RECURRENT PREGNANCY LOSS EVALUATION OF RECURRENT PREGNANCY LOSS An Evidence Based Approach These evaluations are a challenge because it involves a variety of systems that need to be evaluated. Genetic, endocrine, anatomic, immunologic, microbiologic, thrombophilic, environmental and iatrogenic. John A. Schnorr, M.D. Coastal Fertility Specialists Medical University of South Carolina

Recurrent Pregnancy Loss Incidence 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 Using high sensitivity BhCG assay systems we can detect pregnancy as early as 9 days after ovulation. Risk is much higher for older women due to increased risk for trisomic pregnancies.

Fertility and Sterility, December 2012, American Society for Reproductive Medicine

Recurrent Pregnancy Loss When 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 Loss Etiology Two versus Three SAB’s Etiology (n=1021) Two Three My approach is based on the anxiety of the patient and the timing of the miscarriages with early biochemical miscarriages being less concerning. Jaslow and Kutteh . Fertil Steril 93: 2010.

Recurrent Pregnancy Loss Etiology Primary versus Secondary Etiology (n=1017) Primary Secondary My approach is based on the anxiety of the patient and the timing of the miscarriages with early biochemical miscarriages being less concerning. Jaslow and Kutteh . Fertil Steril 86:S472 2006.

Recurrent Pregnancy Loss Risk Factors for Miscarriage Increasing maternal age Past obstetrical history Tobacco use 1.4 to 1.8 fold increased risk Increased risk for trisomic pregnancies

Recurrent Pregnancy Loss Risk Factors for Miscarriage 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 Weng X, Odouli R, and Li D-K. Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study. Am J Obstet Gynecol 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 12 1.2% Five 2 0.2% Jaslow and Kutteh. Fertil Steril 86: S472, 2006.

Recurrent Pregnancy Loss Luteal Phase 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 Bussen S, S€utterlin M, Steck T. Endocrine abnormalities during the follicular phase in women with recurrent spontaneous abortion. Hum Reprod 1999;14:18–20. Hirahara F, Andoh N, Sawai K, Hirabuki T, Uemura T, Minaguchi H. Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials. Fertil Steril 1998;70:246–52.

Recurrent Pregnancy Loss Hypothyroidism 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 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 Restart here.

Congenital Uterine Anomalies

Uterine Septum on MRI

Uterine Septum at Hysteroscopy

Recurrent Pregnancy Loss Uterine Septum Reproductive outcomes of 127 patients with a uterine septum and otherwise unexplained infertility Conception SAB LBR Metroplasty 43.1% 11.4% 35% No Surgery 20% 60% 8% Tonguc, E. A., T. Var, et al. (2011). "Hysteroscopic metroplasty in patients with a uterine septum and otherwise unexplained infertility." Int J Gynaecol Obstet 113(2): 128-130.

Recurrent Pregnancy Loss Asherman’s Syndrome Yu et al. evaluated hscope adhesiolysis 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 hysteroscopic adhesiolysis for Asherman's syndrome." Fertil Steril 89(3): 715-722

Recurrent Pregnancy Loss Uterine Fibroids Controversial issue, literature full of poorly controlled studies… Subserosal myomas 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?" Obstet Gynecol Clin 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?" Obstet Gynecol Clin North Am 33(1): 145-152.

Its Not Just Anticoagulation 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 Inhibits cytotrophoblast fusion, invasion and differentation Girardi,etal.Nature Med 10:1222-1226, 2005.

Antiphospholipid Antibody Syndrome Its 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.

ACOG Practice Bulletin, Number 118, January 2011 Diagnosis of APS, ACOG 2011 1. Patient must have one or more of the clinical criteria and 2. Fulfill the laboratory criteria I personally do not believe in empiric use of Heparin and Aspirin 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 I personally do not believe in empiric use of Heparin and Aspirin 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 I personally do not believe in empiric use of Heparin and Aspirin ACOG Practice Bulletin, Number 118, January 2011

Treatment Options Antiphospholipid Antibody Syndrome None Aspirin Prednisone + Aspirin Heparin + Aspirin Intravenous gammaglobulin

Low Molecular Weight vs Unfractionated Heparin Ziakas, P. D., M. Pavlou, et al. (2010). "Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis." Obstet Gynecol 115(6): 1256-1262.

Treatment Options Antiphospholipid 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 Loss Inherited Thrombophilia Testing… Controversial issue with few if any good quality studies for guidance. Whereas meta-analyses and a retrospective cohort study have revealed an association between inherited thrombophilias and first-trimester pregnancy loss, (30-34) prospective cohort studies have found no association between inherited thrombophilias and fetal loss. The Eunice Kennedy Shriver National Institute of Child Health and Human Development's Maternal-Fetal Medicine Units Network tested low-risk women with a singleton pregnancy less than 14 weeks of gestation. The Maternal-Fetal Medicine Units Network identified 134 women who were heterozygous for factor V Leiden among 4,885 pregnant women, and found no increase in the incidence of fetal loss (35). Similar findings of no increased risk of fetal loss were noted for maternal carriers of the prothrombin G20210A gene mutation (36).

Maternal Thrombophilias are not associated with early pregnancy loss Maternal Thrombophilias are not associated with early pregnancy loss. Roque et al Thromb Haemost 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

Prothrombin Gene Mutation G20212A Maternal Thrombophilias are not associated with early pregnancy loss. Roque et al Thromb Haemost 91:290-5, 2004 Thrombophilia RPL < 10 wks RPL 10-14 wks Losses after 14 wks Factor V Leiden 0.229 (0.03-1.66) 1.07 (0.46-2.5) 3.71 (1.68-8.23) Prothrombin Gene Mutation G20212A 0.21 (0.03-1.67) 0.37 (0.08-1.74) 2.47 (0.71-8.65) Fasting Homocysteine 0.23 (0.03-1.81) 1.12 (0.32-3.89) 2.37 (0.66-8.44) Protein C 0.58 (0.06-5.26) 2.13 (0.34-13.05) 1.16 (0.13-10.62) Protein S 0.54 (0.2-1.49) 0.103 (0.01-1.77) 2.5 (1.04-6.01) ATIII - 1.88 (0.53-6.63) 0.39 (0.05-3.14) >1 thrombophilia 0.48 (0.29-0.78) 1.66 (1.03-2.68) 3.68 (2.26-6.59)

Who do you test?: ACOG Recommendations ACOG 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 Habits Increased SAB Risk Increase risk 1.5 - 2 fold Tobacco (>15/day) 2nd Hand Smoke Ethanol (> 4x/week)

Social Habits Increased 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 Obstet Gynecol 2008;198:279.e1-279.e8. Am J Obstet Gynecol 2008;198:279.e1-279.e8.

Diagnosis and Therapy of RPL Etiology Diag. Eval. Therapy Anatomic HSG, SHSG Surgery Endocrine TSH, Prl, FSH Hormone Immune APA,LAC, UF Hep Beta 2 Gly ASA Genetic Karyotype PGD

Diagnosis and Therapy of RPL Thrombotic Testing not recommended… Progesterone Prometrium 200mg 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

# previous Miscarriages Predicted Chance of Success in Subsequent Pregnancy According to Age and Previous Miscarriage History Brighan SA, Conlon C, Farquharson RG. Hum Reprod 14:2868, 1999 % Live Births (95% CI) Age # previous Miscarriages (unexplained) 2 (n=79) 3 (n=157) 4 (n=43) 5 (n=25) 20 92 (86-98) 90 (83-97) 88 (79-96) 85 (74-96) 25 89 (82-95) 86 (79-93) 82 (75-91) 79 (68-90) 30 84 (77-90) 80 (74-86) 76 (69-83) 71 (61-81) 35 77 (69-85) 73 (66-80) 68 (60-75) 62 (51-74) 40 69 (57-82) 64 (52-76) 58 (45-71) 52 (37-67 45 60 (41-79) 54 (35-72) 48 (29-67) 42 (22-62)