Tekrarlayan ART Başarısızlıklarının Yönetimi

Dr. Aydın ArıcıKadın Sağlığı Bölümü

Anadolu Sağlık MerkeziDepartment of Obstetrics, Gynecology & Reproductive Sciences

Yale University School of Medicine

Live-Birth Rate per patient started in cohort

0

5

10

15

20

25

30

1 2 3 4 5 6 7

Cycle NumberNo. of patients started = 750

Witsenburg et al. 2005

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 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?

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

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

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

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

# Failed# Failed implantationimplantation

cyclescycles Age Age PGD PGD ControlsControlsStudy 1: Study 1: 33 32 32 15%15% 8% (N.S.)8% (N.S.)Study 2: Study 2: 33 30 30 no controls no controlsStudy 3: Study 3: 22 38 38 14%14% 12% (N.S.)12% (N.S.)Study 4:Study 4: 33 36 36 20%20% 24% (N.S.)24% (N.S.)Study 5:Study 5: 22 n.a. n.a. 20%20% 0% (N.S.)0% (N.S.)

Patients with repeated IVF failurePatients with repeated IVF failure

1: Gianaroli et al. 1999, 2: Kahraman et al. 2000, 3: Munné et 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. 2003al., 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?

Aneuploidy No Embryo Transfer

Live Birth per transfer

Implantation

48.3 22.3 29.7 19.5

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).

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.

Platteau et al. 2006

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%).

Growth Hormone

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

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).

DHEA

Barad & Gleicher. Hum Reprod 2006

Higher # oocytes 4.4 vs 3.4Better fertilization rates 3.0 vs 1.4Cumulative embryo score 16.1 vs 8.4Lower cancellation rate 4% vs 32%Transferred embryos 2.4 vs 1.4

DHEA Control

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 Endometrium

Pro– deZiegler et al. Fertil Steril 93, 98, 04

– Basir et al. Hum Reprod, 01

– Kolibianakis et al., 04

EMB on 7 days after hCG

Normal menstrual cycleN=12

COHN=28

• in phase glandular development• lowest amount of edema

• glandular-stromal dyssynchrony • delayed glandular development & highly edematous stroma

Con- Levi et al., Fertil Steril, 01

Basir et al. 01

Endometrial Receptivity Markers

Marker Impact

3-integrin Commercially available but usefulness questioned (Thomas 03)

Progesterone Receptor Not reliable (Lessey 96)

LIF Proven to be critical, but not predictive (Arici 95)

HOXA Not assessed with standard techniques

MUC1 Not tested clinically (Kliman 95, 99, 01)

Cyclins Promising, but not proven (Kliman 00, Dubowy 03)

Subtle endometrial pathologies affect fertility

IVF candidate with a normal HSGIVF candidate with a normal HSG

Normal hysteroscopyNormal hysteroscopy Abnormal hysteroscopyAbnormal hysteroscopy

37.5% pregnant37.5% pregnant 8.3% pregnant8.3% pregnant

Shamma et al. Fertil Steril 1992

Location of Fibroids Affects Success of ART Cycles

Fibroids # of Patients Pregnancy Rates

None 318 30.1%

Subserosal 33 34.1%

Intramural 46 16.4%*

Submucosal 9 10.0%*

Eldar-Geva et al., Fertil Steril 1998

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

HSG Ultrasound MRI

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

ADENOMYOSISADENOMYOSISIVF PREGNANCY RATESIVF PREGNANCY RATES

MRI-DIAGNOSED MRI-DIAGNOSED ADENOMYOSISADENOMYOSIS

YALE REI PRACTICE YALE REI PRACTICE CONTROLCONTROL

n = 22 cyclesn = 22 cycles n = 301 cyclesn = 301 cycles

Mean age = 37.9Mean age = 37.9 Age = 35 – 42Age = 35 – 42

1/22 pregnancies1/22 pregnancies 81/301 pregnancies81/301 pregnancies

Live birth rate = 4.5%Live birth rate = 4.5% Live birth rate = 27%Live birth rate = 27%

Donor oocytesDonor oocytes

(4/11 pregnancies)(4/11 pregnancies)

Donor oocytesDonor oocytes

(81/116 pregnancies)(81/116 pregnancies)

Live birth rate = 36%Live birth rate = 36% Live birth rate = 70%Live birth rate = 70%

P<0.01P<0.01

P<0.01P<0.01

ASRM 2005

IVF in endometriosis vs. tubal infertility

Barnhart et al, Fertil Steril 2002

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

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

Hydrosalpinx and RIF

Commonly ordered immunological tests

• Antiphospholipid Antiphospholipid antibodiesantibodies– Anticardiolipin

– antiphosphatidyl serine

– antiphosphatidyl ethanolamine

– antiphosphatidyl choline

– antiphosphatidyl glycerol

– antiphosphatidyl inositol

– antiphosphatidic acid

• Lupus anticoagulantLupus anticoagulant• Antisperm antibodiesAntisperm antibodies• Antithyroid antibodiesAntithyroid antibodies• Antinuclear antibodiesAntinuclear antibodies• Anti-smooth muscle Anti-smooth muscle antibodiesantibodies• Natural killer cellsNatural killer cells• Embryotoxic assayEmbryotoxic assay

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. Fertil Steril. 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

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

A randomized, placebo controlled trial

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