The Pregnancy Lab

Screening or diagnostic test. What is the difference?

Today was an interesting day at work.  A genetic counselor I work with emailed me that a pregnant patient wanted to have "every single Down syndrome screening test that was available."  While this was problematic in and of itself (more about that later), this patient also planned to have an amniocentsis regardless of the results of the screening test.

Do you see a problem with this line of thinking?  If not, read on.

Let's start with what a screening test is.  I've written about this before here, but to recap: a screening test is NOT the same as a diagnostic test.  A test that screens for Down syndrome doesn’t identify if a woman is pregnant with a baby that has Down syndrome; it identifies women who are pregnant with babies that are at increased risk of having Down syndrome.  In other words, the screening test puts tested women into one of two camps: those without increased risk and those with incrased risk.  Women who screen positive and who are at increased risk are offered a diagnostic test that can confirm if their baby does or does not have Down syndrome.  A screening test cannot do that.

The diagnostic test for Down syndrome is determining the karyotype of the fetus in order to identify how many copies of chromosome 21 have been inherited (unaffected fetuses have 2 copies; affected fetuses have 3 copies).

The results of a Down syndrome screening test are used to identify women who should be offered diagnostic testing (karyotype).  Women who have a positive screening test result are offered amniocentesis in order to obtain  the amniotic fluid required for karyotyping the fetus.  However, because amniocentesis is an invasive procedure, there is a small risk of miscarriage (usually less than 0.5 percent).

The problematic request of the patient to have more than one Down syndrome screening test should now be apparent for two reasons:

1. Her desire to have every available screening test is illogical if she has already made up her mind to have an amniocentesis and diagnostic testing.  The fetal karyotype is THE definitive (i.e. diagnostic) test and so screening for a disorder makes no medical or economic sense because, regadless of the results, the diagnostic test will still be performed.
2. Requesting all available screening tests is a complete waste of health care resources.  Granted, the number of Down syndrome screening tests available is a source of much confusion for both physicians and patients.  That said, patients (with help from their doctors) should choose the screening test that is best for them.  Choosing multiple screening tests is not a wise idea.  Consider what might be done if the results of these tests don't agree with each other.

Consumers of health care often (mistakenly) believe that more testing is better.  Few take the time to consider that tests may have downstream consequences that they might not be prepared for.  In this case, the patient had already decided to have the "best" test.  That is her choice and one that I support.  What I don't support is the wasted time, money, and effort required to perform tests that are, in this specific situation, meaningless.

The gestational diabetes mellitus debate continues

I 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.

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.

A new way to detect gestational diabetes mellitus

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.