Transcript RECURRENT PREGNANCY LOSS CURRENT CONCEPTS

1
RECURRENT
PREGNANCY LOSS
Dr.P.M.GOPINATH
MD, DGO, FMMC, FICS, FICOG, MBA (HSM)
Director of Social Obstetrics i/c
ISO & KGH Chennai 600005
Recurrent Miscarriage-Definition
• Occurrence of 3 or more clinically
recognized consecutive or
nonconsecutive pregnancy losses before
20 weeks from last menstrual period
• Primary- No previous full term pregnancy
• Secondary- At least one successful
pregnancy
Incidence
– 15-20% of all pregnancies
– 11-13 % in first pregnancy
– 13-17 % after first abortion
– 38 % after two abortions
– 55% after three abortions
Recurent
Miscarriage Etiology
Explained
• Anatomic (Sporadic)
12%-16%
• Endocrine
17%-20%
– Luteal phase deficiency
– Uncontrolled DM
– PCOS
• Immunological
10%-16%
– Anti phospholipid syndrome
• Environmental
– Alcohol, Smoking
• Genetic factors
3.5-5%
Un-explained
50%
Anatomical Factors
• What are the congenital & acquired
uterine anomalies leading to RSA?
• How will you manage?
Uterine Abnormalities
• CONGENITAL (Mullerian Duct abnormalities)
• UTERINE NEOPLASMS (Growth)
• IATROGENIC (Acquired)
ANATOMICAL CAUSES
•
•
•
•
•
•
•
Septate uterus
Intrauterine adhesions
Bicornuate ut (unequal horns)
Unicornuate uterus
T shaped uterus
Submucous fibroids
Large endometrial polyps
How they affect…….
•
•
•
•
Smaller Uterine Cavities
Fewer suitable implantation sites
Aberrations of vascularisation
May be accompanied by cervical
incompetence
Lead to both early & later pregnancy losses
Septate Uterus
• Most COMMON anomaly 55%
• May be complete/ incomplete/segmental
25% early abortions
6.2% late abortions &
Premature labors
Unicornuate Uterus
• 20% of anomalies
• Agenesis or hypoplasia of one Mullerian duct
• May be alone or accompanied by Rudimentary
horn
With presence / absence of cavity
Communicating / Non communicating
• Associated Renal anomalies occur in 40%
patients Ipsilateral to hypoplastic horn
Unicornuate Uterus
• Abortion Rate 51%, Premature labours,
malpresentations, IUGR, Uterine rupture &
ectopic pregnancies common
• Cervical encerclage to improve pregnancy
outcome
• Rudimentary Horn resected to prevent
dysmenorrhoea, haematometra,ectopic
pregnancy
Uterus Didelphys
•
•
•
•
Least common anomaly -5-7%
Failure of lateral fusion of uterus &vagina
Abortion rate 43%,Premature birth rate 38%
Resection of Vaginal septum if there is difficulty in
intercourse / vaginal delivery
• Strassmann Operation not indicated
Bicornuate Uterus
• 10% of anomalies
• Incomplete fusion of Uterine horns at level of
fundus
• Two separate but communicating endometrial
cavities
• Abortion rate 32% Preterm labour 21%
• Strassman Metroplasty / Place IUCD in one horn
Arcuate Uterus
•
•
•
•
Near complete resorption of u-v septum
Mild concave indentation at fundus
? Anomaly / ? Anatomic variant
Data conflicting Abortion rates ?45%
?13%
• Treatment expectant
T shaped Uterus
• Diethylstilbestrol treatment for Premature labour
started 1940 Banned 1970
• 69% female foetuses suffered Uterine anomaly
• T-Shaped uterus, small uterus, constriction rings,
• Cervical hypoplasia, cervical incompetence,
Anterior Cervical collar, pseudopolyps
• 2 fold increase in abortion rates & 9 fold increase in
Ectopic pregnancy rates
TMALA
SHAPED
ARORA UTERUS- INFECTION
17
Uterine Neoplasms
• Endometrial Polyps
PERIOSTEALMALA
ENDOMETRIAL
POLYP
ARORA
19
7/17/2015
Leiomyomas (Fibroids)
most common…. 20-50%
of reproductive women
When will you consider
fibroids responsible ?
• Preconception myomectomy to improve
reproductive outcome can be considered on
an individual basis
• It is likely to have a place only in women who
have recurrent pregnancy loss,
– large submucosal fibroids, and no other
identifiable cause for recurrent miscarriage
Ouyang DW, Obstet Gynecol Clin North Am. 2006
Iatrogenic…
Intrauterine adhesions ,“Asherman’s Syndrome”
• Lead to Poor implantation,
• Decreased blood supply ,
• infection
Abortion rates 40% Preterm labour 23%
Management :-Hysteroscopic excision of
adhesions
HYSTEROSCOPIC CORRECTION
• All of the above have a
good pregnancy rate
post hysteroscopic
correction
• Except ashermans
syndrome
Anatomical Factors
• When will you label a patient as a
case of incompetent Cervix?
• What are the different surgical
procedures?
• Role of prophylactic surgery?
• USG follow up weekly in cases of prior 2nd trimester
loss
• Funneling of >25% cervical length and/or <2.5 cms
cervical length before 24 weeks of pregnancy
• Cervical cerclage reduces the rate of preterm birth
Carp et al, 2007
• Emergency cerclage: beneficial if no infection or
uterine contractions
Genetic Etiology
• Chromosomal
3.5%-5%
–Fetal chromosomal abnormalities
–Parental balanced chromosomal
rearrangement
• Single gene disorders
–Alpha thalassemia major
–Thrombophilia
–X linked dominant disorders
Risk Factors for Karyotypic abnormalities
Gestational age
Higher in early gestation
90% in anembryonic preg/Blighted ova
50% at 8-11wk
30% at 16-19 wk
6-12% >20wk
Risk Factors for RM
Advanced maternal age

Affects ovarian function, giving rise to a decline
in the number of good quality oocytes, resulting
in chromosomally abnormal conceptions that
rarely develop further.

RM risk -75% in women >45years
Previous number of miscarriages
28
Spontaneous Miscarriage
• 10-15% of recognized pregnancies
• Mostly sporadic ; 80% losses in 1st 12 wks
• 50-70% due to chromosomal anomalies
–Autosomal trisomy 50-60%
• 13,16,18,21,others
–Monosomy X-20%
– Triploidy –15%
–Tetraploidy-5%
–Unbalanced
translocation-3-5%
Parental Karyotypes normal Minimal recurrence risk
In Recurrent Miscarriage (RM)
Fetal chromosomal abnormality in only 2532% of product of conception (POC)
 This may be due to abnormalities in the egg,
sperm or both.
 The most common chromosomal defects are
Trisomy, Monosomy, Polyploidy
Sperm aneuploidy (13,18,21,X,Y ) directly influences
the rate of aneuploidy in the conceptus (Carrell et
al 2003)
In Recurrent Miscarriage
• Parental chromosomal abnormality (Balanced
chromosomal rearrangements)
–General population
6 in 1000(0.6%)
–RM
4.1-11%
*3-5% of couples with RSA are carriers of
balanced chromosomal rearrangements
Parental Chromosomal Abnormalities
–Translocation (commonest) (1in 500)
• Reciprocal [50%]
• Robertsonian [24%]
–Mosaicism for a numeric aberration [12%]
–Inversion
32
Translocation
Translocation is exchange of chromosomal
segments between two, non-homologous
chromosomes.
Source-Internet
Translocations
Two major types
Reciprocal translocation- two nonhomologous chromosomes
exchange information
Robertsonian translocation -two
non-homologous acrocentric
chromosomes break at the
centromere and the long arms fuse.
The short arms are often lost.
Source- Emery’s book of
principles of Medical Genetics
• Karyotype of the abortus
( fetal/placental tissue)
• Peripheral blood Karyotyping of the parents in
all couples with RM
35
Spontaneous abortion
Recurrent Miscarriage
10-15%
1-3%
50-70% abortuses
25-30% abortuses
chromosomally abnormal chromosomally abnormal
Couple karyotype usually Couple karyotype may be
normal
rearrangement carrier
Recurrence risk negligible Recurrence risk upto 50%
• Successful culture requires healthy cells derived from the fetus
• Unsuccessful in upto 50% of cases
–Maternal overgrowth of fetal cells
–Poor growth of abortus tissue esp. if there is a long time
interval from the demise until the culture is performed
–Poor chromosome morphology
Whether we should do POC
karyotype ????
 No definite recommendations for routinely
obtaining abortus karyotype (ACOG 2001)
 Karyotype analysis of abortus tissue for couples with a
subsequent second or third pregnancy loss
(Hogge,
et al 2003)
 If abortus is aneuploid, maternal cause is excluded
(ACOG, 2001)
 If POC karyotype not possible, do parental karyotype
Normal
Abnormal (trisomy or chromosomal rearrangement)
Both requires parental karyotype
Direct parental karyotype is more cost effective
No need for first abortion
• Individuals with Balanced Chromosomal
Rearrangement usually phenotypically normal
• Are at risk of having conceptus with
– normal
– balanced phenotypically normal
– unbalanced
• spontaneously aborted
• phenotypically malformed
Single Gene Disorders in RM
•
•
•
•
Second and 3rd trimester losses
Alpha Thalassemia
Myotonic dystrophy
X linked Dominant disorder
–
–
–
–
–
Incontinentia Pigmenti
Chondrodysplasia punctata
Focal dermal hypoplasia of Goltz
Rett Syndrome
Aicardi Syndrome
42
Single Gene Disorders in RM
• Hereditary thrombophilia
•
•
•
•
•
– First and later trimester losses
– Microthrombosis in placenta ;Impaired uteroplacental
circulation
Factor V Leiden gene mutation Evidence based Prothrombin G
20210A mutation
inc. risk
Protein C,S deficiency
Antithrombin III
No significant association
MTHFR C677T mutation
Combination of any of above-Increased risk
43
Genetic Evaluation and Testing
Recommendation
• History of
– Recurrent miscarriage
– Clotting disorder
– Still birth/neonatal death
– Babies with dysmorphic features
– Infertility
– Mental retardation /developmental delay
– Inherited disorder
(J Gen Counsel ;14(3)2005)
44
Karyotypic abnormalities in couples with
Recurrent abortions
•
•
•
•
Total Couples n=742(1484 cases)
Duration -12 years
Chromosomal rearrangements = 52 (7% )
Structural aberrations 22 (2.9%)
– Reciprocal (6,8,11,18)=15 (68.2%)
– Robertsonian (21,22,13,14)=4 (18.1%)
– Inversion(4)=1 (9%)
– Deletion=2
• Numerical anomalies (mosaics with XO,XXX, XXY)= 9 (1.2%)
• Chromosomal variants (para centromeric
heterochromatin/fragile sites) = 21 (3.2%)
Dubey et al. Ind J Hum Genet 2005
Role of Infections
Venn diagram of the responsibilities
of Reproductive Failure
EGG
80%
SPERM
10%
UTERUS 10%
Doubtful causes of RSA
• TORCH infections
• Endocrine and metabolic disease
– Untreated adrenal hyperplasia,
hypothyroidism & diabetes mellitus.
• Exogenous causes
– Environmental factors, alcohol, street drugs,
anesthesia gases etc
Its time to say
goodbye to
TORCH tests…….
Cochrane Review has
categorically proven in
multiple meta-analysis
that none of the “TORCH”
group of infections are
responsible for
RECURRENT
SPONTANEOUS
ABORTIONS
So which infections, if any are
responsible for RSA?
Female
• Viral infections ? ?
– Coxasackie B
– Parovo-virus B
• Bacterial infections
– Bacterial Vaginosis
– Tuberculosis
– Chlamydia trachomatis
Male factors:
• Semen infections can cause
anueploidy and be the reason of RSA
Genitourinary diseases prior spontaneous
abortion as a risk factor for RSA
Concluded “infections of the maternal and/or
paternal genitourinary system may be the causal
factor for recurrent pregnancy loss and can also
pre-determine women that are of greater
susceptibility to preterm pregnancy”
• Culić V, Konjevoda P, et al. Coll Antropol. 2009 Mar;33(1):187-92
• Kamilova N, Sultanova I, et al. Georgian Med News. 2008
Nov;(164):23-7
Bacterial Vaginosis
• Commonest cause of vaginitis
• Amsel's criteria for diagnosis of
BV
– Thin, homogeneous discharge
– Release of an amine
(putrescine, cadaverine, &
trimethylamine) or fishy odor
on addition of KOH is to
vaginal discharge
– "Clue cells" (Vaginal epithelial
cells coated with coccobacilli)
– Vaginal pH > 4.5
• Nugent score: Gram Stain of
vaginal swab
Bacterial
Vaginosis
50%
Trichomona Candida
s vaginalis albicans
25%
25%
BV and RSA
• BV one of the most frequently founded cause
of spontaneous abortions and prematurity
birth
• Diagnostics is easy and not expensive
• High vaginal pH is diagnostic
• Treatment is simple using
Metronidazole/Clindamycin
1. Damianov L, Damianova V. Akush Ginekol (Sofiia). 2004;43 Suppl 2:26-7.
2. Mania-Pramanik J, Kerkar SC, et al. J Clin Lab Anal. 2008;22(5):375-9.
3. Li TC, Makris M, et al. Hum Reprod Update. 2002 Sep-Oct;8(5):463-81
The influence of Chlamydia trachomatis
infection on RSA
Specific anti-chlamydial antibodies in 3 groups of women
• IgA class
– 7.9% (p=0.082) in group 1 (RSA group),
– 4.5% (p=0.236) in group 2 (1 abortion)
– 0% in group 3 ( no abortions)
• IgG class in 21.1% (p=0.024), 36.4% (p=0.000) and in
4.4%, respectively.
CONCLUSIONS:
• C.t. infection is an important causative agent in RSA
• Anti-Chlamydial antobodies included in screening tests
Wilkowska-Trojniel M. Adv Med Sci. 2009;54(1):86-90
Kavalier F, BMJ. 2005 Jul 16;331(7509):121-2.
Hattori Y, Nakanishi T.
Am J Reprod Immunol. 2007 Oct;58(4):350-7.
• Uterine cervical inflammatory cytokines, interleukin6 and -8, as predictors of RSA
• Both IL-6 and IL-8 in cervical mucus were significantly
higher in patients who miscarried subsequently than
in those who had a live birth.
Other rare viruses
Coxsackie B virus (CBV) & RSA
Parvovirus B19
Is it time to
look at the
sperm?
Consequences of fertilisation by
sperm with nuclear DNA damage
No DNA Repair
Fertilisation
Failure
Partial DNA Repair
Fertilisation
DNA Repair
Fertilisation
Normal
offspring
?
Abnormal
offspring
SEMEN CULTURE
• Male accessory gland infection with E coli /
Staph aureus /
• Bacteria ride on the sperm tails into uterine
cavity
• Produce low grade endometritis
Possible role of male factors in
recurrent pregnancy loss
• Amongst male partners of women with RSA 3 (4%) had
varicocele, 23 (30.6%) had infection, 1 (1.3%)
immunological and 1 (1.3%) had genetic abnormality
• Sperm motility, viability and sperm function tests were
significantly lower in the RPL group as compared to the
control group (P = 0.000)
• Male factor might be a contributing factor towards RPL
• Both the partners should be evaluated
• Infection treated in both
Saxena P, Misro MM et al. Indian J Physiol
Pharmacol.
2008 Jul-Sep;52(3):274-82
Conclusion
Problems of Research in RSA
• The cause of individual abortion may be different
• More than one factor may exist
• Thorough investigation often fails to reveal a cause
• Infections must be ruled out
Fertil Steril. 2010 Mar 1;93(4):1234-43. Epub 2009 Mar 31
Conclusions
• TORCH group DOES NOT cause RSA
• Infections in both partners need to be
evaluated in cases of RSA
• Therefore the genetic counseling of couples
should include thorough medical examination
and evaluation for infections
Antiphospholipid Antibody
Syndrome
and
Recurrent Pregnancy Loss
63
Autoimmune etiology
• Secondary to autoimmune disease such
as SLE, Polyarteritis nodosa, etc
• Primary Antiphospholipid Syndrome
(PAPS) refers to the association of adverse
pregnancy outcome and presence of
antiphospholipid antibodies
64
Which antibodies ?
• A number of antibodies have been studied
• The antibodies with the greatest significance
and association with obstetric events are
– Lupus anticoagulant (LA)
– Anticardiolipin antibodies (ACL IgG and ACL IgM)
• Others have such as β2glycoprotein-I,
antiphosphatidylserine antibodies, annexin,
etc may not be obstetrically significant
65
Incidence
• About 1% of couples have recurrent miscarriages
• Antiphospholipid antibodies are found in about
2% of a Caucasian population. Not studied in a
general Asian / Indian population
• 5 – 20% of women with recurrent miscarriages
have antiphospholipid antibodies
MacLean AS et al, BJOG 1994
Rai RS et al, Hum Reproduction 1995
Balasch J et al, Hum Reproduction 1996
66
Statistical Distribution
• Prevalence of antiphospholipid antibodies in
various categories of women was studied
Women with 3 or more
early fetal losses
Women with normal
pregnancy outcome
Women who have not
been pregnant (includes
women not desiring
pregnancy and infertile
women)
16%
7%
3%
Parke AL et al, Arch Rheumat 1991
67
Diagnosis of PAPS
• Based on clinical and laboratory criteria
• One obstetric or thrombotic criteria and one laboratory
criteria should be present to diagnose PAPS
• Other autoimmune disease has to be ruled out to make
the diagnosis of PAPS
Wilson A et al, International Consensus statement on APS,
Arthritis Rheumatol 1999
68
Obstetric Criteria
• Three or more consecutive spontaneous
abortion before the 10th week of gestation
• One or more unexplained fetal death at or
beyond the 10th week of gestation
• Severe preeclampsia or placental insufficiency
(IUGR) necessitating birth before the 34th
week of gestation
69
Vascular Thrombosis Criteria
• Unexplained venous thrombosis
• Unexplained arterial thrombosis
• Small vessel thrombosis in any tissue or organ,
without significant evidence of inflammation
of the vessel wall
70
Laboratory Criteria
• Anticardiolipin antibody IgG or IgM isotype in
medium to high titers by standardized ELISA assay
• Lupus anticoagulant present
• A positive test has to be repeated on at least one
more occasion six weeks apart to fulfill the
laboratory criteria
71
Lupus anticoagulant testing
• Screen with demonstration of prolonged
phospholipid dependent coagulation screening
test (eg: activated partial thromboplastin time,
kaolin clotting time, diluted Russell’s viper venom
time, dilute prothrombin time)
• Failure to correct the prolonged screening test by
mixing with normal platelet-poor plasma
• Shortening or correcting the prolonged screening
test by addition of excess phospholipids
• Exclusion of other coagulopathies if clinically
72
indicated
Pitfalls in diagnosis of PAPS
• Usually an overdiagnosed syndrome
• Not meeting clinical and the strict laboratory
criteria
• Not repeating the laboratory test at 6 weeks
• Non standardized ELISA for ACL antibodies
• Interlaboratory variations for phospholipid
dependent coagulation tests used for
screening for lupus anticoagulant
73
False results in PAPS
• Improperly collected and processed samples
• Temporal and trimester wise fluctuations
• VDRL positive patients who may or may not
have syphilis
• General infections and inflammations
• Coagulopathies and anticoagulant medication
users (including aspirin, heparin)
74
Goals for treating PAPS
• Avoid early pregnancy loss
• Normalize placental and fetal circulations to
prevent early birth from obstetric
complications such as preeclampsia and
growth restriction
• Prevent maternal vascular thrombosis in
pregnancy and postpartum
75
Women with PAPS
without a history of
thrombotic events
(most women with RPL)
Women with PAPS with
history of thrombotic
events (past or present)
Prophylactic therapies
such as aspirin, heparin in
pregnancy and 6 to 8
weeks postpartum
Full anticoagulation with
heparin (or warfarin) in
pregnancy and postpartum
76
Aspirin alone v/s Aspirin + Heparin
• Recent metaanalysis shows that the
combination of Aspirin + Heparin is better
than Aspirin alone in achieving live births in
women with recurrent pregnancy loss and
antiphospholipid antibodies
Mak A et al, Rheumatology (Oxford) 2010
77
Is Heparin + Aspirin really better?
• The metaanalysis was based on data from five trials
involving 334 patients across non uniform care
platforms
• Overall live birth rates were 74.27 and 55.83% in the
combination and aspirin alone groups
– RR 1.301; 95% CI 1.040, 1.629
– Number needed to treat is 5.6
• There is no placebo group for comparison
• Another metaanalysis showed that LMW heparin +
Asprin does not significantly improve birth rates. The
benefits is present only with unfractionated heparin
Zikas PD et al, Obstet Gynecol 2010
78
Clinical Tips for using Heparin
• There is controversy as to whether LMW Heparin
is effective in preventing recurrent pregnancy loss
• Consider costs, convenience and compliance
before initiating therapy
• Therapy should be started when fetal cardiac
activity is demonstrated and continued
throughout pregnancy and postpartum
• Heparin in prophylactic doses needs to be
stopped for about 24 hours around the time of
labor and delivery
79
Clinical Tips for using Heparin
• Heparin in prophylactic doses can not be
monitored and does not require monitoring
by coagulation parameters
• Do a platelet count at 3 days, 1 week and
bimonthly when the patient is on heparin
• Standard doses
– Unfractionated heparin – 5000 units sc bd
– Enoxaparin – 40 mg sc daily or in two doses
80
Full Anticoagulation : Practical
• Preconception : Warfarin
• Switch to Heparin when fetal cardiac activity is
demonstrated
• Warfarin should be considered in the second
trimester
• Switch back to Heparin at 34 to 36 weeks
• After delivery : Warfarin
81
What not to do for PAPS
• Steroid therapy should be avoided for PAPS
because it significantly increases morbidity
(hypertension, diabetes, preterm births)
without any demonstrable benefit
• Immunoglobulin therapy is experimental and
not for clinical use at present
82
RECOMMENDED
INVESTIGATIONS
1.
2.
3.
4.
5.
6.
Grade A (FOR ALL PATIENTS)
Hysterosalpingography/ Hysteroscopy
APTT/ dRVVT/ Lupus anticoagulant
IgG & IgM anticardiolipin antibodies
TSH / Prolactin / Testosterone / HbA1C/ 2 hrs
Post Prandial INSULIN
Karyotyping of both parents &
If possible abortus
RECOMMENDED
INVESTIGATIONS
Grade B (FOR SELECTED PATIENTS)
1. ANDROGENS, LH, FSH IN PATIENTS WITH IRREGULAR
MENSTRUATION
2. SERUM PROGESTERONE
3. EB FOR DATING & TB PCR, CULTURE
4. SERUM HOMOCYSTEINE LEVELS / THROMBOPHILIA
SCREEN
5. HVS / WET PREP & pH / KOH Whiff test
6. SEMEN CULTURE / TB PCR
ANTI PHOSPHOLIPID SYNDROME
•
•
•
•
•
LOW DOSE ASPIRIN pre preg clinic
HEPARIN after ultrasound viability
Low molecular weight heparin
Intravenous immunoglobulins
Corticosteroids only used in aps associated with
sle
• Warfarin if previous arterial thrombosis in
second & third trimester
ANATOMICAL CAUSES
• Hysteroscopic evaluation
• Intrauterine adhesiolysis
• Septum resection
• Removal of submucous fibroids and polyps
• CERVICAL CERCLAGE if indicated
INFECTVE CAUSES
• Screening and treatment of bacterial
vaginosis
• Screening and treatment of occult genital
tuberculosis
• Chlamydia screening & treatment
ENDOCRINAL FACTORS
• Polycystic ovaries ? metformin
• Luteal phase defects progesterone /
Duphaston
• Thyroid replacement therapy
• Optimising HbA1c levels
• Correct hyperprolactinaemia
THROMBOPHILIA SCREEN
POSITIVE
• LOW MOLECULAR WEIGHT HEPARIN
• UNFRACTIONATED HEPARIN
(From 6 weeks to 36 weeks of pregnancy)
HAEMATOLOGICAL
• Folic acid, vitamin b6, vitamin b12 in
hyperhomocystinaemia
• Low dose aspirin
• Heparin or LMWH
• Full dose heparin in case of DVT
• WARFARIN if arterial thrombosis
90
ALLOIMMUNE CAUSES
Progesterone therapy
Evidence for use
Dydrogesterone in the reduction of recurrent
spontaneous abortion
El-Zibdeh MY
El-Zibdeh MY. Dydrogesterone in the reduction of recurrent spontaneous abortion.
J Steroid Biochem Mol Biol 2005; 97: 431-434
Methods
Treatment
•Randomised, controlled study
Women randomised to:
•Pregnant women (< 35 years old) who had
– Oral dydrogesterone 10 mg b.i.d.
experienced at least 3 consecutive
– Intramuscular human chorionic
miscarriages with the same partner
gonadotrophin (hCG)
•Only women for whom no explanation
5000 IU every 4 days
could
– No additional treatment
be found for their recurrent miscarriages
•Randomisation according to the day of
were included.
the week they attended clinic
•Treatment started as soon as possible
180 Women of which:
after confirmation of pregnancy and
– 82 Received dydrogesterone
continued until 12th gestational week
– 50 Received hCG
•All women received standard supportive
– 48 Received no additional treatment
care: multivitamin supplements and
(control)
recommended bed rest
Dydrogesterone in the reduction of recurrent
spontaneous abortion
El-Zibdeh MY
El-Zibdeh MY. Dydrogesterone in the reduction of recurrent spontaneous abortion.
J Steroid Biochem Mol Biol 2005; 97: 431-434
Results
Conclusion
Dydrogesterone reduced the
chances of spontaneous
pregnancy loss in women with
recurrent miscarriage
Dydrogesterone was well
tolerated and had no
unwanted effects on the
delivery or outcome of
pregnancy
EVIDENCE - Dydrogesterone
Progressive increase in PIBF
cells with increasing
concentrations of
dydrogesterone.
J Szekeres Bartho 9th World Congress of Gynecological Endocrinology,
Hong Kong, December 2001
Dydrogesterone inhibits the production
of the Th1 cytokines IFN-g and TNF-a
from lymphocytes and up-regulates the
production of the Th2 cytokines IL-4
and IL-6, inducing a Th1 to Th2
cytokine shift.
Raj Raghupathy et al. BJOG 2005;112:1-6
↑Progesterone
Induced
Blocking Factor
Embryo
Protective
Immunomodulation
Protection of
Fetus
Th1
Raj Raghupathy et al. BJOG 2005;112:1-6
Dydrogesterone has an immunomodulatory
capability and appears to induce a maternal
cytokine shift from Th1 cytokine dominance
towards a Th2 bias.
Dydrogesterone
Progesterone
(P) Receptor
Activation
Th2
ROLE OF
TENDER LOVING CARE
DESTRESS & REASSURE
• Psycho-neuro-immunology
• Stress affects immune system
• Changes th2 response in endometrium to th1
response
• Hypothalamus affects endocrine system
• Adrenaline release reduces placental blood
flow
DIAGNOSTIC
IVF / ICSI with
PGD
PICKS UP ANEUPLOIDY IN EMBRYOS
SURROGACY
 If diagnostic IVF & PGD
confirm normal gametes /
embryos
 All treatment modalities
have failed
Conclusion / Problems of RPL
• The cause of individual abortion may be
different
• More than one factor may exist
• Thorough investigation often fails to reveal a
cause
Fertil Steril. 2010 Mar 1;93(4):1234-43. Epub 2009 Mar 31
THANK YOU
for your valuable time