1. Fawaz Edris MD, RDMS, FRCSC, FACOG, AAACS
RECURRENT PREGNANCY LOSS
Fawaz Edris MD, RDMS, FRCSC, FACOG, AAACS

2. INTRODUCTION 
Emotionally traumatic, similar to stillbirth or neonatal death
Etiology is often unknown
Primary or secondary
Live birth occurred at some time in secondary
Better prognosis with secondary

3. DEFINITION  
≥ 3 consecutive losses of clinically recognized pregnancies < 20 week gestation
Ectopic, molar, and biochemical pregnancies not included
15 % experience sporadic loss of clinically recognized pregnancy
2 % experience 2 consecutive losses
0.15 x 0.15 = = 2 %
0.4 to 1 % experience 3 consecutive losses
0.15 x 0.15 x 0.15 = = 0.3 %  observed frequency is higher than expected by chance alone

4. RISK FACTORS AND ETIOLOGY
Only in 50 %, the cause can be determined
Etiological categories:
Uterine
Immunologic
Endocrine
Genetic
Thrombophilic
Environmental

5. UTERINE FACTORS Abnormal implantation:
Acquired or congenital anomalies
Congenital anomalies: % in ♀ with RPL vs. 7 % in all ♀
Abnormal implantation:
↓ vascularity (septum)
↑ inflammation (fibroid)
↓ sensitivity to steroid hormones

6. SEPTATE UTERUS Most common Poorest outcome Miscarriage > 60 %
Fetal survival with untreated cases 6 to 28 %
The longer, the worse
The mechanism
Not clearly understood
Poor blood supply  poor implantation

7. LEIOMYOMA Submucous The mechanism Their position
Poor endometrial receptivity
Degeneration with increasing cytokine production

8. OTHER UTERINE CAUSES Endometrial polyps Intrauterine adhesions
Rx: Polypectomy
Intrauterine adhesions
Curettage for pregnancy complications (4/52)
Traumatize basalis layer  granulation tissue
Insufficient endometrium to support fetoplacental growth
Menstrual irregularities (hypomenorrhea, amenorrhea), cyclic pelvic pain, infertility.

9. OTHER UTERINE CAUSES Cervical insufficiency Other uterine anomalies
Recurrent mid-trimester loss
Other uterine anomalies
Impaired uterine distention

10. IMMUNOLOGIC FACTORS Antiphospholipid syndrome (APAS)
% of ♀ with RPL may have APAS
Other immunological factors
Not well defined

11. ENDOCRINE FACTORS Luteal phase defect
Progesterone is essential for implantation and maintenance of pregnancy
A defect in C.L.  impaired progesterone production
Controversies:
Does this defect really exists?
If it does, is related to miscarriage?
No consensus on method of diagnosis
No consensus on method of treatment

12. ENDOCRINE FACTORS Diabetes mellitus
Poorly controlled  early (and late) loss
No ↑ risk with well-controlled
Mechanism
Hyperglycemia
Maternal vascular disease
Immunologic factors (possible)

13. ENDOCRINE FACTORS Insulin resistance No strong evidence PCOS
Miscarriage % vs. baseline rate %
Mechanism is unknown
↑ LH, Testosterone, and androstenedione  adversely affect the endometrium

14. ENDOCRINE FACTORS Thyroid disease and antibodies Hyperprolactinemia
Poorly controlled hypo- or hyper-thyroidism
Infertility & pregnancy loss
↑ thyroid antibody, even if euthyroid.
No strong evidence
Hyperprolactinemia
Rx  ↑ successful pregnancy (86 vs. 52%)
BUT, need correct diagnosis
At what level to treat?

15. GENETIC FACTORS 
↑ RPL in 1st degree relatives of ♀ with unexplained RPL
Shared HLA types, coagulation defects, immune dysfunction, other undefined heritable factors
Chromosomal rearrangements
5 % of couples with RPL have major chromosomal defects (vs. 0.7 %)
Balanced translocation or an inversion
Even if present, may not be the cause  complete evaluation of RPL is indicated

16. THROMBOPHILIA
Thrombosis on maternal side of the placenta  impair placental perfusion
Late fetal loss, IUGR, abruption, or PIH
Relationship with early loss is less clear
large and contradictory literature
May be restricted to specific defects not completely defined, or presence of multiple defects

17. MISCELLANEOUS Environmental chemicals & stress Personal habits
Anesthetic gases (nitrous oxide), formaldehyde, pesticides, lead, mercury
Sporadic spontaneous loss
No evidence of associations with RPL
Personal habits 
Obesity, smoking, alcohol, and caffeine
Association with RPL is unclear
May act in a dose-dependent fashion or synergistically to ↑ sporadic pregnancy loss
Exercise
does not ↑ sporadic or RPL

18. MISCELLANEOUS Male factor Infection
Trend toward repeated miscarriages with abnormal sperm (< 4% normal forms, sperm chromosome aneuploidy)
ICSI
Paternal HLA sharing not risk factor for RPL
Advanced paternal age may be a risk factor for miscarriage (at more advanced age than females)
Infection
Listeria, Toxoplasma, CMV, and primary genital herpes
Cause sporadic loss, but not RPL

19. MISCELLANEOUS Decreased ovarian reserve Celiac disease
Quality and quantity of oocytes decrease
♀ with unexplained RPL have a higher D3 FSH and E2 than ♀ with known cause
Celiac disease
Untreated & even subclinical, associated with pregnancy loss, menstrual disorders, and infertility
Treatment prevent these problems
No evidence that it causes RPL

20. CANDIDATES FOR EVALUATION
Evaluate and Rx ≥ 2 or 3 consecutive losses
Most have good prognosis for a successful pregnancy, even when no Dx or Rx
The minimum workup:
Complete medical, surgical, genetic, and family history
Physical examination

21. HISTORY 
GA & characteristics (anembryonic pregnancy, live embryo) of all previous pregnancies
RPL typically occurs at a similar GA
Most common causes of RPL vary by trimester
Chromosomal & endocrine earlier than anatomic or immunological causes
Uterine instrumentation  intrauterine adhesions
Menstrual cycles regularity  endocrine dysfunction
Galactorrhea, Headache, Visual disturbances  hyperprolactinemia

22. HISTORY Thyroid related symptoms
Hx of congenital or karyotypic abnormalities  heritable
Was cardiac activity detected? If not  suggests chromosomal abnormality
Does F.Hx display patterns of disease consistent with strong genetic influence? consanguinity
Exposure to environmental toxins
Hx venous thrombosis  thrombophilia or APAS
Information from previous laboratory, pathology, and imaging studies

23. PHYSICAL EXAMINATION General physical
Signs of endocrinopathy (hirsutism, galactorrhea, thyroid)
Pelvic organ abnormalities (uterine malformation, cervical laceration)

24. LABORATORY EVALUATION
Karyotype (Parental)
Low yield & limited prognostic value  only if the other work-up was negative
Karyotype (Embryonic)
Not really needed
May consider after 2nd loss
If abnormal karyotype + normal parents  “bad luck”

25. UTERINE ASSESSMENT Sonohysterography (SIS) Hysterosalpingogram (HSG)
More accurate than HSG
Differentiate septate & bicornuate uterus
Hysterosalpingogram (HSG)
Does not evaluate outer contour
Not ideal for the cavity
Hysteroscopy
Gold standard for Dx + Rx intrauterine lesions
Cannot differentiate septate from bicornuate
Reserved for when no Dx is made

26. UTERINE ASSESSMENT Ultrasound MRI
Presence and location of uterine myomas
Associated renal abnormalities
MRI
Differentiate septate from bicornuate
Hysteroscopy, laparoscopy, or MRI  second-line tests when additional information is required

27. APAS Dx: one lab & one clinical criteria are met Clinical criteria:
Venous or arterial thrmobosis
RPL
Laboratory criteria
Lupus anticoagulant
Anticardiolipin antibody (IgG and IgM)
Medium or high titers of both
Low to mid positive can be due to viral illness
Repeat twice, 6-8 weeks apart

28. THROMBOPHILIA Contradictory literature
Evaluate if loss > nine weeks + evidence of placental infarction or maternal thrombosis

29. THYROID TSH +/- FT4 & FT3 Thyroid peroxidase antibody
More important in ♀ with clinical manifestations but even in asymptomatic
Thyroid peroxidase antibody

30. OVARIAN RESERVE D3 FSH +/- D3 E2 in ♀ of any age or ¼ would be missed
Clomiphene challenge test

31. NONE USEFUL TESTS
Routine cervical cultures for Chlamydia, Mycoplasma & vaginal evaluation for BV & toxoplasmosis serology
ANA
Screening for DM
Immune function (HLA typing, etc)
Progesterone level (Single or multiple)
Endometrial biopsy

32. MANAGEMENT Prognosis for successful future pregnancy is good
live birth rates after normal and abnormal diagnostic evaluations, 77 and 71 percent, respectively
Emotional support is important and enhance success

33. PARENTAL KARYOTYPE ABNORMALITY
Refer for genetic counseling
Information for probability of a chromosomally normal or abnormal conception
May undergo prenatal genetic studies
Amniocentesis
CVS
IVF with PGD

34. UTERINE ABNORMALITIES
Managed hysteroscopically
Septum, adhesions, submucosal myoma
Cervical cerclage
Second trimester loses

35. MANAGEMENT Antiphospholipid syndrome Suspected immunologic dysfunction
Aspirin & Heparin
Suspected immunologic dysfunction 
Several immunologic Rx advocated
None effective
Some are harmful DM
Controlled at least 6/12 prior to conception
Thyroid
Hyper and Hypo thyroid should be controlled
Euthyroid with ↑ peroxidase antibody may benefit from treatment

36. MANAGEMENT Polycystic ovary syndrome Hyperprolactinemia Thrombophilia
No agreed upon protocol
Metformin just as effective when stopped at diagnosis of pregnancy or 12/52 gestation
Hyperprolactinemia 
Normal levels play important role in maintaining early pregnancy (in RPL)
Thrombophilia 
Anticoagulation if loss > 9/52

37. UNEXPLAINED RPL 50% of RPL remain unexplained Prognosis is still good
>50 % live birth even without intervention

38. UNEXPLAINED RPL Lifestyle modification Progesterone
Eliminating use of tobacco, alcohol, and caffeine & reduction in BMI (for obese women).
Progesterone
Widely used but studies on its efficacy are lacking
Vaginally or IM
Human menopausal gonadotropin
Correcting LPD or creating thicker endometrium
Clinical experience supports the efficacy
IVF +/- PGD
Mixed results
Promising

39. UNEXPLAINED RPL Useless interventions: Pregnancy issues hCG CC
Increased risk of :
IUGR
PTD
No increased risk of:
PIH
GDM

40. Thank you