Factors Affecting Pregnancy Rates in IVF
Russian Association ofHuman Reproductive Health
St. Petersburg. September 9, 2011G. David Adamson, MD,FRCSC,FACOG,FACS
Director, Fertility Physicians of Northern CaliforniaAdjunct Clinical Professor, Stanford University
Associate Clinical Professor, UCSF
Disclosures• Advanced Reproductive Care (ARC)
– Founder and CEO• Professional Organizations
– ASRM: Past President– FIGO: Chair, Reproductive Medicine Committee– ICMART: Int’l Committee Monitoring ART– IFFS: Executive Committee– WERF: Chair
• Funded Research Studies– EMD Merck Serono– IBSA– LabCorp– Schering Plough
What is “Success”????????
• Patients– “This glossary does not include specific
measures of “success” which would take into consideration the well-being of babies as well as of their mothers, fathers, surrogates and/or gamete donors.” (1)
• Other Society Stakeholders– Appropriate cost to broader society– Minimized social or ethical issues– Appropriate number of babies for that society
• A healthy singleton baby1. ICMART WHO Glossary 2009. Fertil Steril 2009;92:1520–4.
Patient SelectionFor IVF
Informed Consent and Guidelines For Care*
• Evidence based medicine• Effective consulting and counseling• Informed consent guidelines• Guidelines for providing infertility
services• Practice guidelines• Ethical guidelines
* Significant influence on patient’s decision
Major Categories of Factors That Affect IVF Success
• Patient population• Quality of medical treatment• Quality of gamete/embryology laboratory• Measurement & reporting of outcomes• Resources available for treatment
– Financial– Patient support services
• Values and ethics– Patients– Physicians– Community– Society
PatientPopulation
Pregnancy Rates Following Treatment (Per Cycle)
LIVE BIRTHS PER TRANSFER FOR ART CYCLES USING FRESH EMBRYOS FROM OWN AND DONOR EGGS, BY PATIENT AGE
NATIONAL DATA CDC 2004
0
10
20
30
40
50
60
70
Age25
Age26
Age27
Age28
Age29
Age30
Age31
Age32
Age33
Age34
Age35
Age36
Age37
Age38
Age39
Age40
Age41
Age42
Age43
Age44
Age45
Age46
Patient age
Perc
ent
Ow n eggs Donor eggs
IVF NATIONAL RATES PER CYCLE
Individual Patient “Egg” Factors Affecting IVF Live Birth Rates• Age• Ovarian reserve
– FSH/E2– Antral follicle count– ?Anti Mullerian Hormone (AMH)
• Egg donation (increase)• Recurrent pregnancy loss• Smoking (1)• Alcohol & other drugs• Increased Body Mass Index (BMI)• Excessive exercise• ? Caffeine
1. ASRM Practice Cmttee. Fertil Steril Nov 2008;90(Suppl 3):S254-9)
Individual Patient Pelvic Factors Affecting IVF Live Birth Rates
• Hydrosalpinges (decrease 50%) • Myomas (if cavity distortion decrease)
Endometriomas (?)• Adenomyosis (?)• Congenital uterine abnormalities• Cervical “incompetence”• Intrauterine adhesions• Thin endometrium (< 8 mm)
ASRM Practice Committee. Fertil Steril Nov 2008;90(Suppl 3):S66-7.
Normal Uterus and Endometrium
Uterine Factors andAge-Related Infertility• Polyps increase with age (1)• Myomas increase with age (2,3)• No significant age-related decline in
delivery rates with egg donation
1. Nagele F. Am J Obstet Gynecol. 1996; 88:9002. Baird et al. Am J Obstet Gynecol 2003;188:100-7.3. Peddada et al. PNAS 2008 Dec 16;105(50):19887-92.
Submucous Myoma
Meta-analysis ofMyoma Studies
• Fertility outcomes– decreased in women with submucosal fibroids– removal seems to confer benefit
• Intramural fibroids– appear to decrease fertility– results of therapy are unclear
• More high-quality studies need to be directed toward the value of myomectomy for intramural fibroids, focusing– size– number– proximity to the endometrium
Pritts. Fertil Steril. 2009 Apr; 91(4):1215-23. Epub 2008 Mar 12.
Effects Of Male Age On Fertility
• Many studies confounded by age of female partner
• In studies controlling for female age, MEN age > 50 create pregnancies at a rate 23-38% lower than MEN age <30
• In some studies, male factor is associated with lower IVF pregnancy rates
Kidd SA. Fert Steril. 2001; 75:237.
Race Affects Fertility Outcomes
• African-American1
– Pregnancy rate RR=0.83 (0.67-1.02)– Spontaneous abortion RR=1.57 (1.05-2.36)– Increased prevalence myomas RR=2.85 (2.06-3.95)
• Asian– Decreased live-birth rate2 OR=0.69 (0.61-0.77)– Predictors of outcome3
• Decreased ovarian reserve, endometriosis, nulligravity• Caucasian3
– Predictors of outcome• Male factor, # of 2PN embryos
1Feinberg. Fertil Steril 2006;85:888-94.2Purcell. Fertil Steril 2007;87:297-302.3Purcell. Fertil Steril 2005;83(5):S10-S11.
SART/CDCClinic-specific Reports
Caution:
Patient characteristics vary among programs; therefore, these data
should not be used for comparingclinics.
Quality ofMedical Treatment
1-5 weeks
Sample IVF Cycle Average 2 Month Process
CONTRACEPTION
GnRHa/ant INJECTIONS
FSH INJECTIONS
hCG
Ultrasound and Estradiol
Monitoring
Baseline Ultrasound/ SHG
PROGESTERONE SUPPLEMENTATION
35 hrs
Retrieval forIVF or GIFT
EmbryoTransfer
menses menses
Day1
3-5 days
10-15 days ~ 10 days 9-11 days
PregnancyTest
Current Mandatory Regulation of ARTMandatory for SART Programs
• SART– Personnel requirements: Program, Medical and Lab Directors– On-site accreditation of laboratory by CAP/ASRM, JCAHO or
NY state– Reporting of results to SART/CDC– On-site validation of reported results by SART/CDC– On-site review of adherence to SART Practice, Laboratory,
Advertising and Ethics Guidelines– Mandatory participation in SART quality assurance program
• CDC (“Mandatory”, but not enforceable, for all ART programs)– Reporting of results to SART/CDC– On-site validation of reported results by SART/CDC– Listing of non-responder clinics by CDC
• FEDERAL TRADE COMMISSION (FTC)– Truth-in-advertising
Multiple Birth: ASRM/SART GuidelinesNumber of Embryos to Transfer (2008)
3322All Others
3221Favorable*
Day 5
5432All Others
5321-2Favorable*
>4038-4035-37<35Day 3
* 1st cycle, good embryos, # to * 1st cycle, good embryos, # to cryocryo, or prior IVF success, or prior IVF success
Key Steps in IVFEmbryo Transfer
•Technique•? Ultrasound guidance•Number and quality of embryos transferred
Embryo Transfer Catheter
Clinical Pregnancy Rate per Embryo Transfer
by Age and Cycle Number
Silberstein. Fertil Steril 2005;84(4):1043-5.
All PatientsNumber = 1,177Cycles = 1,788
Age < 35
Age 35-38 Age > 38*1 2 3 4 5
1 2 3 4 51 2 3 4 5
* *20%
*
*
1 2 3 4 5
20%
20% 20%
40% 40%
40%40%
*
Quality ofLaboratory
FPNC Gamete Laboratory
Key Steps in IVFFertilization
• Conventional Insemination
• Intracytoplasmic Sperm Injection (ICSI)
What Can Urologists Do For Severe Male Factor Infertility?
• Genetic testing:– Karyotype (chromosome ‘spread’)– Y chromosome testing– Cystic fibrosis gene testing (obstructive
cases only)• Sperm harvesting:
– Often utilizes microsurgical techniques– Can be done with minimal disruption of the
genitals – Sources of sperm: epididymal vs. testicular
• Advantages and disadvantages of each
Key Steps in IVFEmbryo Development
Day 1 Day 3 Day 6
•Embryology laboratory quality•Useful: PGD for single genes, balanced translocations•HARMFUL: PGS embryo biopsyon Day 3 or day 5
Cryopreservation (Day 1, Day 3 or Day 5)
• “Good quality” embryos which are not transferred can be frozen for future use
• Embryos stored in special straws labeled with patient’s name and unique identifier
• Straws containing embryos are submerged in liquid nitrogen storage environment
• Vitrification better than slow freezing• Replace thawed embryos
– Natural cycle– Medicated cycle
Jane Doe, dd/mm/yy 999-99-9999
OutcomesAssessment
Outcomes Assessment
• Difficulty in measurement• SART/CDC clinic-specific report
– definition of success– calculation of FET cycle pregnancies
in addition to fresh transfers– random variation of results1
– variation of patient populations– variation in patient selection
1 Chapko, Adamson. Fertil Steril1995;64(4):757-63.
Complications of ARTin 3,500 Cycles (Cairo, Egypt)• OHSS moderate 206 5.9%• OHSS severe 60 1.7%• Vaginal bleeding 3 0.09%• Deep vein thrombosis 4 0.1%• Hemiparesis 2 0.06%• Pelvic infection 10 0.3%• Acute abdomen 3 0.09%• Anesthetic complication 2 0.06%• Mortality* (Hep C, OHSS)1 0.03%
TOTAL 291 8.3%Serour. Fertil Steril 1998;70(4):638-42.
Elective Single Embryo Transfer (eSET): An American Perspective
• Decrease in number of embryos transferred from two to one– Reasonable option in one-third of patients– Reduces twin incidence to half its original– No decline in ongoing pregnancy rate overall
• The proportion of patients for whom this is appropriate will vary from program to program, depending on individual patient characteristics.
• Implement the program gradually– Distinct clinical phases– Judicious patient selection
• Cryopreservation
PatientResources
Patient Drop-out Rates Are 37 – 68%:What is Impact on Cumulative eSET?
• A major unknown confounding variableon the overall success of eSET (1,2)– Cost– Physician-recommended– 65% not pregnant did not pursue covered
treatment in Sweden (3)• Psychological –26%• Poor Prognosis – 25%• Spontaneous pregnancy – 19%• Physical burden – 6%• Serious disease – 2%• Other –7% (1) Fertil Steril 2004;81:258-78.
(2) Daya. Hum Reprod 2005;20:1135-43.(3) Olivius. Fertil Steril 2002;77:505-10.
Complements to Fertility Treatments
• Mind-Body 10-Week Fertility Program– Relieve emotional and physical distress and increase chances of
conception– Taught by licensed therapists
• 10 session program • Weekend program• One day program
• Mind-Body ResourcesLocal resources for alternative and complementary medicine– Counseling– Nutrition– Acupuncture*– Yoga*
* NO proven benefit, but may help individuals cope
Values andEthics
The Hierarchy of Interest
PatientsGametic MaterialFuture Children
Physicians andEmbryologists
ART Professional Organizations(SART, ASRM, RESOLVE, Nurses)
Regulatory Agencies(CDC, NIH, FTC, FDA, Gov’t.)
Other Interested Parties (Industry, ABA, Payers, Society)
Adamson. Am Bar Assoc Family Law Fall 2005; 39(3); 727-44.
The Future
“Near Future” Factors That Might Affect IVF Success Rates
• Increased Access– Increased societal support– Increased healthcare coverage
• Better Patient Selection– Increased clinical knowledge
• International factors affecting outcomes• Individual patient characteristics• Cross border reproductive care
– Increased scientific knowledge
“Near Future” Factors That Might Affect IVF Success Rates• Clinical Care Improvements
– Increased knowledge regarding• Endometriosis management pre-IVF
– Endometriomas– Duration of ovarian suppression
• Myomas– Improved ovarian stimulation protocols
• More effective: more higher quality eggs• Safer: lower incidence of ovarian hyperstimulation• Lower cost
– Long-acting gonadotropins• Decreased monitoring and cost• ? Increased safety
• Lower multiple pregnancy rates• Increased Single Embryo Transfer (SET)
“Near Future” Factors That Might Affect IVF Success Rates• Embryology Laboratory Improvements
– More automated, standardized, robust culture systems
– Improved cryopreservation• Slow freezing• Vitrification
– ? In vitro maturation (IVM)• Better embryo selection
– CGH for genetic selection– Metabolomics, proteomics– Other technologies
“Far Future” Factors That Might Affect IVF Success Rates• Better embryo selection
– Choose best embryo– SET in majority of patients
• Oral gonadotropins• More efficient utilization of cryopreserved
embryos• Genetics
– Diagnosis of selected genes associated with causes of infertility
– Treatment of selected genes associated with causes of infertility
– Prevention of genetically identifiable causes of infertility
“Far Future” Factors That Might Affect IVF Success Rates
• Societal recognition of IVF as a disease
• Societal financial support of infertility services, including IVF
• Widespread application of “affordable ART” in low resource environments
• Complete integration of reproductive medicine treatment into comprehensive women’s health prevention and treatment programs
CONCLUSION:Factors That Affect IVF Success
• Define Success: Healthy singleton baby• Infertility is a complex disease
– 2 patients plus child(ren)– Many causes– Some treatments simple, many complex– Multiple treatments simultaneously– Significant scientific and technological advances– Both known and unknown factors affect success
• Known factors affecting success– Types of patients– Quality of care– Quality of laboratory– Complexity and interpretation of outcome assessment– Socioeconomic factors– Patient and physician values and ethics
• Future developments expected and exciting
ThankYou!