Received: 7 May 2017 Revised: 20 July 2017 Accepted: 22 July 2017 DOI: 10.1111/cen.13433 ORIGINAL ARTICLE Thyroid disease symptoms during early pregnancy do not identify women with thyroid hypofunction that should be treated VJ Pop 1 MA Broeren 2 WM Wiersinga 3 A Stagnaro-Green 4 1 Department of Medical Health Psychology, University of Tilburg, Tilburg, The Netherlands 2 Maxima Medical Center, Eindhoven, The Netherlands 3 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 4 University of Illinois College of Medicine, Rockford, IL, USA Correspondence Victor J Pop, Department of Medical Health Psychology, University of Tilburg, Tilburg, The Netherlands. Email: v.j.m.pop@uvt.nl Summary Objective: To evaluate whether women during early pregnancy with hypothyroidism symptoms are at risk of biochemically defined hypothyroidism. The 2017 Guidelines of the American Thyroid Association (ATA) recommend case- finding on the basis of symptoms to identify these women during pregnancy, while evidence is lacking. Design: Construct validation of a thyroid hypofunction symptom checklist during the first trimester of pregnancy comparing high scores with biochemically defined hypothyroidism. Patients: A total of 2198 healthy pregnant women from an iodine- sufficient area in 2013-2014. Measurements: Completion of a draft questionnaire with classical symptoms of hypothyroidism at 12 weeks of gestation. The 2.5th and 97.5th percentiles of TSH and ft4 during pregnancy in TPO- Ab- negative (<35 ku/l) women were used to define euthyroid women and those with overt (clinical) and subclinical hypothyroidism. The prevalence of overt (subclinical) hypothyroidism was compared between women with high symptom scores and those with low symptom scores. Results: According to ft4 and TSH cut- offs (0.23-4.0 miu/l and 11.5-18.0 pmol/l, respectively), there were 15 women with to treat hypofunction (overt hypothyroidism or TSH >10 miu/l) and 68 women with subclinical hypothyroidism. Questionnaire construct validation revealed a 12- item hypothyroid checklist with normally distributed scores. The cut- off indicating high scores of OH was set at 1 SD > mean. Women with high symptom scores did not present more often with biochemically defined thyroid hypofunction. Conclusion: This study does not support the ATA recommendation that pregnant women who require levothyroxine therapy can be identified by case- based screening of women with symptoms of thyroid disease. KEYWORDS case-finding, pregnancy, symptoms, thyroid 1 INTRODUCTION The 2017 American Thyroid Association (ATA) Guidelines on Thyroid and Pregnancy defined overt hypothyroidism as a TSH concentration elevated beyond the upper limit (>97.5th percentile) of the pregnancy- specific reference range with a ft4 below the 2.5th percentile. 1 Furthermore, the ATA Guidelines state that population and trimester- specific reference ranges for serum TSH during 838 2017 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/cen Clinical Endocrinology. 2017;87:838 843.
POP et al. 839 pregnancy should be defined in healthy, TPOAb- negative pregnant women with optimal iodine intake and without thyroid illness (recommendation 26). Because of the detrimental effects of overt hypothyroidism (OHypo, TSH above the upper reference limit and ft4 below the lower reference limit) on both pregnancy and foetal health, the guidelines advocate levothyroxine treatment in women with OHypo and women with TSH >10 IU/L irrespective of the ft4 level (recommendation 27). Subclinical hypothyroidism (SHypo) was defined as a TSH above the reference range with ft4 levels within the normal reference limits. Based on an exhaustive review of the literature, the expert panel concluded that there is insufficient evidence to recommend for or against universal screening of thyroid function during early gestation (recommendation 93). Therefore, they advocate case- finding in recommendation 97, to assess thyroid function in pregnant women with a history of hypothyroidism/hyperthyroidism or current symptoms/signs of thyroid dysfunction (recommendation 97.1). However, we are unaware of any study which demonstrates that the presence of typical signs and symptoms of thyroid disease identifies women with undiagnosed hypothyroidism during pregnancy. The detrimental impact of thyroid hypofunction during pregnancy has been well documented. Therefore, this study, using the abovementioned definitions, reports the incidence of OHypo and SHypo in a large healthy (without thyroid illness) birth cohort of pregnant women from an iodine- sufficient area in whom symptoms possibly related to hypothyroid functioning were assessed. 2,3 The main outcome of the study was to evaluate whether women with high hypothyroid symptom scores are at increased risk of OHypo or SHypo. 2 MATERIALS AND METHODS This study is part of the longitudinal prospective HAPPY project (Holistic Approach to Pregnancy and the first Postpartum Year), of which the details have been described elsewhere. 4 2.1 Participants and procedure From January 2013 to September 2014, pregnant women who had their first antenatal visit at one of the 17 participating community midwife offices in the south- east of the Netherlands were invited to participate in HAPPY. During the 18 months of inclusion, approximately 4150 women visited the participating midwife offices. As most outcomes were assessed using questionnaires, only Dutch- speaking and mostly Caucasian women (N = 3475) were invited to participate, to avoid language problems. Also 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 (eg, diabetes mellitus, rheumatoid arthritis) and the use of drugs that might interfere with thyroid function (eg, use of lithium in bipolar patients). 5 Women who became pregnant after in vitro fertilization (IVF) or hormone stimulation and women with multiple pregnancies were also excluded. This resulted in 3159 eligible women, of whom 2275 (response rate = 72%) signed a written informed consent. The study was approved by the Medical Ethical Committee of the Máxima Medical Center in Veldhoven, the Netherlands. 2.2 Assessments At 12 weeks of gestation, the women completed a set of questionnaires with regard to demographic and obstetric features and lifestyle habits. Moreover, a list of symptoms which have commonly been described to occur in patients suffering from overt hypothyroidism was assessed. These symptoms are summarized in Appendix A. Utilizing a 5- point Likert scale ranging from 0 = never to 4 = very often/nearly always, women were asked: Did you experience any of the following symptoms during the previous weeks of pregnancy? 2.3 Thyroid function assessment and definitions TSH, ft4 and TPO- Abs were determined in lithium heparin plasma using electrochemiluminescence assays (Cobas_e 601; Roche Diagnostics, Mannheim, Germany).The nonpregnant reference range of TSH is 0.40-4.0 mu/l, of ft4 is 10.0-24.0 pmol/l and of TPO- Abs is <35 ku/l. The reference ranges of TSH during early pregnancy were defined in TPO- Ab- negative women, using the 2.5th and 97.5th percentiles to define the upper limit of normal thyroid function ( euthyroid group). The reference range for TSH was 0.23-4.0 IU/L and for ft4 was 11.5-18 pmol/l. Women with a TSH in the total sample above the 97.5th percentile TSH and ft4 below the 2.5th percentile were defined as suffering from OHypo. Women with a TSH above 97.5th percentile and ft4 within reference range were defined as suffering from SHypo. As the ATA Thyroid and Pregnancy Guidelines clearly state that women with OHypo and those with a TSH >10 IU/L (irrespective of their ft4 level) should immediately be treated with thyroid hormone, we combined these 2 categories of thyroid dysfunction into a group defined as to treat hypofunction : THypo. 2.4 Statistics Statistical analysis was performed using the Statistical package for the Social Sciences (spss version 24.0; IBM, Chicago, IL, USA). For the construct validation of the hypothyroid symptom checklist, a principal component explorative factor analysis (EFA) was performed. Factor loadings >.35 were considered important. Internal consistency analyses were conducted using Cronbach s alpha for the total scale and possible subscales derived from factor analysis. Cronbach s alpha reliability statistic of.70 is considered as the minimum acceptable criterion of instrument internal reliability. 6 Higher scores indicate higher intensity of symptoms. A widely used cut- off to define high scores on self- rating scales in psych- social sciences is >1 SD above the mean, assuming a normal distribution of scores in the total sample. 7 This cut- off often results in the most adequate figures of sensitivity, specificity and positive predictive value (PPV) using ROC curves (receiver
840 POP et al. operating characteristics) statistics. For example, when comparing depressive symptom scores with the outcome of a syndromal diagnostic interview of depression (the golden standard), a high cut- off (such as >2 SD above the mean) will result in an appropriate PPV with poor sensitivity: many cases with lower symptom scores but a syndromal diagnosis of depression during the interview will be missed. 7 Descriptive statistics were used to analyse the prevalence of THypo (OHypo + TSH >10 IU/L) and SHypo as well as mean scores on the hypo- symptom checklist. Subsequently, the prevalence of THypo and SHypo in women with high hypo- symptom scores was compared to that of women with lower hypo- symptom scores. Using the euthyroid women as reference group, the RR (95% CI) was calculated of women with high hypo- symptom scores to suffer from THypo or SHypo. Of the 2275 women who were included in the study, thyroid function tests and patient characteristics were available in 2198 women (97%). Of these women, items of the thyroid symptom questionnaire were missing in 119 (5%) women. To achieve maximal statistical power, these items were completed using multiple imputation statistics by chained equations to generate 10 imputed data sets including the variables: age, parity, family history of thyroid problems, smoking, BMI, depression scores, previous history of miscarriage, and the thyroid parameters: ft4, TSH and TPO- Ab status. Statistical analysis was performed in this imputed final sample of 2198 women for whom the characteristics are shown in Table 1. 3 RESULTS As shown in Table 1, there were 251 (11.4%) women who reported thyroid function problems in first- line relatives. There were 193 (8.8%) women with TPO- Ab >35 ku/l. 3.1 Prevalence of overt (or to treat) hypothyroidism and subclinical hypothyroidism The 2.5th and 97.5th percentile cut- offs of TSH in the 2005 TPO- Abnegative women were 0.23 and 4.0 miu/l and of FT4 were 11.5 and 18 pmol/l, respectively. In Table 2, different subgroups of women with thyroid (dys)function are shown. According to these cut- offs, there were 15 women (0.7%) with THypo (to treat hypofunction). Of these 15 women, 11 had OHypo (91% with elevated TPO- Ab titres) and 4 had TSH >10 IU/L (all with elevated TPO- Ab titres). There were 18 women with overt hyperthyroidism (0.8%) and 34 (1.5%) with subclinical hyperthyroidism, of whom 1 (5.6%) and 3 (8.8%), respectively, had elevated TPO- Ab titres (not mentioned in Table 2). 3.2 Hypothyroid symptom scores In Appendix A, 18 symptoms that are generally mentioned in women with hypothyroidism and which were assessed in this study are summarized. Some of these, especially the cognitive and mood symptoms as well as the symptoms general fatigue and shortness of breath, TABLE 1 Characteristics of 2198 women with thyroid function assessment at 12 weeks of gestation Demographic features Age (in years) 30.5 (3.4) Mean (SD) n (%) Women with age >30 y 1042 (47.4) Educational level Low 604 (27.5) Medium 97 (4.4) High a 1512 (68.8) Marital status With partner 2084 (94.8) Obstetric features Primiparous 1073 (48.8) Previous miscarriage 558 (25.4) Lifestyle habits during pregnancy Smoking 144 (6.6) Alcohol 85 (3.9) BMI prepregnancy 23.8 (3.9) Women with BMI >39 6 (0.25%) Family history of thyroid dysfunction Total first line 251 (11.4) Mother 184 (8.4) Father 36 (1.6) Brother/sister 44 (2%) Thyroid parameters logtsh miu/l Range 2.00 to 2.10 Median 0.16 FT4 pmol/l 14.5 (2.5) TPO- Ab >35 IU/L 193 (8.8) a Bachelor s or master s degree. are nonspecific and do also occur in women with hyperthyroidism. Psychometric characteristics of this questionnaire were tested. An EFA revealed a three- dimensional structure. However, the items constipation, feeling cold, dry skin, tingling hand/fingers, brittle hair and dry eyes did not load (item loading <0.35) and were omitted. Factor analysis in the remaining 12- items hypothyroid scale showed again three dimensions: (1) a 7- item cognitive symptoms ; (2) a 3- item muscle- joint symptoms ; and (3) a 2- item fluid retention symptom dimension. The Cronbach alpha (internal consistency) of the total scale was 0.81, of the cognitive subscale was 0.76, of the musclejoint subscale was 0.76 and of the fluid retention subscale was 0.82. For this study, only the total scale was used for further analysis. The higher the score, the higher the intensity of symptoms. For the group as a whole, the mean score on this hypothyroid scale was 9.09 (SD: 4.7), range 0-32, with a skewness and kurtosis of 0.91 and 1.12, respectively, suggesting a normal distribution. Subsequently, women with high hypothyroid symptom scores were defined by a
POP et al. 841 TABLE 2 Different subgroups of pregnant women according to thyroid (dys)function at the first trimester in 2198 healthy women N (%) logtsh (IU/L) FT4 (pmol/l) N (%) TPO- Ab + Median Range Mn (SD) (>35 ku/l) Euthyroid women 2063 (93.8) 0.15 0.62 to 0.60 14.4 (1.4) 155 (7.5) To treat hypofunction 15 (0.7) 0.90 0.67 to 2.10 10.6 (2.3) 14 (93.3) Overt hypothyroidism 11 (0.5) 0.82 0.67 to 2.10 9.8 (2.0) 10 (91) TSH >10 IU/L 4 (0.2) 0.70 0.60 to 2.10 13.4 (2.0) 4 (100) Subclinical hypothyroidism 68 (3.2) 0.69 0.60 to 0.89 13.9 (1.3) 20 (29.4) Clinical hyperthyroidism 18 (0.8) 1.35 2.0 to 0.77 25.1 (17.4) 1 (5.6) Subclinical hyperthyroidism 34 (1.5) 0.88 1.9 to 0.68 15.8 (1.5) 3 (8.8) Reference range for TSH: 0.23-4.0 IU/L; and for FT4: 11.5-18 pmol/l, 2.5th and 97.5th percentiles assessed in 2105 TPO- Ab- negative women. Euthyroid women = both TSH and FT4 within reference limits. Overt hypothyroidism: TSH >4.0 IU/L; and FT4 <11.5 pmol/l. Subclinical hypothyroidism: TSH >4.0 IU/L; and FT4 within reference range. To treat hypofunction: women with thyroid hypofunction who should be treated with thyroid hormone: overt hypothyroidism + those with TSH >10 IU/L irrespective of FT4 level. commonly used cut- off in social sciences of >1 SD > mean: >13.79. (7) In the total sample, there were 320 (14.6%) women with high hypothyroid symptom scores. In the total sample of subgroups presented in Table 2 (2063 euthyroid women +15 to treat hypofunction + 68 SHypo = 2146), there were 302 (14.1%) women with high hypothyroid symptom scores (>1 SD > mean). Of these 302 women with high hypothyroid scores, 297 were euthyroid (98.4%), 1 woman had THypo (0.3%) and 4 (1.3%) women had SHypo. We used the 2063 euthyroid women as reference group. The RR of women with high symptom scores to present with THypo was 0.40 (95% CI: 0.05-3.1, P =.37). Similarly, the RR of women with high symptom scores to have SHypo was 0.36 (95% CI: 0.13-0.98, P =.038). When we in analogy with commonly used cut- offs in medicine defined a high symptom score using >2 SD > mean as cut- off (18.49), we found 60 women (2.7%) with high scores. All of them belonged to the euthyroid reference group, none to the thyroid dysfunction group. We finally calculated the number of women who should be treated (n = 15) and who would be found using the ATA Guidelines of casefinding, applicable to this study: age >30, a family history of thyroid disease, BMI >39 and having high scores on the symptom checklist (cut- off: 1 SD > mean). Eight of the 15 women would have been detected using this risk profile, which means that 47% of the women who need immediate treatment would be missed. When we repeated all the analyses in the nonimputed data set (N = 2198-119 = 2079), the findings were similar (data not shown). 4 DISCUSSION The current study is the first to develop and utilize a self- rating symptom scale of hypothyroidism during pregnancy that has adequate psychometric properties. Women with high scores on this symptom scale showed no increased risk of having overt hypothyroidism (or to treat hypofunction: overt hypothyroidism + TSH >10 IU/L irrespective of FT4) or subclinical hypothyroidism. The recently published guidelines (2017) of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum state that as part of a case- finding strategy all pregnant women should undergo clinical evaluation. (1) If any of the eleven risk factors are identified, testing of serum TSH is recommended. The first risk factor is a history of hypothyroidism/ hyperthyroidism or current symptoms/signs of thyroid dysfunction (recommendation 97.1). The goal of this recommendation is to identify women with overt (or better: to treat) thyroid dysfunction so that appropriate therapy can be instituted and thereby decrease maternal and foetal complications. 1 As far as we know, the current study, which excluded women with a history of thyroid dysfunction, is the first to evaluate whether or not selected case- finding of pregnant women with symptoms of thyroid disease could identify individuals with undiagnosed thyroid disease requiring treatment. Given that only one of the 15 women who required treatment had symptoms of thyroid disease, one can conclude that the ATA 2017 Thyroid and Pregnancy Guideline recommendation to assess TSH in pregnant women with symptoms of thyroid disease to identify women with overt hypothyroidism is not supported by the data of the current study. A recent meta- analysis by Jouyandey et al reviewed 241 articles on case- based screening for thyroid disease in pregnancy and identified 10 articles that met their search criteria. Their meta- analysis showed poor sensitivity of case- based screening when using risk factors such as higher age, BMI and family history of thyroid dysfunction to predict unknown (overt) thyroid dysfunction: on average, 49% of the cases were missed. 8 The 12- item hypothyroid scale showed strong psychometric characteristics with appropriate reliability (Cronbach s alpha >0.70). 7 The 12- item hypothyroid symptom scale developed and utilized in this study contained items related to cognition as well as items referring to fluid retention and muscle- joint problems. In contrast to a hypothyroid symptom checklist developed in 2008 (thyroid symptom rating questionnaire, ThySRQ) which was based on 110 patients with overt and subclinical hypothyroidism on T4 treatment, 9 the classical hypothyroid
842 POP et al. symptoms such as feeling cold, dry hair and skin and constipation did not show appropriate factor loadings in the current study. However, in the ThySRQ validation paper, the symptoms constipation and dry hair showed a factor loading <0.35, 9 which means that they would have been omitted according to our strict validation protocol of construct validation as explained in the method section. Also, during pregnancy, there are increased levels of estrogens which in general are associated with normal hair and skin and a buffer against feeling cold. 10 Moreover, the mean age of the 2008 sample was 55 years (men and women), increasing the likelihood that the (overt) hypothyroid symptoms existed for a longer period of time. 9 It is generally accepted that symptoms as brittle nails and hairs are associated with longer- lasting thyroid hypofunction. For obvious reasons, symptoms such as weight gain and tiredness are less applicable to pregnant women. This comparison (and differences) with the ThySRQ underlines the need for pregnancy- specific instruments to assess thyroid function- related symptoms. The cognitive subscale in the current study shows several symptoms which are commonly reported in patients with depression (forgetfulness, concentration problems, mood changes, worrying). Interestingly, there is some evidence that depressive symptoms do occur more often in patients with subclinical hypothyroidism. 11 However, pregnancy in general is a period where a woman has to face a wide variation of bodily changes which are often accompanied by signs and symptoms such as concentration problems, general fatigue and mood changes. 12 This might explain the lack of difference in symptom scores between cases and controls in our study. Zulewski et al showed no differences in symptoms between cases and controls in a general (nonpregnant) population, and a recent review also showed no difference of neuropsychiatric symptoms between patients with subclinical hypothyroidism and controls of the general population. 13,14 Although the Colorado Thyroid Disease Prevalence Study which included over 25.000 subjects did find small differences in some symptom scores between those with SHypo and controls, 15 a recent review did not show any difference. 16 This was confirmed by a recent large population- based study in the Netherlands including 3993 men and 5498 women showing no significant differences in symptom levels between those with and without elevated or suppressed TSH levels. 17 Another study followed elderly patients over a period of 6 years and found no associations at follow- up between changes of TSH and FT4 levels within the reference range and mood and cognition symptoms. 18 Likewise, another review showed no benefit of symptom relief outcome of T4 substitution of patients with subclinical hypothyroidism compared to controls without replacement therapy. 19 Previous studies have already shown that case- finding by means of the risk factors mentioned by the ATA will miss up to 40%- 60% of the women who need immediate treatment. 20-22 The current study shows that adding assessments of symptoms typically for hypothyroidism to this case- finding strategy will not decrease the number of women who will be missed: almost half of them are not detected. Several limitations of the study need to be mentioned. Only Caucasian women were included with appropriate knowledge of the Dutch language. This means that the questionnaire might need further validation analyses in women of other ethnic minorities. Secondly, the dimension structure of the questionnaire as shown should be further investigated using confirmatory factor analysis in another cohort to test the robustness of the models presented in the current study. Thirdly, there is a preliminary report of the Generation R and our study group questioning whether the cut- off of TPO- Ab titre of 35 IU/L is appropriate during gestation. 23 Korevaar et al showed that based on TSH mean values the cut- off should preferentially be below 20 IU/L. When we repeated the analyses in the current study, defining our control group as TPO- Ab- negative (< below 20 instead of <35 IU/L) similar results were found (data not shown). Finally, the number of women with THypo was rather low, which may result in limited power. However, the RR showed consistently a lower risk of women with high symptom levels to suffer from thyroid hypofunction. It is reasonable to suggest that larger subsamples of women with thyroid hypofunction will not reverse this lower risk into a higher risk, but will instead only increase the statistical significance of the RR. In conclusion, symptoms and signs during early pregnancy will not help a clinician detect women at risk of thyroid hypofunction and should not be used as a risk factor for case- finding strategy to detect women with thyroid function abnormalities that require immediate treatment. ACKNOWLEDGEMENT We would like to thank the 17 community midwifery practices for the recruitment of the participants of the HAPPY study. CONFLICT OF INTEREST All the authors confirm that they have no conflict of interest. ORCID VJ Pop REFERENCES http://orcid.org/0000-0003-2732-7137 1. 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