今日の臨床サポート

習慣流産、不育症

著者: 竹下俊行 竹下レディスクリニック

監修: 杉野法広 山口大学 産科婦人科学

著者校正済:2022/11/09
現在監修レビュー中
参考ガイドライン:
  1. 日本産科婦人科学会日本産婦人科医会:産婦人科診療ガイドライン 産科編2020
  1. 日本産科婦人科学会日本産婦人科医会:産婦人科診療ガイドライン 婦人科外来編2020
  1. 不育症管理に関する提言2021(http://fuiku.jp/common/teigen001.pdf)
  1. ESHRE: Recurrent Pregnancy Loss – Guideline of the European Society of Human Reproduction and Embryology. 2017
  1. ASRM: Evaluation and treatment of recurrent pregnancy loss: A committee opinion.2012
患者向け説明資料

概要・推奨   

  1. 不育症に対して原因究明のための精査を行っても、約半数の症例で原因特定はできない。こうした原因不明症例に対して抗血栓療法(アスピリン、ヘパリンなど)を行っても生児獲得率を改善しないので、抗血栓療法は推奨されない(推奨度3)
  1. 初期流産を繰り返している抗リン脂質抗体症候群による習慣流産患者が妊娠した場合、低用量アスピリンとヘパリンの併用療法が推奨される(推奨度2)
  1. 抗リン脂質抗体症候群は習慣流産の原因として最も重要であり、頻度も高い。したがって、習慣流産(不育症)の原因検索にあたっては抗リン脂質抗体(ループスアンチコアグラント、抗カルジオリピン抗体、抗β2GPI抗体)を測定することが推奨される(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
竹下俊行 : 特に申告事項無し[2022年]
監修:杉野法広 : 研究費・助成金など(浜田市,あすか製薬)[2022年]

改訂のポイント:
  1. AMED研究班がまとめた「不育症管理に関する提言2021」に基づき、血栓性素因に関する検査、治療を追加した。
  1. 胎児(絨毛)染色体検査に関する記載を追加した。
  1. 夫婦染色体異常(転座など)に起因する不育症を対象とした着床前検査、および原因不明不育症を対象とした着床前検査に関する記述を追加した。
  1. 中隔子宮に対する子宮鏡下中隔切除術に関するエビデンスとそれに対するコメントを追加した。
  1. 抗リン脂質抗体検査の一部が保険収載された旨追加記載した。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 習慣流産:自然流産を連続して3回繰り返している状態をいう。
  1. 不育症:妊娠はするが流産・死産を繰り返し、生児が得られない状態。流産を2回繰り返した反復流産もこれに含まれる。
  1. 一般に習慣流産は1%、反復流産は5%の夫婦(カップル)に起こるといわれる[1]
  1. 原因は多岐にわたるが、抗リン脂質抗体症候群、子宮形態異常、夫婦染色体異常、血液凝固異常、内分泌代謝異常などがリスク因子となる。このうち、検出される頻度が最も高いリスク因子は抗リン脂質抗体症候群で、子宮形態異常、血液凝固異常(プロテインS欠乏症や凝固第XII因子欠乏症などの血栓性素因)がこれに続く。
  1. 原因究明のための精査を行っても、約半数の症例で原因特定は困難である[2]
  1. 治療は各原因疾患の病態に応じて行う。
問診・診察のポイント  
  1. それぞれの妊娠について流産、死産を起こした妊娠週数、胎芽・胎児心拍の有無、子宮内容除去術の有無を詳細に問う。

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文献 

D Ware Branch, Mark Gibson, Robert M Silver
Clinical practice. Recurrent miscarriage.
N Engl J Med. 2010 Oct 28;363(18):1740-7. doi: 10.1056/NEJMcp1005330.
Abstract/Text
PMID 20979474
Abstract/Text OBJECTIVE: The purpose of this study was to compare the use of low-dose aspirin alone with heparin and low-dose aspirin in the treatment of the antiphospholipid antibody syndrome.
STUDY DESIGN: A prospective, single-center trial included 50 patients who were alternately assigned to treatment. Each patient had at least three consecutive spontaneous pregnancy losses, positive antiphospholipid antibodies on two occasions, and a complete evaluation. Data were compared by chi(2) analysis and Fisher's exact test.
RESULTS: Viable infants were delivered of 11 of 25 (44%) women treated with aspirin and 20 of 25 (80%) women treated with heparin and aspirin (p < 0.05). There were no significant differences between the low-dose aspirin and the heparin plus low-dose aspirin groups with respect to gestational age at delivery (37.8 +/- 2.1 vs 37.2 +/- 3.4 weeks), number of cesarean sections (18% vs 20%), or complications.
CONCLUSION: Heparin plus low-dose aspirin provides a significantly better pregnancy outcome than low-dose aspirin alone does for antiphospholipid antibody-associated recurrent pregnancy loss.

PMID 9065133
Abstract/Text OBJECTIVE: To determine whether treatment with low dose aspirin and heparin leads to a higher rate of live births than that achieved with low dose aspirin alone in women with a history of recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies), lupus anticoagulant, and cardiolipin antibodies (or anticardiolipin antibodies).
DESIGN: Randomised controlled trial.
SETTING: Specialist clinic for recurrent miscarriages.
SUBJECTS: 90 women (median age 33 (range 22-43)) with a history of recurrent miscarriage (median number 4 (range 3-15)) and persistently positive results for phospholipid antibodies.
INTERVENTION: Either low dose aspirin (75 mg daily) or low dose aspirin and 5000 U of unfractionated heparin subcutaneously 12 hourly. All women started treatment with low dose aspirin when they had a positive urine pregnancy test. Women were randomly allocated an intervention when fetal heart activity was seen on ultrasonography. Treatment was stopped at the time of miscarriage or at 34 weeks' gestation.
MAIN OUTCOME MEASURES: Rate of live births with the two treatments.
RESULTS: There was no significant difference in the two groups in age or the number and gestation of previous miscarriages. The rate of live births with low dose aspirin and heparin was 71% (32/45 pregnancies) and 42% (19/45 pregnancies) with low dose aspirin alone (odds ratio 3.37 (95% confidence interval 1.40 to 8.10)). More than 90% of miscarriages occurred in the first trimester. There was no difference in outcome between the two treatments in pregnancies that advanced beyond 13 weeks' gestation. Twelve of the 51 successful pregnancies (24%) were delivered before 37 weeks' gestation. Women randomly allocated aspirin and heparin had a median decrease in lumbar spine bone density of 5.4% (range -8.6% to 1.7%).
CONCLUSION: Treatment with aspirin and heparin leads to a significantly higher rate of live births in women with a history of recurrent miscarriage associated with phospholipid antibodies than that achieved with aspirin alone.

PMID 9022487
Stef Kaandorp, Marcello Di Nisio, Mariette Goddijn, Saskia Middeldorp
Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome.
Cochrane Database Syst Rev. 2009 Jan 21;(1):CD004734. doi: 10.1002/14651858.CD004734.pub3. Epub 2009 Jan 21.
Abstract/Text BACKGROUND: Since hypercoagulability might result in recurrent miscarriage, anticoagulant agents could potentially increase the live-birth rate in subsequent pregnancies in women with either inherited thrombophilia or unexplained recurrent miscarriage.
OBJECTIVES: To evaluate the efficacy and safety of anticoagulant agents, such as aspirin and heparin, in women with a history of at least two miscarriages without apparent causes other than inherited thrombophilia.
SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2007, Issue 1), MEDLINE (January 1966 to March 2007), and EMBASE (1980 to March 2007). We scanned bibliographies of all located articles for any unidentified articles.
SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that assessed the effect of anticoagulant treatment on the live-birth rate in women with a history of at least two miscarriages (up to 20 weeks of amenorrhoea) without apparent causes other than inherited thrombophilia were eligible. Interventions included aspirin, unfractionated heparin, and low molecular weight heparin for the prevention of miscarriage. One treatment could be compared with another or with placebo.
DATA COLLECTION AND ANALYSIS: Two authors assessed the trials for inclusion in the review and extracted the data. We double checked the data.
MAIN RESULTS: Two studies (189 participants) were included in the review. In one study, 54 pregnant women with recurrent miscarriage (RM) but no detectable anticardiolipin antibodies were randomised to low-dose aspirin or placebo. RM was defined as three or more consecutive miscarriages (occurring before 22 weeks' gestational age (based on last menstrual period)). Similar live-birth rates were observed with aspirin and placebo, both 81% (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.78 to 1.29). In the other study, 107 women with consecutive recurrent miscarriage without any apparent cause and no hereditary thrombophilia were randomised between enoxaparin and aspirin. Here RM was stated as three or more consecutive first trimester miscarriages or at least two consecutive second trimester miscarriages. Similar live birth rates were observed with enoxaparin and aspirin, respectively 82% and 84% (RR 0.97, 95% CI 0.81 to 1.16).
AUTHORS' CONCLUSIONS: There is a paucity in studies on the efficacy and safety of aspirin and heparin in women with a history of at least two miscarriages without apparent causes other than inherited thrombophilia. The two reviewed trials studied different treatments and only one study was placebo-controlled. Neither of the studies showed a benefit of one treatment over the other. Therefore, the use of anticoagulants in this setting is not recommended. However, large randomised placebo-controlled trials are still urgently needed.

PMID 19160241
Stef P Kaandorp, Mariëtte Goddijn, Joris A M van der Post, Barbara A Hutten, Harold R Verhoeve, Karly Hamulyák, Ben Willem Mol, Nienke Folkeringa, Marleen Nahuis, Dimitri N M Papatsonis, Harry R Büller, Fulco van der Veen, Saskia Middeldorp
Aspirin plus heparin or aspirin alone in women with recurrent miscarriage.
N Engl J Med. 2010 Apr 29;362(17):1586-96. doi: 10.1056/NEJMoa1000641. Epub 2010 Mar 24.
Abstract/Text BACKGROUND: Aspirin and low-molecular-weight heparin are prescribed for women with unexplained recurrent miscarriage, with the goal of improving the rate of live births, but limited data from randomized, controlled trials are available to support the use of these drugs.
METHODS: In this randomized trial, we enrolled 364 women between the ages of 18 and 42 years who had a history of unexplained recurrent miscarriage and were attempting to conceive or were less than 6 weeks pregnant. We then randomly assigned them to receive daily 80 mg of aspirin plus open-label subcutaneous nadroparin (at a dose of 2850 IU, starting as soon as a viable pregnancy was demonstrated), 80 mg of aspirin alone, or placebo. The primary outcome measure was the live-birth rate. Secondary outcomes included rates of miscarriage, obstetrical complications, and maternal and fetal adverse events.
RESULTS: Live-birth rates did not differ significantly among the three study groups. The proportions of women who gave birth to a live infant were 54.5% in the group receiving aspirin plus nadroparin (combination-therapy group), 50.8% in the aspirin-only group, and 57.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, -2.6 percentage points; 95% confidence interval [CI], -15.0 to 9.9; aspirin only vs. placebo, -6.2 percentage points; 95% CI, -18.8 to 6.4). Among 299 women who became pregnant, the live-birth rates were 69.1% in the combination-therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, 2.1 percentage points; 95% CI, -10.8 to 15.0; aspirin alone vs. placebo -5.4 percentage points; 95% CI, -18.6 to 7.8). An increased tendency to bruise and swelling or itching at the injection site occurred significantly more frequently in the combination-therapy group than in the other two study groups.
CONCLUSIONS: Neither aspirin combined with nadroparin nor aspirin alone improved the live-birth rate, as compared with placebo, among women with unexplained recurrent miscarriage. (Current Controlled Trials number, ISRCTN58496168.)

2010 Massachusetts Medical Society
PMID 20335572
Roy G Farquharson, Siobhan Quenby, Michael Greaves
Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment.
Obstet Gynecol. 2002 Sep;100(3):408-13.
Abstract/Text OBJECTIVE: To compare the efficacy of low-dose aspirin alone versus low-dose aspirin plus low molecular weight heparin in pregnant women with antiphospholipid syndrome and recurrent miscarriage as prophylaxis against pregnancy loss.
METHODS: From a regional miscarriage clinic, 119 consecutive women with persistently positive tests for lupus anticoagulant and/or anticardiolipin immunoglobulin G and M antibody were invited to participate in a randomized, controlled trial between 1997 and 2000. After ethical approval and adherence to a written protocol, 12 women were unwilling to participate, five failed exclusion/inclusion criteria, and four were nonpregnant. Laboratory analysis was performed by Sheffield University Coagulation Department, electronically generated randomization by Manchester University Centre for Cancer Epidemiology, and data collection and analysis by a research officer at Leeds University. Viability ultrasound every 2 weeks was provided until 12 weeks' gestation before transfer to the pregnancy support antenatal clinic.
RESULTS: Ninety-eight women were randomized before 12 weeks' gestation. Forty-seven received low-dose aspirin 75 mg daily (group A), and 51 received low-dose aspirin plus low molecular weight heparin 5000 U subcutaneously daily (group B) throughout pregnancy. There were 13 pregnancy losses and 34 live births in group A and 11 losses and 40 live births in group B. The live-birth rate was 72% in group A and 78% in group B (odds ratio 1.39, 95% confidence interval 0.55, 3.47). There were no cases of maternal thrombosis in either group.
CONCLUSION: A high success rate is achieved when low-dose aspirin is used for antiphospholipid syndrome in pregnancy. The addition of low molecular weight heparin does not significantly improve pregnancy outcome.

PMID 12220757
Panayiotis D Ziakas, Matthaios Pavlou, Michael Voulgarelis
Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis.
Obstet Gynecol. 2010 Jun;115(6):1256-62. doi: 10.1097/AOG.0b013e3181deba40.
Abstract/Text OBJECTIVE: To estimate the effect of combined heparin and aspirin compared with aspirin monotherapy in pregnant women with antiphospholipid syndrome and recurrent pregnancy loss.
DATA SOURCES: We searched the PubMed database up to December 2009 for English-language studies using the key words "aspirin AND (heparin OR low molecular weight heparin), (antiphospholipid OR anticardiolipin OR aPL) AND pregnancy."
METHODS OF STUDY SELECTION: Two hundred ninety- two studies were initially screened. Randomized controlled trials comparing the effect of heparin (unfractionated heparin or low molecular weight heparin) plus aspirin compared with aspirin alone on the live-birth rate in women with a history of at least two miscarriages and antiphospholipid antibodies were eligible.
TABULATION, INTEGRATION, AND RESULTS: The pooled effect of unfractionated heparin and low molecular weight heparin was evaluable in three and two randomized controlled studies, respectively, with regard to live births, which was the major outcome. Overall, treatment effects were in favor of heparin against first-trimester losses (odd ratio [OR] 0.39, 95% confidence interval [CI] 0.24-0.65, number needed to treat 6). More specifically, unfractionated heparin displayed a significant effect (OR 0.26, 95% CI 0.14-0.48, number needed to treat 4), while the pooled effect of low molecular weight heparin was insignificant (OR 0.70, 95% CI 0.34-1.45). Combination therapy of either unfractionated heparin or low molecular weight heparin with aspirin failed to display any significant effect in the prevention of late-pregnancy losses. No significant differences were observed between treatment and control groups for any other outcomes.
CONCLUSION: The combination of unfractionated heparin and aspirin confers a significant benefit in live births. However, the efficacy of low molecular weight heparin plus aspirin remains unproven, highlighting the urgent need for large controlled trials.

PMID 20502298
B Stray-Pedersen, S Stray-Pedersen
Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion.
Am J Obstet Gynecol. 1984 Jan 15;148(2):140-6.
Abstract/Text A diagnostic screening program was applied to 195 couples with a prior history of habitual abortion (i.e., three or more consecutive abortions). Abnormalities were identified in 110 (56%) of the couples. Such identification was significantly more frequent in couples with primary habitual abortion than in couples with secondary habitual abortion (p less than 0.001) and also more frequent in couples with second-trimester abortions than in those with first-trimester abortions (p approximately equal to 0.01). The abnormalities most commonly observed were anomalies of the uterine body (15%), endometrial infections (15%), and cervical incompetence (13%). Hormonal dysfunctions were detected in 5%, and there were chromosomal aberrations in 3% of the couples. The women in the group showing abnormalities were offered surgical or medical treatment, and 80% of those who subsequently conceived carried their pregnancies to term. Among the couples with no abnormal findings, women receiving specific antenatal counseling and psychological support had a pregnancy success rate of 86%, as compared to a success rate of 33% observed in women who were given no specific antenatal care (p less than 0.001).

PMID 6691389
Eric Jauniaux, Roy G Farquharson, Ole B Christiansen, Niek Exalto
Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage.
Hum Reprod. 2006 Sep;21(9):2216-22. doi: 10.1093/humrep/del150. Epub 2006 May 17.
Abstract/Text Recurrent miscarriage (RM; > or =3 consecutive early pregnancy losses) affects around 1% of fertile couples. Parental chromosomal anomalies, maternal thrombophilic disorders and structural uterine anomalies have been directly associated with recurrent miscarriage; however, in the vast majority of cases the pathophysiology remains unknown. We have updated the ESHRE Special Interest Group for Early Pregnancy (SIGEP) protocol for the investigation and medical management of RM. Based on the data of recently published large randomized controlled trials (RCTs) and meta-analyses, we recommend that basic investigations of a couple presenting with recurrent miscarriage should include obstetric and family history, age, BMI and exposure to toxins, full blood count, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), parental karyotype, pelvic ultrasound and/or hysterosalpingogram. Other investigations should be limited to particular cases and/or used within research programmes. Tender loving care and health advice are the only interventions that do not require more RCTs. All other proposed therapies, which require more investigations, are of no proven benefit or are associated with more harm than good.

PMID 16707507
Hideto Yamada, Masashi Deguchi, Shigeru Saito, Toshiyuki Takeshita, Mari Mitsui, Tsuyoshi Saito, Takeshi Nagamatsu, Koichi Takakuwa, Mikiya Nakatsuka, Satoshi Yoneda, Katsuko Egashira, Masahito Tachibana, Keiichi Matsubara, Ritsuo Honda, Atsushi Fukui, Kanji Tanaka, Kazuo Sengoku, Toshiaki Endo, Hiroaki Yata
Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial.
EClinicalMedicine. 2022 Aug;50:101527. doi: 10.1016/j.eclinm.2022.101527. Epub 2022 Jun 29.
Abstract/Text Background: There is no effective treatment for women with unexplained recurrent pregnancy loss (RPL). We aimed to investigate whether treatment with a high dose of intravenous immunoglobulin (IVIG) in early pregnancy can improve pregnancy outcomes in women with unexplained RPL.
Methods: In a double-blind, randomised, placebo-controlled trial, women with primary RPL of unexplained aetiology received 400 mg/kg of IVIG daily or placebo for five consecutive days starting at 4-6 weeks of gestation. They had experienced four or more miscarriages except biochemical pregnancy loss and at least one miscarriage of normal chromosome karyotype. The primary outcome was ongoing pregnancy rate at 22 weeks of gestation, and the live birth rate was the secondary outcome. We analysed all women receiving the study drug (intention-to-treat, ITT) and women except those who miscarried due to fetal chromosome abnormality (modified-ITT). This study is registered with ClinicalTrials.gov number, NCT02184741.
Findings: From June 3, 2014 to Jan 29, 2020, 102 women were randomly assigned to receive IVIG (n = 53) or placebo (n = 49). Three women were excluded; therefore 50 women received IVIG and 49 women received placebo in the ITT population. The ongoing pregnancy rate at 22 weeks of gestation (31/50 [62·0%] vs. 17/49 [34·7%]; odds ratio [OR] 3·07, 95% CI 1·35-6·97; p = 0·009) and the live birth rate (29/50 [58·0%] vs. 17/49 [34·7%]; OR 2·60, 95% CI 1·15-5·86; p = 0·03) in the IVIG group were higher than those in the placebo group in the ITT population. The ongoing pregnancy rate at 22 weeks of gestation (OR 6·27, 95% CI 2·21-17·78; p < 0·001) and the live birth rate (OR 4·85, 95% CI 1·74-13·49; p = 0·003) significantly increased in women who received IVIG at 4-5 weeks of gestation as compared with placebo, but these increases were not evident in women who received IVIG at 6 weeks of gestation. Four newborns in the IVIG group and none in the placebo group had congenital anomalies (p = 0·28).
Interpretation: A high dose of IVIG in very early pregnancy improved pregnancy outcome in women with four or more RPLs of unexplained aetiology.
Funding: The Japan Blood Products Organization.

© 2022 The Author(s).
PMID 35795714
S Miyakis, M D Lockshin, T Atsumi, D W Branch, R L Brey, R Cervera, R H W M Derksen, P G DE Groot, T Koike, P L Meroni, G Reber, Y Shoenfeld, A Tincani, P G Vlachoyiannopoulos, S A Krilis
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
J Thromb Haemost. 2006 Feb;4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x.
Abstract/Text New clinical, laboratory and experimental insights, since the 1999 publication of the Sapporo preliminary classification criteria for antiphospholipid syndrome (APS), had been addressed at a workshop in Sydney, Australia, before the Eleventh International Congress on antiphospholipid antibodies. In this document, we appraise the existing evidence on clinical and laboratory features of APS addressed during the forum. Based on this, we propose amendments to the Sapporo criteria. We also provide definitions on features of APS that were not included in the updated criteria.

PMID 16420554
Guillermo Ruiz-Irastorza, Mark Crowther, Ware Branch, Munther A Khamashta
Antiphospholipid syndrome.
Lancet. 2010 Oct 30;376(9751):1498-509. doi: 10.1016/S0140-6736(10)60709-X. Epub 2010 Sep 6.
Abstract/Text The antiphospholipid syndrome causes venous, arterial, and small-vessel thrombosis; pregnancy loss; and preterm delivery for patients with severe pre-eclampsia or placental insufficiency. Other clinical manifestations are cardiac valvular disease, renal thrombotic microangiopathy, thrombocytopenia, haemolytic anaemia, and cognitive impairment. Antiphospholipid antibodies promote activation of endothelial cells, monocytes, and platelets; and overproduction of tissue factor and thromboxane A2. Complement activation might have a central pathogenetic role. Of the different antiphospholipid antibodies, lupus anticoagulant is the strongest predictor of features related to antiphospholipid syndrome. Therapy of thrombosis is based on long-term oral anticoagulation and patients with arterial events should be treated aggressively. Primary thromboprophylaxis is recommended in patients with systemic lupus erythematosus and probably in purely obstetric antiphospholipid syndrome. Obstetric care is based on combined medical-obstetric high-risk management and treatment with aspirin and heparin. Hydroxychloroquine is a potential additional treatment for this syndrome. Possible future therapies for non-pregnant patients with antiphospholipid syndrome are statins, rituximab, and new anticoagulant drugs.

Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID 20822807
Abstract/Text Antiphospholipid antibodies (APA), lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACA), are associated with thrombosis and recurrent miscarriage. We studied the outcome of 20 pregnancies in women (median age 32 years; range 23-41) with APA (14 LA positive; three immunoglobulin (Ig) G ACA positive; two IgM ACA positive and one LA and IgG ACA positive) and history of recurrent miscarriage (median 4; range 3-11) who declined pharmacological treatment in their next pregnancy. Comparison was made with a cohort of 100 consecutive women (median age 33 years; range 23-44) with recurrent miscarriage (median 4; range 3-10), in whom no underlying cause to account for their pregnancy losses was found. Of the 20 women with APA, 18 (90%) miscarried compared to 34 of the 100 women (34%) with normal investigations (P < 0.001). The majority (94%) of miscarriages in women with APA occurred in the first trimester. Fetal heart activity was seen prior to fetal death in 86% of women with APA compared to 43% of women with normal investigations (P < 0.01). The first trimester loss of embryonic pregnancies is the most common type of miscarriage in women with APA. This may be a result of defective implantation and subsequent placentation.

PMID 8822463
Y Y Chan, K Jayaprakasan, J Zamora, J G Thornton, N Raine-Fenning, A Coomarasamy
The prevalence of congenital uterine anomalies in unselected and high-risk populations: a systematic review.
Hum Reprod Update. 2011 Nov-Dec;17(6):761-71. doi: 10.1093/humupd/dmr028. Epub 2011 Jun 24.
Abstract/Text BACKGROUND: The prevalence of congenital uterine anomalies in high-risk women is unclear, as several different diagnostic approaches have been applied to different groups of patients. This review aims to evaluate the prevalence of such anomalies in unselected populations and in women with infertility, including those undergoing IVF treatment, women with a history of miscarriage, women with infertility and recurrent miscarriage combined, and women with a history of preterm delivery.
METHODS: Searches of MEDLINE, EMBASE, Web of Science and the Cochrane register were performed. Study selection and data extraction were conducted independently by two reviewers. Studies were grouped into those that used 'optimal' and 'suboptimal' tests for uterine anomalies. Meta-analyses were performed to establish the prevalence of uterine anomalies and their subtypes within the various populations.
RESULTS: We identified 94 observational studies comprising 89 861 women. The prevalence of uterine anomalies diagnosed by optimal tests was 5.5% [95% confidence interval (CI), 3.5-8.5] in the unselected population, 8.0% (95% CI, 5.3-12) in infertile women, 13.3% (95% CI, 8.9-20.0) in those with a history of miscarriage and 24.5% (95% CI, 18.3-32.8) in those with miscarriage and infertility. Arcuate uterus is most common in the unselected population (3.9%; 95% CI, 2.1-7.1), and its prevalence is not increased in high-risk groups. In contrast, septate uterus is the most common anomaly in high-risk populations.
CONCLUSIONS: Women with a history of miscarriage or miscarriage and infertility have higher prevalence of congenital uterine anomalies compared with the unselected population.

PMID 21705770
Christos A Venetis, Stamatis P Papadopoulos, Rudi Campo, Stephan Gordts, Basil C Tarlatzis, Grigoris F Grimbizis
Clinical implications of congenital uterine anomalies: a meta-analysis of comparative studies.
Reprod Biomed Online. 2014 Dec;29(6):665-83. doi: 10.1016/j.rbmo.2014.09.006. Epub 2014 Sep 21.
Abstract/Text The clinical implications of congenital uterine anomalies (CUA), and the benefits of hysteroscopic resection of a uterine septum, were evaluated. Studies comparing reproductive and obstetric outcome of patients with and without CUA and of patients who had and had not undergone hysteroscopic resection of a uterine septum, were evaluated. Meta-analysis of studies indicated that the pregnancy rate was decreased in women with CUA (RR 0.85, 95% CI 0.73 to 1.00; marginally significant finding, P = 0.05). The spontaneous abortion rate was increased in women with CUA (RR 1.68, 95% CI 1.31 to 2.15). Preterm delivery rates (RR 2.21, 95% CI 1.59 to 3.08), malpresentation at delivery (RR 4.75, 95% CI 3.29 to 6.84), low birth weight (RR 1.93, 95% CI 1.50 to 2.49) and perinatal mortality rates (RR 2.43, 95% CI 1.34 to 4.42) were significantly higher in women with CUA. Hysteroscopic removal of a septum was associated with a reduced probability of spontaneous abortion (RR 0.37, 95% CI 0.25 to 0.55) compared with untreated women. Presence of CUA might be associated with a detrimental effect on the probability of pregnancy achievement, spontaneous abortion and obstetric outcome. Hysteroscopic removal of a septum may reduce the probability of a spontaneous abortion.

Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
PMID 25444500
J F W Rikken, K W J Verhorstert, M H Emanuel, M Y Bongers, T Spinder, W K H Kuchenbecker, F W Jansen, J W van der Steeg, C A H Janssen, K Kapiteijn, W A Schols, B Torrenga, H L Torrance, H R Verhoeve, J A F Huirne, A Hoek, T E Nieboer, I A J van Rooij, T J Clark, L Robinson, M D Stephenson, B W J Mol, F van der Veen, M van Wely, M Goddijn
Septum resection in women with a septate uterus: a cohort study.
Hum Reprod. 2020 Jul 1;35(7):1578-1588. doi: 10.1093/humrep/dez284.
Abstract/Text STUDY QUESTION: Does septum resection improve reproductive outcomes in women with a septate uterus?
SUMMARY ANSWER: In women with a septate uterus, septum resection does not increase live birth rate nor does it decrease the rates of pregnancy loss or preterm birth, compared with expectant management.
WHAT IS KNOWN ALREADY: The septate uterus is the most common uterine anomaly with an estimated prevalence of 0.2-2.3% in women of reproductive age, depending on the classification system. The definition of the septate uterus has been a long-lasting and ongoing subject of debate, and currently two classification systems are used worldwide. Women with a septate uterus may be at increased risk of subfertility, pregnancy loss, preterm birth and foetal malpresentation. Based on low quality evidence, current guidelines recommend removal of the intrauterine septum or, more cautiously, state that the procedure should be evaluated in future studies.
STUDY DESIGN, SIZE, DURATION: We performed an international multicentre cohort study in which we identified women mainly retrospectively by searching in electronic patient files, medical records and databases within the time frame of January 2000 until August 2018. Searching of the databases, files and records took place between January 2016 and July 2018. By doing so, we collected data on 257 women with a septate uterus in 21 centres in the Netherlands, USA and UK.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We included women with a septate uterus, defined by the treating physician, according to the classification system at that time. The women were ascertained among those with a history of subfertility, pregnancy loss, preterm birth or foetal malpresentation or during a routine diagnostic procedure. Allocation to septum resection or expectant management was dependent on the reproductive history and severity of the disease. We excluded women who did not have a wish to conceive at time of diagnosis. The primary outcome was live birth. Secondary outcomes included pregnancy loss, preterm birth and foetal malpresentation. All conceptions during follow-up were registered but for the comparative analyses, only the first live birth or ongoing pregnancy was included. To evaluate differences in live birth and ongoing pregnancy, we used Cox proportional regression to calculate hazard rates (HRs) and 95% CI. To evaluate differences in pregnancy loss, preterm birth and foetal malpresentation, we used logistic regression to calculate odds ratios (OR) with corresponding 95% CI. We adjusted all reproductive outcomes for possible confounders.
MAIN RESULTS AND THE ROLE OF CHANCE: In total, 257 women were included in the cohort. Of these, 151 women underwent a septum resection and 106 women had expectant management. The median follow-up time was 46 months. During this time, live birth occurred in 80 women following a septum resection (53.0%) compared to 76 women following expectant management (71.7%) (HR 0.71 95% CI 0.49-1.02) and ongoing pregnancy occurred in 89 women who underwent septum resection (58.9%), compared to 80 women who had expectant management (75.5%) (HR 0.74 (95% CI 0.52-1.06)). Pregnancy loss occurred in 51 women who underwent septum resection (46.8%) versus 31 women who had expectant management (34.4%) (OR 1.58 (0.81-3.09)), while preterm birth occurred in 26 women who underwent septum resection (29.2%) versus 13 women who had expectant management (16.7%) (OR 1.26 (95% CI 0.52-3.04)) and foetal malpresentation occurred in 17 women who underwent septum resection (19.1%) versus 27 women who had expectant management (34.6%) (OR 0.56 (95% CI 0.24-1.33)).
LIMITATIONS, REASONS FOR CAUTION: Our retrospective study has a less robust design compared with a randomized controlled trial. Over the years, the ideas about the definition of the septate uterus has changed, but since the 257 women with a septate uterus included in this study had been diagnosed by their treating physician according to the leading classification system at that time, the data of this study reflect the daily practice of recent decades. Despite correcting for the most relevant patient characteristics, our estimates might not be free of residual confounding.
WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that septum resection, a procedure that is widely offered and associated with financial costs for society, healthcare systems or individuals, does not lead to improved reproductive outcomes compared to expectant management for women with a septate uterus. The results of this study need to be confirmed in randomized clinical trials.
STUDY FUNDING/COMPETING INTEREST(S): A travel for JFWR to Chicago was supported by the Jo Kolk Studyfund. Otherwise, no specific funding was received for this study. The Department of Obstetrics and Gynaecology, University Medical Centre, Groningen, received an unrestricted educational grant from Ferring Pharmaceutical Company unrelated to the present study. BWM reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck, personal fees from Guerbet, other payment from Guerbet and grants from Merck, outside the submitted work. The other authors declare no conficts of interest.
TRIAL REGISTRATION NUMBER: N/A.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
PMID 32353142
J F W Rikken, C R Kowalik, M H Emanuel, M Y Bongers, T Spinder, F W Jansen, A G M G J Mulders, R Padmehr, T J Clark, H A van Vliet, M D Stephenson, F van der Veen, B W J Mol, M van Wely, M Goddijn
Septum resection versus expectant management in women with a septate uterus: an international multicentre open-label randomized controlled trial.
Hum Reprod. 2021 Apr 20;36(5):1260-1267. doi: 10.1093/humrep/deab037.
Abstract/Text STUDY QUESTION: Does septum resection improve reproductive outcomes in women with a septate uterus?
SUMMARY ANSWER: Hysteroscopic septum resection does not improve reproductive outcomes in women with a septate uterus.
WHAT IS KNOWN ALREADY: A septate uterus is a congenital uterine anomaly. Women with a septate uterus are at increased risk of subfertility, pregnancy loss and preterm birth. Hysteroscopic resection of a septum may improve the chance of a live birth in affected women, but this has never been evaluated in randomized clinical trials. We assessed whether septum resection improves reproductive outcomes in women with a septate uterus, wanting to become pregnant.
STUDY DESIGN, SIZE, DURATION: We performed an international, multicentre, open-label, randomized controlled trial in 10 centres in The Netherlands, UK, USA and Iran between October 2010 and September 2018.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with a septate uterus and a history of subfertility, pregnancy loss or preterm birth were randomly allocated to septum resection or expectant management. The primary outcome was conception leading to live birth within 12 months after randomization, defined as the birth of a living foetus beyond 24 weeks of gestational age. We analysed the data on an intention-to-treat basis and calculated relative risks with 95% CI.
MAIN RESULTS AND THE ROLE OF CHANCE: We randomly assigned 80 women with a septate uterus to septum resection (n = 40) or expectant management (n = 40). We excluded one woman who underwent septum resection from the intention-to-treat analysis, because she withdrew informed consent for the study shortly after randomization. Live birth occurred in 12 of 39 women allocated to septum resection (31%) and in 14 of 40 women allocated to expectant management (35%) (relative risk (RR) 0.88 (95% CI 0.47 to 1.65)). There was one uterine perforation which occurred during surgery (1/39 = 2.6%).
LIMITATIONS, REASONS FOR CAUTION: Although this was a major international trial, the sample size was still limited and recruitment took a long period. Since surgical techniques did not fundamentally change over time, we consider the latter of limited clinical significance.
WIDER IMPLICATIONS OF THE FINDINGS: The trial generated high-level evidence in addition to evidence from a recently published large cohort study. Both studies unequivocally do not reveal any improvements in reproductive outcomes, thereby questioning any rationale behind surgery.
STUDY FUNDING/COMPETING INTEREST(S): There was no study funding. M.H.E. reports a patent on a surgical endoscopic cutting device and process for the removal of tissue from a body cavity licensed to Medtronic, outside the scope of the submitted work. H.A.v.V. reports personal fees from Medtronic, outside the submitted work. B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work. M.G. reports several research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the scope of the submitted work. The remaining authors have nothing to declare.
TRIAL REGISTRATION NUMBER: Dutch trial registry: NTR 1676.
TRIAL REGISTRATION DATE: 18 February 2009.
DATE OF FIRST PATIENT’S ENROLMENT: 20 October 2010.

© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.
PMID 33793794
Mayumi Sugiura-Ogasawara, Koji Aoki, Tomoyuki Fujii, Tomio Fujita, Rie Kawaguchi, Tetsuo Maruyama, Nobuaki Ozawa, Toshitaka Sugi, Toshiyuki Takeshita, Shigeru Saito
Subsequent pregnancy outcomes in recurrent miscarriage patients with a paternal or maternal carrier of a structural chromosome rearrangement.
J Hum Genet. 2008;53(7):622-8. doi: 10.1007/s10038-008-0290-2. Epub 2008 Apr 15.
Abstract/Text Information concerning the prognosis of subsequent pregnancies in patients with reciprocal translocations is limited. This study was performed to determine the percentage success rate with first pregnancies after ascertainment of a carrier status. A total of 2,382 couples with a history of two or more consecutive miscarriages were studied in multicenters. The prevalence of an abnormal chromosome in either partner was examined, and subsequent success rates were compared between cases with and without an abnormal karyotype in either partner. A total of 129 couples (5.4%) had an abnormal karyotype in one partner excluding inversion 9 in 44 men and in 85 women. Thus, 2,253 couples had a normal karyotype in both partner. Eighty-five (3.6%) had translocations, 13 being Robertsonian translocations. Twenty-nine of the 46 cases (63.0%) who became pregnant with reciprocal translocations in either partner experienced a live birth with natural conception. In contrast, 950 of 1,207 cases (78.7%) with normal chromosomes had successful live births, the difference being significant (P = 0.019). No infant with an unbalanced translocation was found in 29 cases of successful pregnancy following recurrent miscarriage. Pregnancy prognosis was worsened with either maternal or paternal reciprocal translocations. Explanation of the success rate with natural conception should be provided before the subsequent pregnancy after ascertainment of carrier status.

PMID 18414779
Evelyne Rey, Susan R Kahn, Michèle David, Ian Shrier
Thrombophilic disorders and fetal loss: a meta-analysis.
Lancet. 2003 Mar 15;361(9361):901-8. doi: 10.1016/S0140-6736(03)12771-7.
Abstract/Text BACKGROUND: Our aim was to assess the strength of the controversial association between thrombophilia and fetal loss, and to examine whether it varies according to the timing or definition of fetal loss.
METHODS: We searched Medline and Current Contents for articles published between 1975 and 2002 and their references with terms denoting recurrent fetal and non-recurrent fetal loss combined with various thrombophilic disorders. We included in our meta-analysis case-control, cohort, and cross-sectional studies published in English, the methodological quality of which was rated as moderate or strong. Pooled odds ratios (OR) with 95% CI were generated by random effects models with Cochrane Review Manager software.
FINDINGS: We included 31 studies. Factor V Leiden was associated with early (OR 2.01, 95% CI 1.13-3.58) and late (7.83, 2.83-21.67) recurrent fetal loss, and late non-recurrent fetal loss (3.26, 1.82-5.83). Exclusion of women with other pathologies that could explain fetal loss strengthened the association between Factor V Leiden and recurrent fetal loss. Activated protein C resistance was associated with early recurrent fetal loss (3.48, 1.58-7.69), and prothrombin G20210A mutation with early recurrent (2.56, 1.04-.29) and late non-recurrent (2.30, 1.09-4.87) fetal loss. Protein S deficiency was associated with recurrent fetal loss (14.72, 0.99-218.01) and late non-recurrent fetal loss (7.39, 1.28-42.63). Methylenetetrahydrofolate mutation, protein C, and antithrombin deficiencies were not significantly associated with fetal loss.
INTERPRETATION: The magnitude of the association between thrombophilia and fetal loss varies, according to type of fetal loss and type of thrombophilia.

PMID 12648968
Keiko Morita, Yosuke Ono, Toshiyuki Takeshita, Toshitaka Sugi, Tomoyuki Fujii, Hideto Yamada, Mikiya Nakatsuka, Atsushi Fukui, Shigeru Saito
Risk Factors and Outcomes of Recurrent Pregnancy Loss in Japan.
J Obstet Gynaecol Res. 2019 Oct;45(10):1997-2006. doi: 10.1111/jog.14083. Epub 2019 Aug 9.
Abstract/Text AIM: To clarify the risk factors and pregnancy outcomes for each risk factor of recurrent pregnancy loss (RPL) in Japan.
METHODS: Using a prospective RPL database collected from 16 facilities in Japan, the prevalence of risk factors for RPL, their treatments and pregnancy outcomes were examined.
RESULTS: Of 6663 patients registered in our database, 5708 patients had RPL. All examinations for risk factors were performed for 1340 patients (23.5%). The prevalences of positive antiphospholipid antibodies (aPL), malformation of the uterus, thyroid dysfunction, parental karyotype abnormality, factor XII deficiency, protein S deficiency and unknown risk factors were 8.7%, 7.9%, 9.5%, 3.7%, 7.6%, 4.3% and 65.1%, respectively. Although factor XII deficiency and protein S deficiency are not recognized as risk factors for RPL in general, low-dose aspirin (LDA) or unfractionated heparin + LDA therapy improved live birth rates. In transiently aPL-positive patients, the live birth rate with LDA therapy was similar to that with heparin + LDA. For unknown risk factors of RPL, the live birth rate in normal fetal karyotype in the none treatment group was similar to that in all other treatments group (81.3% vs 86.0%). Of 5708 RPL patients, pregnancy outcomes were known for 2261 patients and 1697 patients (75.1%) had at least one live birth.
CONCLUSION: The risk factors and pregnancy outcomes for each risk factor of RPL are useful for clinicians and patients. Factor XII deficiency and protein S deficiency may be risk factors of RPL.

© 2019 Japan Society of Obstetrics and Gynecology.
PMID 31397532
J C Gris, S Ripart-Neveu, C Maugard, M L Tailland, S Brun, C Courtieu, C Biron, M Hoffet, B Hédon, P Marès
Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study.
Thromb Haemost. 1997 Jun;77(6):1096-103.
Abstract/Text The prevalence of haemostasis abnormalities was evaluated in 500 consecutive women with unexplained primary recurrent miscarriages. Two matched reference groups with no antecedent of miscarriage were studied: 100 healthy mothers and 50 childless women. In the prospective part of the study, we found 9.4% of the patients (95% C.I.: 6.8-12%) with an isolated factor XII deficiency, 7.4% of the patients (5.0-9.8%) with primary antiphopholipid antibodies, 47% of the patients (42.6-51.4%) with an insufficient response to the venous occlusion test and an isolated hypofibrinolysis was found in 42.6% (38.2-47%) of the patients (reference groups: respectively 0/150, 3/150, 2/150, p < 10(-3)). Willebrand disease, fibrinogen, deficiency, antithrombin, protein C or protein S deficiencies were not more frequent in recurrent aborters than in members of the reference groups. In the retrospective part of the study, cases of plasma resistance to activated protein C were not abnormally frequent. Patients had higher Willebrand factor antigen (vWF), tissue-type plasminogen activator antigen (t-PA), plasminogen activator inhibitor activity (PAI) and D-dimers (D-Di) than the reference women. Values of vWF, t-PA, PAI and D-Di were altogether correlated but were not related to C-reactive protein concentrations. Among patients, those with an antiphospholipid syndrome and those with an insufficient response to the venous occlusion test had higher vWF, t-PA, PAI and D-Di values than the patients with none of the haemostasis-related abnormalities. Thus, factor XII deficiency and hypofibrinolysis (mainly high PAI) are the most frequent haemostasis-related abnormalities found in unexplained primary recurrent aborters. In patients with antiphospholipid antibodies or hypofibrinolysis, there is a non-inflammatory ongoing chronic elevation of markers of endothelial stimulation associated with coagulation activation. This should allow to define subgroups of patients for future therapeutic trials.

PMID 9241739
Hans-Ulrich Pauer, Peter Burfeind, Heinz Köstering, Günter Emons, Bernd Hinney
Factor XII deficiency is strongly associated with primary recurrent abortions.
Fertil Steril. 2003 Sep;80(3):590-4.
Abstract/Text OBJECTIVE: To evaluate factor XII deficiency in women with primary and secondary recurrent abortion.
DESIGN: Prospective case-control study.
SETTING: University hospital.
PATIENT(S): Sixty-seven women with primary and 33 women with secondary recurrent abortion of unexplained nature and 49 healthy controls with no history of thrombotic disease or adverse pregnancy outcomes. MAIL OUTCOME MEASURE(S): Plasma factor XII activity, activated protein C resistance, factor V Leiden mutation analysis, protein C, protein S, antithrombin III, karyotyping, and anticardiolipin antibodies.
RESULT(S): Ten of 67 women with primary recurrent abortion (14.9%) and 4 of 33 women (12.1%) with secondary recurrent abortion had reduced factor XII activity (<60%). These results are highly significant in the former group and showed a tendency toward significance in the latter group. All controls had normal factor XII activity.
CONCLUSION(S): Factor XII deficiency is strongly associated with primary recurrent abortion, and women with secondary recurrent abortion show a tendency toward factor XII deficiency.

PMID 12969703
Alexandros Sotiriadis, Antonis Makrigiannakis, Theodor Stefos, Evangelos Paraskevaidis, Sophia N Kalantaridou
Fibrinolytic defects and recurrent miscarriage: a systematic review and meta-analysis.
Obstet Gynecol. 2007 May;109(5):1146-55. doi: 10.1097/01.AOG.0000260873.94196.d6.
Abstract/Text OBJECTIVE: To systematically review evidence of the association between fibrinolytic defects and recurrent miscarriage.
DATA SOURCES: MEDLINE, EMBASE, and references of retrieved articles (last update September 2006) were used.
METHODS OF STUDY SELECTION: Studies comparing the prevalence of fibrinolytic defects in patients with recurrent miscarriage and control women were reviewed. Of 111 potentially relevant studies, data from 14 were integrated with meta-analytic techniques and were presented as odds ratios (ORs).
TABULATION, INTEGRATION, AND RESULTS: Plasminogen activator inhibitor-1 4G/5G polymorphism (OR 1.65, 95% confidence interval [CI] 0.92-2.95) and increased plasminogen activator inhibitor activity were not significantly associated with recurrent miscarriage, although the latter showed profound heterogeneity across studies. Although factor XII C46T polymorphism is not associated with recurrent miscarriage (OR 1.07, 95% CI 0.52-2.22), factor XII deficiency is significantly associated (five studies, 1,096 women; OR 18.11, 95% CI 5.52-59.39), with minimal heterogeneity across studies. Factor XIII Val34Leu and Tyr204Phe polymorphisms were not associated with recurrent miscarriage (OR 1.24, 95% CI 0.46-3.34 and OR 2.61, 95% CI 0.45-15.16, respectively). There were no eligible studies found for the rest of the factors searched (urokinase-type plasminogen activator, tissue-type plasminogen activator, kallicrein, a2-antiplasmin, a2-macroglobulin, thrombin-activated thrombolysis inhibitor, and factor XI). Only a small minority of studies ascertained miscarriage according to specific criteria, and none of the studies provided equal examination for confounders in cases and controls.
CONCLUSION: Factor XII deficiency is associated with recurrent miscarriage. Data on the other factors either fail to show association or are quite limited.

PMID 17470597
M S Ogasawara, Y Iinuma, K Aoki, K Katano, Y Ozaki, K Suzumori
Low-dose aspirin is effective for treatment of recurrent miscarriage in patients with decreased coagulation factor XII.
Fertil Steril. 2001 Jul;76(1):203-4.
Abstract/Text
PMID 11438345
Shakila Thangaratinam, Alex Tan, Ellen Knox, Mark D Kilby, Jayne Franklyn, Arri Coomarasamy
Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence.
BMJ. 2011 May 9;342:d2616. Epub 2011 May 9.
Abstract/Text 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.
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.
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. Meta-analysis 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 meta-analysis 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).
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.

PMID 21558126
Emmy van den Boogaard, Rosa Vissenberg, Jolande A Land, Madelon van Wely, Joris A M van der Post, Mariette Goddijn, Peter H Bisschop
Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review.
Hum Reprod Update. 2011 Sep-Oct;17(5):605-19. doi: 10.1093/humupd/dmr024. Epub 2011 May 28.
Abstract/Text BACKGROUND: Thyroid dysfunction and thyroid autoimmunity are prevalent among women of reproductive age and are associated with adverse pregnancy outcomes. Preconception or early pregnancy screening for thyroid dysfunction has been proposed but is not widely accepted. We conducted a systematic review of the literature on the clinical significance of thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy.
METHODS: Relevant studies were identified by searching Medline, EMBASE and the Cochrane Controlled Trials Register.
RESULTS: From a total of 14 208 primary selected titles, 43 articles were included for the systematic review and 38 were appropriate for meta-analyses. No articles about hyperthyroidism were selected. Subclinical hypothyroidism in early pregnancy, compared with normal thyroid function, was associated with the occurrence of pre-eclampsia [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.1-2.6] and an increased risk of perinatal mortality (OR 2.7, 95% CI 1.6-4.7). In the meta-analyses, the presence of thyroid antibodies was associated with an increased risk of unexplained subfertility (OR 1.5, 95% CI 1.1-2.0), miscarriage (OR 3.73, 95% CI 1.8-7.6), recurrent miscarriage (OR 2.3, 95% CI 1.5-3.5), preterm birth (OR 1.9, 95% CI 1.1-3.5) and maternal post-partum thyroiditis (OR 11.5, 95% CI 5.6-24) when compared with the absence of thyroid antibodies.
CONCLUSIONS: Pregnant women with subclinical hypothyroidism or thyroid antibodies have an increased risk of complications, especially pre-eclampsia, perinatal mortality and (recurrent) miscarriage. Future research, within the setting of clinical trials, should focus on the potential health gain of identification, and effect of treatment, of thyroid disease on pregnancy outcome.

PMID 21622978
Carlo Ticconi, Emma Giuliani, Manuela Veglia, Adalgisa Pietropolli, Emilio Piccione, Nicoletta Di Simone
Thyroid autoimmunity and recurrent miscarriage.
Am J Reprod Immunol. 2011 Dec;66(6):452-9. doi: 10.1111/j.1600-0897.2011.01021.x. Epub 2011 May 30.
Abstract/Text PROBLEM: To investigate the role of antithyroid autoantibodies (ATA) in recurrent miscarriage (RM).
METHODS: In this case-control study, a total of 160 women with RM and 100 healthy women were investigated for the presence of serum ATA directed against thyreoglobulin (TG-Ab), thyroid peroxidase (TPO-Ab) and TSH receptor (TSHr-Ab), which were determined by either chemiluminescence or radioimmunoassay.
RESULTS: Antithyroid autoantibodies were detected in 46 (28.75%) women with RM and in 13 (13%) women of the control group (P < 0.05). The frequencies for TG-Ab and TPO-Ab were higher in RM than in control women. Among the women of RM group, 91.3% of ATA+ women were positive also for other autoantibodies. The majority of study women were euthyroid.
CONCLUSIONS: Antithyroid autoantibodies, particularly TG-Ab, are associated with RM and could be an expression of a more general maternal immune system abnormality leading to RM. ATA could have a role in RM irrespective of thyroid hormone status.

© 2011 John Wiley & Sons A/S.
PMID 21623997
Erik K Alexander, Elizabeth N Pearce, Gregory A Brent, Rosalind S Brown, Herbert Chen, Chrysoula Dosiou, William A Grobman, Peter Laurberg, John H Lazarus, Susan J Mandel, Robin P Peeters, Scott Sullivan
2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum.
Thyroid. 2017 Mar;27(3):315-389. doi: 10.1089/thy.2016.0457.
Abstract/Text BACKGROUND: Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2011, significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid disease in women during pregnancy, preconception, and the postpartum period.
METHODS: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. The guideline task force had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members.
RESULTS: The revised guidelines for the management of thyroid disease in pregnancy include recommendations regarding the interpretation of thyroid function tests in pregnancy, iodine nutrition, thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy, thyrotoxicosis in pregnancy, thyroid nodules and cancer in pregnant women, fetal and neonatal considerations, thyroid disease and lactation, screening for thyroid dysfunction in pregnancy, and directions for future research.
CONCLUSIONS: We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid disease in pregnant and postpartum women. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with these disorders.

PMID 28056690
Brooke Hodes-Wertz, Jamie Grifo, Shahin Ghadir, Brian Kaplan, Carl A Laskin, Michael Glassner, Santiago Munné
Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos.
Fertil Steril. 2012 Sep;98(3):675-80. doi: 10.1016/j.fertnstert.2012.05.025. Epub 2012 Jun 7.
Abstract/Text OBJECTIVE: To determine any beneficial effects of preimplantation genetic screening (PGS) of all chromosomes by array comparative genomic hybridization (aCGH), with either day 3 or blastocyst biopsy, for idiopathic recurrent pregnancy loss (RPL) patients compared with their expected loss rate.
DESIGN: Case series report.
SETTING: Multiple fertility centers.
PATIENT(S): A total of 287 cycles of couples with idiopathic RPL (defined as two or more losses).
INTERVENTION(S): PGS was done with day 3 biopsy (n = 193) or blastocyst biopsy (n = 94), followed by analysis with aCGH.
MAIN OUTCOME MEASURE(S): Spontaneous abortion rate, euploidy rate.
RESULT(S): A total of 2,282 embryos were analyzed, of which 35% were euploid and 60% were aneuploid. There were 181 embryo transfer cycles, of which 100 (55%) became pregnant with an implantation rate of 45% (136 sacs/299 replaced embryos) and 94 pregnancies (92%) were ongoing (past second trimester) or delivered. The miscarriage rate was found to be only 6.9% (7/102), compared with the expected rate of 33.5% in an RPL control population and 23.7% in an infertile control population.
CONCLUSION(S): Current PGS results with aCGH indicate a significant decrease in the miscarriage rate of idiopathic RPL patients and high pregnancy rates. Furthermore, this suggests that idiopathic recurrent miscarriage is mostly caused by chromosomal abnormalities in embryos.

Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
PMID 22683012
Mayumi Sugiura-Ogasawara, Yasuhiko Ozaki, Kinue Katano, Nobuhiro Suzumori, Tamao Kitaori, Eita Mizutani
Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage.
Hum Reprod. 2012 Aug;27(8):2297-303. doi: 10.1093/humrep/des179. Epub 2012 May 31.
Abstract/Text BACKGROUND: We previously found that a normal karyotype in a previous miscarriage is a predictor of subsequent miscarriage. However, the prevalence of recurrent miscarriage caused by an abnormal embryonic karyotype has not yet been reported, since embryonic karyotype is not typically analyzed during conventional examinations.
METHODS: A total of 482 patients who underwent both embryonic karyotype determination and conventional examinations for recurrent miscarriage were enrolled in this study. The distribution of the causes and the live birth rate for each cause were examined.
RESULTS: The total percentage of subjects in whom conventional causes of recurrent miscarriage could be detected was 29.5%. The prevalence of the abnormal embryonic karyotype was 41.1% in the subjects in whom no conventional causes of miscarriage could be identified. The prevalence of recurrent miscarriage of truly unexplained cause, that is, of subjects without conventional causes in whom the embryonic karyotype was ascertained to be normal, was 24.5%. Among the patients in whom the first determination revealed an abnormal embryonic karyotype, 76.2% (32/42) showed an abnormal embryonic karyotype in the repeat determination as well. The cumulative live birth rate (71.9%) in women with recurrent miscarriages caused by the abnormal embryonic karyotype was significantly higher than that (44.7%) in women with recurrent miscarriages associated with the embryonal euploidy.
CONCLUSION: An abnormal embryonic karyotype was found to represent the commonest cause of recurrent miscarriage, and the percentage of cases with recurrent miscarriage of truly unexplained cause was limited to 24.5%.The two groups should be distinguished for both clinical and research purposes.

PMID 22661547
Abstract/Text A total of 500 consecutive women (mean age 32.9 years; SD 5 years) presenting with a history of recurrent miscarriages (median 4; range 3-17) were investigated for the presence of antiphospholipid antibodies (APA), polycystic ovaries (PCO), hypersecretion of luteinizing hormone (LH) and chromosome abnormalities in order to detect an underlying cause of their pregnancy losses. All women had details of their previous reproductive history, investigations and treatment documented: 76% of the women had experienced only early pregnancy losses (miscarriage < 13 weeks gestation); 32% had a history of subfertility; and significant parental chromosome rearrangements were present in 3.6% of couples. An ultrasound diagnosis of PCO was made in 56% of women, 58% of whom were demonstrated to hypersecrete LH, based on early morning urinary LH analysis. Circulating APA were found in 14% of women. An underlying cause of recurrent miscarriage--genetic, endocrine or autoimmune--was found in > 50% of couples. Women in the latter two groups are being recruited to randomized treatment trials which are discussed.

PMID 7962442

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