14 Prevention of infertility – from preconception to post-menopause 3 July 2011
Prevention of infertility – from preconception to post-menopause 14 Task Force Reproduction and Society 3 July 2011 Stockholm, Sweden Prevention of infertility – from preconception to post‐menopause Stockholm, Sweden 3 July 2011 Organised by The Task Force Reproduction and Society Contents Course coordinators, course description and target audience Programme Introduction to ESHRE Speakers’ contributions What is infertility and what is prevention of infertility? ‐ Dik Habbema (The Netherlands) Preconception planning for a healthy start to life‐ Robert Norman (Australia) Raising fertility awareness in young people ‐ Jacky Boivin (United Kingdom) Prevention of sexually‐transmitted diseases – Lone Schmidt (Denmark) Prevention of female infertility at the workplace – Jens Peter Bonde (Denmark) The effect of postponing first child birth on primary and secondary infertility – is prevention possible? ‐ Egbert te Velde (The Netherlands) Policy measures that can affect the timing of the first birth ‐ Ronald Rindfuss (USA) Improving equal and open access to ART: prevention of involuntarily childlessness of the underprivileged.‐ Alan Trounson (USA) Freezing gametes and gonads: the solution to prevent infertility in men and women ‐ Sjoerd Repping (The Netherlands) Upcoming ESHRE Campus Courses Notes Page 3 of 131 Page 5 Page 7 Page 9 Page 17 Page 22 Page 37 Page 50 Page 61 Page 74 Page 84 Page 100 Page 113 Page 123 Page 124 Page 4 of 131 Course coordinators Egbert te Velde (The Netherlands) and Lone Schmidt (Denmark) Course description In this course we aim to go beyond the usual margins of our discipline and catch your attention for the paramount importance of prevention of infertility. In dealing with patients, in our social surroundings but also in our teaching responsibilities prevention of infertility is important, may be more so than you have realized so far. In fact preventive measures can already start before conception, may be even before the time people realize they wish to have children. But preventive thinking might also be important for couples who intend to have children much later in life e.g. around women’s menopause. In between those periods, raising fertility awareness in young people, measures to prevent STDs and giving advice to women and men how to combine a stressful, heavy or responsible job with the wish to have children, are some of the topics to be covered. Much attention is focused on the impact of postponing parenthood on fertility. Can we do something to prevent this, can we predict which women and men rather should not postpone but also: can society play a role and do something about it? Attending this course might change the routine of your daily practice Target audience Reproductive physicians, paramedical personnel and all those who are interested in the epidemiological, social and ethical aspects of our work. Page 5 of 131 Page 6 of 131 Scientific programme 09.00 ‐ 09.30 09.30 ‐ 09.45 09.45 ‐ 10.15 10.15 ‐ 10.30 10.30 ‐ 11.00 11.00 ‐ 11.30 11.30 ‐ 11.45 11.45 ‐ 12.15 12.15 ‐ 12.30 12.30 ‐ 13.30 13.30 ‐ 14.00 14.00 ‐ 14.15 14.15 ‐ 14.45 14.45 ‐ 15.00 15.00 ‐ 15.30 15.30 ‐ 16.00 16.00 ‐ 16.15 16.15 ‐ 16.45 16.45 ‐ 17.00 17:00 ‐ 17:30 17:30 ‐ 17:45 What is infertility and what is prevention of infertility? ‐ Dik Habbema (The Netherlands) Discussion Preconception planning for a healthy start to life‐ Robert Norman (Australia) Discussion Coffee break Raising fertility awareness in young people ‐ Jacky Boivin (United Kingdom) Discussion Prevention of sexually‐transmitted diseases – Lone Schmidt (Denmark) Discussion Lunch Prevention of female infertility at the workplace – Jens Peter Bonde (Denmark) Discussion The effect of postponing first child birth on primary and secondary infertility – is prevention possible? ‐ Egbert te Velde (The Netherlands) Discussion Coffee break Policy measures that can affect the timing of the first birth ‐ Ronald Rindfuss (USA) Discussion Improving equal and open access to ART: prevention of involuntarily childlessness of the underprivileged.‐ Alan Trounson (USA) Discussion Freezing gametes and gonads: the solution to prevent infertility in men and women ‐ Sjoerd Repping (The Netherlands) Discussion Page 7 of 131 Page 8 of 131 ESHRE – European Society of Human Reproduction and Embryology What is ESHRE? ESHRE was founded in 1985 and its Mission Statement is to: • promote interest in, and understanding of, reproductive science • facilitate research and dissemination of research findings in human reproduction and embryology to the general public, scientists, clinicians and patient associations. • inform policy makers in Europe • promote improvements in clinical practice through educational activities • develop and maintain data registries • implement methods to improve safety and quality assurance Executive Committee 2009/2011 Chairman Chairman Elect Past Chairman • Luca Gianaroli • Anna Veiga • Joep Geraedts Italy • • • • • • • • • • • • Jean François Guérin France Timur Gürgan Turkey Spain Netherlands Ursula Eichenlaub-Ritter Germany Antonis Makrigiannakis g Greece Miodrag Stojkovic Serbia Anne-Maria Suikkari Finland Carlos Plancha Portugal Françoise Shenfield United Kingdom Etienne Van den Abbeel Belgium Jolieneke Schoonenberg-Pomper Netherlands Veljko Vlaisavljevic Slovenia Søren Ziebe Denmark Page 9 of 131 General Assembly of Members ESHRE Organisation Executive Committee Committee of Nat. Representatives Central Office ESHRE Consortia EIM Consortium PGD Consortium Sub-Committees Finance Sub-Committee Comm. Sub-Committee Publ. Sub-Committee Editorial Office Publisher Editors-in-Chief Int’l Scientific Committee SIG Sub-Committee SIG Coordinators Task Forces ESHRE Journals Human Reproduction with impact factor 3.859 H Human R Reproduction d ti U Update d t with ith impact i t factor f t 7.042 7 042 Molecular Human Reproduction with impact factor 3.005 Campus Activities and Data Collection Campus / Workshops • Meetings are organised across Europe by Special Interest Groups and Task Forces • Visit www.eshre.eu under CALENDAR Data collection and monitoring • European IVF Monitoring Group data collection • PGD Consortium data collection Page 10 of 131 ESHRE Activities • Embryology Certification • Guidelines • Position papers • News magazine “Focus Focus on Reproduction” Reproduction ESHRE COMMUNITY RSS feeds for news in reproductive medicine Since launch 12/2009: 1,360 Fans Since launch 12/2009: 190 followers (journalists,, scientific organisations, (j g ,p patient societies, governmental bodies) Retweets to MHR Find a member ESHRE Membership (1/3) 103103 103103 79 79 79 79 153153 153153 313313 348348313313 348348 273273298298 273273298298 163163 163163 76 76 76 76 111111 111111 161161 161161 71 71% % 350350 350350 82 82 82 82 4,017 476 372 332 221 142 99 Europe Asia North America Middle East Africa Oceania South America 94 94 94 94 69 69 69 69 301301 301301 173173 173173 120120 120120 TOTAL MEMBERSHIP*: 5 659 members * as of July 2010 Page 11 of 131 ESHRE Membership (2/3) 1 yr 3 yrs Ordinary Member € 60 € 180 Paramedical Member* Paramedical Member € 30 € 90 Student Member** € 30 N.A. *Paramedical membership applies to support personnel working in a routine environment such as nurses and lab technicians. **Student membership applies to undergraduate, graduate and medical students, residents and postdoctoral research trainees. ESHRE Membership – Benefits (3/3) 1) Reduced registration fees for all ESHRE activities: Annual Meeting Workshops* Ordinary € 480 (€ 720) Students/Paramedicals € 240 (€ 360) All members (€ 250) €150 2) Reduced subscription fees to all ESHRE journals – e.g. for Human Reproduction €191 (€ 573!) 3) ESHRE monthly e-newsletter 4) News Magazine “Focus on Reproduction” (3 issues p.a.) 5) Active participation in the Society’s policy-making *workshop fees may vary Special Interest Groups (SIGs) The SIGs reflect the scientific interests of the Society’s membership and bring together members of the Society in sub-fields of common interest Andrology Psychology & Counselling Early Pregnancy Reproductive Genetics Embryology Reproductive Surgery Endometriosis / Endometrium Stem Cells Ethics & Law Reproductive Endocrinology Safety & Quality in ART Page 12 of 131 Task Forces A task force is a unit established to work on a single defined task / activity • Fertility Preservation in Severe Diseases • Developing Countries and Infertility • Cross Border Reproductive Care • Reproduction and Society • Basic Reproductive Science • Fertility and Viral Diseases • Management of Infertility Units • PGS • EU Tissues and Cells Directive ESHRE – Annual Meeting • One of the most important events in reproductive science • Steady increase in terms of attendance and of scientific recognition Track record: ESHRE 2010 – Rome: 9,204 participants ESHRE 2009 – Amsterdam: 8,055 8 055 participants ESHRE 2008 – Barcelona: 7,559 participants Future meetings: ESHRE 2011 – Stockholm, 3-6 July 2011 ESHRE 2012 – Istanbul, 1-4 July 2012 ESHRE 2011, Stockholm, Sweden When: 3 - 6 July 2011 Where: Stockholmsmässan, Mässvägen 1, Älvsjö, Sweden www.stockholmsmassan.se Chair of conference: Kersti Lundin Hotel and Travel: MCI - Stockholm Office Phone: +46 (0)8 54651500 E-mail: eshre@mci-group.com For updates visit www.eshre.eu Page 13 of 131 ESHRE 2011, Stockholm Keynote Lectures Aneuploidy in humans: what we know and we wish we knew – Terry Hassold (USA) Historical Lecture Ab brave new world ld with ith a brave b old ld humankind; h ki d quo vadimus – E. Diczfalusy (SE) MHR Symposium – The paternal genome Sperm chromatin packaging – B. Robaire (CDN) The human sperm epigenome – B. Cairns (USA) ESHRE 2011, Stockholm: Debates This house believes that obese women should not receive treatment until they have lost weight • Yes: Mark Hamilton (UK) • No: Guido de Wert (NL) - TBC Paramedical invited session: Should we pay donors? • Yes: Herman Tournaye (BE) • No: Laura Witjens (UK) Annual Meeting – Pre-Congress Courses • PCC 1: The challenges of embryo transfer (Paramedical Group) • PCC 2: The blastocyst: perpetuating life (SIG Embryology and SIG Stem Cells) • PCC 3: From genes to gestation (SIG Early Pregnancy and SIG Reproductive Genetics) • PCC 4: Lifestyle and male reproduction (SIG Andrology) • PCC 5: Ovarian ageing (SIG Reproductive Endocrinology) • PCC 6: The impact of the reproductive tract environment on implantation success (SIG Endometriosis/Endometrium) • PCC 7: Adhesion prevention in reproductive surgery (SIG Reproductive Surgery) Page 14 of 131 Annual Meeting – Pre-congress Courses • PCC 8: Theory and practice update in third party reproduction (SIG Psychology and Counselling) • PCC 9: Ethical aspects of non-invasive prenatal diagnosis (SIG Ethics & Law) • PCC 10: Patient-centered fertility services (SIG SQUART) • PCC 11: Clinical management planning for fertility preservation in female cancer patients (TF Basic Science and TF Preservation in Severe Disease in collaboration with the US OncoFertility Consortium) • PCC 12: Opportunities for research in female germ cell biology (TF Basic Science) Annual Meeting – Pre-congress courses • PCC 13: Assisted reproduction in couples with HIV (TF Fertility and Viral Diseases) • PCC 14: Prevention of infertility – from preconception to post-menopause (TF Reproduction and Society) • PCC 15: Hot topics in male and female reproduction (ASRM exchange course) • PCC 16: Academic Authorship programme (Associate Editors ESHRE journals) • PCC 17: Science and the media, an introduction to effective communication with the media (Communications SubCommittee ESHRE) Certificate of attendance 1/ Please fill out the evaluation form during the campus 2/ After the campus you can retrieve your certificate of attendance at www.eshre.eu 3/ You need to enter the results of the evaluation form online 4/ Once the results are entered entered, you can print the certificate of attendance from the ESHRE website 5/ After the campus you will receive an email from ESHRE with the instructions 6/ You will have TWO WEEKS to print your certificate of attendance Page 15 of 131 Contact ESHRE Central Office Tel: +32 (0)2 269 09 69 info@eshre.eu / www.eshre.eu Page 16 of 131 WHAT IS INFERTILITY AND WHAT IS PREVENTION OF INFERTILITY? An introduction to the course on “Prevention of infertility- from preconception to post-menopause” Dik Habbema, Chair of Medical Decision Sciences, ErasmusMC University Medical Center Rotterdam, the Netherlands To be presented at ESHRE 2011, Stockholm Preliminary version, March 2011 Learning objectives and reference Learning objectives: *to know and recognize the different meanings of “infertility” and their interrelationships *to have an overview of the possibilities for prevention of infertility as discussed in the course Ref:Human reproduction 2004 Vol 19 1497-1501 (Towards less confusing terminology in reproductive medicine: a proposal) INFERTILITY IS A MULTIFACETED CONCEPT Infertility has many connotations: Infertility as used in common language and in medicine Infertility as a biological condition prohibiting procreation Infertility as a descriptive term for not having produced children Infertility as a prognostic term expressing poor chances of pregnancy Infertility as a medical care term, as a condition for intervention Page 17 of 131 Infertility, common language Oxford English Dictionary: 1. Unable to reproduce 2. Unable to sustain crops or vegetation (of land) Cobuild English Language Dictionary: infertile 2. a person or animal that is infertile is unable to have or to produce babies....infertility is often considered a synonym of sterility Infertility, medical language Dorland Medical Dictionary(25th edition). Infertility: sterility;absence of the ability to conceive, or to induce conception INFERTILITY, causal meaning “The couple can not have children because they are using contraceptives” “The couple is infertile, because the man has no sperm” “The couple is infertile, because the woman has two-sided tubal blockage “The couple is infertile, because the woman is already 45 years old” The examples thus far give absolute causes. Now a few relative ones: “The woman is already 38 years of age” “The man has a reduced sperm quality” Relative causes can be used as an explanation of not getting pregnant, and have probabilistic prognostic value. Page 18 of 131 INFERTILITY, descriptive “ The fertility in this country has decreased over the last decades” (demographical use) “The couple had no child during the last three years” “ The couple has unsuccesfully tried to get children for three years” ANALYSIS: all sentences are descriptive. The last sentence refers to actively trying to get pregnant, the first one not. Descriptive term with duration indication: “x-year infertility” INFERTILITY, prognostic Qualitative prognosis :”the couple has a good/moderate/poor possibility of becoming pregnant without treatment.” Quantitative prognosis : ”the couple has a x% chance of becoming pregnantt within ithi y years.”” Thus, prognostically, infertile means a poor chance (e.g. under 20%) of getting pregnant during the coming year. Infertility in medical care In medical care, “Infertility” justifies medical action, according to guidelines. Examples: *After 1-year infertility (descriptive), a diagnostic fertility investigation is recommended. *After 3-year infertility with unknown cause, IVF is indicated. Page 19 of 131 Infertility and reduced (prognostic) fertility Reduced fertility because of relative factors *Age (ovarian aging) *Duration of trying to get pregnant(adverse selection) *Diagnostic findings( poor semen, adhesions ) Relationships between meanings of infertility Example 1 : 1-year infertility (descriptive) *is at odds with lay- and medical- language use of the term *does not imply prognostic infertility(chance in next year ~ 50%) *does not imply causal infertility *has medical care interpretation of recommendation of fertility investigation Example 2: 1-year infertility with subsequent finding of 2-sided tubal blockage (causal infertility) implies the lay- and medical language interpretation, implies prognostic infertility and has medical care implication of recommendation of immediate IVF treatment. Example 3: 1-year infertility with subsequent finding “unknown cause”. See example 1, but now with recommendation of trying to get pregnant without treatment. CONCLUSIONS ON MEANINGS OF INFERTILITY *Infertility has many meanings. *Try to be precise on your use of the term *Do not try to coin one exclusive definition for “infertility”. Do justice to the multiple meanings by using correct qualifications. *Be aware that one meaning does not necessarily imply other meanings. This applies strongly to “1-year infertility”. Page 20 of 131 PREVENTION OF INFERTILITY There are many exciting and challenging possibilities for prevention of infertility.They will be discussed during this course. Targets are: *Occupational fertility risks(Jens Peter Bonde) *Infertility risks from infectious diseases(Lone Schmidt) *Reproductive knowledge and fertility awareness( Jacky Boivin) *Policy measures for (early) family formation(Ronald Rindfuss) *Age at which family formation is started(Egbert te Velde) *Life-style before and during pregnancy(Robert Norman) *Accessible good quality fertility medicine(Allan Trounson) *Older age fertility “insurance” by cryopreservation(Sjoerd Repping) Page 21 of 131 Preconception planning for a healthy start to life Robert Norman The Robinson Institute Instit te for reproductive reprod cti e health and regenerative medicine The University of Adelaide Peri-conception health “Though it takes a lot of power To make a big tree grow, It doesn’t need a pot of knowledge For a seed knows what a seed must know.” Paul McCartney Off the ground • • • • • • Importance of peri-conception peri conception health Evidence of benefit and harm Building the knowledge base Developing a strategy Setting up the systems in practice Requirements to be bold and innovative Periconception period is critical to health Periconceptional origins “Fetal origins” Nutrition Toxins Genetics Vitamins Infections Chemicals Obesity Radiation Drugs Hormones Page 22 of 131 Early life – maximum opportunity and danger 8 Peri-conception – best return to human development 6 Best return value on investment 4 Pre-conception Pre-implantation First trimester 2 Later pregnancy 7 0 100 270 days Mustard 2006 Lifestyle issue and outcomes for babies PreEarly pregnancy pregnancy Undernutrition Overweight –male male Overweight- female Smoking Alcohol Later age Recreational drugs Caffeine Stress Lack of vitamins Poor sugar control Infertility Subfertility Subfertility Subfertility ?? Subfertility Subfertility ?Subfertility Subfertility ?? Subfertility ?? ?? Miscarriage Miscarriage Abnormality Abnormality ?? Miscarriage Miscarriage Abnormality Abnormality Late Neonatal life pregnancy Small baby ?? Large baby Small baby Abnormality ?? Addiction ?? Preterm birth ?? Fetal death Small baby ?? Large baby Small baby Fetal syndrome ?? Addiction ?? ?? ?? Neonatal death Obesity and reproduction – bad synergies Prior to pregnancy Increases length of time to pregnancy, menstrual disorders, more drugs needed Early pregnancy Miscarriage, fetal anomalies During pregnancy Increased gestational diabetes, high blood pressure, PET, DVT, instrumental and operative delivery Postpartum Haemorrhage, infection, DVT After pregnancy Increases diabetes mellitus, high blood pressure, endometrial cancer, cardiovascular disease, musculoskeletal problems Page 23 of 131 Mice made obese pre-pregnancy Low Fat Diet High Fat Diet “Healthy” “Unhealthy, Western-Style” Nutrition Facts Nutrition Facts Servings Per Mouse Servings Per Mouse Amount Per Serving Amount Per Serving 2.4g/day 6% Total Fat Cholesterol 0% Cholesterol Total Carbohydrate Dietary Fibre Sugars 0.15% 65% Total Carbohydrate 9% Dietary Fibre 50% 9% 34% Sugars 34% Protein 4.5g/day 21% Total Fat 19% Protein 19% Vitamin A 1.2% Vitamin A 1.2% Vitamin C 0% Calcium 0.46% Iron 85mg/kg Vitamin C 0% Iron 85mg/kg Calcium 0.46% • Muesli, skim milk • Fruit salad + yoghurt • Beef salad + multigrain roll • Bacon + eggs • Big Mac + Mars Bar • Fish & chips Minge et al Endocrinology 2008 Early embryo development- cell allocation Inner cell mass Trophectoderm 20 70 % Inner cell mass 30 60 25 Trophectoderm Placenta 14 12 10 8 6 4 2 0 50 Average % ICM ccells 16 Average number of TE cells “Differential stain” Average number of ICM cells 18 40 30 20 * 20 15 10 10 5 0 0 Control Diet Inner cell mass Fetus High Fat Diet Minge et al Endocrinology 2008 Lipotoxicity in response to high fat diet Increased dietary fat Lipid droplet [Ca2+] accumulation Fatty Acids ER Stress ROS [Ca2+] Mitochondrial Damage Unfolded Protein Response (UPR) ATF4, GRP78 Apoptosis Robker et al 2010 Page 24 of 131 Altered follicular environment in obese women With increasing BMI: • Increased follicular fluid insulin and glucose • Glucose:lactate ratios maintained • Increased testosterone, decreased SHBG • Increased Free Androgen Index • Increased free fatty acids and triglycerides Not affected by BMI • Cholesterol • HDL • LDL • Free fatty acids Triglycerides (mmol/L) 0.4 0.3 p = 0.003 0.2 0.1 0.0 20 30 40 50 Body Mass Index (BMI) Robker et.al. JCEM 2009 Peri-conception nutrition -epigenetic • • • • • Sheep fed to weight 15% -60 to +30 days from conception Earlier delivery (139 vs 146 days) Fetal cortisol earlier No IL-6, IL-6 TNF etc • • • • • • Donor ewes different diets -120 to 0 days from conception Control, -30% or +80% diets Adrenal weights in restricted Cortisol secretion in restricted Epigenetic changes in adrenal IGF2/H19 genes in restricted Zhang et al FASEB on line April 6, 2010 Bloomfield et al Science 300:606 (2003) Pre-conception glucose and abnormalities 7 meta-analyses non-diabetic patients peri-conception 1997 patients Standard deviation of GHb peri-conception Absolute values of GH1b peri-conception Keep glucose low at conception Guerin et al 2007 Diabetes Care Page 25 of 131 The role of male obesity • Animal studies indicate non-genetic transmission of metabolic sequelae • Human studies indicate effect of obesity on infertility • Male and female obesity have additive effects • Most clinics ignore male obesity Paternal BMI – infertility and pregnancy loss • • • • 350 cycles of IVF Male BMI documented Decreased pregnancy rates Increased pregnancy loss Bakos et al Fertility and Sterility 95 (2011) Paternal BMI leads to decreased blastocysts Bakos et al Fertility and Sterility 95 (2011) Page 26 of 131 Paternal obesity leads to offspring IGT • Paternal high fat exposure programs beta cell dysfunction in rat female offspring • Earlier impaired insulin secretion and impaired glucose tolerance • Altered pancreatic gene profiles S-F Ng et al. Nature 467, 963-966 (2010) Paternal obesity and offspring insulin resitance S-F Ng et al. Nature 467, 963-966 (2010) Methods of transgenerational reprogramming Epigenetic changes in germ line include DNAmethylation, histone modification, micro-RNAs Skinner Nature 467:922, 2011 Page 27 of 131 Embryo culture changes gene expression P<0.001 p=0.014 1.0 NS Proportion of pups born after culture 0.5 0 Zygote Blastocyst Natural 1.Natural mating 2.Natural blastocyst 3. Zygote embryo culture Morgan et al Biol Reprod 2008 Transgenerational defects Control Vinclozolin •Vinclozolin, a fungicide used in the wine industry, causes reproductive abnormalities in male rats when applied in pregnancy (binds to androgen receptor) •Can be detected in nearly all male offspring for at least 4 generations •Not seen in female siblings Apoptosis Sperm number Sperm motility Transgenerational effects of vinclozolin • Animals exposed to vinclozolin in pregnancy produced offspring with altered brain transcriptomes and altered neurological behaviour Skinner at al PLOS One 2008 Page 28 of 131 Preconception programs • Natural conception • Artificial conception • Less than 50% pregnancies are planned • Smoking, alcohol, no folic acid aaree co common o • Public health programs have not worked well • Role of media and primary care • CDC and Dutch recommendations • Best opportunity for getting change before pregnancy • IVF clinics very poor at instituting s u g lifestyle es y e pprograms og a s • Accreditation and legislation offer opportunity for change • Allows for higher pregnancy rates and better outcomes • If IVF is state funded, allows for more control But we are doing well with IVF……… % Pregnant % implantation Pregnancy chance per embryo transfer Pregnancy chance per embryo New culture conditions Quality systems The start Introduction of new technology eg ICSI IVF pregnancy rates at Repromed Less embryos and lower multiple rate No. of embryos % multiple 3 25 2.5 20 15 2 10 1.5 Multiple pregnancy rate % No. of embryos per ET 0 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 1 5 Page 29 of 131 But we cannot control everything.... Genetic effects on development Chromosomal, single gene, epigenetic Preconception Male behaviour, decisions, lifestyle and environmental exposure Female behaviour, decisions, lifestyle and environmental exposure Quality management Laboratory Healthy baby TQM Management g systems ISO/RTAC Pregnancy ISO/RTAC Clinical procedures and protocols Safe IVF Female behaviour, decisions, lifestyle and environmental exposure Economical procedure Laboratory, drugs, treatment effects Environmental effects on development Dutch Health Council report 2007 Evidence based recommendations by Netherlands Health Council Individual advice eg GP, midwife, other nurse Collective advice ie folate, rubella immunisation, iodisation of salt Genetic eg cystic fibrosis, haemoglobinopathy Working conditions eg radiation, OHSS, pesticides Illness and medications eg diabetes, heart disease, drugs, weight, HIV, hepatitis Food, alcohol, iodine, smoking, recreational drugs, vitamin D Preconception programmes A successful approach to lifestyle modification Fertility Fitness for Women 4-6 month programme of lifestyle Weekly meetings, follow-up Exercise, diet, education, investigation Page 30 of 131 How to get change • Publications • Consumer groups • Systematic reviews • Print and electronic media • Multidisciplinary and collaborative research • Research translation animal data into clinical practice and health policy Strong evidence base in the area • Internet Informing patients of the concerns and opportunities • Personalities • Social networks • Good epidemiology • Education • Professional societies • Consumer groups Influencing leaders in health and politics • Political activity Quality intervention programs that are proven to work • Review other medical issues eg diabetes and heart disease • Research • Use existing mechanisms • Provides economic and legal incentives • Economic arguments Encase in legal and accreditation framework Understanding the evidence • Knowledge of the literature – Systematic reviews and meta-analyses • Knowledge of clinical practices – Active in clinical medicine • Knowledge of interventions – Understanding evidence for treatment and prevention • Knowledge of behaviour – Understanding community, politics, practices Understanding the science • • • • • • • • Nutrition and weight in reproduction Reproductive ageing and the egg Effects of smoking on gametes Effects of alcohol Medication and drugs on reproductive biology Folic acid and antioxidants Infection and immunology Genomics and reproductive success Page 31 of 131 Understanding the patient • • • • • • • Building the evidence base (Homan HRU 2006) Community engagement through hospitals Weight – groups, individual, diet, behavioural Patient perceptions of risks – qualitative, quantitative Medical staff perceptions and practice Education of staff and patients Individual interviews before treatment – Structured, personal, couple, report, intervention, follow-up • Community education to avoid IVF Reproductive life plan and peri-conception advice Reproductive life plan • Concept for individual and couples planning for contraception, fertility, avoidance of pregnancy, PAP smears etc • Can be updated as circumstances change • Needs information and expert advice • Should have some government or health fund support Pre-conception interview • Prior to planned natural or assisted conception • Advice on specific risk factors including nutrition, folate, weight, alcohol smoking alcohol, smoking, caffeine, caffeine stress, vaccination, disease control etc • Needs detailed information and expert advice • Needs health funding to optimise pregnancy health and minimise infertility intervention Making changes • Desire to change • Barriers to making changes: Time Motivation Consumerism • Ignoring “healthy lifestyle choices” – 50% of IVF patients overweight or obese • Methods for encouraging change are not well established but results encouraging Doctors information Written evidence Lifestyle change advised Lifestyle change practised Higher spontaneous and natural pregnancy Page 32 of 131 Patients’ knowledge 45% rated between 8-10 on Likert scale for an effect of diet and exercise on conception Reasons given: • Promotes ggeneral ggood health • The fitter you are the better the body works “Plenty of unfit people get pregnant” 35% rated between 8-10 for a positive effect of over the counter supplements on conception • Not necessary if eating a healthy diet • 10/10 ffemales l 7/10 males l ttaking ki supplements • All females & most males taking supplements • Only half the females taking folic acid Rights and responsibilities Our responsibility: To give advice on optimal peri‐conceptual environment for fertility, ongoing pregnancy , quality babies with best potential for future healthy life Doctor and clinic staff rights and responsibilities Our rights: To expect a reasonable attempt to change lifestyle before we use expensive medical treatments to create new life Patient’s responsibility: To listen to advice, act on things they can change and optimise a healthy start to life Individual and couple rights and responsibilities Patient’s rights: To be given clear understandable information on optimising the environment for a healthy pregnancy. To be shown where to get help to change. Patients and doctors – barriers to change Patient knowledge Patient practice Doctors information X Written evidence X Focus groups and questionnaires Doctors’ notes review and questionnaires Good knowledge about: folate, nutrition, weight, exercise, natural therapies, smoking etc Claims: information on diet, vitamins, exercise, alcohol, weight etc Poor practice with: folate, smoking, exercise, etc Practice: little documentation Lifestyle change advised Lifestyle change practised X Page 33 of 131 Approach to lifestyle in fertility clinics AWARENESS Doctor patient awareness campaigns RESOURCES Provision of lifestyle resources INTERVIEW Individual and couple interview re lifestyle PLANNING Reproductive health pathway planning INFORMATION Reproductive health information sheets ADVICE Reproductive health life script Fertility Assessment and Advice Targeting Lifestyle Choices & Behaviours (FAST) • Individual assessment and advice before treatment • Focused on couples • Support and follow-up Motivational interviewing techniques Recommendations - achievable goals • Referral • Written report • Support • Assessment repeated > 4 months • • • • • • • • • • • • • • Exercise Diet Stress Smoking Recreational drugs Alcohol & caffeine OTC supplements Other factors Lipids Glucose BP BMI Waist circumference Fitness test Why does our advice fail? 1. GP/obstetrician: Lack of information regarding fertility – – Poor knowledge and convictions Poor personal example 2. Patient factors – – 3. Message seen as health and not fertility related Lifestyle change not seen as treatment Reproductive specialist: – – – Expectation that high-tech will work well – and it often does! Financial disincentives for lifestyle programs Message directed at female rather than couple 4. Other clinical staff - Accessibility and information Lack of empowerment to give advice Page 34 of 131 Approach to preconception in the wider community EVIDENCE Determine the evidence for adverse outcomes from lifestyle issues ECONOMIC Assess the economic consequences of poor lifestyle and undiagnosed pre-pregnancy problems EDUCATION Educate g government,, health providers and their staff REPRODUCTIVE LIFE PLANNING Develop individual and couple reproductive life plans HEALTH PATHWAYS Provide health pathways to get change in areas such as obesity, smoking, folate, alcohol, stress etc INFORMATION Inform patients and the community through the media, educational programs RESOURCES Provide resources and preconception consultations Clinical trials in periconception • PREPARE study – Adelaide LIFESTYLE - Netherlands Identification of eligible women Obese or Overweight (BMI >25) Planning pregnancy within 2yrs (Jan 2012-Dec 2012) Decline Participation 5,800 women randomised to PREPARE RCT (March 2012-Dec 2012) Intensive Pre-Pregnancy Intervention Group 2,900 women (Intensive weight loss intervention March 2012-August 2013) Limited Pre-Pregnancy Counselling Group 2,900 women (Limited counselling March 2012-August 2013) 1,300 women conceive (45% conception rate) (April 2012-July 2015) 1,300 women conceive (45% conception rate) (April 2012-July 2015) 1,100 women with established pregnancy (15% early pregnancy loss rate) (March 2013-May 2016) 1,100 women with established pregnancy (15% early pregnancy loss rate) (March 2013-May 2016) Outcomes to 6 months post-partum (Sept 2013 - November 2016) Outcomes to 6 months post-partum (Sept 2013 - November 2016) The next frontier - conclusions 1. Peri-conception and pre-implantation is the most critical time of life for future health • This is the best single health investment we can make 2. We cannot go much further without addressing the environment i t in i which hi h we conceive i • This is our next reproductive frontier 3. This involves the whole of society in natural and assisted conception • Opportunity for fertility specialists to make the biggest contribution to the other 97% of births Page 35 of 131 Thanks to: Gillian Homan Bronwyn Roberts Cadence Minge Helen Alvino Rebecca Robker University of Adelaide Repromed Research Centre for Reproductive Health Page 36 of 131 Raising fertility awareness in young people Jacky Boivin, PhD, CPsychol School of Psychology Cardiff ESHRE, Stockholm, July 2011 Conflict of interest (past three years) Speaker fees, honorarium and/or research funding from Merck-Serono S.A., Merck & Co (then Schering Plough), EMD Serono Inc Cardiff Fertility Studies Learning objectives Learn fertility knowledge source and level among young people Describe the development and validation process of the fertility awareness tool Understand p practical and ethical issues involved in raising fertility awareness among young people Cardiff Fertility Studies Page 37 of 131 Fertility concepts Fertility reproductive health Fertility sexual health Cardiff Fertility Studies Reproductive health …reproductive health addresses the reproductive processes, functions and system at all stages of life… United Nations International Conference on Population & Development Cardiff Fertility Studies Cairo, 1994 Reproductive health United Nations infant and women's health care human sexuality family-planning, prenatal care abortion, consequences/complications of abortion; reproductive tract/sexually transmitted infections, HIV/AIDS infertility safe delivery, complications of pregnancy, post-natal care responsible parenthood other reproductive health conditions breast cancer and cancers of the reproductive system female genital mutilation PubMed (family planning services, maternal health services) Cardiff Fertility Studies Page 38 of 131 Sexual health The National Curriculum for England for Science (1999: 5 to 16 years) Legal responsibility to provide sex education (at secondaryy level)) medical uses of hormones to promote/control fertility pregnancy and sexually transmitted infections benefits and risks of choices relating to sexual activity …mainly in relation to unintended pregnancy/contraception, STIs and HIV Department for Education and Employment, England, 1999 Programme of study (non-statutory) for key stage 4. Crown Publication, 2004 Cardiff Fertility Studies What is sec education: Welsh Assembly Government Circular No: 019/2010 Wales Cardiff Fertility Studies Swedish sex education By 9th year of primary education (about 15 years of age): what conception is biology of sexual life methods of contraception sexually transmitted infections reproductive organs and organ systems function of reproductive organs As per Sydsjo et al. 2006: Europ J Contracept Reprod Health Care Cardiff Fertility Studies Page 39 of 131 Knowledge level 13-14 years: Grade 8 of primary school 15-16 years: 1st & 2nd year of upper secondary 18-25 years: 1st year of engineering Sydsjo et al. 2006: Europ J Contracept Reprod Health Care Cardiff Fertility Studies Sources of information among young people National Institutes of Health Sydsjo et al. 2006 Cardiff Fertility Studies 100 ion 90 Percent correct 80 ion 70 60 50 40 30 20 10 0 Risk N=110 women, n=39 men Norm Illusory benefits of healthy habits Misconception Fertility myths 12 Page 40 of 131 World Fertility Awareness Month (2009) 17, 451 participants, 11 countries General fertility knowledge Specific fertility knowledge After how many months of trying to conceive is a couple considered infertile? Lack of fertility has no borders: A global survey: Scott et al. 2009 Impact of education so far? Risk factors on the increase Cardiff Fertility Studies Seeking timely medical advice 20% delay more than two years Boivin, Bunting, Collins & Nygren, Human Reproduction (2007) Cardiff Fertility Studies Page 41 of 131 Lack of specificity in fertility awareness campaigns American 16 Society for Reproductive Medicine, 2006 Critical thresholds and signs and symptoms of problems National Cancer Institute National Institutes of Health Cardiff Fertility Studies Personal relevance not emphasised [ ] Tick here if you have unprotected intercourse with multiple partners [ ] Tick here if you are more than 13 kilos overweight [ ] Tick here if you smoke more than 10 cigarettes a day 18 Modified advert:ASRM ≈2006 Page 42 of 131 Personally relevance captures attention and produces higher arousal 45 40 35 30 25 General threat Fertility threat 20 15 10 5 0 Non-personal Personal Condition 19 N=152, manuscript under prep Cardiff Fertility Studies Reasons to develop a fertility awareness tool A validated self-administered, multifactorial tool that would enable women to get fertility guidance based on their own lifestyle and reproductive profile did not yet exist A tool would: allow women to make informed decisions about current lifestyle and reproductive behaviour, potentially help women take action to safeguard future fertility where risk exists (e.g. quit smoking) and; motivate women to seek timelymedical advice (if desired) when clear symptoms of disease (e.g. absence of period) are, possibly unknowingly, undermining current attempts to conceive. Cardiff Fertility Studies Steps in FertiSTAT development 1. Comprehensive review of the literature 58 studies reviewed 31 risk factors identified (demographic, reproductive, medical, lifestyle) 2 Mini-delphi 2. Mi i d l hi round d with ith 20 reproductive d ti experts t Selection of risk factors and consensus of critical thresholds 20 factors confirmed as independent risks for reduced female fertility as per clinical practice 2 risk factors associated with reduced male fertility included 3. Consultation and pilot testing for guidance development Cardiff Fertility Studies Page 43 of 131 Risk factors identified in review Lifestyle • Reproductive history No of sexual partners (unprotected) Menstrual cycle (<21days, >35 days, irregular, severe pain, absence of period ) STI (e.g., Chlamydia) Contraceptive use History of pelvic surgery Miscarriage/termination Pelvic inflammatory disease Endometriosis Polycystic ovaries Coeliac Undescended testicles Varicocele Mumps after puberty in males Alcohol use Tobacco use Class A drug use Caffeine use Excessive exercise Steroid use Unable to cope p with current stress Stress at work Overweight Underweight Occupational exposures General medical history Diabetes Thyroid disease Asthma Heart disease Kidney disease SLE (lupus) Epilepsy Sickle cell anaemia Cancer • Demographic Age ≥34 years Years trying to conceive Living standard Ethnicity Cardiff Fertility Studies 23 Assisted Conception Task Force Independent risk factors (key to health campaigns) Lifestyle Alcohol use Tobacco use Class A drug use Caffeine use Excessive exercise Steroid use Unable to cope with current stress Stress at work Overweight Underweight Occupational exposures • Diabetes Thyroid disease Asthma Heart disease Kidney disease SLE (lupus) Epilepsy Sickle cell anaemia Cancer No of sexual partners (unprotected) Menstrual cycle (<21days, >35 days, irregular, severe pain, absence of period) STI (e.g., Chlamydia) Contraceptive use General medical history Reproductive history • History of pelvic surgery Miscarriage/termination Pelvic inflammatory disease Endometriosis Polycystic ovaries Coeliac Undescended testicles Varicocele Mumps after puberty in males Demographic Age ≥34 years Years trying to conceive Living standard Ethnicity Cardiff Fertility Studies Page 44 of 131 Fertility STatus Awareness Tool FertiSTAT is a free one-page questionnaire containing: 22 risks & indicators Guidance about how to take action to safeguard fertility and when to get help Cardiff Fertility Studies Personalised guidance based on individual risk profile Cardiff Fertility Studies i. Preliminary cross-sectional validation Total (N=1073) % Country of Origina United Kingdom America Canada Australia Other 730 128 43 18 29 77.00 13.50 4.54 1.90 3.06 Highest Educational levelb University Post secondary/college Secondary Primary 386 285 119 8 48.37 35.71 14.91 1.00 Age (SD)c Age range 18 – 25 26 – 30 31 – 34 35 – 39 40 – 44 Recruitment Source Online (n = 603) Askbaby Myspace Facebook Verity University Clinic (n = 470) Antenatal Fertility Termination 29.6 (5.8) 250 349 219 155 60 24.20 33.79 21.20 15.00 5.81 172 115 158 26 132 16.03 10.72 14.73 2.42 12.30 326 103 41 30.38 9.60 3.82 Bunting & Boivin (2010) Human Reproduction Eight month collection period 1073 women completed the Fertility Risk Factors Survey Pregnant = 532 (weeks pregnant range = 3 – 40 with 78.82% ≥ 12 weeks) Not Pregnant actively trying = 202 (168 of these women were Cardiff Fertility Studies classified as infertile) Page 45 of 131 Validation sample comparable risk pattern to general population Demographic Education (University level) Reproductive Period pains Endometriosis Pelvic Inflammatory Disease (PID) Menstrual cycle less than 21 days Menstrual cycle more than 35 days Menstrual cycle irregular Period Pelvic surgery Sexually Transmitted Disease (STD) Sample p (%) ( ) Population (%) Lifestyle Overweight Unprotected sexual intercourse with multiple partners* Stress Class A drug ever used Last 12 months Anabolic Steroid* Alcohol ≥ 14 units a week Smoke Caffeine* Marijuana* *Population values include men 0 20 40 60 80 100 Bunting & Boivin (2010) Human Reproduction Cardiff Fertility Studies Discrimination fertile versus infertile 100% 90% 91.0% Percent Classification 80% 73.5% 70% 60% Incorrect 50% 40% 79.6% 66.4% Correct with TT Correct without TT TT = Time Trying 30% TT = 2(19) = 204.21, p < .001, n = 380, eigenvalue .74, canonical correlation = .65 20% 10% 0% Fertile Infertile Bunting & Boivin (2010) Human Reproduction Without TT = 2(18) =125.08, p < .001, n = 446, eigenvalue .33, canonical correlation = .50 Cardiff Fertility Studies Potential as public awareness tool ESHRE 30th June 2009 – released FertiSTAT (www.fertistat.com) 26 July 2009 – th Picked up by Reveal magazine 30th June 2009 – Picked up by The Telegraph, The Times, Daily Mail Cardiff Fertility Studies Page 46 of 131 Potential as public awareness tool ESHRE 30th June 2009 – released FertiSTAT (www.fertistat.com) 26 July 2009 – th Picked up by Reveal magazine 30th June 2009 – Picked up by The Telegraph, The Times, Daily Mail Cardiff Fertility Studies Prospective validation Time 1 EXCLUDED 650 respondents July – September 2009 1 asked to be removed from database 27 no email address 8 less than 18 years old 2 more than 44 years old Time 2 612 emails sent January – March 2010 196 emails returned 3 new email addresses 2 no email address cannot be matched to previous data 191 Time 1 and Time 2 data 612 emails sent Time 3 March 2011 Cardiff Fertility Studies Respondents comparable risk pattern to general population 91.9% respondents from the United Kingdom Time trying to conceive in years = 1.35 (SD=1.77) Average age = 29.26 (SD=6.37) Demographic Education (university level) Reproductive Period Pains Endometriosis Pelvic inflammatory disease Menstrual cycle less than 21 days Menstrual cycle more than 35 days Menstrual cycle irregular No Period Pelvic surgery Sexually transmitted disease Sample (%) (n=612) Population (%) Lifestyle Overweight Unprotected sexual intercourse with multiple partners Stress Class A drug ever used Last 12 months Anabolic steroid* *Population values include men Alcohol ≥14 units a week Smoke Caffeine* Marijuana* 0 10 20 30 40 50 60 70 80 90 100 Cardiff Fertility Studies Page 47 of 131 Application Tool for education in young people, low resource countries, adjunct in primary care Types of knowledge required to safeguard fertility Sydsjo (2006): Fertility/infertility (15 points) Anatomy (14 points) Sexually transmitted diseases (11 points) Menstrual cycle (7 points) Reproduction (7 points) Bunting & Boivin (2006): Factors Affecting Fertility Scale Risk factors (low & high, 7 items) Fertility Myths (7 items) Healthy habits (7 items) Cardiff Fertility Studies Conclusions Self-administered, multi-factorial tool get fertility guidance based on their own lifestyle and reproductive profile Preliminary cross-sectional validation FertiSTAT items correctly classified 85% of women into their fertility status group Achieved without input from medical test results, knowledge of male factors, parity and is similar to that reported for predictive tests (e.g., Anti-Mullerian Hormone Testing of ovarian reserve) Predictive utility needs to be examined in prospective research How best to create an effective public health message on fertility Ethics and value of ‘nudging in the right direction’Cardiff and preFertility Studies symptomatic fertility monitoring needs to be deliberated Bibliography Bunting, L. & Boivin, J. (2010). Development and preliminary validation of the Fertility Status Awareness Tool: FertiSTAT. Human Reproduction, Vol.25, No.7 pp. 1722–1733. Sydsjo, G. Ekholm Selling k, Nystrom K, Oscarsson c, Kjellberg S. Knowledge of reproduction in teenagers and young adults in Sweden. The European Journal of Contraception and Reproductive Health Care June 2006;11(2):117–125 Witte K, Allen M. A Meta-Analysis of Fear Appeals: Implications for Effective Public Health Campaigns. Health Educ Behav 2000 27: 591 Cardiff Fertility Studies Page 48 of 131 Raising fertility awareness in young people Jacky Boivin, PhD, CPsychol School of Psychology Cardiff ESHRE, Stockholm, July 2011 Page 49 of 131 Institute of Public Health Prevention of sexuallysexuallytransmitted diseases Lone Schmidt Associate Professor, DMSci, PhD University of Copenhagen Department of Public Health Denmark PCC 14, ESHRE 3 July 2011 Dias 1 Institute of Public Health Conflict of interest Research funding from Merck, Sharpe & Dohme Dias 2 Institute of Public Health Learning objectives Learn that STDs is a public health problem Know prevalences of Chlamydia infections and know it’s complications Awareness of Chlamydia control and of what is missing Dias 3 Page 50 of 131 Institute of Public Health Sexually-transmitted diseases (STD) Chlamydia trachomatis Neisseria gonorrhea Syphilis H Human papillomavirus ill i Herpes simplex HIV Dias 4 Institute of Public Health STD’s in Europe Surveillance Report, 2009 Chlamydia Gonorrhoea Dias 5 Institute of Public Health STD’s in Europe Surveillance Report, 2009 Syphilis HIV Dias 6 Page 51 of 131 Institute of Public Health Prevention of STDs – general strategies Health promotion and education Safe sex Surveillance of data Diagnostic services and effective treatment Partner management services Opportunistic screening Screening programmes Dias 7 Institute of Public Health Focus on Chlamydia Leading preventable cause of tubal factor infertility infertility Highest incidence among STDs Incidence increasing worldwide Most frequent among young women and men > 50% asymptomatic infection Facilitates transmission of HIV Costs of treating infertility due to chlamydia is high Dias 8 Institute of Public Health Chlamydia in Europe 1998-2007 ECDC Guidance, 2009 Dias 9 Page 52 of 131 Institute of Public Health Men - Chlamydia complications Urethritis Epididymitis Orchitis Prostatitis? Arthritis Co-incubation of spermatozoa with Chlamydia causes decline in motile sperm and results in premature sperm death Affects negatively pregnancy rates in MAR Cunningham & Beagley, 2008 Eley & Pacey, 2005 Dias 10 Institute of Public Health Women – Chlamydia complications Urethritis and cervicites Pelvic inflammatory disease (PID) - inflammation of the uterus, fallopian tubes, ovaries, adjecent peritoneum Loss of tubal functioning Scarring Ectopic pregnancy Chronic pelvic pain Arthritis MMWR, 2011 Dias 11 Institute of Public Health Chlamydia complications – during pregnancy Miscarriage Premature rupture of membranes Low birth weight Transmission T i i ffrom mother th to t child hild - ophthalmia neonatorum - atypical neonatal pneumonitis ECDC Guidance, 2009 Dias 12 Page 53 of 131 Institute of Public Health Chlamydia - prevalences 5-10% among sexually active young women and men Untreated Chlamydia - women - 10-15 % PID 10-15% tubal factor infertility - Not diagnosed as PID tubal factor infertility - 4 % chronic pain - 1-2 % extrauterine pregnancies Dias 13 Institute of Public Health Cohort study – women with laparoscopi because of PID 1960-1984 1,844 women with laparoscopically verified disease 657 control women with normal findings 10.8% of patients and 0 % control women had tubal factor infertility Tubal b l ffactor infertility f l was associated d with h number b and d severity of PID Ectopic pregnancy rate for first pregnancy after laparoscopy was 9.1% among patients and 1.4% among controls Weström et al., 1992 Dias 14 Institute of Public Health Chlamydia control requires different activities Primary prevention – especially among young adults - sexual health and relationship education Promotion of safer sex and condome use Effective diagnosis and treatment Identifying and treating partners of infected individuals Active case-finding = screening - to identify and treat asymptomatic cases ECDC Guidance, 2009 Dias 15 Page 54 of 131 Institute of Public Health Knowledge about Chlamydia Denmark – population-based study among 20-29 years old women and men 70% aware that Chlamydia is a risk factor of infertility 80% aware of symptoms 80% knows that Chlamydia is easy to treat Dias 16 Institute of Public Health University student’s knowledge – men know less than women (Greaves et al., 2009) Dias 17 Institute of Public Health Chlamydia control in Europe ECDC Guidance, 2009 Dias 18 Page 55 of 131 Institute of Public Health Chlamydia testing for asymptomatic individuals (ECDC Guidance, 2009) Dias 19 Opportunistic testing for selected asymptomatic individuals (ECDC Guidance, Institute of Public Health 2009) Dias 20 Institute of Public Health Chlamydia control and per capita gross domestic product (Low, the SCREen Project Team, 2008) Dias 21 Page 56 of 131 Institute of Public Health WHO criteria for screening Important health problem for individual/society Accepted treatment/useful intervention for patients Natural history of disease adequately understood L t t or early Latent l symptomatic t ti stage t Suitable and acceptable screening test available Facilities for diagnosis and treatment available Dias 22 Institute of Public Health WHO criteria for screening (ct.) Agreed policy on whom to treat as patients Treatment started at early stage of more benefit than treatment started later Cost should be economically balanced in relation to possible expenditure on medical care as a whole Case finding is a continuing process and not a once and for all project Dias 23 Institute of Public Health Chlamydia is a disease full-filling the WHO criteria for screening - Why have only few countries implemented screening programmes? Dias 24 Page 57 of 131 Institute of Public Health Effectiveness of Chlamydia screeening – a review 5 reviews recommended screening of women of high risk of chlamydia 2 randomized trials of screening reported reduced incidence of PID at 1 year follow-up 1 randomized trial showed opportunistic screening in women undergoing surgical termination of pregnancy reduced post postabortal PID rates No randomized trials showing benefit of opportunistic screening in other populations No trials examining effect of more than one screening round Low et al., 2009 Dias 25 Institute of Public Health Conclusion ”There is an abscence of evidence supporting opportunistic chlamydia screening in the general population younger than 25 years, the most commonly recommended approach.” Low et al., 2009 Dias 26 Institute of Public Health Researchers’ opinion Additional studies of effectiveness of chlamydia screening Prospective studies assessing rates of PID, subclinical tubal damage, and long-term reproductive sequelae after chlamydia infection Better tools to measure PID and tubal damage Studies on the natural history of repeated chlamydial infections Gottlieb et al., 2010 Haggerty et al., 2010 - More knowledge about the impact of chlamydia in men Dias 27 Page 58 of 131 Institute of Public Health Increasing efforts to control chlamydia Dias 28 Institute of Public Health European Centre for Disease Prevention and Control (ECDC) Chlamydia control in Europe, June 2009 www.ecdc.europa.eu Chlamydia y is a public p health p problem Report provides guidance to health policy makers in EU about national strategies for chlamydia control Dias 29 Institute of Public Health 4 levels for chlamydia control (ECDC, 2009) Step-by-step approach is recommended Level A – primary prevention Level B – case management Level C – opportunistic screening Level D – screening programme Dias 30 Page 59 of 131 Institute of Public Health Bibliography Cunningham KA & Beagley KW. Male genital tract chlamydial infection: Implications for Pathology and infertility. Biology of Reproduction 2008;79:180-9. ECDC Guidance. Chlamydia control in Europe. Stockholm, 2009. Eley A et al al. Can Chlamydia trachomatis directly change your sperm? Lancet Infection Disease 2005;5:53-7. Gottlieb SL et al. Screening and treatment to prevent sequelae in women with Chlamydia trachomatis genital infection: How much do we know? The Journal of Infectious Diseases 2010;201:S156-66. Dias 31 Institute of Public Health Greaves A et al. University undergraduates’ knowledge of chlamydia screening services and chlamydia infection following the introduction of a National Chlamydia Screening Programme. The European Journal of Contraception and Reproductive Health Care 2009;14:61-8. Haggerty Ch et al. Risk of sequelae after Chlamydia trachomatis genital infection in women. The Journal of Infectious Diseases 2010;201:S134-55. Low N, the SCREen project team. Publication of report on chlamydia control activities in Europe. Eurosurveillance 2008;13. Low N et al. Effectiveness of chlamydia screening: systematic review. International Journal of Epidemiology 2009;38:435-48. Dias 32 Institute of Public Health MMWR. CDC Grand Rounds: Chlamydia prevention. Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report, april 2011. Surveillance Report. Annual epidemiological report on communicable diseases in Europe. European Centre for Disease prevention and Control 2009; revised edition. Weström et al. Pelvic inflammatory disease and infertility. Sexually transmitted Diseases 1992;19:185-92. Dias 33 Page 60 of 131 Bispebjerg Hospital (1) Prevention of infertility at the work place Jens Peter Bonde Department of Occupational and Environmental Medicin, Bispebjerg Hospital, University of Copenhagen ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 GLOBULE • Preventable causes of infertility • Occupational risk factors: • • • • Indirect pathways Xenobiotics Heat and posture Stress • Endocrine active compounds • Male mediated developmental toxicity • Concluding remarks Recent reviews for reference • Wirth JJ, Mijal RS. Adverse effects of low level heavy metal exposure on male reproductive function. Syst Biol Reprod Med. 2010 • Jurewicz J, Hanke W, Radwan M, Bonde JP. Environmental factors and semen quality. Int J Occup Med Environ Health. 2009 • Bonde JP. Male reproductive organs are at risk from environmental hazards. Asian J Androl. 2010 • Mendola P, Messer LC, Rappazzo K. Science linking environmental contaminant exposures with fertility and reproductive health impacts in the adult female. • Fertil Steril. 2008 • Hauser R, Sokol R. Science linking environmental contaminant exposures with fertility and reproductive health impacts in the adult male. Fertil Steril. 2008 Page 61 of 131 A well known germ stem cell toxicant! H B Br C H H C Br H C Cl H Bispebjerg Hospital (5) ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 Page 62 of 131 Experimental evidence on male reproductive toxicity Riga september 19-22 2001 ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 Page 63 of 131 Y:X Sperm Ratio in Boron-Exposed Men WENDIE A. ROBBINS et al J Androl 2007: 115-21 ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 ESHRE Symposium on Prevention of Infertility Stockholm July 4Riga 2011september 19-22 2001 ESHRE Symposium on Prevention of Infertility Stockholm July 4Riga 2011september 19-22 2001 Page 64 of 131 Skin temperature in a welder exposed to radiant heat (Bonde JP. Br J Ind Med 1992;49: 5-10) ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 Bispebjerg Hospital (14) Scrotal temperature according to sedentary work in 100 men (Hjøllund et al 2001) Riga september 19-22 2001 Page 65 of 131 Other studies Figa-Talamanca I, Dell'Orco V, Pupi A, Dondero F, Gandini L, Lenzi A et al. Fertility and semen quality of workers exposed to high temperatures in the ceramics industry. Reprod.Toxicol. 1992;6(6):51723. Figa-Talamanca I, Cini C, Varricchio GC, Dondero F, Gandini L, Lenzi A et al. Effects of prolonged autovehicle driving on male reproduction function: a study among taxi drivers. Am J Ind Med 1996;30(6):750-8. Thonneau P, Ducot B, Bujan L, Mieusset R, Spira A. Heat exposure as a hazard to male fertility. Lancet 1996;347(8995):204-5. Effect of inorganic lead on sperm counts Bonde et al OEM 2002: 234-42 Riga september 19-22 2001 Sperm chromatin abnormalities according to concentration of lead in spermatozoa * ** 235 Mean allfaT 230 225 Crude C d Adjusted 220 215 210 <50 50-150 151-400 >400 Lead concentratin in spermatozoa microgr/kg Page 66 of 131 Time to pregnancy according to male lead exposure (Shia Au et al OEM 2004) ESHRE Symposium on Prevention of Infertility Stockholm July 4Riga 2011september 19-22 2001 Impaired Semen Quality Associated With Environmental DDT. Exposure in Young Men Living in a Malaria Area in the Limpopo Province, South Africa (Natalie H et al J Androl 2007: 423-34 Page 67 of 131 Sperm motilitily according to serum concentration of p,p-DDE in Chiapas, Mexico De Jager C J Androl 2006: 16-27 Sperm count i farmers across the spraying season (Larsen SB et al OEM 2001) Page 68 of 131 Effects of environmental and occupational pesticide exposure on human sperm: a systematic review “Although Although suggestive for semen parameters parameters, the epidemiologic evidence accumulated thus far remains equivocal as to the spermatotoxic and aneugenic potential of pesticides given the small number of published studies” Melissa Perry. Human Reproduction Update 14:233–242;2008 ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 POSITIVE REPORTINGS • Reduced sperm count • • • • • Fumigators, EDB (Ratcliffe 1987) Shipyard painters, glycol ethers (Welch 1988) Welders, metals (Bonde 1993) ( 1998)) Lead smelters,, lead (Alexander Greenhouse workers (Abell 2000) • Increased number of abnormal sperm cells • Chemical workers, carbaryl (Wyrobek 1981) • Drycleaners, perchlorethylene (Eskenazi 1991) NEGATIVE REPORTINGS • • • • • • • • Anestesiologists (Wyrobek 1981) Autopsy service workers (Ward 1984) Wastewater treatment workers (Rosenberg 1985) Viscose rayon y p production,, CS2 ((Vanhoorne 1994)) Stainless steel welders, hexavalent chromium (Hjollund 1998) Mild stel welders, manganese (Hjollund 1998) Farmers, pesticides (Larsen 1999) Reinforced plastics workers, styrene (Kolstad 1997) Page 69 of 131 Change of semen values by exposure level in styrene workers Density %normal %non-vital ND Change: 15 10 Mill/ml /% 5 0 -5 -10 -15 -20 -25 AD-49mg/m3 50-99 mg/m3 >=100 mg/m3 Post shift mandelic acid in urine Kolstad et al Int Arch Occup Environ Med ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 Page 70 of 131 ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 Distress and reduced fertility in a follow-up study of first-pregnancy planners. Hjollund et al Fertil Steril. 1999 72(1):47‐53. Adjusted OR for pregnancy per menstrual cycle by MALE GHQ distress scores (Hjollund et al. Epidemiology 2004: 21-27) Sperm count mill/ml Percentile Score All men < 20 20 0-25 0-6 reference reference reference 25-50 7-8 0.91 0.83 0.95 51-75 9-11 0.84 0.44 0.99 76-100 12-36 0.73 0.06 0.98 ESHRE Symposium on Prevention of Infertility Stockholm July 4 2011 Page 71 of 131 Cyclophosphamide exposure of male rats causes fetal loss without affecting male fertility (Trasler et al Nature 1985) Absence of selection against aneuploid mouse sperm at fertilisation Aneuploid sperm may not represent a heriditable risk if they are disadvantaged at fertilisation with respect to normal sperm cells (Marchetti et al Biol Reprod 1999 ) Spontaneous abortions according to paternal blood lead level (Lindbohm et al SJWEH 1991) Page 72 of 131 Risk of embryonal loss according to paternal exposure in a prospective study of first pregnancy planners (Hjollund et al SCJWEH 2000) 6 Odds raatio 5 Biochemical loss 4 Clinical loss 3 2 1 0 Stainless steel welders Mild steel welders Other metal workers Occupational risks in infertility makeup: take home message • Ask about occupation!! - radiant heat lead (above 30-40 microgr lead/l blood) welding (above 5 mg particulates/m3) Ethyleneglycol ethers (painters, printers, glues, metalcast makers) - Fungicides Eliminate expsure or temporary removal of worker Page 73 of 131 The effect of postponing of first child birth on primary and secondary infertility – is prevention possible? Egbert te Velde Department of Public Health, Erasmus University MC, Rotterdam. Emeritus professor Reproductive Medicine, Utrecht University Disclosures I am a retired gynecologist with a long interest in reproductive ageing I have h no commercial i l or other th relationships l ti hi that could be perceived as a conflict of interest. I hope you will learn, understand and accept that 1): • The duration of the infertile period and female age are the most important determinants of infertility • There is a large difference between the prevalence of primary 1-year infertility and of primary sterility • Secondary infertility is a complex concept • There has been an enormous postponement of first childbirths since the 1970s: consequence of the availability of good contraception and female emancipation. • The mean age at first childbirth has risen with 4-5 years: mothers are much older than in former days Page 74 of 131 I hope you will learn, understand and accept that 2): • Because of delay of motherhood we estimate that primary sterility has increased from 2-3% to 5-7% in most Western countries. • This is a large effect when taking into account it is the tip of the iceberg of many more adverse consequences of delay • With the present utilization ART has hardly a compensating effect on the consequences of delay. • Prevention of infertility due to delay is probably possible to a certain degree The contraceptive and sexual revolution liberated women from their reproductive destiny (Van de Kaa 1987) • The unbreakable link between sex and reproduction was broken • Women were liberated from the unavoidable burden of motherhood and male dominance • Women could decide to have children or not, and how many • Freedom at last! • Women could postpone motherhood until later or never, and they did! The two most important determinants of infertility 1. Duration of the infertile period 2. Female age Page 75 of 131 Lessons from demography: becoming pregnant is a matter of selection and chance 7 -12 months 1313-24 months 2525-60 months 0.0 0.1 0.2 0.3 0.4 0.5 0.6 Monthly Fertility Rate = Fecundability Duration of the period of infertility and primary infertility • Primary infertility: not (yet) a child • The prevalence of primary infertility very much depends on the duration couples have tried to conceive: the longer the lower the prevalence (Habbema et al al.2004). 2004) • On the population level of the Netherlands in1970: - 1-year infertility = ~22% - 2-year infertility = ~12% - 3-year infertility = ~9% - Lifelong infertility = primary sterility = ~3% Defining secondary infertility: less simple than primary infertility • The woman has at least one child and becomes infertile thereafter • May occur after the first child but also after the fifth or eighth • The prevalence of secondary infertility also depends on the duration couples have tried to conceive: 1-year, 2-year, 3-year to lifelong secondary infertility = secondary sterility. This may occur after a woman had one child but also after 5 or 8 children • The impact of postponement on secondary infertility is difficult to assess: did infertility start when trying to have a second, third or eighth child? • In Western countries the mean no. of children 1.3 – 2.0. We estimated that the effect of postponement on the prevalence of primary sterility in the population is about 1.5 larger than of secondary sterility (te Velde et al. submitted) Page 76 of 131 The ages of the reproductive periods and milestones in a woman’s life (te Velde and Pearson 2002) 0 10 20 The proportion of women having their first child above age 30 rose from ~ 8% in 1970 to t ~ 40% in i mostt EU countries Period of optimal fecundity(~18-30) 30 40 The proportion of couples who tried but failed to have children because of postponement, must have 50 Period of decreasing g fecundity (~30-41) The end of fecundity (~41) The menopausal transition ~46 Menopause (~51) increased: but how much??. 80 Death (~80) The changing distribution of age at first childbirth in the Netherlands 1970 2007 15 20 25 30 35 40 45 Age at 1s t childbirth % birthrates at age 35 and above in some selected countries 1980-2007 Percent fertility ab bove age 35 25 1980 1990 20 2000 2007 15 10 5 0 US France Spain Sweden Czech Republic Russia Page 77 of 131 Graph based on calculations of monthly chance of live birth conception among Hutterite women (Larsen and Yan, 2000). Natural pregnancy chances leading to first child by duration of trying and female age (adapted from Leridon 2004) Pregnancy chance 100% 80% 60% 40% age 30 age 35 20% age 40 0% 0 12 24 36 48 60 Time (months) The proportion of couples who tried but failed to have children because of the delay of their first child, must have increased: how to estimate this increase? • We simulated the reproductive career of all women going for their first child in 6 representative countries in 1970, 1985 and 2007 using the microsimulation model developed by Leridon (Leridon 1977 and Leridon 2004) • The model accounts for the age-dependent time to pregnancy and the loss of fertility as a woman grows older • After one year off non-conception Aft ti a di diagnostic ti fertility f tilit work k up iis performed. f d Couples with severe causes of infertility get immediate IVF/ICSI treatment. The remaining after another 2 years unless spontaneously pregnant in the mean time • One IVF/ICSI treatment consists of 3 reimbursed IVF/ICSI cycles • Estimations of the effect of ART are based on the 2003-2004 results of all IVF/ICSI cycles in NL (Lintsen et al. 2007). For the incorporation of the effect of ART in the micro-simulation model see Habbema et al. 2009. Page 78 of 131 The countries to be selected: 1)had to be representative of a region 2) the age distribution of the mothers at first childbirth had to be available • The Netherlands NL representative for Western Europe • Sweden SE representative for Northern Europe • Spain ES representative for Southern Europe • West Germany W-Ger and Austria AT representative for Central Europe • The Czech Republic CZ representative for Eastern Europe What did we want to find out? 1) What is the effect of delay of first motherhood on sterility rates during the last decades 2) To what extent can ART compensate for the rise in sterility by delay? As a consequence of delay of first childbirth sterility rates rose by ~ 2.5% in SWE, ~ 3% in AUT, W-GER, CZE and NL, and ~ 4% in ESP since 1985. 8 7 6 5 1970 1985 2007 4 3 2 1 0 AUT CZE NL ESP SWE W-GER Page 79 of 131 Increased sterility is the tip of the iceberg of associated adverse effects caused by delay such as: • More secondary infertility and sterility • More pregnancy complications and premature births • More children from twin/triplet pregnancies • More children with genetic defects • Increased risk of getting breast cancer (Collaborative Group on Hormonal Factors in Breast Cancer 2001 ) To what extent can ART compensate for the rise in sterility by delay? • Scenario 1 = ART 100%: all couples eligible for ART will get the full treatment of 3 IVF/ICSI cycles However, only about one quarter will make use of IVF/ICSI and often less than 3 cycles (Snick et al. 1997, Brandes et al. 2009, van Balen et al. 1997 Boivin et al 1997, al. 2007 2007, Oddens et al al. 1999 1999, Malcolm and Cummings 2004 2004, Crosignani and Collins 2010) • Scenario 2 = ART 25%: only one quarter of the couples eligible for ART will make use of it Does ART compensate the increasing sterility rates caused by delay? ART 100% more or less does; the effect of ART 25% is almost negligible. 8 7 6 STERIL 85 STERIL 07 ART100% ART25% 5 4 3 2 1 0 AUT CZE NL ESP SWE W-GER Page 80 of 131 Is prevention of postponement of first childbirth possible? Much attention of the popular press for the victories of reproduction technology including the possibility of old women to become mother • Young people grossly overestimate the chances of having a child by ART (Lampic et al. 2006; Guardian Fertility Poll 2006) • Young women overestimate the natural chances of having a child after 35 (Lampic et al. 2006, Tough et al. 2007) • Many couples are unaware of the agerelated decline of fertility (Schmidt 2010) Perceived max age until you can wait to have your first child – EU women aged 25-39 (Mills et al. 2011) Page 81 of 131 Prevention 1. Fertility awareness and education • Information at a young age that fertility is declining with age, especially of women • ART can hardly compensate for this trend Prevention 2. Policy measures to enhance the possibility of combining a profession with having children in time • Lecture Ronald Rindfuss Prevention 3. Counsel women at age 20-30. Determine the lifespan until the onset of menopause. If short: do not delay. If long: you can still wait • Age at menopause is a complex genetic trait with a high heritability. Construct a combination of genetic markers predicting onset of menopause (te Velde et al. 2002) • Age at menopause signifies the complete depletion of the oöcyte/follicle pool. Assess ovarian reserve by measuring AMH levels or Antral Follicle Counts. Determine age g at menopause p using g a “nomogram”. If low levels/counts: do not delay (Nelson et al. 2011) • Both approaches are still experimental and far away from clinical use Page 82 of 131 Prevention 4. • Freeze your own eggs at a young age and have a career first: will that be the finishing touch of female emancipation? Lecture Sjoerd Repping References 1. • Boivin, J., Bunting, L., Collins, J.A. and Nygren, K.G. (2007). International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility care. Human Reproduction 22, 1506-12. • Brandes M, van der Steen J.O. and de Bruin J.P. 2009. When and why do subfertile couples discontinue their fertility care? Human Reproduction 24, 3127-3135. • Collaborative Group on Hormonal Factors in Breast Cancer. (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,208 women with breast cancer and 101,986 women without the disease. Lancet, 358, 1389-1399. • Crosignani and Collins. Europe the continent with the lowest fertility. 2010 Human Reproduction Update 2010; 16:590-602 • Habbema et al. Towards less confusing terminology in reproductive medicine. Human Reproduction 2004;19:1497-1501 • Habbema JDF, Eijkemans MJC, Nargund G, Beets G, Leridon H, te Velde ER (2009) The effect of in vitro fertilization on birth rates in Western countries. Human Reproduction 24, 1414-1419 • Van De Kaa, D.J. (1987) Europe's second demographic transition. Popul. Bull., 42, 1-59. • Lampic C, Skoog Svanberg A, Karlström P, Tydén T. Fertility awareness, intentions concerning childbearing and attitudes towards parenthood among female and male academics. Hum. Reprod. 2006: 21; 558–564 • Larsen U, Yan S. The age pattern of fecundability: an analysis of French Canadian and Hutterite birth histories. Soc Biol 2000; 47: 34-50 • Lintsen AM, Eijkemans MJ, Hunault CC, Bouwmans CA, Hakkaart L, Habbema JD and Braat DD (2007) Predicting ongoing pregnancy chances after IVF and ICSI: a national prospective study. Human Reproduction 22, 2455-62. References 2 • Leridon H. (1977) Human fertility: the basic component, Chicago University Press,Chicago. • Leridon H (2004) Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. Human Reproduction 19. 1548-1553. • Malcolm CE, Cumming DC (2004) Follow-up of infertile couples who dropped out of a specialist fertility clinic. Fertil Steril 81, 269-270. • Mills M, Rindfuss RR, mc Donald P, te Velde ER. Human Reproduction Update 2011, accepted for publication. • Nelson et al. Nomogram for the decline in srum AMH. Fetil Steril 2011;95:736-41 • Oddens BJ, den Tonkelaar I, Nieuwenhuyse H (1999) Psychosocial experiences in women facing fertility problems: a comparative survey. Hum Reprod 14, 255-261. • Schmidt, L. Should men and women be encouraged to start childbearing at a younger age? Expert Rev. Obstet. Gynecol. 2010: 5; 145–147 • Snick HKA, Snick TS, Evers JLH, Collins JA (1997) The spontaneous pregnancy prognosis in untreated subfertile couples: the Walcheren primary care study. Hum Reprod 12, 1582-1588. • te Velde, E.R. and Pearson, P.L. (2002) The variability of female reproductive ageing. Human Reproduction Update, 8, 141-154. • Tough S, Tofflemire K, Benzies K et al. Factors influencing childbearing decisions and knowledge of perinatal risks among Canadian men and women. Matern. Child Health J. 2007: 11; 189– Page 83 of 131 Policy measures that can affect the timing of the first bi th birth Ronald R. Rindfuss, Ph.D University of North Carolina at Chapel Hill & East-West Center, Honolulu Disclosures • I am a demographer, sociologist. Not a MD. • I have no commercial or other relationships that are or could be perceived as a conflict of interest to the topics I’ll discuss today. Topics to be covered 1. 2. 3. 4. 5. 6. Fertility measures & some examples Reasons for increase in AAFB Difficulty in evaluating policy effects Institutions and policies Intentional fertility policies Inadvertent fertility policies Page 84 of 131 Countries to be covered • Low fertility countries, basically those that have had replacement or lower fertility for a generation • These also tend to be the richest, richest more economically developed countries, but considerable variation on this among them • Basically, Europe, North America, parts of East Asia and Oceana Fix terms • As a demographer: • “fertility” is performance, that is, the number of children a woman actually has. • “fecundity” “f dit ” iis potential, t ti l that th t is, i the th ability bilit off a woman (and her partner) to conceive and carry the fetus to a live birth. • “Sterility” the inability to conceive and bear a live birth. • We tend not to use the term “infertility” Total Fertility Rate (TFR) • Most commonly used fertility measure • It is a period measure, not a cohort one • (“Period” refers to a time period, such as 1968 or 2011 2011. “Cohort Cohort,” that is, is birth cohort, refers to a group of people born in the same year, such as the birth cohort of 1968.) • (Typically, the TFR is for a single calendar year) Page 85 of 131 Total Fertility Rate (TFR), cont. • Mathematically, the TFR is the area under the age specific fertility rate curve in a given time period • In words: the number of children an average woman would have in her lifetime if she bore children at the rate prevalent in the period measured. Total Fertility Rate (TFR), cont. • Demographers will also calculate cohort TFRs or “children ever born” but you probably will not see this measure often because it requires waiting until the cohort has reached the end of their childbearing years. • Period TFRs reflect both tempo and number factors Total Fertility Rate (TFR), cont. • “tempo” refers to the time (age) when bear their children • “number” refers to the actual number of children women have. have • When childbearing ages are increasing, this tempo factor will decrease the TFR, and vice versa. • If time later, I’ll give the efficient twins example. Page 86 of 131 Total Fertility Rate (TFR), cont. • “replacement rate” = ~ 2.1 • Once positive population momentum (see next slide) works its way out of the age structure then countries below 2 structure, 2.1 1 start losing population (in the absence of inmigration) • Germany, Japan and others are now losing population • Below 2.1 leads to an “aging” population “Positive population momentum” • Other things being equal, if a population with a very young age structure (the classic pyramid) suddenly reaches replacement level period fertility rates rates, its population will continue to grow because the younger groups moving into childbearing ages will have more women than the older women exiting childbearing ages. Total Fertility Rate (TFR), cont. • This audience is concerned with the negative medical effects of late ages of childbearing • Others worry about stress on pay-as-youpay as you go pensions systems, medical costs involving the elderly, declining labor force size, declining tax revenue • But some environmentalists are delighted at the prospect of smaller populations Page 87 of 131 Total Fertility Rate (TFR) • Most commonly used fertility measure • It is a period measure, not a cohort one • Mathematically, it is the area under the age specific fertility rate curve in a given time period • In words: the number of children an average woman would have in her lifetime if she bore children at the rate prevalent in the period measured. • Reflects both tempo and number factors TFR variation: Selected Countries • TFR< or = 1.4: Austria; Germany; Hungary; Italy; Japan; Portugal; Spain; South Korea • TFR 1.5 1 5 – 1.7: 1 7: Belgium; Canada; Lithuania; Luxembourg; Netherlands; Switzerland • TFR 1.8+: France; Iceland; Ireland; New Zealand; Norway; U.K.; U.S. • Considerable variation! • Source: http://www.prb.org/pdf10/10wpds_eng.pdf Some empirical regularities • Later timing of childbearing, higher proportion childless • Interval between the first and second birth is relatively short for closed intervals intervals, that is intervals begun by a birth and ended by a birth (as opposed to open intervals) • Exceptions exist. Page 88 of 131 Mean Age at Childbearing;2004; selected countries • Increased in all countries • Relatively late for all countries • Eastern Europe has the lowest mean age att first fi t bi birth. th • Not a strong correlation between age of childbearing and TFR Mean Age at First Birth; 2004; selected countries • Austria 29; Hungary 26; Italy 28; Latvia 25; Portugal 27 • Lithuania 25; Netherlands 29 • France F 28; 28 IIceland l d 26 26; IIreland l d 28 28; N Norway 28 • Source: http://epp.eurostat.ec.europa.eu/cache/ITY_OFFPUB/KS-EH-06-001/EN/KS-EH-06-001EN.PDF Page 89 of 131 Education and AAFB • Next slide shows that higher education is related to later ages at first birth (AAFB) • C Causality lit runs iin b both th di directions, ti b butt ttends d to be greater from education to AAFB. FIGURE 3 Mean age at first birth by educational level, women born 1960-69, selected European countries Source: European Social Survey, 2006, women only, born 1960-69, N=7,307, calculations by authors. Why the increase in age at first birth? Some broad reasons • Educational attainment levels have increased in all countries; in many countries, female educational attainment is higher than male’s • Increase in female labor force participation, especially “career” type jobs • Extended period of post-adolescence dependency • And in some countries, a lack of movement towards gender equity (in the labor market and within the household). Page 90 of 131 Demographically dense • Traditionally 18-30 were the prime childbearing years – starting to stretch to 35 (& moving towards 40) • These young adult years are demographically dense (leaving school, obtaining employment, migrating, marrying, divorcing, remarrying) • Next figure is U.S. circa 1990, but I expect the picture would be similar for all the countries under consideration To understand the next figure • Shown are fertility, migration, marriage, school leaving & unemployment rates, ages 0 to 80 • Ages 18-30, 18 30 the young adult years years, are shown with a thicker dark line than the other ages • What you should see is that the young adult years are demographically dense! Composite of Fertility, Migration, Marriage, School Leaving, and Unemployment Rates 0 10 20 30 40 Age 50 60 70 80 Page 91 of 131 Basic Sociology – a review • Institutions are the set of norms or rules, formal and informal, which guide relationships among role occupants in areas of structured social interactions. interactions Institutions influence social relations among people. • Examples: housing market, labor market,.. Basic Sociology – a review, cont. • Policies are formal norms or rules within institutions, and exist until formally changed • Policies can influence AAFB intentionally or inadvertently. Inadvertent AAFB policies have received little research attention. • We’ll discuss intentional AAFB policies first, and then inadvertent ones. Do institutions matter? • The next two slides show that the relationship, at the country level, between female labor force participation rates and fertility changed from being negative to positive between 1970 and 1990. • Most argue that this change occurred because of differing institutional responses across countries to the universal rise in female labor force participation. Page 92 of 131 Do institutions matter, cont. • What happened? • My read: in some countries it was (or became) easier to combine the worker and mother roles; in other countries countries, women needed to choose between one or the other. • More on this below. Page 93 of 131 Evaluating policy effectiveness: a high degree of difficulty • Experiments tend not to be used, for ethical, political and practical reasons • Country, rather than provincial, level policies (Thus tends to be a constant within a country and not visible if just studying one country) • Confluence of a country’s policies and its culture & ideology, which is difficult to disentangle Policy evaluation, cont. • A policy’s effect might only occur in the long run • Degrees of freedom problem, that is, relatively few countries available for statistical analysis Policy evaluation, cont. • Upshot: • Need a healthy skepticism regarding currently published evaluations • A shaky h k empirical i i l ffoundation d ti on which hi h tto provide advice to policy makers • Considerable speculation exists in the research literature Page 94 of 131 Intentional AAFB or overall fertility policies 1. Direct cash payments • Examples: baby bonus, family allowances • Evidence on success: at best, mixed. • My read: most studies have been of questionable quality, but it is unlikely that direct cash payments will have a large impact on AAFB Intentional AAFB or overall fertility policies, cont. 2. Indirect transfers • Example: tax exemptions for families with children, housing benefits for families with children or health benefits • Note: Sometimes these are inadvertent policies • Evidence: Modest or no effects • My read: Unlikely to have a big impact on AAFB Intentional AAFB or overall fertility policies, cont. 3. Improve work-family compatibility • Background: Sociologists talk about role incompatibility; economists talk about opportunity costs costs. Both getting at a similar issue: Today’s jobs (and school) are incompatible with taking care of a child, especially a very young child. Workplaces have changed. Parenting demands have changed. Page 95 of 131 Intentional AAFB or overall fertility policies, cont. • Examples: maternity & paternity leave with or without salary maintenance, provision of child care • Evidence: In general general, lowering the incompatibility between the mother and worker roles leads to a younger AAFB. (Very long maternity leaves seem to be an exception.) Intentional AAFB or overall fertility policies, cont. • My read: The evidence is strongest that high quality child care that is available, acceptable, accessible and open during normal working & commuting times decreases AAFB. Page 96 of 131 Policies with inadvertent effects on AAFB • Here we are speculating. There has been relatively little empirical work confirming these effects. Housing policies have received the most attention attention. 1. Housing. General hypothesis is that anything that makes it easier for young adults to obtain their own dwelling unit will lead to younger AAFB. Policies with inadvertent effects on AAFB, cont. • Background: countries differ markedly on the percent of down payment needed to obtain a mortgage, price of housing, size of rental market, market availability of credit reports, and the ease of foreclose. • Example: in Italy, large down payments (40-50%) are required, credit histories are not widely available, and foreclosures cannot be enforced until 48 months after mortgage payments have ceased. Policies with inadvertent effects on AAFB, cont. • Evidence: Relatively weak, but consistently showing a positive association between ease of obtaining a dwelling unit and TFR TFR. • My take: the hypothesis is intuitively plausible and likely true. Page 97 of 131 Policies with inadvertent effects on AAFB, cont. 2. Educational systems: a) are primary school hours compatible with balancing work and family responsibilities. If not, AAFB is likely to be later. later b) Is it feasible to return to school after having dropped out? If not, AAFB likely to be later. • Evidence: not much • My take: both are likely true Policies with inadvertent effects on AAFB, cont. • 3. Job market: Institutional factors that lead to high youth unemployment likely lead to later AAFB. • Evidence: extremely limited limited, but supportive of the hypothesis. • My take: the hypothesis is intuitively plausible and likely true. Policies with inadvertent effects on AAFB, cont. 4. Work re-entry: is it relatively easy for a mother to have her old job or obtain a new one after having stopped working to care for a young child. child • Note: this goes beyond maternity leave issues to include hiring practices of employers. For example in Japan, employers like to hire individuals who have just finished school. • Evidence: none Page 98 of 131 A quick summary • Policies that ease the conflict between mother and worker roles seem to lower AAFB, especially those that make child care more available • Direct and/or indirect transfers seem to, at best, have modest effects • Policies with inadvertent effects on AAFB theoretically are likely to influence AAFB, but the empirical evidence is not yet available. Parting thought • Think about the difference between Oslo’s subway system and Tokyo’s Page 99 of 131 Improving equal and open access to ART: prevention of involuntarily childlessness of the underprivileged Alan O. Trounson, MSc, PhD, Dr. Hon Cau, FRCOG, FRCAOG Emeritus Professor, Monash University President, California Institute for Regenerative Medicine Relationships • Chair, Low Cost IVF Foundation – not for profit • Director, Friends LCIVF Foundation US – not for profit Prevalence of Infertility ‐ Africa (Ombelet et al., 2008; Inhorn 2003) • Very major geographical, ethnic differences: • 9% Gambia, 11.8% Ghana • 21.2% Northwest Ethiopia • 20‐30% Nigeria 20 30% Nigeria • 15‐22% Botswana, Madagascar, Namibia, Zimbabwe, Lesotho • 8‐13% Burundi, Uganda, Rwanda Page 100 of 131 9% Gambia 21.2% Northwest Ethiopia 11.8% Ghana 20-30% Nigeria 32% Namibia Consequences of Infertility From Ombelet etal. 2008 Fear, Guilt, Self‐blame Marital Stress Depression, Helplessness Mild Marital or Social Violence, Social Isolation Severe Economic Depravation Loss of Social Status Moderate to Severe Violence. Loss of Dignity Violence Induced Suicide Starvation/Disease Death A Major Social Problem that Must be Addressed (Inhorn 2003) • WHO multinational study – found 85% of infertile women in sub‐Saharan Africa – their diagnosis attributed to reproductive tract infections • One quarter of all women in the region had secondary infertility due to infection induced blocked tubes ‐ sexually transmitted infections ‐ postpartum complications ‐ postabortive complication ‐ other unhygienic health care practices Treatable by IVF Page 101 of 131 Problems for Providing Infertility Services in Low Income Populations (Nachtigall et al., 2009) • Communication: Language and cultural barriers to understanding treatments and comprehending medical advice • Continuity: Physicians rotate and patients Continuity: Physicians rotate and patients rarely see the same doctor on any visit • Bureaucracy: Patients have problems with appointment scheduling, follow‐up visits, timed laboratory procedures etc. • Accessibility: Limited availability and affordability of treatments Response Needed • Train local practitioners, nursing staff, lab staff • Local public health clinics, specialist IVF doctors who see the patients • Simplify and educate with local nurses, Si lif d d i hl l counselors, young people and elders • Eliminate cost and barriers to access The Cost and Need for IVF (Vayena et al., 2009) • Global provision of ART: < 20% of those needing IVF actually using it • Developing countries ~1% of projected need being met • IVF costs >50% higher than the gross national IVF t >50% hi h th th ti l income per capita in most developing countries • Need to minimize costs and maintain benefits: should we continue to consider costs and success rates/recovery cycle or consider per annum? Page 102 of 131 Reducing Costs – Simplifying IVF (Sallam 2008) • • • • • • • • Basic ultrasound machine with vaginal probe Binocular microscope Basic ELISA reader for hormone assays Regular or Submarine incubator g Centrifuge Laboratory pipette set Refrigerator Solar UPS (uninterrupted power supply) units Cost ~ $15,000 ‐ $20,000 Low Cost IVF Foundation Blog response (>80%) to articles on providing low cost IVF services Do not deserve infertility services Plenty of children for adoption Can’t care for children adequately Social problems and high rates of sexually transmitted diseases including HIV/AIDS • Shouldn’t spend valuable resources on childbearing in low resource communities – better used in other ways • • • • Page 103 of 131 Low Cost IVF •Avoid the excessive costs and procedures •Prescreen couples who are suitable •Reduce costs from >$5000 per cycle to < $300 •Raise $50,000 to establish each clinic and operate IVF for free ‐ 2 yrs ‐ hand over to public sector management •Unable to do sperm injection (ICSI) for severe male •Unable to do sperm injection (ICSI) for severe male infertility (robotic system under development) •Few follicles reduces time, stress of OPU and reduces substantially side effects of high responses to fertility drugs – increases clinic attendance i.e.. more treatments per year increases the chance of successful pregnancy •Regularity of menstrual cycles allows accurate prediction of the expected time of ovulation What is Low Cost IVF Drugs: to stimulate women to overproduce eggs Conventional IVF Low‐Cost IVF Recombinant follicle stimulating hormone (FSH) producing 12+ eggs Cost: $1,000 or more per cycle Generic drug clomiphene produces 4 eggs at most but lower side effects than recombinant FSH $11 per cycle Incubators: Complex electronics and To keep embryos at body controllable temperature temperature before Cost: up to $15,000 transfer Stripped‐down temperature control or Submarine water b h bath Cost $4,000 Embryos incubated in capsule that sits in women’s body Cost: $85‐$185 Embryos Embryos incubated for 2 days eliminating need to perfuse CO2 Cost: $0 CO2 is infused over incubating embryos for 5 days Cost: varies Ultrasound Traditional Cost: $40,000 Portable model Cost: $5,000 Total Cost (per cycle) $6,000 ‐ $12,000 **$300 8‐cell Blastocyst 4‐cell 2‐cell Embryos Single embryo ‐ Transfer to patient IVF MII eggs Clomiphene citrate (50‐100mg) + hCG Page 104 of 131 Gentle induction of Follicle Growth Ultrasound Guided Oocyte Retrieval Rapid oocyte recovery from only 1-3 large follicles under minimum analgesics – encourages return for further oocyte recovery at minimum a u intervals. e as This increases the opportunity for initiating pregnancy when expressed per annum. Overall success rates are Increased by repeated oocyte recovery =? hyperstimulation IVF Chamber Mobile, effective, sterile working laboratory Page 105 of 131 SPERM SEPARATION BY .22 FILTER Simple systems avoid The need for expensive equipment and the dependence on uninterrupted power. Sperm sample Fertilization In Vitro Cumulus Oocyte Complex COC Follicular Fluid Low Cost IVF and Transmission of HIV Sperm washing >3000 inseminations ‐ no vertical transmission Viral load increases with superovulation – hence low stimulation or ovulation control low stimulation or ovulation control Oocyte washing and cumulus removal – no virus detected Antiretroviral therapy decreases transmission from 30% to 2% (0% with IVF) Page 106 of 131 IN VITRO CULTURE MEDIA ONE STEP CULTURE SYSTEM TO DAY 5 KSOMAA potassium simplex optimized medium Sequential media (P1 CCM) 82 zygotes 140 zygotes % ‐ No significant differences in blastocyst formation ‐ Five babies born after the transfer of 9 KSOMAA cultured blastocysts Biggers and Racowsky (2002) Reprod Biomed Online 5, 133‐140 INCUBATION SYSTEMS ‐ Transvaginal culture After 2 days Extended Shelf‐life Culture Medium • Needs to have a shelf‐life of ~2 yrs at RT • Should survive > 100 0F for 7 days • Should be a simple formulation of inorganic salts and energy molecules and stable l d l l d bl antibiotic • Medium to be used for all purposes – sperm washing, oocyte collection, culture and transfer • Currently under test Page 107 of 131 INCUBATION SYSTEMS ‐ Water bath culture A gas mixture is injected into the bag After 2 days Water bath at 37°C Bag seal FERTILIZATION CHECK Fresh 50l microdrop Well 4 – Plate 2 Incubate in Submarine incubator for further 24 h Page 108 of 131 EMBRYO CHECK – DAY 2 If number of embryos ≤ 2 Embryo Transfer on Day 2 Well 3 – Plate 2 ET or Incubate in Submarine incubator for further 24 h Embryo Check – Day 3 If number of embryos ≥ 2 Embryo Transfer on Day 3 Well 3 – Plate 2 Embryo transfer catheter Transfer Slow Page 109 of 131 The plunger of the insulin syringe has a diameter of 4.75 mm with a corresponding surface of 17.34 mm2 (A) catheter syringe plunger the plunger inside the catheter has a diameter of 00.4 4 mm with a corresponding surface of 0.125 mm2 (B). plunger catheter The immediate consequence of those data is that when both plungers move by 1 mm , A transport 140 times more water than B. Low Cost IVF clinics Arusha ‐ St. Thomas’ Hospital, Tanzania Direction: Henry Msuya and Luca Gianaroli ARUSHA HOSPITAL LCIVF Foundation Mission: To reduce the burden of childlessness for couples in underdeveloped and low resource societies. The Foundation is establishing Low Cost IVF Clinics at several sites in low resource countries and ensures that local clinicians and scientists who are identified as key personnel receive adequate training. The Foundation also nominates one or more observers for each site to provide expert advice ensure that established protocols are followed and monitor success rates for advice, ensure that established protocols are followed, and monitor success rates for the simplified procedures. An education program for awareness of reproductive health forms an integral part of the established Low Cost IVF Clinics. This program is aimed at improving couples’ knowledge about reproductive processes, infectious diseases, and safe sex practices. The Low Cost IVF Foundation is committed to maintaining administrative costs to a minimum and all clinical expertise is provided pro bono. Page 110 of 131 Arusha Low Cost IVF activity During the period 7‐11th of August 2009, both the andrology and the embryology laboratories were set up, and some clinical activities were started for training local people. The right to safe reproduction Ian D Cooke (Sheffield), Luca Gianaroli (Lugano), Outi Hovatta (Stockholm), Alan Trounson (San Francisco), Karin Hammarberg (San Fran), John McBain (Melb), Geoff Driscoll (Sydney), Ken Mao (Hong Kong), Rich Murphy (Boston), Dianna DeVore (San Fran), Pasquale Patricio (Yale), Marcia Inhorn (Yale), Elona Baum (San Fran), Gianpiero Palermo (NY), Linda Giudice (San Fran), Pat McShane (Denver) www.lowcost‐ivf.org Page 111 of 131 References • Inhorn MC (2003) Global infertility and the globilization of new reproductive technologies: illustrations from Egypt. Social Sci Med 56; 1837‐51 • Nachtigall RD, Castrillo M, Shah N, Turner D, Harrington J, Jackson R (2009) The challenge of providing infertility services to low income immigrant Latino population Fertil Steril 92;116‐22 Latino population. Fertil Steril 92;116 22 • Ombelet W, Cooke I, Dyer S, Serour G, Devroey P (2008) Infertility and the provision of infertility medical services in developing countries. Hum Reprod Update 14; 605‐21 • Sallam HN (2008) Infertility in developing countries: funding the project. Hum Reprod ESHRE Monographs 2008 (1) 97‐101 • Vayena E, Peterson HB, Adamson D, Nygren K‐G (2009) Assisted reproductive technologies in developing countries: are we caring yet? Fertil Steril 92;413‐6 Further Reading • Cooke ID, Gianaroli L, Hovatta O, Trounson AO (2008) Affordable ART and the Third World: difficulties to overcome, Hum Reprod ESHRE Monographs 2008 (1) 93‐96 • Hovatta O, Cooke I (2006) Cost‐effective approaches to in vitro fertilization; means to improve access. Int J Gynecol Obstet 94; 287‐91 • Nachtigall RD (2006) International disparities in access to infertility Nachtigall RD (2006) International disparities in access to infertility services. Fertil Steril 85;871‐5 • Ombelet W, Campo R (2007) Affordable IVF in developing countries. RMB Online 15; 257‐65 Page 112 of 131 Freezing gametes and gonads the solution to prevent infertility in men and women Sjoerd Repping, Repping, PhD Professor of Human Reproductive Biology Center for Reproductive Medicine Academic Medical Center / University of Amsterdam S.Repping@amc.uva.nl Outline • Men – What causes infertility? – Which infertility can be prevented? – How can infertility be prevented? • Women – What causes infertility? – Which infertility can be prevented? – How can infertility be prevented? • Discussion Male infertility • Impaired semen quality – Below WHO values for normal spermatogenesis – 5th percentile of a cohort of healthy men WHO guidelines, (2010) Page 113 of 131 Male infertility • Correlation between semen quality and chance of pregnancy Van der Steeg, et al., F&S (2010) Causes of male infertility • Causative factors – – – – – Hyperprolactinemia Hypogonadotrophic hypogonadism Bilateral cryptorchidism Orchitis Genetic causes • Numerical and structural chromosome abnormalities • Y-chromosome deletions – Previous chemochemo- or radiotherapy Silber & Repping, HRU (2002), Visser & Repping, Reproduction (2010) Risk of infertility Lee, et al., J. Clin. Oncol. (2006), Wallace, et al., Lancet (2005) Page 114 of 131 Fertility preservation • Cryopreservation of semen – Masturbation – Electroejaculation • Cryopreservation of spermatozoa – Surgical retrieval • MESA (epididymis) • TESE (testis) • Before start of chemotherapy Sperm banking in the AMC • • • • Since 1976 Age 1212-62 ~100 new cases each year Current storage (21 (21--3-2011) – 968 patients ti t – 2.627 ejaculates – 36.199 straws Use of cryopreserved semen • First documented use in 1953 • Treatment option depends on quality – 15% can be used for cervical insemination – 10% requires intrauterine insemination (IUI) • Mild ovarian stimulation • 15% ongoing pregnancy per cycle – 75% requires in vitro fertilization (IVF) w/ or w/o ICSI • Ovarian hyperstimulation • Invasive / burdensome • 25% ongoing pregnancy per cycle Bunge & Sherman, Nature (1953), Repping (unpublished data) Page 115 of 131 Clinical problem • Sperm cryopreservation not possible in children • Increased success in pediatric oncology – ~80% survives childhood cancer – 1:250 young adults is childhood cancer survivor Blatt, et al., Med Pediatr Oncol. (1999), Wallace, et al., Lancet (2005) Theoretical approach Animal models SSCs Brinster & Averbock, PNAS (1994) Page 116 of 131 Animal models Xenotransplantation: Rat to mouse (Cloutier et al., Nature 1996) Hamster to mouse (Ogawa et al., Biol Reprod 1999) Rabbit/dog to mouse (Dobrinski et al., Biol Reprod 1999) Baboon to mouse (Nagano et al., Biol Reprod 2001) Bull to mouse (Izadyar et al., Reproduction 2002) Human to mouse (Nagano et al., Fert Steril 2002) Autotransplantation: Mouse to mouse Bull to bull (Izadyar et al., Reproduction 2003) Goat to goat (Honaramooz et al., Mol Reprod Dev 2003) Ram to ram (Ridriguez-sosa et al., Theriogenology 2006) Dog to dog (Kim et al., Reproduction 2008) Human adult testis Sadri Ardekani, et al., JAMA (2009) Human adult testis Nude mouse 40 mg/kg Busulphan treatment 4-6 weeks before transplantation Colonization? Page 117 of 131 Human adult testis Sadri Ardekani, et al., JAMA (2009) Human prepubertal testis • Two boys with NonNon-Hodgkin (6.5 and 8 years of age) Sadri Ardekani, et al., JAMA (2011) Future developments • Elimination of cancer cells – Do they survive weeks of culture? • Safety – (Epi)genetic stability – Health of offspring (mouse model) • Adapt culture for clinical use – Use of clinical grade products – GMPGMP-setting • Transplantation technique in human testis Page 118 of 131 Alternatives • Tissue transplantation – Autologous / xenografting • In vitro spermatogenesis • Both require ART Van Saen, et al., HR (2011), Sato, et al., Nature (2011) Causes of female infertility • Tubal occlusion • Endometriosis • Anovulation • Imminent ovarian failure Imminent ovarian failure • Gonadotoxic treatment – Chemotherapy Chemotherapy,, radiotherapy radiotherapy,, MTX – Bone marrow transplant • Time / age – Premature • POF • Turner syndrome – “Normal Normal”” – Average maternal age in NL – Average age IVF patients AMC 29.4 years 35.7 years 20% >40 years Page 119 of 131 Fertility preservation Jeruss & Woodruff, NEJM (2009) Oocyte freezing • Widely applied – – – – Rapid introduction Standard procedure > 900 children born Vitrification most applied method Kuwayama, et al., RBMO (2005) Theriogenology (2007) Ovarium cortex transplantation • Freezing ovarian cortex – Can be done rapidly • (Auto)transplanting ovarian cortex – Limited experience – Possible risk of reintroducing malignant cells – Case series monozygotic twins • Discordant for ovarian failure Woodruff, et al., Nat Med (2009), Smitz, et al., HRU (2010), Silber, et al. NEJM (2005) (2007) HR (2008) Page 120 of 131 In vitro folliculogenesis • Freezing ovarian cortex • Freezing GV oocytes • In vitro folliculogenesis – Prevent reintroduction malignant cells – Preclinical breakthroughs – No human pregnancies Woodruff, et al., Nat Med (2009), Schmitz, et al., HRU (2010) Gonadotoxic treatment Lintsen, et al., Hum.Rep. (2008) Time / age Page 121 of 131 Time / age Social versus Medical • Difference in acceptance • But difficult to separate • Phase I (freezing) has different indications – Cancer treatment / age • Phase II (thawing) same indication – Infertility • Dutch view – Both social and medical situation are indications – Dutch embryology / gynecology society September 2010 – Accepted by Dutch parliament April 2011 Discussion • Fertility can be preserved in – Men / women – Prepubertal / adult – Established / experimental • Fertility preservation should be discussed whenever infertility is on the verge of occurring – Oncologists – Family doctor – Society Page 122 of 131 Mark your calendar for the upcoming ESHRE campus workshops! • Early pregnancy disorders: integrating clinical, immunological and epidemiological aspects 23-26 August 2011 - Copenhagen, Denmark • The management of infertility – training workshop for junior doctors, paramedicals and embryologists 7-8 September 2011 - St. Petersburg, Russia • Basic genetics for ART practitioners 9 September 2011 - Bucharest, Romania • • The whole man 22-23 September 2011 - Sevilla, Spain • • Human reproductive tissues, gametes and embryos: Innovations by science-driven culture and preservation systems 9 October 2011 - Cairns, Australia • • • Endometriosis and IVF 28-29 October 2011 - Rome, Italy Accreditation of a Preimplantation Genetic Diagnosis Laboratory 3-4 October 2011 - Athens, Greece Comprehensive preimplantation screening: dynamics and ethics 13-14 October 2011 - Maastricht, The Netherlands Endoscopy in reproductive medicine 23-25 November 2011 - Leuven, Belgium What you always wanted to know about polycystic ovary syndrome 8-10 December 2011 - Sofia, Bulgaria www.eshre.eu (see “Calendar”) Contact us at info@eshre.eu Page 123 of 131 NOTES Page 124 of 131 NOTES Page 125 of 131 NOTES Page 126 of 131 NOTES Page 127 of 131 NOTES Page 128 of 131 NOTES Page 129 of 131 NOTES Page 130 of 131 NOTES Page 131 of 131
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