RECURRENT PREGNANCY LOSS CURRENT CONCEPTS

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(No Transcript)
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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

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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

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Incidence

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

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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

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Anatomical Factors

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

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Uterine Abnormalities

• CONGENITAL (Mullerian Duct abnormalities)
• UTERINE NEOPLASMS (Growth)
• IATROGENIC (Acquired)

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ANATOMICAL CAUSES

• Septate uterus
• Intrauterine adhesions
• Bicornuate ut (unequal horns)
• Unicornuate uterus
• T shaped uterus
• Submucous fibroids
• Large endometrial polyps

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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

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Septate Uterus

• Most COMMON anomaly 55
• May be complete/ incomplete/segmental
• 25 early abortions
• 6.2 late abortions
• Premature labors

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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

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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

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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

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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

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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

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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

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T SHAPED UTERUS- INFECTION
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Uterine Neoplasms

• Endometrial Polyps

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PERIOSTEAL ENDOMETRIAL POLYP
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Leiomyomas (Fibroids) most common. 20-50 of
reproductive women

• When will you considerfibroids responsible ?

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• 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

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Iatrogenic

• Intrauterine adhesions ,Ashermans Syndrome
• Lead to Poor implantation,
• Decreased blood supply ,
• infection
• Abortion rates 40 Preterm labour 23
• Management -Hysteroscopic excision of adhesions

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HYSTEROSCOPIC CORRECTION

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

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Anatomical Factors

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

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• USG follow up weekly in cases of prior 2nd
  trimester loss
• Funneling of gt25 cervical length and/or lt2.5 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

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Genetic Etiology

• Chromosomal 3.5-5
• Fetal chromosomal abnormalities
• Parental balanced chromosomal rearrangement
• Single gene disorders
• Alpha thalassemia major
• Thrombophilia
• X linked dominant disorders

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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 gt20wk

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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 gt45years
• Previous number of miscarriages

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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
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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)

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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

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Parental Chromosomal Abnormalities

• Translocation (commonest) (1in 500)
• Reciprocal 50
• Robertsonian 24
• Mosaicism for a numeric aberration 12
• Inversion

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Translocation
Translocation is exchange of chromosomal segments
between two, non-homologous chromosomes.
Source-Internet
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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- Emerys book of principles of Medical
Genetics
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Diagnosis

• Karyotype of the abortus
• ( fetal/placental tissue)
• Peripheral blood Karyotyping of the parents in
  all couples with RM

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Spontaneous abortion Recurrent Miscarriage
10-15 1-3
50-70 abortuses chromosomally abnormal 25-30 abortuses chromosomally abnormal
Couple karyotype usually normal Couple karyotype may be rearrangement carrier
Recurrence risk negligible Recurrence risk upto 50
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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

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Whether we should do POC karyotype ????
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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

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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
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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

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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

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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

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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)
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Karyotypic abnormalities in couples with
Recurrent abortions

• Total Couples n742(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)
• Deletion2
• 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
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Role of Infections
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Venn diagram of the responsibilities of
Reproductive Failure
EGG 80
SPERM 10
UTERUS 10
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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

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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

TORCH TESTS
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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

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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
• Culic V, Konjevoda P, et al. Coll Antropol. 2009
  Mar33(1)187-92
• Kamilova N, Sultanova I, et al. Georgian Med
  News. 2008 Nov(164)23-7

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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 gt 4.5
• Nugent score Gram Stain of vaginal swab

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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/Clindamyci
  n
• Damianov L, Damianova V. Akush Ginekol (Sofiia).
  200443 Suppl 226-7.
• Mania-Pramanik J, Kerkar SC, et al. J Clin Lab
  Anal. 200822(5)375-9.
• Li TC, Makris M, et al. Hum Reprod Update. 2002
  Sep-Oct8(5)463-81

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 The influence of Chlamydia trachomatis infection
on RSA

• Specific anti-chlamydial antibodies in 3 groups
  of women
• IgA class
• 7.9 (p0.082) in group 1 (RSA group),
• 4.5 (p0.236) in group 2 (1 abortion)
• 0 in group 3 ( no abortions)
• IgG class in 21.1 (p0.024), 36.4 (p0.000) 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.
  200954(1)86-90
• Kavalier F, BMJ. 2005 Jul 16331(7509)121-2.

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Hattori Y, Nakanishi T. Am J Reprod Immunol.
2007 Oct58(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.

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Other rare viruses
Coxsackie B virus (CBV) RSA
Parvovirus B19
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• Is it time to look at the sperm?

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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
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SEMEN CULTURE

• Male accessory gland infection with E coli /
  Staph aureus /
• Bacteria ride on the sperm tails into uterine
  cavity
• Produce low grade endometritis

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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-Sep52(3)274-82

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ConclusionProblems 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 193(4)1234-43. Epub
  2009 Mar 31

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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

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Antiphospholipid Antibody Syndrome and
Recurrent Pregnancy Loss
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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

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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 ß2glycoprotein-I,
  antiphosphatidylserine antibodies, annexin, etc
  may not be obstetrically significant

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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

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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
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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

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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

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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

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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

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Lupus anticoagulant testing

• Screen with demonstration of prolonged
  phospholipid dependent coagulation screening test
  (eg activated partial thromboplastin time,
  kaolin clotting time, diluted Russells 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

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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

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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)

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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

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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
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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

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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

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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

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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

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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

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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

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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

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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

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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

86
ANATOMICAL CAUSES

• Hysteroscopic evaluation
• Intrauterine adhesiolysis
• Septum resection
• Removal of submucous fibroids and polyps
• CERVICAL CERCLAGE if indicated

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INFECTVE CAUSES

• Screening and treatment of bacterial vaginosis
• Screening and treatment of occult genital
  tuberculosis
• Chlamydia screening treatment

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ENDOCRINAL FACTORS

• Polycystic ovaries ? metformin
• Luteal phase defects progesterone / Duphaston
• Thyroid replacement therapy
• Optimising HbA1c levels
• Correct hyperprolactinaemia

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THROMBOPHILIA SCREEN POSITIVE

• LOW MOLECULAR WEIGHT HEPARIN
• UNFRACTIONATED HEPARIN
• (From 6 weeks to 36 weeks of pregnancy)

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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

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ALLOIMMUNE CAUSES

• Progesterone therapy
• Evidence for use

92
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
• Pregnant women (lt 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

93
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
94
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 20051121-6
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 20051121-6
95
ROLE OF TENDER LOVING CARE
96
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

97
DIAGNOSTIC IVF / ICSI with PGD

• PICKS UP ANEUPLOIDY IN EMBRYOS

98
SURROGACY

• If diagnostic IVF PGD confirm normal gametes /
  embryos
• All treatment modalities have failed

99
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 193(4)1234-43. Epub
  2009 Mar 31

100
THANK YOUfor your valuable time