Patient selection and Patient selection and preparing for ARTpreparing for ART

Prof. Dr. Erol TAVMERGENProf. Dr. Erol TAVMERGEN

Ege University Dept.Obst&GynecEge University Dept.Obst&Gynec

Ege University Family Planning and Ege University Family Planning and Infertility Research and Treatment Center Infertility Research and Treatment Center

İzmirİzmir

Infertility

Failure to conceive after regular unprotected sexual intercourse for 1 or 2 years in the absence of known reproductive pathology.

Conception rates for fertile Conception rates for fertile couplescouples

0102030405060708090

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0 6 12 18 24

Months of Treatment (cycles)

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Initial advice for people concerned about delays in conception:

Cumulative probability of pregnancy in general population:

• 84% in first year

• 92% in second year

Fertility declines with a woman’s age

Principles of infertility care

Couple-centred management Access to evidence-based information

(verbal and written) Counselling from someone not directly

involved in management of the couple’s fertility problems

Contact with fertility support groups Specialist teams

Embryo quality Implantation

Embryo transfer

pregnancy Patient selection and preparation Ovulation ind.

Oocyte Oocyte

AgeAge EstradiolEstradiol FSHFSH ObesityObesity Smoking and drugsSmoking and drugs Cyst formationCyst formation EndometriosisEndometriosis Antiboidies etc……….Antiboidies etc……….

Ovarian reserve & reproductive ageOvarian reserve & reproductive age

Fixed pool of primordial folliclesFixed pool of primordial follicles At birth ~ 700,000At birth ~ 700,000 At menarche ~ 300,000At menarche ~ 300,000 At the age 37 ~ 25,000At the age 37 ~ 25,000 Perimenopause ~ 1,000 Perimenopause ~ 1,000 Reproductive period ~ 400 ovulationsReproductive period ~ 400 ovulations

What changes with age?What changes with age?

Oocyte quality decreasesOocyte quality decreases Follicular reponse to gonadotropins Follicular reponse to gonadotropins ↓↓ Implantation rates ↓Implantation rates ↓ Spontaneous abortion rates ↑Spontaneous abortion rates ↑

Age and PregnancyAge and Pregnancy

Pregnancy

Rates %

Cycle number

Age and related miscarriageAge and related miscarriage

Reproductive vs chronological ageReproductive vs chronological age

Ovarian reserve

Content of primordial follicles

Ovarian volume:D1xD2xD3x0.523

Ovarian reserve

Content of primordial follicles

Ovarian volume:D1xD2xD3x0.523

W. Hamish et al 2004

Age is better predictor of pregnancy potential than basal follicle-stimulating hormone levels in women

undergoing in vitro fertilizationChih-Chi Chuang et al: F&S 79:1;63-68,2003

FSH<10 FSH>10

<35 35-39 ≥40 <35 35-39 ≥40

n:526 n:264 n:99 p n:54 n:58 n:44 p

OCCC retv. 13.3 10.6 7.0 <.001 5.6 5.0 3.2 .008

Fert.rate (%) 65.6 65.4 68.6 ns 67.4 74.0 74.4 ns

Impl.rate (%) 17.6 13.4 7.0 <.001 23.2 14.5 7.1 .008

Ong.PR (%) 38.6 27.7 10.1 <.001 27.8 19.0 4.5 .011

Conclusion: Both basal FSH and age contributed to the prediction of the qualitative ovarian reserve as reflected by the number of oocytes collected. However, age is a better predictor of the pregnancy potential for women undergoing IVF. In light of the low success rate, women over 40 years old, especially those with elevated FSH levels,should be informed of the low chance of pregnancy with their own gametes before embarking on expensive IVF treatment

PPredictive models for ovarian responseredictive models for ovarian response

Performances of several logistic models for the prediction of poor Performances of several logistic models for the prediction of poor response at a cut-off point of 0.50 for the probability of poor response at a cut-off point of 0.50 for the probability of poor responseresponse

Predictive modelPredictive model SensSens SpeSpecc

PPVPPV NPVNPV ROC ROC AUCAUC

Correct Correct predictionspredictions

Inhibin BInhibin B 0.420.42 0.920.92 0.680.68 0.790.79 0.770.77 92 (77%)92 (77%)

FSHFSH 0.440.44 0.930.93 0.730.73 0.800.80 0.840.84 94 (78%)94 (78%)

Antral follicle countAntral follicle count 0.610.61 0.880.88 0.690.69 0.840.84 0.870.87 96 (80%)96 (80%)

FSH+inhibin BFSH+inhibin B 0.580.58 0.940.94 0.810.81 0.840.84 0.890.89 100 (83%)100 (83%)

Antral follicle Antral follicle count+inhibin Bcount+inhibin B

0.690.69 0.880.88 0.710.71 0.870.87 0.900.90 99 (83%)99 (83%)

Antral follicle Antral follicle count+FSHcount+FSH

0.720.72 0.930.93 0.810.81 0.890.89 0.900.90 104 (87%)104 (87%)

Antral follicle Antral follicle count+FSH+inhibin count+FSH+inhibin BB

0.750.75 0.950.95 0.870.87 0.900.90 0.920.92 107 (89%)107 (89%)

PPV, positive predictive value; NPV, negative predictive value; ROC AUC, PPV, positive predictive value; NPV, negative predictive value; ROC AUC, area under the receiver operating characteristic curve.area under the receiver operating characteristic curve.

Bancsi et al. (2002) - Predictors of poor ovarian response:

Antral follicle count, FSH, inhibin B

FSHFSH

Differences between cycles and laboratoriesDifferences between cycles and laboratories Increases with agesIncreases with ages High FSH level corraleted with bad respondsHigh FSH level corraleted with bad responds There was an increase in aneuploidy ratio in high There was an increase in aneuploidy ratio in high

FSH levels *FSH levels * Pregnancy losses increase by high FSH levels ** Pregnancy losses increase by high FSH levels ** Increasing FSH levels effect Down syndrome ratio Increasing FSH levels effect Down syndrome ratio

*** ***

**Nasseri A et al., Fertil Steril 1999****Trout SW et al.,Fertil Steril 2000******van Montfrans JM et al.,Human Reprod 2002

0

10

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30

40

50

4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Basal FSH(IU/ml)

% /

Cy

cle

Total pregnancyOngoing pregnancy

Cancelled

Basal FSH/Pregnancy (IVF)

Basal FSH (D3)

Pregnancy

Delivery

Reduction of Fertility with Age:Reduction of Fertility with Age:Putative MechanismsPutative Mechanisms

Small number of available oocytes Poor oocyte quality - Oocytes with

aneuploidies Αnovulation Reduced number of uterine and endometrium

receptors Reduction of blood flow in the endometrium

Reduction of the endometrial stroma

Mild fibrosis of vessel and myometrial walls Reduced receptivity of the endometrium Tubal factors (decilliation)

Quality of embryos available according Quality of embryos available according to woman’s age to woman’s age

Grimbizis et al, Hum. Reprod., 13: 884-9, 1998

Low implantation rates due to ageLow implantation rates due to age

Mitochondrial DNA mutation changes in Mitochondrial DNA mutation changes in mitochondrial activitymitochondrial activity

decreased cytoplasmic ATP productiondecreased cytoplasmic ATP production

Altered spindle formation,decreased free radical Altered spindle formation,decreased free radical clearenceclearence

implantation rates implantation rates aneuploidy, cell damageaneuploidy, cell damage

Bartmann 2004Bartmann 2004

EstradiolEstradiol

Changes in basal E2 levels (<20 pg/mL or >80 pg/mL) may lead to increase in cancellation rates but donot effect success rates (Frattarelli JL ve ark. Fertil Steril 2000)

High basal E2 levels lead to decreases of implantation rates and pregnancy rates when patients age is over 35.(Vazquez ME ve ark. Gynecol Endocrinol 1998)

Values over 90 per. On cycle day 4-6 are together with increases in oocyte number and embryo quality (Papageorgiou T ve ark. Hum Reprod 2002)

Can we do something?Can we do something?

Alcohol, smoking and caffeine consumption

Maternal and paternal alcohol consumption in excess of 12 g (one unit) per day up to one year before assisted reproduction have been associated with a significant decrease in the success rates of IVF and GIFT.*

Maternal and paternal smoking before assisted reproduction have been associated with significant decreases in the success rates of IVF and GIFT.**

*Klonoff-Cohen H et al, Fertil Steril 2003.**Klonoff-Cohen H et al, Hum Reprod 2001.** Feichtinger W et al, J Assist Reprod Genet 1997.**Joesbury KA et al, Hum Reprod 1998.

Alcohol, smoking and caffeine consumption

Smoking by males is also associated with a decrease in the success rates of IVF and ICSI (OR 2.95; 95% CI 1.32 to 6.59).***

Caffeine consumption (over 2–50 mg/day versus 0–2 mg/day; 100 mg caffeine in one cup of coffee) during a lifetime (i.e., usual intake) and during the week of initial visit for infertility were strong risk factors for not achieving a live birth in women undergoing IVF or GIFT. This study also reported an association between maternal coffee consumption and decreased infant gestational age.****

***Zitzman m et al, Fertil Steril 2003.**** Klonoff-Cohen H et al, Hum Reprod 2002.

Body weight Obesity (BMI 25.8 to 30.8 kg/m2) has been shown to be

a risk factor for spontaneous abortion in women after IVF or ICSI.*

Obesity is also associated with lower pregnancy rates after IVF when compared with women with a BMI of 25 kg/m2 or under.**

Extremes of BMI (over 25–28 kg/m2 or under 20 kg/m2) have been associated with negative effects on IVF parameters leading to decreased chances of pregnancy.***

Women should be informed that female body mass index should ideally be in the range 19–30 before commencing assisted reproduction, and that a female body mass index outside this range is likely to reduce the success of assisted reproduction procedures.

*Fedorcsak P et al, Acta Obstet Gynecol Scand 2000.**Loveland JB et al, J Assist Reprod Genet 2001.*** Wittemer C et al, J Assist Reprod Genet 2000.***Nichols JE et al, Fertil Steril 2003.

Evaluation of the uterine cavityEvaluation of the uterine cavity

USUS HSGHSG SISSIS Office hysteroscopyOffice hysteroscopy

Recurrent IVF Failure USG/ HysteroscopyTavmergen et al. World IVF Congr.2005

HysteroscopyHysteroscopyUSG USG AbnormalAbnormal Normal Normal TotalTotal

Anormal 5 6 11 Anormal 5 6 11

Normal 20 67 87 Normal 20 67 87

Total 25 (25%) 73 98Total 25 (25%) 73 98

Goup 1:no hysterosc.Group 2 a: normal hyst

Group 2b: abnormal hyst

Should endometriosis be treated prior to Should endometriosis be treated prior to IVF?IVF?

Is pretreatment usefull before IVF?

Retrospective case control study.

Clinical pregnancy rates Gupta et al., RBM Online 2006Gupta et al., RBM Online 2006

[95% CI: (0.63, 1.81), P =0.79]

arar

Should myomas be treated?Should myomas be treated?

Do myomas lead to implantation failure?

Which kind of myomas should be removed

Myomectomy-DiscussionsMyomectomy-Discussions

Even when <5cm and not distorting the cavity halved the pregnany rates (Hart 2001).

0.5cm-10cm fibroids failed to show any negative effect over pregnancy (Yaralı 2002).

Intramural fibroids>4cm even not distorting the cavity significantly decrease pregnancy rates (Oliveira 2004)

Endometrial Polyps Endometrial polyps have been Endometrial polyps have been

detected in15-25% of infertile detected in15-25% of infertile womenwomen

Pregnancy rates range from Pregnancy rates range from 25-65% increase after 25-65% increase after polypectomiespolypectomies

Group 1:polyp detectedGroup 2:polyp resectedGroup 3:control group

What about Hidrosalpinges?What about Hidrosalpinges?

Should hydrosalpinges be removed?

•All patients with hydrosalpinx are candidates for removal prior to IVF•Laparoscopic salpigectomy improves live birth rates•Removal of hydrosalpinges non detectable by ultrasound?•Concern about especially bilateral removals effect on ovarian reserve?

The Cochrane Library,issue,1 2003

%TPOAb-positive

%TPOAb- negative

20

40

60

80

100

%

0

TPOAb-associated Reproductive -related Complications

Female Infertility(Poppe 2003)

*

IVF Failure(Kim 1998)

*

Preeclampsia(Meccaci 2000)

*

RecurrentFetal Death(Meccaci 2000)

*

Subclin HypoFetal Death

(Allan 2000)

*

* = p < 0.05

The Effect of Ovarian Cyst Formation After Down The Effect of Ovarian Cyst Formation After Down Regulation on The Outcome in ART Cycles. Regulation on The Outcome in ART Cycles. Akdoğan A.,et al, Akdoğan A.,et al,

poster, 2004 ,TAJD Congressposter, 2004 ,TAJD Congress Age <35 – no Age <35 – no

difference on basal difference on basal FSH and E2 levels FSH and E2 levels between the groupsbetween the groups

Down regulation Down regulation started on D21 had started on D21 had less cyst formation less cyst formation

Cysts were aspirated Cysts were aspirated If no cyst was detcted If no cyst was detcted

pregnancy results were pregnancy results were similar similar

If cyst was detected If cyst was detected after down regulation after down regulation pregnancy results were pregnancy results were lower lower

Starting on D21 for Starting on D21 for downregulation gave downregulation gave better pregnancy better pregnancy results. results.

Figure 1.Cyst formation in patients enrolled study

95

13

175153

020406080

100120140160180200

Down regulation started 2nd day Down regulation started 21th day

down regulation starting day

pat

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cyst +

cyst -

Figure 2. Pregnancy rates

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120

Group 1 Group 2 Group 3

Groups

Pat

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Pregnant

Nonpregnant

Other FactorsOther Factors

StressStress Infertility durationInfertility duration Infertiliy cause and multiple causes Infertiliy cause and multiple causes The ART Center :The ART Center : - Pregnancy rates- Pregnancy rates

- IVF Lab conditions- IVF Lab conditions

- Ovulation induction protocols- Ovulation induction protocols

Duration of infertility

Treated or not treated duration of infertiliy is the 2nd most important factor influencing pregnancy rates. HFEA values have shown that infertility duration between 1-12 years show a negative correlation to success rates. (Templeton A, 1996)

Although no specific relation has been detected having had a pregnancy or previous delivery may lead to better success .. (Dor J 1996)

The Ideal ART Ovulation Induction The Ideal ART Ovulation Induction ProtocolProtocol

Secures a high chance of embryo transferSecures a high chance of embryo transfer A low cancellation rateA low cancellation rate A high pregnancy rateA high pregnancy rate A low intervention rateA low intervention rate Low risk and few side-effectsLow risk and few side-effects Low costsLow costs Practical convenience both for the patient Practical convenience both for the patient

and the ART staffand the ART staff

GnRHant GnRHant Use of GnRH ant. brought new Use of GnRH ant. brought new

opportunities to COH regimensopportunities to COH regimens Shortens treatment timeShortens treatment time Prevents harmfull effects of flare-Prevents harmfull effects of flare-

up regimensup regimens Leeds to less risk of OHSS Leeds to less risk of OHSS More soft protocols will be usedMore soft protocols will be used Alternative drugs can be used for Alternative drugs can be used for

triggering ovulationtriggering ovulation Pregnancy rates are comparible Pregnancy rates are comparible

with agonists with agonists Perinatal outcomes are Perinatal outcomes are

comparible with agonistscomparible with agonists

To have a high success rate on ART To have a high success rate on ART depends on several factors.depends on several factors.

Some of them can be changed.Some of them can be changed. Age and biological status of the patient is Age and biological status of the patient is

very important. very important.

Conclusion

Evaluating success in ARTEvaluating success in ART

OPU/ PregnancyOPU/ Pregnancy

ET/ PregnancyET/ Pregnancy

ET/Clinical PregnancyET/Clinical Pregnancy

Success in ARTSuccess in ART

Baby Take Home RateBaby Take Home Rate

1974’de Semm jinekolojik patolojilere laparoskopik girişim imkanlarını yayınlamıştır.

Daha sonra endoskopik alet ve cıhazlardaki hızlı gelişme günümüzde jinekolojik girişimlerin %80’inin endoskopik yapılabilmesine olanak sağlamıştır.