Download factor v leiden mutation

Recurrent Pregnancy
Loss
NOVAK 2003
CONTENTS




Introduction
Etiology
Evaluation
Treatment
INTRODUCTION
70% of pregnancies are lost<viability
50% “”””””””””””””””””””””””<1st missed period
31% “””””””””””””””””””” >implantation(by β-HCG)
15% ””””””””””””””””””””””’ < 20 weeks
Definition:
≥ 3 spontaneous abortions < 20 weeks
% = 1:300
Risk of recurrence :
> 2 abortions = 24%
> 3 “””””””””” = 30%
> 4 “””””””””” = 40-50%
Evaluate RPL after 2 spontaneous abortions if:



age > 35 years
subfertility/infertility
FHMs are seen in both
= 1% of pregnancies require evaluation.
ETIOLOGY
1)
2)
3)
4)
5)
6)
Genetic
Anatomical
Endocrine
Infection
Immunological
Others
= 3.5-5%
= 12-16%
= 17-20%
= 0.5-5%
= 20-50%
= 10%
10-15% of RPL is due to APAS and chromosomal
abnormalities.
GENETIC CAUSES
Mostly due to balanced translocation:
Reciprocal translocation normal gametes
Robertsonian translocationbalanced gametes
or unbalanced gametes
Most embryos with chromosomal abnormalities
do not survive.
Live offspring are either carriers of:


Balanced translocation
Monosomy/trisomy ( in robertsonian T ).
Monosomic fetuses:
may be mosaic
X gametes can only survive
↑ in IVF
Trisomic fetuses:
may also be mosaic.
include trisomies 13,16,18,and 21
survive more than monosomic fetuses
We can't exclude chromosomal
abnormalities by:
 negative family history
 history of a live term birth
The frequency of chromosomal
abnormalities is inversely proportional to the
number of previous abortions.
Couples with genetic abnormalities are
usually with no children.
Parents with history of:

spontaneous abortion

± SB

± live birth ( ± anomalies )
are candidates for parental karyotype, but
this may be insufficient because:
o aneuploid sperm may be motile
o chromosomal abnormality may be in 1
sperm
Other structural chromosomal anomalies
include:
• Inversion
• Insertion
• Chromosomal mosaicism
• X-linked anomalies (males do not survive)
• Single gene anomalies such as cystic
fibrosis (detected by detailed family history).
HERITABLE THROMBOPHILIAS
1.
2.
3.
4.
5.
6.
7.
Hyperhomocysteinemia mutation
Antithrombin III mutation
Protein-C and protein-S deficiency
Factor V Leiden mutation
Prothombin mutation
Factor XII deficiency
Factor XIII and fibrinogen defects
1- HYPERHOMOCYCTEINEMIA
Homocysteine is derived from dietary methionine. It is
metabolized in the presence of methyl-tetra-hydro-folate
reductase enzyme (MTHFR) + dietary folic acid, vit B6, vit B12
into:
Cystathione or back into methionine.
Hyperhomocysteinemia may be either:
- Congenital
due to point mutation in MTHFR (common )
- Acquired
due to dietary deficiency of folic acid, vit B6, or vit B12
Hyperhomocysteinemia is linked to thrombosis and RPL.
2- ANTITHROMBIN III MUTATION
Antithrombin III inhibits:
- thrombin
- factor IXa,Xa,XIa,XIIa
Antithrombin III mutation is rare but it is
the worst prognostic factor of all
heritable thrombophilias. It is associated
with RPL and thrombosis.
3- PROTEIN-C AND PROTEIN-S DEFICIENCY
Protein-C and protein S affect:
- X  Xa reaction
- prothrombin  thrombin reaction
Protein-C and protein S deficiency is
linked to placental thrombosis and
pregnancy complications.
4– FACTOR V LEIDEN MUTATION
Factor V prevents interaction with proteinC. Multiple point mutation in the cleavage
site of factor V Leiden  resistance to
protein-C.
Factor V Leiden is associated with RPL.
It is the most common heritable
thrombophilia among white people.
5– PROTHROMBIN MUTATION
It is linked to thrombosis and pregnancy
loss.
6– FACTOR XII DEFICIENCY
Increase in Japanese people and is
linked to recurrent pregnancy loss.
7- FACTOR XIII AND FIBRINOGEN DEFECTS
Both are associated with fetal loss and
involve other complex mechanisms than
simple thrombosis and infarction.
II-ANATOMICAL CAUSES
1- Congenital causes:

incomplete fusion of Mϋllerian ducts

incomplete septum resorption (septate, subseptate)

cervical anomalies
The most commonest anomalies are septate  60% of spontaneous
abortion in the 2nd trimester and sometimes the 1st trimester.
Inutero exposure to DES may cause congenital anomalies. The most
common lesion in DES is hypopleasia  abortion in the 1st or 2nd
trimesters.
2- Acquired causes:

fibroid

polyps

adenomyosis

Asherman syndrom

cervical incompetence
III- ENDOCRINE CAUSES


Endocrine changes of menstrual cycle
Endocrine factors:
1. Luteal phase defect
2. Diabetes
3. Thyroid disease
4. Hyperprolactinemia
5. Ovarian reserve
ENDOCRINE CHANGES OF MENSTRUAL CYCLE
Follicular phase and ovulation:
- abnormal blastocyst transport
- alteration of uterine receptivity
- improper function of CL
From ovulation until 7-9 weeks
- failure of CL to produce enough P
- impaired delivery of P to the uterus
- inappropriate use of P by the decidua
Near the time of luteal-placental shift
- trophoblast unable to produce biologically active P
ENDOCRINE FACTORS:
1- LPD
It is inadequate or inappropriately timed endometrial
maturation due to:
- Premature aging of the oocyte
- Dyssynchronous maturation of the endometrium
- PCO:
. PCO is present in 80%of RPL
. It is associated with:
, obesity
, ↑ androgen level affect markers of
uterine receptivity
, ↑ insulin resistance
2- DIABETES
DM type II
↑ spontaneous
abortion


IDDM:
- Pregestational glycemic threshold above
which  abortion ↑
- Hyperglycemia damage the embryo
- Vascular changes in advanced IDDM
↓placental blood flow.
3 – THYROID DISEASE
Ovulatory disfunction 
LPD
Pregnancy is associated with ↑ requirement to T4.
Hypothyroidism is associated with ↑ spontaneous
abortion.
Even when T4 is normal, ↑ antithyroid antibodies may
cause ↑ RPL.
(Antithyroid antibodies could be markers of a
generalized autoimmune disease).
4 - HYPERPROLACTINEMIA
Affect reproduction by:
- Direct effect on endometrium
- Indirect immuno-mediator
effect.
5 – DIMINISHED OVERIAN RESERVE
Can be evaluated by:
- Day 3 FSH
- Day 3 estradiol
- CC challenge test.
4 - INFECTION
Mycoplasma
Ureaplasma
Chlamydia
β-streptococcus:
BV is linked to ↑ RPL and PTL in a large study
.
Viral infection as:
- cyromegalovirus
- herpes simplex
Mechanisms of action:
- villitis
- mechanisms protecting the fetus from autoimmune rejection↑
infection
- activation of immune reactions PTL, PROM, IUGR.
5 – IMMUNE CAUSES
I.
II.
III.
Basic immunology
Cellular immunity
Humoral immunity
I - BASIC IMMUNOLOGY
1- Innate responses:
1st line defense.
None antigen specific.
Mechanisms are:
- phagocytosis
- complement fixation,
- lysis by NK cells.
2- Acquired responses:
Antigen-specific.
Modulated by T and B cells.
Divided into:
- Primary immune response: on 1st contact with the Ag
- Secondary immune response: on subsequent contact with the Ag.
Rapid and strong.
ANTIGEN SPECIFICITY
Regulated by 2 sets of genes present at major histocompatability
complex (MHC) located on chromosome 6:
Class I MHC molecules: HLA A, B, C
Present at the surface of nearly all cells for intracellular pathogens.
Major ligand for: TCR on CD 8+ cytotoxic and suppressor cells
many receptors on NK cells.
Class II MHC molecules: HLA DR, DP, DQ
Present on the surface of antigen-presenting cells as:
Dendritic cells, macrophages- monocytes, B-cells, and tissue specific cells.
Protect against extracellular pathogens.
Major ligand for: TCR on CD-4+ T- helper cells.
EDUCATION AND HOMING
Fetal bone-marrow derived T-cells move
with the blood until they reach the thymus.
In the thymus they are divided into:
- Those who will express CD4 co-receptor
- Those who will express CD8 co-receptor
And auto-reactivity is eliminated; that is the
cells can recognize non-self but not react
against self.
MUCOSAL AND PERIPHERAL IMMUNE SYSTEMS
Peripheral immune system:
Located in the blood and spleen.
Responsible for protection against blood-born
pathogens.
Mucosal immune system:
Located in GIT, RT, GUT, lacrimal and
mammary glands. Responsible for protection
against exogenous pathogens.
II - CELLULAR IMMUNE RESPONSE
1.
2.
3.
4.
Resident cells
Immune cell education and homing to the
reproductive tract
Antigen presentation at the maternal-fetal
interface
Regulation of the decidual immune cells
1- RESIDENT CELLS
The endometrium is populated by: T-cells
NK-like cell
Macrophages
Very few B-cells
At implantation, there is a dramatic change in the decidual cells and
70-80% of the cells are called:
Decidual granular lymphocytes, or
Large granular, or
Decidual NK
If these cells are NK, then implantation site represent the largest
accumulation of NK in humans. The function of these cells is unclear.
In animals, peripheral NKT cells (which have the characteristics of both
T cells and NK cells) ↑ spontaneous abortion.
Most peripheral immune system T-cells express TCR-αβ.
In the reproductive system T-cells express in addition to this
TCR-γδ which ↑ early in pregnancy and are responsible for
direct, none MHC restricted immune recognition of Ag
within tissues = more protection.
A subset of macrophage called suppressor cells promot
anti-inflammatory properties and may be implicated in
maintenance of pregnancy.
To sum up:
Human decidua is populated by characteristic immune
cells. Alteration of these cells may  pregnancy loss.
Alteration of these cells occur in RPL and not isolated
abortion.
2 – IMMUNE CELL EDUCATION AND HOMING
How these cells are selected, educated, and how they home to the
reproductive tract is still unknown, but animal studies showed that:
These cells may be educated outside the thymus
They may have different mechanisms other than MHC
They may differ from mucosal and peripheral immune systems.
In the mucosal immune system, cells select these sites through interaction
between:
Cell surface molecules on the immune cell= integrins
“”””””””””””””””””””””””””” endothelial cell= selectins or vascular wall
adhesive molecule (VCAM) == homing.
Animal studies showed that:
Integrins are expressed in the reproductive tract
Knowing the mechanism of selection and homing may aid in ttt of RPL.
3 – ANTIGEN PRESENTATION
In the past  trophoblast escape recognition by ↓ expression
of MHC Ag.
Now obsolete, although trophopblast cannot express class
II MHC molecules and class I MHC HLA: A and B Ags.
Extravillous cytotrophoblast cells express class I: C, E and D
Ags. These cells are characterized by excessive invasive
properties:
They move from the tip of villi deep into the decidua,
invade decidual blood vessels, and replace endothelial cells
of decidual spiral arteries. Their behavior reflect non-MHC
mechanisms as integrin switching and expose the fetus to
recognition.
Any cell not expressing Ag is killed by NK. In addition to
protection from killing by NK cells, expression of MHC HLA: C,
E, and G by the trophoblast may modulate cytokines
expression, aid in invasion, and aid in maternal acceptance.
G Ag was linked to disorders of placental invasion.
MHC polymorphism was not linked to RPL. Interferon-γ
was believed to ↑ spontaneous abortion by ↑ expresion of
class I and class II MHC which ↑ cytotoxic attack of T cells,
but aborted tissues were not shown to express MHC Ags.
Class II genotypes were linked to adverse pregnancy
outcome, RPA, and ↑ susceptibility to disease as autoimmune
disease and DM.
4– REGULATION OF DECIDUAL IMMUNE CELLS
I.
II.
III.
Alterations in T- helper cell
phenotype
Reproductive hormones and
immunosuppression
Tryptophan metabolism
I –ALTERATION IN T-HELPER CELL PHENOTYPE
Ag-stimulated immune responses involving CD4+ cells can be divided into:
T-helper cell subset 1 (TH1)
T-helper cell subset 2 (TH2)
based on the character of CD4+ cell and associated
cytokine.
Undifferentiated T- helper cells are differentiated into:
TH 1 in the presence of interferon γ (INF-γ). TH 1 is associated with
inflammatory responses and: INF-γ, IL 2, IL 12.
TH 2 in the presence of IL 4. TH2 is associated with antibody
responses and IL 4, 5, 6, 10, TNF-β.
TNF-α is expressed by both T-helper cells.
There is a reciprocal relationship between TH 1, TH 2, and cytokines.
Most researches agree that:
TH 1 responses are harmful to the embryo
TH 2 responses are present in most normal pregnancies
TH 1 responses are present in some patients of RPL
60-70% of none pregnant patients with history of RPL show
abnormal T-cell responses invitro compared to <3% in controls.
The type of CD4+ cellular response to the implanting fetus is controlled not
only by the types of cells in the decidua but also by the cytokine
enviroment at the maternal –fetal inteface.
Cytokines may affect reproduction by regulating:
Type of cytokine expressed
Concentration of cytokine expressed
Differential stage of effector cell.
Cytokine alteration can be detected in:
Endometrium
Decidual immune cells
Peripheral blood lymphocytes
Animal studies showed that the only factor absolutely essential for
implantation is:
” Leukemia inhibitory factor “.
II- REPRODUCTIVE HORMONES
Many mechanisms are present to avoid fetal recognition by the mother.
Maternal immune responses to the fetus can be detected and if these
mechanisms are regulated, this may help to treat RPL.
Increased reproductive hormones during pregnancy is known to suppress
maternal immunity, but the overall immune responses during pregnancy
appears to change little, while local immune suppression at the maternalfetal interface may be vital.
PROGESTERONE
Progesterone is partially responsible for pregnancy maintenance.
Progestrone suppress T-cell activity by altering K-channels in cell depolarization
which affect:
gene expression
intracellular Ca
And both may be none receptor mediated, resulting in:
TH 2 responses
LIF expression
Both will help in maintenance.
Recently it was found that progesterone can inhibit CD 8+ T cell proliferation
and cytokine secretion.
ESTROGEN
Estrogen modulate immune reactions.
In male
animals:
Estrogen improve immune responses after hemorrhage, trauma and
thermal injury.
Estrogen protect against chronic renal allograft rejection
In humans:
Estrogen ↓ delayed-type hypersensitivity
Estrogen ↑ TH 2 responses.
III – TRYPTOPHAN METABOLISM
Tryptophan is important for T-cell activity and proliferation. Local
alterations in tryptophan metabolism may either:
activate or
fail to suppress maternal immune response.
In animals:
- Tryptophan rich diet  ↑ spontaneous abortion
- Inhibition of indolamine 2,3 dioxygenase enzyme (IDO) loss of
allogeneic fetuses but not syngeneic.
In humans:
- IDO is expressed in the decidua.
- As GA ↑ alteration in maternal serum tryptophan level
Both= potential local immune regulation.
HUMERAL IMMUNITY
I.
II.
III.
IV.
Antiphospholipid antibody syndrome
Antithyroid antibodies
Blocking antibody deficiency theory
Novel HLA-linked alloantigen
ANTIPHOSPHOLIPID ANTIBODY SYNDROME
In the past , it was thought that these antibodies
were against: cardiolipin and
phosphatidylserine. Now it is believed to be
against a protein cofactor : β2 glycoprotein-1
Which assist antibody association with
phospholipid.
% 3-5
CHARACTERISTICS OF APAS:



Prolonged aPTT
Thrombosis
Obstetric complications:
Abortion
Stillbirth
PTL
PROM
IUGR
Preeclampsia
SAPPORO CRITERIA FOR APAS
DIAGNOSIS(1998)
clinical and ≥ laboratory criteria must be present to diagnose APAS:
clinical criteria:≥
≥ 1 episode of thrombosis in artery, vein, or small vessel
obstetric complication:
≥ 3 spontaneous abortions ≥ 10 weeks
≥ 1 fetal death
≥ 10 weeks
≥ 1 preterm labor
≤ 34 weeks for preeclampsia or
placental insufficiency
laboratory criteria:
2 results must be (+)ve on ≥ 2 occasions with ≥ 6 weeks in between
+ve ACA (Ig G or Ig M medium to high level)
+ve LA
History of systemic lupus erythromatosus=less favorable outcome.
MECHANISMS OF ACTION
↓ prostacyclin, ↑ thromboxane  thrombosis placental infarction
II.
Inhibition of syncytiotrophoblast formation
III.
Increase β2 glycoprotein 1
rapid atherosclerosis in decidual artries
inhibit trophoblast adhesion to endothelial cells
↓ annexin V = placental antithrombotic molecule
To summarize:
Pathological evidence of APAS are often equivocal
Characteristic criteria “””””””””””””””””” lacking
“”””””””””””””””””””””””””””””””””””””””” present in other lesions
I.
ANTITHYROID ANTIBODIES
Controversial
One study link it to RPL
Other study  no link
BLOCKING- ANTIBODY DEFICIENCY THEORY
Studies using mixed lymphocyte culture with
paternal stimulator cells suggest that HLA-sharing
between the two parents may cause blocking-antibody
deficiency.
Larger studies showed that HLA heterogeneity is
not necessary for successful pregnancy, although
complete sharing of the whole genome (occur in
isolated groups of people and is very rare) is
associated with ↑ spontaneous abortion. Thus, HLAtyping is rarely required.
NOVEL HLA-LINKED ALLOANTIGEN SYSTEM
Studies showed that this substance is actually CD 46 which is a
placental complementary receptor responsible for protecting the placenta
from complement -mediated attack.
Conclusion:
Successful pregnancy may not require an intact maternal immune system.
Evidence:
Successful pregnancy can occur in:
 Agamma-globulinemic women
 Severe immune deficiency
 Animals lacking T and C cells
 Animals with congenital absence of the thymus
OTHER FACTORS
VEGF
 Apoptosis
 Uterine receptivity
 Endometrial mucin
 Cellular and extracellular matrix adhesion properties
 Soluble intercellular adhesive molecules.
Environmental factors:
o
Medications:
 Antiprogestogens
 Antineoplastic agents
 Anhalation anesthetics
 Ionized radiation

prolonged organic solvents
o
Heavy metals
o
Alcohol
o
Coitus cause abortion only if the cervix is abnormal or incompetent

EVALUATION
PRECONCEPTION EVALUATION



History
Physical examination
Laboratory investigations
POSTCONCEPTIONAL EVALUATION



Β-hCG
U/S
Α-fetoprotein
HISTORY







History of previous pathologic studies or karyotyping of the abortus tissues.
60% of abortions < 8 weeks are due to chromosomal abnormalities. Most
common anomalies are trisomy 16 or monosomy 45X. Documentation of
aneuploidy in the abortus tissues does not affect future fertility.
GA of previous abortion: Most RPL occur at the same GA every time.
Menstrual history may detect oligomenorrhia or endocrine abnormalities.
The timing of coitus in relation to fertilization may detect dyssynchronous
fertilization or old ovum.
Subfertility or infertility= 33% in RPL couples. Abortion may occur before
the 1st missed period and is diagnosed as subfertility.
Personal or family history of thrombosis or renal abnormalities.
Family history of pregnancy loss or obstetric complications.
Drug intake or environmental exposure.
PHYSICAL EXAMINATION
General examination:
 Obesity
 Hirsuitism and acanthosis
 Brest examination and glactorrhea
 Thyroid
Pelvic examination:
Anatomy: uterus  size, shape, DES
cervix
vagina
Trauma
Infection
Estrogenization
LABORATORY ASSESSMENT
Standard investigations:
I.
Parental peripheral blood Karyotyping
II. Hysteroscopy / HSG
III. Luteal-phase endometrial biopsy at day 24
IV. Thyroid function tests ± prolactin
V. Platelet/ complete blood picture
VI. ACA+LA (aPTT or Russel viper venom)
LABORATORY ASSESSMENT UNDER
INVESTIGATION
•
•
•
•
•
•
•
•
•
Ovarian reserve: day 3 FSH, CC challenge test
PCO: LH, A
ATA
Autoantibodies : antiphospholipid, antiphosphatidylserine,
anti-β2 glycoprotein 1
Nk cells activity
TH 1, TH 2
Hypercoagulability; aPTT
Hyperhomocysteinemia: fasting and after methionine loading
(dangerous to the fetus).
Cervical cultures: mycoplasma, ureaplasma, chlamydia
EXPERIMENTAL STUDIES




Mixed lymphocyte culture
Parental HLA-typing
Serum or site-specific autoantibodies
& alloantibodies
Others:
- Suppressor cell
- Cytokines
- GF
- Embryotoxic factor
- Oncogenes
POSTCONCEPTIONAL EVALUATION
If become pregnant psychological support
Confirm: - intrauterine pregnancy
- viability
Because of ↑ % of ectopic and molar pregnancy
Pregnancy complications
Only ↑ in APAS and intrauterine infections.
Monitoring:

Β-hCG
Not always ↓ before abortion
If missed period Β-hCG until= 1500mIU/ml

U/S
Every 2 weeks GA of abortion
If no FH activity until 6-7 weeks terminate and karyotype

Maternal serum α-fetoprotein
At 16-18 weeks.
Karyotyping of the abortus tissues:
- Suggest chromosomal abnormalities in the
parent
- Prevent other costly investigations ↓ cost
Difficulties:
- Difficult culturing of inflamed or necrotic cells
- Contamination with maternal cells
Recent advances:
 Genomic hybridization technology:
Used on archived and paraffin-embedded tissues
 Karyoyping of nucleated fetal RBCs in maternal blood
TREATMENT
TREATMENT
Most ttt are experimental, use only with informed consent. Most patients
conceive irrespective of ttt.
Genetic causes
Anatomical causes
Endocrine causes
Infection
Immunological ttt
immune-stimulation
immune-suppression
Antithrombotic ttt
TREATMENT OF GENETIC CAUSES
Antithrombotic ttt for inherited thrombophilias
Preimplantation genetic diagnosis in known heritable disorders
Donor oocyte or sperm in robertsonian translocations
Recently:
PGD+antithrombotic ttt+ ART for all unexplained RPL
TREATMENT OF ANATOMICAL CAUSES
Hysteroscopic resection/metroplasty ± laparoscopy
U/S guided transcervical metroplasty
Fluoroscopic guided septum resection
Laparoscopic excision of endometriotic lesions
Cervical cerclage.
TREATMENT OF ENDOCRINLOLGICAL CAUSES
Ovulation induction
Thyroid hormone replacement
Insulin-sensitizing agents for overt DM
Bromocriptine
TREATMENT OF INFECTION
Empiric antibiotics for immunosuppressive patients
Specific antibiotic ttt for known infections to both partners with posttreatment
culture before attempting conception.
TREATMENT OF IMMUNOLOGICAL CAUSES
Immunostimulating ttt
leukocytes
others
Immunosuppressive ttt
I.V. immunoglobulin
progesterone
others
cyclosporine
nifedipine
corticosteroids
LDA
LEUKOCYTES
Large studies  useless
Complications:
 Graft versus host reaction
 Severe IUGR
 Fatal fetal thrombocytopenia
 Autoimmune/isoimmune complications
May benefit 1 : 11 patients
Routine use unjustified
OTHERS
I.
I.V. injection of syncytiotrophoblast
microvillous plasma membrane
vesicles.
II.
3rd party seminal plasma suppositories.
INTRAVENOUS IMMUNOGLOBULIN
Indicated in:
 APAS
 Inappropriate cellular immunity
Possible Mechanisms of action:
 ↓ autoantibodies
 ↑autoantibodies clearance
 T-cell regulation
 Complement inactivation
 ↑ T-cell suppressor function
 ↓ T-cell adhesion to extracellular matrix
 ↓ TH1 cytokine production
Side effects:

nausea

myalagias

hypotension

headache

anaphylaxis
Disadvantages:

expensive

invasive

time consuming

require multiple I.V.D.
PROGESTERONE
Partially responsible for maintenance.
Inhibits TH1 responses shift to TH2
responses
Vaginal progesterone:
Is better than systemic treatment
 ↑ local suppression
 ↑ intrauterine concentrations
 ↓ adverse effects.
OTHERS
Cyclosporine
 Nifedipine
 Plasmaphoreses
 Corticosteroids:
Prednisone + low dose Aspirin
 same pregnancy outcome as controls, but:

↑ HTN

↑ DM

↑ PTL

ANTITHROMBOTIC TREATMENT
For APAS and thrombophilic disorders
Treat hypercoagulability
Start before conception continue although pregnancy
Unfractionated heparin 5000 IU S.C. twice/day
+ low dose Aspirin 75-80mg/day. Monitoring by aPTT/week.
Risks:
 PTL
 PROM
 IUGR
 Preeclampsia
 Abruptioplacenta
 Stillbirth
 Gastric bleeding
 Ostiopenia
Recently: low molecular weight heparin(LMWH)
Indications:
 APAS
 Non-APAS patients with thrombophilia
 Patients without thrombophilia =unexplained RPL
Advantages:
 Less bleeding
 Less osteopenia
 More antithrombotic ratio
 More patient compliance:
- less frequent doses
- less frequent monitoring
The role of LDA alone:
Studies useful for APAS and RPL
Studies useful in unexplained RPL
Routine use alone cannot be justified.
Other antithrombotic treatment:
 Vit B6, B12, folate
 Protein C concentrate
Both for hyperhomocysteinemia whether
congenital or aquired.
PROGNOSIS
Depends on cause and number of abortions. Even
if >4 abortions, successful birth rate may reach 60%
 Genetic causes

20-80% live birth
 Anatomical causes 
60-90% “”””””””””
 Endocrine causes 
> 90% “”””””””””
 Infection

70-90% “”””””””””
 APAS

70-90% “”””””””””
FHM documentation:
It has a prognostic value depending on the cause:
FHM documentation in 77% of live birth
“”””””””””””””””””””””” in 86% of APAS before abortion
“”””””””””””””””””””””” in 3% of unexplained RPL