Low birthweight and childhood obesity: a potentially dangerous mix for cardiometabolic health

Previous studies suggest that babies born underweight have a higher risk of heart disease and metabolic disorders when they grow up. But how early in life does the metabolism begin to struggle?

New research, published in Lancet eBioMedicine, found that people born underweight already show signs of cardiometabolic risk – such as high blood pressure and insulin resistance – in childhood and adolescence.

This effect was heightened among young people who had ended up with obesity, although whether their obesity causes the worrisome metrics or is a symptom of the same process remains to be seen.

“Much research has shown that birthweight is an important factor for determining health risk later in life,” says Sara Elizabeth Stinson, a biologist who led the study as part of her PhD studies at the Novo Nordisk Foundation Center for Basic Metabolic Research of the University of Copenhagen, Denmark. “What we wanted to do is show that this is already happening at an early age.”

Birthweight and healthy fat storage

Worldwide, an estimated 15% of babies weigh less than 2.5 kg at birth. “In Denmark, this is fewer than 5% of babies,” Stinson says. Although premature babies have a whole host of health challenges, metabolic researchers are interested in near- or full-term babies born underweight because this indicates some type of growth restriction that can inform the lifetime risk of such diseases as diabetes.

To assess how low-birthweight babies develop compared with their peers, Stinson and her team used data from the HOLBAEK Study, which examined more than 4000 ethnically European children 4–18 years old in Denmark – some with obesity and some without. The researchers collected detailed biometrics – including height, weight and waist and hip circumference – as well as blood samples, which were analysed for levels of protein in the plasma. Each child’s genetic profile was also determined to assess their inherited risks.

Stinson says that body-mass index (BMI) can be a convenient shorthand for researchers, but it ignores many important factors – including where the body stores fat.

Some people’s bodies more easily store fat subcutaneously – the fat “that you can feel underneath your skin, all over your body,” Stinson explains. This method of fat storage seems to have fewer health effects than visceral fat storage, in which fat wraps around the vital organs.

To transcend the simplistic ratio of height and weight of BMI, the HOLBAEK study incorporated dual-energy X-ray absorptiometry – full-body scans that map precisely where fat is stored – for a subset of the children. “You can quantify the proportions of fat and water and the bone mineral density an individual has,” Stinson says. “We included these measures to get a more accurate picture of the individual’s health, not just based on visual appearance.” Then, magnetic resonance imaging was used to assess the fat deposits in the liver specifically.

Fetal programming

Stinson and her team found that children and adolescents with low birthweight had higher blood pressure and lower insulin sensitivity than those born within the normal weight range. But the association did not end there – “those with low birthweight who then ended up with obesity later had even further reduced insulin sensitivity,” Stinson says. “It is quite striking.”

The scans also revealed that low-birthweight babies stored fat differently as they grew. Children and adolescents with low birthweight had more visceral fat around their organs, especially their liver, which can be “quite dangerous,” Stinson says.

But what causes the association between low birthweight and these cardiometabolic markers in the first place?

One potential explanation is what scientists call the fetal insulin hypothesis. “During pregnancy, insulin can act as a growth factor,” spurring the developing fetus to put on weight, Stinson says. Low birthweight could be early evidence of insulin insensitivity – meaning that the cells of the body are not as responsive to the signals from insulin.

As the child grows into an adult, and especially if other stress factors are present including overweight, insulin insensitivity can cause difficulty in regulating blood glucose and ultimately type 2 diabetes.

Another possibility is the adipose expandability theory, Stinson says. Higher birthweight is associated with higher BMI later in life but can also be a sign that the body can store fat in a healthier way. Low birthweight could reflect an inability to appropriately expand the fat cells distributed under the skin across the body, which means that fat storage will be rerouted to the more problematic visceral fat deposits on the organs. “This drives insulin resistance and inflammation,” Stinson adds.

“If you are restricted in growth during gestation and end up being small, then later on you cannot store fat in healthy places,” Stinson explains.

Next step: do interventions make a difference?

Stinson’s data suggest that young people with low birthweight and obesity have more worrisome risk factors for cardiometabolic disease than young people with low birthweight who fall within a normal weight range as children and adolescents.

The next step is for researchers to determine whether interventions with young people – designed to reduce BMI or improve worrisome markers such as blood pressure – ultimately lower the risk of cardiometabolic disease in adulthood for people with low birthweight. This is not a foregone conclusion, Stinson explains, since weight and cardiometabolic disease for people with low birthweight may be symptoms of the same process and not cause and effect.

“In this cohort study, the children with obesity are also undergoing treatment to try to reduce their degree of obesity and risk through non-drug approaches – diet advice, exercise and other behavioural approaches,” Stinson says. Determining how the HOLBAEK Study participants compare with children with low birthweight and obesity who have not received the same treatments would be informative.

Stinson says she hopes her research will contribute to more tailored treatments as understanding of the relationship between low birthweight and disease matures. “If an individual comes into the clinic and has obesity, healthcare providers could look at their birthweight” for clues as to what might be causing their insulin insensitivity or excess visceral fat, she says, and choose treatment more targeted to their needs.