Feature: Fetal forecasts

2 April 2007. By Lisa Melton

How the fetus foresees adult life and what happens when the world does not fit its expectations.

New York, 11 September 2001. A passenger aeroplane crashes into the upper floors of the north tower of the World Trade Center. Among the survivors and witnesses of the horrific events are pregnant women. From the womb, the infants experience the trauma too, their biology and behaviour changed for life.

'Fetal programming' is a fascinating, burgeoning area of research. In the past two decades it has become clear that events in the womb have far-reaching impact, influencing not just growth as an embryo or child, but also health into adulthood.

Ever since Southampton researcher Dr David Barker, in the late 1980s, linked poor early fetal growth to increased odds of developing cardiovascular and metabolic disease as an adult, mothers' diets have been centre of attention. Obesity, type 2 diabetes, hypertension and cardiovascular disease are usually blamed on sedentary lifestyles and bad eating habits, but babies who are born small because of a poor maternal diet may be particularly at risk of such diseases as adults.

Mismatch

If times are tough, the fetus is programmed to adopt a 'thrifty phenotype'. Fat is stored in order to survive in times of scarcity, and brain growth is protected at the expense of the pancreas and other tissues. Such babies stay small, and have fewer beta cells in the pancreas so insulin production is low. All this is fine if the infant grows up in a nutrient-poor world.

The trouble begins when the environment changes, and the 'thrifty' child is born into a world where sugary and fatty foods are plentiful. "You get the early signals that prepare you for a life of challenge, famine or war zone. Then suddenly we are born in world where there's a McDonald's on every corner. You don't have to hunt, shoot or fish the hamburgers - they come at you," says Professor Jonathan Seckl, a Wellcome Trust-funded researcher at the University of Edinburgh.

"The conditions conflict with the way you've geared up your metabolism," points out Dr Susan Ozanne, British Heart Foundation Lecturer at the University of Cambridge. "These babies are good at storing food for a rainy day, but the rainy day never comes and you are getting fatter and fatter."

The consequences are alarming. In a study of 300 000 19-year-old male survivors from the 1944-45 Dutch famine, there was an almost two-fold increase in obesity risk in men whose mothers were exposed to famine during the first trimester of pregnancy. Similar risk patterns are emerging in contemporary birth cohorts such as the Avon Longitudinal Study of Parents and Children. Infants born relatively thin who gain weight quickly become the heaviest children at age five. And, worryingly, the first signs of insulin resistance appear as early as age eight.

Babies who are thin at birth may show a period of rapid 'catch-up' growth during infancy, and parents are delighted to witness their babies filling out to reach a normal size. But this rapid weight gain may lead to childhood obesity and may predispose to heart disease and type 2 diabetes later in life, especially in people who were small at birth and grow up to be heavy adults.

In Wellcome Trust-funded studies of low-birth-weight mice, Dr Ozanne has found that the mismatch also shortens lifespan. She and her colleagues are investigating the key players involved in this fateful chain of events from poor early growth to premature death. Flaws in insulin signalling pathways in muscle and fat tissue may contribute to these defects, Dr Ozanne believes.

Tug-of-war

Even so, many researchers believe that 'we are what our mothers ate' is too simple an explanation. Nutrition is just one of the many influences on the fetus as it grows in the womb and, through the mother, surveys the outside world.

The size of a newborn is not wholly down to a mum's diet, for example. It's also about genes. As Wellcome Trust-funded Professor David Dunger, at Addenbrooke's Hospital, University of Cambridge, explains: "It's a two-way interaction in which the maternal environment may enhance or restrict fetal fat storage." A baby's size at birth, he argues, is the result of a genetic tussle between the fetal genome, which drives growth, and the pregnant woman's genes, which determine the environment in the uterus and may try to restrain growth.

The conflict is most intense in firstborns. The mother tries to limit the size of the baby, to preserve resources for later offspring. In second and later pregnancies, the restraint eases off and offspring tend to be bigger.

While much is known about small babies and their rocky cardiovascular future, the nine months spent in the mother's womb also affect the baby's brain. "What is really interesting is that the environments [in the womb] that create the risks are not just random," says Professor Anita Thapar at the University of Cardiff, who is funded by the Wellcome Trust. The womb environment is dependent on the mother's behaviour during pregnancy, which may be influenced by genes that predispose her towards depression or anxiety.

Take smoking, for example. Toxins in smoke could be having a direct effect on the growing child's brain. But in addition, the mother's genes are influencing how likely she is to become stressed during pregnancy and to smoke. "The fetus has a double whammy: the inherited genetic susceptibility and exposure to the environmental adversity," Professor Thapar adds.

To disentangle these effects, her team will be studying babies conceived by in vitro fertilisation carried by surrogate mums who are genetically unrelated to them - "it's like an adoption study in the uterus," she says. Direct toxic effects from the intrauterine environment will show up whether the child is genetically related to the mother or not. If the effect is caused by genes, the association will only appear in babies related to the mother.

Placenta power

Maternal stress is also thought to have a lifelong impact on biology and behaviour. "By stress, I don't mean having a bad day at the office, but severe stress or trauma such as breaking a leg or having an operation or bereavement," says Professor Seckl. "At these times you pour out cortisol." Stress during pregnancy has been linked to increasing an offspring's risk of mental illness, including depression, attention deficit hyperactivity disorder and anxiety, as well as violent behaviour.

Take the case of expectant mothers who were present at or near the 9/11 terrorist attack in New York. Professor Seckl, in collaboration with US psychiatrist Professor Rachel Yehuda, has followed 187 women and their babies. Those who developed post-traumatic stress disorder (PTSD) and were in their third trimester at the time gave birth to infants who, at one year of age, showed abnormally low cortisol levels in saliva - a typical biological marker of PTSD. The children of mothers treated with stress 'steroid' hormones while pregnant also have persisting effects, with less confidence and more shyness.

In rodents, if stress hormones soar beyond normal levels, the pups are born small, their hypothalamic-pituitary-adrenal (HPA) system that regulates the response to stress is reset to hypersensitive mode. The stress may be transient, but the effects persist and as adults, the offspring develop high blood pressure, high insulin, high glucose, hyperactivity and anxiety behaviours.

Normally, stress hormone levels in the fetus are kept much lower than in the mother. This gradient is achieved by a placental enzyme, the 11B-hydroxysteroid dehydrogenase type 2 (11B-HSD2). This enyzme forms a 'barrier' to maternal glucocorticoids. Though the barrier is efficient, it is by no means complete, and its efficiency varies considerably from fetus to fetus. An inefficient 11B-HSD2 would lead to smaller babies - indeed, babies who have mutations in the gene that encodes this enzyme are very small.

So if our body is 'programmed' in the womb, the seeds for today's obesity and diabetes epidemic may have been sown long ago. Knowing more about these transgenerational effects may help to anticipate the growing threats to adult health and wellbeing and to inform public health policies. And the corollary: the food you eat and the life you lead may be stacking up problems for future generations. Your grandchildren may not thank you for it.

Lisa Melton is a science writer based in London

Image: Embryo at eight weeks, courtesy of Medical Art Service, Munich

Feature: Fetal forecasts

Mismatch

Tug-of-war

Placenta power

Further reading