Does spending the first 5 days of your life in a test tube affect your health? Lessons from In Vitro Fertilisation

Professor Daniel R Brison, PhD, FRCPath St Mary’s Hospital

Manchester University of Manchester

Ageing, health and early life development: insights from embryology and paediatrics on later life outcomes. MICRA June 23rd, 2015

• In Vitro Fertilisation (IVF) as an artificial intervention in human reproduction

• Long term health of IVF babies

• IVF as an example of early programming of health

Summary

St Mary’s Hospital

IVF x1600 NHS cycles p.a. ~100 clinical staff ~30 scientific staff

Est. 1983

Clinical & Research mission:

“healthy singleton IVF baby with a normal long term health outcome”

Ovarian reserve

AMH FSHR

UK NEQAS

Reproductive Sciences

Embryology STP

RCOG European Academy

of Andrology

Cancer Fertility

Cryopreservation- ovary oocyte

embryo

IVF outcome

data modelling

Oldham General Hospital

July 25th 1978

1:6 couples worldwide suffer infertility Originally, inability of sperm to meet egg (fertilisation) Fertilisation in the lab! Since 1978, >5million IVF babies born 2% (15,000 p.a.) of all UK live births now IVF (ONS, 2011) 60,000 p.a. UK cycles, 70% privately funded

Laboratory and clinical practices in IVF have the potential to affect 10s of 1000s of babies born annually.

Impact of Human IVF

How does IVF work? 5 days after fertilisation

IVF

ICSI

Fertilisation Check

Embryo Monitoring

Pregnancy

Egg Collection

Sperm Collection

and Preparation

Embryo Freezing

Monitoring

Ovarian Stimulation Embryo

Transfer

Embryo Research Follow up

Research

Timelapse monitoring of human embryo

development

Telegraph, Monday 10/11/14

Sex will soon be just for fun not babies, says father of the Pill

Professor Djerassi said that advances in fertility treatment made it much safer for

parents without fertility problems to consider IVF Photo: Alamy

Sex could become purely recreational by 2050 with large numbers of babies in the Western world born through IVF, the professor who invented the contraceptive pill has claimed

Vast majority of IVF babies are healthy…

“We now know that poor fetal growth and small size at birth are followed by increased risk of coronary heart disease, stroke, hypertension, Type-2 diabetes, and osteoporosis.”

Theoretical framework: emphasizes the vulnerability and long-term influence of the very early stages of life including the pre-implantation and perinatal periods of development

Epigenetic re-programming: translation of external influences on the maternal environment into adaptive responses in embryonic and fetal development during peri-conception period of life

Birth weight is a valuable proxy for fetal growth

Early child growth is also important

-David J. P. Barker, 1995

Parenting (and Health) before conception Environmental effects on embryogenesis. During progression from

conception, through first cleavage to morula and blastocyst stages [(A) to (E),

respectively], a preimplantation embryo is vulnerable to perturbations in its

nutritional, biochemical, and physical environment.

Michelle Lane et al. Science 2014;345:756-760 Published by AAAS

1.Embryonic genome, 2.Epigenetic remodelling, 3.Cell allocation to

ICM/TE

Life course leading to health/disease • Maternal/paternal exposures (gametes) • Embryonic development

• Fetal growth trajectory • Birthweight • Child growth

• Indications of early onset adult diseases

• hypertension, insulin resistance • Early onset adult diseases

• type II diabetes, metabolic disease, • cardiovascular problems, stroke)

OOCYTE AGE

EMBRYO CULTURE

EMBRYO FREEZING

EMBRYO GENE EXPRESSION

Embryo cDNA archive

hESC lines

Sue Kimber, Helen Smith

Human ART

OUTCOMES, BIRTHWEIGHT

HFEA register and clinic data

Steve Roberts, Mark Hann, Catherine Castillo

CHILD HEALTH

HFEA register 1990-2009 linked to perinatal and child

health databases

Steve Roberts, Nick Macklon, Mark Hann

• Increased risk of stillbirth & neonatal death (Pinborg 2010, Marino 2014)

• Lower average birth weight within normal bounds (Henningsen 2011)

• Increased rates of LBW and PTD (Schieve 2002, Henningsen 2011, Camarano 2012, Frangez 2014, Marino 2014)

• Increased rates of chromosomal and musculoskeletal birth defects (Hansen 2002)

• Gene expression differences found in placenta and cord blood (Katari 2009; Song 2015)

IVF vs. Spontaneously Conceived Offspring

• Cardiac characteristics (Valenzuela-Alcaraz 2013)

• Increased central, peripheral and total adiposity in pubertal girls (Belva 2012)

• Increased blood pressure & fasting glucose levels in children (Ceelen 2008)

• Hart and Norman, 2013; Kamphuis 2014

IVF: Longer-term Outcomes

Post-natal Health Outcomes of IVF Offspring

• Fresh born smaller than frozen (Pinborg 2010, Henningsen 2011, Kato 2012, Nakashima 2013); accelerated catch-up growth & more favourable lipid profiles in childhood (Green 2013)

• Frozen: Reduced rates of LBW (Kalra 2011), PTD (Pinborg 2010), and SGA (Pelkonen 2010) but increased rates of LGA (Ishihara 2014, Pinborg 2014), macrosomia (Marino 2014) and perinatal mortality (Wennerhold 2013).

Fresh vs. Frozen-thawed

• Blastocyst: increased rate of PTD (Dar 2013, Kalra 2012), increased risk of LGA (Ishihara 2013).

Blastocyst vs. Cleavage Stage ET

• Birth weight differences between Cook & Vitrolife culture media (Dumoulin 2010, Nelissen 2012); other studies found no differences between other media (Eaton 2012, Vergouw 2012) Zandstra 2015

Culture Medium Effect

• Fresh cycles: increased incidence of FGR, placenta previa, pregnancy-induced hypertension (Farhi 2010), SGA & PreE (Imudia 2012/2013)

Oestrogen levels during treatment

Post-natal Health Outcomes of IVF Offspring

OOCYTE AGE

EMBRYO CULTURE

EMBRYO FREEZING

EMBRYO GENE EXPRESSION

Embryo cDNA archive

hESC lines

Sue Kimber, Helen Smith

Human ART

OUTCOMES, BIRTHWEIGHT

HFEA register and clinic data

Steve Roberts, Mark Hann, Catherine Castillo

CHILD HEALTH

HFEA register 1990-2009 linked to perinatal and child

health databases

Steve Roberts, Nick Macklon, Mark Hann

Dumoulin et al., 2010

Birthweight distributions of live born singletons resulting from embryo

culture in two commercial sequential media

Zandstra et al., 2015

Reviewed:

• 11 studies of culture

medium and birthweight

• 5 show a difference

• Many animal studies

In IVF, “maternal” nutrition takes place in the test tube!

Marie Curie Initial Training Network grant; Catherine Castillo

The impact of IVF variables on birthweight

Figure 1: The IVF procedure as an environmental influence on birth outcomes. (A) the disappearance of one

twin/multiple due to miscarriage may affect the remaining embryo’s growth; (B) Embryo quality may be directly affected by

the IVF laboratory environment or related to parental characteristics; (C) Fresh cycles involve replacement of embryos into

a hormonally-altered maternal environment which may have a direct impact on the placenta and, in turn, fetal growth.

OOCYTE AGE

EMBRYO CULTURE

EMBRYO FREEZING

EMBRYO GENE EXPRESSION

Embryo cDNA archive

hESC lines

Sue Kimber, Helen Smith

Human ART

OUTCOMES, BIRTHWEIGHT

HFEA register and clinic data

Steve Roberts, Mark Hann, Catherine Castillo

CHILD HEALTH

HFEA register 1990-2009 linked to perinatal and child

health databases

Steve Roberts, Nick Macklon, Mark Hann

Gene expression during Preimplantation Human Embryonic Development

Niakan, Development 2012;139:829-841; Braude, 1988

Following fertilisation: maternal mRNA degradation/de-adenylation Between 4-8 cell stage: Embryonic Genome Activation (EGA) • Following EGA

Compaction to form morula

• Cavitation to form Blastocyst.

Lineage specific gene expression occurs late in development at blastocyst formation Human embryo development is heterogeneous

Lisa Shaw, Helen Smith, Ben Minogue, Aaron Webber, Maria Keramari

ICM

TE

Shaw et al., 2012; 2013

OCT4, REX1

EOMES ALTERED IN

FROZEN

EMBRYOS

OOCYTE AGE

EMBRYO CULTURE

EMBRYO FREEZING

EMBRYO GENE EXPRESSION

Embryo cDNA archive

hESC lines

Sue Kimber, Helen Smith

Human ART

OUTCOMES, BIRTHWEIGHT

HFEA register and clinic data

Steve Roberts, Mark Hann, Catherine Castillo

CHILD HEALTH

HFEA register 1990-2009 linked to perinatal and child

health databases

Steve Roberts, Nick Macklon, Mark Hann

• IVF has brought joy to millions of couples

• Vast majority of IVF babies are healthy

• Artificial intervention in human reproduction

• Long term health of IVF babies

• IVF as an exemplar of early programming of adult health

Summary

Thank You

St. Mary’s Hospital IVF Ricop Dongal Gregory Horne

Dr. Cheryl Fitzgerald Tope Adeniyi

Dr. Vinay Sharma Karen Thompson Natalie Proctor

Dr. Stephen Troup Hannah Newby Stephen Evans

Dr. Deborah Falconer Dr. Anamika Rao

Claire Kay Alan Birks

Dr. Helen Clarke Rachel Cutting

Mostafa Metwally

Su Barlow Dr. Gill Lockwood

Alison Campbell

University of Manchester

Sue Kimber

Helen Smith

Sharon Sneddon

Lisa Shaw

Robbie Kerr

Ben Minogue

Aaron Webber

Adam Stevens

Steve Roberts

Mark Hirst

Mark Hann

Catherine Castillo

St Mary’s

Greg Horne

Helen Hunter

Ruth Arnesen

Tope Adeniye

Lucy Dwyer

Claudette Wright

Karen Talbot

Sue Kimber

Nicola Bates

Clare Edmond

Lisa Grady

Maria Keramari

Jinpei Ye

Ben Minogue

Robbie Kerr

Alex Ross

EpiHealth

Andras Dinnyes

Tom Fleming, Nick Macklon

Anne Ferguson Smith

Mathew Trotter