CHD and vitamin B3

The common vitamin that could be the key to preventing some cases of heart birth defects and miscarriages

17 October 2023

In Australia, 2400 babies are born each year with congenital heart disease, with four babies dying every week. In at least 80 percent of these cases, the cause of the heart defect is unknown. 

Scientists from the Victor Chang Cardiac Research Institute are hoping to change that. 

Professor Sally Dunwoodie and her team have found a genetic cause for various heart and other birth defects and, crucially, a possible way to prevent some cases. 

The NAD breakthrough

In 2017, Professor Dunwoodie and her team at the Institute discovered that a deficiency in a vital molecule known as NAD prevents a baby's organs from developing correctly in the womb.   

The study published in the New England Journal of Medicine involved 97 people with congenital heart disease. Their whole genome was studied, along with that of their parents and, in some cases, their siblings. 

This research was a mammoth undertaking that included analysing six billion pieces of genetic code per person and identifying what is often just a single change that disrupted embryogenesis.

Professor Dunwoodie and her team found mutations in two genes known as KYNU and HAAO. These mutations resulted in babies with defects of the heart, kidneys, and vertebra, as well as other birth defects. KYNU and HAAO usually help convert an amino acid called tryptophan into a substance called NAD, which plays a crucial role in energy production and repairing DNA. 

After KYNU and HAAO's role was identified, the same mutations and defects were reproduced in mice. Adding vitamin B3 to the pregnant mouse's diet was found to prevent the defects appearing in offspring.

Professor Dunwoodie says "It's very rare to find a mutation and then to find the mechanism behind it and understand it. It's even rarer to identify a possible preventative. NAD is a vital substance required in every cell in our body.

"For women with low levels of NAD we believe this can play out disastrously during pregnancy because the growing baby also needs NAD to develop. We believe this explains not only why some babies have birth defects, but also why some women are prone to miscarriage."

Current clinical studies into NAD and pregnancy

Since 2017, the team has been scrutinising NAD and vitamin B3 in painstaking detail. With this information, the researchers developed a diagnostic test that can accurately measure women's NAD and vitamin B3 levels.

The Institute, in collaboration with the Royal Hospital for Women at Randwick and the University of Sydney, has recruited almost 250 women between the ages of 20 and 40 to participate in the clinical study in Sydney.

The Nicotinamide Adenine Dinucleotide in Pregnancy (NADIP) Study measures the NAD levels of five groups of women, including both pregnant and non-pregnant women, by screening urine and blood samples. 

The team are assessing and comparing NAD levels between pregnant and non-pregnant women with or without diabetes and those having babies with congenital conditions or having had previous miscarriages. 

The results of the study will reveal whether low levels of NAD are more likely to occur in mothers who have a baby with birth defects or women who have recurrent miscarriages. This will help identify how to increase and stabilise NAD levels during pregnancy.

As well as measuring levels of NAD, the team are also measuring 25 other metabolites that are associated with NAD.

The study is expected to be wrapped up in 2024, with data already being analysed.

Testing the effects of vitamin B3 supplementation

Once the team has established the healthy range of NAD in women and identified a link between low NAD levels and adverse pregnancy outcomes, the next stage is a clinical trial to measure the effects of vitamin B3 supplementation to bring NAD to normal levels. Professor Dunwoodie says:

 "We want to take this to a point where women can benefit from our years of research and important findings. This research will take more dedicated time and much more funding."

 The world-first trial will be conducted here in Australia.

Collaborators

Professor Sally Dunwoodie

Professor Sally Dunwoodie is an internationally renowned biomedical researcher and Deputy Director of the Victor Chang Cardiac Research Institute. She established and leads the Chain Reaction Program in Congenital Heart Disease, the largest Australian genome sequencing initiative in congenital heart disease. Professor Dunwoodie is also a world leader in identifying causes of vertebral defects, having discovered six of the seven genes known to cause such defects.

Professor Natasha Nassar

Professor Natasha Nassar is a perinatal and paediatric epidemiologist, the Financial Markets Foundation for Children Chair in Translational Childhood Medicine at the Children's Hospital at Westmead (CHW) Clinical School, University of Sydney, and the Charles Perkins Centre Populations Domain Leader. Professor Nassar has expertise in a wide range of research methodologies including record-linked administrative health data ("big data"), randomised controlled trials, clinical surveys, diagnostic studies and longitudinal studies, systematic reviews, and meta-analyses. 

Dr Antonia Shand

Dr Antonia Shand is an Obstetrician and Gynaecologist, and RANZCOG-certified subspecialist in Maternal Fetal Medicine. Dr Shand is Head of the Department of Maternal Fetal Medicine at the Royal Hospital for Women in Randwick. She is also a Visiting Medical Officer in the Department of Maternal Fetal Medicine Department at Royal North Shore Hospital. She runs the Perinatal Loss Service at the Royal Hospital for Women, Randwick.  

Funders

The National Health and Medical Research Council, the NSW Government Office of Health and Medical Research and philanthropic donations fund this research.

A version of this article was published by Research Australia in INSPIRE Issue 30.