Downloaded 125 times
Uploaded bySujoy Dasgupta
ESHRE Guideline on Recurrent Pregnancy Loss (RPL)
Dr. Sujoy Dasgupta is a consultant in reproductive medicine with several qualifications and recognition in the field. The document discusses the management, testing, and treatment options for recurrent pregnancy loss (RPL), covering etiology, lifestyle factors, genetic considerations, and immunological assessments. It emphasizes personalized treatment plans and the importance of clinical judgment in following guidelines for patient care.
In this document
Powered by AI
Presentation by Dr. Sujoy Dasgupta, a consultant in reproductive medicine with multiple qualifications and awards.
Highlights the role of secondary and tertiary healthcare professionals in providing care.
Discusses RPL definition, diagnostic criteria, and differentiates types of pregnancy loss excluding ectopic and molar pregnancies.
Outlines the RPL clinic's staff, explanation, testing, treatment plan, and focus on shared decision-making.
Identifies age, stress, BMI, smoking, and alcohol as lifestyle factors affecting obstetric outcomes.
Discusses the importance of partners' lifestyle, medical history, family history affecting pregnancy outcomes.
Describes genetic analysis of pregnancy tissue and parental karyotype for assessing risks and treatment options.
Recommendations for screening hereditary and acquired thrombophilia in relation to recurrent pregnancy loss.
Describes different immunological screenings such as anti-nuclear antibodies and human leukocyte antigen.
Further elaboration on various immunological tests and their associations with pregnancy loss and treatment options.
Recommends thyroid screening for women with RPL and highlights the significance of abnormal TSH levels.
Discusses various endocrine tests like PCOS and their associations with recurrent pregnancy loss.
Techniques for assessing uterine malformations through imaging tests and their implications for RPL.
Addressing cervical weakness as a potential cause of miscarriages and lack of objective tests.
Sperm DNA fragmentation and lifestyle influences on male factor infertility related to pregnancy loss.
How to assess prognosis based on age, previous pregnancy history and losses using prognostic tools.
Genetic counseling recommendations for couples with abnormal karyotype results to identify treatment pathways.
Treatment recommendations for women with hereditary and acquired thrombophilia to manage pregnancy loss.
Recommendations for managing overt and subclinical hypothyroidism as well as thyroid autoimmunity in patients.
Continues discussion on treatments for luteal phase insufficiency and vitamin D supplementation.
Guidelines for treating congenital and acquired uterine abnormalities related to recurrent pregnancy loss.
Management strategies for cervical insufficiency in women experiencing recurrent losses.
Emphasizes lifestyle changes such as smoking cessation and limits on alcohol for improving reproductive health.
Recommendations for vaginal progesterone and intravenous immunoglobulin in the treatment of unexplained RPL.
Lists treatments like glucocorticoids and lymphocyte immunization therapy that are not supported by evidence.
Discusses the psychological impact of recurrent pregnancy loss and the limited evidence for supportive care.
Summarizes various tests recommended for assessing recurrent pregnancy loss and their implications.
Provides a brief overview of treatment options encompassing genetic, lifestyle, and medical management for RPL.
Discusses controversies and unresolved issues in treating recurrent pregnancy loss based on current guidelines.
States the purpose and limitations of clinical practice guidelines in RPL management.
More Related Content
Similar to ESHRE Guideline on Recurrent Pregnancy Loss (RPL)
More from Sujoy Dasgupta
ESHRE Guideline on Recurrent Pregnancy Loss (RPL)
- 1. Dr Sujoy Dasgupta MBBS(Gold Medalist, Hons) MS (OBGY- Gold Medalist) DNB (New Delhi) MRCOG (London) Advanced ART Course for Clinicians (NUHS, Singapore) M Sc, Sexual and Reproductive Medicine (South Wales, UK) Consultant: Reproductive Medicine, Genome Fertility Centre, Kolkata Managing Committee Member, BOGS, 2022-23 Executive Committee Member, ISAR Bengal, 2022-24 Clinical Examiner, MRCOG Part 3 Examination Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress, London, 2019 RPL- ESHRE
- 2. “covers the careprovided by secondary and tertiary healthcare professionals”
- 4. • Chance ofAPS, other etiology same between 2 and 3 losses (van den Boogaard et al., 2013) • From the time of conception until 24 weeks of gestation (RCOG, 2011) • Includes- nonvisualized pregnancy losses 1. biochemical losses 2. resolved and treated PUL 3. ultrasound done after complete expulsion of embryo • Excludes ectopic and molar pregnancy • Consecutive vs non-consecutive- same etiology, same prognosis (van den Boogaard et al., 2013; van den Boogaard et al., 2010; Youssef et al., 2020; Egerup et al., 2016) • Avoid using- Spontaneous abortion, Chemical pregnancy, Blighted ovum
- 5.
- 6. Good practice point AgeLowest risk- 20-35 yr Risk rapidly increases after 40 yr Stress Cause vs effect BMI Very high or low- poor obstetric outcome Obesity- lowers live birth Impact of weight loss? Optimum BMI is recommended Smoking Poor obstetric outcome Impact of quitting? Cessation of smoking is recommended Alcohol Poor fetal outcome Impact of limiting alcohol? Limiting alcohol is recommended
- 8. •Lifestyle factors ofboth the partners •Medical history- thrombophilia, PCOS, and diabetes, •Family history- hereditary thrombophilia. •Longer time to pregnancy (TTP ) (Arge et al., 2022).
- 9. Screening for geneticfactors Test Recommendation Association Contributing factor Prognosis Treatment Genetic analysis of pregnancy tissue • Not routinely recommended • Can be done for explanatory purpose • By a-CGH Yes Yes No No Parental karyotype After individual risk assessment • previous child with congenital abnormalities/ unbalanced chromosome abnormalities • translocation in the pregnancy tissue Yes Yes Yes PGT Adoption Gamete donation Prenatal invasive test
- 10. Thrombophilia screening Test RecommendationAssociation Contributing factor Prognosis Treatment Hereditary thrombo- philia Not recommended except 1. Research setting 2. Additional risk factors (personal/ family) for thrombophilia • FVL mutation • Prothrombin mutation • MTFHR mutation • Protein C deficiency • Protein S deficiency • Antithrombin III deficiency No/ weak Unclear yes No Acquired thrombo- philia (APS) • Postpone until 6 weeks after pregnancy loss • Repeat test after 12 wk • Lupus anticoagulant (LA) • Anti-cardiolipin antibody (IgG, IgM) Yes Yes Yes Weak evidence (2 vs 3 loss) • Anti-β2 glycoprotein (aβ2GPI) Possible (not statistically significant) Possible No data No data
- 11. Immunological screening Test RecommendationAssociation Contributing factor Prognosis Treatment Anti-nuclear antibodies (ANA) • Could be considered for explanatory purpose Possible Possibly no Unclear Not available Human Leukocyte Antigen (HLA) • Not recommended in clinical practice. • Only Maternal HLA class II determination (HLA- DRB1*15:01, HLA- DRB1*07 and HLADQB1*05:01/05:2) could be considered in Scandinavian women with secondary RPL after the birth of a boy, for prognostic purposes. Strong Yes Negative impact on future live birth Not available Tests could be considered
- 12. Immunological screening Test AssociationContributing factor Prognosis Treatment HLA compatibility Controversial No No Not available HLA-G Significant but weak No data No data Not available KIR and HLC-C Significant but weak No data No data Not available Cytokines Yes Unclear Unknown Not available Polymorphism in cytokine genes No association No No Not available Anti-HY immunity Moderate (Only Scandinavian) Yes (after birth of baby boy) Negative impact on live-birth Not available NK cell number in peripheral blood Weak Unclear Unclear Not available NK cell cytotoxicity in peripheral blood Unclear No No Not available NK cell in uterus/ endometrium Weak Unclear No Not available Anti sperm antibody No good quality evidence Anti HLA antibody Celiac disease antibody Tests NOT recommended
- 13. Metabolic and endocrinescreening • Thyroid screening (TSH and TPO-antibodies) is recommended in women with RPL • Abnormal TSH levels should be followed up by T4 testing Thyroid screening
- 14. Metabolic and endocrinescreening Test Association Contributing factor Prognosis Treatment PCOS Yes Yes No Metformin in sporadic PL No studies in RPL Insulin resistance Yes No studies No studies No studies Fasting Insulin Inconsistent Unclear No studies No studies Fasting glucose No No No studies No studies Androgen (testosterone) Inconsistent No studies No studies No studies Free androgen index No studies No studies Possible No studies Elevated serum LH Inconsistent No studies Inconsistent No studies Prolactin Inconsistent No studies Possible Yes (Dopamine agonist) Ovarian reserve Unclear Unclear Low live-birth No studies Luteal phase insufficiency testing (Endometrial biopsy, midluteal progesterone) Inconsistent No studies No Possible (Progesterone, hCG) Homocysteine Inconsistent Possible in PCOS No studies High dose folate, Vit B6 Aspirin+ LMWH Vitamin D Possible Possible No studies Vitamin D supplementation Tests NOT recommended
- 15. Screening for anatomicaldisorders Test Recommendation Association Contributing factor Prognosis Treatment Congenital uterine malformations • Uterine cavity assessment in all women • 3D US- high sensitivity and specificity to d/d between septate and bicorporeal uterus • Sonohysterography (SHG)- more accurate than HSG • MRI- if 3D US not available • Renal tract assessment if Mullerian anomaly is diagnosed Yes Some malformation No studies Surgical trial in septate uterus Acquired uterine malformations • All women should have 2D US to rule out adenomyosis Yes Unclear No studies Unclear
- 16. Screening for anatomicaldisorders • Cervical weakness- diagnosis based on a history of second-trimester miscarriage preceded by PPROM or painless cervical dilatation. • No objective test in the non-pregnant state.
- 17. Male Factor Test RecommendationAssociation Contributing factor Prognosis Treatment Sperm DNA fragmentation (SDF) • Consider for diagnostic purpose • Correct assay of SDF? Yes Yes Needs further studies •Lifestyle changes •ICSI using hyaluronan (PICSI) Assess lifestyle factors in the male partner • Age • Smoking • Alcohol • Exercise • BMI • SDF is associated with advanced paternal age, unhealthy lifestyles (smoking, obesity and excessive exercise) (de Ligny, et al., 2022, Sharma et al., 2013, Wright et al., 2014).
- 19. Assessing prognosis ofRPL • Base prognosis on 1. woman’s age 2. her complete pregnancy history, 3. including number of previous pregnancy losses, live births and their sequence. • Prognostic tools (Kolte & Westergaard) can be used (Kolte AM, Westergaard D, Lidegaard Ø, Brunak S, Nielsen HS. Chance of live birth: a nationwide,registry-based cohort study. Human reproduction (Oxford, England) 2021;36: 1065-1073.
- 20. Treatment of RPLwith genetic background Recommendation • All couples with results of an abnormal fetal or parental karyotype should receive genetic counselling. • Inform about the possible treatment options 1. PGT 2. Natural conception with prenatal testing 3. Gamete donation 4. Adoption Rationale • Very low quality of evidence • PGT-SR could reduce the miscarriage rate but will not improve live birth rate or time to pregnancy (Brezina et al., 2016). • Needs good-quality RCT with modern technology and methodology
- 21. Treatment of RPLwith Thrombophilia Recommendation Rationale Hereditary thrombophilia Antithrombotic ONLY • Research setting • VTE prophylaxis • Systematic review- no benefit of LMWH for prevention of pregnancy loss in hereditary thrombophilia (Skeith et al., 2016). Acquired thrombophilia (APS) Women who fulfil the laboratory criteria of APS and ≥3 pregnancy losses- • Low-dose aspirin (75 to 100 mg/day) starting before conception • prophylactic dose heparin (UFH, LMWH) after positive pregnancy test • Combination of heparin and aspirin improves LBR in women with APS and RPL to 80% (≥3 PLs, no evidence for 2PLs) (Hamulyák, et al., 2020; Middeldorp, 2014). • Continue until delivery
- 22. Treatment of RPLwith metabolic and endocrine abnormalities Recommendation Rationale Overt hypothyroidism before conception or during early gestation • treat with levothyroxine • Benefit overweighs risks Subclinical hypothyroidism (SCH) • Treatment may reduce the risk of miscarriage • Balance potential benefit of treatment against the risks. • Once pregnant, recheck TSH by 7-9 weeks • conflicting evidence Thyroid disorders Thyroid autoimmunity • Euthyroid- do not treat • Once pregnant, recheck TSH by 7-9 weeks • TABLET trial and T4life trial → L-T4 treatment does not increase the chance of a live birth in RPL and thyroid autoimmunity (Dhillon-Smith, et al., 2019, van Dijk, et al., 2022)
- 23. Other endocrine disorders Lutealphase insufficiency Progesterone- insufficient evidence to improve live birth hCG- insufficient evidence to improve live birth Ovulation induction in PCOS Evidence too limited Glucose metabolism defects Metformin- insufficient evidence to prevent pregnancy loss Vitamin D Preconception care – consider supplemental vitamin D (ACOG Committee Opinion No. 495: 2011, Del Valle et al., 2011). Treatment of RPL with metabolic and endocrine abnormalities
- 24. Treatment of RPLwith uterine abnormalities Recommendation Congenital disorders Septate uterus Septum resection- No benefit based on international, multicentre, open label, RCT (Rikken, et al., 2021) Bicorporeal uterus with normal cervix (former AFS bicornuate uterus) Metroplasty- Not recommended Hemi-uterus (former AFS unicornuate uterus) Uterine reconstruction- Not recommended Bicorporeal uterus and double cervix (former AFS didelphic uterus) Insufficient evidence Acquired disorders Submucosal fibroid Endometrial polyp Hysteroscopic removal- insufficient evidence Intramural fibroid Myomectomy- Not recommended Fibroid distorting uterine cavity Myomectomy- Insufficient evidence Intrauterine adhesion Hysteroscopic removal- Insufficient evidence
- 25. Treatment of RPLwith uterine abnormalities Recommendation H/O second-trimester losses s/o cervical weakness serial cervical sonographic surveillance. Cervical insufficiency Singleton pregnancy + H/O second-trimester recurrent loss attributable to cervical weakness, a cerclage could be considered. No evidence that this treatment increases perinatal survival. • Actual groups that benefit of cerclage include 1. ≥3 prior adverse events 2. Short cervix (<25 mm) + prior preterm birth (Story and Shennan, 2014). • Possible harms associated with any surgery • The GDG is cautious in the recommendations on cerclage for RPL, but strong in recommending ultrasound surveillance.
- 26. Lifestyle changes •Cessation of smoking • Normal body weight • Limited alcohol consumption • Normal exercise pattern Physiological intracytoplasmic sperm injection (PICSI) No evidence to support Antioxidants Does not increase livebirth rate Treatment of RPL with Male factor
- 27. Treatment of unexplainedRPL Recommendation Rationale Vaginal Progesterone • May improve live birth rate in women with ≥3 pregnancy losses and vaginal bleeding • BD 400 mg from <12 weeks to 16 weeks • A meta-analysis and a Cochrane review → benefit of progestogen on miscarriage rate and live birth rate (Haas, et al., 2019, Saccone, et al., 2017). • Oral dydrogesterone after fetal heart action is seen, may be effective. High doses of Intravenous immunoglobulin (IvIg) • May improve live birth rate in women with ≥4 unexplained RPL • 400 mg/kg for 5 consecutive days very early in pregnancy • High-quality RCT→ IvIG given in to women with ≥4 unexplained RPL increased the LBR significantly (OR 2.60; 95%CI 1.15-5.86) (Yamada et al., 2022).
- 28. Lymphocyte immunization therapy (LIT) Shouldnot be used • No significant effect • May be serious adverse effects Glucocorticoids Not recommended 1. Unexplained RPL 2. RPL with selected immunological biomarkers. Intralipid Insufficient evidence G-CSF No evidence Heparin ± Low dose aspirin Not recommended • Does not improve livebirth IVF+ PGT Insufficient evidence Endometrial scratch No evidence to recommend Low dose folic acid For prevention of NTD Not for RPL Treatment of unexplained RPL Not recommended
- 29. Psychological impact ofRPL • TLC- Only limited evidence- itself improves pregnancy outcome (Clifford et al., 1997, Liddell et al., 1997, Stray- Pedersen and Stray-Pedersen, 1984) • Even if not, it is hard to argue against this approach.
- 30. List of investigations •LA, ACA (IgG, IgM) ± aβ2GPI • TSH + anti-TPO • 3-D Ultrasound (otherwise SHG/ MRI) Routinely recommended • ANA • Sperm DNA fragmentation • a-CGH for pregnancy tissue Explanatory purpose • Parental karyotype • HLA class II→ Scandinavian women- secondary RPL after the birth of a boy Selective cases • Other immunological tests • Other metabolic/ endocrine markers Not recommended
- 31. Summary of treatment •Genetic counseling • Pros and cons of PGT Genetic defects • Aspirin before conception • LMWH after positive pregnancy test APS • Insufficient evidence on surgical correction Uterine anomaly • Serial surveillance in pregnancy • Cerclage in selective cases Cervical insufficiency • L thyroxine for overt hypothyroidism • Sublinical hypothyroidism- ? • Anti-TPO positive, euthyroid- ? Thyroid problem • Lifestyle changes • PICSI, Antioxidants- no role High sperm DNA fragmentation • No specific treatment ANA +ve HLA class II (DR, DQ) • Vaginal progesterone if ≥3 loss and vaginal bleeding • Consider IVIG if ≥4 loss • No role- LIT, steroid, intralipid, G-CSF, aspirin/ heparin, high dose folic acid, scratching, Unexplained
- 32. Grey areas • APSdiagnosed after 2 pregnancy loss • ANA positive or HLA-II (DR, DQ) • SCH, anti-TPO positive- conflicts with ATA guideline • Surgical correction of uterine defects • Cerclage- when, how • Hyperhomocysteinaemia • Unexplained RPL- progesterone and IVIG
- 33. Disclaimer • The aimof clinical practice guidelines is to aid healthcare professionals in everyday clinical decisions about appropriate and effective care of their patients. • However, adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. • Clinical practice guidelines do not override the healthcare professional's clinical judgment in diagnosis and treatment of particular patients. • The information provided in this document does not constitute business, medical or other professional advice, and is subject to change.