Should all women be screened for hypothyroidism? An update

ThyroidA few months ago, I wrote about thyroid testing during pregnancy.    As I mentioned, there was a study published in 1999 that examined the association of hypothyroidism in mothers and the neurocognitive development in their children.  The study demonstrated that, at 7-9 years of age, children from the women with abnormal thyroid measurements performed slightly less well than the control children on 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.

That study prompted a follow-up study to address the question of whether intervention (i.e. T4 treatment for hypothyroidism) would prevent the difference in IQ.  This study has been referred to as the CATS (Controlled Antenatal Thyroid Screening) study and it was recently published.    This was a prospective, randomized, controlled trial where pregnant women at 15 weeks 6 days gestation or less were assigned to a screening group, in which TSH and fT4 measurements were performed or a control group in which blood was drawn but not tested until after delivery. Women in the screening group who were found to have TSH concentrations above the 97.5th percentile, free T4 concentrations below the 2.5th percentile, or both were given daily T4 treatment.   

21,846 women in the UK and Italy provided blood samples for the study. Of those, 390 in the screening group and 404 women in the control group had abnormal thyroid hormone concentrations. The authors measured IQ in their children at 3 years of age, but found no statistical difference between the control and screening groups. These findings support the idea that there is not enough evidence for universal thyroid function screening of pregnant women or for treatment of subclinical hypothyroidism.

There are a number of limitations to this study which have been outlined nicely in an editorial that accompanies the CATS study publication.  First, the women in the CATS study had milder hypothyroidism than in the previous observational study. The previous study included women with a mean TSH concentration of 13.2 mIU/L whereas the present study had median TSH concentrations of 3.8 (UK) and 3.1 (Italy) mIU/L. Second, the T4 therapy was not started until a median gestational age of around 13 weeks which may be too late to obtain benefit from the T4 therapy. Third, the earlier observational study measured IQ in 7-9 year old children, whereas the present study examined 3 year olds. It is possible that it is too early to measure the differences in the IQs of the two groups. Follow-up studies in these children would be useful.

An additional randomized trial is in progress that will examine the IQ in children at 5 years of age as well as other maternal complications between treated and placebo treated groups. This study, which began in 2006, may help put this discussion to rest, however we will have to wait until 2015 until the results of the study are complete.

Is it time to abandon the hCG discriminatory zone?

I've written about ectopic pregnancy a few times now (see this and this).  The use of hCG testing in the evaluation of a woman with a suspected ectopic pregnancy is invaluable.  For many years doctors have relied upon the concept of a "discriminatory zone."  That is, an hCG concentration above which an intrauterine pregnancy should always be visible using transvaginal ultrasound.  The hCG concentration that is often used as the discriminatory zone is between 1,000 and 2,000 IU/L.  If no fetus is seen then the woman may receive treatment for a presumed ectopic pregnancy.

Early recognition and treatment of an ectopic pregnancy is critical because it is a leading cause of maternal death in the first trimester.  Ectopic pregnancies are terminated by the use of the drug methotrexate or surgery.  Methotrexate is a folic acid antagonist and a powerful teratogen that causes malformations in a developing fetus.  The use of methotrexate has increased substantially in the last few years because it has fewer risks and is less expensive than surgery.  However, methotrexate is sometimes given to women with an erroneous diagnosis of ectopic pregnancy which results in the loss of a viable pregnancy or the delivery of infants with birth defects.

Two recent reports have shown a spotlight on this problem:

  • The first study reported the outcomes of 8 pregnancies that were incorrectly diagnosed as ectopic and in whom the mother was treated with methotrexate.  Sadly and unsurprisingly, all 8 pregnancies had terrible outcomes.  Two pregnancies resulted in severely malformed infants.  One was liveborn at 37 weeks and had Tetralogy of Fallot, pulmonary atresia, congenital scoliosis, 7 ribs on left side and 11 ribs on right side, and a single kidney.  The other was stillborn at 30 weeks and had Tetralogy of Fallot, horseshoe kidney, and a single umbilical artery.  The other 6 pregnancies were aborted, 3 spontaneously and 3 deliberately.
  • The second study addressed the reliability of the hCG discriminatory zone by evaluting 202 patients that met the following criteria: 1) a transvaginal sonogram showing no intrauterine pregnancy; 2) an hCG test performed on the same day as the ultrasound; 3) documentation of a subsequent viable intrauterine pregnancy.  80% had an hCG concentration less than 1,000 IU/L (well below the discriminatory zone), in 9% it was between 1,000 and 1,499 IU/L, in 6% it was between 1,500 and 1,999 IU/L, and in 5% it was 2,000 IU/L or greater (above the discriminatory zone).  The highest hCG concentration observed was 6,567 IU/L.

While the idea of an hCG discriminatory zone is an appealing one, it is clearly not something that can be relied on to make an important therapeutic decision.  The authors of the second study (above) concluded exactly that and recommend using follow-up sonography and serial hCG testing in hemodynamically stable patients before treating for presumed ectopic pregnancy.

        What is TORCH Testing?

          TorchTORCH testing (sometimes called TORCHES testing) includes tests for a group of infectious diseases that can infect pregnant women and cause birth defects or death in their infants. TORCHES is an acronym for the following infectious diseases:

        Toxoplasma gondii (toxoplasmosis)- a parasite that can be acquired from ingesting cysts from the feces of infected cats, drinking unpasteurized milk, or eating undercooked contaminated meat. Infection early in pregnancy can cause miscarriage. Later in pregnancy it can cause eye infections, and mental retardation.

        Other– Other infections that may be screened for at the same time include Parvovirus B19 and sometimes varicella zoster virus (chicken pox). 

        Rubella (German Measles)-Infection early in pregnancy can cause birth defects such as heart disease, growth retardation, and eye defects. It can also cause problems later in childhood such as hearing loss. Following the introduction of the vaccine in the 1970s, the incidence of Rubella has now dropped to approximately 1 in 10,000 births.

        Cytomegalovirus (CMV)- This virus is transmitted through body secretions (including breast milk) as well as sexual contact. Infection can cause death, hearing loss and mental retardation.

        Herpes simplex virus (HSV)- is a common infection that is spread by oral and genital contact. Most infections are spread to infants during the birth process. Infected infants may have localized infections of the mouth, eyes or skin, and some may have disseminated infection. Infant mortality from neonatal infection can be very high.

        Syphilis (Treponema pallidum) – this bacterial infection can cause stillbirth or infant death shortly after birth. Untreated babies may become developmentally delayed, have malformations, seizures, or die.

        In practice, TORCH testing in the United States is most commonly targeted toward high-risk groups, or women from areas where the prevalence of the diseases is high. In these situations, the screening serves to identify women with active infection as well as those who lack immunity to the diseases.  Those who aren’t immune can be vaccinated or more specifically counseled to limit risk of exposure.

        The use of TORCH testing to diagnose these infections is becoming less common since more specific and sensitive tests, that don't rely on the detection of antibodies are available. Note that false positive results are possible and all positive TORCH tests should be followed-up with more specific confirmatory tests.  

        Routine screening of pregnant women for underlying infectious disease or immunity is consistently performed to identify:

        Chronic carriers of hepatitis B virus
        HIV infection
        Group B streptococcal colonization
        Immunity to Rubella virus

        In fact, the CDC 2010 "Sexually Transmitted Diseases Treatment Guidelines" recommend that pregnant women be screened on their first prenatal visit for sexually transmitted diseases which may include Hepatitis B, HIV, Syphilis as well as Gonorrhea & Chlamydia.

        In addition to being tested for sexually transmitted diseases, the CDC also has a list of tips on how to avoid infections during pregnancy.

        We will discuss testing for each of these infectious diseases individually in future blogs, so stay tuned!


        Molecular testing for Down syndrome: proceed with caution

        Ann recently posted about massively parallel genomic sequencing using maternal blood as a
        screening test for Down syndrome.  In it, she described a recently published, multi-center clinical study that validated this molecular test in just over 1,600 women.  The test detected 98.6% of the Down syndrome fetuses and had a false-positive rate of 0.2%.  Notably, this performance is considerably better than current biochemical marker Down syndrome screening tests.

        However, there are some important limitations to this new test.

        1. It’s expensive and available from only one company.  The Sequenom Center for Molecular Medicine, located in Grand Rapids, MI, developed the test and is currently the only place in the US that can do it.  It's marketed as the MaterniT21 test and costs $1,900 for the uninsured and ~$235 for those with insurance.  Biochemical screening tests cost much less.
        2. After the blood sample arrives in the lab, test results are available in about 10 days.  Results for biochemical screening tests take about 1 day.
        3. The test can only be performed in singleton pregnancies (not twins, triplets, etc).  Biochemical screening tests work best in singleton pregnancies, too, although risks can be estimated from a twin pregnancy.
        4. The test fails to work in about 2% of cases, usually as a result of there not being enough fetal DNA detected in the mother's blood.  This is more likely to be the case in overweight women who have a higher blood volume which dilutes the amount of the fetal DNA.  The concentrations of the markers used in biochemical screening tests are also effected by maternal weight but there are effective ways to account for that so that the final result is not affected.
        5. The test is only validated for the detection of Down syndrome and not other fetal aneuploidies such as trisomy 18 or trisomy 13.  The test does have the capability of detecting these disorders and, if they are detected, will be reported.  However, because the test has not been thoroughly investigated for detecting T18 or T13 a negative result doesn't rule out their presence.  Biochemical screening tests can detect these disorders although the detection rates are lower than they are for Down syndrome.
        6. The test does not detect open neural tube defects (e.g. spinal bifida) that are usually screened for using biochemical screening tests.

        I have no doubt that as the technology required to do massively parallel genomic sequencing becomes less expensive, tests like the MaterniT21 will become more affordable and mainstream.  Most of the limitations I described above will also be addressed with time and technological improvements.  As Ann indicated, this is the dawn of a new era in screening for fetal disorders.

        Screening for Down syndrome: Beginning of a New Era?

        DNADavid has written previously about the different types of screening tests for Down syndrome (trisomy 21). Although these tests have certainly gotten better over time, even the best among them is subject to less than perfect sensitivity (90%) and a false positive rate of between 2 and 5%. Given the prevalence of Down syndrome, this means that out of 16 women that screen positive for Down syndrome, only one will carry an affected infant. Therefore, 15 women are unnecessarily subject to potentially dangerous amniocentesis procedure. Recently, there have been reports of some molecular testing that may change the way we screen women for Down syndrome forever.

        In 1997, researchers discovered that DNA from a fetus actually circulates in the blood of the mother during pregnancy. It goes away very rapidly after the baby is delivered. This amazing observation meant that it might be possible to diagnose certain diseases in the fetus by simply taking a sample of mom's blood. Since then, many studies have been done to try to develop a method to screen for Down syndrome using maternal circulating fetal DNA.

        In 2008, two papers were published, from different laboratories, which described the detection of trisomy 21 using "massively parallel genomic sequencing" (MPGS). In this method, DNA fragments are isolated from a sample of mom's blood. These include a mix of mom's DNA and infant DNA. The ends of the DNA fragments get a small piece of adapter DNA attached to it which allows the fragments to hybridize to a surface coated with the complimentary adapter DNA sequence. All the fragments bound to the surface are then simultaneously amplified. After amplification, the DNA is sequenced. With the help of bioinformatics, the researchers are able to determine what chromosome the DNA fragment came from. The number of sequences that originate from a particular chromosome is counted and tabulated for each chromosome. If a fetus has an extra chromosome, then the percentage of chromosome 21 fragments is higher than expected.  Early studies suggested that this method might work with high sensitivity, but the studies were small.

        Recently, a very large validation study was published that demonstrated that this method is not only sensitive, but also had a very low false positive rate. 

        The study involved women at high risk of delivering an infant with Down syndrome from 27 prenatal diagnostic centers worldwide. The authors compared fetal karyotyping (the gold standard for diagnosing Down syndrome) to MPGS in 212 Down syndrome and 1484 matched normal pregnancies. Their research demonstrated that MPGS was able to detect Down syndrome with 98.6% sensitivity and only a 0.20% false positive rate. This represents a huge improvement over currently available methods.

        Currently, MPGS is only available at specialized centers and is quite expensive. However, with the advent of studies such as this, the availability and price of MPGS is bound to come within reach. Hopefully, within the next 10 years, we will see the end of maternal serum screening for Down syndrome as we currently know it.

        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.

        FDA and FTC Crack Down on hCG Diet Products

        HCG photo
        Although the hCG diet is slightly outside of the realm of The Pregnancy Lab, we have discussed it in the past because we get questions about it all the time. Don't even consider doing this diet to shed your extra holiday pounds. On December 6, 2011, the FDA and Federal Trade Commission issued warnings to a number of companies ordering them to stop selling their homeopathic hCG products.  The warning letter states that, it is unlawful to "advertise that a product can prevent, treat, or cure human disease unless you possess competent and reliable scientific evidence". In addition, the FDA says a 500-calorie diet by itself is pretty risky. You can get gallstones and develop other health problems from such severe restrictions on what you eat.

        If you are considering this or any diet a good resource is an article by American Dietetic Association.

        Are there any good markers to predict preeclampsia?

        David has written about preeclampsia in the past, but I thought I'd talk about some specific studies that have been published on that topic.

        Recall that preeclampsia is when a pregnant woman develops high blood pressure and protein in the High blood pressure urine after the 20th week of pregnancy and it is usually associated with edema (swelling). Although preeclampsia occurs in only 5 to 8% of pregnancies, it is a major contributor of premature deliveries and neonatal morbidity in the United States. Because the etiology of preeclampsia is not well understood, the ability to predict and prevent preeclampsia continues to be poor.

        Numerous biochemical markers have been studied for their ability to predict the onset of preeclampsia. Why do we seek a marker to predict preeclampsia when there is not a good treatment? It is hoped that if we could identify who was likely to develop preeclampsia then we could study interventions in that group which may ultimately lead to a way to prevent it. Unfortunately, no good markers have been identified as of yet.

        In 2004 the World Health Organization did a systematic review of 7,191 potentially relevant scientific papers on this topic. Eighty-seven articles were ultimately included in the analysis and the WHO concluded that “As of 2004, there is no clinically useful screening test to predict the development of preeclampsia.”

        However, also in 2004, Levine et al published a paper indicating that the circulating angiogenic factors called soluble fms-like tyrosine 1 (sFLT-1) and placental growth factor (PlGF) could be potential markers for the early prediction of preeclampsia. These proteins play a role in angiogenesis and are hypothesized to be required for normal embryonic vascularization. This caused a lot of excitement and led to many promising studies that examined the clinical utility of measuring Sflt-1 and PlGF to predict the onset of preeclampsia.

        Unfortunately, these markers have not turned out to be all we had hoped they would be. In 2007 Widmer et al published the results from a systematic review of studies of sFlt-1 and PlGF. Ten of 184 available studies analyzing sFlt-1 and 14 of 319 studies analyzing PlGF were included in their review. The authors said that the evidence supports the possibility that sFlt-1 and PlGF are associated with the pathophysiology of preeclampsia or its phenotypes. In addition, third trimester changes in the blood concentrations of the markers were associated with preeclampsia, especially when the disease was severe. However, they concluded that “… the evidence is neither strong enough nor sufficient to recommend placental growth factor and sFlt-1 to screen women at risk to develop preeclampsia…" and "Prospective studies employing rigorous laboratory and study design criteria are needed to determine the clinical usefulness of these tests."

        Apparently, there is a study called the "WHO Global Program to Conquer Preeclampsia" which was scheduled to start mid 2006; in this investigation approximately 10,000 women will be screened serially to evaluate these biomarkers for preeclampsia. So far, no data has been published on the results of this study…so stay tuned!

        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.