2015 Women's Health Conference Presentations

Public Funding for Fer0lity Dr Olivia Stuart Fer.lity Specialist

Initial Fertility Consultation Fer.lity specialist • Public • Private

Private consultation option • Pa.ents can self refer • Pa.ents can choose their fer.lity specialist • No mandatory tests required pre-­‐referral • Fer.lity Associates’ specialists can see new pa.ents within 2 weeks in all our clinics • consulta.on, scan, organise all their tests, assessed for public treatment, nurse

Public consultation • Condi.ons apply • Referring doctor needs to do a preliminary workup • Wait .me 3-­‐4 months • Randomly allocated to one of 3 Auckland units, no choice

Eligibility criteria for public consultation NZ residency Both partners must have • NZ residency, citizenship or • Work visa showing at > 2 years

Additional criteria for initial consultation

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 • Clinical Priority Access Criteria (CPAC) form • Criteria are the same across New Zealand • People need > 65 points using the fer.lity CPAC scoring tool • Score > 65 means eligible • All have same wait .me .l treatment • The CPAC score can only be calculated by a fer5lity specialist.

CPAC Form

6

> 65

Couple A – Unexplained Infertility 10 10 1 50 30 20 6

100

Couple B – Male vasectomy 10 10 1 40 30 10 6

80

Couple C – Same sex couple 10 10 1 20 30 20 6

70

Waitlist for treatment • The wait to treatment varies across the country • Generally 12–18 months • Pa.ents can access private fer.lity treatment whilst on the public wai.ng list

Second publicly funded packages

• • • • •

Requires rescoring All same eligibility criteria apply S.ll need CPAC score > 65 wait .me less Same unit

Treatment pathways to having a baby‌

All public…

First Appointment Public ($0) 6 Months

Laparoscopy Public ($0)

Couple Start Trying

3 Months

12 Months

See GP

6 Weeks

Follow Up Public ($0) Need IVF 6 Weeks

Funded Appointment FA ($0) 12 Months

Funded IVF ($0)

• Do everything Publicly Funded • Total Cost $0 • Total Time from GP to IVF – 24 months

Public and private 1…

Couple Start Trying

First Appointment FA ($270)

12 Months

See GP

Laparoscopy Public ($0)

2 Weeks

6 Months

2 Weeks

Funded IVF ($0) 12 Months

Follow Up Private ($165) Need IVF

• 1st Appointment in Private then Lap and IVF Public • Total Cost $435 • Total Time GP to IVF – 19 Months

Public and private 2…

Couple Start Trying 12 Months

First Appointment FA ($270) 2 Weeks

Laparoscopy Public ($0)

See GP 6 Months

2 Weeks

Follow Up Private ($165) Need IVF 4 weeks

• 1st Appointment in Private then Lap in Public and IVF Private • Total Cost $10435 • Total Time GP to IVF – 8 Months

Private IVF ($10,000)

All private…

Couple Start Trying 12 Months

First Appointment FA ($270) 2 Weeks

See GP

2 Weeks

Laparoscopy Private (?

Insurance) 2 Weeks

• 1st Appointment in Private then Lap and IVF Private • Total Cost $10435 +/-­‐ Lap cost (insurance) • Total Time GP to IVF – 10 weeks

Follow Up Private ($165) Need IVF 4 weeks

Private IVF ($10,000)

On the horizon…

• Male smokers • Unexplained infer.lity for > 3 years in > 36 year old women • BMI < 36

Ques0ons?

Infertility Diagnosis When to refer?

Whatâ&#x20AC;&#x2122;s New? Dr Simon Kelly Medical Director Fertility Associates, Auckland

Look how far we have come?

The amazing story of IVF: 37 years and 5 million babies later!

Infertility â&#x20AC;˘ 1 in 7 couples â&#x20AC;˘ Age single most important factor Combined 10%

Other 5%

Male 30%

Unexplained 25%

Female 30%

When to refer?

• Trying for 12 months • Ask about contraception

Infertility: (n) A medical condition that diminishes self-esteem, your social life as well as your checking and savings accounts. Causes sudden urges to pee on sticks, cry,scream and a fear of pregnancy announcements.

Treated by a Medical Specialist who you pay to knock you up-this does not always work Affects about 1 in 10 couples

Who to refer?

• Consider early referral if: • >35yrs • Irregular or absent periods • Medical or surgical conditions that may affect fertility eg endometriosis/pelvic surgery/chemo or radiotherapy • Family history early menopause • Recurrent miscarriage • Genetic conditions amenable to PGD • Patient Request

Free Nurse Consult - available for your patients • 15 minute phone consult with a fertility nurse • Answers questions like: • When to seek help • Treatment options • Costs • Public funding • Their % chance of having a baby • Chinese speaking Free Nurse Consult now available

Investigations • Male • Semen Analysis • Hep B/C/HIV • Female • FSH/Estradiol day 2-4cycle • Thyroid function • Rubella status/ Hep B/C HIV • Prolactin if irreg cycles/galactorhoea • HSG or HYCOSY if suspect tubal disease or previous PID* • Ultrasound* • AMH* • Chlamydia swabs • Check smear current

Advice- Improving Fertility •Start Folic Acid and Iodine •Minimize alcohol •Reduce caffeine consumption •Stop smoking •Maintain ideal BMI (20-25) •Improve diet •Exercise •Reduce Stress

New Diagnostic Tools • AMH – Currently best measure of ovarian reserve – produced by small follicles as they grow on ovary

• Sperm DNA Fragmentation Testing

AMH

Sperm DNA Fragmentation Testing • High levels DNA fragmentation may be associated with: – Poor fertility outcome – miscarriage

• Causal Factors: – – – – – –

Environmental / pollution exposure Advanced age Varicocoele Drug use Smoking Chronic Disease

Sperm Chromatin Structure Assay - SCSA

Sperm DNA Fragmentation How do we treat?

-Antioxidants -IMSI -Surgical sperm retrieval

Matthew (Tex) VerMilyea, PhD, HCLD/CC

Scientific Director

Technologies

How to Choose the Best Embryo for Transfer? ² Observational Analysis: Embryo Development Morphology Assessment ² Genomic Analysis: Trophectoderm Cell Biopsy ² Transcriptomic / Metabolomic Analysis: Granulosa cells Cumulus cells Culture medium

TiMI

Embryo Development

One frame at a time

TimeLapse Morphometry Imaging

t3

t2

t4

t5

s3

s2

1-cell

cc1 t2: division to 2-cells t3: division to 3-cells t4: division to 4-cells t5: division to 5-cells t8: division to 8-cells

4-cells

2-cells

cc2

t8

8-cells

cc3

cc1: duration of first cell cycle (cc1 = t2-t1) cc2: duration of second cell cycle (cc2 = t3-t2) cc3: duration of third cell cycle (cc3 = t5-t3) s2: duration of transition from two-blastomere embryo to four-blastomere (s2 = t4-t3) s3: duration of transition from five-blastomere embryo to eight-blastomere (s3 = t8-t5)

Photos courtesy of Matthew (Tex) VerMilyea, PhD, HCLD/CC Adapted from Meseguer et al., 2011

ACCEPT

Discard?

DISCARD

(Morphology) INCLUDE

WITHIN RANGE

Exclude?

OUTSIDE RANGE

t5

s2

s2 OUTSIDE RANGE

WITHIN RANGE

cc2 WITHIN RANGE

A+

A-

WITHIN RANGE

B+

OUTSIDE RANGE

WITHIN RANGE

cc2

cc2 OUTSIDE RANGE

EXCLUDE

OUTSIDE RANGE

B-

WITHIN RANGE

C+

cc2 OUTSIDE RANGE

C-

WITHIN RANGE

D+

OUTSIDE RANGE

D-

E

F

ORIGINAL ARTICLES: ASSISTED REPRODUCTION

Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope Irene Rubio, Ph.D.,a Arancha Gal! an, Ph.D.,a Zaloa Larreategui, Ph.D.,b Fernando Ayerdi, Ph.D.,b Jose Bellver, M.D.,a Javier Herrero, Ph.D.,a and Marcos Meseguer, Ph.D.a a

Instituto Universitario IVI Valencia, University of Valencia, Valencia; and b IVI Bilbao, Bilbao, Spain

Objective: To determine whether incubation in the integrated EmbryoScope time-lapse monitoring system (TMS) and selection supported by the use of a multivariable morphokinetic model improve reproductive outcomes in comparison with incubation in a standard incubator (SI) embryo culture and selection based exclusively on morphology.

Design: Prospective, randomized, double-blinded, controlled study.

Setting: University-affiliated private in vitro fertilization (IVF) clinic.

Patient(s): Eight hundred forty-three infertile couples undergoing intracytoplasmic sperm injection (ICSI).

Intervention(s): No patient intervention; embryos cultured in SI with development evaluated only by morphology (control group) and embryos cultured in TMS with embryo selection was based on a multivariable model (study group).

Main Outcome Measure(s): Rates of embryo implantation, pregnancy, ongoing pregnancy (OPR), and early pregnancy loss.

Result(s): Analyzing per treated cycle, the ongoing pregnancy rate was statistically significantly increased 51.4% (95% CI, 46.7–56.0) for the TMS group compared with 41.7% (95% CI, 36.9–46.5) for the SI group. For pregnancy rate, differences were not statistically significant at 61.6% (95% CI, 56.9–66.0) versus 56.3% (95% CI, 51.4–61.0). The results per transfer were similar: statistically significant differences in ongoing pregnancy rate of 54.5% (95% CI, 49.6–59.2) versus 45.3% (95% CI, 40.3–50.4) and not statistically significant for pregnancy rate at 65.2% (95% CI, 60.6–69.8) versus 61.1% (95% CI, 56.2–66.1). Early pregnancy loss was statistically significantly decreased for the TMS group with 16.6% (95% CI, 12.6–21.4) versus 25.8% (95% CI, 20.6–31.9). The implantation rate was statistically significantly increased at 44.9% (95% CI, 41.4–48.4) versus 37.1% (95% CI, 33.6–40.7).

Conclusion(s): The strategy of culturing and selecting embryos in the integrated EmbryoScope time-lapse monitoring system improves reproductive outcomes.

Clinical Trial Registration Number: NCT01549262. (Fertil Steril! 2014;102:1287–94. "2014 Use your smartphone

by American Society for Reproductive Medicine.) to scan this QR code Key Words: Early pregnancy loss, embryo culture, embryo selection, implantation, ongoing and connect to the pregnancy rate, time-lapse Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/rubioi-embryo-culture-selection-morphokinetic-analysis/

I

n recent years, clinical practice efforts have been directed toward improving embryo selection. The

identification of embryos with a higher capacity for implantation means we can reduce the number of embryos for

Received January 17, 2014; revised and accepted July 9, 2014; published online September 11, 2014.

I.R. has nothing to disclose. A.G. has nothing to disclose. Z.L. has nothing to disclose. F.A. has nothing to disclose. J.B. has nothing to disclose. J.H. has nothing to disclose. M.M. has received payment for lectures from Ferring and Merck Serono.

The instrumentation, disposables, and utensils used in this study were fully paid for by IVI. IVI is a minor shareholder in UnisenseFertiliTech A/S, but none of the authors have any economic affiliation with UnisenseFertiliTech A/S. Reprint requests: Marcos Meseguer, Ph.D., Instituto Valenciano de Infertilidad, Plaza de la Policía Local, 3, Valencia 46015, Spain (E-mail: marcos.meseguer@ivi.es).

Fertility and Sterility® Vol. 102, No. 5, November 2014 0015-0282/$36.00 Copyright ©2014 The Authors. Published by Elsevier Inc. on behalf of the American Society for Reproductive Medicine. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/3.0/). http://dx.doi.org/10.1016/j.fertnstert.2014.07.738 VOL. 102 NO. 5 / NOVEMBER 2014

discussion forum for this article now.*

* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.

transfer without reducing the chances of pregnancy in a cycle of assisted reproduction. To this end, different noninvasive embryo selection methods have been designed that provide information on how to distinguish embryos with better prognosis (1) There are different methods of embryo gradation (2), but they are all based on morphology, and evaluation of morphology under microscope is subject to observer subjectivity (1). One of the noninvasive embryo evaluation methods to have come into the limelight in recent years is the time-lapse 1287

• Time-Lapse and multivariable morphokinetic classification tree improves outcomes compared to standard incubators and traditional morphology assessment.

• Ongoing pregnancy rate increased from 41.7% to 51.4% (95% CI P-value .005) • Early pregnancy loss decreased from 25.8% to 16.6% (95% CI P-value .01) • Implantation rate increased from 37.1% to 44.9% (95% CI P-value .02)

Reproductive BioMedicine Online (2014) 29, 729–736

w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m

ARTICLE

Computer-automated time-lapse analysis results correlate with embryo implantation and clinical pregnancy: A blinded, multicentre study Matthew D VerMilyea a, Lei Tan b, Joshua T Anthony a, Joe Conaghan c, Kristen Ivani d, Marina Gvakharia e, Robert Boostanfar f, Valerie L Baker g, Vaishali Suraj b, Alice A Chen b, Monica Mainigi a, Christos Coutifaris a, Shehua Shen b,* a Penn Fertility Care, University of Pennsylvania, 3701 Market St. Suite #800, Philadelphia, PA 19104, USA; b Auxogyn, Inc, 1490 O’Brien Drive, Suite A, Menlo Park, CA 94025, USA; c Pacific Fertility Center, 55 Francisco Street, Fifth Floor, San Francisco, CA 94133, USA; d Reproductive Science Center of the Bay Area, 3160 Crow Canyon Road, San Ramon, CA 94583, USA; e Palo Alto Medical Foundation Fertility, Fertility Physicians of Northern California, 2581 Samaritan Drive, San Jose, CA 95124, USA; f HRC Fertility, 15503 Ventura Blvd, Suite 200, Encino, CA 91436, USA; g Stanford Fertility & Reproductive Medicine Center, 900 Welch Road, Suite 350, Palo Alto, CA 94304, USA

* Corresponding author. E-mail address: sshen@auxogyn.com (S Shen).

Matthew VerMilyea, PhD, HCLD, is Director of Assisted Reproductive Technologies and Andrology Laboratories at the University of Pennsylvania, USA, and Scientific Director of Fertility Associates, New Zealand. He graduated from Cornell University, and received training in human embryology at Shady Grove Fertility, USA. He then obtained his PhD in Epigenetics from the University of Birmingham, UK. Matthew received a postdoctoral fellowship from the Japanese Society for the Promotion of Science for mammalian molecular embryology research at the RIKEN Institute, Kobe. Research interests include non-invasive and uninterrupted embryo culture protocols, time-lapse video imagery, micro-environment culture settings and early embryo histone modifications.

Abstract Computer-automated time-lapse analysis has been shown to improve embryo selection by providing quantitative and ob-

jective information to supplement traditional morphology. In this multi-centre study, the relationship between such computerderived outputs (High, Medium, Low scores), embryo implantation and clinical pregnancy were examined. Data were collected from six clinics, including 205 patients whose embryos were imaged by the EevaTM System. The Eeva scores were blinded and not considered during embryo selection. Embryos with High and Medium scores had significantly higher implantation rates than those with Low scores (37% and 35% versus 15%; P < 0.0001; P = 0.0004). Similar trends in implantation rates were observed in different IVF centres each using their own protocols. Further analysis revealed that patients with at least one High embryo transferred had significantly higher clinical pregnancy rates than those with only Low embryos transferred (51% versus 34%; P = 0.02), although patients’ clinical characteristics across groups were comparable. These data, together with previous research and clinical studies, confirm

http://dx.doi.org/10.1016/j.rbmo.2014.09.005 1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Known Implantation 40% 30%

37% (41/111)

p = 0.003

20% 23% (50/220)

10% 0%

High Eeva High

Low Eeva Low

Multi-well Eeva™ Dish provides individual culture within the same media drop

Eeva Test results provide objective information to assist embryo selection

Eeva System using /me lapse imaging and intelligent computer vision so6ware collects data inside a standard incubator

Using a proprietary algorithm, images are automatically analyzed

How to Choose the Best Sperm for Fertilisation?

WHO ‘Normal Range’ Semen Volume

1.5 ml or more

Sperm Concentration

15 million /ml or more

Proportion of sperm motile

40% or more

PICSI IMSI Proportion& with progressive motility Choosing the Proportion of sperm with normal shape, using strict best criteria sperm • •

32% or more 4% or more

There are several ways to ensure that you are getting the best chance of pregnancy in IVF treatment. This fact sheet summarises the techniques available to help sperm selection in IVF-related treatment.

Conventional IVF: ~100,000 sperm added to each egg Mature sperm bind to a substance called hyaluronic acid (HA) as they make their way through the cells protecting the egg in the human Fallopian tube. This is one of several mechanisms the body is known to use to select a good sperm to fertilise the egg.

ICSI : Poor movement, number and shape ICSI with PICSI • Washed sperm are tested to see what

PICSI may improve pregnancy rates

Conventional In-Vitro Fertilisation

Intracytoplasmic Sperm Injection (ICSI)

Intracytoplasmic Morphologically selected Intracytoplasmic Sperm Injection (ICSI) Sperm Injection (IMSI)

x100 Magnification

x600-6,000 Magnification

Knez et al. Reproductive Biology and Endocrinology 2011, 9:123 http://www.rbej.com/content/9/1/123

Page 4 of 8

• Sperm do not have efficient DNA repair mechanisms.

• Round vacuoles identified in sperm heads are associated with DNA fragmentation.

Figure 1 Classification of spermatozoa selected at 6,000 × magnification into 3 different categories. Class I - spermatozoa of good quality, Class II - spermatozoa of worse quality, and Class III - spermatozoa of poor quality. Legend: a,b,c - spermatozoa of Class I; d,e,f spermatozoa of Class II; g,h,i - spermatozoa of Class III.

• DNA damage caused by Reactive Oxygen Species (ROS) can be associated with age, temp, varicocele, smoking, diet, environmental toxins.

• No implantation after >4 embryos transferred.

embryos at the blastocyst stage were transferred into the uterus on day 5 by the TDT catheter set (CCD, Neuilly, France); if blastocysts did not develop, one or two morula were transfered, whereas lower-cell embryos were not transfered. Biochemical pregnancy was confirmed by the positive serum b-hCG test (> 48 mIU/ml) 15 days after the embryo transfer, and clinical pregnancy by an ultrasound scan of the gestational sac and the embryo heart beats 14 days after the positive b-hCG test.

SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) statistical program for Microsoft Windows was used for statistical calculations. The laboratory outcomes were expressed as fertilization rate (number of fertilized oocytes per injected oocytes), number of blastocysts (%), number of blaststocysts per cycle, and number of cycles with at least one blastocyst (%). The clinical outcomes were expressed as implantation rate (number of implanted embryos per transferred embryos), number of pregnancies, pregnancy rate per cycle, and number of spontanous abortions. For comparing categorical data, the chi-square (c2) test was performed, and Spearman’s rank correlation coefficient was used as a non-parametric measure of statistical dependence between the two variables.

• Poor embryo development from Day3.

Statistics

To evaluate the role of sperm selection by their morphology, the laboratory and clinical outcomes between the IMSI and ICSI groups of couples were compared. The

• Recurrent miscarriage from natural miscarriage.

• Fertility Associates is committed to providing the latest technology to our patients.

• Time Lapse Morphometry Imaging (TiMI) service now available at FA which provides an uninterrupted growth environment and detailed assessment of embryological milestones.

• Intracytoplasmic Morphologically selected Sperm Injection (IMSI) by Ultra-high magnification selection is available and can improve reproductive outcomes.

Matthew (Tex) VerMilyea, PhD, HCLD/CC

Scientific Director

One Healthy BabyTechnologies at a Time.

Thanks for the opportunity!

Fertility Preservation

By Dr Mary Birdsall Chair, Fertility Associates

Freezing Sperm • 60 years ago first human pregnancy from frozen sperm • 60 years ago first sperm bank • Able to freeze low numbers • Use insemination or ICSI

Who Should Freeze Sperm?

• Chemotherapy or radiotherapy or experimental medications • Surgery eg prostatectomy or major pelvic surgery or orchidectomy • Pre vasectomy or geographical challenges • Pre gender reassignment surgery • Sperm donors • Klinefelters 47 XXY

Heterosexual couples

Single women

Donor Sperm

Lesbian couples

Freezing testicular sperm • • • •

Unable to ejaculate Spinal injury Vasectomy Congenital bilateral absence of vas • Azospermia • Testicular cancer

Should young men freeze sperm for later? â&#x20AC;˘ Sperm quality reduces with age â&#x20AC;˘ Increase in schizophrenia, autism, achondroplasia with increasing paternal age

Prepubertal boys and fertility preservation • No mature spermatogenesis • Testicular tissue currently not being frozen • No proven method to transform immature germ cells into functional sperm • In mice: germ cell extraction, cryopreservation and re-injection with recovery of fertility

Spermatogenesis

Funding and the Law • Pre cancer treatment sperm may be frozen free of charge • Usual criteria for public funding for partners apply (woman less than 40, non smoker, BMI 19 to 32) • May be stored for 10 years then must be discarded unless application for extension for storage made to ECART

Women

AMH

Embryo Freezing • First pregnancy - 1983 • Slow cooling • Vitrification • Need consent from both parties to thaw and use • Who freezes embryos ?: surplus from IVF, pre chemo if have a partner and time, social, reduced ovarian reserve

Slow cooling

Vitrification

Programmed equipment

RT

Equlibration with cryoprotectant

Equlibration with cryoprotectant RT

-6째C

seeding

Slow cooling rate

-35째C

LN2

LN2

time time

Vitrification 2013 • • • • •

262 warming cycles 289 embryos warmed (1.1 per cycle) 279 embryos survived (96%) 258 embryo replacement cycles (98%) 115 pregnancies (44%)

Perinatal outcomes in Fresh IVF cycles vs Frozen cycles

Frozen vs Fresh: antepartum haemorrhage

Frozen vs Fresh: SGA

Frozen vs Fresh: perinatal mortality

Fetal Abnormalities Frozen vs Fresh • Reproductive Technologies and the Risk of Birth Defects M Davies et al NEJM 2012 366 1803-13 • South Australia population cohort study of more than 327,000 births • Birth defects 8.3% after IVF vs 5.8% in spontaneous OR 1.47 (CI 1.33-1.62) • No increased risk seen in frozen embryos

Summary Fresh IVF vs Frozen • Frozen embryo cycles appear to have fewer obstetric and perinatal complications compared with fresh IVF cycles • Suggests that ovarian stimulation may have a detrimental impact ? on endometrium • So are frozen embryo pregnancy cycles comparable to spontaneous pregnancies?

Singletons after frozen transfer vs singletons after spontaneous conception Outcome

FET pregnancies

Overall effect (RR, 95% CI)

Caesarean section

2947

1.76 (1.65 - 1.87)

Birthweight <2500g

2947

1.27 (1.05 – 1.52)

Birthweight <1500g

2787

1.51 (1.01 – 2.27)

Delivery at < 37 weeks

2947

1.39 (1.20 – 1.61)

Delivery at < 32 weeks

2947

1.45 (0.98 - 2.13)

Egg Freezing Fertility preservation: cancer, social, religious or ethical objections to embryo freezing, no sperm at IVF, rapid reduction of ovarian reserve • Vitrification • Not funded $10,000 • 3000 babies

Ovarian Tissue Cryopreservation

Ovarian Tissue Cryopreservation • Oncological fertility preservation • Only option for pre-pubescent girls • Laparoscopy required • Malignant cells being re-implanted a concern • 32 babies in world • HRT

Ovarian cryopreservation in NZ â&#x20AC;˘ 46 ovarian tissue samples stored â&#x20AC;˘ Permission to store but not yet an approved procedure â&#x20AC;˘ 2 pregnancies in Australia

Summary • Men: can freeze sperm or testicular tissue • Prepubertal boys: no options • Couples: can freeze embryos • Women: can freeze eggs or ovarian tissue or embryos with donor sperm • Prepubertal girls: can freeze ovarian tissue

Questions from the floor

Babies, bones and body fat percentage Why worry about hypothalamic amenorrhea?

Dr Megan Ogilvie The Endocrine Group Fertility Associates

Outline • What is Hypothalamic Amenorrhea?

• Nomenclature – Female athlete triad – IOC consensus statement – REDs

• How to diagnose – PCOS vs HA

• Why should we worry?

– Bone Density – Future Fertility

• What can we do?

– Multidisciplinary approach – Timing

Too Fat Too Thin or Just Right?

Energy Deficit (Weight/ fat mass loss, reduced nutrition, exercise)

Stress (Physical or psychological)

Leptin Kisspeptins

Hypothalamus GnRH

Pituitary FSH, LH

Ovary Estrogen

Hypothalamic Amenorrhoea Suppressed gonadotropin levels/function due to: chronic energy deficit and/or psychological stress

Lawson EA and Klibanski A (2008) Endocrine abnormalities in anorexia nervosa

IOC consensus Statement: RED-S • Energy deficiency – Balance between energy intake and expenditure – No standard method for assessing energy availability

• Specific sports at high risk – Runners, cyclists, jockeys, ballet

• Possibly effects males (need more studies) – Lowered BMD – Multisystem presentation, can be subtle (Br J Sports Med 2014;48:289)

Relative Energy Deficiency in Sport (RED-S)

Mountjoy et al, Br J Sports Med 2014;48:491â&#x20AC;&#x201C;497.

Anna Smith • • • •

25 year old woman Secondary amenorrhea 9 months Regular periods prior What will you ask her: – No acne, hirsutism – Busy lawyer – 60 hour weeks – Recent relationship break up – 7 hours/ week at gym, low carb diet, gluten free – BMI 21, 5 kg weight loss 1 year ago

Polycystic ovarian syndrome vs hypothalamic amenorrhea HA

PCOS – Periods weight – Androgen excess symptoms – Test, PRL, normal E2 – USS – normal endometrium

– Periods weight – Lanugo hair – E2, LH, FSH – USS – thin endometrium – Spinal osteopenia

Don’t forget a mixed picture

Robin, 2012

Assessment (What to Ask) Take your time with history – often the most informative Aim is early diagnosis and intervention  Current BMI and pattern of weight change  Period pattern with weight change  Menarchal weight  Eating and exercise patterns - specifics  What else is going on - ?psychological stressors

Assessment (What to Measure) Weight, BMI, waist circumference LH, FSH and estradiol levels – FSH 5.4 LH 1 E2 <150 Prolactin, testosterone, TSH, pituitary testing Venous bicarbonate if concerned about purging Pelvic USS – thin endometrium Bone Mineral Density ?Pituitary MRI

Diagnosis o Clinical history o Less periods with energy deficit o Psychological stressors o Personality type â&#x20AC;&#x201C; Type A, goal orientated

o Investigations o Normal prolactin, TSH, T o Low LH and oestradiol o Thin endometrium o Relative spinal bone loss THINK â&#x20AC;&#x201C; hypothalamic amenorrhea

Why Worry?

• Serious end points without intervention: – Clinical eating disorders – Osteoporosis – Infertility

• Physical and emotional well being – Decreased physical performance, injury rate – Decreased cognitive performance

• Endothelial dysfunction due to low oestrogen • High cortisol levels, low IGF1, low T

Effects on Bone • 90% of peak bone mass attained by 18 years • Advantage of weight bearing exercise on bone lost in amenorrheic athletes • Relative spinal BMD loss often seen • Continued amenorrhea – 2-3% loss bone mass/year • OCP ineffective • Transdermal oestrogen possibly

Effects on Fertility • Infertility: anovulatory cycles and shortened luteal phase • Reduced response to treatment: possible reduced pregnancy rates to IVF and increased miscarriage rate

• Adverse pregnancy outcomes: higher risks of pre-term birth and low birth weight

Prevalence of subtle menstrual disturbances among sedentary and exercising volunteers Assessed by daily hormone levels A = sedentary women BMI 22.7 =/- 0.9 < 2 hr/week 100% regular periods

B = exercising women BMI 21.3 =/- 0.2 Purposeful exercise > 2 hr/week 7% oligomenorrheic 37% amenorrheic

De Souza M et al. Hum. Reprod. 2010;25:491-503 Š The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Association between hours of vigorous physical activity per week and fecundability (BMI < 25)

Women age 18 â&#x20AC;&#x201C; 40 yrs Self report of physical activity 12 month study Relationship preserved even when excluding women with BMI < 18.5

Wise et al. Fertil Steril. 2012 May;97(5):1136-42.

Lifestyle Management

Key to the reversal of all complications Multidisciplinary approach: – – – – – – –

Specialist and GP Sports physician Nursing support Dietician Psychologist – CBT/hypnotherapy Psychiatrist Eating Disorder Unit (urgent: BMI<15.5, >4kg in 6/52, medical complications)

Lifestyle Management Need to find a reason relevant to the patient to reverse The art of negotiation

Adequate nutrition and maintenance of BMI within the ‘normal’ range (> 22) Reduce exercise (at least 1 ‘rest day’ per week) Minimise high impact exercise as much as possible

Keep addressing the anxiety caused by changes

It can take 9-12 months of stable weight before menstruation resumes The weight needed for restoration of menses is typically higher than the weight at which menses was lost Discuss body “burn out” Warn that fertility may return quickly Monitor gonadotropins – LH increases first Unclear why some respond quickly – May be a genetic contribution

Take Home Messages Common diagnosis with the potential for long term complications Think about energy balance, not just BMI Limit cardiovascular exercise fuel for exercise Often multifactorial cause so discuss the issues and get support early (be alert to disordered eating) Aim for a multidisciplinary approach

CBT and FHA • 20-week randomized trial CBT vs Ob • 16 normal-weight women BMI 21-23 • < 10 hours exercise/week, no psychiatric diagnosis • 16 CBT sessions – Healthy eating, exercise – Problem solving and coping skills – Body image

• Ovulation returned in 6/8 (CBT) vs 1/8(observation) BMI unchanged Berga et al. Fertil Steril 2003;80:976-981.

Performance consequences of RED-S

Mountjoy et al, Br J Sports Med 2014;48:491â&#x20AC;&#x201C;497.

The Female Athlete Triad

De Souza M J et al. Br J Sports Med 2014;48:289

Copyright Š BMJ Publishing Group Ltd & British Association of Sport and Exercise Medicine. All rights reserved.

Ante Natal Screening An update about the latest screening available in NZ including the new non-invasive prenatal diagnosis Professor Peter Stone Womenâ&#x20AC;&#x2122;s Health Update 14 March 2015

SCOPE • • • • • • • •

Antenatal(pre) natal screening-for what The role of the GP What is currently available Problems at present-how is the process performing?

What is new -NIPT what does it mean for screening what is it used for what are the challenges

NIPT is screening

?

Are you interested in finding out about the health of the baby?

We can be specific about what “health” means

The offer of prenatal screening â&#x20AC;˘ An offer of prenatal screening provides prospective mothers the option of choosing or declining to receive (genetic) information pertinent to their personal situation prior to conception. â&#x20AC;˘ After conception, prenatal screening-diagnosis provides various benefits: it determines the outcome of pregnancy and identifies possible complications that can arise during birth.

It can be helpful in improving the outcome of pregnancy using fetal treatment.

Screening can help couples determine whether to continue the pregnancy and prepares couples for the birth of a child with an abnormality

It is all about the offer- what is being offered and why

The role of the GP-primary carer • At first chance- get involved!

• Lock in pregnancy care • Be part of “life course” approach

~70% women have pregnancy confirmed by GP or FPC Many opportunities to influence care are missed

There is evidence that most women-couples want screening There is also evidence that carers often prejudge woman’s approach to screening

% Women with LMCs by gestation and ethnicity

The question is • Chromosomal • Genetic-identified-known De novo Risk recurrence What goes wrong • Structural • Environmental-Infection with babiesEpigenetic?

And worries • Unknown-multiple abns parents Cerebral palsy Neurodevelop.delay

• What do you want to know?

•

What goes “wrong” with babies Microdeletion syndromes • DiGeorge 22q11 del • Miller Dieker 17p13.3 del • Prader Willi 15q11-13 del • Smith Magenis 17p11.2 del • Wolf Hirshhorn 4p16.3 del • WilliamsBeuren 7q11.23 del

Nonsyndromic Microdel/dup • 16p11.2 Autism • 1q21.1 ID, microceph,cardiac cataracts • 16p13.11 Austism, ID, schizophrenia ID: Intellectual disability Postnatally 15-20% by CMA vs 3% by G-band karyotype

T21 may be in the lexicon of many when they really are thinking of other problems Some NIPT can do some of these

Perceptions T21 could be the lexicon for all this • • • • •

•

Spectrum of disability Extra help at school Sequelae of prematurity-NICU ADHD Cerebral palsy Profound developmental delay-mental retardation Outcomes of structural fetal abnormality

What are the problems?

What are we trying to detect and avoid?

• • • • • • •

Preeclampsia Fetal growth restriction Gestational diabetes Fetal abnormalities* Risk of Preterm birth Obstetric problems current pregnancy Historical problems

3-5% 5-10% 5+% 3% 2-7% 5% 5%

Factors are additive and change risk eg obesity, hypertension, history

What we do now • Current pathways • Antenatal and newborn screening history*-what are key questions?

Bloods, incl HIV,Chlamydia,smear as needed Screening for Down Syndrome and other conditions • Newborn metabolic and audiology

The current pathways and outcomes offer

1stT combined

Nt + 2nd T serum

Increased risk

Low risk 62%

No action

+2ndT serum

Invasive diagnostic Low risk

outcome

1st and 2nd T serum

National Practitioner Guidelines Laminated summary sheet

Most common chromosomal abnormalities • • • • • • •

Trisomy 21 (Downs Syndrome) Trisomy 18 (Edwards Syndrome) Trisomy 13 (Patau’s Syndrome) 45XO (Turners Syndrome) 47XXY (Klinefelters Syndrome) Triploidy 69xxx or 69xxy Mosaics/translocations/inversions

NIPT

Young women are less likely to be screened and less likely to have a T1 screen 35 30

100.0

% births

89.9

% Screens

90.0 80.0

25

91.0

91.9

91.9

83.4 77.1 71.4

70.0

20

60.0 50.0

15

40.0

10

30.0 20.0

5 10.0 0.0

0 Under 16

16–19

20–24

25–29

30–34

35–39

40 and over

15-20

21-25

26-30

31-35

36-40

41-45

>45

Maori and Pacific peoples less likely to be screened, less likely to have T1 screen 70.0 60.0

% births %screens

50.0 40.0

100.0

93.4 87.7

90.0

30.0

80.0

87.3

87.1

Other

Not stated

78.9 67.5

70.0 60.0

20.0

50.0 40.0 30.0

10.0

20.0 10.0

0.0

0.0

MÄ ori

MÄ ori

Pacific peoples

Asian

European

Other

Total screens

Not stated

Pacific peoples

Asian

European

1st T screens (of all screens done)

NZDep v relative amount of screening 140 120 100 80 60 R2 = 0.6647 40

Rich

20

Poor

0 4

4.5

5

5.5

6

6.5

7

7.5

8

Performance Issues in NZ Detection rate

78%

False pos rate

~3%

Ultrasound NT performance standards

Meet standard

22%

Too few scans to analyse Underperforming to 0.4mm Unclassifiable

40% 31% 7%

(nasal bone reporting very low-2 practices only)

>100 sonographers < 25 NT scans /year

We are in a revolution Non Invasive Prenatal Testing

THE LANCET Vol 350 â&#x20AC;˘ August 16, 1997

Presence of fetal DNA in maternal plasma and serum Y M Dennis Lo, Noemi Corbetta, Paul F Chamberlain, Vik Rai, Ian L Sargent, Christopher W G Redman, James S Wainscoat

485

Single base change

Microarrays ď&#x192;

3-4Mb Slide courtesy of Trent Burgess GHSV

Why is NIPT not diagnostic?

• Not only fetal DNA-placental as well • It is a counting exercise with bioinformatics and cut offs • It needs diagnostic tests for confirmation

“Data obtained from a variety of clinical scenarios suggest that the placenta is the predominant source of the circulating fetal nucleic acids, although apoptotic haematopoietic cells may contribute to the pool as well”. Bianchi DW Placenta 2004

73µm

Syncytial knots 53µm

Or

Syncytial nuclear aggregates

Schmorl 1893

NIPT techniques • Massively Parallel Sequencing Fetal chromosome copy number determined by comparing number of sequence reads from chromos of interest to those from reference chromos • SNPs targetted amplification and sequencing of SNPs • Microarray based cf DNA analysis

DANSR- digital analysis of selected regions

Juneau K et al Fetal Diag Ther 2014

Normalised chromosome values

Massively Parallel Sequencing Counting statistics Follow a normal distribution

Cut off determines false positive rate 3SD above mean 4SD above mean

~0.13% ~0.003%

Factors affecting test performance Bianchi D Obstet Gynecol 2012

Maternal Obesity Gestation Chromosome Biology Depth of sequencing Bioinformatics

Effect of Gestation and Maternal weight on fetal fraction

Dars et al 2014

maternal

fetal

Fetal Fraction- important

Reference chromo

Chrom 21

Low fetal fraction may occur in: Overweight Low PAPP-A and low bHCG T18 and T13

Companies need to test and report this It affects the results

Performance 1stT Combined screening

NIPT

• • • • •

• • • • •

Detect rate False neg False pos False pos rate PPV (NZ)

78-88% >20% 95% 3-5% 8%

>99% <2% <2% <1% >80%

NIPT is very attractive as those positive-increased chance are highly likely to be a true positive on diagnostic-invasive testing And also fewer false negatives

DOWN SYNDROME SCREENING APPROACH OBSERVED DETECTION RATES FOR 5% FALSE POSITVE RATES 100%

FPR 0.1%

FPR ~3%

90% 80% Current NZ performance

70% 60% 50% 40% 30% 20%

1:100

1:60

1:40

1:25

1:5

1:4

10% 0%

Age Triple Quad Comb Int cfDNA 1960 1970 1990 2005 2005 2012

OAPR

Meta analysis • • • • •

T21 DR99.2%(98.5-99.6) FPR0.09% (0.05-0.14) T18 DR 96.3%(94.3-97.9) FPR0.13%(0.07-0.20) T13 DR 91.0%(85.0-95.6) FPR 0.13%(0.05-0.26) X O DR 90.3%(85.7-94.2) FPR 0.23%(0.14-0.34) SCA DR93.0%(85.8-97.8) FPR 0.14% (0.06-0.24)

Ultrasound Obstet Gynecol 2015 DOI: 10.1002/uog.14791 Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis M. M. GIL, M. S. QUEZADA, R. REVELLO, R. AKOLEKAR, K. H. NICOLAIDES

Summary of NIPTclinically realistic setting • • • •

T21 DR 100% no false -ve Repeat testing 1.16% (Lau et al 2014) Non reportable-failure rate 0-4.9% (Benn P 2013) T18 DR~100%, T13 DR~91.% (Dan S 2012;Palomaki GE 2012)

Ultrasound Obstet Gynecol 2014; 43: 254–264Non-invasive prenatal testing for fetal chromosomal abnormalities by low-coverage wholegenome sequencing of maternal plasma DNA: review of 1982 consecutive cases in a single centerT. K. LAU, S. W. CHEUNG, P. S. S. LO, A. N. PURSLEY,M. K. CHAN, F. JIANG,H. ZHANG, W. WANG, L. F. J. JONG, O. K. C. YUEN, H. Y. C. CHAN, W. S. K. CHAN K. W. CHOY n=1982cases

Other examples of use of NIPT • Fetal blood group genotyping* Targeted antenatal AntiD Determining surveillance in sensitised women • Fetal congenital adrenal hyperplasia • Cystic fibrosis • Spinal muscular atrophy etc * Available now

Some Companies • ARIOSA (US)

«Harmony» (?array approach)

• VERINATA (US)

«verifi» (Illumina)

• NATERA (US)

«Panorama» (SNP approach)

• SEQUENOM (US)

«MaterniT21»

• BGI (China)

«NIFTY»

• LIFE-CODEXX (Germany) «PrenaTest» Ask about fetal fraction, risk approach, failed test rate, what result is produced, coping with problems such as obesity, claims for twins- “expanded” screens and perhaps lastly cost

Verifir – by Illumina From 10 weeks 7 day turn around 21 18 13, ask doctor other SCAs Can do twins Cost-negotiate

basic verifi® Test screens for: T21 (Down syndrome) T18 (Edwards syndrome) T13 (Patau syndrome) Now a wider option is available for sex chromosomes at no extra charge: Monosomy X (MX; Turner syndrome) XXX (Triple X) XXY (Klinefelter syndrome) XYY (Jacobs syndrome) Fetal sex (XX or XY)—aids in stratifying the risk for X-linked disorders such as hemophilia, Duchenne muscular dystrophy, or cases of ambiguous genitalia, such as congenital adrenal hyperplasia

Panoramaâ&#x201E;˘ provides sensitivity >99% and positive predicted value (PPV) > 91% for Down syndrome. A microdeletion panel (including 22q11.2 deletion syndrome) is also available to provide unparalleled scope and reliability among non-invasive prenatal screens.

MATERNIT21速 PLUS 22q deletion syndrome (DiGeorge) 5p (Cri-du-chat syndrome) 15q (Prader-Willi/Angelman syndromes) 1p36 deletion syndrome 4p (Wolf-Hirschhorn syndrome) 8q (Langer-Giedion syndrome) 11q (Jacobsen syndrome) Trisomy 16 Trisomy 22

From 10 weeks From 5 day turnaround Can expand Can do twins

Request form You do need to have counselled patient and you do need to know what you are requesting

MATERNIT21® PLUS

The clinician has to explain the results and discuss the limitations In practice, probably no difference from currently and for common trisomies Probably much more straightforward as the difference in likelihood of a true pos or neg result Is very wide compared with current tests ( eg 1:2chance of pos versus 1:1000 if negative)

Main difference is that clinicians are dealing with off shore companies and we have little idea of their QA and science We also take all responsibility for outcomes and it is no easy to “call up the lab”

The pathway and outcomes Future

Current Pathway offer

offer

1stT combined Low risk

Increased risk

No action

1stT combined Low risk

No action Invasive diagnostic

outcome

Risk cut off

NIPT

outcome

Increased risk

Invasive diagnostic

A radical option?

Offer* NIPT + scan**

Low risk

High risk Invasive-amnio CVS

outcome • *Be clear and simple what is the question?

• **scan check list- no NT no part charge • Decide best timing of scan and ?do NIPT after

What might be missed-at this time cfDNA may not detect: • rare trisomies • unbalanced structural rearrangements • deletions and duplications • triploidy • marker chromosomes • mosaicism.

Challenges • Making a decision to do it- we have to -it speaks for itself • What are “the other conditions”?

- what trade offs - understanding we get what we ask for - Where would NIPT fit in- for all women or some?

• Costing the format • Getting started in the Lab and validation • Impact on invasives- skills of invasive operators

Cost- its not too bad actually • Funded in Canada • Insurance pays in USA • UK study suggests can be cost neutral (Morris S PLoS 2014)

• Costs vary with Company Techniques eg MPS vs SNPs Volumes Cutoffs in risk (if contingent) What is screened for No one costs false negs

Currently , on bulk contract could get for ~$250 NZ per test

Assumptions Number screened now 45,000 Serum Costs

Identifiable costs Screening and invasives

Serum 120 Scan

112

Total

232

$10,440,000

FPR 3%

1350

Invasives (75%)

1013@$1,000

$1013000

Missed cases

16

?$$$

11,453,000

Total NIPT Costs NIPT

200

Scan

87

Total

287

12,915,000

False pos ~0.1 Invasives (80%) Missed cases Total

~50

50,000

1-2

12,965,000

Not included: Capital costs to set up Falling costs with volumes Doing in a contingent way Changed costs to patients eg cheaper scans less travel, less anxiety, fewer false pos and false negs for trisomies

Summary • • • • • • •

NIPT a great new advance- a new paradigm!!

New era in performance Very low false pos and neg Much more reassuring for women Will further reduce invasive tests Provides a platform for the future- can change It is here now – lets do it well and ?offer to all

Medscape Medical News > Conference News Test for Fetal Abnormalities Finds Maternal Cancer Neil Osterweil March 06, 2015

"I feel like the luckiest person alive," Dr Lee, a San Francisco-based anesthesiologist, When she was 15 weeks pregnant, she underwent a wholebody MRI scan and a 7 cm tumor in the sigmoid colon was detected.

With laparoscopic resection, the surgeons were able to completely remove the tumor. Postsurgical staging showed that it was T3N0M0 colon cancer â&#x20AC;&#x153;The abnormalities seen are not diagnostic of cancer, Dr van den Boom explained. They could come from systemic lupus erythematosus, organ transplant rejection, or other causes, but test results in several cases have come back suggestive of various malignanciesâ&#x20AC;?.

As this expands do we need national and bioethical standards and controls?

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Breast Cancer Update Click to edit Master subtitle style

Wayne Jones

3/17/2015

FRACS

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Sentinel Node Biopsy • 40% lymph node involvement Tumour Click to edit Master title style • U/S and FNA biopsy • Pre-op ID of sentinel node 95%+ • Smaller operation, less morbidity eg shoulder pain, lymphoedema Click to edit Master subtitle style • No difference in DFS or OS v AND Nodal Basin

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Patent Blue V Dye

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Is Axillary Dissection Needed?

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• Micrometastases >2mm – Do ALND

• If 3 or more nodes involved omit ALND if getting systemic tx and DXR (Z-0011 trial, IBCSG 23-01) 3/17/2015

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Breast Reconstruction • Offered to all ‘Mastectomy Patients’

Click to edit Master title style • Psycho-social & sexuality reasons Click to edit Master title style • Immediate or Delayed

• Implants – one or two stage

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Permanent Implants

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Nipple Sparing Mastectomy •Click No increased riskMaster breast cancer if preserve to edit title stylenipple − If >2cm fromMaster nipple, not multifocal Click to edit title style − Frozen Section at surgery

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Radiotherapy •Click All cases PartialMaster Mastectomy for DXR toofedit title style •Click Nodal status important to edit Master title style − Was >3 nodes, now 1 node treated (EBCTG 2014)

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• Partial breast irradiation

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Endocrine Therapy • Aromatase Inhibitors more effective than Tamoxifen

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Chemotherapy rd generation chemo •Click More effective 3 to edit Master title style • Use of multi-agents eg AC & Taxol, FEC & Taxol • Tailor treatment eg basal type, gene array analysis Click to Master • Neo-adjuvant tx edit for Her2 +ve subtitle & “triple style negative” • Management of Her2 +ve Ca <1cm controversial • Consider fertility treatment

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Herceptin (Trastuzumab) • 20% women HER2 +ve Click to edit Master title style • HERA Study – recurrence ↓46% • 12m course $80,000 • Give with chemo • 3m versus 12m?

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