Gestational Diabetes During and After Pregnancy

1. An Overview of Problems and Solutions in the Diagnosis and Treatment of Gestational Diabetes

John L. Kitzmiller 

(1)

Maternal-Fetal Medicine, Santa Clara Valley Health Center, 750 South Bascom, Suite 340, San Jose, CA 95128, USA

John L. Kitzmiller

Email: john.kitzmiller@hhs.sccgov.org

Abstract

The present volume presents exciting advances in the knowledge of the pathophysiology, epidemiology, and management of gestational diabetes (GDM), and the maternal-fetal-placental-neonatal effects of metabolic imbalance. GDM is also described as temporary hyperglycemia during pregnancy, or glucose intolerance in pregnancy, that impairs perinatal outcome. However, we now know that abnormalities in insulin sensitivity and insulin secretion1,2 are detectable before pregnancy in women with GDM and that the abnormalities often persist afterwards.3 GDM predicts increased risk of later diabetes in the mother and metabolic abnormalities in the offspring (as reviewed in chapters in this book), so there is nothing temporary about it. GDM was actually first known as prediabetes.

1.1 Introduction

The present volume presents exciting advances in the knowledge of the pathophysiology, epidemiology, and management of gestational diabetes (GDM), and the maternal-fetal-placental-neonatal effects of metabolic imbalance. GDM is also described as temporary hyperglycemia during pregnancy, or glucose intolerance in pregnancy, that impairs perinatal outcome. However, we now know that abnormalities in insulin sensitivity and insulin secretion12 are detectable before pregnancy in women with GDM and that the abnormalities often persist afterwards.3 GDM predicts increased risk of later diabetes in the mother and metabolic abnormalities in the offspring (as reviewed in chapters in this book), so there is nothing temporary about it. GDM was actually first known as prediabetes.

Since insulin resistance and glucose intolerance in women are associated with excess cardiovascular disease later in life, and pregnant women are usually motivated to improve health behaviors, pregnancy is a good time to educate women with GDM. The long-term effects of GDM, available postpartum prevention trials, and the need for further research are well covered in this book. Effects of glucose intolerance on pregnancy outcome and the debate as to whether the effects are independent of confounders or preventable, have been more controversial.

1.2 Controversy Regarding Screening

My purpose is to give a personal view of the evidence relating to the diagnosis and treatment of GDM. As recently as May 2008 the U. S. Preventive Services Task Force (USPSTF) concluded45:

·               Current evidence is insufficient to assess the balance between the benefits and harms of screening women for GDM either before or after 24 weeks gestation.

·               Harms of screening include short-term anxiety in some women with positive screening results; [there is] inconvenience to many women and medical practices because most positive screening test results are probably false positive [as is true with prenatal genetic risk screening].

·               The extent to which these interventions [dietary modification, medication, support from diabetes educators and nutritionists, increased surveillance in prenatal care] improve health outcomes is uncertain.

·               Until there is better evidence, clinicians should discuss screening for GDM with their patients and make case-by-case decisions. This discussion should include information about the uncertain benefits and harms as well as the frequency and uncertain meaning of a positive screening test result.

·               Nearly all pregnant women should be encouraged to achieve moderate weight gain based on their prepregnancy body mass index and to participate in physical activity.

The Task Force cited prior recommendations of the American College of Obstetricians and Gynecologists,6 the American Academy of Family Physicians,7 and the American Diabetes Association8 that asymptomatic low-risk pregnant women need not be screened with glucose testing. Low risk was defined as (a) age younger than 25 years, (b) not a member of a racial/ethnic group with increased risk for developing type 2 diabetes, (c) body mass index (BMI) of 25 kg/m2 or less, (d) no previous history of abnormal glucose tolerance or adverse obstetrics outcomes usually associated with GDM, and (e) no known history of diabetes in a first-degree relative. There is also no consensus on routine diagnosis in other countries, as reviewed in this book. The USPSTF did point to ongoing large prospective studies that would provide helpful information, and the results are now available.

1.3 History of GDM Screening

In the 1940–1950s, it was recognized that women developing type 2 diabetes had excess perinatal mortality and very large infants in their prior pregnancies. Therefore, investigators began to study glucose levels in nondiabetic women during pregnancy in relation to pregnancy outcome and to long-term development of maternal diabetes. In the USA, O’Sullivan pioneered the use of 100-g oral glucose tolerance testing during pregnancy.9 He conducted a randomized controlled trial in 599 women classified as “potentially diabetic,” comparing diet management and a small dose of Neutral Protamine Hagedorn (NPH) insulin vs. routine prenatal care. A normal control group was also included. The study demonstrated a significant reduction in babies with birth weight above 4,090 g (4.3 vs. 13.1 vs. 3.7%, p <0.05) but no difference in preterm delivery (8.5 vs. 7.8 vs. 7.7%) or perinatal mortality (3.8 vs. 4.9 vs. 1.9%).10 The randomized controlled trial was conducted prior to the availability of glucose monitoring or fetal surveillance.

So then, what is the importance of reducing fetal macrosomia? Macrosomia (variously defined by absolute birth weight) or large birth weight for gestational age and gender (LGA) have been considered major indicators of the effects of hyperglycemia during pregnancy.1114 The association of fetal macrosomia and excess adiposity with fetal hyperglycemia and hyperinsulinemia is strong1518 and is supported by experiments in pregnant monkeys.19Fetal macrosomia and adiposity may also be related to maternal triglyceridemia and free fatty acids, as reviewed in this book. The intuitive risks of difficult delivery and maternal/neonatal damage associated with fetal macrosomia20are confirmed in recent large data sets.2123 The long-term risks of fetal macrosomia (independent of confounders) in infants of women with GDM include increased childhood overweight2427 and association with metabolic factors that are expected to increase risk of cardiovascular disease.2831 Since there are many causes of high birth weight and childhood obesity or later diabetes, it might be assumed that their associations have not been universal.3237 It may be preferable to include fetal insulin or neonatal adiposity or lipid markers as indicators of the quality of treatment for maternal glucose intolerance or as predictors of problems with childhood development.183842

In the decades following O’Sullivan’s work, there was uncertainty about the methods of screening and the diagnostic glucose values to use for GDM, as reviewed in this book. Many investigators found that maternal glucose levels lower than those used to indicate treatment of GDM were associated with increased perinatal complications.254357 However, associations do not prove cause and effect, and observational studies may be biased in many ways. Although the evidence is strong that marked fasting and postprandial hyperglycemia in early and later pregnancy is linked to excess risk of congenital malformations, fetal death, and costly neonatal morbidity,5862 large randomized controlled trials have been needed to prove or disprove that treatment is indicated for women with mild GDM.

1.4 Recent Randomized Controlled Trials-Australia

The first multicenter randomized controlled trial was conducted in Australia and the United Kingdom during 1993–2003 in women with risk factors or a 50-gram (g) 1-hour (h) oral glucose challenge >140 mg/dL (>7.8 mM).63GDM diagnosis was based on fasting plasma glucose (FPG) <140 mg/dL (<7.8 mM) and 2-h plasma glucose (2-h PG) 140–198 mg/dL (7.8–11.0 mM) on a 75-g glucose tolerance test (GTT) at 24–34 weeks gestation. As the trial moved along, the FPG exclusion threshold was lowered to 126 mg/dL (7.0 mM), when the World Health Organization changed the definition of diabetes.63Median entry gestational age was 29 weeks and 25% were beyond 30 weeks gestation; 24.8% were nonwhite. Average GTT FPG was 86.4 ± 12.6 mg/dL (4.8 ± 0.7 mM) and median 2-h PG was 154 mg/dL (8.55 mM) for subjects enrolled in the trial.

Women with GDM were randomized to intervention (n = 490) with “individualized dietary advice from a qualified dietitian, which took into consideration a woman’s prepregnancy weight, activity level, dietary intake, and weight gain; instructions on how to self-monitor glucose levels, which the woman was then asked to do four times daily until the levels had been in the recommended range for 2 weeks (fasting blood glucose (BG) 63–99 mg/dL (3.5–5.5 mM), 2-h postprandial BG <126 mg/dL (<7.0 mM), followed by daily monitoring at rotating times during the day)”.63 Insulin therapy was required in only 20%, “if there were two capillary-blood glucose results during the 2-week period in which the fasting level was at least 99 mg/dL (5.5 mM) or the postprandial level was at least 126 mg/dL (7.0 mM) at 35 weeks gestation or less; or if there was one BG at least 162 mg/dL (9.0 mM)”.63 Higher postprandial values were used to indicate insulin therapy >35 weeks gestation (144 mg/dL; 8.0 mM).

Women with glucose intolerance randomized to routine prenatal care (n = 510) and their caregivers were not aware of the diagnosis. Very few women in this group required a physician clinic visit after enrollment (median antenatal clinic visits 5.2), but 10.5% had a visit to a dietitian or a diabetes educator and 3% used insulin based on attending clinician suspicion of diabetes.63 There were five perinatal deaths (three stillborn, two neonatal) among infants born to women in the routine-care group, but none in the intervention group (p = 0.06). The rate of serious perinatal complications (death, shoulder dystocia, bone fracture, and nerve palsy) was less in the intervention group (1 vs. 4%; relative risk adjusted for maternal age, race or ethnic group, and parity, 0.33; 95% CI 1.03–1.23; p = 0.01). Statistical analysis was based on intention to treat. Secondary outcomes are presented in Table 1.1. The authors concluded that treatment of GDM reduces serious perinatal morbidity; the number needed to treat to benefit was 34 (95% CI, 20–103). Intervention also reduced gestational weight gain, gestational hypertension, and fetal macrosomia.63

Table 1.1

Pregnancy outcomes in mild GDM: randomized controlled trials of medical nutrition therapy and self-monitoring of blood glucose (with insulin treatment as necessary) compared to routine prenatal care with blinding of GTT results

Characteristics, outcomes

Crowther et al 200563

Landon et al 200966

Groups

Intervention

Routine care

Intervention

Routine care

Number of subjects

490

510

485

473

Required insulin (%)

20

3

7.8

0.6

Perinatal death

0

p 0.07

0

0

Pregnancy hypertensive disorder

12%

18% p 0.02

8.6%

13.6% p 0.01

Induction of labor

39%

29% p 0.003

27.3%

26.8%

Gestational age at birth (week)

39.0

39.3

39.0 ± 1.8

38.9 ± 1.8

Cesarean delivery

31%

32%

26.9%

33.8% p 0.02

Shoulder dystocia

1%

3% p 0.08

1.5%

4.0% p 0.02

Birth trauma

0

2

3/476

6/455 p 0.33

Birth weight >4,000 g

10%

21% p 0.001

5.9%

14.3% p 0.001

Large for gestational age

13%

22% p 0.001

7.1%

14.5% p 0.001

Small for gestational age (%)

7

7

7.5

6.4

Admission to intensive neonatal observation

71%

61% p 0.01

9.0%

11.6%

Respiratory distress syndrome (%)

5

4

1.9

2.9

Hypoglycemia requiring intravenous treatment (%)

7

5

5.3

6.8

Hyperbilirubinemia requiring phototherapy or >95th percentile

9%

9%

9.6%

12.9% p 0.12

Maternal anxiety score at 6 weeks after enrollment

11.2 ± 3.7

11.5 ± 4.0

   

Depression at 3 months postpartum

8%

17% p 0.001

   

The “clinical cost” of intervention in this trial was a higher rate of induction of labor (39 vs. 29%) and of admission to neonatal nursery (71 vs. 61%), possibly since clinicians were aware of the GDM intervention.63 However, intervention was not associated with increased cesarean sections (31 vs. 32%) or small-for-gestational age infants <10th percentile on Australian charts (7 vs. 7%).64 The frequency of antenatal admission was similar (29 vs. 27%), the interquartile gestational age at birth was 38–40 weeks gestation for both groups, and the interquartile length of postnatal stay was 3–5 days for both groups. Maternal anxiety score was not increased during the intervention or 3 months postpartum and several quality of life measures were consistent with improved health status in the intervention group. Postnatal depression was reduced in the intervention group (8 vs. 17%; relative risk 0.46, 95% CI 0.29–0.73; p = 0.001).63

Subsequent economic costs-consequences evaluation of data in this trial showed that the incremental cost per additional serious perinatal complication prevented was $27,503 (2002 Australian dollar = 0.74 U.S, dollar, 0.48 UK pounds or 0.66 Euros), per perinatal death prevented was $60,506, and per discounted life-year gained was $2,988. The authors concluded that, “it is likely that the general public in high-income countries such as Australia would find reductions in perinatal mortality and in serious perinatal complications sufficient to justify additional health service and personal monetary charges. Over the whole lifespan, the incremental cost per extra life-year gained is highly favorable”.65

1.5 Recent Randomized Controlled Trials-United States

The second multicenter randomized controlled trial was conducted during 2002–2007 in 16 maternal-fetal medicine units in the USA.66 Women at 24–30 weeks gestation with 50-g 1-h glucose challenge results of 135–200 mg/dL (7.5–11.1 mM) and gestational age confirmed by ultrasound and no prior history of GDM, hypertension, or stillbirth were invited to participate in the study; 7,381 women consented. Then a 100-g 3-h oral GTT was performed. If the FPG was ≥95 mg/dL (<5.3 mM) the subject was excluded from the trial. If 2 of 3 post-load levels were >180 mg/dL (>10 mM) at 1-h, >155 mg/dL (>8.6 mM) at 2-h, >140 mg/dL (>7.8 mM) at 3-h, the glucose intolerant subjects were randomized to usual prenatal care, blinded to glucose results (n = 473), or to formal nutritional counseling and diet therapy with self-monitoring of blood glucose (n = 485), and insulin if necessary (only 7.6%). Insulin was prescribed if the majority of capillary glucose values between visits exceeded 95 mg/dL fasting or 120 mg/dL 2-h postprandial. If there was clinical suspicion of hyperglycemia in a routine care subject and a random PG of ≥160 mg/dL was detected, the patient’s caregiver initiated treatment of some kind. Results were analyzed on the basis of intention to treat.66

Mean gestational age at randomization was 28 ± 1.6 weeks gestation for both groups. Maternal age, parity, BMI, and ethnicity did not differ in the two groups. Hispanic race/ethnicity was claimed by 58% in the treatment group and 56% in the routine care group. Mean GTT FPG was 86 ± 5.7 mg/dL (4.8 ± 0.3 mM) in both groups, mean 1-h PG was 192 vs. 193 ± 22–20 mg/dL in the two groups, mean 2-h PG was 173 ± 20 mg/dL in the two groups, and mean 3-h on the GTT was 137 vs. 134 ± 29–31.5 mg/dL in the two groups (a non-significant difference).66

After randomization, there were seven prenatal visits on average in the treatment group, compared to an average of five visits in the routine care group. Weight gain from enrollment to delivery was less in the treatment group, 2.8 ± 4.5 kg vs. 5.0 ± 3.3 kg, (p <0.001). Capillary blood glucose treatment targets were largely achieved: for the diet-treated subgroup, the interquartile self-monitored fasting BG levels were 76–86 mg/dL, 90.5–104 mg/dL after breakfast, 96–109 mg/dL after lunch, and 102–115 mg/dL after dinner. Treatment values were about 10 points higher in the small group of 37 requiring insulin treatment. Two subjects in the routine care group ended up with insulin treatment, although glucose monitoring was not used in this group.66

Women in both groups assessed fetal movements daily, and there were no perinatal deaths in either group. The primary outcome was a composite of the neonatal complications hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma (32.4% in the treatment group, 37.0% in the routine treatment group; a non-significant difference).66 Predetermined secondary outcomes are presented in Table 1.1. Shoulder dystocia, cesarean delivery, birth weight >4,000 g, frequency of LGA infants, estimated neonatal fat mass, and preeclampsia were all significantly reduced by intervention. Intervention did not increase induction of labor, preterm birth, the frequency of small-for-gestational age infants, or admission to the neonatal intensive care unit. The authors concluded that risks associated with fetal overgrowth are most sensitive to treatment of mild GDM, and that inclusion of patients with more severe hyperglycemia is probably necessary to demonstrate reduction in perinatal death and neonatal morbidities.66

Thus, we have proof of benefit that medical nutrition therapy and self-monitoring of blood glucose enhance short-term outcomes from two similar large, well-conducted intervention trials in women with mild GDM. Insulin treatment was needed in a minority of subjects in both trials. It is hoped that subjects will be followed to determine if there are long-term benefits from such intervention during pregnancy. The evidence regarding different treatment modalities for the management of GDM is covered in chapters of this book. Given the difficulties of conducting blinded studies and withholding proven treatments from pregnant women, it is not likely we will have more randomized trials of treatment compared to no treatment. Since the benefit was much stronger than the harm of treatment, it is worthwhile to diagnose GDM during pregnancy. The diagnostic entry criteria were somewhat different in the two trials, and the question remains of the best way to diagnose women with GDM.

1.6 Current Screening Criteria

In January 2009, the American Diabetes Association recommended: “Screen for GDM using risk factor analysis and, if appropriate, use of an OGTT”.67 The ADA further stated: “because of the risks of GDM to the mother and neonate, screening and diagnosis are warranted… Women at very high risk for GDM should be screened as soon as possible after the confirmation of pregnancy.” Criteria for very high risk are:

·               Severe obesity

·               Prior history of GDM or delivery of LGA infant

·               Presence of glycosuria

·               Diagnosis of polycystic ovarian syndrome

·               Strong family history of type 2 diabetes

The ADA also noted that screening/diagnosis at this stage of pregnancy should use standard diagnostic testing, i.e., an FPG ≥126 mg/dL (7.0 mM) or random PG ≥200 mg/dL (11.1 mM) or 2-h 75-g GTT value ≥200 mg/dL (11.1 mM).67

The ADA also recommended that women at greater than low risk of GDM, including those above not found to have diabetes early in pregnancy, should undergo GDM testing at 24–28 weeks of gestation.67Low risk status, which does not require GDM screening, is defined as women with ALL of the following characteristics:

·               Age < 25 years

·               Weight normal before pregnancy

·               Member of a racial/ethnic group with a low prevalence of diabetes

·               No known diabetes in first-degree relatives

·               No history of abnormal glucose tolerance

·               No history of poor obstetrical outcome

Many clinicians have opined that few women satisfy all these low-risk exclusion criteria in US clinics today. Many of the criteria are not specifically defined, which allows clinicians some latitude in judgment.

In 2009, the ADA recommended67 either of two approaches to GDM diagnostic testing according to the 2004 ADA Position Statement on GDM8: (1) two-step approach with 50-g 1-h PG screen ≥140 mg/dL (7.8 mM) or ≥130 mg/dL (7.2 mM) (better sensitivity), followed by the 100-g 3-h GTT; or (2) a one step approach “which may be preferred in clinics with high prevalence of GDM”. To make a diagnosis of GDM, at least two of the following plasma glucose values must be found: fasting ≥95 mg/dL (5.3 mM), 1-h ≥180 mg/dL (10 mM), 2-h ≥155 mg/dL (8.6 mM), 3-h ≥140 mg/dL (7.8 mM). It should be noted that the Proceedings of the ADA-sponsored Fifth International Workshop-Conference on Gestational Diabetes Mellitus published in 2007 had recommended use of either the 100-g 3-h or the 75-g 2-h oral GTT, with the same glucose thresholds.68

1.7 Diagnostic Screening Cutpoints and HAPO

Due to the inconsistencies around the world and in the USA regarding diagnosis of GDM, the National Institutes of Health and other organizations sponsored a large-scale (23,216 pregnant women ≥18 years of age) multinational epidemiologic study of the relationship of 75-g GTT values at 24–28 weeks gestation to perinatal outcome measures – the Hyperglycemia and Pregnancy Outcomes study.69 The GTT results were blinded to subjects and caregivers. Such a large study was necessary to control for confounders like age, weight, ethnicity, family history and geographic region. Women with FPG >105 mg/dL (5.8 mM), 2-h PG >200 mg/dL (11.1 mM), any PG <45 mg/dL (2.5 mM), or subsequent random PG >160 mg/dL (8.9 mM) at 34–37 weeks gestation were unblinded and treated as deemed locally appropriate. Thus, this was a huge study of untreated mild glucose intolerance. The results and implications of the HAPO study are discussed in detail in this book in the chapter by Lowe, Metzger, Dyer et al.1869

The major conclusion of the HAPO investigators was that the risk of adverse pregnancy outcomes (maternal, fetal, and neonatal) continuously increased as a result of maternal fasting or postload glycemia at 24–28 weeks gestation, at levels previously considered normal, and no obvious glucose thresholds were detected for most outcomes.69 Importantly, the relationships were independent and not confounded by risk factors like maternal age, obesity, race/ethnicity, and family history. That is not to say that the risk factors are not real, but that low risk women also have significant relationships between their test glucose levels and key outcomes. The investigators showed a continuous glucose relationship with fetal macrosomia, cord C-peptide, and neonatal adiposity assessed either by skinfolds or by derived percent body fat, supporting the determining role of fetal hyperinsulinemia.18,70 The continuous maternal glucose relationship with fetal macrosomia is similar to that seen in smaller scale observational studies.4748507174 Since there were no apparent maternal glucose thresholds to predict risk, the HAPO investigators concluded that consensus methods were needed to set global diagnostic standards for GDM. The standardization will assist interpretation of clinical research studies in which investigators use different diagnostic approaches, and should allay confusion among clinicians and health plan managers.

To help achieve that aim, a global conference sponsored by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) was convened in Pasadena, California in June 2008. After complete interactive presentation of the many aspects of the HAPO results, some other relevant studies, and poster presentations, eleven caucuses representing the major international and US stakeholder organizations and attending clinicians and investigators from all continents discussed the implications of the data. The caucus recommendations were then considered by a 50-person IADPSG Consensus Panel representing the whole group, the health organizations, and the IADPSG members unable to attend.75 The Consensus Panel concluded that (1) single-step testing should be used for all pregnant women at 24–28 weeks gestation, (2) the 75-g GTT should be used as the test for GDM with any one abnormal value counting as the diagnosis, and (3) criteria and methods should be developed to identify marked hyperglycemia early in pregnancy, since many women have undiagnosed diabetes when they become pregnant, and they have increased risks of fetal malformations and maternal vascular complications for which extended testing is indicated. The task remained for the IADPSG Consensus Panel to develop the glucose threshold criteria to use to make these diagnoses.75

During the subsequent 15 months, the IADPSG Consensus Panel used online and writing group conference call communications to develop the recommendations, with open presentations of the pros and cons at many international conferences, including at least three major ones in the USA. The review paper appears in Diabetes Care.75 Panel members agreed to use glucose values with odds ratios of 1.75 for the various perinatal risks, compared to mean glucose values at each testing time. The chosen thresholds represent a compromise between users of glucose measurement as mg/dL or mM, choosing numbers that should be easy to remember. For GDM diagnosis at 24–28 weeks gestation, the recommended plasma glucose thresholds are fasting ≥92 mg/dL (5.1 mM) or 1-h ≥180 mg/dL (10 mM) or 2-h ≥153 mg/dL (8.5 mM).

For diagnosis of marked hyperglycemia in early pregnancy that may represent undiagnosed diabetes, the panel members agreed to use standardized hemoglobin A1c (HbA1c) ≥6.5 or FPG ≥126 mg/dL (7.0 mM) or random PG ≥200 mg/dL (11.1 mM), with abnormal results to be confirmed by subsequent testing. The panel recommended that local conditions should determine if the early pregnancy screening should be universal or selective. It is of interest that an international panel has recommended use of standardized HbA1c ≥6.5 for the diagnosis of diabetes in general.76 High-risk women with negative early tests should undergo a 75-g 2-h GTT at 24–28 weeks gestation.

It is anticipated that concerned health care organizations in different countries will adopt these recommendations. Do they represent an “inconvenient truth” with reference to the concerns of the 2008 USPSTF? Yes, because the projected prevalence of GDM according to the HAPO data will be ±16% of pregnancies. That figure will vary in different communities. The prevalence is in agreement with the increasing rates of obesity and prediabetes found in all parts of the world.

Managers and planners are concerned these numbers will overly burden existing prenatal care facilities and personnel. An ethical consideration of not using the new criteria is whether it is right to deny women diagnosis and treatment that has been shown to benefit them and their offspring, at some cost. Undoubtedly, some triage methods will be developed to decide the intensity of treatment regimens offered to the women diagnosed with GDM. We may take heart that the excellent randomized controlled trials show that medical nutrition therapy, physical activity, and self-monitoring of blood glucose and fetal activity are sufficient to achieve good outcomes in most cases. It should be possible to find ways of delivering this care at reasonable cost.

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