This is the last of the How to improve your child’s success before they are even born series. See Part 1, Part 2 and Part 3. OK, its pretty heavy going on the science, but if you really want to understand anxiety then its worth a read.

Most people are aware that stress and anxiety are not good for pregnant mothers. Even in 400 B.C., Hippocrates espoused the influence of emotions on pregnancy outcomes, leading to a plethora of literary dramas old and new where stress has caused the leading lady to miscarry or go into premature labour. More recently though, following Barker’s theories of foetal adaptation to the mother’s womb environment (see my post How to improve your child’s success before they are even born: Part 3), scientists have found that a mother’s anxiety in pregnancy can influence psychological and behavioural outcomes of her developing foetus over and above those caused by premature delivery.  There is now a well-established literature base linking mother’s anxiety in pregnancy to several psychological and psychiatric outcomes in children, including: anxiety, attention deficit hyperactivity disorder (ADHD), cognitive problems, changes in temperament, aggression, conduct problems and even schizophrenia (Beydoun & Saftlas, 2008; Talge et al. 2007; Van den Bergh et al., 2005).

 

Animals stressed in pregnancy give birth to anxious baby animals

The first evidence for this came from animal studies. Researchers found that rats and monkeys exposed to stress in pregnancy produced offspring that had long-term difficulties with attention, motor behaviour, aggression, memory and showed “hyper-vigilant behaviour” (Van den Bergh et al., 2005). Hyper-vigilant behaviour in animals is a proxy for human anxiety. It incorporates being alert to potential threat with corresponding changes in body systems to prepare to respond to threat. Think about how you would have felt travelling to work on the underground the day after the 7/7 London bombings of 2005, and this is probably a good picture of human “hyper-vigilant” state. Darting eyes on the look-out for suspicious bags with no owner, or people with over-sized back packs, slight tension in muscles, slightly increased heart rate and breathing rate, a little bit more perspiration than usual and if someone were to pop a balloon behind you, you’d probably have been ready to run. Hyper-vigilance is a good thing if you are in a stressful situation. It has served me well on many a walk home from the night-bus stop. If you are continually hyper-vigilant or hyper-vigilant in non-threatening situations like social situations or on aeroplanes; it can be very problematic and is called “anxiety”.

In animals it is easy to experiment and find out what is happening, you can wire animals up to measure muscle tension, heart rates and perspiration fairly unobtrusively. Even better, you can take blood samples and measure the levels of “stress hormone” cortisol. By doing these experiments, scientists have been studying the various effects of maternal stress on animal offspring and among several suspected effects, they have found pretty conclusively that in animals stress in pregnancy causes changes in the development of the foetal stress regulation system, the Hypothalamic-Pituitary-Axis (HPA) re-setting it to be on heightened alert.

 

How does the body deal with stress? What goes wrong to cause anxiety? – an analogy

What is the HPA-axis? The HPA axis is a collection of parts of the body that communicate by hormones to regulate certain bodily responses, including the stress response. In its function to regulate stress-response, it works pretty much like the emergency fire service. When you see a fire, you pick up the phone and dial 999. This puts you through to a national call centre, where you are asked which emergency service you would like. Once they realise that it is the fire service you need, they contact the regional fire control centre which contacts your local fire brigade which sends out an engine to where you are. The firemen hopefully put out the fire and call back the fire brigade centre to report that the job is done, which then feeds this information back regionally so that the case can be closed. Alternatively, if the fire has gotten out of hand, they can report regionally or nationally depending on the extent of the fire to request more engines to help.

The hypothalamus (a region in the brain) is the national call centre. When the eyes see threat, they alert the hypothalamus. This lets the brain’s pituitary gland, (regional fire control centre) know that there is a threat and a stress response is required. The pituitary communicates with the kidneys (local fire brigade), which then provides the stress response: the steroid hormone cortisol (fire engine). The fire engine goes out to sort the problem. Cortisol does this by going to the heart and making it pump harder, it goes to the lungs and makes it breathe quicker, it goes to the sweat glands and makes them produce sweat, it goes to the muscles and makes them tense and ready for action. All so that you can either fight or flee the threat.

If a city undergoes a heat wave and there is an increased propensity to fires starting and burning out of control. The fire service would probably request more resources on standby and be on heightened alert to send out more engines. More engines than needed might be sent out to small fires to ensure that they did not catch and turn into large fires. This is precautionary and helpful in the short term, but is an over-reaction if continued long term, beyond the time of realistic threat. The same thing happens to our body’s emergency response system. If there is a history of heightened stress, the body responds by increasing the base level of cortisol in the blood stream and increasing the amount of cortisol released in response to stress. This is not a problem if there is continued threat, but if the situation calms down and the body does not down regulate its stress-response system, the result is persistent anxiety.

In animals at least, it has been shown that the animals themselves do not need to have been exposed to stress for their bodies to be placed on heightened alert, they merely have to be exposed to their mother’s heightened alert system in the womb. Thus in animal experiments, giving pregnant mothers injections of cortisol equivalent substances can cause their children to have higher base levels of cortisol and heightened cortisol response when they are born and with continued effect into adult life (Van den Bergh et al., 2005). These animals went on to display a range of long-term behavioural and cognitive impairments. This can be thought of as part of Barker’s hypothesized foetal programming whereby the foetus exposed to high levels of maternal stress hormone predicts a hostile environment and prepares itself by adapting its HPA-axis to best cope with impending fight for survival. Where the resulting environment is actually not that stressful; the HPA-axis is now not working properly and leads to a range of problems.

 

Who cares about animals? What about humans?

Stressing humans to study anxiety is rather unethical. Shockingly, it used to be allowed and “Little Albert” is a classic case in psychology literature. Little Albert was a 9 month old boy who was not afraid of rats and was given a rat to play with. A dastardly psychologist John B. Watson wanted to see if it was possible to cause a phobia of rats. Every time little Albert touched the rat, a man stood behind him and banged a piece of metal with a hammer making a loud noise scaring little Albert. Needless to say, after a while of this, Albert became afraid of rats and stopped going near them, proving it is possible to induce a phobia[1]. No wonder experimental psychology has a bad name!

These days, we are thankfully not allowed to do such things, but it does mean that extrapolating work from animal studies into humans is harder. We have to rely on stress that occurs naturally in the lives of pregnant women rather than purposefully causing stress in order to study its effects on offspring. Natural and man-made disasters have been used to study the effects of anxiety in pregnancy.

Studies of children who were in the womb of mothers affected by 9/11 showed that these children were born with lower birth weights even though they were born at term, compared to children conceived following 9/11 (Berkowitz et al., 2003). Infants whose mothers were pregnant during the 1998 Canadian ice storm that led to electricity and water shortages for up to 5 weeks scored lower on mental development indices and tests of language development compared to other children, even after taking into account birth complications, birth weight, prematurity and post-natal depression (La Plante et al., 2004).

It is not just extreme stress such as a national disaster that can cause effects. Studies have also used questionnaires asking pregnant mothers about their levels of stress at varying times in their pregnancy and then studied their children at varying ages from newborn to adolescence. In general the link between maternal stress and impaired offspring outcome is borne out, sometimes even with a direct dose-response effect[2] (Beydoun & Saftlas, 2008; Talge et al. 2007; Van den Bergh et al., 2005). Results from different studies vary as each study is different in terms of the stress they are measuring (some studies ask for work stress, bereavement, marital stress, criticism from partners, or just how anxious you feel), the time in pregnancy the stress occurs (studies vary in studying stress in the first, second or third trimester), and the outcome and age of children they are studying (some studies look at language and development in the first year, others look at ADHD symptoms in childhood and yet others look for anxiety and conduct problems in adolescence). Despite this, the majority consensus of all the studies is that there is a significant negative effect of maternal pre-natal anxiety which can have lasting effect. In this way, it is not just your DNA that is biologically influencing your child’s outcome, but environment, via biological mechanisms.This is epigenetics, the new buzz in child psychiatry research.

 

Interesting finer details

The theory regarding differences in timing effects is that this relates to timing of brain development. Throughout pregnancy the developing foetal brain goes from a neural tube to a baby’s brain which is a complicated journey. Different parts of the brain are forming throughout the 40 weeks, and the effects of insult to the brain at a particular period in pregnancy will depend on the part of the brain that is forming at that time. So for instance, a brain insult (such as anxiety) occurring at the time that the language centres in the brain are forming may lead to language deficits down the line.  It is known that the links between pre-natal anxiety and schizophrenia are related only to stress that occurs in the first trimester (Khashan et al., 2008), whilst maternal anxiety experienced in the third trimester is more likely to cause offspring anxiety (O’Connor et al., 2002). Even more interestingly, there appear to be differential effects depending on the gender of the developing foetus, females more likely to develop anxiety, males more likely to be affected by attention, cognitive problems and aggressive tendencies! There is strong evidence for this in animal models and supportive evidence for this from human studies (Glover 2011; Glover & Hill, 2012)

The reason for these different gender outcomes has been thought about from an evolutionary perspective. Historically the female role in species survival in animals and humans has been to bear children and look after them, the male role has been to protect and provide resources. Different skills are required for these different roles. Thus, in a hostile environment, it pays for the mother to be fertile to ensure succession and hyper-vigilant to prey and threat. It pays for the father to go and explore new territory for food and shelter, to take risks to achieve this and to be aggressive enough to fight others for territory and food. In this context, the effect of stress in generating anxiety in females and cognitive impairment and aggression in males can be understood. Hey, in an Armageddon situation I think we would all want rough and tough Bruce Willis at our side not intellectual Stephen Fry.

In animal models it has also been found that stressed out female rats reach sexual maturity earlier, are sexually active earlier, have more offspring but invest less time in the care of each (Meaney, 2007). We have to remember we are talking about rats here, but in humans there is evidence that a harsh early environment (poverty, neglect, abuse) can lead to precocious puberty. You can draw any other rat-human parallels yourself.

The astute amongst you, might be complaining that this is all hogwash and that so many things might be confounding the picture. A confounder is something that can be related to both the purported cause and the outcome. The main ones affecting our current scenario are things like poverty, post-natal depression and maternal educational level. One could argue that a deprived, uneducated mother prone to depression is more likely to experience stress during pregnancy and more likely to have difficulty raising children, thereby causing the psychological deficits seen in their offspring in childhood and adolescence. In animal studies, this is easy to exclude, the new born pups or monkeys are cross fostered so that the mother stressed in pregnancy is replaced once the baby is born by an unstressed mother. Results remain. It is not possible to do this with humans.

In the majority of human studies, known and suspected confounders (social class, post-natal depression, maternal education to name a few) were measured and significant results remained even when these confounders were taken into account. What about the effect of genetics? It is possible to argue that a mother genetically predisposed to anxiety is likely to be anxious in pregnancy and to pass on anxiety genes thereby causing offspring to be anxious. You can see how hard it is to prove anything in science, yet clever research designs continue to come up to try and get to the answers. In a master-stroke of research design now possible due to the frequency of in-vitro fertilisation, Rice (2010) compared, in a cohort of IVF children, the association between prenatal stress and child outcome in those who were genetically related to the mother with those who were not (i.e. receiving egg donation). They found there was an association between mother’s stress in pregnancy and child’s symptoms of anxiety and conduct disorder even in the unrelated mothers.

 

How does this relate to you and me?

So, how to prevent anxiety in pregnancy? For me, I was smug reaching pregnancy having achieved a stable, loving relationship, stable financial and employment situation and having lived child-free life to the full. I felt I was ready to face pregnancy and motherhood in the best position that I could be in to avoid anxiety. There would have been nothing to stop a loved one being run over by a bus or being faced with infertility problems or illness but, at least the readily controllable variables were answered for.

Things can’t always go as planned though! Typical of most pregnant ladies, the thought of a new bald addition to the family somehow provokes the mental image of bald addition being placed into a beautiful, white cot with pressed linen sheets in a light and bright nursery attached to a south-facing home with wooden floors, modern furniture and period features. Hence in the first trimester of pregnancy Banker and I embarked on a 10 month process of flat hunting, flat offers, flat rejections, flat offer accepted, flat exchange of contracts, flat completion delay, eviction from rental and 2 weeks of homelessness, worldly goods in storage and 2 week enforced holiday in France to avoid sleeping on the street, flat completion, moving in, moving out, flat total remodelling and renovation, all of which no doubt sent the cortisol flying through my placenta!

Here biology and scientific literature come to the rescue again. Thankfully, like all natural miracles, the pregnant body seems to do all it can to protect itself and its prize. It is well known that in the third trimester of pregnancy and for a period post-natally the body dumbs itself right down (Henry & Rendell, 2007). Having for many years prized myself on my amazing memory and lauded it over my husband who seems to have been born with the happy disposition of the forgetful, I became just the same. Misplacing things left, right and centre, but instead of fretting and panicking, just sitting back and saying “Ah, sod it”. During my last week at work, I merrily typed away at a patient’s report only to re-read it to find that it was gobbledegook! Evolutionarily this dumbing down particularly affecting memory impairment is likely to protect against the harmful effects of third trimester anxiety, as well as to help block out the trauma of childbirth so that we become willing victims for another round!

Further, there was a caveat in the maternal anxiety literature! In a review of the literature, Vivette Glover (2011), a fellow North West London resident, describes studies selecting only well-off middle to upper class women in stable circumstances. They found that in this group mild stress in pregnancy had a beneficial influence on child outcome with better mental and physical development of the children and a similar trend for IQ. The suggestion is that in this group of women, a small amount of pre-natal stress may actually enhance foetal brain development. This inverted-U shaped dose-response effect is typical of anxiety and you will be familiar with the idea that a small amount of anxiety helps you sharpen your attention to perform on stage or in an exam, but too much anxiety can cripple your efforts. If Big Sis wins the Nobel Prize, I’ll be remembering to send a bottle of bubbly to my builders for the aptly timed “mild” stress!

References and Influences:

Beydoun H, Saftlas AF. Physical and mental health outcomes of prenatal maternal stress in human and animal studies: a review of recent evidence (2008). Paediatric and Perinatal Epidemiology, 22, 438–466.

Talge, N.M., Neal, C., Glover, V. and the Early Stress, Translational Research and Prevention Science Network: Fetal and Neonatal Experience on Child and Adolescent Mental Health (2007). Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? Journal of Child Psychology and Psychiatry, 48, 245–261.

Van den Bergh, B.R.H., Mulder, E.J.H., Mennesa, M. & Glover, V. (2005). Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms. A review. Neuroscience and Biobehavioral Reviews, 29, 237–258.

Berkowitz, G.S., Wolff, M.S., Janevic, T.M., Holzman,I.R., Yehuda, R., & Landrigan, P.J. (2003). The World Trade Center disaster and intrauterine growth restriction. Journal of the American Medical Association, 290, 595–596.

LaPlante, D. P., Barr, R.G., Brunet, A., Du Fort, G.G., Meaney, M.J., Saucier, J.F., Zelazo, P.R., & King, S. (2004). Stress during pregnancy affects general intellectual and language functioning in human toddlers. Pediatric Research, 56, 400–410.

Khashan, A.S., Abel, K.M., McNamee, R., Pedersen, M.G.,Webb, R.T., Baker, P.N., et al. (2008). Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Archives of General Psychiatry, 65, 146–152.

O’Connor, T.G., Heron, J., Golding, J., Beveridge, M., & Glover, V. (2002b). Maternal antenatal anxiety and children’s behavioural/emotional problems at 4 years. Report from the Avon Longitudinal Study of Parents and Children. British Journal of Psychiatry, 180, 502–508.

Glover, V. (2011). Annual Research Review: Prenatal stress and the origins of psychopathology: an evolutionary perspective. Journal of Child Psychology and Psychiatry 52, p 356–367.

Glover, V. & Hill, J. (2012). Sex differences in the programming effects of prenatal stress on psychopathology and stress responses: An evolutionary perspective. Physiology & Behavior 106 (2012) 736–740.

Meaney, M.J. (2007). Environmental programming of phenotypic diversity in female reproductive strategies. Advances in Genetics, 59, 173–215.

Rice, F., Harold, G.T., Boivin, J., van den Bree, M., Hay, D.F., & Thapar, A. (2010). The links between prenatal stress and offspring development and psychopathology: Disentangling environmental and inherited influences. Psychological Medicine, 40, 335–345.

Henry, J.D. & Rendell, P.G. (2007). A review of the impact of pregnancy on memory function. Journal of clinical and experimental neuropsychology, 29 (8), 793–803.

[1] Interestingly, there appears to be an evolutionarily hard-wired biological predisposition to phobia development to things which are traditionally harmful. Thus, it is easy to induce a phobia for things like rodents, snakes and spiders but very difficult to induce a phobia to cars, guns and knives which are more likely to be a threat in the modern age.

[2] A dose-response effect is an effect whereby the greater dose of something purported to cause a particular effect, will cause a greater effect. For example, if sun exposure is linked to tanned skin, a dose response effect would mean that more sun exposure leads to a deeper tan. Finding a dose-response effect is good (but not necessarily definitive) evidence that a causal link exists.