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RECURRENT MISCARRIAGE CURRENT CONCEPTS

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					RECURRENT MISCARRIAGE

CURRENT CONCEPTS



           SUSHANTA BHADRA
             FEBRUARY 2004
             WEXHAM PARK
DEFINITION
• Loss of three or more clinically
  recognized pregnancy losses
  before 20 wks gestation.

• Clinical investigation should
  however be initiated after 2
  consecutive losses specially
  when fetal heart activity has
  been identified before any
  pregnancy losses, when the
  woman is >35 yr or when the
  couple has difficulty conceiving.
epidemiology

• Affects 0.5-3% of all women

• Risk of subsequent loss - 24% after 2
                         30% after 3
                         40% after 4
PROPOSED ETIOLOGIES

•   Genetic - 5 %
•   Anatomic- 15%
•   Endocrine- 20%
•   Infections- 5%
•   Immunologic/ Thrombotic -30%
•   Other factors – 10%
•   Unknown
Genetic mechanisms

• Chromosomal abnormalities
  numerical – aneuploidies
  structural - translocations

• Single gene ( Mendelian)

• Polygenic ( single anatomic defect)
Chromosomal
abnormalities
Spontaneous abortions



Normal chromosomes – 40-50%

Abnormal chromosomes- 50-60%
aneuploidies

• Trisomies (extra chromosome) and
  monosomies (missing chromosome)

• Segregation errors during cell division

• Sporadic

• Nonrecurrent

• Trisomies associated with maternal age
Abnormal chromosomes

• Autosomal trisomy –50%
• Monosomy X – 25%
• Polyploidy –20%
• Sex chromosome polysomy -
  rare
• Translocations - < 5%
Autosomal trisomies
• Chromosomes
 1—0%                 13– 5.8%
2—5%                  14, 18 —5%
3,5,6 ,11,12,17 - <1%   15—7.2%
4 , 20 –2.5%          16—31%
7—4.5%                21 – 8.4%
8,9—3.5%              22 ---11%
Parental origin - trisomy

• Maternal –90—95% --
   age related
   recurrent

• Paternal – 5—10%
Aneuploid screening

 • There is an increased rate of
   numerical chromosomal
   abnormalities in human
   periimplantation embryos in women
   with RSA
 • There is also an increased incidence
   of chromosomal abnormalities in the
   sperm from RSA couples
 • Role of preimplantation genetic
   diagnosis (day3 - blastomeres )
   using FISH
Structural chromosomal
abnormalities
• Defect in structure of 1 or more
  chromosomes
• Inversions, translocations
• 7% couples affected
• Risk of spontaneous abortions vary
  from 25-50%
• May be passed from parent to child
• Karyotype indicated
TRANSLOCATIONS

• Reciprocal --- any chromosome
• Robertsonian –(centric fusion)
     only acrocentric chromosomes
     13,14,15,21,22
• Cryptic translocations - balanced
  translocations involving only the
  telomeric regions of the
  chromosomes – not detectable by
  conventional cytogenetics
Other chromosomal
rearrangements
• Inversions
• Balanced complex
  translocations
• Interchromosomal insertions
• Jumping chromosomes
X Chromosome
inactivation
• Occurs in female mammals
• Random inactivation of a X
  chromosome to compensate for the
  difference in x linked gene dosage
• Preferential inactivation of x
  chromosome is directly correlated
  with RM
• Underlying causes include cryptic x
  chromosome aberrations, gene
  microdeletions, gene mutations and
  genetic imprinting
Chromosomal causes
Conclusions
• Aneuploidies are responsible in 55-85% of
  EPL
• Trisomies are usually maternal meiotic in
  origin and age related.
• Polyploidy(67%) and Monosomy X(80%) are
  usually paternal in origin
• Trisomies can be recurrent
• Parental translocations found more often
  in female, not highly correlated with
  number of losses and show 2-5%
  unbalanced offspring
Single gene defects
• Maternal – endometrial,
  immunologic, vascular

• Embryonic – developmental

• Genes conferring pharmacologic
  susceptibility to toxins or infections

• Genes causing aneuploidy
Polygenic
• 2 or more genes cumulatively affect
  presence or absence of a given trait
• Unequivocal relationship to 2nd and 3rd
  trimester losses
• Associated with anatomic defects
  involving single organ system
• Associated with subsequent live born ntd
  and prior polygenic defects
• Fetuses with anatomic defects
  (embryoscopy) usually show cytogenetic
  abnormalities
• Recurrence risk 1-5% limited to first
  degree relatives
Maternal gene
perturbations
 Mutant maternal gene likely to be
 associated with consecutive losses
 not interspersed as in genes acting
 through embryos

• Endometrial receptivity (PR)
• Luteal Function (CYP 17)
• Alloimmune (HLA G promoter
  polymorphism)
Lethal genes affecting
fetus
• Early lethal – Surf 1 , ETA2 , OCT 4(
  mice models – human analogies
  present – neurodevelopmental
  problems )

• Placental – trophoblast
  differentiation , fetoplacental
  vascular development , trophoblast
  transcription factors

• Homebox and other developmental :
  HOX PAX
Hla genotypes
The REMIS Trial
• analysis of 12 HLA g alleles in
  prospectively followed cohorts of
  couples with recurrent miscarriages
  using PCR sequence specific
  oligonucleotides for 12 alleles

• 113 couples studied- 63 with
  successful pregnancy, 50 with rm
Remis trial

• HLA g gene genotype 0104 and
  0105n is predictive of low successful
  pregnancy rates
• Presence of HLA G isoform 1 and
  725C/G polymorphism in promoter
  regions are associated with an
  increased risk of recurrent
  miscarriages if both partners carried
  the allele
The Paternal
contribution
• Balanced structural chromosomal
  abnormalities
• Sperm abnormalities
• Sub chromosomal abnormalities
• subtle chromosome rearrangements
• gene dosage imbalances
• Mutations
Sperm abnormalities
• 24 couples with   rm – semen
  analysis&Fish
Characteristic      rec misc fertile
  donors
Motile              46%      49%
Tapered             38%      16%
Amorphous           9%       5%
Viable              56%      71%

(Carrell 2003)
Sperm abnormalities

Disomy   rec misc   sperm donors
Xy       0.77%         0.31%
13       1.02%         0.39%
18       0.51%         0.25%
21       0.47%         0.28%
Sperm aneuploidy

• Mechanisms
• Quality marker ?
• Carrier of a defect that
  influences post zygotic
  aneuploidy , implantation,
  embryonic growth
The role of the
trophoblast
• Placental development
• Continuous turnover
• CT proliferation – differentiation –
  fusion – aging – shedding as syncitial
  knots into maternal circulation over
  3- 4 weeks
• CT / ST ratio – reduced in apl
  pregnancies and rsas
• Tenney Parker changes
Placental oxidative stress

• Human fetus develops in a low oxygen
  environment

• Intraplacental oxygen conc increases from
  < 20mm Hg at 10 wks to > 50 at 12 wks

• Trophoblastic cells are extremely sensitive
  to oxidative stress

• Mounting evidence that in most
  miscarriages the onset of intervillous
  circulation is premature and widespread
  due to incomplete transformation of
  uteroplacental arteries leading to high
  oxygen concentrations in early pregnancy
Placental oxidative stress
                                                                          Impalntation



                                                     Trophoblastic invasion and formation of endothelial shell



Unplugging in trophoblast invasion and increased blood flow – 8-9wks



                                        Increased oxidative stress
                                                                                                                   mild

                                                                                                                            resolution

                                                                                                                 moderate

                                                                                                                               pet

                                                                                                                  severe

                                                                                         epl
Endometrial receptivity
 • INFERTILITY          RM

 • 50-75% of pregnancies lost
   represent a failure of implantation

 • Failure of implantation may result
   from a non receptive endometrium

 • Involves a complex synchronous
   interaction between embryo ,
   endometrium and ovary
Endometrial receptivity

• Growth factors –LIF,HB EGF
• Cytokines
• Adhesion molecules- integrins A5, B3
• Steriod hormones and receptors
• Immunologic factors-- NK Cells, T
  cells
• Prostaglandins
RX to improve endometrial
receptivity
• Progesterone—at best controversial ,
  at worst ineffective

• Immunomodulation
     paternal cell immunization
     intravenous immunoglobulin
Novel Therapies
• Intrauterine Prostaglandins

• Intrauterine steroids

• Intrauterine Peripheral blood mononuclear
  cells

• L arginine

• Glue– Fibrin!
Infections

• 1 in 20 women are exposed to
  pathogens
• Majority are harmless
• Early infection – congenital problems
• Delayed infection -
Infections - spectrum

•   MISCARRIAGES
•   CONGENITAL INFECTIONS
•   STILL BIRTH
•   NEONATAL DEATHS
•   ASYMPTOMATIC INFECTIONS
•   NORMAL FINDINGS
INFECTIONS

•   Rubella
•   CMV
•   HBV
•   VZ
•   HSV
•   HIV
•   GBS
•   Syph
Infections – What do
they do ?
• Direct effect on ova
• Endometrial infection – implantation
  defects
• Embryopathy
• Placental infections
• Amniotic fluid infection
UTERINE PATHOLOGY

•   Septate uterus-
•   Asherman’s Syndrome-
•   Uterine Fibroids- esp. sub mucous
•   Primary endometrial defects
•   Des exposure
Cervical Cerclage

•   Shirodhkar
•   McDonalds
•   Lash
•   Benson Durfee
Indication for abd cerclage

•   Congenital short cx
•   Amputated cx
•   Torn cx
•   Severe scarring
•   Chronic cervicitis
•   Cervicovaginal fistula
•   Failed shirodhkar
•   Rec pproms
•   Cervical dysfunction
Cervical cerclage

Steer Modifications
• Nuchal first
• USS guidance – before , during and
  after
• No bladder dissection
• Straight blunt needle
PROTHROMBOTIC
STATES
• Antiphospholipid syndromes

• Heritable Thrombophilia-antithrombin def
                            protein C & S
  def
                           Factor V Leiden

 Prothrombin20210 A

• Thrombocythemia
ANTIPHOSPHOLIPID
SYNDROME
• 7-42 % OF WOMEN
• Wide variation
• Poor laboratory standardization
  APL – diagnostic criteria
• 3 or more unexplained consecutive
  spontaneous abortions before 10 wks with
  exclusion of maternal anatomic or hormonal
  abnormalities and maternal and paternal
  chromosomal abnormalities
                     OR
• One or more unexplained deaths of a
  morphologically normal fetus at or beyond 10
  wks with normal fetal morphology
  documented by USS or direct examination of
  the fetus
                     OR
• One or more PTBs of a morphologically
  normal neonate at or before 34wks gest
  because of severe PET or Placental
  Insufficiency
AND

Persistent abnormality of the following
 tests when measured twice at least
 6 wks apart

Lupus anticoagulant

Antiphospholipid antibodies – IgG or
 IgM
Pathophysiology of APS

• Thrombotic

• Lack of Trophoblastic invasion in 1st
  trimester decidua
APL – Maternal Risks
 • Thrombosis –Heparin RX
                 Access to prenatal care and pt
                 education

 • Hypertension –       antenatal care and pt
                        education

 • Thrombocytopenia
 • Secondary conditions           rheumatologist
  involvement

 • Treatment Complications–
           hge, osteopenia, thrombocytopenia

 • Catastrophic APS
FETAL RISKS

• Miscarriage
• Uteroplacental insufficiency
                            IUD
                            IUGR
                            Fetal
  Distress
• Preterm birth
• SLE and Thrombosis
Heritable thrombophilias
• 5 recognized defects – antithrombin
  def, protein c def, protein s def, v
  leiden, prothrombin 20210A variant
• EPCOT – European study analysed
  pregnancy outcome in women with
  known thrombophilia – v leiden not
  associated with rm, better
  association with activated protein c
  resistance
• Essential thrombocythemia
ENDOCRINOLOGICAL
FACTORS
 • Hypersecretion of LH(>10IU/L)In the
   follicular phase is a marker for RM

 • Androgen levels in the follicular
   phase have been shown to be high in
   pts with RM- This correlates
   negatively with the conc. of Placental
   Protein 14 a biochemical marker for
   endometrial function

 • Hyperprolactinemia – no firm
   evidence
IMMUNOLOGICAL
FACTORS

• Autoantibodies – 18-43% of pts with
                   RM
                  APL --14%
                   ANA – 7%
                   Antisperm AB
                   Thyroid Peroxidase
Immunology – Alterations
in Cellular Immune
Function


• NK cells-

• LGL cells – CD56+ increased in
  endometrium of RM pts
OTHER FACTORS
• COFFEE
• SMOKING AND ALSCOHOL
• HYPERHOMOCYSTENEMIA-
  Interferes with embryonic
  development
• SELENIUM DEFICIENCY
• CELIAC DS
• STRESS
• PCP EXPOSURE
• MATERNAL DS
BASELINE
INVESTIGATIONS
• ENDOCRINE–LH,FSH,TSH,PRL,PRG
• BIOCHEMICAL– BLOOD SUGAR ,
                 HOMOCYSTEINE
• UTERINE– USS, HSG
• IMMUNOLOGICAL – LUPUS,APL,C3,4
• THROMBOPHILIA SCREEN
• GENETIC
PROGNOSTIC FACTORS

•   Fetal Heart Beats
•   No of prev misc
•   Age
•   Underlying etiology
•   History of live birth
•   Underlying infertility
•   BMI
•   Menstrual cycles
Neonatal Outcome

• Increased Risk of
                SFD
                PTL
                PNM
                LSCS
MANAGEMENT
• CAUSE SPECIFIC
• Uterine anomalies – metroplasty,
  hysteroscopic surgery
• Endometrial defect- prime endometrium in
  follicular phase with estrogen, GnRH
• Prothrombotic states- aspirin, heparin,
  steroids
• PCOS – laparoscopic drilling associated
  with reduced miscarriage rate
MANAGEMENT

•   TLC including serial uss
•   Progestogens- no clear benefit
•   Hcg- no evidence of benefit
•   Immunotherapy- Unproven
•   Aspirin – empirical use not justified
•   Thyroid hormones
•   Folic acid
THANK
YOU

				
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posted:10/5/2011
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