|Where the prenatal stress occurs. Picture take from http://www.douglas.qc.ca/info/prenatal-stress|
Stress can affect an organism before its birth, and prenatal stress during critical periods of development can influence the development of the brain. The brain acts as the centre of control for organisms and imbalances in it can result in greater susceptibility to disease and/or predispositions to psychological and psychiatric disorders . Areas affected have been found to be involve, but not be limited to, the prefrontal cortex, hippocampus, amgydala and cerebellum, with symptoms ranging from poorer intellectual functioning, to behavioural problems to impaired motility . At this point in development individuals lack consciousness and their quality of life and societal contributions are the responsibility of the parentals: thus, it is vital to raise awareness and take preventative measures so as to ensure a healthy future population.
1 Prenatal Stresses
1.1 Gestational Diabetes
Gestational diabetes is a condition in which the mother develops high blood glucose levels during pregnancy, either previously unidentified diabetes or recently acquired. This can be potentially harmful as it exhibits no symptoms during gestation and is associated with excessive fetal growth, often leading to offspring impaired glucose tolerance and/or obesity . It can also lead to large gestational size and birth injuries (e.g. broken bones), hypoglycemia and impaired intelligence .
It generally occurs during the third trimester and although there is no universal method for diagnosing it, it can be treated by controlling carbohydrate intake and by use of medication that increases maternal insulin production or increases insulin sensitivity . The combination of using glucose monitoring, insulin therapy and dietary advice has been shown to produce offspring with less serious perinatal problems . Labour induction was also more common, though offspring had smaller birth weight and were born earlier . Metformin, a drug that increases insulin sensitivity, has been associated with with preterm birth . Although in either case little has been said in terms of adverse effects, preterm birth has been associated with smaller brain volumes . In the Rowan et al (2008) study where metformin was tested on mothers with gestational diabetes, hypoglycemia occurred less in the metformin intervention group. Its mechanism of action is poorly understood though, thus more studies are required to determine its long term safety.
1.2 Pregnancy Anxiety
Pregnancy-related anxiety has been significantly related to spontaneous preterm birth . Preterm birth is associated with smaller birth weight , which is in turn related to smaller brain volume, and a decrease in hippocampus size has been said to be a risk factor for development of psychiatric disorders . The Buss et al (2010) paper tested for changes in fetal brain morphology at different times during pregnancies relative to perceived stress. What they found was that there was regional grey matter reduction at 19 weeks in the prefrontal cortex (mostly bilaterally in the anterior, orbitofrontal, dorsolateral and ventrolateral areas) and medial temporal lobe, including the parahippocampal gyrus. This follows the literature that claims that these regions are susceptible at earlier gestational times . It is important to note that these areas are mainly associated with cognitive performance and memory thus perhaps providing an anatomical basis for consequences of prenatal stress. 
Smoking during pregnancy has been shown to be a risk factor for intrauterine growth restriction, preterm birth (and by extension low birth weight ) and sudden infant death syndrome  . Placental abruption (placenta detaches prior to birth) and placental previa (embryo incorrectly implants itself in the lower uterus) are two conditions that have often lead to perinatal deaths . The latter has been weakly associated with smoking in a dose-response gradient only in cases of heavy smoking, whereas smoking has been shown to increase the risk of placental abruption by almost two fold ).
|Smoking and uterine complications|
|From Ananth et al (1996). The association between placental abruption (•), placenta previa (O), and uterine bleeding (0)|
Smokers who quit smoking prior to/early on in the pregnancy, or were with spouses that smoked, gave birth to offspring with similar measurements as nonsmokers . In a different study though, the same category of individuals did make offspring with greater abdominal circumference . This perhaps points to critical periods existing for smoking as well.
|Standard deviations for women that smoked throughout their pregnancy|
|From Jaddoe et al, 2007. Standard deviations for fetal head circumference, abdominal circumference, and femur length compared to nonsmokers.|
The nicotine content in cigarettes is inversely associated with birth weight and head circumference, which, given its vasoconstricting effects and its effect on placental circulation, could be a mechanism by which defects can occur .
In cases of prenatal stress not relevant to nutritional deficiencies, effects on the fetal brain are likely to be mediated by maternal stress . During pregnancy women have naturally higher levels of cortisol required for proper fetal growth . Maternal cortisol travels through the placenta and as it can cross the blood brain barrier, it can modify glucocorticoid receptors throughout the central nervous system . The mother being stressed results in the activity of the partial barrier enzyme that protects the fetus from cortisol, 11β-HSD, to decrease thus allowing more exposure to glucocorticoids . Evidence has shown that this affects neuron development, production of glucocorticoid-sensitive proteins/hormones (like estrogen and GLUT1), fetal HPA axis function and in particular, shrinks the size of the hippocampus  . To read into the HPA axis and how its affected by stress, please see http://neurowiki2013.wikidot.com/individual:the-effects-of-stress-on-memory
|Maternal cortisol and its effects|
|The pathway by which maternal stress is thought to affect the fetus.|
Another contributing factor that can cause fetal brain alterations is through the interruption of placental circulation. Maternal stress can activate catecholamines such as adrenaline and noradrenaline which increase vascular resistance, impeding blood flow through the placenta . This can lead to oxidative stress and generation of pro-inflammatory cytokines, which have been associated with neurodevelopmental disease .
3 Animal Models
Due to ethical concerns with human testing, animal models have been used as a way to test the effects of prenatal stress. Structures that have shown modification as a result include the hippocampus, amygdala, cerebellum and hypothalamus: consequences generally produced latency to play, attention deficit or anxiety .
|Animal prenatal stresses|
|From Charil et al, 2010. Abbreviated chart of studies on prenatal stresses on animals.|
In the 1996 Clark study, several female rhesus monkeys were unpredictably stressed (via loud random noises, denoted by measured cortisol levels) throughout their pregnancy. In group caging offspring were found to be more inactive, marked by less exploration and 6 times less play behaviour. Mobility increased as time went on, whereas control's exploration activity decreased, implying increasing agitation . Evidence also exists in rats whereby prenatal stress during gestation caused an increase in susceptibility to being stressed postnatally . In the Weinstock et al (1992) study, these mice produced more fecal droppings during stressful situations and were less inclined to taking risky, exploratory behaviour.
As per the  study, there is now evidence suggesting that single exposures to prenatal stress are sufficient to cause changes in brain development. Pregnant mice were injected once with a clinically relevant dosage of betamethasone, a glucocorticoid steroid used on mothers during pregnancy to prevent respiratory syndrome in babies. On postnatal day one, mice were found to have a significant decrease in brain weight, cell proliferation and head diameter. Inconclusively though, most observed phenotypic differences reverted back to wildtype as time progressed. Beginning on postnatal day two, male rat brain cells rebounded and began overproliferating. This did not seem to compensate for the decrease in brain weight though as there was still a deficiency in males by postnatal day 21. Decreased head diameter did persist, modelling what is seen in humans that have had prenatal injections of betamethasone. As smaller head circumferences have been associated with learning disabilities, neuromotor and behavioural issues at ages two and three respectively, and given that women can be given up to 4 injections prior to delivery, it is essential to conduct more research on impact of glucocorticoid before introducing them prenatally.
As there is no universal protocol for translating and applying animal study results to humans, the findings must be interpreted with caution. While true that many brain regions are similar in structure and function to that of a human, this does not imply that development time periods and resiliency to stress are the same. As human brains mature more prenatally than the brains of rodents, it is evident that different gestational periods will likely result in different critical periods . As shown in studies with humans, the time of exposure to prenatal stress during gestation can have a greater or lesser influence on the unborn child  . This means that the same stressor may result in different effects on the brain depending on the time of its exposure. With animal studies particularly, the time of assessment is critical. Cases have been documented in which animals demonstrated a form of deficiency due to having been prenatally stressed, but such impairments were compensated for/recovered at a later time  .
4 Future Implications
Given that prenatal stress may alter one's susceptibility in coping with stress later in life, one may postulate that this threshold to cope may influence performance and learning. Academic performance for example may be associated with the capability to deal with stress, influenced in part by their prenatal experiences. Silverstein and Silverstein (2010) that stressors are stressful depending on how it's perceived, and are often seen so in cases where it results in new or overwhelming demands. Using DES, a stress scale specifically for dental students, Silverstein and Silverstein (2010) found that across four American dental schools students rated higher stress levels at the end of first year versus during orientation or three months into their program. There was an association with higher levels of stress and lower GPA. Across all four schools the students with the highest reported stress were found to have the lowest GPA. The more stressed students also rated their health perception as worse, symptoms ranging from depression to lack of concentration to intense fatigue. Interestingly, women and single students reported more symptoms than men and married students
|Average morning and afternoon cortisol levels.|
|From Tseng et al (2010). Cortisol levels based on gender. AM cortisol levels were significantly higher in females than in males. Afternoon levels were similar.|
In the Tseng et al (2010) study, salivary cortisol samples of third year medical students were taken in the morning within one hour of waking and one hour before sleeping, on a day in the last two weeks of a clinical rotation. Cortisol, indicative of stress level, overall was found to be higher in the mornings but were seen to be much higher in females.
4.2 Mental Illness
Researchers have had the opportunity to study a limited number of effects of prenatal stress on humans due to natural disasters. Autism and schizophrenia, among other psychological conditions, have been reported to be associated with prenatal stress  . Autism prevalence dramatically increased in Louisiana during severe storms from 1980-1995 . Autism frequency was higher in those that were prenatally exposed to more intense storms and those specifically exposed during gestation months of 5-6 and 9-10 . For those cases, where exposure occurred during those sensitive months and to high intensity storms, had about 26 autism cases for 10 000 births versus control (in utero during nonsensitive months and exposure to low/no storm) which had 5 cases of 10 000 births . Mothers of autistic children have reported recalling more prenatal stressors than in control mothers, although this may be potentially bias as the prior may remember more negative aspects during that pregnancy . In the Beversdorf et al (2005) study, there was a statistically significant increase in stressors reported during weeks 21-32. Albeit based on recall, this evidence of second and third trimester exposure to prenatal stress does support autism development during the Louisiana storms.
The Hunger Winter of 1944 in the Netherlands, a famine that lasted about half a year, has been another event in which researchers have studied prenatal stress and mental illness development. A study looking into prenatal stress and addiction took patients with registered addictions conceived during that time and found that most had exposure during their first trimester . This was a statistically significant relationship only present in males . A different study had found evidence that first trimester exposure was also a risk factor for developing schizophrenia . Using relative risk calculations (http://en.wikipedia.org/wiki/Relative_risk) during severe famine, it was found that women were at a much higher risk for developing chronic and episodic schizophrenia . Men were slightly at risk for developing episodic schizophrenia, but results otherwise were not significant . This is evidence suggesting female susceptibility to prenatal nutritional deficiency.
Addiction and schizophrenia were both found to be more prominent during first trimester exposure, which contrasts with autism which was associated with second and third trimester exposure. These are not necessarily contradicting but rather perhaps exemplifying of the fact that the type of psychological disorder can have different periods during gestation to which it is most harmful.