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Prenatal Distress and Anxiety and Fetal Neurobehavioral Development
Running Head: Prenatal Distress and Anxiety and Fetal Neurobehavioral Development
Prenatal Distress and Anxiety in Fetal Neurobehavioral Development
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Institution
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Prenatal Distress and Anxiety and Fetal Neurobehavioral Development
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Prenatal Distress and Anxiety and Fetal Neurobehavioral Development
Chapter 1: Introduction
Gestational period is one of the most crucial stages in the development of a person.
During this highly sensitive stage, significant care ought to be taken by the mother to avert any
conditions or events that may predispose them to emotional swing. The mother is faced with the
challenge of taking care of both herself and the child from any unwanted incidences that may
impact adversely on herself, the baby or both. Besides healthy eating and living, the mother
ought to take deliberate measures to actively avoid stress at all cost. Stress is of many types and
forms majorly, physical, emotional and psychological stress. The impact of stress on fetal
development varies from physical malformation to severe nervous disorientation. Though some
stress has been known to be part of the daily normal lives, elevated exposure to stressing
conditions may have detrimental effects on an individual, whether pregnant or otherwise. Normal
stress has no adverse consequences on the health of the mother and the fetus
Maternal stress during pregnancy is among the major factors influencing fetal neural
development. Stress camouflages in many forms and varying environmental setups depending on
the roles of the mother and their daily obligations. In this respect it is difficult to quantify with
certainty the critical level of maternal stress that impacts significantly on the fetal brain
development. However it is apparent that maternal stress bears adverse effects on the fetal brain
development which may present with severe complications later during subsequent
developmental stages of the child. Cortisol hormone released during stress is attributed for these
unwanted effects on brain development (Claudia et al, 2012).
Numerous studies have been carried out worldwide by different psychologists and other
scientists in this school of thought around this subject matter. The key objective in these studies
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being to quantify and determine with certainty the relation between maternal stress and neural
development in the fetus. Sabri and Nabel (2014), derive the argument that common stress
factors among pregnant women range from many responsibilities in their lines of duty, family
issues, low income as well as health related complications associated with pregnancy. According
to Davis and Sandman 2010, the amount and duration of exposure of the fetus to
Hypothalamic-Pituitary-adrenal hormones in the internal environment forms a basis for
explanation of the adverse effects experienced in the fetal brain development.
Arnaud et al. 2010 asserts that the impact of prenatal stress has far reaching influence that
stretches back to other stages of development. The complications related to prenatal stress
includes but is not limited to autism, Attention Deficit Hyperactivity Disorder, cognitive
disorders and emotional disorders in children. In adults, schizophrenia is the main presentation of
predisposition to prenatal stress. The available information in this field is scanty and
inconclusive due to several limitations facing studies in this field. Some of the limitations
include the challenge of carrying out a procedural experiment on human subjects due to the
challenge of getting participants. In this light therefore, most studies have been limited to use of
animals in the study. The objective of this study is to quantify and expound on the available
information as regards to the impact of prenatal stress in fetal brain development in different
environmental setups. The study also undertakes to quantify how much of stress is regarded
normal and how much is detrimental to the fetal brain development.
Chapter 2: Literature Review
Studies using animal model subjects have revealed significant detrimental effects on the
fetal brain development (Arnaud et al 2010). In line with these studies, presence of high levels of
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cortisol hormone in the mother and ultimately in the intrauterine space culminates to interference
with neuronal development coupled with relatively small hippocampus size to the detriment of
the fetus. The hippocampus is an organ in the brain responsible for numerous functions, among
them memory and navigation (Mandal, 2015). Any interference with hippocampus development
results into severe memory challenges in the fetus in later stages of development as well as
impaired locomotion. Extrapolating these results to human subjects, it is expected that the same
if not worse is a likely outcome. Outlined herein are the role of different stress related hormones
and their impact if elevated or diminished in levels to the fetal brain development. The
assessment of the impact of prenatal stress on fetal neurobehavioral development would be
insufficient without considering effects witnessed in major sections of the brain.
The hippocampus has been identified as one of the primary target organs by maternal
stress hormones. Maternal glucocorticoid stress hormones tend to alter the functioning and the
morphology of the fetal hippocampus if released during its development. By administering
varying amounts of dexamethasone into pregnant animal models, and thereafter assessing their
hippocampus volumes and functioning, Coe et al, 2003 demonstrated marked decline in the
number of neurons in the hippocampus in addition to volume decrease though the overall volume
of the brain is found to be constant regardless. According to this study, apparently the impact on
the hippocampal development in the fetus precipitated b the same stressing factor is the same
regardless of the stage at which the pregnant animal or human model is exposed to the stress.
Decline in hippocampal volumes in the fetus has been demonstrated to be related to
inhibition of the process of neurogenesis more so in the dentate region. The decrease in volume
can be assessed via macroscopic examination of the hippocampus soon after birth. Schmitz et al,
2002 also demonstrated a direct relationship between the decreases in hippocampal volumes to
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the number of granule cells in the hippocampus. The marked decline in size of the hippocampus
in the pregnant animal model has been associated with a decline in cell proliferation in the region
induced by prenatal stress hormones.
The anterior end of neurons has highly branched fingerlike processes extending from the
axon known as dendrites. Prenatal stress has been found to cause a sharp decline in the branching
ability of the dendrites by over 75 % which is compounded by a lower decline in synapse loss of
functionality in the hippocampus (Barros et al., 2006). However, it has come to light that the
impact of prenatal stress on fetal hippocampus development may be either beneficial or
detrimental depending on the duration of exposure of the pregnant dam to the stressor. In this
light, a long duration of exposure to stress of high magnitude for which the animal has little to no
control over culminates into adverse consequences on the hippocampal neuron development. On
the centrally, a short term exposure to mild stress for which the animal has relative control
stimulates neurogenesis in addition to cell differentiation in hippoccampal neurons. This
condition is referred to as hormesis. Though several scholars have carried out studies on this area
of interest in animal models, the study remains unexplored in human populations due to the
numerous challenges experienced in studying human models.
The amygdale is also an area of interest in evaluating the impact of prenatal stress in fetal
neurobehavioral development. The amygdale is a small portion of the brain that is involved
majorly with emotional behavior, emotional variation as well as motivation. On this basis, any
adverse consequences on this region due to any factor or prenatal stress would translate into a
significant interference with fetal mood and emotion. Different studies reveal different impact on
the amygdale due to prenatal depression and anxiety. Of importance in impact on the amygdale
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is the point that any observable or decrease in neurogenesis in this organ upon successive
monitoring is found to be self limiting and recovers shortly after birth.
At this latter evaluation period it is observed that while the cell population, neurogenesis
and other amygdale parameters resume to normal, others portray marked increase as compared to
the control test animal. Salm et al., 2004 derive the discussion that four main parameters are
found to be elevated in the fetal amygdale in the pregnant test animal; the number of glial cells,
the nucleus of the amygdale, neuronal population as well as neuronal density. The changes
pointed out above are only observed in the lateral amygdale. Besides, the changes vary with time
in prenatal and postnatal time frames which emphasizes the importance of identifying the
duration of assessment when reporting the findings and more so in the event that there is any
intention of extrapolating the test findings in other populations.
A larger portion of the fetal brain is comprised of the cerebral cortex which is one of the
major sections in the brain. Among the key functions of the cerebral cortex are storage of
memory, control and co-ordination of body movement. The cerebral cortex is not spared by
prenatal depression and anxiety in animal models. An earlier study reveals that in males the right
cerebral cortex is more pronounced as compared to the left while in females, the left lobe of the
cerebral cortex is larger than the right. On exposure of the pregnant test animal to prenatal
distress and anxiety, it’s found that in males, the cerebral cortex morphology is found to
resemble that of the female implying the loss of masculine appearance. In addition to this, there
is a notable decline in the branching tendency of neuronal dendrites coupled with a marked loss
of functionality of the synapses in the frontal cerebral cortex in males as discussed by Barros et
al., 2006.
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Pyramidal neurons in the cerebral cortex are also slightly reduced in either gender; in
particular the density of the dendritic spines of the apical as well as basal dendrites. The results
in male infants only demonstrate slightly higher decrease in the length of basal dendrites of the
same neurons. Moreover, in males, arbonization of the dendrites is compromised while in
females, this result is not observed. The difference in findings between males and females and
the in the same gender by different studies may be attributed to use of different stressors as well
as variation in the duration of exposure as well as the timing for assessment of the results.
Effect of prenatal stress on fetal cerebellum development is assessed in connection to the
production of the purkinje cells in fetal cerebellum. The cerebellum is associated with
coordination of neurons in the body besides the development of mental disorders. According to
Arnaud et al. 2010 it is observed that prenatal stress adversely affects the structure of granule
cells within the cerebellum. In addition, the number of synapses per unit area as well as the
number per given neuron in the fetal cerebellum granular layer is diminished which translates
into a major interference in the effective interconnection between associated neurons. Since the
exposure of the pregnant dam to stress in this case is aligned to the duration during which the
purkinje cells are produced, the ratio of granule cells to purkinje cells is reduced since there is an
inhibitory effect to the production of purkinje cells.
Cortisol, a steroid hormone, is the major contributing factor for the fetal brain
development. The hormone is released during incase of stressing experiences in every individual.
The hormone is released in response to sympathetic stimulation in body systems of man, rodents
as well as other primates. The body responds to cortisol release by drawing together all the body
energy sources in readiness to initiate either a fight or flight mode since this has been pointed out
as the major roe of the sympathetic nervous system. According to Arnaud et al. 2010, in pregnant
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women, normally cortisol levels in the body are significantly elevated without any clinical
implication.
Cortisol plays a major role in pregnant women to support growth and development of the
fetus. Garberecht et al., 2006 derives the argument that cortisol induces the synthesis and release
of pulmonary surfactant besides preparing the fetus for life in the external environment.
On exposure of the pregnant woman to stress, cortisol hormone levels I blood as well as in body
fluids raises to levels beyond the higher limit. The increased cortisol hormone level circulating in
blood eventually finds its way to the intrauterine environment precipitating severe impacts on
fetal brain development. According to Arnaud et al., 2010, much of the hormone undergoes
transformation by the fetoplacental into its inactive precursor. However besides this inactivation,
the hormone still gets its way into the developing fetus in the woman and cause grave alteration
in its normal development and growth as discussed by Seckl and Holmes, 2007.
As the pregnancy progresses, the amount of cortisol released declines progressively
(Michael & Catherin, 2009). In addition, 11 β-hydroxysteroid dehydrogenase type 2 (11 β-HSD2), which is a hormone released by the placenta converts cortisol into an inactive form cortisone
besides inhibiting fetal exposure to maternal hormones known as glucocorticoids. However, a
significant proportion of cortisol still manages to cross the 11 β-HSD-2 barrier and reach the
fetus despite best efforts by the hormone to control fetal exposure to cortisol. Upon crossing the
placenta, cortisol retards fetal brain development to the detriment of the fetus.
As has already been discussed herein, prenatal stress stimulates an increase in the
production and activity of hypothalamic-pituitary- adrenal hormones. The increase in HPA
activity coupled with the presence of significant quantities of cortisol to which the fetus is
exposed leads to pronounced and far reaching effects on brain development in the fetus. An
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extremely high level of cortisol in the intrauterine space alters the development and migration of
neurons in the brain. In addition, Kristin et al., (2010) assert that elevated cortisol levels interfere
with the expression of a significant portion of genes in the fetal brain to the upward of a
thousand.
The distortion in expression of these genes becomes more pronounced with time as the
fetus develops and may become life threatening in later stages of development. Consequently,
fetal brain development is not only incomplete but also distorted leading into congenital
malformation and neural disorders in the fetus as well as the infant if the pregnancy lasts. In the
event that pregnancy is considered to be at risk of not growing to full term, artificial synthetic
glucocorticoids may be administered to the pregnant woman. However, some of these artificial
glucocorticoids administered during pregnancy such as dexamethasone are capable of passing
through the placenta into the uterofetal space as discussed by Kristin et al., (2010). Being
glucocorticoids, they adversely affect fetal brain development.
Corticotrophin releasing hormone (CRH) is also a major player in fetal brain
development. The hormone is released by the placenta under the control of Hypothalamicpituitary adrenal hormone. Arnaud et al., 2010 argues that corticotrophin releasing hormone
plays is a vital component in facilitating the development and growth of the fetal hippocampus.
On exposure of the woman to abnormal stressing conditions constantly during pregnancy, the
hypothalamic pituitary adrenal hormone is stimulated to release increased quantities of placental
CRH into maternal blood circulation. Presence of increased circulating amounts of placental
CRH in maternal blood circulation eventually leads to elevated levels of the hormone in the fetal
plasma. In the event that the placental corticotrophin releasing hormone reaches the fetal brain, it
impacts adversely to the development of the hippocampus.
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 10
Studies have revealed that prenatal stress has significant impact on placental roles. In this
light, constant exposure to stress during gestation alters the functions of the placental some of
which relates to fetal brain development. Among the major functions of the placenta is the
transfer of important nutrients and oxygen to the fetus and elimination of waste products of
metabolism. In the event this function is inhibited through the influence of prenatal stress fetal
brain development is impaired due to derivation of oxygen and nutrients which are essential for
its development. Besides, the accumulation of toxic products of metabolism in fetal brain may
result to necrosis of vital cells within the brain which is fatal.
The placenta has been known to play a critical role as far as regulating exposure of the
fetus to stress related hormones in maternal circulation is concerned. In the event of any
alteration in this role, the result is that the fetus is exposed to exponentially high levels of
maternal glucocorticoid stress hormones, among them being cortisol throughout the gestation
period. Though some of the maternal stress hormones have been proven to bear positive effects
onto the developing fetus unrelated to brain development, some have far reaching adverse effects
on fetal neural development. Among those with positive implications is corticotrophin releasing
hormone (CRH) which has been associated with a complex series of processes which takes place
in the woman upon conception to suppress the immune system and ensure that the fetus is not
attacked and rejected by her immune system. Extremely high levels of cortisol however
jeopardize chances of fetal survival and her brain development.
Arnaud et al., 2010 argues that occlusion of blood flow to the fetal brain results to severe
congenital malformation in the fetus which is fatal. In the event that the fetus undergoes normal
development to parturition stage, the baby suffers from congenital brain development anomalies
which may result to conditions such as brain injury or at best, Attention Deficit Hyperactivity
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 11
Disorder among other disorders. Crocker, 2006 supplements Arnaud’s discussion by
hypothesizing that prenatal stress elevates levels of certain risk factors in the tissues of the
placenta which plays a critical role in as far as disorders of the brain in the fetus are concerned.
The factors in question in his hypothesis are cytokines of pro-inflammatory nature and oxidative
stress. Some of the disorders of the brain are related to the insufficient development of the brain
during the fatal stage some of which may be due to prenatal stress and related factors.
In addition to occlusion of the transport mechanism by the placenta, studies reveal that
the placenta plays a significant role regulating fetal brain development. To achieve this, the
placenta regulates fetal exposure to developmental hormones by inhibiting or selectively
allowing passage of these hormones. Arnaud et al., 2010 asserts that two hormones are of
particular importance; the 11 β-hydroxysteroid dehydrogenase type 2 and corticotrophin
releasing hormone. By controlling exposure to these hormones, the placenta is able to regulate
the fetal neural development. In this light therefore, it is evident that interference of placental
roles precipitates severe neural malformation of the brain which may adversely impact on the
baby in later stages of development. However, the interrelation between prenatal stress and
neural development in man is yet to be fully explained and demonstrated due to the challenges
explained herein. Studies on this subject in animal models have revealed significant interrelation
between the two.
Prenatal stress in the mother has been associated with alteration of the mother’s vaginal
microbial flora. In the initial developmental stages as well as later during early childhood, the
baby’s gut contains some vaginal microbes comprising the maternal vaginal microbial flora
known as microbiota. The microbiota enters the fetal gut during delivery as the fetus passes
through maternal vagina. According to recent studies, the mother’s vaginal microbiota is capable
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 12
of interfering with the fetal neural development by stimulating reprogramming of the brain
development mechanisms. Any alteration in the vaginal bacterial flora therefore precipitates
adverse outcomes in fetal brain development. Of importance in this case is that while babies born
by natural means faces this risk, those born by caesarian section evade the risk but are
consequently faced with a more life threatening condition if the appropriate measures are not
taken to introduce maternal microbiota into their gut.
In particular, prenatal stress during the first trimester results into long term alteration in
the woman’s vaginal microbiota. The alteration culminates into adverse variation in amino acid
processing and metabolism in the brain. In effect, this reaction causes otherwise an
unexplainable variation in the normal brain development system whose gravity is experienced in
later stages of development in neural conditions such as schizophrenia and autism. Besides, the
study also reveals that male gender is more affected by the variation in maternal vaginal
microbiota variation due t stress which may be used to explain the reason as to why
schizophrenia and autism are more pronounced in the males. Oral administration of the maternal
microbiota to the infant immediately after birth is one of the measures that are and may prove
essential in circumventing the outcome of absence of the same following lack of exposure during
birth.
Maternal vaginal micribiota are essential in fetal and infant gut to boost their immune
system prior to maturity of their body immune system. The microbiota is meant to enable them
counter invasion by pathogenic microbes in the early stages of development and ensuring brain
development assumes the normal course. Studies in animal models have demonstrated the link
and importance of the microbiota in brain development. Naturally it is hereby expected that on
extrapolating the same to human models the outcome is the same. In line with this study;
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 13
prenatal stress predisposes infants to the risk of developing acute variation in the brain
development processes which may result into severe malformation of their brain.
Michael and Catherin (2009) in their study on this subject matter reveal a different point
of view to the same. According to their discussion, some sea foods contain significant quantities
of methyl mercury, a neural toxin. In the event that the pregnant woman consumes such foods
frequently and in large quantities, the methyl mercury accumulates in maternal body causing
stress and pressure in neural functioning. In the event that the toxin reaches the fetus via the
placenta, the outcome is detrimental. In the fetus, methyl mercury particularly targets neural
development, migration of neurons as well as differentiation of neurons. In this case, neural
development in the fetus is hampered. The outcome of such eventuality is not felt until the later
stages of development where the fetus or the baby demonstrates brain conditions ranging from
severe to acute depending on the amount of methyl mercury they were exposed to as well as the
timing during pregnancy.
Brain development, whether fetal or otherwise requires the presence of some essential
nutrients and minerals in the maternal diet. According to Michael and Catherin (2009), in the
event that the pregnant woman is under any form of stress leading into her having either
insufficient or totally lacking these nutrients in her diet, the outcome on fetal brain development
is nearly fatal. Such circumstances may include times of drought or famine, wars and in
underdeveloped nations, inability to afford foods rich in the required proportions in the required
quantities. Lack of information or misinformation on the subject of dietary concerns in the
mother during pregnancy may also result into the same phenomenon. Communities that are
deeply set into the interior of developing countries and with conservatism ideologies are more
likely to fall culprit in this case.
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 14
Besides, the mother is likely to develop psychological stress due to the realization of the
adverse outcomes the shortage may bear on her unborn child. The mother may also indulge into
vigorous activities in attempt to secure some food in case of famine. In so doing this may cause
physical in addition to psychological stress on the mother which may trigger other mechanisms
such as the release of stress hormones which impacts adversely on fetal brain development. In
such circumstances, the mother’s body is under physiological stress due to absence or
insufficiency of these vital nutritional requirements. In effect, after depleting all the maternal
reserves of the nutrients, the fetal brain development is incomplete which may precipitate neural
development disorders in the fetus and in the baby in case it comes to full term.
Chapter 3: Methodology Description
Basically this study is meant to assess the impact of prenatal depression and anxiety in
fetal neurobehavioral development qualitatively and quantitatively followed by progressive
monitoring of the brain development post partum. The objective of the study is to provide
accurate results on the relationship, if any, between prenatal stress and anxiety and fetal brain
development and more so explore the impact at different stages of gestation. However, due to
the numerous challenges and ethics facing use of human models as well as the rationale and
logistics of the same, this study focuses on the use of appropriate animal models and then
extrapolating the result findings to the human population.
Various animals are suitable for this study including the Rhesus monkeys and different
strains of rats such as the Long Evans, Wister, Sprague-Dawley and the Sabra strains. For
purposes of this study the rats are the most suitable due to the relative ease of handling and
monitoring as compared to the rhesus monkey. Besides, the rats require less space therefore
feeding and restraining them is also relatively easy as compared to the monkey. Moreover, rats
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 15
give birth to a larger litter unlike the monkey whose litter size is limited to one or two and their
gestation period is relatively short. The large litter size makes it easier to monitor progress with
time since upon death of any during routine brain surgery; the study is not compromised as there
are other similar specimens that are equally reliable. For relevance, this study proposes the use of
four strains of rats to provide a large sample size and allow for inter species comparison. The
strains under consideration are the Wister, Long Evans, Sprague Dawley and the Sabra strains.
The study proposes the use of a combination of stressors for optimal productivity and
also to allow for a comparison between the effects of different stressors. Some of the stressors in
this study are physical whereas some are physiological as well as psychological. Physical
stressors are restraint, immersion in water to stimulate them to swim, physical handling,
exposure to noise and illumination with bright light. Physiological stressors are hormonal in
nature and are meant to alter normal body mechanisms; this study considers using
dexamethasone as the physiological stressor of choice. Outlined herein is the rationale of this
study.
The materials required in this study include a restraining cage, a syringe and needle,
dexamethasone (100 milliliters), source of light, source of mild heat, handling gear, saline
solution, source of noise (loud music preferably) a water basin (preferably with a volume of
about 20 liters). In addition, 12 winstar rats, 12 Long Evans rats, 15 Sprague Dawley and 12
Sabra rats. Out of the 12 test rats, three of each strain are to be used as control while the
remaining are to be used actively in the experiment. The methodology is as follows.
Three Winstar rats at the 15th day in their gestation are to be subjected to the following
stressors: restrain in individual cages for duration of half an hour trice per day at random time
intervals. Out of the remaining, three rats at their 15th gestation day are to be restrained in a small
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 16
cage following an intramuscular injection with 5 milliliters saline solution per day to induce
pain. The remaining three winstar rats at 15th to 21st gestation days are to be restrained in
individual cages and exposed to bright light for duration of 45 minute per day thrice per day at
random time intervals followed. In addition, this lot is to be handled for durations of up to 20
minutes once daily at a random time. All the twelve Long Evans rats at exactly the 18th gestation
day are to be restrained in individual cages for duration of half an hour, once daily at a random
time.
Three of the Sprague Dawley rats in their 15th to 21st gestation day are to be restrained in
individual cages and exposed to bright light thrice a day for duration of 45 minutes at a random
time interval. Three of the remaining rats of the same species in their 11th to 21st gestation day
are to be restrained in individual cages; subjected to bright light and mild heat thrice per day for
duration of 45 minutes at random time intervals. Out of the remaining two rats are to be
subjected to restraint in individual cages for half an hour, while one of the rats is to be restrained
for four hours, once daily at a random time at their 15th to 17th gestation day.
A final lot of three is to be subjected restrained in individual cages for up to 45 minutes
on their 15th and 18th gestation day, restraint in the same cage for 8 hours on their 16th and 19th
gestation days and in addition, immersion in water in the basin to stimulate them to swim for
quarter an hour on the 17th and 20th gestation days. All the Sabra rats at the 15th gestation day are
to be subjected to noise and illumination with bright light for alternating 10 minute intervals for
duration of up to 4 hours, thrice weekly.
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 17
Chapter 4: Expected Results
For the Winstar rats that are to be restrained in individual cages for half an hour, the
results are to be obtained at day 90 into their gestation. In this case, a remarkable decrease in
their fetal hippocampus wet weights is expected with the decline in male fetuses being greater in
males than females. According to this study proposal, timing is of essence for correct results and
interpretation. In those that are restrained in a small cage, with intramuscular injection of saline
solution, the assessment is to be done at the 35th gestation day. The expected results are; marked
decrease in synapse density in their hippocampus. For those winstar rats that are to be restrained
in cages followed by illumination to bright light, the assessment of the impact is to be made at
the fourth week into gestation whereby it is expected that hippocampal neurogenesis is decreased
by half in the dentate gyrus region. However, frequent handling reverses this effect to normal
later with time.
In the Long Evans strain of rats, notable impact is expected in their hippocampus. In
particular, it is expected that their hippocampus volumes is reduced especially in female fetuses.
In females, it is expected that the number of granule cells while in males this is not expected. No
considerable variation in the pyramidal cells in either gender is expected in this strain of rats.
The assessment in this strain is to be made strictly at the 75th day for accuracy.
For the first lot of Sprague Dawley rats which were restrained and subjected to bright
light, the assessment is to be made at the 28th day. In this case, it is expected that; there is marked
decline in hippocampal neurogenesis which is observed in the left dentate gyrus area. In addition,
progressive monitoring a different ages is likely to reveal the same results. After the third month,
it is expected that there will be an observable decline in the number of granule cells in the left
dentate gyrus region. The second lot was subjected to restraint, mild heat and bright light and the
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 18
evaluation was made at the 110th and 130th day. In this case it is expected that; there is marked
decrease in hippocampal neurogenesis in the dentate gyrus region in males while females display
no significant impact. In addition exploring the cerebral cortex reveals a reversed morphology in
males whereby the structure of their cerebral cortex is found to resemble that of the female.
In the lot of Sprague Dawley rats that is to be restrained, evaluation of prenatal distress
and anxiety on fetal neurobehavioral development is to be done at the 15th day. It is expected that
for the two rats that were restrained for half an hour, there is increased hippocampal
neurogenesis in the dentate gyrus coupled with increased differentiation of neuronal processes.
On the contrally, for the rat that was restrained for 4 hours per day, there is marked decrease in
hippocampal neurogenesis followed by distorted morphology of neuronal processes.
In the lot that was restrained in individual separate cages, subjected to overcrowding
conditions by restraining them in the same cage besides forcing them to swim, evaluation of the
total cumulative effect is to be made on the 23rd day. The areas of interest in this case are the
orbitofrontal cortex and the dorsal anterior cingulated cortex. Basal and apical dendrites of the
pyramidal neurons are expected to be decreased in either gender.
The Sabra rats were subjected to noise coupled with bright light illumination and the
assessment was made at the 60th day. In this case it is expected that in females, there is a reduced
hippocampal receptors for glucocorticoids while in males, there is no significant expectation in
the same light.
Chapter 5: Discussion
Predominant studies in this area of study have been carried out using animal models,
usually rats, to demonstrate the effect of prenatal stress on the fetal brain development due to the
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 19
limitations of human models or the efficiency of animal models. Animal models provide an
invaluable intermediate via which similar processes in humans occur. Extrapolation of results in
animal models provides a reliable basis for explaining complex mechanisms in human
populations. Nevertheless, several factors contribute immensely to the outcome of the studies.
Examples of these factors are different stress inducers, differences in the environment and most
importantly interspecies variations as discussed herein.
Timing is critical in this area of study. Different points in time may translate into
completely different sets of results which may lead to inappropriate interpretation of the results.
Timing in this case implies the particular point in time during which the pregnant animal model
is exposed to the stressing factors. Exposure at different gestational periods may result into
different results due to the fact the uterofetal environment changes significantly in different
trimesters. During various stages in gestation, the type and quantity of hormone to which the
fetus is exposed to vary significantly throughout the gestation period. Arnaud et al., 2010
highlights the major differences in the neurodevelopment processes between mammals.
Prenatal brain development process represents only a tip of the complex series of brain
development processes that occurs throughout the lifetime of an individual. Brain ontogeny is
characterized by several major processes as discussed herein.
According to Arnaud et al., 2010, cell proliferation occurs shortly after formation of the
neural tube.
The duration varies from species to species ranging from day 11 in rats to
approximately day 21-28 in human. The proliferating brain cells are evident in the ventricular as
well as sub ventricular portions of the brain. Neurogenesis then precedes the movement of
neuroblasts into the three sections of the brain; the fore brain, midbrain and hind brain. At this
point the neuroblasts are largely undifferentiated. Differentiation of neuroblasts may assume
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 20
either the same or different differentiation paths or different differentiation processes leading into
formation of similar or different cells though stemming from the same parent cells. On this basis,
the neuroblasts may differentiate into either glial cells or neurons.
In the event that prenatal stress comes into play during cell differentiation phase, the
outcome is unpredictable largely because this would depend on the cells affected. On the other
hand, in the event that the normal cell proliferation mechanism is affected by action of prenatal
stress, the result is that the fetus may experience difficulties in the normal brain development. At
the cell proliferation stage, prenatal stress may result into either of three eventualities. In the
worst case scenario, prenatal stress may inhibit cell proliferation and in consequence the normal
brain development. Alternatively, prenatal stress may accelerate the rate of cell proliferation
exponentially leading into formation of excess brain cells. Additionally, prenatal stress may
interfere with the normal synchrony of cell proliferation. Either way, the impact is adverse and
fatal. In this light it is vital to match the administration or exposure to the stressing factor with
the developmental stage in order to obtain accurate results (Arnaud et al., 2010).
Early exposure of the pregnant experimental animal to stress factors has been shown to
cause an early adaptation of the placenta to withstand environmental stress factors. As discussed
herein, the placenta plays a key role in fetal neurodevelopment. In this light early placental
development places the placenta in a position to retain and carry out its normal functions in spite
of the stress. It therefore follows that the placenta will carry out its normal functions under
optimal conditions oblivious of the induced stress. Consequently there will be no observable
impact on the fetal neurodevelopment which eventually culminates into a normal brain
development. According to Arnaud et al., 2010, studies in human models have revealed that the
impact of prenatal stress on fetal neurodevelopment is more profound when it occur mid-
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 21
gestation as opposed to later stages of the pregnancy while in non primate models, the opposite is
true.
The type of stressing factor to which a particular strain of a test organism is subjected to
determines the outcome. The stress factor to which the organism is subjected to ought to be one
which is generally unpredictable, the organism has no control over and which focuses on HPA
response in the test model. The response obtained from the pregnant test organism is directly
proportional to the type and magnitude of the stress factor. In addition, the amount of control the
test organism has over the stress factor also affects the outcome of the test. In this light, the more
control the pregnant test organism has over the stress factor, the less the response to the stress
observed in the animal (Arnaud et al., 2010).
Severe prenatal stress for which the animal has little or totally no control over culminates
into a high response in the animal. High response may be quantified by the amount of
stimulation of the activity of maternal HPA axis leading to production of larger quantities of
stress hormones to the detriment of the fetal neurobehavioral development. On the other hand,
subjection of the pregnant dam to mild stress for a short time frame whereby the animal has
relatively more control over results into lower response in the animal. The lower response may
be in term of production of lower quantities of stress hormones to the benefit of the fetal
neurobehavioral development.
Murmur et al., 2006 derives the argument that even in this case, quantifying the amount
of response is pegged on the fact that different animals of the same species tend to portray
marked differences in their ability to withstand stress. While some stressors are beyond the
control of certain individuals, the same are within the control of other individuals of the same
species. In addition, while some individuals may have control over some stressing conditions or
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 22
circumstances, others may have absolutely no control over the same conditions. Consequently,
the impact on the fetal neurobehavioral development varies respectively depending on individual
response to prenatal anxiety and depression which occurs due to individual adaptation.
Arnaud et al., 2010 point out the fact that though the exploration of this subject heavily
relies on making the study in animal models and extrapolating the results to human population,
the stressors that animals and human models face are different. Though it is acceptable to
introduce or subject animal test models to artificial stressors, it is unethical to consciously
subject a human model to artificial stressors. In this light therefore, studying the human
population in this area of interest is relatively cumbersome as researchers and scholars have to
rely on naturally occurring stressors such as natural calamities. Human study is faced with
numerous challenges in addition to ethics as discussed herein.
According to Arnaud et al., 2010 animal models are modeled in such a manner to
allow for effective collection and evaluation of the results. Obtaining results is one of the
hindrances for the use of human models for experimental purposes on this subject matter.
Evaluating outcome of different test parameters on the fetal neurobehavioral development
involves undertaking a comprehensive brain surgery on the test specimen. Besides, besides the
first initial assessment after parturition, it is vital for the researcher to progressively monitor the
brain of the test specimen to evaluate progress over time. On this basis therefore, the researcher
has to operate the brain under study from time to time and in so doing jeopardize chances of
survival for the specimen. In case a human model is the subject of study, this would imply that
the infant is repeatedly subjected to brain surgery which is unethical and fatal.
An effective study requires the use of a large specimen or sample in order to make it
representative and reflective of the total population. Undertaking an effective human study on
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 23
this subject would require that the researcher incorporates many pregnant women in the study
and this presents another double edged challenge. Securing a group of pregnant women that is
large enough is not an easy task. In addition, due to the sensitivity of this test, the researcher
ought to monitor the sample effectively throughout the duration of the study and more so control
the interaction between the test sample and the external environment. Essentially this would
mean that the researcher restricts interaction between the sample and their environment which
may not be achievable.
An earlier study in this subject matter reveals that anxiety may be genetically linked. In
this light, it is cumbersome to distinguish between the anxieties that occurs independent of
hereditary acquired factors. Moreover, due to the ethics related with subjection of human model
to stressors coupled with the fact that majority of the natural calamities happened relatively long
time ago, obtaining an effective stressor that is effective to the large sample size is relatively
cumbersome (Arnaud et al., 2010). Consequently effective studies using human models are
nearly impossible to carry out conclusively.
However, Arnaud et al., 2010 suggests useful measures that may be put in place to
circumvent the challenges of carrying out research studies in human models. The major measure
is utilizing natural calamities both natural and manmade to carry out the study. Natural and
manmade calamities present an appropriate scenario for the study by exposing an exponentially
large proportion of pregnant women at different stages of pregnancy to the stressor. In so doing,
this averts several challenges hindering human studies. Following the occurrence of the calamity,
researchers may then embark to quantitatively assess the impact of the calamity on fetal brain
development. In addition, disasters present events whereby individuals have little to no control
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 24
over the events which provide a suitable parameter since the individual response to the stressor is
bound to be significantly high as discussed previously.
Prenatal Distress and Anxiety and Fetal Neurobehavioral Development 25
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