Category Archives: Guidelines

Guidelines

Conventional aneuploidy screening remains “most appropriate” choice for general population


OpinionThe American Congress of Obstetricians and Gynecologists (ACOG) have updated their guidance on cell-free DNA (cfDNA) screening tests for fetal aneuploidy. In it, they state that any patient (i.e. women at high-risk OR low-risk for having an affected pregnancy) may choose cfDNA testing but they caution that conventional screening tests are more appropriate. This document replaces an earlier opinion, published in 2012, which clearly stated that cfDNA screening tests should not be offered to the general obstetrical population because they are considered to be at low-risk.

So ACOG went from recommending that cfDNA testing not be performed on low-risk women to say that they may choose cfDNA testing. Why the subtle change? Well, as ACOG correctly notes, the landscape of cfDNA is changing rapidly. New studies are published frequently and those that have examined the performance of cfDNA tests in  low-risk women have reported that the test performs just as well in them as it does in high-risk women.

However, they make an important point about a metric that doesn't get the attention it deserves. The positive predictive value (PPV). See here for background. Because the prevalence of fetal aneuploidy in low-risk women is lower than it is in high-risk women, a "positive" or "abnormal" test result in low-risk women is more likely to be a false-positive result. For example, a positive result in a 25-year-old woman gives a 33% chance that the fetus is affected but that chance increases to 87% in a high-risk woman.

The report also calls out the "no result" problem. cfDNA tests fail to produce a result in 1-8% of samples tested, usually due to a low amount of fetal DNA in the blood sample. It's becoming clear that women with samples that fail to produce a result are at increased risk of having an affected fetus. According to ACOG, these women she be offered diagnostic testing such as fetal karyotyping using amniotic fluid obtained by amniocentesis.

Other notable points contained within the updated guidance include:

  • Caution about not routinely performing microdeletion screening (offered by some labs) because it has not been fully validated in clinical studies.
  • Clearly indicating that a negative or normal result does not rule out the possibility of an affected fetus.
  • Providing genetic counseling to patients about test limitations and that decisions such as pregnancy termination should not be based on these screening tests.
  • A reminder that cfDNA tests do not screen for neural tube or ventral wall defects

This certainly won't be the final say that ACOG has on cfDNA aneuploidy screening tests. Indeed, they state that "It will be critical to remain abreast of this rapidly changing technology to provide patients with the most effective, accurate, and cost-conscious methods for aneuploidy screening."

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.

      Screening tests for group B strep infection


      StreptococcusThe most common cause of life-threatening infections in newborns comes from a bacteria known as Streptococcus agalactiae (more commonly referred to as group B streptococcus or GBS).  This was stressed in a recent meta-analysis that reported that GBS infection remains an important, global cause of infant mortality.

      The overall infection rate was 0.53 per 1,000 live births and, on average, about 10% of infected infants died.  Infants born in Africa were more likely to be infected (1.21 per 1,000) and die (22%) from the infection than infants born in the Americas or Europe (0.67-0.57 per 1,000 with 11 and 7% fatality rates).

      It doesn't have to be this way because GBS infection is treatable with antibiotic therapy.  Indeed, in more developed countries, therapy is provided to women who carry the bacteria which prevents their baby becoming infected during delivery.  However, in poorer countries this is less likely to happen due to fewer resources.

      Providing therapy to every pregnant women is not practical because not all women are colonized with GBS and so a key preventative strategy is to identify those women who do carry the bacteria.  The most sensitive test is culture performed on samples collected from the vagina and rectum.  The Centers for Disease Control and Prevention (CDC) published guidelines in 2010 that called for the routine GBS screening in all pregnant women at 35 to 37 weeks of gestation.  Testing needs to happen close to delivery (normally at ~40 weeks) because women can be colonized with GBS at anytime.  That is, a negative test result obtained earlier in pregnancy wouldn't rule-out the possibility that colonization then occured sometime after testing.  Women with a positive culture are treated with antibiotics during labor to prevent the transmission of GBS to their infant.

      Although culture is considered the gold standard test for GBS screening, it is not perfect because some infants born to culture-negative women still get infected with GBS.  Also, culture techniques give results in 1–3 days, a time frame that may not be useful should an expectant mother go into labor prior to having the culture test performed.  For these women, DNA-based tests can be used.

      These tests detect the presence of GBS using a DNA amplification technique like PCR and give results in a few hours rather than days.  Currently, these types of tests are not as sensitive as culture (i.e. they can give false-negative results) and so they aren't recommended for routine screening of women who are not in labor.  Their sensitivity is improved by using an enriched sample (one where the bacteria are allowed some time to multiply in a growth media), the use of this type of sample is impractical for women in labor when results are needed quickly.

      Until an effective vaccine to prevent GBS infection is available, laboratory testing will remain an essential tool for identifying and preventing GBS.

      CLSI publishes guideline on the assessment of fetal lung maturity by the lamellar body count


      I’ve blogged about fetal lung maturity (FLM) tests before but this is exciting news!

      The Clinical and Laboratory Standards Institute (CLSI) has just published a document that provides guidance to labs that wish to perform the lamellar body count as a test for fetal lung maturity. Disclaimer: I participated in creating this guideline.

      So why is this exciting news? Currently, the most widely used FLM test is one made by Abbott Diagnostics called the “TDx Fetal Lung Maturity II” test. It’s popular because it’s commercially available, it can be performed quickly, it’s precise, and it’s an excellent predictor of fetal lung maturity. Abbott is the only in vitro diagnostic company that makes this test and a couple of years ago they announced that they would stop doing so at the end of 2011. Labs that perform this test have been left wondering what test they would replace it with. While the lamellar body count is the most logical option, it’s not a well-known test and there are some issues that have to be considered.

      One of the biggest hurdles facing labs that wish to offer the lamellar body count test is the fact that it’s a laboratory developed test. The test is performed on FDA-approved automated blood cell counters but the manufacturers of those cell counters have never sought FDA approval for using them to count lamellar bodies in amniotic fluid. Lack of FDA approval doesn’t mean that the test can’t be performed because FDA doesn’t regulate clinical laboratories. In the U.S., The Centers for Medicare & Medicaid Services regulates lab testing performed on humans through the Clinical Laboratory Improvement Amendments (CLIA). CLIA requires that all clinical tests be validated before they are used but the requirements for a laboratory developed test are more stringent than they are for FDA-approved tests.

      Many labs are not accustomed to validating laboratory developed tests because they only perform those that are FDA-approved. After Abbott announced the retirement of their FLM test it became clear that labs would need some sort of guidance if they wanted to offer the lamellar body count tests as a replacement. In 2009 I proposed to CLSI that a guideline document on this topic be created. The proposal was approved and several well-qualified volunteers stepped up to help write it. Writing began at the end of 2010 and the final version was approved by CLSI earlier this month.

      The new CLSI guidelines will help educate people about the lamellar body count test and it provides a framework that labs can use to validate the test for clinical use. According to a press release, the guideline 1) describes the use of automated cell counting to perform the lamellar body count test, 2) describes methods to assist in test verification and validation, and 3) describes methods to select an appropriate maturity cutoff.

      Should all pregnant women be screened for hypothyroidism?


      Thyroid glandHypothyroidism affects about 2% of all women but occurs in only about 0.5% of pregnant women. The discrepancy is probably due to the known association between hypothyroidism and infertility. Other causes of inadequate thyroid function during and after pregnancy include iodine deficiency, Hashimoto’s disease, thyroidectomy, radioactive iodine treatment, and subacute. Inadequate treatment of hypothyroidism can have serious consequences for both the mother and fetus. Hypothyroidism during pregnancy has been associated with pregnancy-induced hypertension, placental abruption, postpartum hemorrhage, and an increase in the frequency of low birth weight infants.

      A study published in 1999 examined the association of hypothyroidism in mothers and neurocognitive development in their children. Serum concentrations of thyroid stimulating hormone (TSH) were measured in 25,216 pregnant women and 62 had a TSH result that was greater than 98th percentile, suggesting that they had clinical or subclinical hypothyroidism. These 62 women were then matched with 124 healthy women and 15 tests of IQ were determined in their 7-9 year old children. The children from the 62 women with thyroid disease performed slightly less well than the control children on all 15 IQ tests. 48 of the 62 women with thyroid disease were not treated for their hypothyroidism and the children from those women had significantly lower IQ scores than the control children.

      The study suggests an association between an underactive thyroid gland during pregnancy and delayed neurodevelopment in the offspring and begs the question:

      "Should all pregnant women be screened for hypothyroidism?"

      Several medical associations have weighed in on this subject. Guidelines from the American Association of Clinical Endocrinologists, indicate that TSH screening should be routine before pregnancy or during the first trimester. If the TSH is greater than 10 mU/L or if the TSH is 5-10 mU/L and the patient has goiter or positive anti-thyroid peroxidase antibodies, then thyroid hormone replacement therapy should be initiated.

      The American Thyroid Association and the Endocrine Society agree that there are not enough data for or against universal screening but also acknowledge that just because there is no evidence of benefit doesn’t mean that there is no benefit. They recommend the screening of pregnant women who are at high risk of overt hypothyroidism (e.g. history of thyroid dysfunction, TPO antibody positive, goiter etc). If the TSH is greater than 10 mU/L, this indicates overt hypothyroidism, and thyroid hormone replacement therapy should be initiated.

      However, the American Congress of Obstetricians and Gynecologists has recommended against screening all pregnant women for hypothyroidism. They argue that there is lack of clear evidence that the identification and treatment of women with subclinical hypothyroidism will improve maternal or infant outcomes.

      To date, there is no clear evidence to suggest that the treatment of pregnant women with subclinical hypothyroidism prevents neurodevelopmental in their offspring. Perhaps a clinical trial funded by the National Institute of Child Health & Human Development will clear away the controversy.