This patient has a history of 6 miscarriages between 8-9 weeks of pregnancy. Testing showed normal hormone levels, thyroid function, parental karyotypes, and other factors. The patient was treated with various medications for subsequent pregnancies with one live birth. For the seventh pregnancy, the patient underwent paternal leukocyte immunization and developed antibodies, resulting in an uneventful pregnancy and live birth. The eighth pregnancy is currently ongoing.

1. DR/AHMED MOSAAD
LECTURER OF OBSTETRICS AND GYNECOLOGY

3. This patient, age 22, para 0, presented after six
miscarriages between 8 and 9 weeks. No fetal
heart had ever been detected, except in the
fourth pregnancy, when a fetal heart was said to
be present at 6 weeks. However, the pregnancy
showed no fetal shadow from 7 weeks onwards
until curettage was performed for a blighted
ovum at 9 weeks.

4. The fourth pregnancy was found to have
a normal 46,XX karyotype. The following
features had been investigated and
found to be normal. Parental karyotypes
were 46,XX and 46,XY. LA, aCL, and
hereditary thrombophilias were normal

5. Hormone levels (luteinizing hormone, follicle-stimulating
hormone, and prolactin) were normal. Midluteal
progesterone levels were 18 ng/ml. Thyroid function was
normal There was no diabetes. Hysteroscopy showed a
normal cavity. APCA were negative. NK-cell testing was
not performed at that time. The third pregnancy was
treated with progesterone supplements. The fourth and
fifth pregnancies were treated with enoxaparin and aspirin
on an empirical basis. The sixth pregnancy was untreated

6. The patient was treated by paternal leukocyte immunization
between the sixth and seventh pregnancies. Immunizations
were boosted until seroconversion ocurred with the
development of APCA directed towards paternal HLA
antigens. This is our current regimen.18 The seventh
pregnancy was uneventful. No additional medications were
administered. The seventh pregnancy terminated in the
delivery of a female infant, 3580 g, at 40 weeks. The
eighth pregnancy is presently 7 weeks, with a live embryo.

8. 1.INCIDENCE
• Recurrent miscarriage
• 2 or more: 3%
• 3 or more: 1% of the population (Regan et al, 2000).
• 1st T: 75% of RM
• 2nd T: 25% of RM
• Can be established in: 50% (ACOG,2001)

11. POSSIBLE CAUSES
I. Anatomic:10%
1. Congenital uterine malformation.
2. Submucous fibroid
3. Cervical incompetence
4. Severe IU synechiae
II. Endocrine: 5% 1.Uncontrolled DM 2. Clinical and sub clinical thyroid disorders.
III. Atiphospholipid antibody syndrome

13. Basic investigations
1.Pelvic US (or HSG or SIS)
2.Antiphospholipid Ab: LAACL Anti-ß2 glycoprotein-I
3. TSH
4. Thombophylia screen: Factor V Leiden mutation FactorII(prothrombin) gene mutation Protein S
deficiency
5. If the above examinations are normal: karyotype of the abortus: abnormality: Parental karyotype

14. 3. TYPES (Saravelos and Regan,2013)
Classified type I and type II
Type I: chance alone
Type II: genuine abnormality.
Help in selecting investigation and tt: improve cost-effectiveness and overall clinical care.

15. I.Type I.
The Factor of Chance
No abnormality other than embryonic aneuploidy which may not have been tested
before the referral to a specialist clinic.
Healthy women
Prognosis: very good in their future pregnancy without the need for surgical or
pharmacologic intervention.

16. II. Type II.
Genuine pathology (other than embryonic aneuploidy): that
cannot be identified by the current investigations:
Typically younger
Higher order of miscarriages (4, 5, or more)

18. 4. CAUSES
1.Oocyte:
Premature ovarian aging: reduced oocyte quality and quantity.
Oocyte quantity and quality cannot be easily assessed

19. 2. The Sperm: Paternal causes
Original reports: Y-chromosome microdeletions sperm oxidative stress sperm
concentration, morphology, and function.
DNA fragmentation (Vissenberg R, Goddijn, 2011)
SDF is significantly associated with miscarriage
Methods to select sperm without DNA damage: reduce miscarriage in ART.
(Robinson et al, SR, 2012)

20. 85% of uRM (Maynou et al, 2012) Advanced paternal age: Risk factor for
miscarriage {SDF: increases}
important to evaluate sperm DFI in uRM
Methods:
DFI
≥30: male infertility 15-30: RM. ≤15: Excellent to Good fertility potential

23. SPERM CHROMATIN DISPERSION TEST. SPERM 1
TO 3: LARGE HALO- UNFRAGMENTED DNA. SPERM
4 AND 5: SMALL HALO- FRAGMENTED DNA

24. ASRM Guidelines 2012:
Insufficient evidence (Level C)
to recommend routine SDF
testing to predict pregnancy
loss.

25. Evgni et al, 2014: Clinical indications for SDF tests
1.Prolonged idiopathic infertility
2.Low fertilization rate or bad quality embryos in IVF
3.Implantation failure following IVF
4.Repeated abortions
5.Prolonged exposure to toxic environmental conditions affecting fertility
6.Conventional seminal parameters found below the reference range
7.Advanced male partner age
8.Varicocele patients
9.Cancer patients

26. 3. The Embryo
ART, and PGS of the embryo for
aneuploidy in women with uRM, may
improve the prognosis

27. 4. The Endometrium
Normal endometrium can distinguish between good-quality and
poor-quality embryos. (Teklenburg etal, 2010)
RM: {increased levels of proimplantation cytokines}. (Salker et al,
2010) : disables the natural selection of healthy embryos:
implantation of poor-quality embryos: miscarriage

29. THIS IS WHAT WE WANT TO TALK ABOUT
Endometrial &subendometrial flow

30. 5. Systemic Factors
Until these conditions are proved to have a causal
effect, most women with these abnormalities may
still be diagnosed as having uRM.

31. I.Anatomic Arcuate Uterus
II. Endocrine:
1.Inadequate luteal phase
Short luteal phase: pregnancy loss but the assessment and
interpretation of a putative LPD is problematic.
The use of histological and biochemical endpoints as diagnostic
criteria for endometrial dating are unreliable (Evidence level III).

32. 2. Thyroid antibodies:
have been associated with miscarriage (MA, Thangaratinam et al, 2011)
[Chen et al, 2011; Thangaratinam et al, 2012]
Not linked to RM {in uRM is not higher than in the general population,
does not have a prognostic value regarding the outcome of a
subsequent pregnancy (Yan et al, 2012)}
high risk of developing hypothyroidism in 1st T
autoimmune thyroiditis postpartum: should be followed appropriately
[Marcus, 1999].

33. 3. PCOS:
linked to an increased risk of M (Smith and Schust, 2011)
Mechanism: unclear Not a cause
1.Elevated LH
2.Elevated serum testosterone levels
3.Ovulatory PCOS: No increase risk May be:
1.Insulin resistance hyperinsulinaemia 2. Hyperandrogenaemia: elevated FAI: RM.
Metformin to reduce RM: debatable.
MA: preconception metformin did not reduce RM
Small retrospective: reductions in RM. (Glueck etal, 2001; Jakubowicz et al, 2001)

34. 4. Obesity increases the risk of
both sporadic and RM
independent factor: increased
risk of miscarriage in couples
with uRM. (Lo et al, 2012).

35. 5. Hyperprolactinemia
Normal PRL: important in maintaining early pregnancy.
High Prolactin:
In early pregnancy: significantly increase M [Hirahara et al, 1998]. RCT
Bromocriptine: significantly higher rate of successful pregnancy (86 Vs 52%)
TT of hyperprolactinemia and RM is recommend (Up to date, 2013)
Low prolactin: increased risk of M (Li et al, 2013)

36. III. INFECTIONS
TORCH test not recommended (Evidence level II).
Bacterial vaginosis
Risk factor for PTL and 2nd TM [Leitich et al, 2007]
Vaginal swabs as screening tests during pregnancy in high risk women with previous
history of 2nd TM. [Trojniel et al, 2009]
Oral clindamycin early in 2nd T: significantly reduces rate of 2nd TM and PTL [Leitich
et al, 2007] (Evidence II).

37. IV. THROMBOPHILIAS
Controversial. [McNamee et al, 2012]
Methylene tetrahydrofolate mutation: Hyperhomocysteinemia, Protein C deficiency,
Antithrombin deficiency: Not associated with RM
The evidence is conflicting on hyperhomocysteinaemia as a risk factor for RM: testing
for MTHFR mutation is not a part of routine evaluation for RM. (Evidence level II).

38. • Hyperhomocysteinemia
• High dose folic acid (5 mg) and vit B12 (0.5
mg) once daily: reduce levels of homocysteine
• No evidence to support usage of 5 mg folic
acid from prepregnancy stage purely to
reduce the risk of RM (Evidence level III).

39. V. ALLOIMMUNE FACTORS
No clear evidence related to RM.
1.human leucocyte antigen incompatibility between couples
2.absence of maternal leucocytotoxic antibodies
3. absence of maternal blocking antibodies.
4.altered peripheral blood NK cells
5.raised uNK cell numbers : should not be offered routinely in the investigation
of RM. (RCOG, 2011)

40. 5. PROGNOSIS
Traditional View
uRM: excellent prognosis in subsequent pregnancies without the need for any surgical or
pharmacologic intervention.
Psychological supportive care: tender love and care (TLC):
:reduction in RM up to 50% (Pedersen et al, 1984 Clifford et al, 1997)
limitations in these trials. No enough investigations Small number High drop out
Difficult to examine the mechanism through which it operates. (Li et al, 2002)

41. TREATMENT
• 1.Psychological supportive care/TLC.
• 2. Lifestyle modification
• 3. Decrease SDF
• 4. Progestogen

42. • 5. Aspirin with or without heparin
• 6. Combination therapy
• An observational study before and during pregnancy with Prednisone (20
mg/day), Progesterone (20 mg/day), Aspirin (100 mg/day) and Folate (5 mg
every second day)
• 7. HCG
• 8. HMG
• 9. Immunotherapy
• ICSI and PGD