Empirical in vitro fertilization for recurrent pregnancy loss

Empirical in vitro fertilization for
recurrent pregnancy loss

    Raoul Orvieto M.D. and Michal Kirshenbaum M.D.
-    Department of Obstetrics and Gynecology,
     Chaim Sheba Medical Center, Ramat Gan, Israel
-    The Tarnesby-Tarnowski Chair for Family Planning and Fertility Regulation,
     Sackler Faculty of Medicine, Tel-Aviv University, Israel.

No relevant financial relationships
           to disclose

Recurrent pregnancy loss (RPL)
    Non fertile- Infertility treatment including
     assisted reproductive technique (ART)
    Fertile- Empirical adjunct treatments or
     ‘add-ons’
        Improving the chance of a live birth
        Shortening the time to conception
        Improving embryo quality
        Improving implantation
        Improving synchrony between endometrium &
         embryo
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Improving the chance of a live birth

 Subsequent live birth rate is dependent on:
  # of previous live births
  Maternal age
  Genetic aberrations
  Whether the losses are early or late

Improving the chance of a live birth
    Quoting success
    RPL- Number of live births per pregnancy
    IVF - Clinical pregnancy rate per cycle
         - Live births per cycle
                                           (2015)

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Shortening the time to conception
    Previous studies have reported a longer
    mean interval to subsequent conception after
    a pregnancy loss, compared to the time to
    conceive before a pregnancy [Hassan 2005; Sapra 2014]

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(2016)

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Improving embryo quality

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Sperm selection techniques
    Sperm of men with RPL have significantly
    reduced viability, increased proportion of
    DNA damage (Ruixue 2013; Gil-Villa 2010; Brahem 2011)
    and reduced sperm function parameters
    such acrosomal status and nuclear
    chromatin decondensation (Saxena 2008)

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Sperm selection techniques
      Washing
      Density gradient centrifugation
      Swim up
      Electrophoretic sperm selection
      Magnetic activated cell sorting and glass wool
       separation columns utilizing the magnetic
       properties of phosphatidylserine to separate
       apoptotic from non‐apoptotic sperm.
      Physiological intracytoplasmic sperm
       injection (PICSI)
      Intracytoplasmic morphologically selected
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       sperm injection (IMSI)

Sperm selection techniques

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Sperm selection techniques
Intracytoplasmic morphologically selected
sperm injection (IMSI)           (2013)
A technique to select sperm for injection to the egg
by examining the organelle morphology, such as the
acrosome, postascrosomal lamina, neck,
mitochondria, tail and nucleus using ultra-high
magnification (≥6000x) microscopy.

Selecting the best embryo
     Embryo morphology

           17 ± 1 h   27 ± 1 h   44 ± 1 h   68 ± 1 h   92 ± 2 h   116 ± 2 h

     Time- lapse system Embryoscopy

     Preimplantation genetic testing- aneuploidy
     (PGT-A )

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Embryo morphology

Embryo morphology is thought to be highly
indicative of pregnancy outcome.

Morphological grading of the embryo may allow
the selection of "the best" embryos for transfer.

Selecting the best embryo
     Relationship Between Morphology, Euploidy
     and Implantation Potential of Cleavage and
     Blastocyst Stage Embryos. (Majumdar et al 2017)

                         <
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Embryo morphology
Correlation between standard blastocyst
morphology, euploidy and implantation Capalbo et al, 2014

A moderate relation between blastocyst morphology and CCS
data was observed, but the ability to implant seems to be
mainly determined by the chromosomal complement of
preimplantation embryos, rather than developmental and
morphological parameters conventionally used for blastocyst
evaluation.

Time- lapse system Embryoscopy

     Conclusion:
     Five TLM parameters, all related to
     timing of blastocyst development,
     have limited ability to predict
     euploidy when patient and ovarian
     stimulation related factors are taken
     into account.

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Time- lapse system Embryoscopy
              (2018)

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Preimplantation genetic testing-
     aneuploidy (PGT-A)

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Improving implantation

      Assisted hatching
      Biologic glue
      Immunological “add ons”

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Assisted hatching (AH)
Assisted hatching (AH) is a manipulation of
the zona pellucida in order to facilitate
implantation.
Several techniques:
 Partial mechanical zona   • Acid tyrodes
  dissection                • Proteinases
 Zona drilling             • piezon vibrator
 Zona thinning               manipulators
                            • Lasers

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Biologic glue
     Various compounds have been added to the
     embryo transfer medium in order to improve
     adherence and subsequent implantation and
     pregnancy rates.
     Hyaluronic acid forms a viscous solution, that
     might prohibit embryo expulsion, and may
     facilitate diffusion and integration of the embryos
     in the viscous solution that characterizes
     intrauterine secreted fluid.
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Biologic glue

           (2017)

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(2015)

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Immunological “add ons”
                                     (ASRM 2018)

Given the lack of evidence to support improved IVF outcomes, there isgood
evidence to recommend against the routine use of low-dose
aspirin to improve the outcome of live birth in ART cycles in the general population.
(From Level-I studies of Good and High quality). (Grade A).
There is good evidence to recommend
                              against the routine use of
corticosteroids during stimulation to improve the outcome of live birth in
ART cycles in the general population. (From principally Level-I studies of Good quality).
(Grade A).
There is good evidence to recommend against the routine use of corticosteroids    during
the implantation window to improve the outcome of live birth in ART cycles in
the general population. (From principally Level-I studies of Good quality). (Grade A).

There is insufficient
                 evidence to recommend for or against local G-CSF to
improve endometrial thickness in women with thin endometrium or clinical
pregnancy rates with IVF. (From principally Level-I studies of Good quality and Level-II
studies of Low and Good quality with inconsistent findings). (Grade C). There is
insufficient evidence to recommend for or against G-CSF or GM-CSF administered locally
or systemically to improve IVF outcomes. (From principally Level-I studies of Good
quality and Level-II studies of Low and Good quality with inconsistent findings). (Grade C).
There is insufficient evidence to routinely recommend intravenous fat
emulsions for infertile women pursuing IVF. (From one Level-I study of High quality and
one Level-II study of Low quality). (Grade C).
There is insufficient evidence to recommend IVIG administration as part of IVF
to improve IVF outcomes. (From two Level-I, but underpowered, studies, one Good quality
and one Low quality). (Grade C).
There is insufficient evidence to recommend adalimumab treatment to
improve IVF outcome. (From Level-II studies of Low quality). (Grade C).
There is insufficient evidence to recommend intrauterine infusion of
autologous peripheral mononuclear cells prior to ET to improve IVF outcome.
(From one Level-I study of Low quality and one Level-II study of Low quality). (Grade C).
There is insufficient evidence to recommend tacrolimus to improve IVF-ET
outcome. (From a single Level-II study of Low quality). (Grade C).

Improving synchrony between
     endometrium & embryo

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Improving synchrony between
     endometrium & embryo
     Timing of conception in relation to ovulation may affect
     the spontaneous miscarriage rate.
     Furthermore, aging of both spermatozoa and ova before
     fertilization is accompanied by a higher probability of
     miscarriage. (Guerrero et al. 1975; France et al. 1984)

                                                  (Gray et al 1995)
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EFFECT OF COH ON ENDOMETRIAL
   DEVELOPMENT AND RECEPTIVITY
 Estradiol and P are closely linked to endometrial
  development and maturation.
 Two frequently observed features of endometria
  after COH are:
     advanced histology
     advanced down-regulation of the P receptor
       Indicating an advanced receptive phase
      An embryo–endometrium asynchrony.

Horcajadas et al. 2007
                                     Dıaz-Gimeno et al. 2011

Endometrial gene expression profile reflects
human endometrial cycle and specifically its
receptive status based on its transcriptomic profile.

IVI group has developed a molecular diagnostic tool
based on the specific transcriptomic signature that
identifies the receptive endometrium (at LH7 in a
natural cycle or at day 5 of P (P 5) after proper E2
priming in a hormonal replacement therapy cycle).

The endometrial receptivity array (ERA) consists of
a customized array containing 238 differentially
expressed genes, which is able to identify
endometrial samples that are within the window of
implantation regardless of their histologic
appearance.
Genes whose expression was
consistent among three different
models of endometrial receptivity:
the natural cycle as the optimal
model,
the COH cycle as suboptimal,
the refractory endometrium as a
negative control.

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THANK YOU

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