RPL

1. RPL
Case scenario1
Prof. Aboubakr
Elnashar
elnashar53@hotmail.com
ABOUBAKR ELNASHAR

2. 28 y old
Married since 7 y
No living children
G7P0+7
Miscarriages
At 12w, 10w, 14w,10w, 12w, 12w, 11w
2DUS:
Normal uterus
PCO

3. WHAT ARE INVESTIGATIONS?
1. 3DUS or Sonohysterography
2. TSH, TPO
3. Brucellosis IGM
4. Cultures for bacteria, virus
5. GTT
6. Parental human leukocyte antigen (HLA)
7. Maternal antipaternal antibodies
8. Antiphospholipid antibodies
9. Factor V Leiden, factor II (prothrombin) gene
mutation and protein S.
10.SDF testing

4. INVESTIGATIONS
1. 3DUS or Sonohysterography
2. TSH, TPO
3. Brucellosis IGM
4. Antiphospholipid antibodies
5. Factor V Leiden, factor II (prothrombin) gene
mutation and protein S. (RCOG, 2011)
6. SDF testing

5. ALL INVESTIGATIONS: NORMAL
WHAT IS DIAGNOSIS?

6. Unexplained:
Possible (definite or probable) causes
(Good correlation between the cause & RM) are
excluded by basic investigations
No more than 2 doubtful causes
(Christiansen et al, 2008)

7.  WHAT ARE CAUSES OF RPL?

8.  Possible: strong correlation between the cause and
miscarriage
I. Anatomic:10%
1. Congenital uterine malformation.
2. Submucous fibroid
3. Cervical incompetence
4. Severe IU synechiae
II. Endocrine: 5%
1.Uncontrolled DM
2.Hypothyroidism
ABOUBAKR ELNASHAR

9.  WHAT ARE INFECTIONS CAUSING RPL?
III. Infection:
1. Brucellosis
2. Bacterial vaginosis
IV. Atiphospholipid antibody syndrome
V. Paternal causes
DNA fragmentation
(Vissenberg R, Goddijn, 2011)
VI. Genetic: 25%
1. Parental chromosomal abnormalities
2–5% of couples with RM
2. Embryonic chromosomal abnormalities
30–57% of further
ABOUBAKR ELNASHAR

10. 2. Doubtful causes: weak correlation between the cause and
miscarriage
I. Local:
1. Oocyte:
Premature ovarian aging: reduced oocyte
quality and quantity.
2. Embryo
 Aneuploidy
ABOUBAKR ELNASHAR

11. II. Systemic Factors
1. Anatomic:
 Arcuate uterus
 Not: RVF, Mild IU adhesions, Subserous fibroid
2. Endocrine:
1. PCOS
2. Endometriosis.
3. Inadequate luteal phase
4. Hyperprolactinemia
5. Obesity or significantly underweight :negative
impact on chances of a live birth (ESHRE, 2017)
ABOUBAKR ELNASHAR

12. 3. Inherited Thrombophilic Defects
1. Factor V Leiden mutation
2. Prothrombin gene mutation,
3. Protein s deficiency
(RCOG, 2011)
Hyperhomocysteinemia
Protein c def
Antithrombin III def
ABOUBAKR ELNASHAR

13. 4. Infections:
 Chronic endometritis
 IS TORCH TEST INDICATED IN RPL?
 TORCH test
not recommended
(Evidence level II).
 Not:
Toxoplasmosis, Mycoplasma
L. monocytogenes, C. trachomatis
HSV, CMV
ABOUBAKR ELNASHAR

14. Chronic endometritis (CE)
Diagnosis:
Histopatholgy: plasma cell
Office hysteroscopy :
Oedema
Micropolyposis
Hyperaemia
Culture
High prevalence in RM.
(McQueen et al, 2015; Bouet et al, 2016)
Further research is needed before screening for
endometritis can be recommended.
(ESHRE, 2017)
ABOUBAKR ELNASHAR

15. 5. Immunologic
Autoimmune antibodies
Immune reaction against self
Antithyroid antibodies
 Alloimmune factors
immune reaction against another
ABOUBAKR ELNASHAR

16. 6. Environmental and occupational
(few small studies) exposure to
1. heavy metals
2. solvents& industrial chemicals
3. Pesticide: increased risk of PL
(ESHRE, 2017)
4. Herbicide spraying.
5. Electromagnetic field
6. Radiation
7. anesthetic gases
ABOUBAKR ELNASHAR

17. Stress:
no evidence that stress causes PL.
(ESHRE, 2017)
Age:
risk of PL
lowest between 20 to 35 years
rapidly increases after the age of 40
(ESHRE, 2017)
ABOUBAKR ELNASHAR

18. 1. Smoking
negative impact on chances of a live birth
2. Caffeine intake
late PL.
(Some studies)
3. Alcohol consumption
risk factor for
PL
fetal problems (Fetal alcohol syndrome).
ABOUBAKR ELNASHAR

19.  HOW TO TREAT UNEXPLAINED RPL?
1. TLC
2. Life style modification
3. Progestagen
4. Combination
5. Aspirin, Heparin
6. HCG, HMG
7. Intralipid, Endometrial scraching
8. PGS
ABOUBAKR ELNASHAR

20.  TREAT UNEXPLAINED RPL
 Treatment of doubtful causes
1. PCOS
2. Autoimmune thyroid
3. Hyperprolactnaemia
4. Chronic endometritis
ABOUBAKR ELNASHAR

21.  WHAT IS EVIDENCE OF USE OF METFORMIN
DURING PREGNANCY IN PCOS?
1. PCOS
Metformin : debatable.
MA: preconception Met did not reduce RM
Small retrospective: reductions in RM.
(Glueck etal, 2001; Jakubowicz et al, 2001)
Insufficient evidence to recommend metformin
Pituitary suppression before induction of ovulation
could be an option to reduce the risk of PL
(ESHRE, 2017)
ABOUBAKR ELNASHAR

22.  HOW TO TREAT INCREASED SPERM DNA
FRAGMENTATION?
2. Increased SDF
1. Oral antioxidant
have not been shown to improve the chance of a
live birth
(ESHRE, 2017)
2. Life style modifications:
stop smoking and wt loss
3. Identify and tt underlying condition:
GTI and varicocele
4. Consider TESA-ICSI
ABOUBAKR ELNASHAR

23. 2. Euthyroid women with high serum thyroid peroxidase
antibody
RCT: [Negr et al, 2006].
levothyroxine (50 mcg daily): decreased
miscarriage rate (13.8 to 3.5%)
PTL (22,4 to 7%).
ABOUBAKR ELNASHAR

24. 3. Hyperprolactinemia
RCT
[Hirahara et al, 1998].
Bromocriptine
significantly higher rate of successful pregnancy
(86 Vs 52%)
Bromocriptine treatment is recommended to increase
LBR
(ESHRE, 2017)
ABOUBAKR ELNASHAR

25.  HOW TO TREAT CHRONIC ENDOMETRITIS?
4. Chronic endometritis
Regimen:
Ofloxacin: 400 mg daily for 2w
Doxycycline: 100 mg twice daily for 2 w
Persistent CE:
Ciprofloxacin: 500mg and
Metronidazole: 500 mg twice daily for 2 weeks.

26.  Treatment of Unexplained miscarriage
 No evidence-based tt.
 Low risk, simple, and cheap
1. TLC
2. Life style modification: No RCT.
3. Progestagen
4. Combination: Prednisone: 20 mg/d; Dydrogesterone: 20 mg/d
Aspirin: 100 mg/d.; Folate: 5 mg/second day: No RCT
[Tempfer et al, 2006].
5. Aspirin, Heparin: No improvement
6. HCG, HMG: equivocal
7. Intralipid, Endometrial scraching: No improvement
8. PGS: Not recommended
ABOUBAKR ELNASHAR

27. 3 or more consecutive miscarriages
Progestogen tt:
significant decrease in miscarriage rate
compared to placebo or no tt
(Peto OR 0.39; 95% CI 0.21 to 0.72).
2 prior miscarriages.
a trend but not a significant reduction in
miscarriage rates
(Peto OR 0.68; 95% CI 0.43 to 1.07).
Limitations of MA:
these 4 trials were of poorer methodological
quality.
ABOUBAKR ELNASHAR

28. Coomarasamy et al, 2015: NEMJ
PROMISE STUDY: 836 patients
Multicenter, double-blind, placebo, RCT
Vaginal suppositories:
400 mg micronized progesterone in 1st T
did not result in a significantly higher LBR
among women with a history of un RM.
ABOUBAKR ELNASHAR

29. Mechanism:
Immmunomodulatory actions:
Decreasing proinflammatory
Increasing anti-inflammatory cytokines in early
pregnancy
[Choi et al, 2000].
Start:
3 days after the LH surge
{not to inhibit ovulation}
Continue:
until 10 w
{placental progesterone production fully functional}
ABOUBAKR ELNASHAR

30. ABOUBAKR ELNASHAR
 ≥3 consecutive miscarriages of unknown cause.
(Roepkke et al, SR &MA, 2018)
 21 RCT regarding
 No significant difference in LBR
 acetylsalicylic acid
 LMWH
 IV Img
 leukocyte immune therapy
 Treatment with progesterone
 starting in the luteal phase effective in increasing
LBR
 RR 1.18 (95% CI1.09-1.27) but not when started
after conception.

31. 3. Treatment of Infection
Brucellosis
• Rifampin: 900 mg once daily for 6 w
• Rifampin: 900 mg once daily plus
trimethoprim-Sulphmethoxazole
(TMP-SMX; 5 mg/kg of the trimethoprim component twice
daily) for 4 w
ABOUBAKR ELNASHAR

32. Asymptomatic abnormal vaginal flora and
bacterial vaginosis
Oral clindamycin
•early in 2nd T:
•300mg PO BID x 7 days
 significantly reduces
 late miscarriage and
 spontaneous preterm birth
(Evidence II).
ABOUBAKR ELNASHAR