recurrent miscarriage

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					Management of recurrent miscarriage
• Done by:Arwa abu-sheikha
•         Tharwat quteineh
•          ali aqleh
•          sakher al sayegh
recurrent miscarriage
• Recurrent abortion is the term applied to the
  situation where a woman has three or more
  consecutive spontaneous abortions.
• Most important predictive factor is having
  previously miscarried. Primigravida and
  women with a history of successful pregnancies
  miscarry infrequently.
-primary:all pregnancies,this mother had,
have ended in abortion(para0).
-secondary:one pregnancies(or more)has
proceeded to viability with all other
pegnancies ended in abortion.
•   Spontaneous pregnancy loss is a common event.
•   The most common complication of pregnancy.
•   Approximately 70% of human conceptions fail to achieve viability.
•   An estimated 50% are lost before the first missed menstrual
    period . Most are unrecognized.
•   The actual rate of pregnancy loss after implantation is 31% of
    clinically recognized pregnancies.
•   loss occurs in 15% of pregnancies before 20 weeks of gestation.
•   Recurrent pregnancy loss (RPL) occurs in approximately 1 in 300
•   In a history of RPL, the risk for subsequent loss is estimated 24%
    after two clinically recognized losses, 30% after three , and 40% to
    50% after four.
• Parental chromosomal abnormalities and thrombotic complications of
  the Antiphospholipid Antibody Syndrome (APAS) are the only
  undisputed causes of recurrent abortion. Collectively they account for
  less than 10% to 15% of RPLs.

• Anatomic Abnormalities (12%–16%).

• Endocrine Problems (17%–20%).

• Infections (0.5%–5%).

• Immunologic Factors, including APAS (20%–50%).

• Miscellaneous Factors are approximately 10% .

• Even after a thorough evaluation, the potential cause remains
  unexplained in about one third to one half of cases.
• Ideopathic:in about 50% of cases no
  cause has been found after intensive
• Fetal chromosomal abnormalities.
• Parental balanced translocations.
• RH –isoimmunisation.
.Uncontrolled endocrine disorders: DM,
  thyroid disorders, PCOS, and corpus
  luteal insufficiency.
.Uncontrolled immunological
  disorders:antiphospholipid and
  anticardiolipin antibodies.
• Uterine disorders: uterine anomalies,
  cervical incompetence, submucous
  fibroids, asherman syndrome.
• TORCH infection.
 Genetic Factors
• The most common inborn parental chromosomal abnormalities
  contributing to recurrent abortion are Balanced Translocations.

• The carrier has an overall normal gene content but has a piece of
  one chromosome inappropriately attached to another.

• The gametes produced by the translocation carrier will be Normal
  (reciprocalonly), Balanced, or Unbalanced.

• If fertilized by a chromosomally normal gamete, the resulting
  embryo may be either normal (reciprocal only), balanced or
  unbalanced carrier of the translocation.
• Most gametes and embryos with abnormal chromosomal status will
  not survive.

• For those that survive, live offspring will either be carriers of a
  balanced translocation or, for Robertsonian translocations, be
  monosomic or trisomic.

• Among the possible chromosomal monosomies, only that of the X
  chromosome typically permits viable offspring.

• Many of these may exhibit mosaicism.
•   Family history and a history of prior term births is not sufficient to rule out a
    potential parental chromosomal abnormality.

•   The use of parental karyotyping in the evaluation of structural chromosomal
    causes of RPL may be insufficient.

•   Evidence suggests that paternal chromosomal abnormalities may be isolated
    within particular fertilizing spermatozoa, and an aneuploid spermatozoa may
    be motile.

•   Other structural chromosome anomalies contributing to recurrent abortion
             1. Inversions.
             2. Insertions.
             3.   Chromosomal mosaicism.
             4.   Single gene defects.
             5.   X-linked disorders (linked to recurrent abortion in female offspring ,
                  uncommon for male offspring).
Parental balanced translocation
• It is detected by doing chromosomal
  karyotyping for the parents .if one of the
  parents has it , helshe has 46
  chromosomes functioning but 45 when
  being counted ,this happens because
  one of the chromosomes is attached to
  another one, so it is functioning but
  counted as one.
• So they both go to one cell during
  spermatogenesisloogenesis ,making a
  cell with 24,and another one with 22,so
  trisomy and monosomy will happen
  leading to abortion with a chance of
  about 30-40%.the parents here just need
  to try and try till successful prgnancy
 .Polycystic ovary syndrome
• In the UK, up to 33% of women have
  polycystic ovaries (i.e. 10 or more follicles per
  ovary detected on ultrasound).
• Of these, an estimated 33% have polycystic
  ovarian syndrome, generally defined in the UK
  as polycystic ovaries together with one or
  more characteristic features (hirsutism, acne,
  male-pattern baldness, amenorrhoea or
  oligomenorrhoea, or raised serum
  concentrations of testosterone and/or
  luetinising hormone).
    . Uterine abnormalities
• Complete failure results in uterus didelphys. This
  extremely rare condition is characterised by:
•   double vagina
•   double cervix
•   entirely double uterus ie. two single-horned uteruses
• A variant of this is the uterus bicornis bicollis which is
  characterised by:
•   double or single vagina
•   double cervix
•   two single-horned uteruses which show partial fusing of their muscular walls
• More extensive fusion of the Mullerian ducts results in
  the uterus bicornis unicollis which is characterised by:
•   single vagina
•   single cervix
•   double, single-horned uteruses which are partially fused
• Other abnormalities include:
• uterus subseptae - uterus has midline septum
• uterus arcuatus - uterus slightly indented in the
• uterus unicornis - with a second blind-ending
  rudimentary horn
• A septate vagina or a double vagina may occur in isolation if
  canalisation of the most caudal part of the fused Mullerian
  duct is incomplete.

• Intervention depends on whether the
  abnormality interferes with coitus or
• A septate vagina and the rudimentary horn of
  a bicornis uterus are best removed.
• Utriculoplasty is usually recommended in a
  bicornute or septate uterus which has been
  shown to be the cause of several - usually
  three or more - abortions. The septum is
  excised or the two uteri reconstructed into a
  single organ.
 .Cervical incompetence

• Cervical incompetence describes a cervix that is
  abnormally prone to dilate in the second
  trimester of pregnancy, resulting in spontaneous
  abortion of the fetus.
• Uterine contractions are uncommon
 Antiphospholipid syndrome

• This syndrome was first described in 1983-1986 as
  the association of arterial and venous thrombosis
  with antibodies directed against phospholipids.

• Originally noted as a complication in approximately
  30% of patients with systemic lupus erythematosus,
  it is now also diagnosed in patients with thrombotic
  episodes and anti-phospholipid antibodies (aPL)
  but without clinical features of SLE - primary
  antiphospholipid syndrome.

• There is a familial association in some cases of APS. HLA
  studies suggest DR7, DR4 and DQw7 plus DRw53 are risk
• The aPL antibody is targeted to the combination of cardiolipin
  with a plasma protein called beta-glycoprotein I.
• In vivo aPL has a procoagulant effect on:
• platelet membranes
• endothelium
• prothrombin, protein C and protein S
• aPL is found in the serum of 30% of patients with SLE, in this
  context it is termed "lupus anticoagulant".
clinical features
• The clinical features are presented
  according to the systems affected:
• neurological
• cardiac
• renal
• endocrine
• dermatological
• haematological
• obstetric
• thrombotic

• Venous:
• DVTs - these may be recurrent. In women these may appear to
  be triggered by the use of the oral contraceptive pill
• hepatic thrombosis - antiphospholipid syndrome is the second
  most common cause of hepatic thrombosis
• retinal vein thrombosis
• renal vein thrombosis
• major vein thrombosis may involve thoracic outlet veins or the
  inferior vena cava
• Arterial thrombosis may cause ischaemia of almost any organ
 detection of anticardiolipin
• The risk of thrombosis or spontaneous abortion
  increases with the titre of aCL and are greater with IgG
  antibodies than with IgM - for example, of 39 patients
  with IgG greater than 20 GPL units, 70% had a
  thrombotic event.

• first-line treatment is low dose aspirin - 75-
  100 mg daily .
• patients with APS who have had a documented
  major thrombotic event require long-term
  treatment with warfarin or coumarin
 treatment of antiphospholipid
 syndrome during pregnancy
• low-dose aspirin and low-molecular weight heparin are
  now the treatment of choice for women with
  antiphospholipid syndrome and a history of miscarriage.

• usually, self-administered low-molecular weight is given
  if there is a past history of thrombosis .

• the use of this may reduce the loss by 54%.

•  An inherited tendency to thrombosis is
   termed thrombophilia.
• In many cases, specific prothrombotic
   mutations in antithrombotic factors are
• There are three systems which are commonly
   involved in the pathogenesis of
1. the antithrombin / heparin system
2. the protein C / protein S system
3. the fibrinolytic system
 antithrombin / heparin system
• Antithrombin is a serine protease inhibitor which inhibits
  the following coagulation factors:
• thrombin
• factor Xa
• factors XIIa, XIIIa and IXa
• Binding of heparin to antithrombin improves the speed
  with which antithrombin can neutralise these
  prothrombotic factors. In vivo, glycosaminoglycans on
  the endothelial cells serve as the endogenous catalysts
  for antithrombin activation.
• Antithrombin deficiency is a cause of thrombophilia.
• Heparin cofactor II is a distinct serine protease inhibitor which inhibits thrombin
  in the presence of heparin. Deficiency of heparin cofactor II may cause
 protein C / protein S system
• Protein C is a vitamin K-dependent
  protease which complements the
  anticoagulant activity of antithrombin
  III by inactivating factors VIII and V. It
  also stimulates fibrinolysis. It is
  regulated by protein S on the surface of
  endothelial cells and requires calcium as
  a co-factor.
• Homozygotes lacking protein C die in the early neonatal
  period, if not before, from overwhelming coagulation.
 protein C deficiency
• This is an autosomal codominant condition in which
  there is a deficiency of protein C.
• Both quantitative and qualitative abnormalities of
  protein C have been identified. For this reason,
  functional tests are preferred over antigenic tests for
  protein C.
• The frequency of defective protein C genes is 0.1-0.5%
  in the general population.
• The prevalence in patients with venous
  thromboembolism is about 3% (1).
• Protein C deficiency results in a 10-15x increased risk of
  thrombosis (1).
• In neonates it may present as a life-threatening thrombotic disorder; this tends
  to be in individuals homozygous for protein C deficiency.

• This includes:
• long-term warfarin treatment - note
  that protein C is vitamin K dependent
  and thus treatment with warfarin may
  cause a further decrease in protein C
  levels and therefore an increased risk of
  thrombosis Warfarinisation should be
  covered with concurrent heparin
  treatment during the initial 10 days
• some centres have used protein C
  replacement therapy
 protein S deficiency
• Protein S deficiency results in a primary
  hypercoagulable state.
• Both quantitative and qualitative abnormalities of
  protein S have been identified.
• In the normal individual, 60% of protein S in the plasma
  is inactive, being bound to the C4b-binding protein.
  Excessive binding of protein S to C4b-binding protein
  may result in a deficiency of active protein S in the
• Protein S deficiency is associated with (1):
• 10x increased risk of thrombosis
• 3% prevalence in patients with venous
• 2% prevalence in normal population
 fibrinolytic system
• Fibrinolysis, the breakdown of fibrin
  polymer, occurs by at least two
  pathways resulting in the active agents
  protein C and plasmin. The latter is the
  better characterised and the term
  fibrinolysis is commonly taken to mean
  the plasmin pathway.
• Drugs which affect plasmin production are clinically
  important: accelerating agents include streptokinase;
  retarding agents include tranexamic acid.
    thrombophilia screen
    Timing of thrombophilia screening:
•   patient should not be pregnant , or on oral contraceptive pill or HRT
•   patient should not be on anticoagulation (discontinued for at least 1 month)
•   screening during an acute event should be avoided
•   repeated screening is inappropriate
•   Thrombophilia screening for VENOUS thrombosis:
•   Appropriate indications:
•   patients < 40 years old with spontaneous venous thromboembolism (VTE)
•   family history of VTE in young patients (<40 years old), with a known defect
•   patients < 60 years old with a history of VTE + family history (1st degree relative, or known
    thrombophilia defect in family) of VTE or thrombophilia
•   patients < 60 years with unusual site of VTE (includes sagital sinus, axillary, mesenteric)
•   history of recurrent miscarriage, preeclampsia, placental abruption, IUGR; or history of unexplained
•   There is no indication to screen women before they start OCP or HRT unless any of the above risk
    factors are also present
•   Thrombophilia screen to include:
•   FBC and clotting screen - Activated Protein C resistance
•   protein C - Factor V Leiden (if APCR positive)
•   protein S - prothrombin gene mutation
•   antithrombin
•   lupus anticoagulant - anticardiolipin antibodies
•   Thrombophilia screening for ARTERIAL thrombosis:
•   Appropriate indications:
•   arterial thrombosis (e.g. TIA. cerebral thrombosis, MI) in patient < 40 years
•   severe migraine (limited to anticardiolpin antibodies and lupus anticoagulant)
•   Thrombophilia screen to include:
•   lupus anticoagulant
•   anticardiolipin antibodies
•   homocysteine
•   lipoprotein A
•   (clinicians not to forget other risk factors: smoking, BP, lipids,diabetes etc)
• Dx is usually made on the basis of woman past
  pregnancy Hx.
• Classically this is following one or more late 2nd
  trimester or early 3rd trimester losses (still birth).
  Usually they begin with painless leakage of likor,
  or finding during pregnancy a gradual painless
  dilation of the cervix, with membranous bulging
  into the vagina.
• Cervical cerclage is treatment of choice, involves
  placing a stitch high up around the cervix to close it.
• Types: McDonald or Shirodkar.
• It is removed around 37 weeks.
• Abdominal cerclage requires an elective C/S and the
  stitch is usually left in situ for future pregnancy.
• Complications:1. Rupture pf membrane at time of
  placement. 2. Infection.
.systemic lupus erythematosus
• Systemic lupus erythematosus is the
  classic prototype of a multisystem
  disease of autoimmune origin. It is non-
  organ specific and characterised by
  vasculitis and anti-nuclear antibodies
• Other manifestations of this disease are
  not vasculitic, for example cutaneous
  and some CNS signs.
 lupus anticoagulant
• The lupus anticoagulant is an immunoglobulin, IgG or
  IgM, which binds to phospholipids and prevents
  coagulation reactions from taking place on the platelet
• It is associated with arterial and venous thrombosis,
  and recurrent spontaneous abortions. It occurs in about
  30% of patients with systemic lupus erythematosus but
  may be found in other autoimmune diseases, in
  response to drugs such as phenothiazine, and in
  patients with infectious diseases such as AIDS. Often,
  no underlying condition may be found.
• The LA anti-phospholipid often occurs in association with anti-cardiolipin
  antibodies (aCL) - 59% of patients with SLE having LA also have aCL, and
  45% with SLE and aCL, also have LA.
 management of lupus
• Prednisolone usually eliminates lupus anticoagulant and it is
  claimed, reduces the risk of spontaneous abortions.

• Patients with thromboses should be treated with oral
  anticoagulants in standard dose. Heparin therapy is difficult to
  monitor due to the artificially prolonged PTT.

• low dose aspirin in SLE patients

• patients with SLE and any additional cardiovascular risk factor
  patients, and patients who are positive for antiphospholipid
  antibodies or the lupus anticoagulant should be treated with
  low-dose aspirin

• does not appear to be an additional benefit of aspirin in
  patients with the antiphospholipid syndrome already treated
  with warfarin
 Smoking in pregnancy
• Various effects of smoking in pregnancy are described:
• increased risk of premature delivery.
• associated with intrauterine growth retardation - infants
  born to mothers who smoke are, on average, 170 g
  lighter; there is x2 risk of having an infant with a
  birthweight of under 2500g compared with non-smoking
• perinatal deaths are more common in infants born to
  mothers who smoke.
• spontaneous abortions are more common in mothers
  who smoke.
• The risk of pre-eclampsia is LOWER for women who
  smoke than for non-smoking mothers.

• Bacteria, viruses and other organisms such as
  toxoplasma and listeria can all interfere with
  pregnancy but none seems to be significant
  causes of recurrent abortion.-
• TORCH screening should be done in the cases
  of recurrent miscarriage.
•   Autoantibodies:
•   antibodies to double stranded DNA and the antinuclear antibody anti-Sm, are
    highly specific for SLE but are poor "markers" because of their low
    prevalences, 50-70% and 7-30%
•   anti-Ro and anti-La antinuclear antibodies occur in both SLE and Sjogren's
•   anti-Ro is important in pregnancy since it is associated with babies born with
    congenital heart block
•   anti U1 ribonucleoprotein, formerly, anti-RNP, is not specific for SLE
•   anti-histone antibodies indicate drug induced SLE
•   anti-cardiolipin is associated with thrombosis (arterial or venous), chorea, and
    livedo reticularis
•   Lupus anticoagulant in 30% of cases - with prolonged PTT and false-positive
    VDRL test for syphilis.
 Investigations for
 recurrent miscarriages:
•     Usually include:
1.    FBC
2.    serological tests e.g. for syphilis
3.    blood group and antibodies of patient and partner
4.    Ìndirecrt Coomb’s test in Rh-ve women.
5.    chromosome analysis of patient and partner
6.    HLA, SLE, antinuclear antibodies
7.    screening for hypercoagulable states e.g. factor V Leiden
8.    Blood sugar.
9.    Antiphospholipid and anticardiolipin antibody.
10.   Infection profile.
11.   Parenteral karyotype.
12.   thyroid function tests
13.   pelvic ultrasound scan
14.   hysteroscopy, hysterosalpingogram

• After three previous miscarriages the chance
  of a successful pregnancy is between 60 and
  85% - high enough to question whether any
  treatment is justified in the majority of cases.
  In some circumstances such as
  antiphospholipid antibodies and incompetent
  cervix, the prognosis is less good without
• 15% of pregnancies miscarry, thus one might expect 0.4% of all
  women to miscarry 3 times. The observed frequency is 0.8%
 Alloimmune disorders.
Alloimmune traits(immunologic differences between
individuals)have been proposed as factors between
     reproductive partners that cause otherwise
       unexplained recurrent pregnancy loss.
• The tendency for
• 1)partners with recurrent loss to share human
  leukocyte antigens.
• 2)the female partner to fail to produce serum
  ‘blocking factor’
• 3)the female partner to produce
  antileukocytotoxic antibodies against paternal
  leukocytes have been described.
• -no test for these traits provides results that predict the
  next pregnancy outcome in patients treated or untreated
  for recurrent prgnancy loss.
• -more recently,some researchers have claimed that flow
  cytometric assays for maternal antibodies to paternal
  leukocytes are useful in evaluating couples with
  recurrent prgnancy loss.however ,studies of these
  assays have lacked appropriate controls and are of
  unproven value in terms of indicating an efficacious
• -more recent investigations of the maternal-fetal
  immunologic relationship suggest that prgnancy losses
  may result from dysregulation of normal immune
  mechanisms .
• -it has been proposed that a predominance of TH-2
  cytokines is crucial for successful prgnancy and that
  TH-1 cytokines such as interferone gamma and tumor
  necrosis factor alpha,adversely affect embryo and
  trophoblast viability.
• -the presence of NK-like ceels secreting a
  transforming growth factor at the maternal-fetal
  interface may be necessary for successful
• -clinical studies have found decreased or
  increased numbers of these cells in the luteal
  phase endometria of women with recurrent
  prgnancy loss.
• -pegnancy outcomes may be worse in women with
  recurrent prgnancy loss found to have increased
  numbers of NK-like cells in the luteal phase
  endometria,but further studies are necessary before
  valid conclusions can be drawn.
• -there is ,however ,no proven treatment for women with
  recurrent prgnancy loss found to have increased
  percentages of circulating NK cells.
Management of idiopathic
recurrent miscarriages:
1. Support.
2. Advice: stop smoking and alcohol intake,
   decrease physical activity.
3. Tender loving care.
 A List of Major Psychological
 Sequelae of Abortion
1.    POST-TRAUMATIC STRESS DISORDER (PTSD or PAS): 19% of post- abortion
      women suffer from diagnosable post-traumatic stress disorder (PTSD).
5.    ALCOHOL ABUSE: 2 folds increased
6.    DRUG ABUSE drug abuse is linked with increased exposure to HIV/AIDS
      infections, congenital malformations, and assaultive behavior
7.    EATING DISORDERS such as binge eating, bulimia, and anorexia nervosa
10.   REPEAT ABORTIONS Women with a prior abortion experience are 4 times more
      likely to abort
Thank you…..
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