Tamara C. Takoudes1
(1)
Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Department of Maternal-Fetal Medicine, Brookline, MA, USA
Tamara C. Takoudes
Email: ttakoude@bidmc.harvard.edu
Keywords
DiabetesGestationalPregestationalMacrosomiaShoulder dystociaInsulinObesityMetforminGlyburide
Case #1
This is a 41-year-old gravida 1 para 0 Asian woman at 28 weeks who comes in for glucose testing during pregnancy. She is 5 feet 2 inches tall and 115 pounds prior to pregnancy (BMI = 21, normal). Her 1-h 50-g non-fasting glucose is 151 mg/dL (normal < 130–140 mg/dL). One week later she has a 3 h 100 g fasting glucose load and her results are 105/190/143/135). She is diagnosed with GDM based on the Carpenter and Coustan criteria (95/180/155/140) of two abnormal values [1]. She has diabetes counseling with a Registered Dietitian Nutritionist (RDN) and follows the diabetic diet recommended. The fetus is measured on ultrasound and the estimated fetal weight is >90 %. All fasting glucose levels are above the goal of <95 mg/dL; thus, she is started on NPH insulin at bedtime. At 37 weeks she goes into labor and delivers an 8.5 pound female infant. At her 6-week follow-up, she has a 2-h 75-g glucose loading test that is 95 mg/dL fasting and 150 mg/dL at 2 h. She is diagnosed with IGT.
Discussion
Glucose intolerance that begins or is first recognized during pregnancy is the definition of GDM [2]. As pregnancy progresses, maternal insulin resistance rises with increasing placental hormones. GDM is commonly diagnosed in the late second or early third trimester. Risk factors for GDM include previous history of GDM or glucose intolerance, BMI > 30, maternal age > 25 years old, first-degree relatives with type 2 diabetes, multiple gestations, previous infant > 9 pounds, previous malformed or unexplained perinatal demise, underlying medical issues such as metabolic syndrome, polycystic ovarian syndrome (PCOS), glycosuria at first prenatal visit, and certain ethnic groups especially Hispanic-American, African-American, Native American, South or East Asian, and Pacific Islanders.
In 2015, controversy still exists about the screening and diagnostic criteria for GDM. Universal screening versus targeted screening for high-risk populations (only patients with risk factors listed above) has been debated. In the United States, only 10 % of patients meet criteria for low risk (absence of all listed risk factors) thus universal screening is generally employed [3]. Universal screening is performed between 24 and 28 weeks as this is when insulin resistance increases. Early screening is important for patients with high-risk factors such as previous GDM, obesity, and strong family histories but no consensus on how or when to screen exists. In our practice, we offer all pregnant patients random glucose or hemoglobin A1c (HgA1c) at the first visit with routine prenatal labs and consider oral glucose challenges if the values are >140 random glucose or >5.7 % HgA1c.
There are two approaches for oral glucose challenges: one-step and two-step methods. The two-step method has been in use longer and involves a non-fasting 1-h value after consuming 50 g of liquid glucose. If the 1-h glucose is elevated, then a second step is performed. This is a 100-g glucose drink consumed with or without carbohydrate loading for 3 days. The threshold for a 50-g test is ≥130, ≥135, or ≥140 mg/dL. If a lower threshold is used, a higher number of patients will require a second step. This involves a 3-h test with a higher sensitivity [4]. The higher the threshold for the 1-h test, the specificity will increase but will have lower sensitivity. If the value after 50-g glucose exceeds 200 mg/dL, then GDM is diagnosed. If the value is between 180 and 200 mg/dL, then a fasting glucose should be checked. If a fasting value is greater than 95 mg/dL, then GDM is diagnosed and no further testing is needed [5]. The 3-h 100-g glucose challenge is considered diagnostic for GDM if two of the four values are abnormal based on Carpenter and Coustan criteria or the NDDG (National Diabetes Data Group) [1]. See Table 1 for the criteria. Both are modifications of thresholds proposed by O’Sullivan and Mahan [6], originally based on venous whole blood samples now converted to plasma samples. The Carpenter and Coustan values are lower because the thresholds derived from the older Somogyi-Nelson method of glucose analysis were also corrected to account for the enzymatic assays currently in use. If only one value of the 3-h 100-g test is abnormal, there is increased morbidity in patients even though frank GDM is not diagnosed. The clinician must decide how to approach these patients taking into consideration risk factors and history to treat as GDM or retest at a later date [7].
Table 1
Diagnostic criteria for the 100-g 3-h GTT to diagnose gestational diabetes mellitus
|
Plasma or serum glucose level |
Plasma level |
|||
|
Carpenter/Coustan |
National Diabetes Data Group |
|||
|
mg/dL |
mmol/L |
mg/dL |
mmol/L |
|
|
Fasting |
95 |
5.3 |
105 |
5.8 |
|
One hour |
180 |
10.0 |
190 |
10.6 |
|
Two hours |
155 |
8.6 |
165 |
9.2 |
|
Three hours |
140 |
7.8 |
145 |
8.0 |
Data from: VanDorsten et al. [29]
100-g oral glucose load is given in the morning to a patient who has fasted overnight for at least 8 h. Glucose concentration greater than or equal to these values at two or more time points is a positive test
Two different classification schemes of GDM based upon results of the 3-h GTT results have been proposed. The Fourth International Workshop-Conference on Gestational Diabetes GTT values cited above are based upon the Carpenter and Coustan modification of earlier values. They are lower than those proposed by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus and the National Diabetes Data Group (NDDG), which used cutoff values of 105, 190, 165, and 145 mg/dL (5.8, 10.6, 9.2, and 8.0 mmol/L), respectively. The values are lower because the thresholds derived from the older Somogyi-Nelson method of glucose analysis were corrected to account for the enzymatic assays currently in use
GTT: glucose tolerance test
In 2008 the HAPO (Hyperglycemia and Adverse Pregnancy Outcomes) data was published and validated the 75-g 2-h “one-step” screening. The 75-g 2-h test is more convenient, better tolerated, and more sensitive for identifying pregnancies at risk for adverse outcome than the 100-g 3-h oral GTT. Increased sensitivity is primarily related to the fact that only one elevated glucose value is needed for a positive test [8] although the cutoffs are also slightly lower. Since this publication in 2008, much controversy has existed about one-step versus two-step testing. Most organizations except the American Congress of Obstetrics and Gynecology (ACOG) recommend using one-step testing (International Association of Diabetes and Pregnancy Study Groups(IADPSG)), World Health Organization, The Endocrine Society, Australian Diabetes in Pregnancy Society and more). The American Diabetes Association (ADA) recommends one- or two-step testing. While the goal of this chapter is not to promote one method over the other, one-step testing has many advantages including earlier diagnosis and thus less delay in intervention as a second oral test is not needed. In addition further studies continue to show that one-step testing may identify more women at increased risk of adverse outcomes [9–11]. More research is needed to explore the cost-effectiveness of the testing.
In our case, the patient was diagnosed with GDM, and initially dietary changes helped but she ultimately needed more treatment than diet and exercise. Once the diagnosis of GDM is made, glucose monitoring with four times daily (fasting and 1- or 2-h postprandial) measurements can help assess the effectiveness of dietary interventions described below. One- or two-hour postprandial glucose can be used although our center uses 1-h as the 2-h assessment may miss a peak in glucose. Postprandial glucose values are considered the gold standard in pregnancy based on data that assessed outcomes for preprandial versus postprandial glucose in GDM patients. Postprandial measurements resulted in a lower HgA1c and less incidence of macrosomia and cesarean delivery for cephalopelvic disproportion as compared to preprandial values [12]. Goal values are variable as hyperglycemia is a continuum and there are no values below which to prevent all complications [8]. The ADA and ACOG recommend fasting blood glucose ≤95 mg/dL, 1-h postprandial ≤140 mg/dL, and 2-h postprandial ≤120 mg/dL.
The goal of dietary changes is to decrease hyperglycemia, prevent ketosis, provide adequate weight gain based on maternal BMI, and prevent fetal macrosomia [13]. Dietary changes include distribution of calories into three small to moderate meals and two to four snacks per day. Smaller frequent meals decrease postprandial hyperglycemia. Caloric intake is based on maternal BMI; see Table 2. Once the caloric needs are calculated, the distribution of calories is recommended by the American Diabetes Association (ADA) to be about 40 % carbohydrates evenly distributed among meals and snacks, 20 % protein, and 40 % fats with <7 % saturated fats comprising total calories. The least information is known about calorie intake for obese women (BMI > 30) but the ADA recommends restricting caloric intake by 30 % [14].
Table 2
Weight gain recommendations from WHO based on BMI and plurality of gestation
|
Pregravid weight BMI (kg/m2) |
Energy needs (kcal/kg) |
Total weight gain (singleton) |
Total weight gain (twins) |
|
<18.5 Underweight |
36–40 |
28–40 |
No data |
|
18.5–24.9 Normal |
30 |
25–35 |
37–54 |
|
25–29 Overweight |
24 |
15–25 |
31–50 |
|
≥30 Obese |
No data |
11–20 |
25–42 |
If there are no medical contraindications to exercise, moderate physical activity is recommended in patients with GDM. Data to support this recommendation is limited in pregnant patients, but in one study pregnant GDM patients showed a decrease in mean HgA1c; fasting and 1-h glucose were seen after 6 weeks of arm ergometry three times a week for 20 min [15].
Follow-up of patients during pregnancy with GDM should include measurement of maternal weight and fetal assessment (see Case #2), but both HgA1c and daily measurement of ketones are optional. HgA1c in pregnancy is lowered by the increase in red cell mass, increase in red blood cell turnover, ethnicity, as well as anemia [16]; therefore, it is not usually helpful in monitoring of patients with GDM. If noncompliance is suspected, then HgA1c may be helpful to correlate with daily logs. Ketones have a controversial association with poor cognitive development on the fetus [17, 18], yet other studies in nondiabetics have shown no difference in long-term neonatal outcome. Development of ketones in GDM is usually from starvation ketosis and not diabetic ketosis as can be the case in preexisting type 1 diabetes. Ketones may be useful to follow especially if a patient is losing weight as strict adherence in order to avoid medications such as insulin result in ketones and weight loss. Maternal starvation and weight loss especially in GDM may lead to fetal growth restriction [19].
In this case, as insulin resistance increased with advancing gestation, the patient could not meet the goal glucose values and needed additional therapy. Oral hypoglycemic medication will be discussed in the following two cases but here insulin was recommended. Most commonly insulin is recommended when the glucose targets are not achieved. New evidence is developing that targeting patients when the fetal ultrasound measured abdominal circumference is more than 75 % may allow for prevention of fetal macrosomia as well. Meta-analysis of the two largest studies showed this approach limited the incidence of fetal macrosomia but increased the frequency of ultrasound and the number of patients requiring insulin therapy. The number of women with GDM needed to treat with insulin to avoid a newborn with abnormal birth weight was ten [20].
Insulin analogs best studied in pregnancy with good safety profiles and similar to human insulin are lispro (rapid acting), aspart (rapid acting), NPH (intermediate), and Levemir (long acting). Dosing of insulin depends on the patient weight, ethnicity, and timing of hyperglycemia. Generally 0.7–2 units/kg is used and this increases in later gestation as well. If a patients’ fasting glucose is elevated, NPH is usually recommended at bedtime, and if postprandial glucose is elevated, rapid-acting insulin is given with a meal. If both fasting and postprandial glucose are elevated, then both NPH and rapid-acting insulin are recommended. The distribution of insulin is about 50 % NPH and 50 % rapid-acting split between three meals. Rough estimates can be used to calculate doses by trimester: 0.7 units/kg up to 12 weeks, 0.8 units/kg up to 26 weeks, and 0.9–1.0 units/kg up to term. In an obese patient, these doses may need to be significantly increased. Twins (discussed in Case #2) will also need increased insulin dosing. Adjustments upward are generally 10–20 % if hyperglycemia persists. Many patients fear that insulin is a permanent treatment and fear injections into the subcutaneous fat especially near the fetus. Reassurance that insulin does not cross the placenta in significant amounts and needles are too small to reach the fetus should be reviewed. High serum glucose rapidly crosses the placenta and increases the risk of macrosomia.
Finally, this patient is diagnosed with impaired glucose tolerance after delivery and has a significantly increased lifetime risk of diabetes. About 20 % of women who have GDM in pregnancy will be diagnosed with IGT after delivery [21]. About 60 % of patients will develop type 2 diabetes after the index pregnancy with GDM. Modifiers that can help decrease that risk may include breastfeeding, weight loss, and exercise. Further studies are in progress to assess the specific decreased risk of T2 DM from breastfeeding [22].
Complications of gestational diabetes are preeclampsia, macrosomia, birth injury to the neonate from shoulder dystocia, maternal trauma from delivery including operative delivery, neonatal demise, and hypoglycemia. Management and care of diabetes decreases these risks. Careful monitoring of the pregnant gravida will be discussed in Case #2.
Case #2
This is a 28-year-old with dichorionic diamniotic twins who presents for prenatal care. She is about 200 pounds and 5 feet 4 inches (BMI = 34). She conceived on metformin and Clomid. She had a hemoglobin A1c checked just after conceiving and it was 6.6 %. She had GDM in her first pregnancy but never had testing in between pregnancies. Her last delivery was complicated by shoulder dystocia of a 10 pound infant born at 39 weeks vaginally.
Discussion
This case highlights multiple issues with diabetes care in pregnancy including infertility problems, medications such as metformin to treat infertility, undiagnosed diabetes prior to pregnancy, effects on glucose by multiple gestations, and pregnancy complications from GDM in pregnancy.
This patient was very likely a pregestational diabetic based on her HgA1c early in pregnancy. Case #1 reviewed that HgA1c may be lower in pregnancy, thus her HgA1c may have even been higher prior to conception. GDM does not increase the risk of congenital fetal anomalies, but elevated HgA1c in the first trimester esp values greater than 7 % have been associated with increased risk of heart, renal, and central nervous system anomalies (see Table 3). Patients with suspected diabetes prior to pregnancy should have complete assessment of other organ systems early in pregnancy such as neurologic (especially eyes), endocrine (thyroid) and cardiac systems. A thorough physical exam, dilated eye exam, screening for thyroid disease with TSH, liver assessment, renal assessment with serum creatinine and urine analysis for proteinuria, and baseline EKG is recommended. Miscarriage is also increased thus early fetal assessment with dating ultrasound should be performed. This patient will need diligent care after delivery as she most likely has type 2 diabetes.
Table 3
Association of major malformations in IDM with initial maternal glycohemoglobin level. Degree of Elevation of Glycohemoglobin malformations/Infants)
|
Degree of elevation of glycohemoglobin (malformations/infants) |
||||
|
Author, date |
n |
Moderate |
High |
Highest |
|
Miller et al. 1981 |
106 |
<7 [2/48 (4.2)] |
7–9.8 [8/35 (22.9)] |
≥10 [5/23 (21.7)] |
|
Ylinen et al. 1984 |
142 |
<6 [2/63 (3.2)] |
6–9.8 [5/62 (8.1)] |
≥10 [4/17 (23.5)] |
|
Reid et al. 1984 |
127 |
<6 [2/58 (3.4)] |
6–9.9 [5/44 (11.4)] |
≥10 [6/25 (24)] |
|
Key et al. 1987 |
61 |
<5.8 [2/45 (4.4)] |
5.8–9.4 [4/13 (30.8)] |
≥9.5 [3/3 (100)] |
|
Greene et al. 1989 |
250 |
<6 [3/99 (3.0)] |
6–12 [6/123 (4.9)] |
≥12 [11/28 (39.3)] |
|
Hanson et al. 1990 |
491 |
<6 [3/429 (0.7)] |
6–7.9 [2/31 (6.5)] |
≥8 [5/31 (16.1)] |
|
Rosenn et al. 1994 |
228 |
<4 [4/95 (4.2)] |
4–9.9 [7/121 (5.8)] |
≥10 [3/12 (25.0)] |
|
Total |
1,405 |
[18/837 (2.2)] |
[37/429 (8.6)] |
[37/139 (26.6)] |
Adapted from Kitzmiller et al. Diabetes Care 1996;19(5)
Data are SD above normal mean [n/n (%)]
Multiple gestations pose challenges in pregnancy too as the increased placenta mass significantly increases insulin resistance and makes euglycemia harder to achieve. Multiple gestations also increase the risk of hypertension in pregnancy, growth restriction, stillbirth, and premature delivery compounded by the risks of diabetes. Careful surveillance is recommended and outlined in this discussion.
This patient does not require any screening for GDM given her HgA1c but immediate referral for diabetes care is needed. Metformin is a biguanide used in the treatment of both infertility and diabetes. It decreases hepatic glucose production and intestinal glucose absorption as well as increases insulin sensitivity. In our case, metformin was used for conception. The history suggests this patient may have polycystic ovarian syndrome (PCOS) which increases the risk of miscarriage as well as gestational diabetes due to associated insulin resistance [23]. Metformin has both supportive as well as nonsupportive data in regard to decreasing the risk of miscarriage when used in the first trimester. If used throughout pregnancy, metformin may decrease the risk of GDM. One study of over 270 women with PCOS were treated with metformin or placebo until delivery, and metformin did not reduce the risk of pregnancy complications specifically GDM [24]. Specifically for glycemic control in GDM, our center does not use metformin for many reasons including it crosses the placenta and there have been high levels noted in cord blood and up to one-half of women on metformin will need additional insulin therapy (and the use of metformin may delay starting insulin therapy). More safety data about the use of metformin in pregnancy is needed.
In this patient who was on metformin when she conceived, usually the medication is weaned by the end of the first trimester. This patient already has an abnormal HgA1c and thus prompt referral, and institution of insulin is needed if her fasting and postprandial glucose values are not at goal as described in Case #1. Glyburide will be discussed in Case #3.
Weight gain in twins is less clear, but specific recommendations are noted in Table 2 for twins except those that are underweight. This patient would be recommended to gain between 31 and 50 pounds maximum based on the Institute of Medicine guidelines.
Fetal follow-up is more frequent for twins, but specifically for GDM even in a singleton pregnancy, ultrasound follow-up is recommended. ACOG is very nondirective but our maternal-fetal medicine unit recommends fetal testing in GDM patients. Fetal testing is the assessment of fetal well-being by daily kick counts, nonstress test (NST), biophysical profile (BPP, ultrasound), combination of both, or a contraction stress test. Generally estimated fetal weight (EFW) by ultrasound is performed once a month after the diagnosis of GDM is made. If a patient has poor control or suspected pregestational diabetes, then fetal testing should begin by no later than 32 weeks with weekly or 2× a week intervals. If a patient has well-controlled GDM with diet alone, then weekly testing begins at 36 weeks. If a patient has well-controlled GDM on insulin, then weekly testing commences at 32 weeks and 2× a week testing begins at 36 weeks. Any change in maternal or fetal condition can prompt increased testing as well.
Delivery in patients with GDM is a two-part decision as it involves proper timing as well as discussion about the mode of delivery. Delivery in pregestational diabetes is generally recommended between 39 and 40 weeks given association with stillbirth and poorer perinatal outcomes, but GDM is not by itself an indication for delivery. When active versus expectant management was reviewed, no evidence-based recommendation can be made as long as fetal testing is reassuring and the patient is compliant/well controlled [25].
Mode of delivery for GDM is based on the ultrasound EFW. The risk of shoulder dystocia is increased in patients with GDM compared to women without GDM. Approximately 588 cesareans are needed to prevent one case of a permanent brachial plexus injury in a GDM patient [26]. Despite this large number of cesareans, the risk of permanent nerve injury remains, and this is the cutoff that is recommended by ACOG for both pregestational as well as GDM patients (see Table 4). In this case, the patient had a previous delivery complicated by shoulder dystocia, and thankfully her infant did not have any permanent injuries. Twins have a lower risk of reaching the size of her previous delivery, but shoulder dystocia cannot be predicted by birth weight alone. The recurrence risk ranges from 1 to 17 % (the large range is likely as many patients do not attempt vaginal birth after an index pregnancy complicated by shoulder dystocia) [27]. Her prior pregnancy may have been complicated by poor diabetes control hence the neonatal birth weight was large. Twins have a higher rate of cesarean birth regardless over singleton pregnancies for fetal and maternal indications. This patient chose an elective cesarean given her history and current pregnancy of twins. She delivered healthy twins at 37 weeks after she broke her water weighing about 7 pounds each. After delivery, she was diagnosed with type 2 diabetes and was able to lose weight to avoid insulin therapy.
Table 4
Rate of shoulder dystocia by birth weight in nondiabetic and diabetic women
|
Birth weight, g |
Nondiabetic women, % |
Diabetic women, % |
|
≤4,000 |
0.1–1.1 |
0.6–3.7 |
|
4,000–4,449 |
1.1–10.0 |
4.9–23.1 |
|
≥4,500 |
2.7–22.6 |
20.0–50.0 |
Adapted from ACOG Practice Pattern No 7, Oct 1997
Case #3
A 32-year-old G1P0 conceives 2 years after bariatric surgery with a laparoscopic Roux-en-Y procedure. She had a diagnosis of glucose intolerance prior to the surgery. She lost 120 pounds; she was 350 pounds prior and now weighs 230 pounds and is 5 feet 6 inches (BMI 56 prior to bariatric surgery now 37). Her fasting glucose is 82 early in pregnancy and her HgA1c is 5.5 %. During the pregnancy she gained about 10 pounds and exercised daily. She monitored her fasting and 1 h glucose intermittently. By 28 weeks, her fasting glucose was 100s and 1-h postprandial values were above 130s. She changed her diet and was managed on glyburide 5 mg. She received iron transfusions and B 12 injections starting at 28 weeks. She delivered a healthy baby boy at 39 weeks by planned cesarean for breech. The neonate was 8 pounds and had normal glucose values after delivery. She breastfed and lost the weight she gained in the pregnancy.
Discussion
Bariatric surgery is more common as the epidemic of obesity especially in the United States increases. Pregnancy outcomes are generally more favorable in a patient who has lost weight but poses more complex issues in relationship to pregnancy. Obesity significantly increases the risk of GDM and yet screening for GDM can be difficult in patients after bariatric surgery. “Dumping syndrome” is related to simple sugars that rapidly empty into the small intestine causing a release of insulin and hence severe hypoglycemia. These patients cannot be screened for GDM with the usual oral glucose challenges. There is no standard for screening but especially since this patient population is at increased risk of GDM, screening should be pursued. Options include but are not limited to hemoglobin A 1c measurements (as this patient had), fasting glucose, postprandial glucose values done in the office after a meal, and home glucose monitoring especially in the time frame of 24–28 weeks. No standards exist for testing these patients but vigilance is required. In addition, this patient was screened and treated for the vitamin deficiencies most common in bariatric surgery patients such as B12 and iron. Also in this case, she did well with exercise and weight gain in pregnancy but still developed GDM by the third trimester due to increasing insulin resistance.
As discussed previously, the gold standard of treatment is insulin, but some centers are using oral hypoglycemics more commonly due to obvious patient and provider convenience. Our center does not use metformin or glyburide as first-line therapy due to the controversies about placenta passage of the medication as well as lack of long-term data on safety. Regardless, glyburide is very commonly used and is considered in patients with mild glucose elevations especially if they refuse insulin therapy. Glyburide, similar to metformin, has been studied in pregnancy yet clear guidelines and use of these medications vary from practice to practice. Glyburide is a sulfonylurea that stimulates pancreatic islet beta cell insulin release. Both ACOG and ADA endorse the use of oral agents in pregnancy but the FDA has not approved these medications. While some centers use glyburide as a first-line therapy for GDM in women who fail to control glucose with diet alone, our center uses glyburide for women who refuse or are unable to use insulin. Glyburide has less “failures” than metformin (up to 16 % need supplemental insulin with glyburide vs up to 50 % in metformin) thus is preferred as an oral agent over metformin. Glyburide was not originally felt to cross the placenta but follow-up data shows significant levels in the fetal cord blood. Patients need to be counseled on the uncertainties of the affect on the neonatal pancreas. A meta-analysis also showed glyburide-exposed pregnancies had higher rates of macrosomia and neonatal hypoglycemia when compared to insulin [28].
This case demonstrates how a motivated and well-counseled patient can succeed despite her increased BMI.
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