Diabetes in Pregnancy: Detection, Intervention, Prevention Michael Shannon, MD Chair, Providence Endocrinology/Diabetes CAT Diabetes in Pregnancy: Outline Prevalence, Pathophysiology and Complications of diabetes in pregnancy Risk factors and screening of diabetes in pregnancy Treatment of diabetes in pregnancy: nutrition, insulin therapy, and newer technologies Prevention of postpartum diabetes & recurrence (if time allows) Diabetes in Pregnancy Approximately 200,000 pregnancies each year are complicated by diabetes (up to 9.2% of all pregnancies, CDC 2014) Includes: Type 1 (DM1) Type 2 (DM2) 13% DM at conception Gestational Diabetes Mellitus: any degree of glucose intolerance, with onset or first recognition during pregnancy (87% of cases) 1
Diabetes in Pregnancy: Pathophysiology The hypoglycemic potency of insulin is diminished [in pregnancy] as insulin resistance supervenes (N Freinkel Banting Lecture 1980) Possible candidates that increase across gestation hcg, E/P, human placental lactogen Growth hormone-like activity is seen in the placenta but unclear if contributor; other associations are seen with leptin, IGFBP-1, and triglycerides HD McIntyre et al, Diabetes Care 2018 Diabetes in Pregnancy: Pathophysiology Diabetes in Pregnancy: Complications There are two distinct groups of complications Congenital malformations These are related to 1 st trimester hyperglycemia Seen in pre-pregnancy diabetics only; not seen in GDM, diabetic fathers, or pre-diabetics Complications related to fetal macrosomia Mostly related to fat deposition after 24-28 weeks This 2 nd -3 rd trimester hyperglycemia causes birth injury and possibly increased adult BMI, DM risk 2
Infant Malformations Occur Before the Seventh Gestational Week Anomaly Ratio of incidence Gestational age after ovulation in weeks Caudal regression 252 3 Situs inversus 84 4 Spina bifida, hydrocephalus 2 4 Anencephalus 3 4 Renal anomalies 5 Agenesis 6 5 Cystic kidney 4 5 Ureter duplex 23 5 Heart anomalies Transposition great vessels 5 4 Ventricular septal defect 6 Atrial septal defect 6 Anal/rectal atresia 3 6 JL Mills et al. Diabetes 1979 Diabetes in Early Pregnancy Trial Prevalence of Major Fetal Complications Prevalence rate (%) 10 9 8 7 6 5 4 3 2 1 0 No Diabetes Diabetes <21 days postconception Diabetes >21 days postconception 9.0% 4.9% 2.1% No Diabetes Early-entry diabetes Late-entry diabetes Mills JL et al. NEJM. 1988 Pregnancy loss % 45 Diabetes in Early Pregnancy (DIEP) Pregnancy Loss by A1C Status 40 35 30 25 20 15 10 5 Diabetes No diabetes 0 3 2 1 0 1 2 3 4 5 6 7 8 9 JL Mills et al, NEJM 1988 A1C: Standard deviation from control mean 3
Placenta Fetal Macrosomia Fetal macrosomia is closely related to glucose levels in the 2 nd, and especially the 3 rd, trimester Fetal macrosomia associated with adverse effects: Shoulder dystocia and brachial plexus injury Hepatomegaly and cardiomegaly Neonatal hypoglycemia, other organ failure, NICU stay Increased rate of C-sections Best theorized with the Pedersen hypothesis Maternal Glucose and Macrosomia Modified Pedersen Hypothesis Maternal hyperglycemia Fetal pancreas stimulated Fetal hyperinsulinemia Insulin Extra Glucose Stored as Fat: Macrosomia and Insulin Resistance Fetus Mother Fetal Macrosomia 4
Fetal Macrosomia Macrosomia and Child Obesity The neonatal environment and macrosomia may also give imprinting on future obesity risk A study of multi-ethnic women from 1990s and measured offspring weight assessed 5-7 yrs later Increasing maternal blood sugars was associated with greater macrosomia and later childhood obesity Even without macrosomia, however, maternal high blood sugars nearly doubled the risk of childhood obesity at age 5-7 TA Hillier et al, Diabetes Care 2007 At age 17, children of mothers with DM in pregnancy are more likely to be overweight (whether GDM or pre-preg) Zvi Laron et al, ADA 2013 5
Obesity and Macrosomia: Cycle of Maternal and Infant Consequences Obesitogenic and Diabetogenic Environment Pregnancy with GDM or DM2 Adult Obesity and Diabetes Fetal/Neonatal Macrosomia Childhood Obesity Can glycemic control in pregnancy break obesity cycle? Macrosomia and Child Obesity The neonatal environment and macrosomia may also give imprinting on future obesity risk A study of multi-ethnic women from 1990s and measured offspring weight assessed 5-7 yrs later Increasing maternal blood sugars was associated with greater macrosomia and later childhood obesity Even without macrosomia, however, maternal high blood sugars nearly doubled the risk of childhood obesity at age 5-7 Successfully treated sugars greatly reduced childhood obesity TA Hillier et al, Diabetes Care 2007 Diabetes in Pregnancy Approximately 200,000 pregnancies each year are complicated by diabetes in pregnancy (about 7-8% of all pregnancies) Includes: Type 1 (DM1) Type 2 (DM2) 13% DM at conception Gestational Diabetes Mellitus: any degree of glucose intolerance, with onset or first recognition during pregnancy (87% of cases) 6
Diabetic Pregnancies in the Past 100 Joslin <1922 Infant mortality (%) 50 0 Tyson 1976 Martin 1979 Essex 1973 Jovanovic 1980 Joslin 1956 75 Karlsson 1972 Tyson 1979 Joslin 1924 38 Essex 1951 55 Pedersen 1969 Karlsson 1972 0 100 200 DKA Mean maternal blood glucose (mg/dl) Adapted from Jovanovic L, Peterson CM. Diabetes Care. 1980 What s a Woman with Diabetes to Do? Do women plan their pregnancies? 85 women with preconception DM; most women (79%) knew should optimize their glucose before conception but fewer than half (41%) of their pregnancies were planned More planned pregnancies with higher income, private insurance, education, happily married, and seeing an endocrinologist Most unplanned pregnancies were not contraceptive failures, but may have been consciously or subconsciously intended. Women who felt that their doctors discouraged pregnancy were more likely to have an unplanned pregnancy than were women who had been reassured they could have a healthy baby. EV Holing et al, Diabetes Care 1998 7
Preconception DM Care Possible Contraindications to Pregnancy Coronary artery disease (heart attacks/stents) Active, untreated severe diabetic retinopathy Kidney insufficiency Kidney function < 1/3 normal Very large amounts of protein in urine Very high blood pressure despite treatment Severe gastroparesis American Diabetes Association, Diabetes Care Who To Screen for GDM? Increasing Rates of GDM Source: CDC 8
Increasing Rates of GDM Source: DS Feig et al, Diabetes Care 2014 Increasing Rates of DM2 in Youth Gestational Diabetes: Risk Factors Overweight / obesity Age High risk ethnic group Others: previous child > 9 pounds, polycystic ovary syndrome, hypertension, family history of gestational diabetes 9
GDM: Age Source: CDC GDM: Body Mass and Ethnicity Source: CDC Who and How To Screen for GDM? Screen almost all patients at 24-28 weeks Screen high risk individuals at first prenatal visit and then retest at 24-28 weeks if negative on first screen Patients for Early GDM Testing Considerations Maternal age >35 years Previous infant >4kg Previous GDM Strong FH of Type II or GDM Obesity or PCOS ADA Position Statement, Diabetes Care 2007 10
ACOG: Screening and Diagnosis of GDM Initial Screen: 50 g OGTT, test 1 hr glucose If >140 or > 130 mg/dl requires further test My option = consider > 180 mg/dl diagnostic Diagnostic: fasting 100 g OGTT, at least 2+ Fasting glucose: 95 mg/dl 1 hour glucose: 180 mg/dl 2 hour glucose: 155 mg/dl 3 hour glucose: 140 mg/dl Why not ADA/IADPSG Criteria? One Step Approach recommended by IADPSG and one of two choices per ADA Diagnostic: one or more elevated with 75 g Fasting glucose: 92 mg/dl 1 hour glucose: 180 mg/dl 2 hour glucose: 155 mg/dl Treatment of Diabetes in Pregnancy Testing well-timed, recorded, and lots of it Treatment foundation is medical nutrition therapy In patients who are not controlled by diet or preexisting diabetes, insulin is preferable (ADA) ADA recommends insulin for optimal control in Type 1 and Type 2 diabetics ACOG has endorsed the use of oral agents (metformin, glyburide, acarbose) and insulin No oral DM agent is approved in pregnancy All of this is better with diabetes educators! 11
Self-Monitored Blood Glucose: SMBG Goals and Testing Frequency Preexisting diabetes Frequency 7X/day =1 fasting + 2 premeal + 3 postprandial + 1 nighttime (2-4 AM) if hypoglycemia Goals Timing Fasting 60 95 mg/dl Test on waking Premeal 60 95 mg/dl Test before each meal 1-hour postprandial 100 120 mg/dl Test 1 hour after each meal The perfect is the enemy of the good (Voltaire) Medical Nutrition Therapy Treatment foundation is medical nutrition therapy and intensive insulin therapy Carbohydrate control at meals: 30 grams for breakfast, 45-60 with lunch and dinner 15 gram snacks between meals Post meal walking/exercise may reduce sugars All of this requires diabetes educators! 12
Oral Medications Insulin is recommended as the standard treatment by the ADA (ADA recommends discontinuing noninsulins and starting insulin) ACOG in Aug 2013 endorsed use of some orals Glyburide is pill that stimulates insulin production in pancreas; one good trial of this in 2000; can have lows Fifth International Workshop states caution in its use Metformin has had some successful trials; many stay on it (especially fertility docs); it does cross placenta Limited trials on other diabetes drugs in pregnancy Insulins Approved in Pregnancy These are Category B by FDA in old system Short acting insulins: Regular insulin Lispro (Humalog) insulin Aspart (Novolog) insulin Long acting insulins: NPH insulin Detemir (Levemir) insulin Initiating Insulin Therapy in Pregnancy If not controlled by diet, initiate stepwise insulin -> do not let patients starve themselves away from insulin! Give insulin for abnormal sugars May only need at certain times (not all meals) Need to analyze blood sugar readings to make more specific interventions 13
Initiating Insulin Therapy in Pregnancy If not controlled by diet, initiate stepwise insulin -> do not let patients starve themselves away from insulin! Give insulin for abnormal sugars High fasting sugars = bedtime long acting (NPH or detemir) Abnormal postprandial glucose with regular insulin or rapid-acting insulin (lispro or aspart) immediately before the meal with elevations May only need at certain times (not all meals) Insulin Algorithm Human Insulins (NPH/Regular) Plasma insulin Breakfast Regular Lunch Regular Dinner Regular 24:00 NPH 4:00 8:00 12:00 16:00 20:00 24:00 NPH NPH NPH 14
Insulin Algorithm With Category B Analog Insulin U/mL 100 80 Lispro (Humalog) or Aspart (Novolog) B L D Detemir (Levemir) 60 40 20 Normal pattern 0600 0800 1200 1800 2400 0600 Time of day Carbohydrate Counting in Pregnancy Carbohydrate counting during pregnancy is essential Detailed counting and carbohydrate ratios with insulin (i.e. 2 units per 15 grams) Often different ratios as different meals (more with breakfast carbohydrates) Harm reduction Optimizing Insulin in Pregnancy Patients may do well with adjusting their own with guidance: i.e. go up 2 units of bedtime insulin for every two days your fasting sugars are > 90 Patients can use carbohydrate ratio dosing: i.e. take 3 units for every 15 grams (exchange) of carbohydrates Patients can take VERY large doses of insulin my highest was 900 units per day Where possible, insulin pens are a lot easier to teach (for providers) and learn (for patients) Patients will have (mostly) increasing insulin needs in pregnancy -> the moving dartboard 15
Newer Technology for Diabetes in Pregnancy Insulin Pumps Insulin pumps can benefit many pregnant diabetics; about 28% of all DM1 patients have pumps, and pregnancy may be a good time to initiate pump usage Patients should already be able to manage frequent blood sugar checks, count carbohydrates, and give multiple daily insulin injections (may need to show insurance plans) 16
Insulin Pump in Pregnancy - Data 2007 study of CSII showed no benefit 2016 Cochrane Review compared CSII vs MDI in pregnancy key findings No evidence to support the use of one particular form of insulin administration over another Only a few trials appropriate for meta-analysis, a small number of women included and questionable generalisability of the trial population. D Farrar et al, Cochrane Database of Systematic Reviews, 2016 Patient-Driven CGM Patients can often utilize personal continuous glucose monitoring for their sugars, especially those with type 1 diabetes Can pick up patterns in mealtime dosing and basal rates -> also can separate out basal and bolus problems with their interpretation Sensors are not perfect and require calibration and interpretation but newer technology is (obviously, CDEs) an improvement 17
Questions and Thanks to WADE What to expect at the hospital for delivery A hospital is no place to be sick. Samuel Goldwyn (1882-1974) 18
At the time of delivery Very little insulin is needed during active labor, and some people need an IV with glucose to avoid ketones RIGHT after pregnancy, insulin needs will drop dramatically -> often reset almost all the way to prepregnancy levels (plus some weight) Go over postpartum insulin dosing with your doctor After Delivery: Patients with GDM can stop medications, and if preexisting DM, usually can reduce or stop insulin If GDM, need a 75 gram 2-hour glucose tolerance test 6-12 weeks after (this catches unmasked DM) In 5-15 years, about half of women with GDM will develop DM2 (about 7x normal population) 66% will have GDM in any subsequent pregnancy (risks: can modify body weight, can t change aging!) Prevention: Future GDM Weight loss: obese women who lost at least 10 pounds between pregnancies reduced GDM risk by one third Bariatric surgery in one study (of 700 women) reduced the risk of gestational diabetes by three-quarters Exercise may reduce gestational diabetes (mixed data) Few studies on roles of specific dietary factors 19
Prevention: Future Type 2 Diabetes Reach and maintain a reasonable weight. Even if you stay above your ideal weight, losing 5 to 7 percent of your body weight is enough to make a big difference. Physically active for 30 minutes most days. Walk, swim, exercise. (Accountability partner ) Healthy eating plan. Eat more grains, fruits, and vegetables. Cut down on fat and calories. Check your blood glucose levels regularly. Women who have had gestational diabetes be tested for diabetes or pre-diabetes every 1 to 2 years; also recommend before next conception 20