The Key Ingredients for Conception Wharewaka Wellington April 2018 Dr Andrew Murray
What are we going to talk about? •Basic Fertility Ingredients •How we test them •How can the environment effect them •Funding of fertility treatment •When and how to refer •New Developments in Fertility Treatment
3 Basic Ingredients to get pregnant
Fertility Problems
Unexplained 10%
Male 30%
Male and Female 30%
Female 30%
Ingredient 1: Eggs
NZ Mothers are Aging
Why do older mothers affect fertility rates?
Egg Quantity
7 x10 6
Ovary - Follicle Atresia/Aging
1 x10 6 300K 25K Birth
Puberty
Mid 30’s
55
Egg Quality
“Spindle� Problems
Young Egg Chromosomes line up in straight line on spindle
Older Egg Chromosomes line up erratically
So which tests need to be performed and why?
Female Day 2 Estradiol FSH Day 21 Progesterone Antenatal bloods Hep B, C, HIV Chlamydia and HVS
E2
FSH
E2
FSH
E2
FSH
E2
FSH
Menstrual Cycle D21 P4 Day 2-3 E2
Day 2-3 FSH
AMH (Anti Mullerian Hormone)
AMH : Anti-Mullerian Hormone Fertility Associates offers AMH testing to help predict: •
Ovarian reserve
•
Likely response to ovarian stimulation for IVF
Ingredient 2: Sperm
Causes of Infertility - Male • • • • • • •
Genetic Developmental High body temperature Physical injury Chemicals/ hormones Medical Lifestyle factors
Causes of Infertility - Male • • • • • • •
Unknown
Genetic –Developmental 60-70% High body temperature Physical injury Chemicals/ hormones Medical Lifestyle factors
Sperm Count - Fertile Man - Once/wk for 2 yrs Density *106/ml
Male Semen Analysis x2 Hep B,C, HIV
Sperm are like DNA Delivery Vans
…but what if the cargo is damaged
Sperm Chromatin Assessment DNA Damage can be due to: • • • •
Smoking Infections Trauma Age effects
Sperm Chromatin Assessment (SCSA) • •
•
Analyses sperm DNA for damage DNA damage is independent of normal semen parameters >30% DNA fragmentation poor fertility rates and increased risk miscarriages
ANTI-OXIDANTS RCT Menevit vs Placebo and IVF-ICSI Outcomes (Tremellen et al 2007) 38% vs 16 % viable pregnancy/transfer
ADAM Study (Tunc et al 2009) 18% reduction DNA Fragmentation 33% reduction in Oxidative Stress
Ingredient 3. Tubes and Uterus
Ultrasound
Suspect Tubal Pathology or Endometriosis
• • • •
• •
Painful Periods Pain with Bowels or Bladder Pain with Gold Standard = laparoscopy Intercourse History of previous abdominal or pelvic surgery PID Chlamydia and other STIs
Hysterosalpingogram
What other factors might effect the “quality� of our ingredients?
What lifestyle factors are important? • • • • • • • •
Age Smoking Weight Diet and Exercise Psychological stress Caffeine consumption Alcohol consumption Exposure to environmental pollutants
Percentage of adults who smoke in NZ
Cigarette smoking and male fertility • •
In males smoking affects sperm production, motility, morphology and increases DNA damage Child born to a father who smokes has 4 X risk of childhood cancer
Smoking and female fertility • • •
Cotinine and cadmium detectable in follicular fluid Menopause occurs 1 to 4 years earlier Zona pellucida thicker
Implications of smoking in ART population • • •
9 studies OR 0.66 (95%CI 0.49-0.88) for pregnancy per number of IVF cycles Male smoking significantly reduced ICSI and IVF success rates Female smoking doubles risk of early pregnancy loss
What can I do?
Relative risk of infertility vs BMI Relative risk Public funding cut off
4.0
3.0
2.0
1.0
0.0 <16
16-18
18-20
20-22
22-24
24-26
26-28
28-30
30-32
>32
BMI 56
What can I do?
Weightâ&#x20AC;Ś
Overweight men Body Mass Index (BMI > 28) have sperm counts 22% lower
57
Stress May reduce female reproductive performance through effects on autonomic, endocrine and immune systems
Effects of counselling and support on ART pregnancy rates
Homan, G.F. et al. Hum Reprod Update 2007 13:209-223; doi:10.1093/humupd/dml056
What can I do?
Caffeine…
Caffeine may impact on treatment • • • •
221 women (Cohen et al, 2002) Caffeine 2-50mg/day compared with nil OR 3.1(95%CI 1.0-9.7) for no livebirth Caffeine>50mg/day OR 3.9 (95%CI 1.3-11.6) Starbucks grande latte 150mg caffeine
61
Alcohol is not good for fertility, or baby •
Known teratogen (affects embryo/fetus development)
•
Reduces female fertility
•
Increases miscarriage risk
•
Unknown safe level during pregnancy
•
Men >20 standard drinks per week reduced numbers of pregnancies
Don’t forget Folic Acid? • • •
What dose? Folic acid alone or Multi vitamins? How long for?
So when do you need help?
Human Conception Rate 113 90 68 45 23 0 0
3 6 12 Months of unprotected intercourse
24
Early Referral If • • • • • • •
Couple wants to see us Woman under 28 Woman older than 35 Known ovulation or sperm factor Known tubal problem Recurrent miscarriage Family history of early menopause
Funding Funded Consultation Funded Treatment
Initial Fertility Consultation Fertility specialist â&#x20AC;˘ â&#x20AC;˘
Public Private
Private consultation option • • • •
Patients can self refer Patients can choose their fertility specialist No mandatory tests required prereferral Fertility Associates’ specialists can see new patients within 2 weeks in all our clinics
Public consultation • • •
Conditions apply Referring doctor needs to do a preliminary workup Wait time 1-2 months
Northern Region Fertility Service (NRFS)
Eligibility Criteria for a Public Referral NZ Resident (or Work Permit of at least 2 years) Womanâ&#x20AC;&#x2122;s age <40 at time of referral BMI <32 Non smoker of >3 months Duration of infertility at least 12 months
Work-up tests for initial consultation Female
Male
Day 2-3 FSH Oestradiol
Semen analysis
Hepatitis B,C HIV syphilis rubella
Hepatitis B,C HIV
Blood Group FBC Smear Day 21 Progesterone
Publicly funded treatment • • • • • •
Criteria are the same across New Zealand People need > 65 points using the fertility CPAC scoring tool Score > 65 only means eligible All have same wait time til treatment Higher score doesn’t mean more urgent treatment The CPAC score can only be calculated by a fertility specialist.
Criteria Ovulation problems Male Factor Endometriosis Tubal Factor Length of time trying Previous children Previous sterilisation
Waitlist for treatment • •
•
The wait to treatment varies across the country Generally 12–18 months, you can check this when you make your referral to your local clinic. Patients can access private fertility treatment whilst on the public waiting list
Second publicly funded packages
â&#x20AC;˘ â&#x20AC;˘
Requires rescoring All same eligibility criteria apply wait time less
Fertility preservation
All cancer patients requiring gonadectomy or gonadotoxic therapy All patients with severe medical disease requiring gonadotoxic therapy
Take Home Messages for Patients
Hi Alex Can you have a look at the attached proposal for Markâ&#x20AC;&#x2122;s remuneration, and let me know your feedback please?
Take Home Messages for Referrers Consider Early Referral. Remember the Biological Clock.
Take Home Messages for Referrers
Take Home Messages for Referrers Consider Early Referral Remember the Biological Clock
IVF Intrauterine Inseminations Surgery
Clomiphene Consultation & Advice
Dr Andrew Murray Medical Director Fertility Associates Wellington 04 3848401 amurray@fertilityassociates.co.nz www.fertilityassociates.co.nz
Fertility preservation Simon McDowell FRANZCOG CREI MbCHB MRMed PGDipOMG Fertility specialist Gynaecologist
What will we discuss? • ‘Fertility threatening’ treatment • Assessing current fertility • Options for fertility preservation – Female and Male
• Social egg freezing
• Fertility preserving surgery
...in the end... I am grateful to [clinic] that I’m still here. I know why the doctors treated my cancer so urgently... but no one gave me any choices about my fertility. I’m upset that as a result I am now left with no options…. Patient, aged 34
Cancer
Surgery
What may â&#x20AC;&#x2DC;threatenâ&#x20AC;&#x2122; fertility? Endometriosis
Medical
Workup • x2 public clinics per week • Multiple private clinics • Desire future fertility • Age awareness • Assess threat of treatment • Current fertility potential
AMH: Anti mullerian hormone
Effect of gonadotoxic therapy
Effect of chemotherapy on women
age / drug / dose
Temporary/Permanent Ovarian Failure
Effect of radiation therapy on women
age / extent / type
Temporary/Permanent Ovarian Failure
Risk of ovarian failure based on chemotherapeutic agents • (1) High • Cyclophosphamide; Chlorambucil; Melphala; Busulfan; Nitrogen mustard; Procarbazine; Ifosfamide; Chlormethine • (2) Moderate • Cisplatin; Carboplatin; Paclitaxel; Bleomycin; Mercaptopurine; Vinblastine; Adriamycin • •
(3) Low or no risk Methotrexate; 5-Fluorouracil; Vincristine; Actinomycin D
“Risk of amenorrhoea post treatment” HIGH RISK: >80% chance INTERMEDIATE RISK: 30-70% chance LOWER RISK: <20% chance VERY LOW / NO RISK: 0% chance UNKNOWN RISK
www.livestrong.org
Options: female • No action • Cryopreservation oocytes (eggs) • Cryopreservation embryos • Cryopreservation ovarian cortex • Ovarian ‘protection’
No action
Cryopreservation oocytes • Single • In a relationship but “not sure if want to make babies with him” • Have a ‘few weeks’ and well enough
Cryopreservation oocytes 10-14 days hormonal stimulation vaginal egg retrieval freezing of eggs recovery ------------thawing of eggs
fertilisation by IVF-ICSI embryo transfer
Cryopreservation oocytes Live birth rate 6% per egg frozen
>900 babies born with no apparent increase in congential anamalies â&#x20AC;&#x201C; Noyes et al RBM 2009
Embryo cryopreservation 10-14 days hormonal stimulation vaginal egg retrieval
Age dependent recovery chance of success fertilisation of mature eggs
-------thawing of embryos embryo transfer
How long?
We have no time for this!
2-3 weeks
Early foll: start stim immediately Late foll or ovulating: trigger ovulation & start stim few days later Luteal phase: start stim immediately Irregular/absent: basal screen, trigger or start
Between surgical recovery and chemotherapy
Public funding is now available for fertility preservation
Ovarian tissue freezing • Younger woman • No time • Surgery for other reasons • Requiring ovarian surgery / oophorectomy
Ovarian protection • Ovarian transplantation • GnRH agonist treatment – Well tolerated, no serious side effect – Contraception – Reduce rate of chemotherapy related menstrual dysfunction – ‘May’ reduce risk of premature ovarian failure
Effect of chemotherapy and radiation on males dose / agent
Temporary/Permanent Spermatogenic damage
Sperm cryopreservation
Social egg freezing
Odds success? Live birth rate 6% per egg frozen 16 eggs to make a healthy pregnancy
When is the best time?
Cost? $9,000 May need Viable option, woman can 10,000 more than make their own informed 1 cycle choice
Fertility preserving surgery
Antenatal Screening Dr Jay Marlow Clinical Leader MFM Wellington Hospital
Senior Clinical Lecturer University of Otago
Private Obstetrician
Overview • • • • •
What is screening? Combined First Trimester Screen Non-Invasive Prenatal Screening Gestational Diabetes Group B Strep
www.wellingtonobstetrics.co.nz
WHAT IS SCREENING?
What is screening? • Screening tests are
– carried out on a large number of apparently healthy people to separate those who probably have a specified disease from those who probably do not
• Antenatal screening
– separates pregnancies into high and low risk groups for various conditions
• Purpose of Antenatal Screening is to:
– Ensure health care professionals are aware of potentially complicated pregnancies and can arrange appropriate care • e.g. transfer for delivery at a tertiary centre
– To allow parents the opportunity to
• decide whether to continue with the pregnancy in cases of fetal abnormality • prepare for the arrival of a potentially disabled child
– To allow the possibility for intrauterine therapy
• Screening in pregnancy aims to detect conditions in both mother and fetus. – Early detection allows more time for decision making and early intervention
www.wellingtonobstetrics.co.nz
Types of Screening Maternal • Anaemia • Thalassemia • Rhesus status • Infections
Fetal • Down Syndrome and other conditions • Structural anomaly • Growth restriction
– Syphilis, HIV, Hep B, Asymptomatic bacteriuria
• GDM • Pre-Eclampsia
www.wellingtonobstetrics.co.nz
COMBINED FIRST TRIMESTER SCREEN
Detection Rate (%)
Aneuploidy Screening Approach: Observed Detection Rates
1960
1980
1990
2005
www.wellingtonobstetrics.co.nz
2011
Maternal Risk of T21 increase with age
• Maternal bloods – From 10 weeks – PAPP-A – Free HCG
• Nuchal translucency – 11-13+6 weeks
• Combined – DR of 91-92% – FPR 5%
• However NSU – DR 72-75%
www.wellingtonobstetrics.co.nz
• 62% underestimated weight • 15% overestimated weight • Only 30% reported the correct height
– most thought they were taller than they were
• Only 6% gave weight and height giving their actual BMI • 69% underestimated their BMI • 25% overestimated
www.wellingtonobstetrics.co.nz
In this study of cases: â&#x20AC;˘ Real woman in study: 25y, P3G2. Measured data
MSS1 data (form to lab)
Weight (kg)
80
70
Height (m)
1.60
1.64
BMI
31.3
26
MSS1 risk
Low risk
High risk
www.wellingtonobstetrics.co.nz
Implications • BMI should be measured – (height and weight at the booking / first visit )
• Ideally before 10 weeks
www.wellingtonobstetrics.co.nz
The 12 week Scan • Combined First Trimester Screening (CFTS) – ???replaced with Non Invasive Prenatal Screening/Testing (NIPS/T)
• Accurate dating • Early diagnosis of fetal abnormalities
www.wellingtonobstetrics.co.nz
Nuchal Translucency (NT)
www.wellingtonobstetrics.co.nz
Nuchal Translucency • Subcutaneous fluid-filled space located between back of fetal neck and skin • Measured on USS between 11-13+6 weeks • measurement is not valid outside of this time period
• NT increases with gestational age www.wellingtonobstetrics.co.nz
NT Standard (FMF) • • • •
CRL 45 – 84mm Midline- Sagittal fetus plane Mid sag face echogenic tip of nose Neutral position •
• • •
not extended or flexed
Away from amnion Head and thorax occupy >1/3 of the image Widest part of translucency measured •
“on-to-on technique”
www.wellingtonobstetrics.co.nz
Nuchal Translucency • Between 11-13+6 weeks >3.5mm considered elevated • Diagnostic testing indicated • Tertiary anatomy scan at 18-20 weeks • Fetal screening echocardiogram indicated ~24 weeks
• Increased NT thickness is associated with: • Trisomies 21, 18, 13, triploidy and Turner syndrome • Spontaneous fetal loss • With normal chromosomes: • • • •
cardiac defects, diaphragmatic hernia, pulmonary defects, skeletal dysplasias congenital infection metabolic/haem disorders rare single gene disorders Nicolaides. Am J Obstet Gynecol 2004;191:45 Souka et al. Ultrasound Onstet Gyncol 2001;18:9
www.wellingtonobstetrics.co.nz
Chance of a normal birth varies with size of NT measurement
Nasal Bone
www.wellingtonobstetrics.co.nz
Why is our detection rate so low? • Incorrect maternal data • Lack of certification/quality control for nuchal • Erroneous reporting of the nasal bone • Self reported postnatal diagnosis of T21. www.wellingtonobstetrics.co.nz
NON INVASIVE PRENATAL SCREEN
What’s in a name? • NIPTest • NIPScreen • Down Syndrome blood test
SCREENING TEST www.wellingtonobstetrics.co.nz
What is NIPT? • Screening test to prenatally detect – Down syndrome – other aneuploidies (extra or missing chromosomes) • • • •
trisomy 21, 18, 13 trisomy of sex chromosomes (XXX, XXY, XYY) Turner syndrome (monosomy X) triploidy (extra copy of all chromosomes)
www.wellingtonobstetrics.co.nz
NIPT •
Measures circulating cell-free DNA (cfDNA) from placenta present in maternal blood
•
~10% of DNA in maternal blood –
•
As early as 9-10 weeks gestation –
•
Increases with gestational age
(company specific)
Dating U/S – –
cfDNA comes from apoptotic cells derived from: Maternal Circulation
viability, accurate GA, exclude multiples
• •
Adipocytes White Blood Cells
• Fetal •
Placental cells (trophoblasts) in the maternal circulation
www.wellingtonobstetrics.co.nz
NIPT Methodologies Massively Parallel Shotgun Sequencing
Sequenom MaterniT21T M
Targeted Sequencing
Verinata Verifi速
Ariosa HarmonyTM
COUNTING
www.wellingtonobstetrics.co.nz
Targeted Sequencing
Natera PanoramaTM
SNPs
Fetal Fraction Matters “An aneuploidy sample with a lower fetal fraction has a higher probability of resulting in a false negative result.” Thomas Musci, MD
Prenatal Perspectives. Volume 1, No.2 2013.
0-4% Fetal Fraction too low to report
4-8% Intermediate fetal fraction – decreased sensitivity with counting methodology
8%+ Fetal fraction adequate to achieve best performance
www.wellingtonobstetrics.co.nz
Understanding Discordance • Maternal contribution • Sex chromosome abnormalities in the mother1
• Vanishing twins • Vanishing twin with an abnormality can cause incorrect fetal results2
• Gender • Incorrect gender calls can cause complicated clinical care and unnecessary concern3 Wang et al. Clinical Chemistry 2014; v. 60, p.251-259. et al. Prenat Diagn 2013 Jun;33(6):569-74. 3Bretelle F, et al. Ultrasound Obstet Gynecol. 2002: 20: 286-289. 1Yanlin
2Futch,
www.wellingtonobstetrics.co.nz
Twin Gestations • More difficult to analyze because each fetus will release different amounts of cfDNA • Increased no-call rate – Doubled by one counting method (Struble 2014)
• There is limited data – <200 total samples in any study – 4-11 positives
www.wellingtonobstetrics.co.nz
Company Comparison- Twins Sequenom1 MaterniT21 PlusTM
Verinata2 Verifi速
Ariosa3 HarmonyTM
Number of total cases
25
115
207
Number of abnormal cases correctly reported
8
4
11
Failure rate
Not reported
Not reported
7%
False negatives
Not reported
Not reported
1
1. Canick et al. DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenatal Diagnosis, August 2012 2. www.verifitest.com 3. Gil et al. Cell-Free DNA Analysis for Trisomy Risk Assessment in First-Trimester Twin Pregnancies. Fetal Diagnosis and Therapy, 2014
www.wellingtonobstetrics.co.nz
How good is Non-Invasive Prenatal Testing? • Moving target • Currently literature is primarily from companies or those holding patents • *ASHG Oct
Overall ranges T21
T18
T13
Specificity (%)
99-100
99-100
99-100
Sensitivity (%)
98-100
97-100
79-100
Positive Predictive Value [PPV] (%)
90-95*
84*
52*
Negative Predictive Value [NPV] (%)
99.9
99
100
www.wellingtonobstetrics.co.nz
â&#x20AC;˘ By far most accurate performance for T21/18 Benn et al, Ultras Obstet Gynecol 2013, 42: 15-33
www.wellingtonobstetrics.co.nz
NIPT in a Low Risk Population • Studies suggesting FPR and failure rate should be consistent1 – Larger studies are coming from multiple companies
• Fetal fraction seems to have largest impact on results – SNP method uses DNA, which shouldn’t change with indication – Fetal fraction not correlated with risk category3 1Brar,
et al. 2012. J Matern Fetal Neonatal Med. et al. 2013. Prenat Diagn. 3Hudecova et al. 2014. PLoS ONE. 2Canick
www.wellingtonobstetrics.co.nz
Low Risk - False Positive Rate False positive rate for NIPT is significantly lower than traditional maternal serum screening.
NIPT MSS
Trisomy 21 FPR
Aneuploidy + Microdeletions FPR 1Bianchi, 2
www.wellingtonobstetrics.co.nz
et al. NEJM. Natera Internal Data.
What is a microdeletion? • 1MB (megabase) = 1 million base pairs • Microdeletions are 100kb to several MB • Karyotype can usually only visually detect >7-10 MB
Outcome will depend on the size & the genes involved
www.wellingtonobstetrics.co.nz
High Incidence Conditions Incidence out of 100,000 Live Births
1Nussbaum
et al 2007. Thompson and Thompson Genetics in Medicine (7th edn). Oxford Saunders: Philadelphia 2http://www.genetests.org. 3http://ncbi.nlm.nih.gov
www.wellingtonobstetrics.co.nz
Common microdeletions included on panels • 22q11.2 deletion/DiGeorge • • • •
1p36 deletion Angelman Prader-Willi Cri-du-chat
Cardiac indications on ultrasound but many missed
Vast majority missed on ultrasound
www.wellingtonobstetrics.co.nz
Benefits of NIPT • Fewer women having diagnostic tests – associated risk of pregnancy loss
• Early test result (drawn at ≥ 9-10 weeks at earliest) • No risk of miscarriage • Detects the most common chromosomal aneuploidies • Higher detection rates and lower false positive rates than CFTS
www.wellingtonobstetrics.co.nz
NIPT Landscape •
Increasing demand from women
•
Increasing uptake in most (urban) centres
•
3 separate companies, 3 separate technologies Has NIPT become “standard of care”?
• •
Costs between $595 and $1200
•
8-10 days for result
www.wellingtonobstetrics.co.nz
INTEGRATION OPTIONS www.wellingtonobstetrics.co.nz
What about the 12 week scan? • 11 to 14 week scan has value to pregnancy care – Raised NT may suggest other chromosomal, genetic and structural disorders – Accurate dating/establishment of live fetus – Multiples/chorionicity affects management – Detects structural abnormalities www.wellingtonobstetrics.co.nz
Examples of integration Option One • Offer to all at beginning • Have CFTS as usual • NIPT used as modifier to the priori risk • Invasive testing
– Structural anomalies – High risk – Wishes for definitive testing
Option Two • Offer to high risk patients • Risk probably 1:20-1:1000 • Invasive testing if – Risk >1:20 – Structural anomalies – Definitive result desired
www.wellingtonobstetrics.co.nz
High Risk Screening Algorithm WOMEN SHOULD BE OFFERED INVASIVE TESTING ACOG PRACTICE BULLETIN #88, 2007 ACMG GUIDELINES 2009
Want further information but do not want risk of invasive procedures
Do not want further information
Women who want to know everything
SCREENING
Detailed ultrasound is still recommended for all patients regardless of testing decisions. Nuchal translucency provides information beyond fetal aneuploidy status.
Serum Screening
NIPT
11-13 wks and/or 15-22 wks
>_9 weeks
5%
<1%
2-3 Conditions T21 T18
Chromosome! Conditions T21 T18 T13 Triploidy X,Y
Microdeletions** 22q11.2 1p36 Angelman Cri-du-chat Prader-Willi
www.wellingtonobstetrics.co.nz
Amniocentesis or CVS
www.wellingtonobstetrics.co.nz
Thank you!!
www.wellingtonobstetrics.co.nz