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
100
0 6 12 18 24
Months of Treatment (cycles)
Per
cen
t o
f C
ou
ple
s C
on
ceiv
ing
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
20
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
ien
ts n
um
ber
cyst +
cyst -
Figure 2. Pregnancy rates
0
20
40
60
80
100
120
Group 1 Group 2 Group 3
Groups
Pat
ien
ts N
um
ber
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.
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