Around 1–5% of all couples experience recurrent pregnancy loss (RPL). Established risk factors include anatomical, genetic, endocrine, and hemostatic alterations. With around 50% of idiopathic cases, immunological risk factors are getting into the scientific focus, however international guidelines hardly take them into account. Within this review, the current state of immunological risk factors in RPL in international guidelines of the European Society of Reproduction and Embryology (ESHRE), American Society of Reproductive Medicine (ASRM), German/Austrian/Swiss Society of Obstetrics and Gynecology (DGGG/OEGGG/SGGG) and the Royal College of Obstetricians and Gynecologists (RCOG) are evaluated. Special attention was drawn to recommendations in the guidelines regarding diagnostic factors such as autoantibodies, natural killer cells, regulatory T cells, dendritic cells, plasma cells, and human leukocyte antigen system (HLA)-sharing as well as treatment options such as corticosteroids, intralipids, intravenous immunoglobulins, aspirin and heparin in RPL. Finally, the current state of the art focusing on both diagnostic and therapeutic options was summarized.

While roughly 30% of all women experience a spontaneous miscarriage in their lifetime, the incidence of recurrent (habitual) spontaneous miscarriage is 1 – 3% depending on the employed definition. The established risk factors include endocrine, anatomical, infection-related, genetic, haemostasis-related and immunological factors. Diagnosis is made more difficult by the sometimes diverging recommendations of the respective international specialist societies. The present study is therefore intended to provide a comparison of existing international guidelines and recommendations. The guidelines of the ESHRE, ASRM, the DGGG/OEGGG/SGGG and the recommendations of the RCOG were analysed. It was shown that investigation is indicated after 2 clinical pregnancies and the diagnosis should be made using a standardised timetable that includes the most frequent causes of spontaneous miscarriage. The guidelines concur that anatomical malformations, antiphospholipid syndrome and thyroid dysfunction should be excluded. Moreover, the guidelines recommend carrying out pre-conception chromosomal analysis of both partners (or of the aborted material). Other risk factors have not been included in the recommendations by all specialist societies, on the one hand because of a lack of diagnostic criteria (luteal phase insufficiency) and on the other hand because of the different age of the guidelines (chronic endometritis). In addition, various economic and consensus aspects in producing the guidelines influence the individual recommendations. An understanding of the underlying decision-making process should lead in practice to the best individual diagnosis and resulting treatment being offered to each couple.

ZusammenfassungEine Schwangerschaft kann intrauterin, ektop oder an einem unklaren Ort liegen und entwicklungsphysiologisch vital oder gestört sein. Die transvaginale Sonographie ermöglicht die Darstellung einer intrauterinen Schwangerschaft ab einem Schwellenwert des humanen Choriongonadotropins (hCG) von 1000 IU/l in der etwa sechsten Schwangerschaftswoche (SSW). Ektope Schwangerschaften sind abhängig von der SSW gegebenenfalls erschwert sonographisch erkennbar. Der Verlauf des hCG-Werts kann hilfreich dabei sein, eine physiologische von einer gestörten Frühschwangerschaft zu unterscheiden, muss aber immer in Zusammenschau mit der Klinik und dem Ultraschallbefund interpretiert werden. Bei einem frühen Abort kann abhängig von der Klinik exspektativ oder medikamentös vorgegangen werden. Die Indikation zur Kürettage sollte insgesamt zurückhaltend gestellt werden. Bei einer ektopen Schwangerschaft sollte abhängig von SSW und Klinik eine operative Therapie oder eine Methotrexattherapie durchgeführt werden.

No abstract

Study question To which extent do the current international guidelines and recommendations concerning recurrent pregnancy loss (RPL) differ? Summary answer All guidelines apply definitions for RPL, however few diagnostic and therapeutic options are described. Diagnostics should be based on best evidence and current scientific knowledge. What is known already Established risk factors for RPL include anatomical, genetic, endocrine, hemostatic and immune alterations. The European Society of Reproduction and Embryology (ESHRE), American Society of Reproductive Medicine (ASRM), German/Austrian/Swiss Society of Obstetrics and Gynecology (DGGG/OEGGG/SGGG) and the Royal College of Obstetricians and Gynecologists (RCOG) published guidelines concerning diagnostic and therapeutic options in RPL. Due to the different guideline processes and date of publication actuality as well as complexity differ widely. Study design, size, duration We compared the guidelines of the ESHRE, ASRM, DGGG/OEGGG/SGGG and RCOG with regard to definition, diagnostic and therapeutic aspects. The guidelines were published between 2011 and 2018. Structured guideline processes with regular (complete) updates are only provided by the DGGG/OEGGG/SGGG. Participants/materials, setting, methods After thorough literature research (Pubmed, Embase) all existing guidelines and recommendations were analysed and compared considering the current state of knowledge. The RCOG recommendations from 2011 were updated in 2014 and 2017, the ARSM expert letter was last updated in 2012. The ESHRE guideline was published in 2017. The first version of the DGGG/OEGGG/SGGG guideline was published 2006, updated in 2013 and upgraded to a higher evidence-level in 2018 and is currently under review. Main results and the role of chance All guidelines agree that a diagnostic work-up is indicated after at least two clinical pregnancies and should exclude anatomical malformations, an antiphospholipid syndrome and thyroid dysfunction. Furthermore, lifestyle modifications are recommended by all. The general evaluation of an inherited thrombophilia is not recommended by any guideline. Exclusion of other risk factors like parental chromosomal disorders, a polycystic ovary syndrome or insulin resistance are only included in some guidelines, partly due to a lack of diagnostic criteria (luteal phase insufficiency) or due to the different year of publication of the recommendations (e.g. chronic endometritis). All guidelines recommend treating APLS by administering low-dose aspirin (75–100mg daily) in combination with unfractionated/low-molecular-weight heparin. With regard to uterine malformations whether or not a septum should be dissected is still a matter of debate: ESHRE and RCOG consider evidence insufficient, while DGGG/OEGGG/SGGG and ASRM recommend a surgical intervention. In case of chronic endometritis, the DGGG/OEGGG/SGGG recommends antibiotic therapy e.g. with doxycycline (200 mg daily for 14 days). Limitations, reasons for caution Different health economic as well as consensus aspects in the process of guideline development have a significant influence on the individual guidelines and recommendations. Wider implications of the findings: Since personalized diagnostic and therapeutic strategies in RPL patients are required, physicians have to decide when to follow the guideline and when to expand diagnostics and therapy. Therefore, the knowledge of the weaknesses of each guideline and its developmental process is helpful for treating RPL couples. Trial registration number -