Special Feature: Should Gynecologists Screen for Hypothyroidism?
By Sarah L. Berga, MD
It is hard to believe, but whom, how, and when to screen for thyroid disease is a highly controversial topic. The controversy is fueled by uncertainty about which populations are at risk, short-term cost vs benefit considerations, lack of consensus about when to initiate treatment, whether to use a mix of thyroxine and thyronine, and debate about the long-term risks of treating vs not treating asymptomatic individuals. From the gynecologist’s perspective, there are 2 populations that need to be screened for hypothyroidism: those who are getting older and those who might get pregnant. There is less controversy about screening for thyroid disease in older women. The debate centers on when to screen asymptomatic women, but there is generally consensus that it should start no later than age 50 years and be done at intervals of 1-3 years, with some professional groups advocating that screening begin at age 35 years in women but not men. Surprisingly, although the risks to the fetus of undetected maternal hypothyroidism are known and untoward, there is much more controversy about screening younger, asymptomatic women who might get pregnant.
Getting ready for pregnancy has now become a big deal and the responsibility for counseling women about what to do in advance of conceiving generally rests with the gynecologist and his or her designate. At a minimum, we need to counsel women about smoking, alcohol, and other drug cessation, talk about issues such as exposures to cats, workplace toxins, and exercise, ascertain whether she is immune to rubella, review folate use and other nutritional issues, and offer genetic counseling or testing for a growing list of conditions. Less well recognized is the need and rationale for ascertaining thyroidal status.
Why does this responsibility for preconceptual screening for hypothyroidism fall largely to the gynecologist? There are 2 main reasons. The first is that we are already in the business of preconceptual counseling. The second is that few, if any, other specialists are likely to have the opportunity to screen, if only because most women would not think to tell them about their plans to attempt to conceive.
A recent article and accompanying editorial in the New England Journal of Medicine (Alexander EK. Timing and Magnitude of Increases in Levothyroxine Requirements during Pregnancy in Women with Hypothyroidism. N Engl J Med. 2004;351:241-249) provides a fresh perspective on why it is imperative to ascertain thyroidal status in women prior to conception. The source article by Alexander et al focused on determining thyroxine needs in pregnancy in women with known thyroid disease. Levothyroxine requirements increased as early at the fifth week of gestation, well before the time of the first prenatal visit. The increased requirement was substantial, in the range of 30%. After about 20 weeks of gestation, the increased need for levothyroxine had reached a plateau and remained steady throughout the rest of gestation. In the introduction, the authors point out that 3-10% of women develop primary hypothyroidism and that 1-2% of women of child-bearing age take levothyroxine. They estimate that a minimum of 12,000 to 16,000 infants are born each year to women with either inadequately treated or undetected primary hypothyroidism.
The accompanying editorial (Toft A. Increased Levothyroxine Requirements in Pregnancy—Why, When, and How Much? N Engl J Med. 2004;351:292-294) points out that there is ongoing concern that "even borderline maternal hypothyroxinemia early in pregnancy may compromise fetal neuropsychological development." This is not entirely surprising when one considers, as an obstetrician-gynecologist might, that the fetal brain is entirely dependent on maternal thyroxine (T4) for making its own triiodothyronine (T3) until the fetal hypothalamic-pituitary-thyroidal axis becomes active, which is certainly no sooner than the second trimester. Further, since maternal thyroid-stimulating hommone (TSH) is partly regulated by feedback mechanisms that include the circulating concentration of T3, but the fetal brain cannot use maternal T3, it may not be possible to rely on solely on TSH as an indicator of maternal thyroidal status to reflect fetal needs.
On the basis of the foregoing considerations, Alexander et al recommend that women increase their dose of levothyroxine by the equivalent of 2 daily doses each week as soon as pregnancy is confirmed. However, in his editorial, Toft suggests that it would be simpler to immediately raise the daily dose by 25 to 50 microgram daily. Toft further suggests that screening during pregnancy should occur promptly after the diagnosis of pregnancy is made and that screening can be relaxed after the 20th week of gestation. Toft also advocates for universal screening of women of childbearing age, but if universal screening is not adopted, he suggests then that it should certainly be performed for those with any evidence of an underlying autoimmune diathesis, including type 1 diabetes mellitus, and those a family history of thyroid disease. Most authorities now recommend screening with both a TSH and a free thyroxine, as there are many circumstances in which the TSH does not adequately reflect thyroxine status. Now that highly specific and sensitive assays for free thyroxine have been developed and disseminated, it has become nearly universal to bundle the cost of the TSH and free T4, with the usual cost for both in the range of $30 with usual turnaround time of less than 24 hours.
This brings me to my final point. Those of us in the infertility field bear a special burden in terms of screening for maternal thyroid status. First, it is generally recognized that stress suppresses TSH, rendering it unreliable as an index of euthyroidism. The condition of "sick euthyroid syndrome" was first recognized in hospitalized patients, but it is also seen in ambulatory populations as well. Of particular concern is the anovulatory woman who does not have an obvious cause for her anovulation. I am thinking of those who have variants of functional hypothalamic amenorrhea in its subtler, oligo- or eumenorrheic forms. We (Berga SL, et al. Fertil Steril. 1997;67:1024-1030) and others have clearly described what amounts to hypothalamic hypothyroidism in women with frank functional hypothalamic amenorrhea, with a deficit of thyroxine in the range of 30% before pregnancy. If pregnancy is to be induced in these women, one would clearly need to be mindful of the notion that the suppressed hypothalamic thyroid-releasing hormone (TRH) drive may not correct during prenancy, that there may be a pre-existing thyroxine deficit, and there may be an even greater need for increased thyroxine than in women with organic forms of hypothyroidism. There are no studies to guide us in this regard, but as both Alexander et al and Toft point out, in pregnancy a little too much thyroxine appears to be a far better tactic than too little. The safest alternative would be to bypass the use of ovulation-inducing agents in favor of measures that reduce stress and the accompanying hypothalamic hypogonadism, such as variants of cognitive behavior therapy (Berga SL, et al. Fertil Steril. 2003;80:976-981) or hypnosis (Tschuggel W, et al. Fertil Steril. 2004), but I understand that this approach is not always acceptable to patients and physicians.
In summary, the mother is the sole source of thyroxine for the fetal brain during the first trimester and the maternal requirement for thyroxine increases as early as the 5th week of gestation. Obstetrician-gynecologists need to remember to screen for functional and organic forms of hypothyroxinemia in women of childbearing age by obtaining a TSH and free thyroxine prior to conception and to recommend an increase of 25 to 50 micrograms daily as soon as pregnancy is recognized.
Sarah L. Berga, MD, James Robert McCord Professor and Chair, Department of Gynecology and Obstetrics, Emory University School of Medicine, is Associate Editor of OB/GYN Clinical Alert.