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 :

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