Gestational Diabetes

Gestational diabetes is defined by the Third International Workshop Conference on Gestational Diabetes Mellitus³ as “carbohydrate intolerance of varying severity with onset or first recognition during pregnancy.” According to the Workshop Summary and Recommendations, “This definition applies irrespective of whether or not insulin is used for treatment or the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated the pregnancy.“ The existence of this disorder was first suspected on the basis of increased perinatal mortality rates among pregnancies in women later developing overt diabetes,⁴ and was first diagnosed by the same criteria as were used for the diagnosis of diabetes in the nonpregnant state.⁵ Because pregnancy exerts significant effects on maternal metabolism, with a decrease in fasting and an increase in postprandial circulating glucose Levels and a marked increase in insulin resistance,⁶ the development of pregnancy-specific glucose tolerance test criteria for gestational diabetes by O'Sullivan and Mahan⁷ in 1964 marked another important milestone in clinical obstetrics. The criteria were based on tests administered to 752 consecutive prenatal patients, primarily in the second and third trimesters, and were validated based on the likelihood of patients who previously developed gestational diabetes mellitus developing overt diabetes during a 7-year follow-up of a separate group of subjects. In a long-term follow-up study O'Sullivan, utilizing current criteria for nonpregnant individuals, found an approximately 40% prevalence of overt diabetes at an average of 20 years after the index pregnancies.⁸ It is important to note that the O'Sullivan criteria were validated on the basis of their predictive value for subsequent maternal diabetes, not for pregnancy outcome.

GLUCOSE TOLERANCE TESTING.

The glucose tolerance test (GTT) standard for pregnant women in the United States and recommended for use in pregnancy by the American Diabetes Association (ADA)⁹ is the 100-g, 3-hour oral GTT. The 100-g glucose challenge is administered after an overnight fast of 8 to 14 hours, and after 2 to 3 days of an unrestricted diet containing at least 150 g of carbohydrate per day. The dietary preparation is important because carbohydrate-depleted persons do not mount as effective an insulin response to a glucose challenge, and they may manifest higher glucose levels than they would have if properly prepared. Blood samples are drawn in the fasting state, and at 1, 2, and 3 hours after ingestion of the glucose challenge. Glucose should be analyzed with standard laboratory technology, not with test strips and reflectance meters, which are designed for self-monitoring of glucose levels. Although quite useful in the management of the person with already-diagnosed diabetes, the latter method is too imprecise for use in diagnostic testing.^3,10 Newly developed refinements may make such systems more suitable for diagnostic testing.^10a.

When O'Sullivan and Mahan⁷ originally derived their criteria for the diagnosis of gestational diabetes, they opted for the presence of at least two of four values exceeding the given thresholds in order to improve specificity and to avoid reliance on a single laboratory value in arriving at a diagnosis. They analyzed venous whole-blood samples using the Somogyi-Nelson method of glucose analysis, and the thresholds established are depicted in Table 1. Currently most laboratories measure glucose in plasma or serum specimens, whose results are approximately 14% higher than those for whole blood. In 1979 The National Diabetes Data Group (NDDG)¹¹ published an adaptation of O'Sullivan and Mahan's oral GTT thresholds, applying them to plasma and serum specimens. These conversions are shown in Table 2, and have been recommended by the ADA.⁹

TABLE 1. Pregnancy Oral Glucose Tolerance Test Thresholds of O'Sullivan and Mahan*

TABLE 2. ADA and NDDG Pregnancy Oral Glucose Tolerance Test Thresholds*

The original method of glucose analysis, which also measured some non-glucose-reducing substances, has been replaced by more specific enzymatic methods, such as glucose oxidase and hexokinase. Consequently, our center¹² uses oral GTT criteria that are somewhat lower than those recommended by the ADA, having been corrected first for the more specific enzymatic methodology by the subtraction of 5 mg/dL from each value, and then increased by 14% to compensate for the change from whole blood samples to plasma or serum. These thresholds are shown in Table 3.

TABLE 3. Pregnancy Oral Glucose Tolerance Test Thresholds Established by Carpenter and Coustan, based on those of O'Sullivan and Mahan*

Although the thresholds shown in Table 2 are used most widely and represent the current standard of care in the United States, it should be pointed out that both sets (see Table 2 and Table 3

When performing the oral GTT in pregnancy, it is important that the laboratory understand that a 100-g, 3-hour test is required, rather than the 75-g, 2-hour test that is standard in nonpregnant persons. Furthermore, diagnostic criteria for pregnancy should be applied to the results. If the laboratory is unaware of the fact that the patient is pregnant, or of the need for different criteria in pregnancy, it is possible that gestational diabetes could be overdiagnosed or underdiagnosed. Another problem that may arise is the patient who is unable to undergo an oral GTT because of vomiting. It may help in this case to offer a different flavor of glucose challenge and to administer the oral load on crushed ice. Another option is the use of a relatively tasteless glucose polymer as the challenge.¹⁹ If oral testing still is not possible, an intravenous GTT²⁰ may be substituted, although there are fewer supportive data for the use of specific thresholds during pregnancy.

SCREENING.

Population-based screening for gestational diabetes has been called into question because of the lack of well-controlled outcomes research to determine the overall benefit to society of such programs.²¹ Despite this lack of unassailable epidemiologic data, the risks of gestational diabetes to the fetus/neonate as well as its implications for the mother's future likelihood of diabetes are well documented (see below). Furthermore, in every series of gestational diabetic patients, some patients are found to have had preexisting diabetes that had gone undiagnosed before the pregnancy. Some sort of screening for this disorder is deemed appropriate by most authorities in the field, The simplest approach to screening for gestational diabetes is the taking of a history and the performance of a full 3-hour, 100-g oral GTT whenever risk factors for diabetes are present. Traditional risk factors include the following:

  A family history of diabetes in a first- or second-degree relative
  A previous perinatal loss or other adverse pregnancy outcome
  Previous birth of a large infant (variously defined as 8.5 pounds, 9 pounds, 4000 g, and 4500 g)
  Glycosuria detected during the current pregnancy
  Obesity

Unfortunately, when risk factors such as these have been sought in universally screened populations, only approximately 50% of persons with gestational diabetes have such factors.^2,22,23,24 The ADA has recommended universal screening of all pregnant women at 24 to 28 weeks with a 50-g, l-hour glucose challenge.⁹ If the venous plasma or serum glucose is equal to or greater than 140 mg/dL (7.8 mmol/L), a full 100 g, 3-hour oral GTT is performed. Until recently, the American College of Obstetricians and Gynecologists (ACOG)²⁵ recommended that the 50-g, l-hour oral GTT be administered only to gravidas who were 30 years or older and to those who were younger than 30 if risk factors were present. However, fewer than 50% of women with gestational diabetes are 30 years old or older.² In a population-based study: of screening for gestational diabetes, the use of the former ACOG screening recommendations²⁵ would have resulted in the identification of only 65% of affected women. Lowering the age threshold for universal screening to 25 years or older in the same study² would have increased the sensitivity to 85%, with no appreciable increase in cost per case diagnosed. Because 10% of gravidas with gestational diabetes (NDDG criteria) manifest screening test values of 130 to 139 mg/dL, a reduction of the screening test threshold to equal to or greater than 130 mg/dL combined with an age threshold of 25 years or older would have yielded a 95% sensitivity in the same population.²

Universal screening of all pregnant women, without regard to age, allows for efficient office management and decreases the likelihood of a woman with indications for screening to be overlooked; however, such screening would increase the number of tests performed by approximately 22% in order to detect 6% of the cases in the general population. To confuse the issue further, it is clear that different ethnic groups have different prevalence rates for gestational diabetes,²⁶ just as they do for non-insulin-dependent (type II) diabetes mellitus. Thus reports from one center may differ from those of another with respect to prevalence, and the differences are not necessarily explained by differing methodologies. The most recent ACOG recommendations²⁷ noted that no well-controlled studies have been carried out to evaluate the overall benefit to the population of screening for gestational diabetes. A number of options were described. For example, some Native American populations have such a high prevalence of gestational diabetes that membership in such an ethnic group carries a higher a priori risk than does a positive screening test. Thus it may be appropriate to perform a full oral GTT on all such persons, without a prior glucose challenge screening; however, the prevalence of gestational diabetes may be low enough among some groups, such as adolescents, that history-based screening may be more appropriate. Individual office practices may choose to modify screening protocols depending on the characteristics of the population served and the resources available. One typical example is the early screening of persons with a history of gestational diabetes in a previous pregnancy; since this historic risk factor predicts a likelihood of recurrence of approximately 50%.^28,29

Preexisting Diabetes

A number of different classification schemes have been proposed for pregnancies in women with preexisting diabetes. White devised a classification of diabetes³⁰ based on the likelihood of the presence of vascular disease (Table 4); this classification was intended to help prognosticate the outcomes of pregnancies. It is worth noting that the White Classification did not include a category for gestational diabetes. The class A person, as described by White, had an abnormal GTT before pregnancy but was treated only by diet, not insulin. Although the White Classification scheme is learned by every resident in obstetrics and gynecology, and is often a subject for examination questions, its value in clinical management is dubious. All women with preexisting diabetes mellitus who become pregnant should be considered to carry high-risk pregnancies. Although the presence of vascular disease clearly increases certain maternal and fetal risks, the apparent absence of vascular disease should not be considered reassuring. Another approach to classification is that of Pedersen,³¹ who based his Prognostically Bad Signs in Pregnancy (PBSP) system on easily recognizable signs associated with perinatal mortality (Table 5). In our own anecdotal experience, the patient who is a “neglector”(i.e., one who neglects her medical treatment and prenatal appointments) has the highest risk. Although these classification schemes have not been altogether helpful in the care of the individual patient, they are a very important means of comparing data from different centers.

TABLE 4. White Classification of Diabetes Mellitus in Pregnancy

TABLE 5. Pedersen's Prognostically Bad Signs in Pregnancy (PBSP)

1. Clinical pyelonephritis: Positive urine culture with acute temperature elevation exceeding 39°C
   
2. Precoma: Diabetic acidosis with venous bicarbonate <10 mEq/L or severe acidosis venous bicarbonate10–17 mEq/L
   
3. Toxemia:Two of the following three sypmtoms and signs (a) BP >150/100 for at least 5 day before deliver; (b) >0.1% proteinuria for at least 24 hours before deliver; (c) edema or weight gain >20 kg
   
4. Neglectors: First medical care is in labor, or “psychopathic or of low intelligence,” or “women in poor social circumstances who present themselves… less than 60 days before term”
   

Currently, preexisting diabetes is classified into insulin-dependent (type I) and non-insulin-dependent (type II) diabetes mellitus. These terms can be confusing. The term insulin dependent is not synonymous with insulin treated. A patient who is insulin dependent will lapse into diabetic ketoacidosis (DKA) if insulin is withheld for a substantial length of time: She is dependent on insulin to avoid DKA. In persons with type I diabetes, the primary defect is presumably pancreatic islet cell dysfunction or obliteration, widely believed to occur on an autoimmune basis. Type I diabetes usually, but not always, has its onset during the first two or three decades of life. Persons with non-insulin-dependent (type II) diabetes usually are thought to have a defect in the action of insulin at the insulin receptor or postreceptor level. Early in the course of their disorder, their metabolic derangement may be characterized by insulin resistance. Later in the progression of their disease, however, many become insulinopenic. Persons with type II diabetes may be insulin treated, but if they require insulin to avoid DKA they should then be considered to have type I diabetes. In general terms, persons with type II diabetes are more likely than not to be obese, older, and to have residual pancreatic islet cell function as measured by C-peptide immunoreactivity. Although persons with type I diabetes of childbearing age are more likely to have diabetic vascular complications, such problems also may be found in people with longstanding type II diabetes. When there is preexisting diabetes, pregnant women and their fetuses are at increased risk for a variety of disorders; specific organ system involvement may entail specific types of risk, as described below. It is best to classify preexisting diabetes as type I or type II, and then to describe whatever accompanying diabetic sequelae are present.

Mortality

Before the availability of insulin, maternal mortality among diabetic women approached 50%.³² This rate decreased immediately after insulin was discovered and presently is 0.5% or less.³³ This maternal death rate is still considerably higher than that for the general obstetric population, and it can be thought of as the sum of the general maternal mortality rate plus the mortality rate attributable to having diabetes for any 9-month period of time. Persons with apparently particularly high risk for maternal death are those with previous myocardial infarction,³⁴ and it is important to counsel such women about the grave risks associated with pregnancy. Diabetic women without coronary artery disease, however, need not be advised to avoid pregnancy, as they may have been in previous years.

Glucose Control

HYPERGLYCEMIA AND DIABETIC KETOACIDOSIS.

Perinatal mortality and morbidity appear to be directly related to the degree to which ambient maternal glucose levels during pregnancy exceed nondiabetic limits. The achievement of near-euglycemia is the usual goal in managing diabetic pregnancy. The diabetogenic effects of pregnancy on maternal metabolism complicate attempts at glucoregulation, but an understanding of these effects can aid the clinician in formulating a strategy. Fasting plasma glucose levels tend to decrease by the end of the first trimester, whereas the response to a glucose challenge increases in amplitude and duration as pregnancy progresses.³⁵ The latter change generally is ascribed to increased insulin resistance⁶ and is most pronounced after a pure glucose challenge, rather than a mixed nutrient meal.

Among persons with diabetes, pregnancy has been associated with increasing insulin requirements,³⁶ particularly in the second half of gestation, and a tendency toward DKA at lower ambient glucose levels, presumably because of the insulin resistance mentioned above. Because of the extremely high perinatal mortality rate associated with any episode of DKA, prompt and intensive treatment of this disorder is essential. It should be remembered that DKA is not a disorder of “too much glucose,” but rather is related to “too little insulin,” causing increased hepatic glucose production and the breakdown of stored fats to produce the ketone bodies, acetoacetate and β-hydroxybutyric acid. Because one of the major problems in DKA is osmotic diuresis with resultant dehydration, large volumes of fluid should be infused initially, along with a constant intravenous insulin infusion. Further details of the management of this problem are available elsewhere.³⁷

HYPOGLYCEMIA.

Whenever persons with type I diabetes attempt near-normalization of circulating glucose levels the likelihood of hypoglycemia is presumably increased. Symptomatic hypoglycemia may occur with particular frequency during attempts at glucoregulation in the first half of pregnancy,^38,39 particularly among patients with a previous history of symptomatic hypoglycemia.³⁸ There is conflicting evidence suggesting that the glucose counter-regulatory response may⁴⁰ or may not⁴¹ be impaired during pregnancy in persons with type I diabetes. Adverse fetal effects of maternal hypoglycemia have not been documented in human pregnancy, and fetal heart rate^40,41 as well as fetal movements⁴² and placental perfusion^41,42 appear to be unchanged during conditions of maternal hypoglycemia in the range of 45 to 55 mg/dL. It is clear, however, that maternal compromise may result (e.g., coma, convulsions, trauma). Thus maternal hypoglycemia should be avoided if possible; however, the relaxing of metabolic control to levels of hyperglycemia that are potentially dangerous to the fetus usually is not justified. Studies of GTTs among nondiabetic pregnant women suggest that mild degrees of hyperglycemia and hypoglycemia⁴³ may carry similar fetal risk, and that the safest levels of glucose are those that are within normal ranges for pregnancy. The work of Lev-Ran and Goldman⁴⁴ suggests that brittleness, or the tendency toward wide swings in glucose levels even under the best of circumstances, tends to ameliorate in midpregnancy, and improved metabolic control may be more easily accomplished at this time than in the nonpregnant state.

Medical Problems of Diabetes

NEPHROPATHY.

Diabetic nephropathy, defined as “the presence of a persistently positive urinary dipstick test for albumin in a person with diabetes (or a urinary albumin excretion rate 300 mg/day) in the absence of other renal disease,”⁴⁵ complicates both type I and type II diabetes. However, because type II diabetes tends to have a later age at onset than type I diabetes, and because the prevalence of nephropathy is associated with the duration of diabetes, pregnant women with type I diabetes are considerably more likely to have nephropathy than are those with type II diabetes. In one series from a tertiary-care institution 23% of pregnant women with preexisting diabetes manifested nephropathy, which was defined as a urinary protein excretion equal to or greater than 300 mg/ day before the third trimester.⁴⁶ Nephropathy appears to develop in five stages.⁴⁵ The first two stages are manifested by renal hypertrophy and hyperfunction, and then renal lesions without clinical signs. In the third stage, occurring within 7 to 15 years in 25% to 40% of persons with type I diabetes, microalbuminuria becomes evident (only 30 to 300 mg/day). Once microalbuminuria is present in a given person, it is highly likely that she will progress to clinically evident diabetic nephropathy and ultimately end-stage renal disease; this progressive decrease in glomerular filtration rate usually occurs at a rate of 10 mL/min/year. Hypertension and retinopathy usually are present when nephropathy is detected.

Probable risk factors predisposing a patient to the development of diabetic nephropathy include genetic factors, hyperglycemia in the first two stages, hypertension in the later stages, and possibly excess protein content in her diet, which is believed to be associated with increased intracapillary pressure in the glomeruli. Restriction of dietary protein may slow the progression of renal damage in diabetic persons with clinically manifest nephropathy,⁴⁷ but the benefits appeared to be only modest in a randomized trial involving a population with chronic renal disease not due to type I diabetes.⁴⁸ In a randomized trial involving nonpregnant, nonhypertensive persons with type I diabetes, angiotensin-converting enzyme (ACE) inhibitors significantly impeded the progression of nephropathy.⁴⁹ Unfortunately, ACE inhibitors are contraindicated during pregnancy because of potential adverse fetal effects. Most important, in a randomized study of 1441 patients with type I diabetes, the 1993 Diabetes Control and Complications Trial (DCCT)⁵⁰ demonstrated that intensive control of ambient glucose levels to an average of approximately 150 mg/dL, in a 6- to 7-year period, significantly reduced the appearance and progression of nephropathy. The ADA and the National Kidney Foundation subsequently issued a consensus statement⁵¹ recommending that optimization of metabolic control is the cornerstone to preventing the progression of diabetic nephropathy. Protein restriction may be of value, and control of hypertension also may be advantageous, particularly with ACE inhibitors in the nonpregnant state.

During normal pregnancy, renal plasma flow and glomerular filtration rate are markedly increased. In women with diabetic nephropathy, the quantity of albuminuria tends to increase dramatically, such that many persons with microalbuminuria in early pregnancy excrete more than 5 g/day by the third trimester. This not only raises concerns about a possible adverse effect of pregnancy on nephropathy, but it can make the diagnosis of hypertensive disorders of pregnancy quite difficult. Most of the evidence available to date suggests that pregnancy has no long-lasting effect on diabetic nephropathy, and that most women who develop marked proteinuria during pregnancy revert to their prepregnancy renal status after delivery.^52,53 One small case series, however, suggested that there was an increase in the rate of deterioration in renal function associated with pregnancy, leading to an earlier need for renal transplantation.⁵⁴ Because the study was small and uncontrolled, no conclusions can be drawn. Approximately one third of women with nephropathy experience a decrease in creatinine clearance during the course of pregnancy.^46,52

Diabetic nephropathy clearly is associated with a greater risk of adverse outcomes in pregnancy.⁵² Perinatal mortality is higher, and preterm delivery is necessary in more than one half of patients, and in one fourth before 34 weeks. Approximately 18% of infants are growth retarded, and fetal distress is common. Preeclampsia develops in nearly one half of women with nephropathy. Severe anemia, due to both the renal disease and the usual hemodilution of pregnancy, also often accompanies pregnancy in these women.

The management of nephropathy during pregnancy may be difficult because risks and benefits must be constantly balanced. For example, it is usual to prescribe a relatively high-protein diet to pregnant women in order to provide amino acids for fetal growth and development, and also to help maintain relative euglycemia in persons with diabetes. High-protein intake, however, may have an adverse effect on the progression of nephropathy. A middle ground is probably most appropriate, and it may be reasonable to decrease the protein content of the diet to 60 g/day.⁵² Renal function should be evaluated early in the course of pregnancy in order to detect the presence of incipient nephropathy, lest its discovery later in pregnancy be confused with preeclampsia. This evaluation should include 24-hour urinary protein and creatinine measurements as well as serum creatinine and blood urea nitrogen.

At least two studies have demonstrated an increased risk of preeclampsia in diabetic women who manifest mild to moderate microalbuminuria during the first half of pregnancy.^55,56 To compare values obtained later in pregnancy, we have found it helpful to obtain a baseline serum uric acid measurement if preeclampsia is suspected. Follow-up renal function studies are obtained at least once per trimester if proteinuria was present early in pregnancy. Hypertension should be treated to maintain diastolic blood pressure less than 100 mmHg (or even 90 mmHg) if the patient does not have a history of preexisting chronic hypertension. As stated above, ACE inhibitors should be avoided during pregnancy because of potential adverse fetal effects. Methyldopa, beta-blockers, and hydralazine all have been used in this situation. One group has reported the successful use of recombinant human erythropoietin to treat severe anemia during pregnancy in three patients with chronic renal disease, one of whom had diabetic nephropathy.⁵⁷ Because of the propensity of patients with diabetic nephropathy for intrauterine growth retardation it is appropriate to use ultrasound on a regular basis to evaluate fetal growth. In women with vascular disease, antepartum fetal testing is instituted earlier in pregnancy than in those who do not have the disease.

RETINOPATHY.

Diabetic retinopathy is a form of vascular disease, resulting from damage to retinal capillaries and arterioles; the exact mechanism is unclear at present. An association between elevated glycosylated hemoglobin and retinopathy has been demonstrated.^58,59 Background retinopathy, the earliest manifestation, includes microaneurysms, small vessel obstruction, cotton wool spots, intraretinal microvascular abnormalities (e.g., venous abnormalities, small retinal hemorrhages), and hard exudates.⁶⁰ Vision generally is not threatened by background retinopathy unless macular edema or ischemia supervenes. Background retinopathy is present in 17% of diabetic persons 5 years after the diagnosis, and in more than 90% after 15 years.⁶⁰

Proliferative diabetic retinopathy is characterized by new vessel formation, or neovascularization. This growth may be a response to underlying retinal ischemia.⁶⁰ The new vessels are poorly supported, and may leak and adhere to the vitreous. Resultant shrinkage and contraction of the vitreous can put pressure on the new vessels, causing retinal hemorrhages.⁶⁰ These hemorrhages can lead to scarring or retinal detachment, or both, and are the primary cause of visual loss in affected patients. One of the most important advances in recent years has been the discovery that laser photocoagulation therapy can prevent or forestall retinal hemorrhage and visual loss if applied at the appropriate time. It is unusual for proliferative diabetic retinopathy to appear before 10 to 12 years after the diagnosis of diabetes, but it afflicts 26% of diabetic persons after 15 to 16 years.⁶⁰ The DCCT results⁵⁰ demonstrated that improved metabolic control in persons with type I diabetes is associated with a decreased rate of development of both retinopathy and nephropathy.

Among persons with preexisting nonproliferative diabetic retinopathy, intensive management has been associated with a higher likelihood of progression of retinopathy during the first year. By 36 months of therapy, however, retinopathy was less likely to advance in the intensive management group, and this benefit continued throughout the study period. Overall, subjects in the intensive management group manifested a 50% lower likelihood of significant progression compared with those in the conventional treatment group. This and other studies confirm that the institution of “tight” metabolic control may be associated with a transient worsening of diabetic retinopathy. but that long-term good control has a salutary effect.⁵⁰

Currently it is uncertain whether pregnancy exerts any independent effect on accelerating the progression of retinopathy, although the most appropriately controlled prospective study suggested that there is such an effect independent of glycemic control.⁶¹ Factors such as hyperglycemia and hypertension⁶² appear to accelerate the course of retinopathy in pregnancy. The sudden institution of intensive metabolic control that generally is carried out in early pregnancy may be expected to have a transient adverse effect on retinopathy. This phenomenon has been demonstrated in persons with glycohemoglobin as low as 6 standard deviations above the control mean.⁶³ The effect of diabetic retinopathy on pregnancy outcome has not been widely investigated. One small retrospective series of 20 subjects with advanced retinopathy, none of whom underwent pregnancy termination, reported a perinatal survival rate of 94%.⁶⁴

NEUROPATHY.

Little information is available about the frequency with which diabetic neuropathy complicates pregnancy. However, because various forms of neuropathy are common among persons with diabetes, and because pregnancy is not known to be protective against these problems, it is likely that they will be encountered among pregnant women.³⁴ Autonomic neuropathy can cause symptoms referable to the bladder or gastrointestinal tract. Gastroparesis, with gastric atony and delayed emptying, can cause early satiety, fullness, nausea, vomiting, and pain.³⁴ This disorder has been described in pregnant women with diabetes, and in one case series of four affected persons, the gastric symptoms were associated with cardiovascular problems, particularly postural blood pressure changes.⁶⁵ The vomiting in such cases can be intractable, interfering with nutrition and hence fetal growth. Symptoms can be confused with hyperemesis, but their persistence and severity in a woman with diabetes should alert the clinician. Various treatments, including metoclopramide and, more recently, erythromycin,⁶⁶ have been utilized in nonpregnant persons. Based on available case reports, pregnancy outcome often is suboptimal in cases of gastroparesis.⁶⁷ Autonomic dysfunction also may cause defective glucose counterregulation, and its presence may be suggested by the absence of normal respiratory variation in heart rate as well as the presence of postural hypotension. In one controlled study, autonomic dysfunction was associated with a higher frequency of pregnancy complications, but not with any specific complication.⁶⁸

Peripheral neuropathies are the most commonly encountered nerve disorder in persons with diabetes.³⁴ These neuropathies usually are sensory in nature, with paresthesias followed by anesthesia. They occur most often in the lower extremities, and they can lead to skin ulceration, deep-seated infection, and in extreme cases amputation.

HYPERTENSION.

Hypertension is commonly present in diabetic gravidas with nephropathy; however, even in the absence of nephropathy, women with diabetes are more likely than nondiabetic women to have hypertensive complications during pregnancy. Cousins, in a thorough literature review,³³ found that chronic hypertension was present in 8% of pregnant women with preexisting diabetes, without known vascular disease, and in 2.5% of patients with gestational diabetes. Preeclampsia or hypertensive disorders of pregnancy were reported in only 14% of the class B and class C diabetic women and in those with gestational diabetes. but in nearly 30%. of those with known vascular disease.

URINARY TRACT INFECTIONS.

Urinary tract infections appear to be generally more common among patients with diabetes versus nondiabetic patients. In Cousins' literature review,³³ pyelonephritis complicated approximately 3% of pregnancies in women with preexisting diabetes. In pregnant women with diabetes, urinary tract infections are of particular significance because they can have an adverse impact on metabolic control. DKA as well as more subtle derangements of control are commonly brought about by infections.

HYDRAMNIOS.

Hydramnios, or excessive amniotic fluid, was found to complicate approximately 18% of overt diabetic pregnancies in Cousins' literature review.³³ Recent studies, however, have suggested that this problem complicates only 2% of gestational diabetic pregnancies.³³ Varying definitions of this complication, along with our inability to measure amniotic fluid volume accurately by noninvasive means, make its diagnosis problematic. Although it is tempting to speculate that maternal hyperglycemia with fetal osmotic diuresis is responsible for hydramnios, supportive data have not been convincing, and the cause of this complication in diabetic pregnancies must be considered unknown at the present time. One study has detected significantly higher mean blood glucose values among 13 gestational diabetic subjects when hydramnios was present, compared with the same patients at times when amniotic fluid volumes were closer to normal.⁶⁹ In the general population, the presence of hydramnios is associated with an increased risk for congenital malformations. This is no doubt also true in diabetic pregnancies, in which the a priori risk for malformations is increased, but most diabetic pregnancies with hydramnios produce structurally normal offspring. Hydramnios also is considered a potential inducer of preterm labor and can cause maternal respiratory embarrassment. Nevertheless, it is distinctly unusual for diabetes-associated hydramnios to require therapeutic amniocentesis.

A number of studies of placental alterations in diabetic pregnancy have been published, but there is little agreement as to which constitute typical changes.⁷⁰ The placenta is responsible for fetal gas exchange, nutrition, waste removal, and hormone production and release into both the maternal and fetal circulations. Any or all of these functions may be affected by diabetes, particularly by the vascular disease present in women with longstanding diabetes. Placental passage of glucose from mother to fetus is probably responsible for most of the abnormalities seen in infants of diabetic mothers. Placental glycogen stores are increased in diabetic pregnancy.⁷¹ Placentas from diabetic mothers weigh more and are larger than those from nondiabetic controls, with cellular hyperplasia dominating over hypertrophy, and may in fact compete with the fetus for oxygen and nutrients. In the presence of maternal vascular disease, the placentas may be smaller, rather than larger, than those of nondiabetic controls. Both premature senescence and immaturity of chorionic villi have been described in placentas of diabetic mothers.⁷² A great deal of information remains to be uncovered regarding the participation of the placenta in the pathophysiologic alterations of diabetic pregnancy.

Perinatal Mortality

Although the perinatal mortality rates associated with diabetes in pregnancy have declined considerably during the past seven decades and are now near those in the general population, it is only through continuing vigilance that such advances can be maintained. Both fetal and neonatal deaths occurred with increased frequency in diabetic pregnancies before the advent of modern management methods. The cause of fetal death remains incompletely understood. Maternal DKA, associated with a 50% to 90% fetal mortality rate,³⁷ is currently rare among appropriately treated diabetic women. There appears to be a clear association between suboptimal metabolic control and perinatal death,⁷³ but appropriately controlled studies have not been carried out. Animal studies, however,^74,75 suggest that fetal hyperinsulinemia, which may be brought about by maternal hyperglycemia, may cause fetal hypoxemia and lactic acidosis, with fetal death in extreme cases. Similarly, the infusion of large amounts of glucose-containing solutions to pregnant women before delivery has been associated with fetal acidosis.^76,77 It thus seems likely that maternal hyperglycemia is at least partially the cause of the increased fetal death rate among diabetic pregnancies.

These observations are consistent with the Pedersen hypothesis,⁷⁸ which states that maternal hyperglycemia is translated into fetal hyperglycemia, which in turn causes fetal hyperinsulinemia, which is the cause of most abnormal outcomes in the fetus of the diabetic mother. Perinatal mortality rates are higher in poorly controlled diabetic pregnancies, as evidenced by the study of Karlsson and Kjellmer,⁷⁹ in which perinatal deaths ranged from 4% when mean third-trimester blood glucose was less than 100 mg/dL, to 16% when glucose levels ranged from 100 to 150 mg/dL, to 24% for when mean glucose levels exceeded 150 mg/dL. In the aforementioned study, modern technology for intervention in jeopardized pregnancies (e.g., tests of lung maturity, fetal monitoring, and antepartum testing) was not utilized. The differences in perinatal mortality rate could not be attributed to timely delivery because it was not generally possible to identify fetuses in jeopardy, and the goal of treatment was to bring the pregnancies to term. A subsequent series from our center⁸⁰ included 73 mothers with preexisting diabetes whose mean plasma glucose levels (14% higher than corresponding whole blood glucose levels) in the third trimester averaged 108 mg/dL, with 77% having mean levels less than 120 mg/dL. The perinatal mortality rate was 4%, and only 2 of the 77 babies were delivered because of deterioration of fetoplacental function test results. Countless other series have demonstrated perinatal mortality rates of 4% or less with attempts to achieve maternal near-euglycemia. Strict metabolic control thus may be considered prevention, as opposed to intervention attributable to technologic advances allowing identification of the fetus at high risk for death in utero.

Perinatal mortality consists of both fetal and neonatal deaths. Although fetal death probably is directly related to metabolic derangement in diabetic pregnancies (described above), neonatal deaths appear to be caused more indirectly. In the past, the threat of fetal death has prompted attempts at prevention by early delivery. Thus, prematurity and its sequelae increased the neonatal death rate. In addition, infants of poorly controlled diabetic mothers are more likely to develop respiratory distress syndrome at a given gestational age than are infants of nondiabetic controls.⁸¹ Studies in which maternal metabolism was maintained at near-normal levels suggest that respiratory distress does not disproportionately occur in infants of diabetic mothers.⁸² Congenital anomalies (described below) are another important cause of increased neonatal mortality. Approaches to maintaining perinatal mortality rates in diabetic pregnancies at levels similar to the general population are discussed below (see section on Management of Diabetes Mellitus in Pregnancy).

Congenital Anomalies

At a time when perinatal mortality ranged from 10% to 33% among diabetic pregnancies, the fact that birth defects occurred in 7% to 10% of the offspring of diabetic mothers was seemingly of minor significance, and attention was directed toward reversing the unacceptably high stillbirth rate. Now that perinatal mortality risks are similar to those seen in the general population, it is apparent that at least one half of the perinatal mortality observed, and a good deal of the morbidity, is related to congenital anomalies. Infants of diabetic mothers are three times more likely than infants in the general population to manifest all types of birth defects.⁸³ Cardiac, neural tube, and skeletal defects are most common, but a particular set of anomalies affecting the lower half of the body, the caudal regression syndrome, is highly specific for diabetic pregnancy. Therefore, much recent effort has been focused on improving our understanding of the genesis of these malformations, as well as on their prevention. Remarkable success has been achieved in both of these endeavors.

In attempting to prevent birth defects in the offspring of diabetic women, it was first necessary to improve our understanding of their genesis. In reviewing the embryology literature, Mills and colleagues⁸⁴ determined that the structural birth defects seen in infants of diabetic mothers all occurred by the end of the 6th week after conception (i.e., the 8th week after the last menstrual period). This finding presented a major problem in understanding the etiology of such birth defects. Because most women are not under a physician's care during the first 6 weeks after conception, it is difficult to observe possible contributors to teratogenesis. Studies in animal models suggested that maternal hyperglycemia during the period of organogenesis is capable of inducing anomalies in the offspring.⁸⁵ Currently there is a lack of agreement as to whether hyperglycemia itself, or other factors such as ketone bodies⁸⁶ or arachidonic acid deficiency,⁸⁷ may be of greatest importance. Some investigators postulated that free oxygen radicals, resulting from enhanced mitochondrial substrate oxidation in the developing embryo, may be causative in teratogenesis.⁸⁸ One group proposed that the embryonic yolk sac is the site most critical for teratogenesis.⁸⁹

When the blood test for glycosylated hemoglobin became available, enabling researchers to observe retrospectively over the previous 2 months a marker that correlated with maternal glycemic control, an association between elevated glycosylated hemoglobin in the first trimester and congenital anomalies in the offspring was quickly recognized.^89,90 Such an association raised the possibility that improving maternal glucose control around the time of conception and organogenesis might lower the birth defect rate. Shortly after these studies were published, Fuhrmann⁹¹ reported that attendance at a prepregnancy and early pregnancy program that featured tight metabolic control of diabetes was associated with a congenital malformation rate similar to the 2% to 3% in the general population, compared with a rate of 7% among diabetic pregnancies whose care commenced after the 8th week of gestation. In 1988, a multicenter observational study of metabolic control in early pregnancy⁹² found that diabetic women recruited before conception, or within 21 days after conception, had approximately one half the likelihood of birth defects in their offspring than did women enrolled into the study later. It was disappointing, however, that the neonatal malformation rate (4.9%) was still approximately twice that seen among nondiabetic control pregnancies, and that there was no apparent relationship between indices of glycemic control in early pregnancy and the likelihood of malformations in the offspring. It is possible that this lack of relationship between glycemic control and malformations was due to the characteristics of the population studied: only 5% of mothers had near-euglycemia, with mean glucose values less than 140 mg/dL during organogenesis, whereas a similar 5% had extreme hyperglycemia, with mean glucose values greater than 235 mg/dL. Thus there may not have been enough subjects at the extremes of glucose control to demonstrate a relationship, if one exists.

A number of other studies have demonstrated a correlation between first-trimester glycohemoglobin levels and birth defects.^{93,94,95,96,97} What is not clear at this time, however, is exactly how close to normal maternal glucose levels must be for the lowest possible risk of anomalies to be achieved. The large study by Greene and colleagues⁹⁶ suggested that there may be a rather broad range of acceptable control: hemoglobin A₁ levels were up to 12 standard deviations higher than nonpregnant means before significant increases in malformation rates were observed. One study of a series of 215 pregnancies in women with type I diabetes suggested that those with hyperglycemia in the first trimester exceeding an apparent threshold (glycohemoglobin equal to or greater than 12%, or median glucose value equal to or greater than 120 mg/dL) were at increased risk for spontaneous abortion or congenital malformations.⁹⁸ Although this question has not yet been settled, there is general agreement that the onset of care before conception or soon thereafter, along with efforts to attain improved metabolic control, can decrease the malformation rate among infants of diabetic mothers. Interestingly, similar effects of glycemic control on the rate of spontaneous abortion have been reported from a number of centers,^96,97,99 suggesting that there may be a continuum of reproductive damage and loss associated with maternal hyperglycemia or other metabolic derangements.¹⁰⁰

Macrosomia

As described above, efforts to reduce the perinatal mortality rate among diabetic pregnancies have been relatively successful, and the potential now exists to reduce the prevalence of congenital anomalies. Other forms of morbidity, however, continue to complicate these pregnancies. Macrosomia, or the “large-for-dates” baby, usually is defined in terms of a specific birth weight (i.e., 4000 or 4500 g) , or as a relative weight for factors such as gestational age, gender, and birth order (i.e., 90th, 95th, or 97.5th percentile). The latter designation is probably more scientifically correct, because a premature baby may be macrosomic for its age, but may not exceed any of the usual absolute-weight thresholds. Not all studies report birth weight in such a standardized manner, so not all data are comparable. Nevertheless, it is clear that however it is defined, macrosomia is considerably more prevalent among offspring of diabetic versus nondiabetic pregnancies.¹⁰¹ This is true for gestational diabetes as well as preexisting diabetes. Typically, macrosomic infants of diabetic mothers have increased body fat and increased length, but not increased head or brain size. Because their shoulders may be abnormally broad in comparison to their head size,¹⁰² shoulder dystocia may be a problem when they are delivered.¹⁰³ Infants of diabetic mothers have been shown to be at greater risk for shoulder dystocia than infants of nondiabetic mothers, even when corrected for birth weight.¹⁰⁴

The cause of macrosomia in infants of diabetic mothers appears to be similar to the cause of other problems encountered in these pregnancies: fetal hyperinsulinemia.^78,105 A number of studies have demonstrated increased pancreatic insulin content in infants of diabetic mothers, as well as increased C-peptide and proinsulin in their cord blood.⁷⁴ The landmark studies of Susa and co-workers¹⁰⁶ demonstrated that fetal hyperinsulinemia, even in the absence of hyperglycemia, can cause macrosomia in the rhesus monkey. Nevertheless, a number of unresolved issues remain. Glucose is not the only important secretogogue for fetal pancreatic insulin production and release. Freinkel¹⁰⁷ developed the modified Pedersen hypothesis, which proposes that other substrates, such as amino acids, are capable of stimulating the fetal pancreas to produce and release excessive insulin. It also is not certain whether insulin itself is the cause of macrosomia, or whether some other insulin-like factor might act at the same or similar cellular receptors to stimulate fetal growth in diabetic pregnancies.

The prevention of macrosomia has received much attention in recent years because this form of morbidity is easily measurable and has definite adverse consequences, including a greater likelihood of operative delivery and birth trauma. Given the Pedersen hypothesis,⁷⁸ it would seem that improving maternal metabolic control should help to avoid fetal macrosomia. Although generally this has been true, there is still a significant proportion of macrosomic newborns when maternal glucose metabolism is maintained within generally accepted goals, even among gestational diabetic pregnancies.¹⁰⁸ A number of possible explanations exist, and evidence exists to support each of them.¹⁰⁹

For example, our current understanding of “good control” may not be good enough. We attempt to maintain circulating glucose levels below approximately 100 mg/dL fasting, and 120 mg/dL 2 hours postprandially, based on studies of normal pregnant women.¹¹⁰ The goals utilized represent two standard deviations above the mean, but most of us do not exist at two standard deviations above the mean; such a value defines the upper limit of normal, not the average. Thus, our therapeutic goals may be too high. Another possibility is that we are not sampling glucose levels often enough. Although we may measure glycemia 4 to 6 times per day, the pancreas samples ambient glucose levels constantly, and is constantly readjusting insulin release to maintain a steady glycemic level. Finally, it is possible that glucose does not tell the whole story. Glucose is easy to measure, but other substrates may be important as well. For example, Persson and associates¹¹¹ found a correlation between maternal branched-chain amino acid levels and fetal hyperinsulinemia, and Freinkel and Metzger¹¹² showed a relationship between birth weight and maternal levels of alanine, serine, and leucine. A number of investigators¹¹³ have demonstrated a significant reduction in the likelihood of macrosomia with the use of one or more of the following: frequent self-monitoring of glucose levels, lower goals for metabolic control, or the use of prophylactic insulin despite apparently acceptable maternal glycemic control in gestational diabetes.

Neonatal Hypoglycemia

Given the presence of fetal hyperinsulinemia in the offspring of diabetic mothers, it is easy to understand how neonatal hypoglycemia can occur once the maternal glucose contribution to the fetal circulation has been interrupted by the process of delivery. This complication usually is defined as a plasma glucose concentration less than 35 mg/dL in a term infant or less than 25 mg/dL in a preterm infant.¹¹⁴ Its likelihood in an infant of a diabetic mother has been positively associated with maternal hyperglycemia at delivery¹¹⁵ and the rapid infusion of glucose-containing intravenous fluids during labor.¹¹⁶ Hypoglycemia is most likely to occur during the first 60 to 90 minutes of life, and is often asymptomatic. Infants who manifest symptoms usually are irritable, jittery, may have apneic spells, tachypnea, hypotonia, and at the extreme, convulsions. If hypoglycemia does not occur early in the neonatal period it is unlikely to show up later. Early institution of oral feeding may be helpful in preventing hypoglycemia. Hypoglycemia, which is promptly treated generally, is not associated with adverse sequelae.¹¹⁴

Neonatal Respiratory Problems

Respiratory distress syndrome, as well as other forms of neonatal respiratory distress, occurs with increased frequency in infants of diabetic mothers.^81,114,117 Because maturation of the surfactant system may be delayed in diabetic pregnancies, it is common to use a test of stable lung maturity, such as the presence of phosphatidylglycerol in amniotic fluid, before elective delivery of a diabetic pregnancy. A number of investigators, however, have concluded that with maintenance of good metabolic control during pregnancy, respiratory distress syndrome may be no more common in infants of diabetic mothers than in those of the general population.^118,119,120

Other Neonatal Problems

A number of other problems are reported to occur with increased frequency among infants of diabetic mothers.¹¹⁴ These include polycythemia, hyperviscosity, hyperbilirubinemia, and hypocalcemia; all are likely to be explainable on the basis of fetal hyperinsulinemia. Studies of fetal blood obtained by cordocentesis at 36 to 40 weeks' gestation have demonstrated significantly higher hematocrits and lower platelet counts in fetuses of diabetic mothers compared with normative values.¹²¹ Umbilical venous pH was also significantly lower than in controls, although still within the normal range. Transient cardiac dysfunction, presumably due to increased thickness of the intraventricular septum, has been reported in neonates of diabetic mothers even when metabolic control was reported to be good during pregnancy.^122,123,124

Growth and Development

The intrauterine environment may have lasting effects on subsequent development in the offspring. Childhood and adolescent obesity has been demonstrated in offspring of diabetic Pima Indian mothers¹²⁵ as well as in macrosomic offspring of diabetic mothers followed in the Collaborative Perinatal Project.¹²⁶ Similarly, the group at Northwestern University reported that obesity was more common among offspring of diabetic mothers by the age of 6, and that a relationship existed between the degree of maternal hyperglycemia during pregnancy and the degree of subsequent obesity.¹²⁷ These findings are consistent with studies showing increased numbers of adipocyte cells in the offspring of diabetic mothers.¹²⁸ Investigators at Northwestern University also have demonstrated a relationship between second- and third-trimester maternal hyperglycemia and a lower performance of offspring on the neonatal Brazelton behavioral assessment scale.¹²⁹ An inverse correlation also was found between maternal ketone body levels in the second half of pregnancy and intellectual development of the offspring up to 5 years of age,^130,131 a relationship that could not be explained by obstetric and neonatal complications or socioeconomic status.¹³²

In animal studies, exposure to a hyperglycemic intrauterine environment has been demonstrated to cause gestational diabetes in the female offspring for at least two generations.^133,134 Studies of the Pima Indian population have demonstrated a correlation between maternal hyperglycemia during pregnancy and subsequent diabetes and gestational diabetes among the offspring, even when corrected for obesity, genetic predisposition to diabetes, and age of the offspring.¹³⁵ A similar association was found between maternal hyperglycemia during pregnancy and impaired glucose tolerance among teen-age offspring in the Northwestern University study.¹³⁶ Thus, the concept of. fuel-mediated teratogenesis¹³⁷ not only may be applied to structural birth defects caused during the period of organogenesis, but may also describe the way in which maternal metabolic aberrations may leave a legacy that continues to be played out into adulthood, and possibly into the next generation.

Preexisting Diabetes

MATERNAL GLUCOSE CONTROL.

As outlined above, maternal metabolic control to near-euglycemic levels, at least in the latter half of pregnancy, can reduce the perinatal mortality rate and may prevent various manifestations of perinatal morbidity by preventing or reducing fetal overproduction of insulin. Before pregnancy and during early pregnancy, improved metabolic control has the potential to prevent congenital malformations. Indeed, a program of preconception counseling and care has been demonstrated to be effective in reducing the likelihood of birth defects in the offspring^138,139 and also has been shown to be cost-effective.^140,141 Unfortunately, only about one third of persons with preexisting diabetes currently receive preconception care according to a multicenter study.¹⁴² It is critical for obstetricians and other primary care providers, such as internists, family physicians, and pediatricians, to provide effective counseling to all diabetic women in or approaching the reproductive age. The importance of family planning, the evaluation of co-morbid conditions, and the importance of good metabolic control before conception are all part of preconception care. The question is still unsettled as to precisely how close to normal maternal circulating glucose values must be in order to maximize the likelihood of a favorable outcome. Various opinions exist, and the suggestions outlined below must be considered tentative; they are based on the practices at our institution, and they have neither been proved nor universally accepted. Nevertheless, virtually all investigators in the field agree that the best outcomes are associated with “good” control.

The ideal approach to management of diabetic pregnancy is the “team approach,” in which the high-risk pregnancy obstetrician and the diabetologist collaborate as part of a multidisciplinary team, which also includes specialized nurses, dietitians, social workers, and other health-care providers. Not every component of this team is expected to be available in every center. In addition, even if the diabetes is being managed by a diabetologist, it is important for the obstetrician to understand what is being done, and why. Therefore, the foregoing discussion of medical management is included in this obstetrics textbook.

Modern management of diabetes in pregnancy relies on the use of self-monitoring of glucose levels. Test strips, impregnated with glucose oxidase and an indicator, are covered with a drop of blood, and the reaction is allowed to proceed for a predetermined period of time. The blood is then washed or wiped off, depending on the type of strip, and inserted into a reflectance meter that interprets the blood glucose. These machines, originally quite complicated to use and expensive to purchase, have come down in purchase price and are all relatively simple to work with. They are battery powered and portable. Various schemes exist as to the timing and frequency of self-testing of blood. In some centers, the patient is asked to measure glucose just before meals and snacks, three to four times per day. In other centers, glucose levels are checked at fasting and at 1 or 2 hours after each meal. In yet other centers, the time of glucose measurement after meals is determined by testing initially every 15 minutes in order to choose the interval of peak glucose levels. Relatively little in the way of comparative data are available. Diabetologists tend to rely more heavily on fasting than on postprandial hyperglycemia in managing non-pregnant adults with diabetes, but existing studies suggest that in pregnancy postprandial glucose values are better predictors of fetal macrosomia than are fasting values.^143,144,145 When 1-hour postprandial values exceed 130 mg/dL¹⁴⁵ or average glucose values exceed 130 mg/dL,¹⁴⁶ macrosomia has been found to be significantly more likely.

A 1995 randomized trial compared daily preprandial glucose measurements with postprandial testing. When insulin dosage was adjusted according to postprandial values, macrosomia, neonatal hypoglycemia and cesarean section rates were significantly lower compared with the group using preprandial measurements.¹⁴⁷ The single most important issue may well be whether patients are frequently self-monitoring their glucose levels! In our own center we ask patients to measure glucose a minimum of four times per day. This includes fasting and 2 hours after each meal. Additional times are chosen if they seem clinically necessary: for example, a 2 AM measurement if there is a question of morning rebound hyperglycemia (the Somogyi effect) or early morning insulin depletion (the “dawn phenomenon”). An outline of our approach is depicted in Table 6.

TABLE 6. Daily Self-Monitoring of Glucose in Diabetic Pregnancy

There are also a number of different approaches to insulin administration in diabetic pregnancy.¹⁴⁸ It is rare for satisfactory metabolic control to be attained in a pregnant woman with preexisting diabetes by a once daily insulin regimen. We have found that a minimum of two injections of mixtures of short- and intermediate-acting insulins are generally necessary, and that many persons require three or four injections daily. To begin insulin therapy in a previously uncontrolled patient, one should use a formula that was developed on the basis of the normal insulin release pattern of nondiabetic pregnant women.¹⁴⁹ Insulin is injected before breakfast and before dinner. The morning total dose is twice the evening total dose. The ratio of intermediate- to short-acting insulin in the morning is 2:1; in the evening it is 1:1. For example, a patient may receive 40 U of NPH insulin and 20 U of regular insulin, mixed in the same syringe, before breakfast each day. The total morning dose is thus 60 U. Before dinner she would receive one half that dose, or 30 U, and it would be composed of a 1:1 ratio, or 15 U each of NPH and regular insulins. This formula should be considered a starting point. Subsequent adjustments are based on self-monitoring results at particular times of day. For example, if the 2-hour post-breakfast glucose exceeds our goals, we would increase the dose of short-acting insulin given the following morning. If the post-lunch glucose level is high, an adjustment in the morning dose of intermediate-acting insulin would be made. The fasting glucose reflects the pre-dinner intermediate dose, and so on. Few patients remain on the formula for very long: individual dose adjustments are the rule. The following tricks of the trade may be useful:

1. Many patients use Lente insulin as their intermediate-acting insulin. This was historically preferable because Lente insulin was formerly available as a pure pork formulation, whereas NPH insulin was a mixture from beef and pork. Because pork insulin is immunologically closer to human insulin than is beef, Lente was preferred in order to reduce immunologic complications. Currently, both Lente and NPH insulins are available as recombinant DNA preparations of human insulin, and thus the issue of antigenicity is moot. It has been found, however, that when Lente and regular insulin are mixed together in the same syringe and injected, an absorption peak results that is intermediate between the absorption peaks of the two formulations if injected separately. NPH and regular insulin, when mixed in the same syringe, provide absorption peaks that are distinct and resemble those resulting from separate injections.^150,151 Because the goal of the mixed, split-insulin regimen outlined above is to provide an insulin absorption peak to cover each of the meals, it generally is advantageous to use NPH rather than Lente as the intermediate-acting insulin. However, if a particular patient is doing well with Lente and her metabolism is in good control, it is not appropriate to change to NPH merely for the sake of a principle.
   
2. If a patient manifests consistently high fasting glucose levels despite increases in her pre-dinner intermediate insulin dose, particularly if her 2-hour post-dinner glucose value is normal or low, her intermediate insulin may be peaking too early in the morning and wearing off by the time she arises (the dawn phenomenon). She should measure her blood glucose at 2 AM. If it is normal or low, she should move the pre-dinner intermediate-acting insulin dose to bedtime in order to get a longer effect. If the 2 AM glucose is quite high, it is reasonable for her simply to increase the pre-dinner intermediate-acting insulin.
   
3. Some patients will manifest very high glucose levels after breakfast and then become relatively hypoglycemic before lunch. This is often due to morning insulin absorption lagging behind the absorption of the food eaten at breakfast. A useful solution is to increase the interval between the morning insulin injection and breakfast. We have occasionally had to prescribe the morning insulin as much as 1 hour before breakfast was consumed.
   

To approximate physiologic insulin release more closely, one approach is to use the continuous subcutaneous insulin infusion pump. With the insulin pump, a continuous basal insulin infusion is provided, and bolus doses are administered before each meal. Advantages of the pump are greater flexibility with regard to meal timing. The disadvantages are that it is expensive, that only short-acting insulin is infused, and that interruption of infusion can more rapidly lead to DKA. A prospective randomized trial of pump versus intensive conventional insulin therapy in pregnant women with diabetes failed to reveal any difference in metabolic control or perinatal outcomes,¹⁵² so the pump must be viewed as elective for most patients. The occasional highly motivated and intelligent subject with diabetes who is very difficult to control with conventional therapy may indeed benefit from a trial of pump therapy.

Although relatively strict goals for metabolic control in the second half of pregnancy are outlined in Table 6, it is likely that somewhat more liberal goals can be used in the periconceptional period. As pointed out earlier, there is a lack of universal agreement as to exactly how close to normal maternal glucose levels need to be during the period of organogenesis in order to minimize the risk of birth defects. In our center, if we are fortunate enough to make initial contact with a diabetic woman before conception, we attempt to maintain glucose levels less than 150 mg/dL, with glycosylated hemoglobin levels in the near-normal range (depending on the method). Once conception has been established, we aim for the glucose levels outlined in Table 6. When a patient is first seen during the first 8 weeks of pregnancy, we often hospitalize her to improve control as rapidly as possible. This is not the ideal situation, as rapid normalization of metabolic control may be associated with deterioration of retinopathy, at least transiently. Therefore, ophthalmologic consultation is appropriate for these patients, as it is for all pregnant women with overt diabetes.

Insulin requirements can be expected to increase markedly as pregnancy progresses,¹⁵³ and this should not be cause for alarm. Brittleness, defined as marked instability of diabetic control seen in some persons who are apparently following their regimen assiduously (see above), appears to decrease during the second half of pregnancy,⁴⁴ and this phenomenon may be quite helpful in the management of these difficult cases. Although there has been a persistent adherence to the clinical “pearl” that states that decreasing insulin requirement is an ominous sign for perinatal well-being in diabetic pregnancy, proof of this assertion is lacking. When a significant decrease in insulin requirement occurs in the third trimester, it is reasonable to step up the pace of fetal surveillance, but there is little or no evidence that early delivery should be based on this finding in the absence of signs of fetal compromise.

In addition to daily self-monitoring of glucose, frequent contact with a member of the health-care team is important in diabetes management. In our center, a diabetes nurse educator is in telephone contact with each patient initially on a daily basis, with longer intervals instituted later as deemed appropriate. Such a practice is invaluable not only in helping maintain good metabolic control, but also in reassuring the patient that help and counseling are always readily available, and in preventing problems such as mild upper respiratory infections from developing into DKA. Indeed, one of the most common misconceptions among our patients is that insulin dosage must be reduced if food intake is decreased because of illness. Of course, the opposite is true. Illness often causes insulin resistance, and hepatic glucose production increases in the face of illness despite decreased caloric intake. Therefore insulin dosage should be increased or should remain the same during illness, depending on circulating glucose levels and the presence or absence of ketonuria.

PRENATAL SCREENING AND DIAGNOSIS.

Because congenital anomalies occur with increased frequency among diabetic pregnancies, it is important that available methods of prenatal diagnosis be applied, where appropriate. Serum alpha-fetoprotein (AFP) testing, either alone or in combination with measurement of human chorionic gonadotropin and estriol, is commonly offered to pregnant women throughout the United States in order to detect open neural tube defects, ventral wall defects, and a number of other potential problems including chromosomal trisomies. Women with diabetes should likewise be offered these tests; however, it is important to note that maternal serum alpha-fetoprotein values have been demonstrated to be lower in diabetic pregnancies than in other pregnancies,^154,155,156 while diabetic pregnancies have been demonstrated to be at increased risk for neural tube defects.¹⁵⁷ In one study,¹⁵⁵ maternal serum unconjugated estriol levels were also significantly lower than those of controls. Evidence now exists that the decrease in AFP values may be related to poor metabolic control,^158,159 suggesting that the patients whose glucose levels place their babies at the greatest risk for congenital anomalies are also the ones most likely to have lower AFP levels, which might thus be misleading. Unfortunately, it is not clear at present what the temporal relationship is between poor control, organogenesis, and low AFP levels. Insufficient data exist to determine whether fetuses of diabetic mothers, in whom neural tube defects are present, manifest low enough AFP levels to cause their diagnosis to be missed.

Structural anomalies, known to be more prevalent among infants of diabetic mothers, may sometimes be diagnosed prenatally with targeted (level II) ultrasound examinations.¹⁶⁰ Because virtually all types of anomalies are more prevalent among these pregnancies, it is difficult to target the ultra-sound examination. In addition, diabetic women whose glucose metabolism is well controlled during the time of organogenesis may have birth defect risks that are only slightly elevated, if at all. Level II ultrasound facilities and expertise are not universally available, and existing centers do not have limitless resources. The success of ultrasonographers in identifying birth defects is greatest if the particular patient has a high a priori risk of a particular anomaly; in such cases, the sonographer will be highly motivated to search for the presumed anatomic abnormality until he or she has either found it or determined that it does not exist.

An ultrasound examination performed to “rule out birth defects” in a low-risk pregnancy, however, could miss a subtle abnormality. Therefore we perform level II ultrasound examination and echocardiography when there is evidence that metabolic control during organogenesis was poor, usually on the basis of a glycosylated hemoglobin level that is markedly elevated. A specific cutoff level cannot be supplied because this varies with the method of measurement used in a particular laboratory. In fact, in one series of diabetic pregnancies, the critical threshold of glycohemoglobin for cardiac defects was the upper limit of normal (6.1% in the laboratory reporting these results).¹⁶¹ The authors of this report recommended fetal echocardiography for every diabetic pregnancy unless glycohemoglobin levels were within the normal range. Ultrasound also is used to monitor fetal growth and amniotic fluid volume at intervals throughout the third trimester. Umbilical artery blood flow velocity measured by Doppler velocimetry has been found to be similar between diabetic and non-diabetic pregnancies.¹⁶² Such measurements are not a standard method of fetal evaluation at the present time, and their value is uncertain.

Other screening tests that we have found to be helpful include renal function testing in early pregnancy, including blood urea nitrogen, serum creatinine, uric acid, 24-hour urinary protein, and 24-hour urinary creatinine clearance determinations. These help to evaluate early nephropathy, and serve as a baseline for later comparison, because diabetic persons are more likely to develop hypertensive disorders of pregnancy. Ophthalmologic examination should be carried out, preferably by an ophthalmologist. To diagnose asymptomatic bacteriuria before pyelonephritis can develop, urine cultures are obtained initially and at 1- to 2-month intervals. Electrocardiography should be obtained in diabetic women with vascular disease or longstanding diabetes.

TIMING OF DELIVERY.

Although at one time maternal diabetes meant automatic early delivery because of the high risk of fetal death near term, the advances already described have made it possible for most diabetic pregnant women managed with contemporary approaches to deliver at or near term. The achievement of near-euglycemia in diabetic pregnancy is the major preventive measure that has allowed this dramatic change in management. Elective delivery generally should not be undertaken if fetal lung maturity is in doubt. To document lung maturity, we usually perform amniocentesis and test the fluid for the presence of phosphatidylglycerol. We have found a 20% prevalence of absent phosphatidylglycerol as late as 39 weeks in pregnancies complicated by preexisting diabetes.¹⁶³ Current approaches emphasize term vaginal delivery after spontaneous labor has begun if no undue risk to mother or fetus is engendered, but situations still may arise where intervention is necessary. The general approach used in our center is as follows¹⁶⁴:

1. Deliver even without documented fetal lung maturity if maternal or fetal compromise puts the life of either at risk. Examples of this situation would be maternal eclampsia or severe preeclampsia even in a very preterm diabetic pregnancy, or proven severe fetal compromise.
   
2. Deliver as soon as fetal lung maturity can be documented when there is a significant maternal or fetal problem that does not pose an immediate risk to the life of either. Examples of this situation would be poor or undocumented maternal metabolic control, hypertensive disorders of pregnancy or chronic hypertension, previous classic cesarean section, intrauterine growth retardation of the fetus, suspected fetal macrosomia, or equivocal antepartum fetal testing without definite fetal compromise.
   
3. If none of the above conditions are present, consider elective delivery at 38 weeks' gestation if the patient expresses a high level of anxiety because of the physical, emotional, and monetary expense of having diabetes and going through pregnancy.
   

For elective delivery, the cervix should be favorable and lung maturity should be present. We consider the presence of oligohydramnios at or after 38 weeks as reason to forgo amniocentesis and to proceed with delivery. It should be noted that in some centers amniocentesis for fetal lung maturity is not considered necessary, even in diabetic pregnancy, if a gestational age of 39 weeks or more has been attained and dates are well documented. In our study of lung maturity,¹⁶³ patients in whom phosphatidylglycerol was not present were not delivered, and thus it is impossible to state how many infants, if any, would have developed respiratory distress syndrome.

A repeat cesarean section, if desired by the patient, is scheduled for 38 weeks' gestation after lung maturity has been documented; however, vaginal birth after cesarean is encouraged. We have allowed patients with diabetes to proceed past 40 weeks when the cervix is unfavorable for induction, metabolic control is excellent, and the pregnancy is otherwise uncomplicated. However, the recent availability of various means to induce cervical ripening hold promise in such cases, and we have frequently had success using prostaglandin gel or laminaria, or both.

FETAL-PLACENTAL FUNCTION TESTING.

A number of different techniques for assessing fetal well-being in diabetic pregnancy are available. These include fetal movement determinations (“kick counting”), nonstress testing, contraction stress testing, and the biophysical profile. Urine or serum estriol determinations, once the mainstay of antepartum testing in diabetic pregnancy, have been largely abandoned because of their poor positive predictive accuracy and the expense and inconvenience associated with their use.¹⁶⁵

Most current approaches utilize either the biophysical profile¹⁶⁶ or the nonstress test¹⁶⁷ as the primary testing modality. When the nonstress test is used, either contraction stress testing or the biophysical profile is used as a backup procedure when the nonstress test is nonreactive. Some investigators advocate twice-weekly nonstress testing in diabetic pregnancies.^167,168 It should be pointed out that no antepartum test is predictive of fetal compromise that may result from an acute event, such as maternal DKA or umbilical cord accident. Poor metabolic control, even in the absence of DKA, has been associated with pathologic antepartum and intrapartum fetal heart rate tracings.¹⁶⁹ The potential effects of maternal hypoglycemia on fetal heart rate tracings are controversial. Increased fetal activity has been noted when blood glucose levels less than 60 mg/dL were induced in one study.¹⁷⁰ In another report, no decrease in reactivity was present when gravidas with diabetes underwent insulin clamp studies to reduce their glucose levels to approximately 40 mg/dL.¹⁷¹ In our own center, we perform nonstress testing weekly in otherwise uncomplicated diabetic pregnancies. More frequent testing, ranging from twice weekly to daily, is used when complications such as hypertension, intrauterine growth retardation, vascular disease, or suboptimal metabolic control are encountered.

The contraction stress test or biophysical profile is used as a secondary test if the nonstress test is nonreactive. In patients at particularly high risk, such as those with vascular disease or hypertensive disorders plus intrauterine growth retardation, or both, the contraction stress test or biophysical profile is substituted for the nonstress test at least once weekly, even when all nonstress tests are reactive. The gestational age when antepartum testing is to be initiated varies according to each patient's circumstances. There is no point initiating antepartum testing at a gestational age when delivery is not a viable alternative (i.e., before 24 to 25 weeks). Even after this gestational age, patients with a low likelihood of fetal compromise, if tested positive, are likely to have a false-positive rather than a true-positive result, and delivery may be more likely to harm the pregnancy than to benefit it. Therefore patients with a very high likelihood of fetal compromise, such as those with evident intrauterine growth retardation and vascular disease, may be tested as early as 24 to 25 weeks.^172,173 The majority of diabetic pregnant women begin testing at 28 to 34 weeks, depending on the adequacy of metabolic control and the presence or absence of vascular complications.

MODE OF DELIVERY.

Maternal diabetes is not an indication for cesarean section, but its complications may be. Fetal macrosomia occurs with increased frequency in diabetic pregnancies, as described earlier in this chapter. Presumably because the fetal head size is normal but the trunk large,¹⁰² shoulder dystocia may be a significant problem in such cases. If shoulder dystocia could be anticipated, it would be best to deliver the macrosomic fetus by cesarean section. However, current approaches to estimating fetal weight are imprecise at best, and no prospectively tested approach to the prenatal diagnosis of macrosomia, or potential shoulder dystocia, is clearly effective. Therefore a compromise must be reached between an inappropriately aggressive approach toward cesarean section and an increased likelihood of shoulder dystocia with attempts at vaginal delivery.

In our center, most pregnancies with a fetus estimated to weigh 4500 g or more are delivered by cesarean section without a trial of labor. When the estimated fetal weight is between 4000 and 4499 g, other factors are taken into consideration, including the mother's past obstetric history, clinical assessment of pelvic architecture, and the progress of labor. What used to be called midforceps deliveries, and under current nomenclature are called low-forceps deliveries, are generally inadvisable when fetal macrosomia is believed to be present and the second stage of labor is prolonged.¹⁷⁴ A previous history of shoulder dystocia is also a relative contraindication to vaginal delivery unless the circumstances are clearly favorable (i.e., a much smaller fetus). In the absence of macrosomia, the decision to perform a cesarean section should be based on the usual obstetric indications. Although cesarean section is more likely to be necessary when labor is induced in the presence of an unfavorable cervix, there is no compelling reason to proceed with operative delivery without an adequate trial of labor, just as in a nondiabetic pregnancy. Similarly, diabetes is not a contraindication to attempted vaginal birth after cesarean.

METABOLIC MANAGEMENT FOR LABOR AND DELIVERY.

During labor, attention must be paid to the maintenance of maternal euglycemia in order to lessen the likelihood of neonatal hypoglycemia, and in extreme cases, to avoid maternal DKA. Studies utilizing animal models suggest that maternal hyperglycemia may predispose the fetus to lactic acidemia and hypoxemia.^175,176 The combination of hypoxia and hyperglycemia in primates has been associated with central nervous system damage.¹⁷⁷ Studies of pregnant women have linked the infusion of large amounts of glucose-containing solutions to fetal acidosis.^76,77 The need for meticulous control of glucose metabolism during labor has led to the application of constant intravenous glucose and insulin infusions in this setting. Glucose is needed to prevent starvation ketosis; studies utilizing an artificial pancreas^178,179 during labor have demonstrated that many women with type I diabetes require no insulin during the first stage, despite glucose infusion rates of 6 to 10 g/hour. Monitoring of circulating glucose levels throughout labor is thus critical, so that insulin can be supplemented if hyperglycemia is present. To avoid inadequate circulating insulin levels and resultant ketonemia, some centers routinely use constant insulin infusions during labor for persons with type I diabetes.

When labor is to be induced, it is reasonable to begin early in the morning, after the usual insulin and snack the night before. If a patient's diabetes has been well controlled, it can be anticipated that her fasting glucose levels will be within the target range. To provide basic caloric requirements, an intravenous line is established, and 5% dextrose in one-half normal saline is infused with a mechanical device at a constant rate of 100 to 125 mL/hour. Blood glucose is measured every 1 to 2 hours; reflectance meters are very useful in this situation. The target for glucose is 60 to 120 mg/dL. If this level is exceeded, an insulin infusion is begun, usually at a rate of 1 to 1.25 U/hour. This can be accomplished either through a “piggyback” intravenous line using a separate mechanical infusion device, or by adding insulin to the 5% dextrose solution already running at a constant rate, at a concentration of 10 U/L. Adjustments in the insulin infusion rate can be made if glucose levels either fall below or exceed the target range. This is achieved by an adjustment of either the infusion rate of the separate insulin drip or the concentration of insulin in the glucose-and-insulin solution.

Patients entering the hospital in spontaneous labor may require a modification of this adjustment approach, depending on when their last insulin injection occurred. If induction is carried out for more than 1 day, and the patient is to be allowed to rest for the night, care should be taken to avoid disturbed glucose metabolism. One useful approach is to discontinue induction just before dinner time, and to give the patient her usual subcutaneous pre-dinner (and bedtime) insulin and her usual evening meal and snack. The procedure is begun the next morning as before. If the evening insulin dose is omitted, it is possible for DKA to ensue during the night, so close attention is warranted.

Patients admitted for elective cesarean section are best scheduled for induction in the early morning. The usual meal, snack and insulin are administered the night before so that the morning blood glucose will be within the target range. An intravenous line is initiated, and normal saline or some other non-glucose-containing solution is infused. Once delivery has been accomplished, glucose can be infused in order to maintain the circulating glucose value within a reasonable range.

During the immediate postpartum period, insulin requirements often decrease precipitously to levels below the prepregnancy dose. This is particularly true in women who have undergone cesarean section because they are not allowed to eat during the first day or two after the operation. Fortunately, the kind of meticulous metabolic control that is the cornerstone of management of diabetic pregnancy is no longer necessary after delivery, and glucose levels may be allowed to increase up to 150 or 200 mg/dL without major short-term risk. The subcutaneous insulin dose can then be slowly increased as the patient's dietary restrictions are lifted, and fine-tuning of control can be accomplished at home after discharge.

Gestational Diabetes

The principles guiding management of the pregnancy complicated by gestational diabetes are the same as for preexisting diabetes: maintenance of relative euglycemia to prevent perinatal mortality and morbidity. A panel of circulating glucose measurements should be performed a minimum of once weekly. Many centers now recommend daily self-monitoring for persons with gestational diabetes, similar to the recommendations outlined for preexisting diabetes. In our center glucose values at fasting, 2 hours post-breakfast, and 2 hours post-lunch are monitored at least once weekly. If the fasting value exceeds 100 mg/dL or either of the other two values exceed 120 mg/dL, the patient is considered to require more intensive monitoring or therapy. Because the patient knows in advance the day on which glucose measurements are to be made, we consider it most likely that her blood glucose levels are no better on days when metabolic monitoring is not carried out. Because gestational diabetes usually is diagnosed in the third trimester and thus presents a limited time in which there is an opportunity to reduce perinatal morbidity and mortality, we believe that an immediate response to maternal hyperglycemia is preferable to waiting 1 week to see if the elevated glucose level is consistent. Therefore, we prescribe daily self-monitoring of glucose immediately, bring the patient back within 1 to 2 days for repeat testing, or start insulin therapy.

Insulin therapy initiated in response to elevated maternal glucose levels (described above) is aimed at reducing the perinatal mortality risk; in our experience, approximately 28% of women with gestational diabetes require such treatment.¹⁸⁰ It generally is true that the more abnormal the GTT results are, the more likely is the patient to require insulin; however, 26% of women with gestational diabetes whose GTT results were ranked in the lower third manifested hyperglycemia to the extent that insulin was needed.¹⁸⁰ Therefore GTT results should not be the sole determinant of the mode of therapy to be used.

The above discussion of insulin therapy used to reduce the perinatal mortality rate does not include insulin used to reduce the rate of morbidity, particularly macrosomia. Prophylactic insulin, given without regard to the level of fasting or postprandial glucose, has been suggested as effective in preventing macrosomia.¹¹³ Other apparently effective approaches include daily self-monitoring of glucose with institution of insulin if relatively strict thresholds, such as 90 mg/dL fasting and 100 mg/dL postprandially, are exceeded.¹¹³ Buchanan and colleagues¹⁸¹ studied gestational diabetic pregnant women whose fasting serum glucose was less than 105 mg/dL and who underwent ultrasound evaluation at 29 to 33 weeks' gestation. The 98 persons whose fetal abdominal circumference measurement met or exceeded the 75th percentile for gestational age were randomized to diet only (N := 29) or diet plus twice daily insulin (N = 30). The prevalence of large-for-gestational-age newborns was reduced from 45% in the diet group to 13% in the insulin-treated group. The authors concluded that ultrasound in the early third trimester can identify candidates who would benefit from insulin treatment. Although none of these approaches should be considered the standard of care at the present time, it is reasonable to apprise patients of such options, considering that the prevention of macrosomia could help some of them avoid a cesarean section or difficult vaginal delivery.

Antepartum testing of fetal and placental well-being is recommended in gestational diabetes, but there is a lack of universal agreement as to the optimum time for initiation of testing or the most appropriate test to be used. Landon and Gabbe¹⁸² suggest daily maternal assessment of fetal movements beginning at 28 weeks' gestation, with weekly nonstress testing beginning at 40 weeks' gestation, in otherwise uncomplicated gestational diabetic pregnancies without identifiable risk factors. Earlier initiation of nonstress testing is recommended if risk factors (i.e., hypertensive disorders, previous stillbirth, poor or undocumented metabolic control) are present. In our center, we initiate weekly nonstress testing at approximately 36 weeks' gestation in otherwise uncomplicated gestational diabetic pregnancies in order to avoid inadvertently omitting testing for patients with prospectively or retrospectively identified risk factors.

Decisions concerning the timing and mode of delivery in gestational diabetic pregnancy should be made on the basis of the same considerations described for those with preexisting diabetes. A randomized trial of induction of labor at 38 weeks versus expectant management included 200 women who required insulin during pregnancy, 187 of whom had gestational diabetes and 13 of whom had preexisting diabetes.¹⁸³ Cesarean section rates were not significantly different between the induction group (25%) and the expectant management group (31%). Although 23% of newborns in the expectant management group were equal to or greater than 90th percentile, only 10% of those in the induction group were large for gestational age. These findings suggest that induction of labor at 38 weeks is not associated with increased risk of cesarean section in this group of patients. Insulin is usually not required during labor, but circulating glucose levels should be monitored in order to identify those patients who would benefit from this form of therapy (i.e., those with glucose levels equal to or greater than 120 mg/dL).

Because gestational diabetes is a relatively potent predictor of the later development of diabetes, with approximately 40% of such persons developing this disorder within 20 years of their index pregnancies,⁸ it is appropriate to test women with previous gestational diabetes annually⁹ for disorders in glucose tolerance. The first such test usually is recommended to be given during the postpartum visit: The patient already must be seen for other reasons, and therefore she is likely to find this to be a convenient time to undergo the test. Diagnostic criteria for the 75-g, 2-hour oral GTT, recommended for nonpregnant patients, are outlined in Table 7.

TABLE 7. Diagnostic Criteria forth 75-g, 2-hour Oral Glucose Tolerance Test in the Nonpregnant State

  Diabetes mellitus is diagnosed if:

1. Fasting plasma glucose is 140 mg/dL on at least two occasions, or
   
2. On a 75-g, 2-hour oral glucose tolerance test the 2-hour value is 200 mg/dL and at least one other value (30, 60, or 90 minutes) is 200 mg/dL.
   

Diagnosis of gestational diabetes early in pregnancy has been found to be significantly predictive of persistent glucose abnormality at the time of postpartum testing.^184,185 It should be remembered, however, that early testing usually is performed because the patient has some indication or risk factor, and in neither of these studies were all gravidas tested early. Nevertheless, it makes physiologic sense that persons whose glucose abnormality is present early in pregnancy are at higher likelihood of having had abnormal glucose tolerance before pregnancy. Apparently independent risk factors for subsequent diabetes include the following:

  Elevated fasting glucose in the oral GTT performed during pregnancy 184,185,186,187
  Obesity184,187,188
  Elapsed time since the index pregnancy187
  Degree of abnormality of the postpartum GTT186

The likelihood of persistent diabetes after pregnancy, and of subsequent development of diabetes, may vary with the particular population being studied. For example, in the Danish population studied by Damm and associates,¹⁸⁶ nearly one third of the subsequent diabetes reported was type I diabetes. This is a possible explanation for the lack of correlation between maternal obesity and subsequent diabetes in this study, because obesity is not a feature of type I diabetes. In fact, the data from this study suggest that body mass index equal to or greater than 25 kg/m² was present in 30% of those with subsequent normal glucose tolerance, in 46% of those with subsequent impaired glucose tolerance, and in 58% of those with type II diabetes, but in only 11% of those with subsequent type I diabetes. In contrast, the study of Kjos and co-workers¹⁸⁴ encompassed a Mexican-American population with a high prevalence of type II diabetes (9% had diabetes during the first 2 months postpartum and an additional 10% had impaired glucose tolerance). Because the average body mass index in these patients was approximately 30 kg/m², it was not surprising that obesity was not discernible as an independent risk factor. None of these studies of risk factors for future diabetes allow the exclusion of certain subsets of former gestational diabetic persons from further testing. Indeed, in the Kjos study¹⁸⁴ even the lowest risk group, who had maintained all fasting glucose levels during pregnancy below 105 mg/dL, manifested a 10% prevalence of impaired glucose tolerance or diabetes within 2 months postpartum.

Contraception

Pregnancy in any woman with preexisting diabetes ought to be planned, not unintentional. Unless the person is in excellent metabolic control throughout her reproductive years, unplanned pregnancies are likely to be associated with a greater risk of major congenital malformations than are those in which prepregnancy counseling and planning have taken place. Family planning, including a discussion of contraception, is appropriate-in fact mandatory--for any adolescent or adult woman with diabetes who has reached menarche. Virtually the full range of contraceptive options is open to women with diabetes mellitus; however, specific risks may be different for such women than for the general population. Because the health risks associated with pregnancy are greater for a woman with diabetes than for women in general, the benefits of contraception may also be considered to be greater.¹⁸⁹

If a diabetic woman and her husband have completed their family, permanent surgical sterilization may be the method of choice. The method risks are all taken at the time of surgery, and no further attention need be paid by the couple to contraception, other than an awareness that no method is 100% effective.

Oral contraceptive preparations are second in effectiveness to permanent sterilization. Potential risks associated with oral contraceptive use include cardiovascular, thromboembolic, and lipoprotein disorders. Because many of these risks are also increased in persons with diabetes, there has been longstanding concern about the use of this method of contraception in diabetic women. Data suggesting a multiplicative effect are lacking, however, and current very-low-dose formulations appear to have minimal demonstrable risk,¹⁹⁰ even with respect to renal and retinal complications¹⁹¹ specific to diabetes. Another concern with oral contraceptives is the potential worsening of glucose metabolism in persons who are unable to compensate fully with an augmented insulin response. Theoretically type I diabetic women can simply increase their insulin dose; however, type II diabetic women who do not receive insulin therapy might need to do so if their metabolism were to worsen with the use of oral contraceptives. For this reason it is necessary to monitor glucose metabolism closely in women with diabetes and in those with former disturbances in carbohydrate metabolism (e.g., gestational diabetes) when they are taking oral contraceptives. It makes sense to use formulations with the lowest dose of estrogens and progestins when prescribing oral contraceptives to such women. At least two studies have failed to demonstrate an adverse effect of modern low-dose oral contraceptives on carbohydrate metabolism in persons with previous gestational diabetes.^192,193

Currently, subcutaneous levonorgestrel implants (Norplant System), have gained popularity in the United States. There are no available long-term studies specific to diabetes, but mild alterations in carbohydrate metabolism have been reported with their use in nondiabetic women.¹⁹⁴ This form of contraception should not be considered contraindicated in women with diabetes or previous gestational diabetes, but patients should be apprised of the lack of data.

The intrauterine device, slightly less effective than combined oral contraceptives, has the advantage of requiring no active effort by the user once it has been inserted. The known risk of infection and subsequent infertility is a disadvantage of this method, although there is currently no evidence to suggest that this risk is higher among diabetic persons. Although some studies have reported a high failure rate of this method in persons with diabetes,¹⁹⁵ others^196,197,198 have found no such problem.

Barrier methods of contraception appear to have virtually no risk of medical complications, but they require faithful adherence by the user and partner and have a relatively higher failure rate compared with the above approaches. The condom also offers an advantage in protection against sexually transmitted diseases.

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