Kathryn Jean Lucas, MD
611 N 35th St
Morehead City, North Carolina 28557

inside health

PREGNANCY COEXISTING WITH DIABETES

by: K. Jean Lucas, M.D., John H. "Chip" Reed, III, M.D., Leigh Steed, RN, CDE, Cathy Johnson, RN, CDE, and Fiona Farrelly, RD.

Introduction

Prior to the development of home glucose monitoring and the ability to achieve almost perfect control of blood glucose levels, becoming pregnant for a woman who had diabetes was, at best, frowned on and, at worst, prohibited by her physician. Achieving pre-conception glucose control by the instruction of and follow-up with a professional diabetes team and knowing that excellent control through pregnancy lowered poor pregnancy outcomes have removed much of the risk of miscarriages, congenital malformations, and complications of delivery associated with having diabetes.

In addition to diabetes predating the pregnancy, diabetes may also develop during the pregnancy, so-called gestational diabetes. The third trimester of pregnancy is an insulin resistance state; gestational diabetes is the inability of the body to overcome this resistance in late pregnancy. Control of the blood glucose is not only important to avoid macrosomia but also to protect the baby from later obesity. Having gestational diabetes and remaining obese will greatly increase the risk of permanent diabetes in the mother within ten years of delivery.

 CASE I

After getting married, she started thinking about becoming pregnant, but she was very scared. The stories that people told about mothers with diabetes and their deformed babies alarmed her and made her seriously consider adoption.

Birth-defects occur in 2% of normal pregnancies; major congenital anomalies occur in 1% of normal pregnancies. Estimates of the increased risk of mothers with diabetes having a child with major, life-threatening anomalies vary from study to study and range from 7-10 times the risk of a normal pregnancy. The discrepancy in the estimates relates to the year the study was done, the type of population studied, the timing of the intervention, and the control of the diabetes in the population. When control of the diabetes before conception is equalized, racial, ethnic, and socioeconomic factors do not add to the risk.

The organ systems of the fetus most affected by the elevation in blood glucose are the skeleton, heart, central nervous system, gastrointestinal, and genitourinary systems. The most common skeletal defect is caudal regression. Central nervous system anomalies include spina bifida, anencephaly, encephalocele, and meningomyelocele. Cardiac defects include transposition of the great vessels, VSD, situs inversus, and hypoplastic left ventricle. Gastrointestinal anomalies may be anal/rectal atresia and small left colon. Kidneys may show multicystic dysplasia. Major congenital abnormalities occur during blastogenesis, i.e. the first four weeks from fertilization. Minor abnormalities occur later from four to eight weeks after fertilization. The period of time during the first 6 weeks after conception is the crucial interval in which tight control of the diabetes reduces the risk of these severe abnormalities to normal.

The correlation between control (see figure #1) of the diabetes and the risk of congenital malformations was first noted in the 1970s. In 1978, the hemoglobin A1C (a measure of the average blood glucose over the lifespan of the red blood cell, 90 to120 days) was correlated with major anomalies. The higher the A1C above normal, the greater the percentage of abnormalities. Also, early pregnancy losses were found to correlate with high hemoglobin A1C values at the time of conception. Hypoglycemia does not increase the rate of anomalies in humans.

Metabolic control, not the duration of diabetes, appears to play the largest role in congenital abnormalities. The presence of vascular disease in the mother is also an important contributing factor in the development of pregnancy complications. Ischemic heart disease leads to an increased maternal mortality, perinatal losses, and congenital abnormalities.

If the mother has background diabetic retinopathy, she has a 7-10% risk that the retinopathy will worsen during the pregnancy. An increased risk of development of diabetic retinopathy also exists during pregnancy. Part of the reason for the acceleration of the retinopathy may be the tightening of the control of the diabetes early in pregnancy; growth factors in pregnancy may also play a role in the proliferation of new, fragile blood vessels in the retina of the mother. If a patient has retinopathy, it is important to control and stabilize it prior to conception. During the pregnancy, frequent eye exams (at least once each trimester) and treatment when necessary may prevent damage later on. If retinopathy is present, the patient should be closely followed by a retinal specialist and laser photocoagulation used when necessary to prevent retinal bleeding.

Nephropathy may worsen with pregnancy, especially from the first to the third trimester. However, follow-up studies in many of these women showed return to pre-pregnancy levels of proteinuria 6 months post-partum. The risk of pre-eclampsia is directly related to the degree of proteinuria in early pregnancy. Certain anti-hypertensive agents (such as ACE inhibitors) that treat nephropathy pre-pregnancy cannot be used during pregnancy because of teratogenecity. Control of the blood pressure during the pregnancy is very important in preventing further renal damage. Measurement of a 24-hour urine for microalbumin or protein during the pregnancy (at least once a trimester) is one way to quantitate these abnormalities.

Prior to becoming pregnant, Elizabeth went on 4 shots of insulin daily and started counting carbohydrates at each meal in order to give the appropriate insulin for the food she was eating. Because of her changing schedule and difficulty controlling her blood glucose level overnight, she was started on an insulin pump. She discussed her pregnancy concerns with her diabetes educator, her endocrinologist, and her obstetrician. They had been very encouraging; the diabetes team emphasized excellent control of the diabetes and good health in general prior to becoming pregnant. She began to feel like other women when she started planning her pregnancy. Until she was able to achieve a normal hemoglobin A1C, she remained on her oral contraceptive agents. She had a baseline dilated funduscopic exam and 24 hour urine for microalbumin prior to becoming pregnant. The tests were completely normal.

Women with diabetes who desire pregnancy are considered high risk pregnancies and, therefore, need pre-conception counseling by a team of professionals who deal with diabetes full time. The diabetes educator and dietitian will instruct the woman in insulin adjustments, testing of blood glucose more frequently pre- and post-prandially and a diabetic meal plan. The insulin requirements and diet will change during the pregnancy. During the first trimester, increased fetal demands for a glucose supply as well as the nausea and anorexia which may occur in the mother cause a decreased requirement for insulin and an increased risk of hypoglycemia. During the last trimester, one sees a dramatic increase in the insulin requirements as well as the caloric requirements. Patients will either need to be able to adjust their insulin doses upward or be able to fax their blood glucose results several times a week and have quick input on the changes needed in their insulin regimen. Women are told to monitor their sugar level before meals, 1-2 hours after eating, at bedtime, and overnight. The goals are: FBS 60-100 and <120, 2 hours after eating. Adjustments in the insulin requirements will need to be made for changes in diet, exercise, or blood glucose level.

Hemoglobin A1C values should to be in the normal range prior to the pregnancy and every 1-2 months during the pregnancy. Weight gain during the pregnancy should be limited to 20-25 pounds depending on the pre-pregnancy weight. Monitoring the baby with non-stress testing and ultrasounds is done more frequently during these high-risk pregnancies. The timing of the delivery will depend on the health of the mother and the baby. The mother may not only have difficulty with her blood glucose level but is also at risk for pregnancy induced hypertension, worsening of retinopathy and nephropathy, and toxemia.

Fetal death occurs most often after the 36^th week of pregnancy in women with poorly controlled diabetes, hydramnios, fetal macrosomia, or in women with vascular disease and pre-eclampsia. In the latter two conditions, fetal growth retardation may also be present. Monitoring of the baby by non-stress tests and fetal biophysical profiles using ultrasonography may detect early fetal compromise.

Elizabeth delivered on her due date. The baby weighed 8lbs. 6oz. and was completely normal. The rewards of this intensive, continuing control during the 9 months of gestation are healthy mother and child at the end of the term. Pregnancy, alone, generates fear and uncertainty. Adding diabetes to that emotional mixture magnifies the stress of the pregnancy and delivery. An understanding team of endocrinologists, diabetes educators, perinatologists, and obstetricians who work together towards an ideal pregnancy help the woman overcome these fears.

Elizabeth’s HMO sent her a congratulatory letter for such hard work during the pregnancy and agreed to pay for all those home glucose monitoring strips they had denied previously. The rewards for the insurance plan of covering this intensive pre-conception through delivery counseling is that for every $1.00 spent on educating and controlling the patient, over $5.00 is saved in terms of perinatal morbidity and the prevention of the most serious and expensive outcomes.

In the past, prior to the advent of home glucose monitoring, pregnant women with diabetes would have had to be hospitalized in order to achieve good control. These hospitalizations often occurred during the first few weeks of the pregnancy. With the current knowledge that excellent control of diabetes prior to pregnancy prevents miscarriages and major malformations, hope was raised for these patients that they could undergo a normal pregnancy. The ability to monitor the blood glucose and information on insulin adjustment that patients need in order to correct an abnormal blood glucose provides the patients with the ability to keep their blood sugar levels controlled throughout the entire pregnancy. The development of very short acting Humalog insulin has enabled these women to decrease post-prandial blood sugar levels very quickly to normal. Insulin pumps have become smaller and more acceptable to patients and provide a way of dealing with erratic schedules, changes in eating patterns through the day, and nocturnal changes in blood sugar not controlled with the routine types of long, intermediate, and short acting insulins given in injections.

With the team of diabetes educators, dietitians, perinatologists, obstetricians, and endocrinologists, the patient will have the most up-to-date and thorough care as well as instruction in how to control her diabetes during the different stages of pregnancy. Having a patient with diabetes who wants to become pregnant involves planning by the patient and her team of professionals in order to achieve a healthy outcome.

 CASE 2

Joan had always been overweight. Her mother had had diabetes and was on insulin when she had Joan. Joan had weighed over 9 pounds at birth. When she was planning on getting pregnant, she thought of what her mother had gone through with those insulin shots; but maybe she would be lucky and not develop diabetes during her pregnancy. Joan’s mother had gone on to develop diabetes 15 years after delivering Joan and now takes several of the new oral medications for diabetes.

Gestational diabetes (GDM), defined as carbohydrate intolerance of variable severity with onset or first recognition during the present pregnancy, occurs in up to 5% of pregnancies. In 97.5% of diagnosed cases, the diabetes disappears after the delivery of the baby. Risk factors for GDM include a previous history of GDM, a family history of GDM or diabetes, obesity, age over 30 and a history of having babies over 9 pounds in weight at delivery. However, checking patients with risk factors will only identify 50% of the patients with GDM. Universal screening for all women at 24-28 weeks of gestation is recommended. The screening is done with 50g of glucola given without regard to time of day, fasting or non-fasting. If this level is greater than 140, then a 3-hour GTT is given.

Joan was hungry throughout her pregnancy. She had gained 30 pounds by the time she received her 50g glucola as a screen for GDM. The screening test showed a blood glucose of 150. (normal <140) She had to undergo a 3-hour GTT, which confirmed gestational diabetes. The ultrasound of Joan’s baby showed development of increasing abdominal fat.

If a screening test is abnormal, then the patient undergoes a 3-hour GTT after 100g of glucola. The test is given fasting after 3 days of an unrestricted diet in which at least 600 calories of carbohydrates is ingested. The definition of gestational diabetes by GTT is that at least 2 of the values are above the following: fasting-105, 1 hour-190, 2 hour-165, 3 hour-145.

Identifying patients with gestational diabetes enables the health care team to control the blood glucose as close to normal as possible. Control of the blood sugar prevents hyperinsulinemia in the fetus. High insulin levels in the fetus in response to increased blood glucose levels in the mother causes excessive growth in the central fatty tissues of the baby levels leading to a high birth weight. High birth weight may lead to excessive number of complications at delivery. Congenital anomalies, as mentioned as a concern in patients with diabetes prior to pregnancy, do not occur with GDM because of the late onset of the hyperglycemia. The risk of hyperbilirubinemia, hypocalcemia, and hypoglycemia is increased in the babies of mothers with GDM.

Her dietitian counseled Joan. After starting the diet with in-between meal snacks of protein and complex carbohydrate, she felt full throughout the day. Her weight gain stabilized; she felt more energetic. She started walking at night after dinner.

Control of the blood sugar is the main goal of treatment of GDM. The first component of care is a diabetic diet, composed of 50% carbohydrate divided into 3 meals and 3 snacks. This arrangement prevents excursions of blood glucose during the day and leads to less hunger. Emphasis on complex carbohydrates instead of simple sugars eliminates many of the post-meal excursions. Total weight gain during the pregnancy aims at 15-25 pounds depending on the degree of obesity prior to the pregnancy. Lowering the caloric requirement to a weight reduction level is not the goal of this diet. With excessive weight loss during the pregnancy, ketone development may occur which could influence the baby’s health as well as mental development.

Joan was instructed in home glucose monitoring. She checked her blood sugar levels 2 hours after each meal and in the morning before breakfast. Her glucose levels remained below 120 post-prandially and less than 95 in the morning. The absence of ketones in her urine was comforting. She realized she was less hungry and that she was receiving appropriate nutrition during the day even though she was eating only 1800 calories.

The goals of blood glucose control in GDM are the same as in pregnant women with diabetes preceding the pregnancy. If the patient did not have diabetes prior to pregnancy, she can reassured that the risk of congenital abnormalities is not greater than normal since the diabetes occurred after organogenesis.

Insulin therapy is used when the target glucose levels are not met by diet alone. The patient should have a fasting sugar level well below 105 and 2-hour post-prandial levels of less than 120. Patients should monitor their blood sugars at least fasting and after every meal and use supplemental insulin if their sugar levels begin to elevate. When a pattern of hyperglycemia is perceived, combination therapy with intermediate and short acting insulins should be instituted. No oral medication for diabetes has yet been approved in this country for use in gestational diabetes. As in pregnancy occurring in patients who already have diabetes, the degree of blood glucose control in GDM correlates with the development of macrosomia and other complications.

During her 32^nd week, Joan noticed that she was taking supplemental insulin more often for blood sugar levels that were greater than 120. She started cutting back on her diet, but then developed ketones in the morning. Her diabetes educator, after consulting with her endocrinologist, recommended that she take three shots of insulin daily ad add supplements when needed. After starting the insulin, Joan noticed that her glucose level was much improved. Over the next 6 weeks, her insulin requirements increased almost each week. Insulin adjustments by the educator were done by fax twice weekly. Joan did not feel comfortable adjusting her own insulin regimen.

As with any pregnancy, insulin resistance will increase throughout the third trimester until delivery because of the hormones produced by the placenta which accelerate the growth of the baby. It is not unusual to have a greatly increased insulin requirement when one is approaching delivery. Fetal and neonatal outcomes are associated with maternal glucose levels. With mean blood glucose levels of 100, outcomes approach normal levels. If the maternal mean glucose levels exceeds 150, the incidence of fetal macrosomia greatly increases.

Joan was induced 2 weeks early because of the fear that her first baby would be large and would have problems being delivered. She did well. Her insulin requirements dropped to almost zero prior to the induction. The blood glucose levels stayed normal as long as she was not eating during labor. After delivery, her sugar level went back to normal. Her baby had transient hypoglycemia and weighed 9’ 12". The big question for Joan was how to prevent the development of diabetes in the future.

Because of her family history and obesity, Joan has a 90% chance of developing diabetes within 10 years of this pregnancy. Because of her mother’s gestational diabetes, little Cindy will have an increased risk of childhood obesity, insulin resistance, and impaired glucose tolerance. When she grows up, Cindy will have an increased risk of having gestational diabetes when she becomes pregnant and an increased risk of permanent diabetes.

She received a GTT at 8 weeks post-partum since she did not breast-feed. The GTT was normal. Since Joan wanted to have other children, she began an intensive exercise and nutritional program to get the 40 pounds she had gained during the pregnancy off as well as the weight she already had prior to the pregnancy. As soon as the baby was old enough to walk, Joan got her involved in walking with her to help prevent her daughter from having the same metabolic abnormalities that she had had.

By identifying patients at high risk for development of Type II diabetes in the future, we can encourage and educate these people to work hard at exercise and diet especially prior to their next pregnancy. If their post-partum GTT is abnormal but not diagnostic of diabetes, use of metformin or troglitazone may be helpful in keeping them from developing Type II diabetes. The diabetes prevention trial is underway using these agents and we’ll know of their preventive value in about 6 years. Stay tuned, trim, and be aware of these patients in your practice.

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• Elixhauser, Anne et al., Cost-Benefit Analysis of Preconception Care for Women with Established Diabetes Mellitus, Diabetes Care 16:8. August 1993, pp.1146-1157.
• Freinkel, Norbert et al., Care of the Pregnant Woman with Insulin Dependent Diabetes, NEJM 313:2, July 11, 1985, pp. 96-100.
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• Jovanovic-Peterson, Lois and Charles M. Peterson, The Art and Science of Maintenance of Normoglycemia in Pregnancies Complicated by Insulin-Dependent Diabetes Mellitus, Endocrine Practice 2:2, March/April 1996, pp. 130-142.
• Kitzmiller, J.L et al., Pre-Conception Care of Diabetes, congenital Malformations, and Spontaneous Abortions, Diabetes Care 19:5, May 1996, pp. 514-541.
• Pettitt, D.J. et al., Gestational Diabetes Mellitus and Impaired Glucose Tolerance During Pregnancy, Diabetes 34 suppl:2, June 1985, pp.119-122.
• Ratner, R.E., Gestational Diabetes, JCEM 77:1, 1993, pp. 1-4.
• Solomon, C.G. et al., A Prospective Study of Pregravid Determinants of Gestational Diabetes Mellitus, JAMA 2278:13, October 1, 1997, pp. 1078-1083
• Solomon, C.G. et al., Variability in Diagnostic Evaluation and Criteria for Gestational Diabetes, Diabetes Care 19:1, January 1996, pp. 12-15

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