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Introduction
Recurrent pregnancy loss is frequently associated with immunological causes Most frequently the ANTI PHOSPHOLIPID SYNDROME
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Definition:
Anti-phospholipid antibodies are a group of heterogeneous family of auto antibodies directed against phospholipid binding proteins Of approximately 20 antibodies, two are mostly significant
Lupus Anticoagulant (LA) Anticardiolipin Antibody (aCL)
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APLA is present when one or more of the following Clinical and one or more of the Laboratory criteria is present
CLINICAL
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CLINICAL CRITERIA
Vascular thrombosis:
Any
Pregnancy morbidity:
Any
birth of a morphologically normal neonate before 34 weeks of gestation because of severe preeclampsia or severe placental insufficiency Any unexplained death of a morphologically normal fetus at or beyond 10th week of gestation, normally documented by direct examination or ultrasound Atleast three consecutive abortions before the 10th week with maternal anatomic chromosomal and hormonal causes excluded
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LABORATORY CRITERIA
Anti Cardiolipin (aCL) IgG and/or IgM in medium or high titre on two or more separate occasions atleast 6 weeks apart measured by standardised ELISA for 2 Glycoproetein inhibitor-dependant aCL Lupus Anticoagulant- on two or more occasions atleast 8 weeks apart detected according to guidelines of standard committee
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Incidence:
In women with normal pregnancy: 0.2% for LA,2% for aCL In women with h/o Reccurent miscarriage:5% In women with 3/4th fetal losses: 7% In women with diagnosed APLA:80% pregnancies resulted n fetal loss
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Recurrent pregnancy loss Unexplained 2nd or 3rd trimester abortions Early onset severe pre eclampsia Venous or arterial thrombosis Unexplained fetal growth restriction Auto immune or connective tissue disorder False positive serological test for syphilis Prolonged coagulation studies Positive antibody tests
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Pathophysiology
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Thrombotic theory:
Anti phospholipid antibodies bind to negatively charged phospholipids a phenomenon which is dependant on certain co factors Both LA and aCL need a cofactor for exerting their action
LA-
of platelets causing release of procoagulant thromboxane 2 GP I causes natural inhibition of the coagulation pathway, platelet prothrombinase activity
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of prostacyclin by endthelial cells Endothelial cell damage leading to increased pro coaugulant activity Inhibition of protein C/S
Annexin hypothesis:
Annexins are soluble hydrophillic proteins tat bind to negatively charged phospholipids in a reversible calcium dependant manner Annexin V is produced by villous trophoblast and by binding with phospholipids,acts as an anti coagulant in intervillous space aPL reduces level of annexin hypothesis
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Pregnancy loss in APLA may be due to defective embryonic implantation and subsequent placentation. Circulating estrogen and progestrone levels induce morphological changes n endometrium during menstural cycle
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Prolactin and insulin growth factor binding protein -1 (pRL , IGFPP-1) expression increases during progesterone induced decasualization in vivo Monoclonal Anti Cardiolipin Antibody ID2 acts on pRL and IGFPP-1 levels significantly reducesthereby reducing endometrial function
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CLINICAL FEATURES:
NEUORLOGICAL
Transient ischemic attacks Cerebrovascular attacks Chorea Peripheral neuropathy Migraine Epilepsy
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OBSTERIC
Recurrent miscarriage Intra uterine growth retardation Intra uterine death Pre eclampsia Chorea Gravidarum Neonatal thrombosis
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DERMATOLOGICAL
Livedo reticularis Prothrombin deficiency
HEMATOLOGICAL
Thrombocytopenia Prothrombin deficiency
VASCULAR
Venous thrombosis Arterial thrombosis Mitral valve prolapse Thrombotic endocarditis
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Investigations:
Laboratory detection
Abnormality
Tests are
APTT (Activated partial TT) KCT (Kaolin clotting time) TTIT (Tissue thromboplastin inhibition time) dRVVT (Dilute russel vipers venom time)
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Treatment:
A variety of treatment regimes have been used in attempt to improve fetal outcome in APLA Treatment can be mainly classified into following categories
Steroids Low dose aspirin Heparin Other treatments
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Steroids
Rationale behind use of steroids in immunosuppressive doses to normalize the prolongation of in vitro coagulation times and to decrease the titers of ACA. Although the initial response o treatment was promising ,on subsequent follow up ,fetal outcome was poor
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Many studies have confirmed a steady deterioration of fetal outcome with Prednisolone The dose initially prescribed was 10-60 mg daily Complications associated:
Increased risk of pre term delivery Intra uterine fetal growth restriction Development of hypertension Cushnoid features Vertebral body collapse Significant infections
In view of the above complications , Prednisolone as treatment for APLA has been abandoned
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HEPARIN
Heparin is a mixture of polysaccharides with an average molecular mass of 15 000 Da After administration it has immediate effect on coagulation system potentiating the formation of irreversible complexes between antithrombin III and the activated serine protease coagulation factors ( thrombin , XII a , XI a , I X a , and V II a)
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Unfractioned heparin
Dose ranges between 10, 000-36 000 ) Initial dose 12 500 U subcutaneously ,upto a full loading dose of 24 500 U. Dose of heparin is adjusted to maintain a mid interval ratio of 1.5-2 times that of control Most significant complication is osteopenia due to bone mineralization Has number of advantages over Unfractioned heparin It has increased anti thrombotic ratio, associated with lower incidence of abnormal bleeding , thrombocytopenia , and osteopenia Dose- 5,000 10 ,000 subcutaneously
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Other treatments
These alternative treatment intravenous Immunoglobin ,Plasmapheresis, Azathioprine. Immunoglobin causes idiotypic down regulation of auto antibody production
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Conclusion:
Anti phospholipid antibodies are associated with recurrent miscarriage ,early onset pre eclampsia , placental abruption and infertility At present low dose Aspirin in combination with low molecular weight heparin are favored therapies In pregnancies beyond 24 weeks gestation close antenatal surveillance required in the form of regular ultrasound to assess fetal growth, Doppler studies for uterine and umbilical artery flow is required.
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