The Attitude Toward Hypothyroidism

8/10/2019 The Attitude Toward Hypothyroidism

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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 conictingevidence of whether treatment of women with mild hypothyroidism is benecial. However, there is consensusthat all women with overt hypothyroidism (OH) and those with a thyrotropin (TSH) > 10 mIU/L should betreated immediately, but data on these conditions are scarce. We assessed the prevalence of OH and a TSH > 10mIU/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 thesoutheast of The Netherlands. We dened the rst trimester specic cutoffs (2.5th97.5th percentile) for TSHand free thyroxine (fT4) in thyroid peroxidase antibody (TPO-Ab) negative women in each study to determinethe prevalence of women with OH and those with a TSH > 10 mIU/L. We extrapolated these gures to thepregnant 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 caseswould be 1000, 4500, and 25,000 respectively. However, the United Kingdom and parts of the United Stateshave 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 bebased on data of overt hypothyroidism in healthy pregnant women. Screening of thyroid function is notexpensive because all pregnant women have a standardized blood sample test at 812 weeks gestation. Positivepatients largely benet from a cheap, safe, and effective treatment.

Introduction

D uring the last decade , whether to screen for thyroidfunction during early pregnancy has been hotly debated.The American Thyroid Association (ATA) pregnancyguidelines published in 2011 recommended against universalscreening and advocated a case-nding approach to identifywomen at high risk for hypothyroidism (1) because there isinsufcient evidence to recommend for or against universalthyrotropin (TSH) screening at the rst trimester visit. In theguidelines published in 2012, The Endocrine Society Task Force (ESTF) could not reach agreement on thyroid testingrecommendationsfor pregnant women (2); some recommendedscreening while others advocated aggressive case nding inhigh 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 amild degree of thyroid dysfunction such as subclinical hypo-thyroidism (elevated TSH with normal free thyroxine (fT4)levels) or hypothyroxinemia (normal TSH with low fT4 levels),women or their offspring will benet from treatment withthyroid hormone replacement therapy during pregnancy (4,5).However, there is uniform consensus that overt hypothyroid-ism (OH) should be treated in pregnancy. This includes womenwith a TSHconcentration above the trimester-specic referenceinterval with a decreased free-thyroid hormone (fT4), and allwomen with a TSH concentration above 10.0 mIU/L, irre-spective of the level of fT4 because numerous retrospectiveand case-controlled studies conrm the detrimental effects of OH on pregnancy and fetal health. Though no prospective,

1Department of Medical Health Psychology, University of Tilburg, Tilburg, The Netherlands.

2Department of Clinical Chemistry, Ma xima Medical Center, Eindhoven, The Netherlands.

3 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

THYROIDVolume 24, Number 10, 2014 Mary Ann Liebert, Inc.DOI: 10.1089/thy.2014.0007

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randomized investigation of LT4 intervention has occurred inOH pregnant women, such an investigation would be unethicaland prohibitive to complete. The available data conrm thebenets of treating OH during pregnancy (1). Finally, theATA 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 threeissues are concerned. However, the question remains of howprevalent untreated OH is in healthy pregnant women.There are very few data available in the literature, which wasreviewed by Stagnaro-Green in 2011 (6). He concluded thatthe actual rate of OH (0.3%) is probably greater because fourof the six studies in the review used an upper TSH limit whichis 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, andAmerican Caucasian women in 2012.

Materials and Methods

Subjects

Studies of Dutch Caucasian women were undertaken in thesame iodine sufcient areasoutheast of The Netherlandsin2002, 2005, and 2013. All participants were recruited accord-ing to the same protocol, and the studies were approved by theMedical Ethical Review Board of the Maxima Medical Hos-pital Veldhoven. Pregnant women who underwent their rstantenatal appointment at the community midwifeofce (whichin general represents 85% of all pregnant women in TheNetherlands) were invited for thyroid function screening. Theresponse rate varied between 74% and 82%. Through all threestudies, the NHANES exclusion criteria were used: a knownhistory of previous thyroid dysfunction (Hashimoto thyroiditisor Graves disease, on hormone replacement therapy or not), aknown history of autoimmune disease (e.g., diabetes mellitustype 1, rheumatoid arthritis), and the use of drugs that mightinterfere with thyroid function (e.g., use of lithium in bipolarpatients) (1). Women who became pregnant after in vitro fer-tilization (IVF) or hormone stimulation and women withmultiple pregnancies were also excluded. After receivingwritten 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 ina prospective follow-up study throughout gestation. Dataanalysis in the current study refers only to the thyroid outcomeresults of the rst trimester assessment and included 1354women from 2002, 1602 women from 2005, and 1243 womenfrom 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-sitechemiluminescent enzyme immunometric assay (IMMULITE

Third generation TSH; Diagnostic Products Corporation, LosAngeles, CA). The nonpregnant reference range of TSH is0.454.5 mIU/L. fT4 concentration was measured in serumwith a solid-phase immunometric assay (IMMULITE FreeT4). The nonpregnant reference range of fT4 is 10.325.7pmol/L. Thyroid peroxide antibodies (TPO-Abs) weredetermined in serum by means of the IMMULITE Anti-TPO-Ab kit. Women were dened as TPO-Ab-positive when the

titer was > 35 IU/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 0.404.0mU/L,of fT4 10.024.0pmol/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 fT4were dened following the same principles. In TPO-Ab neg-

ative women, the 2.5th and 97.5th percentiles were used todene the lower and upper limit of normal thyroid function.

Statistical analysis

Statistical analysis was performed using the IBM SPSSStatistics 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 wereTPO-Ab-positive. In the 1241 TPO-Ab-negative women, the2.5th and 97.5th percentiles of TSH and fT4 were 0.112.8

mIU/L and 11.221.5pmol/L respectively. In Table 1, thenumbers of women of the total group with TSH and fT4outside this reference range, together with their TPO-Abstatus, are shown. There were ve women with overt hypo-thyroidism and two women with a TSH > 10 mIU/L; all wereTPO-Ab positive.

This means that 7 of 1354 (0.5%) healthy pregnant womenhad unknown OH or a TSH > 10 mIU/L, all with (markedly)elevated TPO-Ab titers. In the 2005 study, 137 of 1602 womenhad elevated TPO-Ab (8.5%) titers. The 2.5th and 97.5th per-centiles of TSH and fT4 in the 1465 TPO-Ab negative womenwere 0.142.9 mIU/L and 12.020.6 pmol/L respectively. Asshown in Table 1, there were seven women with OH and threewith a TSH > 10 mIU/L. This means that of a healthy sampleof pregnant women, 10 out of 1602 (0.6%) had unknown OHor a TSH > 10 mIU/L. In the 2013 study, 97 of 1243 women(7.8%) had elevated TPO-Ab titers. In the remaining 1146TPO-Ab-negative women, the 2.5th and 97.5th cutoffs of TSHand fT4 were 0.193.9 mIU/L and 11.218.0 pmol/L respec-tively. As shown in Table 1, six women had OH and three had aTSH > 10 mIU/L (total of 0.7%). When we take the data of thethree studies together, there were 26 of a total of 4199 womenwith OH or a TSH > 10 mIU/L = 0.62%. The prevalence of subclinical hypothyroidism (elevated TSH with fT4 withinreference limits) in the 2002, 2005, and 2013 studies was 3.4%(n = 46), 3.6% ( n = 58), and 3.3% ( n = 41) respectively.

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We subsequently extrapolated these data to the annualbirth-rate gures in The Netherlands where, in 2012 (16million population, 85% Caucasian), there were 177,000births (Ofce for National Statistics 2012). It is well knownthat about 20% of pregnant women suffer from bleedingduring the rst 16 weeks, half of which will result in abor-tion (9). This means that there were approximately 195,000pregnancies annually, of which 160,000 were of DutchCaucasian women (estimated, because non-Western peoplehave higher birth-rate gures). Hence, screening all thesewomen would result in the detection of about 992 womenwith OH or a TSH > 10 mIU/L. In the United Kingdom (63million population), there were 730,000 living births in 2012,from approximately 800,000 pregnancies (Ofce for Na-tional Statistics 2012). Because 84% were from Caucasianmothers, it is estimated that there were 672,000 pregnanciesof white Caucasians. Using the data of the current study, this

would suggest that screening of all these pregnant womenwould result in about 4166 women with OH or a TSH > 10mIU/L. In the United States (population 312 million, 80%Caucasian), there were 4,270,000 births in 2012. Based on theNational 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 ratein this group, a conservative gure of four million white

Caucasian pregnancies is estimated. This would mean thatby nationwide thyroid screening during gestation, annuallyabout 24,800 pregnant women would be detected with OH ora 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 totalsample of 4199 women. The gure has been obtained usingrst 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 extrapolatingthis gure to the annual number of pregnant women in dif-

ferent countries (The Netherlands, the United Kingdom, andthe United States), every year a substantial number of womenwith OH (992, 4166, and 24,800 respectively) are missed,who, according to the ATA pregnancy guidelines, shouldreceive 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 havebeen published, reporting gures of OH (6). It is beyond thescope of the current study to review these in detail. However,in general, they are difcult to compare because they useddifferent 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 andfT4 in TPO-Ab negative low-risk women (using the NHANEScriteria) in each trimester (1). In the absence of these cutoffs,several authors use the TSH cutoff recommended by the ATAof 2.5 mIU/L for the rst trimester. Using this cutoff in thecurrent study, this upper limit of 2.5 mIU/L would correspondto the 93th, 92th, and 88th TSH percentile in TPO-Ab negativewomen in the 2002, 2005, and 2013 samples respectively,resulting in an overall prevalence of OH of 35 (0.8%), of whom 63%wereTPO-Ab positive. When in additionthe lowercutoff of fT4 of the 5th percentile recommended by the ATAwas used (instead of the 2.5th), the overall number of womenwith OH in the current study would further increase to 46(1.1%), of whom 54% were TPO-Ab positive. Other studiesdid assess TSH between 8 and 26 weeks gestation, but it iswell known that with increasing term, the median TSH levelincreases, making it difcult to use these data to dene the rsttrimester cutoff. Some studies did not include the categoryof women with a TSH level > 10 mIU/L with normal fT4, asubgroup 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 fromobstetric medical record reports in order to calculate theprevalence number, but it is well known that a substantialnumber of OH cases are missed when, for example, case

Table 1. SH, f T4, and TPO- Ab Status of Womenof a General Healthy Pregnant Population

with Unknown OH or a TSH > 10 mIU/L, Using FirstTrimester 2.5th and 97.5 th Percentile Cutoffs

of TSH and f T4 in TPO- Ab Negative Women

TSH (mIU/L)

fT4(pmol/L)

TPO-Abtiter IU/mL

2002 study, n = 1354Reference: TSH: 0.112.8 mIU/LfT4: 11.221.5 pmol/LHypothyroidism: 6.40 10.2 141

8.72 7.8 19509.70 8.9 450

14.70 8.7 26530.70 6.9 4816

TSH > 10 mIU/L: 10.70 12.7 48211.84 13.1 792

2005 study, n = 1602Reference: TSH: 0.142.9 mIU/LfT4: 12.020.6 pmol/LHypothyroidism: 9.2 11.0 31,000

3.1 11.1 667.9 10.9 36006.2 7.1 2400

86.0 2.5 9304.4 11.0 9

22.0 9.4 2200TSH > 10 mIU/L: 10.8 13.4 920

11.4 12.9 38914.2 13.2 212

2013 study, n = 1243Reference: TSH: 0.193.9 mIU/LfT4: 11.218.0 pmol/LHypothyroidism: 120 4.6 550

5.1 11.0 7213.0 11.0 750

6.7 10.4 2308.1 9.9 2008.6 10.7 350

TSH > 10 mIU/L: 12.0 15.0 35011.4 12.9 38211.8 11.9 470

TSH, thyrotropin; fT4, free thyroxine; TPO-Ab, thyroid perox-idase antibody; OH, overt hypothyroidism.

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nding in high risk women is applied instead of universalscreening (11). Most studies reporting high numbers of hy-pothyroidism (up to 15%) often did not discriminate betweensubclinical and overt hypothyroidism. Therefore, in Table 2,the prevalence rate of OH is shown of studies using more orless the same (NHANES) criteriaas in the current study (5,1018). Studies reporting other cutoffs (5th95th percentiles, notexcluding TPO-Ab positive cases) are not included.

The study by Potlukova et al . of 5223 women from theCzech Republic (also an iodine sufcient area) using a sim-ilar methodology as the current study showed an overallprevalence 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 inour 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 thesubgroup with a TSH > 10 mIU/L (13). If one assumes asimilar 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. inan iodine sufcient area of China, eight (0.3%) women hadOH, with no data on the subgroup with a TSH > 10 mIU/L(18). These studies clearly show that there is a variableprevalence of OH (with or without low fT4). The overallnumber of 0.62% of OH in the current study, resulting in anestimated number of 24,000 women in the United States whoannually suffer from undiagnosed OH, is rather close to theestimated 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 outcomesinclude gestational hypertension, pre-eclampsia, and in-

creased placental weight. Fetal adverse outcomes includecretinism, 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 aTSH > 10 mIU/L had (highly) elevated TPO-Ab titers, whichmeans that thyroid dysfunction was of autoimmune origin.This number dropped to 54% when using a lower TSH upperlimit (2.5 mIU/L) and/or a higher fT4 lower limit (5th per-centile), suggesting that the 2.5th97.5th percentile referencerange in TPO-Ab negative women of the current study israther 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 in2006 and 2007 resulted in the detection of 13 (1.5%) new-borns with a TSH > 5 mIU/L, a gure that is < 3%, a generallyaccepted cutoff showing sufcient iodine intake at a popu-lation level (21,22). In contrast to The Netherlands, a recentBritish study revealed iodine deciency in 737 adolescentschoolgirls: 51% with mild, 16% with moderate, and 1% withsevere deciency (23). A further British study performed in2013 in 1000 pregnant women found severe and mild-to-moderate iodine deciency in 7% and 60% of the womenrespectively (24). During pregnancy, the iodine requirementis sharply elevated, and it has long been demonstrated that

iodine deciency during pregnancy will result in highermaternal TSH levels (22). This implies that more women areexpected to have elevated TSH levels, and these should beadded 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 sufcientcountry, although there are concerns that this may not be thecase 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 therelevance of detecting subtle (subclinical) thyroid dysfunc-tion during early gestation, prevalent in 13% of the generalpregnant population (1). Because the negative consequenceson pregnancy outcomes for both mother and child are still

debated, and the few intervention studies showed ratherconicting results (4,5), there is still no agreement for ad-vocating universal screening. However, we and others, asrecently stated in a review on thyroid dysfunction duringgestation, 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 PregnantWomen in Different Studies, Using Trimester-Specic 2.5th and 97.5 th Percentile Cutoffs

of TSH and f T4 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.

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that should denitely be treated) instead of subclinical hy-pothyroidism, the number of women that would annually befound in our country (at least 1000, all ethnic groups in-cluded), in the United Kingdom (at least 4500, all ethnicgroups included), and in the United States (up to 25,000women, all ethnic groups included) make screening of allpregnant women worthwhile. It does not make sense to statethat because we do not know whether there is any benet of

treating a relatively large group of pregnant women withmild (sub-clinical) hypothyroidism that will be found whenscreening is implemented, we do not advocate nationwidescreening, although we know that there is a (smaller) groupof 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 easyto perform: all pregnant women in Western societies have astandardized blood assessment at 812 weeks gestation.Adding a TSH measurement would cost 612 US dollars.Subsequent treatment with T4 is also cheap, effective, andsafe. The studies that investigated the cost-effectiveness of screening showed that universal screening was by far themost cost-effective strategy (28,29).

We feel that thehigh number of healthy pregnant womenwith unknown severe hypothyroidism according to recentreference criteria of trimester-specic normal thyroid functionin an iodine sufcient area underlines the need of screeningthe thyroid function of the general pregnant population.

Acknowledgment

We would like to thank all the community midwives of thesoutheast area of The Netherlands for their participation intothe 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 intheprevious three years, andno other relationships or activitiesthat could appear to have inuenced the submitted work.

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29. Dosiou C, Barnes J, Schwartz A, Negro R, Crapo L,Stagnaro-Green A 2012 Cost-effectiveness of universaland risk-based screening for autoimmune thyroid diseasein pregnant women. J Clin Endocrinol Metab 97: 15361546.

Address correspondence to:Victor J. Pop, MD, PhD

Department of Medical Health Psychology

University of TilburgPO Box 901535000 LE TilburgThe Netherlands

E-mail: [email protected]

1546 POP ET AL.

Documents

The Attitude Toward Hypothyroidism