ACUTE COMPLICATIONS OF DIABETES 0889-8529/00 $15.00 + .OO

MEDICAL EMERGENCIES IN THE PATIENT WITH DIABETES

DURING PREGNANCY

Lois Jovanovic, MD

Pregestational diabetes mellitus complicates approximately 0.2% to 0.5% of pregnancies, or approximately 10,000 to 16,000 pregnancies per year.13 A nationwide population-based survey revealed that nearly 4% of pregnant women in the United States had diabetes (a proximately

12% were known to have diabetes.2O Of the women with pregestational diabetes, 35% had type 1 and 65% type 2 diabetes. As pregnancy is deferred until the later childbearing years and as population demo- graphics change, more pregnancies can be expected to occur in women with type 2 diabetes.

Pregnancy in diabetic women is associated with an increase in risk for the fetus and the gravida. Early in pregnancy, there is an emergency to normalize the blood glucose to prevent congenital anomalies and spontaneous abortions. As the pregnancy progresses, the gravida is at increased risk for syncope, hypoglycemia, and diabetic ketoacidosis, all needing emergency attention. Later in the pregnancy, the woman is at risk for accelerated retinopathy and blindness, pregnancy-induced hypertension and preeclampsia / eclampsia, urinary tract infections in- cluding pyelonephritis, and polyhydramnios. The greatest concern is the increased risk of sudden death in utero for the fetus. All of these dreaded complications can be obviated or at least minimized with careful plan- ning of the pregnancy and attention to glucose control. This article discusses the emergencies that may occur in pregnancies complicated

135,000); 88% had gestational diabetes mellitus, whereas tK e remaining

From the Sans- Medical Research Institute, Santa Barbara, California

ENDOCRINOLOGY A N D METABOLISM CLINICS OF NORTH AMERICA

VOLUME 29 - NUMBER 4 ' DECEMBER 2000 771

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by diabetes and suggests protocols for care to improve the outcome of these pregnancies.

FIRST-TRIMESTER EMERGENCIES

An increased prevalence of congenital anomalies and spontaneous abortions occurs in diabetic women who are in poor glycemic control during the period of fetal organogenesis, which is nearly complete at 7 weeks' postconception. Because a woman may not even know she is pregnant at this time, pre-pregnancy counseling and planning are essen- tial for women of childbearing age who have diabetes. If a woman presents to her health care provider and announces that she has missed her period by only a few days and blood glucose levels are immediately normalized, there is a chance that cardiac fetal anomalies can be pre- vented (although neural tube defects are probably already set in stone by the time the period is missed).

Women with type 2 diabetes are less likely to have preconception care and counseling, often because the diagnosis of diabetes has not yet been made, and are at even greater risk of bearing a birth-defective child. In one study 40% of women with type 1 diabetes but only 14% of women with type 2 diabetes received preconception care.%

Another problem for some women with type 2 diabetes is gaining access to adequate medical care before and after conception. This lack of care is most evident among Hispanic women in whom a higher prevalence of obesity, ty e 2 diabetes, and gestational diabetes and

tions.2l, x* 59 Pima Indian women are also at increased risk. They have a 19-fold higher incidence of type 2 diabetes when compared with the general US population, with an age-adjusted prevalence rate approxi- mately eight times 50

Hemoglobin A, (HbA,) values provide the best assessment of the degree of chronic glycemic control, reflecting the average blood glucose concentration during the preceding 6 to 8 weeks. Measurement of HbA, in early pregnancy can estimate the level of glycemic control during the period of fetal organogenesis. There are two important observations in this regard. First, HbAlc values early in pregnancy are correlated with the rates of spontaneous abortion and major congenital malformations.16, 24, 293 47, 60, Although most studies have been performed in women with type 1 diabetes, the same risk of hyperglycemia applies to women with type 2 diabete~.~, 70 Second, normalizing blood glucose concentrations before and early in pregnancy can reduce the risk for spontaneous abortion and congenital malformations nearly to that of the general

In one study 110 women who were already 6 to 30 weeks' pregnant at the time of referral were compared with 84 women recruited before conception and started on a daily glucose-monitoring regimen.R The mean blood glucose concentration was between 60 and 140 mg/dL (3.3

increased fertility raise tl! e risk for maternal and neonatal complica-

population.23, 29,47,69

MEDICAL EMERGENCIES IN THE PATIENT WITH DIABETES DURING PREGNANCY 773

and 7.8 mmol/L) in 50% of the nonpregnant women. The incidence of anomalies was 1.2 percent in the women recruited before conception versus 10.9% in the women first seen during pregnancy. Similar findings were noted in another study-a 1.4% versus 10.4% incidence of congeni- tal abn0rmalities.6~ Major congenital malformations that require surgical correction or that significantly affect the health of the child are more common in the infants of diabetic mothers (13% versus 2% in the infants of nondiabetic mothers).14

The increased rate of spontaneous abortion in poorly controlled diabetic women is thought to be secondary to hyperglycemia, maternal vascular disease including uteroplacental insufficiency, and possibly im- munologic factors.48, 6o In addition, animal studies suggest that hypergly- cemia regulates the expression of an apoptosis (programmed cell death) regulatory gene as early as the preimplantation blastocyst stage, re- sulting in increased DNA fragmentation.62 These findings emphasize the importance of glycemic control at the earliest stages of conception.

Ideally, if a diabetic woman plans her pregnancy, there is time to create algorithms of care that can be individualized, and the woman can be given choices. When a diabetic woman presents in her first few weeks of pregnancy, there is no time for individualization; rather, rigid protocols must be urgently instituted to provide optimal control within 24 to 48 hours.

DELETERIOUS EFFECTS OF STRICT GLYCEMIC CONTROL

Despite the clear benefits to the fetus of strict glycemic control, there is a hazard of hypoglycemia. Major complications of hypoglycemia can usually be prevented with careful monitoring and education of the gra~ida.4~. 69

Very strict glycemic control (mean blood glucose, 86 mg/dL 14.8 mmol/L]) may be deleterious to the fetus and should be avoided. In one study, the overall incidence of small-for-gestational age infants was higher among women with very strict compared with strict (mean blood glucose, 87 to 104 mg/dL [4.8 to 5.8 mmol/L]) controI-20% versus 11%, respe~tively.~~

EYE EMERGENCIES

There are three situations in which rapid normalization of blood glucose levels increases the risk for deterioration of diabetic retinopathy: p~berty,’~ pregnancy,52 and insulin-like growth factor treatment (IGF-l).71 If two of these events occur in the same patient, the risk for retinopathy progression is p~tentiated.~~, 64 All three situations are associated with increased serum concentrations of growth-promoting factor.I6 It is hy- pothesized that when the blood glucose level is rapidly decreased,

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there is increased retinal extravasation of serum proteins. If there is a concomitant increased concentration of serum growth-promoting factors, a predisposed retina may deteriorate.=, 55, 58

Pregnancy is the most frequently reported situation in which rapid normalization of blood glucose is associated with deterioration of the retina.16, 30, 55, 57, 583 64 Normal pregnancy is associated with a high concen- tration of many growth-promoting 35* 57 Hill and co-workers= reported that a potent mitogen and angiogenic factor normally absent from the adult circulation became detectable by 14 weeks’ gestation and was maximally present at 22 to 32 weeks‘ gestation. A placental growth hormone variant had been found to increase throughout pregnancy, along with the human somatomammotropin, pr0lactin.5~ Maternal IGF-1 production has been shown to increase significantly above nonpregnant levelsJ6 Diabetes mellitus is associated with perturbations of growth hormone IGF-1 in cases of poor metabolic

If treatment with lispro insulin, a short-acting insulin analogue, increases the rate whereby the hyperglycemic state is normalized, it may have a role in the rapid deterioration of retinopathy. In the few case reports of rapidly deteriorating retinopathy in patients taking lispro insulin, it is unlikely that this effect was caused by activity of this insulin because pregnancy alone is associated with elevated IGF-1 levels.

Human insulin binds to the IGF-1 receptor with an affinity 0.1% to 0.2% that of IGF-1. A comparison of lispro and human insulin was carried out to determine the relative IGF-1 receptor binding affinity in human placenta membranes, skeletal muscle, smooth muscle cells, and mammary epithelial cells. Lispro had slightly higher affinity for the human placenta membranes when compared with human insulin. No other differences were observed in any other cell lines. Despite the suggested increased affinity, the absolute affinity for the IGF-1 receptor is extremely low for lispro and human insulin. Concentrations more than 1000 times above normal physiologic range are needed to reach 50% receptor binding. IGF-1 is a much larger protein chain than insulin, and there is a 49% homology between human insulin and IGF-1. The reversal of the B28 and B29 amino aids in lispro insulin increases this homology to 51% because of the analogous position in the IGF molecule. Because insulin lispro has the same affinity for the IGF-1 receptor as human insulin, and because the dissociation kinetics of lispro and hu- man insulin on the insulin receptor are identical, insulin lispro should have no excess mitogenic effect by way of the IGF-1 or insulin re~eptor.’~, 56

Phelps and co-workersffl clearly showed that deterioration of reti- nopathy correlated signhcantly with the levels of plasma glucose at entry and with the magnitude of improvement in glycemia during the first 6 to 14 weeks after entry, although the 13 patients with no retinopa- thy at baseline did not progress to proliferative retinopathy. One patient had moderate hemorrhages, exudates, and intraretinal microaneurysms. Of the 20 patients with initial background retinopathy 2 progressed to proliferative retinopathy. Laatikainen and co-w~rkers~~ confirmed that the decrease in HbA,, levels was most rapid in the 2 patients with the

MEDICAL EMERGENCIES IN THE PATIENT WITH DIABETES DURING PREGNANCY 775

worst progression. They concluded that a rapid near-normalization of glycemic control during pregnancy can accelerate the progression of retinopathy in poorly controlled diabetic patients. The Diabetes in Early Pregnancy Study (DIEP)16 reported that the 10.3% of diabetic women who progressed despite no retinopathy at baseline had an initial glyco- hemoglobin elevation four standard deviations above the mean of a normal population (risk progression, 40%; odds ratio, 2.4). Independent of retinal status, the DIEP reported that the duration of diabetes in- creased the risk of progression such that after 6 years, the odds ratio was 3.0; after 11 to 15 years, 9.7; and after 16 years, 15.0. Hyperglycemia was a stronger risk factor. Additional evidence has been reported by The Diabetes Control and Complications In the conventional care group who became pregnant and who had immediate intensification of glucose control (n = 135), 47% had a worsened retinal status. The odds ratio for progression by the second trimester was 2.6 when compared with the odds ratio for diabetic women in the conventional group who did not become pregnant.

One case report in the literature clearly shows that the combination of pregnancy and rapid normalization of severe hyperglycemia is suffi- cient to explode a previously normal retina. Hagay and colleagues31 described a woman with no previously documented hyperglycemia who presented at 8 weeks’ gestation with an HbAI, level of 16%. An ophthal- mic examination was reported to reveal completely normal findings. The woman was treated with intensive insulin therapy, and at 12 weeks, the HbA, was 5.9%. By the second trimester, the woman had severe bilateral proliferative diabetic retinopathy requiring photocoagulation.

Five risk factors that emerge for the prediction of pregnant diabetic women who will progress to proliferative retinopathy are (1) baseline evidence of some retinopathy, (2) an elevated €-%A1, at conception, (3) rapid normalization of blood glucose, (4) a duration of diabetes greater than 6 years, and (5) proteinuria.

Lispro insulin may have a role in the progression of retinopathy by facilitating the rapid normalization of blood glucose levels. In pregnant and nonpregnant diabetic patients, lispro insulin improves glucose con- trol and significantly lowers the HbA,, compared with the effects in patients who are administered human regular ins~l in .~, 37 The literature clearly shows the danger of normalizing blood glucose quickly, regard- less of the type of insulin used, in pregnant women with a long duration of diabetes and elevated HbA,, in the first trimester, proteinuria, and before retinopathy.

Busy clinicians may have a decreased ability to examine the retina completely. Mild background retinopathy may be missed, even in the best of settings. The presence of any retinopathy increases the risk of further retinal deterioration, especially if the blood glucose level is elevated. Rather than recommending angiography for all women before each pregnancy is planned, when no retinopathy is seen on retinal examination, it is prudent to improve the glucose control slowly. Case reports reinforce the need to intensify preconceptional care programs to

776 JOVANOVIC

allow clinicians the luxury of slowly normalizing the blood glucose and to permit the patient to plan the pregnancy only after blood glucose levels have been stabilized into normal ranges for at least 6 months.16

Because of the possibility of explosive retinopathy when patients present already pregnant with high levels of glycosylated hemoglobin, regardless of the retinal status, the woman needs to have an ophthalmol- ogy consultation on the first day of admission. As the glucose normaliza- tion protocol is initiated a retinal specialist should be available to provide laser therapy if the retina deteriorates.

THYROID DISEASE

Type 1 diabetes is commonly associated with other autoimmune endocrine disorders. Thyroid autoantibodies occur more frequently in these patients than in the normal population.s Furthermore, an increased prevalence of subclinical hypothyroidism has been reported in pregnant diabetic women.6, 8, 39 Several studies have found a wide range (10% to 25%) in the prevalence of postpartum thyroid dysfunction in type 1 diabetic women?, 25 A study by Haddow and co-w~rkers~~ suggested that screening pregnant women for hypothyroidism by measuring thyro- tropin may be worthwhile, and that treating women with serum thyro- tropin concentrations at or above the 98th percentile could lead to "an increase of approximately 4 points in IQ scores in their children." Be- cause there is an increased risk of gestational hypothyroidism in diabetic women, all pregnant diabetic women should be screened for hypothy- roidism early in the pregnancy and treated immediately if hypothyroid- ism is

DIABETIC KETOACIDOSIS

Urinary ketone tests should be performed periodically especially when the patient is ill or when any blood glucose value is over 200 mg/ dL (11.1 mmol/L). At these times, ketoacidosis may occur, a complica- tion that is associated with a high mortality rate in the fetus. In addition, ketonemia during pregnancy has been associated with decreased intelli- gence in offspring.39 In early pregnancy, ketonuria sometimes occurs in women who are limiting their caloric intake because of nutritional recommendations. Caloric restriction as a cause of ketonuria is not associated with adverse outcome in the fetus. In fact, there is no associa- tion of ketonuria and outcome." The serum P-hydroxybutyrate level correlates with decreased intelligence in offspring. When home blood testing for P-hydroxybutyrate becomes easily available, the results can be used to guide therapy. In the meantime, many clinicians do not recommend routine urinary ketone checking if blood glucose levels are maintained in the normal range. Women with moderate-to-large ketonu- ria should alert their physician immediately. If a type 1 diabetic woman

MEDICAL EMERGENCIES IN THE PATIENT WITH DIABETES DURING PREGNANCY 777

is using an insulin infusion pump, even short periods of interruption in the infusion may result in ketoacidosis owing to the increased metabolic rate in pregnancy. Many clinicians recommend the added use of NPH insulin injected at bedtime in an amount 0.1 times the weight in kilo- grams, with an appropriate adjustment in the overnight basal dose.

PREGNANCY-INDUCED HYPERTENSION

Normal first-trimester blood pressure is less than 120 / 80 mm Hg.@ Fetal complications from maternal hypertension include intrauterine growth retardation and fetal demise. Antihypertensive medications that have been proved to be safe include methyldopa and hydralazine. These medications have been prescribed for over 50 years and have been time- tested not to cause malformations in two generations of children. When stronger medication is needed, the risk of drug-induced toxicity is out- weighed by the benefit of improved blood pressure control. The next level of antihypertensive medications that can be used are the P-blockers. Specifically the use of labetalol has been recommended. Nifedipine has also been reported to be safe when added after the first trimester. Angiotensin-converting enzyme inhibitors in pregnancy have been asso- ciated with congenital anomalies, specifically renal agenesis or renal failure; thus, they are absolutely contraindicated in ~regnancy.~~ Al- though the management of elevated blood pressure in a diabetic preg- nant woman is an urgent priority, the means to achieve these goals are limited in pregnancy.

DIABETIC NEPHROPATHY

Diabetic nephropathy when not associated with hypertension does not impact on fetal outcome unless the kidney function is more than 50% impaired. Normal creatinine clearance is increased in pregnancy owing to the increased metabolic rate and the increased cardiac output by the 10th to 12th week of gestation. A depression of the creatinine clearance below 50 mL/min is associated with increased fetal loss. Proteinuria greater than 250 mg/24 hours in the first trimester has been associated with nephrotic syndrome by the third trimester, requiring bed rest and, in some cases, replacement of protein losses with parenteral supplementation of albumin." Maternal anasarca is not associated with fetal hydrops as long as maternal nutrition includes enough protein for fetal growth.

MONITORING AND TREATMENT

There are several components to the treatment of diabetes in preg- nant women: careful monitoring of blood glucose, the administration of insulin, exercise, and diet.

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Glucose Monitoring

Frequent measurements of blood glucose are the mainstay of ther- apy for women with type 1 diabetes during pregnancy. In most women, multiple tests should be performed. If the first morning blood glucose value is high, testing should also be performed at bedtime and in the middle of the night (3 AM).^^ Bedtime and middle of the night tests are important to discover, treat, and prevent nocturnal hypoglycemia, which may be frightening and harmful to the woman. Pregnancy is associated with an exaggerated rebound from hypoglycemia owing to the h ercor-

phenomenon is caused by insulinopenia, the combination of hypercorti- solemia of pregnancy and the stress-related hormonal rise from a severe hypoglycemic event can produce an elevated fasting glucose level. An elevation in morning blood glucose values should initiate a 3 AM blood glucose check to decide whether more or less insulin is needed.

Blood glucose goals in a pregnant diabetic woman include the

A fasting capillary blood glucose concentration of 55 to 65 mg/ dL (3.1 to 3.6 mmol/L), equivalent to a venous plasma concentra- tion of 63 to 75 mg/dL (3.5 to 4.2 mmol/L) A 1-hour postprandial blood glucose concentration less than 120 mg/dL (6.7 mmol/L), equivalent to a venous plasma concentra- tion of 140 mg/dL (7.8 mmol/L)

tisolemia potentiated by pregnancy. Although it is thought that ti? e dawn

following:

Importance of Postprandial Glucose Control

The effect of strid glycemic control on fetal outcome in pregnant women with diabetes has been demonstrated in several studies.ls, One study compared the results of monitoring fasting blood glucose plus either preprandial or postprandial glucose in women with gestational diabetes.% Postprandial monitoring was associated with the following benefits when compared with preprandial monitoring: better glycemic control (mean HbA,, value 6.5% versus 8.1%), a lower incidence of large- for-gestational age infants (12% versus 42%), and a lower rate of cesarean section for cephalopelvic disproportion (12% versus 36%).

Glycosylated Hemoglobin

Hemoglobin A,, should be measured every 4 to 6 weeks and more frequently if the woman’s glycemic control is poor. Average blood glu- cose concentrations and HbA,, values fall by approximately 20% in normal pregnant women, and similar values should be the goal in diabetic women to minimize fetal risk.

MEDICAL EMERGENCIES IN THE PATIENT WITH DIABETES DURING PREGNANCY 779

Insulin Doses

The starting insulin dose is calculated to be 0.7 U/kg/d divided into three to four injections of short- and intermediate-acting insulin. The capillary blood glucose should be measured before and 1 hour after each meal, at bedtime, and at 3 AM to ensure around-the-clock glucose control. Each day the insulin should be adjusted based on the blood glucose measurements so that the optimal dose of insulin is delivered on a daily basis. Only human insulin should be used in pregnant women. Most women with type 1 diabetes require at least three injec- tions per day.37, 39, A two-injection regimen can cause nocturnal hypo- glycemia if the evening meal dose of intermediate-acting insulin peaks during the middle of the night.

Total insulin requirements typically rise during gestation, primarily owing to the effects of human placental lactogen, which has somato- tropic properties. The average insulin requirement in pregnant women with type 1 diabetes rises from 0.7 U/kg in the first trimester to 0.8 U/ kg for weeks 18 to 26 to 0.9 U/kg for weeks 26 to 36 to 1.0 U/kg for weeks 36 to term. Massively obese women may need initial doses of 1.5 to 2.0 U/kg to overcome the combined insulin resistance of pregnancy and obesity.4I

The author administers a combination of regular insulin and inter- mediate-acting insulin (such as NPH). Long-acting insulin (Ultralente) is avoided because it may be too slow to respond to the everchanging insulin needs of pregnancy.

There are no studies to date on the safety of insulin analogues, such as lispro, glargine, and aspart, in pregnancies complicated by type 1 diabetes. Only one report describes the use of the insulin analogue lispro in gestational diabetic women. This study found that lispro improved glycemic control without causing an increase in hypoglycemic episodes and was not immunogeniF7; however, more than 1000 type 1 diabetic women would need to be observed during pregnancy to prove the null hypothesis that insulin analogues do not cause malformations. Until a definitive study is performed, it is prudent to use these insulins with informed consent of the woman.

Some clinicians have recommended insulin pumps to achieve opti- mal glycemic control during ~regnancy.'~, 67 Most pregnant women re- quire at least three infusion rates in a 24-hour period-a low-dose basal rate from 12 midnight to 4 AM, an increased rate in the early morning hours from 4 AM to 10 AM to counteract the increased release of the anti- insulin hormones cortisol and growth hormone, and an intermediate basal rate during the rest of the day from 10 AM to 12 midnight. A protocol for calculating infusion rates has been

Women with type 2 diabetes also should be treated with insulin for blood glucose control, preferably started during the preconception pe- riod. During the first trimester, insulin requirements are similar in women with type 1 and type 2 diabetes; however, as the pregnancy proceeds into the third trimester, insulin requirements increase propor-

780 JOVANOVIC

tionately more in women with type 2 diabetes. In one study, the respec- tive insulin doses were 1.6 and 1.2 U/kg/d.22 Measures that ameliorate insulin resistance, such as avoiding excessive weight gain and moderate low-impact exercise, can be expected to improve glycemic control.

Oral hypoglycemic drugs should not be given to pregnant women. These drugs do not provide strict glycemic control and, when adminis- tered near delivery, may cause severe prolonged neonatal hypoglyce- mia.'* When metformin is used to induce ovulation in patients with the polycystic ovary syndrome and insulin resistance, it should be stopped as soon as pregnancy is diagnosed. The available data (based on a small number of observed pregnancies) do not show harmful effects from metformin treatment in either early or late pregnancy.@,

Role of Exercise

Gestational diabetes differs from type 1 diabetes in pregnancy be- cause the former is primarily a disorder of impaired glucose clearance. Therapies that overcome peripheral resistance to insulin, such as exer- cise, are preferable to insulin. In contrast, in women with type 1 diabetes who are already taking insulin, the benefits of exercise are not so clear. Exercise can contribute to the brittleness of diabetes, with the risk of exercise-induced hypoglycemia. Women who have exercised before pregnancy can usually continue that activity under the supervision of an obstetrician. Exercise is not recommended in women who are deconditioned and who have not exercised before pregnancy.

Diet

The optimal diet takes into account caloric intake, carbohydrate content, and distribution of meals throughout the day. The appropriate calorie intake depends on the pregravid weight. The following general recommendations can be made:

Approximately 30 kcal/ kg / d if the woman is at ideal body weight 24 kcal/ kg/d if the woman is 20% to 50% above ideal body weight 12 to 18 kcal/kg/d if the woman is more than 50% above ideal

36 to 40 kcal/kg/d if the woman is more than 10% below ideal

The recommended distribution of calories is 40% to 50% carbohy- drate, 20% protein, and 30% to 40% fat. Many physicians find that maintenance of glycemic control requires a diet in which carbohydrate accounts for no more than 40% of calories.4l Postprandial blood glucose values are largely dependent on the carbohydrate content of the meal,

body weight

body weight

MEDICAL EMERGENCIES IN THE PATIENT WITH DIABETES DURING PREGNANCY 781

and the postprandial blood glucose concentration has the most im- portant role in macrosomia.43

Most nutritional programs recommend three meals and three snacks per day. An acceptable calorie distribution would be 10% of calories at breakfast, 30% at lunch and dinner, and 30% as snacks. A daily supple- ment of ferrous sulfate and folate is also recommended.

FETAL SURVEILLANCE

The high perinatal mortality rate previously associated with a dia- betic pregnancy has decreased significantly largely owing to improved glycemic control.*,% In the past, unexplained fetal death occurred in 10% to 30% of type 1 diabetic pregnancies. It typically occurred after the 36th week of gestation in women with poor glycemic control, associated with macrosomia, hydramnios, preeclampsia, and vascular disease. Fetal surveillance is of utmost importance in optimizing a good outcome for the woman and the fetus, especially in the perilous third trimester. Ultrasonography is the most useful tool for assessment of the fetus. It can be used to estimate gestational age, screen for structural anomalies, evaluate growth, assess amniotic fluid volume, and determine fetal status dynamically through Doppler and biophysical studies.

Ultrasound estimates of gestational age are most accurate if per- formed in early pregnancy. Gestational age determined by a crown- rump length measured in the first trimester will be accurate within 5 days. Ultrasound estimates of gestational age are not reliable after the 28th week and cannot be used to determine the estimated date of delivery.

RISKS ASSOCIATED WITH UNDIAGNOSED MACROSOMIA

Macrosomia is more apparent in fetal structures such as the liver and abdomen. As a result, ultrasound estimates that use the fetal abdom- inal circumference to calculate fetal weight may not be as accurate as in normal fetuses in whom growth is proportional. Macrosomia is usually defined as fetal weight greater than 4.0 to 4.5 kg or birth weight above the 90th percentile for gestational age.7, 27, Macrosomic fetuses are at increased risk for a prolonged second stage of labor, shoulder dystocia, operative delivery, and perinatal death.7

Macrosomia occurs in approximately 88% of fetuses in whom the abdominal circumference and estimated fetal weight both exceed the 90th percentile.61, The biparietal diameter and head circumference are less predictive of macrosomia. Undiagnosed macrosomia may lead to birth trauma if vaginal delivery ensues. Before the onset of labor, an assessment of the fetal size is paramount.

In contrast to macrosomia, intrauterine growth retardation (usually

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defined as birth weight below the 10th percentile for gestational age) is uncommon in diabetic pregnancies. It is associated with uteroplacental insufficiency and primarily occurs in pregnancies complicated by dia- betic vasculopathy or preeclampsia.

CONGENITAL ANOMALIES

Ultrasonography is essential for the evaluation of congenital anoma- lies. Infants of diabetic mothers are at increased risk for neural tube defects, which occur in approximately 2% of diabetic pregnancies (versus 0.1% to 0.2% in the general population).61 Other congenital anomalies that occur with higher frequency in the infants of diabetic mothers include anencephaly, microcephaly, caudal regression syndrome, and genitourinary and gastrointestinal anomalies. Congenital heart disease is also common, including a specific type of hypertrophic cardiomyopa- thy, atrial and ventricular septa1 defects, transposition of the great ves- sels, and coarctation of the aorta. Hydramnios can occur because of increased amniotic fluid osmolality and polyuria secondary to fetal hyperglycemia.=

Maternal diabetes alone does not increase the risk for chromosomal abnormalities such as Down syndrome. As a result, the indications for invasive testing, such as amniocentesis and chorionic villous sampling, are the same as in the general population.

Guidelines for antepartum surveillance vary and are usually depen- dent on the clinical situation and the discretion of the physician. In women with diet-controlled gestational diabetes, fetal surveillance is usually not initiated until 40 weeks' gestation because these women are at low risk for complications. More rigorous monitoring is recommended for women who have additional indications for closer fetal surveillance. Most clinicians defer testing until the 35th week of gestation if there is excellent glycemic control but start much earlier in women with poor control, nephropathy, or hypertension. In these women, antepartum testing is begun at 26 to 28 weeks when fetal survival is likely if delivery were to occur. Antepartum fetal testing should be performed twice per week. Doppler umbilical artery velocimetry has shown increased placental resistance in women with vasculopathy and poor glycemic control, which increase the risk for intrauterine growth retardation and pree~lampsia.~, 93

I

LABOR AND DELIVERY

Maternal hyperglycemia is the major cause of neonatal hypoglyce- mia. Peripartum maintenance of maternal euglycemia is essential. Gener- ally, insulin is still required before active labor and can be given subcuta- neously or by intravenous infusion with the goal of maintaining blood glucose concentrations between 70 and 90 mg/dL (3.9 and 5.0 mmol/L).

MEDICAL EMERGENCIES IN THE PATIENT WITH DIABETES DURING PREGNANCY 783

One method of insulin infusion consists of intravenous administration of 15 units of regular insulin in 150 mL of normal saline at a rate of 1 to 3 U/hr. Normal saline may be sufficient to maintain euglycemia when labor is anticipated. As the woman with diabetes enters active labor, insulin resistance rapidly decreases (because expulsion of the fetoplacen- tal unit leads to cessation of production of somatomammotropin, which has a short half-life), and insulin requirements drop to zero. Continuing insulin therapy is likely to lead to hypoglycemia. To prevent hypoglyce- mia, glucose should be infused at a rate of 2.5 mg/kg/minute." Capil- lary blood glucose should be measured hourly. The glucose infusion should be doubled for the next hour if the blood glucose value is less than 60 mg/dL (3.3 mmol/L). Values of 120 mg/dL (7.8 mmol/L) or more require the administration of regular insulin subcutaneously or intravenously until the blood glucose value falls to 70 to 90 mg/dL (3.9 to 5.0 mmol/L). At this time, the insulin dose is titrated to maintain normoglycemia while glucose is infused at a rate of 2.5 mg/kg/min. Bolus doses of glucose should not be given because they can raise maternal blood glucose concentrations and increase the risk for neonatal hypoglycemia, fetal hypoxia, and fetal or neonatal acidosis.

If a cesarean section is planned, the bedtime NPH insulin dose may be given on the morning of surgery and every 8 hours thereafter if surgery is delayed.

POSTPARTUM

Insulin requirements drop sharply after delivery, and the new mother may not require insulin for 24 to 72 hours. Insulin requirements should be recalculated at this time at approximately 0.6 U/kg/d based on postpartum weight. Postpartum calorie requirements are approxi- mately 25 kcal/kg/d and somewhat higher (27 kcal/kg/d) in lactating women.

Glycemic control is somewhat more erratic in lactating diabetic women, with more frequent episodes of hypoglycemia. Because the risk of life-threatening hypoglycemia is increased in the immediate postpar- tum period, especially if a woman is lactating, prevention of postpartum hypoglycemia is the primary goal. Middle of the night hypoglycemia can be prevented if the NPH dose before bed is deleted and the 3 AM regular insulin is given instead in low doses after the mother is finished nursing the infant.

SUMMARY

Although the outcome of pregnancies com licated by diabetes is

lation, this improvement is only realized when careful attention is paid to the metabolic, hemodynamic, and vascular perturbations associated

now approaching the success seen in the normal R ealthy pregnant popu-

784 JOVANOVIC

with the changes of pregnancy. The diabetic woman must not only pay attention to nutrition but also blunt moment-to-moment swings in blood glucose by taking frequent does of insulin. In addition, she must be under constant surveillance for a host of other complications of preg- nancy, such as hypertension, retinopathy, infection, acidosis, thyroid dysfunction, nephropathy, and sudden death in utero. Any or all of these problems become medical emergencies if left untreated. Rigorous vigdance to sustain normoglycemia and normotension, examination of the retina, culture of urine, assays for ketosis, measurements of thyroid function, and monitoring of renal function and fetal status are para- mount in the management of pregnancy complicated by diabetes.

References

1. Adashi EY, Pinto H, Tyson JE: Impact of maternal euglycemia on fetal outcome in diabetic pregnancy. Am J Obstet Gynecol 133:268, 1979

2. AIvarez-Marfany M, Roman SH, Drexler AJ, et ak Long-term prospective study of postpartum thyroid dysfunction in women with insulin dependent diabetes mellitus. J Clin Endocrinol Metab 7930, 1994

3. American College of Obstetricians and Gynecologists: Diabetes and Pregnancy. ACOG Technical Bulletin No. 200. Washington, DC ACOG, 1995

4. Anderson JH, Brunelle RL, Koivisto VA: Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Diabetes 46:265, 1997

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