EVALUATION OF RECURRENT PREGNANCY LOSS An Evidence Based Approach John A. Schnorr, M.D. Coastal Fertility Specialists Medical University of South Carolina
Recurrent Pregnancy LossIncidence of Miscarriages • 30 to 50% of all conceptions • 15% of all clinically recognized pregnancies • Above 40 years of age clinical SAB risk is as high as 45% • RPL effects up to 5% of all people
Fertility and Sterility, December 2012, American Society for Reproductive Medicine
Recurrent Pregnancy LossWhen to Start the Work-up? • Typically three SABs makes the diagnosis; clinical evaluation can start at 2 SABs • Two or more (ACOG, ASRM) • Need to be confirmed by • BHCG titers, or • Pathology, or • Ultrasound ASRM Practice Bulletin, 2012
Recurrent Pregnancy LossEtiology Two versus Three SAB’s Etiology (n=1021) Two Three Jaslow and Kutteh . FertilSteril93: 2010.
Recurrent Pregnancy LossEtiology Primary versus Secondary Etiology (n=1017) Primary Secondary Jaslow and Kutteh . FertilSteril86:S472 2006.
Recurrent Pregnancy LossRisk Factors for Miscarriage • Increasing maternal age • Past obstetrical history • Tobacco use 1.4 to 1.8 fold increased risk
Second hand smoke 1.52 to 2.18 increased risk Alcohol use 4.84 increased risk Caffeine use > 200 mg/day 1.54 to 3.85 increased risk Recurrent Pregnancy LossRisk Factors for Miscarriage Weng X, Odouli R, and Li D-K. Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study. Am J ObstetGynecol 2008;198:279.e1-279.e8.
Recurrent Pregnancy Loss Evaluation • Genetic • Endocrinologic • Anatomic • Immunologic • Environmental
Recurrent Pregnancy Loss Causes of RPL in 1017 Women Abnormalities Number Percent None 319 31.4% One 413 40.6% Two 227 22.3% Three 44 4.3% Four 121.2% Five 20.2% Jaslow and Kutteh. FertilSteril 86: S472, 2006.
Recurrent Pregnancy Loss LutealPhase Defect • May effect up to 20% of all RPL patients • Endometrial biopsies are not recommended • Inter and intra-observer variation high • Frequent finding of out of phase endometrium in fertile women • Serum P4 levels not predictive • Empiric treatment recommended: Prometrium® 200mg PV QHS starting 4 days after LH surge
Recurrent Pregnancy Loss Prolactin and Thyroid Hyperprolactinemia Elevated levels in women with unexplained RPL versus controls Causes follicular and luteal phase dysfunction Cause of luteal phase defect Bromocriptine improved SAB rates in patients with elevated prolactin levels BussenS, S€utterlin M, Steck T. Endocrine abnormalities during the follicular phase in women with recurrent spontaneous abortion. Hum Reprod 1999;14:18–20. HiraharaF, Andoh N, Sawai K, Hirabuki T, Uemura T, Minaguchi H. Hyperprolactinemicrecurrent miscarriage and results of randomized bromocriptine treatment trials. FertilSteril 1998;70:246–52.
Negro, et al. in 2010 performed a prospective trial, 4,123 patients. No intervention SAB rate if: TSH < 2.5 3.6% TSH 2.5 to 5.0 6.1% P= 0.006 No data yet on if treatment helps… No effect on preg rates in infertile patients Recurrent Pregnancy Loss Hypothyroidism Negro, et al. Increased Pregnancy Loss Rate in Thyroid Antibody Negative Women with TSH Levels between 2.5 and 5.0 in the First Trimester of Pregnancy J. Clin. Endocrinol. Metab. 2010 95
Recurrent Pregnancy Loss Anatomic Causes • Congenital (Mullerian anomalies): • Uterine Sepum • Bicornuate Uterus • Unicornuate Uterus • Acquired: • Fibroids • Asherman’s Syndrome
Recurrent Pregnancy Loss Uterine Septum • Reproductive outcomes of 127 patients with a uterine septum and otherwise unexplained infertility Tonguc, E. A., T. Var, et al. (2011). "Hysteroscopicmetroplasty in patients with a uterine septum and otherwise unexplained infertility." Int J GynaecolObstet113(2): 128-130.
Recurrent Pregnancy Loss Asherman’s Syndrome • Yu et al.evaluated hscopeadhesiolysis in 85 women with Asherman's Syndrome • After surgery live birth in women amenorrheic 18.2% vs those with menses 50%. P< 0.05 • At second look hscope, the live birth rate in women who had reformation of adhesions 11.8% vs normal cavity 59.1%. P< 0.05 Yu, D., T. C. Li, et al. (2008). "Factors affecting reproductive outcome of hysteroscopicadhesiolysis for Asherman's syndrome." FertilSteril89(3): 715-722
Recurrent Pregnancy Loss Uterine Fibroids • Controversial issue, literature full of poorly controlled studies… • Subserosalmyomas little, if any, effect on reproductive outcome • Intramural myomas less than 4 cm that do not encroach upon the endometrium unlikely to effect reproduction Kolankaya, A. and A. Arici (2006). "Myomas and assisted reproductive technologies: when and how to act?" ObstetGynecolClin North Am 33(1): 145-152.
Recurrent Pregnancy Loss Submucus Uterine Fibroids • Submucus fibroids can cause miscarriage and infertility. Should be resected, ideally hysteroscopically. • Recurrence rate higher if > 10mm intramural depth Kolankaya, A. and A. Arici (2006). "Myomas and assisted reproductive technologies: when and how to act?" ObstetGynecolClin North Am 33(1): 145-152.
Antiphospholipid Antibody Syndrome Its Not Just Anticoagulation • Inhibition hCG release from placental explants • Blockage of in vitro cytotrophoblast fusion, migration, invasion, and giant multinucleated cell formation Girardi,etal.Nature Med 10:1222-1226, 2005.
Antiphospholipid Antibody SyndromeIts Not Just Anticoagulation • Inhibition of trophoblast cell adhesion molecules (alpha 1 and 5 integrins, E and VE cadherins) • Activates complement on the trophoblast surface inducing an inflammatory response Girardi,etal.Nature Med 10:1222-1226, 2005.
Diagnosis of APS, ACOG 2011 • 1. Patient must have one or more of the clinical criteria and • 2. Fulfill the laboratory criteria ACOG Practice Bulletin, Number 118, January 2011
Clinical Criteria for the Diagnosis of APS, ACOG 2011 • 1. History of vascular thrombosis • 2. Pregnancy morbidity a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, b) eclampsia or severe preeclampsia before the 34th week of gestation c) Three or more unexplained consecutive pregnancy losses before the 10th week ACOG Practice Bulletin, Number 118, January 2011
Laboratory Criteria for the Diagnosis of APS, ACOG 2011 • At least one of the below must be positive on two occasions greater than 12 weeks apart 1. Lupus anticoagulant 2. Anticardiolipin antibody IgG or IgM greater than 40 GPL 3. Anti-β2-glycoprotein I (in titer greater than 99th percentile for abnormal population as defined by the laboratory ACOG Practice Bulletin, Number 118, January 2011
Treatment OptionsAntiphospholipid Antibody Syndrome • None • Aspirin • Prednisone + Aspirin • Heparin + Aspirin • Intravenous gammaglobulin
Low Molecular Weight vsUnfractionated Heparin Ziakas, P. D., M. Pavlou, et al. (2010). "Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis." ObstetGynecol115(6): 1256-1262.
Treatment OptionsAntiphospholipid Antibody Syndrome Treatment# Treated Liveborn None 33/166 20% Aspirin (80mg/d) 39/81 48% Prednisone+ Asp 82/145 57% IV Immunoglobulin 91/141 64% UF Heparin + Asp 114/151 75% ASRM Guidelines: Unfractionated heparin recommended as comparable efficacy low molecular weight heparin had not be established.
Recurrent Pregnancy LossInherited Thrombophilia Testing… • Controversial issue with few if any good quality studies for guidance.
Maternal Thrombophilias are not associated with early pregnancy loss.Roque et al ThrombHaemost 91:290-5, 2004 • Goal: Is there an impact prior to development of intravillous circulation? • Patients: • n = 491 • NYU Faculty Practice ‘95-’01 • Evaluated for 9 thrombophilias at 12-17 wks • pts with RPL (>2), PIH, IUGR, 2nd/3rd trimester loss, abruption, PTD • Excluded uterine anomalies, DM, renal dz CHTN, mult. Gestation, heparin/ASA use • 133 women with thrombophilias: • 225 first trimester losses in 596 pregnancies (37.7% loss rate) • 36.4% prior to 10 wks • 63.6% 10-14 wks
Maternal Thrombophilias are not associated with early pregnancy loss.Roque et al ThrombHaemost 91:290-5, 2004
Who do you test?: ACOG RecommendationsACOG Practice Bulletin 124, September 2011 • Women with a personal history of thrombosis, or a first degree relative with thrombosis at age < 50 yo should be offered testing for hereditary thrombophilias
Testing for inherited thrombophilias in women who have experienced recurrent fetal loss or placental abruption is not recommended. • Although there may be an association in these cases, there is insufficient clinical evidence that antepartum prophylaxis with unfractionated heparin or low molecular weight heparin (LMWH) prevents recurrence in these patients
Social HabitsIncreased SAB Risk • Increase risk 1.5 - 2 fold • Tobacco (>15/day) • 2nd Hand Smoke • Ethanol (> 4x/week)
Social HabitsIncreased SAB Risk with Caffeine • Prospective study of 1,063 pregnant patients. Weng X, Odouli R, and Li D-K. Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study. Am J ObstetGynecol 2008;198:279.e1-279.e8. • Am J ObstetGynecol 2008;198:279.e1-279.e8.
Diagnosis and Therapy of RPL Etiology Diag. Eval. Therapy Anatomic HSG, SHSG Surgery Endocrine TSH, Prl, FSH Hormone ImmuneAPA,LAC, UF Hep Beta 2 Gly ASA GeneticKaryotypePGD
Diagnosis and Therapy of RPL ThromboticTesting not recommended… ProgesteronePrometrium200mg PV QHS start 4 days after LH surge Microbiologic Testing/treatment not recommended Environment Eliminate TOB/ETOH/Caffeine
Unhelpful in the Evaluation of RPL • Antithyroid Antibodies if normal TSH • Endometrial Biopsies • Natural Killer Cells • ANA • Embryotoxicity assay • Immunophenotyping • Inherited Thrombophilia’s