Michaela Granfors, Helena Åkerud, Anna Berglund, Johan Skogö, Inger Sundström-Poromaa, and Anna-Karin Wikström

ORIGINAL ARTICLE Endocrine Care Thyroid Testing and Management of Hypothyroidism During Pregnancy: A Population-based Study Michaela Granfors, Helena Åkerud, Anna Berglund, Johan Skogö, Inger Sundström-Poromaa, and Anna-Karin Wikström Department of Women s and Children s Health and National Centre for Knowledge on Men s Violence Against Women, Uppsala University, SE 751 85 Uppsala, Sweden Context: There are international guidelines on thyroid function testing and management of hypothyroidism during pregnancy. Few studies have evaluated how they are implemented into clinical practice. Objective: In this descriptive study, we assessed the implementation of international guidelines in this field into local guidelines and also into clinical practice. Design and Participants: In a nationwide survey, all guidelines in Sweden were collected (n 29), and the adherence of the local guidelines to The Endocrine Society Guidelines 2007 was evaluated. In a follow-up in 1 district, 5254 pregnant women with an estimated date of delivery between January 1, 2009, and December 31, 2011, were included for subsequent review of their medical reports. Results: All but 1 district had guidelines on the subject. All local guidelines included fewer than the 10 listed reasons for thyroid testing recommended by The Endocrine Society Guidelines. Furthermore, most guidelines recommended additional types of thyroid function tests to TSH sampling and lower trimester-specific TSH upper reference limits for women on levothyroxine (P.001). In the follow-up, the thyroid testing rate was 20%, with an overall frequency of women with trimester-specific elevated TSH of 18.5%. More than half of the women (50.9%) who were on levothyroxine at conception had an elevated TSH level at thyroid testing according to The Endocrine Society Guidelines. Conclusions: The local guidelines are variable and poorly compliant with international guidelines. Performance of thyroid testing is not optimal, and rates of elevated TSH at testing are extremely high in subgroups. (J Clin Endocrinol Metab 98: 2687 2692, 2013) Hypothyroidism is one of the most common endocrine disorders in women of reproductive age (1). The prevalence of overt hypothyroidism during pregnancy has commonly been estimated to be 0.3% 0.5%, but in addition, 2% 3% of pregnant women may suffer from subclinical hypothyroidism (2 4). However, the prevalence of hypothyroidism is dependent on several factors, and other studies have described prevalence as high as 12.3% (5). While overt hypothyroidism is defined as a serum TSH level above the defined upper limit of the reference range, in combination with a serum free T 4 below the lower limit of the reference range, subclinical hypothyroidism is defined as elevated TSH, combined with normal T 4 levels (6). Iodine deficiency is the most common cause of hypothyroidism worldwide (7), but in areas of iodine sufficiency, as in Sweden, chronic autoimmune thyroiditis is the main cause of hypothyroidism (8). Other causes of hypothyroidism include previous thyroidectomy or ablative radioiodine therapy, but secondary (pituitary) and tertiary (hypothalamic) causes of hypothyroidism are rare. Overt hypothyroidism, and, to some extent, even subclinical hypothyroidism, is associated with adverse effects ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright 2013 by The Endocrine Society Received February 4, 2013. Accepted May 16, 2013. First Published Online May 20, 2013 Abbreviation: TPOAb, thyroid peroxidase antibody. doi: 10.1210/jc.2013-1302 J Clin Endocrinol Metab, July 2013, 98(7):2687 2692 jcem.endojournals.org 2687

2688 Granfors et al Thyroid Testing During Pregnancy J Clin Endocrinol Metab, July 2013, 98(7):2687 2692 on pregnancy and neonatal outcome as well as on fetal brain development (1). It is generally accepted that overt hypothyroidism should be treated with levothyroxine during pregnancy, whereas for of subclinical hypothyroidism, current evidence is insufficient (9). Moreover, how to test for hypothyroidism is a matter of controversy worldwide (7, 10, 11). In recent years, 2 evidence-based international guidelines have been published: The Endocrine Society Guidelines from 2007, with a recent update in August 2012 (2, 12), and the guidelines from the American Thyroid Association from 2011 (13). Even so, a recent European survey demonstrated a lack of consensus in thyroid testing and the of hypothyroidism during pregnancy (14). The aims of this study were to determine the adherence of nationwide guidelines to international guidelines on thyroid testing and management of hypothyroidism during pregnancy. Second, we aimed to analyze the final degree of implementation of guidelines into everyday clinical practice. Subjects and Methods National survey on adherence to international guidelines In Sweden, there were no national recommendations concerning thyroid testing or of maternal hypothyroidism during pregnancy. To identify the local guidelines, a nationwide survey was conducted in 2011 and completed in 2012. Antenatal care in Sweden is standardized, free of charge, and decentralized to maternity care areas (n 41). Within each maternity care area, a consultant in obstetrics is responsible for development and implementation of guidelines. All maternity care consultants (n 41) were asked by e-mail whether they had guidelines concerning thyroid testing and management of hypothyroidism during pregnancy and, if so, to provide the guidelines. All maternity care consultants replied after 1 or more reminders. The guidelines were analyzed with respect to 4 different aspects: 1) the degree of adherence to The Endocrine Society Guidelines 2007 (2), where 10 high-risk groups as reasons for thyroid testing are described, and the proportion of these reasons that were found in the local guidelines was calculated; 2) recommended thyroid function tests; 3) the trimester-specific TSH upper reference limit for intervention with levothyroxine; and 4) the trimester-specific TSH upper reference limit for monitoring women on with levothyroxine. Follow-up: implementation of guidelines into clinical practice A total of 5254 pregnant women from Uppsala county with an ultrasound-estimated date of delivery between January 1, 2009, and December 31, 2011, were included. Pregnant women, 18 years or older, Swedish-speaking and without blood-borne from the whole of Uppsala county, were approached for participation in a study cohort when attending the second-trimester routine ultrasound screening at 17 to 18 weeks of gestation. Participation in this study cohort included both biobank research and clinical approaches, such as, for example, medical record reviews. Inquiry for participation was done at random when the research nurse was available. Approximately 30% of the respondents declined participation, mainly due to lack of time or fear of blood or needles, because blood samples were collected to be used not in this but in other clinical studies. During our inclusion period, there were about 12 000 deliveries in the district of Uppsala county. Thus, nearly half of the women from the whole district, pregnant in the second trimester at approach for participation, were included in our study. The included women s medical reports, including any thyroid function tests taken in clinical practice, were reviewed between February and May 2012 concerning: 1) if and when thyroid testing had been performed, and in case of repeated testing, only the first TSH analyzed during the pregnancy (from gestational week 4 0 d until delivery) was considered and defined as thyroid testing; 2) the specified reasons for thyroid testing; and 3) the frequency of women with trimester-specific elevated TSH, overall, and within the groups with specified reasons for thyroid testing. Serum TSH levels were measured by an electrochemiluminescent immunoassay (Cobas E601; Roche Diagnostics, Basel, Switzerland; normal range for nonpregnant women, 0.40 4.0 miu/l). According to international guidelines, we used the trimesterspecific TSH upper reference limits for intervention or dose adjustment of levothyroxine of 2.5 miu/l in the first trimester and 3.0 miu/l in the second and third trimester for the follow-up (2, 12, 13). Pregnancy trimesters were defined as follows: first trimester until 13 completed gestational weeks, second trimester gestational week 14 to 27, and third trimester 28 completed gestational weeks or later. In the guidelines from the district, valid during the entire follow-up period, 5 reasons for thyroid testing were found: personal history of thyroid dysfunction with or without ongoing levothyroxine, family history of thyroid dysfunction, goiter, type 1 diabetes, and other autoimmune s (Morbus Addison, celiac, and atrophic gastritis with vitamin B12 deficiency were specified). The participating women gave written informed consent and the Ethical Review Board at Uppsala University, Sweden, approved the study. The statistical software package SPSS including 1-sample t tests was used for all data analyses. Results National survey on adherence to international guidelines Forty of 41 maternity care areas had written guidelines on thyroid testing and management of hypothyroidism during pregnancy. In some parts of Sweden, groups of maternity care areas had chosen to use common guidelines. All in all, 29 different guidelines were available. We defined the areas with common or unique local guidelines as districts (n 29). All districts recommended thyroid function testing as targeted case finding in high-risk women.

doi: 10.1210/jc.2013-1302 jcem.endojournals.org 2689 The 10 reasons for thyroid testing identified in The Endocrine Society Guidelines 2007 and the implementation of these thyroid testing reasons in the Swedish local guidelines are displayed in Table 1. The most commonly stated reasons for thyroid testing were personal and/or family history of thyroid (both 86.3%). Of the local guidelines, only 17.2% recommended thyroid testing solely with TSH. Most local guidelines (82.8%) recommended additional analyses such as free T 4 (75.9%), thyroid peroxidase antibodies (TPOAbs) (37.9%), free T 3 (6.9%), and TSH receptor antibodies (6.9%). In Figure 1A, recommended first-trimester TSH upper reference limits for intervention with levothyroxine are shown. Approximately 50% of the local guidelines advocated intervention with levothyroxine when first-trimester TSH exceeded 2.5 miu/l, which was in accordance with The Endocrine Society Guidelines (P.39) (2). In Figure 1, B and C, recommended trimester TSH upper reference limits for women on levothyroxine are shown. The TSH upper reference limits recommended by the local guidelines were significantly lower than those recommended by The Endocrine Society Guidelines (2), with reference to both the first trimester (P.001) and second and third trimester (P.001). Only 3 of the 29 local guidelines were completely consistent with the international guidelines with respect to TSH trimester-specific upper reference limits for women with ongoing levothyroxine, recommending both 2.5 miu/l for the first and 3.0 miu/l for the second and third Table 1. Adherence of Local Guidelines (n 29) to The Endocrine Society Guidelines 2007 Concerning Reasons for Thyroid Testing Numbers (n) and Proportion (%) of Swedish Guidelines Listing the Reason Reason for Thyroid Testing Number Proportion, % Personal history of thyroid 25 86.2 Family history of thyroid 25 86.2 Goiter 20 69.0 Type 1 diabetes 17 58.6 Other autoimmune disorders 15 51.7 Symptoms or clinical signs 10 34.5 History of miscarriage or 4 13.8 preterm delivery Infertility 1 3.4 Previous head or neck 1 3.4 irradiation Thyroid antibodies (when 0 0 known) trimester of pregnancy as TSH trimester-specific upper reference limits. Guidelines from 2 districts are not represented in the figure. In 1 of these districts, referral of hypothyroid women to an endocrinology department was recommended without indicating any TSH upper reference limit. In the other district, the upper TSH limit varied depending on the presence of TPOAbs. For women already on levothyroxine at conception, The Endocrine Society Guidelines 2007 state that the levothyroxine dose usually needs to be incremented by 4 to 6 weeks of gestation and may require a 30% to 50% increase in dosage (2). The latter Guidelines of the American Thyroid Association from 2011 clearly recommend an empiric 25% to 30% dose increase as soon as pregnancy has been confirmed (13). None of the local guidelines contained this recommendation. Follow-up: implementation of guidelines into clinical practice In the follow-up population, the thyroid testing rate was 20.1%. Most tested women (65.7%) had their tests taken in the first trimester, whereas 23.9% and 10.4% were tested in the second and third trimester, respectively. Most of the 163 women who were on levothyroxine at the time of conception were tested in the first trimester of pregnancy (91.4%). Only in 4 of those 163 women was the dose of levothyroxine increased at an early stage of pregnancy, before thyroid testing. The reasons for thyroid testing at any time during pregnancy are shown in Table 2. The most common reason was family history of thyroid (33.5%). Although not recommended in the local guidelines of the district, thyroid testing was (according to the medical records review) even performed for the remaining 5 testing reasons stated in The Endocrine Society Guidelines (2). Of those 5 reasons, symptoms or clinical signs were predominant as the reason for thyroid testing. The reasons for thyroid testing varied during different trimesters of pregnancy. Although personal or family history of thyroid were the most common reasons for thyroid testing in the first trimester (28.9% and 43.6%, respectively), symptoms or clinical signs were the most common reasons for thyroid testing in the second and third trimester (42.1% and 56.4%, respectively). However, the reason for thyroid testing was often unclear when tests were taken in the second and third trimester (25.8% and 24.5%, respectively). The overall frequency of women with trimester-specific elevated TSH was 18.5% in the follow-up population. In Table 3, the proportion of women with trimesterspecific elevated TSH in relation to the respective reason for thyroid testing is shown. More than half of women

2690 Granfors et al Thyroid Testing During Pregnancy J Clin Endocrinol Metab, July 2013, 98(7):2687 2692 Figure 1. TSH upper reference limits according to the local guidelines. A, First-trimester limit for intervention with levothyroxine (mean TSH 2.59 miu/l; 95% confidence interval [CI] 2.37 2.81 miu/l). B, First-trimester limit for women on with levothyroxine (mean TSH 2.22 miu/l; 95% CI 2.08 2.36 miu/l). C, Second- and third-trimester limit for women on with levothyroxine (mean TSH 2.31 miu/ L; 95% CI 2.14 2.49 miu/l). who were already on levothyroxine at conception had trimester-specific elevated TSH when first tested (50.9% of cases). Discussion The local guidelines for thyroid testing and management of hypothyroidism during pregnancy differed in several aspects from the international guidelines (2). In the followup, we found a thyroid testing rate of 20.1%, with an overall frequency of women with trimester-specific elevated TSH of 18.5%. More disturbingly, half of the women who were on levothyroxine at the time of conception had an elevated TSH level at thyroid testing (50.9%). In the national survey, the number of reasons for which thyroid testing was advised varied among the guidelines, and no guidelines included all 10 reasons stated by The Endocrine Society (2). Instead, thyroid testing was advised for between 2 and 7 reasons. In addition, more than 80% of the local guidelines advocated thyroid function testing with additional tests to TSH sampling. This is in contrast to The Endocrine Society Guidelines and the guidelines from the American Thyroid Association (2, 13), both of which recommend further thyroid tests only in case of abnormal TSH. At present, it thus appears as if too few pregnant women are advised for thyroid testing with too many thyroid function tests. In compliance with the international guidelines, most local guidelines recommend levothyroxine when TSH is above the upper reference limit of 2.5 miu/l in the first trimester. Surprisingly, most of the Swedish guidelines advocate lower target TSH levels for women on levothyroxine than the international guidelines (2, 12, 13). The rationale for the recommendations in the

doi: 10.1210/jc.2013-1302 jcem.endojournals.org 2691 Table 2. Reasons for Thyroid Testing in the Follow-up Population Reason for Thyroid Testing Number Proportion, % Personal history of thyroid Ongoing levothyroxine 163 15.5 No ongoing levothyroxine 60 5.7 Family history of thyroid 353 33.5 Goiter 14 1.3 Type 1 diabetes 8 0.8 Other autoimmune disorders 12 1.1 Symptoms or clinical signs 226 21.4 History of miscarriage or 16 1.5 preterm delivery Infertility 5 0.5 Previous head or neck 2 0.2 irradiation Thyroid antibodies (when 3 0.3 known) Blood sampling as part of a 15 1.4 medical investigation Unclear reason 177 16.8 Total 1054 100 local guidelines and their implications for pregnancy outcomes are unclear. In our follow-up in 1 of the districts, 5 of 10 reasons for thyroid testing from The Endocrine Society Guidelines 2007 were recommended. Interestingly, in clinical practice, all of the 10 reasons were applied. In addition, 16.8% of the tested women in our follow-up population were tested for reasons that were unclear. Moreover, our results raise suspicions that, in clinical practice, women with risk factors for hypothyroidism during pregnancy are poorly identified and tested. The thyroid testing rate in the district (20.1%) was in accordance with a study from Negro et al (15) who classified 20.5% of their study population in the first trimester of pregnancy to be at high risk for thyroid. However, Negro and colleagues (15) did not include women with personal history of thyroid, women with known TPOAbs, or women with infertility. When we exclude women tested due to personal history of thyroid (n 226), known TPOAbs (n 3), or infertility (n 5) and women screened for unknown reasons (n 178), the thyroid testing rate in our follow-up within 1 district dropped to 12.2%. Finally, when only first-trimester thyroid testing is considered (excluding women tested in the second and third trimester; n 248), the thyroid testing rate in the first trimester was as low as 7.5%. In the follow-up, we found elevated TSH levels at thyroid testing in half of women who were on levothyroxine at conception. Untreated, or insufficiently Table 3. Women With Trimester-Specific Elevated TSH in Relation to Reason for Thyroid Testing in the Followup Population Reason for Thyroid Testing Number (Total) Proportion,% Personal history of thyroid Ongoing levothyroxine 83 (163) 50.9 No ongoing levothyroxine 15 (60) 25.0 Family history of thyroid 51 (353) 14.4 Goiter 2 (14) 14.3 Type 1 diabetes 2 (8) 25.0 Other autoimmune disorders 1 (12) 8.3 Symptoms or clinical signs 23 (226) 10.2 History of miscarriage or 2 (16) 12.5 preterm delivery Infertility 2 (5) 40.0 Previous head or neck 0 (2) 0 irradiation Thyroid antibodies (when 1 (3) 33.3 known) Blood sampling as part of a 6 (15) 40.0 medical investigation Unclear reason 7 (177) 4.0 treated, overt and subclinical hypothyroidism in early stages of pregnancy may have detrimental effects on pregnancy outcome and on the neuropsychological development of the unborn child (9, 16 20). Surprisingly, none of the Swedish guidelines contained The Endocrine Society Guideline s recommendation to consider an increment of the levothyroxine dose by 4 to 6 weeks of gestation (2), probably resulting in many insufficiently treated hypothyroid women in the early stages of pregnancy. One major strength of our study is the populationbased design. In the survey, the response rate was 100%, and due to the organization of the healthcare system, the local guidelines are applied nationwide to the whole pregnant population of the country. Furthermore, in contrast to earlier studies, we were able to show how subsequent thyroid testing was performed in clinical practice in addition to a comprehensive survey (14, 21). A limitation of our study is its descriptive nature. In addition, as a consequence of the study design, we do not know the TSH levels of the untested women. Moreover, less than half of the pregnant women at 17 to 18 weeks of gestation from the district were included in the follow-up. However, the sample is probably representative for the population of the district, because inquiry for participation was done at random and declined participation was mainly due to lack of time or fear of blood or needles, which are unlikely markers for thyroid.

2692 Granfors et al Thyroid Testing During Pregnancy J Clin Endocrinol Metab, July 2013, 98(7):2687 2692 Our results show that the local guidelines were not in compliance with the guidelines from The Endocrine Society (2), and in clinical practice, thyroid testing and of hypothyroidism were suboptimal. In a recent report from the United States, awareness of The Endocrine Society Guidelines had a significant positive impact on patient care with regard to thyroid testing and management of thyroid during pregnancy (22). However, only 11.5% of providers in the American survey had read The Endocrine Society Guidelines. This highlights the importance of implementing evidence-based guidelines. It is highly probable that the international guidelines are too extensive to be studied by a significant proportion of caregivers (2, 12, 13). As a consequence, a 2-step procedure seems to be adequate: establishment of short but concise evidence-based guidelines with local or national modifications for differences in maternal healthcare and subsequent efforts to improve the implementation of these guidelines. These efforts should be of a multilevel approach, involving interventions in the policy-making, managerial, educational, and practical areas (23). Finally, follow-up of adherence to guidelines is essential and should be used as a marker of high-quality care. In conclusion, on a nationwide basis, local guidelines on thyroid testing and of hypothyroidism during pregnancy were variable and poorly compliant with international guidelines. Performance of thyroid testing in clinical practice was not optimal, and rates of elevated TSH at thyroid testing were extremely high in women already on levothyroxine at the time of conception. Improvements are desirable. Acknowledgments Address all correspondence and requests for reprints to: Michaela Granfors, Department of Women s and Children s Health, University Hospital, SE 751 85 Uppsala, Sweden. E- mail: michaela.granfors@kbh.uu.se. This work was supported by grants from the Gillbergska Foundation, and by grants from the Department of Women s and Children s Health, Uppsala University Hospital, Uppsala, Sweden. Disclosure Summary: The authors have nothing to disclose. References 1. Reid SM, Middleton P, Cossich MC, Crowther CA. Interventions for clinical and subclinical hypothyroidism in pregnancy. Cochrane Database Syst Rev. 2010;7:CD007752. 2. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2007;92: S1 S47. 3. Casey BM, Leveno KJ. Thyroid in pregnancy. Obstet Gynecol. 2006;108:1283 1292. 4. Casey BM, Dashe JS, Wells CE, et al. 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