Highlighting the Differences between Preexisting Type 1 and Type 2 Diabetes in Pregnancy and Gestational Diabetes

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1 Highlighting the Differences between Preexisting Type 1 and Type 2 Diabetes in Pregnancy and Gestational Diabetes Elizabeth (Libby) Downs Quiroga, MS, RD, CDE Tandem Diabetes Care Clinical Specialist Grand Rapids MI Geetha Rao, MS, RD, CDE, CDTC, CPT, CLE Palo Alto Medical Foundation Freemont, CA Abstract Diabetes is the most common metabolic complication of pregnancy. Placental hormones, growth factors, and cytokines can cause increased insulin resistance. The different types of diabetes seen in pregnancy present challenges to clinicians; each type has different guidelines for treatment based on the pathogenesis. Medical nutrition therapy (MNT) and medication management are key components to achieving the goal of normoglycemia. Understanding the pathogenesis and classification of diabetes during pregnancy can help clinicians to provide appropriate care. Introduction Diabetes is the most common metabolic complication of pregnancy, and all forms of diabetes can occur in pregnant women. Diabetes in pregnancy is characterized by the time of diagnosis in relationship to pregnancy (preexisting versus gestational) and the etiology of beta cell dysfunction and hyperglycemia (e.g., immune for type 1 diabetes and nonimmune with insulin resistance for type 2 diabetes). Preexisting diabetes (types 1 and 2) complicates 0.1% to 0.3% of all pregnancies (1). Gestational diabetes (GDM) complicates 1% to 14% of all pregnancies. Characteristics of Preexisting Diabetes during Pregnancy Women who have preexisting diabetes may experience greater problems with blood glucose control in pregnancy, and diet and exercise changes alone might not successfully compensate for increased insulin needs. Preexisting diabetes is primarily treated with insulin during pregnancy. The progressive increase in insulin resistance caused by placental hormones, growth factors, and cytokines in pregnancy requires intensive MNT and frequent insulin dose adjustments to prevent worsening of complications from diabetes. Women with preexisting diabetes have a four- to fivefold increase in perinatal mortality and a four- to sixfold increase in stillbirth compared to the population without diabetes (2). Insulin needs vary throughout the pregnancy. From week 17 and on, insulin needs start to rise sequentially until 35 weeks at which point the needs level off or decline (3). However, women with type 1 diabetes might see significantly low glucose values during gestational weeks 9 through 16 unless they adjust their insulin doses (4). In contrast, women with type 2 diabetes may have improved glucose values during this phase of pregnancy. Women who live with type 1 diabetes may experience a 60% to 200% increase in insulin needs during the second and third trimesters (3). Those with type 2 diabetes may see insulin doses double by the middle of the second trimester and even triple or more by term (3). Hence, the net change in insulin resistance and increase in insulin requirement is less in those who have type 2 diabetes, but the final level of insulin resistance and insulin requirement may be the same or more than in those who have type 1 diabetes. The incidence of diabetes ketoacidosis (DKA) in pregnancy is 1% to 3% of patients with preexisting diabetes, and women with type 1 diabetes are more prone to DKA than those with gestational or type 2 diabetes (3). The fetal mortality rate during this condition is approximately 9% to 35%, and the risk of maternal death is estimated at 5% to 15% (3). DKA can occur in pregnancy at blood glucose levels of less than 200 mg/dl, and most cases of DKA develop in the second and third trimester when insulin needs are rising (3). Accordingly, insulin should not be withheld for more than a few hours in a patient with type 1 diabetes, even if she has normal blood glucose values, to prevent the onset of DKA (3). Glucose and ketones readily cross the placenta while maternal volume depletion and acidosis may cause fetal hypoxia (3). Hemoglobin A1c (HbA1c) testing for this population should be addressed 5

2 before conception. High blood glucose levels at conception and during organogenesis increases the risk of spontaneous abortion and major congenital malformations. Hyperglycemia reduces oxygen supply to the fetus and when combined with maternal acidosis, can lead to fetal demise. Table 1. Plasma Glucose Values Indicating Gestational Diabetes for the Two-step Strategy Oral Glucose Tolerance Test Time Carpenter/Coustan (9) National Diabetes Data Group (10) Fasting 95 mg/dl (5.3 mmol/l) 105 mg/dl (5.8 mmol/l) 1 hour 180 mg/dl (10.0 mmol/l) 190 mg/dl (10.6 mmol/l) 2 hours 155 mg/dl (8.6 mmol/l) 165 mg/dl (9.2 mmol/l) 3 hours 140 mg/dl (7.8 mmol/l) 145 mg/dl (8.0 mmol/l) 6 Gestational Diabetes GDM is defined as the onset of varying degrees of glucose intolerance during the second or third trimester that is not clearly overt diabetes (5). GDM results from an imbalance between tissue insulin requirements for glucose regulation and the ability of the pancreatic beta cells to meet these requirements. GDM is typically diagnosed late in pregnancy (between 24 and 28 weeks of gestation) and is generally not associated with the early gestational age birth defects that can be seen in babies of mothers with preexisting diabetes. GDM accounts for approximately 90% of all cases of diabetes in pregnancy and is associated with overweight/obesity, history of GDM in prior pregnancy, polycystic ovary syndrome, presence of glucosuria, family history of diabetes, and certain ethnic groups (e.g., Asians, African Americans, and Hispanics). It resolves in 90% of cases after delivery (6). Diagnosing Gestational Diabetes GDM can be diagnosed via one- or two-step approaches (5): 1. One-step 75-g oral glucose tolerance test (OGTT) 2. Two-step 50-g (nonfasting) screen followed by a 100-g OGTT for those who have positive screen results One-step Approach The American Diabetes Association (ADA) recommends that all pregnant women who are not known to have prior diabetes undergo a 75-g OGTT at 24 to 28 weeks of gestation, based on the recommendation of the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) (5,7). The IADPSG defined diagnostic cut points for GDM as the average glucose values (fasting, 1-hour, and 2-hours after glucose testing) in the Hyperglycemia and Adverse Outcomes Study (HAPO), at which odds for adverse outcomes was 1.75 times the odds of these outcomes at mean glucose levels of the study population (5). For the one-step strategy, the diagnosis of GDM is made when one glucose reading is equal to or greater than: Fasting glucose: 92 mg/dl (5.1 mmol/l) 1-hour glucose: 180 mg/dl (10.0 mmol/l) 2-hour glucose: 153 mg/dl (8.5 mmol/l) Two-step Approach In the two-step strategy, a nonfasting 50-g oral glucose challenge test is administered to women not previously diagnosed with overt diabetes. If the 1-hour plasma glucose measures 140 mg/dl (7.8 mmol/l) or greater, the woman undergoes a 100-g OGTT. The American College of Obstetricians and Gynecologists (ACOG) recommends a lower threshold of 135 mg/dl (7.5 mmol/l) in high-risk populations that have higher prevalences of GDM. According to ACOG, treatment of higher-threshold maternal hyperglycemia reduces the risks of neonatal macrosomia, largefor-gestational age births, and shoulder dystocia without increasing small-for-gestational age births (8). The patient must be fasting for the OGTT. GDM is diagnosed if at least two of the four plasma glucose level values (fasting, 1 hour, 2 hours, and 3 hours after OGTT) are met or exceeded. There are two sets of OGTT glucose diagnostic criteria currently in use for diagnosing GDM; one is by Carpenter and Coustan (this is the more sensitive criteria thus will include more diagnoses of GDM) and the other by the National Diabetes Data Group (NDDG) (Table 1). ACOG updated their guidelines in 2013 to support the two-step approach (11). The ADA suggests that a GDM diagnosis can be established with either of the two strategies. For a comparison, criteria to diagnose type 2 diabetes in the first trimester of pregnancy are: Fasting blood glucose: 126 mg/dl (7.0 mmol/l) HbA1c: 6.5% Random plasma glucose: 200 mg/dl (11.1 mmol/l) Monitoring Patient monitoring during pregnancy should include daily blood glucose testing, ketone evaluation, and HbA1c measurement. An overview of monitoring for treatment of diabetes in pregnancy is presented in Table 2.

3 Blood Glucose Monitoring Preprandial and postprandial monitoring of blood glucose is recommended to achieve metabolic control in pregnant women with diabetes (5). ACOG recommends the following targets for women with preexisting type 1 or type 2 diabetes (5): Fasting: 90 mg/dl One-hour postprandial: mg/dl Two-hour postprandial: 120 mg/dl Clinicians should note that these values represent optimal control if they can be achieved safely. However, women with type 1 diabetes may find that achieving these targets without hypoglycemia is a challenge, particularly women who have a history of severe hypoglycemia or hypoglycemia unawareness (5). If women cannot achieve these targets without significant hypoglycemia, the ADA recommends liberalized targets that are individualized (5). The following glucose targets are recommended by the Fifth International Workshop-Conference on Gestational Diabetes Mellitus (5): Fasting: 95 mg/dl and either One-hour postprandial: 140 mg/dl or Two-hour postprandial: 120 mg/dl Women with preexisting diabetes should measure their blood glucose eight to 12 times or more a day and document food and blood glucose daily (3). Experts recommend that those who are diagnosed with GDM periodically self-monitor or test their blood glucose (3). Ketones Ketones are usually present in normal pregnancies after a 14-hour fast. The goal for fasting urinary ketone levels is none or trace in those with diabetes during pregnancy. Urine ketone testing is not routinely recommended for those who have GDM unless they are experiencing persistent weight loss (12). Urine ketone testing is recommended for women who have poorly controlled or newly diagnosed type 1 diabetes. Urine ketone testing is also recommended when blood glucose persistently measures greater than 200 mg/dl in pregnancy complicated with type 1 diabetes (3). Commonly reported symptoms of DKA are gastrointestinal upset such as nausea, vomiting, poor oral intake, or flu like symptoms (3). If the registered dietitian nutritionist has any suspicion of the presence of DKA, the woman should be referred to her physician immediately. Hemoglobin A1C The ADA recommends maintaining HbA1c of less than 6% to 6.5% in the second and third trimesters to avoid large-for-gestational-age infants and women with preexisting diabetes. However, the recommendation states that a value of less than 6% may be optimal as the pregnancy progresses without hypoglycemia to avoid the risk of low-birth weight infants. If women cannot achieve these targets without significant hypoglycemia, the ADA suggests less stringent Table 2. Monitoring During Pregnancy Gestational Diabetes Type 2 Diabetes Type 1 Diabetes Frequency of daily (depending on if patient 7-8 BG testing is on medications) BG goals (mg/dl) Fasting: 95 Fasting: 90 Fasting: 90 1-hr PP: hr PP: hr PP: hr PP: hr PP: hr PP: 120 Hemoglobin A1c may be useful, it should 6%-6.5% recommended 6% to 6.5% recommended A1c target be used as a secondary if can be achieved without if can be achieved without measure, after BG monitoring significant hypoglycemia significant hypoglycemia Ketone testing Test only if persistent 1. With start of MNT for 1. Anytime BG is persistently weight loss or need to 1-2 weeks and if rapid >200 mg/dl, if moderate to identify if a woman is weight loss occurs large, contact health care consuming adequate 2. Anytime BG is persistently provider calories and/or >200 mg/dl, if moderate 2. Newly diagnosed carbohydrates to large, contact health 3. Every 4 hours if ill until care provider ketones cleared BG=blood glucose, MNT=medical nutrition therapy, PP=postprandial 7

4 8 targets based on clinical experience and individualization of care. Medical Nutrition Therapy with Diabetes and Pregnancy During any pregnancy, energy needs increase during the second and third trimesters. Nutrition needs for those who are overweight or obese are explored in other articles in this issue of On The Cutting Edge. However, moderate caloric restriction (30%- 33% energy needs) in obese women with GDM may improve glycemic control without ketonemia and reduced weight gain (13) and prevent macrosomia. The Institute of Medicine (IOM) recommends the following estimated energy requirement (EER) for those ages 19 years and older for preconception needs (3): Nonpregnant EER = 354 (6.91 x age in years) + Physical Activity (see below) x [(9.36 x weight in kilograms) + (726 x height in meters)] Physical Activity coefficient guide: Sedentary: 1.0; Low active: 1.12; Active: 1.27; Very Active: 1.45 The following IOM formulas are for pregnant women who are of normal weight: First trimester: EER = Nonpregnant EER + 0 kcal Second trimester: EER = Nonpregnant EER kcal Third trimester: EER = Nonpregnant EER kcal Multifetus pregnancy increases caloric needs by about 150 kcal/day over the needs of a singleton pregnancy (3). The Recommended Daily Allowance (RDA) for carbohydrates during pregnancy is a minimum of 175 g/day to provide 33 g/day for fetal brain development (3). However, contributions of carbohydrate to energy intake should be individualized (3). To address the sensitivity that many women experience with carbohydrates, a meal pattern of three meals plus two to four snacks daily may help with careful distribution of carbohydrates and individualization to preference and tolerance (3). Because the first meal of the day (breakfast) is when insulin resistance is greatest, improved postprandial glucose management may be achieved if carbohydrates are more limited at this meal (3). Helping the patient with preexisting diabetes, especially type 1 diabetes, understand the use of intensive carbohydrate counting and the insulin-to-carbohydrate ratio is essential (3). The RDA for protein requirements during pregnancy is 71 g/day, but the preconception protein RDA is 0.8 g/kg/day and requirements do not increase to 1.1 g/kg/day until the second half of pregnancy (3). Inclusion of protein at snacks can increase satiety (3). Also, inclusion of protein at the bedtime snack and waiting no longer than 10 hours between a bedtime snack and breakfast may prevent starvation ketosis (3). The goals of MNT for women with preexisting diabetes are to meet nutrition needs, achieve appropriate weight gain, and reduce maternal and fetal mortality and morbidity. MNT for women who have GDM is designed to meet nutrition needs of mother and fetus while maintaining normoglycemia and appropriate weight gain. For women with GDM, low-glycemic index foods provide potential benefits beyond simply reducing postprandial hyperglycemia (3). Foods that rapidly absorb into the blood stream (high glycemic index foods) should not be included in a GDM meal plan. Examples include: refined sugars, fruit juices, regular sodas and sports drinks, highly processed cereals, and instant potatoes and noodles. The use of glycemic index and glycemic load is controversial but when establishing an individualized meal plan for a woman with diabetes, a prudent approach may be to advise her to use her blood glucose results to determine the effect of various foods on her glucose levels and make modifications to her food choices as necessary (3). Of note, avoiding fruit and milk at breakfast may help improve glycemic control after that meal (3). Those with GDM and type 2 diabetes often have dyslipidemia and a high risk for cardiovascular disease (CVD) (3). In general, limiting total fat is a good recommendation for women at high risk for CVD. However, limiting total fat may not be best for patients with high triglyceride and/or low high-density lipoprotein values (3). Nutrition education should include the following, as appropriate: Rationale for the meal plan, including achieving glycemic control, optimal nutrient intake throughout pregnancy, and appropriate weight gain Spacing of meals and snacks to avoid hypoglycemia and hyperglycemia Use of blood glucose values and food records to problem-solve and/or identify blood glucose excursions related to food intake The need for medications and dose adjustments The role and timing of exercise to improve blood glucose levels

5 Different methods of carbohydrate counting and meal plan flexibility Use of non-nutritive sweeteners Use of herbs Reading of food labels Treatment and prevention of hypoglycemia Menu ideas and restaurant ordering skills Handling sick days, hyperemesis, and carbohydrate replacement if taking glyburide or insulin Long-term healthy eating habits to avoid type 2 diabetes or its complications if GDM Weight Gain The IOM currently has no specific weight gain recommendations for pregnant women with diabetes. Gestational weight recommendations are listed in Table 3. Some weight loss may follow initiation of MNT due to diuresis related to decreased carbohydrate intake (3). Such fluid loss is often seen in women with GDM (3). Weight begins to increase once the fluid shifts have subsided within 1 to 2 weeks of MNT initiation (3). If weight loss persists, clinicians may recommend that patients monitor their urinary ketones and adjust calorie/carbohydrate intake accordingly (3). Summary Different types of diabetes in pregnancy are associated with different issues. Managing preexisting diabetes and GDM can present significant challenges to both health care providers and patients. Understanding the pathogenesis of each type of diabetes greatly aids in providing appropriate care. Optimal care requires attention to nutrition, maternal glycemia, comorbid conditions, and patient selfmanagement skills. References 1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2011;34(suppl 1):S62 S Platt MJ, Stanisstreet M, Casson IF, et al, St. Vincent s Declaration: 10 years on: outcomes of diabetic pregnancies. Diabet Med. 2002;19(3): Shields L, Tsay GS (eds). California Diabetes and Pregnancy Program Sweet Success Guidelines for Care. Sacramento, CA: California Department of Public Health; Table Institute of Medicine Gestational Weight Gain Guidelines Mean Rate of Weight Gain in Prepregnancy Total Weight Second and Third Trimesters Body Mass Index Gain Range (lb) (range in lb/wk) Underweight <18.5 (1-1.3) Normal Weight (0.8-1) Overweight ( ) Obese ( ) Adapted with permission from Weight Gain During Pregnancy: Re-examining the Guidelines, 2009 by the National Academy of Sciences, courtesy of the National Academies Press, Washington, DC. Is it Pregestational or Preexisting Diabetes? The 2016 American Diabetes Association Standards of Care refer to women with preexisting type 1 or type 2 diabetes who are pregnant as having pregestational diabetes (5). The American College of Obstetricians and Gynecologists refer to women with preexisting diabetes during pregnancy (either as type 1 or type 2) as having preexisting diabetes (9). On The Cutting Edge authors prefer to use the term preexisting diabetes when referring to women with type 1 or type 2 diabetes who become pregnant. Maternal Child and Adolescent Health Division; Garcia-Patterson A, Gich I, Amini SB, Catalano PM, de Leiva A, Corcoy R. Insulin requirements throughout pregnancy in women with type 1 diabetes mellitus: three changes of direction. Diabetologia. 2010;53(3): American Diabetes Association. Standards of medical care in diabetes Diabetes Care. 2016;39(suppl 1). 6. Jovanovic I. Medical Management of Pregnancy Complicated by Diabetes. 3rd ed. Alexandria, VA: American Diabetes Association; 2000: , Metzger BE, Gabbe SG, Persson B, et al; International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International Association of Diabetes and Pregnany Study Group s recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):

6 10 8. Horvath K, Koch K, Jeitler K, et al. Effects of treatment in women with gestational diabetes mellitus: systematic review and metaanalysis. BMJ. 2010; 340:c Carpenter MW, Couston DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol. 1982;144(7): National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979;28(12): Committee on Practice Bulletins- Obstetrics. Practice Bulletin No. 137: Gestational diabetes mellitus. Obstet Gynecol. 2013;122(2 pt1): International Federation of Clinical Chemistry and The American Association for Clinical Chemistry Critical Care and Point of Care Testing Division. Critical Care Testing in the New Millennium: The Integration of Point of Care Testing. Presented at the 18th International Symposium, Helsingor, Denmark. June 1-4, American Diabetes Association. Nutrition recommendations and interventions for diabetes: A position statement of the American Diabetes Association. Diabetes Care. 2007;30(suppl 1): S48 S Rasmussen KM, Yaktine AL, Editors: Committee to Reexamine IOM Pregnancy Weight Guidelines Food and Nutrition Board, Board on Children, Youth and Families. National Academies Press Washington DC; Preconception and Internatal Nutrition Recommendations for Women with Diabetes Jamie Stang, PhD, MPH, RD Associate Professor University of Minnesota, School of Public Health Minneapolis, MN Abstract All women want to have healthy babies, but few women prepare adequately for pregnancy. Nutrition programs and services can have a positive impact on the health of women before and between pregnancies, reducing their risk for poor pregnancy outcomes. Preconception and internatal nutrition services for women with diabetes should focus on: identifying and treating comorbid conditions such as hypertension and obesity, achieving tight blood glucose control at least 1 to 3 months before conception, helping women attain and maintain a healthy body weight before and between pregnancies, encouraging consumption of 0.4 to 4 mg of folic acid supplementation daily for at least 2 to 3 months before conception, and fostering a dietary pattern that can reduce the risk of inflammation and infection. Introduction All women want to have healthy babies, but not all women prepare for pregnancy to ensure a positive outcome. Many factors contribute to the lack of preconception or internatal (the period of time following one pregnancy and preceding another that may also be referred to as interconception) planning. In the United States, 51%, or nearly 3.4 million pregnancies each year, are unintended (1), and data suggest that the rate of unintended pregnancy among women with diabetes may be considerably higher, with rates of up to 66% (2). Thus, little or no preconception planning occurs in one-half to two-thirds of pregnancies among women with diabetes. In addition, many women are unaware of the additional risks that chronic health conditions such as obesity, diabetes, and hypertension place upon mother and fetus during pregnancy. Lack of awareness of these risk factors before conception dramatically reduces the window of opportunity for ameliorating risk. Addressing Chronic Conditions Among Women of Reproductive Age One of the most vulnerable periods of fetal development is the first 14 to 56 days after conception. During this early developmental period, when many organs and appendages are formed, fetuses are susceptible to congenital anomalies such as neural tube defects (NTDs) (spina bifida and anencephaly); limb reduction; and heart, brain, ear, and eye defects. The increased risk can result from poor nutrition status, elevated blood glucose levels, or exposure to medications known to cause birth defects such as statins, angiotensinconverting enzyme inhibitors, diuretics, beta-blockers, and other antihypertensive medications (3, 4). Many women are not aware of their