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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.

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recurrent pregnancy loss

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
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
Incidence
  • 15-20% of all pregnancies
  • 11-13 % in first pregnancy
  • 13-17 % after first abortion
  • 38 % after two abortions
  • 55% after three abortions
slide5

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%

slide6

Anatomical Factors

  • What are the congenital & acquired
  • uterine anomalies leading to RSA?
  • How will you manage?
slide7

Uterine Abnormalities

  • CONGENITAL (Mullerian Duct abnormalities)
  • UTERINE NEOPLASMS (Growth)
  • IATROGENIC (Acquired)
anatomical causes
ANATOMICAL CAUSES
  • Septate uterus
  • Intrauterine adhesions
  • Bicornuateut (unequal horns)
  • Unicornuate uterus
  • T shaped uterus
  • Submucous fibroids
  • Large endometrial polyps
slide9

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
Septate Uterus
  • Most COMMON anomaly 55%
  • May be complete/ incomplete/segmental

25% early abortions

6.2% late abortions &

Premature labors

unicornuate uterus
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 uterus12
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
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
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
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
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
slide18

Uterine Neoplasms

  • Endometrial Polyps
leiomyomas fibroids most common 20 50 of reproductive women

Leiomyomas (Fibroids) most common…. 20-50% of reproductive women

When will you considerfibroids responsible ?

slide21

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
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
HYSTEROSCOPIC CORRECTION
  • All of the above have a good pregnancy rate post hysteroscopic correction
  • Except ashermans syndrome
slide24

Anatomical Factors

  • When will you label a patient as a case of incompetent Cervix?
  • What are the different surgical procedures?
  • Role of prophylactic surgery?
slide25

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
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
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
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
spontaneous miscarriage
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
In Recurrent Miscarriage (RM)
  • Fetal chromosomal abnormality in only 25-32% 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
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
Parental Chromosomal Abnormalities
  • Translocation (commonest) (1in 500)
    • Reciprocal [50%]
    • Robertsonian [24%]
  • Mosaicism for a numeric aberration[12%]
  • Inversion
slide33

Translocation

Translocation is exchange of chromosomal segments between two, non-homologous chromosomes.

Source-Internet

slide34

Translocations 

Two major types

Reciprocal translocation-two non-homologous 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

diagnosis
Diagnosis
  • Karyotype of the abortus

( fetal/placental tissue)

  • Peripheral blood Karyotyping of the parents in all couples with RM
karyotype of products of conception
Karyotype of Products of Conception
  • 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
karyotype of products of conception39
Karyotype of Products of Conception
  • 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
karyotype of products of conception40
Karyotype of Products of Conception
  • Normal
  • Abnormal (trisomy or chromosomal rearrangement)

Both requires parental karyotype

Direct parental karyotype is more cost effective

No need for first abortion

why karyotype of the parents
Why Karyotype of the Parents ??
  • Individuals with Balanced Chromosomal Rearrangement usually phenotypically normal
  • Are at risk of having conceptus with
    • normal
    • balanced phenotypically normal
    • unbalanced
      • spontaneously aborted
      • phenotypically malformed
slide42

Single Gene Disorders in RM

  • Second and 3rd trimester losses
  • Alpha Thalassemia
  • Myotonic dystrophy
  • X linked Dominant disorder
    • IncontinentiaPigmenti
    • Chondrodysplasiapunctata
    • Focal dermal hypoplasia of Goltz
    • Rett Syndrome
    • Aicardi Syndrome
slide43

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
slide44

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)

karyotypic abnormalities in couples with recurrent abortions
Karyotypic abnormalities in couples with Recurrent abortions

Dubey et al. Ind J Hum Genet 2005

  • 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%)
doubtful causes of rsa
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
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

TORCHTESTS

so which infections if any are responsible for rsa
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
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

Bacterial Vaginosis

50%

Trichomonas vaginalis

25%

Candida albicans

25%

Bacterial Vaginosis
  • Commonest cause of vaginitis
  • Amsel's criteriafor 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
bv and rsa
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
  • Damianov L, Damianova V. Akush Ginekol (Sofiia). 2004;43 Suppl 2:26-7.
  • Mania-Pramanik J, Kerkar SC, et al. J Clin Lab Anal. 2008;22(5):375-9.
  • Li TC, Makris M, et al. Hum Reprod Update. 2002 Sep-Oct;8(5):463-81
the influence of chlamydia trachomatis infection on rsa
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-Chlamydialantobodies 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
Hattori Y, Nakanishi T. Am J Reprod Immunol. 2007 Oct;58(4):350-7.
  • Uterine cervical inflammatory cytokines, interleukin-6 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
Other rare viruses

Coxsackie B virus (CBV) & RSA

Parvovirus B19

slide58

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
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
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

ConclusionProblems of Research in RSA
conclusions
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
autoimmune etiology
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
which antibodies
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
incidence66
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

statistical distribution
Statistical Distribution
  • Prevalence of antiphospholipid antibodies in various categories of women was studied

Parke AL et al, Arch Rheumat 1991

diagnosis of paps
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

obstetric criteria
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
vascular thrombosis criteria
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
laboratory criteria
Laboratory Criteria
  • Anticardiolipin antibody IgG or IgMisotype 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
lupus anticoagulant testing
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 indicated
pitfalls in diagnosis of paps
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
false results in paps
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)
goals for treating paps
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
aspirin alone v s aspirin heparin
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

is heparin aspirin really better
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, ObstetGynecol 2010

clinical tips for using heparin
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
clinical tips for using heparin80
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
full anticoagulation practical
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
what not to do for paps
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
recommended investigations
RECOMMENDED INVESTIGATIONS

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 investigations84
RECOMMENDED INVESTIGATIONS

Grade B (FOR SELECTED PATIENTS)

  • ANDROGENS, LH, FSH IN PATIENTS WITH IRREGULAR MENSTRUATION
  • SERUM PROGESTERONE
  • EB FOR DATING & TB PCR, CULTURE
  • SERUM HOMOCYSTEINE LEVELS / THROMBOPHILIA SCREEN
  • HVS / WET PREP & pH / KOH Whiff test
  • SEMEN CULTURE / TB PCR
anti phospholipid syndrome
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 causes86
ANATOMICAL CAUSES
  • Hysteroscopic evaluation
  • Intrauterine adhesiolysis
  • Septum resection
  • Removal of submucous fibroids and polyps
  • CERVICAL CERCLAGE if indicated
infectve causes
INFECTVE CAUSES
  • Screening and treatment of bacterial vaginosis
  • Screening and treatment of occult genital tuberculosis
  • Chlamydia screening & treatment
endocrinal factors
ENDOCRINAL FACTORS
  • Polycystic ovaries ? metformin
  • Luteal phase defects progesterone / Duphaston
  • Thyroid replacement therapy
  • Optimising HbA1c levels
  • Correct hyperprolactinaemia
thrombophilia screen positive
THROMBOPHILIA SCREEN POSITIVE
  • LOW MOLECULAR WEIGHT HEPARIN
  • UNFRACTIONATED HEPARIN

(From 6 weeks to 36 weeks of pregnancy)

haematological
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
alloimmune causes

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

Dydrogesterone in the reduction of recurrent spontaneous abortion

  • Randomised, controlled study
  • Pregnant women (< 35 years old) who had experienced at least 3 consecutive miscarriages with the same partner
  • Only women for whom no explanation could be found for their recurrent miscarriages were included.

180 Women of which:

– 82 Received dydrogesterone

– 50 Received hCG

– 48 Received no additional treatment (control)

Women randomised to:

– Oral dydrogesterone 10 mg b.i.d.

– Intramuscular human chorionic gonadotrophin (hCG) 5000 IU every 4 days

– No additional treatment

  • Randomisation according to the day of the week they attended clinic
  • Treatment started as soon as possible after confirmation of pregnancy and continued until 12th gestational week
  • All women received standard supportive care: multivitamin supplements and recommended bed rest
dydrogesterone in the reduction of recurrent spontaneous abortion93
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

slide94

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

Dydrogesterone has an immunomodulatory capability and appears to induce a maternal cytokine shift from Th1 cytokine dominance towards a Th2 bias.

Raj Raghupathy et al. BJOG 2005;112:1-6

destress reassure
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

DIAGNOSTIC IVF / ICSI with PGD

PICKS UP ANEUPLOIDY IN EMBRYOS

surrogacy

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

Conclusion / Problems of RPL