Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04613583 |
| Other study ID # |
2-051-15 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2016 |
| Est. completion date |
October 1, 2025 |
Study information
| Verified date |
May 2022 |
| Source |
University of Aberdeen |
| Contact |
Paul A Fowler, PhD |
| Phone |
+44 1224 437528 |
| Email |
p.a.fowler[@]abdn.ac.uk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
In-utero exposure to drugs and chemicals through maternal smoking, alcohol use, drug abuse,
prescription medicines and occupational/lifestyle exposures is widespread. Such exposures can
alter fetal development and programming, leading to the effects becoming "locked in" from
birth and causing long-term adverse consequences for the individual. These include costly and
widespread conditions such as obesity, hypertension, metabolic syndrome and infertility. The
weight of evidence linking these conditions to fetal recreational drug or environmental
chemical exposures, including cigarettes, alcohol, air pollution, food contact materials, is
overwhelming. What is lacking is an understanding of how fetal drug exposure translates to
adult ill-health and this is due, largely, to an inability to study the problem directly in
affected human fetuses. The investigators, and others, have shown that human fetal
development, which lays the foundations of adult health and function (fetal programming), is
quite different from the rodent and frequently exhibits surprising aspects. It has become
evident that the close interconnectivity of the developing fetal organs and also the
placenta, means that a much more holistic approach to research aiming to understand human
fetal development and the challenges posed to programming for a health adulthood is critical.
To that end the investigators have established a carefully considered gestational age range
(7-20 weeks of gestation) of fetuses we can study together with multiple fetal organs and
body fluids collected and maternal information recorded.
The overarching objective of the study is to intensively and systematically study the human
fetus during a normal pregnancy and pregnancies where aspects of maternal lifestyle and
environment will challenge the fetus. The investigators aim to provide fundamental
information to better understand the mechanisms involved and to detect and treat or
ameliorate adverse effects during pregnancy (such as maternal smoking/drinking, deprivation,
exposure to pollution). In the long term findings from this research will be important for
future studies aimed at enabling better health in later life.
Description:
Primary Objective
To provide fundamental information to better understand the mechanisms involved and to detect
and treat or ameliorate adverse effects during pregnancy.
Secondary Objectives
The secondary objectives of this study are aimed at better understanding of normal processes
during development and how maternal lifestyle and environment can affect it. The
investigators' research will involve a wide range of laboratory, cell and tissue culture and
xenografting as well as microscopic techniques to study chemicals, hormones, proteins, genes
and DNA in the fetal tissues. The investigators have developed sophisticated approaches to
minimise how much tissue is required to carry out as many different measurements as possible
in the same sample. It should be noted that the proposed studies are collaborative with
different research groups since no single research group could carry out all the studies in
isolation. Furthermore, the proposed studies will inform back to animal and cell studies,
enabling more accurate interpretation of their own findings in light of mechanisms and
specific conditions actually at play in the human fetus.
1. Human fetal endocrine system
The investigators aim to investigate how the different hormone systems in the fetus
develop and are affected by adverse maternal factors such as cigarette smoking and
obesity. These include the testis, ovary, adrenal gland, thyroid gland, kidney and the
hypothalamus, pineal gland and pituitary gland in the brain. In addition, the
investigators also aim to study the placenta, including its endocrine function, and how
it is affected by maternal environment, since it is a key organ of pregnancy. Changes in
programming that establishes the endocrine system can have lifelong consequences for
health and wellbeing.
2. Human fetal reproductive and urogenital system
The investigators aim to investigate how the ovary, testis, urogenital tract (including
prostate gland, breast buds and uterus), genitalia and kidney develop in the human
fetus. There is considerable evidence that maternal smoking and over the counter
medicine use can have negative impacts on this system and we will investigate when such
impacts begin and what mechanisms are involved. In addition, common cancers, such as
testis cancer, may have fetal origins and certainly events in fetal life may predispose
the resulting adult to develop cancers. In the case of testis, ovary, breast buds and
prostate gland, an additional aim is to determine whether and how events between 7 and
20 weeks of gestation increase the likelihood of cancers in these organs in adulthood.
3. Mechanistic studies, Epilepsy and other brain disorders
The investigators aim to investigate development of the fetal central nervous system,
including the brain. The first study planned is to investigate changes in genes and the
structure of DNA in the brain related to epilepsy and other neurodevelopmental disorders
linked with maternal cigarette smoking during pregnancy. A second aim is to use the
smoke-exposed fetuses to better understand the role vitamin A plays in normal fetal
development, including development of the central nervous system. Similar concerns are
expressed in the literature with respect to maternal alcohol consumption and by
accessing data from the Fast Alcohol Screening Test alcohol questionnaire that is
already collected at clinic, the investigators will be able to address this issue
systematically with respect to all the studies, including fetal brain development.
4. Metabolism and liver disease
The investigators aim to continue their studies (funded by the Medical Research Council)
of the human fetal liver and other organs important for metabolism, including pancreas
and fat cells and cells that will become fat cells (precursor cells). Programming of
metabolism during life in the womb is important for adult health and better
understanding of the development of the metabolic systems and how they are perturbed by
factors such as maternal smoking and deprivation is an important basis of developing
strategies for wellbeing post-natally. A critical disease of growing importance in these
studies is non-alcoholic fatty liver disease, which is increasing in incidence,
especially in obese individuals. Given that the human fetal liver is active and
responding to maternal environment, some of the basis of this disease may be established
in fetal life. In addition, the development of thyroid and adrenal glands is also
essential in establishing normal metabolic processes. Cutting edge techniques, such as
large-scale metabolomic and lipidomic studies, including analysis of a wide range of
dietary metabolites, will also be used.
5. Heart and cardiovascular system
The development of the heart and the major artery, the aorta, between 7 and 20 weeks of
gestation will be characterised. The effects of adverse in-utero environment of the
developmental processes will then be investigated.
6. Immune system development
The thymus is critical and large organ in fetal development that is important to
establish the immune system. The spleen manufactures antibodies and, in fetal life, red
blood cells (as does the fetal liver) and recycles red blood cells. Both organs have
important role in maintaining the immune system. The investigators aim to investigate
whether adverse maternal lifestyle and/or environment can alter thymus and spleen
development and function.
7. Bone, cartilage and joints
Very little is known about normal bone and cartilage development in the human fetus.
Importantly, it is not even know when the cells involved in bone, cartilage and joint
development begin to alter their behaviour into a more "adult" format. The reason this
is important is that in musculoskeletal disease in the elderly, especially
osteoarthritis, early stages of disease is usually characterised by renewed tissue
growth - i.e. a return to a more "fetal" pattern of cell behaviour. The role of cell
programming during fetal life and better understanding of the correct development and
maintenance of bone, cartilage and joints, and how programming is affected by the fetal
environment, is therefore one of the investigators' aims.
8. The development of the placenta between 7 and 20 weeks of gestation
A great deal is known about the term placenta because it is so easy to obtain and to
relate directly to the accompanying new-born and its parents. However, the placenta is a
dynamically developing organ that is vital for normal pregnancy and that is affected by
maternal lifestyle (e.g. placental growth is reduced if the mother continues to smoke
while pregnant). The investigators aim therefore to better understand how the placenta
develops during this window in gestation and how it is affected by maternal environment.
9. Nerve repair
Spinal cord injury is a massive health problem globally. Recently it has been shown that
human fetal central nervous system cells or embryonic nerve stem cells have the
potential to assist in novel treatment strategies to repair spinal cord injury. This
final secondary objective is focussed on a proof of concept study to determine whether
culturing severed nerves in the presence of human fetal nerve cells assists in correct
and functional nerve regrowth and re-joining across the induced gap. Any further
studies, if the proof of concept aim is realised in a satisfactory manner would require
a separate ethic application.
10. Maternal emotional health and wellbeing effects on the fetus
Maternal stress is a well-known negative influence on fetal development. The
investigators' aim is to perform a pilot study relating indices of fetal development,
such as morphology, endocrine status, to maternal records of emotional health and
wellbeing and abuse. The principal outcome will be an indication as to whether maternal
stress is affecting fetal development at a general level between 7 and 20 weeks of
gestation. Placental biomarkers identified in other studies listed above will also be
related to measures of maternal stress in order to establish whether there may be
placental biomarkers of early fetal response to maternal stress.
11. Fetal lung
While it is well known that the adverse effects of maternal smoking include increased
incidences of respiratory problems, such as asthma. However, there are also data
suggesting that the offspring exposed to cigarette smoke may be more likely to develop
lung cancer. The investigators' aim is to determine whether maternal smoking disturbs
fetal lung development early in pregnancy and if this includes signs of increased
likelihood of cancer development, such as polycyclic aromatic hydrocarbon-DNA adducts in
the fetal lungs.
12. Quantifying human fetal exposure to pollutants, drugs, pharmaceuticals and other
chemicals
It is simple to measure chemicals in the blood or urine of the mother, or in amniotic
fluid collected during amniocentesis. However, amniocentesis is not performed for
research purposes because of not inconsiderable risk to the fetus. This means reliance
on animal studies of such chemicals getting to the fetus but this is rather inadequate
due to major species differences. Therefore the investigators aim to measure chemicals
and drugs of potential health concern (such as bisphenol A which is in plastics and over
the counter drugs taken by mothers which may affect the fetus, such as paracetamol) in
the fetal tissues, including blood and urine where available. This is the only way to
accurately assess how much of these compounds actually get into the fetus itself. This
is important since the fetus is considered much more vulnerable than the adult to toxic
chemicals. In addition, the investigators aim to also measure these compounds in the
placentas (and cord blood where available) from the same fetuses. Because the placenta
is readily available at term, placental biomarkers of fetal exposure to adverse
compounds (e.g. alcohol) that are detected in the second trimester fetal liver will be
investigated in the term placenta.
13. Non-genetic programming of the fetus for adult life
Epigenetic changes are changes that involve marks being put onto DNA that affects how genes
are activated. Therefore, an epigenetic change can change, sometimes greatly, the link
between the amount of a gene present in cell and its effect. This linkage can be quite large
with a gene being practically silenced in terms of its effect, even though there may be
plenty of the gene present in the cell. Conditions within the womb, such a maternal smoking,
can have epigenetic effects. The investigators aim therefore to better understand how the
environment experience by the fetus can affect development and programming of adult health
and disease by epigenetic mechanisms.
