OVERVIEW
· Can the origins of disease be traced back to the womb?
· Did you know that your birth weight could be a powerful predictor of your future risk of numerous chronic diseases?
· We look at how rapid growth in the early years can predispose us to future illness.
· And we ask: could the first 1,000 days of life be the most important of all in determining our health and susceptibility to disease?
Medicine spends the vast majority of its time and effort treating serious illnesses that have typically been years, even decades, in the making. Whether it is type 2 diabetes driven by years of excess weight and sedentary living, the imperceptible loss of bone that culminates in an osteoporotic fracture, or the gradual silting up of our coronary arteries that finally results in a heart attack, this is where the mighty resources of medicine are deployed. As the growing burden of chronic disease threatens to overwhelm healthcare systems, we are rightly shifting our attention to prevention, for, as we all know, prevention is better than cure. We’re implored to be more active, shed some kilos, eat our fill of fruit and vegetables, cut the salt and so on and so on.
But what if we’ve missed a trick here? What if the most critical time for preventing disease has long since passed? What if that was actually right back at our conception, and during the first 1,000 days of our life? What if our future health and susceptibility to disease was ‘programmed’ before we’d even taken our first breath?
A life mapped out?
A bit like outer space or the depths of the oceans, we are only just beginning to understand the ‘environment’ of the mother and how it affects the susceptibility to health and disease of the developing offspring. And just as we once thought the Earth was flat, so too have we had to have a serious rethink on this. As recently as the 1950s, it was commonly believed that the foetus was the perfect parasite. In similar style to the US Cold War stronghold built into Cheyenne Mountain, Colorado, it was believed to be impervious to outside stresses and attacks. There was just one way in: a tunnel with an impenetrable barrier that ensured what wasn’t wanted stayed out. For the baby this tunnel is known as the placenta. Back then, we thought the placenta allowed the developing foetus to block all noxious substances, while preferentially taking up the nutrients it needed. The foetus looked after itself and all mum had to do was house it for 40 weeks. Just think, it was only a few short decades ago that it was commonplace for mums-to-be to regularly drink alcohol and smoke (in the 1950s about half of US mothers smoked during pregnancy1).
Of course, things are a bit different now. Hard lessons have taught us not to take such a lackadaisical approach to prenatal care. We’re now fully aware that harmful substances, such as certain medications, recreational drugs, alcohol and cigarette smoke, can cross the placenta and wreak damage. Likewise, we recognize the need for good nutrition to ensure the birth of a healthy child (sufficient folic acid to prevent neural tube defects being a classic example). As long as our child is born healthy, and is seen to develop normally early on, the time in the womb was a success, right?
But what if we are still being too complacent about the potential of those formative months to mould and shape our health as adults? What if this period turned out to be the most critical time in our lives when it comes to disease prevention? What if our health throughout our entire life was predestined there, the blueprint of wellness (or lack of) laid down before we even took our very first breath? Perhaps that all sounds a bit far-fetched? But it’s exactly what UK doctor David Barker of Southampton University has proposed. In 1986 he made the ‘heretical’ claim in a paper published in the prestigious Lancet journal that heart disease in adult life is ‘related to nutrition during prenatal and early postnatal life2’.
The Foetal Origins Hypothesis
In the early 1900s the health of Britain was in a dire state. One in ten infants failed to see his or her first birthday, and those who did survive were often rife with maladies. In the national press of the time, it was claimed that up to two thirds of young men who volunteered to fight in the Boer War were rejected because of their unsatisfactory physique3. So worrying was this downturn in the nation’s health that one medical officer described it as a sign of the ‘doom of modern civilization as it did that of Rome and Greece3’. Then, something special happened, thanks to the dedicated work of a midwife, Ethel Margaret Burnside. Having persuaded the clerk to Hertfordshire county council to provide 60 spring balances, she set to work with her army of nurses, recording the weight of every baby in the county, both when they were born and again at one year of age3. This information was meticulously stored in ledgers and gave rise to the famous Hertfordshire Records. Decades later, it was here that the Barker/Foetal Origins Hypothesis was discovered.
With access to these records, Dr Barker was able to track down 15,000 men and women who were born between 1911 and 1930. He found that 3,000 had passed away, almost half from coronary heart disease or related disorders3. There was a striking finding. A disproportionately large number of these deaths had occurred among people who had been born underweight. Dr Barker’s team found that those who had weighed 5lbs (2.25kg) or less at birth had twice as many fatal heart attacks as those who weighed more than 10lbs (4.5kg)3. It wasn’t just about being born small, either. There was a change in risk right across the normal range of birth weights, meaning that as you move up through the birth weights, so heart disease risk in later life falls4. So if you were born 7lbs (3.2kg), you had less risk than if you were born 6lbs (2.7kg), and if you were born 8lbs (3.6kg) you had less risk than if you were born 7lbs (3.2kg). And it was with these eyebrow-raising findings that the Barker Hypothesis was born.
There’s a limit to the benefits of a high birth weight. Mothers who are overweight and/or with diabetes going into pregnancy, or who develop gestational diabetes, are at risk of giving birth to high birth weight babies. As well as increased birth complications, these infants also have a greater predisposition to become overweight in later life5,6.
Later, a systematic review of 18 studies of 147,009 individuals examining birth weight and ischemic heart disease risk, found a consistent 10–20% reduction in risk for every kilogram increase in birth weight7. Similarly, researchers have calculated that a 100g increase in birth weight would reduce coronary heart disease deaths in later life by 2.5% in men and 1.9% in women8.
What we’re left with is a quite remarkable discovery. If you were small at birth you are biologically different and these differences stick with you for the rest of your life. Blood pressure is higher, levels of fats in the bloodstream differ, the artery walls are less elastic, the stress response is altered, as too are hormone levels, the risk of type 2 diabetes is amplified and ageing is accelerated3. In essence, the foetal origins hypothesis proposes that the effect of under-nutrition in early life alters the structure of the body and how it functions… permanently.
While we blame an unhealthy diet and lifestyle for many of our Western chronic diseases – such as heart disease, high blood pressure, diabetes and osteoporosis – could they actually be instigated during our time spent in the womb? Could it be that poor nutrition in pregnancy causes deleterious physiological changes that predispose us to these diseases in later life?
It’s not just nutrition but other stresses that have a programming effect. When mothers smoke during pregnancy, birth weights are lower but infants are more likely to become overweight in childhood1.
Programming
So what’s going on here? How could something as apparently innocuous as birth weight exert such profound effects on the risk of disease decades later and with such unerring accuracy?
It looks likely that some adaptation occurs in the foetus during pregnancy in response to poor nutrition. From nine weeks post-conception onwards, the foetus starts to experience rapid growth. Different tissues grow at different times and these have been labelled ‘critical periods’. Optimal growth and development of these tissues is dependent on an adequate supply of nutrients, and if this is not available, the growth rate slows down and the number of cells, and the structure of the organs, can be permanently altered.
The Barker Hypothesis is not about babies who are born prematurely – it is full-term babies born small because of restricted growth in the womb that are at risk.
But there’s something else going on here too, something quite amazing. The low nutrient state of the mother acts as a signal to the developing child that the environment it will be born into is going to be a nutrient-impoverished one. The message is clear: you will be born into surroundings where food and nutrients will be scarce, so you’d better be prepared. As a consequence, what takes place is a ‘programming’ effect, thought to occur through hormone changes. The anabolic hormones IGF-1 and insulin are reduced and the catabolic hormone cortisol is increased. Cortisol is thought to be particularly significant here, exerting a growth-inhibiting effect on all tissues when the levels are raised in the developing foetus9,10,11.
If you think about it, it’s actually a very clever early warning system. The foetus is sensing its environment and based on this, is making predictions for the future – will it be born into a world of plenty, or will it be born into a harsh world of scarcity? Either way, it needs to be ready. If the latter is the case, this in-utero programming prepares the foetus for optimal survival advantage in an environment where nutrition is poor. In essence, a ‘thrifty phenotype’ is developed12.
But what happens when this baby, primed for a nutrient-poor environment, is actually born into a world where food is plentiful – i.e. the affluent Western world? Suddenly, the programming is at odds with the environment. Alas, the ‘window of opportunity’ for ‘programming’ is now closed, and the ‘lasting memories’ have been created. With the baby’s metabolism geared up to survive in nutrient shortage, the sudden exposure to plentiful nutrition means that nutrients are efficiently hoarded away as fat, serving as a store for any perceived future famines. Programmed at birth to conserve and store energy, yet bombarded with a lifetime of high-energy foods and a sedentary lifestyle, it becomes susceptible to the chronic diseases of our times – heart disease, obesity and diabetes.
Catch-up
If we’re not careful, we can end up compounding this problem. If a child is born at a weight below the ‘norm’, our natural inclination is to increase its calories to encourage ‘catch-up’ growth. This has long been viewed as an essential feature of recovery from the possible ill-effects of restricted growth in early life. As we begin to better appreciate the ‘thrifty phenotype’, it looks increasingly likely that this is the very worst thing we could be doing. It might intuitively seem right to ‘feed them up’ if they are small, but by doing this, all we’re actually doing is increasing their future risk of disease13,14.
So-called ‘catch-up’ growth in infants is consistently linked with increased fat mass, especially central fat, in childhood and adulthood15,16. And with this comes the highest rates of blood pressure17, heart disease18 and, potentially, diabetes19 in adult life. It seems we’re not just talking about the first year or two either, but into early childhood. Infants who were born small and remained thin at two years of age, but thereafter put on weight rapidly, had insulin resistance and higher coronary events in adulthood20. What we’re talking about here is not nutritionally depriving the infant – on the contrary, we need to be especially conscious of giving high-quality nutrition – but rather to avoid going overboard and giving excessive calories to try and rapidly promote growth back into the ‘normal’ range, as the infant is simply too susceptible to fat gain. As the infant grows into early childhood, this is a key time to really emphasize the promotion of a healthful diet and physical activity to negate any deleterious programming effects.
A ‘natural’ experiment
Despite the mounting number of supportive observational studies, and the convincing mechanistic and animal data, the problem is this may all just be circumstantial, and falls short of proving cause and effect. This was borne out by a meta-analysis of 110 studies investigating birth weight and later life blood pressure, which suggested there was too much random error and too many confounding effects to accurately illustrate the effect of the apparent association21.
One of the big criticisms of this whole theory is that factors such as smoking or socio-economic class could act as major confounders, in which case the low birth weight is just a reflection of some other factor, and not a direct cause. So for example, if you are poor you are more likely to have a worse diet during pregnancy, leading to a lower birth weight. Of course, being in poverty doesn’t stop just because you were born, it’s likely to remain with you throughout all stages of your growth and development, and as we know, being less well off is generally associated with worse health outcomes overall. So maybe we’re reading too much into the significance of a low birth weight when in fact it’s just a reflection of levels of affluence.
If you could conduct any research you wanted to sort this out, then ideally you’d perform an intervention trial. You’d take a population of women trying to conceive, some rich and some poor, and divide them equally into two groups. You’d restrict the nutritional intake of just one of the groups during the pre- and early postnatal period, before returning them to their normal diets. Then you’d follow the newborns for life to see if those with the restricted nutrition ended up with more health problems like heart disease, obesity and diabetes. It would ‘control’ for socio-economic status and give you a pretty good idea of whether the whole foetal origins hypothesis holds true. The big problem with our study is probably obvious – it’s completely unethical and would never be allowed!
But sometimes we’re offered the next best thing – a ‘natural’ randomized intervention trial that is conducted courtesy of circumstances, as was presented by the Dutch Famine of 1944. During the winter of 1944–45 half of Holland was under Allied control while the other half was under German control. An embargo was placed on food transport into the west of Holland, and by the time it was lifted, frozen canals and other waterways ensured a state of famine with severely rationed food supply. Upon the German surrender in the spring of 1945, this state of starvation ended, and nutritional intake was once again unified across Holland. And by the fate of history, a ‘natural’ experiment was conducted. In a population of diverse socio-economic status, we had an experimental group (exposed to famine and thus a deprived nutritional status for a defined period of time) and a ‘control’ group (consuming their typical diets throughout). Which leads us nicely on to the big question: would the offspring of pregnant women from the famine group experience worse health than those in the well-fed population? Could exposure to low nutrition in the womb affect lifelong health?
The results were striking. Nutritional deprivation at any stage of pregnancy increased insulin resistance in the offspring22. When deprivation occurred early in pregnancy, greater heart disease, as well as an increased prevalence of obesity, was observed22. In the case of females, the risk of developing breast cancer in later life increased almost fivefold22. Interestingly, it was found that the programming of chronic disease that occurred wasn’t always linked to a reduced birth weight.
This suggests that birth weight is just one obvious marker of under-nutrition, and that more subtle nutritional insults may occur which predestine future risk of chronic disease, remaining hidden until it presents in later life.
Indeed, the effects of under-nutrition encompass not just ‘physical’ disease, but mental health problems, too. A twofold increase in schizophrenia was reported in the follow-up of the offspring of the Dutch famine and also in a study of famine in China23. And perhaps that’s only the tip of the iceberg. Low birth weight children demonstrate lower cognitive ability and attain fewer advanced educational qualifications24,25, as well as being less likely to be employed in later life26. Other studies have even shown that low birth weight individuals are less likely to get married27.
What does it mean for us?
Of course, we don’t really experience things like famine here in the developed world. But perhaps our problem is not a lack of food per se, but a lack of the correct foods. We have many women of child-bearing age who consume unbalanced junk-food diets high in sugar, salt and trans-fats, but deficient in key vitamins, minerals and essential fats. We may not be calorie deprived but many remain nutrient-deprived. It may be different from the chronic malnutrition we see all too frequently in the developing world, but it still results in poor nutrition for the foetus. A junk-food diet could be hard-wiring the next generation for disease.
The optimal development of the foetus is highly dependent on the delivery of appropriate levels of a spectrum of essential vitamins and minerals. A shortfall of these can impair tissue development and induce hormonal changes, and has been associated with a reduced birth weight28,29.
So, what does this contentious hypothesis mean for us? Do we sit back and just blame mum for our disease risk? While the arguments are compelling, we need to get it into perspective and remember that it is just one factor among many we experience throughout our lives that may increase or decrease our risk to disease. Not every ‘programmed’ baby goes on to develop disease. For most of us, it is better viewed as determining the degree of our susceptibility to the ill-effects of our environments, i.e. the poor diet and inactivity that defines our modern lives. By partaking in a lifestyle of proper nutrition and regular activity we can minimize the influence of this risk factor. For example, while the incidence of coronary heart disease was highest in women who were born underweight and went on to be overweight in adulthood30, those who stayed lean into adulthood despite being born underweight had no observed increased risk. Your fate still remains in your hands, and whether you fulfil the plan imprinted on to you in early life is up to you.
If you were born full-term weighing less than 5lbs (2.25kg) – and possibly even 7lbs (3.2kg) or less – it becomes even more pertinent that you ensure you follow a healthy diet and lifestyle.
THE PARTING SHOT
The public health implications of this provocative hypothesis are potentially enormous. Rather than frantically firefighting the over-whelming burdens of obesity, heart disease and diabetes that we see all around us, should we be focusing our efforts on ensuring optimal nourishment during early life? Are we on the brink of a brave new world of medicine that prevents chronic disease before we’ve even taken our first breath?
Exciting as it sounds, it’s all too easy to get carried with this. All we’re doing here is bringing to light one more factor that may influence your health throughout your lifespan. It’s the realization that any serious attempt at reducing the epidemic of chronic illness we face in the twenty-first century requires us to take a whole lifespan approach to health. Strategies for preventing chronic disease shouldn’t start when we’re in our 40s or 50s, but by our parents before conception, and then continued throughout all stages of life.
With that nailed, in the next chapter we’ll move on to discussing exactly which key nutrients are needed, and at what levels, to ensure you give your child not only the best start in life, but also the gift of health that lasts long into adulthood.
SUMMARY AND RECOMMENDATIONS
· Chronic diseases such as heart disease and diabetes may not be all down to genetics and lifestyle – rather, our experiences in the womb, and during our first few years, could shape and mould them too.
· Poor nutrition in the womb can lead to restricted growth and permanent changes in the body that set the scene for chronic disease later in life.
· If we are serious about preventing disease, we need to ensure that future generations receive the best possible nutrition in-utero, and throughout early childhood.
· Optimal nutrition for women of childbearing age now, and especially during pregnancy, will help ensure that the next generation is a healthier one.