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Journal Club

Journal Club. Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A . Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ. 2011 May 9;342:d2616. doi : 10.1136/bmj.d2616 .

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Journal Club

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  1. Journal Club Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ. 2011 May 9;342:d2616. doi: 10.1136/bmj.d2616. Ferrannini E, Betteridge DJ, Dormandy JA, Charbonnel B, Wilcox RG, Spanheimer R, Erdmann E, Defronzo RA, Laakso M. HDL-cholesterol and not HbA1c was directly related to Cardiovascular Outcome in PROactive. Diabetes ObesMetab. 2011 Apr 1. doi: 10.1111/j.1463-1326.2011.01404.x. [Epub ahead of print] 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文 Matsuda, Masafumi 2011年5月19日8:30-8:55 ８階　医局

  2. BMJ 2011;342:d2616

  3. Objectives To evaluate the association between thyroid autoantibodies and miscarriage and preterm birth in women with normal thyroid function. To assess the effect of treatment with levothyroxine on pregnancy outcomes in this group of women.

  4. Design Systematic review and meta-analysis. Data sources Medline, Embase, Cochrane Library, and SCISEARCH (inception-2011) without any language restrictions. We used a combination of key words to generate two subsets of citations, one indexing thyroid autoantibodies and the other indexing the outcomes of miscarriage and preterm birth. Study selection Studies that evaluated the association between thyroid autoantibodies and pregnancy outcomes were selected in a two stage process. Two reviewers selected studies that met the predefined and explicit criteria regarding population, tests, and outcomes. Data synthesis Odds ratios from individual studies were pooled separately for cohort and case-control studies with the random effects model.

  5. Fig 2 | Association between thyroid autoantibodies and miscarriage in cohort studies

  6. Fig 2 | Association between thyroid autoantibodies and miscarriage in cohort studies

  7. Pathogenesis of adverse pregnancy outcomes with thyroid autoantibodies The frequent presence of thyroid autoantibodies in several non-thyroidal autoimmune diseases supports a hypothesis of global immune dysfunction being relevant to these clinical outcomes. There is evidence that there is an alteration in cytokine expression by peripheral T lymphocytes in women positive for thyroid antibodies outside of pregnancy. Pregnancy is an inflammatory process involving a shift in the regulation of cytokine networks within the local placental-decidualenvironment. Dysregulation of local inflammatory processes can be associated with miscarriage and premature delivery. The presence of thyroid autoantibodies can reflect a generalised activation of the immune system and specifically a dysregulated activity of the immune systemat the fetal-maternal interface. Thyroid hormones can directly influence angiogenic growth factor and cytokine production as well as trophoblast proliferation, survival, and invasion. Furthermore, the presence of thyroid autoantibodies might be a marker of underlying subtle alteration in thyroid reserve. A reduction in the functional reserve of the thyroid gland associated with reduced adaptation to the physiological changes of pregnancy could contribute to minor changes in circulating thyroid hormone concentrations within the reference range. The increase in thyroid stimulating hormone concentrations in euthyroid women with thyroid autoantibodies supports this hypothesis. There were insufficient data to identify any differences in the concentrations of triiodothyronine (T3) between the two groups.We postulate that treatment with levothyroxine might correct any relative deficiency of thyroid hormones and impact on both systemic immune regulation and the local placental-decidualenvironment.

  8. Results 30 articles with 31 studies (19 cohort and 12 case-control) involving 12 126 women assessed the association between thyroid autoantibodies and miscarriage. Five studies with 12 566 women evaluated the association with preterm birth. Of the 31 studies evaluating miscarriage, 28 showed a positive association between thyroid autoantibodies and miscarriage. Metaanalysis of the cohort studies showed more than tripling in the odds of miscarriage with the presence of thyroid autoantibodies (odds ratio 3.90, 95% confidence interval 2.48 to 6.12; P<0.001). For case-control studies the odds ratio for miscarriage was 1.80, 1.25 to 2.60; P=0.002). There was a significant doubling in the odds of preterm birth with the presence of thyroid autoantibodies (2.07, 1.17 to 3.68; P=0.01). Two randomised studies evaluated the effect of treatment with levothyroxine on miscarriage. Both showed a fall in miscarriage rates, and metaanalysis showed a significant 52% relative risk reduction in miscarriages with levothyroxine (relative risk 0.48, 0.25 to 0.92; P=0.03). One study reported on the effect of levothyroxine on the rate of preterm birth, and noted a 69% relative risk reduction (0.31, 0.11 to 0.90).

  9. Conclusion The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks.

  10. Message/Comments 橋本病の妊婦では甲状腺機能が正常であっても、チラーヂンSを投与するとよいらしい。 普通は機能が正常なら投与しないと思いますが．．．ともかく 甲状腺自己抗体と流産および早産の関係、レボチロキシンの妊娠への影響をメタアナリシスで調査。母体における甲状腺自己抗体の存在は、流産および早産に強く関連していた。2つの無作為化試験では、レボチロキシンの投与により流産の相対リスクは52％と有意な減少が見られ、他の試験でも早産の相対リスク69％の減少が見られた。

  11. 主要評価項目の結果（Kaplan-Meier） （%） 25 イベント数 572/2,633 514/2,605 3年時評価* 23.5% 21.0% 10%減少 プラセボ ピオグリタゾン　 累積イベント発症率 20 15 10 5 0 （ヵ月）　 0 6 12 18 24 30 36 追跡期間 症例数 ピオグリタゾン 2,488 2,373 2,302 2,218 2,146 348 プラセボ 2,530 2,413 2,317 2,215 2,122 345 *:EASD 41st Annual Meetings,Sep.,2005,Athens.のみ発表 Dormandy J.A. et al.：Lancet,366,1279,2005.

  12. 急性冠症候群（ACS）（心筋梗塞既往例） （%） 6 イベント数　 54/1,215 35/1,230 発症率　4.4% 2.8% プラセボ ピオグリタゾン　 5 累積イベント発症率 37％減少 4 （p=0.035） 3 2 1 0 2,445 2,397 2,351 2,308 2,265 2,222 406 （139） 症例数 （ヵ月）　　 0 6 12 18 24 30 36 追跡期間 無作為化から急性冠症候群（ACS）が最初に起こるまでの期間　 NNT 43.5 アクトスでは心不全発症のおそれのある心筋梗塞、狭心症、心筋症、高血圧性心疾患等の心疾患のある患者は慎重投与です。 Erdmann. E. et al.： AHA scientific sessions,Nov.,2005,Dallas.

  13. 脳卒中の再発 脳卒中既往例サブグループ解析 PROactive （%） イベント数 発症率 12 プラセボ 51/498 ピオグリタゾン 27/486 10.2% 5.6% 10 47%減少（p=0.008） 累積イベント発症率 8 6 4 2 0 症例数 984 952 926 903 877 849 132 （ヵ月）　 0 6 12 18 24 30 36 追跡期間 無作為化から脳卒中が最初に起こるまでの期間　 Wilcox RG. et al.：World Congress of Cardiology,Sep,2006,Barcelona.

  14. ～ ～ HbA1Cの推移 （%） 10 ピオグリタゾン群 プラセボ ピオグリタゾン 中央値（error barsは四分位範囲を示す） 1.0 ベースラインからの変化量（％） プラセボ群 9 0.5 7.9 8 7.5 HbA1C 7.8 0 7 * * * 6.9 * -0.3 -0.5 6 *p<0.001 vs プラセボ -0.8 -1.0 0 p<0.001 0 6 12 24 最終評価時 追跡期間 （ヵ月） EASD 41st Annual Meetings,Sep.,2005,Athens.

  15. ～ ～ トリグリセリドに対する影響 ピオグリタゾン群 （mg/dL） 250 プラセボ 20 プラセボ群 ベースラインからの変化率（％） 中央値（error barsは四分位範囲を示す） 230 ピオグリタゾン 210 トリグリセリド 10 190 1.8 159 170 159 0 150 159 * 142 130 * * -10 * -11.4 110 *p<0.001 vs プラセボ -20 p<0.001 0 0 6 12 24 最終評価時 （ヵ月） 追跡期間 EASD 41st Annual Meetings,Sep.,2005,Athens.

  16. ～ ～ HDL-Cに対する影響 （mg/dL） 中央値（error barsは四分位範囲を示す） p<0.001 プラセボ 60 ピオグリタゾン 19.0 20 ベースラインからの変化率（％） 55 * 10.1 * 50 10 * 50 * 46 HDL-C 43 45 0 ピオグリタゾン群 プラセボ群 43 40 -10 35 *p<0.001 vs プラセボ -20 0 0 6 12 24 最終評価時 （ヵ月） 追跡期間 EASD 41st Annual Meetings,Sep.,2005,Athens.

  17. ～ ～ LDL/HDLの推移 3.5 プラセボ 中央値（error barsは四分位範囲を示す） ピオグリタゾン 3.0 2.5 LDL/HDL * * * * 2.0 *p＜0.001 vs プラセボ 0 0 6 12 24 最終評価時 追跡期間 （ヵ月） アクトスでは心不全発症のおそれのある心筋梗塞、狭心症、心筋症、高血圧性心疾患等の心疾患のある患者は慎重投与です。 EASD 41st Annual Meetings,Sep.,2005,Athens.

  18. JAMA. 2010 Jul 28;304(4):411-8.

  19. Trial registration number: NCT00174993, www.ClinicalTrial.gov Diabetes, Obesity and Metabolism doi: 10.1111/j.1463-1326.2011.01404.x

  20. Aims In PROactive, pioglitazone reduced the incidence of death, myocardial infarction, and stroke and significantly improved HbA1c, systolic blood pressure (SBP), triglycerides, and HDL-cholesterol relative to placebo. As these glycaemic and lipid parameters are major cardiovascular risk factors, we assessed their separate contribution to the reduced incidence of cardiovascular outcomes.

  21. Materials and Methods Patients (n=5,238) with type 2 diabetes and macrovascular disease were randomised to 45 mg pioglitazone or placebo. Relationships between treatment, outcome (time to first event of all-cause mortality, myocardial infarction, and stroke), and 10 laboratory measurements and vital signs were investigated using log-linear models. Continuous variables measurements (percent changes from baseline to average of all postbaseline values prior to censoring) were made discrete by categorizing into tertiles. Loglinear models were fitted to multi-way tables of discrete data and analysis of deviance used to summarize sources of variation in the data.

  22. TABLE 1. Four-Way Table for the Variables Treatment (Pioglitazone vs Placebo), Outcome (Event=Death, Myocardial Infarction, or Stroke), HbA1c, and HDL-cholesterol (HDL-C, in Tertiles) in PROactive. Entries are the Number of Subjects in Each Group

  23. Figure 2. Schematic summary of the exploratory analysis: pioglitazone treatment is associated with a decrease in HbA1c concentrations and rise in HDL-cholesterol levels, but only HDL-cholesterol is independently associated with the outcome (reduced incidence of death from any cause, myocardial infarction, and stroke). Statin use makes a separate contribution to event reduction.

  24. Results Although pioglitazone treatment was associated with a decrease in HbA1c and an increase in HDL-cholesterol, only the change from baseline HDL-cholesterol predicted outcome (χ2=28.89, p<0.0001). No other variables, including HbA1c, triglycerides, and systolic blood preessure, showed significant direct associations with outcome. When the analysis was extended to include baseline statin use, this was associated with an improved outcome independently of HDL-cholesterol changes.

  25. Conclusions This post-hoc analysis suggests that HDL-cholesterol, but probably not HbA1c, is a driver of pioglitazone’s favorable influence on cardiovascular outcome.

  26. Message/Comments PROactiveは基本的にはprimary endopointで有意差がつかなかった研究でFDAの評価は低いのだが。 ピオグリタゾンはともかく既に大血管合併症が存在している患者にはよいのであろう。 心血管障害の減少は血糖改善よりも脂質改善が影響していることが再確認された。インスリン感受性改善での脂質改善であれば、ロジグリタゾンやムラグリタザールで死亡が低下しなかったことは説明がやはり難しいと感じる。

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