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Why Size Matters at Birth

Credit: Dmitry Lobanov/Adobe

Credit: Dmitry Lobanov/Adobe

By Marie-Jo Brion

A large genetic study has determined why small babies are at greater risk of disease as adults.

There’s a longstanding interest in birthweight, with documented examples of its routine assessment in European hospitals as far back as the 1850s. Today, birthweight is an established indicator of an infant’s health at birth, but it also relates to a baby’s chances of survival and health later in life. As such, measurement of birthweight is almost universally a part of all modern newborn health assessments.

Birthweights vary widely, spanning from 2500–4500 grams within the normal range. Around one in 16 Australians are born in the low birthweight category of less than 2500 grams.

Birthweight is a blunt measure of the overall growth and development of a foetus in the womb. It reflects the accumulation of many biological processes, some of which are known but many of which have simply not yet been identified.

Pre-term births, as well as multiple births, are associated with low birthweight because an early birth or a shared womb limits the extent to which a baby can grow in utero. However, the causes of low birthweight for a full-term infant are not entirely clear.

Parental size, as well as maternal health and behaviour during pregnancy, play a role. In particular, smoking during pregnancy and poor prenatal nutrition can adversely affect the developing foetus and reduce its size at birth. These factors are also linked to lower socioeconomic status, which is a known general risk factor for having a low birthweight infant.

However, these factors can’t fully explain differences in infant birthweight. A new study has found that genetics plays a more important role than previously thought.

Genetic Factors Influence Birthweight

Traits like birthweight are influenced by a large number of different genes, most with very small individual effects. Trying to identify these small individual genetic factors is a little bit like looking for needles in a haystack, and it’s not uncommon for genetic studies of this type to uncover only a few genetic factors. However, the larger the study, the better the chances are of uncovering the genes involved.

This is why a team of more than 300 scientists from around the world pooled their resources to compile a study of more than 150,000 individuals born at full term. This is currently the largest-ever study of the genetics of birthweight. The study was co-led by Prof David Evans and Dr Nicole Warrington of The University of Queensland’s Diamantina Institute, together with research teams in Exeter and Oxford. It was published recently in Nature (http://tinyurl.com/jay3u8x).

These kinds of studies are important because they not only discover new genes, but they also implicate biological pathways involved in the trait being studied. In this way, genetic studies of birthweight can provide vital clues about the biology of birthweight, and can identify important processes that are both genetically and environmentally determined.

An example where this is clearly evident is in genetic studies of heart attack. Of the genetic regions that contribute to the risk of heart attack, a number of them affect lipid activity and blood pressure. This points to a general involvement of lipids and blood pressure in the risk of heart attack, which can then be altered by non-genetic means, as is done commonly in the treatment of cardiovascular disease.

The new genetic study of birthweight linked 60 genetic regions to birthweight. The findings confirmed that birthweight is determined by many different biological pathways, including those related to metabolism, growth and development. Specifically, these involved insulin, glycogen, cholesterol and growth hormones.

Armed with their new findings on the genetics of birthweight, the authors of the study were then able to investigate the intriguing relationship between birthweight and adult disease.

Small Babies and Adult Cardiometabolic Disease

Low birthweight correlates with the risk of many different diseases in later life, including cardiovascular disease, Type 2 diabetes, asthma, cancer and mental health conditions. A popular theory called the “Developmental Origins of Health and Disease” argues that undernutrition during early stages of development, such as when a foetus is developing in the womb, causes permanent changes to the structure and function of developing tissue and organs. According to this theory, these adverse changes persist in the infant over time, leading to increased risk of various diseases in later life.

The support for the developmental undernutrition explanation stems mostly from correlational studies in humans and animal research. This body of literature is vast, yet many question marks hang over the theory primarily because it is extremely difficult to prove in humans that factors producing low birthweight causally affect the future risk of cardiometabolic disease. Since we cannot experimentally induce inadequate prenatal nutrition in humans, studies have to rely on non-experimental observational data. This makes it very difficult to pin down the exact causal variables in these types of studies. This is particularly the case with nutritional factors and determinants of health, which are hard to measure, highly correlated with one another and difficult to separate.

There are also common confounding variables, such as socio­economic factors, that relate strongly to both size at birth and various aspects of health and disease. This could also potentially account for the observed relationship between low birthweight and disease.

However, the large Nature study opens up a new window of insight. The scientists combined their genetic data on birthweight together with data from previous genetic studies of adult traits, including blood pressure, heart disease, Type 2 diabetes and body mass index, and found that many of the genetic factors contributing to birthweight are also contributing to these adult traits.

For some of these traits, such as blood pressure, the genetic correlation with birthweight was very high. This is the first time researchers have found such strong evidence that genetics plays an important role in determining why smaller babies are at increased risk of later cardiometabolic disease.

Genetics Links birthweight and Adult Disease

So what does this genetic link mean? It is not yet fully understood how these genetic factors are having common effects across birthweight and adult outcomes.

The genes could be having different effects on the body at different stages of life. In the study, some of the genetic regions influencing birthweight are involved in insulin signalling, which affects both growth and metabolism. Reduced insulin activity could result in impaired growth during periods of early development, while in adults it could adversely affect metabolic processes that predispose to Type 2 diabetes.

In addition, because a mother and her baby share many of the same genes, it is difficult to know if the correlation between reduced birthweight and increased risk of disease in later life is due to the baby’s genes alone or the baby’s and mother’s genes combined. The evidence from this recent study seems to point more towards effects that are coming from the baby’s own genes. However, it is also possible that maternal genes affect the intrauterine environment in which the foetus develops.

Either way, the existence of a genetic component in the link between low birthweight and the risk of cardiometabolic disease in later life does not exclude a role for modifiable environmental factors. In general, both genetic and non-genetic factors seem to explain the link between birthweight and adult health.

In short, the new study suggests that at least some component of a baby’s birthweight and their later risk of disease is predetermined by their genetic make-up, and confirms that there are indeed specific biological pathways linking the two. This opens up new possibilities for disease intervention.

While we can’t (yet!) alter our genetics through intervention, we can modify the biological pathways the genetic findings point to. For example, knowing that insulin genes play a role in birthweight and adult health is informative because we can target insulin levels in the body.

What Does This Mean for Small Babies?

Mothers and individuals of low birthweight need not despair. Birthweight is just one of many modest predictors of cardiometabolic disease risk. In fact, by far the strongest predictors of cardiometabolic disease are risk factor levels in adulthood, such as cholesterol and blood pressure in adults. Lowering these risk factor levels in adulthood is highly effective for reducing the risk of heart attack and stroke.

Of course, adult health and behaviours can sometimes be very difficult to target, as lifelong habits are often resistant to change. Reversing disease, once physiological processes have already set in, can also be limited.

Because of these and other challenges, many believe that the impact of traditional approaches for preventing cardiovascular disease has plateaued. In this context, identifying additional areas where improvements in health can be attained, such as in the early stages of life, can add value.

There is already a focus on certain prenatal factors, including adequate nutrition and the overall health of mothers during pregnancy. The genetic findings are now providing new places to look within our complex biology. The hope is that this will improve our understanding of what determines birthweight and how we can improve health outcomes throughout the course of life.

Minimising disease risk from the earliest stages of life could lead to improved health for everyone. However, early interventions to reduce the risk of disease could be particularly important for low birthweight babies.


Marie-Jo Brion is a Research Fellow in Genetic Epidemiology at The University of Queensland.