-effectiveness with respect to perinatal out- macrosomia was demonstrated.205,206 However, subsequent studiescomes and neonatal costs have not yet been performed.198 have reported signiﬁcantly lower sensitivities.207,208 Inferior sensitivity and predictive values have been reported for MAXIMUM VALUE FOR THE GLUCOSE glycohemoglobin measurements (i.e., Hb A1 and Hb A1c) by Shah andCHALLENGE TEST colleagues,209 Baxi and associates,210 and Artal and coworkers211 (22%, The risk of GDM is approximately proportional to the result of the 63%, and 74%, respectively). A study by Agarwal and associates2121-hour GCT. Dooley and coworkers199 found that among nonwhite assessed the use of lower cutoffs for fructosamine and Hb A1c to excludewomen, the risk of GDM with a 1-hour glucose value of 200 mg/dL or subjects from further GDM screening and higher cutoffs for one-stepmore is greater than 90%. Bobrowski and colleagues200 reported that diagnosis. The lower cutoffs achieved sensitivities of 90% and negativeall patients with a screening result above 216 mg/dL had a positive 3- predictive values of more than 85%. However, the upper cutoff valueshour OGTT result. Most experts omit the 3-hour OGTT for patients did not achieve acceptable positive predictive values to be useful forwith GCT results of 200 mg/dL or greater and manage the patient as diagnosing GDM. Thus the role of these tests would be to identifya gestational diabetic. patients rather than to screen for GDM, but using them would impose
CHAPTER 46 Diabetes in Pregnancy 973 TABLE 46-13 PREVALENCE OF GESTATIONAL TABLE 46-14 RISK FACTORS FOR DIABETES IN VARIOUS NATIONAL GESTATIONAL DIABETES AND ETHNIC GROUPS Patients with any of these factors should be screened for GDM at the ﬁrst prenatal visit: Study Population Prevalence (%) Maternal age >25 yr Previous macrosomic infant Harris et al, 1997 Native American (Cree) 8.3 Previous unexplained fetal demise Henry et al, 1993 Australian 7.8 Previous pregnancy with GDM Vietnamese 4.3 Strong immediate family history of NIDDM or GDM Nahum et al, 1993 African American 7.5 Obesity (>90 kg) White 4.7 Fasting glucose >140 mg/dL (7.8 mM) or random glucose Asian 4.2 >200 mg/dL (11.1 mM) Lopez-de la Pena et al, Mexican 6.9 1997 GDM, gestational diabetes mellitus; NIDDM, non–insulin-dependent Yalcin et al, 1996 Turkish 6.6 diabetes mellitus. Rith-Najarian et al, 1996 Native American 5.8 (Chippewa) Fraser et al, 1994 Israeli 5.7 the third trimester limits the time in which metabolic intervention can Bedouin 2.4 take place. For this reason, it is recommended that glucose tolerance Rizvi et al, 1992 Pakistani 3.5 Miselli et al, 1994 Italian 2.3 testing be performed in all patients at 24 to 28 weeks’ gestation.214 Serirat et al, 1992 Thai 2.2 Whether administered at 12 or 26 weeks, the GCT can be per- Jang et al, 1995 Korean 2.2 formed without regard to recent food intake (i.e., nonfasting state). Mazze et al, 1992 White, Minnesota 1.5 Coustan and coworkers215 have shown that tests performed in fasting subjects are more likely to yield falsely elevated results than are tests conducted between meals. This ﬁnding was conﬁrmed by Sermer and colleagues.216an additional step and cost on the diagnostic regimen. Althoughscreening with glycosylated proteins could theoretically reduce thenumber of two-step diagnostic procedures, their lack of sensitivity indiagnosis and the additional time and cost have left these studies of Metabolic Managementlimited use in screening for GDM. of Women withTiming of Gestational Diabetes Screening Pregestational Diabetes FIRST-TRIMESTER SCREENING The timing of glucose tolerance testing during pregnancy is critical, The primary goals of metabolic management (i.e., glycemic monitor-because delayed diagnosis increases the duration of deranged maternal ing, dietary regulation, and insulin therapy) in diabetic pregnancy aremetabolism and accelerated fetal growth. However, because the preva- to prevent or minimize the postnatal sequelae of diabetes—macroso-lence of GDM increases with advancing gestation due to rising insulin mia, shoulder dystocia, birth injury, and postnatal metabolic instabil-resistance mediated by placental hormones, testing too early can over- ity—in the newborn. A secondary goal is to reduce the risk of pediatriclook some patients who will develop disease later. and adult metabolic syndrome in the offspring. If this goal is to be A surprising percentage of patients (6% to 20%) with GDM can be achieved, glycemic control must be instituted early and aggressively.diagnosed in the ﬁrst trimester. Most have signiﬁcant risk factors forglucose intolerance. Moses and associates213 assessed the prevalence ofGDM in patients with various risk factors. GDM was identiﬁed in 6.7% Principles of Medicaloverall, in 8.5% of women 30 years old or older, in 12.3% of women Nutritional Therapywith a BMI of 30 or more, and in 11.6% of women with a family There is a surprising lack of well-controlled research on the optimalhistory of diabetes. A combination of risk factors predicted GDM in diet for lean or obese women with diabetes. Most recommendations61% of cases compared with 4.8% of those without risk factors. The regarding dietary therapy are based on common sense and experience.additional effect of ethnicity on the prevalence of GDM is summarized Because women with all types of diabetes experience inadequatein Table 46-13. insulin action after feeding, the goal of medical nutritional therapy is Risk factor assessment for GDM (i.e., maternal age, ethnicity, to avoid single, large meals containing foods with a high percentage ofobstetric and family history, body habitus, prior GDM, prior IGT, prior simple carbohydrates that release glucose rapidly from the maternalmacrosomic infant, or unexplained stillbirth) should be performed at gut. Three major meals and three snacks are preferred, because thisthe ﬁrst prenatal visit of all pregnant women. Patients with any of these multiple-feeding regimen limits the amount of calories presented torisk factors (Table 46-14) should undergo screening as soon as feasible, the bloodstream during any given interval. The use of nonglycemicand if results are negative, tests should be repeated at 24 to 28 weeks’ foods that release calories from the gut slowly also improves metabolicgestation. control. Examples include foods with complex carbohydrates and ﬁber, such as whole-grain breads and legumes. Carbohydrates should THIRD-TRIMESTER SCREENING account for no more than 50% of the diet, with protein and fats equally Because the insulin resistance that causes hyperglycemia increases accounting for the remainder.19as the third trimester progresses, early testing may miss some patients Medical nutritional therapy should be supervised by a trainedwho later become glucose-intolerant. Performing the test too late in professional—ideally, a registered dietitian. In many programs, die-
974 CHAPTER 46 Diabetes in Pregnancytary counseling is capably provided by a certiﬁed diabetes educator. ated with impairment of neuropsychological development of offspring.In any case, formal dietary assessment and counseling should be This report has resulted in admonitions to avoid caloric reduction inprovided at several points during the pregnancy to design a dietary any pregnant woman. The methodology in Churchill and associates’prescription that can provide adequate quantity and distribution of study has been criticized, however, because the ketonuria data werecalories and nutrients to meet the needs of the pregnancy and support obtained from many different hospitals by having a nurse obtain aachieving the plasma glucose targets that have been established. For single urine sample for ketone testing on the day of delivery.obese women (BMI > 30 kg/m2), a 30% to 33% calorie restriction Coetzee and colleagues220 found morning ketonuria in 19% of(to 25 kcal/kg of actual weight per day or less) has been shown to women with insulin-independent diabetes on a 1000-calorie diet, 14%reduce hyperglycemia and plasma triglycerides with no increase in of those on a 1400- to 1800-calorie diet, and 7% of normal pregnantketonuria. women on a free diet. There were no untoward neonatal events in Moderate restriction of dietary carbohydrates to 35% to 40% of infants of any of the ketonuric mothers. Rizzo and coworkers174 studiedcalories has been shown to decrease maternal glucose levels and 223 pregnant women with diabetes and their offspring and 35 withimprove maternal and fetal outcomes.217 In a nonrandomized study, normal glucose tolerance and found no relationship between maternalsubjects with low-carbohydrate intake (<42%) frequently required the hypoglycemia and intellectual function of the offspring.addition of insulin for glucose control (RR = 0.14; P < .05), had a sig- There may be a difference between starvation ketosis and the ketosisniﬁcantly lower rate of macrosomia (RR = 0.22; P < .04), and had a that develops with poorly controlled diabetes. Ketonuria develops inlower rate of cesarean deliveries for cephalopelvic disproportion and 10% to 20% of normal pregnancies after an overnight fast and maymacrosomia (RR = 0.15; P < .04). protect the fetus from starvation in the nondiabetic mother. In the ﬁnal analysis, signiﬁcant maternal ketonemia resulting in maternal acid-Low-Glycemic Foods emia is probably unfavorable for the mother and fetus. The smallManipulation of the type of carbohydrate in the diet can provide degrees of ketosis occurring in many pregnant women, includingadditional beneﬁts in glycemic control. Crapo and coauthors218 com- those with diabetes, are unlikely to lead to measurable deﬁcits in thepared the blood glucose excursions induced by the ingestion of 50 g of newborn.carbohydrate from dextrose, rice, potatoes, corn, and bread. Theyobserved that the highest glucose response occurred with dextrose andpotatoes, with much lower peaks occurring after intake of corn and Principles of Glucose Monitoringrice. This led to the concept of classifying foods by their glycemic indexrelated to their tendency to induce hyperglycemia. In general, low- Glycohemoglobinglycemic foods, such as complex (rather than simple) carbohydrates Measurements of glycosylated hemoglobin have proved to be a usefuland those with higher soluble ﬁber content, are associated with a more index of glycemic control over the long term (4 to 6 weeks), providinggradual release of glucose into the bloodstream. a numeric index of the patient’s overall compliance.221 Although assess- Formal dietary consultation at periodic intervals during the preg- ing Hb A1c levels every 4 to 6 weeks during pregnancy rarely altersnancy improves metabolic control. Timing and content of meals management signiﬁcantly, it can provide the patient with a score byshould be reviewed at each visit together with the patient’s individual which she can rate the success of her hourly efforts to keep her bloodfood preferences. In all pregnant women, the continuing fetal con- glucose levels within a narrow range. Glycohemoglobin levels are toosumption of glucose from the maternal bloodstream results in a steady crude to guide the adjustments to insulin.downward drift in maternal glucose levels unless feeding occurs. Inpatients taking insulin or oral hypoglycemics, prolonged periods (>4 Self-Monitoring of Blood Glucosehours) without food intake increase the risk of hypoglycemic episodes. The availability of capillary glucose chemical test strips has revolution-In these patients, a rather rigid schedule of three meals plus snacks ized the management of diabetes, and they should be considered theat mid-morning, mid-afternoon, and bedtime is often necessary to standard of care for pregnancy monitoring. The discipline of measur-achieve smooth control. Because insulin resistance changes dynami- ing and recording blood glucose levels before and after meals has acally during pregnancy, the dietary prescription must be continually positive effect on improving glycemic control.222adjusted according to the patient’s weight gain, insulin requirement,and pattern of exercise. TIMING OF CAPILLARY GLUCOSE MONITORING The frequency and timing of self-monitoring of blood glucoseAvoiding Nocturnal Hypoglycemia should be individualized (Table 46-15). However, because postprandialUnopposed intermediate-acting insulin action during the hours of values have the strongest correlation with fetal growth, checking aftersleep frequently results in severe nocturnal hypoglycemia at 3 to 4 AM meals is essential. The DIEP study reported that when postprandialin individuals with type 1 diabetes. Reducing the insulin dose to avoid glucose values averaged 120 mg/dL, approximately 20% of infants werethis complication typically leads to unacceptably high glucose levels on macrosomic, whereas a modest 30% rise in postprandial glucose levelsrising at 6 to 7 AM, whereas adding a bedtime snack helps to moderate to a mean level of 160 mg/dL resulted in a 35% rate of macrosomia.223the effect of bedtime insulin and to sustain glucose levels during the Similar results emphasizing postprandial blood glucose monitoringnight. The snack should contain a minimum of 25 g of complex car- were reported by de Veciana and associates,224 who randomized dia-bohydrate and enough protein or fat to help prolong release from the betic women to use of preprandial or postprandial blood glucose levelsgut during the hours of sleep. for dietary and insulin management. The women managed using post- prandial levels had markedly better results than did those managedAvoiding Ketosis using preprandial levels. In the postprandial group, with the meanThe issue of maternal ketosis and its potential effect on childhood (± standard deviation) change in the glycosylated hemoglobin valuemental performance is a source of continuing controversy. Churchill greater (−3 ± 2.2% versus 0.6 ± 1.6%; P < .001), the birth weights wereand associates219 reported that ketonuria during pregnancy is associ- lower (3469 ± 668 g versus 3848 ± 434 g; P = .01), and the rates of
CHAPTER 46 Diabetes in Pregnancy 975 TABLE 46-15 TIMING OF HOME CAPILLARY GLUCOSE MONITORING Capillary Glucose Assessment Advantage Disadvantage Preprandial Permits prospective adjustment of food intake, Preprandial or fasting glucose levels correlate supplementation of preprandial insulin poorly with fetal morbidity. Signiﬁcant postprandial hyperglycemia may go undetected. Postprandial Permits supplementation of insulin to reduce postprandial Results are obtained after food intake. glucose overshoots; improved postprandial control correlates with improved fetal or neonatal outcome Bedtime Permits adjustment of calories at bedtime snack, adjustment of bedtime insulin 3-4 AM Enables detection of nocturnal hypoglycemia Interrupts sleep, may increase stressneonatal hypoglycemia (3% versus 21%; P = .05) and macrosomia(12% versus 42%; P = .01) were lower. Glucose Sleep With these facts in mind, a typical glucose monitoring schedule 120involves capillary glucose checks on rising in the morning, 1 or 2 hours Postpartumafter breakfast, before and after lunch, before dinner, and at bedtime. 100For patients taking intermediate- or long-acting medication at bedtime, mg/100 mLa capillary glucose level between 3 and 4 AM (the lowest glucose levelof the day) two to three times per week is helpful in interpreting the 80glucose values in the morning. The clinician should be aware of the speciﬁc type of capillary 60 Fasting 85.2 3.8glucose reﬂectance meter being used by the patient, because plasma 24 hr mean 93.4 1.9glucose values are 10% to 15% less than those measured in whole 40blood from the same sample. Most of the newer reﬂectance meters arecalibrated for plasma glucose readings. The target glucose values used 120 2nd trimesterin management depend on the type of meter used. 100 TARGET CAPILLARY GLUCOSE LEVELS mg/100 mL Controversy exists about whether the target glucose levels to be 80maintained during diabetic pregnancy should be designed to limitmacrosomia or to closely mimic nondiabetic pregnancy proﬁles. TheFifth International Workshop-Conference on Gestational Diabetes195 60 Fasting 77.7 2.3recommends the following: 24 hr mean 85.6 2.9 40 Fasting plasma glucose level of 90 to 99 mg/dL (5.0 to 120 5.5 mmol/L) 3rd trimester and 100 1-hour postprandial plasma glucose level less than 140 mg/dL mg/100 mL (<7.8 mmol/L) or 80 2-hour postprandial plasma glucose level less than 120 to 127 mg/ dL (<6.7 to 7.1 mmol/L) 60 Fasting 74 2.7 24 hr mean 87.3 1.7 Only recently have data been reported that describe normal glucose 40variations during pregnancy in nondiabetic gravidas. The proﬁles 0800 1200 1600 2000 2400 0400 0800described by Cousins and colleagues225 (Fig. 46-12) are derived from Clock hourshighly controlled studies in which volunteer subjects were fed testmeals with speciﬁc caloric content on a rigid schedule. Parretti and FIGURE 46-12 Glucose variations during pregnancy. Proﬁle ofcoworkers226 proﬁled normal pregnant women twice monthly prepran- blood glucose over 24 hours in the second and third trimesters ofdially and postprandially during the third trimester. Testing was done pregnancy, with postpartum observations used as a control. Errorwith capillary glucose meters, and the women followed an ad libitum bars represent standard error. Arrows indicate time of test mealdiet. The results of the 95th percentile of the plasma glucose excursions administration. (From Cousins L, Rigg L, Hollingsworth D, et al: The 24-hour excursion and diurnal rhythm of glucose, insulin and Care shown in Figure 46-13. Fasting and premeal plasma glucose levels peptide in normal pregnancy. Am J Obstet Gynecol 136:483, 1980.)are usually below 80 mg/dL and often below 70 mg/dL. Peak postpran-dial plasma glucose values rarely exceed 110 mg/dL. Yogev and colleagues227 obtained continuous glucose informationfrom nondiabetic pregnant women using a sensor that monitored
978 CHAPTER 46 Diabetes in Pregnancy3. The kinetics of NPH insulin are such that care must be taken to with gestational diabetes by Pettitt and associates237 found that time peak action at 5 to 7 AM and avoid peaking at 4 AM, when glucose areas under the curve were signiﬁcantly lower with insulin maternal glucose levels are lowest. For many women, whose bedtime aspart (180-min area, 7.1 mg·h·dL−1; P = .018) but not with regular may be at 8 or 9 PM, NPH peaks early and exposes the mother and insulin (30.2 mg·h·dL−1; P = .997) or with no insulin (29.4 mg·h·dL− 1 fetus to nocturnal hypoglycemia. It is often better to administer ), indicating the potential for improved glycemic control with NPH at a set time between 10 and 11 PM, not the less accurate short-acting insulins compared with regular insulin. timing of “bedtime,” to optimize needed insulin action during the 7. The use of insulin glargine during pregnancy is problematic because hours of 5 to 7 AM. of its 20- to 26-hour duration. In three large comparative trials of4. A combination of short- and intermediate-acting insulins is nonpregnant subjects, glargine decreased glycosylated hemoglobin employed to maintain glucose levels in an acceptable range. A or fasting blood glucose levels, or both, to an extent similar to that typical regimen involves intermediate-acting insulin (NPH) before seen with NPH insulin. A lower incidence of hypoglycemia, espe- breakfast and at bedtime, with injections of regular or short-acting cially at night, was reported in most trials with insulin glargine insulin before breakfast and before dinner. Two thirds of insulin is compared with NPH insulin.238 Experience is limited in pregnancy, given in the morning and one third in the afternoon and at bedtime. but the few studies existing demonstrate satisfactory results.239,240 For example, the regimen may be 20 units of NPH and 10 units of Although the relatively ﬂat activity proﬁle of glargine is attractive, regular insulin in the morning, 8 units of regular insulin with the dose must be regulated to keep basal insulin action during the dinner, and 8 units of NPH at 10 PM. The AM dose of NPH covers night from causing hypoglycemia. During the day, when insulin the periods before and after lunch. Avoid NPH injections at din- resistance and insulin requirements are higher, the nocturnal basal nertime because the peak occurs at 2 to 3 AM, creating symptomatic rate is usually inadequate, and NPH must be added. As shown in hypoglycemia. Figure 46-14, the nocturnal low glucose level (typically at 4 AM)5. Preprandial doses of regular insulin sufﬁcient to keep 1-hour post- decreases as the third trimester progresses. Great care must be exer- prandial plasma glucose levels below 130 mg/dL may result in hypo- cised in using glargine to avoid severe nocturnal hypoglycemia. glycemia 2 to 4 hours later (e.g., regular insulin before breakfast Glargine appears to be safe for use during embryogenesis if glucose often causes hypoglycemia at 10 AM). When regular insulin is used control is adequate.241 to cover the major meals, snacks are essential in the late morning, the late afternoon, and before bedtime to avoid interprandial hypo- glycemia. This interprandial hypoglycemia effect is intensiﬁed if the Adjusting Insulin Dosage Using Carbohydrate regular insulin injection is not given at least 20 to 30 minutes before Counting, Preprandial Glucose Levels, and the meal. This precaution is particularly relevant for hospitalized Insulin Corrections patients (because meals do not always arrive on schedule) and when Intermediate- and long-acting insulins should be adjusted no more taking meals in restaurants. frequently than weekly or biweekly to maintain preprandial plasma6. The short-acting insulins lispro or aspart are preferred during dia- glucose levels in the target range (70 to 105 mg/dL). However, with betic pregnancy. Lispro is manufactured by inverting a short amino short-acting insulins, glycemic control is better when the patient is able acid sequence within the insulin molecule, resulting in a signiﬁ- to vary, within a reasonable range, the insulin dose she uses to cover a cantly faster onset of action. Lispro injections immediately before meal, depending on its calorie content (or grams of carbohydrate) and meals reduce the risk of hangover hypoglycemia because of the plasma glucose level existing at the time she begins eating. This the short duration of action. Using an in vitro perfusion model, often means varying short-acting insulin dosage with every injection. Holcberg and colleagues230 reported that lispro does not cross the human placenta. Compared with regular human insulin, the peak CARBOHYDRATE COUNTING serum lispro concentration is three times higher, time to peak is 4.2 Patients with pregestational diabetes are usually taught to count the times faster, the absorption rate constant is double, and the dura- grams of carbohydrate in their meals and adjust the short-acting tion of action is one half as long.228 These kinetics allow the patient insulin dosage accordingly. A typical meal containing 60 grams of to inject insulin just before eating, rather than having to delay 20 carbohydrate may require 4 to 6 units of lispro (ratio of 1 unit of to 30 minutes to allow regular insulin to begin its effect. Compared insulin to grams of carbohydrate of 1 : 15) in the nonpregnant indi- with regular insulin, lispro reduced postprandial hyperglycemia and vidual. In the ﬁrst trimester, a typical ratio is approximately 1 : 12. decreased the rate of mild hypoglycemic episodes; it was also associ- However, by the second trimester, more insulin is required (1 : 10 to ated with lower predelivery Hb A1c values and received higher 1 : 6), and in the third trimester, especially in patients with some degree patient satisfaction scores.231 Similar ﬁndings have been reported of insulin resistance, ratios fall to 1 : 6 or even 1 : 2. The clinician should when insulin aspart was compared with regular insulin.232 In anticipate these increases in insulin as pregnancy progresses, because summary, lispro or aspart can be substituted 1 : 1 for regular insulin, the patient often interprets these changes as errors or failure. and each is highly effective when given before meals in reducing Carbohydrate counting has limits in accuracy (e.g., miscalculation postprandial glycemia while avoiding insulin hangover, which of carbohydrate content, individual differences in glucose uptake increases patient compliance. Short-acting insulins are effective dynamics), which may result in erratic control. During pregnancy, when used in the insulin pump (discussed later).233 With regard to women who relatively strictly regiment their food quantity, content, safety and effectiveness, small studies have indicated equivalent and timing, so that carbohydrate calculations are within a reasonably perinatal outcomes.234,235 Mathieson and coworkers236 reported narrow range, have better control. similar perinatal outcomes but improved maternal glycemic control in pregnant women randomized to aspart or regular insulin, dem- PREPRANDIAL GLUCOSE LEVELS onstrating signiﬁcantly lower mean postprandial plasma glucose Given the same calorie content of a meal, achieving target post- levels with aspart (P = .003). A more detailed study of glucose prandial plasma glucose levels requires more insulin if the preprandial dynamics after administration of aspart or regular insulin to women glucose level is higher. Allowing patients to add 2 units of lispro when
CHAPTER 46 Diabetes in Pregnancy 979the preprandial glucose level exceeds 120 mg/dL and to reduce lispro A properly designed insulin pump infusion scheme allows conve-dosage by 2 units when the preprandial glucose level is below 80 mg/dL nient tailoring of the insulin administration proﬁle to the patient’sprovides smoother control and avoids undesired postprandial glyce- individual metabolic and lifestyle rhythms. A sample regimen is shownmic excursions when the preprandial glucose is outside the target in Table 46-18. The lowest infusion rate of the day is between 11 PMrange. and 4 AM, when it is set at about 70% of the mean rate needed during the day. The basal rate must be increased to 1.3 to 1.5 times the mean INSULIN CORRECTIONS daily rate between 5 AM and 10 AM to provide extra insulin coverage Women with pregestational diabetes are frequently taught how to for the high insulin-resistance period as the day begins (i.e., dawnperform preprandial and postprandial insulin corrections. A typical effect). For the remainder of the day (10 AM to 11 PM), a steady meanregimen is to add 1 to 2 units of lispro for every 50 mg/dL that the infusion rate is usually sufﬁcient. Insulin boluses, programmed to limitglucose level is out of target range. A preprandial glucose level of the postprandial excursion to 130 mg/dL or less at 1 hour, are given as130 mg/dL would require 1 unit of lispro over the prescribed dose for often as needed. The enhanced ability for the patient to administerthat meal. As pregnancy progresses, corrections increase from 1 per extra insulin doses without syringes and insulin vials is of great value50 mg/dL to 1 per 20 mg/dL. However, the patient must be instructed in improving the smoothness of glycemic control.not to take more than 4 to 6 correction units in a single bolus duringpregnancy and instead retest glucose in 1 to 2 hours and apply an Starting Insulin with Gestational Diabetesadditional correction at that time. Clinicians and patients are reluctant to start insulin in patients with gestational diabetes, but this intervention may be essential if macroso-Use of the Insulin Pump mia is to be reduced or avoided. Because the period of maximum fetalMost of the principles described to enhance and smooth glycemic growth velocity (200 g/wk) and fat accretion occurs at approximatelycontrol by manipulating timing, quantity, and type of insulin can be 33.5 weeks’ gestation, delaying deﬁnitive therapy with repeated attemptsused with greater facility with continuous, subcutaneous insulin infu- to correct a suboptimal glucose proﬁle with dietary adjustments may,sion delivered by a programmable pump. These devices, which infuse by 33 to 34 weeks, have missed the time when glycemic interventioninsulin by means of a convenient catheter placed into the subcutaneous is most effective in modulating fetal growth. It is reasonable to allowtissue near the abdomen, can be programmed to provide varying basal a 1- to 2-week trial of dietary management before resorting to otherand bolus levels of insulin, which change smoothly even while the measures, but waiting longer does not signiﬁcantly increase the likeli-patient sleeps or exercises. hood of good control. McFarland and colleagues248 have shown that The effectiveness of continuous, subcutaneous insulin infusion in approximately 50% of patients achieve good glycemic control duringpregnancy is well established.242-244 Hieronimus and colleagues245 com- the ﬁrst 2 weeks of dietary therapy, but by the 4th week, only an addi-pared outcomes of 33 pregnant women managed with insulin pumps tional 10% attain acceptable blood glucose levels.with 23 receiving multiple injections and reported similar Hb A1c levels The value of insulin administration in gestational diabetes wasand rates of macrosomia and cesarean deliveries. Lapolla and cowork- assessed by Crowther and associates,249 who randomized 1000 womeners246 reported a small cohort of 25 women treated with insulin pumps with gestational diabetes to insulin treatment or no medical therapyin pregnancy compared with conventional insulin treatment (n = 68) in the Australian Carbohydrate Intolerance Study in Pregnant Womenand found no differences in glycemic control or perinatal outcome. (ACHOIS trial). Controls with normal OGTT results were included Use of continuous, subcutaneous, programmable insulin infusion in the trial. In the insulin group, glucose levels were maintained athas several advantages over conventional intermittent insulin admin- less than 99 mg/dL before meals and less than 126 mg/dL 2 hoursistration, including the convenience of changing basal rates automati- postprandially. The rate of serious perinatal complications was signiﬁ-cally when the patient is asleep or otherwise occupied and providing cantly lower among the infants of 490 women in the interventionadjustable boluses discreetly from a pump worn under the clothing group than among the infants of 510 women in the routine-care groupwithout the need for needles, syringes, and medication vials. Because (1% versus 4%; RR adjusted for maternal age, race or ethnic group,pump malfunctions, precipitation of insulin inside the pump mecha- and parity = 0.33; CI, 0.14 to 0.75; P = .01). The intervention groupnism, abscess formation, and poor uptake from the infusion site can had a signiﬁcantly higher rate of labor induction than the routine-careoccur unexpectedly, successful insulin pump use requires a meticulous group (39% versus 29%), but the rates of cesarean delivery werepatient, a knowledgeable diabetologist or perinatologist, and prompt similar. Cord plasma glucose levels were higher in women receivingavailability of emergency counseling and assistance on a 24-hour routine care compared with controls, but it was normalized bybasis.247 treatment for mild GDM (P = .01). At 3 months after delivery, the TABLE 46-18 TYPICAL SECOND-TRIMESTER CONTINUOUS ADMINISTRATION PROFILE USING A SUBCUTANEOUS INSULIN INFUSION PUMP Time Basal Rate Bolus (U) Comment 12 midnight 0.6 U/hr Lower basal rate for sleep 5 AM 1.5 U/hr Higher basal rate opposes the “dawn effect” of rising serum glucose from 4 to 6 AM 7 AM 8 Prebreakfast bolus 9 AM 1.0 U/hr Lower basal rate to match increased physical activity, decreased insulin needs 12 noon 4 Prelunch bolus 6 PM 4 Predinner bolus 10 PM 0.6 U/hr Lower basal rate for sleep
980 CHAPTER 46 Diabetes in Pregnancyintervention group had lower rates of depression and higher quality- have not been performed to assess these agents during pregnancy.of-life scores. Reports of fetal anomalies have been largely anecdotal. An increased With regard to newborn outcomes in the ACHOIS trial, umbilical rate of congenital malformations, particularly ear anomalies, has beencord serum insulin and insulin to glucose ratio were similar between reported from a small case-control study.254 When Towner and cowork-the three groups, but leptin concentration, an indicator of fat mass, ers255 evaluated the frequency of birth defects in fetuses of patients whowas lower in treated women with GDM compared with routine care took oral hypoglycemics during the periconceptional period, they(P = .02), suggesting that treatment of GDM using diet, blood glucose found that the ﬁrst-trimester glycohemoglobin level and duration ofmonitoring, and insulin, if necessary, inﬂuences the fetal adipoinsular diabetes were strongly associated with fetal congenital anomalies butaxis, which may reduce the risk of childhood and adult obesity late in that use of oral hypoglycemic medications was not.life.250 Interest in glyburide, a second-generation oral sulfonylurea avail- Jovanovic-Peterson and colleagues251 reported a protocol in which able in the United States since 1984, has recently been rekindled. WhenGDM patients were treated with insulin if any fasting glucose level glyburide was compared with ﬁrst-generation sulfonylureas, it wasexceeded 90 mg/dL or postprandial glucose level exceeded 120 mg/dL. equally effective, had a lower incidence of side effects, and reducedOver a period of 6 years, this protocol resulted in a decrease in the rate fasting blood glucose and glycohemoglobin levels, without the incon-of macrosomic infants from 18% to 7% and a drop in the cesarean rate venience of the additional training required to administer insulin.from 30% to 20%. Buchanan and associates252 used ultrasound screen- Because of its ability to enhance target tissue insulin sensitivity, glybu-ing of fetal abdominal circumference in 303 diet-controlled GDM ride has been shown to improve glycemic control in many type 2 dia-patients at 28 weeks to identify early macrosomia that might beneﬁt betic patients who have previously failed therapy. As adjunctive therapy,from insulin treatment. When pregnancies with a fetal abdominal cir- glyburide can reduce the daily dosage for those who require largecumference above the 75th percentile were randomized to continued amounts of insulin.256diet or twice-daily insulin therapy, birth weights and percentage ofmacrosomic infants were reduced in the insulin group (3647 ± 67 g Glyburideversus 3878 ± 84 g; P < .02 and 13% versus 45%; P < .02). Neonatal A unique characteristic of glyburide that allows its use in pregnancy isobesity, as reﬂected by skinfold measurements at three sites (P < .005), its minimal transport across the human placenta.257 A study by Elliottalso was lower. and colleagues258 evaluated glyburide transport in 10 term human The insulin regimen used in managing women with gestational placentas with the single-cotyledon placental model and found virtu-diabetes should be designed to address the patient’s individual glucose ally no transfer of glyburide even at concentrations 100 times theproﬁle, because some women require insulin to prevent only fasting typical therapeutic levels. This surprisingly low placental transfer mayAM hyperglycemia and others only for postprandial excursions. Typi- result from the very high plasma-protein binding of glyburide coupledcally, one to several postprandial glucose levels become consistently with a short elimination half-life of 4 to 8 hours.257,259above target as the patient’s ability to compensate for rising insulin Based on ﬁndings consistently showing minimal transfer of glybu-resistance becomes inadequate with diet alone. In such cases, giving ride across the placenta, Langer and colleagues260 designed a random-short-acting insulin such as lispro or aspart (4 to 8 units to start) before ized trial to compare this oral agent with insulin in patients withmeals is helpful. If more than 10 units of short-acting insulin is needed gestational diabetes. They randomized 404 women with second- andbefore the noon meal, adding a 6- to 8-unit dose of NPH before break- third-trimester singleton pregnancies who had gestational diabetesfast helps to achieve smoother control. If the fasting glucose levels rise requiring treatment to receive glyburide or insulin in an intensiﬁedabove 90 to 95 mg/dL, 4 to 6 units of NPH insulin should be admin- treatment protocol. At the conclusion of the trial, there was no differ-istered between 10 to 11 PM. The doses are scaled up as necessary, twice ence between the groups in mean maternal blood glucose, percentageweekly or more often, to keep glucose levels within the target range. of infants who were LGA (12% and 13%, respectively), birth weight at or above 4000 g (7% and 4%), or neonatal complications (pulmonary, 8% and 6%; hypoglycemia, 9% and 6%; admission to neonatal inten-Use of Oral Hypoglycemic Agents sive care unit, 6% and 7%; fetal anomalies, 2% and 2%). Only 4% ofMaintaining glucose levels within the target range requires meticulous the glyburide group required insulin therapy. Glyburide was notattention to diet and physical activity. For many patients, injecting detected in the cord serum of any infant in the glyburide group.insulin frequently is impossible, and there are many initiatives to However, only 82% of the glyburide and 88% of the insulin-treatedaugment glucose control with oral agents, particularly in patients with patients achieved the target level of glycemic control, representing ainsulin-resistant type 2 diabetes. An ideal treatment would reduce glyburide “failure rate” of 18%. With regard to glyburide dosing duringinsulin resistance, improve insulin secretion or action, and delay the the trial, 31% of patients were treated with 2.5 mg, 21% with 5 mg,uptake of glucose from the gut. Current strategies are aimed at aug- 19% with 10 mg, 9% with 15 mg, and 20% with 20 mg. The meanmentation of insulin supply (i.e., sulfonylurea and insulin therapy), glyburide dose was 9.2 mg. Of the maternal outcome variables assessed,amelioration of insulin resistance (i.e., exercise, weight loss, and met- none was signiﬁcantly different between groups except the dramaticformin and troglitazone therapy), and limitation of postprandial (P = .03) reduction in maternal hypoglycemic episodes in the glybu-hyperglycemia (i.e., acarbose therapy). ride-treated group (2%) compared with the 20% rate for insulin. Beyond this single encouraging study, further nonrandomizedPharmacology and Safety experience with glyburide during pregnancy is accumulating.261,262Sulfonylurea compounds, commonly prescribed in the past for patients Chmait and coworkers,263 describing their experience with 69 patientswith type 2 diabetes, have been considered contraindicated during with gestational diabetes managed on glyburide, reported that 19% ofpregnancy because of the high degree of transplacental penetration of patients required adjunctive insulin therapy to keep glucose values inmost of these agents and the clinical reports of drug concentrations in the target range. The adjunctive insulin rate was higher for womenthe neonate higher than maternal levels associated with prolonged and diagnosed earlier in pregnancy (20 versus 27 weeks; P < .003) and thosesevere neonatal hypoglycemia.253 However, rigorously designed trials whose average fasting glucose in the week before starting glyburide was
CHAPTER 46 Diabetes in Pregnancy 981higher (126 versus 101 mg/dL). No cases of neonatal hypoglycemia in pregnancy. During development of the drug in the late 1960s, single-occurred in the glyburide group. dose studies in nondiabetic subjects demonstrated glyburide absorp- Langer and colleagues264 reanalyzed the previously cited random- tion within 1 hour, peak levels at about 4 hours, and low but detectableized, controlled trial, addressing the issues of glyburide dose, GDM levels at 24 hours. The decrease of glyburide in the serum yielded aseverity, and pregnancy outcome and grouping trial participants into terminal half-life of about 10 hours, and the glucose-lowering effectlow (≤10 mg) and high (>10 mg) daily glyburide dose groups and low could be expected to persist for 24 hours after a single morning dose.(≤95 mg/dL) or high (>95 mg/dL) GDM severity groups based on Later data have shown that glyburide peaks earlier in the serum andfasting OGTT values. The rates of macrosomia were 16% versus 5%, has a signiﬁcantly shorter half-life than previously believed. Theseand the rates of infants who were LGA were 22% versus 8%, (P = .01), effects reﬂect the fact that glyburide has two major hydroxyl metabo-respectively, in the high-dose and low-dose glyburide groups. Stratiﬁ- lites, both of which are biologically active and excreted equally in thecation by disease severity (using the level of fasting glucose on glucose bile and urine. Although advice in the Physician’s Desk Reference indi-tolerance testing) revealed equally lower rates of LGA for the glybu- cates that the glyburide metabolites provide no signiﬁcant contribu-ride- and insulin-treated subjects in the low-severity group. In the tion to glyburide’s hypoglycemic action (1/400 and 1/40, respectively, ofhigher-severity group, the rates of macrosomia and LGA were similar glyburide’s potency), these data were obtained in rabbits.in the glyburide and insulin arms. The study authors suggested that Yin and associates272 studied the glucose and insulin responses toachieving an excellent level of glycemic control, rather than the mode glyburide in a group of nonpregnant, nondiabetic subjects. After a 5-of pharmacologic therapy, is the key to improving outcomes in cases mg oral dose, serum glyburide levels peaked at 2.75 hours and hadof GDM. sustained levels with a half-life ranging from 2 to 4 hours, considerably There is a growing acceptance of glyburide use as a primary therapy shorter than the quoted half-life of 10 hours.for GDM.265 Although no new randomized trials have been completed, To clarify the potential difference in drug action when given as aseveral retrospective series have been published comprising 504 single dose or chronically over weeks, Jaber and colleagues273 studiedglyburide-treated patients, and these studies have been summarized by glyburide pharmacodynamics during multiple-dose administration. AMoore.266 signiﬁcant prolongation in the half-life (week 0 = 4.0 ± 1.9 hr; week 6 Jacobson and coworkers267 performed a retrospective cohort com- = 13.7 ± 10.5 hr; and week 12 = 12.1 ± 8.2 hr) was observed duringparison of glyburide and insulin treatment of gestational diabetes. chronic dosing. These results suggest possible drug accumulation orPatients with fasting plasma glucose levels greater than 140 mg/dL on tissue sensitization by glyburide.glucose tolerance testing were excluded. The insulin group (n = 268) Yogev and coworkers274 examined the prevalence of undiagnosed,consisted of those diagnosed in 1999 through 2000, and the glyburide asymptomatic hypoglycemic events in diabetic patients using a con-group (n = 236) was diagnosed in 2001 through 2002. Glyburide tinuous glucose monitoring system for 72 consecutive hours. Hypo-dosing was begun with 2.5 mg in the morning and increased by 2.5 to glycemia was deﬁned as more than 30 consecutive minutes of a glucose5.0 mg weekly. If the dose exceeded 10 mg daily, twice-daily dosing was value below 50 mg/dL. Asymptomatic hypoglycemic events wereconsidered. If glycemic goals were not met on a maximum daily dose recorded in 63% of insulin-treated patients but in only 28% of glybu-of 20 mg, patients were changed to insulin. The study size was insufﬁ- ride-treated patients. The mean number of hypoglycemic episodes percient to detect less than a doubling of the rate of macrosomia or LGA day was signiﬁcantly higher in insulin-treated patients (4.2 ± 2.1) thanand a 44% increase in neonatal hypoglycemia, but there were no sta- in glyburide-treated patients (2.1 ± 1.1; P = .03). In insulin-treatedtistically signiﬁcant differences in gestational age at delivery, mode of patients, most hypoglycemic events were nocturnal (84%), whereas indelivery, birth weight, LGA, or percent of macrosomic infants. The rate glyburide-treated patients, episodes occurred equally during the dayof preeclampsia doubled in the glyburide group (12% versus 6%; P < and night, suggesting a potential beneﬁt of glyburide over insulin.02). Women in the glyburide group also had signiﬁcantly lower post- therapy in clinical use.treatment fasting and postprandial blood glucose levels. The glyburide Based on these data, glyburide should be taken at least 30 minutes—group was superior in achieving target glycemic levels (86% versus and preferably 60 minutes—before meals so that the peak action (2.563%; P < .001). The failure rate (i.e., transfer to insulin) was 12%. hours after dosing) covers the postprandial glucose surge. Because of Conway and associates268 reported a retrospective cohort of 75 its extended duration of action, glyburide taken at 10 to 11 PM is effec-glyburide-treated GDM patients. Good glycemic control was achieved tive in lowering fasting plasma glucose levels in the morning. Signiﬁ-by 84% of the subjects with glyburide, and 16% were switched to cant interprandial hypoglycemia can occur with glyburide, and patientsinsulin. The rate of fetal macrosomia was similar between women suc- should carry glucose tablets with them at all times as a precaution. Thecessfully treated with glyburide and those who converted to insulin maximum dose is 20 mg per day, and no more than 7.5 mg should be(11.1% versus 8.3%; P = 1.0), and the mean birth weight was also taken at a single time.similar. A not signiﬁcantly higher proportion of infants in the gly-buride group required intravenous glucose infusions because of Other Agentshypoglycemia (25.0% versus 12.7%; P = .37). Metformin is frequently employed in patients with polycystic ovary Small cohorts reported by Kremer and colleagues269 and Chmait syndrome and type 2 diabetes to improve insulin resistance andand coworkers270 demonstrated glyburide failure requiring adjunctive fertility.275 Although it has been documented that metforminor substitutive insulin rates in the range of 15% to 20%. In these therapy improves the success of ovulation induction276 and probablystudies, higher GCT results (>160 to 200 mg/dL) were predictive of an reduces ﬁrst-trimester pregnancy loss in women with polycysticapproximate 50% failure rate.271 ovary syndrome,181 the effects of continuing metformin during The recommended glyburide dosing regimen, based largely on pregnancy are not clear. Coetzee and Jackson277 treated pregestationalanimal studies and a few human studies of nonpregnant subjects, is to and gestational diabetics with metformin, but the treatment failedadminister the agent once daily, with twice-daily doses reserved for in 54% and 29%, respectively. The perinatal mortality rate amongrefractory cases. Later studies of glyburide pharmacodynamics suggest the metformin patients was 61 per 1000, and the rate of neonatalthat the previously recommended dosing protocols may not be optimal jaundice was increased. Hellmuth and colleagues278 reported a series of
982 CHAPTER 46 Diabetes in Pregnancywomen with gestational diabetes treated with metformin or tolbuta- TABLE 46-19 FETAL SURVEILLANCE IN TYPES Imide before 1984. Women treated with metformin had a fourfold AND II DIABETIC PREGNANCIESincrease in preeclampsia and a higher perinatal mortality ratecompared with those who were receiving tolbutamide. However, Time Testmetformin-treated women were older, more obese, and treated later in Preconception Maternal glycemic controlpregnancy. 8-10 wk Sonographic crown-rump measurement A cohort study of metformin in pregnancy reported by Hughes and 16 wk Maternal serum α-fetoprotein levelassociates187 in 2006 included 93 women with metformin treatment 20-22 wk High-resolution sonography, fetal cardiac(only 32 continued until delivery) and 121 controls. There was no dif- echography in women in suboptimal diabeticference in perinatal outcomes between the groups. Glueck and cowork- control (abnormal Hb A1c value) at ﬁrst prenatalers183 compared nondiabetic women with polycystic ovary syndrome visit(n = 28) who conceived while taking metformin and continued the 24 wk Baseline sonographic growth assessment of theagent through delivery with matched women without metformin fetustherapy (n = 39). Gestational diabetes developed in 31% of women 28 wk Daily fetal movement counting by the mother 32 wk Repeat sonography for fetal growthwho did not take metformin and in 3% of those who did (OR = 0.115; 34 wk Biophysical testing:CI, 0.014 to 0.938). Two times weekly nonstress test or Because of the beneﬁcial effect of metformin on ﬁrst-trimester Weekly contraction stress test ormiscarriage, many patients with polycystic ovary syndrome enter pre- Weekly biophysical proﬁlenatal care taking this medication. Because metformin readily crosses 36 wk Estimation of fetal weight by sonographythe placenta,184 greater experience with this agent is necessary before 37-38.5 wk Amniocentesis and delivery for patients in poorit can be recommended for use throughout pregnancy.279 A large, control (persistent daily hyperglycemia)properly powered, randomized, controlled trial is in progress to explore 38.5-40 wk Delivery without amniocentesis for patients inthese issues.280 good control who have excellent dating criteria The α-glucosidase inhibitors, another class of oral agents, reversiblyinhibit pancreatic amylase and α-glucosidase enzymes in the smallintestine, delaying cleavage of complex sugars to monosaccharides andreducing the increase of blood glucose levels after a meal. Although A variety of fetal biophysical tests are available, including fetal heartthese agents offer particular promise in pregnant women because of rate testing, fetal movement counting, ultrasound biophysical scoring,limited uptake from the gut, only a few studies of the drugs in preg- and fetal Doppler studies. These tests, which are described in Chapternancy are available. Bertini and colleagues281 compared insulin treat- 21, are summarized in Table 46-20.ment (n = 27), glyburide (n = 24), and acarbose (n = 19) in gestational Testing should be initiated early enough to avoid the risk of still-diabetes. No difference was observed in maternal glucose levels or in birth but not so early that a high rate of false-positive results is encoun-mean birth weight, although the rates of LGA fetuses were 3.7%, 25%, tered. Because the risk of fetal death is roughly proportional to theand 10.5% for the groups, respectively. Neonatal hypoglycemia was degree of hyperglycemia, testing should begin as early as 28 weeks’observed in eight newborns, six of whom were from the glyburide gestation in patients with poor glycemic control or signiﬁcant hyper-group. Glucose control was not achieved in ﬁve (20.8%) of the patients tension. In lower-risk patients, testing should begin at 34 to 36 weeks.using glyburide and in eight (42.1%) of the patients using acarbose. Fetal movement counting should be performed in all pregnancies fromAcarbose is given before meals, initially in a dose of 25 mg taken orally 28 weeks onward. A fetal movement card for monitoring fetal move-three times daily up to a maximum of 100 mg taken orally three times ment is shown in Figure 46-16.daily. Timing and Route of DeliveryPregnancy Management Assessing Fetal Sizeof the Diabetic Patient Monitoring fetal growth and predicting birth weight continue to be challenging and highly inexact processes. The purpose of such moni-and Fetus toring is to identify the obese fetus and, if possible, avoid birth injury. Newborns weighing more than 4000 g are responsible for 42% to 74%Fetal Surveillance of shoulder dystocias and 56% to 76% of all brachial plexus injuries,The goals of third-trimester management of diabetic pregnancy are to even though they account for only 6% of births.282 To identify theprevent stillbirth and asphyxia while optimizing the opportunity for a highest-risk fetuses, use of third-trimester ultrasound has been pro-safe vaginal delivery. This involves monitoring fetal growth to deter- posed, including serial plotting of biometric parameters, using a cutoffmine the proper timing and route of delivery and testing for fetal value for estimated fetal weight and applying a cutoff to a speciﬁcwell-being at frequent intervals. parameter (e.g., abdominal circumference).283 A regimen for fetal surveillance throughout pregnancy is provided Because the risk of birth injury is proportional to birth weight,142in Table 46-19. The goals are to much effort has been focused on sonographic estimation of fetal weight (EFW). Several polynomial formulas using combinations of Verify fetal viability in the ﬁrst trimester head, abdomen, and limb measurements have been developed.284,285 Validate fetal structural integrity in the second trimester Unfortunately, even small errors in measurements of the head, Monitor fetal growth during most of the third trimester abdomen, and femur are multiplied together in such formulas, result- Ensure fetal well-being in the late third trimester ing in accuracies of no better than ± 15%. In the obese fetus, the inac-
CHAPTER 46 Diabetes in Pregnancy 983 TABLE 46-20 TESTS OF FETAL WELL-BEING Test Frequency Reassuring Result Comment Fetal movement counting Every night from 28 wk 10 movements in <60 min Performed in all patients Nonstress test Twice weekly 2 heart-rate accelerations in 20 min Begin at 28-34 wk with insulin- dependent diabetes; start at 36 wk in diet-controlled gestational diabetes Contraction stress test Weekly No heart-rate decelerations in response Same as for nonstress test to ≥3 contractions in 10 min Ultrasound biophysical proﬁle Weekly Score of 8 in 30 min 3 movements = 2 1 ﬂexion = 2 30-sec breathing = 2 2-cm amniotic ﬂuid = 2 FETAL MOVEMENT RECORD Time First Time 10th Date Movement Felt Movement Felt Total Time Name: EXAMPLE 11/4/91 6:50 p.m. 7:28 p.m. 38 minutes Due Date: Start Number of weeks Date pregnant INSTRUCTIONS 1. Count the baby’s movements EVERY NIGHT. 2. A movement may be a kick, swish or roll. Do not count hiccups or small flutters. 3. You can start counting any time in the evening when the baby is active. BUT: COUNT EVERY NIGHT. 4. Count baby’s movement while lying down, preferably on your left side. 5. Mark down the time you feel the baby move for the first time. 6. Mark down the time you feel the 10th fetal movement. 7. You should feel at least 10 fetal movements within one hour. Call Labor and Delivery immediately if a) you do not feel 10 movements with 1 hour; b) it takes longer and longer for your baby to move 10 times; c) you have not felt the baby move all day DO NOT WAIT UNTIL TOMORROW. FIGURE 46-16 Fetal movement card. The patient is instructed to note the time at which she begins monitoring fetal movements and then note the time at which the 10th movement is felt. If she has not recorded 10 movements in 1 hour, she is to call her physician.curacies are further magniﬁed. Perhaps this is why no single formula In an attempt to improve detection of macrosomia, Hackmon andhas proved adequate for identifying the macrosomic fetus.286 In the coworkers288 performed a retrospective comparison of sonographicstudy by Combs and colleagues,287 an EFW of 4000 g had a sensitivity imaging results (i.e., EFW and amniotic ﬂuid index [AFI]) for 50of 45% and a positive predictive value of 81%. To achieve 90% sensitiv- newborns with severe macrosomia (birth weight ≥ 97th percentile) andity would have required using an EFW cutoff of 3535 g, which would 100 infants of normal weight. The mean middle-third-trimester AFIhave included 46% of the population and produced a 42% false-posi- percentile and EFW percentiles for severe macrosomic infants weretive rate. signiﬁcantly higher than for controls (P < .0001). Signiﬁcant correla-
984 CHAPTER 46 Diabetes in Pregnancytions were detected for birth weight and the AFI and EFW percentiles formed for suspected macrosomia to prevent one case of permanent(r = 0.44 and r = 0.72, respectively; P < .0001). The best predictors of injury from shoulder dystocia.293macrosomia were an AFI equal to the 60th percentile or higher and anEFW equal to the 71st percentile or higher, with a positive predictive Delivery Timingvalue of 85%. However, even this enhanced protocol had a high-false Timing of delivery should minimize neonatal morbidity and mortalitypositive rate. while maximizing the likelihood of vaginal delivery. Delaying delivery Considering the inaccuracy of weight prediction from a single set to as near the estimated due date as possible increases cervical ripenessof sonographic measurements, serial analysis of parameters every 1.5 and improves the chances of vaginal birth. However, the risks of fetalto 3 weeks is commonly used. However, trended serial EFW calcula- macrosomia, birth injury, and fetal death increase as the due datetions compared with a single measurement appear to be no better approaches. Earlier delivery may reduce the risk of shoulder dystocia,than a single estimate performed near term. Predictions based on the but the increase in failed labor inductions and neonatal respiratoryaverage of serial EFWs, linear extrapolation from two estimates, distress is appreciable.or extrapolation by second-order equations ﬁtted to four estimates Rayburn and colleagues294 reported a case-control study of out-were no better than the prediction from the last estimate before comes of women with GDM requiring insulin who delivered at 38delivery.289 weeks compared with normoglycemic controls. The study group was In view of the inadequate methods used to diagnose macrosomia more likely to have an unfavorable cervix, but cesarean rates were notantenatally, the widespread practice of estimating fetal weight using different between the study and control groups (12.7% versus 11.7%;ultrasound near term in diabetic pregnancy must be questioned. Parry P < .8). Mean birth weights and the frequency of birth weights greaterand colleagues290 compared the cesarean rate for neonates falsely diag- than 4000 g were not different between the groups, suggesting thatnosed on ultrasound as macrosomic (i.e., false positives) with the rate delivery at 38 to 39 weeks does not compromise maternal and infantfor those correctly diagnosed as nonmacrosomic (i.e., true negatives). outcomes signiﬁcantly.They found that the cesarean rate was signiﬁcantly higher among When all these factors are considered, the optimal time for deliverythe false-positive macrosomics than among the true negatives (42.3% of most diabetic pregnancies is between 38.5 and 40 weeks. Indicationsversus 24.3%; RR = 1.74; P < .05). Even with nonmacrosomic fetuses, for delivery of the diabetic pregnancy are summarized in Table 46-21.the availability to the clinician of a sonographic estimate of fetal weight Because of the apparent delay in fetal lung maturity in diabetic preg-signiﬁcantly increases the risk of cesarean delivery. nancies, delivery before 38.5 weeks’ gestation should be performed only for compelling maternal or fetal reasons.Predicting Shoulder Dystocia It may be tempting to consider early delivery in a diabetic preg-Because of the asymmetrical adipose deposition around the fetal chest nancy with evolving macrosomia identiﬁed on ultrasonography.and trunk, deliveries of macrosomic infants from women with diabetes Because fetal growth between 37 and 40 weeks’ gestation in a 90th-are at high risk for shoulder dystocia and injury. However, prediction percentile fetus is approximately 100 to 150 g per week, inducing laborof this risk is not possible with adequate precision to avoid excessive 2 weeks early may reduce the risk of shoulder dystocia in some cases.unnecessary interventions.291 Kjos and coauthors295 compared the outcomes associated with labor In a subanalysis of the ACHOIS trial, Athukorala and associates138 induction at 38 weeks with expectant management of women withidentiﬁed a linear increase in the risk of shoulder dystocia and the gestational diabetes. They found that expectant management increasedfasting glucose level on the glucose tolerance test, with an 18-mg/dL the gestational age at delivery by 1 week, but the cesarean delivery rate(1-mmol) increase in the fasting oral glucose tolerance test result was not signiﬁcantly different. Macrosomia was present in 23% ofleading to a relative risk of 2.09 (CI, 1.03 to 4.25). As reported by the expectantly managed group versus 10% in those induced at 38others, shoulder dystocia was 10-fold more common with operative weeks.vaginal delivery of GDM infants. However, there was no clear cutoff Fetal lung maturity should be veriﬁed in all patients deliveredfor the glucose tolerance test fasting value that was adequately predic- before 38.5 weeks by the presence of greater than 3% phosphatidyl-tive of shoulder dystocia. glycerol or the equivalent on an amniocentesis specimen (Table 46-22). In an effort to minimize the incidence of shoulder dystocia and If obstetric dating is suboptimal, amniocentesis should be performed.associated birth injury associated with suspected macrosomia, anumber of management schemes have been proposed. Weeks and col-leagues292 assessed the management of 500 pregnancies with suspected TABLE 46-21 INDICATIONS FOR DELIVERY INmacrosomia and found a high bias toward cesarean section and failed DIABETIC PREGNANCYinduction. Patients with a sonographic EFW greater than 4200 g Type Indications for Deliveryunderwent induction more often (42.5% versus 26.6%), failed toachieve active labor more frequently (49% versus 16.5%), and under- Fetal Nonreactive, positive contraction stress testwent cesarean section more frequently (52% versus 30%), regardless Reactive positive contraction stress test, mature fetusof actual birth weight. Despite these changes in labor management, the Sonographic evidence of fetal growth arrestincidence of shoulder dystocia in the predicted and nonpredicted Decline in fetal growth rate with decreased amnioticgroups was the same (11.8% and 11.7%, respectively). ﬂuid 40-41 weeks’ gestation There is no clinical method of reliably identifying the fetus likely Maternal Severe preeclampsiato experience shoulder dystocia and injury during birth without an Mild preeclampsia, mature fetusunacceptably high false-positive rate. Because 8% to 20% of fetuses Markedly falling renal function (creatinine clearancefrom diabetic pregnancy weighing 4500 g or more will have shoulder <40 mL/min)dystocia, 15% to 30% of these will have recognizable brachial plexus Obstetric Preterm labor with failure of tocolysisinjury, and 5% to 15% of these injuries will result in permanent deﬁcit, Mature fetus, inducible cervixapproximately 443 to 489 cesarean sections would have to be per-
CHAPTER 46 Diabetes in Pregnancy 985 TABLE 46-22 CONFIRMATION OF FETAL TABLE 46-23 INTRAPARTUM MATERNAL MATURITY BEFORE INDUCTION GLYCEMIC CONTROL OF LABOR OR PLANNED Insulin Infusion Method CESAREAN DELIVERY IN 1. Withhold AM insulin injection. DIABETIC PREGNANCIES 2. Begin and continue glucose infusion (5% dextrose in water) at 100 mL/hr throughout labor. Phosphatidylglycerol >3% in amniotic ﬂuid collected from vaginal 3. Begin infusion of regular insulin at 0.5 U/hr. pool or by amniocentesis 4. Begin oxytocin as needed. Completion of 38.5 weeks’ gestation 5. Monitor maternal glucose levels hourly using a capillary Normal last menstrual period reﬂectance meter at bedside or laboratory determinations, First pelvic examination before 12 wk conﬁrms dates or both. Sonogram before 24 wk conﬁrms dates 6. Adjust insulin infusion. Documentation of more than 18 wk of unampliﬁed (fetoscope) fetal heart tones Plasma/Capillary Glucose (mg/dL) Infusion Rate (U/hr) <80 Insulin off 80-100 0.5*After more than 40 weeks, the beneﬁts of continued conservative man- 101-140 1.0agement are less than the danger of fetal compromise. Induction of 141-180 1.5 181-220 2.0*labor before 42 weeks in diabetic pregnancy—regardless of the readi- >220 2.5*ness of the cervix—is prudent. Intermittent Subcutaneous Injection MethodLabor or Cesarean 1. Give one half of the usual insulin dose in AM.The ACOG296 has recommended that primary cesarean delivery be 2. Begin and continue glucose infusion (5% dextrose in water) atdiscussed with diabetic gravidas with an EFW greater than 4500 g. This 100 mL/hr throughout labor.may reduce the risk of shoulder dystocia to some degree for an indi- 3. Begin oxytocin as needed.vidual patient, but the effect on the larger obstetric population is less 4. Monitor maternal glucose levels hourly using a capillaryclear. reﬂectance meter at bedside or laboratory determinations, or Gonen and associates297 retrospectively assessed the impact of a both. 5. Administer regular insulin in small doses (2 to 5 U) to maintainpolicy of elective cesarean in cases with an EFW above 4500 g. During glucose levels of 80 to 120 mg/dL.the 4 years of the study with more than 16,000 deliveries, macrosomiawas correctly predicted in only 18% of cases. Of the 115 undiagnosed *Intravenous bolus of 2 to 5 units when the rate increases.macrosomic cases, 13 infants were delivered by emergency cesarean,and 99 were delivered vaginally. Three infants (3%) with macrosomiaand 14 infants (0.1%) without macrosomia sustained brachial plexus and low pelvic or even outlet operative deliveries must be approachedinjury. The policy of preemptive cesarean for an EFW greater than with extreme caution if labor is protracted. With an EFW greater than4500 g prevented at most a single case of brachial palsy. 4500 g, a prolonged second stage of labor or arrest of descent in the Conway and Langer298 performed a prospective trial enrolling dia- second stage is an indication for cesarean delivery.296 Most large seriesbetic women among whom those with an EFW of 4250 g or more of diabetic pregnancies report a cesarean section rate of 30% to 50%.underwent elective cesarean section. Ultrasonography correctly identi- The best means by which this rate can be lowered is by early and strictﬁed the presence or absence of macrosomia in 87% of patients. The glycemic control in pregnancy. Conducting long labor inductions incesarean section rate increased slightly after the protocol was initiated patients with a large fetus and a marginal pelvis may increase, rather(22% versus 25%), but overall, shoulder dystocia was less common than lower, morbidity and costs.(2.4% versus 1.1%). Herbst299 conducted a cost-effectiveness analysis of “prophylactic”delivery (i.e., induction or cesarean) of the fetus with an EFW greater Intrapartum Glycemic Managementthan 4500 g using risk and beneﬁt rates estimated from the existing Perinatal asphyxia and neonatal hypoglycemia correlate with maternalmedical literature.299 For an infant of a normoglycemic pregnancy hyperglycemia during labor.300 Unfortunately, strict maternal euglyce-weighing 4500 g or more, routine obstetric management was the least mia during labor does not guarantee newborn metabolic stability inexpensive ($4014 per injury-free child) compared with elective cesar- infants with macrosomia and islet cell hypertrophy. The use of aean cost of $5212 and induction cost of $5165. However, a sensitivity combined insulin and glucose infusion during labor maintains theanalysis suggested that with a shoulder dystocia risk higher than 10% maternal plasma glucose level in a narrow range (80 to 110 mg/dL)(as is the case with a fetus weighing more than 4500 g in a diabetic and reduces the incidence of neonatal hypoglycemia.301 A protocol forpregnancy), primary cesarean or early induction is somewhat more administration of a continuous insulin infusion in labor is outlined inﬁnancially advantageous. The current recommendation that cesarean Table 46-23. Typical infusion rates are 5% dextrose in Ringer’s lactatesection be considered when fetal weight is suspected to exceed 4500 g at 100 mL per hour and lispro or aspart insulin at 0.5 to 1 units perappears to confer a modest improvement in neonatal outcome. hour. Capillary blood glucose is monitored hourly in these patients. The decision to attempt vaginal delivery or perform a cesarean For patients with diet-controlled GDM or mild type 2 diabetes, avoid-delivery is inevitably based on limited data. The patient’s obstetric ing dextrose in all intravenous ﬂuids during labor usually maintainshistory, the best EFW, a fetal adipose proﬁle (i.e., abdomen larger than excellent glucose control.head), and clinical pelvimetry should all be considered. Midpelvic When cesarean section is planned in a woman with diabetes, theoperative deliveries should be avoided when macrosomia is suspected, procedure should be performed early in the day to avoid prolonged
986 CHAPTER 46 Diabetes in Pregnancyperiods of fasting. On the night before surgery, patients should be a risk factor for childhood diabetes (OR = 2.13; CI, 1.8 to 3.55) andinstructed to take their full dose of NPH or glyburide. No morning that the introduction to cow’s milk products before age 8 days was aninsulin or glyburide should be taken. A glucose-containing intravenous important risk factor for the disease. Given the increased risk of dia-line should be established promptly on arrival at the hospital, with betes in offspring of women with diabetes, these data underscore theinsulin given as intravenous boluses on a sliding scale as needed every importance of encouraging breastfeeding in all postpartum women1 to 4 hours to maintain maternal plasma glucose in the range of 80 with diabetes.to 160 mg/dL. Most neonatologists maintain strict monitoring of glucose levels in newborn IDMs for at least 4 to 6 hours (frequently 24 hours), often necessitating admission to a newborn special care unit. This early sepa-Postpartum Metabolic Management ration of mother and neonate impedes breastfeeding and infant attach-In the recovery room and after delivery, insulin can be given subcuta- ment, and it may delay the onset of lactogenesis in the diabetic mother.neously to women with type 2 diabetes using a sliding scale until a Neubauer and colleagues306 observed that milk of women with insulin-regular diet is established. The insulin doses required after delivery are dependent diabetes came in later than it did in controls and had sig-typically 30% to 50% of the preprandial doses required during preg- niﬁcantly lower lactose and higher total nitrogen at 2 to 3 days afternancy just before delivery. Type 1 diabetes patients require more inten- delivery. The infants of these diabetic mothers had signiﬁcantly lesssive glucose monitoring after delivery, because many experience a milk intake 7 to 14 days after delivery than did those of the controlhoneymoon phase, in which insulin requirements fall dramatically. women. Delayed lactogenesis in the women with insulin-dependentThe glucose-insulin intravenous infusion should be continued in type diabetes most likely occurred in those with poor metabolic control. A1 diabetes patients, especially those who have had a cesarean delivery, study by van Beusekom and coauthors307 analyzed concentrations ofuntil the diet has normalized. micronutrients and macronutrients in milk and capillary blood and found that tight glycemic control was associated with normal propor- tions of milk nutrients, compared with the multitude of milk abnor- malities seen with moderate and poor control.Management of the Neonate Evidence indicates that with proper encouragement, sustained breastfeeding is possible for a signiﬁcant proportion of patients withNeonatal Transitional Management overt diabetes. Webster and coworkers308 longitudinally comparedUnmonitored and uncorrected neonatal hypoglycemia can lead to breastfeeding habits between women with diabetes and normal women.neonatal seizures, brain damage, and death. The degree of hypoglyce- At discharge, 63% of mothers with insulin-dependent diabetes andmia correlates roughly with the degree of maternal glycemic control 78% of mothers without diabetes were breastfeeding. At 8 weeks, theduring the 6 weeks before birth. Pancreatic hypertrophy and chronic proportions of each were nearly identical (58% and 56%, respectively),fetal hyperinsulinemia—holdovers from the chronically glucose-rich and when the infants were 3 months old, 47% of mothers with insulin-intrauterine environment—can lead to signiﬁcant hypoglycemia after dependent diabetes and 33% of women without diabetes continued tothe umbilical supply of nutrients is interrupted by delivery. IDMs also breastfeed. The study showed that IDMs were delivered atraumatically,appear to have disorders of catecholamine and glucagon metabolism and infants who are well oxygenated with mature lungs and who haveand have diminished capability to mount normal compensatory excellent antecedent glucose control can be kept with their mothersresponses to hypoglycemia. The current recommendations specify fre- under close glycemic monitoring for the ﬁrst 1 to 2 hours of life. Thisquent blood glucose checks and early oral feeding when possible permits early breastfeeding, which may reduce the need for intrave-(ideally from the breast), with infusion of intravenous glucose if oral nous glucose therapy.measures prove insufﬁcient. The actual techniques of infant nursing require some modiﬁcation Ordinarily, blood glucose levels can be controlled satisfactorily with in women with overt diabetes, especially insulinopenic patientsan infusion of 10% glucose. If greater amounts of glucose are required, with type 1 diabetes. Increased maternal calorie and ﬂuid intakebolus administration of 5 mL/kg of 10% glucose is recommended, with is necessary to maintain milk supply in all women. The caloriegradually increasing concentrations of glucose administered every 30 expenditure during nursing and for the 30 to 45 minutes thereafterto 60 minutes, if necessary. (probably during post-nursing lactogenesis) may precipitate severe hypoglycemia if compensatory calories are not ingested. This is espe- cially common during nursing late at night. Breastfeeding women withBreastfeeding type 1 diabetes should be encouraged to take in ﬂuids and food (100Considering the number of perinatal complications experienced by to 300 calories per feeding episode) while nursing to avoid reactivemany women with diabetes (e.g., preeclampsia, macrosomia-induced hypoglycemia.cesarean section, neonatal hypoglycemia), achieving a high rate of Fortunately, studies of breastfeeding women with diabetes indicatebreastfeeding may seem to be a superﬂuous goal. However, mounting that lactation, even for a short duration, has a beneﬁcial effect onevidence indicates that breastfed infants have a much lower risk of overall maternal glucose and lipid metabolism. For postpartum womendeveloping diabetes than do those exposed to the proteins in cow’s who have GDM during their pregnancies, breastfeeding may offer amilk.302,303 Pettitt and associates304 found that children who were exclu- practical, low-cost intervention that helps to reduce or delay the risksively breastfed had signiﬁcantly lower rates of non–insulin-dependent of subsequent diabetes.diabetes mellitus than did those who were exclusively bottle-fed in allage groups. The odds ratio for non–insulin-dependent diabetes melli-tus in exclusively breastfed persons, compared with exclusively bottle-fed individuals, was 0.41 (CI, 0.18 to 0.93), adjusted for age, sex, birth References 1. Wild S, Roglic G, Green A, et al: Global prevalence of diabetes. Estimatesdate, parental diabetes, and birth weight. A study by Gimeno and de for the year 2000 and projections for 2030. Diabetes Care 27:1047-1053,Souza305 found that a shorter duration of exclusive breastfeeding was 2004.
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