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Pregnancy Loss Research Group, Department of Obstetrics and Gynaecology, University College Cork, Cork T12 DC4A, IrelandThe Irish Centre for Maternal and Child Health, University College Cork, Cork University Maternity Hospital, Cork T12 DC4A, IrelandCollege of Medicine and Health, University College Cork Cork T12 EKDO, Ireland
Pregnancy Loss Research Group, Department of Obstetrics and Gynaecology, University College Cork, Cork T12 DC4A, IrelandThe Irish Centre for Maternal and Child Health, University College Cork, Cork University Maternity Hospital, Cork T12 DC4A, IrelandCollege of Medicine and Health, University College Cork Cork T12 EKDO, Ireland
Pregnancy Loss Research Group, Department of Obstetrics and Gynaecology, University College Cork, Cork T12 DC4A, IrelandThe Irish Centre for Maternal and Child Health, University College Cork, Cork University Maternity Hospital, Cork T12 DC4A, IrelandCollege of Medicine and Health, University College Cork Cork T12 EKDO, IrelandNational Perinatal Epidemiology Centre, University College Cork, Cork University Maternity Hospital Cork T12 DC4A, Ireland
Pregnancy Loss Research Group, Department of Obstetrics and Gynaecology, University College Cork, Cork T12 DC4A, IrelandThe Irish Centre for Maternal and Child Health, University College Cork, Cork University Maternity Hospital, Cork T12 DC4A, IrelandCollege of Medicine and Health, University College Cork Cork T12 EKDO, Ireland
The Irish Centre for Maternal and Child Health, University College Cork, Cork University Maternity Hospital, Cork T12 DC4A, IrelandSchool of Nursing and Midwifery, National University of Ireland, Galway, Galway H91 E3YV, IrelandEvidence Synthesis Ireland, National University of Ireland, Galway, Galway H91 E3YV, Ireland
Pregnancy Loss Research Group, Department of Obstetrics and Gynaecology, University College Cork, Cork T12 DC4A, IrelandSchool of Applied Social Studies, University College Cork, Cork T12 D726, Ireland
Pregnancy Loss Research Group, Department of Obstetrics and Gynaecology, University College Cork, Cork T12 DC4A, IrelandThe Irish Centre for Maternal and Child Health, University College Cork, Cork University Maternity Hospital, Cork T12 DC4A, IrelandCollege of Medicine and Health, University College Cork Cork T12 EKDO, Ireland
Recurrent miscarriage affects 1–2% of women of reproductive age, depending on the definition used. A systematic review was conducted to identify, appraise and describe clinical practice guidelines (CPG) published since 2000 for the investigation, management, and/or follow-up of recurrent miscarriage within high-income countries. Six major databases, eight guideline repositories and the websites of 11 professional organizations were searched to identify potentially eligible studies. The quality of eligible CPG was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE II) Tool. A narrative synthesis was conducted to describe, compare and contrast the CPG and recommendations therein. Thirty-two CPG were included, from which 373 recommendations concerning first-trimester recurrent miscarriage were identified across four sub-categories: structure of care (42 recommendations, nine CPG), investigations (134 recommendations, 23 CPG), treatment (153 recommendations, 24 CPG), and counselling and supportive care (46 recommendations, nine CPG). Most CPG scored ‘poor’ on applicability (84%) and editorial independence (69%); and to a lesser extent stakeholder involvement (38%) and rigour of development (31%). Varying levels of consensus were found across CPG, with some conflicting recommendations. Greater efforts are required to improve the quality of evidence underpinning CPG, the rigour of their development and the inclusion of multi-disciplinary perspectives, including those with lived experience of recurrent miscarriage.
Recurrent miscarriage is estimated to affect 1–2% of women of reproductive age, depending on the definition used, and with the caveat that the actual prevalence is difficult to obtain owing to difficulty accessing data (
). The term used to describe the condition varies between countries and professional bodies (Youssef et al., 2020); for example, ESHRE uses the term ‘recurrent pregnancy loss’ (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
). For the purposes of reporting within this paper, the latter term is used throughout, and the focus is on recurrent first-trimester miscarriage given that this should be treated differently to second-trimester miscarriage (
) now define recurrent miscarriage as the loss of two or more consecutive pregnancies for investigations; however, the previous definition of three or more consecutive pregnancy losses remains in use by others, such as the
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
). As the revised definition of recurrent miscarriage is used across more countries and regions, more women and/or couples will be accessing services for investigation and management.
Evidence-based, up-to-date clinical practice guidelines (CPG) are required to inform the effective management of recurrent miscarriage (
). The risk of further miscarriage increases after each successive pregnancy loss, reaching about 40% after three consecutive pregnancy losses; a previous live birth does not prevent a woman experiencing recurrent miscarriage, and the prognosis worsens with increasing maternal age (
The suggested causes of recurrent miscarriage include uterine anomalies (inclusive of common acquired anomalies, such as fibroids, and more uncommon anatomical defects, such as uterine septae), endocrine disorders (such as thyroid disease), autoimmune diseases (such as lupus), acquired thrombophilia and genetic causes, in particular balanced translocations (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
). Others, such as chronic endometritis, infectious diseases, inherited thrombophilia, luteal phase deficiency, high sperm DNA fragmentation levels, polycystic ovary syndrome and high body mass index, have been proposed, but remain debated (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
What has to be pointed out in unexplained recurrent pregnancy loss research in the unsolved fields: lessons from clinic. An Italian RPL Unit experience.
). Nevertheless, standard investigations for recurrent miscarriage continue to be important in evaluating potential factors responsible for pregnancy loss (
It is also important that the provision of care meets the needs of those who experience recurrent miscarriage. The psychological wellbeing of women and men who experience recurrent miscarriage can be negatively affected in the medium- to long-term (
). In addition, women and men report gaps in their perceived needs and their care experience after recurrent miscarriage, highlighting the need for more information, psychological support, the inclusion of partners in consultations, and follow-up care (
Clinical practice guidelines synthesize the best available evidence to guide clinician and patient decision-making, with the aim of improving care quality and patient outcomes (
Graham, R., Mancher, M., Wolman, D. M., Greenfield, S., Steinberg, E. 2011. Clinical Practice Guidelines We Can Trust National Academies Press, Washington, DC.
). They are ‘statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options’ (
Institute of Medicine, 2011. Clinical Practice Guidelines We Can Trust. In M. M. Graham R, Wolman DM, Greenfield S, Steinberg E (Ed.). The National Academies Press, Washington DC.
). The identification, appraisal and description of published CPG in high-income countries would be a valuable first step in informing efforts to promote the optimization and standardization of recurrent miscarriage care. Given the large discrepancies in pregnancy outcomes and care structures between high, low and middle-income countries (
recently conducted a comparison and appraisal of the ESHRE, ASRM and RCOG recurrent miscarriage CPG using the Appraisal of Guidelines, Research and Evaluation version 2 (AGREE II) criteria, an accepted and validated tool for assessing the methodological quality of CPG (
review and compare the ASRM and ESHRE CPG, noting the lack of consensus on standard evaluation of recurrent pregnancy loss. Each of these studies focused on a select group of CPG. Therefore, a more systematic approach to identifying CPG concerning recurrent miscarriage would add to the body of evidence.
The aim of the present systematic review was to identify, appraise and describe published CPG for the investigation, management, and/or follow-up of first-trimester recurrent miscarriage within high-income countries. The specific objectives were to identify published CPG for the investigation, management, and/or follow-up of recurrent miscarriage within high-income countries; appraise the quality of included CPG using the AGREE II instrument; and describe recommendations from the included CPG concerning first-trimester recurrent miscarriage.
Materials and methods
This systematic review is reported following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance. The protocol for the review was published in advance (
A protocol for a systematic review of clinical practice guidelines for recurrent miscarriage [version 3; peer review: 3 approved, 1 approved with reservations].
) and pre-registered on PROSPERO, the International Prospective Register of Systematic Reviews (CRD42020173881; registered 28 April 2020).
Eligibility criteria
Inclusion and exclusion criteria were developed according to the ‘PICAR’ (population and clinical areas, interventions, comparators, attributes of CPG and recommendation characteristics) framework (Table 1). For this review, CPG were defined as ‘systematically developed statements to assist practitioners about appropriate health care for specific clinical circumstances’; an adaptation of the definitions used by the
TABLE 1ELIGIBILITY CRITERIA PERTAINING TO THE POPULATION AND CLINICAL AREAS, INTERVENTIONS, COMPARATORS, ATTRIBUTES OF CLINICAL PRACTICE GUIDELINES AND RECOMMENDATION CHARACTERISTICS (PICAR) STATEMENT
PICAR framework
Eligibility criteria
Population, clinical indication(s), and condition(s)
Study population •Women or couples experiencing recurrent miscarriage. •Humans only. Clinical indication •Investigation, management and/or follow-up of women and/or or couples with recurrent miscarriage, specifically first-trimester recurrent miscarriage. Clinical condition •Recurrent miscarriage is defined by the review team as the loss of two or more consecutive pregnancies (
), with a specific focus on first-trimester recurrent miscarriage. For the purposes of this review, all clinical practice guidelines (CPG) that focus on recurrent miscarriage, regardless of the definition used, will be included. The definition applied by each included CPG will be extracted and considered when synthesizing and interpreting the review findings.
Interventions
•Any intervention focusing on the investigation, management and/or follow-up of recurrent miscarriage.
Comparator(s), Comparison(s), and (key) Content
•Any comparator or comparison.• No ‘key’ CPG content is of interest, unless CPG are broader in scope; in such instances, content specific to recurrent miscarriage is only of interest.
Attributes of eligible CPGs
Language •Available in English.• CPG in which summaries are available in English, but full text is not, will be excluded. Year of publication• 2000 onwards.• In Ireland, the National Clinical Effectiveness Committee, requires a full guideline update within 3 years (
). To be comprehensive, CPG published within the last 20 years (January 2000 to date) will be eligible for inclusion given that international CPG concerning recurrent miscarriage can fall well outside the 3-year period (
American College of Obstetricians and Gynecologists ACOG practice bulletin. Management of recurrent pregnancy loss. Number 24, February 2001. (Replaces Technical Bulletin Number 212, September 1995).
). Developing or publishing organization• Only CPG issued or endorsed by national or international scientific societies, professional colleges, charitable organizations and government organizations will be included. Country of publication• High-income countries, as defined by the World Bank (
) Version• Latest version only. Development process• Evidence-based, consensus-based, or both. System of rating evidence• Use of a system to rate the level of evidence within CPG is not an eligibility criterion; however, such data will be extracted to inform synthesis and interpretation of findings. Quality of evidence• The eligibility of CPG will not be based on a specific minimum quality cut-off score based on the AGREE II criteria.• We are interested in all guidance generated regardless of quality, e.g. because CPG determined to be of ‘high quality’ may not necessarily report recommendations that are highly valid and implementable (Johnston et al., 2019); this will, however, be taken into consideration when synthesizing and interpreting the review findings. Scope• Must have a primary or secondary focus on the investigation and treatment of recurrent miscarriage. Must be national or international in scope.• Covers any aspect of recurrent miscarriage care and its organization, including the provision of dedicated pregnancy loss clinics, treatment and management of recurrent miscarriage, investigations carried out after recurrent miscarriage to inform prognosis of future pregnancy outcomes and counselling of parents after recurrent miscarriage.• Must be clearly identified as a CPG.• Must be published. Unpublished CPG, conference papers, discussion papers, drafts and opinions will be excluded.
Recommendations
Must have ‘recommendations’ concerning the identification, management and/or follow-up of recurrent miscarriage (either explicitly highlighted as such within the document or noted within the body of the document, but not explicitly identified as a recommendation). To be eligible, recommendations need not be accompanied by an explicit level of confidence (and quality assessment criteria system used specified); however, these data will be extracted (where available) and considered during the synthesis and interpretation of findings.
The following databases were systematically searched to identify eligible CPG, published between January 2000 and March 2020: CINAHL Plus (EBSCOhost; 1994), Embase® (Elsevier; 1980), MEDLINE (Ovid®; 1946), Open Grey (INIST-CNRS; 2011), Scopus (Elsevier; 2004), and Web of Science™ (Thomson Reuters). Guideline repositories (n = 8) and the websites of professional organizations and associations from around the world (n = 11) were also searched. The search strategy was developed with the assistance of a specialist librarian. Key word searches, using combinations of key words and Medical Subject Headings (or equivalent), were used across two concepts using the AND Boolean operator: clinical guidelines; recurrent miscarriage. Within each of the categories, keywords were combined using the ‘AND’ or ‘OR’ Boolean operators. Information sources and search terms applied are detailed in Supplementary Table 1.
Study selection
Retrieved records were imported firstly into EndNote X9 and de-duplicated using the ‘remove duplicates’ function, as well as manually screening results for accuracy. They were then imported into Rayyan and screened again for duplicates. Two independent reviewers (MH and RD) subsequently screened titles and abstracts of retrieved records against the inclusion criteria; this process was repeated for full texts. Any disagreements were discussed and resolved via consensus, with the input of a third reviewer (SM/KOD), where necessary.
Data collection process
To ensure that the most up-to-date versions of CPG were included in the final results, MH conducted searches and contacted authors where necessary. Once the final set of included CPG was agreed, MH retrieved all documents related to the CPG (such as supplemental documents, methodology papers and others) before data extraction or quality assessment was undertaken. RD independently verified all documents collected to confirm the completeness and ensure that companion documents were matched appropriately.
Data extraction
Key features of CPG and the documented recommendations were extracted using a structured data extraction form in Microsoft Excel (Microsoft Corporation, Redmond, WA, USA) (
A protocol for a systematic review of clinical practice guidelines for recurrent miscarriage [version 3; peer review: 3 approved, 1 approved with reservations].
), which was piloted in advance. Data were extracted by MH and verified for accuracy and completeness by RD. Discrepancies were resolved through consensus and, where agreement could not be reached, SM/KOD reviewed and made a final decision. To facilitate data synthesis, reviewers assigned categories and sub-categories to each recommendation during data extraction; some were pre-defined whereas others were generated iteratively. Details on the level of evidence (and strength, if provided) associated with each recommendation were also extracted.
Quality assessment
The quality of included CPG was assessed using the AGREE II criteria (
). The criteria encompass 23 items, over six domains, rated on a seven-point Likert scale: scope and purpose of the guideline; stakeholder involvement in the development of the guidelines; rigour of development and formulation of the recommendations within the guideline; clarity of presentation of the guideline; applicability of the guideline; and editorial independence in the formulation of recommendations within the guideline. As part of the overall assessment, two global ratings are included: a rating on the overall quality of the guideline; and whether the guideline would be recommended for use in practice. Three reviewers with methodological, clinical expertise, or both (MH, LL and SM), conducted an independent quality assessment of the CPG. Major discrepancies in the scores (where assigned scores differed by more than two points) were discussed and independently reassessed and consensus reached. Domain scores were calculated by summing up all the scores of the individual items in a domain and by scaling the total as a percentage of the maximum possible score for that domain, as per the AGREE II User Manual. To make the scores more relevant to readers and enable fair comparison, the AGREE II outcomes are reported categorically using the five-point Likert scale described by other reviews (
AGREE II assessments of recent acne treatment guidelines: how well do they reveal trustworthiness as defined by the U.S. Institute of Medicine criteria?.
): excellent (>80%), good (>60–80%), average (>40–60%), fair (>20–40%) and poor (≤20%).
Data synthesis
A narrative synthesis is used to describe, compare and contrast CPG and the recommendations therein, taking account of quality appraisal (using the AGREE II tool) and recency of publication. The levels of evidence associated with the recommendations within each CPG is reported, and quality assessment rating system used; no attempt was made to standardize evidence ratings across CPG.
Patient and public involvement
The protocol for this systematic review was developed in conjunction with a pregnancy loss parent advocate (RR) and through consultations with Specialist Bereavement and Loss Midwives. This work is part of a broader project evaluating current services for recurrent miscarriage in the Republic of Ireland. The RE:CURRENT project Research Advisory Group includes representation from healthcare and allied health professionals, advocacy and support organizations, those involved in the administration, governance and management of maternity services, academics, and women and men who have experienced recurrent miscarriage. RR is a member of this group and was involved in discussions and decisions concerning the conduct, findings and outputs of the review.
Results
Guideline selection
A total of 6065 records from the planned searches of databases (n = 5536), guideline repositories (n = 395) and websites of professional bodies and organizations (n = 134) were retrieved; the PRISMA flow chart is presented in Figure 1.
Figure 1PRISMA flow diagram. aPlus two addenda (Arachchillage, 2020; Bashford, 2020). bD2, duplicate; E1, not a clinical practice guideline; E2, not focused (primary/secondary) on the investigation, management and/or follow-up of recurrent miscarriage; E3, not issued, endorsed, or both, by national or international scientific societies, professional colleges, charitable organizations and/or government organisations; E7, not published in English; E8, not latest version; E11, withdrawn or no longer available; E12, cannot access full text; EE, meets two or more exclusion criteria.
After removing duplicates, the titles and abstracts of 4108 records were screened and, subsequently, 170 full texts were assessed. Thirty-two CPG were included in the final synthesis (Table 2); the original data extraction file (containing CPG characteristics and recommendations) is available in an open access repository (
Hennessy, M., Dennehy, R., Meaney, S., Linehan, L., Devane, D., O'Donoghue, K., 2021. Clinical practice guidelines for recurrent miscarriage in high-income countries: A systematic review. Retrieved from osf.io/xbfyp
). Details of records excluded at the full-text review stage are presented in Supplementary Table 2.
TABLE 2SUMMARY OF INCLUDED CLNICAL PRACTICE GUIDELINES
Title
Author, year
Developing or publishing organization, or authors
Country or countries of publication
Description provided by authors (e.g. guideline or algorithm)
Type of guideline (formulated, adapted, updated or revised)
Topic addressed (recurrent miscarriage, RPL or broader)
Number of recommendations specific to recurrent miscarriage
Development process (evidence-based, consensus-based, or both)
System of rating evidence or quality instrument used during guideline development (GRADE, Oxford, not mentioned, or other)
Funding
American Association of Gynecologic Laparoscopists (AAGL) practice report: practice guidelines for the diagnosis and management of submucous leiomyomas
AAGL, 2012
Practice Committee of the AAGL
Global
Practice guidelines
Not specified; formulated
Broader: submucous leiomyomas
3
Evidence-based; expert consensus-based
Modified method outlined by the US Preventive Services Task Force [USPSTF]; criteria described in the Report of the Canadian Task Force on the Periodic Health Examination
Not specified
American College of Obstetrics and Gynaecology (ACOG) practice bulletin number 200: early pregnancy loss
ACOG, 2018
ACOG
USA
Practice Bulletin/clinical management guidelines
Update
Broader: early pregnancy loss
2
Evidence-based; expert opinion
USPSTF
Not specified
The Society for Translational Medicine: clinical practice guidelines for sperm DNA fragmentation testing in male infertility
Agarwal, 2017
The Society for Translational Medicine
Global
Clinical practice guidelines
Not specified
Broader: male infertility
2
Not specified
Modified from Oxford Centre for Evidence-Based Medicine (http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/)
Not specified
Guidelines of the American Thyroid Association (ATA) for the diagnosis and management of thyroid disease during pregnancy and the postpartum
Alexander, 2017
ATA
USA
Guidelines
Revised
Broader: thyroid disease during pregnancy and the postpartum
2
Evidence-based; expert consensus-based
American College of Physicians Guideline Grading System
ATA without support from any commercial sources
Saudi guidelines for threatened and recurrent miscarriage management; the role of progestogens in threatened and idiopathic recurrent miscarriage
Arab, 2019
Saudi Society of Obstetrics and Gynecology
Saudi Arabia
Guidelines
Updated
Recurrent miscarriage
9
Evidence-based; expert consensus-based
Not mentioned
Abbott, Saudi Arabia provided funding for medical writing assistance, & sponsored the two consensus meetings
Practice guideline: Joint Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada
Armour, 2018
SOGC–CCMG
Canada
Practice guideline
Updated
Broader: use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss
1
Evidence-based
Modified criteria described in the Report of the Canadian Task Force on Preventive Healthcare
The Hospital for Sick Children Centre for Genetic Medicine and the University of Toronto McLaughlin Centre
Evaluation and treatment of recurrent pregnancy loss: a committee opinion
American Society for Reproductive Medicine (ASRM), 2012
ASRM
USA
Committee opinion
Not specified
Recurrent pregnancy loss
26
Not specified
None/not mentioned
Not specified
Subclinical hypothyroidism in the infertile female population: a guideline
ASRM, 2015
ASRM
USA
Guideline
Not specified; formulated
Broader: treating subclinical hypothyroidism in female patients with a history of infertility and miscarriage
3
Evidence-based; expert consensus-based
Described, but system name not mentioned
Not specified
Uterine septum: a guideline
ASRM, 2016
ASRM
USA
Guideline
Formulated
Broader: treatment of septate uterus
2
Evidence-based
Described, but system name not mentioned
Not specified
Removal of myomas in asymptomatic patients to improve fertility and/or reduce miscarriage rate: a guideline
ASRM, 2017
ASRM
USA
Clinical practice guideline
Formulated
Broader: removal of myomas in asymptomatic patients to improve fertility/reduce miscarriage rate
2
Evidence-based
Described, but system name not mentioned
Not specified
The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion
ASRM, 2018
ASRM and the Society for Assisted Reproductive Technology (SART)
USA
Committee opinion
Formulated
Broader: use of preimplantation genetic testing for aneuploidy
1
Evidence-based
None/not mentioned
Not specified
Venous thromboembolism (VTE), thrombophilia, antithrombotic therapy, and pregnancy; antithrombotic therapy and prevention of thrombosis, 9th edn: American College of Chest Physicians evidence-based clinical practice guidelines
Bates, 2012
American College of Chest Physicians
USA
Clinical practice guidelines
Updated/ revised
Broader: VTE disease; this section is specifically on the management of VTE and thrombophilia as well as the use of antithrombotic agents during pregnancy
5
Evidence-based
GRADE
National Heart, Lung, and Blood Institute (R13 HL104758) and Bayer Schering Pharma AG. Educational grants provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharma-ceuticals; Sanofi -Aventis USA.
Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline
DeGroot, 2012
Endocrine Society. Co-Sponsoring Associations: Asia and Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society
Global
Clinical practice guideline
Update
Broader: management of thyroid dysfunction during pregnancy and postpartum
3
Evidence-based
GRADE and USPSTF
Co-Sponsoring Associations: Asia and Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society
Recurrent pregnancy loss: guideline of the European Society of Human Reproduction and Embryology (ESHRE)
ESHRE, 2017
ESHRE
Europe
Guideline
Formulated, although previous version existed
Recurrent pregnancy loss
92
Evidence-based; expert consensus-based
GRADE
ESHRE
ESHRE PGT Consortium good practice recommendations for the organization of PGT
ESHRE, 2020
ESHRE
Europe
Good Practice Recommenda-tions
Updated
Broader: preimplantation genetic testing
3
Expert consensus-based
None
ESHRE
Clinical practice guidelines for hypothyroidism in adults
Garber, 2012
American Association of Clinical Endocrinologists (AACE) in association with ATA
USA
Clinical practice guidelines
Updated
Broader: clinical management of hypothyroidism in ambulatory patients
1
Evidence-based; expert consensus-based
Approach outlined in the AACE's Protocol for Standardized Production of Clinical Guidelines: 2010 update
Not specified
The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies
Grimbizis, 2016
ESHRE/European Society for Gynaecological Endoscopy (ESGE)
Europe
Consensus
Formulated
Broader: diagnosis of female genital anomalies
6
Evidence-based; expert consensus-based
None/not mentioned
ESHRE and ESGE
American College of Medical Genetics and Genomics (ACMG) practice guideline: lack of evidence for MTHFR polymorphism testing
Hickey, 2013 (Addendum: Bashford, 2020)
ACMG
USA
Clinical practice resource (practice guideline until 27 April 2020)
Unclear/not specified
Broader: MTHFR polymorphism testing
1
Not specified
Not mentioned
Not specified
Clinical practice guideline: venous thromboprophylaxis in pregnancy
Health Service Executive (HSE), 2013
Institute of Obstetricians and Gynaecologists, Royal College of Physicians of Ireland; HSE Clinical Care Programme in Obstetrics and Gynaecology
Ireland
Clinical practice guideline
Formulated
Broader: venous thromboprophylaxis in pregnancy
4
Consensus-based
None/not mentioned
Not specified
National standards for bereavement care following pregnancy loss and perinatal death
HSE, 2016
HSE
Ireland
Standards
Formulated
Broader: bereavement care following pregnancy loss and perinatal death
2
Evidence-based; expert consensus-based
None/not mentioned
Not specified
Pregnancy loss: French clinical practice guidelines
Huchon, 2016
College National des Gynecologues Obstetriciens Francais (CNGOF)
France
Clinical practice guidelines
Formulated
Broader: pregnancy loss
24
Evidence-based; expert consensus-based
Rating scheme developed by the Haute Autorite de Sante (French National Authority for Health)
Not specified
Guidelines on the investigation and management of antiphospholipid syndrome
Keeling, 2012 (Addendum: Arachchillage, 2020)
British Society for Haematology
UK
Guideline
Update
Broader: investigation and management of APS
6
Evidence-based; expert consensus-based
GRADE
Not specified
Hysteroscopic metroplasty of a uterine septum for recurrent miscarriage: Interventional procedures guidance
National Institute for Health and Care Excellence (NICE), 2015
Recurrent miscarriage: hysteroscopic metroplasty of a uterine septum
3
Evidence-based; expert consensus-based
Not mentioned
Not specified
Recurrent pregnancy loss care pathway for Northern Ireland
Public Health Agency, 2020
Public Health Agency (Northern Ireland)
Northern Ireland
Care pathway
Formulated
Recurrent pregnancy loss
64
Evidence-based
None/not mentioned
Not specified
Maternity and neonatal clinical guideline: early pregnancy loss
Queensland Clinical Guidelines, 2018
Queensland Clinical Guidelines
Australia
Clinical Guideline
Update
Broader: early pregnancy loss
19
Evidence-based; expert consensus-based. Best described as ‘evidence informed consensus guidelines’
National Health and Medical Research Council (NHMRC, 2009). Note: the ‘consensus’ definition is different from that proposed by the NHMRC. Instead, it relates to forms of evidence that are not identified by the NHMRC/that arise from the clinical experience of the guideline's clinical lead and working party
Healthcare Improvement Unit, Queensland Health
Green-top guideline number 17: the investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage
Royal College of Obstetrics and Gynaecology (RCOG), 2011
The role of natural killer cells in human fertility: scientific impact paper number 53
RCOG, 2016
RCOG
UK
Scientific impact paper
Formulated
Broader: role of natural killer cells in human fertility
1
Not described
None/not mentioned
Not specified
SIGN 129: antithrombotics: indications and management
SIGN, 2013
SIGN
UK
Clinical guideline
Update
Broader: antithrombo-tics
5
Evidence-based
SIGN
NHS Quality Improvement Scotland
Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines
Sung, 2017
Korean Society for Reproductive Immunology
Korea
Practice guidelines
Formulated
Broader: intravenous immuno-globulin G in women with reproductive failure
6
Evidence-based; expert consensus-based
System used by Fauser et al. (2012); available at https://www.fertstert.org/article/S0015-0282(11)02552-0/fulltext#appsec1
Partially supported by a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea
Recurrent miscarriage: diagnostic and therapeutic procedures. Guideline of the German Society of Gynecology and Obstetrics (DGGG), Austrian Society of Gynecology and Obstetrics (OEGGG) and the Swiss Society of Gynecology and Obstetrics (SGGG) (S2k-Level, AWMF Registry Number 015/050)
Toth, 2018
DGGG, ÖGGG and SGGG
Germany, Austria, Switzer-land
Guideline
Update
Recurrent miscarriage
45
Evidence-based (though no systematic search); expert consensus-based
Guideline does not discuss levels of evidence. The recommendations are graded according to their own instrument, described but name not mentioned
Not specified
American College of Radiology (ACR) appropriateness criteria infertility
Wall, 2020
ACR
USA
Guidelines
Revised
Broader: infertility
2
Evidence-based
RAND/UCLA Appropriateness Method and ACR's own criteria for Study Quality and Strength of Evidence, using concepts from GRADE (https://www.acr.org/-/media/ACR/Files/Appropriateness-Criteria/EvidenceTableDevelopment.pdf)
Not specified
Woman's pre-conception evaluation: genetic and fetal risk considerations for counselling and informed choice
Wilson, 2018
Genetics Committee of The SOGC
Canada
Consideration for Care Statement
Not specified (an update is implied however)
Broader: pre-conception evaluation
9
Evidence-based
GRADE
None
MTHFR, methylenetetrahydrofolate reductase; PGT, preimplantation genetic testing; Rand/UCLA, Rand Corporation and University of California at Los Angeles; RPL, recurrent pregnancy loss.
Most of the included CPG were described by their authors as guideline(s) (n = 9 [28%]), clinical practice guideline(s)/clinical guidelines (n = 9 [28%]), or practice guideline(s) (n = 3 [9%]) (Table 1). Seven (22%) CPG focused specifically on recurrent miscarriage, recurrent pregnancy loss (RPL), or both (including one focused on a specific procedure) (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
American Association of Gynecologic Laparoscopists (AAGL) AAGL practice report: practice guidelines for the diagnosis and management of submucous leiomyomas.
Practice Committee of the American Society for Reproductive Medicine Removal of myomas in asymptomatic patients to improve fertility and/or reduce miscarriage rate: a guideline.
Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association.
Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada.
Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion.
VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Institute of Obstetricians and Gynaecologists Royal College of Physicians of Ireland, HSE Clinical Care Programme in Obstetrics and Gynaecology, Irish Haematology Society Clinical practice guideline: Venous thromboprophylaxis in pregnancy.
Royal College of Physicians of Ireland,
Dublin2013
IVIG Task Force, Korean Society for Reproductive Immunology Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines.
The CPG were predominantly country-specific, with most originating in the USA (n = 11 [34%]), with others from Australia (n = 1 [3%]), Canada (n = 2 [6%]), France (n = 1 [3%]), Ireland (n = 2 [6%]), Korea (n = 1 [3%]), Northern Ireland (n = 1 [3%]), Saudi Arabia (n = 1 [3%]), and the UK (n = 5 [16%]). Seven CPG (22%) focused on more than one country, with one CPG from Germany, Austria and Switzerland (3%), three European (9%) and three global (9%) CPG. The CPG were published between 2011 and 2020: 2011 (n = 1 [3%]), 2012 (n = 6 [19%]), 2013 (n = 3 [9%]), 2015 (n = 2 [6%]), 2016 (n = 5 [16%]), 2017 (n = 5 [16%]), 2018 (n = 6 [19%]), 2019 (n = 1 [3%]) and 2020 (n = 3 [9%]). Seventeen (53%) CPG specifically mentioned a system of rating evidence and/or quality instrument used during CPG development, four (13%) described a system but did not specifically mention a name, whereas 11 (34%) did not report or use any. Of the 17 that specifically mentioned a system of rating the evidence, a variety were mentioned, with GRADE (Grading of Recommendations, Assessment, Development and Evaluations) being the most common, mentioned by five CPG (29%).
The terms used to describe recurrent miscarriage within the included CPG, as well as the definitions provided, are presented in Table 3. Most CPG used the term RPL (n = 15 [47%]), whereas others used recurrent miscarriage (n = 8 [25%]), a combination of terms such as RPL, recurrent miscarriage or other (n = 7 [22%]); two CPG (6%) did not specify a term. Definitions of these terms also varied. Of the 17 CPG that provided a description of recurrent miscarriage, RPL or other, nine referred to three or more losses (53%), seven referred to two or more losses (41%) and one referred to two consecutive spontaneous losses or three or more spontaneous losses (6%). Fifteen CPG did not provide a definition (47%); however, two of these referred to three losses within their texts.
TABLE 3DEFINITION OF RECURRENT MISCARRIAGE USED WITHIN CLINICAL PRACTICE GUIDELINES
Title
Author, year
Terminology used
Definition provided
AAGL practice report: practice guidelines for the diagnosis and management of submucous leiomyomas
AAGL, 2012
Recurrent pregnancy loss
None.
ACOG practice bulletin number 200: early pregnancy loss
ACOG, 2018
None
None; however, they refer to ‘women who have experienced three prior pregnancy losses’. Early pregnancy loss is defined as loss of an intrauterine pregnancy in the first trimester.
The Society for Translational Medicine: clinical practice guidelines for sperm DNA fragmentation testing in male infertility
Agarwal, 2017
Recurrent pregnancy loss
Three consecutive pregnancy losses before 20-week gestation.
Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum
Alexander, 2017
Recurrent pregnancy loss
Two consecutive spontaneous losses or three or more spontaneous losses.
Saudi guidelines for threatened and recurrent miscarriage management; the role of progestogens in threatened and idiopathic recurrent miscarriage
Arab, 2019
Recurrent miscarriage
The loss of two or more pregnancies (biochemical/ultrasound confirmation). Note: drew on ESHRE guidelines
Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada
Armour, 2018
None
None. They refer to ‘third pregnancy loss’
Evaluation and treatment of recurrent pregnancy loss: a committee opinion
ASRM, 2012
Recurrent pregnancy loss
Two or more failed clinical pregnancies; pregnancy is defined as a clinical pregnancy documented by ultrasonography or histopathological examination. Ideally, a threshold of three or more losses should be used for epidemiological studies while clinical evaluation may proceed following two first-trimester pregnancy losses.
Subclinical hypothyroidism in the infertile female population: a guideline
ASRM, 2015
Recurrent miscarriage; recurrent pregnancy loss
None.
Uterine septum: a guideline
ASRM, 2016
Recurrent pregnancy loss
None.
Removal of myomas in asymptomatic patients to improve fertility, reduce miscarriage rate. or both: a guideline
ASRM, 2017
Recurrent pregnancy Loss
None (note: one of the included studies defines as two or more miscarriages).
The use of PGT-A: a committee opinion
ASRM, 2018
Recurrent pregnancy loss
None.
VTE, thrombophilia, antithrombotic therapy, and pregnancy; antithrombotic therapy and prevention of thrombosis, 9th edn. American College of Chest Physicians evidence-based clinical practice guidelines
Bates 2012
Recurrent pregnancy loss; recurrent first trimester loss; recurrent early pregnancy loss
Recurrent early pregnancy loss: three or more miscarriages before 10 weeks of gestation. Note: In Table 1, defined as ‘Preferred as defined by three early losses before 12 weeks; if not able to extract by this definition’.
Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline
DeGroot, 2012
Recurrent miscarriage; recurrent abortion; recurrent pregnancy loss
None.
Recurrent pregnancy loss: guideline of the European Society of Human Reproduction an Embryology
ESHRE, 2017
Recurrent pregnancy loss
The loss of two or more pregnancies. It excludes ectopic pregnancy and molar pregnancy. A pregnancy loss (miscarriage) is defined as the spontaneous demise of a pregnancy before the fetus reaches viability. The term, therefore, includes all pregnancy losses from the time of conception until 24 weeks of gestation. Primary RPL is described as RPL without a previous ongoing pregnancy (viable pregnancy) beyond 24 weeks’ gestation, while secondary RPL is defined as an episode of RPL after one or more previous pregnancies progressing beyond 24 weeks’ gestation. A pregnancy in the definition is confirmed at least by either serum or urine beta-HCG, i.e. including non-visualized pregnancy losses (biochemical pregnancy losses, resolved and treated pregnancies of unknown location, or both). Recurrent ‘early’ pregnancy loss is the loss of two or more pregnancies before 10 weeks of gestational age. Recommend the use of ‘recurrent pregnancy loss’ to describe repeated pregnancy demise and to reserve ‘recurrent miscarriage’ to describe cases where all pregnancy losses have been confirmed as intrauterine miscarriages.
ESHRE PGT Consortium good practice recommendations for the organisation of PGT
ESHRE, 2020
Recurrent miscarriage
Two or more pregnancy losses before 24 weeks of gestation (including chemical pregnancy).
Clinical practice guidelines for hypothyroidism in adults
Garber, 2012
Recurrent miscarriage
None.
The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies
Grimbizis, 2016
Recurrent pregnancy loss
None.
ACMG practice guideline: lack of evidence for MTHFR polymorphism testing
Hickey, 2013
Recurrent pregnancy loss
None.
Clinical practice guideline: venous thromboprophylaxis in pregnancy
HSE, 2013
Recurrent miscarriage
None.
National standards for bereavement care following pregnancy loss and perinatal death
HSE, 2016
Recurrent miscarriage
The loss of three or more consecutive pregnancies before 24 weeks’ gestation.
Pregnancy loss: French clinical practice guidelines
Huchon, 2016
Recurrent pregnancy loss (also known as repeated miscarriages)
The experience of three or more consecutive miscarriages before 14 weeks’ gestation.
Guidelines on the investigation and management of antiphospholipid syndrome
Keeling, 2012
Recurrent pregnancy loss; recurrent fetal loss
Three or more pregnancy losses, before 10 weeks’ gestation.
Hysteroscopic metroplasty of a uterine septum for recurrent miscarriage: interventional procedures guidance
NICE, 2015
Recurrent miscarriage
Usually defined as three or more miscarriages in a row
Recurrent pregnancy loss care pathway for Northern Ireland
Public Health Agency, 2020
Recurrent pregnancy loss
A diagnosis of RPL could be considered after the loss of two or more pregnancies (ESHRE). Pregnancy loss is defined as the spontaneous loss of a pregnancy before the fetus reaches viability. It therefore includes all pregnancy losses from the time of conception until 24 weeks of gestation.
Maternity and neonatal clinical guideline: early pregnancy loss
Queensland Clinical Guidelines, 2018
Recurrent miscarriage
Three or more consecutive miscarriages. There is no specific term for non-consecutive pregnancy losses. Note: scope of document is women experiencing pregnancy loss before 20 weeks’ gestation.
Green-top guideline number 17: the investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage
RCOG, 2011
Recurrent first-trimester and second-trimester miscarriage
Three or more first-trimester miscarriages, or one or more second-trimester miscarriages. Includes all pregnancy losses from the time of conception until 24 weeks of gestation.
The role of natural killer cells in human fertility: scientific impact paper number 53
RCOG, 2016
Recurrent miscarriage; recurrent spontaneous pregnancy loss
None.
SIGN 129: antithrombotics: indications and management
SIGN, 2013
Recurrent pregnancy failure; recurrent miscarriage; recurrent pregnancy loss
None.
Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines
Sung, 2017
Recurrent pregnancy loss
State recurrent pregnancy loss traditionally defined as three or more consecutive miscarriages, but ASRM define as two or more failed pregnancies, based on the risk of recurrence and the prevalence of etiologies.
Recurrent miscarriage: diagnostic and therapeutic procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050)
Toth, 2018
Recurrent miscarriage
Three or more consecutive recurrent miscarriages (WHO definition).
ACR appropriateness criteria infertility
Wall, 2020
Recurrent pregnancy loss
Two or more consecutive early pregnancy losses (ASRM definition).
Woman's pre-conception evaluation: genetic and fetal risk considerations for counselling and informed choice
Wilson, 2018
Recurrent pregnancy loss
None.
AAGL, American Association of Gynecologic Laparoscopists; ACMG, American College of Medical Genetics and Genomics; ACOG, American College of Obstetrics and Gynaecology; ACR, American College of Radiology; ASRM, American Society for Reproductive Medicine; CCMG, Canadian College of Medical Geneticists; DGGG, German Society of Gynecology and Obstetrics; ESGE, European Society for Gynaecological Endoscopy; ESHRE, European Society of Human Reproduction and Embryology; HSE, Health Service Executive; MTHFR, methylenetetrahydrofolate reductase; NICE, National Institute for Health and Care Excellence; OEGGG, Austrian Society of Gynecology and Obstetrics; PGT-A, preimplantation genetic testing for aneuploidy; RCOG, Royal College of Obstetrics and Gynaecology; RPL, recurrent pregnancy loss; SGGG, Swiss Society of Gynecology and Obstetrics; SIGN, Scottish Intercollegiate Guidelines Network; SOGC, Society of Obstetricians and Gynaecologists of Canada; VTE, Venous thromboembolism; WHO, World Health Organization.
Quality assessment findings (AGREE II evaluations)
The quality assessment scores for the 32 included CPG are presented in Figure 2 and Table 4; the original data file, with individual reviewer scores, is available in an open access repository (
Hennessy, M., Dennehy, R., Meaney, S., Linehan, L., Devane, D., O'Donoghue, K., 2021. Clinical practice guidelines for recurrent miscarriage in high-income countries: A systematic review. Retrieved from osf.io/xbfyp
VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
). Applicability and editorial independence were the two domains in which CPG scored most poorly; 84% and 69% of CPG rated these domains as poor, respectively.
Figure 2AGREE II Domain scores for the 32 guidelines, percentage (%). Excellent (>80%), good (>60–80%), average (>40–60%), fair (>20–40%) and poor (≤20%)
TABLE 4AGREE II QUALITY ASSESSMENT RATINGS, BY DOMAIN (% CLINICAL PRACTICE GUIDELINES)
Title
Author, year
Domain 1: scope and purpose (%)
Domain 2: stakeholder involvement (%)
Domain 3: rigour of development (%)
Domain 4: clarity of presentation (%)
Domain 5: applicability (%)
Domain 6: editorial independence (%)
Overall quality of the guideline (%)
Recommend for use
AAGL practice report: practice guidelines for the diagnosis and management of submucous leiomyomas
AAGL, 2012
Average (43)
Poor (9)
Fair (35)
Good (67)
Poor (6)
Poor (17)
Average (56)
YWM
ACOG practice bulletin number 200: early pregnancy loss
ACOG, 2018
Average (57)
Fair (24)
Poor (20)
Good (63)
Poor (4)
Poor (8)
Average (50)
YWM
The Society for Translational Medicine: clinical practice guidelines for sperm DNA fragmentation testing in male infertility
Agarwal, 2017
Average (46)
Poor (17)
Poor (13)
Average (48)
Poor (0)
Poor (6)
Fair (33)
YWM
Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum
Alexander, 2017
Good (67)
Average (44)
Average (42)
Good (69)
Poor (7)
Good (67)
Good (67)
YWM
Saudi guidelines for threatened and recurrent miscarriage management; the role of progestogens in threatened and idiopathic recurrent miscarriage
Arab, 2019
Average (50)
Fair (37)
Fair (21)
Average (54)
Poor (0)
Poor (19)
Fair (39)
YWM
Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada
Armour, 2018
Average (54)
Average (48)
Fair (28)
Good (72)
Poor (15)
Poor (17)
Average (56)
YWM
Evaluation and treatment of recurrent pregnancy loss: a committee opinion
ASRM, 2012
Average (41)
Poor (9)
Poor (16)
Average (41)
Poor (3)
Fair (22)
Fair (39)
YWM
Subclinical hypothyroidism in the infertile female population: a guideline
ASRM, 2015
Average (50)
Poor (11)
Fair (27)
Average (56)
Poor (4)
Fair (22)
Average (44)
YWM
Author, Year
Domain 1: scope and purpose
Domain 2: stakeholder involvement
Domain 3: rigour of development
Domain 4: clarity of presentation
Domain 5: applicability
Domain 6: editorial independence
Overall quality of the guideline
Recommend for use
Uterine septum: a guideline
ASRM, 2016
Average (44)
Poor (17)
Average (41)
Average (57)
Poor (0)
Poor (17)
Average (44)
YWM
Removal of myomas in asymptomatic patients to improve fertility and/or reduce miscarriage rate: a guideline
ASRM, 2017
Fair (31)
Poor (15)
Fair (34)
Average (54)
Poor (1)
Poor (19)
Fair (33)
YWM
The use of PGT-A: a committee opinion
ASRM, 2018
Fair (26)
Poor (15)
Fair (31)
Fair (37)
Poor (8)
Fair (22)
Fair (33)
YWM
VTE, thrombophilia, antithrombotic therapy, and pregnancy; Antithrombotic therapy and prevention of thrombosis, 9th edn: American College of Chest Physicians evidence-based clinical practice guidelines
Bates, 2012
Good (76)
Average (57)
Good (65)
Good (76)
Fair (22)
Good (72)
Excellent (83)
Yes
Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline
DeGroot, 2012
Average (57)
Fair (28)
Fair (38)
Good (74)
Poor (3)
Fair (22)
Average (56)
YWM
Recurrent pregnancy loss: guideline of the European Society of Human Reproduction and Embryology
ESHRE, 2017
Good (74)
Good (61)
Good (66)
Excellent (81)
Poor (19)
Average (50)
Good (72)
Yes
ESHRE PGT Consortium good practice recommendations for the organization of PGT
ESHRE, 2020
Average (46)
Average (41)
Poor (20)
Average (52)
Poor (7)
Poor (14)
Fair (33)
YWM
Clinical practice guidelines for hypothyroidism in adults
Garber, 2012
Good (61)
Fair (30)
Fair (37)
Good (70)
Poor (8)
Poor (14)
Average (50)
YWM
The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies
Grimbizis, 2016
Fair (39)
Fair (30)
Poor (20)
Average (48)
Poor (11)
Poor (14)
Fair (33)
YWM
ACMG practice guideline: lack of evidence for MTHFR polymorphism testing
Hickey, 2013
Poor (15)
Poor (13)
Poor (9)
Average (44)
Poor (0)
Poor (6)
Poor (11)
No
Clinical practice guideline: Venous thromboprophylaxis in pregnancy
HSE, 2013
Average (54)
Average (41)
Fair (26)
Good (72)
Poor (15)
Poor (0)
Average (44)
YWM
National standards for bereavement care following pregnancy loss and perinatal death
HSE, 2016
Average (50)
Good (65)
Poor (10)
Average (54)
Fair (22)
Poor (0)
Fair (33)
YWM
Pregnancy loss: French clinical practice guidelines
Huchon, 2016
Poor (17)
Fair (26)
Poor (16)
Average (48)
Poor (10)
Poor (0)
Fair (33)
YWM
Guidelines on the investigation and management of antiphospholipid syndrome
Keeling, 2012
Average (43)
Fair (28)
Fair (35)
Average (54)
Poor (0)
Poor (8)
Fair (50)
YWM
Hysteroscopic metroplasty of a uterine septum for recurrent miscarriage: interventional procedures guidance
NICE, 2015
Average (44)
Poor (13)
Average (58)
Good (70)
Poor (18)
Poor (14)
Average (50)
YWM
Recurrent pregnancy loss care pathway for Northern Ireland
Public Health Agency, 2020
Average (54)
Average (48)
Poor (7)
Average (56)
Fair (21)
Poor (0)
Fair (22)
YWM
Maternity and neonatal clinical guideline: early pregnancy loss
Queensland Clinical Guidelines, 2018
Good (63)
Average (48)
Fair (33)
Excellent (81)
Fair (40)
Fair (36)
Good (61)
YWM
Green-top guideline number 17: the investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage
RCOG, 2011
Average (57)
Fair (22)
Average (42)
Good (76)
Poor (8)
Poor (6)
Average (50)
YWM
The role of natural killer cells in human fertility: scientific impact paper number 53
RCOG, 2016
Fair (28)
Poor (20)
Poor (17)
Average (54)
Poor (0)
Poor (8)
Fair (22)
YWM
SIGN 129: antithrombotics: indications and management
SIGN, 2013
Average (54)
Good (70)
Average (56)
Good (72)
Fair (26)
Fair (25)
Good (61)
YWM
Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines
Sung, 2017
Fair (30)
Poor (13)
Fair (22)
Average (43)
Poor (0)
Poor (14)
Fair (33)
YWM
Author, Year
Domain 1: Scope & purpose
Domain 2: Stakeholder involvement
Domain 3: Rigour of development
Domain 4: Clarity of presentation
Domain 5: Applicability
Domain 6: Editorial independence
Overall quality of the guideline
Recommend for use
Recurrent miscarriage: diagnostic and therapeutic procedures. Guideline of the DGGG, OEGGG 7 SGGG (S2k-level, AWMF registry number 015/050)
Toth, 2018
Fair (39)
Fair (35)
Fair (31)
Average (59)
Poor (7)
Poor (14)
Fair (33)
YWM
ACR appropriateness criteria infertility
Wall, 2020
Average (52)
Fair (31)
Average (56)
Good (67)
Poor (3)
Poor (6)
Average (50)
YWM
Woman's pre-conception evaluation: Genetic and fetal risk considerations for counselling and informed choice
Wilson, 2018
Average (44)
Poor (19)
Fair (24)
Average (54)
Poor (10)
Fair (22)
Poor (17)
YWM
Excellent (>80%), good (>60–80%), average (>40–60%), fair (>20–40%), poor (≤20%).
AAGL, American Association of Gynecologic Laparoscopists; ACMG, American College of Medical Genetics and Genomics; ACOG, American College of Obstetrics and Gynaecology; ACR, American College of Radiology; ASRM, American Society for Reproductive Medicine; CCMG, Canadian College of Medical Geneticists; DGGG, German Society of Gynecology and Obstetrics; ESGE, European Society for Gynaecological Endoscopy; ESHRE, European Society of Human Reproduction and Embryology; HSE, Health Service Executive; MTHFR, methylenetetrahydrofolate reductase; NICE, National Institute for Health and Care Excellence; OEGGG, Austrian Society of Gynecology and Obstetrics; PGT-A, preimplantation genetic testing for aneuploidy; RCOG, Royal College of Obstetrics and Gynaecology; SGGG, Swiss Society of Gynecology and Obstetrics; SIGN, Scottish Intercollegiate Guidelines Network; SOGC, Society of Obstetricians and Gynaecologists of Canada; VTE, Venous thromboembolism; YWM, yes with modifications.
Each included recommendation was assigned to one of the following categories: structure of care; investigations; treatment; and counselling and/or supportive care, with further sub-categories assigned. The number of recommendations by category and sub-category are presented in Table 5. Given the diversity of the CPG included, and the varying quality of CPG and evidence underpinning recommendations therein, the recommendations were not synthesized further. Instead, a narrative description is provided, comparing and contrasting the recommendations under each category and sub-category.
TABLE 5NUMBER OF RECOMMENDATIONS BY CATEGORY AND SUB-CATEGORY
Sub-total of the number of recommendations may be higher than the number of recommendations highlighted under the category as some recommendations were categorized under more than one sub-category.
Sub-total of the number of clinical practice guidelines (CPG) is not the sum of the number of CPG; it is the total number of CPG with recommendations within the particular category.
Risk factors mentioned could include the following: age; successive pregnancy losses; anatomical, endocrine/metabolic and genetic factors; smoking; drug, alcohol use, or both; obesity or underweight; diet (including caffeine consumption); and physical inactivity.
4
4
Screening for genetic factors
22
9
Tailoring
4
3
Thrombophilia screening
29
12
Unexplained recurrent miscarriage
2
2
Sub-total
146
23
Treatment (n = 153)
Antiphospholipid syndrome
18
10
Assisted reproductive technology
1
1
Genetic factors
11
6
Immunotherapy
15
6
Male factors
4
2
Metabolic or endocrinologic factors
44
12
Microbiological factors
2
2
Prognosis
1
1
Risk factors
1
1
Tailoring
1
1
Thrombophilia
12
7
Unexplained recurrent miscarriage
21
6
Uterine factors
22
10
Vitamins
4
3
Sub-total
157
24
Counselling and/or supportive care (n = 46)
Clinician knowledge/skills/expertise
1
1
Genetic counselling
4
4
Informational support
3
2
Investigations
4
3
Prognosis
6
5
Psychological and/or emotional counselling
11
5
Research
2
2
Risk factors3
13
5
Tailoring
2
1
Treatment
1
1
Sub-total
47
9
Total (n = 373)
375
32
a Sub-total of the number of recommendations may be higher than the number of recommendations highlighted under the category as some recommendations were categorized under more than one sub-category.
b Sub-total of the number of clinical practice guidelines (CPG) is not the sum of the number of CPG; it is the total number of CPG with recommendations within the particular category.
c Risk factors mentioned could include the following: age; successive pregnancy losses; anatomical, endocrine/metabolic and genetic factors; smoking; drug, alcohol use, or both; obesity or underweight; diet (including caffeine consumption); and physical inactivity.
Forty-two recommendations from nine CPG were categorized under ‘Structure of care’ (Supplementary Table 3 and Supplementary Table 4). Two of these recommendations were categorized under two or more sub-categories. Forty recommendations within this category did not have associated strength of recommendation, quality of evidence ratings, or both, primarily because they were statements, good practice points, or both, within the relevant CPG. Ten recommendations from six CPG (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
) related to ‘clinician knowledge/skills/expertise’ referring to individual clinicians and/or multi-disciplinary teams that should be involved in the care of those who experience recurrent miscarriage, either within specialist clinics, elsewhere, or both. A further 10 recommendations from three CPG (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
) related to ‘specialist clinic’, specifically around how women who experience recurrent miscarriage should be referred to and/or seen in a specialist clinic, with two of the CPG including recommendations about the location of the clinic, and one CPG making recommendations around what should happen at the first visit, and the equipment and facilities needed.
) related to ‘counselling (psychological and/or emotional), recognizing the effect of recurrent miscarriage on those who experience recurrent miscarriage, as well as the provision of appropriate support services, referral to these services, or both. Five recommendations from two CPG (
) related to ‘referral’. One CPG contained one recommendation to ensure that those who experience recurrent miscarriage are referred to a pregnancy loss or gynaecological clinic (
). Another CPG included recommendations on referral criteria, information to be provided on referral and information about referrals outside of a particular jurisdiction (
) related to ‘investigations’. Two of these recommendations related to proceeding with investigations for recurrent miscarriage after two consecutive clinical pregnancy losses (
), one recommendation concerned the tailoring of investigation plans, i.e. matching an intervention or components to previously measured characteristics of the participant (
) related to ‘treatment’ and concerned tailored treatment plans, including plans for future pregnancies; one CPG referred to experimental treatments and how they should not take place outside of research settings (
) related to ‘informational support’ and concerned information (written, spoken, or both) that should be provided to those who experience recurrent miscarriage at the outset, including information about what will happen, sources of support, or both. Two recommendations from one CPG (
) related to ‘research’; these related to experimental investigations and treatments mentioned earlier under those sub-categories, as well as travel funding requests for assessment of trial eligibility.
Investigations
One hundred and thirty-four recommendations from 23 CPG were categorized under ‘Investigations’ (Supplementary Table 5 and Supplementary Table 6). Nine of these recommendations were categorized under two or more sub-categories. Fifty-six recommendations did not have the strength of recommendation, quality of evidence ratings, or both, to accompany them, as they were statements, good practice points, or both, within the relevant CPG, or were not specified.
Thirty recommendations from nine CPG related to ‘metabolic and endocrinologic factors’. No clear agreement was reached, with some conflicting recommendations. Thyroid-stimulating hormone (TSH) was recommended by three CPG (
recommended an overall endocrine assessment, but no evidence for any particular investigation or test.
Twenty-nine recommendations from 12 CPG related to ‘thrombophilia screening’. Greater consensus was reached in this section with 10 CPG recommending antiphospholipid antibodies (APLA) after two or three miscarriages as standard (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Institute of Obstetricians and Gynaecologists Royal College of Physicians of Ireland, HSE Clinical Care Programme in Obstetrics and Gynaecology, Irish Haematology Society Clinical practice guideline: Venous thromboprophylaxis in pregnancy.
Royal College of Physicians of Ireland,
Dublin2013
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
Institute of Obstetricians and Gynaecologists Royal College of Physicians of Ireland, HSE Clinical Care Programme in Obstetrics and Gynaecology, Irish Haematology Society Clinical practice guideline: Venous thromboprophylaxis in pregnancy.
Royal College of Physicians of Ireland,
Dublin2013
suggested methylenetetrahydrofolate reductase (MTHFR) genetic screening and did not recommend it as standard.
Twenty-six recommendations from 12 CPG concerned ‘anatomical investigations’. It was generally agreed that uterine anatomy should be assessed as part of the routine investigation of recurrent miscarriage. Opinions differed, however, on what the most appropriate investigation was, with little supporting evidence. Many CPG agreed that ultrasound is a suitable primary investigation for assessing pelvic anatomy (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
). No consensus, however, was reached on what second-line investigations were more appropriate, with saline infusion sonohysterogram, hysterosalpingography (HSG), hysterosalpingo-contrast-sonography, three-dimensional ultrasound and magnetic resonance imaging all suggested. Some CPG recommended the use of HSG (
both stated that HSG is not an appropriate first-line investigation for uterine anomalies.
Twenty-two recommendations from nine CPG related to ‘screening for genetic factors’. Five CPG recommended karyotyping of pregnancy tissue as standard (
); a further one stated that, in cases of congenital anomalies, intrauterine growth restriction, or both, in any fetal loss before 20 weeks’ gestation, if quantitative fluorescent polymerase chain reaction methodologies, other-directed diagnostic inquiries, or both, did not provide a diagnosis and further cytogenetic analysis is intended, karyotype should be replaced with chromosomal microarray analysis (
Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada.
Thirteen recommendations from seven CPG related to ‘immunological screening’. Five of these CPG made recommendations around natural killer cell testing: four did not recommend such testing (
IVIG Task Force, Korean Society for Reproductive Immunology Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines.
). The consensus amongst CPG in relation to immunological screening was that human leukocyte antigen analysis, peripheral and uterine natural killer cell analysis, T helper type 1 and type 2 measurements were all experimental, with the exception of the guidelines from
IVIG Task Force, Korean Society for Reproductive Immunology Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines.
cited an exception for one disorder in which women had miscarriages after one previous male child.
Five recommendations from four CPG related to ‘male factors’, with one of these relating to risk factors (mentioned later also). Four of the recommendations concerning male factors related to sperm testing: three recommended sperm testing, with two specifically recommending sperm DNA fragmentation (
); the strength of recommendation, quality of evidence, or both, was not assessed, i.e. they were statements, or was low for these. Five recommendations from three CPG related to ‘medical and family history’, i.e. the need to take such a history, and four of these related to tailoring investigations accordingly (mentioned later also) (
); only two had the strength of recommendation, quality of evidence ratings (expert consensus), or both. Four recommendations from three CPG related to ‘tailoring’ investigations to each woman or couple (
). Four recommendations from four CPG related to ‘risk factors’, e.g. alcohol, smoking, caffeine, weight status, physical activity, and the need to evaluate these (
). Two recommendations from one CPG related to ‘haematology’ and stated that full blood count and electrolytes and liver function tests should be standard investigations (
). Two recommendations from two CPG related to ‘unexplained recurrent miscarriage’ and how this diagnosis can be made when investigations have been conducted, and no cause of recurrent miscarriage found (
One hundred and fifty-three recommendations from 24 CPG were categorized under ‘Treatment’ (Supplementary Table 7 and Supplementary Table 8). Three of these recommendations were categorized under two or more sub-categories. Sixty-two recommendations did not have the strength of recommendation, quality of evidence ratings, or both, to accompany them, as they were statements, good practice points, or both, within the relevant CPG, or were not specified.
Forty-four recommendations from 12 CPG related to ‘metabolic or endocrinologic factors’. Three CPG recommended that overt hypothyroidism is treated in recurrent miscarriage (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
Twenty-two recommendations from 10 CPG related to ‘uterine factors’. Three CPG stated that the evidence for any of the mentioned procedures in recurrent miscarriage was insufficient (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
American Association of Gynecologic Laparoscopists (AAGL) AAGL practice report: practice guidelines for the diagnosis and management of submucous leiomyomas.
Practice Committee of the American Society for Reproductive Medicine Removal of myomas in asymptomatic patients to improve fertility and/or reduce miscarriage rate: a guideline.
stated that myomectomy makes no difference to live birth rates after assisted reproductive technology but that it also does not reduce the miscarriage rate.
stated that some evidence suggested that uterine surgery may be of some efficacy but with rare serious side-effects. Overall, the evidence seems insufficient to merit advising procedures on anything but an individual basis.
Twenty-one recommendations from six CPG related to ‘unexplained recurrent miscarriage’. Two CPG recommended reassurance of excellent prognosis for future pregnancy and supportive care (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
IVIG Task Force, Korean Society for Reproductive Immunology Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines.
); this CPG also recommended against glucocorticoids in recurrent miscarriage with selected immunological biomarkers, folic acid for treatment of unexplained recurrent miscarriage, progesterone, intralipid therapy and endometrial scratching (
Eighteen recommendations from 10 CPG related to ‘antiphospholipid syndrome’. The CPG consistently recommended that antiphospholipid syndrome requires treatment with aspirin and heparin (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Institute of Obstetricians and Gynaecologists Royal College of Physicians of Ireland, HSE Clinical Care Programme in Obstetrics and Gynaecology, Irish Haematology Society Clinical practice guideline: Venous thromboprophylaxis in pregnancy.
Royal College of Physicians of Ireland,
Dublin2013
VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
) compared with low-molecular-weight heparin, and whether a prophylactic or intermediate dose was required, were inconsistent. Some also recommended treatment with the caveat that they fulfilled clinical and laboratory criteria for antiphospholipid syndrome (
VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
specified that antiphospholipid syndrome and recurrent miscarriage only warranted aspirin and heparin if there was a history of venous thromboembolism.
Fifteen recommendations from six CPG related to ‘immunotherapy’. All CPG were in agreement that immunotherapies were not recommended outside of clinical trials or in specific autoimmune diseases (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
IVIG Task Force, Korean Society for Reproductive Immunology Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines.
, which recommended IVIG for recurrent miscarriage and cellular immune abnormalities. One recommendation from one CPG related to ‘non-conventional treatments’ and how intralipid therapy should not be recommended (
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Institute of Obstetricians and Gynaecologists Royal College of Physicians of Ireland, HSE Clinical Care Programme in Obstetrics and Gynaecology, Irish Haematology Society Clinical practice guideline: Venous thromboprophylaxis in pregnancy.
Royal College of Physicians of Ireland,
Dublin2013
IVIG Task Force, Korean Society for Reproductive Immunology Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines.
). Most were in agreement that inherited thrombophilia and a history of recurrent miscarriage are insufficient to warrant aspirin and heparin prophylaxis in the absence of thrombotic events or risk factors.
IVIG Task Force, Korean Society for Reproductive Immunology Intravenous immunoglobulin G in women with reproductive failure: The Korean Society for Reproductive Immunology practice guidelines.
). Preimplantation genetic diagnosis (PGD) and PGT are the terms used within the respective guidelines. For consistency in reporting, the term PGT is used; furthermore, PGT has replaced PGD and preimplantation genetic screening (PGS) after changes to terminology in infertility care (ESHRE PGT
Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion.
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
Royal College of Obstetricians and Gynaecologists Green-top Guideline Number 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage.
) and another recommended smoking cessation, normal body weight, limited alcohol consumption and a normal exercise pattern in couples who have experienced recurrent miscarriage (
); this recommendation was also categorized under ‘risk factors’ (the only recommendation in this sub-category).
Four recommendations from three CPG related to ‘vitamins’. One CPG recommended pre-conceptual folic acid supplementation, and pre-conceptual vitamin B6 and vitamin B9 (and during pregnancy, if occurs), in women who had experienced recurrent miscarriage and a diagnosis of B9 deficiency, hyperhomocysteinaemia, or both (
Two recommendations from two CPG related to ‘microbiological factors’: one consensus-based CPG recommended that antibiotics may be administered to women who had experienced recurrent miscarriage and chronic endometritis (
). One recommendation from one CPG related to assisted reproductive technology and how oocyte donation could be discussed as an alternative treatment in women with low ovarian reserve who have experienced recurrent miscarriage (
Forty-six recommendations from nine CPG were categorized under ‘Counselling/supportive care’, which includes anything from general supportive care, informational support, to psychological counselling and genetic counselling (Supplementary Table 9 and Supplementary Table 10). Three of these recommendations were categorized under two sub-categories. Thirty-six recommendations did not have the strength of recommendation, quality of evidence ratings, or both, to accompany them, as they were statements, good practice points, or both, within the relevant CPG, or were not specified.
) related to ‘risk factors’ and providing information, discussing risk factors for recurrent miscarriage with patients, or both. Risk factors primarily included age, successive pregnancy losses and anatomical, endocrine or metabolic and genetic factors, as well as smoking, drug and/or alcohol use, obesity or underweight, diet (including caffeine consumption) and physical inactivity. Eleven recommendations in five CPG (
) related to ‘psychological and/or emotional counselling’. These included acknowledging the emotional effect of pregnancy loss; offering (or highlighting the availability of) counselling and support (psychological and/or emotional) to couples who had experienced recurrent miscarriage, including exploring which support might be best for the woman or couple; and offering access or referral to the Bereavement Specialist Teams and others. Recommendations in this sub-category also encompassed reassurance with repeated consultations with ultrasounds in women who had experienced recurrent miscarriage and the provision of ‘tender loving care’ for psychological support, despite its efficacy for recurrent miscarriage being unproven. Discussion to identify preferred language or terminology to be used in discussions, and offering additional emotional support if necessary in future pregnancies, were also recommended.
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