Autoimmunity and Recurrent Pregnancy Loss

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Autoimmunity and Recurrent Pregnancy Loss

• Emad El-Din Khalifa M.D.
• Professor OB/GYN
• Faculty of Medicine - Alexandria University
• Clinical Director of IVF-ICSI Unit
• Dar Al-Khosouba Centre

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General Concepts of Immunology of Pregnancy

• The immune system protects cells , tissues
• and organs perceived as self and attacks
• and destroys foreign or non-self biological
• materials.
• Both Cellular and Humoral Factors are Involved.

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• Cellular Factors lymphocytes and
• macrophages .
• Humoral Factors Antibodies and
• complement system.

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Cellular Factors

• Lymphocyte populations originate at the
• thymus ( T lymphocytes) and bone marrow
• ( B lymphocytes) .
• T lymphocytes - T helper and T suppressor.
• - Produce cytokines
  which promote
• and activate resting
  lymphocytes
• and phagocytes.
  
• B lymphocytes antibody biosynthesis.

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Humoral Factors

• Antibodies or Immunoglobulins (Ig) are
• serum glycoproteins , synthesized and
• secreted by the plasma cells originating
• from B lymphocytes in response to
• antigenic stimulation.
• The most abundant antibody Ig G
• .

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• Ig G
• is transported actively and selectively
• across the placenta to the fetal circulation
• by a process called transcytosis , conveying
• passive immunity to the fetus.

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• Ig M
• -the largest Ig molecule
• -the first class of antibody produced by a
• developing B cell (hence a useful marker for
• recent infection)

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Pregnancy Effects on the maternal immune response

• 1. A unique immunologic state a natural
• homeostasis exists between antigenically
• different tissues.

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• 2. Normal maternal levels of the various
• immunoglobulins and their normal response
• to vaccination have been demonstrated.
• 3. Numerous studies have shown normal
• number and functions of circulating B and
• T lymphocytes during pregnancy.

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• 4. Several immunoregulatory substances
• have been shown to be produced at the
• maternal embryonal interface and may
• cause local immunosuppresion.

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Immune mediated diseases and pregnancy

• 1. Erythroblastosis fetalis.
• 2. Immune thrombocytopenic purpura.
• 3. Preeclampsia.
• 4. Recurrent abortion.
• 5. Type I Diabetes Mellitus.
• 6. Graves disease.
• 7. Hashimoto thyroiditis.
• 8. Pregnancy specific dermatoses.

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Immune mediated diseases and pregnancy

• 9. Antiphospholipid antibodies.
• 10. Systemic lupus erythematosus
• 11. Rheumatoid arthritis.
• 12. Scleroderma.

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• ANTIPHOSPHOLIPID ANTIBODY SYNDROME
• (aPLS)

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Antiphospholipid antibody syndrome(aPLS)

• The relation between antiphospholipid
• antibodies and pregnancy loss has been
• suggested 25 years ago.
• aPLS is a treatable cause of fetal loss,
• recurrent pre-embryonic and embryonic
• loss .

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Diagnosis of aPLS

• ONE MAJOR clinical criterion
• TWO LAB. Criteria
• 1. ve serum lupus anticoagulant (LA)
• on 2 occasions 8 or more weeks
• apart.
• 2. ? anticardiolipin (aCL) Ig G or Ig M in
  the
• medium or high titre on 2 occasions
• 8 or more weeks apart.

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Clinical criteria of aPLS

• 1. Pregnancy morbidity
• a) one or more unexplained deaths of a
• morphologically normal fetus at or
• beyond 10th week of gestation.
• b) one or more premature births at
• or before 34th week of gestation due
• to severe PET or placental
• insufficiency.

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Clinical criteria of aPLS

• 1. Pregnancy morbidity
• c) Three or more consecutive
• spontaneous abortions before the 10th
• week (no maternal anatomic and
• hormonal abnormalities , maternal
• and paternal chromosomal
• abnormalities)

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Clinical criteria of aPLS

• 2. Vascular thrombosis
• a) Recurrent DVT.
• b) Peripheral arterial gangrene.
• c) Cerebrovascular stroke.
• d) Coronary thrombosis.
• e) Pulmonary hypertension.
• 3.Other immune or connective tissue disease
• a) SLE.
• b) Thrombocytopenia.

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LAB. Criteria

• Anticardiolipin antibodies are antibodies
• against certain phospholipid component
• of cell walls.
• The higher the levels ? the greater the
• risks to the fetus.
• Lupus anticoagulant has to be positive
• on 2 occasions , 6-8 weeks apart to avoid
  false positive result (e.g. infective disease)

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LAB. Criteria

• The incidence of various pregnancy
• morbidities and thrombotic complications are
• higher in women with ve lab. Criteria .

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Impact of aPLS on pregnancy

• Recurrent or early onset PET and fetal growth
  restriction.
• Recurrent early pregnancy abortion of both
  embryonic or pre-embryonic pregnancy
• Three consecutive abortions are usually necessary
  for suspecting aPLS

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Pathological Findings in aPLS

• The placenta is one of the major targets
• 2nd and 3rd trimester fetal death is very
  specific for aPLS.
• Fetal death is usually preceded by IUGR and
  oligohydramnios.
• Uteroplacental insufficiency is due to
  vasculopathy of the spiral arteries.

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Pathological Findings in aPLS

• Decreased placental weight
• Massive infarction of the placenta
• Intravasular thrombosis

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Pathophysiology of aPLS

• Hypothesis suggested for the Hypercoagulable
  state of the placental circulation
• 1. thromboxane A2 a potent
• vasoconstrictor favouring platelet
• aggregation. Ig G of patients with
• aPLS can ? endothelial cell
• production of prostacyclin and ?
• placental thromboxane A2.

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Pathophysiology of aPLS

• 2. Antiheparin sulphate /heparin activity
• may be responsible for autoimmune
• vascular thrombosis.
• 3. Antiphospholipid antibodies?
• procoagulant effect by inhibiting the
  
• phospholipid dependent activation of
• protein C

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Pathophysiology of aPLS

• 4. Increased platelet secretion of
• thromboxane A2.

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Management of aPLS

• A classification system of aPLS has been
• proposed to aid in the choice of appropriate
• treatment ?? three grades
• 1.Definite / Classical aPLS patients with
• a)LA or medium to high level of IgG or IgM aCL
  and history of prior fetal death.

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Management of aPLS

• b) Recurrent pre-embryonic or
  embryonic
• pregnancy loses.
• c) Neonatal death after delivery following
• severe PET
• d) IUGR.

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Management of aPLS

• 2.Syndrome of low levels of IgG or IgM aCLwith a
  history of fetal death or recurrent pre-
  embryonic or embryonic loss
• 3. Syndrome of aPLS without lab. criteria of LA
  and aCL but associated with a history of fetal
  death or recurrent pre- embryonic or embryonic
  loss

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Lines of management

• Preconception councelling.
• Low dose aspirin.
• Heparin
• Corticosteroids
• Immunoglobulins
• Treatment of patients with history of thrombosis
• Prevention of complications of placental
  insuffuciency.
• Postpartum treatment
• Treatment of syndrome with low level antibodies

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Lines of management

• Preconceptional counselling
• patients with classical aPLS should be
• frankly counselled about the risk
• entailed in any future pregnancy upon
• their health and the outcome of the
• pregnancy.
• Patients with secondary aPLS ( SLE ,renal disease
  , HTN, haemolytic anaemia) may need additional
  care due to exacerbations occurring with
  pregnancy.

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Lines of management

• 2. Low dose aspirin
• Daily intake of 60-80 mg of aspirin blocks
• the conversion of arachidonic acid to
• thromboxane A2 while sparing
• prostacyclin production.

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Lines of management

• 3. Heparin
• Given in a dose of 5000 10,000 units
• S.C. , every 12 hours.
• It prevents thrombosis in the
• microcirculation of decidual/trophoblastic
• interface that may put part of the
• placenta out of function

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Lines of management

• 3. Heparin
• It binds to ß2 glycoprotein I on the
• syncitiotrophoblasts?preventing binding
• of anti CL and anti ß2 glycoprotein I
• antibodies to their surfaces ?
• preventing surface damage and initiation
• of clotting.
• Start treatment early in pregnancy? 34th week
  gestation.

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Lines of management

• 3. Heparin
• Side effects bleeding tendency
• osteoporosis , heparin
  
• induced
  thromboctopenia.
• Monitoring twice weekly aPTT (
  activated partial thromboplastin time)

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Lines of management

• 3. Heparin
• Low molecular weight heparin( LMWH)
• - replaced unfractionated heparin
• -better bioavalability
• -increased half life
• -e.g. clexane, fraxiparine
• - administered S.C. once daily without the
  necessity of lab. Monitoring.
• - do not cross the placenta ? no adverse
  effects on the fetus and neonate

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Lines of management

• 4. Prednisone
• 40 mg per day in combination with low
• dose aspirin.
• Lower doses resulted in 60 success
• rate in preventing complications of
• pregnancy.
• Long term use may induce D.M. or
• predispose to infections.

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Lines of management

• 5.Immunoglobulins
• When other first line therapy has failed
• especially in associated PET and IUGR.
• Administered I.V. In a dose of 0.4g/kg
• daily for 5 days . Repeated monthly.
• RCT of aPLS treatment indicate that
• heparin plus low dose aspirin are more
• effective than aspirin alone.

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Lines of management of aPLS

• Heparin should better not be used with
• prednisone because both predispose to
• osteoporosis.

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Lines of management of aPLS

• 6.Women with aPLS and history of
• thrombosis during or before pregnancy
• Should be fully anticoagulated by heparin
• ( or LMWH) throughout the pregnancy and
• in the postpartum period when the patient
• can be switched to warfarin.

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Lines of management of aPLS

• 7.Prevention of complications of pregnancy
• (PET, IUGR , prematurity ,neonatal death)
• Intensive surveillance of the patients
• Weekly clinic visit and NST
• Sonography every 2 weeks

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Lines of management of aPLS

• 8.Treatment of patients with low level of
• antibodies ( aCL)
• (Recurrent pre-embryonic or embryonic
• pregnancy loss , no history of thrombosis or
• SLE)
• ??? ?? NO NEED FOR HEPARIN
• May benefit from LOW DOSE ASPIRIN
• ALONE

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Take home message

• aPLS is an important preventable cause
• of pregnancy wastage.
• Timely and appropriate treatment ?
• improved perinatal outcome.
• Patients with definite aPLS need adequate
• doses of heparin for thromboprophylaxis.
• Special care is needed for early detection
• and prevention of late pregnancy
  complications

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Take home message

• Patients who develop thrombotic
• complication during pregnancy or have a
• past history should be fully
• anticoagulated throughout the pregnancy
• and puerperium .
• Patients with repeatedly ve aCL and
• recurrent pregnancy loss but no history of
• thrombosis or SLE may be treated with
• low dose aspirin alone

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• SYSTEMIC LUPUS ERYTHEMATOSUS
• (SLE)

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Clinical significance of SLE

• A disease of unknown etiology.
• Certain tissues are damaged by
• autoantibodies.
• A disease of serious consequence and
• high case mortality due to renal or
• cardiovascular affection.
• 90 of patients are young women and
• thus frequently complicates pregnancy.

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Clinical and lab. In SLE

• May be confined initially to one body
• system or may affect multiple systems
• from the start (SLE).
• Commonly
• malaise , fever , arthritis , malar
• erythematous rash , discoid rash ,
• photosensitivity , pleurisy ,
  pericarditis,
• proteinuria , glomerulonephritis ,
• psychotic dysfunction , seizures.

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Lab . Findings in SLE

• Anaemia ,leukopenia ,thrombocytopenia.
• Antinuclear factor and anti-DNA
• Anti Smith antigen antibodies (anti-Sm)
• False positive VDRL
• Abnormal levels of IgM and IgG
• anticardiolipin antibodies.

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American Rheumatism Association basis for
diagnosis of SLE

• Presence of 4 or more of the 11 criteria
• 1.Malar rash
• 2.Discoid rash
• 3.Photosensitivity
• 4.Oral ulcers
• 5.Arthritis
• 6.Serositis
• 7.Renal disorders
• 8.Neurological disorders
• 9.Hematological disorders
• 10.Immunogical disorders
• 11.Antinuclear antibodies

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Effect of pregnancy on SLE

• More flare ups particularly during the
• puerperium which take the form of
• worsening renal function or the
• development of chorea gravidarum.
• Less Flare ups if pregnancy is
• during a period of quiescence .
• No affection of the long term prognosis of
• the disease.

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Effect of SLE on pregnancy

• Three main ways
• 1. ? pregnacy loss due to PET and renal
• failure.
• 2. Frequently associated with
• antiphospholipid antibody syndrome.
• 3. Neonatal lupus syndrome
• congenital heart block.

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Effect of SLE on pregnancy

• 1. PET and Lupus nephropathy
• - may be difficult to differentiate severe
• PET from lupus nephropathy.
• - CNS involvement may cause seizures
• similar to those of eclampsia.
• - thrombocytopenia with or without
• hemolysis may simulate HELLP
• syndrome.

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Effect of SLE on pregnancy

• 2.Secondary antiphospholipid antibody syndrome
• Incidence of abortion with SLE as high as 40.
• Patients with insignificant cardiolipin
• antibodies and lupus anticoagulant do
• not have excessive fetal loss
• ? Likelihood of IUGR and perinatal
• mortality

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Effect of SLE on pregnancy

• 3.Neonatal lupus syndrome
• Majority of women with SLE deliver
• normal babies.
• Occasionally , they deliver babies with
• neonatal lupus characterized by skin
• erythematous rash , hematological and
• cardiac abnormalities( congenital heart
• block).
• Maternal intake of corticosteroids does not
  always cure the condition

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Management of SLE

• 1. Patient is counselled to avoid conception
• until the disease is quiescent.
• 2. OCs are not the best choice for
• contraception because of risk of vascular
• disease .
• 3. IUDs may cause PID.
• 4. Progestogen only contraception is safe
• 5. Frequent clinic visits to detect lupus flare
  and PET and close fetal surveillance.

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Management of SLE

• Pharmacologic therapy
• 1. Paracetamol
• - the drug most frequently used in mild
• SLE.
• - Effective in relieving pain and
  pyrexia
• - No adverse effects.
• 2. Low dose aspirin
• - given throughout pregnancy in
• women with secondary aPLS

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Management of SLE

• Pharmacologic therapy
• 3. Heparin (prophylactic dose)
• - given to patients with high level of
• anticardiolipin antibodies.
• 4. Corticosteroids
• - In life-threatening and severe
• manifestations
• - prednisone 1 to 2 mg/kg/day and taper
  the
• dose to 10 to 15 mg each morning.

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Management of SLE

• Obstetric management
• Pregnancy is allowed to progress to term
• unless the patient develops
• - hypertension
• - deteriorating renal function
• - IUGR
• - fetal distress.

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Thank You