Important find will help design appropriate screening and therapy for women carrying fetuses impaired in their growth

In her research, Dr. Andree Gruslin encountered many pregnant women who could not carry their fetuses to term because the placenta, and in turn the fetus, were too small. In once case, she followed a woman who had had eight consecutive miscarriages due to this condition. Thanks to this latest discovery, she now understands why.

Fetal growth restriction is the second leading cause of infant mortality in the developed world - with about 3 per cent of pregnant women being diagnosed with the condition. And of those babies who do survive, the condition can lead to severe complications in adulthood such as heart disease and diabetes. Up until now, doctors understood that the condition was often the result of abnormally small placentas but they had no more information to go on.

Enter Dr. Gruslin and her Ottawa Health Research Institute (OHRI) research team.

Through years of research, Dr. Gruslin, in collaboration with Dr. Qing Qiu (research associate), and Drs. Tsang, Dr. Ajoy Basak and Dr. Majambu Mbikay - all from OHRI - have finally determined that a specific enzyme, known as pro-protein convertase 4 ( PC4) may be responsible for the problem. The discovery is published in this month's edition of the Proceedings of the National Academy of Sciences (PNAS).

In order for the placenta to grow, the IGF2 molecule (the most important growth factor for the placenta and fetus) must be activated. The activation is triggered when the molecule is repeatedly cut. The problem in these specific cases, according to Dr. Gruslin, is that the IGF2 is not being processed (or cut) adequately and that is where Dr. Gruslin's discovery comes into play.

"What we have discovered is what regulates the activation of this molecule," explained Dr. Gruslin, who is also an associate professor at the University of Ottawa and a Maternal and Fetal Specialist at The Ottawa Hospital. "In cases where there is fetal growth restriction, the molecule is much less active because the enzyme is not working enough." She describes the process as being akin to starting a fire with a match. "There is no fire if there is no match. You need the match to ignite the fire."

With this knowledge, doctors will soon be able to screen women for this defective enzyme early in the pregnancy and monitor the situations more closely. In the past, women could lose a baby several times before doctors became aware of a potential problem. And in time, it is also hoped that researchers will discover a new therapy, likely targeted to the gene encoding for the enzyme, to treat the defect.

The condition currently exacts a huge financial burden on the system, with surviving babies often being treated in neo-natal intensive care units for lengthy periods as well as any future complications that may arise in adulthood. It obviously also takes a heavy emotional toll on the mother. This latest discovery will likely lessen both.

"This is an exciting discovery that holds great clinical potential," noted Dr. Nathalie Fleming, an OB/GYN and Assistant Professor at the University of Ottawa. "It is often difficult to identify the reason for these growth restricted fetuses. Having discovered a marker like this may help us diagnose the cause of these small fetuses and allow us to monitor these high risk pregnancies more carefully."

"I am delighted that we are able to collaborate in this exciting project where basic science research helps to unravel the mysteries of human reproductive diseases. With the human genome sequenced, treatment of human diseases in the future may be revolutionized and tailored to the patient's genetic makeup," said Dr. Ben Tsang, Senior Scientist at the Ottawa Health Research Institute and Professor of Obstetrics & Gynaecology at the University of Ottawa.

The research was funded thanks to a grant from the Canadian Institutes of Health Research.