Diabetes Mellitus and Pregnancy

INTRODUCTION

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Background: Depending on the specific population, abnormal maternal glucose regulation occurs in 3-10% of pregnancies. Although 80% or more of this glucose intolerance occurs in patients with gestational diabetes mellitus (GDM), the associated fetal and newborn morbidity rates are disproportionate. Infants of diabetic mothers (IDMs) experience a doubled risk of serious injury at birth, a tripled likelihood of cesarean delivery, and a quadrupled incidence of newborn intensive care unit admission. Recent studies indicate that the risk magnitude of these morbidities in individual cases is proportional to the degree of maternal hyperglycemia. For this reason, the excessive fetal and neonatal morbidity attributable to diabetes in pregnancy should be considered preventable.

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Pathophysiology:
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Maternal-fetal metabolism in normal pregnancy

With each feeding, the pregnant woman undergoes a complex combination of maternal hormonal actions (ie, a rise in blood glucose; the secondary secretion of pancreatic insulin, glucagon, somatomedins, and adrenal catecholamines). These adjustments ensure that an ample, but not excessive, supply of glucose is available to the mother and fetus. The key features of this complex interaction include the following:

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• There is a maternal tendency to develop hypoglycemia between meals and during sleep. This occurs because the fetus continues to draw glucose across the placenta from the maternal bloodstream, even during periods of fasting. Interprandial hypoglycemia becomes increasingly marked as pregnancy progresses and the glucose demand of the fetus grows.

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• Placental steroid and peptide hormones, eg, estrogens, progesterone, and chorionic somatomammotropin, rise linearly throughout the second and third trimesters. Because these hormones confer increasing tissue insulin resistance as their levels rise, the demand for increased insulin with feeding escalates progressively during the pregnancy. Twenty-four–hour mean insulin levels are 30% higher in the third trimester than in the nonpregnant state.

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• If the maternal pancreatic insulin response is inadequate, maternal and, then, fetal hyperglycemia results. This typically manifests as recurrent postprandial hyperglycemic episodes.

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• Surging maternal and fetal glucose levels are accompanied by episodic fetal hyperinsulinemia. Fetal hyperinsulinemia promotes excess nutrient storage, resulting in macrosomia while fetal oxygen levels deplete.

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• These episodes of fetal hypoxia are accompanied by surges in adrenal catecholamines, which, in turn, cause hypertension, cardiac remodeling and hypertrophy, stimulation of erythropoietin, red-cell hyperplasia, and increased hematocrit. High hematocrits in the neonate lead to vascular sludging, poor circulation, and postnatal hyperbilirubinemia.

During a healthy pregnancy, mean, fasting, blood sugar levels decline progressively to a remarkably low value of 74 ?2.7 mg/dL. On the other hand, peak postprandial blood sugar values rarely exceed 120 mg/dL. Effective management of diabetes in pregnant patients, with a goal of avoiding these morbidities, requires meticulous replication of the normal glycemic profile of pregnancy.

Frequency:
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• In the US: Approximately 4% of pregnancies in the U.S. are complicated by diabetes, of which 90% is gestational diabetes and 3% is insulin-resistant, "adult onset" diabetes. The incidence of insulin resistant diabetes is increasing markedly in the United States, probably related to rising population obesity and shifts in ethnicity. The prevalence of gestational diabetes is strongly related to the patient's race and culture: only 1.5-2.0% of midwestern whites typically develop GDM while Native Americans from the southwestern U.S. may have rates as high as 15%. In the Hispanic, African American, and Asian populations, the incidence is 5-8%.

CLINICAL

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History:

• Fetal morbidity with diabetes in pregnancy

WORKUP

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Lab Studies:
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• First trimester (in addition to normal prenatal laboratory tests)

• HbA1C

• BUN

• Creatinine

• Thyroid-stimulating hormone (TSH)

• Free thyroxine (T4)

• Twenty-four–hour urine collection for protein and creatinine

• Blood sugar levels from a capillary device 4-7 times daily

• Second trimester

• Repeat 24-hour urine studies in women with elevated first trimester creatinine or 24-hour protein or creatinine clearance less than 100 mL/min.

• Repeat HbA1C.

• Blood sugar levels from capillary device 4-7 times daily in all women with diabetes

• If preeclampsia is suspected, perform the following tests:

• BUN

• Creatinine

• Uric acid

• CBC with platelets

Imaging Studies:
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• First trimester - Sonogram (crown rump length) for dating and viability

• Second trimester

• Detailed anatomy sonogram at 18-20 weeks

• Fetal echocardiogram if HbA1C was elevated in first trimester

• Third trimester

• Growth sonogram to assess fetal size every 4-6 weeks from 26-36 weeks in women with overt preexisting diabetes

• Growth sonogram for fetal size at least once at 36-37 weeks for women with GDM (Consider this study more frequently if macrosomia is suspected.)

Other Tests:
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• First trimester - Ophthalmologic evaluation

Procedures:
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• Third trimester - Amniocentesis for fetal lung profile if delivery is contemplated prior to 39 weeks gestation

TREATMENT

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Medical Care:

• Pregnancy management of women with preexisting diabetes

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  Dietary therapy: The goal of dietary therapy is to avoid single large meals and foods with a large percentage of simple carbohydrates. A total of 6 feedings per day is preferred, with 3 major meals and 3 snacks to limit the amount of calories presented to the bloodstream at any interval. Examples include foods with complex carbohydrates and cellulose, such as whole grain breads and legumes. Carbohydrates should comprise approximately 50-60% of the diet, with protein and fats each accounting for 20%; this provides a balanced mixture of nutrients while promoting slow uptake from the gut (American Diabetes Association, 1979).

  A formal dietary consultation at periodic intervals during the pregnancy improves control. Review timing and content of meals together with the patient’s food preferences at each visit. Because insulin resistance changes dynamically during pregnancy, continually adjust the dietary prescription according to the patient's weight gain, insulin requirement, and pattern of exercise.

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  • Glucose monitoring: The availability of capillary, glucose, and chemical test strips has revolutionized the management of diabetes and should now be considered the standard of care for pregnancy monitoring. The discipline of measuring and recording blood glucose levels prior to and after meals clearly has a positive effect on improving glycemic control. Individualize the frequency and timing of home glucose monitoring. A typical schedule involves capillary glucose checks on rising in the morning, 1 or 2 hours after breakfast, before and after lunch, before dinner, and at bedtime. Place emphasis on gaining and sustaining compliance with the target glucose levels mentioned above. Superb glycemic control requires attention to both preprandial and postprandial glucose levels.

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  • Insulin therapy: The goal of exogenous insulin therapy during pregnancy must be to achieve diurnal glucose excursions similar to those of pregnant women who are not diabetic. Given that healthy pregnant women maintain their postprandial blood sugar excursions within a relatively narrow range (70-120 mg/dL), the task of reproducing this profile is daunting and requires meticulous daily attention by both the patient and physician.

    As pregnancy progresses, the increasing fetal demand for glucose fasting and the progressive lowering of fasting and between-meal blood sugar levels increases the risk of symptomatic hypoglycemia. Upward adjustment of short-acting insulins to control postprandial glucose surges within the target band only exacerbates the tendency to interprandial hypoglycemia. Thus, any insulin regimen for pregnant women requires combinations and timing of insulin injections quite different than those that are effective in the nonpregnant state. Further, continuously modify the regimens as the patient progresses from the first to the third trimester and insulin resistance rises. Strive to stay ahead of the rising need for insulin and increase insulin dosages preemptively.

• Pregnancy management of women with GDM

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  • Unique pathophysiological features: Women diagnosed with GDM present particular challenges to the clinician because they have their metabolic disorder for a limited time, and they may not perceive the potential risks to their fetus of uncontrolled glucose excursions following meals (macrosomia, hypoglycemia, and poor neonatal transition). For this reason, early and thorough education about the effects of their disordered metabolism on fetal growth and oxygenation are necessary. Once the patient understands the benefits of maintaining excellent glucose control for approximately 10 weeks, compliance improves markedly.

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  • Dietary therapy: Metabolic management of a patient with GDM is focused on dietary control, regular home glucose monitoring, and judicious use of insulin therapy. Most patients with GDM diagnosed in the third trimester can maintain 1-hour postprandial blood glucose levels less than 130 mg/dL via diet manipulation alone (multiple, small, nonglycemic meals and increased exercise).

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  • Glucose monitoring: A home glucose monitor is essential to assist the patient in choosing the types and timing of food ingestion. For the first 1-2 weeks, the patient should perform capillary glucose checks on rising (fasting) and 1 hour after each major meal. Midmorning, midafternoon, and bedtime snacks are essential to blunt the glucose surge occurring after meals. Once the patient has demonstrated success in controlling postprandial glucose with diet, it is exceedingly rare for her fasting levels to be abnormal, and the morning checks can be discontinued. Fasting checks are reinstituted if any postprandial glucose levels are abnormal.

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  • Insulin therapy: Clinicians and patients are reluctant to start insulin therapy in patients with GDM, but this intervention may be key in achieving a good outcome. Recent research from a study in which randomized patients with GDM whose fetuses had abdominal circumferences above the 75th percentile either dieted or took twice-daily insulin therapy suggests that the earlier insulin therapy is started, the better the outcome. Although the gestational age at delivery was similar in insulin-treated and diet-treated groups, birth weights (3,647 g ?67 g vs 3,878 g ?84 g; P <0.02), the prevalence of infants who were large for gestational age (13% vs 45%, P <0.02), and neonatal skin-fold measurements at 3 sites (P <0.005) were reduced in the insulin-treated group.

    In a historical-control study of early aggressive insulin treatment of patients with GDM, fasting or postprandial glucose exceeded 120 mg/dL when the patient exceeded 90 mg/dL. In 1992, the prevalence of macrosomia decreased from 18 to 7%, and the cesarean section rate had dropped from 30 to 20%. A policy of insulin treatment was suggested to possibly save more than $800,000 yearly in one county.

    Determine the choice of insulin and insulin regimen by the patient’s individual glucose profile. Typically, one to several postprandial glucose levels become consistently above target because the patient’s ability to compensate for rising insulin resistance with diet becomes inadequate. When more than 10% of postprandial blood sugars exceed 130 mg/dL, administering regular or lispro insulin injections (4-8 U to start) before meals with abnormal postprandials usually is successful in controlling glucose overshoots. If more than 10 U of regular insulin is needed prior to the noon meal, adding an 8-12 U dose of neutral protamine Hagedorn (NPH) prior to breakfast helps achieve smoother control. When more than 10% of fasting glucose levels rise above 95 mg/dL, a starting dose of 6-8 U of NPH insulin at bedtime can be used. The doses are scaled up as necessary once or twice weekly to keep glucose levels on target.

• Peripartal management of patients and fetuses with diabetes

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  • Prenatal obstetric management: The goals of management of third trimester pregnancies in diabetic women are to prevent stillbirth and asphyxia, while minimizing maternal morbidity associated with delivery. Monitoring fetal growth is essential to select the proper timing and route of delivery. This is accomplished by frequent testing for fetal well-being and serial ultrasound examinations for trending of fetal size.

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  • Periodic fetal biophysical testing: Various fetal biophysical tests are available to the clinician to ensure that the fetus is well oxygenated, including fetal heart rate testing, fetal movement assessment, ultrasound biophysical scoring, and fetal umbilical Doppler studies. Most of these can be used with confidence to provide assurance of fetal well-being while awaiting fetal maturity, if applied properly.

    Table 5. Biophysical Tests of Fetal Well Being for Diabetic Pregnancy

    Test	Frequency	Reassuring Result	Comment
    Fetal movement counting	Every night from 28 wk	10 movements in <60 min	Performed in all patients
    Nonstress test (NST)	Twice weekly	2 heart rate accelerations in 20 min	Begin at 28-34 wk with insulin-dependent diabetes, and being at 36 wk in diet-controlled GDM.
    Contraction stress test	Weekly	No heart rate decelerations in response to 3 contractions in 10 min	Same as for NST
    Ultrasound biophysical profile	Weekly	Score of 8 in 30 min	3 movements = 2;1 flexion = 2;30 s breathing = 2;2 cm amniotic fluid = 2

    Initiate testing early enough to avoid significant stillbirth but not so early that a high rate of false-positive test results is encountered. In patients with poor glycemic control or significant hypertension, begin formal biophysical testing as early as 28 weeks. In patients who are at lower risk, most centers begin formal fetal testing by 34 weeks. Fetal movement counting is performed in all pregnancies from 28 weeks onward.

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  • Assessing fetal growth: Monitoring fetal growth continues to be a challenging and highly inexact process. Although the tools available now, serial plotting of fetal growth parameters, are superior to earlier clinical estimations, accuracy is still ?15%. Several polynomial formulas utilizing combinations of head, abdominal, and limb measurements have been proposed to predict the weight of a macrosomic fetus from ultrasound parameters (Tongsong et al, 1994). Unfortunately, in these formulae, small errors in individual measurements of the head, abdomen, and femur are typically compounded. In the obese fetus, the inaccuracies are further magnified. In 1994, Bernstein and Catalano observed that significant correlation exists between the degree of error in the ultrasound estimated fetal weight (EFW) and the percent of body fat on the fetus (r = 0.28, P <0.05). Perhaps this is why no single formula has proven to be adequate in identifying a macrosomic fetus with certainty.

    Despite problems with accuracy, estimation of fetal size ultrasonographically has become the standard of care. Estimate fetal size once or twice at least 3 weeks apart in order to establish a trend. Time the last examination to be at 36-37 weeks or as close to the planned delivery date as possible.

• Timing and route of delivery

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  • Select the timing of delivery to minimize morbidity for the mother and fetus. Delaying delivery to as near as possible to the expected date of confinement (EDC) helps maximize cervical maturity and improves the chances of spontaneous labor and vaginal delivery. However, the risks of advancing fetal macrosomia, birth injury, and in utero demise increase as the due date approaches.

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  • Although delivery as early as 37 weeks might reduce the risk of shoulder dystocia, consider the increased incidence of failed labor inductions and poor neonatal pulmonary status. Because fetal growth from 37 weeks onward may be 100-150 g/wk, the reduction in net fetal weight and the risk of shoulder dystocia by inducing labor 2 weeks early may improve outcome.

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  • In 1993, when Kjos et al compared the outcomes associated with labor induction in patients with gestational diabetes at 38 weeks versus expectant management with fetal testing, they found that expectant management increased the gestational age at delivery by 1 week, but the cesarean delivery rate was not significantly different. However, the prevalence of infants who were macrosomic in the expectantly managed group (23%) was significantly greater than those in the active induction group (10%). This suggests that routine induction of women with diabetes on or before 39 weeks does not increase the risk of cesarean section and may reduce the risk of macrosomia.

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  • If the fetus is not macrosomic and biophysical testing is reassuring, the obstetrician can await spontaneous labor. In patients with GDM and superb glycemic control, continued fetal testing and expectant management can be considered until 41 weeks. In the fetus with an abdominal circumference measurably greater than the head circumference, consider induction. After 40 or more weeks, the benefits of continued conservative management are likely to be less than the danger of fetal compromise. Induction of labor before 42 weeks in pregnancy in diabetic women, regardless of the readiness of the cervix, is prudent.

• Thus, an optimal time for delivery of most diabetic pregnancies is typically on or after the 39th week. Deliver a patient with diabetes before 39 weeks gestation without documented fetal lung maturity only for compelling maternal or fetal indications. In such cases, verify fetal lung maturity by amniocentesis.

MEDICATION

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Clinicians and patients with GDM are reluctant to start insulin therapy, but it is the key to achieving a good outcome. Research suggests that early intervention with insulin is superior to diet therapy alone. Patients with GDM whose fetuses had abdominal circumferences above the 75th percentile were randomized to receive either diet or insulin therapy. Gestational age at delivery was similar in insulin-treated and diet-treated groups. Statistically significant reductions were observed in the insulin-treated group for birth weights (3647 g ?67 g vs 3878 g ?84 g; P <0.02), the prevalence of infants who were large for gestational age (13% vs 45%, P <0.02), and neonatal skin-fold measurements at 3 sites (P <0.005).

Determine the choice of insulin and regimen by the patient’s individual glucose profile. Postprandial glucose levels become consistently above the target with diet therapy. When more than 10% of postprandial blood glucose exceeds 130 mg/dL, administer regular or lispro insulin (4-8 U SC initially) before meals. If more than 10 U of regular insulin is needed before the noon meal, adding 8-12 U of NPH before breakfast helps achieve control. When more than 10% of fasting glucose levels exceed 95 mg/dL, initiate 6-8 U NPH insulin hs. Titrate doses prn according to blood glucose levels.
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Drug Category: Insulins -- Essential in regulating carbohydrate, protein, and fat metabolism. Primarily affects carbohydrate homoeostasis by binding to specific cell-surface receptors on insulin-sensitive tissues (eg, liver, muscles, adipose tissue).

FOLLOW-UP

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Further Inpatient Care:
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• Avoiding shoulder dystocia: Although ultrasound measurements of the fetus have proven to be poor predictors of the risk of shoulder dystocia, this technique continues to be the mainstay for assessing risk in pregnancy in diabetic women. The commonly utilized formulas derived from a multivariate regression multiply multiple coefficients together, with the resultant product (EFW) typically having an accuracy that seldom is less than ?15%. Fetuses predicted to weigh 4000 g and 4500 g by ultrasound actually only weighed that much 50% of the time.

• In a study involving more than 300 fetuses that weighed more than 4000 g at birth, ultrasound was found to have a sensitivity of only 65% in identifying macrosomic fetuses.

• However, a sensitivity of approximately 80% typically is associated with a specificity of 50-60%. This means a false-positive rate of 30-50% occurs even with the more predictive formula, possibly requiring an unnecessary cesarean section of more than 100 fetuses in order to prevent 1 from having permanent Erb palsy.

• Thus, no good data to support a policy of cesarean section or early induction of labor in cases of suspected fetal macrosomia really exist. If one accepts that 8-20% of IDMs born weighing 4500 g or more will experience shoulder dystocia, and 15-30% of these will have recognizable brachial plexus injury, and 5% of these injuries will result in permanent deficit, approximately 333-1667 cesarean sections would have to be performed for suspected macrosomia to prevent one case of permanent injury due to shoulder dystocia.

• Intrapartum glycemic management: Maintenance of intrapartum metabolic homeostasis optimizes postnatal infant transition. The use of a combined insulin and glucose infusion during labor to maintain maternal blood sugars in a narrow range (80-110 mg/dL) during labor is a common and reasonable practice. Typical infusion rates are 5% dextrose in Ringer lactate solution at 100 mL/h and regular insulin at 0.5-1.0 U/h. Capillary blood sugars are monitored hourly in these patients. For patients with diet-controlled gestational or mild type II diabetes who are in labor, avoiding dextrose in all intravenous fluids normally maintains excellent blood glucose control. After 1-2 hours, no further assessments of capillary blood sugar typically are necessary.

• Management of the neonate (neonatal transitional management): The most critical metabolic problem afflicting IDMs is hypoglycemia. Unmonitored and uncorrected hypoglycemia can lead to neonatal seizures, brain damage, and death. The degree of hypoglycemia correlates roughly with the degree of maternal glycemic control over the 6-12 weeks prior to birth. IDMs also appear to have disorders of both catecholamine and glucagon metabolism and have a diminished capability to mount normal compensatory responses to hypoglycemia. Thus, current recommendations specify frequent blood glucose checks and early oral feeding when possible (ideally from the breast), with infusion of intravenous glucose if oral measures prove insufficient. Most neonatologists maintain strict monitoring of the glucose levels of newborn IDMs for at least 4-6 hours (frequently 24 h), often necessitating admission to a newborn special care unit.

• Current evidence indicates that, with proper encouragement, sustained breastfeeding is possible for a significant proportion of patients with overt diabetes. Webster et al longitudinally compared breastfeeding habits among women with diabetes and without diabetes. At discharge, 63% of IDMs and 78% percent of mothers without an IDM were breastfeeding. At 8 weeks, the proportions of each were nearly identical (58% and 56% respectively). At 3 months, 47% percent of diabetic mothers and 33% mothers without diabetes continued to breastfeed.

• Recent studies of breastfeeding women with diabetes indicate that lactation, even for a short duration, has a beneficial effect on overall maternal glucose and lipid metabolism. For postpartum women who had GDM during their pregnancies, breastfeeding may offer a practical low-cost intervention that helps reduce or delay the risk of subsequent diabetes in women with prior GDM.

• Intensive management of women with glucose intolerance during pregnancy has resulted in markedly improved outcomes in recent years. Despite these advances, care of the infant of a mother with diabetes continues to require vigilance and meticulous monitoring with a full understanding of the quality of glycemic milieu in which it developed.

Deterrence/Prevention:
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• Prevention of gestational diabetes is an attractive concept, but no progress has been made, despite attempts in smaller studies. Since body fat and diet contribute to the risk of GDM, patients who slim down prior to pregnancy and follow an appropriate diet may lower their risk of GDM. However, the pregnancy hormones impose such a high degree of insulin resistance, in very susceptible individuals even marked weight loss and attention to diet are not likely to be successful.

Patient Education:
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• Education is the cornerstone of effective metabolic management of the patient with diabetes during pregnancy. The American Diabetes Association offers educational curricula specific to each type of diabetes encountered during pregnancy (IDDM, NIDDM, GDM) specifically organized around each phase of pregnancy. This information can be transmitted to the patient by office staff and labor/delivery nurses. However, specially trained and certified nurses and dietitians (Certified Diabetes Educators) are the most effective in this regard. Most large programs managing women with diabetes during pregnancy assist the patient with a staff that includes an RN CDE, a pregnancy-knowledgeable dietitian and a social worker. Successful management of diabetic pregnancy is optimized when this type of "team care" is available.

• The diabetes-in-pregnancy team is also able to help the patient during the puerperal period with the challenges of lactation, diet, sleep and glycemic control. This team is also most effective in providing a smooth return to non-pregnant metabolic management.

MISCELLANEOUS

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Medical/Legal Pitfalls:
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• Two main issues present medicolegal pitfalls for the clinician managing patients with diabetes in pregnancy.
  First is the occurrence of a severe, debilitating congenital anomaly in the infant of a diabetic mother. Structural defects occur in 3-8% of offspring of diabetic pregnancy, but this rate drops by 3 to 4 fold if excellent glycemic control exists during the period of embryogenesis.

  Thus it is incumbent upon the medical provider, when discussing pregnancy plans with a woman with preexisting diabetes, to mention the preventability of these birth defects with good periconceptional glycemic control. The patient should be advised to use a reliable method of contraception until she has achieved a hemoglobin A1c in the normal range preconceptionally. This counseling should be recorded in the patient’s medical record.

  A second risk is birth injury, which may include perinatal asphyxia, clavicle or humerus fracture, brachial plexus disruption or, less commonly, direct cerebral or cervical spine trauma. Permanent palsy of arm and hand after a difficult delivery of an obese fetus usually leads to litigation and, in some cases, large judgments. Although there are presently not adequate scientific data establishing the foreseeability and preventability of these injuries, defending obviously high-risk cases can be difficult.

  The obstetrician managing the patient’s third trimester prenatal care and labor may be judged at fault should an injury occur during delivery if an ultrasound suggests that fetal weight exceeds 10 pounds, labor proceeds slowly, and a difficult forceps or vacuum procedure is necessary to deliver the fetal head. Thus it is prudent to obtain an ultrasound estimate of fetal weight in the last 2-3 weeks prior to delivery, and to offer cesarean delivery to a patient with an estimated fetal weight >4500 g or has a labor course that is protracted and she is unable to expel the fetal head spontaneously after 2-3 hours of pushing effort.