Tekrarlayan art ba ar s zl klar n n y netimi
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Tekrarlayan ART Ba şarısızlıklarının Yönetimi. Dr. Ayd ı n Ar ı c ı Kadın Sağlığı Bölümü Anadolu Sağlık Merkezi Department of Obstetrics, Gynecology & Reproductive Sciences Yale University School of Medicine. Live-Birth Rate per patient started in cohort. Cycle Number

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Tekrarlayan ART Ba şarısızlıklarının Yönetimi

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Tekrarlayan art ba ar s zl klar n n y netimi

Tekrarlayan ART Başarısızlıklarının Yönetimi

Dr. Aydın Arıcı

Kadın Sağlığı Bölümü

Anadolu Sağlık Merkezi

Department of Obstetrics, Gynecology & Reproductive Sciences

Yale University School of Medicine


Live birth rate per patient started in cohort

Live-Birth Rate per patient started in cohort

Cycle Number

No. of patients started = 750

Witsenburg et al. 2005


Assumed etiologies for repeated art failures

Assumed Etiologies for Repeated ART Failures

  • Defective embryonic development

    • Genetic abnormalities (male/female/gametes/embryos)

    • Zona hardening

    • Suboptimal culture conditions

  • Decreased endometrial receptivity

    • Uterine cavity abnormalities

    • Thin endometrium

    • Altered expression of adhesive molecules

    • Immunological factors

    • Thrombophilias

  • Multifactorial effectors

    • Endometriosis

    • Hydrosalpinges

    • Suboptimal ovarian stimulation


Embryo quality

Embryo quality

  • Very important

  • Can the quality of an embryo improved?

  • Presently we try to increase chances by transferring the best embryos (i.e., morphology, PGD)

  • Embryo quality is affected by:

    • Maternal age

    • Very poor semen

    • Endometriosis

    • PCOS (insulin resistance)

    • Hyperstimulation?


Tekrarlayan art ba ar s zl klar n n y netimi

Live Births per transfer using a woman’s own or donor eggs

2002 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Report. CDC


The role of genetics in repeated implantation failure

The Role of Genetics in Repeated Implantation Failure

  • Embryonic chromosomal anomalies

    • Most common etiology of age-related pregnancy failure

  • Euploidic but with lethal gene mutations

    • Difficult to diagnose but probably common in “idiopathic” recurrent implantation failures

  • Parental genetic structural abnormalities

    • Balanced translocations, female:male ratio 3:1; but overall rare (3%)


Suggested treatments for repeated art failures

Suggested Treatments for Repeated ART Failures

  • Treatment of the embryos

    • Preimplantation genetic screening

    • Assisted hatching

    • Co-culture

    • Blastocyst transfer

    • Improving ET technique

  • Improving endometrial receptivity

    • Hysteroscopic correction of cavity pathology

    • Myomectomy

    • Treatment of thin endometrium

    • Endometrial stimulation (biopsy)

    • Immunotherapy (IVIg, steroids, aspirin and heparin)

  • Multifactorial treatment options

    • Treating endometriosis

    • Salpingectomy in case of hydrosalpinges

    • Tailoring the stimulation protocols

    • Psychological assistance


Tekrarlayan art ba ar s zl klar n n y netimi

Patients with repeated IVF failure

# Failed

implantation

cycles AgePGD Controls

Study 1: 3 3215%8% (N.S.)

Study 2: 3 30 no controls

Study 3: 2 3814%12% (N.S.)

Study 4: 3 3620%24% (N.S.)

Study 5: 2 n.a.20%0% (N.S.)

1: Gianaroli et al. 1999, 2: Kahraman et al. 2000, 3: Munné et al., RBO 2003, 4: Pehlivan et al. 2003, 5: Werlin et al. 2003


Which patients with recurrent implantation failure may benefit from pgd for aneuploidy screening

Which patients with recurrent implantation failure may benefit from PGD for aneuploidy screening?

Patients with recurrent IVF failure are defined as younger than 37 years and who have had at least 3 consecutive unsuccessful IVF/ICSI cycles with good-quality embryos.

  • To have a 90% probability of having an embryo transfer after PGD-AS, the patient should have at least 10 mature oocytes, 8 fertilized oocytes and 6 embryos for biopsy.

  • This study suggests that some patients with recurrent IVF failure may benefit from PGD-AS (but no controls).

Platteau et al. 2006


Growth hormone

Growth Hormone

In a systematic review of adjuvant GH treatment on IVF outcomes, in women without a history of poor response, there was no evidence to support the use of GH (Harper K, 2003).

There was, however, a small but significant improvement in pregnancy rates in poor responders, although cost is a limiting factor (Harper K, 2003).

Tesarik et al. evaluated adjuvant GH in women >40-year-old undergoing IVF. Women co-treated with GH had more pregnancy (26 vs 6%) and delivery rates (22 vs 4%).


Tekrarlayan art ba ar s zl klar n n y netimi

Growth Hormone


Tekrarlayan art ba ar s zl klar n n y netimi

Metformin treatment increased the number of oocytes in insulin-resistant women with PCOS,(Fedorcsák, 2003). This finding, however, was not supported in otherRCT’s

Kjotrod, 2004;

Duration of FSH stimulation→

The number of oocytes retrieved→

Fertilization rates →

Embryo quality →

Pregnancy and live birth rates →

Onalan, 2005;

Total FSH→

Fertilization rate, →

Oocytes retrieved and placebo→

Pregnancy or miscarriage rates →

Insulin Sensitizers


Insulin sensitizers

Insulin Sensitizers

A 28-day course of metformin during the IVF cycle improved pregnancy outcome and reduced the risk of OHSS. Pregnancy rate per ET was 44.4% vs 19% and live birth rate per ET was 37.8% vs 14.3%(Tang, 2006).

Meta-analysis demonstrated that metformin use in ART does not improve pregnancy (OR=3.46; CI=0.98-12.2) or live birth rates (Costello, 2006).


Tekrarlayan art ba ar s zl klar n n y netimi

DHEA

DHEA Control

Higher # oocytes 4.4 vs 3.4

Better fertilization rates3.0 vs 1.4

Cumulative embryo score16.1 vs 8.4

Lower cancellation rate 4% vs 32%

Transferred embryos 2.4 vs 1.4

Barad & Gleicher. Hum Reprod 2006


Suggested treatments for repeated art failures1

Suggested Treatments for Repeated ART Failures

  • Treatment of the embryos

    • Preimplantation genetic screening

    • Assisted hatching

    • Co-culture

    • Blastocyst transfer

    • Improving ET technique

  • Improving endometrial receptivity

    • Hysteroscopic correction of cavity pathology

    • Myomectomy

    • Treatment of thin endometrium

    • Endometrial stimulation (biopsy)

    • Immunotherapy (IVIg, steroids, aspirin and heparin)

  • Multifactorial treatment options

    • Treating endometriosis

    • Salpingectomy in case of hydrosalpinges

    • Tailoring the stimulation protocols

    • Psychological assistance


Negative impact of coh on e ndometri um

Negative Impact of COH on Endometrium

  • Pro

    • deZiegler et al. Fertil Steril 93, 98, 04

    • Basir et al. Hum Reprod, 01

    • Kolibianakis et al., 04

  • Con

    - Levi et al., Fertil Steril, 01

EMB on 7 days after hCG

COH

N=28

Normal menstrual cycle

N=12

  • glandular-stromal dyssynchrony

  • delayed glandular development & highly edematous stroma

  • in phase glandular development

  • lowest amount of edema

Basir et al. 01


Endometrial receptivity m arkers

Endometrial ReceptivityMarkers


Subtle endometrial pathologies affect fertility

Subtle endometrial pathologies affect fertility

IVF candidate with a normal HSG

Normal hysteroscopy

Abnormal hysteroscopy

37.5% pregnant

8.3% pregnant

Shamma et al. Fertil Steril 1992


Location of fibroids affects success of art cycles

Location of Fibroids Affects Success of ART Cycles

Eldar-Geva et al., Fertil Steril 1998


Adenomyosis

Adenomyosis

  • Until recently, there was no accurate preoperative diagnostic methods.

  • Therefore, the relationship of adenomyosis to infertility has not been possible to assess.

  • Recently, a clear relationship between adenomyosis and infertility was described in the baboon. (Barrier et al. Fertil Steril 2004)


Adenomyosis imaging

Adenomyosis: Imaging

HSG

Ultrasound

MRI


Adenomyosis imaging1

Adenomyosis: Imaging

  • HSG has 25% positive predictive value

  • Ultrasound has 71% positive predictive value

  • MRI has 95-100% positive predictive value

Reinhold et al. Hum Reprod Update 1998


Tekrarlayan art ba ar s zl klar n n y netimi

ADENOMYOSIS

IVF PREGNANCY RATES

P<0.01

P<0.01

ASRM 2005


Ivf in endometriosis vs tubal infertility

IVF in endometriosis vs. tubal infertility

Barnhart et al, Fertil Steril 2002


Gnrh agonist vs no agonist before ivf clinical pregnancy rate per woman

GnRH agonist vs. no agonist before IVF(Clinical pregnancy rate per woman)

Sallam, Garcia-Velasco, Dias, and Arici, Cochrane Database 2006


Hydrosalpinx and rif

Hydrosalpinx and RIF


Commonly ordered immunological tests

Commonly ordered immunological tests

  • Antiphospholipid antibodies

    • Anticardiolipin

    • antiphosphatidyl serine

    • antiphosphatidyl ethanolamine

    • antiphosphatidyl choline

    • antiphosphatidyl glycerol

    • antiphosphatidyl inositol

    • antiphosphatidic acid

  • Lupus anticoagulant

  • Antisperm antibodies

  • Antithyroid antibodies

  • Antinuclear antibodies

  • Anti-smooth muscle antibodies

  • Natural killer cells

  • Embryotoxic assay


A ntiphospholipid a ntibodies apa

Antiphospholipid Antibodies (APA)

  • There is evidence that women with APA syndrome do not have decreased conception but experience pregnancy loss after 10 weeks of gestation.

    Rai et al . Hum Reprod. 1995; Oshiro et al. Obstet Gynecol. 1996; Simpson et al. FertilSteril. 1998

  • Retrospective cohort study of 491 patients with a history of adverse pregnancy outcomes:

    • Thrombophilia was protective of recurrent losses at <10 weeks with OR of 0.55 (95% CI: 0.33-0.92).

    • Thrombophilia was associated risk of recurrent losses >10 weeks with OR of 1.76 (1.05-2.94).

      Roque et al., Thromb Haemost. 2004


Infertility apa

Infertility & APA

  • There are no large, controlled studies that establish the antiphospholipid antibodies as a cause of infertility

  • The use of antiphospholipid antibody testing in the fertility practice can not be supported by current data

  • Presence of antiphospholipid antibodies does not adversely affect the IVF cycle outcome. No testing or treatment are indicated. ASRM Report-1999


Use of ivig for implantation failure

Use of IVIg for Implantation Failure

A randomized, placebo controlled trial


Conclusions

Conclusions

  • While there exists strong motivation to find answers to explain repeated implantation failure, this impulse should be resisted if it leads to the practice of medicine that is not evidence-based

  • The benefit of PGD has not been shown to improve the outcome in repeated implantation failure (except for >40 years old or for balanced translocation)

  • Re-evaluation and treatment of pelvic pathologies is crucial:

    • Myomas, adenomyosis, endometriosis, polyps, Asherman, hydrosalpinx

  • Less aggressive COH (natural cycle?) ART may be beneficial

  • Certain patient subpopulations may benefit from additional treatments, such as GH for poor responders or metformin for some PCOS patients or longer GnRH agonist for endometriosis.

  • Immune testing and unproven treatments in repeated implantation failure is not recommended


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