Case Study
Research into the Effects of Sildenafil
Citrate on Severe Intrauterine Growth
Restriction
Gravida Centre of Research Excellence
September 2013
1
Contents
KEY CONCLUSIONS ...................................................................................................................... 3
EXECUTIVE SUMMARY................................................................................................................. 5
1.
INTRODUCTION ................................................................................................................ 7
2.
INTRAUTERINE GROWTH RESTRICTION .............................................................................. 9
2.1
2.2
2.3
2.4
INTRAUTERINE GROWTH RESTRICTION ....................................................................................... 9
ADVERSE OUTCOMES ASSOCIATED WITH IUGR ............................................................................ 9
TREATMENT OF IUGR .......................................................................................................... 12
SILDENAFIL A POTENTIAL TREATMENT OPTION FOR IUGR ............................................................. 12
3.
GRAVIDA’S RESEARCH ..................................................................................................... 14
3.1
3.2
HUMAN IUGR - SILDENAFIL TRIAL .......................................................................................... 14
SHEEP IUGR – SILDENAFIL TRIAL ............................................................................................ 15
4.
BENEFITS OF THE RESEARCH ............................................................................................ 15
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
HEALTH IMPACTS ................................................................................................................ 16
SOCIETAL IMPACTS .............................................................................................................. 17
ECONOMIC IMPACTS ............................................................................................................ 17
BENEFITS TO AGRICULTURE.................................................................................................... 21
COLLABORATION & LINKAGES ................................................................................................ 22
KNOWLEDGE TRANSFER ........................................................................................................ 24
REPUTATIONAL BENEFITS ...................................................................................................... 25
SUMMARY OF BENEFITS ........................................................................................................ 28
2
KEY CONCLUSIONS
Working with its partners and collaborators around the world Gravida has been central to initiating
a major three year trial which will determine whether Sildenafil (Viagra) increases the growth of the
fetus for severe, early onset Intrauterine Growth Restriction (“IUGR”) in humans. Gravida has also
initiated a trial of Sildenafil on sheep with induced IUGR. Key conclusions reached in the Case Study
are:
1. IUGR results in a baby failing to reach its genetic growth potential. It is associated with a
wide range of serious short and long term health issues, particularly when it is severe and
occurs early in pregnancy. A key cause is placental insufficiency which results in the baby
not reaching sufficient oxygen and nutrients as a result of the placenta not being attached
properly or not working correctly. IUGR babies are typically very low birth weight and are
born early.
2. The medical issues associated with IUGR are often serious, distressing for those involved
and can be expensive to treat. These include stillbirth, hypertension (high blood pressure),
neonatal death / Sudden Infant Death Syndrome, hypoglycaemia (low blood sugar level),
necrotizing enterocolitis (bowel tissue death), hypoxic brain injury (caused by a lack of
oxygen), blindness, chronic lung disease, damage to the retina, brain dysfunction and neurodevelopmental impairment, lower nonverbal and verbal IQ, cerebral palsy, chronic lung
disease , attention deficit-hyperactivity disorder, behavioural problems, type 2 diabetes and
cardiovascular disease. Of the IUGR babies born alive between 24 to 28 weeks, 75% survive
to be discharged from hospital, but fewer than 25% are free of major disease or condition.
3. Studies to date indicate Sildenafil has promising potential for use in the treatment of IUGR
through improving uteroplacental blood flow and thereby enhancing fetal growth. Currently
there is no treatment for IUGR other than the early delivery of the baby, which carries a
range of significant health risks. If Sildenafil could enable delivery to be deferred to 30
weeks, the mortality risk would reduce to around 20% and the prospects of survival free of
major disease or disability would improve significantly.
4. For Sildenafil to be successfully incorporated into clinical practice it must first be proven
scientifically to be effective and safe through research of the highest quality in terms of
scope, methodology, integration of multiple scientific and professional disciplines, and
research leadership. Gravida provides this research credibility through the leadership of
eminent maternal fetal health specialist and Gravida Director Professor Philip Baker,
together with Dr Katie Groom (a Senior Lecturer in the Department of Obstetrics and
Gynaecology at the University of Auckland) and an outstanding multi-disciplinary research
team.
3
5. If successful, the trial may allow a delay in delivery which would improve survival rates and
may reduce serious disability and disease associated with IUGR. This is the first major trial
of the use of Sildenafil to treat IUGR in humans and involves international collaboration with
similar trials planned in the UK/Ireland, Netherlands, USA and Canada.
6. IUGR affects 10% of pregnancies which, in New Zealand, is approximately 7500 pregnancies
per annum. Severe IUGR affects around 0.2% which equates to 150 pregnancies per annum.
Ministry of Health Diagnostic Related Groups 2013/14 cost data has been used to calculate
the costs of hospital care for IUGR pregnancies. The costs of care for low birthweight
neonates (less than 2.5kg at birth) have been used as a proxy for IUGR babies, which by
definition are low birthweight. While not all low birthweight babies suffer from IUGR it is the
primary cause. The in-hospital costs for babies suffering from severe IUGR are estimated at
$8.0m per annum which, discounted over 20 years at 7%, has a present value of $84.2m.
The in-hospital costs of non-severe IUGR care are estimated at $39.0m per annum which
discounted over 20 years at 7% has a present value of $412.7m.
7. Some conditions and disabilities associated with IUGR (e.g. hypertension) have significant
links with the incidence of other conditions while others may involve high treatment costs
(e.g. cardio-vascular disease). While the data are not available to calculate the costs directly
associated with IUGR indications are they are very significant. In addition to medical
treatment costs also include educational costs, parental costs, reduced productivity costs.
These could potentially add hundreds of millions of dollars more of additional lifetime costs
for IUGR babies.
8. Any significant positive clinical results of the Sildenafil research are therefore very likely to
have multi-million dollar health, productivity and educational benefits across multiple
cohorts of IUGR babies. The implementation and on-going costs of Sildenafil therapy for
IUGR babies would not be expected to be particularly inexpensive.
9. An adjunct research project is currently underway to administer Sildenafil to ewes which are
IUGR induced. Testing of lamb growth in utero will be used to establish whether Sildenafil
may be an effective treatment option to better ensure lambs’ survival. On a present value
basis the potential savings from improved lamb survival are estimated at $14 million over
5 years and $23 million over 10 years.
4
EXECUTIVE SUMMARY
Research into Effects of Sildenafil on Severe Intrauterine
Growth Restriction
The Problem
Intrauterine Growth Restriction (“IUGR”) arises where a baby suffers
nutritional deprivation in the womb and fails to reach its genetic growth
potential. The primary cause is the placenta not being attached properly
or not working correctly. There is no treatment for intrauterine growth
restriction other than delivery. Being born premature and growth
restricted may result in short and long term health problems including:
 stillbirth
 hypertension
 neonatal death / Sudden Infant Death Syndrome
 low blood sugar level (hypoglycemia)
 necrotizing enterocolitis (bowel tissue death)
 hypoxic brain injury (due to lack of oxygen)
 chronic lung disease
 damage to the retina
 brain dysfunction and neurodevelopmental impairment
 lower nonverbal and verbal IQ
 cerebral palsy
 chronic lung disease
 attention deficit-hyperactivity disorder
 behavioural problems
 type 2 diabetes
 cardiovascular disease
Research to
Date
A number of studies have indicated the promising potential for IUGR to be
treated by administering Sildenafil to improve uteroplacental blood flow.
If delivery can be deferred to 30 weeks, the mortality risk would reduce to
around 20% and may help reduce the many complications that follow and
can lead to life-long disability or disease.
Gravida's Role
Gravida has been central to the collaboration for the international
STRIDER IPD clinical trial, the world’s first major trial of Sildenafil as a
treatment for IUGR. Gravida has progressed the research to where the
trial is underway and will continue with studies to ensure Sildenafil is safe.
Gravida will also be involved in the disseminating trial results.
5
Key Research
Question
The aim of this trial is to determine whether Sildenafil (Viagra) will
increase fetal growth velocity and allow a delay in delivery which may
improve survival and reduce complications that lead to handicap and
disease. An on-farm research study is also being conducted which will
examine the impacts of Sildenafil on pregnant sheep with induced IUGR.
Research
Methodology
This randomised placebo controlled trial will recruit women from
Maternal-Fetal Medicine (MFM) units in Auckland Wellington and
Christchurch and in Australia (Melbourne (2), Sydney (2), Brisbane,
Adelaide and Perth. Women with very small babies <30 weeks will be
invited to take part. They will receive a Sildenafil or placebo tablet up to
delivery (or 32 weeks). All women and babies will be monitored closely.
The trial will demonstrate if Sildenafil improves fetal growth velocity, the
results will also be used in an international collaboration to demonstrate
if Sildenafil improves rates of neonatal survival free of major morbidity.
Potential
Impacts of
Gravida
Research
Health - reduced impact of IUGR resulting in improved short and long
term health outcomes for babies through childhood and into adulthood
Societal – alleviating the impacts on the IUGR baby, parents and family of
outcomes such as still birth, lifelong disability, learning difficulties and
reducing the risk of major metabolic disease later in life
Economic - decreasing the very high health costs of dealing with IUGR
babies and the serious medical conditions often associated with it at birth
and later in life. Lessening the adverse impacts IUGR has on productivity
as a result of impaired mental and physical capabilities. The parallel onfarm project could improve sheep productivity through higher survival
rates and healthier lambs.
High Quality Research – the high calibre team which has designed the
trial methodology in collaboration with international partners and which
will conduct the trial will best ensure high quality research and increase
Gravida’s visibility and reputation.
Knowledge Transfer: - findings will be disseminated amongst maternal
fetal specialists in New Zealand, Australia and internationally at
conferences, in international peer-reviewed journals, and through the
development of new clinical guidelines.
Risks and their
Mitigation
Patient safety is key focus of the study design. A central data safety
monitoring board (DSMB) has been established and will be used by all
national trials. It includes experts in obstetrics, Maternal Fetal Medicine
units, neonatology, clinical pharmacology and epidemiology.
6
1. Introduction
Gravida National Centre for Growth and Development is a collaborative network of six partner
institutions: Canterbury, Massey and Otago universities, the Liggins Institute at the University of
Auckland, AgResearch Ltd and Landcorp Farming Ltd. Together these institutions span the
developmental, biomedical, animal and population sciences. Gravida was selected as a CoRE in
2003 during the second selection round with funding being renewed in the 2008 round.
Gravida conducts research into the biology of mammalian development, which seeks to reveal how
events during pregnancy and childhood influence the health of the individual throughout life. Its
research findings are applied in the clinical, agricultural, public policy and education sectors.
The key concept underpinning Gravida’s research strategy is that the developing organism responds
to its environment from the earliest stages of life, a concept known as developmental plasticity.
Gravida’s research themes fall within four research domains mandated by Gravida’s funder, the
Tertiary Education Commission. The four domains address key aspects of developmental plasticity:
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the origins, evolution and fundamental mechanisms of developmental plasticity
the impact throughout the life-course of environmental factors that induce, mitigate or
reverse plastic responses
the prevalence of plasticity-related changes in livestock and humans, and the application and
effectiveness of interventions that predict, reverse or mitigate their consequences across the
life-course
the economic and societal impacts of plastic responses in humans and livestock, and the
feasibility and effectiveness of proposed interventions.
The importance of Gravida’s scope of activity and targeted research themes is not always easily
discerned. The early stage growth and problems of our unborn and newborn citizens and our farm
animals have critical causal relationships with a wide range of major health and economic outcomes
7
– relationships that are sometimes highly complex, long term and poorly understood. Gravida’s
work covers several scientific domains and involve a number of technological platforms:
This case study is one of two that are illustrative of Gravida’s work. They demonstrate the
exceptional quality and broad value of the CoRE’s research, the prominent researchers and
prestigious international collaborations and the potential substantial return on investment in both
health and economic terms.
The case studies cover research that is consistent with the goal of the Government to lift science
excellence through the CoREs, and also with the Government’s increased focus on children’s
vulnerability, and on research impacts, including health and economic gains.
8
2. Intrauterine Growth Restriction
This case study focuses on trials to study the effects of Sildenafil (Viagra) on pregnancies in humans
and sheep affected by intrauterine growth restriction (“IUGR”). Currently the only treatment option
is to deliver the baby early however this carries significant risks.
2.1
Intrauterine Growth Restriction
Intrauterine growth restriction arises where a baby suffers nutritional deprivation in the womb and
fails to reach its genetic growth potential.1 IUGR, also referred to as Foetal Growth Restriction, is
indicated where the estimated weight of the baby is below the 10th percentile for its gestational
age and its abdominal circumference is below the 2.5th percentile. The cutoff birth weight at term
for IUGR is 2,500gm.
The primary cause of IUGR is placental insufficiency where the baby does not receive sufficient
oxygen and nutrients due to the placenta not being attached properly or not working correctly.
Factors associated with the occurrence of placental insufficiency include: smoking, drinking alcohol,
drug abuse, exposure to infections, certain medications, high blood pressure and genetic disorders.
Survival rates for severely growth-restricted fetuses at less than 28 weeks are dismal, with rates
varying between 7-33%. Those that survive are generally born at 30 weeks or more, but carry
significant risk of neonatal mortality, major and minor morbidity, and long term health
consequences.
IUGR affects approximately 10% of pregnancies; 0.2% are severe. Based on data for pregnancies in
New Zealand for 2008 this indicates approximately 150 cases of severe IUGR and 7500 cases nonsevere IUGR will occur each year in New Zealand.
2.2
Adverse Outcomes Associated with IUGR
The adverse outcomes associated with IUGR, particularly severe early-onset IUGR, include:
Fetus
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IUGR is a major cause of mortality and incidence of perinatal morbidity (disease or medical
condition in the five months before and one month after birth).2 In one study IUGR was
identified as the largest single factor identified in stillborn babies 3
increased likelihood of preterm birth
1
D. G. Jang, Y. S. Jo, S. J. Lee, N. Kim, and G. S. R. Lee, “Perinatal outcomes and maternal clinical characteristics
in IUGR with absent or reversed end-diastolic flow velocity in the umbilical artery,” Archives of Gynecology
and Obstetrics
2
A. A. Baschat, “Fetal responses to placental insufficiency: an update,” BJOG, vol. 111, no. 10, pp. 1031–1041,
2004
3
Journal of Pregnancy, Volume 2011 (2011), Article ID 364381, “Consequences in Infants That Were
Intrauterine Growth Restricted” Cosmi et al
9
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decreased tolerance for birth, resulting in increased likelihood of Caesarean delivery (in one
study the incidence of Caesarean births was 92% in the IUGR group compared with 25% in
the Appropriate for Gestational Age group) 4
hypertension.
Neonate
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increased risk of neonatal death 5
small size at birth
difficulty maintaining body temperature
Sudden Infant Death Syndrome (one study found 30% of babies who succumb to SIDS had
IUGR)6
abnormal blood cell counts
low blood sugar level (hypoglycemia)
weak muscle tone and poor circulation
decreased ability to fight infection
damage to the retina 7
increased likelihood of neurological problems
problems with breathing and feeding
elevated cardiovascular mortality rate 8
necrotizing enterocolitis (bowel tissue death)
hypoxic brain injury
respiratory distress syndrome
prolonged stay in neonatal intensive care unit (NICU).
IUGR also has adverse impacts later in pregnancy. In a Brazilian study of babies born at 3437 weeks the stay in the Neonatal ICU was 4.6 times longer than non-IUGR babies born at
the same gestational age 9
4
Obstetrics and Gynecology International Volume 2010 (2010), Article ID 231842, 5 pages “Neonatal
Outcomes of Late-Preterm Birth Associated or Not with Intrauterine Growth Restriction” Ortigosa et al
5
http://kidshealth.org/parent/medical/endocrine/iugr.html#
6
http://pregnancy.familyeducation.com/expecting-multiples/intrauterine-growth-restriction/57001.html
7
Journal of Pregnancy, Volume 2011 (2011), Article ID 364381, “Consequences in Infants That Were
Intrauterine Growth Restricted” Cosmi et al
8
D. J. P. Barker, J. G. Eriksson, T. Fors´en, and C. Osmond, “Fetal origins of adult disease: strength of effects
and biological basis,” International Journal of Epidemiology, vol. 31, no. 6, pp. 1235–1239, 2002
9
Obstetrics and Gynecology International Volume 2010, Article ID 231842, 5 pages “Neonatal Outcomes of
Late-Preterm Birth Associated or Not with Intrauterine Growth Restriction Rocha et al
10
Child
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brain dysfunction and neurodevelopmental impairment. These clinical consequences may
not be apparent until later in childhood development and may involve academic
performance, memory, visual-motor, and language difficulties, and executive function
problems 10
In other studies, IUGR children have lower nonverbal and verbal IQ than controls 11
According to data from the National Collaborative Perinatal Project (1959–1976) the IQ
scores of 2719 IUGR children tested at age 7 were 6 points lower than Appropriate for
Gestational Age children 12
cerebral palsy
hypertension (high blood pressure)13
hearing impairment
blindness
small kidneys in relation to body weight14
reduction in cerebral cortical grey matter and hippocampal volume. These macrostructural
alterations have been associated with microstructural and metabolic changes 15
chronic lung disease16
attention deficit-hyperactivity disorder 17
10
M. Yanney and N. Marlow, “Paediatric consequences of fetal growth restriction,” Seminars in Fetal and
Neonatal Medicine, vol. 9, no. 5, pp. 411–418, 2004.
11
M. Yanney and N. Marlow, “Paediatric consequences of fetal growth restriction,” Seminars in Fetal and
Neonatal Medicine, vol. 9, no. 5, pp. 411–418, 2004.
12
Journal of Pregnancy, Volume 2011 (2011), Article ID 364381, “Consequences in Infants That Were
Intrauterine Growth Restricted” Cosmi et al]
13
C.M. Law and A.W. Shiell, “Is blood pressure inversely related to birth weight? The strength of evidence
from a systematic review of the literature,” Journal of Hypertension, vol. 14, no. 8, pp. 935–941, 1996
14
N. Teeninga, M. F. Schreuder, A. Bokenkamp, H. A. Delemarre-van de Waal, and J. A. E. Van Wijk, “Influence
of low birth weight on minimal change nephrotic syndrome in children, including a meta-analysis,”
Nephrology Dialysis Transplantation, vol. 23, no. 5, pp. 1615–1620, 2008.
15
N. Padilla, J. Perapoch, A. Carrascosa, R. Acosta-Rojas, F. Botet, and E.Gratacós, “Twelve-month
neurodevelopmental outcome in preterm infants with and without intrauterine growth restriction,” Acta
Paediatrica, vol. 99, no. 10, pp. 1498–1503, 2010.
16
Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes;
Behrman RE, Butler AS, editors. Washington (DC): National Academies Press (US); 2007.
14
Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes;
Behrman RE, Butler AS, editors. Washington (DC): National Academies Press (US); 2007.
11
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behavioural problems, which might manifest only at school age, can have a great impact on
school performance and social competence and have a negative influence on quality of life 18
learning difficulties are reported more often in IUGR preterm infants compared to
Appropriate for Gestational Age infants. 19
Adult
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2.3
dyslipidaemia (high blood cholesterol)
obesity
type 2 diabetes
hypertension (high blood pressure)20
cardiovascular disease.
Treatment of IUGR
There are currently no evidence-based therapies for the treatment of IUGR in humans. Often the
only option for treatment is to deliver the affected baby (or babies) however this carries significant
risk, particularly at early gestational ages. The challenge for obstetricians is to determine the
optimal timing of delivery, balancing the risks to the baby of remaining in utero with the
complications of pre-term birth and the likely requirement for intensive intervention.
2.4
Sildenafil a Potential Treatment Option for IUGR
A number of studies have indicated the promising potential for IUGR to be treated by administering
Sildenafil to improve uteroplacental blood flow and delay delivery. If delivery can be deferred to 30
weeks, the mortality risk would reduce to around 20% and would also help reduce the many
complications that follow and can lead to life-long disability or disease. 21
The studies that indicate the potential of Sildenafil include:

in a small study conducted in British Columbia Sildenafil treatment was included in the
management of a series of 10 women with severe early onset IUGR. Their outcomes were
compared with a series of 17 women who fulfilled the treatment criteria but either declined
or were not offered Sildenafil. Other than one woman who suffered a stillbirth within 48
hours of commencing Sildenafil treatment, all Sildenafil treated fetuses had increased fetal
18
A. J. M. van den Broek, J. H. Kok, B. A. Houtzager, and S. A. Scherjon, “Behavioural problems at the age of
eleven years in preterm-born children with or without fetal brain sparing: a prospective cohort study,” Early
Human Development, vol. 86, no. 6, pp. 379–384, 2010
19
J. H. Kok, A. L. den Ouden, S. P. Verloove-Vanhorick, and R. Brand, “Outcome of very preterm small for
gestational age infants: the first nine years of life,” British Journal of Obstetrics and Gynaecology, vol. 105, no.
2, pp. 162–168, 1998
20
C.M. Law and A.W. Shiell, “Is blood pressure inversely related to birth weight? The strength of evidence
from a systematic review of the literature,” Journal of Hypertension, vol. 14, no. 8, pp. 935–941, 1996
21
Kamoji VM et al. Pediatrics 2006; 118:758.
12
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abdominal circumference growth velocity after treatment. Sildenafil treated fetuses tended
to be more frequently live born and to survive intact to primary hospital discharge. Gravida’s
Director, Professor Philip Baker, was involved in this study 22
Measures of pup growth, including body weight, crown-rump length and abdominal
circumference were reduced compared to control mice when treated with Sildenafil.
Treatment at mid gestation demonstrated normalisation of all growth measures in the IUGR
mice. Similar increased growth parameters have also been demonstrated with Sildenafil in
rat, guinea pig and sheep models 23
In a human study, small arteries dissected from samples obtained at caesarean section from
normal pregnancies were compared to small arteries from pregnancies complicated by IUGR.
Sildenafil significantly reduced vasoconstriction and significantly improved relaxation of
small arteries from IUGR pregnancies. 24
Sildenafil is already used in clinical practice for:

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the management of hypertension in pregnancy resulting in improved maternal
cardiorespiration, improved echocardiographic status and delivery of healthy infants. 25
the treatment of persistent pulmonary hypertension of the newborn infants (including those
born preterm). Sildenafil is increasingly used as an adjunctive therapy to current care of
inhaled Nitrous Oxide therapy, surfactant and ventilation. 26
Interest in the use of Sildenafil for the treatment of placental ischaemic conditions led to a small
randomised placebo controlled trial in women with early onset preeclampsia. In this UK study led
by Professor Baker, women with preeclampsia were randomly assigned Sildenafil or a placebo at
22
von Dadelszen P, Dwinnell S, Magee LA, Carleton BC, Gruslin A, Lee B, Lim KI, Liston RM, Miller SP, Rurak D,
Sherlock RL, Skoll MA, Wareing MM, Baker PN. Sildenafil citrate therapy for severe early-onset intrauterine
growth restriction. BJOG 2011;118:624-8.
23
Stanley JL, Andersson IJ, Poudel R, Rueda-Clausen CF, Sibley CP, Davidge ST, Baker PN. Sildenafil citrate
rescues fetal growth in the catechol-o-methyl transferase knockout mouse model. Hypertension
2012;59:1021-8.
24
Wareing M, Myers JE, O'Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth
restriction. J Clin Endocrinol Metab 2005;90:2550-5.
25
Lacassie HJ, Germain AM, Valdes G, Fernandez MS, Allamand F, Lopez H. Management of Eisenmenger
syndrome in pregnancy with Sildenafil and L-arginine. Obstet Gynecol 2004;103:1118-20: Molelekwa V, Akhter
P, McKenna P, Bowen M, Walsh K. Eisenmenger's syndrome in a 27 week pregnancy--management with Streit
M, Speich R, Fischler M, Ulrich S. bosentan and Sildenafil. Ir Med J 2005;98:87-8: Successful pregnancy in
pulmonary arterial hypertension associated with systemic lupus erythematosus: J Med Case Rep2009;3:7255.]
26
Latini G, Rosati E, De Felice C, Del Vecchio A. Sildenafil administration to a patient with refractory persistent
pulmonary hypertension of the newborn. J Matern Fetal Neonatal Med 2008;21:671-3.
13
gradually increasing daily doses. The study resulted in higher median birthweights for the Sildenafil
group. Sildenafil was well tolerated with no increase in maternal or fetal morbidity or mortality.27
3. GRAVIDA’S Research
3.1
Human IUGR - Sildenafil Trial
The trial will test the effects on fetal growth of Sildenafil administered to pregnant women with
severe IUGR. It is the world’s first major trial of the use of Sildenafil for this purpose. Gravida is at
the forefront of the international collaborative network, known as the STRIDER IPD (individual
patient data) Collaboration, which is running trials throughout 2013–2017 in the UK/Ireland,
Netherlands, Canada and the US. Each trial will share and compare results across countries. The
New Zealand trial is the first to start recruiting women. The international collaboration is supported
by the GoNet (Global Obstetrics Network) Initiative which aims to support and synergise global
alignment, coordination and collaboration of perinatal research.
The STRIDER NZAus trial is a bi-national trial with Australia, and is being run from Auckland.
Recruiting centres include Maternal-Fetal Medicine (MFM) units in Auckland Wellington and
Christchurch and in Australia (Melbourne (2), Sydney (2), Brisbane, Adelaide and Perth. Preliminary
studies were funded by a Gravida grant in 2012 followed by Health Research Council of New
Zealand funding of $1.15m in June 2013.
The STRIDER NZAus trial will be led by Dr Katie Groom (Principal Investigator) and Professor Philip
Baker (Gravida Director and STRIDER IPD Collaboration Co- Principal Investigator). The team
includes a trial co-ordinator, local investigators, research midwives and research fellow responsible
for myometrial and placental studies.
The STRIDER IPD Collaboration has worked together on study design, outcomes and data collection.
All STRIDER trials will use similar methodologies and outcomes to ensure they are comparable and
compatible for future analysis. This IPD will be powered to assess a primary outcome of survival free
of major morbidity at time of hospital discharge.
The trial is a multicentre double blind randomised placebo controlled trial which will be
administered under close clinical obstetric care. Recruitment of a total of 122 women with severe
early onset IUGR from maternal-foetal medicine units in New Zealand and Australia has commenced
and will proceed over a three year period. Publication of the results is expected early in 2017.
The project will investigate the hypothesis that Sildenafil will increase uteroplacental and/or
fetoplacental blood flow, thereby improving fetal nutrition, growth and outcome. If Sildenafil is to
be of clinical benefit it needs to improve neonatal survival and survival free of major morbidity.
27
Samangaya RA, Mires G, Shennan A, Skillern L, Howe D, McLeod A, Baker PN. A randomised, double-blinded,
placebo-controlled study of the phosphodiesterase type 5 inhibitor Sildenafil for the treatment of
preeclampsia. Hypertens Pregnancy 2009;28:369-82.
14
If the trial is successful, Gravida’s aim is to translate the science into clinical practice and to trial the
therapy on later stage less severe cases of IUGR where it could benefit for many more at-risk babies
and families and the overall impact may be greater
Vascular physiology studies and uteroplacental Doppler waveform studies will also run alongside the
clinical trial to provide further insight into pathophysiology of placental ischaemic (restricted blood
supply) conditions enhance Gravida’s current knowledge and provide direction for future work.
Tests will be performed using placental and myometrial tissue from subjects recruited to the trial.
Placental size, shape, cell turnover, structural morphology, and epigenetic regulation will be studied
and changes in resistance artery reactivity will be determined.
3.2
Sheep IUGR – Sildenafil Trial
Gravida is funding a randomised placebo controlled trial of Sildenafil on sheep at the Liggins
Institute’s Ngapouri Farm Laboratory near Rotorua with a $150,000 grant. Sildenafil will be
administered at varying doses over a four week period to sheep in which IUGR has been induced.
Maternal and fetal blood samples will be collected every 2–3 days. Following the trial the sheep will
be euthanized, the uterus and its contents weighed, fetal external body measurements taken, fetal
organs and placentomes dissected and weighed. Comparisons will be made between the placebo
and control groups of:
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
fetal growth: fetus, fetal organ, and placental weight measurements. Fetal biparietal
diameter, total chest, and abdominal girth and limb length measurements. Fetal chest girth
increments.
measurements of uterine and umbilical artery blood flow
placental morphology and vascularisation
blood gases
metabolites: Fetal plasma glucose, lactate and urea concentrations
plasma levels of Sildenafil
brain tissue which will be sent to Otago University for analysis.
The objective of the trial is to further investigate the hypothesis that Sildenafil will increase fetal
growth by increasing uteroplacental and/or fetoplacental blood flow thereby decreasing losses at
lambing. An advantage of the research model is that exposure to Sildenafil can be trialled over a
number of weeks (compared with just a few days for mice) and good tissue samples will be
available. The trials have commenced and will be completed by November 2013.
4. Benefits of the Research
Although advances in high-risk obstetric and neonatal care have resulted in improved survival of
infants born with IUGR, the associated adverse outcomes have significant economic, health and
societal impacts which extend to adolescence and on into adulthood. If Sildenafil proves to be a
viable option for the treatment of IUGR the potential benefits of the research are very significant.
15
A number of other benefits are likely to accrue regardless of whether Sildenafil proves to be a viable
treatment for IUGR. These include enhanced multi-disciplinary linkages and collaboration nationally
and internationally, knowledge transfer, the development of human capital and international
recognition as a result of conducting major pieces of high quality research.
4.1
Health Impacts
As discussed at above (at 2.2 Adverse Outcomes Associated with IUGR) IUGR pregnancies,
particularly severe early-onset IUGR, carry a significantly increased risk of a number of adverse
medical outcomes including:

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







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
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stillbirth
preterm birth
decreased tolerance for birth / increased likelihood of a Caesarean brith
high blood pressure
neonatal death / Sudden Infant Death Syndrome
low blood sugar level (hypoglycemia)
weak muscle tone and poor circulation
decreased ability to fight infection
problems with breathing and feeding
bowel tissue death
hypoxic brain injury (caused by a lack of oxygen) and its long-term consequences
chronic lung disease
damage to the retina
elevated cardiovascular mortality rate
prolonged stay in neonatal intensive care unit (NICU)
brain dysfunction and neurodevelopmental impairment
lower nonverbal and verbal IQ
cerebral palsy
chronic lung disease
attention deficit-hyperactivity disorder
behavioural problems
learning difficulties
high blood cholesterol
obesity (in adulthood)
type 2 diabetes (in adulthood)
cardiovascular disease (in adulthood).
These outcomes have both short and long term health consequences for the individual, which in
some cases are severe and life-threatening, and require a range of medical interventions.
16
4.2
Societal Impacts
Coping with an IUGR pregnancy and delivery is highly stressful for parents and family. Early-onset
severe IUGR generally results in a pre-term birth at a very low (or extremely low) birthweight.
Families face a significant risk of a stillbirth, death as a neonate or disability.
Families are likely to experience a significant period during which the neonate experiences a
number of health challenges and struggles to thrive. Extended stays and ongoing medical
interventions in a Neonatal Intensive Care Unit (NICU) are often involved. This can be highly
disruptive to the lives of parents requiring significant absences from work which may result in
reduced income or even job loss.
In childhood the IUGR baby may have disabilities (such as cerebral palsy, blindness or brain injuries)
which constrains their ability to live a fully independent life requiring support from family or support
services. They will not usually have the same life expectancy of others and face a higher likelihood
of developing serious illnesses.
Schooling may present difficulties with the impacts of attention deficit-hyperactivity disorder,
behavioural problems, learning difficulties and brain dysfunction. In addition to the potential
requirement for support, the likelihood of becoming a fully productive member of society is often
reduced.
As an adult IUGR individuals face an increased likelihood of metabolic diseases such as obesity, type
2 diabetes and cardiovascular disease. These diseases have significant impacts on their lives and
those around them affecting productivity and giving rise to costs including ongoing medical
treatments.
4.3
Economic Impacts
The key economic impact likely to result from the successful use of Sildenafil to treat IUGR would be
a reduction in health costs. A longer term benefit would is the potential to avoid the adverse
impact on the productive capacity of individuals who may otherwise be constrained by handicap or
disease.
Estimating the potential benefit is challenging because of the lack of New Zealand and international
data regarding:


the costs of medical treatment including:
- treatment for IUGR during pregnancy
- medical interventions to ensure the survival of IUGR babies or to treat abnormalities,
including surgical interventions and infection control
- maternal treatment costs, particularly in-hospital costs following an IUGR birth
- treatment of the adverse outcomes in childhood and adulthood associated with IUGR
e.g. cerebral palsy
the frequency of the occurrence of each of the adverse outcomes associated with IUGR,
together with comparable data for non-IUGR babies
17


data regarding the extent of the linkages between IUGR and each of the adverse outcomes
associated with it
long term or lifetime costs of the range of problems associated with IUGR.
To estimate the potential benefit of successfully treating IUGR with Sildenafil we have assessed two
categories of costs associated with IUGR:


3.1.1
in-hospital perinatal care for IUGR: we have used the Ministry of Health’s Casemix data for
Diagnostic Related Groups (“DRG”) which sets out the funding of DHB’s for each specific
category of medical care. 28 This provides base data regarding the costs of in-hospital
perinatal care (care prior to birth and in the month following).
medical and other costs associated with the adverse outcomes of IUGR following discharge
of the baby: our desktop research has obtained data regarding the adverse outcomes
associated with IUGR including:
- educational costs and additional use of health specialists and educational professionals
associated with IUGR neurodevelopmental disadvantage
- costs of surgery required throughout life
- employment and productivity costs associated with lower capability or performance as a
result of neurodevelopmental, disease or other IUGR induced disadvantages
- support services costs because of IUGR caused frail condition, effect of disease or early
entry into care facilities
- ancillary costs, eg need for greater support by IUGR parents, additional travel for medical
treatment or surgery, parental employment and productivity impacts.
In-hospital Perinatal IUGR Care Costs
Perinatal care costs are estimated using the Ministry of Health Diagnostic Related Groups (“DRG”)
data for 2013/14, which provides the basis for calculating Ministry of Health funding for DHB’s. We
note the data are current; relate specifically to New Zealand; and, are from a reliable source.
For birth related costs, the Ministry of Health data includes multiple subcategories according to the
weight of babies born. Each subcategory includes a weighting based on the average number of days
stay in hospital and DRG defined medical, surgical and related equipment costs, such as ventilation.
The calculations are based on DRG data regarding low birthweight babies (less than 2.5kg).
Birthweights of below 2.5kg are a clinical indicator of IUGR and therefore this data is considered a
reasonable proxy for IUGR babies. However it should be noted not all low birthweight babies suffer
from IUGR, although it is the primary cause of low birthweight.
We estimate the costs of in-hospital perinatal care for mothers and IUGR babies as follows:
28
New Zealand Casemix Framework For Publicly Funded Hospitals including WIESNZ13 Methodology and
Casemix Purchase Unit Allocation for the 2013/14 Financial Year (Ministry of Health)
18
Pe rina ta l Costs for IU GR Pre gna ncie s
Se ve re IU GR
Number of IUGR pregnancies
150
N on-se ve re
IU GR
7350
T ota l
7500
Average cost per pregnancy
- antenatal (additional)
-$
3,000 -$
300 -$
3,300
- postnatal
-$
50,000 -$
5,000 -$
55,000
Total Average annual costs of IUGR per pregnancy
-$
53,000 -$
5,300 -$
58,300
Total Annual IUGR care for all pregnancies
-$
7,950,000 -$
38,955,000 -$
46,905,000
7%
7%
Discount Rate
Period (years)
PV of pe rina ta l costs for IU GR pre gna ncie s
20
$84,222,413
20
$412,689,825
7%
20
$496,912,238
a) Severe IUGR perinatal costs
The Present Value of in-hospital perinatal care costs for severe IUGR cases is estimated at $84.2m
(when discounted at 7% over 20 years).
This calculation assumes an aggregate average cost of $50,000 per severe IUGR baby, based on the
range of costs for each DRG category of low birthweight baby which go from <750gms up to 2,000 –
2,500 gms. The associated costs range from $39k through to $58k, to which an amount to reflect
the costs of maternal perinatal care, from $4k through to $8k, has been added.
This calculation is likely to significantly underestimate the costs of care for severe IUGR cases
because:


the calculation makes no allowance for the costs of treatment for other conditions
associated with IUGR which are classified under another DRG category e.g. cerebral palsy
severe early onset IUGR babies are expected to tend towards the Very Low and Extremely
Low birthweight categories, for which the costs are higher.
b) Non-severe IUGR perinatal costs
The Present Value of in-hospital perinatal care costs for non-severe IUGR cases is estimated at
$412.7m (discounted at 7% over 20 years).
This calculation should be treated with some caution as it is based on an estimate the costs of nonsevere IUGR cases are 10% of those for severe IUGR cases. While there is no firm basis for this we
note the Ministry of Health DRG costs for 2000-2500gm category are 67% of costs for babies in the
<750gm category. These categories are arguably reasonable proxies for severe IUGR and nonsevere IUGR cases respectively. Also it appears reasonable to assume that if Sildenafil was of
benefit to cases of severe IUGR it would also benefit non-severe cases.
In combination the PV of the costs of in-hospital perinatal care for all cases are estimated at
$496.9m when discounted at 7% over 20 years.
19
3.1.2
Costs of Care for Adverse Outcomes Associated with IUGR
As discussed at 4.1 Health Impacts above a number of adverse medical outcomes are associated
with IUGR. However these medical conditions are not solely associated with IUGR and therefore
without data regarding the frequency these occurred in conjunction with IUGR it is not possible to
estimate the associated costs. However some limited information is available which provides a
broad indication.




Increased Caesarean Births: IUGR babies show a decreased tolerance for birth, resulting in
increased likelihood of Caesarean delivery. In one study the incidence of Caesareans was
92% in the IUGR group compared with 25% in the Appropriate for Gestational Age group). 29
The average DRG cost of Caesarean delivery with complications is $7.7k
Cerebral Palsy: the US Government’s Centers for Disease Control and Prevention calculated
in 2003 that the Present Value of the lifetime economic costs of cerebral palsy was
USD921,000 per person.30 Medical costs for children with cerebral palsy alone were 10
times higher than for children without cerebral palsy or intellectual disability. The average
DRG cost for cerebral palsy procedures is $13k
High blood pressure: IUGR increases the risk of hypertension in adult life 31 It is the most
common chronic medical problem prompting visits to primary health care providers in the
USA. The medical, economic, and human costs of untreated and inadequately controlled
high blood pressure are enormous. The recurrent and chronic diseases associated with
hypertension are costly to treat. 32 69% of people who have a first heart attack, 77% of
people who have a first stroke, and 74% of people with chronic heart failure have high blood
pressure. High blood pressure is also a major risk factor for kidney disease. 33
Type 2 diabetes: a 2008 study estimated the total cost of Type 2 diabetes in New Zealand at
$600m. 34 The average DRG cost for diabetes is $5k
29
Obstetrics and Gynecology International Volume 2010 (2010), Article ID 231842, 5 pages “Neonatal
Outcomes of Late-Preterm Birth Associated or Not with Intrauterine Growth Restriction” Ortigosa et al
30
January 30, 2004 / 53(03);57-59 Economic Costs Associated with Mental Retardation, Cerebral Palsy,
Hearing Loss, and Vision Impairment --- United States, 2003 Morbidity and Mortality Weekly Report, Centers
for Disease Control and Prevention, US Government
31
Gortner L; Intrauterine growth restriction and risk for arterial hypertension: a causal relationship? J Perinat
Med. 2007 Jul 12
32
J Clinical Hypertension (Greenwich). 2003 May-Jun;5(3 Suppl 2):3-13. The economic impact of
hypertension. Elliott WJ.
33
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke
statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2–220.
34
Diabetes New Zealand and Pricewaterhouse-Coopers (2008)
20
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
Coronary artery disease: studies have shown that infants with birth weight below 2.5 kg
have a three times increased risk of death due to coronary artery disease later in life. 35
Indirect Costs of IUGR: the cost burden is not just restricted to the health system and direct
health costs. In New Zealand indirect costs such as lost productivity, lost wages, support
services costs are roughly estimated to equal the direct costs of a given condition.36
This body of data must be interpreted with great care because it relates to different periods of time
and to a range of countries which have different medical practices and cost structures. However it
does signal the broad dimensions of the costs of dealing with conditions associated with IUGR. It
makes it reasonably clear the lifetime costs of IUGR babies are much higher than for non-IUGR
babies.
4.4
Benefits to Agriculture
Gravida’s funding of a trial at the Ngapouri Farm Laboratory of the effects of Sildenafil on the growth
of unborn IUGR lambs draws on the work previously undertaken on women, sheep and mice. If
treatment with Sildenafil is successful lambing percentages and the overall health of lambs which
suffer from IUGR is expected to improve.
Potential Impact of Sildenafil on Lambing Percentages
Lambs born in New Zealand annually (2012 data)
Lambs suffering IUGR (10%)
Uptake of sildenafil usage
Lambs saved through 5% reduction in IUGR lamb losses
Present value of each lamb saved
Total value of lambs saved in one year
Discount Rate
27,000,000
2,700,000
20%
54,000
$80
4,320,000
10%
Present Value over 5 years
16,376,199
Present value over 10 years
26,544,530
The economic benefits of commercially administering Sildenafil to pregnant sheep cannot be
accurately calculated at present because the percentage of lambs which suffer IUGR and which may
be saved and the rate farmers would take up administering Sildenafil are not known. However the
table above sets out an arguable view of the potential impact of the administration of Sildenafil on
long-term lamb survival. This is based on 10% of lambs suffering IUGR, a 5% reduction in lamb
mortality and a 20% uptake rate of the treatment by farmers. Discounting at 10% p.a. results in a
PV of $16.4m over 5 years and $26.5m over 10 years.
35
Gortner L; Intrauterine growth restriction and risk for arterial hypertension: a causal relationship? J Perinat
Med. 2007 Jul 12
36
Ministry of Health. 2009. Report on New Zealand Cost-of-Illness Studies on Long-Term Conditions.
Wellington: Ministry of Health.
21
It is important to note that, given the lack of available data, the assumptions are necessarily
speculative.
4.5
Collaboration & Linkages
The collaboration and linkages developed through these studies will create reputational benefits
and open further opportunities for Gravida and New Zealand.
Human IUGR Sildenafil Study
Gravida’s Director, Professor Philip Baker, has a 15 year history of involvement in investigating
Sildenafil as a treatment for IUGR. Since arriving in New Zealand in 2012 to take up joint positions
at Gravida and the Liggins Institute (University of Auckland), he has collaborated with local
researchers and clinicians to progress the research into the use of Sildenafil in pregnancy.
The Sildenafil study is the first of a number of similar trials planned in Ireland, Canada, UK, USA and
the Netherlands. The international collaboration is supported by the GoNet (Global Obstetrics
Network) Initiative which aims to support and synergise global alignment, coordination and
collaboration of perinatal research.
Recruiting centres will include Maternal-Fetal Medicine (MFM) units in New Zealand (Auckland,
Wellington and Christchurch) and Australia (Melbourne (2), Sydney (2), Brisbane, Adelaide and
Perth). During the planning and research design phase the team members worked in close
consultation with members of the international STRIDER IPD Collaboration. The STRIDER NZAus trial
investigators have engaged with other members of the local multidisciplinary high risk care team,
members of the NZMFM network, members of the RANZCOG MFM Network (covering all MFM
units in Australia and New Zealand), the ADHB Research Review Committee and the NZ Multi-region
Ethics Committee.
22
Trial Collaboration
Auckland City
Hospital
Melbourne
Hospitals (2)
British Columbia
Women’s
Hospital
(Vancouver)
Randomisation
and data
capture
Wellington
Hospital
Recruitment at Maternal Fetal
Medicine Units 10 leading Australasian hospitals
Christchurch
Hospital
Perth
Hospital
GRAVIDA
Sydney
Hospitals (2)
Brisbane Hospital
Adelaide Hospital
23
Sheep IUGR – Sildenafil Trial
The trial of Sildenafil on sheep with induced IUGR provides an opportunity for a multi-disciplinary
crossover between health and agriculture with human maternal fetal health and neonatology
specialists working with animal physiologists. Gravida Director, Professor Philip Baker is Primary
Supervisor with Frank Bloomfield, Associate Professor of Neonatology, Liggins Institute and Dr Katie
Groom, Senior Lecturer, Department of Obstetrics and Gynaecology are Co-Supervisors. The trial
will also involve Dr Mark Oliver a Senior Animal Physiologist and Ngapouri Farm Laboratory
Research Director. Brain tissues will also be sent to Otago University for assessment.
4.6
Knowledge Transfer
An important principle common to all Gravida’s research is to maximise the transfer of science into
clinical practice. This process can never be taken for granted; there is extensive literature citing the
difficulties of doing so. Issues such as organisational culture, clinical leadership and attitudes of
senior management, the credibility of the research itself, and the infrastructure dedicated to
research translation are important determinants of practical uptake. Gravida already has
considerable experience in transfer of its research outcomes into clinical practice. For example, it is
funding the adaptation of research into the administration of corticosteroids for sick babies into
clinical guidelines.
Human IUGR Sildenafil Study
This trial provides an opportunity for New Zealand researchers to lead the way in the exploration of
this therapy. If successful there is scope for extension of the use of Sildenafil to later gestations
where disease prevalence is higher and the overall impact of the therapy may be greater.
Once the study is complete results will be shared with the STRIDER IPD Collaboration. Local and
regional educational meetings will be held for clinicians to report the trial results and comment on
clinical implications. Regardless of the trial result, there will be international interest as this will be
the first randomised trial of a therapy with potential to improve outcomes in severe early onset
IUGR.
The results are expected to generate significant international interest and will be presented at
international scientific meetings and Gravida anticipates a key note publication in a high impact
scientific journal. The key trial investigators are regarded as opinion leaders with strong
international reputations who influence obstetric practice and clinical guidelines throughout New
Zealand, Australia and internationally. As Co-Principal Investigator (and Gravida Director) Professor
Baker will be central to presentations and publications.
Coverage of the recent announcement of the Sildenafil study resulted in more than 70 articles, radio
and TV items in both NZ and overseas including the UK, US, Australia and China. The potential
readership of these stories equated to 2.7 million people in NZ and 26 million people overseas. If
the trial shows a positive effect on fetal growth it is likely local media will take further interest in the
story, particularly as New Zealand investigators are leading the way in furthering knowledge in the
treatment of these very small, at risk babies.
24
The study has the potential to build Gravida’s and New Zealand’s research reputation in the
treatment of IUGR and its ability to produce practical outcomes for clinical practice. It will also
contribute to the development of human capital and research capability within New Zealand In
addition to the collaboration with hospitals in New Zealand (3) and Australia (7) and institutions
running comparable Strider IPD trials in England, Ireland, Nether land, USA and Canada it is
important to note. It will involve a number of people including the PI, STRIDER IPD Collaboration
Co-PI, trial co-ordinator, local investigators, research midwives and the research fellow (responsible
for myometrial and placental studies).
Gravida will also pursue educational and outreach activities undertaken, increasing public
understanding of research, fostering interest in scientific fields of study, and raising awareness of
science-related educational pathways and employment opportunities.
Sheep IUGR – Sildenafil Trial
Knowledge transfer could lead to the commercialisation of an alternative treatment of IUGR in
sheep with the potential to improve lambing percentages and boost the condition of young lambs.
Gravida partners LandCorp Farming Ltd and AgResearch would be in a position to assist with
commercialisation.
4.7
Reputational Benefits
The engagement of a high quality research team in a major trial with linkages to similar trials in the
Netherlands, UK, Ireland, USA and Canada has the potential for significant positive impact on the
international reputations of Gravida and its partners and may lead to further collaborations.
High quality research team
Professor Philip Baker is Director of Gravida, Professor of Maternal & Fetal Health at The University
of Auckland, Liggins Institute, Maternal Fetal Medicine Subspecialist at Auckland City Hospital and
Co-Investigator for the Strider IPD NZ/Aus trial
Professor Baker has balanced a clinical practice in obstetrics with an extensive research career. He
has achieved research funding of more than $40 million over the past 10 years and published more
than 250 peer reviewed manuscripts. He is internationally recognised as a clinician scientist and
expert in the placental ischaemic conditions of IUGR and preeclampsia. He is the senior author of
work on Sildenafil: animal models of IUGR; ex-vivo studies in human myometrial vessels; RCT in
women with early onset preeclampsia; and the small case control series in women with severe early
onset IUGR.
Professor Baker’s track record is of building high calibre research groups:

after training in Nottingham, Cambridge and Pittsburgh, he was appointed Professor of
Obstetrics and Gynaecology at the University of Nottingham, establishing a group of
researchers which had more abstracts accepted at the Society of Gynecologic Investigation
than any other Centre.
25



in 2001, he was appointed Director of the newly established Maternal and Fetal Health
Research Centre at the University of Manchester which is a major focus of obstetric
research. This group became the largest obstetric research group in Europe.
in 2007-8, he led the successful Manchester application for an NIHR Biomedical Research
Centre (approximately £30M funding from partner organisations) and became the Centre's
inaugural Director. In 2009 he joined the University of Alberta which is home to the Human
Metabolome project which used metabolomics to develop screening tests for major
pregnancy complications.
In 2012 he was appointed Director of Gravida: National Centre for Growth and Development.
Honours and awards include:
2004
2005
Sir William Liley Lecturer (Perinatal Research Society)
President’s Achievement Award of the Society of Gynecologic Investigation (the
first time this award had been made outside North America).
2008
Elected a Fellow of the Academy of Medical Sciences (UK)
2010
International strategy: Principal author of the position paper on “Health of
Women and Children”, presented to The Science Academies of the G8 countries,
and considered at the G8 Summit held in Huntsville, Ontario.
Teaching, affiliations and collaborations




Research Professor of Obstetrics and Gynaecology, University of Keele, UK (part-time)
Honorary Distinguished Professor, Chongqing Medical University
Visiting/Honorary Professor: Universities of Auckland and Alberta
Scientific Director of the International Pregnancy Research Alliance (Western China, Alberta,
Auckland).
Dr Katie Groom is Principal Investigator for the Strider IPD NZ/Aus trial and a Maternal Fetal
Medicine Subspecialist at Auckland City Hospital. Dr Groom has past experience as PI of
randomised controlled trials, successfully completing multi-centre (TOCOX trial) and single centre
(Kiwi-OmniCup trial) studies. She is currently the PI for the multi-centre EPPI trial (Enoxaparin for
the Prevention of Preeclampsia and IUGR). She leads a research team involved in several other
multicentre RCTs and observational studies for which she is local PI, trials include; ASTEROID
(Australasian Antenatal Study To Evaluate Role of Intramuscular Dexamethasone vs betamethasone
prior to preterm birth trial), PPROMT (Preterm Prelabour Rupture of Membranes near Term trial),
MAGENTA (Magnesium sulphate at 30-34 weeks for neuroprotection) and the FOX Study (free fetal
RNA in maternal circulation: a biomarker of intrauterine hypoxia in growth-restricted fetuses). She
has an established network of collaborations with clinical researchers across New Zealand and
Australia and as Secretary of the Perinatal Society of New Zealand she is well known to many
obstetricians, midwives and neonatologists throughout the country. Dr Groom works at Auckland
City Hospital as a Maternal Fetal Medicine Subspecialist and has expertise in the management of
severe early onset IUGR and clinical and research ultrasound. Dr Groom is the Principal Investigator
26
for STRIDER NZAus Sildenafil trial and will lead the trial across all centres and will have significant
involvement in local recruitment and the study ultrasound scans.
Professor Lesley McCowan is Head of the Department of Obstetrics and Gynaecology at the
University of Auckland and a Maternal Fetal Medicine Subspecialist at Auckland City Hospital. She is
highly regarded throughout New Zealand and internationally for her extensive work on IUGR
pregnancies. She was recently an organiser and plenary speaker at the first international Fetal
Growth Conference (Birmingham, UK 2012). As a key opinion leader she is regularly invited to speak
at national and international conferences and is currently the lead author developing guidelines for
the management of SGA/IUGR which will be used throughout New Zealand. Professor McCowan
will be an on-going advisor to study design, execution and analysis and will recruit patients in
Auckland.
Professor Peter Stone is a leader in Maternal Fetal Medicine across New Zealand and Australia. He
has been involved with national policy and guideline development in many areas of obstetrics. He
has extensive basic science research experience in placental ischaemic conditions and has several
publications in obstetric ultrasound. Professor Stone is a Maternal Fetal Medicine Subspecialist at
Auckland City Hospital. He will be an on-going advisor to study design, execution and analysis and
will lead Auckland ultrasound providing expert advice for Doppler studies.
Dr Arier Lee is a senior biostatistician with a particular interest in design and analysis of randomised
controlled trials and observational studies. She has previously worked in the pharmaceutical
industry as a senior project statistician for Eli Lilly and so is very familiar with drug therapeutic trials.
She also has considerable past experience within the University of Auckland including roles in the
Clinical Trials Research Unit and the Growing Up New Zealand Project. Dr Lee will lead further
development of the full analysis plan and be responsible for data analysis at study completion.
[GRAPHIC TO BE ADDED SHOWING THE INDIVIDUALS INVOLVED AND AREAS OF EXPERTISE]
Quality Research Design
The design and implementation of the research is critical to the quality of the research. The
STRIDER IPD Collaboration has worked together on study design, outcomes and data collection. All
STRIDER trials will use very similar methodologies and outcomes to ensure they are comparable and
compatible for future analysis.
Patient safety
A central data safety monitoring board (DSMB) has been established by the STRIDER IPD
Collaboration has been established and will be used by all national trials. It includes experts in
obstetrics, maternal fetal medicine, neonatology, clinical pharmacology and epidemiology.
The trial will assess safety of Sildenafil use with many other secondary outcome measures including
assessment of fetal well-being (uteroplacental Doppler waveforms), delivery intervals, maternal
27
effects, neonatal outcomes and, in a subgroup of participants, effects of Sildenafil on vascular
physiology. Close observation will continue for the first 24-48 hours after stopping treatment.
Adverse events will be reviewed by the PI using predefined parameters.
Due to the severe nature of early onset IUGR the majority of participants will be delivered by 32
weeks due to concerns for fetal and/or maternal well-being. If women remain undelivered at 32
weeks the drug will be stopped as the prognosis is significantly improved by this gestation. Patients
are free to withdraw at any time. Maternal and neonatal outcomes to time of hospital discharge
will be collected and review made at 18-36 months of age.
4.8
Summary of Benefits
The Sildenafil research initiated by Gravida has the potential for wide-ranging impacts on New
Zealand’s society and economy through taking research into clinical practice to alleviate and
potentially eliminate some of the wide range of adverse impacts of IUGR. Gravida will disseminate
its findings to health professionals and government agencies nationally and internationally to inform
public health policy and practice. The studies are expected to improve the international standing
and linkages of Gravida and its partner institutions and will enhance the depth and capability of its
researchers.
28