IS ASSISTED REPRODUCTIVE TECHNOLOGY THE ANSWER TO INFERTILITY IN THE AGING OVARY ?

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How do improve our pregnancy rates?

• Clexane is directly or indirectly
  involved in adhesion of the
  blastocyst to the endometrium and the
  subsequent invasion (?!)

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How can clexane help with so many genetically
abnormal embryos?
normal chromosomal status (46,XX)
abnormal chromosomal status (45,XY,-12)
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Association of common thrombophilias and
antiphospholipid antibodies with success rate of
in vitro fertilisation.

• None of the common thrombophilias tested was
  found to be significantly associated with the
  number of IVF cycles or with lower fertility
  success rate.

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Association of common thrombophilias and
antiphospholipid antibodies with success rate of
in vitro fertilisation.

• Women who had APCR and /or factor V Leiden and
  lupus anticoagulant had significantly higher live
  birth rates (12.3 and 12.6, respectively) in
  comparison to women who were tested negative
  (9.0 and 9.7, respectively).

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Association of common thrombophilias and
antiphospholipid antibodies with success rate of
in vitro fertilisation.

• Hypercoagulability is not associated with failure
  to achieve pregnancy.
• These data suggest that neither screening for
  thrombophilia nor anticoagulant treatment is
  indicated in cases with unexplained reproductive
  failure.

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" In GOD we trust all others must bring
data. - W. Edwards Deming
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The Evidence Pyramid
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GiGo Garbage in Garbage out principle
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Meta-analysis Cooking PotAll depends on the
quality of the ingredients
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A meta-analysis is like a sausage, only God and
the butcher knows what goes in it, neither would
ever eat any.
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Conclusions and Relevance

•   Estimation of treatment outcomes in
  meta-analyses differs depending on the strategy
  used.
• This instability in findings can result in
  major alterations in the conclusions derived
  from the analysis and underlines the need for
  systematic sensitivity analyses.

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Caution !

• Despite the lack of evidence-based information,
  empirical low-molecular-weight heparin (LMWH) is
  widely used in recurrent implantation failures.
•  
• Bulent Berker, M.D.
• Salih Taskin, M.D.
• Department of Obstetrics and Gynecology, Medical
  School,
• Ankara University, Ankara, Turkey

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Conclusions

• In women with 3 RIF, the use of adjunct LMWH
  significantly improves LBR by 79 compared with
  the control group.

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• "There are three kinds of lies lies, damned
  lies and statistics. - Benjamin DIsraeli
• (1804-1881)

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Live birth rate (LBR) in women with 3 recurrent
implantation failure and LMWH as treatment adjunct
?
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2013 Impact Factor 1.018
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Risk of bias summary review authors
judgments about each risk of bias item for each
included study.
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Live birth rate of 2.4?!
3 consecutive failed IVF cycle, Age lt35 years
with at least one coagulation defect
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Implantation rate (IR) in women with 3 recurrent
implantation failure and LMWH as treatment adjunct
IR was not significantly improved !
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Shortcomings in the study by Qublan et al., 2008

• Included women with both inherited and acquired
  thrombophilia.
• Acquired thrombophilia like APA are associated
  with recurrent miscarriage and possibly RIF
  compared with certain heterozygous inherited
  thrombophilia.
• In this study, a third of the patients were
  carriers of MTHFR C677T polymorphism, and there
  is no conclusive evidence in the literature
  regarding the adverse effect of this
  heterogeneous mutation on IVF or pregnancy
  outcomes

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Shortcomings in the study by Qublan et al., 2008

• A single test with low positivity cut-off was
  used in this study to check for lupus
  anticoagulant and anticardiolipin antibodies, yet
  for diagnosis of acquired thrombophilia these
  antibodies should be confirmed by a repeat test
  12 weeks apart (Miyakis et al., 2006).
• These observations indicate that the study
  population was heterogenous and that the women
  did not necessarily have thrombophilia which is
  associated with adverse IVF or pregnancy
  outcomes.

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Conclusions

• In women with 3 RIF, the use of adjunct LMWH
  significantly improves LBR by 79 compared with
  the control group
• however, this is to be considered with caution,
  since the overall number of participants in the
  studies was small.
• Further evidence from adequately powered
  multi-centered RCTs is required prior to
  recommending LMWH for routine clinical use.
• This review highlights the need for future basic
  science and clinical research in this important
  field.

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Live birth rate(LBR) in women with 3 unexplained
recurrent implantation failure and LMWH as
treatment adjunct
It is important to note that these beneficial
effects of LMWH were not significant when only
the two studies with unexplained RIF were pooled.
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Flow chart of the study
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Conclusion

• The data in this study show that low-dose aspirin
  and/or heparin as adjuvant therapies during IVF
  do not improve live birth rates in an unselected
  group of subfertile women who have previously had
  one or more unexplained implantation failure
  following IVF.

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Results
Control group LMWH group
33.9 34.6 Clinical pregnancy rate
29.1 30.7 Live birth rate
21.1 22.6 Implantation rate
42.8 41.6 Multiple pregnancy rate
No statistically significant difference
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Conclusion

• No beneficial effect of LMWH on pregnancy
  outcomes in patients with two or more
  implantation failures and without coagulation
  disorders.
• Use of LMWH should be limited to research
  purposes until its beneficial effects have been
  proved by studies

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Clexane Hemorrhagic Side effects

• Occur in 3 to 7 of patients.
• A meta-analysis of published studies reported an
  overall incidence of major bleeding with low
  molecular weight heparins of 0.7 to 1.4.
• Hemorrhage may occur at any site in the body.

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Clexane Side effects

• Hematologic side effects including
• wound hematoma (11)
• anemia (3)
• ecchymosis (3)
• thrombocytopenia (1.5)
• Local side effects have included
• pain
• erythema
• ecchymosis
• hematoma

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Clexane Side effects

• Heparin-induced thrombocytopenia (HIT) is an
  immune-mediated, prothrombotic reaction that
  occurs in less than 1 of patients treated with a
  low molecular weight heparin (LMWH).

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My lovely clexane bruises!
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Clexane Pain!!!
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Cochrane Conclusion

• The results of this Cochrane review of three
  randomised controlled trials with a total of 386
  women suggested that peri-implantation LMWH in
  assisted reproduction treatment (ART) cycles may
  improve the live birth rate in women undergoing
  assisted reproduction.

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Cochrane Conclusion

• However, these results were dependent on small
  low quality studies with substantial
  heterogeneity, and were sensitive to the choice
  of statistical model.
• There were side effects reported with use of
  heparin, including bruising and bleeding, and no
  reliable data on long-term effects.

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Cochrane Conclusion

• Overall, this evidence does not justify the
  present widespread use of LMWH in this population
  subgroup (previous failed IVF), outside
  well-conducted randomised trials. Such trials
  should be a priority.

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• Thank You!