Patient selection and preparing for ART

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Patient selection and preparing for ART

• Prof. Dr. Erol TAVMERGEN
• Ege University Dept.ObstGynec
• Ege University Family Planning and Infertility
  Research and Treatment Center Izmir

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Infertility

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

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Conception rates for fertile couples
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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 womans age

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Initial advice for people concerned about delays
in conception

• Lifestyle advice
• Sexual intercourse every 23 days
• 12 units alcohol/week for women 34
  units/week for men
• Smoking cessation programme for smokers
• Body mass index of 1929
• Information about prescribed, over-the-counter
  and recreational drugs
• Information about occupational hazards
• Offer preconceptional advice
• Folic acid
• Rubella susceptibility and cervical screening

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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 couples fertility problems
• Contact with fertility support groups
• Specialist teams

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pregnancy
Patient selection and preparation
Ovulation ind.
Embryo quality
Implantation
Embryo transfer
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Oocyte

• Age
• Estradiol
• FSH
• Obesity
• Smoking and drugs
• Cyst formation
• Endometriosis
• Antiboidies etc.

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Ovarian reserve reproductive age

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

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Female age

• The highest live birth rates were in the age
  group 25 to 30 years younger women had lower
  rates and there was a decline in older women.
• At all ages over 30 years, use of donor eggs was
  associated with a significantly higher live birth
  rate than use of the womans own eggs, but there
  was also a downward trend in success rate with
  the recipients age.
• Above the age of 33 years, live birth rates per
  treatment cycle declined, falling below 10 (i.e.
  less than half the rate in 23 to 33 year-olds) by
  the age of 40 years.
• Women of 40 and older have a declining chance,
  which reduces to 1 at the age of 45 years. Since
  the effectiveness of IVF treatment for women aged
  less than 23 years is uncertain.
• Templeton A et al, Lancet 1996.

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What changes with age?

• Oocyte quality decreases
• Follicular reponse to gonadotropins ?
• Implantation rates ?
• Spontaneous abortion rates ?

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Age and Pregnancy
Pregnancy Rates
Cycle number
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Age and related miscarriage
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Reproductive vs chronological age
Ovarian reserve Content of primordial
follicles Ovarian volumeD1xD2xD3x0.523
W. Hamish et al 2004
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Age is better predictor of pregnancy potential
than basal follicle-stimulating hormone levels in
women undergoing in vitro fertilizationChih-Chi
Chuang et al FS 79163-68,2003

• FSHlt10
  FSHgt10
• lt35 35-39
  40 lt35
  35-39 40
• n526 n264
  n99 p n54 n58
  n44 p
• OCCC retv. 13.3 10.6
  7.0 lt.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 lt.001 23.2 14.5
  7.1 .008
• Ong.PR () 38.6 27.7
  10.1 lt.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

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Cumulative live birth rate acc.to age
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Age
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Predictive models for ovarian response
Bancsi et al. (2002) - Predictors of poor ovarian
response Antral follicle count, FSH, inhibin B
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 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 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 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 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 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 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
Predictive model Sens Spec PPV NPV ROC AUC Correct predictions
Inhibin B 0.42 0.92 0.68 0.79 0.77 92 (77)
FSH 0.44 0.93 0.73 0.80 0.84 94 (78)
Antral follicle count 0.61 0.88 0.69 0.84 0.87 96 (80)
FSHinhibin B 0.58 0.94 0.81 0.84 0.89 100 (83)
Antral follicle countinhibin B 0.69 0.88 0.71 0.87 0.90 99 (83)
Antral follicle countFSH 0.72 0.93 0.81 0.89 0.90 104 (87)
Antral follicle countFSHinhibin B 0.75 0.95 0.87 0.90 0.92 107 (89)
PPV, positive predictive value NPV, negative predictive value ROC AUC, area under the receiver operating characteristic curve. PPV, positive predictive value NPV, negative predictive value ROC AUC, area under the receiver operating characteristic curve. PPV, positive predictive value NPV, negative predictive value ROC AUC, area under the receiver operating characteristic curve. PPV, positive predictive value NPV, negative predictive value ROC AUC, area under the receiver operating characteristic curve. PPV, positive predictive value NPV, negative predictive value ROC AUC, area under the receiver operating characteristic curve. PPV, positive predictive value NPV, negative predictive value ROC AUC, area under the receiver operating characteristic curve. PPV, positive predictive value NPV, negative predictive value ROC AUC, area under the receiver operating characteristic curve.
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FSH

• Differences between cycles and laboratories
• Increases with ages
• High FSH level corraleted with bad responds
• There was an increase in aneuploidy ratio in high
  FSH levels
• Pregnancy losses increase by high FSH levels
  
• 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

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Basal FSH/Pregnancy (IVF)
Pregnancy
Delivery
Basal FSH (D3)
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Reduction of Fertility with AgePutative
Mechanisms

• Small number of available oocytes
• Poor oocyte quality - Oocytes with aneuploidies
• ?novulation
• 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)

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Quality of embryos available according
to womans age
Grimbizis et al, Hum. Reprod., 13 884-9, 1998
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Low implantation rates due to age

• Mitochondrial DNA mutation changes in
  mitochondrial activity
• decreased cytoplasmic ATP
  production
• Altered spindle formation,decreased free radical
  clearence
• implantation rates
• aneuploidy, cell damage
• Bartmann 2004

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Estradiol

• Changes in basal E2 levels (lt20 pg/mL or gt80
  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)

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• Can we do something?

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Chances of a live birth per treatment cycle are

• Greater than 20 for women aged 2335 years
• 15 for women aged 3638 years
• 10 for women aged 39 years
• 6 for women aged 40 years or older.

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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.

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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 250 mg/day versus 02
  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.

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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 2528 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 1930 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.

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Evaluation of the uterine cavity

• US
• HSG
• SIS
• Office hysteroscopy

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

• Hysteroscopy
• USG Abnormal Normal
  Total
• Anormal 5
  6 11
  
• Normal 20
  67 87
  
• Total 25 (25)
  73 98

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Goup 1no hysterosc. Group 2 a normal hyst Group
2b abnormal hyst
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• Should endometriosis be treated prior to IVF?

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Is pretreatment usefull before IVF?
Sallam HN, Garcia-Velasco JA, Dias S,Arici A 2006
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Retrospective case control study.
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Clinical pregnancy rates Gupta et al., RBM
Online 2006
95 CI (0.63, 1.81), P 0.79
40
ar
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Should myomas be treated?

• Do myomas lead to implantation failure?
• Which kind of myomas should be removed

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Myomectomy-Discussions

• Even when lt5cm and not distorting the cavity
  halved the pregnany rates (Hart 2001).
• 0.5cm-10cm fibroids failed to show any negative
  effect over pregnancy (Yarali 2002).
• Intramural fibroidsgt4cm even not distorting the
  cavity significantly decrease pregnancy rates
  (Oliveira 2004)

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Endometrial Polyps

• Endometrial polyps have been detected
  in15-25 of infertile women
• Pregnancy rates range from 25-65 increase
  after polypectomies

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Group 1polyp detected Group 2polyp
resected Group 3control group
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What about Hidrosalpinges?
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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
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Tyroid disease in infertile patients

• Ege Univ ART Center Total 840 infertility pts
• Hypotyroidism
  47 pts (5.6)
• 
  Hypertyroidism 25 pts (2.9)
• Tyroid ab
  106 (12.6)
• In pregnancy Hyperthyroidism 0.24
• Hypothyroidism (TSH) 2-2.5
• Thyroid Ab antiTPO 10
• Postpartum PPTD
  5-9
• PP depression 30 vs 20
• PP Graves 40 E

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TPOAb-associated Reproductive -related
Complications
p lt 0.05
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Thyroid Antibodies and Pregnancy Risk

• Infertility
• Pooled studies RR 1.95(1.5-2.53) plt.0001
• IVF failure
• Miscarriage
• sig increase (2-4x) in 10/13 studies in gt 5200
  women Ab 10.4 - 67
• Pre eclampsia
• Fetal death
• Allan 2000,Mecacci 200,Poppe and Glinoer 2003

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The Effect of Ovarian Cyst Formation After Down
Regulation on The Outcome in ART Cycles. Akdogan
A.,et al, poster, 2004 ,TAJD Congress

• Age lt35 no difference on basal FSH and E2
  levels between the groups
• Down regulation started on D21 had less cyst
  formation
• Cysts were aspirated
• If no cyst was detcted pregnancy results were
  similar
• If cyst was detected after down regulation
  pregnancy results were lower
• Starting on D21 for downregulation gave better
  pregnancy results.

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Other Factors

• Stress
• Infertility duration
• Infertiliy cause and multiple causes
• The ART Center
• - Pregnancy rates
• - IVF Lab conditions
• - Ovulation induction protocols

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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)

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The Ideal ART Ovulation Induction Protocol

• Secures a high chance of embryo transfer
• A low cancellation rate
• A high pregnancy rate
• A low intervention rate
• Low risk and few side-effects
• Low costs
• Practical convenience both for the patient and
  the ART staff

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GnRHant

• Use of GnRH ant. brought new opportunities to COH
  regimens
• Shortens treatment time
• Prevents harmfull effects of flare-up regimens
• Leeds to less risk of OHSS
• More soft protocols will be used
• Alternative drugs can be used for triggering
  ovulation
• Pregnancy rates are comparible with agonists
• Perinatal outcomes are comparible with agonists

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Conclusion

• To have a high success rate on ART depends on
  several factors.
• Some of them can be changed.
• Age and biological status of the patient is very
  important.

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Evaluating success in ART

• OPU/ Pregnancy
• ET/ Pregnancy
• ET/Clinical Pregnancy
• Success in ART

Baby Take Home Rate
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• 1974de Semm jinekolojik patolojilere
  laparoskopik girisim imkanlarini yayinlamistir.
• Daha sonra endoskopik alet ve cihazlardaki hizli
  gelisme günümüzde jinekolojik girisimlerin
  80inin endoskopik yapilabilmesine olanak
  saglamistir.

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