ABOUBAKR ELNASHAR

1. Recurrent
Pregnancy
Loss
An interactive session
Prof. Aboubakr Elnashar
Benha university Hospital, Egypt
elnashar53@hotmail.com
ABOUBAKR ELNASHAR

2.  Spontaneous miscarriage:
12% to 15% of all pregnancies.
 RPL:
 3%-5% of all pregnancy losses.
 Causes: 50% unexplained
 The management:
 an unsolved problem
 one of the most debated topics.
ABOUBAKR ELNASHAR

3.  Types of Guidelines
Evidence Based Guideline:
 Developed after
 systematic retrieval
 Appraisal of information from the literature
 Strength of the evidence.
Consensus Based Guideline:
 The most common form
 Agreement among a group of experts.
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4. ABOUBAKR ELNASHAR

5. I. Evaluation of RPL
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6. Q1. RPL
1.Loss of 2 or more pregnancies.
2.Ectopic and trophoblastic pregnancies are
included
3.1st trimester RPL account for 75% and 2nd
trimester 25%
4.Chronic endometritis is a definite cause of RPL
5.There is an evidence that stress causes RPL
ABOUBAKR ELNASHAR

7. A1. RPL
1.loss of 2 or more pregnancies.
2.Ectopic and trophoblastic pregnancies are not
included
3.1st trimester RPL account for 75% and 2nd
trimester 25%
4.Chronic endometritis is not a definite cause
Further research is needed before screening for endometritis can be
recommended.
5.No evidence that stress causes RPL
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8. Chronic endometritis (CE)
Diagnosis:
 Histopatholgy: plasma cell
 Office hysteroscopy :
 Oedema
 Micropolyposis
 Hyperaemia
 Culture
High prevalence in RPL.
(McQueen et al, 2015; Bouet et al, 2016)
Treatment::
Ofloxacin: 400 mg daily for 2w
Doxycycline: 100 mg twice daily for 2 w
Persistent CE:
Ciprofloxacin: 500mg and
Metronidazole: 500 mg twice daily for2w
Plasma cells identified by
morphology using H&E staining.
ABOUBAKR ELNASHAR

9. Q2. Risk factors of RPL
1.Rapidly decrease after the age of 40.
2.Obesity or significantly underweight are risk factors
3.Smoking has no impact on chances of a live birth
4.An association between caffeine and late
pregnancy loss
5.Excessive alcohol consumption is a risk factor
ABOUBAKR ELNASHAR

10. A2. Risk factors of RPL
1.Rapidly increases after the age of 40.
2.Obesity or significantly underweight
3.Smoking has a negative impact on chances of a
live birth
4.An association between caffeine and late PL.
5.Excessive alcohol consumption
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11.  Caffeine
affects ovulation and corpus luteum function through changing hormone
levels
1. ≥500 mg caffeine/d: increases the risk of infertility
2. ≥ one cup/d:
 Decrease conception significantly
(Wilcox et al.)
 Increased risk of spontaneous abortion
3. Moderate to high doses: Low birth weight
(Fernandes et al, MA1995).
Not confirmed in other studies
(Christian et al, 2001)
To avoid receiving very high doses of caffeine.
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12. Q3. Anatomical factors
1.RVF, Mild IU adhesions, subserous fibroid are
causes of RPL
2.The preferred technique for uterine malformation is
TV 3D US
3.Sonohysterography is less accurate than HSG in
diagnosing uterine malformations.
4.MRI is recommended for the assessment of uterine
malformations in women with RPL.
5.If a Müllerian uterine malformation is diagnosed:
Investigation of the kidneys and urinary tract
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13. A3. Anatomical factors
1. RVF, mild IU adhesions, subserous fibroid are not a cause
of RPL
2. The preferred technique for uterine malformation is TV 3D
US
{1. high sensitivity and specificity
2. distinguish between uterus septum and bicornuate uterus}.
3. Sonohysterography is more accurate than HSG in
diagnosing uterine malformations.
4. MRI is not recommended for the assessment of uterine
malformations in women with RPL
{higher costs and the absence of a diagnostic benefit compared to 3D
US. However, if 3D US is not available, MRI is a good alternative}.
5. If a Müllerian uterine malformation is diagnosed.
Investigation of the kidneys and urinary tract
US, MRI or CT. {with uterine malformations, 36% had associated
abnormalities, mostly renal
(Oppelt et al., 2007; Ramanathan et al., 2016).
ABOUBAKR ELNASHAR

14. Q4. Endocrinologic factors
1.TSH and Thyroid peroxidase-antibodies is not
recommended
2.Prolactin testing is not recommended in absence of
clinical symptoms of hyperprolactinemia.
3.Fasting insulin and fasting glucose are routinely
recommended
4.Ovarian reserve testing is not recommended
5.Testing vit D status is recommended
ABOUBAKR ELNASHAR

15. A4. Endocrinologic factors
1.TSH and TPO-antibodies is recommended
2.Prolactin testing is not recommended in absence of
clinical symptoms of hyperprolactinemia.
(oligo/amenorrhea)
3.Fasting insulin and fasting glucose are not routinely
recommended
4.Ovarian reserve testing is not recommended
5.Testing vit D status is not recommended
ABOUBAKR ELNASHAR

16.  Vit D
immune regulatory effects on NK cell cytotoxicity,
cytokine secretion and degranulation
(Ota et al., 2015).
 vit D deficiency (<20 ng/ml)
 Risk factor for gestational diabetes, SFGA and PET
(Aghajafari et al., SR, 2013).
 was associated with the increased prevalence of antiphospholipid antibody, antinuclear
antigen antibody (ANA), anti-ssDNA, and anti-thyroid peroxidase antibody (TPOAb), and
with higher peripheral blood CD19+ B and CD56+ NK cell levels and NK cytotoxicity
(Ota et al., 2014).
 Testing vit D status: not recommended in RPL
1. Although detected in 47.4% of RPL
2. No indications that vit D status is a contributing factor for RPL
3. Results for an association between vit D deficiency and RPL are less
consistent.
vit D
(ng/ml)
vit D
(nmol/l)
Category
>30 >75 Sufficiency
20-29 50-75 Insufficiency
<20 <50 Deficiency
ABOUBAKR ELNASHAR

17. Q5. Thrombophilia screening
1. Screening for inherited thrombophilia is
recommended.
2. Screening for antiphospholipid antibodies is
recommended
3. Antiphospholipid antibodies are LA , ACA IgG and
IgM, aβ2GPI .
4. For diagnosis of antiphospholipd syndrome 2
clinical and 2 lab finding are necessary
ABOUBAKR ELNASHAR

18. A5. Thrombophilia screening
1. Screening for inherited thrombophilia is not
recommended.
{No or weak association}
2. Screening for antiphospholipid antibodies is
recommended
3. Antiphospholipid antibodies are LA , ACA IgG and
IgM, aβ2GPI
4. For diagnosis of antiphospholipd syndrome one
clinical and one lab finding are necessary
ABOUBAKR ELNASHAR

19.  Thrombophilia
 Predisposition to thrombosis
 Causes:
I. Acquired:
antiphospholipid syndrome (APS).
II. Inherited
1. Factor V Leiden mutation (FVL) (homozygous or
heterozygous)
2. Prothrombin (FII) G20210A mutation
(Pm) (homozygous or heterozygous)
3. Deficiencies of the endogenous anticoagulants
Antithrombin (AT)
Protein C
Protein S.
4. Hyperhomocysteinemia (C677T) mutation
Methyl tetrahydrofolate reductase (MTHFR C677T)
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20.  RCOG, 2011
Inherited Thrombophilia: 2nd TRM
1. Factor V Leiden mutation
2. Prothrombin gene mutation
3. Protein S deficiency
 SMFM, 2016
Do not screen
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21. APS
Sydney criteria, 2006
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22. Non-criteria (clinical and laboratory) obstetric APS., 2014
Diagnosis:
a) Non-criteria clinical manifestations with
international consensus laboratory criteria OR
b) International consensus clinical criteria with
non-criteria laboratory manifestation.
ABOUBAKR ELNASHAR

23. Q6. Male factors
1. Assessment of life style factors, smoking, alcohol
consumption, exercise pattern, and body weight is
recommended
2. Assessing sperm DNA fragmentation can be
considered in RPL
3. There is no correlation between SDF score more
than 30 and RPL
4. Increased SDF is found in 8% of unexplained RPL
according to some studies
ABOUBAKR ELNASHAR

24. A6. Male factors
1. Assess life style factors smoking, alcohol
consumption, exercise pattern, and body weight
2. Assessing sperm DNA fragmentation can be
considered in RPL
There is a moderate body of evidence indicating associations between RPL
with elevated DNA fragmentation.
3. There is a significant correlation between SDF
score more than 30 and RPL
4. Increased SDF is found in 80% of unexplained RPL
according to some studies
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25. ABOUBAKR ELNASHAR

26. Normal= 10
Fragmented= 4
DFI= 4X100/10+4
=28.5%
normal
normal
normal
normal
normal
normal
normal
normal
normal
fragmented
fragmented
fragmented
fragmented
normal
≥30: male infertility
15-30: RM.
≤15: Excellent to Good fertility potential
ABOUBAKR ELNASHAR

27. Q7. Immunological screening
1.Antinuclear antibodies testing could be considered
for explanatory purpose
2. Measurement of anti-HY* antibodies is
recommended
3.Cytokine testing or cytokine polymorphisms is not
recommended
4.NK cell testing is recommended
5. Human leukocyte antigen (HLA) determination in
women with RPL is not recommended
ABOUBAKR ELNASHAR

28. A7. Immunological screening
1.Antinuclear antibodies testing could be considered
for explanatory purpose
The majority of case-control studies document an association to RPL.
There is some evidence that ANA presence affects the prognosis
negatively
2. Measurement of anti-HY antibodies is not
recommended
3.Cytokine testing or cytokine polymorphisms is not
recommended
4.NK cell testing is not recommended
1. weak association between NK cells in peripheral blood and RPL,
2. NK cell testing cannot be used to select women with RPL for
immunological treatments
3. There are significant technical challenges
5.Human leukocyte antigen is not recommended
{no significant effect on RPL}
ABOUBAKR ELNASHAR

29. Q8. Screening for genetic factors
1.Genetic analysis of pregnancy tissue is routinely
recommended
2.For genetic analysis of the pregnancy tissue, array-
Comparative Genomic Hybridization (CGH) is
recommended
3.Parental karyotyping is routinely recommended.
4.In case of established carrier status: the long-term
prognosis of a live birth is good in carriers of a
structural chromosome abnormality
ABOUBAKR ELNASHAR

30. A8. Screening for genetic factors
1.Genetic analysis of pregnancy tissue is not
routinely recommended
but it could be performed for explanatory purposes.
2.For genetic analysis of the pregnancy tissue,array-
Comparative Genomic Hybridization (CGH) is
recommended
{based on a reduced maternal contamination effect}.
3.Parental karyotyping is not routinely recommended.
But could be carried out after individual assessment of risk.
4.In case of established carrier status: the long-term
prognosis of a live birth is good in carriers of a
structural chromosome abnormality
(LBR of 71% in 2 years).
ABOUBAKR ELNASHAR

31. Genetic techniques
1. Conventional karyotyping:
 failure of tissue culture
 it does not distinguish between maternal contamination and a
normal (euploid) female fetus
(Robberecht et al., 2009).
2. Fluorescence in situ hybridization [FISH]
 only uses probes for certain chromosomes, and therefore does not
necessarily detect the chromosomal cause of the miscarriage.
3. Array–based comparative genomic hybridization [array-CGH]).
preferred technique
 looking at all chromosomes
 avoiding the limitations associated with karyotype and FISH
(Kudesia et al., 2014, Mathur et al., 2014).
4. Next generation sequencing (NGS)
have not yet been extensively investigated in genetic analysis of
pregnancy tissue but may be useful in the near future
(Shamseldin et al., 2013).
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32. II. Treatment of RPL
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33. Q9. Treatment for uterine abnormalities
1. Uterine septum: hysteroscopic septum resection
has beneficial effects
2. Didelphic uterus: insufficient evidence in favor of
metroplasty.
3. Bicornuate uterus: Metroplasty is recommended
4. Unicornuate uterus: uterine reconstruction is not
recommended.
ABOUBAKR ELNASHAR

34. A9. Treatment for uterine abnormalities
1. More research: whether hysteroscopic septum
resection has beneficial effects?
1. Improving LBR, and decreasing miscarriage rates, without doing
harm, should be evaluated.
2. Observational studies suggest
1. benefit of treatment in reducing the miscarriage rate,
2. but women were less likely to get pregnant after surgery.
2. Didelphic uterus: insufficient evidence in favor of
metroplasty.
3. Bicornuate uterus: Metroplasty is not
recommended
4. Unicornuate uterus: uterine reconstruction is not
recommended.
ABOUBAKR ELNASHAR

35. Q10. Treatment for uterine abnormalities
1. Intramural fibroids: Surgical removal is
recommended.
2. Fibroids distorting the uterine cavity: insufficient
evidence to recommend removing.
3. Submucosal fibroids or endometrial polyps:
hysteroscopic removal is recommended
4. Intrauterine adhesions: insufficient evidence of
benefit for surgical removal.
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36. A10. Treatment for uterine abnormalities
1. Intramural fibroids: Surgical removal is not
recommended.
2. Fibroids distorting the uterine cavity: insufficient
evidence to recommend removing.
No evidence that
 fibroids or polyps are associated with RPL
 myomectomy increases the chance of a live birth in RPL.
3. Submucosal fibroids or endometrial polyps: No
evidence supporting hysteroscopic removal.
4. Intrauterine adhesions: insufficient evidence of
benefit for surgical removal.
1. Small observational studies have shown that surgery may decrease
miscarriage rates in women with RPL.
2. However, uterine surgery is a known cause for adhesions, and
treatment should attempt to prevent recurrence of adhesions.
ABOUBAKR ELNASHAR

37. Q11. Cervical incompetence
1. History of recurrent 2nd trimester pregnancy loss
and suspected cervical weakness: Serial cervical
sonographic surveillance is recommended
2. History of recurrent 2nd trimester pregnancy loss
attributable to cervical weakness in singleton
pregnancy: Cerclage could be considered.
3. Two or more previous preterm births and/or
second-trimester losses is a sound indication for
cerclage
4. For Uterine anomalies: cerclage is recommended
ABOUBAKR ELNASHAR

38. A11. Cervical incompetence
1. History of recurrent 2nd trimester pregnancy loss
and suspected cervical weakness: Serial cervical
sonographic surveillance is recommended
2. History of recurrent 2nd trimester pregnancy loss
attributable to cervical weakness in singleton
pregnancy: Cerclage could be considered.
 Inconclusive evidence on the benefit
 No evidence increase perinatal survival
 Possible harms
3. Three or more previous preterm births and/or
second-trimester losses is a sound indication for
cerclage
4. For Uterine anomalies. History-or ultrasound-
indicated cerclage cannot be recommended
ABOUBAKR ELNASHAR

39. Q12. Treatment of endocrinologic abnormalities
1. Clinical hypothyroidism: Levothyroxine is not
recommended
2. Subclinical hypothyroidism: Levothyroxine may
reduce the risk of miscarriage
3. Thyroid autoimmunity: TSH level should be
checked in early gestation (7-9 w) and eventual
hypothyroidism should be treated with levothyroxine.
4. Euthyroid women with thyroid antibodies:
insufficient evidence to support treatment with
levothyroxine.
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40. A12. Treatment of endocrinologic abnormalities
1. Clinical hypothyroidism: Levothyroxine is recommended.
 Maternal and fetal complications associated with untreated
hypothyroidism
 Dose: 1.7 μg/kg/d or 25 μg/d adjusted by 25 μg/d every 2 to4 w until
euthyroid state is achieved.
2. Subclinical hypothyroidism: Treatment may reduce the risk
of miscarriage
3. Thyroid autoimmunity: TSH level should be checked in early
gestation (7-9 w) eventual hypothyroidism should be treated
with levothyroxine.
4. Euthyroid women with thyroid antibodies: insufficient
evidence to support treatment with levothyroxine.
T3FT4TSHHypothyroidism
decreaseddecreasedincreasedClinical
NormalNormalincreasedSubclinical
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41. Q13. Treatment of endocrinologic abnormalities
1. Hyperprolactinemia: Bromocriptine treatment is
recommended to increase LBR.
2. Luteal phase insufficiency: strong evidence to
recommend the use of progesterone.
3. Luteal phase insufficiency: insufficient evidence to
recommend the use of hCG.
4. PCOS: strong evidence to recommend metformin.
ABOUBAKR ELNASHAR

42. A13. Treatment of endocrinologic abnormalities
1. Hyperprolactinemia: Bromocriptine treatment is
recommended to increase LBR.
Bromocriptine or cabergoline during pregnancy
not associated with increased risk of
Teratogeniccity
abortion
1. Microadenoma:
dopamine agonist is stopped
[risk of tumour expansion is low]
2. Macroadenoma:
dopamine agonist is advised
[avoid significant tumour expansion]
2. Luteal phase insufficiency: insufficient evidence to
recommend the use of progesterone.
3. Luteal phase insufficiency: insufficient evidence to
recommend the use of hCG.
4. PCOS. Insufficient evidence to recommend metformin.
ABOUBAKR ELNASHAR

43. Q14. Treatment of RPL
1. Preconception counseling include the general
advice to consider prophylactic vit D
supplementation.
2. Inherited thrombophilia: antithrombotic
prophylaxis is recommended
3. APS: low-dose aspirin (75 to 100 mg/d), and heparin
(UFH or LMWH) starting at date of a positive pregnancy test
4. Assessing homocystein levels is routinely
recommended.
5. If Hyperhomocysteinaemia is detected treatments
are available that can lower Hcy levels and
possibly improve the chance of LBR
ABOUBAKR ELNASHAR

44. A14. Treatment of RPL
1. Preconception counseling include the general
advice to consider prophylactic vit D supplementation.
Even though evidence for the effectiveness is absent.
1. Significant prevalence of vit D deficiency in RPL (47%)
2. Vit D def: possibly associated obstetrical / fetal complications
Vit D supplementation can be considered safe.
Dose: RDR:
400 to 800 IU daily=10-20 ug daily
vit D def:
2,000 IU to 5,000 IU daily
2. Inherited thrombophilia: Not to use antithrombotic
prophylaxis
3. APS: low-dose aspirin (75 to 100 mg/d), and
heparin (UFH or LMWH) starting at date of a positive
pregnancy test .
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45. 4. Assessing Hcy levels is not routinely recommended.
5. If HHcy is detected treatments are available that can
lower Hcy levels and possibly improve the chance of
LBR
 Folic acid (5 mg) and vit B12 (0.5 mg) once daily
 No evidence to support 5 mg folic acid from prepregnancy stage purely
to reduce the risk of RPL
 Based on
 the absence of evidence for a benefit
 possible harms of high-dose folic acid supplementation
ABOUBAKR ELNASHAR

46. Q15. Treatment of RPL
1. Cessation of smoking, normal body weight, normal
exercise pattern is recommended.
2. Sperm selection is recommended as a treatment in
couples with RPL.
3. Antioxidants for men improve the chance of a live
birth.
4. No immunological biomarker, except for high-titer
antiphospholipid antibodies can be used for selecting
RPL patients for specific treatments.
5. An abnormal fetal or parental karyotype
genetic counseling is recommended
6. Prognosis depends on the number of preceding
pregnancy losses and female age.
ABOUBAKR ELNASHAR

47. A15. Treatment of RPL
1. Cessation of smoking, normal body weight, normal exercise
pattern is recommended.
2. Sperm selection is not recommended as a treatment in
couples with RPL.
In the absence of any data in RPL
ABOUBAKR ELNASHAR

48.  Sperm Selection from the ejaculated semen samples
(Sakkas and Alvarez, 2010).
i. Annexin-V columns:
reduce the percentage of spermatozoa with DNA fragmentation as
measured by the TUNEL test
ii. Sperm hyaluronic acid binding:
(Jakab et al., 2005; Said et al., 2005, 2006).
iii. Onfocal light absorption scattering spectroscopy (CLASS) technology
iv. Intracytoplasmic morphologically selected sperm injection (IMSI)
 high-magnification microscope (6000x), to identify spermatozoa
devoid of surface vacuoles
(Bartoov et al., 2003).
ABOUBAKR ELNASHAR

49. 3. Antioxidants for men not improve the chance of a live birth.
In a Cochrane review, antioxidants
did improve live birth rate in subfertile men
did not significantly decrease the risk of a pregnancy loss
4. No immunological biomarker, except for high-titer
antiphospholipid antibodies can be used for selecting RPL
patients for specific treatments.
5. An abnormal fetal or parental karyotype genetic counseling is
recommended
6. Prognosis depends on the number of preceding pregnancy
losses and female age.
ABOUBAKR ELNASHAR

50. Q16. Treatment for unexplained RPL
1. Lymphocyte immunization therapy should not be
used.
2. Intravenous immunoglobulin is recommended.
3. Glucocorticoids is not recommended.
4. Heparin or low dose aspirin does not improve LBR.
5. Low dose folic acid prevent pregnancy loss.
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51. A16. Treatment for unexplained RPL
1. Lymphocyte immunization therapy should not be
used.
{no significant effect and there may be serious adverse effects}.
2. Intravenous immunoglobulin is not recommended.
Expensive
Serious adverse effects: transfusion reaction, anaphylactic shock and
hepatitis.
(Stephenson et al, 2010MA)
3. Glucocorticoids not recommended.
Further studies
1. some beneficial effect of prednisolone in selected women with RPL
2. adverse events associated with the use of prednisolone,
4. Heparin or low dose aspirin does not improve LBR.
5. Low dose folic acid prevent NTD Not prevent
pregnancy loss.
ABOUBAKR ELNASHAR

52. Q17. Treatment for unexplained RPL
1. Vaginal progesterone improve LBR.
2. Intralipid therapy can be used.
3. Granulocyte colony stimulating factor (Neupogen):
insufficient evidence to recommended.
4. Endometrial scratching: strong evidence to be
recommended.
5. Multivitamin supplements are recommended as
treatment.
ABOUBAKR ELNASHAR

53. A17. Treatment for unexplained RPL
1. Vaginal progesterone does not improve LBR.
There is some evidence that oral dydrogesterone initiated when fetal
heart action can be confirmed may be effective but more trials are
needed.
2. Intralipid therapy should not be used.
{it could be harmful for the mother}
3. Ganulocyte colony stimulating factor: insufficient
evidence to recommended.
4. Endometrial scratching: no evidence to be
recommended.
5. Multivitamin supplements are not recommended as
treatment.
ABOUBAKR ELNASHAR

54. CONCLUSIONS
Routine Investigations after two consecutive
miscarriages:
1. 3D US or Sonohysterography
2. TSH, TPO Ab
3. Antiphospholipid antibodies
4. Sperm DNA fragmentation
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55. Treatment of possible causes
1. Uterine septum, submucous fibroid, severe IU
adhesions: Hysteroscopic surgery.
2. Cervical incompetence: cervical cerclage
3. Hypothyroidism or SCH: Eltroxin
4. APA: Low dose aspirin & heparin.
5. High SDF: Life style changes
6. Hyperprolactinemia: Dopamine agonist
ABOUBAKR ELNASHAR