1. 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

2. 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.

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

4. 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

5. 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.

6. 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:S

7. 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

8. Recurrent Pregnancy Loss Risk Factors for Miscarriage
Second hand smoke 1.52 to increased risk
Alcohol use 4.84 increased risk
Caffeine use > 200 mg/day 1.54 to 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.

9. Recurrent Pregnancy Loss Evaluation
Genetic
Endocrinologic
Anatomic
Immunologic
Environmental

10. Recurrent Pregnancy Loss Causes of RPL in 1017 Women
Abnormalities Number Percent
None %
One %
Two %
Three %
Four %
Five %
Jaslow and Kutteh. Fertil Steril 86: S472, 2006.

11. 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

12. 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.

13. Recurrent Pregnancy Loss Hypothyroidism
Negro, et al. in 2010 performed a prospective trial, 4,123 patients.
No intervention
SAB rate if:
TSH < %
TSH 2.5 to % 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

14. Recurrent Pregnancy Loss Anatomic Causes
Congenital (Mullerian anomalies):
Uterine Sepum
Bicornuate Uterus
Unicornuate Uterus
Acquired:
Fibroids
Asherman’s Syndrome
Restart here.

15. Congenital Uterine Anomalies

16. Uterine Septum on MRI

17. Uterine Septum at Hysteroscopy

18. 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):

19. 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):

20. 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):

21. 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):

22. 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: , 2005.

23. 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: , 2005.

24. 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

25. 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

26. 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

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

28. 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):

29. Treatment Options Antiphospholipid Antibody Syndrome
Treatment # Treated Liveborn
None / %
Aspirin (80mg/d) 39/81 48%
Prednisone + Asp 82/ %
IV Immunoglobulin 91/ %
UF Heparin + Asp / %
ASRM Guidelines: Unfractionated heparin recommended as comparable efficacy low molecular weight heparin had not be established.

30. 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).

31. 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 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% wks

32. 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 wks
Losses after 14 wks
Factor V Leiden
0.229
( )
1.07
( )
3.71
( )
Prothrombin Gene Mutation G20212A
0.21
( )
0.37
( )
2.47
( )
Fasting Homocysteine
0.23
( )
1.12
( )
2.37
( )
Protein C
0.58
( )
2.13
( )
1.16
( )
Protein S
0.54
( )
0.103
( )
2.5
( )
ATIII -
1.88
( )
0.39
( )
>1 thrombophilia
0.48
( )
1.66
( )
3.68
( )

33. 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

34. 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

35. Social Habits Increased SAB Risk
Increase risk fold
Tobacco (>15/day)
2nd Hand Smoke
Ethanol (> 4x/week)

36. 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.

37. 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

38. 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

39. Unhelpful in the Evaluation of RPL
Antithyroid Antibodies if normal TSH
Endometrial Biopsies
Natural Killer Cells
ANA
Embryotoxicity assay
Immunophenotyping
Inherited Thrombophilia’s

40. # 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)