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Management of Diabetes in Pregnancy

Page history last edited by Robert Rushakoff, MD 10 years, 6 months ago
The Web diabetesmanager

 

MANAGEMENT OF DIABETES IN PREGNANCY

 

Linda A Barbour, MD, MSPH

Jacob E Friedman, PhD

 

 

Last Author Revision: May 2010

Reviewed by Authors:  December 2010

 


 

 

 

INFLUENCE OF METABOLIC CHANGES IN PREGNANCY

Pregnancy is a complex metabolic state that involves dramatic alterations in the hormonal milieu (increases in estrogen, progesterone, prolactin, cortisol, human chorionic gonadotropin, placental growth hormone and human placental lactogen) in addition to decreases in adiponectin and increases in leptin and TNF α accompanied by an increasing burden of fuel utilization by the conceptus. [1] Metabolically, the first trimester is characterized by increased insulin sensitivity which promoted adipose tissue accretion in early pregnancy.  Women are at increased risk for hypoglycemia, especially if accompanied by nausea and vomiting in pregnancy.  In the fasting state, pregnant women deplete their glycogen stores quickly due to the fetoplacental glucose demands and switch from carbohydrate to fat metabolism within 12 hours, resulting in increased lipolysis and ketone production[2][3][4][5]. The second and third trimesters, in contrast, are characterized by insulin resistance with a nearly 50% decrease in insulin mediated glucose disposal (assessed by the hyperinsulinemic-euglycemic clamp technique) and a 200-300% increase in the insulin response to glucose [6][7][8][9][10]. This serves to meet the metabolic demands of the fetus, which requires 80% of its' energy as glucose, while maintaining euglycemia in the mother. The placental and fetal demands for glucose are considerable and approach the equivalent of ~150 grams per day of glucose in the third trimester [11][12]. In addition, the maternal metabolic rate increases by ~300 kcal/day in the third trimester. These increased nutritional needs place the mother at risk for ketosis which occurs much earlier than usual when without adequate oral or intravenous nutrients, frequently referred to as "accelerated starvation of pregnancy" [13][14][15][16]. Glucose transport to the fetus occurs in direct proportion to maternal glucose levels, and is augmented by a five-fold increase in a placental glucose transporter, (GLUT-1) which increases transplacental glucose flux even in the absence of maternal hyperglycemia [17]. At the same time it has been demonstrated that in the third trimester of normal pregnancy there is decreased expression of the GLUT-4 glucose transporter protein in maternal adipose tissue [18][19] and decreased translocation of GLUT-4 to the plasma membrane in skeletal muscle, both of which contribute to the insulin resistance of pregnancy.

 

Human placental growth hormone (hPGH) has been recently characterized as a metabolically active hormone capable of causing severe insulin resistance in transgenic animals which express this hormone at levels comparable to those measured in the third trimester of pregnancy [20]. This key hormone may mediate insulin resistance as does excess pituitary growth hormone (pit GH) when it is administered or expressed chronically. Human placental growth hormone differs from pit GH by 13 amino acids. It almost completely replaces pit GH in the maternal circulation by 20 weeks, and it is unregulated by growth hormone releasing hormone. [21][22][23] The placenta is responsible for the production of hormones which reprogram maternal physiology to become insulin resistant in the 2nd and 3rd trimester of pregnancy to ensure an adequate supply of nutrients to the growing fetus [24]. Most probably, this is due to an increase in placental growth hormone [25][26] in combination with human placental lactogen, progesterone, and TNFa, which correlates with maternal insulin resistance measured by hyperinsulinemic-clamps [27]. Human placental lactogen may play a key role in stimulating insulin production in human islets [28][29][30] in order for the mother to increase her insulin secretion 2-3 fold.  . At the insulin signaling level in skeletal muscle, the insulin resistance of pregnancy involves reduced tyrosine phosphorylation of the insulin receptor, decreased expression of IRS-1, and increased levels of the p85α subunit of phosphatidylinositol kinase (PI 3-kinase), all serving to attenuate glucose uptake [31].     

 

Normal pregnancy is associated with lower fasting plasma glucose and higher fasting insulin levels, especially later in pregnancy, presumably due to an increase in glucose uptake by the fetoplacental unit. In spite of the lower fasting glucose levels and higher fasting insulin levels, hepatic glucose production is increased suggesting hepatic insulin resistance which increases glucose availabilty to the fetus in the fasted state [32].Postprandial glucoses are slightly elevated associated with maternal postprandial hyperinsulinemia, especially in the second and third trimester. Glucose is not the only fuel altered in normal pregnancy. Amino acids are decreased, whereas triglycerides, cholesterol, and free fatty acids are increased; the latter may serve to further increase the insulin resistance of pregnancy [33].  There is a 2-4 fold increase in TGs and a 25-50% increase in total cholesterol and LDL during pregnancy [34].  During the first trimester of pregnancy when insulin sensitivity is increased, lipogenesis is favored and centrally distributed subcutaneous fat mass is increased so that there is a significant increase in adipose tissue stores.  However, later in pregnancy, coincident with the insulin resistance, lipolysis is enhanced and the subcutaneous fat stores are a source of calories for the fetus during pregnancy and for lactation postpartum.  The ability of insulin to suppress whole body lipolysis is reduced resulting in an increase in FFAs, which can also be used as a fuel by the fetoplacental unit [35][36].  The placental has both lipoprotein lipase as well as TG-hydrolase enzymes so that maternal TGs can be used in addition to FFAs for fetoplacental fuels.

 

 

Effect of Metabolic Changes on Diabetes Management Throughout Gestation

 

Diabetes should optimally be under tight control before conception. During the first trimester before the placenta increases the production of hormones, nausea, and increased insulin sensitivity (possibly by estriol) may place the mother at risk for hypoglycemia. Women must be counseled that their insulin requirements in the first trimester are likely to decrease by 10-20% [37][38]. This is especially true at night when prolonged fasting and continuous fetal glucose utilization places the woman at even a higher risk for hypoglycemia. Women with Type 1 diabetes mellitus must have a bedtime snack and usually need to have their evening dose of NPH insulin lowered and moved from suppertime to bedtime to avoid early morning hypoglycemia [39]. The effect of short-term maternal hypoglycemia on the fetus is not well understood. For women with Type 1 diabetes and hypoglycemic unawareness, it may not be possible to achieve a HgbA1C of <6%  without severe hypoglycemia therefore glycemic control just above the normal range may thus be safer and decrease the risk of fetal hypoglycemia [40].

 

After 20 weeks of gestation, peripheral insulin resistance increases insulin requirements so that it is not unusual for a pregnant woman to require 2-3 times as much insulin as she did prior to pregnancy. If the woman becomes ill, her insulin requirements are likely to be even higher due to the addition of high counterregulatory hormones in the face of pre-existing insulin resistance of pregnancy. Diabetic ketoacidosis carries the highest risk of fetal mortality in the third trimester thought in part due to the extreme insulin resistance in these patients and insulin requirments to treat DKA that are nearly twice as high as in the second trimester [41]. It has been demonstrated that both postprandial hyperglycemia and fasting hyperglycemia are risk factors for  fetal macrosomia [42][43]. Therefore, tight glucose control in women with preexisting diabetes (both Type 1 and Type 2) often requires insulin administration with each meal with a short acting insulin preparation such as Lispro [44]. Frequent monitoring allows appropriate insulin dosage adjustments. The maintenance of normal glucose control is the key to prevention of complications such as fetal malformations in the first trimester, macrosomia in the second and third trimesters, and neonatal metabolic abnormalities.

 

 

PRECONCEPTION COUNSELING AND PREPARING THE WOMAN WITH PRE-EXISTING DIABETES FOR PREGNANCY

 

Glycemic Control Objectives

Most important in preconception counseling is the message of optimal glucose control prior to conception [45][46][47] which favorably impacts the rates of congental malformations, stillbirth, neonatal death, and very premature delivery.  In a retrospective study, < 40% of women attempted to achieve optimal glycemic control before becoming pregnant [48]. Four times as many fetal and neonatal deaths and congenital abnormalities occurred in a group of women who did not receive prenatal counseling in comparison to those who did [49]. Hyperglycemia is a known teratogen [50]  and can result in complex cardiac defects, CNS anomalies such as anencephaly and spina bifida, skeletal malformations and genitourinary abnormalities [51][52].  The incidence of congenital abnormalities in offspring of diabetic mothers in the early era of insulin use was 33%. Over the past two decades, with the advent of home blood glucose monitoring and more rigid objectives, this percentage has fallen to <11% of offspring [53][54][55][56] but has not significantly improved in nearly 15 years [57]. In one of the largest studies in 462 pregnancies in women with Type 1 DM from 10 centers over a 5 year period in England, there were 76% live births, 17% pregnancy losses, and 2% still births (five times the rate of the normal population). The congenital malformation rate was nearly 10% (94/1000 versus 9.7/1000) and directly related to the Hemoglobin A1C. [58]. Epidemiologic and prospective studies have shown that the level of HgbA1C in the 6 months before conception and during the first trimester correlates with the incidence of major malformations such as neural tube and cardiac defects as well as spontaneous abortions. It has been shown that diabetes-induced fetal abnormalities may be mediated by a number of metabolic disturbances including elevated superoxide dismutase activity, reduced levels of myoinositol and arachidonic acid, and inhibition of of the pentose phosphate shunt pathway. Oxidative stress appears to be involved in the etiology of fetal dysmophogenesis and neural tube defects in the embryos of diabetic mice are also associated with altered expression of genes which control development of the neural tube [59][60]. These experimental results may help to explain the high spontaneous abortion rate in women with poorly controlled diabetes. The neural tube is completely formed by 4 weeks and the heart by 6 weeks after conception; many women do not even know they are pregnant at these times. It has been demonstrated that women with a normal HgbA1C at conception and during the first trimester have no increased risk while women with a HgbA1C of 10-12% or a fasting blood glucose >260 have up to a 25% risk of major malformations [61][62]. The randomized, prospective Diabetes and Complications Trial has shown that timely institution of intensive therapy for blood glucose control is associated with rates of spontaneous abortion and congenital malformations that are similar to those in the nondiabetic population [63]. In 270 pregnancies studied, the hemoglobin A1C at conception was 7.4% in the intensively treated mothers and 8.1% in the conventional group but similar during later gestation (6.6%) in both groups. Nine congenital malformations were identified (4.7%), eight which occurred in women originally assigned to conventional therapy.  Current recommendations by the American College of Obstetrics and Gynecology, the ADA, and recent ADA Consensus Panel are to try to achieve a pre-conception HgbA1C of 6% or less pre-conception and throughout pregnancy unless the mother has severe hypoglycemia and hypoglycemic unawareness [64][65].    

 

 

Use of Oral Hypoglycemic Agents

 

No oral hypoglycemics are approved for pre-exisiting diabetes in pregnancy.  However, there is no data that any of the oral hypoglycemics are teratogens although there is minimal data on thiozolidinediones or metiglanides and all are likely to cross the placenta [66].  There is  significant data on Metformin and Glyburide in women with gestational diabetes.  (see GDM section). 

 

Small trials have recently been conducted using Metformin pre-conception and throughout the first trimester in women with polycystic ovary disease to improve fertility and prevent early miscarriage [67][68]. In one trial, Metformin was continued through pregnancy in 65 women [69]. In the metformin group, 62 pregnancies resulted in live births. Of these, 53 were term deliveries and 8 were preterm. All babies were normal neonates with appropriate size for gestational age. One baby demonstrated achondrodysplasia. However, metformin, crosses the placenta more readily than glyburied.  Until more definitive experience in pregnancy is obtained, it should be discontinued and replaced with insulin if treatment is necessary in the first trimester [70]. In a cohort of 50 pregnant women treated with metformin, 68 women treated with a sulphonylurea and 42 women treated with insulin, there was an increase in preeclampsia in the metformin group and an increase in perinatal mortality [71]. The only possible exception to its continued use in the first trimester may be in women with polycystic ovarian disease with recurrent fetal losses where it has been suggested that continuing its use during the first trimester may decrease early pregnancy losses [72][73][74]. However, the woman should be counseled that such treatment is off label, not approved for use in pregnancy, and the long-term offspring implications are unknown.  There is significant experience with Glyburide in GDM women (see GDM section) but it is highly likely to fail in women with pre-existing diabetes and is only concerned an alternative to insulin by the Fifth International Workshop-Conference on GDM for women with GDM [75][76].  There is no data that it is a teratogen but recent data shows that it crosses the placenta to a greater degree than originally though [77][78].  It is recommended that women with Type 2 DM who are actively trying to become pregnant should be switched from oral hypoglycemic agents to insulin prior to conception if possible because it may take some time to determine the ideal insulin dose prior to the critical time of embryogenesis. However, women who conceive on any oral agents should not have them stopped until they can be switched effectively to insulin because hyperglycemia is potentially much more dangerous than any of the current available therapies to treat diabetes [79][80].

 

 

Risks of Pregnancy Complications

Women who are taking ACE-inhibitors or angiotensin receptor blockers should be counseled that these agents are contraindicated in all semesters of pregnancy due to an increased risk of CNS and cardiac malformations in the first trimester [81] and due to the risk of fetal anuria in the 2nd and 3rd trimester, which may be irreversible [82]. Women who desire pregnancy should be switched to calcium channel blockers, methyldopa, hydralazine , or selected B-adrenergic blockers which includes Labetalol [83]. Non-hydropyridine calcium channel blockers such as diltiazem may be preferred over the dihydropyridine in women with proteinuria because of their tendency to dilate glomerular arterioles and reduce renal albumin excretion, although evidence for the latter effect in pregnancy is only anecdotal [84].   Although mild renal disease does not seem to be accelerated by pregnancy, women with more severe renal disease (Cr > 1.5) are at a high risk of pregnancy complications and potentially more rapid progression of their renal disease [85][86]. Therefore, women with diabetic nephropathy should be counseled to have their children when their diabetes is optimally controlled and preferably early in the course of their nephropathy. Preeclampsia complicates ~20% of pregnancies in women with Type 1 diabetes [87] and 92% of women with a Cr > 1.5 [88]. The rate of preeclampsia ranges from 9%-92%, the highest rates in women with increased severity of diabetes by White's classification and especially in women with diabetic nephropathy (proteinuria >300 mg), renal insufficiency, or who are hypertensive [89][90]. Unfortunately, there is no known effective therapy to prevent preeclampsia. Although antihypertensive therapy should be instituted to maintain BP at <130-140/80-90 in order to protect the maternal kidney, it does not prevent preeclampsia [91]. Women with longstanding Type 1 DM, and with nephropathy or hypertension, should be told that there is a substantial risk for preeclampsia complicating the pregnancy and this can lead to growth restriction, preterm delivery, and fetal lung immaturity in the infant [92].

 

Proliferative retinopathy may also progress during pregnancy; it is imperative, therefore, that this condition be optimally treated with laser therapy prior to pregnancy. The rapid institution of tight control in the face of increased volume expansion, anemia, placental angiogenic growth factors, and the hypercoagulable state of pregnancy may accellerate disease in women with moderate to severe retinopathy [93].  Hypertension is a known risk factor in its acceleration in pregnancy [94].  Optimal glycemic control and treatment of retinopathy and hypertension prior to conception are of paramount importance.

 

Women with Type I diabetes have a 5-10% risk of developing autoimmune thyroid disease first diagnosed in pregnancy (usually Hashimoto's thyroiditis). TSH should be checked prior to pregnancy since the fetus is completely dependent on maternal thyroid hormone in the first trimester [95].  Women with positive TPO antibodies should have their TSH checked each trimester (Table 2) since the demands of pregnancy can unmask decreased thyroid reserve from Hashimoto’s thyroiditis [96][97].  Thyroid hormone requirements increase by 30-50% in most women, often early in pregnancy due to increase in thyroid binding globulin.  A TSH of >3.0 is considered abnormal in the first trimester and > 3.5 in the 2nd and 3rd due to the thyrotropic influence of hCG [98].

 

Because of the high morbidity and mortality of coronary artery disease in pregnancy, women with pre-existing diabetes and cardiac risk factors such as hyperlipidemia, hypertension, smoking, advanced maternal age (>35) or a strong family history should have their cardiac status assessed with functional testing prior to conception [99] Due to the increase cardiac output of pregnancy, decrease in systemic vascular resistance, and increase in oxygen consumption, the risk of myocardial ischemia is higher in pregnancy. Myocardial oxygen demands are even higher at labor and delivery, and activation of catecholamines and stress hormones can cause myocardial ischemia.  An EKG should be done preconception for any woman with diabetes >35 [100].  Women with atypical chest pain, significant dyspnea, or an abnormal resting EKG should also have a cardiology consultation for consideration of a functional cardiac stress test before pregnancy [101].  Statins should be discontinued before conception since there is inadequate data about their safety during pregnancy and a concern for teratogenicity.  However, if a woman has severe hypertriglyceridemia with TG >1000, placing her at high risk for pancreatitis, it may be necessary to continue fibrate therapy if a low fat diet, fish oils, or niacin therapy is not effective or tolerated. Triglycerides typically double to quadruple in pregnancy placing women at high risk for this condition.  All women should also be taking folic acid supplements (1 mg per day) before conception and the benefit of increasing this to 5 mg per day at conception in women with pre-existing diabetes is not known.

 

Offspring of women with Type 1 DM have a risk of developing Type 1 DM of about 1-3% [102]. The risk is higher to the offspring if the father has Type 1 DM rather than the mother (~3-6%) and if both parents have Type 1 diabetes, the risk if ~20%. The infant can be tested with HLA typing and a battery of antibodies associated with Type 1 diabetes to better predict the risk of developing Type 1 diabetes later in childhood [103].   Offspring of infants with preexisting diabetes and GDM have an increased risk of childhood obesity, glucose intolerance and childhood diabetes, especially if glycemic control is not optimal. [104][105][106]

 

Smoking continues to be the leading cause of low birth weight infants in patients with and without diabetes and places the infant at increased risk for respiratory infections, reactive airway disease, and sudden infant death syndrome. Smoking cessation efforts need to be intensified before conception as there continue to be concerns about the use of Wellbutrin in the first trimester of pregnancy [107].

 

Obesity is a significant risk for many pregnancy complications independent of preexisting diabetes (see Type 1 versus Type 2 and Effect of Obesity section) and prepregnancy BMI is one of the strongest risk factors for macrosomia [108].  Every attempt should be made for overweight or obese women to lose weight before pregnancy and adopt healthy nutrition and physical activity lifestyles.   

 

 

DIABETIC CLASSIFICATION: THE WHITE CRITERIA FOR SEVERITY OF DIABETES DURING GESTATION

Although this classification is foreign to internists, it is used by obstetricians who take care of pregnant women with diabetes and is advocated by the American College of Obstetricians and Gynecologists in order to stratify both maternal and fetal risk in pregnant women with diabetes. Priscilla White, working with Elliot Joslin at the Joslin Clinic observed that a patient's age at onset of diabetes, its duration, and the severity of complications including vascular disease, nephropathy, and retinopathy influenced maternal and perinatal outcome adversely (Table 1). She developed a classification scheme in 1949 that is still widely used in the obstetric community due to its predictive value in identifying patients who are at greatest risk for obstetric complications during pregnancy. The updated classification scheme allows physicians to focus on intensified management and fetal surveillance on those patients who pose the highest risk for poor maternal and obstetric outcome during pregnancy. Pre-gestational (women with pre-existing diabetes) diabetic women are designated by the letters B,C,D,F,R,T, and H according to their duration of diabetes and complications. There is not a separate classification scheme for Type 1 and Type 2 diabetes but the initial scheme was developed for women with Type 1 DM.

 

Table 1. Modified White Classification of Pregnant Diabetic Women
Class  Diabetes onset age (yr)  Duration (yr)  Type of Vascular Disease  Medication Need
Gestational Diabetes (GDM)
A1  Any  Pregnancy  None None 
A2  Any  Pregnancy  None  Yes
Pre-gestational Diabetes
20  <10  None  Yes
10-19 OR  10-19  None  Yes
<10 OR  20  Benign Retinopathy  Yes
Any  Any  Nephropathy  Yes
Any  Any  Proliferative Retinopathy  Yes
Any  Any  Renal Transplant  Yes
Any  Any  Coronary Artery Disease  Yes

 

 

 

MANAGEMENT OF PRE-EXISTING DIABETES IN PREGNANCY

 

Medical Nutrition Therapy

Women with preexisiting diabetes (dm) as well as gestational diabetes (GDM) should receive individualized medical nutrition therapy (MNT) as needed to achieve treatment goals [109][110].  Pregravid BMI should be assessed and weight gain recommendations should be consistent with the current Institute of Medicine IOM) weight gain guidelines [111], which recommend that obese women not gain more than 20 lbs.  For women obese women, a 33% calorie restriction of their estimated energy needs is recommended (~25 kcal/kg)  [112][113][114], although other invstigators would argue for a lower caloric intake (1600-1800 calories/day) [115].  The diet should be culturally appropriate and women should consume at least 175 grams of carbohydrate, primarily as complex carbohydrate and limitation of simple carbohydrates, especially those with high glycemic indices.  Protein intake should be at least 1.1 g/kg/day unless patients have severe renal disease.  Patients should be taught to control fat intake and to limit saturated fat to <10% of energy intake, trans fats to the minimal amount possible, and encourage consumption of the n-3 unsaturated fatty acids that supplies DHA intake of at least 200 mg/day [116].  A fiber intake of at last 28 g/day is advised [117] and the use of artificial sweeteners, other than saccharin, is considered safe in pregnancy and may be useful in controlling total calories and glycemic excursions.

 

Emphasize consistent timing of meals with at least a bedtime snack to minimize hypoglycemia and in proper relation to insulin doses.  Patients should be encouraged to record all food and beverage intake for at least 1 week before each visit and those patients receiving insulin based on a carbohydrate to insulin ratio should estimate grams of carbohydrate with each meal.  Preferably blood glucoses can be recording on the same food and beverage record for comparison of carbohydrate intake with glucose excursions.   

 

The Role of Exercise

There is a consensus that exercise is an important component of healthy lifestyle it is recommended in pregnancy by ACOG, the ADA, and Society of Obstetricians and Gynaecologists of Canada [118][119].  Furthermore, the 5th International Workshop on GDM recommends that pregnant women follow similar guidelines as for nonpregnant individuals, which includes 30 mins of exercise five times per week [120].  A decreased risk of preeclampsia was associated with physical activity in several studies and the greatest benefits appear to occur if it is started before 20 weeks. However, a large epidemiologic trial in Danish women suggested that there was an increased risk of preeclampsia in women who had high physical activity levels exceeding 270 minutes per week in the first trimester [121], and is the only study to suggest an increased risk.  There was no increased risk at physical activity levels up to 270 minutes per week.  Brief submaximal exertion (≤70% maximal aerobic activity) does not appear to affect the fetal heart rate and although high intensity at maximal exertion has not been likened to adverse pregnancy outcomes, transient fetal bradycardia and shunting of blood flow away from the placenta and to exercising muscles has been observed.  There is some data that found women who continued endurance exercise until term gained less weight and delivered slightly earlier than women who stopped at 28 weeks but they had a lower incidence of cesarean deliveries, shorter active labors, and fewer fetuses with intolerance of labor [122]. Babies who were slightly lighter were born to women who continued to exercise during pregnantcy compared with a group of women who reduced their exercise after the 20th week (3.39 kg versus 3.81 kg) but the lighter neonates were the result of decreased body fat [123].  Whether this strategy might be a benefit in obese women with or without Type 2 DM or GDM at risk of delivering infants with excess body fat remains to be tested.  Fetal safety has been established if the maternal heart rate is maintained < 150 beats per minute at durations of less than 1 hour and if the mother is well hydrated and does not get overheated. Contraindications for a controlled exercise program include women at risk for preterm labor or delivery or any obstetric or medical conditions predisposing to growth restriction.

 

Goals of Glycemic Control and Insulin Therapy

The goals of blood glucose control during pregnancy are rigorous and may be modified even lower based on the HAPO trial [124] and observations using continuous glucose monitoring sensor technology (CGMS) that the mean fasting glucose in normal pregnancy is 75 mg/dl and the peak postprandial mean value is 110 mg/dl [125].  Current guidelines are that pre-meal whole blood glucose should be 60-90 mg/dl, the 1 hour postprandial glucose <130-140mg/dl and the 2 hour glucose <120mg/dl [126][127]. Since fetal macrosomia (overgrowth) is also related to the postprandial glucose excursions, pregnant diabetic women need to monitor their pre-meal and postprandial glucose values regularly [128].   A HgbA1C should be done at first visit and every 1-3 months thereafter depending on whether it is normalized. Additional labs and exams recommended for women with preexisiting diabetes are listed in Table 2.   Type 1 diabetic patients usually require 3-4 injections per day or an insulin pump to achieve adequate control during pregnancy and multiple injections with short acting insulin analogs are often needed in women with Type 2 diabetes as well.  Lispro and Aspart have been used in multiple trials in pregnancy and their safety and efficacy have been well established [129][130].  Their use over Regular insulin has been shown in both gestational and pregestational diabetes to result in improved glycemic control, fewer hypoglycemic episodes, and improved patient satisfaction.  Lispro or Aspart  insulin may be especially helpful in women with hyperemesis or gastroparesis because they can be dosed after a successful meal and still be effective [131][132].  There is inadequate data on the use of glulisine in pregnancy.  

 

Increasingly, pregnant women with Type I diabetes are being managed with a flexible intensive self management program in which they learn to dose their short acting insulin according to a pre-meal correction factor and carbohydrate to insulin ratio [133][134].  Two doses of NPH are typically used to try and achieve a basal insulin.  Although insulin Glargine has not been recommended in the past, primarily due to its potential mitogenic effect and higher affinity to the IGF-1 receptor, there are a number of case series, especially in women with Type 1 diabetes, showing an incidence of congenital malformations similar to that obtained with human insulin and to date, reports show rates of progression of retinopathy to be similar to NPH [135][136].   To obtain better safety data, the pharmaceutical company is performing a 5 year randomized multicenter study that compares Glargine with NPH insulin on the progression of retinopathy (Clinical trials.gov identifier: NCT00174824).  However, the absence of a peak with Glargine may result in inadequate control of fasting glucoses, which can often be ameliorated by the use of NPH before bedtime to take advantage of its 8 hour peak.  The p.m. dose of NPH usually needs to be moved to before bedtime to avoid nocturnal hypoglycemia and prevent fasting hyperglycemia.  There inadequate data for the use of detemir in pregnancy but results of a prospective study are expected in 2010.  

 

The insulin pump is gaining favor in the treatment of Type 1 DM in pregnancy. In a non-randomized trial in which 24 women began insulin pump therapy during pregnancy and were compared to 12 women using the pump before pregnancy and 24 women treated with multiple insulin injections. There was no deterioration of glycemic control and maternal and perinatal outcomes were similar [137]. However, 2 of the 24 women who began using the pump in pregnancy developed ketoacidosis due to pump failure compared to no cases of ketoacidosis in the two other groups. Randomized control trials (RCTs) of multiple daily injections versus the insulin pump generally showed equivalent glycemic control and perinatal outcome and the pump can be especially useful for patient with nocturnal hypoglycemia or a prominent dawn phenomenon.  However, disadvantages include cost and the risk for marked hyperglycemia or DKA as a consequence of insulin delivery failure from a kinked catheter or infusion site issues [138][139][140]. Therefore, it may be optimal to begin pump therapy before pregnancy due to the steep learning curve involved with its use and the need to continually adjust basal and bolus rates due to the changing insulin resistance in pregnancy. 

 

Women with Type 2 DM may sometimes achieve adequate glycemic control with twice daily injections because they tend to be more insulin resistant and experience less hypoglycemia. However, if postprandial lunch excursions are too high or Regular insulin causes inadequate control of the 1 or 2 hour postprandial glucose and between meal hypoglycemia, three injections a day of a rapid acting insulin (Lispro) may be necessary. Perinatal outcomes were better with four times daily compared to twice daily regimens in both women with Type 2 DM and GDM in a randomized study [141].

 

Maternal hypoglycemia is common and often severe in pregnancy in women with Type 1 DM.  In a series of 84 pregnant women with Type 1 DM, hypoglycemia requiring assistance from another person occurred in 71% of patients with a peak incidence at 10-15 weeks gestation [142]. One third of subjects had a least one severe episode resulting in seizures, loss of consciousness, or injury. In pregnancy there appears to be an increase in hypoglycemic unawareness with the institution of intensive therapy, and this is worsened by the nausea and vomiting of pregnancy. There is also data to suggest that the counter-regulatory hormonal responses to hypoglycemia are diminished in pregnancy [143][144][145]. One of the highest risk periods for severe hypoglycemia is between midnight and 8:00 a.m, but diabetic women who have gastroparesis or hyperemesis gravidarum are at the greatest risk for daytime hypoglycemia [146]. Occasional monitoring in the middle of the night is recommended in women with Type I diabetes because of the increased risk of nocturnal hypoglycemia, especially if the woman has hypoglycemia unawareness. The continuous glucose monitoring system (CGMS) can be helpful, especially in women with type 1 DM who are having frequent hypoglycemic episodes and suffer from hypoglycemic unawareness and was shown to improve 3rd trimester glycemic control [147].The physician must have a low threshold for bringing the expectant mother into the hospital to optimize education and glycemic control, especially during the first trimester when organ development is occurring and the risk of hypoglycemia is greatest.  The risk of hypoglycemia to the fetus is difficult to study but animal studies indicate that hypoglycemia is potentially teratogenic during organogenesis which would translate into a gestational age between 3-10 weeks in the human [148]. Exposure to hypoglycemia in utero may have long-term effects on the offspring including neuropsychological defects [149] so intensive efforts must made to avoid it. The patient should have a glucagon kit and carry easily absorbed carbohydrate with her at all times.

 

Failure to achieve optimal control in early pregnancy may have teratogenic effects in the first 3-10 weeks of gestation or lead to early fetal loss. Poor control later in pregnancy increases the risk of intrauterine fetal demise, macrosomia, cardiac septal enlargement in the fetus, perinatal death, and metabolic complications in the newborn [150]. An early dating ultrasound is necessary to accurately determine the gestational age of the fetus and a formal anatomy scan at 18-20 weeks should be done to evaluate for fetal anomalies [151]. A fetal echocardiogram should be offered at 20-22 weeks, especially if the HbgA1C was elevated during the first trimester. Women with Type 1 diabetes can be at risk for macrosomic infants (due to excess delivery of nutrients to the fetus from poor glycemic control) or intrauterine growth restriction (IUGR) due to the common finding of poor placental perfusion in women with longstanding diabetes and microvascular disease [152]. Most recently, it is being recognized that although the mother may have glucoses in the target range, the fetus may still demonstrate abnormal growth (large for gestational age i.e. LGA) due to excessive nutrients being shunted to the fetus. This appears to be due to increased glucose transport across the placenta and also the effect of high lipids on fetal fat accretion, most importantly TGs .[153]  This abnormal growth is usually in a characteristic pattern of head to body disproportion. The fetus exhibits advanced growth in the abdominal circumference measurement due to excessive subcutaneous fat, compared to the head measurement [154]. This places the mother at an increased risk for cesarean section due to difficult delivery of the baby's enlarged abdomen. This abnormal growth pattern can be seen between 29-32 weeks. Increasingly, fetal criteria and growth patterns are dictating the aggressiveness of maternal glycemic treatment rather than simply using mother's glucoses as the goal for therapy [155][156][157].

 

 

Table 2 Evaluation of Women with Preexisting Diabetes in Addition to Prenatal Labs

HgA1C Initially and every 1-3 months
TSH Especially in Type 1 DM; Consider TPO antibodies and repeat TSH every trimester if + TPO antibodies
TGs Repeat if borderline due to doubling in pregnancy
ALT; AST To evaluate for non alcoholic fatty liver disease and as baseline preeclampsia labs
Cr; Urine albumin or protein

If abnormal, obtain 24 hr urine for protein and estimated CrCl

Repeat Prot/Cr ratio or 24 hr urine every 1-3 months if significant proteinuria

Ferritin, B12 Obtain for anemia or abnormal MCV, especially B12 if Type 1
Baseline preeclampsia labs Consider Uric Acid; Obtain CBC with platelet count in addition to AST, ALT, BUN, Cr, 24 hr urine for protein, Cr 
EKG For women ≥35 or CV risk factors; Consider further evaluation if indicated
Dilated Retinal Exam Every 1-6 months according to risk of progression

 

 

Fetal Surveillance

In addition to fetal ultrasound, antepartum fetal monitoring including fetal movement records, the nonstress test, and the biophysical profile are usually recommended for women with pregestational diabetes with initiation of testing typically at 32-34 weeks.  However, due to the increased risk of uteroplacental insufficiency and an intrauterine fetal demise in patients with longstanding Type 1 diabetes, especially in those women with microvascular disease, diabetic nephropathy, hypertension, or evidence of poor intrauterine growth, fetal surveillance may be recommended earlier [158][159]. Serial ultrasounds are used to monitor growth and if the estimated fetal weight is less than the 10th percentile (small for gestational age or SGA), umbilical artery dopplers may be useful to estimate the degree of uteroplacental insufficiency and predict poor obstetric outcome [160].

 

Labor and Delivery

Delivery management and the timing of delivery is made according to maternal well being, the degree of glycemic control, the presence of diabetic complications, growth of the fetus, evidence of uteroplacental insufficiency, and the results of fetal surveillance. Stillbirth can occur near term, especially in women with poorly controlled diabetes and complications, so the optimal timing of delivery requires a balance of the risk of intrauterine fetal death with the risks of preterm birth [161].  An amniocentesis may be useful to determine fetal lung maturity if delivery before 38-39 weeks is being considered [162]. A cesarean delivery (C-section) may be recommended for obstetric indications such as severe preeclampsia with an unfavorable cervix, estimated fetal weight >4500 grams, history of a C-section, or fetal distress. If there are no obstetric indications for a cesarean delivery, a vaginal delivery is optimal in the woman with Type 1 DM due to the higher risk of infectious complications, thromboembolism, and delayed recovery with cesarean delivery.

 

At labor and delivery, most women with preexisting diabetes should be managed with an insulin drip and a dextrose infusion to maintain the glucose in the desired range (70-110 mg/dl) which decreases the incidence of neonatal hypoglycemia  [163][164].  Once the woman is eating, the drip can be discontinued and subcutaneous insulin started.  However, insulin requirements postpartum drop dramatically and most women need only ~1/3 to 1/2 of their previous insulin dosages and some women require no insulin for the first 24-48 hours [165][166].  A glucose goal of 100-180 mg/dl seems prudent to avoid hypoglycemia given the high demands in caring fr an infant and especially in nursing women who may have a further decline in insulin requirements [167].   

 

Postpartum Concerns

A number of critical issues including maintenance of glycemic control, diet, exercise, weight loss, blood pressure management, breastfeeding, contraception and postpartum thyroiditis need to be addressed in the postpartum period. It has been demonstrated that the majority of women with pre-existing diabetes, even those who have been extremely compliant and who have had optimal glycemic control during pregnancy, have a dramatic worsening of their glucose control after the birth of their infant [168]. Furthermore, many quit seeking medical care for their diabetes. The postpartum period is relatively neglected, therefore, as both the new mother and her physician relax their vigilance. However, this period offers a unique opportunity to institute health habits that could have highly beneficial effects on the quality of life of both the mother and her infant.

 

Home glucose monitoring should be continued vigilantly in the postpartum period because insulin requirements drop almost immediately and often dramatically at this time, increasing the risk of hypoglycemia [169]. Women with Type 1 DM often need to decrease their insulin by ~50%, immediately after delivery and may have a "honeymoon" period for several days in which their insulin requirements are minimal [170]. Also, women who are candidates for an ACE-inhibitor can be started on one of these agents at this time as they have not been shown to appear in breast milk. [171]. Women with Type 1 diabetes have been reported to have a 25%% incidence of postpartum thyroiditis [172][173]. Hyperthyroidism can occur in the 2-4 month postpartum period and hypothyroidism may present in the 4-8 month period. Given the significance of this disorder, a TSH measurement should be offered at 3 and 6 months postpartum and before this time if a patient has symptoms [174].  Statins should not be started if the woman is nursing due to inadequate studies in nursing mothers. 

 

Breastfeeding

Women with Type 2 DM may be able to discontinue insulin and use diet/exercise and oral agents in the postpartum period.  Breastfeeding is recommended by the American College of Pediatricians in women with preexisting diabetes [175] and it facilitates weight loss. Breastfeeding is encouraged in women with Type 1 DM and some data suggest it might decrease the risk of Type 1 DM in the offspring. [176] There is a study with opposing findings primarily done in women with Type 1 diabetes that the breast milk of these women might increase the risk of becoming overweight at age 2 compared to nondiabetic banked donor breast milk [177].  However, the study was only conducted during the first week of life and is the only study to suggest a unfavorable effect. For mothers with Type 1 DM who are lean, it is recommended that an additional 400-500 calories be ingested to prevent excess weight loss but this weight loss is likely beneficial in the women with Type 2 DM who are overweight.  Insulin requirements are likely to diminish with nursing, especially in women with Type 1 diabetes and the mother must be vigilant of possible hypoglycemia.   For women with Type 2 DM, there has been a reluctance to reintroduce oral agents during the breast feeding period due to early reports fo high breast milk concentrations of first-generation sulfonylureas and lack of saftery data.  However, a study with a small sample size suggest that glyburide and glipizide do not appreciably cross into breast mild and may be safe [178].  Very low Metformiin levels were detected in breast milk in 3 studies with very low or undetectable serum leves in the infant [179].   If these agents are used, the lowest possible dose should be prescribed, the pediatrician should be aware of this decision, and the medications should be taken immediately after nursing to avoid a peak effect.   There are no adequate data on the use of thiazolidinediones or meglitinides in nursing mothers.

 

Contraception

It should be documented at every visit that women are using or have been offered an effective birth control method. The vast majority of contraceptive methods are relatively safe in women with diabetes who do not have poorly controlled hypertension or hypertriglyceridemia and who are not at increased risk for thromboembolic disease [180][181]. Triglycerides should be measured after the initiation of oral contraceptives in all women with diabetes or a history of GDM because of the significant incidence of hypertriglyceridemia and the associated risk of pancreatitis with oral estrogen use in these women [182]. Low dose combined oral contraceptives and the Nuva Ring have been shown to be effective and to have minimal metabolic effects in women with diabetes [183][184], however their use in women with known micro- or macrovascular disease is more controversial. Progestational agents such as Implenon are also alternatives. Depo-Provera has been associated with weight gain in GDM women [185].  There is no increase in pelvic inflammatory disease with the use of intrauterine devices in women with well controlled Type 1 or Type 2 diabetes after the post-insertion period [186][187]. Therefore, this may be an attractive choice in older women who do not desire future pregnancies.  Nearly any contraceptive method is superior to an unwanted pregnancy given the maternal risks to the mother with preexisting diabetes [188].

 

 

PREGNANCY COMPLICATIONS

 

Diabetic Ketoacidosis in Pregnancy

Pregnancy predisposes the mother to accelerated starvation with enhanced lipolysis, which can result in ketonuria after an overnight fast [189][190]. DKA may therefore occur at lower glucose levels, often referred to as "euglycemic DKA" of pregnancy, and may develop more rapidly than it does in non-pregnant individuals [191][192][193][194]. Women also have a lower buffering capacity due to the progesterone-induced respiratory alkalosis resulting in a compensatory metabolic acidosis. Furthermore, euglycemic DKA is not uncommon in pregnancy due to earlier ketosis in pregnant women [195] and glomerular hyperfiltration in pregnancy which causes glucosuria at lower serum glucoses. Any pregnant woman with Type 1 diabetes unable to keep down food or fluids should check urine ketones at home and if positive, a chemistry panel should be ordered to rule out an anion gap even if the maternal glucose is < 200 mg/dl.

 

In a study of 20 consecutive cases of DKA, only 65% of fetuses were alive on admission to the hospital [196]. Once the patient was hospitalized and treated, the risk of fetal loss declined dramatically. Risk factors for fetal loss included DKA presenting later in pregnancy (mean gestational age 31 weeks versus 24 weeks); glucose > 800 mg/dl; BUN > 20 mg/dl; osmolality > 300 mmol/L; high insulin requirements; and longer duration until resolution of DKA. The fetal heart rate must be monitored continuously until the acidosis has resolved. There was no maternal mortality in this small series. Causes of DKA in pregnancy are often different with infection less common as a precipitant [197]. Of the infectious causes, pyelonephritis was the most common. However, there is often no precipitant other than emesis in the pregnant woman who can develop starvation ketosis very quickly. In a series of 37 pregnant women with DKA, emesis alone accounted for 42% of the cases (60% of these women had gastroparesis), and 17% were non-compliant. Beta agonist therapy, pump failure, infection, undiagnosed pregnancy, and new onset diabetes each accounted for 8% of the cases [198]. Prolonged fasting is a common precipitant for DKA and it has been shown that even women with GDM can become severely ketotic if they are given B-mimetic tocolytic medications or  betamethasone (to accelerate fetal lung maturity) in the face of prolonged fasting [199]. It is imperative to remember that the pregnant woman unable to take glucose orally requires an additional 100-150 grams of intravenous glucose to meet the metabolic demands of the pregnancy [200]. Without adequate carbohydrate (often a D10 glucose solution is needed), fat will be burned for fuel and the patient in DKA will remain ketotic [201].

 

Diabetic Nephropathy and Hypertensive Disorders in Pregnancy

In normal pregnancy, urinary albumin excretion incrases up to 30 mg/day and total protein excretion increases up to 300 mg/day.   Women with pre-existing proteinuria often have a significant progressive increase in protein excretion, frequently into the nephrotic range, in part due to the 30-50% increase in glomerular filtration rate (GFR) that occurs during pregnancy [202].  A 24 hr urine for protein and CrCl is recommended, since estimated GFR by the Modification of Diet in Renal Disease (MDRD) study equation is not accurate in gestation [203].  Dipstick methods or random urine protein/creatinine ratios are not accurate methods to carefully quantifyproteinuria in pregnancy [204].  In most cases the proteinuria returns to the pre-pregnancy baseline after delivery. In some patients, however, the proteinuria can become massive and result in significant edema, hypoalbuminemia, and a hypercoagulable state. Factors which could accelerate nephropathy in pregnancy include the hyperfiltration of pregnancy, increase in protein intake, hypertension, and withdrawal of ACE Inhibitors or ARBs.  [205]  Fortunately, in an observational study of 26 women with Type 1 DM with preserved renal function, the decline in creatinine clearance over time appeared to be no different in women who became pregnant versus those who did not [206].

 

While women with mild renal insufficiency are not at an appreciable risk for irreversible progression of their nephropathy [207][208][209], those with more severe renal insufficiency (creatinine >1.5 mg/dl) have a 30-50% risk of a permanent pregnancy-related decline in GFR [210]. In a series of 36 women with Type 1 DM and nephropathy, maternal and obstetric outcomes were strongly dependent on the degree of maternal renal function [211]. In women with a creatinine clearance of >80 cc/min, the prematurity rate was 19% and the mean birth weight was 2670 grams in comparison to women with a creatinine clearance of 30-80 cc/min in whom 60% of the infants were premature and the mean birth weight was only 1640 gms. Overall, ~50% of the patients developed nephrotic range proteinuria, 97% of the patients required antihypertensive treatment, and 20% of the children had psychomotor retardation. Approximately 30% of mothers developed end stage renal disease and required dialysis at follow-up in 10 years and 4 women had died.

 

Long term outcome of infants born to mothers with nephropathy was studied in a 3 year follow-up of infants of ten diabetic mothers with stage IV diabetic nephropathy compared to 30 diabetic women without nephropathy [212]. The mean birthweight was 1000 grams less in those women with nephropathy, births were premature in 60% of the women with nephropathy but in none without nephropathy, and 30% of the infants born to mother with nephropathy showed respiratory distress syndrome compare to 6% without nephropathy. Nephrotic range proteinuria developed in 70% of women with nephropathy in contrast to none without nephropathy. Three years postpartum, 60% of the children of nephropathic mothers had a body weight <50th percentile in comparison to none of the children of the women without nephropathy. In addition, the children of mothers with nephropathy started to speak significantly later (15 months versus 12 months) and had infectious disease more commonly (60% versus 6%).

 

Women with diabetic nephropathy are also at extremely high risk of developing preeclampsia which often leads to prematurity and intrauterine growth restriction. Even women with microalbuminuria are at a higher risk of preeclampsia than women without microalbuminuria. In a study of 240 women categorized according to their urinary albumin excretion (normal, <30 mg/24hr; microalbuninuria, 30-300 mg/24 hr; and diabetic nephropathy, >300 mg/24 hr), the incidence of preterm delivery, small for gestational age, and preeclampsia, were highly significantly different [213]. Of all deliveries in women with normal urinary albumin excretion, microalbuminuria, and diabetic nephropathy, 35, 62, and 91% were preterm, 2, 4, and 45% were small for gestational age, and preeclampsia developed in 6, 42, and 64% of the women, respectively. Blood pressure control is imperative to try to minimize the deterioration of renal function. The goal for blood pressure control is not as low in pregnancy (<130/80) as outside of pregnancy due to the concerns about decreasing uteroplacental blood flow in the face of high vascular resistance in women at high risk of preeclampsia [214][215]however suboptimal hypertensive control has been associated with preterm delivery [216][217].

 

Hypertension should be treated in the pregnant woman with pre-existing diabetes at a BP level of ~130-140/80-90, especially if the patient has underlying diabetic nephropathy[218]. Although women with a blood pressure of >130/80 appear to do worse than women with a pressure < 130/80 in regards to preterm delivery, women with a higher BP tended to have worse renal function and greater proteinuria [219].  Although outside of pregnancy achieving a BP < 130/80 is renoprotective, there are no prospective trials that have demonstrated that achieving this goal improves pregnancy outcome and there is a potential risk that lowering maternal blood pressure too aggressively could decrease placental perfusion, especially if the placental blood flow is already compromised.  After 24 weeks any further elevation of BP requires an evaluation of superimposed preeclampsia given the risk is so high in women with pre-exisiting diabetes. Treating mother's blood pressure has not been shown to prevent preeclampsia given it is characterized by an abnormality in placentation early in pregnancy. Agents such as Methydopa, Hydralazine, Calcium channel blockers, Clonidine, or Labetalol can all be used. Clearly there is most clinical experience using Methyldopa, Hydralazine, Nifedipine, or Labetalol in pregnancy but there may be as yet an unproven benefit to using Diltiazem to prevent further increases in proteinura. Ace-Inhibitors and Angiotensis Receptor blockers are contraindicated in all trimesters of pregnancy due to the increased incidence of major malformations early and the later risks of fetal anuria, oligohydramnios, and pulmonary hypoplasia[220].

 

Women with severe renal insufficiency should be counseled that their chances for a favorable obstetric outcome may be higher with a successful renal transplant. Women with good function of their renal allografts who have only mild hypertension, do not require high doses of immunosuppressive agents, and are 1-2 years out from their renal translplant have a much better prognosis than women with severe renal insufficiency. Successful pregnancy outcomes have been reported in 89% of these patients [221].

 

Diabetic Retinopathy in Pregnancy

Progression of retinopathy during pregnancy is well documented[222]. This phenomenon is most prevalent in women with high-risk diabetic eye disease such as severe preproliferative or proliferative retinopathy. Recent data suggest that rapid institution of tight control may be associated with subsequent progression of retinopathy. However it is unclear whether the tight control often achieved during pregnancy or the changes of pregnancy per se, including increased cardiac output by 20-40%, the production of placental angiogenic factors, anemia, the hypercoagulable state of pregnancy or pregnancy-induced hypertension account for this deterioration [223]. In the Diabetes Control and Compliations trial, the effect of pregnancy was studied in women randomized to the intensive group before pregnancy versus those assigned to the conventional treatment who were then intensively controlled as soon as pregnancy was documented [224]. Compared to the non-pregnant group, pregnant women had a 1.6 fold risk of worsening retinopathy from before to during pregnancy in the intensive group compared to 2.5 fold greater in the control group. However, by the end of the DCCT, the degree of retinopathy and albuminuria in subjects who became pregnant were not different than those women who did not.

 

In 179 prenancies in women with Type 1 diabetes who were followed prospectively, progression of retinopathy occurred in 5% of women. Risk factors for progression were duration of diabetes >10 years (10% versus 0%), moderate to severe background retinopathy (30% vesus 3.7%), and a trend for those women who had the greates fall in hemoglobin A1C [225]. Fortunately, retinal changes appear to regress in the postpartum period in many patients [226]. Given this uncertainty, it is best to intensify glycemic control and to stabilize retinopathy before conception [227].  Laser photocoagulation is indicated to reduce vision loss in pregnant patients with high risk proliferative retinopathy, clinically significant macular edema, and is  some cases of ssever non-proliferative retinopathy [228].  Women with low-risk eye disease should be followed by an ophthalmologist during pregnancy, but significant vision-threatening progression of retinopathy is rare in these individuals[229].  In women with severe untreated proliferative retinopathy, vaginal delivery with the Valsalva maneuver has been associatd with retinal and vitreous hemorrhage.  As assisted second-stage delivery or desearean delivery should be considered [230].

 

Coronary Artery Disease in Pregnancy

Pregnancy causes ~25% increase in cardiac output, a significant decrease in system vascular resistance which can shunt blood away from the coronary arteries, and an increase in oxygen consumption, all of which contribute to a decrease in the ability of maternal coronary blood flow to meet the demands of the myocardium. At labor and delivery there is a 60-80% increase in cardiac output caused by the release of venocaval obstruction, autotransfusion of uteroplacental blood, and rapid mobilization of extravascular fluid resulting in a marked increase in venous return and stroke volume [231]. This in combination with acute blood loss and an activation of catecholamines at labor and delivery can result in acute mycardial ischemia and decompensation in a woman who has preexisting coronary artery disease. The mortality rate of a myocardial infarction in pregnancy prior to 1980 was ~60-70% versus very few in reported cases since that time [232], thought secondary to improved care or counseling in diabetic women with coronary artery disease. However, maternal morbidity is extremely high. Women with any complaints suggestive of ischemic heart disease should be fully evaluated in pregnancy. Cardioautonomic neuropathy is also a risk factor.  The increasing rise in Type 2 DM is further increasing the prevalence of CVD in pregnant women with biomarkers of insulin resistance and chronic inflammationCarefully monitored treadmill testing or stress echocardiography are not contraindicated nor is a revascularization procedure if indicated[233].  It is recommended that women with preexisting coronary artery disease not become pregnant in spite of good left ventricular function, even though the risk of mortality is less if the myocardial infarction occurred before pregnancy than during pregnancy. Women with longstanding diabetes and especially those with other risk factors for coronary artery disease (hyperlipidemia or hypertension) should be evaluated for asymptomatic coronary artery disease before becoming pregnant [234][235]. HMG Co-A reductase inhibitors are contraindicated in pregnancy, but if necessary, triglyceride lowering agents such as Gemfibrozil or Niacin can be used [236]. There is inadequate data on the use of Ezetimibe in pregnancy.

 

 

Type 1 versus Type 2 Diabetes and the Effect of Obesity

The epidemic of Type 2 diabetes has resulted Type 2 DM being more common than Type 1 DM in pregnancy.   Women with Type 2 DM are at least as high of a risk of pregnancy complications as women with Type 1 DM, especially if they have hypertension, obesity, or in poor glycemic control.  Many series suggest these women have an even higher risk for a poor pregnancy outcome, including a higher perinatal mortality rate [237][238][239].  The reasons for this may include older age, a higher incidence of obesity, a lower rate of preconception counseling, disadvantaged socioeconomic backgrounds, and the co-existence of the metabolic syndrome including hyperlipidemia, hypertension, and chronic inflammation. ([240].    Furthermore, the causes of pregnancy loss appear to differ in women with Type 1 versus Type 2 DM.  In one series comparing outcomes, >75% of pregnancy losses in women with Type 1 DM were due to major congenital anomalies or prematurity [241].  In women with Type 2 DM, >75% were attributable to stillbirth or chorioamniotis, suggesting that obesity plays a major role.      

 

Obesity alone carries significant risks to both the mother and the infant and has been identified by ACOG as the leading health concern in pregnant women [242][243][244]. Independent of preexisting diabetes or GDM, obesity increases the maternal risks of hypertensive disorders, non alcoholic fatty liver disease, gall bladder disease, aspiration pneumonia, thromboembolism, sleep apnea, cardiomyopathy, and pulmonary edema [245][246][247][248].  In addition it increases the risk of induction of labor, failed induction of labor, Cesarean delivery, multiple anesthesia complications, postoperative wound infections, postpartum hemorrhage, and lactation failure. Maternal obesity independently increases the risk of first trimester and recurrent pregnancy losses and congenital malformations including CNS, cardiac, and GI defects and cleft palate.  Furthermore it is associated with higher rates of shoulder dystocia and meconium aspiration and it quadriples the risk of perinatal mortality.  Because so many women with Type 2 DM are also obese, all of these complications increase the risk of poor pregnancy outcome in this population [249][250][251][252].

 

Overweight and obese women are at increased risk of deliverying a macrosomic infant by ~2 fold and given the prevalence of overweight and obese women is ~ 10 times that of gestational or preexisting diabetes, maternal body habitus is likely to have the strongest attributable risk on the prevalence of macrosomia [253].  More concerning, the prevalence of childhood obesity is ~2.5 times higher in offspring of obese women compared to women with normal BMIs [254].  There is abundant evidence linking macrosomia to increased overweight and obesity in adolescents as well as adults [255].   Maternal BMI is also the strongest predictor of excess neonatal adiposity which has been associated with childhood obesity and is probably a better predictor of the risk of childhood obesity than birth weight alone [256][257][258][259].  Many obese women are also insulin resistant which is associated with altered placental function and increased feto-placental availability of nutrients including glucose, FFAs, TGs, and amino acids [260].  Excess weight gain contributes further to this risk and the current IOM guidelines recommends that obese women do not gain more than  20 pounds.  Furthermore, it has been demonstrated that most pregnant women do not return to their pre-pregnancy weight and enter the subsequent pregnancy with even a higher BMI [261]. Some investigators would argue that weight gain during pregnancy in obese women does not correlate with birth weight and there are a number of studies that support that obese women have the most optimal pregnancy outcomes when they gain no weight [262][263][264].   

 

Morbidly obese women actually have improved pregnancy outcomes if they undergo bariatric surgery before becoming pregnant given such surgery decreases insulin resistance resulting in less diabetes, hypertension, and macrosomia compared to those who have not had the surgery [265][266][267].  However, pregnancy should not be considered until 12-18 months after surgery and after the rapid weight gain phase has been completed.  Close attention to nutritional deficiencies must be maintained, especially with fat soluble vitamins D and K as well as folate, iron, thiamine, and B12.  Women who have undergone malaborption procedures such as the Roux-en-Y may be at increased risk for internal hernia formation and any abdominal pain and vomiting must be investigated promptly. [268][269]    

Given the strong associations between maternal diabetes and obesity and the risk of childhood obesity and glucose intolerance, the metabolic milieu of the intrauterine environment is now considered to be a critical risk factor for the genesis of adult diabetes and cardiovascular disease [270][271][272][273].  The evidence of this fetal programming effect and its contribution to the development origins or human disease (DoHAD) is one of the most compelling reasons why optimizing maternal glycemic control, identifying other nutrients contributing to excess fetal fat accretion, weight loss efforts before pregnancy and avoidance of excessive weight gain are so critical and carry long term health implications to both the mother and her offspring.

 

 

 

GESTATIONAL DIABETES

 

Diagnosis of Gestational Diabetes

Gestational diabetes mellitus (GDM) is defined as glucose intolerance of variable severity with onset or first recognition during pregnancy [274][275]. However, this definition is extremely problematic because it does not exclude women with glucose intolerance or frank diabetes predating the pregnancy who are not identified until pregnancy.  Given women with undiagnosed diabetes predating the pregnancy who exhibit hyperglycemia in the first trimester have an increased risk for having an infant with a major malformation, there is ongoing discussion about redefining the definition of GDM to exclude women with a random glucose of ≥200 mg/dl or HgbA1C of ≥6.5% before 20 weeks gestation and consider these women as having preexisting diabetes [276].  The prevalence  of GDM is rapidly rising and ranges from 3-14%% of pregnancies throughout the world and is highest in ethnic groups that have a higher incidence of Type 2 diabetes (Hispanic Americans, African Americans, Native Americans, and Pacific Islanders; [277]).

 

Pathophysiology of Gestational Diabetes

GDM is caused by abnormalities in at least 3 aspects of fuel metabolism: insulin resistance, impaired insulin secretion, and increased hepatic glucose production [278]. The beta cell defects reflect the spectrum of B-cell defects that  leads to diabetes in nonpregnant individuals [279].  Although women with GDM increase their insulin secretion during pregnancy as glucose tolerant women do, their B-cell compensation is inadequate for the level of insulin resistance in order to maintain euglycemia. The insulin resistance of normal pregnancy is thought to be due primarily to the effects of increased production of human placental lactogen and placental growth hormone, both which peak in the third trimester when insulin resistance is greatest [280][281][282]. An increase in circulating TNF-a has has also been reported recently in human pregnancy [283], and may be an important additional contributing factor to insulin resistance. In GDM women, serum adiponectin levels were decreased and leptin, IL-6, and TNFα were increased [284].   Insulin resistance during pregnancy is usually compensated for by a considerable increase in insulin secretion. However, in 3-14% of women, insulin resistance is more profound and this challenge, combined with decreased pancreatic beta-cell reserve, triggers GDM [285][286].  Investigators have also shown more pronounced insulin resistance during pregnancy in GDM patients compared to women with normal glucose tolerance, that may contribute to hyperglycemia in addition to defects in insulin secretion [287][288].

 

Although diabetes usually remits after pregnancy, 30-50% of women diagnosed with GDM go on to develop type 2 diabetes mellitus (T2DM) later in life, particularly if obesity is present. GDM shares many of the characteristics of T2DM. Both are aggravated by increasing obesity and age, suggesting that the components of insulin resistance and decreased insulin secretion, which lead to GDM, may be common to Type 2 DM. Thus, GDM may represent an unmasking of the genetic predisposition of Type 2 DM induced by the hormonal changes of pregnancy [289][290].

Although insulin resistance is a universal finding in pregnancy and GDM, the cellular mechanisms for this type of insulin resistance are multi-factorial and just beginning to be understood. Insulin binding to its receptor is unchanged in pregnant and GDM subjects, and in skeletal muscle, GLUT4 is unchanged in pregnancy and GDM. Pregnancy reduces the capacity for insulin-stimulated glucose transport independent of obesity, due in part to a tissue-specific decrease in insulin receptor phosphorylation and decreased expression of Insulin Receptor Substrate-1 (IRS-1), a major docking protein in skeletal muscle. In addition to these mechanisms, in muscles from GDM subjects,IRS-1 is further decreased and there are reciprocoal and inverse changes in the degree of serine and tyrosine phosphorylation of IR and IRS-1 further inhibiting insulin signaling.  [291][292][293]. GDM subjects also tend to have higher circulating FFA and reduced PPARg expression in adipose tissue, a target for thiazolidinediones [294]. There is also evidence for a decrease in the number of glucose transporters (GLUT-4) in adipocytes in GDM subjects and an abnormal translocation of these transporters that results in reduced ability of insulin to recruit them to the cell surface, which contributes to the overall insulin resistance of GDM [295].

 

Risks to the Mother with Gestational Diabetes

The immediate risks to the mother with GDM are an increased incidence of cesarean delivery (~30%), preeclampsia (~20-30%), and polyhydramnios (~20%) which can result in preterm labor [296]. The long-term risks to the mother are related to recurrent GDM pregnancies and the substantial risk of developing Type 2 DM. Women with GDM represent a group of patients with an extremely high risk (~50%) of developing Type 2 diabetes in the subsequent 5-10 years. Women with fasting hyperglycemia, GDM diagnosed prior to 24 weeks (preexisting glucose intolerance), obesity, those belonging to an ethnic group with a high prevalence of Type 2 DM, or who demonstrate impaired glucose tolerance or fasting glucose at 6 weeks postpartum, have the highest risk  [297][298][299][300] of developing Type 2 GDM. Women with impaired glucose tolerance postpartum have up to an 80% risk of developing Type 2 DM within five years and should be targeted for primary prevention [301]. Counseling with regard to diet, weight loss, and exercise is essential and is likely to improve insulin sensitivity. Such dietary modifications should be adopted by the family since the infant is also at increased risk of developing impaired glucose tolerance [302][303]. Thiazolididiones, metformin, and lifestyle modifications have all been demonstrated to decrease the risk of developing Type 2 DM in GDM women who have impaired fasting glucose or glucose intolerance postpartum [304][305][306]

 

Risks to the Infant from Gestational Diabetes

Macrosomia is the major risk to the fetus in women with GDM, as is the case with Type 2 DM and also Type 1 DM in women without placental insufficiency. Many theories have been generated over the years to explain the macrosomia associated with diabetes in pregnancy [307][308][309][310][311]. Overall, the theory of excessive fetal insulin due to increased transport of maternal fuel to the conceptus holds the most credence and has the most supportive data (Freinkel hypothesis). Diabetes in pregnancy is associated with increased delivery of glucose and amino acids to the fetus via the maternal circulation (98). These fuels can stimulate increased production of fetal insulin which promotes somatic growth. Other maternal substrates (e.g., free fatty acids, triglycerides) add to the burgeoning supply of fetal substrate and further support excessive growth [312][313].   It is, therefore, the goal of management of pregnancies complicated by diabetes to normalize the above parameters with good metabolic control.   However, even infants born average for gestational age (AGA) from offspring of GDM women have increased neonatal fat as do offspring of obese women [314].  Maternal obesity appears to be an independent risk factor for LGA, macrosomia, and excess neonatal fat and it is clear that some mothers who appear to have optimal metabolic control still give birth to macrosomic infants [315][316]. It has recently been shown that women may have glucoses within target range yet there is excess shunting of glucose to the fetus as demonstrated by increased amniotic fluid insulin levels reflecting fetal hyperinsulinemia [317]. In some countries, amniotic fluid insulin levels are thought to be best predictor of macrosomia and decisions about treatment therapy in the mother are based on this evidence of fetal hyperinsulinemia [318]. Recently, the level of maternal triglycerides (TGs) have been strongly correlated with excess fetal growth and LGA [319], supporting that other maternal fuels such as TGs and FFAs play an important role in excess fetal fat accretion.  It has also been shown that  there is differential placental regulation of placental genes involved in lipid transport in GDM women [320].  The results suggest that fatty acids as preferential lipoggenic substrates for placental cells and suggest that genes for fetoplacental lipid metabolism are enhanced selectively in GDM women. Furthermore, the placenta has both a lipoprotein lipase and TG hydrolase capable of hydrolyzing maternal TGs for fuel as FFAs. 

 

Even with the advent of screening and aggressive management of GDM, the incidence of neonatal complications ranges from 12-28% [321][322]. Macrosomia places the mother at increased risk of requiring a cesearean section and the infant at risk for shoulder dystocia.  Shoulder dystocia can result in Erb's palsy, clavicular fractures, fetal distress, low APGAR scores, and even birth asphyxia when unrecognized [323]. Shoulder dystocia occurs nearly 50% of the time when a 4500 gram diabetic infant is delivered vaginally [324]. Preterm labor can result due to polyhydramnios from the fetus ultrafiltrating glucose through the kidneys. In mothers who have poor glycemic control, respiratory distress syndrome may occur in up to 31% of infants while cardiac septal hypertrophy may be seen in 35-40% [325][326]. With extremely poor glucose control, there is also an increased risk of fetal mortality due to fetal acidemia and hypoxia. Common metabolic abnormalities in the infant of a GDM mother include neonatal hypoglycemia, hypocalcemia, hyperbilirubinemia and polycythemia. Neonatal hypoglycemia is common in women in suboptimal glycemic control because the infant may continue to produce excessive insulin for up to 24 hours after birth before the normal feedback loop is operating.

 

The long-term sequelae of preexisiting Type 2 DM or GDM for offspring are being increasingly recognized. Reports of an increased risk of adolescent obesity and of Type 2 diabetes are compelling and it appears that fetal islet hyperplasia occurs in-utero with maternal hyperglycemia resulting in an increased risk of developing Type 2 diabetes in teenage years or as a young adult [327][328]. In Pima Indians, the incidence of childhood Type 2 DM at 10-14 years in the offspring of GDM mothers was 20 times higher compared to the offspring of non-diabetic mothers and 5-fold higher than that of pre-diabetic mothers who develop Type 2 DM after pregnancy [329]. Elevated amniotic fluid insulin levels (due to fetal hyperinsulinemia as a result of maternal hyperglycemia) predicted teenage obesity in one study, independent of fetal weight, and one-third of these offspring had impaired glucose tolerance by 17 years of age [330]. This scenario creates enormous potential on a public health level for the incidence of Type 2DM to escalate as these children with impaired glucose tolerance become mothers themselves, perpetuating the cycle [331][332][333][334].

 

 

Data to Support the Screening, Diagnosis, and Treatment of Gestational Diabetes

Although there used to be significant controversy in the utility of screening and treatment of GDM, due to the absence of high-quality randomized controlled trials [335][336], two major randomized controlled trials have been recently published demonstrating the benefit in identifying and treating GDM  [337][338] . The first was a landmark trial conducted in Austria and New Zealand referred to as the ACHOIS trial (Australian Carbohydrate Intolerance Study in Pregnant Women).  This RCT enrolled 1000 women to receive dietary advice, self blood glucose monitoring (SBGM), and insulin therapy as needed versus routine care and the results of the 2 hr 75 gram oral glucose tolerance test (OGTT) were blinded to practitioners and subjects.  Entry criteria included women whose FBG was less than 140 mg/dl (7.8 mmol/L) with a mean FBG of 86 mg/dl (4.8 mmol/L) and a 2 hour value between 140-199 mg/dl (7.8-11.0 mmol/L) corresponding to a mean of 155 mg/dl (8.6 mmol/L).  Primary outcomes included serious perinatal complications including death, shoulder dystocia, bone fracture, and nerve palsy.  The rate of serious perinatal complications was significantly lower among infants whose mothers were identified and treated compared to those mothers who were not treated (1% versus 4%), although 10% more infants in the treated group were admitted to the neonatal nursery.  Although the induction of labor rate was higher in the intervention group, the cesarean delivery rate was not different.  Furthermore, maternal quality-of-life evaluation at 3 months postpartum revealed lower rates of depression and higher improved health status cores in the intervention group [339].

 

A second landmark RCT, the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network study (JICHD MFMU Network), examined whether the treatment of mild GDM improves pregnancy outcome [340].  A total of 958 women who met criteria for mild GDM between 24-31 weeks were randomly assigned to usual prenatal care (control) or dietary interventions, SBGM, and insulin therapy if necessary (treatment group).  Women with fasting hyperglycemia (FBG ≥95 mg/dl) were excluded so that only women who had two elevated values on the 1 hour, 2 hour, or 3 hr 100 gm OGTT were included.  Furthermore, an additional 931 women with normal results on the 3 hr OGTT were included in the usual prenatal care group in order to mask the status of the control group.  The primary outcome was a composite of stillbirth or perinatal death and neonatal complications including hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma.  Although there was no significant difference in groups in the frequency of the composite outcome and no perinatal deaths in this population with very mild GDM, there were significant reductions with treatment in several pre-specified secondary outcomes including birth weight (3302 vs 3408 gm), neonatal fat mass by anthropometric measurements, the frequency of large-for-gestational-age (LGA) infants (7.1% vs 14.5%), macrosomia (5.9% versus 14.3%), shoulder dystocia (1.5% versus 4.0%),  and cesarean delivery (26.9% vs 33.8%).  Furthermore, treatment of mild GDM was also associated with reduced rates fo preeclampsia and gestational hypertension (8.6 versus 13.6% for combined rates).

 

There is also new compelling data that the risk of adverse maternal-fetal outcomes from maternal carbohydrate intolerance is along a graded continuum [341][342].  For the first time, there is evidence based outcomes regarding the level of maternal hyperglycemia at which adverse pregnancy outcomes clearly increase and the glucose thresholds at which they occur was found to be lower than the currently used diagnostic criteria for GDM in the United States (Carpenter and Coustan criteria for the 100 gram OGTT). The HAPO trial (Hyperglycemia and Adverse Pregnancy Outcomes), the largest ever conducted in pregnant women, enrolled 25,505 pregnant women at 15 centers in nine countries.  All underwent a 2 hr 75 gm OGTT at 24-32 weeks gestation and the data remained blinded if the FBG was  ≤105 mg/dl (5.8 mmol/l) and the 2 hour plasma glucose was ≤ 200 mg/dl (11.1 mmol/l).  Primary outcomes were LGA infants, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide >90th percentile (a biomarker of fetal hyperinsulinemia).  Secondary outcomes were delivery < 37 weeks, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia.  This trial demonstrated that a FBG ≥90 mg/dl, a 1 hr value ≥172 mg/dl, or a 2 hour value of ≥ 140 mg/dl increased the risk of an LGA infant by more than 2-fold and was also associated with ≥ 2-fold risk of an elevated cord-blood C-peptide consistent with fetal hyperinsulinemia and neonatal adiposity.  Furthermore, the FBG was more strongly predictive of these outcomes than the 1 hr or 2 hr value.  The results also indicated a strong and continuous association with these outcomes and maternal glucose levels below those diagnostic of GDM.  The results of this landmark trial will radically change the screening, diagnosis, and treatment of GDM using lower glucose thresholds and will likely adopt the 75 gm OGTT as the international for diagnosis instead of the 100 gm OGTT which is currently used in the United States.

 

 

Screening and Diagnosis of GDM

The criteria for diagnosis of GDM differs and most countries, except the United States, use the WHO one-step 75 gram OGTT (fasting ≥ 126 mg/dl/7.0 mmol/L or 2 hr ≥ 140 mg/dl/7.8 mmol/L; [343]) rather than a 2 step screen and diagnostic test.  However, in the United States , most obstetricians screen with the 50 gram glucose load and if the patient fails this screen, adopt the Carpenter and Coustan criteria using a 100 gm OGTT.   [344][345][346][347]. However, the glucose thresholds for the 100 gram OGTT were originally designed to predict the later development of Type 2 DM in the mother, not adverse pregnancy outcomes.  As a result, diagnostic criteria based on adverse pregnancy outcomes using the 75 gm OGTT utilized in the HAPO study are likely to be implemented in the near future.  In early 2010, based on the HAPO study and other recent trials, a concensus panel of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) published recommendations on the diagnosis and classification of hyperglycemia in pregnancy.  [348]These recommendations are shown below.

 

 

 

Currently,  screening recommendations using a 50 gram glucose challenge have been stratified according to low risk status, average risk status, and high risk status of GDM. Most obstetricians employ universal screening of all women at 24-28 weeks which is a reasonable approach, especially in a population that contains ethnic groups with a higher prevalence of GDM. However in populations with a lower incidence of GDM, selective screening has been shown to be effective [349][350].

 

SCREENING FOR GESTATIONAL DIABETES

Low Risk Status: Low risk status requires no glucose testing, but this category is limited to those women meeting all of the following criteria:

  • Age <25 years
  • Weight normal before pregnancy
  • Member of an ethnic group with a low prevalence of GDM
  • No known diabetes in first-degree relatives
  • No history of abnormal glucose tolerance
  • No history of poor obstetric outcome or macrosomic infant

High Risk Status: High risk status requires glucose testing as soon as pregnancy is diagnosed and again at 24-28 weeks if the early testing is normal. Women meeting any of these criteria should be tested early:

  • Obesity
  • Personal history of GDM or previous macrosomic infant
  • Glycosuria
  • Family history of diabetes in a first degree relative
  • Polycystic ovarian disease (PCOS)

 

 

Women with a fasting blood glucose >125 mg/dl or a random or postprandial glucose of > 200 mg/dl meet the criteria for GDM and this precludes the need for any glucose challenge. Currently in the United States, all other high risk status women should be given a 50 gm glucose challenge (Glucola test) or proceed directly to a 100 gm oral glucose tolerance test as soon as they establish prenatal care. If initial testing is normal, repeat testing should be done at 24-28 weeks gestation.

 

Average Risk Status: These are women who do not fall in the low risk or high risk status. They should receive a 50 gm glucose challenge at 24-28 weeks and if positive, undergo diagnostic testing with a 100 gm 3 hour oral glucose tolerance test (3 hr OGTT).

 

50 Gram Glucola: The 50 gram glucose challenge is the accepted screen for the presence of GDM but, if positive, must be followed by a diagnostic 100 gm 3 hour oral glucose tolerance test (3 hr OGTT). A positive screen is in the range of 130-140 mg/dl. The sensitivity and specificity of the test will depend on what threshold value is chosen and the cutoff may be selected according to the prevalence of GDM in the population being screened. The test does not have to be done fasting, but a serum sample must be drawn exactly one hour after administering the oral glucose.

 

CRITERIA FOR A POSITIVE 50 gm GLUCOLA CHALLENGE

Glucose > 140 mg/dl (7.8 mmol/l): Identifies ~80% of women with GDM at the cost of performing a 3 hr OGTT in ~15% of patients.

Glucose > 130 mg/dl (7.2 mmol/l): Identifies ~90% of women with GDM at the cost of performing a 3 hr OGTT in ~25% of patients.

 

The 100 gm 3 hour test must be done after 3 days of an unrestricted carbohydrate diet and while the patient is fasting. A positive test requires that 2 values be met or exceeded. One abnormal value should be followed with a repeated 3 hour test one month later because a single elevated value increases the risk of macrosomia and one-third of patients will ultimately meet the diagnostic criteria for GDM.

 

Criteria for a Positive 100 gm OGTT
  • Fasting glucose: 95 mg/dl
  • 1 hour glucose: 180 mg/dl
  • 2 hour glucose: 155 mg/dl
  • 3 hour glucose: 140 mg/dl

 

International Association of Diabetes and Pregnancy Study Groups Recommendations on the Diagnosis and Classification of Hyperglyemia in Pregnancy:  2010  

  Threshold Values for Diagnosis of GGM or Overt Diabetes In Pregnancy 

 

 

 

 

Stratagy for Detection and Diagnosis of Hyperglycemia Disorgers in Pregnancy

 

 

 

 

Treatment Strategies for Gestational Diabetes

 

Medical Nutrition Management:

Women with GDM should be taught home glucose monitoring to ensure that their glycemic goals are being met throughout the duration of pregnancy. The best therapy for GDM depends entirely on the severity of the glucose intolerance and on the mother's response in addition to the effect on fetal growth. In at least half of the cases, diet alone will maintain the fasting and postprandial blood glucose values within the target range. Since postprandial glucose levels have been strongly associated with the risk of macrosomia [351] modest carbohydrate restriction to ~45% of total calories may be helpful to blunt the postprandial glucose excursions, however a growing concern is that women are substituting fat for carbohydrates which has recently been associated with adverse fetal programming including oxidative stress as well as an insulin resistant phenotype [352][353].  A higher fat diet when given to non-human primates is capable of causing TG deposition in the liver of the offspring, histologically identical to non-alcoholic fatty liver disease [354]. Therefore, recommendations are to consume at least 175 gm of carbohydrate but substitute complex for simple carbohydrates, increase the amount of fiber and protein, and avoid of saturated fats , consistent with the recommendation discussed above in women with Type 2 DM [355]. The caloric intake and weight gain recommendations are also consistent with what is recommended in women with obesity or Type 2 DM as previously discussed.  For obese women (BMI >30, a 30% caloric restriction (an intake of ~1800 calories per day) has been shown to reduce hyperglycemia and plasma triglycerides with no increase in ketonuria [356]

 

Exercise

The role of exercise in GDM may be even more important than in women with preexisting diabetes given exercise in some women may lessen the need for medical therapy (see exercise section in Preexisting Diabetes) and the same considerations apply.   Moderate exercise is well tolerated and has been shown in several trials in GDM women to lower maternal glucose levels [357][358]. Potentially, exercise could prevent progression from management by diet alone to the need for oral agents or insulin in women with GDM [359][360]. Using exercise after a meal in the form of a brisk walk may blunt the postprandial glucose excursions sufficiently in some women that medical therapy might be avoided. Establishing a regular routine of modest exercise during pregnancy may also have long lasting benefits for the GDM patient who clearly has an appreciable risk of developing Type 2 diabetes in the future.

 

Medical Treatment Options

Metformin

The largest experience with Metformin has been in GDM women later in pregnancy [361][362].  In the randomized, controlled Metformin in Gestation (MIG) trial [363], 751 women with GDM were randomized to Metformin versus insulin.  Due to concerns about the possible risk of fetal lactic acidosis, women with fetal anomalies, gestational hypertension, preeclampsia, fetal growth restriction, and ruptured membranes were exclused.  Metformin did not appear to increase any adverse outcomes, although it was associated with a slight increase in preterm birth and 46% of the women in the Metformin group required supplemental insulin.  The offspring are being followed for evidence of any long-term effects.  Metformin is concentrated in the fetal compartment with umbilical artery and vein levels being up to twice those seen in the maternal serum [364][365]. Given this single RCT in GDM women using an agent that crosses the placenta, it is not yet approved for use in pregnancy until long term follow-up in the offspring is completed.  Both ACOG and the ADA consider that its use should be limited beyond the first trimester, especially in women with preexisting diabetes, until further trials and longer follow-up is available.  Its effect on fetal insulin sensitivity, hepatic glucoeneogenesis, and the long term fetal programming implications are unknown.      

 

Glyburide

Glyburide is the only sulfonylurea that has been studied in a large randomized trial in GDM women.  It was approved by the 5th International Workshop as a possible alternative to insulin in GDM women [366][367] due to a randomized controlled trial in 400 women and maternal glycemic control, macrosomia, neonatal hypoglycemia, and neonatal outcomes were not different between groups [368].  Although it was initially thought not to appreciably cross the placenta using HPLC ultraviolet detection or significantly effect fetal insulin levels, a recent publication using HPLC mass spectrometry reported that the umbilical cord levels of glyburide averaged 70% of maternal levels [369][370].    Glyburide exposure in this RCT was limited to after 24 weeks gestation so the effect on embryogenesis was not studied [371]. Its use in women with Type 2 diabetes has not been adequately studied, and given it has been shown to have a high failure rate in women diagnosed with GDM < 24 weeks [372] and in women with fasting hyperglycemia, it is expected to have a high failure rate in women with preexisting diabetes.  There are no sufficient data available on thiazolidinediones, metglitinide inhibitors, and incretins and such agents should only be used in the setting of approved clinical trials [373] and their teratogenicty is unknown. Acarbose was studied in two very small studies in GDM women given its minimal GI absorption but GI side effects are likely to be prohibitive [374]

 

Although Glyburide is not FDA approved for use in pregnancy, increasing experience in other centers have supported its use although the recent data documenting that it does cross the placenta more than originally reported [375] may affect future recommendations.  Women are highly likely to fail glyburide if they are diagnosed before 24 weeks or have fasting hyperglycemia [376].  Furthermore, due to its peak at 3-4 hours, many women have inadequate control of their 1 or 2 hour postprandial glucoses and then become hypoglycemic 3-4 hours later and recent data suggests that serum concentrations with usual doses are lower in pregnant women [377].   If used, it should be given 30 mins-1 hour before breakfast and dinner and should not be given before bedtime due to the risk of early a.m. hypoglycemia.  If unsuccessful in optimally controlling fasting and postprandial blood glucoses, women should be switched to insulin.

 

Institution of Medical Therapy, Fetal Surveillance, and Delivery Considerations

Women who have fasting blood glucose levels > 95 mg/dl, 1 hour postprandial glucose levels >140 mg/dl or 2 hour postprandial glucose levels > 120 mg/dl should be started on medical therapy. [378].  In 5  randomized trials it was demonstrated that if insulin therapy is started in women with GDM whose maternal glucoses are at target levels on diet alone but whose fetuses demonstrate excessive growth by an increased abdominal circumference (AC), the rate of fetal macrosomia can be decreased [379][380][381]. This fetal based strategy using ultrasound at 29-33 weeks to measure the AC in order dictate the aggressiveness of maternal glycemic control has been recommended by the Fifth International Workshop-Conference on Gestational Diabetes [382].  Gestational diabetes can often be treated with twice daily injections of NPH and Regular insulin but occasionally postprandial glycemic excursions are so excessive that three times daily mealtime injections of Lispro or Aspart  are necessary. Alternative treatment with glyburide, especially if women do not have severe fasting or postprandial hyperglycemia may be an option and starting doses of 2.5 q.d. to b.i.d. were used in the study and titrated up to a maximal dose of 10 mg b.i.d.   A RCT compared the efficacy of metformin with glyburide for glycemic control in gestational diabetes.  In the patients who achieved adequate glycemic control, the mean fasting and 2-hour postprandial blood glucose levels were not statistically different between the two groups. However, 26 patients in the metformin group (34.7%) and 12 patients in the glyburide group (16.2%) did not achieve adequate glycemic control and required insulin therapy (P=.01). Thus in this study, the failure rate of metformin was 2.1 times higher than the failure rate of glyburide when used in the management of gestational diabetes. [383]  These findings are consistant with the general finding that approximately, 15% of patients will fail maximum dose Glyburide therapy and need to be switched to insulin, especially if dietary restriction is not carefully followed [384]. For women who have postprandial glucoses well controlled by Glyburide but have inadequate control of their fasting glucoses, adding NPH before bedtime to the Glyburide can sometimes be useful.  Severe hypoglycemia tends to be an infrequent occurrence in GDM patients because of their underlying insulin resistance.

 

Women with GDM who require insulin, glyburide, or metformin or those who are not taking medical therapy but who have suboptimal glycemic control should undergo fetal surveillance at ~32 weeks gestation and an earlier delivery should be considered after fetal lung maturity is confirmed by amniocentesis [385]. An ultrasound for growth to look for head to body disproportion (large AC compared to the biparietal diameter (BPD) and evidence of LGA should be obtained at ~28-32 weeks [386], especially if it would influence treatment. An estimated fetal weight of > 4500 grams carries such a high risk of shoulder dystocia that an elective cesearan delivery is usually recommended for all diabetic women [387][388][389]. Women with good dating criteria, a favorable cervix, and an estimated fetal weight <4000 grams are often electively induced at 39 weeks in an attempt to decrease macrosomic births [390].

 

 

Postpartum Issues in Women with GDM

Women with a history of GDM should have their glycemic status reassessed at 6 weeks postpartum. A weight loss program consisting of diet and exercise should be instituted for women with GDM in order to improve their insulin sensitivity and hopefully to prevent the development of Type 2 diabetes [391][392][393]. Hyperglycemia generally resolves in the majority of patients during this interval but up to 10% of patients will fulfill criteria for Type 2 DM [394][395][396][397]. At the minimum, a fasting blood glucose should be done to determine if the woman has persistent diabetes (glucose >125 mg/dl) or impaired fasting glucose tolerance (glucose of at least 100 mg/dl). A 75 gm 2 hour glucose tolerance test is recommended by the ADA and Fifth International Workshop since most women with impaired glucose intolerance will be missed if only a FBG is checked [398][399]and unfortunately, this is seldom accomplished A 2 hour value of at least 200 mg/dl establishes a diagnosis of diabetes and a 2 hour value of at least 140mg/dl but less than 200 mg/dl makes the diagnosis of impaired glucose tolerance. Utilty of using the HgA1C postpartum to predict the subsequent occurrence of Type 2 DM in women with a history of GDM remains to be studied.  The importance of diagnosing impaired glucose intolerance lies in its value in predicting the future development of Type 2 diabetes. In one series, a diagnosis of impaired glucose tolerance was the most potent predictor of the development of Type 2 diabetes in women with a history of GDM; 80% of such women developed diabetes in the subsequent 5-7 years [400]. Intensified efforts promoting diet, exercise and weight loss should be instituted in these patients. 

 

The TRIPOD study demonstrated that the use of a thiozolidinedione postpartum in women with a history of GDM and persistent impaired glucose intolerance decreased the development of Type 2 diabetes. The rate of Type 2 DM in the 133 women randomized to Troglitazone was 5.4% versus 12.1% in the 133 women randomized to placebo at a median follow-up of 30 months [401]. The protection from diabetes was closely related to the degree of reduction of insulin secretion three months after randomization and persisted 8 months after the medication was stopped. In the PIPOD study, use of Pioglitazone to the the same high-risk patient grtoup stabilized previously falling B-cell function and revealed a close association between reduced insulin requirments and low risk of diabetes.  [402][403][404].   However, using thiazolidinediones for the purpose of preventing the development of Type 2 DM in women with a history of GDM has not been recommended.   Recently, the Diabetes Prevention Trial analyzed their data in women with a history of GDM [405].  A total of 349 subjects had a history of GDM, and such a history conferred a 74% hazard rate to the development of Type 2 DM compared to women without a history of GDM.  In the placebo arm, women developed Type 2 DM at an alarming rate of 17% per year but this rate was cut in half by either use of Metformin or diet and exercise [406].  The DPP, TRIPOD, and PIPOD  studies support clinical management that focuses on aggressive interventions to decrease insulin resistance to reduce the risk of Type 2 DM.

 

 

Breastfeeding

Women who breastfeed appear to have a lower incidence of developing Type 2 diabetes and it also appears to decrease the risk of developing infant obesity and impaired glucose tolerance [407]. Recent studies that included GDM women have also shown it to decrease the risk of childhood obesity [408][409].  Calcium intake should be at least ~1500 mg per day since exclusive breast-feeding for an extended period of time can cause a modest decrease in bone density [410].

 

 

Contraception

The same contraception choices recommended for preexisting diabetes apply for women with GDM with the possible exception of Depo-Provera injections.  In a retrospective cohort of 904 women with GDM, combined oral contraceptives did not influence the development of Type 2 diabetes [411].  However, Depo-Provera was shown in one trial to increase the subsequent risk of developing Type 2 DM in women with GDM, but this was largely due to the weight gain associated with it use  [412]. Effective contraception is critical given there is data that subsequent pregnancies in women with GDM appear to increase the risk of later development to Type 2 DM [413][414][415].

 

 

CONCLUSION

The obstetric outlook for pregnancy in women with pre-existing diabetes has potential to improve as rapid advances in diabetes management, fetal surveillance, and neonatal care emerge. However, the greatest challenge to face is the growing number of women developing GDM and Type 2 DM as the obesity epidemic increases and obesity-related complications exert a further deleterious effect.  The development of Type 2 DM in the mother of GDM women as well as obesity and glucose intolerance in the offspring of women with preexisting DM or GDM set the stage for a perpetuating cycle that must be aggressively addressed with effective primary prevention strategies that begin in-utero   Pregnancy is clearly a unique opportunity to implement strategies to improve the mother’s lifetime risk for CV disease in addition to that of her offspring and offers the potential to decrease the intergenerational risk of obesity and diabetes.

 

 

Footnotes

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