RECURRENT PREGNANCY LOSS CURRENT CONCEPTS

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					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
                                                     Un-explained
                                                         50%
• 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%
       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
T SHAPED UTERUS- INFECTION
 MALA ARORA         17
  Uterine Neoplasms
• Endometrial Polyps
           ENDOMETRIAL POLYP
PERIOSTEALMALA ARORA
3/27/2012              19
 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%
 –UnbalancedKaryotypes normal Minimal recurrence risk
      Parental
               translocation-3-5%
    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

• 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 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
• 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         UTERUS 10%
        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
                                              Bacterial
   – Thin, homogeneous discharge              Vaginosis
   – Release of an amine                        50%
     (putrescine, cadaverine, &
     trimethylamine) or fishy odor      Trichomona Candida
     on addition of KOH is to           s vaginalis albicans
     vaginal discharge                  25%           25%
   – "Clue cells" (Vaginal epithelial
     cells coated with coccobacilli)
   – Vaginal pH > 4.5
• Nugent score: Gram Stain of
                     vaginal swab
                           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, 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

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


          DNA Repair          Partial DNA Repair
                                 Fertilisation
          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   Women with normal       Women who have not
  early fetal losses   pregnancy outcome      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
  indicated                               72
   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               Women with PAPS with
without a history of          history of thrombotic
thrombotic events             events (past or present)
(most women with RPL)

Prophylactic therapies        Full anticoagulation with
such as aspirin, heparin in   heparin (or warfarin) in
pregnancy and 6 to 8          pregnancy and postpartum
weeks 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
     Grade A (FOR ALL PATIENTS)
1.   Hysterosalpingography/ Hysteroscopy
2.   APTT/ dRVVT/ Lupus anticoagulant
3.   IgG & IgM anticardiolipin antibodies
4.   TSH / Prolactin / Testosterone / HbA1C/ 2 hrs
     Post Prandial INSULIN
5.   Karyotyping of both parents &
6.   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                                                 Dydrogesterone
                                                                                               Progesterone
                                                                                               (P) Receptor
cells with increasing                                                                            Activation

concentrations of
                                                                                                 Embryo
dydrogesterone.                                                              ↑Progesterone
                                                                                               Protective
J Szekeres Bartho 9th World Congress of Gynecological Endocrinology,            Induced
                                                                                                Immuno-
Hong Kong, December 2001                                                     Blocking Factor
                                                                                               modulation

Dydrogesterone inhibits the production
of the Th1 cytokines IFN-g and TNF-a                                          Protection of
from lymphocytes and up-regulates the                                             Fetus
production of the Th2 cytokines IL-4
and IL-6, inducing a Th1 to Th2
cytokine shift.                                                                     Th1
Raj Raghupathy et al. BJOG 2005;112:1-6


Dydrogesterone has an immunomodulatory
capability and appears to induce a maternal                            Th2
cytokine shift from Th1 cytokine dominance
towards a Th2 bias.
Raj Raghupathy et al. BJOG 2005;112:1-6
     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

				
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