Assisted Reproductive Technologies Research

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The Liggins Institute and Fertility Associates: Assisted Reproductive Technology Research Studies 

The effect of in vitro fertilisation (IVF) on childhood growth and metabolism.

Scientists: Dr Harriet Miles, Dr John Peek (Fertility Associates) and Prof Wayne Cutfield.

Research summary: This experiment was one of the first in the world to examine the long-term effects of IVF on the resulting children, rather than investigating short-term changes in gene expression of the embryo before implantation. Growth and metabolic (glucose tolerance) parameters were determined in IVF children and control; naturally conceived, contemporaries.

Key findings include the following:
• IVF children are taller, especially female offspring, when corrected for parental height than their contemporaries.
• No differences in body composition were evident between the two groups.
• The metabolic profiles differed in IVF children, who had higher plasma IGF-I and IGF-II concentrations and have a slightly more favourable lipid profile than controls.

The findings are published: Miles HL, Hofman PL, Peek J, Harris M, Wilson D, Robinson EM, Gluckman PD, Cutfield WS (2007) In vitro fertilization improves childhood growth and metabolism. J Clin Endocrinol Metab 92: 3441-3445.

The influence of IVF methods on childhood growth and metabolism

Scientists: Dr Fran Mouat, Dr John Peek (Fertility Associates) and Prof Wayne Cutfield.

Research summary: Previous phenotypic differences in IVF children established by our previous research were investigated further by examining the effect of generating IVF pregnancies from fresh or frozen embryos. In IVF procedures, approximately 70% of embryos are transferred back immediately after treatment, whilst 30% are frozen and transferred at a later time. Embryos that are frozen usually have reduced quality compared to freshly transferred embryos. In addition frozen embryos have to survive the freeze thaw process unlike their fresh counterparts. Hence the research focussed on establishing whether both of these factors resulted in changes in a child’s phenotype; measured by growth and metabolic parameters, compared to fresh IVF and naturally conceived (control) embryos.

Key provisional findings include the following:
• IVF children are taller (both fresh and frozen), especially female offspring, when corrected for parental height than their contemporaries. Children from fresh IVF children are significantly taller than frozen IVF children, and these in turn are taller than naturally conceived controls.
• The metabolic profiles of the children involved are currently being analyzed.

Provisional findings from the study highlight that IVF regimes alter the growth and development of the early embryo, which is still evident into childhood.

Identifying early embryonic predictors of childhood phenotype

Scientists: Dr Mark Green, Dr John Peek (Fertility Associates) and Prof Wayne Cutfield.

Research summary: Changes in the phenotype of IVF children identified from two previous studies by our group have lead to the question of whether early embryonic predictors of these changes can be identified. In a retrospective study of these IVF cohorts, greater than 30 criteria; parental, embryonic and environmental, will be used to investigate the correlation of these criteria to the differences in offspring phenotypes identified. It is also postulated that if identified, such a predictor could also be used to select the highest quality embryos for transfer that would have the greatest chance of establishing a successful pregnancy.

Key questions to be addressed include the following:
• Are early predictors of childhood phenotype able to be identified from the retrospective study?
• Which of the three criteria types; parental, embryonic and environmental, has the greatest influence on future phenotype, or do all of these contribute equally to phenotype?
• Can a predictor be utilised by embryologists in the future to select the highest quality embryos for transfer that would have the greatest chance of establishing a successful pregnancy?

The project will hopefully provide important information regarding criteria that can be assessed at the embryonic stage of development to predict future phenotype, and also potentially the establishment of a successful pregnancy.

Determination of the affect of IVF stimulation regimes on oocyte quality in young and old females

Scientists: Dr Mark Green, Dr John Peek (Fertility Associates), Prof Ken McNatty (Victoria University) and Prof Wayne Cutfield.

Research summary: Human ovarian stimulations rely on the use of a variety of drugs, dosages of drugs and different drug combinations to increase the number of oocytes that can be harvested for IVF. Despite this, a successful outcome is far from certain, as less than 10% of oocytes collected in human IVF typically result in the birth of a child. Data from IVF suggests 50-70% of human embryos are aneuploid (have an incorrect number of chromosomes) in women in the mid-30s, rising to 90% around 40. Hence the focus of the current study is to investigate in an animal model, through manipulation of ovarian stimulation protocols, how the efficiency of IVF regimes can be increased and whether increased dosages of stimulation drugs are detrimental to oocyte quality and development. Specifically, the rate of aneuploidy and the level of expression of genes concerned with metabolism and hormone production by the oocyte and surrounding cells will be examined. Moreover, this study will identify the variation in response of females in relation to maternal age.

Key questions to be addressed include the following:
• Does the tailoring of ovarian stimulation protocols by using hormone concentrations closer to natural occurring concentrations increase oocyte quality and reduce the rate of aneuploidy, thereby increasing overall IVF efficiency?
• Could the identification and measurement of the expression level of key metabolic and hormone regulatory genes in the cells surrounding the oocyte be used as a reliable non-invasive predictor of oocyte and ultimately embryo quality?
• Does maternal age compromise the ovarian response; both follicle number and quality, to stimulation protocols?

The project will provide important information regarding the affect of exogenous hormone stimulation regimes on the quality of oocytes and the efficiency of the IVF process.

The effect of maternal age and IVF procedures on offspring characteristics

Scientists: Prof Wayne Cutfield, Dr Tim Savage and Dr Mark Green.

Research summary: This research will be undertaken in humans and will examine whether children born to older mothers or born as a result of infertility treatments, show differences in growth and metabolism. The theme of the project focuses on the long term consequences and mechanisms of assisted and delayed reproduction; events that are becoming more prevalent in developed populations.

Key questions to be addressed include the following:
• How does maternal age impact on childhood growth and development and on metabolic function?
• Are these alterations in growth and development underpinned by changes in epigenetic regulation in the early embryo?

The project will provide important information regarding the clinical management of children born through assisted reproductive technology or to older first-time mothers, and will also improve our basic scientific understanding of early epigenetic regulation of embryonic growth, potentially leading to changes in human IVF methodology.

Fundamentals of epigenetics in human and livestock development.

Scientists: Prof Ian Morison (University of Otago) and Prof Wayne Cutfield.

Research summary: This is a series of experimental projects that aims to identify epigenetic variation that leads to variation in human phenotypes. The projects focuses on the hypothesis that during embryo development in vitro, there are significant changes in the epigenetic regulation of genes that impact on growth, development, and adult disease phenotypes.

Key questions to be addressed include the following:
• Does the profoundly abnormal ex-utero environment associated with IVF lead to measurable epigenetic perturbation?
• What are the major differences in DNA methylation that distinguish placental tissues from somatic tissues, and to what extent might variation in this methylation contribute to altered placental function, and subsequent fetal growth abnormalities?
• Which genes and genomic regions show epigenetic variation, which of these can be associated with candidate epigenetically-mediated post-natal phenotypes?

Answers to these questions will begin to test the hypothesis that post-natal human developmental and disease phenotypes are controlled by epigenetic modifications early in embryonic development.


About the Scientists

Professor Wayne Cutfield MBChB, DCH, FRACP
Deputy Director , Liggins Institute

Wayne Cutfield is a paediatric endocrinologist and an expert on insulin sensitivity and action in children. He is Director of Endocrinology at Auckland's Starship Hospital, and co-ordinates the paediatric training programme for the Royal Australasian College of Physicians. As Director of the Liggins Institute's Maurice and Nessie Paykel Clinical Research Unit he leads clinical research which shows how environmental influences early in life can affect childhood growth and development in ways that could lead to chronic conditions in adult life. He is currently president of the Asia Pacific Paediatric Endocrine Society, a large regional umbrella society representing 15 countries and over half the world’s population.




Dr Mark Green BSc (Hons), PhD
Research Fellow, Liggins Institute, NRCGD

Mark Green is a reproductive physiologist who completed his PhD on the effect of progesterone concentration on early embryo development at the University of Nottingham, UK. Following his PhD Mark undertook a two year postdoctoral fellowship at the University of Missouri USA investigating how nutrition influences embryonic sex ratio and growth both in vivo and in vitro, as well as the signalling involved in the maternal recognition of pregnancy. In 2004 Mark joined the Liggins Institute after becoming the inaugural recipient of the Maurice Paykel Postdoctoral Fellowship working on the relationship between maternal nutrition and early fetal development. He currently holds a joint appointment with AgResearch Ltd and continues his research into factors that influence early embryonic development and the subsequent phenotype of the offspring. Recently, he embarked upon research with Fertility Associates that aims to improve the efficiency of in vitro reproductive technologies in humans


John Peek PhD
Group Operations Manager, Fertility Associates

John is the Group Operations Manager for the Fertility Associates clinics, and also oversees science, research and development. After gaining his degrees in aspects of medical research, John worked in one of the pioneering IVF units in the early 1980s in Adelaide, Australia, before heading the Infertility Laboratory at National Women's Hospital in 1984, and then science at Fertility Associates in 1987.