Impact of borderline subclinical hypothyroidism on subsequent pregnancy outcome in women with unexplained recurrent pregnancy loss

Transcription

1 doi: /jog J. Obstet. Gynaecol. Res. Vol. 43, No. 6: , June 2017 Impact of borderline subclinical hypothyroidism on subsequent pregnancy outcome in women with unexplained recurrent pregnancy loss Sayaka Uchida, Tetsuo Maruyama, Maki Kagami, Fumie Miki, Hanako Hihara, Satomi Katakura, Yushi Yoshimasa, Hirotaka Masuda, Hiroshi Uchida and Mamoru Tanaka Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan Abstract Aim: Because subclinical hypothyroidism (thyroid-stimulating hormone [TSH] > 4.5 IU/mL) is associated with adverse pregnancy outcome, including early pregnancy loss, TSH is recommended to be titrated to 2.5 miu/l in levothyroxine-treated women before pregnancy. The purpose of this study was to determine whether borderline subclinical hypothyroidism (borderline-sch; 2.5 < TSH 4.5 IU/mL) affects the outcome of subsequent pregnancies in women with unexplained recurrent pregnancy loss (urpl). Methods: After workup for antinuclear antibody (ANA), anti-phospholipid syndrome, thrombophilia, uterine abnormalities, hormone disorders, and/or chromosomal abnormalities, 317 women with a history of urpl were enrolled. The women were classified into two groups: borderline-sch, and euthyroidism (0.3 TSH 2.5 IU/mL). All women had normal serum free thyroxine (T4) and did not receive levothyroxine before or during the subsequent pregnancy. Results: There were no significant differences in age, number of previous pregnancy losses, number of live births, or body mass index between the borderline-sch (n = 56) and the euthyroid (n = 261) groups, but the rate of ANA positivity differed significantly (53.6% vs 33.7%, respectively; P = 0.005). The subsequent pregnancy rate did not differ between the two groups (55.4%, 31/56 vs 51.3%, 134/261, respectively). The pregnancy loss rate (<22 weeks of gestation) tended to be higher in the borderline-sch than the euthyroid group (29.0%, 9/31 vs 17.9%, 24/134), although not significantly so (P =0.16). Conclusions: Although some subset of urpl is though to be due to as-yet-unidentified cause(s), borderline-sch is unlikely to be involved in urpl. Key words: borderline subclinical hypothyroidism, recurrent pregnancy loss, subclinical hypothyroidism. Introduction Recurrent pregnancy loss (RPL) is classically defined as the loss of three or more pregnancies. 1 As a common problem in reproduction, RPL occurs in approximately 1% of women of reproductive age. 2 Recently, however, the term has been revised to include two pregnancy losses at any gestational age. 3 One reason for this revision is the advancing maternal age among couples attempting to have a child in developed countries. 4 When cases of two pregnancy losses are included, the prevalence of RPL increases to 5%. 3 Recurrent pregnancy loss is a heterogeneous condition with various causes, and several factors may be contributory. 1 The major causes of RPL based on the literature include parental structural chromosome rearrangement, immunologic factors (i.e. antiphospholipid syndrome), thrombophilic factors Received: October Accepted: January Correspondence: Dr Tetsuo Maruyama, Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo , Japan. tetsuo@keio.jp 1014

2 Subtle hypothyroidism in unexplained RPL (both inherited and acquired), anatomic factors of uterine anomalies, and endocrinologic disorders. Nevertheless, a definite cause of RPL is identified in only half of the couples. 2 More than 50% of couples have unexplained RPL (urpl), in whom the cause and risk are not identifiable, and therefore are believed to mostly experience RPL attributable to chance alone. 5 It remains possible, however, that some population of women with urpl may have a definite, but as-yet-unidentified cause and risk for RPL that requires investigation and is amenable to treatment. 5 Among the endocrinologic factors associated with RPL, thyroid function has not been the focus of much research. Because thyroid disease has not been reported to be more prevalent in women with RPL than the general population of pregnant women, the guidelines for evaluation of RPL do not include assessment of thyroid status. 1,2,6 With respect to RPL as an autoimmune abnormality, screening for thyroid antibodies is not recommended because the association with RPL was not statistically supported in a prospective study. 7 Hypothyroidism is common during pregnancy. Population studies indicate that 2 3% of all pregnant women have undiagnosed hypothyroidism. 8,9 Approximately two-thirds of such women have subclinical hypothyroidism (SCH), which is defined as elevated thyroid-stimulating hormone (TSH) in the presence of normal circulating free T4. 8 The upper limit of normal TSH is 4.5 miu/l in non-pregnant women, but TSH should be titrated to 2.5 miu/l in levothyroxine-treated women before pregnancy, according to the American Association of Clinical Endocrinologists/American Thyroid Association (AACE/ATA) recommendation. 10 Lowering TSH to <2.5 miu/l is recommended, not only for women planning to become pregnant, but also for pregnant women, 11 although there is insufficient evidence to evaluate the effect of SCH in women with RPL. In Japan, the normal range for TSH is miu/ml; therefore, patients with RPL with serum TSH within this range are not considered to have SCH. Based on these findings, we have hypothesized that some population of women with urpl may have borderline subclinical hypothyroidism (borderline- SCH; 2.5 < TSH 4.5 IU/mL), which is a milder form of SCH (TSH > 4.5 IU/mL), but may have the potential to negatively affect pregnancy. The aim of this study was to determine the prevalence of borderline-sch in patients with urpl and to assess the impact of borderline-sch on the outcome of subsequent pregnancies. Methods Patients In this retrospective study, we accessed the Keio University RPL database and followed all women who attended the outpatient clinic of Keio University Hospital between January 2008 and December 2013 with a history of RPL, which was defined as two or more documented pregnancy losses at any gestational age. Keio University School of Medicine Institutional Review Board approved the study. RPL Evaluation The women underwent RPL evaluation consisting of cytogenetic analysis of both partners, lupus anticoagulant, anticardiolipin IgG and IgM, β-2 glycoprotein-1 IgG, and antinuclear antibody (ANA) titers to assess antiphospholipid syndrome or other autoimmunerelated disorders; protein C, protein S, and coagulation factor XII for thrombophilia; and hysterosalpingography and office hysteroscopy to assess uterine anatomic factors. To investigate endocrine status, serum TSH, free triiodothyronine (T3), free T4, prolactin (PRL), day 3 basal follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were also measured. In particular, TSH, free T3, and free T4 were measured on electrochemiluminescence immunoassay (ECLusys TSH/FT3/FT4 Kit; Roche Diagnostics, Tokyo, Japan). Criteria Unexplained RPL is defined as the inability to identify a major cause for RPL. Thus, patients without a chromosomal rearrangement, such as a balanced chromosomal translocation in themselves or their partners, negative antiphospholipid antibody titers, and no thrombophilic disorders, endocrinologic disorders, and/or a uterine abnormality were defined as having urpl in the current study. The normal range for serum TSH is miu/ml at the present clinical laboratory. Patients with no measured serum TSH, elevated serum TSH (>4.5 miu/l), or a history of hypothyroidism prior to the first consultation were excluded from the study. Patients with urpl were divided into two groups: borderline-sch (2.5 < TSH 4.5 IU/mL), and euthyroid (0.3 TSH 2.5 IU/mL). Serum free T4 and free T3 were within the normal range in all patients. Both groups were followed without prescribed medications. 1015

3 S. Uchida et al. Outcome Measures The urpl patients enrolled in this study were followed for subsequent pregnancy outcome for at least 2 years. The outcome of the next pregnancy was investigated from medical records. Women who did not attend the present outpatient clinic were contacted by letter to write down information about the outcome of their pregnancy. Live birth included term birth, defined as delivery 37 weeks of gestation, and preterm birth, defined as delivery between 22 and 37 weeks of gestation. The primary outcome was the rate of pregnancy loss before 22 weeks of gestation. Statistical Analysis The data were transferred to Microsoft Excel 2008 or IBM SPSS Statistics for analysis. Data are presented as mean ± SD. Subsequent and successful pregnancy rates were analyzed using chi-squared test. Statistical significance was defined as P < Figure 1 Subject selection. APA, antiphospholipid antibody; RPL, recurrent pregnancy loss; TSH, thyroidstimulating hormone. Results Data from 605 women who underwent evaluation for RPL between January 2008 and December 2013 were included in the database. Among the 605 women, 413 were diagnosed with urpl after the following common causes for RPL were excluded: chromosomal rearrangement; positive lupus anticoagulant/anticardiolipin IgG and IgM/β-2 glycoprotein-1 IgG; abnormal protein C/protein S/coagulation factor; uterine anomaly; or intrauterine mass, such as submucosal myoma or endometrial polyp. Subsequently, 60 and 32 women were excluded because of no measurement of thyroid function and a diagnosis of hypothyroidism (serum TSH > 4.5 miu/l), respectively. Four patients were excluded due to history of treatment for hypothyroidism. Thus, 317 women were available for analysis (Fig. 1). According to serum TSH, 56 and 261 patients were classified as borderline-sch and euthyroid, respectively. The baseline characteristics of the 317 women included in the analysis are listed in Table 1. No significant difference was observed between the two groups in terms of age, number of previous pregnancy losses, live births, or body mass index (BMI). Mean serum TSH was 3.28 miu/l in the borderline-sch group and 1.49 miu/l in the euthyroid group. Interestingly, significantly more patients were positive for ANA in the borderline-sch group than the euthyroid group (53.6% vs 33.7%, P = 0.005). Among the 317 women, 31 of the 56 borderline-sch patients and 134 of the 261 euthyroid patients achieved a subsequent pregnancy after completion of the routine evaluation for RPL. The subsequent pregnancy rate was not significantly different between the two groups (55.4% vs 51.3%, P =0.58). Table 2 lists the baseline characteristics of the 165 women with urpl who achieved a subsequent pregnancy. No significant difference was observed between the two groups in terms of age, number of previous pregnancy losses, live births, or BMI. Mean serum TSH was Table 1 Baseline urpl subject characteristics Borderline-SCH (n =56) Euthyroid (n =261) P-value Age at first visit (years) 35.8 ± 3.9 (29 43) 35.9 ± 4.3 (25 46) No. pregnancy losses 2.7 ± 0.8 (2 5) 2.6 ± 1.0 (2 8) No. live births 0.1 ± 0.3 (0 1) 0.2 ± 0.5 (0 1) BMI (kg/m 2 ) 21.2± 1.9 ( ) 19.1 ± 2.5 ( ) TSH (miu/l) 3.28 ± 0.6 ( ) 1.49 ± 0.5 ( ) <0.001 Positive ANA 53.6 (30/56) 33.7 (88/261) Positive pregnancy test 55.3 (31/56) 51.3 (134/261) ANA, anti-nuclear antibody; BMI, body mass index; borderline-sch, borderline subclinical hypothyroidism; TSH, thyroid-stimulating hormone; urpl, unexplained recurrent pregnancy loss. 1016

4 Subtle hypothyroidism in unexplained RPL Table 2 urpl patients with 1 subsequent pregnancy: Baseline characteristics Borderline-SCH (n =31) Euthyroid (n =134) Age at first visit (years) 35.2 ± 3.8 (29 41) 35.0 ± 3.8 (25 43) No. pregnancy losses 2.6 ± 0.9 (2 5) 2.5 ± 1.0 (2 5) No. live births 0.1 ± 0.3 (0 1) 0.3 ± 0.5 (0 1) BMI (kg/m 2 ) 21.1± 2.0 ( ) 20.7 ± 2.5 ( ) TSH (miu/l) 3.23 ± 0.6 ( ) 1.47 ± 0.5 ( ) <0.001 Positive ANA 45.2 (14/31) 30.6 (41/134) P-value ANA, anti-nuclear antibody; BMI, body mass index; borderline-sch, borderline subclinical hypothyroidism; TSH, thyroid-stimulating hormone; urpl, unexplained recurrent pregnancy loss miu/l in the borderline-sch group and 1.47 miu/l in the euthyroid group. As in the total group of 317 patients, more patients were positive for ANA in the borderline-sch group than in the euthyroid group, but the significant difference that existed in the entire cohort of women with RPL was lost in the subsequent pregnancy groups (45.2% vs 30.6%, P = 0.12). We followed the subsequent pregnancy of urpl patients without any pharmacological treatment but with early pregnancy supportive care including weekly or biweekly ultrasound. Among the 31 borderline-sch patients, however, four, one, and two desired and received lowdose aspirin (LDA), LDA in combination with unfractionated heparin, and dydrogesterone for luteal support, respectively. Similarly, among the 134 euthyroid patients, 20, seven, and 20 desired and received LDA, LDA in combination with heparin, and dydrogesterone, respectively. The prevalence of each treatment did not differ significantly between the two groups. The subsequent pregnancy outcomes are listed in Table 3. In the euthyroid group, one patient had a pregnancy loss at 16 weeks of gestation secondary to preterm premature rupture of membranes, and one patient underwent induced abortion because of fetal severe cardiac anomaly detected on routine ultrasound at 20 weeks of gestation. The latter case was included in pregnancy loss before 22 weeks gestation. The rate of subsequent pregnancy loss before 22 weeks gestation was higher in the borderline-sch group than in the euthyroid group, but not significantly so (29.0%, 9/31 vs 17.9%, 24/134, P = 0.16). Among the four borderline-sch and eight euthyroid urpl patients who underwent chromosome testing of miscarried chorionic villi, no significant difference was observed in the frequency of aneuploid pregnancy loss between the two groups (75.0%, 3/4 vs 75.0%, 6/8; Table 3), suggesting that fetal chromosomal abnormality might equally contribute to each RPL group. After exclusion of three women with borderline-sch whose subsequent pregnancy resulted in miscarriage due to aneuploidy, more patients tended to be positive for ANA in the borderline-sch pregnancy loss group than in the successful borderline-sch group (83.3%, 5/6 vs 40.9%, 9/22, P = 0.065). After exclusion of six euthyroid women whose subsequent pregnancy resulted in miscarriage due to aneuploidy, there was no difference in the ANA positivity rate between the unsuccessful and successful euthryoid groups (29.4%, 5/17 vs 30.9%, 34/110, P =0.901). Table 3 urpl patients: Subsequent pregnancy outcomes Borderline-SCH (n =31) n or % (n) Euthyroid (n =134) n or % (n) Pregnancy loss (<22 weeks) 9 23 <8 weeks <12 weeks <22 weeks 0 1 Chromosomal abnormality 75.0 (3/4) 75.0 (6/8) 1.00 Induced abortion (<22 weeks) 0 1 Preterm delivery 1 5 Term delivery Pregnancy loss rate 29.0 (9/31) 17.9 (24 /134) 0.16 P-value On testing of miscarried chorionic villi. Due to fetal severe cardiac anomaly. Including one neonatal death beyond 37 weeks gestation due to diaphragmatic hernia. Including the patient with induced abortion before 22 weeks gestation. Borderline-SCH, borderline subclinical hypothyroidism; urpl, unexplained recurrent pregnancy loss. 1017

5 S. Uchida et al. Discussion Dramatic changes in physiologic status occur during pregnancy; likewise, thyroid function is also affected. For example, direct stimulation of the thyroid by TSH receptor binding of β-human chorionic gonadotropin, a hormone synthesized in rapidly increasing levels in early pregnancy, transiently increases T4 production. 12 In addition, the iodine concentration decreases as a result of the increased glomerular filtration rate. 12 Furthermore, increased production of thyroid-binding globulin and the subsequent binding of circulating thyroxine result from the increased level of estrogen that occurs in early pregnancy. 13 In pregnant women with limited thyroid reserves, hypothyroidism may be unmasked by these increased demands. 14 Primary maternal hypothyroidism is defined as elevated TSH concentration during gestation. Reference ranges for serum TSH have historically been derived from the sera of non-pregnant, healthy individuals. On the basis of these data, serum TSH >approximately 4.0 miu/l is considered abnormal. 11 Normative data from healthy pregnant women suggest that the upper reference range is miu/l; 15 thus, the diagnostic criteria for SCH in pregnancy have been reconsidered. During the adjustment to these new guidelines, 10 concern regarding SCH in pregnancy has been growing. Using the new TSH thresholds, recent studies have reported a higher prevalence of SCH in pregnant women: in 2010, Negro et al. reported a prevalence of SCH in pregnant women of 15.6%, 16 and in 2012 Blatt et al. reported a prevalence of 15%. 17 Subclinical hypothyroidism is associated with an increased risk of pregnancy complications and may confer an increased risk of neurocognitive deficits in the developing fetus. 11 In a systematic review, 28 of 31 cohort and case control studies demonstrated a positive association between anti-thyroid antibodies and pregnancy loss. 18 It has been reported that women at or before 8 weeks of gestation with SCH (2.5 TSH < 5.22 IU/mL) and thyroid autoimmunity have a significantly higher risk of miscarriage, although women with SCH (2.5 TSH < 4.0, 4.5 or 5.22 IU/mL) alone have no such association. 19 Nevertheless, there is still insufficient evidence to recommend screening or treatment for women with desired fertility and those with sporadic pregnancy loss or RPL. A positive relationship was identified between higher TSH in early pregnancy and the risk of child loss, defined as spontaneous abortion, fetal death, or neonatal death. 20 A prospective cohort study demonstrated that women with SCH had higher TSH and prevalence of pregnancy loss at earlier gestational ages than euthyroid women. 21 Most recently, in an observational cohort study Bernardi et al. reported that there is a high prevalence of SCH in women with early RPL, but no statistically significant difference in the subsequent live birth rate compared with euthyroid women. 14 The present subjects, however, were women with two or more pregnancy losses and urpl. These previous studies, however, did not focus on women with urpl who are thought to be heterogeneous, consisting of subgroups of women with as-yet-unidentified risk factors or causes, and therefore require further investigation. In this study we focused on women with urpl by excluding patients with major known causes of RPL, and for the first time have demonstrated the prevalence of borderline-sch and its impact on pregnancy outcomes in those women. We found that the subsequent pregnancy loss rate (<22 weeks of gestation) tended to be higher in the borderline-sch than in the euthyroid patients (29.0%, 9/31 vs 17.9%, 24/134), but not significantly so (P = 0.16). One can argue that, in addition to the present small sample size, the large proportion of women with only two miscarriages (n = 163) in the total cohort (n = 317) may have diluted any possible difference in subsequent pregnancy outcomes. To address this argument, we conducted similar analysis focusing on the RPL patients with a history of three or more miscarriage (n = 154). In agreement with the results on RPL patients with two or more pregnancy losses, significantly more patients were positive for ANA in the borderline- SCH group than in the euthyroid group (57.7%, 15/26 vs 33.5%, 43/128, P = 0.021), but there was no difference in the pregnancy loss rate between the borderline-sch and euthyroid groups (23.1%, 3/13 vs 23.0%, 14/61). Accumulating evidence indicates an association between thyroid dysfunction and autoimmune abnormalities that have a negative impact on the maintenance of pregnancy. 19 For example, thyroid autoimmunity with or without thyroid dysfunction is frequently noted concurrently with other autoimmune diseases, such as systemic lupus erythematosus and Sjögren s syndrome. 22 ANA testing is not recommended for RPL screening according to current RPL guidelines. 2,3 Based on the present data, we also confirmed that women with RPL and positive ANA have an equivalent pregnancy loss rate to that of ANA-negative women (data not shown). Nevertheless, a higher prevalence of ANA positivity was observed in the borderline-sch group than in the euthyroid group (Table 1). Increased prevalence of ANA in patients with autoimmune thyroid disease is well known. 11,23 Taken together, an association between 1018

6 Subtle hypothyroidism in unexplained RPL ANA and borderline-sch, as presented herein, suggests that thyroid autoantibodies may be more prevalent in the borderline-sch group than in the euthyroid group. Furthermore, there was a greater tendency for women with borderline-sch RPL and unsuccessful pregnancy outcomes to be ANA positive than women with successful pregnancies, but no such tendency was apparent for euthyroid women, raising the possibility that borderline-sch in combination with ANA positivity or possibly other autoimmune problems, such as autoimmune thyroid disorders, would have a negative impact on subsequent pregnancy outcomes. A very recent study has reported that among healthy fecund women with a history of pregnancy loss, TSH 2.5 miu/l or the presence of anti-thyroid antibodies were not associated with fecundity, pregnancy loss, or live birth. 24 That study, however, enrolled women with a history of pregnancy loss but did not focus on urpl. One of the limitations of the present study was that the sample size was too small to enable the drawing of a definitive conclusion. Second, because we could not verify whether or not all the past and subsequent pregnancy losses were based on chromosomal aberrations, the patient cohort may still be heterogeneous. Third, we did not examine whether or not the patients had anti-thyroid autoantibodies, especially anti-thyroid peroxidase antibodies. In the present study, patients considered to be euthyroid (0.3 TSH 4.5 IU/mL) did not undergo further evaluation for the presence of anti-thyroid autoantibodies. Thus, the prevalence of thyroid autoantibodies in the present urpl patients is unknown. Further studies with precise evaluation of thyroid autoimmunity in women with urpl will help to clarify SCH and the necessity of treatment for urpl. In conclusion, there was no definite evidence for an association between borderline-sch and RPL, but there was a definite subset of women with newly diagnosed borderline-sch and possible autoimmune problems, as reflected by ANA positivity, in the urpl group. Based on these results, further studies are warranted to elucidate whether a combination of borderline-sch and autoimmune disorders, especially autoimmune thyroid disorders, acts as an as-yet-unidentified cause of urpl. Acknowledgments We thank all participating patients for their cooperation, TakashiNagashima,ToruArase,HideyukiOda,Kaoru Miyazaki and Masanori Ono for recruitment of patients, and Rika Shibata for assistance with the manuscript. This study was partly supported by a Health Labour Sciences Research grant (H20-KODOMO-IPPAN-002 to T.M.) from The Ministry of Health Labour and Welfare, Japan. Disclosure The authors declare no conflict of interest. References 1. Royal College of Obstetricians and Gynaecologists. 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