This document provides an overview of recurrent miscarriage, including its definition, causes, evaluation, and treatment. It discusses possible causes like anatomic, endocrine, infectious, and genetic factors. Evaluation involves assessing history, physical exam, pelvic ultrasound, thyroid function, infections, antiphospholipid antibodies, and thrombophilias. Treatment targets identified causes and includes surgical correction of anomalies, treating hypothyroidism, infections like brucellosis, antiphospholipid syndrome with aspirin and heparin, inherited thrombophilias with heparin, and genetic counseling. Progesterone, lifestyle modifications, and hCG have uncertain benefits for unexplained recurrent miscarriage.

1. Recurrent
miscarriage
Aboubakr Elnashar
Benha university, Egypt
elnashar53@hotmail.com
ABOUBAKR ELNASHAR

2. Contents
Introduction
Causes
Evaluation
Treatment
Conclusion
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3. Definition
Miscarriage
Spontaneous loss of pregnancy before the fetal
viability.
includes all pregnancy losses from the time of
conception until 24w.
ectopic and molar pregnancies are not included.
Recurrent miscarriage
3 or more consecutive pregnancies
(RCOG, 2011)
2 or more
(ASRM, 2008)
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4. CAUSES
1. Possible
2. Doubtful
unexplained
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5.  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.Uncontrolled thyroid disease
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6. III. Infection:
1. Brucellosis
2. Bacterial vaginosis
IV. Atiphospholipid antibody syndrome
V. Inherited Thrombophilic Defects
1. Factor V Leiden mutation
2. Prothrombin gene mutation,
3. Protein s deficiency
VI. Genetic: 25%
1. Parental chromosomal abnormalities
2–5% of couples with RM
2. Embryonic chromosomal abnormalities
30–57% of further
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7. Brucellosis and pregnancy outcome:
Higher rate of
Abortion
Preterm labour
IUFD
Causes of spontaneous abortion and IUFD
maternal bacteremia
Toxemia
acute febrile reaction
DIC
Diagnosis:
IgM: 1 : 160 - non endemic area
1 : 320 - endemic area
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8. 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]
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9. 2. Doubtful causes: weak correlation between the cause and
miscarriage
I. Local:
1. Oocyte:
Premature ovarian aging: reduced oocyte
quality and quantity.
2. Sperm: Paternal causes
DNA fragmentation
(Vissenberg R, Goddijn, 2011)
3. Embryo
 ART, and PGS of the embryo for aneuploidy in
women with uRM: ±improve the prognosis
4. Endometrium
Normal endometrium can distinguish between
good-quality and poor-quality embryos.
(Teklenburg etal, 2010)
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10. SDF
MA: significant increase in RM
(Robinson et al, 2012)
85% of u RM
(Maynou et al, 2012)
DFI
•≥30: male infertility
•15-30: RM.
•≤15: Excellent to Good fertility potential
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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
3. Thrombophilia
1. Hyperhomocysteinemia
2. Protein c def
3. Antithrombin III defABOUBAKR ELNASHAR

12. 4. Infections:
 Chronic endometritis
 TORCH test
not recommended
(Evidence level II).
 Not:
Toxoplasmosis, Mycoplasma
L. monocytogenes, C. trachomatis
HSV, CMV
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13. Chronic endometritis (CE)
Immunohistochemically
Office hysteroscopy
High prevalence in RM.
(McQueen et al, 2015; Bouet et al, 2016)
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14. 5. Immunologic
Autoimmune antibodies
Immune reaction against self
Antithyroid antibodies
 Alloimmune factors
immune reaction against another
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15. 6. Environmental:
1. Alcohol & smoking
2. Herbicide spraying.
3. Electromagnetic field
4. Radiation
7. Inhalation of anesthetic gases
8. Exposure to solvents, heavy metals & industrial chemicals.
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16. EVALUATION
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17. HISTORY
 Obstetric
Gestational age
Chromosomal and endocrine defects: 1st TM
Anatomic or immunological: 2nd TM
There is significant overlap.
Embryonic/fetal cardiac activity
chromosomal abnormality: RM prior to detection
of embryonic cardiac activity
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18. Surgical:
uterine instrumentation (intrauterine adhesions)
Menstrual:
Irregular menstrual cycles (endocrine dysfunction).
Galactorrhea (hyperprolactinemia)
Family:
Eenvironmental (toxins)
Venous or arterial thrombosis (APA synd)
Previous investigations
Laboratory
Pathology
imaging
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19. Physical examination
Signs of endocrinopathy
Hirsutism
Galactorrhea
Pelvic organ abnormalities
uterine malformation
cervical laceration.
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20. INVESTIGATIONS
1. Anatomical factors
Pelvic ultrasound and/or HSG or
sonohysterography
initial screening test
Hysteroscopy, laparoscopy or 3DUS
definitive diagnosis.
2. Endocrine
TSH
3. Infection
IgM for Brucellosis
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21. 4. Antiphospholipid antibodies
Diagnosis:
2 positive tests at least 12 w apart for either
LA or
ACL or
Anti-B2 glycoprotein-I antibodies
of IgG and/or IgM
medium or high titre over 40 g/l or ml/l, or
above the 99th percentile.
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22. 5. Thrombophilias
Screening for
factor V Leiden,
factor II (prothrombin) gene mutation
protein S deficiency
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23. 6. Karyotyping
Cytogenetic analysis of products of conception
of 3rd and subsequent consecutive
miscarriage(s).
Parental peripheral blood karyotyping
of both partners where testing of products of
conception reports an unbalanced structural
chromosomal abnormality.
.
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24. TREATMENT
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25. Treatment of possible causes
1. Anatomical factors
1. Congenital uterine malformations
uterine septum
hysteroscopic resection
2. Submucosal fibroid:
Hysteroscopic myomectomy
3. Severe IU adhesions:
Hysteroscopic surgery
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26. 4. Cervical incompetence
Cervical cerclage:
Indication:
1. one or more 2nd TM or PTL before 24 w.
TVS: cervix is 25 mm or less
2. Three or more previous PTL and/or 2nd TM.
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27. 2. Treatment of hypothyroidism
Eltroxin
Objective
TSH: 2.5 mIU/L
Dose
Non pregnant:
1.7 μg/kg/d or
25 μg/d adjusted by 25 μg/d every 2 to 4 ws
until euthyroid state is achieved.
Pregnant:
Increase 30%
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28. ABOUBAKR ELNASHAR

29. 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
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30. Asymptomatic abnormal vaginal flora and
bacterial vaginosis
Oral clindamycin
•early in 2nd T:
•300mg PO BID x 7 days
significantly reduces the rate of late miscarriage
and spontaneous preterm birth in a general
obstetric population
(Evidence II).
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31. 4. Antiphospholipid syndrome
low-dose aspirin plus heparin
reduces the miscarriage rate by 54%
No difference in efficacy and safety between
unfractionated heparin and LMWH when
combined with aspirin
Low dose Asprin
no adverse fetal outcomes
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32. 5. Inherited thrombophilias
Heparin
R 1st TM
insufficient evidence may improve LBR for
these women
R 2nd TM
improve the LBR
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33. 6. Genetic factors
Abnormal parental karyotype:
I. Referral to a clinical geneticist.
1. Prognosis for the risk of future pregnancies
with an unbalanced chromosome complement
2. Familial chromosome studies.
3. Proceeding to a further natural pregnancy with
or without a prenatal diagnosis test
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34. II. PGD/IVF
a. For translocation carriers.
be aware of
financial cost
implantation and live birth rates following IVF
higher (60%) chance of a healthy live birth in
future untreated pregnancies following
natural conception than achieved after
PGD/IVF (30%).
B. For unexplained RM:
does not improve live birth rates.
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35. Treatment of doubtful causes
1. PCOS
Metformin : debatable.
MA: preconception Met did not reduce RM
Small retrospective: reductions in RM.
(Glueck etal, 2001; Jakubowicz et al, 2001)
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36. 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%).
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37. 3. Hyperprolactinemia
RCT
[Hirahara et al, 1998].
Bromocriptine
significantly higher rate of successful
pregnancy (86 Vs 52%)
Treatment of hyperprolactinemia and RM, even in
the absence of overt hypogonadism : recommend
(Up to date, 2013)
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38.  Treatment of unexplained RM
 No evidence-based tt.
 Low risk, simple, and cheap
1. Psychological supportive care/TLC.
 Early and frequently repeated ultrasounds
βHCG monitoring
practical advice concerning life style and diet,
emotional support in the form of counselling,
Clear policy for the upcoming 12 w and medication.
 Chance of a live birth is good: over 50%
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39. 2. Lifestyle modification
 Stop smoking, alcohol
 Caffeine reduction
 Reduction BMI (for obese women).
 No RCT.
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40. 3. Decrease SDF
1. Oral antioxidant
2. Life style modifications:
stop smoking and wt loss
3. Identify and tt underlying condition:
GTI and varicocele
4. Consider TESA-ICSI
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41. 4. Progestogen
Cochrane Database S R. 2013
4 trials, 225 women
El-Zibdeh
2005
Goldzieher 1964Le Vine
1964
Swyer
1953
1805456113
10 mg bid oral
Dydrogesterone,
5000 IU IM
hCG/4d
Duration: 12th w
10 mg/d oral
Dydrogesterone,
Duration: not
stated.
500 mg/w
IM
17 oh PC
Duration:
until 36 w
6 x 25 mg
progesterone
pellets
Duration: unclear.
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42. 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.
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43. 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.
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44. 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}
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45. 5. Aspirin with or without heparin
No improvement
Insufficient evidence to support the routine use of
LMWH to improve pregnancy outcomes in women
with a history of pregnancy loss.
(Mantha et al, 2009, MA)
No support of the use of anticoagulants in women
with unRM.
(Cochrane Database Syst 2014)
Daily LMWH injections do not increase ongoing pregnancy or livebirth
rates in women with unexplained RPL. Given the burden of the
injections, they are not recommended for preventing miscarriage
Schleussner et al, 2015.
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46. 6. Combination therapy
An observational study
before and during pregnancy with
Prednisone: 20 mg/d
Dydrogesterone: 20 mg/d
Aspirin: 100 mg/d
Folate: 5 mg/second day
[Tempfer et al, 2006].
In treated group:
1st T M : 19% Vs 63% (not statistically significant).
LBR: 77 Vs 35%, respectively (P = 0.04).
The nonrandomized design and small number of cases
also limits the usefulness of this study.
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47. 7. HCG
During early gestation may be useful in
preventing miscarriage
{endogenous hCG plays a critical role in the
establishment of pregnancy }
The evidence: equivocal
(Chochrane S R, 2013)
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48. 8. HMG
observational study:
effective for tt of endometrial defects in
women with RPL
[Li et al, 2001].
Mechanism:
correction of a luteal phase defect
stimulation of a thicker endometrium: better implantation
site.
Clinical experience supports the efficacy of this
treatment
(Tulandi et al, 2013).
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49. 9. Immunotherapy
Paternal cell immunisation
third-party donor leucocytes
trophoblast membranes
IVIG in women with previous uRM
does not improve LBR
(Cochrane systematic review, 2006 ; RCOG, 2011)
Immunotherapy should not be advised.
[Porter etalm 2006] (Evidence level II)
IVIG:
confirmed this conclusion
Expensive
Serious adverse effects: transfusion
reaction, anaphylactic shock and hepatitis.
(Stephenson et al, 2010MA)
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50.  Intralipid Therapy
Form:
20% IV administered fat emulsion routinely used as
a source of fat and energy for patients in need of
extra intake
Composed of :
purified soybean oil, purified egg
phospholipids, glycerol, and water.
Some evidence effective in
1. RM due to immunologic causes, particularly
elevated natural killer cells or other unidentified
immunologic causes.
2. uRM
3. uRIF ABOUBAKR ELNASHAR

51. In vitro studies:
Intralipid suppress Natural Killer cell cytotoxicity:
decreases the number of natural killer cells.
Administration:
IV infusion in an office setting.
100 mls of Intralipid are mixed with 500 mls NS.
60-90 minutes.
TT start at the start of the IVF cycle
continued monthly should a positive pregnancy test
result until the 24th w of pregnancy.
Side effects
No
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52.  Endometrial scratching
 When:
cycle preceding the actual treatment cycle.
(Friedler et al., 1993; Barash et al., 2003; Raziel et al., 2007; Zhou et
al., 2008).
7 days prior to the onset of menstruation,
immediately before the start of ovarian
stimulation for IVF tt.
In the follicular phase of the index cycle : no
benefit
(Karimzade et al., 2010; Zhou et al., 2008).
Not on the day of OR:
significantly reduce CPR
(Nastri et al, 2012)
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53. How and results:
biopsy/scratch or hysteroscopy:
CPR doubled.
(Raziel et al., 2007 ; Narvekar et al, 2010)
CPR:
wice as high with biopsy/scratch as opposed to
hysteroscopy
(Potdar et al, 2012)
(2 syst reviews: Potdar et al, 2012; El-Toukhy et al, 2013)
Uses:
 RIF:
increase both LBR or OPR and CPR
(Cochrane SR; Nastri , 2015)
 Un-infertility
 UnRM ABOUBAKR ELNASHAR

54. 10. ICSI and PGD
Evidence is lacking: Similar results.
(Pellicer et al, 1999)
Not recommend
(Visenberg, 2012)
SR (Musters et al, 2011):
Miscarriage rates following PGS may be slightly
lower , but
lack of RCTs
invasiveness of ART
relatively good prognosis of women with uRM and
natural conception
: this tt is inappropriate.ABOUBAKR ELNASHAR

55. CONCLUSIONS
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56. Investigations
After two or three consecutive miscarriages:
1. Pelvic US (or HSG or Sonohysterography)
2. TSH
3. Brucellosis IGM
4. Antiphospholipid antibodies
5. Factor V Leiden, factor II (prothrombin) gene
mutation and protein S.
6. If the above examinations are normal: karyotype of
the abortus: unbalanced structural chromosomal
abnormality: Parental karyotype
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57. Treatment
1. Uterine septum, submucous fibroid, severe IU
adhesions: Hysteroscopic surgery.
Cervical incompetence: cervical cerclage
2. Subclinical hypothyroidism: Eltroxin
3. Brucellosis: Rifamycin
4. APA: Low dose aspirin & heparin.
5. Inherited thrombophilias: Heparin
6. Karyotyping abnormalities: Clinical geneticist.
7. Treatment of doubtful causes
8. Treatment of Unexplained miscarriageABOUBAKR ELNASHAR

58. ABOUBAKR ELNASHAR