Fertility Issues Update. Dr Sarah Wakeman FRANZCOG, CREI, Medical Director, Fertility Associates Christchurch

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2 Fertility Issues Update Dr Sarah Wakeman FRANZCOG, CREI, Medical Director, Fertility Associates Christchurch

3 Disclaimer Attendance paid for by Fertility Associates Christchurch - Medical Director of Fertility Associates Christchurch Fertility Associates holds the public contract for provision of tertiary fertility services for Canterbury, Nelson Marlborough and West Coast regions

4 Outline of workshop Changing face of fertility problems Age Social situations Lifestyle obesity Assessment of fertility problems in General Practice Treatment what s new Public referral and funding Case studies

5 Changing face of fertility problems

6 Female Age Average age of first birth in NZ was 28 in 2008 Statistics NZ

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10 Chance of Pregnancy About 80% after 12 months of trying

11 Chance of Pregnancy Drops with age Age < 30 years 37 years 40 years

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13 You have all the time in the world so party, study, travel. You can always have babies later

14 Male Age Does Not Matter

15 Male age Male age negatively influences clinical pregnancy rate in women younger than 40 years undergoing donor insemination cycles Original Research Article Reproductive BioMedicine Online, Volume 27, Issue 2, August 2013, Pages

16 Male age Evidence for longer time to pregnancy with greater paternal age Evidence for decreased semen quality with male aging Less dramatic effects than female aging

17 Paternal age and schizophrenia risk

18 Sperm DNA fragmentation: the effect of age

19 Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies C M Hultman, S Sandin, S Z Levine, P Lichtenstein and A Reichenberg Paternal Age Group (years) OR (Model Adjusted for All Potential Confounders) 95%CI Maternal Age Group (years) OR (Model Adjusted for All Potential Confounders) 95%CI

20 Changing social situations Good contraception More accepting society Rising cost home ownership Higher material expectations Increase in women studying and working

21 Changing social situations Single women Same-sex couples (female) 2 nd relationships Gamete donation We ALWAYS need more donors Surrogacy Social egg freezing

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23 Impact of BMI on female fertility Public funding cut off Human Reproduction Update Homan, G.F. et al. Hum Reprod Update : ; doi: /humupd/dml056

24 Female obesity Increased risk of ovulation problems with increased weight Less chance of pregnancy with treatment More complications in pregnancy Mother HT, PET, gestational diabetes, LSCS Baby macrosomia, prematurity, stillbirth, congenital abnormalities, childhood obesity 24

25 IVF and increased BMI 2011 Rittenburg et al (London) updated systematic rv and meta-analysis 33 studies, treatment cycles Women with BMI >25 signif lower clinical preg rate (RR=0.9, p<0.0001) and live birth rate (RR = 0.84, p=0.0002), and higher misc rate (RR = 1.31, p<0.0001) compared to women with BMI <25. Subgroup analysis of BMI compared to BMI <25, signif lower CPR (RR = 0.91, p= ) and LBR ( RR = 0.91, p=0.01) and inc MR( RR=1.24, p< )

26 Female obesity What to do? Reduce BMI diet, exercise, bariatric surgery CPAC BMI = 32 RANZCOG statement on Ovarian stimulation in assisted reproduction states BMI >/=35 should be regarded as a contraindication to fertility treatment Screen for diabetes, hypertension, endometrial hyperplasia Lifestyle modification groups

27 Impact of BMI on male fertility Overweight men (BMI over 28) have sperm counts 22% lower Pregnancy and live birth outcomes according to paternal BMI Pregnancy loss Live birth/opu % Bakos et al., 2011, Paternal Obesity and ART Pregnancy Paternal BMI range

28 Underweight women Possibly increased miscarriage risk Hypothalamic amenorrhea Weight gain will often improve Over exercise

29 Assessment of fertility problems in General Practice

30 JL and SR J 34 yrs GOPO TTC 29 mo Reg pds /25-27 Seen at CWH SIS normal CC 6/12 S 32 yrs SA normal at SCL History of testicular pain for a yr 3 yrs ago Treated with antibiotics

31 Female assessment History Examination smear, swabs Day2/3 FSH and E2, day 21 progesterone Rubella, syphilis, Hep B,C, HIV, TFTs? AMH? USS/tubal patency

32 Follicular phase Luteal phase The Menstrual Cycle Gonadotropic hormone levels Ovarian cycle Preovulatory phase Ovulation Postovulatory phase Ovarian hormone levels Estrogens Progesterone Uterine cycle Phases MENSES PROLIFERATIVE PHASE DAYS SECRETORY PHASE

33 Assessing Ovulation Typically day 21 progesterone level Adjust to cycle length Document date of next period Luteal phase should be 14 days

34 AMH Anti-mullerian hormone Secreted by granulosa cells of antral and preantral follicles In male fetuses prevents development of uterus and tubes Reflects ovarian reserve

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37 AMH and reduced ovarian reserve AMH more sensitive than FSH Antral follicle count also useful No level of AMH that predicts non-pregnancy AMH does predict number of eggs collected at IVF Evidence of reduced AMH after ovarian cyst surgery especially endometriomas Remember peak AMH not reached until age 25 years

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40 Tubal patency HSG - hysterosalpingogram SIS saline infusion sonohysterogram, detailed pelvic USS included Pelvic USS

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45 Male History Examination Semenalysis - if abnormal REPEAT

46 WHO Standard (World Health Organisation) 15 million / ml

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48 FA Semen analysis - (Original signed copy with Lab) Number of days since last ejaculation: 0.5 All ejaculate collected: Yes Sample collected by: Masturbation Semen collected at: Clinic Have you had any significant health issues in the last 3 months: No Consent for partner to receive results: Yes Semen sample Date 18/06/14 Analyst CTIN Time to analysis 15 min Reference Range Viscosity 2 (1-4) 2 Volume 0.6 ml > 1.5 ml Sperm conc 92 M/ml > 15 m/ml Total motility 60 % > 40% Progressive motility 55 % > 32% Rapid 49 % Slow 6 % Non-progressive 5 % Conc. Of Motile 55 M/ml # motile 33 M Con non-sperm M/ml <1M/ml Sperm MAR binding0 % NEGATIVE >50% positive Morphology of motile sperm Comments: 4+ % Normal (wetslide)

49 Current success rates and new treatments

50 Clomiphene / Ovulation Induction (OI) Tablet taken between day 3 and 7 Increases the level of FSH to stimulate egg production Mainly used where there is a problem with ovulation e.g. irregular menstrual cycles Involves some blood tests and scans

51 Intra-Uterine Insemination (IUI) Number of sperm to fertilise an egg 20,000,000 Sperm for Intercourse 1,000,000 for IUI

52 IVF and ICSI Newer shorter cycles less injections, quicker Excellent pregnancy rates

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56 The Basics = Sperm + Egg

57 In Vitro Fertilisation (IVF) Conception takes place outside the body Work with 100,000 sperm

58 Intra-Cytoplasmic Sperm Injection (ICSI) A single sperm is injected directly into each mature oocyte Male factor infertility or previous poor/failed fertilisation with conventional IVF insemination

59 Embryo development (I) Fertilised egg 18hrs after adding sperm 8 cell embryo day 3 after egg collection

60 Embryo development (II) Blastocyst day 5-6 Hatching blastocyst day 5-6

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62 New treatments PICSI and IMSI PGS

63 IMSI What is it? Much higher magnification to select sperm for ICSI ICSI sperm magnified x IMSI sperm magnified >6300x With IMSI can see sperm morphology in more detail especially sperm head vacuoles. Evidence of improved outcomes for couples with previous poor icsi outcome

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66 PICSI What is it? A test of sperm function, hyaluronan binding. - Hyaluronan is a high molecular weight glycosaminoglycan and is a major component of the cumulus oophorus matrix surrounding the human oocyte. Developmentally mature sperm bind to hyaluron Evidence of a lower rate of miscarriage after sperm chosen using PICSI (for ICSI)

67 PGS What is it? Preimplantation genetic screening Doing genetic testing on 1 or more cells from a day 3 or day 5 embryo to check chromosome number Many embryos are aneuploid Can now screen all 24 chromosomes In past as few as 3-5 checked

68 Indications for PGS Recurrent implantation failure Recurrent miscarriage Maternal age Embryo selection, successful pregnancy more quickly

69 Public referral and funding

70 Public fertility referral Direct to fertility clinic Fertility Associates Christchurch Otago Fertility Services Fertility Associates elsewhere in NZ If CPAC high enough offered FSA first specialist assessment appointment Already on public funded waiting list, further investigations arranged as appropriate, treatment options discussed and planned

71 Public fertility referral Via secondary care E.g. CWH Less strict criteria to be met (Health Pathways) Assessment and further investigation will be undertaken USS, tubal patency testing, laparoscopy if appropriate If CPAC high enough then referred to tertiary fertility service for treatment

72 Private fertility referral Direct to fertility clinic Further investigations arranged as appropriate Public funding eligibility always considered CPAC scoring when appropriate Many patients have a mix of both public and private treatment

73 Public Funded Fertility Treatment Points s given CPAC Points system with a threshold score of 65 Waiting list for treatment- around 12 months Female partner less than age 40, BMI 19-32, non-smoker, <2 children at home Points given for duration of fertility delay Points given for pathology Total score also takes into account social factors Number of children at home Children to other relationships Previous sterilisation procedure

74 What medical issues contribute to the CPAC score? Endometriosis Tubal disease Irregular or absent ovulation Semen analysis abnormalities Length of fertility delay (otherwise unexplained fertility delay for >/=5 years) More severe the problem-more points given

75 What Does Public Funding provide? A review with a specialist (before fertility treatment) Up to two cycles of treatment (or a baby)-you must remain eligible to receive second cycle Can choose what treatment the funding pays for- IUI, IVF, testicular biopsy, sterilisation reversal, Donor egg/embryo, surrogacy An IVF cycle includes all frozen embryos created in that cycle

76 JL and SR J 34 yrs GOPO TTC 29 mo Reg pds /25-27 Seen at CWH SIS normal CC 6/12 S 32 yrs SA normal at SCL History of testicular pain for a yr 3 yrs ago Treated with antibiotics What are we going to do?

77 JL and SR Further investigation More detailed SA 15% ASAB binding Options IUI IVF Continue trying naturally CPAC not high enough

78 JL and SR Private IVF cycle Short cycle 12 eggs, 11 fertilized with standard ivf SET day 5 Pregnant 3 embryos frozen

79 Case JO and BO JO 28 yrs, BO 31 yrs J reg pds, well, GOPO, no contraception 10 y B treated for lymphoma aged 10 yrs with chemo and full body DXRT Testes 10ml and soft FSH 17 Azoospermia

80 Case JO and BO CPAC eligible, donor sperm treatment Public funding 1 st package 4 x DIUI Conceived on 3 rd, miscarriage SIS small anterior wall polyp Hysteroscopy polyp removed 4 th DIUI not pregnant Public funding 2 nd package IVF, short cycle, pregnant and 7/40 USS good 3 embryos frozen for future use.

81 Case AS and LS A 34 yrs L44 yrs GOPO TTC 19/12 Reg pds /28 until now when day 37 d3fsh = 9, AMH <0.5 L SA 13/42/5 USS at 1 st visit only 5 antral follicles Tried CC, ovulated 1 st cycle, 2 nd and 3 rd ovulated day 6-7 Then no period and no response to CC

82 Case AS and LS Further discussion re ovarian reserve, donor eggs mentioned Tried 2 IUI cycles First poor follicle growth 2 nd went ahead but np Now doing a donor egg cycle CPAC eligible as premature ovarian failure More detailed SA only 3% normal morphology

83 Case RD and GD R 37 yrs, G 36 yrs GOPO TTC 13/12, reg pds /27-29 R BMI = 30.5 G inguinal hernia repair and post op infection as a baby, testicular torsion aged 11 SA 4.6/13 SA 14.2/40/5 Discussed wt loss, detailed SA Detailed SA 15.4/47/9, no anti-sperm antibodies

84 Case RD and GD Tried naturally for another 3/12 SIS normal Discussed IUI and IVF Decided to just take CC 1 st cycle monitored and np 2 nd cycle not monitored, pregnant but 5/40 with hcg levels rising less well than expected What next if miscarriage??

85 Questions