Category Archives: Diabetes


Thyroid Hormones and the Risk of Gestational Diabetes

Diabetes definitionThyroid hormones play an important role in glucose metabolism and homeostasis. They regulate hepatic gluconeogenesis, intestinal absorption of glucose, and glucose uptake in peripheral tissue. In addition, thyroid hormones modify circulating insulin concentrations. Thyroid function and metabolism undergo significant changes during pregnancy. For these reasons, thyroid hormones have been implicated in the development of gestational diabetes mellitus (GDM).

Published evidence has been conflicting about a possible relationship between overt or subclinical hypothyroidism and development of GDM. Recently, Rawal, et. al. reported an association between elevated concentrations of serum triiodothyronine (T3) and the ratio between elevated free T3 (fT3) and free thyroxine (fT4) ratio. This ratio is a surrogate marker for the body’s conversion of T4 to T3 and has been associated with development of GDM. 

The study was a multicenter and multiracial case-control study nested within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort.  GDM cases and 214 controls were included in the study. GDM was determined using the Carpenter-Coustan diagnostic criteria.   Blood was collected at four visits across pregnancy (targeted at gestational weeks8-13, 16-22, 24-29, and 34-37), and thyroid stimulating hormone (TSH), fT3, and fT4, were measured using the Roche Cobas e411. TSH concentrations that were ≤4 mIU/L were considered to be normal. Isolated low fT4 (hypothyroxinemia) was defined as having normal TSH with fT4 that was less than the 10th percentile of controls. Overt hypothyroidism was defines as elevated TSH with low or normal fT4 concentrations (less than the 90th percentile of controls).  

The authors reported that increased concentrations of fT3 and increased fT3:fT4 ratio were both associated with a greater risk of developing GDM even after adjusting for the pre-pregnancy body mass index and the family history of diabetes.  The fT3:fT4 ratio was most strongly associated with GDM with women in the highest quartile in the second trimester at a 14-fold increased risk, compared to women at the lowest quartile. Consistent with previous reports, the authors found lower concentrations of fT4 associated with GDM, but the associations were not significant after adjusting for confounders.

The authors suggest that higher fT3 concentrations (perhaps from increased conversion of T4 to T3) may be involved in the pathophysiology of GDM. They also conclude that their finding support the potential importance of thyroid screening for pregnant women. Naturally, these conclusions will need to be validated with a randomized controlled interventional study.

Screening recommendations for gestational diabetes mellitus

Green check markThis blog has covered the topic of gestational diabetes mellitus several times. Recent big news in this arena is the recommendation from the U.S. Preventative Services Task Force (USPSTF) that all pregnant women be screened for gestational diabetes mellitus (GDM) after 24 weeks of gestation.

The USPSTF is an "independent panel of non-Federal experts in prevention and evidence-based medicine and is composed of primary care providers." Their job is to "conduct scientific evidence reviews of a broad range of clinical preventive health care services and develop recommendations for primary care clinicians and health systems." For the USPSTF to "recommend" a practice means that there is evidence to suggest that the benefits of that practice outweigh the harms.

First, a few facts about GDM:

  • Each year, about 4 million women give birth and about 240,000 of these women (6%) develop diabetes during their pregnancy. The actual number of women identified as having GDM depends on the screening test that is used.
  • Over the last 2 decades, GDM has become more common because more women are at risk of developing diabetes. Risk factors include being overweight or obese or having a family history of diabetes.
  • Even though GDM usually goes away after pregnancy ends, it still puts the mother and the fetus at risk of serious health issues. For the mother these include preeclampsia and an increased chance for the development of type 2 diabetes after pregnancy. For the fetus these include macrosomia (a high birth weight which makes delivery difficult and Cesarean section more likely), shoulder dystocia, and an increased risk of becoming obese during childhood.

The USPSTF recommended screening for GDM after 24 weeks of pregnancy in all women who do not already have symptoms of diabetes. They gave this recommendation a grade of "B," meaning that there is a high certainty that there is moderate certainty that the net benefit of GDM screening is moderate to substantial.

Women benefit from GDM screening because it:

  • Identifies those who have GDM and who should be treated (usually with diet modifications, glucose monitoring, and, if needed, insulin therapy).
  • Lowers the risk of preeclampsia, fetal macrosomia, and shoulder dystocia.

The harms of screening were minimal and included:

  • Anxiety in some women.
  • The use of unnecessary tests and services.

The Task Force did not find sufficient evidence to support screening for GDM before 24 weeks of pregnancy and gave that statement a grade of "I," meaning was insufficient evidence to assess the balance of the benefits and harms of GDM screening.

The USPSTF did not make any recommendations regarding what GDM screening test to use. As this blog has noted before, there is no universally accepted method for diagnosing GDM and this has resulted in 5 different approaches (and considerable debate).

NIH Consensus Meeting on Diagnosis of GDM

Diabetes definitionDavid has blogged in the past about the diagnosis of gestational diabetes mellitus (GDM). In July 2012 he discussed a debate that was underway among experts regarding newly proposed diagnostic guidelines.

Just to recapitulate the debate, for at least 10 years we have been diagnosing GDM with a two-step process.

  1. First, there is a screening test performed by giving a non-fasting woman a 50-gram dose of glucose and then measuring her serum glucose 1 hr later. If the woman's glucose concentrations were higher than expected in that screen, then she went on to a diagnostic test.
  2. For the diagnostic test, a fasting patient is given 100-gram of glucose and then serum glucose concentrations are measured at 0, 1, 2 and 3 hours.

In 2010, the International Association of Diabetes in Pregnancy Study Groups (IADPSG) made recommendations for glucose tolerance testing in pregnancy based on the results of a study called HAPO (Hyperglycemia and Adverse Pregnancy Outcomes).  That study clearly demonstrated that the risks of adverse maternal and fetal outcomes continually increase as maternal glucose concentrations increase. In 2011, the American Diabetes Association adopted these new diagnostic criteria. In the new diagnostic approach, a 75-gram load is given to fasting women and blood is collected at 1 and 2 hours. However, also in 2011, the American College of Obstetricians and Gynecologists issued a statement indicating:

"Diagnosis of GDM based on the one-step screening and diagnosis test outlined in the International Association of Diabetes in Pregnancy Study Group guidelines is not recommended at this time because there is no evidence that diagnosis using these criteria leads to clinically significant improvements in maternal or newborn outcomes and it would lead to a significant increase in health care costs."

This is not surprising coming from ACOG. Their position is always to ask for evidence that new protocols: a) positively affect outcomes; and, b) do not harm the mother or infant. However, this division between the ADA and ACOG left everyone with the debate that David discussed in July 2012.

In March 2013, the National Institutes of Health (NIH) held a consensus development conference which convened an independent panel of health professionals and public representatives. During the conference invited experts presented and discussed current scientific data.

They addressed the following questions:

    1. What are the current approaches for GDM, what are the glycemic thresholds for each approach, and how were they chosen?
    2. What are the effects of various screening/diagnostic approaches for patients, providers, and U.S. healthcare systems?
    3. In the absence of treatment, how do the outcomes of mothers and their offspring compare with those who do not?
    4. Does treatment modify the health outcomes of mothers and their offspring?
    5. What are the harms of treating?
    6. Given all of the above, what diagnostic approach(es) for gestational diabetes mellitus should be recommended, if any?
    7. What are the key research gaps in the diagnostic approach of gestational diabetes mellitus?

      The committee felt that a one-step approach would, in many ways, be advantageous over the two-step approach. First, the current two-step approach is not used other than during pregnancy and is largely restricted to the United States. Second, there would be value in a consistent diagnostic approach across an individual's lifespan, within the United States, and during pregnancy around the world. This would allow better standardization of best practices and comparability of research outcomes. The one-step approach would also allow a diagnosis to be made within a single healthcare visit.

      The committee felt that there is good evidence that increasing glucose concentrations during pregnancy are associated with greater maternal and perinatal morbidities. They also state that there is evidence that treatment of women with GDM—diagnosed either by the one-step or two-step approach—may improve some outcomes. However, the new one-step approach, as proposed by the IADPSG, is anticipated to increase the diagnosis of GDM by 2-3 fold, to a prevalence of approximately 15-20%. Because it is unclear if these women will benefit from treatment and these additional diagnoses will increase health care costs, the consensus committee concluded that the old two-step method for diagnosis should be retained.

      "…at present, the panel believes that there is not sufficient evidence to adopt a one-step approach, such as that proposed by the IADPSG. The panel is particularly concerned about the adoption of new criteria that would increase the prevalence of GDM, and the corresponding costs and interventions, without clear demonstration of improvements in the most clinically important health and patient-centered outcomes. Thus, the panel recommends that the two-step approach be continued. However, given the potential benefits of a one-step approach, resolution of the uncertainties associated with its use would warrant reconsideration of this conclusion."

      The panel went on to identify 9 areas of research that are needed including outcomes and cost benefit ratio studies. This certainly lays the groundwork for years of future studies. In the meantime, there seems to be a great deal of support for maintaining the two-step approach for diagnosis of GDM.

      The gestational diabetes mellitus debate continues

      Discussion_icon_noshadowI have just returned from the annual meeting of the AACC where I attended a very interesting debate on the diagnosis of gestational diabetes mellitus (GDM). I've written about the current controversy in diagnosing GDM before and you can read about those here and here. Basically, the controversy boils down to one issue: should recently recommended criteria for identifying pregnant women with GDM be globally implemented or not? 

      Arguing for that position was Dr. Donald Coustan from Brown University and regional principal investigator for North America of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. He correctly pointed out that lack of a universal testing strategy when screening for GDM makes it impossible to compare clinical studies on GDM. He reviewed how the new IADPSG glucose cutoffs came into being (they were based on risk of adverse infant outcomes) that he advocates referring to as the ADA criteria because the ADA is recommending the use of the new testing method.

      Arguing against the use of the ADA criteria was Dr. Sean Blackwell from the University of Texas Health Science Center at Houston, TX. He agreed with several of Dr. Coustan points. Among them that:

      1. The HAPO study was well conducted.
      2. There was a positive association between glucose concentration and adverse infant and maternal outcomes at lower glucose cutoffs than are currently used to diagnose GDM.
      3. There is benefit in having a single, universal screening test for GDM.
      4. There is evidence that, as currently defined, treatment of GDM improves outcomes.

      He had two major problems with use of the new ADA criteria. The first was that its use would double the number of women diagnosed with GDM (from about 7% to 16%). The second was that the HAPO study was an observational study, not a treatment trial and, as such, there is no evidence that treating these additional women for GDM is effective or safe.

      Dr. Coustan argued that the increase in the number of GDM diagnoses is not surprising given that, in the US, 31% of adult US women have either diabetes or pre-diabetes. He also argued that the Australian Carbohydrate Intolerance Study of Pregnant Women (ACHOIS) study demonstrated that treatment of women with mild GDM reduced adverse outcomes such as large for gestational age newborns, macrosomia, and preeclampsia.

      Dr. Blackwell pointed out that most of the additional 10% of women that would be diagnosed with GDM under the ADA criteria would, by definition, have "milder" GDM and would only require nutritional modification and glucose monitoring rather than drugs to control their GDM. These women would have glucose control similar to those of obese women without diabetes. Further, he added that several studies in obese women without diabetes have failed to demonstrate that nutritional interventions have any impact on any infant health outcome.

      The moderator of this debate was my co-blogger, Ann Gronowski. Prior to its start, she polled the audience of (mostly) laboratorians to see which testing strategy they currently offered at their institutions. Most indicated they offered the current ACOG criteria (advocated by Dr. Blackwell). At the end of the debate, the audience was asked if they would support switching to the new, ADA criteria. The majority response was "yes." Dr. Coustan argued his points effectively.

      It's my belief that the evidence, while not complete, is strong enough to support widespread adoption of the ADA criteria when screening for and diagnosing GDM.

      Diabetes, fetal lung maturity, and the lamellar body count

      I've written a few posts on diabetes during pregnancy lately so thought I'd stick with it a bit longer. This time, however, the focus is on the effect that maternal diabetes has on fetal lung maturity.

      It's generally believed that fetal lung maturity is delayed in women who have diabetes (gestational or otherwise). The reasons for this problem are not well understood, however high concentrations of glucose and insulin in the fetal blood have been postulated as a possible cause. Despite this, respiratory distress syndrome rarely occurs in term infants born to mothers with diabetes. Still, the issue of delayed fetal lung maturity and diabetes remains controversial.

      I'll go on record for saying that there is no valid reason to perform amniocentesis solely to determine fetal lung maturity if maternal diabetes is well-controlled. However, if mom's diabetes is poorly controlled, then there may be value in performing fetal lung maturity tests. I'd like to emphasis the "may" in that last statement. As I've written before, it seems like all tests of fetal lung maturity should become obsolete. Realistically, however, they probably aren't going to go away any time soon.

      Because the most widely used test of fetal lung maturity is about to disappear forever, many clinical laboratorians are planning to offer the lamellar body count test as a replacement. I've been asked several times what, if any, effect that maternal diabetes has on the results of this test.

      Not surprisingly, that issue has been addressed only by a few published studies. In one study from 2002, a mature result from the LBC result was believable regardless of diabetes status (note, however, that this study did not include any neonates with RDS so a true assessment of the performance of the LBC could not be made). Another study from 2009 determined that the results of an LBC test were not influenced by maternal diabetes although it did suggest that the test was still useful in preterm pregnancies and in poorly controlled maternal diabetes.

      What the take-home message? Granted, the data are limited but it's probably no more necessary to perform the LBC test in women with diabetes than it is in women without the disorder.

      A new way to detect gestational diabetes mellitus? Not so fast.

      In May I wrote about recommendations made by the International Association of Diabetes in Pregnancy Study Groups (IADPSG) for glucose tolerance testing in pregnancy.  Those recommendations advocate for the use of a 75-gram oral glucose tolerance test to detect gestational diabetes mellitus (GDM) in pregnant women between 24 and 28 weeks gestation and were based on findings of the Hyperglycemia and Adverse Outcomes (HAPO) study.  That study clearly demonstrated that the risks of adverse maternal and fetal outcomes continually increased as maternal glucose concentrations increased.  The American Diabetes Association adopted the IAPDSG criteria and recommends that approach to identifying women with GDM.

      In the September 2011 issue of Obstetrics and Gynecology, the American Congress of Obstetricians and Gynecologists (ACOG) opt to stick to their guns.  The ACOG continues to recommend the "two-step" approach to screen and diagnose GDM.  Step one is a screening test using either patient history, clinical risk factors, or with a 50 gram glucose administered orally followed by the measurement of blood glucose 1 hour later (a result greater than 140 mg/dL is considered abnormal).  Those with an abnormal screening test go on to have the diagnostic test: a 100 gram oral glucose tolerance test with blood glucose measured over 3 hours.

      The ACOG rightfully acknowledges that while the treatment of mild GDM decreases adverse infant outcomes there is no evidence to indicate that use of the IADPSG recommendations would result in any significant improvements in outcomes.  Of course, lack of evidence doesn't mean that there is no benefit, it simply means that any benefits have not yet been demonstrated.  The fact that widespread adoption of the IADPSG screening test would double the number of women diagnosed with GDM was also noted by the ACOG.  This increase is notable because it would lead to a considerable increase in health care costs and likely overwhelm health care delivery systems.

      In contrast to the ACOG, the National Academy of Clinical Biochemistry (NACB) have published guidelines that recommend the approach advocated by the IADPSG.  Confused yet?  Disagreement among professional groups is not unusual and consensus is not easy to come by.  As usual, a lot more research is required before widespread agreement is achieved.

      When it comes to screening for gestational diabetes, you can’t have your jelly beans and eat them, too

      I recently got a phone call from a colleague asking me what I knew about jelly beans and their use Jellybeans
      in screening for gestational diabetes mellitus (GDM). Other than being only vaguely familiar with the notion, I have to admit I didn’t know much.

      Screening for GDM is fairly straightforward and is performed between 24 and 28 weeks of gestation. The non-fasting pregnant patient drinks 150 milliliters (about 5 ounces) of a solution containing 50 grams of glucose. One hour later a blood sample is collected and blood glucose measured. If the result is greater than or equal to 140 mg/dL the screening test is considered positive and a formal oral glucose tolerance test (OGTT) is performed. Women with a positive OGTT test are diagnosed as having GDM.

      So how do jelly beans fit into all of this? Well the glucose solution that has to be consumed is sickly sweet tasting and many women find it difficult to drink. Many complain about side effects and 15 to 20 percent have nausea and vomiting (which requires re-scheduling of the test). Jelly beans offer an attractive solution to delivering a glucose load into the stomachs of moms-to-be. They are easy and fun to eat (candy at the doctor’s office!) and women report fewer unpleasant side effects when eating them compared to the glucose drink. As a bonus, their use in health care delivery systems portrays a “patient friendly” attitude (and who doesn’t want a happy patient?). Sounds like a win-win situation, right? Maybe not.

      A study of 136 women compared screening for GDM with the glucose drink and jelly beans. Regardless of the results, all of them also had the diagnostic OGTT performed. The jelly beans they used were Brach's No. 110 Jelly Beans made from sugar, corn syrup, modified cornstarch, and glucose. Based on an analysis performed by Brach, it was determined that 28 jelly beans provided 50 grams of glucose.

      Of those 136 women, 5 of them were diagnosed with GDM based on the results of the OGTT. Screening with the glucose drink identified 80 percent (4/5) of those with GDM and screening with jelly beans identified only 2 of them (40 percent). The diagnostic specificity (the percentage of truly negative results) was similar for both tests at approximately 85 percent.

      Tests that screen for a disorder like GDM should be able to detect a high percentage of women with the disease. The use of jelly beans failed to detect more than half of the women with GDM. The authors of the paper recognized that limitation and commented that if other studies found low detection rates the use of jelly beans in a GDM screening test would prevent their use for that purpose. I searched the medical literature using the terms “jelly beans” and “jellybeans” and was unable to identify any similar studies.

      When it comes to glucose challenge tests to screen for GDM, I’d lock up the jelly beans and refuse any requests to use them or any other substitute for a 50 g glucose solution.

      A new way to detect gestational diabetes mellitus

      Diabetes definition At first glance, screening pregnant women for gestational diabetes mellitus (GDM) seems like it should be straightforward.  After all, the tests are designed to identify pregnant woman with high concentrations of glucose (sugar) in their blood and laboratory tests that measure glucose are accurate and precise.  So what’s the problem?

      For one, experts don’t agree on how best to screen pregnant women for GDM.  While nearly everyone agrees that both mom and baby can have adverse outcomes if GDM goes undetected and untreated, there is lack of consensus on the best way of identifying GDM.

      Consider how it has been done for several years here in the United States using either a 1 or 2 step process.  In the 2-step approach, a screening test is done first followed by a diagnostic test if the screening test is abnormal.  To do the screening test, blood glucose is measured 1 hour after the non-fasting patient drinks a 50-gram dose of glucose.  A glucose result that is greater than 140 mg/dL is usually used as the cutoff although a lower cutoff of 130 mg/dL is also used (again, no consensus).  A woman that has an abnormal screening test (i.e. glucose concentration greater than the cutoff) will go on to have the diagnostic test.  In the 1-step approach the screening test is skipped completely and only the diagnostic test is performed.

      The test used to diagnose GDM is the oral glucose tolerance test (OGTT).  The OGTT requires women to be fasting and then drink either a 75- or a 100-gram dose of glucose.  Blood samples are collected every hour for 2 or 3 hours if using the 75- or 100-gram dose, respectively.  The test is considered positive, and GDM confirmed, if 2 or more of the glucose results are above designated cutoffs (which differ depending upon the glucose dose given).

      Now, new criteria have recently been advocated.

      The International Association of Diabetes in Pregnancy Study Groups (IADPSG) has made recommendations for glucose tolerance testing in pregnancy based on the results of the Hyperglycemia and Adverse Outcomes (HAPO) study.  That study clearly demonstrated that the risks of adverse maternal and fetal outcomes continually increase as maternal glucose concentrations increased.  Importantly, the relationship between glucose concentration and risks were continuous.  That is, there were no obvious glucose cutoffs above which risks increased.  The new recommendations from the IADPSG address this issue.

      The IADPSG advocates for the use of the 75-gram OGTT in pregnant women between 24 and 28 weeks gestation.  The test is performed following an overnight fast of at least 8 hours and blood is collected at 1 and 2 hours after the glucose load.  A diagnosis of GDM is made when any of the following glucose results are met:

      • Fasting: greater or equal to 92 mg/dL
      • 1 hour: greater or equal to 180 mg/dL
      • 2 hour: greater or equal to 153 mg/dL

      A couple of questions are called for here: 

      1. Why were those cutoff selected?  These are the glucose concentrations above which the adverse risks of hyperglycemia were 1.75-fold higher than for women whose glucose results were lower.  Other thresholds were considered but higher cutoffs missed lots of women with adverse pregnancy outcomes and lower cutoffs identified 25% of women as having GDM.
      2. What is the impact will this test have on the prevalence of GDM?   It will definitely increase.  Currently, about 7% of pregnant women are diagnosed with GDM in the US each year.  Using the IADPSG approach that will more than double to about 18% of pregnant women.

      Although the American Diabetes Association adopted the IAPDSG criteria and recommends that approach to identifying women with GDM, it does recognize that there is the potential for harm.  For example, more interventions such as earlier delivery and increased C-section rates are likely to occur due to the increase in the prevalence of GDM.  Also, an increased number of women being diagnosed with GDM will be accompanied by a rise in health care costs.  Despite those considerations, the ADA supports the new criteria in light of the increased rates of obesity and diabetes throughout the US and the world.