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Recurrent pregnancy loss: causes and diagnosis, myths and facts (evidence based)
- 1. RPL: Myths andfacts evidence-based Ali Bendary Assistant Lecturer Benha University Hospitals
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- 12. Scope • Definitions • Incidence •Candidates for evaluation • Causes • History and Ex • Investigations
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- 14. • Miscarriage: Spontaneous lossof clinically recognized pregnancies before the fetus reaches viability. • Viability: Includes all pregnancy losses from the time of conception until 24 weeks of gestation.
- 15. ≥3 • Recurrent miscarriage lossof three or more consecutive pregnancies
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- 17. We support allmothers who are living childless life due to miscarriage, stillbirth, neonatal death, as well as any other form of child loss.
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- 21. Relatively common, occursin about 10-15% of clinically recognized pregnancies under 20 weeks of gestation. Stirrat GM. Recurrent miscarriage. Lancet 1990; 336:673. • Should woman undergo extensive evaluation after a single first trimester or early second trimester spontaneous miscarriage? • There is a general consensus that healthy women should not undergo extensive evaluation after a single spontaneous miscarriage. why?
- 22. chemical pregnancies Ectopic and molar pregnancies DO YOU REMEMBER THE DEFINITION? Spontaneous loss of clinically recognized pregnancies before the fetus reaches viability not including confirmed by ultrasound histopathologic evaluation
- 23. Q1 • A 37-year-oldwomen is seen in clinic after her third consecutive early pregnancy loss. What is the most likely cause of recurrent miscarriage? a) Antiphospholipid syndrome b) Cervical factors c) Genetic causes d) Genital infections e) Uterine anatomical abnormality
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- 25. • Epidemiological • APLS •Anatomic • Genetic • Endocrine • Immune • Infection • Inherited thrombophilia • Male factor • Psychological • Unexplained
- 26. Clifford K etal., Future pregnancy outcome in unexplained recurrent first trimester miscarriage. Hum Reprod 1997 Apreviouslivebirthdoesnot precludeawomandeveloping recurrentmiscarriage.
- 27. Q2 • Incidence ofRPL in female patient 42 years old a) 15% b) 35% c) 50% d) 75% e) 90%
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- 30. 12–19 years 20–24 years 25–29 years 30–34 years 35–39 years 40–44 years ≥45 years 13% 11% 12%15% 25% 51% 93% Nybo Anderson AM et al., Maternal age and fetal loss: population based register linkage study. BMJ 2000 • Maternal age and number of previous miscarriages are two independent risk factors for a further miscarriage. 1. Advancing maternal age is associated with a decline in both the number and quality of the remaining oocytes.
- 31. N.B. Is advancedpaternal age identified as a risk factor for miscarriage?! The risk of miscarriage is highest among couples where - woman ≥35 years of age + - man ≥40 years of age de la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study. Hum Reprod 2002.
- 32. Q3 • A 39-yearold woman has been referred with a history of 3 consecutive miscarriages. The first 2 miscarriages occurred before 10 weeks and the third was at 12 weeks of gestation. She has no significant medical history, and no uterine abnormality were identified on a pelvic US scan. What is the risk of miscarriage in the next pregnancy for this woman? a) <10% b) 20% c) 30% d) 50% e) 60%
- 33. Toth B etal., Recurrent miscarriage: current concepts in diagnosis and treatment. J Reprod Immunol 2010; previous miscarriages Miscarriage rate (%) 3 34/119 (29%) 4 13/49 (27%) 5 7/16 (44%) ≥ 6 9/17 (53%) 2. Previous reproductive history is an independent predictor of future pregnancy outcome.
- 35. - Smoking, alcoholand caffeine consumption: a dose- dependent manner. - Anesthetic gases for theatre workers the evidence on the effect of is conflicting. - Obesity increases the risk of both sporadic and recurrent miscarriage. McGregor DG. Occupational exposure to trace concentrations of waste anesthetic gases. Mayo Clin Proc 2000 Metwally M et al., Body mass index and risk of miscarriage in women with recurrent miscarriage. Fertil Steril 2010 • Exposure to some environmental factors may cause sporadic rather than recurrent miscarriage.
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- 38. aPLsantibodies • A heterogenousgroup of antibodies directed against phospholipids and/or phospholipid binding proteins. • The commonest detected aPLs are: - Anticardiolepin (aCL) - Lupus anticoagulant (LA)
- 40. 1. aPL bindingwith phospholipids may interfere with the coagulation cascade pro-coagulant. pathophysiology The in Vivo mechanisms responsible for thrombosis and fetal loss are uncertain, But several pathways are suggested: 2. Annexin-V (anticoagulant on normal placental villi) is ↓ with aPL placental thrombosis and infarction.
- 42. 3. aPL affecttrophoblast differentiation, proliferation and invasion impaired implantation.
- 43. 4. in themouse model, the mechanism of APLS pregnancy loss is complement activation not thrombosis.
- 44. Pregnancy complications ↓ is related to antibodytitre, especially IgG aCL Thrombosis ↓ is more strongly associated with LA than with aCL.
- 45. Q4 • A 28-year-oldwoman para 0+3 known to have antiphospholipid syndrome who never took treatment of her condition. What is the possibility of live birth rate of her next pregnancy without pharmacological intervention? a) 10% b) 30% c) 50% d) 70% e) 90%
- 46. Incidence of RPL of SLEpatients - Most APS patients do not fulfill the diagnostic criteria for SLE - Most 1ry APLS do not progress to SLE Rai RS et al., High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod 1995 In women with APLS + RPL LBR without ttt 10% 15% 30%
- 47. • of patientwith thrombosis. • of sever, early onset pre-eclampsia (may develop as early as 15 weeks) • Risk of FGR • Risk of PTL in those with SLE, previous thrombosis or late fetal death 30% 30%
- 48. TypesofAPLS Occurs alone Associatedwith other conditions, mainly SLE 1. Primary 2. Secondary
- 50. Presence of aPL (eitheraCL &/or LA) on 2 separate occasion at least …. wks apart RCOG 6 wks ASRM 12 wks • Anti-ß2GP1 are more specific for APLS but there is poor lab standarization 1. Thrombosis (venous, arterial , microcirculation) 2. Pregnancy morbidity i.e: • ≥ 3 consecutive miscarriage <10wks • ≥ 1 fetal death >10wks • ≥ 1 preterm birth <34wks with normal fetal morphology due to pre-eclampsia or placental insufficiency. Criteriafordiagnosis (at least 1 lab & 1 clinical) Clinical Laboratory
- 51. • Other clinicalfeatures: - Autoimmune throbocytopnia (ITP), hemolytic anemia - Cerebral involvement: epilepsy, cerebral infarction, chorea, migraine, transverse myelitis. - Heart valve involvement (particularly mitral) - Systemic and pulmonary hypertension. - Leg ulcers.
- 52. APTT dRVVT LaboratorycriteriaforaPL • LA requires2 phospholipid-dependent coagulation tests. Addition of normal plasma fails to correct prolonged time Addition of excess phospholipid correct prolonged time Both prolonged • aCL measured using commercially avialable enzyme-linked immunosorbent assay (ELISA) kits.
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- 54. 1. CONGENITAL 2. ACQUIRED 3.CERVICAL WEAKNESS
- 55. 1. Congenital • Prevalenceof uterine anomalies in recurrent miscarriage • delivery rates of miscarriage and preterm delivery in women with untreated uterine anomalies Salim R et al., A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first trimester miscarriage. Hum Reprod 2003 50% 12.6%
- 58. Incidence of pregnancyloss septate bicornuate arcuate 44.3% loss 36.0% loss 25.7% loss in particular Correction of septate defects may have beneficial effects live birth rate 83.2% should be considered in women with RPL. Grimbizis GF et al., Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update 2001 More likely to miscarry in 1st T More likely to miscarry in 2nd T
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- 60. • The clinicalmanagement of pregnancy-loss patients with Asherman syndrome, uterine fibroids, and uterine polyps is also controversial • There is no conclusive evidence that surgical treatment reduces the risk of pregnancy loss.
- 61. • General consensusis: surgical correction of significant uterine cavity defects should be considered.
- 62. 3. Cervical weakness History?! Ultrasound ?! Pre- pregnancy diagnostic tests ?!
- 63. History?! • History-indicated cerclageshould be offered to women with ≥ 3 previous PTL and/or 2nd trimester losses.
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- 65. • aimed atdiagnosing ‘cervical weakness’ include - assessment of cervical resistance index - hysterography - insertion of cervical dilators. in women with a history of PTL and/or 2nd trimester loss insufficient evidence to recommend the use of these techniques Pre-pregnancydiagnostic techniques?!
- 66. TVUS between 16+0and 24+0 weeks reveals a cervical length < 25 mm. + history of spontaneous PTL or 2nd trimester loss between 16+0 and 34+0 weeks of pregnancy Offer a choice of either prophylactic vaginal progesterone or prophylactic cervical cerclage Ultrasound?!
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- 69. TVUS between 16+0and 24+0 weeks reveals a cervical length < 25 mm. + either P-PROM in a previous pregnancy or History of cervical trauma Offer a choice of prophylactic cervical cerclage
- 70. Q5 • A 20-year-oldPG has an incidental finding of cervical length of 20 mm at her routine routine 20- week anomaly scan. She is asymptomatic and has no significant past medical or surgical history. What is the most appropriate management? a) Abdominal cerculage b) Cervical cerculage c) Counsel the women that no further action is required d) Progesterone pessaries e) Serial ultrasound scan to assess cervical length
- 71. cerclage is notrecommended • incidentally identified short cervix of 25 mm or less without a history of spontaneous preterm delivery or second-trimester loss? • funnelling of the cervix (dilatation of the internal os on ultrasound) in the absence of cervical shortening to 25 mm or less? cerclage is not recommended
- 74. Q6 • A 28-year-oldnulliparous woman has had 2 consecutive miscarriage in the first trimester. She is referred with a further incomplete miscarriage What is the most appropriate genetic test to perform? a) karyotype both partners. b) Karyotype chorionic villus sample in next pregnancy c) Karyotype mother d) Karyotype father e) Karyotype products of conception
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- 76. • There isa very high frequency of sporadic karyotypic abnormalities (60%) in products of conception while incidence of karyotypic abnormalities in the parents is low. Stephenson MD et al., Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study. Hum Reprod 2002 60%
- 77. • 2–5% ofcouples with RPL , one of the partners carries a balanced structural chromosomal anomaly: Stephenson MD, Sierra S. Reproductive outcomes in RPL associated with a parental carrier of a structural chromosome rearrangement. Hum Reprod 2006 2-5% - balanced reciprocal - Robertsonian translocation
- 78. • Although carriersof a balanced translocation are usually phenotypically normal their pregnancies are at ↑ risk of miscarriage, CFMF and mental disability.
- 79. • Cytogenetic analysisshould be performed on products of conception (RCOG, class D) • Parental peripheral blood karyotyping of both partners should be performed in couples with RPL (RCOG, class D) • Testing of products of conception reports an unbalanced structural chromosomal abnormality. • The third and subsequent consecutive miscarriage(s)
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- 81. 1. thyroid dysfunction: •This is problematic given the lack of consensus regarding the definition of a normal upper limit of TSH. • Whereas TSH values of 4.0–5.0 mIU/L were once considered normal, a consensus is emerging that TSH values > 2.5 mIU/L are outside the normal range.
- 82. • As longas thyroid-stimulating hormone (TSH) levels are in the normal range there is insufficient evidence to recommend: - Thyroxine (T4) testing - Screening for anti-thyroid antibodies. Abalovich M et al., Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007
- 83. 2. Diabetes • Well-controlleddiabetes is not a risk factor for RPL. • Uncontrolled diabetes is associated with increased pregnancy loss
- 84. 3. Polycystic ovarysyndrome (PCOS) has been linked to an increased risk of miscarriage but the exact mechanism remains unclear. - insulin resistance and hyperinsulinaemia - hyperandrogenaemia.
- 85. 4. Hyperprolactinemia: may beassociated with recurrent pregnancy loss through: alterations in the hypothalamic-pituitary-ovarian axis Impaired folliculogenesis and oocyte maturation Short luteal phase.
- 86. • Normalization ofprolactin levels with a dopamine agonist improved subsequent pregnancy outcomes in patients with recurrent pregnancy loss Treated group untreated group Live-birth rate 85.7% 52.4% Hirahara F et al.,Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials. Fertil Steril 1998
- 87. 5. luteal phasedefect: • Problematic. • The use of histologic and biochemical endpoints as diagnostic criteria for endometrial dating are unreliable Coutifaris C et al., Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril 2004 Therefore, routine endometrial biopsy for dating is not recommended
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- 89. • Studies of -Human leukocyte antigen (HLA) typing - Embryotoxic factors - Decidual cytokine profiles - Blocking or antipaternal antibody levels - HLA-G polymorphism immunologic factors have produced inconsistent data that generally have not been reproduced in more than one laboratory. Proposed immuno-modulatory treatments for RPL in the setting of one or more of these findings have not been proven effective.
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- 91. Q7 • From thefollowing infective casues, which has been strongly related to preterm labor and 2nd T miscarriage? a) Toxoplasmosis b) Rubella c) Listeria d) CMV e) Bacterial vaginosis
- 92. • Any severeinfection that leads to bacteraemia or viraemia can cause sporadic miscarriage. • The role of infection in recurrent miscarriage is unclear.
- 93. • For aninfective agent to be implicated in the etiology of RPL, it must be capable of: - persisting in the genital tract - avoiding detection - must cause insufficient symptoms to disturb the woman. Toxoplasmosis, rubella, cytomegalovirus, herpes and listeria infections do not fulfill these criteria Routine TORCH screening should be abandoned MacLean AB et al., Infection and pregnancy loss. London: RCOG Press; 2001
- 94. What about BACTERIALVAGINOSIS ?!!
- 95. • The presenceof bacterial vaginosis in the first trimester of pregnancy has been reported as a risk factor for 2nd T miscarriage and PTL. • the evidence for an association with first trimester miscarriage is inconsistent. Leitich H, Kiss H. Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome. Best Pract Res Clin Obstet Gynaecol 2007
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- 97. • inherited thrombophiliashave been implicated as a possible cause in - Recurrent miscarriage - Late pregnancy complications The presumed mechanism being thrombosis of the uteroplacental circulation
- 98. - prothrombin genemutation 20210 - antithrombin III deficiency - Factor V Leiden mutation - deficiencies of protein C/S - hyperhomocysteinaemia - Methylenetetrahydrofolate mutation
- 99. • The associationbetween thrombophilia and late pregnancy loss has been consistently stronger than for early pregnancy loss. recurrent 1st T fetal loss recurrent 2nd T fetal loss factor V Leiden OR 2.01 OR 7.83 Prothrombin gene mutation OR 2.32 OR 2.56 Protein S deficiency OR 14 Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003
- 100. • Women with2nd T miscarriage should be screened for inherited thrombophilias including: - Factor II (prothrombin) gene mutation - Factor V Leiden - protein S deficiency (RCOG, class D)
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- 103. • Standard semenparameters, including sperm morphology, do not appear to be predictive of recurrent pregnancy loss.
- 104. • Abnormal DNAfragmentation may be seen in the setting of - advanced paternal age - exogenous heat - toxic exposures - varicoceles
- 106. Benchaib M etal.,Sperm deoxyribonucleic acid fragmentation as a prognostic indicator of ART outcome. Fertil Steril 2007 • Currently, there are contradictory data regarding a causal effect between pregnancy loss and fragmentation of sperm DNA in IVF cycles.
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- 108. Recurrent pregnancy loss patients areprone to: - Anger - Depression - Anxiety - grief and guilt.
- 109. • TLC wasdefined as: - psychological support - weekly medical and ultrasonographic examinations - instructions to avoid heavy work, travel, and sexual activity.
- 110. A cohort of158 couples with 3 consecutive pregnancy losses and no otherwise identifiable etiology were divided into 2 groups One receiving routine care during the next pregnancy (n =42) Live birth rate: The other additionally receiving tender-loving care (TLC) (n =116) Live birth rate 36% 85% Sugiura-Ogasawara M et al., Depression as a potential causal factor in subsequent miscarriage in recurrent spontaneous aborters. Hum Reprod 2002
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- 114. History Should include adescription of: - characteristics (eg, anembryonic pregnancy, live embryo) of all previous pregnancies. - Gestational age RPL typically occurs at a similar gestational age in consecutive pregnancies and the most common causes of RPL vary by trimester.
- 115. As an example, Miscarriage relatedto - chromosomal - endocrine defects Losses due to - anatomic - immunological abnormalities tends to occur earlier in gestation than However, there is significant overlap
- 116. Is there exposureto environmental toxins, which may be lethal to developing embryos? Has there been uterine instrumentation, which may have caused intrauterine adhesions? Additionalinformationtoconsider: Is there a history of venous or arterial thrombosis suggestive of antiphospholipid syndrome? What information is available from previous laboratory, pathology, and imaging studies? Are the menstrual cycles normal? Abnormalities in cycle length may be due to endocrine dysfunction. Is there galactorrhea, which also suggests endocrine dysfunction (hyperprolactinemia)?
- 117. Physical examination • shouldinclude - General physical assessment with attention to signs of endocrinopathy (eg, hirsutism, galactorrhea) - Pelvic organ abnormalities (eg, uterine malformation).
- 118. Mental health evaluation RPLis a source of great stress for couples. One study of 301 women with RPL reported: - fourfold higher rates of depression (8.6 versus 2% in women without RPL) - doubling of severe stress (41 versus 23% in women without RPL) Kolte AM, Olsen LR, Mikkelsen EM, et al. Depression and emotional stress is highly prevalent among women with recurrent pregnancy loss. Hum Reprod 2015
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- 127. Incidence of contributingcauses to RPL
- 128. • Women shouldnot undergo extensive evaluation after a single first trimester or early second trimester spontaneous miscarriage • We evaluate women for recurrent pregnancy loss (RPL) after three consecutive miscarriages. • The history should include a description of - gestational age (RPL typically occurs at a similar gestational age) - characteristics (eg, anembryonic pregnancy, live embryo) of all previous pregnancies.
- 129. Additional testing dependsupon the diagnosis suggested by the history, physical examination, and laboratory results. • Vaginal scan, 3D-TVUS, Sonohysterography or hyseroscopy for assessment of uterine abnormalities • Anticardiolipin antibody (IgG and IgM) titer and lupus anticoagulant performed twice, six weeks apart • Thyroid stimulating hormone (TSH), prolactin and HbA1C • karyotype of the abortus and Parental karyotype if the above examinations are normal. The following tests are recommended for the initial evaluation of women with RPL: