Management of recurrent miscarriage
• Done by:Arwa abu-sheikha
• Tharwat quteineh
• ali aqleh
• sakher al sayegh
• 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
-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
• Uterine disorders: uterine anomalies,
cervical incompetence, submucous
fibroids, asherman syndrome.
• TORCH infection.
• 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
• 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
• Other structural chromosome anomalies contributing to recurrent abortion
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
. 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
• 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
• 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
• 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
• 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
• 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
• 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".
• The clinical features are presented
according to the systems affected:
• 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
• 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
• 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:
• 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
• 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
• 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
• 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
protein S deficiency
• Protein S deficiency results in a primary
• 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
• 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.
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
• 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
• lipoprotein A
• (clinicians not to forget other risk factors: smoking, BP, lipids,diabetes etc)
• Dx is usually made on the basis of woman past
• 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.
• 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
• does not appear to be an additional benefit of aspirin in
patients with the antiphospholipid syndrome already treated
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
• 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.
• 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
• Lupus anticoagulant in 30% of cases - with prolonged PTT and false-positive
VDRL test for syphilis.
• Usually include:
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 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
• 2)the female partner to fail to produce serum
• 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
• -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
• -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
• -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
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).
2. SEXUAL DYSFUNCTION 30-50%
3. SUICIDAL IDEATION AND SUICIDE ATTEMPTS: up to 60%
4. INCREASED SMOKING WITH CORRESPONDENT NEGATIVE HEALTH
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
8. CHILD NEGLECT OR ABUSE
9. DIVORCE AND CHRONIC RELATIONSHIP PROBLEMS
10. REPEAT ABORTIONS Women with a prior abortion experience are 4 times more
likely to abort
Wake up now to go