Thyreopathy examination during pregnancy – results of pilot project

Summary

This Pilot Project (PP), sponsored by the Preventative Department of the General Health Insurance Company, was carried out in the Czech Republic in 2009. The aim was to assess the feasibility of applying selected thyroid tests in all women in the first trimester of pregnancy, and evaluate the results. The project arose from the fact that the normal function of the thyroid ensures that pregnancy takes it proper course, and that sufficient level of thyroxin is necessary for healthy foetus development. Thyroid disorders are quite frequent among fertile women. In a group of 2937 asymptomatically pregnant women in their 9th-11th week, thyroid blood tests were carried out (TSH, FT4 and TPOab). The choice these three indicators is optimal for the diagnosis of thyroid dysfunction in pregnancy. It was possible to time the tests with blood tests intended to diagnose genetic disorders. In a total of 109 women FT4 levels were lower; in such cases brain development is endangered and there is a risk of poor psychomotoric development of the child. Higher TSH had 228 women and in these cases the thyroid function is sub-optimal. The presence of TPOab in 262 women indicates that the thyroid is not able to adapt well to the increased demands made on it during pregnancy. The Pilot Project proved that a minimum of 7-10% of pregnant women have no knowledge of the fact that they have some kind of thyroid disorders. The project was carried out for the first time in the Czech Republic, and resulted in important information and confirmation of the benefits of the chosen approach.

Key words:
pregnancy, thyroid, screening, TSH, FT4, TPOab, General Health Insurance Company

Introduction:

Thyroid disease need cause no troubles during the course of life, but if left undetected it may have serious consequences. It is thus the aim of medical care to diagnose thyroid function failure as soon as possible, which in practical terms means when the disease is easily curable or when negative consequences can be avoided. This is extremely important in pregnancy. Pregnancy is a physiological process, but the marked increase of miscarriage, the rise in the number of sterile couples and other complications during pregnancy force physicians to seek the cause of these phenomena. Undiagnosed thyroid disease must be taken into consideration, because normal thyroid gland function is necessary for the maintenance of normal reproduction. Endocrinal changes and metabolic demands during pregnancy result in major alterations in the biochemical parameters of thyroid function. The increasing number of studies and various reports with new findings describing the relation between the thyroid gland and the reproduction system justifies physicians’ concern (1, 2, 3). However, research has alerted us to the fact that awareness among physicians of this complicated problem is still deficient (4). For many years in the Czech Republic there has been professional discussion about benefit of targeted or universal examination for thyropathies (5), and this discussion continues. Based on cooperation between world-renowned endocrinologists, the Clinical Guidelines of the Endocrine Society for the management of thyroid disorders during pregnancy was published in 2007 (6). It responds to the fact that hypothyroidism is diagnosed in 0.3-0.5% of pregnant women, subclinical hypothyoidism in 2-4% and TPOab positivity without thyroid dysfunction in 5-15% of pregnant women, and isolated hypothyroxinemia in 1.3-2%. In the Czech Republic the incidence of thyroid dysfunction in pregnant women is even higher (7,8). The results may differ partly according reference intervals used for pregnancy, which differ from ranges for nonpregnant persons, and according the method used. The effort to unify diagnostic and treatment procedures especially in borderline findings in pregnancy and to minimize false positive or negative findings resulted in creating intervals for TSH and suitable cut-off for antibodies. In the first trimester the TSH is artificially low (9, 10). In the case of targeted examination (6) a minimum of 30-50% of pregnant women would escape proper diagnosis (11, 12, 13). At present the practice of examination of pregnant women in relation to thyroid gland function in the Czech republic is as follows: the gynecologist may recommend laboratory examination of thyroid gland function, which is an expense recoverable from the health insurance system in cases of higher risk (i.e., thyroid gland disease in close relatives or if the woman has already been treated for thyroid disease or has symptoms of thyroid disease). Despite the intensive efforts of endocrinologists to explain the problem (14, 15) some gynecologists show no interest in systematic examination of thyroid gland function. Investigation of the parameters of the thyroid function, including antibodies, is for most laboratories absolutely routine practice, and results are available within a few days. The Society for Clinical Biochemistry has supported the idea of thyroid examination during pregnancy for PP even at the price slightly lower than the usually applied price.

Method

Based on negotiations between ČES, ČSKB-JEP and the General Insurance Company (VZP) we have succeeded in gaining support for our Pilot Project (PP). The Preventive Department of VZP granted means for the examination of 5000 pregnant women. The aim of the project was to ascertain the optimal combination and economic feasibility of diagnostic tests, the timing of the blood test and the possibility of connecting the test with genetic-disorder screening in the first trimester of pregnancy. The purpose of the study was also to provide information about cooperation among gynecologists, laboratories and endocrinologists. The interest of pregnant women in the examination was also evaluated, as well as the confirmation of previous results (8). Nearly two years of organizational measures preceded the implementation of the PP. The project started in spring 2009 and the first part was concluded by December 31, 2009. In the 13 chosen Czech regions with good laboratory and endocrinological backup, examinations were offered to pregnant women registered with the General Insurance Company (VZP). Prior to the PP information for the professional community concerning frequency of thyrepathies and consequences of untreated diseases as well as information for gynecologists about the beneficial nature of examination to pregnant women in the first trimester of pregnancy was made public through the mass media and professional events during the years 2007 to 2009. In the chosen regions (illustration 1) the gynecologists were informed by personal letter or by means of individual laboratory representatives. This happened prior to the commencement of the PP. It was necessary to notify pregnant women about the possibility of examination through their gynecologists, and especially so that they were informed about the importance of the whole project. To improve interdisciplinary collaboration, gynecologists were given contacts to endocrinologists in their vicinity, who were in turn informed about the necessity of making an appointment results within one or two weeks with pregnant women whose laboratory results diverged from the norm (telephone consultation was also possible). Endocrinologists were informed about the significance of the PP and also about the process of monitoring and treating pregnant women with thyropathies. Their response and interest was explicitly positive.

Three tests were chosen for the PP: examination of free thyroxine (FT4), antibodies against thyroid peroxidasis (TPOab) and thyrostimulating hormone (TSH). The FT4 examination yields information concerning actual hormone supply in the pregnant woman. The thyroxine level must not only be within the norm, but should be in the upper half of the normal range. The existence of TPOab provides information about thyroid gland autoimmunity and reveals women with higher risk to be unable to fully compensate for the required increment in thyroid hormone production, which hence leads progressively to subclinical or overt hypothyroidism, and eventually the development postpartum thyroiditis. The most important marker of thyroid gland function generally is TSH; in the first trimester, moreover, its value is influenced by hCG. Laboratories differed not only in the methods employed but also in the reference intervals (Table 1). Three laboratories made their own reference intervals for TSH in the first trimester of pregnancy. Organizational considerations dictated that the previously established term for blood tests was optimum, since the 9^th to 11^th weeks of pregnancy are used for screening genetic disorders. In this period it is possible to diagnose asymptomatic women with thyroid disease and to catch women with a higher risk of thyroid disease. Blood tests were carried out only after gaining the informed consent of the women. The expenses of these chosen tests were covered by the VZP’s Preventive Fund and did not encroach upon the gynecologists’ budgets.

Results:

Alltogether 2937 asymptomatic women in 9th to 11th week of pregnancy were examined. In 569 (18%) some positive results were found. Such results required telephone consultation, but for the most part further examination by the specialist. For these results, reference intervals in laboratories were used (table 1). The women’s mean age for the entire group was 29.4 years of age. The mean age of women with negative results was 29.2 years of age and was 33 years of women who were positive in all parameters tested , which is not of statistical significance. Deviations in the TSH level were found in 11% of women: elevation of the TSH level was found in 7.8%, and a suppressed level in 3.2% of women. But only in 15 (0.5%) women with TSH suppression was a diagnosis of hyperthyroidism established, as the TSH suppression was accompanied by FT4 elevation. A significantly lower FT4 level was found in 3.7%, of women, and the distribution of levels is shown on illustration 3. TPOab positivity was found in 262 women, i.e. in 8.9% of all examined , in 158 only positive antibodies without thyroid gland function change were found (illustration 4 ). Cooperation with the gynecologists varied individually, despite the fact that they were provided with all necessary information well in advance. The laboratories analyzed the samples promptly, and many of them took part in providing publicity and further information to other cooperating colleagues.

Discussion

The finding of increased TSH level in 7.8% women in our study indicates suboptimal or even low thyroid gland production, which may negatively influence the outcome of their pregnancies and my have other negative consequences as well. Thyroid hyperfunction was rather seldom, and was apparently only in 15 (0,5%) women from the whole group; in the remaining women TSH suppression was most likely due to hCG influence, i.e.,a relatively frequent finding in the third trimester and without any clinical significance. On the other hand a very important finding is low FT4 level in 3.7% of all women, as insufficient hormone supply may directly influence foetus development. TPOab positivity in 8.9% of all examined patients is noteworthy. Women who were discovered to have only positive antibodies even without actual thyroid function change are at much higher risk of thyroid dysfunction in the course of pregnancy or postpartum thyroiditis after delivery (16). Examination after delivery examination is desirable for these women. Some of the women with positive antibodies may later or during subsequent pregnancies have insufficient thyroid gland function. These women should be informed about the increased risk.

The PP was based on the fact that thyroid hormones play an important role during the whole life span; as well as an extremely important role in the period of development and during hormonal changes. Thyroidal hormones influence not only the actual conception, course and outcome of pregnancy, but also foetus development and the child’s later physical and mental status. Based on experimental animal studies Gabriela Moreales showed (17) the negative impact of insufficient levels of thyroid hormones during pregnancy on brain tissue growth. She emphasized the fact that even a mother’s borderline low thyroxin level during pregnancy may negatively influence the psychomotoric function of offspring. Up to the 12^th to 14^th week the embryo depends completely on the mother’s thyroxine, and even after that is still partially dependent on it. In the 1990s Moreales was followed by a group of clinical workers who warned that not only low FT4 levels, but also bordeline low FT4 may may cause psychomotoric failure in children (18, 19, 20,21). The consequences of T4 insufficiency may reveal themselves even later, since thyroid gland dysfunction in pregnancy proceeds unnoticed, either because it takes subclinical form, or because the symptoms are obscured by pregnancy difficulties. The problems are more complicated due to the fact that the thyroid hormone demands in pregnancy are higher, partly mediated physiologically by high hCG levels. If the thyroid gland is not able to react properly, hypothyroidism develops. Available evidence indicates that if maternal hypothyroidism is diagnosed and treated in early pregnancy the excess risk will be eliminated (18). Thus active case finding in early pregnancy is warranted. Even if the evidence is less clear, therapy is also advised in women with serum TSH above the reference range but normal serum T4.Thyrotoxicosis also has a negative impact on pregnancy outcome, but this situation is rather rare (22.15).

The worsening of the child’s mental development due to suboptimal maternal thyroid function has negative economic consequences resulting in inferior study performances and poorer professional performance. The first economic evaluation in USA calculates a loss of ,182 per adjusted life year according Stanford University researchers. The authors also conclude that universal thyroid screening in pregnancy is cost-effective (23). Based on our PP, Telička et al. (24) calculated the unit price for the diagnosis of subclinical and overt hypothyroid pregnant women in the Czech Republic.

Conception and the course of pregnancy in the last twenty years in the Czech Republic is influenced by many circumstances. Family planning based on birth-control medication is common; the age of pregnant women has shifted from approximately 22 to an average of 32, and mothers of 40 and over are no longer exceptions. Pregnancy is possible for women after oncological treatment or organ transplants, for women with heart disease or who have undergone heart operations. On the other hand the amount of infertile women and men has risen so that artificial fertilization has become much more common. Among women who have been artificially fertilized a fairly high amount of thyreopathies have been found (25). Even this process influences the demands made on the thyroid gland (26). Given this shifting situation it is the physicians’ duty not only to underline the significance of thyroid hormones for conception, for the physiological process of pregnancy, and for correct foetus development, but at the same time to promote the thyroid-function test in early pregnancy.

The laboratory findings are extremely important. There is consensus that for women who have already been treated for hypothyroidism, the upper limit of TSH should be 2.0 mIU/l. The hyperemesis gravidarum rather than thyrotoxicosis, which is rare, is mostly the cause of TSH suppression in the 1^st trimester, thus TSH suppression in pregnancy must be assessed only with respect to FT4, with respect to TPOab presence and always in accord with clinical signs

Discussions concerning the upper limit of physiological TSH of the reference range for the 1^st trimester (and which could be used for screening) are still in progress. A study was recently published which contributes to this discussion. It describes a group of 4123 women (those with thyrotoxicosis were excluded). In a group of TPOab negative women with TSH 2.5-5.0 mIU/l miscarriages were more frequent than in women with TSH lower than 2.5mIU/l (6.1 % vs 3.6%) with p less 0.006, but premature deliveries were not affected (27). The aforementioned study was logically followed by an analysis of TPOab-positive pregnant euthyroid women. Full-term pregnancies were more successful for women with T4 treatment (28), analogous to women in the study Poppe et al (29). It is clear that at the very beginning of pregnancy an appropriate level of thyroid hormones plays an important role. It is obvious that thyroid-thyroxine treatment improves the obstetrical outcome but in some women the presence of TPOab plays a role, and thus also the reaction of the immune system.

To set the individual analytes various methods are used, for which producers even give different reference intervals; especially in the case of anti-TPO antibodies the ranges cannot be compared. Analysis of laboratory results of individual methods confirmed the lack of reference intervals for different trimestr in pregnancy. The experience of endocrinologists and peer-to-peer network, along with cooperation with the laboratory provide the best solution. The combination of chosen methods in the PP is both rational and satisfactory. It allows access to information within 24-48 hours, and if the women with laboratory results meet the endocrinologist immediately, it is possible to commence treatment without delay.

The relatively high number of thyreopaties convinced some endocrinologists as early as 1997 to recommend inclusion of the thyroid-function test as a routine part of pregnancy examinations. The survey published by Glinoer (1) thirteen years ago is a basic review and documents the necessity to check on pregnant women for thyreopathies. The update in 2010 not only summarizes and supplements knowledge of autoimmune-thyroid disease as a frequent cause of thyroid dysfunction but expands our knowledge of aspects of IVF. The consequent sharp increase of estradiol may increase the need for thyroxine, and autoimmunity itself may have negative effects in the miscarriages among women in IVF treatment (3, 25). A well known factor which influences the activity of the thyroid gland is iodine, and the public has been informed about its important for many years now. (30). Further impacts, for instance selenium infliction as a thyroid autoimmunity lowering factor, should be taken in consideration (31). This short review provides a synopsis of our present understanding of thyroid and immune adaptation in pregnancy. Based on our experiences and the facts enumerated here we consider early diagnosis of thyroid dysfunction necessary. General discussion between specialists, insurance companies and health providers should be broached. The discussion should concentrate also on women who are planning pregnancy. As matters stand, there is no discussion of this issue on a global footing. The possibility of introducing the thyroid function test at an earlier stage of pregnancy (eventually prior to planned pregnancy), closer cooperation with general practitioners, utilization for premium care in the frame of insurance companies’ plans – all this awaits answers from professional societies and other subjects involved.

Conclusion

Timely diagnosis of thyroid disorders and their treatment during pregnancy not only prevents complications in the course of pregnancy, but also the possible problems with the embryo’s brain development as well as the danger of poor psychomotoric development of the child. The treatment is inexpensive in the beginnings of the illness. The PP verified the practicability of universal testing of selected thyroid indicators in pregnant women in their first trimester and provided a range of useful information. Examination of TSH, FT4 and TPOab provides the required information: it catches not only women with thyroid disorders , but also women with a heightened risk of thyroid illness. In 18% of asymptomatic pregnant women aberrations were ascertained in some of the selected indicators. The fact that 7.8% of the women had explicit pathological finding (heighted TSH and/or lower FT4) and clearly should be treated proves the sense of the whole project.

The challenge remains to raise the interest of gynecologists and pregnant women in this issue. The cost of examination of the necessary parameters is about 850 CZK. It is in the interest of medical professionals to seek ways of informing fertile women about the complexity of the problem, as well as use the mass media to pay attention to the issue of pregnancy and thyropathy. It is desirable to increase interdisciplinary cooperation. Certainly representatives of public health insurance companies should consider whether it is possible in the Czech Republic’s public health system to find financial sources for general screening or seek different ways (supplementary insurance, co-pay, as a service for patients with better coverage, exclusions paid completely by the insured themselves). In 2009 in Slovakia the Minister of Health brought in general screening for pregnant women.

We are gratefull to all participants ( gynecologist, laboratories, endocrinologists) who took care of pregnant women.

Doc. MUDr. Zdeňka Límanová, CSc,

III^rd Medical Clinic of Charles University, Prague

U nemocnice 1, Prague 2, 128 18

e-mail: liman@vfn.cz