Recurrent miscarriage RCOG, 2011 Up to date, 2013

1. Recurrent miscarriage
RCOG, 2011
Up to date, 2013
Aboubakr Elnashar
Benha university, Egypt
elnashar53@hotmail.com
ABOUBAKR ELNASHAR

2. Contents
Introduction
Causes
Evaluation
Treatment
Conclusion
ABOUBAKR ELNASHAR

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
2 or more
(ASRM, 2008)
ABOUBAKR ELNASHAR

4. INCIDENCE
Recurrent miscarriage
2 or more: 3%
3 or more: 1%
of the population
(Regan et al, 2000).
1–2% of 2nd T pregnancies miscarry before 24 w
1st T: 75% of RM
2nd T: 25%
ABOUBAKR ELNASHAR

5. CAUSES
ABOUBAKR ELNASHAR

6.  Possible
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,
subclinical hypothyroidism
3. PCOS
ABOUBAKR ELNASHAR

7. III. Atiphospholipid antibody syndrome
IV. Inherited Thrombophilic Defects
1. Factor V Leiden mutation
2. Prothrombin gene mutation,
3. Hyperhomocysteinemia
4. protein c, protein s, antithrombin III deficiency
V. Genetic: 25%
1. Parental chromosomal abnormalities
2–5% of couples with RM
2. Embryonic chromosomal abnormalities
30–57% of further
ABOUBAKR ELNASHAR

8.  Doubtful causes
I. Anatomic:
1. RVF
2. Mild IU adhesions.
3. Subserous fibroid
4. Arcuate uterus
II. Endocrine:
1. Endometriosis.
2. Inadequate luteal phase
3. Hyperprolactinemia
ABOUBAKR ELNASHAR

9. III. Infections:
1. Toxoplasmosis 2. Mycoplasma
3. L. monocytogenes 4. C. trachomatis
5. HSV 6. CMV
IV. Immunologic:
1. Alloimmune
2. Antithyroid antibodies
V. 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.ABOUBAKR ELNASHAR

10. Paternal causes
MA: significant increase
in miscarriage in patients with high DNA damage
compared with those with low DNA damage
(Robinson et al, 2012)
85% of u RM
(Maynou et al, 2012)
Men with higher DFI are infertile
Men with lower DFI (26 %) are able to conceive
but experience RM.
ABOUBAKR ELNASHAR

11. EVALUATION
ABOUBAKR ELNASHAR

12. 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
ABOUBAKR ELNASHAR

13. Surgical:
uterine instrumentation (intrauterine adhesions)
Menstrual:
Irregular menstrual cycles (endocrine
dysfunction).
Galactorrhea (hyperprolactinemia)
Family:
Eenvironmental (toxins)
Venous or arterial thrombosis (APA synd)
Previous laboratory, pathology, and imaging
ABOUBAKR ELNASHAR

14. Physical examination
Signs of endocrinopathy
Hirsutism
Galactorrhea
Pelvic organ abnormalities
uterine malformation
cervical laceration.
ABOUBAKR ELNASHAR

15. INVESTIGATIONS
1. Anatomical factors
Pelvic ultrasound and/or HSG or
sonohysterography
initial screening test
Hysteroscopy, laparoscopy or 3DUS
definitive diagnosis.
ABOUBAKR ELNASHAR

16. 2. Endocrine
TSH
1. clinical manifestations
2. personal history of thyroid disease.
3. asymptomatic for subclinical hypothyroidism
[Negro et al, 2010]
Thyroid peroxidase (TPO) antibodies
Controversial
[Chen et al, 2011; Thangaratinam et al, 2012].
ABOUBAKR ELNASHAR

17. 3. 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.
ABOUBAKR ELNASHAR

18. 4. Thrombophilias
screening for inherited thrombophilias
factor V Leiden,
factor II (prothrombin) gene mutation
protein S deficiency
ABOUBAKR ELNASHAR

19. 5. 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.
.
ABOUBAKR ELNASHAR

20. TREATMENT
ABOUBAKR ELNASHAR

21. 1. Anatomical factors
1. Congenital uterine malformations
uterine septum
hysteroscopic resection
2. Submucosal fibroid:
Hysteroscopic myomectomy
3. Severe IU adhesions:
Hysteroscopic surgery
ABOUBAKR ELNASHAR

22. 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.
ABOUBAKR ELNASHAR

23. 2. Endocrine factors
PCOS
Metformin supplementation
No RCT
Metformin during pregnancy: reduction in the
miscarriage rate
ABOUBAKR ELNASHAR

24. 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

25. 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 is recommend
(Up to date, 2013)
ABOUBAKR ELNASHAR

26. 3. Antiphospholipid syndrome
low-dose aspirin plus heparin
reduces the miscarriage rate by 54%
No difference in efficacy and safety between
unfractionated heparin and low-molecular-weight
heparin when combined with aspirin
Low dose Asprin
no adverse fetal outcomes
ABOUBAKR ELNASHAR

27. 4. Inherited thrombophilias
Heparin
R 1st TM
insufficient evidence may improve LBR for these
women
R 2nd TM
improve the live birth rate
ABOUBAKR ELNASHAR

28. Infection
Treatment of asymptomatic abnormal vaginal flora
and bacterial vaginosis with oral clindamycin
early in the second trimester significantly reduces
the rate of late miscarriage and spontaneous
preterm birth in a general obstetric population
[20,94] (Evidence II).
ABOUBAKR ELNASHAR

29. 5. 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
ABOUBAKR ELNASHAR

30. 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.
ABOUBAKR ELNASHAR

31. Unexplained recurrent miscarriage
I. No treatment:
supportive care alone
Chance of a live birth is good: over 50%
ABOUBAKR ELNASHAR

32. II. Treatments:
Low risk, simple, and cheap
1. Lifestyle modification
 Stop tobacco products, alcohol
 Caffeine reduction
 Reduction BMI (for obese women).
 No RCT.
ABOUBAKR ELNASHAR

33. 2. Progesterone
controversial
MA: significant benefit
[Haas et al, 2008; Coomarasamy et al, 2011].
{small, number of women <140
wide confidence intervals
methodological problems in study design}.
Beneficial: 203 cases: natural progesterone
vaginal pessaries 400 mg 12-h until 12 w (Munawar et
al, 2012)
Mechanism:
Progesterone is necessary for successful implantation and
maintenance of pregnancy.
immmunomodulatory actions
[Choi et al, 2000].
ABOUBAKR ELNASHAR

34. Dose:
Progesterone vaginal Supp
200 mg three times daily,
Progesterone vaginal gel
90 mg once daily
Micronized oral progesterone:
100 mg orally, two to three tablets per day
Duration:
Start: 3 days after the LH surge {not to inhibit
ovulation}
Continue: until 10 w {placental progesterone
production fully functional}
ABOUBAKR ELNASHAR

35. 3. Aspirin with or without heparin
No improvement
ABOUBAKR ELNASHAR

36. 4. 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)
[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.
ABOUBAKR ELNASHAR

37. 5. Human chorionic gonadotropin
insufficient evidence , No RCT
During early gestation may be useful in
preventing miscarriage
{endogenous hCG plays a critical role in the
establishment of pregnancy }
ABOUBAKR ELNASHAR

38. 6. Human menopausal gonadotropin
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).
ABOUBAKR ELNASHAR

39. 7. IVF and PGD
Evidence is lacking: Similar results.
(Pellicer et al, 1999)
Embryos of women with uRM have a higher
incidence of aneuploidy for chromosomes 13,16,18,
21, 22, X, and Y than embryos obtained from
healthy women
[Hassold et al, 1980)
Not recommend
(Visenberg, 2012)
ABOUBAKR ELNASHAR

40. 8. 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. RPL due to immunologic issues, particularly
elevated natural killer cells or other unidentified
immunologic causes.
2. uRPL
3. uRIF ABOUBAKR ELNASHAR

41. 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
ABOUBAKR ELNASHAR

42. CONCLUSIONS
ABOUBAKR ELNASHAR

43. Investigations
After two or three consecutive miscarriages:
1. Pelvic US (or HSG or Sonohysterography)
2. Antiphospholipid antibodies
3. TSH ±thyroid peroxidase antibodies
4. Factor V Leiden, factor II (prothrombin) gene
mutation and protein S.
5. If the above examinations are normal: karyotype
of the abortus: unbalanced structural chromosomal
abnormality: Parental karyotype
ABOUBAKR ELNASHAR

44. Treatment
1. Uterine septum, submucous fibroid, severe IU
adhesions: Hysteroscopic surgery.
Cervical incompetence: cervical cerclage
2. PCOS: Metformin.
Subclinical hypothyroidism: Eltroxin
3. Positive APA: Low dose aspirin & heparin.
4. Inherited thrombophilias: Heparin
5. Karyotyping abnormalities: Clinical geneticist.
6. Unexplained: Reassurance
ABOUBAKR ELNASHAR

45. Thank youABOUBAKR ELNASHAR