الرحمن الله بسم الرحيم

Recent Evidence For Aspirin and Unfractionated Heparin in

Recurrent Miscarriage

Ahmed Mostafa Sadek

Lecturer of Obs / Gyn

Benha Faculty of Medicine

Objectives

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

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)

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

INCIDENCE. RM occurs in ( 1 - 2 % )of women in reproductive age

1 st T : 75 %

2 nd T : 25 %

(Alijotas-Reig & Garrido- Gimenez, 2013)

Recurrence suggests a persistent cause which must be identified

and treated

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- EpidemiologicalHowever non of these factors are specific to RM

(Laresen et al , 2013)

Impact

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

TYPES

-Primary : couples never had a live birth

- Secondary : couples had a previous successful pregnancy

Work up U/S , 3 D U/S , HSG , and Hysteroscopy Anatomical

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 PCO Endocrine

Karyotyping Chromosomal

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

ASPIRIN

Its acetyl derivative of salicylic acid

3 hours Half life

80 % in liver Metabolism

kidney Excretion

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

Role of Aspirin in RM with APL and IT1- 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) .

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 )

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 )

- 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

LMWH UFH

1000 - 10000 3000 - 30000 Mol. Wt. range

Inhibit - FXa (Bind to (AT- III

Mechanism of action

Anti – FXa aPPT Monitoring

3 - 7 h 1 - 5 h Half - life

Partially reversed

Fully reversed Protamine sulfate

Less Osteoporosis-HIT

Side effects

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)

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) ?

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

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 )

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 )

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 )

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. )

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)

RCOG guidelines 2011,

Although Aspirin plus Heparin treatment improves the live birth rate of women with RM with APL abs ,these pregnancies remain at high risk of developing complications during all

three trimesters .

Combined aspirin / heparin treatment versus placebo in

women with unexplained RM

No difference in Live birth rate

(Kaandorp , 2010)

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).

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.

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.

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.

- 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.

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 .

- 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.

Thank You