EXPERT REACTION: Inflammation in pregnant women linked to bubs' brain development

This study provides compelling evidence of a link between inflammatory exposure in utero and cognitive function in infants after birth.

There is substantial evidence from animal studies demonstrating a cause-and-effect pathway between inflammatory injury to the fetus in utero, with altered brain development and function after birth. This important works shows similar mechanisms may operate in children.

The work strengthens the evidence base linking pre-birth events and exposures with the origin of cognitive behavioural disorders in children. Evidence from children born pre-term, which often involves inflammation in the mother and fetus, also point in this direction. The new findings add to a building consensus amongst specialists that when the brain is forming in utero, maternal inflammation due to uncontrolled infection or even non-infectious inflammatory triggers, such as air pollution and environmental toxins, can accumulate to inflict fetal injury and potentially have a life-long impact.

We need more studies to substantiate the link between inflammation before birth and brain development in humans, to identify the most important inflammatory triggers, and to advise on which triggers should be avoided. Even so, the study should raise awareness and strengthen our resolve to ensure women can achieve the best possible health before and during pregnancy, to enable the best start to life for infants and children.

Ultimately, I expect we will develop new approaches and interventions to assist women in avoiding elevated and/or sustained inflammatory exposures and events in pregnancy. This will likely include a combination of lifestyle advice, public health measures and possibly medical treatments to prevent undue inflammatory activation.

This interesting study adds to our understanding of how the ‘envirome’, or total environmental exposures, of parents can influence brain development and function of children. Inflammation (a response of the immune system) can be affected by a range of environmental factors, including infection, stress, poor diet and sedentary behaviour.

Increased maternal inflammation during pregnancy has been linked to increased risk of particular brain disorders in children, including autism and schizophrenia. This study needs to be followed up in larger cohorts of mothers and children to look at longer-term effects, to establish whether maternal inflammation contributes to long-term brain function and cognition in adolescents and adults, and risk of specific brain disorders.

The broader implications include how we think about parental health, both before and after conception. Our own work, and that of others, suggests that the lifestyles of males (including stress and physical activity) can affect brain development and function of their offspring, via epigenetic changes in sperm.

This latest study could link to lifestyle factors of females both before and after conception, which may impact on their levels of inflammation during pregnancy, and brain development of their children.

The study provides little insight into the mechanisms involved, nor the potential long-term effects, so much more research is needed

Work carried out at Oregon Health & Science University (OSHU) and University of California, Irvine (Nature Neuroscience) shows that inflammation in pregnant mothers is linked to their offspring’s brain organisation as newborns, and working memory performance at age two.

The study measured blood levels of a key inflammatory mediator, interleukin 6, throughout pregnancy. Next, the authors measured the infants’ brain activity at rest with functional magnetic resonance imaging to determine the pattern of brain network organisation.

The work suggests a link between the amount of inflammation women experienced during pregnancy and brain development. Experimental studies, including work from our lab, indicate that increased inflammation in areas of the brain known to be important for memory can occur in response to a range of exposures early in life, including stress, infection, and poor diet in the mother.

We also know that adverse experiences early in life, such as extreme stress or abuse, increase the risk of poor mental health and psychiatric disorders later in life. What is exciting here is that the work represents one of the first demonstrations in humans linking inflammation during early development to effects on memory, and functional connectivity in the brain. The authors showed that the neonate functional connectome could predict the maternal level of inflammation, which in turn predicted a toddler’s working memory function.

The findings support the need for research that focuses on how factors before and after birth – during the critical ‘first 1,000 days’, such as key environmental influences, can interact to impact brain function and cognition. 

Research around this concept of Developmental Origins of Disease (DoHaD) will be discussed at the national DOHaD meeting in Sydney in July.

Inflammation is an old phenomenon that affects the human body as a result to injury or infection. For decades, animal studies have shown that inflammation during pregnancy can alter fetal brain development and cause brain injury in the offspring later in life.

A new human study has shown that high levels of inflammatory markers found in the pregnant mum’s blood are associated with altered neonatal brain organisation at birth and affects working memory at 2 years of age. With no surprises, the higher the inflammatory markers found in the maternal blood, the poorer working memory in the offspring.

Currently, there are no treatments for fetal or neonatal brain injury following inflammation. However, there are several researchers in Melbourne and around Australia that are investigating potential therapeutics for treatment of fetal and neonatal brain injury. This new study provides vital information for clinicians and scientists to target early interventions

The reason why I decided to specialise in prenatal nutrition is because of the growing body of evidence that what we eat during pregnancy impacts the future health and wellbeing of our children. This new research is a great example. The results of this study suggest that inflammation during pregnancy can impact our baby’s brain development. That’s why it’s essential for mothers-to-be to consume a low inflammation diet during pregnancy. 
 
Having worked with thousands of mothers-to-be, I know that eating a nutritious diet during pregnancy can be extremely challenging, especially when you’re fighting morning sickness, fatigue and heartburn, but reading evidence like this shows just how important eating well during this window is for the future learning ability of your baby.
 
Some of my favorite tips for reducing inflammation during pregnancy include:
- including adequate amounts of low mercury, omega 3 rich fish in your diet 
- snack on a small handful of nuts each day
- use a good quality extra virgin olive oil
- include antioxidant rich fruits and vegetables such as tomatoes and blueberries 
- ensure you don’t gain too much weight during pregnancy 
- avoid foods high in saturated fats such as potato chips and biscuits.

The concentration of a single pro-inflammatory mediator in a mother’s blood is a fairly simplistic assessment of inflammation. There are countless other inflammatory markers that the investigators might have chosen as indicators of maternal inflammation. I’d like to see if the associations the researchers describe can be replicated using some of these other indicators.

An interesting aspect of the study is that the investigators excluded women and their infants if birth occurred before 34 weeks of gestation. The incidence of inflammation during pregnancy is actually highest for infants born early, before the study’s cut-off, and early preterm births have the worst neurological outcomes, so it would be interesting to see if the described relationship between mothers’ IL-6 levels and their babies’ brain function is seen in children born earlier.

This is an interesting paper, whose findings are not really unexpected. It's concordant with previous work suggesting that environmental factors in pregnancy affect the likelihood of later mental health or illness. Infections in pregnancy, maternal stress, smoking and diet are all examples.

Importantly, many of these stressors and risk factors for mental health problems are transduced through inflammatory signalling, so this finding is concordant. It would have been nice to know of maternal exposure to poor or good quality diet, smoking, major stressors and illnesses, to explain where the inflammation is coming from. That persistent inflammation is deleterious to the brain is well understood, but the links to functional connectivity and later cognition are important findings.

The paper also implies, but does not state, that preventive interventions at a public health level should be targeted at prenatal care. Indeed there already are such programs and studies underway predicated on data such as this study.

Inflammation is important for appropriate neural development; a recent example of this is the severe abnormalities that can occur if a pregnant mother becomes infected with Zika virus, where the damage is likely done not by the virus itself, but by the inflammatory response to the virus.

It has been speculated for a while that chronic low grade inflammation, unrelated to infection, may also contribute to differences in neural development, but the changes are likely to be subtle and difficult to measure. 

The advance here is using sophisticated machine learning to examine connections in the brain of newborns, and finding that this can predict the prior level of inflammation during pregnancy. 

Remarkably, this also had predictive power for behaviour of the children when they became toddlers.

Neural differences associated with inflammation in pregnancy are so small that they can only be found by machine-learning, but this work provides more evidence that they are relevant for cognition later in life.

The study is consistent with other research emphasising the key role that inflammatory processes play in the brain – from the earliest moments in life and brain development.

New opportunities for preventing early difficulties in brain development are likely to arise as a consequence of this type of research.