Recurrent miscarriage (RM) occurs in 1-2% of women and is emotionally traumatic. While the cause is often unknown, risk factors include anatomical, immune, and thrombotic issues. Low dose aspirin and unfractionated heparin are used to treat RM caused by antiphospholipid syndrome and inherited thrombophilia. Meta-analyses show that combining aspirin and heparin increases live birth rates for women with RM associated with antiphospholipid antibodies. For unexplained RM, aspirin and heparin combined may potentially increase live birth rates by reducing hypercoagulability, though evidence is mixed. Unfractionated heparin is advocated as an effective and low-cost treatment

2. Ahmed Mostafa Sadek
Lecturer of Obs / Gyn
Benha Faculty of Medicine

3. Objectives
• INTRODUCTION
• INCIDENCE
• RISK FACTORS
• IMPACT
• TYPES
• LOW DOSE ASPIRIN
• UNFRACTIONATED HEPARIN

4. INTRODUCTION
According to the Royal College of
Obstetricians and Gynecologists (RCOG) , a
miscarriage can be defined as the
spontaneous loss of a pregnancy before the
fetus has reached viability at 24 weeks .
( Regan I. et al , 2011 )

5. The American Society for Reproductive
Medicine defines recurrent miscarriage
(RM) as two or more failed pregnancies,
which have been documented by either
ultrasound or histopathological
examination .
Ectopic and Molar pregnancy are not included

6. INCIDENCE
. RM occurs in ( 1 - 2 % )of women in
reproductive age
1 st T : 75 %
2 nd T : 25 %
(Alijotas-Reig & Garrido- Gimenez, 2013 )

7. Recurrence suggests a persistent cause
which must be identified and treated

8. RISK FACTORS
only in 50 % , the cause can be determined
1- Anatomical 10 %
2- Immune dysfunction 5 - 15 %
3- Maternal Thrombophilic disorder
4- Chromosomal anomalies 5 %
5- Endocrine disorder 5%
6- Epidemiological
However non of these factors are specific
to RM
(Laresen et al , 2013 )

9. Impact
It is emotionally traumatic to the parents
similar to neonatal death And frustrating
to the Doctor as etiology is not
determined in 50 %

10. TYPES
- Primary : couples never had a live birth
- Secondary : couples had a previous
successful pregnancy

11. Work up
U/S , 3 D U/S , HSG , and HysteroscopyAnatomical
Anticardiolipin antibodies & Lupus anticoagulant and
Anti B2 – glycoprotien -1 abs
APL
Factor V Leiden, Prothrombin gene Mutation and
protein S/C deficiency
Thrombophilia
Diabetes ,Thyroid disorder and PCOEndocrine
KaryotypingChromosomal

12. MANGMENT
- RM remains a great challenge as 50 %
are idiopathic
- Aspirin and Unfractionated Heparin are
used in RM caused by :
1- APS,
2- Inherited thrombophilia and
3- Unexplained RM

13. ASPIRIN
Its acetyl derivative of salicylic acid
3 hoursHalf life
80 % in liverMetabolism
kidneyExcretion

14. Low dose Aspirin therapy (60 – 150 mg/day )
is safe during pregnancy

15. 1- Irreversible blocking action of platelet
cyclo- oxygenase enzyme inhibit
platelet thromboxane A2 prevent
platelet aggregation
2 -The daily administration of LDA induce a
shift in the balance towards prostacycline ,
leading to VD and enhanced blood flow .
(Patrono C.et al, 2005).

16. 3- APL abs bind to negative charged
phospholipid membranes
- Activation of endothelial cells
activate complement pathway .
-Aspirin has capacity in complement
inactivation
protective effect against RPL and
Thrombosis .
(ALvaro -Danzo et al , 2011 )

17. Role in Unexplained RM
- In Unexplained RM recent studies show
impaired uterine perfusion with decrease
uterine and sub – endometrial blood flow
which play a central core in the pathogenesis
( Gunzel- Apel et al , 2009 )
- LDA shift balance towards Prostacycline
synthesis in endothelial cells  enhance
Nitric Oxide production  increase uterine
and sub-endometrial blood flow
( Rouzer &Marnett , 2009 )

18. - Highly sulfated glycosaminoglycan .
- Its molecular weight ranges from 3 kD to 30 kD,
containing approximately 45 monosaccharide
chains.
- Its anticoagulant activity varies because only one
third of Heparin has anticoagulant function.
( Hirsh et al , 2008 )
Heparin

19. LMWHUFH
1000 - 100003000 - 30000Mol. Wt. range
Inhibit - FXaBind to (AT- IIIMechanism of
action
Anti – FXaaPPTMonitoring
3 - 7 h1 - 5 hHalf - life
Partially reversedFully reversedProtamine sulfate
LessOsteoporosis-
HIT
Side effects

20. Role of Heparin in preventing
RM
Heparin may act to reduce fetal loss by ;
1-Binding to phospholipid Abs thus protecting
trophoblast phospholipid from attack.
2-Anti-coagulant action
(Mcintry JA. et al , 1995)
3-Recent studies show that Heparin
possibly can improve implantation
(Check et al , 2012)

21. There are multiple questions required to
be answered for evaluation of efficacy of
anti-thrombotic therapy for women with
RM:
1-Is it mandatory to use combination of heparin and
aspirin ?
2-Which type of heparin to be used ? unfractionated
heparin (UFH) or low-molecular weight heparin
(LMWH) ?

22. 3. If antithrombotic therapy succeeded to
control early pregnancy loss, is it effective
for prevention of late pregnancy loss and
prevent maternal morbidity?

23. Meta-analysis of randomized
controlled trials in women with RM
has shown that :
Combination of UFH and LDA could
reduce further pregnancy loss by 54 % .
( Empson et al, 2005 )

24. Meta-analysis studies of Randomized Controlled
Trials examined the outcomes of various
treatment including Aspirin, Steroids , I.V.
Globulin and Heparin given to improve
pregnancy outcomes of women with RM
associated with APL reported that ,
The only treatment accompanied by significant
live birth rates are among women treated by
Aspirin + UFH
(Cochrane library . 2005 )

25. In Unexplained RM and Inherited
Thrombophilia ,
LDA plus Heparin could potentially
increase live birth rates, since hyper
coagulability might result in RM .
( Cochrane Library . 2009 )

26. Systematic Review and Meta – analysis on
292 studies show that :
- The combination of UFH and Aspirin
had a significant benefit in live birth
rates .
( 0bst Gyne ,june 2010,115 (6) 1256-62. )

27. Meta -analysis studies show that :
The combination of Heparin and
Aspirin is superior to Aspirin alone in
enhancing live birth rates in women with
RM and + ve APL abs
(Mak A. et al , 2010)

28. RCOG guidelines 2011 ,
Although Aspirin plus Heparin treatment
improves the live birth rate of women with
these pregnancies remain atRM with APL abs ,
high risk of developing complications during
.all three trimesters

29. Combined aspirin / heparin treatment
versus placebo in women with
unexplained RM
No difference in Live birth rate
( Kaandorp , 2010 )

30. In 2011; Histological examination of the
placenta from pregnancies complicated
with APS and IT showed that :
Anticoagulant therapy does not prevent
either fibrin deposits or other placental
changes
(Skrzypczak et al , 2011).

31. In 2012; Check et al; found that :
-Either UFH or LMWH is recommended for
APS.
-Possibly UFH is superior to LMWH in
improving implantation.
-There is no evidence that UFH has any
benefit in preventing miscarriage from
unexplained causes.
-However the exact timing of heparin is still
being evaluated.

32. In 2014; de Jesús et al., documented that
Treatment of patients with APS during
pregnancy with UFH and aspirin can act
by :
improving live birth rates, but
other obstetric morbidities remain high.

33. Finally according to Royal Collage green top
guidelines, April 2011
-No difference in efficacy and safety between UFH
and LMWH when combined with aspirin in
recurrent miscarriage with APS.
-LMWH is safe as UFH and have a potential
advantage during pregnancy since it is once daily
, less thrombocytopenia and low risk for
osteoporosis.
- Empirical treatment with Aspirin alone or
combined with heparin is unnecessary for
unexplained RM.

34. - Neither corticosteroids nor intravenous
immunoglobulin therapy improve live birth
rate of women with RM associated with APL
abs , their use may provoke significant
maternal and fetal morbidity
-Women with APL should considered for
postpartum thrombo-prophylaxis.

35. conclusions
- RM has multi factorial causes with bad
psychological impact on parents.
- LDA plus UFH are used safely in RM with
APL abs , Thrombophilia and Unexplained
RM .

36. - Postpartum thrombo-prophylaxis is mandatory .
- Considering cost/effectiveness, UFH is
available, cheap and with the same efficacy on
pregnancy as LMWH, so it is advocated as a
therapeutic modality.