The Attitude Toward Hypothyroidism During Early Gestation:
Time for a Change of Mind?
Victor Pop, 1 Maarten Broeren, 2 and Wilmar Wiersinga 3 Background: The approach not to screen thyroid function of all pregnant women is mainly based on conicting evidence of whether treatment of women with mild hypothyroidism is benecial. However, there is consensus that all women with overt hypothyroidism (OH) and those with a thyrotropin (TSH) >10 mIU/L should be treated immediately, but data on these conditions are scarce. We assessed the prevalence of OH and a TSH >10 mIU/L during the rst trimester of pregnancy. Methods: Thyroid function was assessed at 1012 weeks gestation in 4199 Dutch Caucasian healthy pregnant women from three studies conducted in 2002, 2005, and 2013 from the same iodine sufcient area in the southeast of The Netherlands. We dened the rst trimester specic cutoffs (2.5th97.5th percentile) for TSH and free thyroxine (fT4) in thyroid peroxidase antibody (TPO-Ab) negative women in each study to determine the prevalence of women with OH and those with a TSH >10 mIU/L. We extrapolated these gures to the pregnant population of 2012 in The Netherlands, the United Kingdom, and the United States. Results: The prevalence of OH or a TSH >10 mIU/L in these 4199 women was 26 (0.62%) of whom 96% had (highly) elevated TPO-Ab titers. Based on the birth gures of 2012, if all pregnant women from The Neth- erlands, the United Kingdom or the United States were screened, the conservative annual number of cases would be 1000, 4500, and 25,000 respectively. However, the United Kingdom and parts of the United States have recently been demonstrated to be iodine decient, which will result in even higher numbers. Conclusion: Our ndings show that the discussion concerning thyroid screening during pregnancy should be based on data of overt hypothyroidism in healthy pregnant women. Screening of thyroid function is not expensive because all pregnant women have a standardized blood sample test at 812 weeks gestation. Positive patients largely benet from a cheap, safe, and effective treatment. Introduction D uring the last decade, whether to screen for thyroid function during early pregnancy has been hotly debated. The American Thyroid Association (ATA) pregnancy guidelines published in 2011 recommended against universal screening and advocated a case-nding approach to identify women at high risk for hypothyroidism (1) because there is insufcient evidence to recommend for or against universal thyrotropin (TSH) screening at the rst trimester visit. In the guidelines published in 2012, The Endocrine Society Task Force (ESTF) could not reach agreement on thyroid testing recommendations for pregnant women (2); some recommended screening while others advocated aggressive case nding in high risk women, an approach similar to the 2011 ATA guide- lines. The American Association of Clinical Endocrinologists/ ATA (AACCE/ATA) hypothyroidism guidelines also cur- rently recommend a case-nding approach (3). This contro- versy is mainly based on conicting evidence that, in case of a mild degree of thyroid dysfunction such as subclinical hypo- thyroidism (elevated TSH with normal free thyroxine (fT4) levels) or hypothyroxinemia (normal TSHwith lowfT4 levels), women or their offspring will benet from treatment with thyroid hormone replacement therapy during pregnancy (4,5). However, there is uniform consensus that overt hypothyroid- ism (OH) should be treated in pregnancy. This includes women with a TSHconcentration above the trimester-specic reference interval with a decreased free-thyroid hormone (fT4), and all women with a TSH concentration above 10.0 mIU/L, irre- spective of the level of fT4 because numerous retrospective and case-controlled studies conrm the detrimental effects of OH on pregnancy and fetal health. Though no prospective, 1 Department of Medical Health Psychology, University of Tilburg, Tilburg, The Netherlands. 2 Department of Clinical Chemistry, Maxima Medical Center, Eindhoven, The Netherlands. 3 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. THYROID Volume 24, Number 10, 2014 Mary Ann Liebert, Inc. DOI: 10.1089/thy.2014.0007 1541 randomized investigation of LT4 intervention has occurred in OH pregnant women, such an investigation would be unethical and prohibitive to complete. The available data conrm the benets of treating OH during pregnancy (1). Finally, the ATA pregnancy guidelines summarize the basic principles of thyroid function screening in all pregnant women: The con- dition must be (a) prevalent in asymptomatic individuals; (b) there must be a reliable and readily available test to identify the cases; (c) there must be a benecial intervention available; which should be (d) cost-effective (1). With regard to OH, there is consensus as far as the last three issues are concerned. However, the question remains of how prevalent untreated OH is in healthy pregnant women. There are very few data available in the literature, which was reviewed by Stagnaro-Green in 2011 (6). He concluded that the actual rate of OH(0.3%) is probably greater because four of the six studies in the review used an upper TSH limit which is now believed to be inappropriately high (6). Moreover, ethnic differences should also be taken into account (7,8). To address these issues, we investigated the prevalence of OH and of a TSH >10 mIU/l in white Dutch Caucasian wo- men using strict criteria as advocated by the NHANES (National Health and Nutrition Examination Survey) criteria (1). Subsequently, we extrapolated these ndings to gures of the whole pregnant population of Dutch, British, and American Caucasian women in 2012. Materials and Methods Subjects Studies of Dutch Caucasian women were undertaken in the same iodine sufcient areasoutheast of The Netherlandsin 2002, 2005, and 2013. All participants were recruited accord- ing to the same protocol, and the studies were approved by the Medical Ethical Review Board of the Maxima Medical Hos- pital Veldhoven. Pregnant women who underwent their rst antenatal appointment at the community midwife ofce (which in general represents 85% of all pregnant women in The Netherlands) were invited for thyroid function screening. The response rate varied between 74% and 82%. Through all three studies, the NHANES exclusion criteria were used: a known history of previous thyroid dysfunction (Hashimoto thyroiditis or Graves disease, on hormone replacement therapy or not), a known history of autoimmune disease (e.g., diabetes mellitus type 1, rheumatoid arthritis), and the use of drugs that might interfere with thyroid function (e.g., use of lithium in bipolar patients) (1). Women who became pregnant after in vitro fer- tilization (IVF) or hormone stimulation and women with multiple pregnancies were also excluded. After receiving written informed consent, thyroid function was assessed be- tween 10 and 12 weeks gestation in all participants; a sub- stantial proportion of these women subsequently participated in a prospective follow-up study throughout gestation. Data analysis in the current study refers only to the thyroid outcome results of the rst trimester assessment and included 1354 women from 2002, 1602 women from 2005, and 1243 women from 2013, resulting in a total of 4199 women for the analysis. Thyroid function assessment in 2003 and 2005 TSH was measured in serum using a solid-phase, two-site chemiluminescent enzyme immunometric assay (IMMULITE Third generation TSH; Diagnostic Products Corporation, Los Angeles, CA). The nonpregnant reference range of TSH is 0.454.5 mIU/L. fT4 concentration was measured in serum with a solid-phase immunometric assay (IMMULITE Free T4). The nonpregnant reference range of fT4 is 10.3 25.7 pmol/L. Thyroid peroxide antibodies (TPO-Abs) were determined in serum by means of the IMMULITE Anti-TPO- Ab kit. Women were dened as TPO-Ab-positive when the titer was >35IU/mL. Thyroid function assessment in 2013 TSH, fT4, and TPO-Abs were determined in lithium- heparin plasma using electrochemoluminescence assays (Cobas
e 601; Roche Diagnostics, Mannheim, Germany).
The nonpregnant reference range of TSH is 0.404.0 mU/L, of fT4 10.024.0 pmol/L, and of TPO-Abs <35 kU/L. Denition of reference range of thyroid function at rst trimester In all three studies, the reference ranges of TSH and fT4 were dened following the same principles. In TPO-Ab neg- ative women, the 2.5th and 97.5th percentiles were used to dene the lower and upper limit of normal thyroid function. Statistical analysis Statistical analysis was performed using the IBM SPSS Statistics for Windows v19.0 (IBM Corp., Armonk, NY). Descriptive statistics were used to analyze the prevalence of abnormal thyroid dysfunction. Results In the 2002 study, 113 (8.3%) of the 1354 women were TPO-Ab-positive. In the 1241 TPO-Ab-negative women, the 2.5th and 97.5th percentiles of TSH and fT4 were 0.112.8 mIU/L and 11.221.5 pmol/L respectively. In Table 1, the numbers of women of the total group with TSH and fT4 outside this reference range, together with their TPO-Ab status, are shown. There were ve women with overt hypo- thyroidism and two women with a TSH >10 mIU/L; all were TPO-Ab positive. This means that 7 of 1354 (0.5%) healthy pregnant women had unknown OH or a TSH >10 mIU/L, all with (markedly) elevated TPO-Ab titers. In the 2005 study, 137 of 1602 women had elevated TPO-Ab (8.5%) titers. The 2.5th and 97.5th per- centiles of TSH and fT4 in the 1465 TPO-Ab negative women were 0.142.9 mIU/L and 12.020.6 pmol/L respectively. As shown in Table 1, there were seven women with OH and three with a TSH >10 mIU/L. This means that of a healthy sample of pregnant women, 10 out of 1602 (0.6%) had unknown OH or a TSH >10 mIU/L. In the 2013 study, 97 of 1243 women (7.8%) had elevated TPO-Ab titers. In the remaining 1146 TPO-Ab-negative women, the 2.5th and 97.5th cutoffs of TSH and fT4 were 0.193.9 mIU/L and 11.218.0 pmol/L respec- tively. As shown in Table 1, six women had OHand three had a TSH >10 mIU/L (total of 0.7%). When we take the data of the three studies together, there were 26 of a total of 4199 women with OH or a TSH >10 mIU/L=0.62%. The prevalence of subclinical hypothyroidism (elevated TSH with fT4 within reference limits) in the 2002, 2005, and 2013 studies was 3.4% (n =46), 3.6% (n =58), and 3.3% (n =41) respectively. 1542 POP ET AL. We subsequently extrapolated these data to the annual birth-rate gures in The Netherlands where, in 2012 (16 million population, 85% Caucasian), there were 177,000 births (Ofce for National Statistics 2012). It is well known that about 20% of pregnant women suffer from bleeding during the rst 16 weeks, half of which will result in abor- tion (9). This means that there were approximately 195,000 pregnancies annually, of which 160,000 were of Dutch Caucasian women (estimated, because non-Western people have higher birth-rate gures). Hence, screening all these women would result in the detection of about 992 women with OH or a TSH >10 mIU/L. In the United Kingdom (63 million population), there were 730,000 living births in 2012, from approximately 800,000 pregnancies (Ofce for Na- tional Statistics 2012). Because 84% were from Caucasian mothers, it is estimated that there were 672,000 pregnancies of white Caucasians. Using the data of the current study, this would suggest that screening of all these pregnant women would result in about 4166 women with OH or a TSH >10 mIU/L. In the United States (population 312 million, 80% Caucasian), there were 4,270,000 births in 2012. Based on the National Vital Statistics report of 2012, this birth rate cor- responds to more than ve million pregnancies. With 80% white Caucasian females and a relatively lower birth rate in this group, a conservative gure of four million white Caucasian pregnancies is estimated. This would mean that by nationwide thyroid screening during gestation, annually about 24,800 pregnant women would be detected with OH or a TSH >10 mIU/L in the United States. Discussion The current study underlines the relatively high number of unknown cases of pregnant women with OH (0.6%) in a total sample of 4199 women. The gure has been obtained using rst trimester-specic reference ranges for TSH and fT4 as- sessed in TPO-Ab negative pregnant women under applica- tion of the NHANES exclusion criteria. When extrapolating this gure to the annual number of pregnant women in dif- ferent countries (The Netherlands, the United Kingdom, and the United States), every year a substantial number of women with OH (992, 4166, and 24,800 respectively) are missed, who, according to the ATA pregnancy guidelines, should receive immediate treatment. The prevalence of elevated TPO-Ab in the three studies (7.88.5%) is comparable with the gures in the literature (1) and with two other reports from The Netherlands (7,10). During the last decade, several population-based studies have been published, reporting gures of OH (6). It is beyond the scope of the current study to review these in detail. However, in general, they are difcult to compare because they used different methods of dening cutoffs of reference ranges of TSH and fT4. It is now generally accepted that trimester- specic reference ranges should be dened for both TSH and fT4 in TPO-Ab negative low-risk women (using the NHANES criteria) in each trimester (1). In the absence of these cutoffs, several authors use the TSH cutoff recommended by the ATA of 2.5 mIU/L for the rst trimester. Using this cutoff in the current study, this upper limit of 2.5 mIU/L would correspond to the 93th, 92th, and 88th TSHpercentile in TPO-Ab negative women in the 2002, 2005, and 2013 samples respectively, resulting in an overall prevalence of OH of 35 (0.8%), of whom63%were TPO-Ab positive. When in addition the lower cutoff of fT4 of the 5th percentile recommended by the ATA was used (instead of the 2.5th), the overall number of women with OH in the current study would further increase to 46 (1.1%), of whom 54% were TPO-Ab positive. Other studies did assess TSH between 8 and 26 weeks gestation, but it is well known that with increasing term, the median TSH level increases, making it difcult to use these data to dene the rst trimester cutoff. Some studies did not include the category of women with a TSH level >10 mIU/L with normal fT4, a subgroup that should also receive immediate treatment as re- commended by the ATA pregnancy guidelines (1). Again, other studies with a retrospective design did use a diagnosis of hypothyroidism based on discharge data or extracted from obstetric medical record reports in order to calculate the prevalence number, but it is well known that a substantial number of OH cases are missed when, for example, case Table 1. SH, fT4, and TPO-Ab Status of Women of a General Healthy Pregnant Population with Unknown OH or a TSH >10 mIU/L, Using First Trimester 2.5th and 97.5th Percentile Cutoffs of TSH and fT4 in TPO-Ab Negative Women TSH (mIU/L) fT4 (pmol/L) TPO-Ab titer IU/mL 2002 study, n = 1354 Reference: TSH: 0.112.8 mIU/L fT4: 11.221.5 pmol/L Hypothyroidism: 6.40 10.2 141 8.72 7.8 1950 9.70 8.9 450 14.70 8.7 265 30.70 6.9 4816 TSH >10 mIU/L: 10.70 12.7 482 11.84 13.1 792 2005 study, n = 1602 Reference: TSH: 0.142.9 mIU/L fT4: 12.020.6 pmol/L Hypothyroidism: 9.2 11.0 31,000 3.1 11.1 66 7.9 10.9 3600 6.2 7.1 2400 86.0 2.5 930 4.4 11.0 9 22.0 9.4 2200 TSH >10 mIU/L: 10.8 13.4 920 11.4 12.9 389 14.2 13.2 212 2013 study, n = 1243 Reference: TSH: 0.193.9 mIU/L fT4: 11.218.0 pmol/L Hypothyroidism: 120 4.6 550 5.1 11.0 72 13.0 11.0 750 6.7 10.4 230 8.1 9.9 200 8.6 10.7 350 TSH >10 mIU/L: 12.0 15.0 350 11.4 12.9 382 11.8 11.9 470 TSH, thyrotropin; fT4, free thyroxine; TPO-Ab, thyroid perox- idase antibody; OH, overt hypothyroidism. GESTATIONAL HYPOTHYROIDISM: TIME FOR A CHANGE OF MIND 1543 nding in high risk women is applied instead of universal screening (11). Most studies reporting high numbers of hy- pothyroidism (up to 15%) often did not discriminate between subclinical and overt hypothyroidism. Therefore, in Table 2, the prevalence rate of OH is shown of studies using more or less the same (NHANES) criteria as in the current study (5,10 18). Studies reporting other cutoffs (5th95th percentiles, not excluding TPO-Ab positive cases) are not included. The study by Potlukova et al. of 5223 women from the Czech Republic (also an iodine sufcient area) using a sim- ilar methodology as the current study showed an overall prevalence rate of 0.75% (0.4% of OH and 0.35% of a TSH >10 mIU/L), which is comparable to the current study (14). The 0.2% of women with isolated TSH levels >10 mIU/L in our study is comparable to the gure of 0.33% of the Con- trolled Antenatal Thyroid Screening (CATS) study per- formed in the United Kingdom and Italy (unpublished data) in which more than 20,000 women were screened (5). An- other large study from The Netherlands (Generation-R) re- ported a prevalence of 0.3%, although it does not mention the subgroup with a TSH >10 mIU/L (13). If one assumes a similar number of these women as in the Czech Republic or the current study, their number should increase to 0.50.6%, comparable to our study. In the 2011 study by Wang et al. in an iodine sufcient area of China, eight (0.3%) women had OH, with no data on the subgroup with a TSH >10 mIU/L (18). These studies clearly show that there is a variable prevalence of OH (with or without low fT4). The overall number of 0.62% of OH in the current study, resulting in an estimated number of 24,000 women in the United States who annually suffer from undiagnosed OH, is rather close to the estimated gure of Stagnaro-Green of 20,000 (19). The maternal and fetal adverse outcomes of OH have re- cently been reviewed elsewhere and are remarkably consis- tent throughout the literature (6). Maternal adverse outcomes include gestational hypertension, pre-eclampsia, and in- creased placental weight. Fetal adverse outcomes include cretinism, low birth weight, fetal deaths, spontaneous abor- tion, intrauterine growth retardation, and pre-eclampsia. These ndings are the basis for the well-accepted recom- mendation that OH during pregnancy should be treated im- mediately and appropriately (1). In the current study, up to 96% of the women with OH or a TSH >10 mIU/L had (highly) elevated TPO-Ab titers, which means that thyroid dysfunction was of autoimmune origin. This number dropped to 54% when using a lower TSH upper limit (2.5 mIU/L) and/or a higher fT4 lower limit (5th per- centile), suggesting that the 2.5th97.5th percentile reference range in TPO-Ab negative women of the current study is rather accurate. The area where the studies were conducted is iodine suf- cient as shown in 2001 (20). Moreover, in the 2005 study, results of congenital heel screening in 886 neonates born in 2006 and 2007 resulted in the detection of 13 (1.5%) new- borns with a TSH >5 mIU/L, a gure that is <3%, a generally accepted cutoff showing sufcient iodine intake at a popu- lation level (21,22). In contrast to The Netherlands, a recent British study revealed iodine deciency in 737 adolescent schoolgirls: 51%with mild, 16%with moderate, and 1%with severe deciency (23). A further British study performed in 2013 in 1000 pregnant women found severe and mild-to- moderate iodine deciency in 7% and 60% of the women respectively (24). During pregnancy, the iodine requirement is sharply elevated, and it has long been demonstrated that iodine deciency during pregnancy will result in higher maternal TSH levels (22). This implies that more women are expected to have elevated TSH levels, and these should be added to the estimated number of 4166 women with (auto- immune-based) thyroid dysfunction in the United Kingdom. The United States is considered a relatively iodine sufcient country, although there are concerns that this may not be the case for all pregnant women, especially during the rst tri- mester (25). During recent decades, the discussion on whe- ther to screen for thyroid function has focused on the relevance of detecting subtle (subclinical) thyroid dysfunc- tion during early gestation, prevalent in 13% of the general pregnant population (1). Because the negative consequences on pregnancy outcomes for both mother and child are still debated, and the few intervention studies showed rather conicting results (4,5), there is still no agreement for ad- vocating universal screening. However, we and others, as recently stated in a review on thyroid dysfunction during gestation, feel that it is time for a change of mind (26,27). If one focuses on OH and a TSH >10 mIU/L (both conditions Table 2. Prevalence of Unknown OH and a TSH >10 mIU/L in Healthy First Trimester Pregnant Women in Different Studies, Using Trimester-Specic 2.5th and 97.5th Percentile Cutoffs of TSH and fT4 of TPO-Ab Negative Women N (%) of cases Total sample size OH TSH >10 mIU/L Total Casey et al. 2005 (10) 17,298 32 (0.18) 50 (0.29) 82 (0.47) Vaidya et al. 2007 (11) 1560 16 (1) 3 (0.2) 19 (1.2) Cleary-Goldman et al. 2008 (12) 10,990 33 (0.3) ? Wang et al. 2011 (18) 2899 8 (0.3) ? Lazarus et al. 2012 (5) 21,000 55 (0.26) 69 (0.33)* 124 (0.59) Blatt et al. 2012 (16) 117,892 436 (0.36) ? Medici et al. 2012 (13) 3944 12 (0.3) ? Potlukova et al. 2012 (14) 5223 21 (0.49) 18 (0.3) 39 (0.75) Goel et al. 2012 (15) 1005 2 (0.02) ? Moreno-Reys et al. 2013 (17) 640 5 (0.4) ? *Unpublished data. 1544 POP ET AL. that should denitely be treated) instead of subclinical hy- pothyroidism, the number of women that would annually be found in our country (at least 1000, all ethnic groups in- cluded), in the United Kingdom (at least 4500, all ethnic groups included), and in the United States (up to 25,000 women, all ethnic groups included) make screening of all pregnant women worthwhile. It does not make sense to state that because we do not know whether there is any benet of treating a relatively large group of pregnant women with mild (sub-clinical) hypothyroidism that will be found when screening is implemented, we do not advocate nationwide screening, although we know that there is a (smaller) group of women that will be found during screening with untreated serious overt hypothyroidism to whom it is even unethical not offering treatment. The TSH test is reliable, cheap, and easy to perform: all pregnant women in Western societies have a standardized blood assessment at 812 weeks gestation. Adding a TSH measurement would cost 612 US dollars. Subsequent treatment with T4 is also cheap, effective, and safe. The studies that investigated the cost-effectiveness of screening showed that universal screening was by far the most cost-effective strategy (28,29). We feel that the high number of healthy pregnant women with unknown severe hypothyroidism according to recent reference criteria of trimester-specic normal thyroid function in an iodine sufcient area underlines the need of screening the thyroid function of the general pregnant population. Acknowledgment We would like to thank all the community midwives of the southeast area of The Netherlands for their participation into the recruitment of pregnant women for more than a decade. Author Disclosure Statement The authors declare no support from any organization for the submitted work, no nancial relationships with any orga- nizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have inuenced the submitted work. References 1. 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Am J Obstet Gynecol 200:267.e 17. 29. Dosiou C, Barnes J, Schwartz A, Negro R, Crapo L, Stagnaro-Green A 2012 Cost-effectiveness of universal and risk-based screening for autoimmune thyroid disease in pregnant women. J Clin Endocrinol Metab 97:1536 1546. Address correspondence to: Victor J. Pop, MD, PhD Department of Medical Health Psychology University of Tilburg PO Box 90153 5000 LE Tilburg The Netherlands E-mail: v.j.m.pop@uvt.nl 1546 POP ET AL.