EVALUATION OF RECURRENT PREGNANCY LOSS

An Evidence Based Approach

John A. Schnorr, M.D.Coastal Fertility Specialists

Medical University of South Carolina

• 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

Recurrent Pregnancy LossIncidence of Miscarriages

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)

Jaslow and Kutteh . Fertil Steril 93: 2010.

2.8

18.7

5

15.6

4.2

8.1

GeneticsUterineLACACAFVLTSH

5.4

18.2

2.9

13.1

8.1

6.5

Two Three

Recurrent Pregnancy LossEtiology Primary versus Secondary

Etiology (n=1017)

Jaslow and Kutteh . Fertil Steril 86:S472 2006.

3.3

20.5

24.2

24

6.5

21.5 GeneticsAnatomicEndocrineImmuneMicrobesUnknown

2.8

23.4

21.426.8

4.8

20.8

Primary Secondary

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

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 LossRisk Factors for Miscarriage

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.

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 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

Recurrent Pregnancy Loss Anatomic Causes

• Congenital (Mullerian anomalies):

– Uterine Sepum

– Bicornuate Uterus

– Unicornuate Uterus

• Acquired:

– Fibroids

– Asherman’s Syndrome

Congenital Uterine Anomalies

Uterine Septum on MRI

Uterine Septum at Hysteroscopy

Recurrent Pregnancy Loss Uterine Septum

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.

• 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%

Recurrent Pregnancy Loss Asherman’s Syndrome

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

• 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

Recurrent Pregnancy Loss Uterine Fibroids

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.

• 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

Recurrent Pregnancy Loss Submucus Uterine Fibroids

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.

• Submucus fibroids can cause miscarriage and infertility. Should be resected, ideally hysteroscopically.– Recurrence rate higher if >

10mm intramural depth

Antiphospholipid Antibody Syndrome Its Not Just Anticoagulation

Girardi,etal.Nature Med 10:1222-1226, 2005.

• Inhibition hCG release from placental explants

• Blockage of in vitro cytotrophoblast fusion, migration, invasion, and giant multinucleated cell formation

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.

Diagnosis of APS, ACOG 2011

ACOG Practice Bulletin, Number 118, January 2011

• 1. Patient must have one or more of the clinical criteria

and

• 2. Fulfill the laboratory criteria

Clinical Criteria for the Diagnosis of APS, ACOG 2011

ACOG Practice Bulletin, Number 118, January 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

Laboratory Criteria for the Diagnosis of APS, ACOG 2011

ACOG Practice Bulletin, Number 118, January 2011

• At least one of the below must be positive on two occasions greater than 12 weeks apart1. Lupus anticoagulant2. Anticardiolipin antibody IgG or IgM greater than 40

GPL3. Anti-β2-glycoprotein I (in titer greater than 99th

percentile for abnormal population as defined by the laboratory

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 OptionsAntiphospholipid Antibody Syndrome

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%

Treatment # Treated Liveborn

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 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

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 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 Obstet Gynecol 2008;198:279.e1-279.e8.

•Am J Obstet Gynecol 2008;198:279.e1-279.e8.

Diagnosis and Therapy of RPL

Anatomic HSG, SHSG Surgery

Endocrine TSH, Prl, FSH Hormone

Immune APA,LAC, UF HepBeta 2 Gly ASA

Genetic Karyotype PGD

Etiology Diag. Eval. Therapy

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

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)