RECURRENT MISCARRIAGE CURRENT CONCEPTS

1
RECURRENT MISCARRIAGECURRENT CONCEPTS

• SUSHANTA BHADRA
• FEBRUARY 2004
• WEXHAM PARK

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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
  gt35 yr or when the couple has difficulty
  conceiving.

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epidemiology

• Affects 0.5-3 of all women
• Risk of subsequent loss - 24 after 2
• 30 after 3
• 40 after 4

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PROPOSED ETIOLOGIES

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

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Genetic mechanisms

• Chromosomal abnormalities
• numerical aneuploidies
• structural - translocations
• Single gene ( Mendelian)
• Polygenic ( single anatomic defect)

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Chromosomal abnormalities

• Spontaneous abortions
• Normal chromosomes 40-50
• Abnormal chromosomes- 50-60

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aneuploidies

• Trisomies (extra chromosome) and
• monosomies (missing chromosome)
• Segregation errors during cell division
• Sporadic
• Nonrecurrent
• Trisomies associated with maternal age

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Abnormal chromosomes

• Autosomal trisomy 50
• Monosomy X 25
• Polyploidy 20
• Sex chromosome polysomy - rare
• Translocations - lt 5

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Autosomal trisomies

• Chromosomes
• 10 13 5.8
• 25 14, 18 5
• 3,5,6 ,11,12,17 - lt1 157.2
• 4 , 20 2.5 1631
• 74.5 21 8.4
• 8,93.5 22 ---11

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Parental origin - trisomy

• Maternal 9095 --
• age related
• recurrent
• Paternal 510

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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

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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

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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

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Other chromosomal rearrangements

• Inversions
• Balanced complex translocations
• Interchromosomal insertions
• Jumping chromosomes

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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

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Chromosomal causesConclusions

• 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

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Single gene defects

• Maternal endometrial, immunologic, vascular
• Embryonic developmental
• Genes conferring pharmacologic susceptibility to
  toxins or infections
• Genes causing aneuploidy

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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

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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)

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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

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Hla genotypesThe 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

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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

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The Paternal contribution

• Balanced structural chromosomal abnormalities
• Sperm abnormalities
• Sub chromosomal abnormalities
• subtle chromosome rearrangements
• gene dosage imbalances
• Mutations

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Sperm abnormalities

• 24 couples with rm semen analysisFish
• Characteristic rec misc fertile donors
• Motile 46 49
• Tapered 38 16
• Amorphous 9 5
• Viable 56 71
• (Carrell 2003)

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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

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Sperm aneuploidy

• Mechanisms
• Quality marker ?
• Carrier of a defect that influences post zygotic
  aneuploidy , implantation, embryonic growth

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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

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Placental oxidative stress

• Human fetus develops in a low oxygen environment
• Intraplacental oxygen conc increases from lt 20mm
  Hg at 10 wks to gt 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

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Placental oxidative stress
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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

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Endometrial receptivity

• Growth factors LIF,HB EGF
• Cytokines
• Adhesion molecules- integrins A5, B3
• Steriod hormones and receptors
• Immunologic factors-- NK Cells, T cells
• Prostaglandins

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RX to improve endometrial receptivity

• Progesteroneat best controversial , at worst
  ineffective
• Immunomodulation
• paternal cell immunization
• intravenous immunoglobulin

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Novel Therapies

• Intrauterine Prostaglandins
• Intrauterine steroids
• Intrauterine Peripheral blood mononuclear cells
• L arginine
• Glue Fibrin!

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Infections

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

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Infections - spectrum

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

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INFECTIONS

• Rubella
• CMV
• HBV
• VZ
• HSV
• HIV
• GBS
• Syph

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Infections What do they do ?

• Direct effect on ova
• Endometrial infection implantation defects
• Embryopathy
• Placental infections
• Amniotic fluid infection

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UTERINE PATHOLOGY

• Septate uterus-
• Ashermans Syndrome-
• Uterine Fibroids- esp. sub mucous
• Primary endometrial defects
• Des exposure

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Cervical Cerclage

• Shirodhkar
• McDonalds
• Lash
• Benson Durfee

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Indication for abd cerclage

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

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Cervical cerclage

• Steer Modifications
• Nuchal first
• USS guidance before , during and after
• No bladder dissection
• Straight blunt needle

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PROTHROMBOTIC STATES

• Antiphospholipid syndromes
• Heritable Thrombophilia-antithrombin def
• protein C S def
• Factor V Leiden
• Prothrombin20210 A
• Thrombocythemia

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ANTIPHOSPHOLIPID SYNDROME

• 7-42 OF WOMEN
• Wide variation
• Poor laboratory standardization

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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

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AND

• Persistent abnormality of the following tests
  when measured twice at least 6 wks apart
• Lupus anticoagulant
• Antiphospholipid antibodies IgG or IgM

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Pathophysiology of APS

• Thrombotic
• Lack of Trophoblastic invasion in 1st trimester
  decidua

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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

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FETAL RISKS

• Miscarriage
• Uteroplacental insufficiency
• IUD
• IUGR
• Fetal Distress
• Preterm birth
• SLE and Thrombosis

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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

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ENDOCRINOLOGICAL FACTORS

• Hypersecretion of LH(gt10IU/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

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IMMUNOLOGICAL FACTORS

• Autoantibodies 18-43 of pts with RM
• APL --14
• ANA 7
• Antisperm AB
• Thyroid Peroxidase

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Immunology Alterations in Cellular Immune
Function

• NK cells-
• LGL cells CD56 increased in endometrium of RM
  pts

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OTHER FACTORS

• COFFEE
• SMOKING AND ALSCOHOL
• HYPERHOMOCYSTENEMIA- Interferes with embryonic
  development
• SELENIUM DEFICIENCY
• CELIAC DS
• STRESS
• PCP EXPOSURE
• MATERNAL DS

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BASELINE INVESTIGATIONS

• ENDOCRINELH,FSH,TSH,PRL,PRG
• BIOCHEMICAL BLOOD SUGAR , HOMOCYSTEINE
• UTERINE USS, HSG
• IMMUNOLOGICAL LUPUS,APL,C3,4
• THROMBOPHILIA SCREEN
• GENETIC

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PROGNOSTIC FACTORS

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

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Neonatal Outcome

• Increased Risk of
• SFD
• PTL
• PNM
• LSCS

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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

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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

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THANK YOU