Introduction

Begin Before Birth is a website about how the influence of the environment begins in the womb. It is based on evidence showing what a mother feels during pregnancy can have a lasting effect on the development of her child.

It provides a clear and concise introduction to the areas of fetal programming, fetal development and epigenetics.  It examines the evidence and the mechanisms for how stress in the mother’s environment can affect her foetus.

This website was put together by researchers from the Institute of Reproductive and Developmental Biology at Imperial College London under the guidance of Professor Vivette Glover, Professor of Perinatal Psychobiology. The films were produced by Windfall Films.

Requirements:

Students will need access to individual PCs with Internet access and sound. Ideally, the room will be equipped with a projector to display the teacher’s PC.

Related Curricula:

In schools:

• A Level Psychology courses
• AQA A – ‘Schizophrenia and Mood disorders’ and ‘Stress’
• AQA B – ‘Genetic explanation of behaviour’  ’Schizophrenia and Mood disorders’ and ‘Stress’
• Higher Tier GCSE Science and Biology courses where discussion of environmental vs inherited factors takes place – epigenetics and evolution sections are particularly relevant
• A Level Biology courses

Health professionals:

• The website contains many links to related areas as well as links to key pieces of research. It could be used as a summary of the key ideas and a basis to start a research project.

Suggested Lesson Plan

An alternative idea would be to set the activities as homework and ask students to prepare responses to the discussion questions that includes references to the key pieces of research. This material could be used to debate the questions outlined in the lesson plan during the next lesson.

1. How may a mother’s emotional state affect the development of her baby in the womb?

2. How can the father help?

3. What do you think the evolutionary reasons may be for the mother’s emotional state during pregnancy having an effect on her unborn baby?

4. What is epigenetics?

5. When do you think the fetus may start to feel pain?

6. Charlie’s Story:

Stress can have a variety of physiological effects on the body.

During pregnancy, excessive stress can adversely affect fetal development, and thus it is important for the mother to remain calm.
Cortisol is particularly important for mediating the effects of maternal stress, and the placenta acts a barrier to limit fetal cortisol exposure.

The placenta does this through the action of the enzyme 11-β hydroxysteroid dehydrogenase type 2 (11-βHSD2) which converts active cortisol to inactive cortisone
However, increased maternal stress has been shown to reduce placental 11-βHSD2 expression and increase fetal cortisol exposure.

See if you can use placental 11-βHSD2 to protect the fetus from maternal cortisol and keep the ratio of cortisol:cortisone below 1:10

Thank you for taking the time to view this site. Please use the space below to leave any comments or suggestions.

This is a story about Charlie

Charlie, age 19 years, is just leaving prison. He has been convicted of stealing. He is also often aggressive. He generally behaves badly, and most people would think he was responsible for his crimes and deserves to be punished.

But let’s look at his story.

His mother was very stressed while she was pregnant, had no support from her family or friends and her partner did not want the child.

Charlie was a very difficult baby, often crying and hard to soothe. His mother became depressed. She was not able to give him love, warmth or encouragement. His father treated him harshly.

He did badly at school, was slow at learning, showed readily distracted attention, and often broke the rules. He was often excluded and then started to truant.

In his early teens he turned to crime.

How should we think about this?

His mother’s stress while she was pregnant could have caused him to be a difficult baby and hard to soothe. It could also have led him, as he got a little older, to show signs of ADHD and being hard to control.

All this made it tough for his family to deal with him, and show him affection. His mother’s depression made it harder for her to give him the sensitive mothering that might have helped.

His slowness at learning, ADHD and tendency to break rules (conduct disorder) are all strong risk factors for later criminal behaviour.

So one could say that a mixture of his genes and his early environment, starting in the womb, predisposed him to becoming a criminal.

We might still think he is responsible for what he did. Certainly not all those who have a hard start in life turn to crime. But maybe if Charlie had had a different start in life things would have turned out differently.

Watch the video to learn more about Charlie’s story

Charlie’s Story

Click here to see the video

It is interesting to ask why all this should happen. Why does what a mother eats, or how she feels, change the development of her baby in the womb?

These changes may be an evolutionary mechanism to prepare the baby to be ready for the environment into which they are going to be born. This has been called the Predictive Adaptive Response (see Gluckman and Hanson 2004).

If, in prehistoric times, a mother was living in a dangerous environment, she would have felt stressed.

Many of the changes caused to her fetus by prenatal stress may have helped her child to survive. (See Glover 2011).

For example being more anxious, can make one more vigilant, and thus quicker to spot something dangerous in the distance, like a snake. Having readily distracted attention, as happens with ADHD, may make one notice a rustle in the undergrowth more easily, whilst being more aggressive may make it easier to quickly get rid of the danger.

Importantly, the degree to which offspring are affected is directly related to the severity of the mother’s stress during pregnancy. This supports the above theory, in which a more dangerous environment will cause the mother more stress, thereby increasing the severity of the effects on the offspring. In these circumstances a child whose attention is even more readily distracted may be better equipped to deal with the prevailing danger, e.g. a large number of predators.

What is also interesting is that maternal stress during pregnancy appears to have sex-specific effects on the resulting offspring. Animal models have demonstrated that male offspring are more likely to display learning deficits and increased aggression, whilst females are more prone to anxious behaviour and hyper-responsiveness of the HPA axis (See Weinstock 2007).

These sex-specific differences can potentially be explained by extending the theory above. Since females are traditionally the primary care givers, then an increased level of anxiety may help them to remain vigilant in a dangerous environment, whilst exploratory males would experience greater exposure to threats and increased aggression may increase their chances of quickly and successfully resolving conflict.

However, what was helpful in dangerous prehistoric times is not so helpful in our modern society, in which education and concentration are highly prized.

Fetal programming and Public policy

Although ‘Charlie’s story‘ is an extreme example, it contains elements that apply to many children who later turn to crime.

People are starting to realise that if we want to reduce crime in our society we need to start very early, preferably first by giving support to pregnant women.

The Family Nurse Partnership in action

An intervention for deprived teenage mothers, the Nurse Family Partnership has been developed in the USA. It gives much support and education about parenting to these mothers during pregnancy and for the first two years after birth. The  children of the mothers  who have had this  help showed a much reduced rate of probation and criminal behaviour in their teens (click here for published research papers from the NFP).

The programme is now being tried out in the UK, as the Family Nurse Partnership.

Graham Allen MP  recommends the Family Nurse partnership in his report “Early Intervention. The Next Steps”

Giving extra emotional support to pregnant women should do much more than help reduce crime. It should reduce the level of emotional and behavioural problems in many children. We have estimated that if women are in the top 15% for anxiety in a normal population their child will have double the risk of a mental/behavioural disorder later (O’Connor et al 2003; Talge et al 2007). The risk  is increased from about 5% to 10%. Most children are not affected, but in terms of public health this is significant.

Women should be screened for anxiety/depression/relationship problems when they first see a health professional when pregnant, and appropriate help should be provided.  Family, friends and employers should all be more aware of how important it is to give emotional support to pregnant women.

Background

We are starting to understand the fundamental biological changes which underlie fetal programming. Of particular importance is the field of epigenetics, which means ‘on top’ of genetics.

Epigenetic changes are modifications of DNA, which occur without any alteration in the underlying DNA sequence and can control whether a gene is turned on or off and how much of a particular message is made. Every cell in our body has the same DNA sequence but different genes are turned on or off to make our different tissues, such as muscle or liver.

Epigenetic changes can also be caused by the environment and lead to differences in individual characteristics. In the womb both the mother’s diet and her stress can cause epigenetic changes in the fetus.

The effects of maternal licking and grooming on the epigenetic regulation of GR expression in pups. (Image taken from Feder and Colleagues 2009)

The early emotional environment can lead to long lasting epigenetic changes in the brain. One of the first examples of this came from animal studies of maternal care. Rats pups who were licked and groomed a lot by their mother, showed reduced anxiety and lower stress responses in adulthood. These effects were due to epigenetic changes within the brain of the offspring, specifically at the receptor for the stress hormone cortisol (Weaver and Colleagues, 2004 ). Similar epigenetic modifications of the cortisol receptor were identified in the brain of rat fetuses whose mother’s were exposed to prenatal stress during pregnancy see Mueller and Bale, 2008

In human studies, child abuse has been shown to alter the epigenetic profile of the brain when examined post-mortem (McGowan and Colleagues, 2009), and maternal prenatal stress, caused by violence from the partner, promotes epigenetic changes in the DNA for this same cortisol receptor, in the blood of their adolescent children (Radtke and colleagues, 2011).

These epigenetic changes can be passed down from the mother or the father (see Franklin, 2010 and Champagne, 2008) and may even persist across multiple generations, being passed on from grandparents to grandchildren. Thus, acquired characteristics can sometimes be inherited. However, whilst certain epigenetic changes can last a lifetime, others are much more temporary, and a lot of research is currently being conducted to establish how epigenetic changes can be reversed.

The Molecular Basis of Epigenetics

The two main epigenetic mechanisms are shown below. These are termed DNA methylation and histone modification, and both determine whether the underlying DNA code can be read or not, and thus whether the DNA is able to make RNA. In particular, the methylation of target genes is usually associated with a dramatic reduction in their level of expression.

Two epigenetic mechanisms are described above, histone modifications and DNA methylation both of which determine whether the underlying DNA code can be read or not

The Agouti Mice

One example of the effect of epigenetic changes is shown in a special type of mouse called the Agouti mouse. These animals have the same genes, but have different epigenetic modifications to a single gene, which controls coat colour. During pregnancy, the mother of the smaller mouse with the brown coat was fed a diet rich in supplements, including folic acid. Folic acid serves as a methyl donor, and this allows the agouti gene to become methylated and switched off, resulting in brown fur.

However, the mother of the mouse with the yellow coat was not fed these supplements. As a result, the agouti gene remained unmethylated and expressed in all cells, leading to a yellow colouration of the fur, as well as adult-onset obesity, diabetes, and tumorigenesis. So these genetically identical mice look so radically different due to epigenetic changes, caused in the womb, by their pregnant mothers’ diet.

The Agouti mice above show the effects of different diets during pregnancy

Why not take a look at our film for more information on epigenetics and how it relates to fetal programming

Epigenetics

Click here to see the video

Research is showing that the placenta is very important in filtering what passes from the mother through to the fetus (see O’Donnell and colleagues, 2009).

It seems that the emotional state of the mother can change this filtering capacity.

If the mother is stressed more of the stress hormone cortisol may pass through, and this in turn can alter the development of the fetal brain.

Cortisol is usually broken down by an enzyme called 11β-HSD2:

Click Here To See How Placental 11β-HSD2 Works

If the mother is stressed there is less of this enzyme in the placenta and so more cortisol can filter through and affect the development of the fetal brain.

This has been shown in animals (see Mairesse and colleagues, 2007) and there is some new evidence that the same happens in humans too (see O’Donnell and colleagues 2011).

There is also evidence that exposure to higher levels of cortisol in the womb can alter the development of the fetal brain (See Bergman and Colleagues 2010).

The Placenta and the Fetal Brain

The primary function of the placenta is to maintain an adequate supply of nutrients to fetus. This is especially important for fetal brain development which undergoes rapid growth in the prenatal period:

Image courtesy of Sandman and colleagues Univesrity of California Irvine

A 3mm neural tube will grow into a whole brain containing 100 billion neurons and 100 trillion connections.

Proliferation (production of new neurons) starts at 5 weeks continues through 18 months.

Precursor cells give rise to neurons which migrate to specific brain areas and differentiate to perform specialised functions.

New neurons form connections between one another, termed synaptogenesis.

An excess of neurons are produced prenatally. Neural pruning removes the unused neurons, a process which continues at least until puberty.

Although recent evidence has shown that new brain cells are formed well into adulthood, termed adult neurogenesis, the brain experiences the greatest growth before birth as shown in the figure below:

It can be hard to establish the effects of prenatal stress on the fetus and the child in humans, because so many problems can occur together. If the mother is stressed, anxious or depressed while she is pregnant she is likely to be the same after the baby is born. Many studies have tried to take account of this, but it is difficult.

But the evidence from animals is quite clear. Prenatal stress has a long term effect on the offspring. It is possible to foster the newborn rat of a stressed mother to a new mother, on the first day after birth and compare their behaviour as they grow up with that of a newborn rat whose mother was not stressed in pregnancy. One method used is shown in the diagram. The pregnant rat is stressed by exposing her to the smell of a cat.

Example of a prenatal stress study using rats

Animal experiments have shown that prenatal stress can cause all the following effects on the offspring:

• More anxiety
• Reduced attention
• Learning deficits
• Less difference in function between the left and right sides of the brain
• Effects different on male and female offspring
• Altered sexual behaviour – males show homosexual behaviour and females are less nurturing mothers.

Importantly, all these effects have also been demonstrated in humans, except for the alterations in sexual behaviour.