Thyroid Function Testing and Management During and After Pregnancy Among Women Without Thyroid Disease Before Pregnancy

RESEARCH HEALTH SERVICES

Thyroid function testing and management during and after pregnancy among women without thyroid disease before pregnancy

Jennifer M. Yamamoto MD, Amy Metcalfe PhD, Kara A. Nerenberg MD, Rshmi Khurana MD, Alex Chin PhD, Lois E. Donovan MD

n Cite as: CMAJ 2020 June 1;192:E596-602. doi: 10.1503/cmaj.191664

ABSTRACT

BACKGROUND: Screening in pregnancy between October 2014 and September initiated at a median gestational age of for subclinical hypothyroidism, often 2017. We used delivery records, phys 7 (interquartile range 5–12) weeks. defined as thyroid-stimulating hormone ician billings, and pharmacy and labora- Among women with first TSH measure- (TSH) greater than 2.5 mIU/L or greater tory administrative data. Our key out- ments of 4.01 to 9.99 mIU/L who were than 4.0 mIU/L, is controversial. We comes were characteristics of TSH not immediately treated, the repeat TSH determined the frequency and distribu- testing and the initiation and continua- measurement was 4.00 mIU/L or below tion of TSH testing by gestational age, tion of thyroid hormone therapy. We in 67.9% of pregnancies. Thyroid hor- as well as TSH values associated with calculated the proportion of pregnan- mone was continued post partum for treatment during pregnancy and the fre- cies with thyroid testing and the fre- 44.6% of the women who started ther- quency of postpartum continuation of quency of each specific thyroid test. apy during their pregnancy. thyroid hormone therapy. RESULTS: Of the 188 490 pregnancies INTERPRETATION: The findings of our METHODS: We performed a retrospec- included, 111 522 (59.2%) had at least study suggest that current practice pat- tive cohort study of pregnancies in 1 TSH measurement. The most common terns may contribute to overdiagnosis Alberta, Canada. We included women time for testing was at gestational week of hypothyroidism and overtreatment without thyroid disease who delivered 5 to 6. Thyroid hormone therapy was during pregnancy and post partum.

n the past 3 decades, undiagnosed or subclinical hypothyroidism Known changes in thyroid physiology during pregnancy during pregnancy has been variably associated with adverse have led to controversy about the upper TSH reference limit in maternal and childhood outcomes in observational studies.1,2 pregnancy. Specifically, human chorionic gonadotropin is a IHowever, in the absence of strong evidence showing a benefit of levo- weak TSH receptor stimulator that contributes to a decline in thyroxine therapy for subclinical hypothyroidism in pregnancy, confu- TSH after 7 weeks’ gestation and a return of TSH to pre- sion has arisen about the utility of screening using thyroid- pregnancy ranges after human chorionic gonadotropin peaks, stimulating hormone (TSH) during pregnancy. A common challenge at about 10 to 11 weeks’ gestation. Studies to establish with TSH screening is that it identifies many women with minor eleva- pregnancy-specific reference ranges, which were initially done tion of TSH, specifically subclinical hypothyroidism. Subclinical hypo- in the United States and Europe late in the first trimester or thyroidism in pregnancy has a variety of definitions, such as TSH early in the second trimester, led to the recommendation to use greater than 2.5 mIU/L, TSH greater than 4.0 mIU/L or TSH above the a TSH upper limit of 2.5 mIU/L in the first trimester and upper limit of the assay-specific reference range for gestational age in 3.0 mIU/L in the second and third trimesters.10–12 Subsequent combination with a normal level of free thyroxine.3 Recent evidence studies in other populations and earlier in pregnancy found from large, high-quality randomized controlled trials (RCTs) has con- that these upper limits were not appropriate for all ethnicities sistently shown no benefit for the mother or child from levothyroxine and that their use, especially early in the first trimester, could treatment of pregnant women with subclinical hypothyroidism, hypo- lead to misclassification of up to 37% of pregnant women as thyroxinemia or presence of thyroid peroxidase antibodies.4–9 having subclinical hypothyroidism.13

11 E597 given that given that 3 testing to com- ISSUE 22 ISSUE value of less than 0.05 was considered statistically sig value of less than 0.05 was considered statistically | not all regions in the province have locally established, trimester- locally established, province have in the not all regions in the TSH because of variations ranges and specific reference - province. We defined the subclinical hypo assay used across the - as 4.01 to 9.99 mIU/L and overt hypothyroid thyroid range of TSH or higher. We also analyzed TSH meas ism as TSH of 10.00 mIU/L the of 2.51 to 4.00 mIU/L, in keeping with urements in the range of the American Thyroid Association. 2011 pregnancy guidelines Ethics approval Health Research Ethics approval was obtained from the Conjoint Ethics Board, University of Calgary (REB18–0223). Results A total of 188 490 deliveries were included in this cohort study Of these, 111 5221). (Figure least at measured had TSH (59.2%) once during the pregnancy, 10 685 (5.7%) had free thyroxine TSH testing Maternal characteristics for deliveries with and without TSH test- logistic Multiple 1. Table in summarized are pregnancy during ing regression showed that women who were 35 years of age or older, who were nulliparous, who were from an urban area, who had gestational hypertension or who had other medical disorders were more likely to have TSH measured during pregnancy, whereas those who smoked were less likely to have TSH meas ured during pregnancy (Appendix 1, Table A1, available at www. cmaj.ca/lookup/suppl/doi:10.1503/cmaj.191664/-/DC1). Key definitions and outcome measures and outcome Key definitions as 0.10 topregnancy was defined range for TSH in The reference Thy- in keeping with the American This definition was 4.00 mIU/L. recommendations, 2017 guideline roid Association’s Statistical analysis with thyroid testing andWe calculated the proportion of pregnancies TSH, thyroid peroxi- the frequency of each specific thyroid test (e.g., multivariable logisticdase antibodies). We used univariable and patient characteris- regression to examine the association between U tics and TSH testing, and we used Mann–Whitney with thyroid hor- pare TSH results that were and were not associated We performedmone initiation and repeat TSH testing in pregnancy. IBM Corporation, ver- all analyses using SPSS (IBM SPSS Statistics, sion 25). A p to examine the con nificant. We also performed a sensitivity analysis partum, comparing 1tinuation of thyroid hormone therapy post postpartum year. versus 2 or more prescriptions filled in the first (2.5%) 4662 and pregnancy, the during once least at measured measured at least once during had thyroid peroxidase antibodies the pregnancy. - preg during therapy hormone thyroid of initiation defined We desiccatedprescription for levothyroxine, filling of a nancy as the We after conception and before delivery. thyroid or liothyronine as of thyroid hormone therapy post partum defined continuation for any of these medications after the filling of a prescription whichin pregnancies for partum post year first the within delivery the pregnancy. thyroid hormone therapy was initiated during VOLUME 192 VOLUME | - 15 JUNE 1, 2020 | CMAJ Using maternal personal health care numbers, 16 All of these factors may contribute to substantial varia- substantial to contribute may factors these of All 3,14 Potential participants were excluded if they had evidence of had evidence of Potential participants were excluded if they - treat of levothyroxine benefit the both about Controversy There is a paucity of data about the routine clinical practice ofThere is a paucity of we linked the data to the Discharge Abstract Database for hospi- from databases laboratory province-wide the data; talization Alberta Health, Alberta Health Services and Alberta Precision Laboratories; the Pharmaceutical Information Network database for details on prescription medications; and physician claims for outpatient physician visits from Alberta Health. thyroid disease in the 2 years before conception, defined as any thyroid disease in the 2 years before conception, any thyroid medication of the following: filled a prescription for methimazole or (levothyroxine, desiccated thyroid, liothyronine, propylthiouracil); had any International Statistical Classification 10th Revision (ICD-10) of Diseases and Related Health Problems, e89.0, r94.6, t38.1, codes for thyroid disease (E00–E07, e35.0, International Classifi- t38.1, t38.2, y42.2, y42.3) or the equivalent - cation of Diseases, 9th Revision (ICD-9) codes for outpatient bill 0.20 less than measurement a TSH had 240–249); or data (i.e., ing or greater than 5.00 mIU/L (chosen because these levels are outside the nonpregnant reference range). ment. ment and the upper limit of TSH during pregnancy, as well as the during pregnancy, upper limit of TSH ment and the to discor- RCTs, has contributed newer, high-quality results of univer- guidelines regarding professional societies’ dance among and about the TSH thresholds as well as confusion sal screening, treat trigger should that status antibody peroxidase thyroid

Data sources iden- to database Program Health Perinatal Alberta the used We tify deliveries in Alberta. This database includes information hospital all for collected records delivery provincial the from in midwives registered by attended births home and births Alberta from 20 weeks’ gestation. The Alberta Perinatal Health Program database is validated frequently, a process that vital statistics and regis- health records, includes validation with tered midwives. Study design, setting and population administrative In this retrospective cohort study, we collected delivered in Alberta, data for women aged 15 to 49 years who 2017. Alberta has an Canada, between Oct. 1, 2014, and Sept. 30, 4 million people. ethnically diverse population of more than Methods tion in clinical practice. Importantly, thyroid hormone therapy Importantly, thyroid hormone therapy tion in clinical practice. is often continued post partum, started during pregnancy this practice is unknown. although the extent of - for initiation of thyroid hormone ther thyroid testing and patterns - and its continuation post partum. There apy during pregnancy thyroid of management current the describe to aimed we fore, thyroid without women in pregnancy during treatment and testing the Specifically, we aimed to determine disease before pregnancy. of TSH testing by gestational age, thefrequency and distribution initiation of thyroid hor- TSH measurement values associated with continuation ofmone therapy and the frequency of postpartum pregnancy. thyroid hormone therapy after initiation during RESEARCH E598 Alberta PerinatalHealthProgram,TSH=thyroid-stimulatinghormone. Figure 1: Flowdiagramforderivationofthestudypopulation.Note:APHP = Unique valuesforpersonalhealthcare Unique personalhealthcarenumbers li nked withadministrativedatabase Deliveries withatleast1TS numbers identifiedfromAPHP Deliveries by173973women, Oct. 1,2014,to Deliveries withoutevid Maternal characteristic Age, yr, mean ±SD Age ≥ 35yr ‡Denominators usedfor calculating percentages for this variable were 110909 and76309,respectively. †Defined as>50000residents. *Except where indicated For otherwise. allcharacteristics, data were missingfor lessthan1%ofdeliveries. Note: CI=confidence interval, NA=not applicable; OR =oddsratio, Ref. =reference category, SD= standard deviation, TSH =thyroid-stimulating hormone. pregnancy Table 1:Maternal characteristics associated withdeliveries withandwithoutTSH testing duringthe Urban residence† Nulliparous ≥ 91 46–90 ≤ 45 Pre-pregnancy kg‡ weight, Smoking Gestational hypertension Pre-pregnancy hypertension Heart disease Other medical disorders Chronic disease kidney of thyr du ring n =18849 n =202900 n =111522 n =17568 n =173973 oid disease pr egnanc Se pt 4 0 pregnancy Deliveries ex disease) Deliveries ex

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100 064(90.2) 21 421(19.2) 79 934(71.7) 48 069(43.1) n=111522 10 621(9.5) TSH tested 9814 (8.8) 1031 (0.9) 6386 (5.7) 1279 (1.1) 9144 (8.2) 30.2 ±5.1 591 (0.5) 116 (0.1)

Group; no. (%)of deliveries*

| VOLUME 192 (99.6%) ofthesepregnancies.Themeandoselevothyroxine was the type of thyroid hormone therapy initiated in 5028 (median 7[IQR5–12]v.96–13]wk;p<0.001).Levothyroxine who hadaTSHtestbutdidnotinitiatethyroidhormonetherapy nancy hadtheirfirstTSHtestearlieringestationthanwomen Women whoinitiatedthyroidhormonetherapyduringpreg- was initiatedatamediangestationalageof7(IQR5–12)weeks. TSH measurements during pregnancy. Thyroid hormone therapy ated onthyroidhormone therapy hadamedianof4(IQR2–5) women werestartedonthyroidhormonetherapy.Thoseiniti- For atotalof5050(4.5%)pregnancieswithTSHtesting,the Initiation ofthyroidhormonetherapy TSH measurementforeachpregnancyissummarizedinTable2. orabove(Table2).Thehighest pregnancy range,”10.00 mIU/L (1.5%) hadafirstTSHmeasurementinthe“overthypothyroid and1709 hypothyroid range,”between4.01and9.99 mIU/L, 4417 (4.0%)hadafirstTSHmeasurementinthe“subclinical deliveries thathadTSHtestingduringthepregnancy.Atotalof (92.9%)of range,” between0.10and4.00mIU/L,for103 616 respectively). second TSHmeasurements(Figure2andAppendix1,FigureA1, tional age for TSH testing was bimodal for both the first and gestational week5to6(Figure2).Thedistributionofgesta- range [IQR]1–2).Themostcommontimefortestingwasaround the mediannumberofTSHtestsperformedwas1(interquartile The firstTSHmeasurementwasinthe“normalpregnancy Among deliverieswithatleast1TSHtestduringpregnancy, TSH not tested 12 843(16.7) 44 495(57.8) 28 182(36.6) 68 486(89.7) 9971 (13.0) n=76968 7215 (9.4) 3669 (4.8) 5015 (6.5) 29.4 ±5.4 | 608 (0.8) 785 (1.0) 332 (0.4) ISSUE 22 63 (0.1) 1.18 (1.16–1.21) 1.85 (1.81–1.88) 1.16 (1.05–1.28) 0.93 (0.90–0.96) 0.69 (0.67–0.71) 1.12 (1.03–1.23) 1.20 (1.05–1.37) 1.24 (0.91–1.68) 1.21 (1.16–1.26) 1.28 (1.23–1.32) OR (95%CI) 1.0 (Ref.) NA RESEARCH E599 All 5050 (4.5) 5050 (4.5) 42 n = 111 522 n = 111 522 2252 (44.6) 1591 (31.5) 2252 (44.6) 1591 (31.5) 41 40 39 38 ≥ 10.00 n = 2002 n = 1709 37 249 (68.8) 198 (54.7) 362 (18.1) 211 (70.1) 300 (17.6) 169 (56.3) 36 35 34 33 32 31 n = 4953 n = 4417 932 (33.5) 844 (34.4) 4.01 –9.99 1312 (47.1) 2783 (56.2) 1175 (47.9) 2451 (55.5) 30 29 28 27 26 ISSUE 22 ISSUE 25 | 24 n = 16 141 n = 15 082 426 (31.1) 270 (19.7) 1371 (8.5) 499 (32.8) 314 (20.7) 2.51–4.00 23 1520 (10.1) 22 21 The management of pregnancies with initial TSH between 4.01 The management of pregnancies with initial TSH between 4.01 in displayed is range) hypothyroid (subclinical mIU/L 9.99 and Table 2 and Figure 3. Of the 4417 women with subclinical hypothyroid values, 2451 (55.5%) were initiated on thyroid hormone therapy. Measured patient characteristics, including TSH ordered by a family physician, parity, age, hypertension, weight and smoking, did not differ between patients who were and were not treated for a single minor elevated TSH value (Appendix 1, Table A2). Among Pregnancies with first TSH in subclinical hypothyroid range 20 VOLUME 192 VOLUME 19 | 18 First or highest TSH value (mIU/L); no. (%) of deliveries* (%) of no. (mIU/L); value TSH or highest First 17 532 (0.6) 750 (0.8) n = 87 835 265 (49.8) 191 (35.9) 357 (47.6) n = 88 534 256 (34.1) 16 0.10–2.50 15 14 13 JUNE 1, 2020 | 12 0 (0) 0 (0) n < 5 11 < 0.10 n = 591 8 (27.6) 29 (1.6) n = 1780 10 (34.5) 10 Gestational age at first TSH test during pregnancy, wk Gestational age at first TSH test during CMAJ 0123456789 0 0 0 0 0 0 0

200 400 600 800

12 00 10 00 Frequency Among the 16 141 pregnancies with a highest TSH value rang- TSH value highest with a pregnancies the 16 141 Among Continued on thyroid hormone Continued on thyroid delivery after Continued on thyroid hormone after hormone after Continued on thyroid year† in first delivery with ≥ 2 prescriptions Initiated on thyroid hormone on thyroid Initiated Continued on thyroid hormone Continued on thyroid delivery after Continued on thyroid hormone after hormone after Continued on thyroid year† in first delivery with ≥ 2 prescriptions Initiated on thyroid hormone on thyroid Initiated By highest TSH value during pregnancy value TSH highest By By first TSH value during pregnancy value TSH first By Variable Note: TSH = thyroid-stimulating hormone. = thyroid-stimulating TSH Note: unless otherwise indicated. (same column), row in the previous is the n value percentage each calculating for *The denominator (same column). during the pregnancy hormone therapy of thyroid with initiation of pregnancies is the count in this row percentage each calculating for †The denominator Table 2: Initiation of thyroid hormone therapy during pregnancy and continued after delivery in relation to first and highest and highest to first relation in delivery after and continued during pregnancy hormone therapy thyroid of 2: Initiation Table values TSH

initiated in pregnancy was 44.1 (standard 24.0) µg/day, deviation and the median dose was 50 (IQR- 25–50) µg/day. For the remain ing 22 (0.4%) pregnancies, desiccated thyroid was prescribed. was initi- 4.00 mIU/L, thyroid hormone therapy ing from 2.51 to ated during 1371 (8.5%) of the pregnancies (Table 2). Among the 1709 pregnancies with a first measured TSH value of 10.00 mIU/L or higher, thyroid hormone therapy was initiated during only 300 (17.6%) of the pregnancies (Table 2). Gestational age at the time of first measurement of thyroid-stimulating hormone (TSH) in pregnancy. hormone (TSH) of thyroid-stimulating measurement of first the time at age Figure 2: Gestational RESEARCH E600 in pregnancywas 25µg/day.Inthepostpartum period,TSHwas nancy andstoppedpostpartum, themediandosageprescribed median dosagewas50 roxine started inpregnancy and continued post partum, the therapy wascontinuedpostpartum for691(36.3%).Forlevothy- the pregnancyandhighestTSH between0.10and4.00mIU/L,the 1903 deliveries with initiation of thyroid hormone therapy during tion ofsuchtherapyduringthepregnancy(Table2).Among post partum for 2252 (44.6%) of the 5050 deliveries with initia Thyroid hormonetherapywascontinuedduringthefirstyear Continuation ofthyroidhormonetherapypostpartum ing aresummarizedinAppendix1,TableA3andA4. with initiationofthyroidhormone(p<0.001).Detailsthistest - all pregnancies. When the result was positive, it was associated Thyroid peroxidaseantibodiesweremeasuredin4662(2.5%) of Thyroid peroxidaseantibodymeasurements mIU/L; Mann–WhitneyU TSH testinginpregnancy(4.9[IQR4.3–5.8]v.4.74.3–5.4] median TSHvaluesthatwereandnotassociatedwithrepeat (67.9%) cases(Figure3).Therewasconsiderableoverlapinthe testing showed normalization, to 4.00 mIU/L or below, in 1201 5 (IQR3–9)weeksafterthefirstTSHmeasurement.Therepeat state. Theserepeatmeasurementswereperformedatamedianof range, 1770(40.1%)hadrepeatTSHtestinginatreatment-naive women whoseinitialTSHwasinthesubclinicalhypothyroid sented asnumber(%)ofparticipants,withthedenominatorusedtocalculateeachpercentagebeing Figure 3: Follow-up testing of pregnant women with initial value for thyroid-stimulating hormone (TSH) between 4.01 and 9.99 mIU/L. Data are pre- Starte µg/day. Forlevothyroxinestarted inpreg- n =514( test,Z=–4.71,p n =74( ≤ hormon 2.50 mI d on thyr 14.4% 29.0% U/L e oid ) ) <0.001). CMAJ Starte 2.5 n =158( n =687( 1–4 hormon | JUNE1, 2020 d . Pregnancies withsecond on thyr 00 mI 23.0% 38.8% Pregnancies withfirstTS in atreatment-naivestate e U/L oid of 4.0 ) ) n =1770( n =441 1–9 - | VOLUME 192 . 99 mI Starte 40.1% 4.0 ment wascommonlycontinuedpostpartum(Table2). hormone inthefirstyearpostpartumalsoshowedthattreat- tivity analysiswithfillingof2ormoreprescriptionsforthyroid mone therapyinpregnancyandcontinuedpostpartum.Asensi- or higher for only 5 women who started thyroid hor- 10.00 mIU/L post partum. and colleaguesdidnotreport on continuationoflevothyroxine 10 mIU/Lwerestartedonthyroid hormonetherapy.Maraka whereas wefoundthatabout20% ofwomenwithTSH2.5to women receivedlevothyroxine treatmentduringpregnancy, measurements of2.5to10mIU/L. Theyfoundthat15.2%ofthe Maraka andcolleagues after pregnancy. nosis andunnecessarythyroidhormonetherapyduring testing earlyinthefirsttrimestermayberesultingoverdiag - was frequently continued post partum. The practice of TSH ized withouttherapy.Inaddition,thyroidhormonetherapy measurement, althoughTSHinthisrangefrequentlynormal - 4.01–9.99 mIU/L)wasmostofteninitiatedafteronly1TSH Thyroid hormonetherapyforsubclinicalhypothyroidism(TSH than halfofallpregnancies,usuallyearlyinthefirsttrimester. ease before pregnancy, TSH testing was performed in more We foundthatamongwomenwhodidnothavethyroiddis- Interpretation n =395( n 7 •T Excl •D = 526( 1–9 hormon Our population-basedcohortstudyaugmentstheby U/L d n =838 ) hyroid hormon id nothaveTS

. uded TS on thyr 99 mI 75.1% 29.7% H H test e

U/L n =264 | ISSUE 22 oid ) ) H testrepeatedduringpregnancy e 7 starte

Starte d aerfirstTS n valueintheprecedingrow. n =13 ≥1 n =43 17 hormon of7990pregnantwomenwithTSH 0.00 mI d on thyr (3 (2 0.2% .4 U/L e %) H test oid )

n = 1809

RESEARCH E601 ISSUE 22 ISSUE | J Clin Endocrinol Metab 2012;97:2543-65. Li C, Shan Z, Mao J, et al. Assessment of thyroid function during first-trimester pregnancy: What is the rational upper limit of serum TSH during the first trimester in Chinese pregnant women? J Clin Endocrinol Metab 2014;99:73-9. Practice Committee of the American Society for Reproductive Medicine. Sub- clinical hypothyroidism in the infertile female population: a guideline. Fertil Steril 2015;104:545-53. Lazarus J, Brown RS, Daumerie C, et al. 2014 European Thyroid Association Lazarus J, Brown RS, Daumerie C, et al. 2014 European Thyroid Association pregnancy in guidelines for the management of subclinical hypothyroidism and in children. Eur Thyroid J 2014;3:76-94. Casey BM, Thom EA, Peaceman AM, et al. Treatment of subclinical hypothyroidismCasey BM, Thom EA, Peaceman AM, et al. Treatment of subclinical or hypothyroxinemia in pregnancy. N Engl J Med 2017;376:815-25. and screening thyroid Antenatal al. et S, Channon JP, Bestwick JH, Lazarus childhood cognitive function. N Engl J Med 2012;366:493-501. of levothyroxine ther- Yamamoto JM, Benham JL, Nerenberg KA, et al. Impact women with subclinical apy on obstetric, neonatal and childhood outcomes in meta- and review systematic a pregnancy: in diagnosed hypothyroidism analysis of randomised controlled trials. BMJ Open 2018;8:e022837. in women Dhillon-Smith RK, Middleton LJ, Sunner KK, et al. Levothyroxine N Engl J Med with thyroid peroxidase antibodies before conception. 2019; 380: 1316-25. among miscarriage on levothyroxine of Effect al. et H, Chi H, Gao H, Wang women with normal thyroid function and thyroid autoimmunity undergoing in vitro fertilization and embryo transfer: a randomized clinical trial. JAMA 2017; 318:2190-8. Hales C, Taylor PN, Channon S, et al. Controlled antenatal thyroid screening II: effect of treating maternal sub-optimal thyroid function on child behaviour. J Clin Endocrinol Metab 2020;105:e417-27. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081-125. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during thyroid deficiency during Haddow JE, Palomaki GE, Allan WC, et al. Maternal of the child. pregnancy and subsequent neuropsychological development N Engl J Med 1999;341:549-55. of subclinical hypo- Negro R, Stagnaro-Green A. Diagnosis and management thyroidism in pregnancy. BMJ 2014;349:g4929. of the American ThyroidAlexander EK, Pearce EN, Brent GA, et al. 2017 guidelines disease during preg- Association for the diagnosis and management of thyroid nancy and the postpartum. Thyroid 2017;27:315-89.

5. 6. 7. 8. 9. 1. 2. 3. 4. 14. 13. 10. 11. 12. Conclusion practice for TSH testing and management Current patterns of women of overtreatment and overdiagnosis to contribute may post partum. Clinical practice guidelines during pregnancy and the a stepwise approach, based on are needed to give clinicians - for deciding whether and when TSH test best existing evidence, - is also needed as to when it is appro ing should occur. Guidance treatment continue and pregnancy in treatment initiate to priate in the postpartum period. References treated; however, we cannot rule out unmeasured differences differences unmeasured rule out we cannot however, treated; treated, it is the women who were groups. Among between these have nor- whose TSH would to know the proportion not possible suggest that our findings treatment. However, malized without especially is warranted, testing before intervention repeat TSH to 4 of range the in elevation TSH initial with women among 10 mIU/L. VOLUME 192 VOLUME | Our Our 4–7 JUNE 1, 2020 | CMAJ Additionally, higher rates 9 - concerns about overmedi This raises 3,13 18 The commonest timing of the first TSH measurement (5–6 wk (5–6 measurement the first TSH timing of The commonest It is not clear from these data why some women with TSH of TSH with women some why data these from clear not is It Data from high-quality RCTs have consistently shown that RCTs have consistently shown that Data from high-quality gestation) and the median timing of thyroid hormone initiation initiation of thyroid hormone and the median timing gestation) - when it is well estab in a period both occurred (7 wk gestation) physiologic because of normal TSH level falls rapidly lished that pregnancy. changes of study provides a baseline for future comparison that will allow that will allow study provides a baseline for future comparison this newer evidence. assessment of knowledge translation of treating from harm potential of evidence is there Furthermore, In a 9-year follow- minor thyroid test abnormalities in pregnancy. minor abnormalities up study of an RCT, children of women with compared with chil- who were overtreated with levothyroxine, frequently scored dren of women who were untreated, more poor conduct, hyper- above clinical thresholds for symptoms of activity and autism spectrum disorder. of preterm delivery, pre-eclampsia and gestational diabetes have of preterm delivery, pre-eclampsia and gestational with levothyroxine for been observed among women treated relative to those who subclinical hypothyroidism in pregnancy were not treated.

Limitations patient information We used population-level data, so detailed testing or initiation on the specific clinical indications for thyroid To mitigate this of thyroid hormone therapy was not available. 2 years before concep- limitation, we used a look-back period of pre-pregnancy thyroid tion to identify and exclude women with of combination comprehensive thorough, a of means by disease, the following: ICD-9 and ICD-10 diagnostic codes for thyroid disease, prescriptions filled for thyroid hormone therapy or antithyroid medication, and abnormal results on laboratory thy- in lived who mothers among pregnancies Some tests. roid outside was residence whose but delivery of time at the Alberta the province in the 2 years before conception may not have been may thus and disease thyroid pre-existing having as identified not have been excluded from this cohort. This limitation likely affected only a minority of pregnancies. 10 mIU/L or higher did not receive treatment with thyroid hor- below This may have occurred in part because TSH fell mone. 4.01 mIU/L in more than 60% of those with repeat TSH measurement. Alternatively, it may have been a result of women not filling prescriptions from their care providers or using thyroid hormone that was not distributed by a pharmacy. Among women with minor elevation of TSH (4.01–9.99 mIU/L), patient characteristics did not differ between those who were and were not calization during pregnancy, given that minor, untreated TSH TSH that minor, untreated during pregnancy, given calization - as indicated by repeat measure elevation usually normalized, continuation of thyroid hormone ment. The frequent postpartum pregnancy during therapy the started who those for therapy Although these factors may be contributing adds to this concern. of of pregnancy, a small proportion to the overmedicalization overt hypothyroidism that would have women (1.5%) had required treatment. - elevation (i.e., subclinical hypothyroid treatment of minor TSH - antibodies in pregnancy has no bene ism) or thyroid peroxidase neonate or the developing child. fit for the mother, the RESEARCH E602 16. 15.

be accountable for all aspects of the work. be accountableforallaspectsofthework. authors gavefinalapprovaloftheversiontobepublishedandagreed the authorscontributedtocriticalreviewofmanuscript.All Jennifer YamamotoandLoisDonovandraftedthemanuscript,allof Khurana). LoisDonovanwastheprojectadministratorandsupervisor. Chin) andconductedtheformalanalysis(withinputfromRshmi Nerenberg and LoisDonovancuratedthedata(withinputfrom Alex Khurana andAlexChin.JenniferYamamoto,AmyMetcalfe,Kara Lois Donovanconceivedanddesignedthestudy,withinputfromRshmi Contributors: JenniferYamamoto,AmyMetcalfe,KaraNerenbergand (Khurana), UniversityofAlberta,Edmonton,Alta. Alta.; andDepartmentsofMedicineObstetricsGynecology Hospital ResearchInstitute(Yamamoto,Metcalfe,Donovan),Calgary, Cumming SchoolofMedicine,UniversityCalgary;AlbertaChildren’s Nerenberg, Donovan),andofPathologyLaboratoryMedicine(Chin), Donovan), of Obstetrics and Gynecology (Yamamoto, Metcalfe, Affiliations: DepartmentsofMedicine(Yamamoto,Metcalfe,Nerenberg, This articlehasbeenpeerreviewed. Competing interests:Nonedeclared. the riskofsubsequentprematurebirth.AmJObstetGynecol2017;217:63.e1-10. Wood SL,TangS,CrawfordS.Cesareandeliveryinthesecondstageoflaborand 28). about/publications/2017-18-annual-report-web-version.pdf (accessed2019Oct. ton: AlbertaHealthServices;2018.Available:www.albertahealthservices A healthierfuture.Together:AlbertaHealthServicesannualreport2017–18.Edmon- CMAJ | JUNE1, 2020 .ca/assets/ | VOLUME 192 Correspondence to:LoisDonovan,[email protected] Accepted: Mar.17,2020 Codan forassistancewithmanuscriptpreparation. mission feedbackonthismanuscript,andSharonVenantiusCassidy Lemieuxforconstructivepresub- tance withdatacollection,Dr. Patricia authors thankPatriciaJohnsonofAlbertaPrecisionLaboratoriesforassis- Alberta HealthServices,forhisworkondatalinkagesthisstudy.The support. TheauthorsarealsogratefultoJackM.S.Yeung,senioranalyst, gram, includingSusanCrawford,epidemiologist,whoprovidedstatistical Acknowledgements: TheauthorsthanktheAlbertaPerinatalHealthPro- similar contractualagreementsaresignedwiththedataproviders. approached directlyfordata,providedethicsapprovalisgrantedand ever, thedatasourcesarelistedwithinarticleandcanbe sources nottosharethedatathatwereprovidedforthisstudy.How- Data sharing:Theauthorshavecontractualagreementswiththedata the manuscriptordecisiontosubmitforpublication. analysis orinterpretationofthedata.Thefunderalsohadnoroleinwriting Grant Fund.Thefunderhadnoroleinstudydesignorthecollection, Funding: ThisstudywasfundedbytheAlbertaChildren’sHospitalSeed 17. 18.

2019 Apr. 24. [Epub ahead of print]. pii: jc.2019-00057. doi: 10.1210/jc.2019-00057. 2019 Apr.24.[Epubaheadofprint].pii:jc.2019-00057.doi:10.1210/jc.2019-00057. hypothyroidism inpregnancy:USnationalassessment.JClinEndocrinolMetab Maraka S,MwangiR,YaoX,etal.Variationintreatmentpracticesforsubclinical BMJ 2017;356:i6865. pregnant womenwithsubclinicalhypothyroidism:USnationalassessment. Maraka S,MwangiR,McCoyRG,etal.Thyroidhormonetreatmentamong | ISSUE 22