Canadians Find Gene Tied To Late Miscarriage

Discovery raises possibility of screening women at risk, developing treatment

By CAROLYN ABRAHAM Globe and Mail 
Tuesday, July 19, 2005

Ottawa researchers have discovered the molecular glitch that explains why so many women lose their babies late in their pregnancies -- a condition that is also the second leading cause of infant deaths in the developed world.

Scientists at the Ottawa Health Research Institute have found that a particular gene can produce an underactive enzyme that interferes with the proper growth of a woman’s placenta, the crucial organ that forms within the walls of the uterus to feed a developing fetus.

Too many times, obstetrician and scientist Andrée Gruslin felt helpless and heartbroken watching excited mothers-to-be with "big bellies" and big plans miscarry more than 20 weeks into their pregnancies. In one case, a woman lost eight babies in a row.

"This is a lot more dramatic than [an early-stage] miscarriage," which usually happens within the first trimester, Dr. Gruslin said. "These are pregnancies that can end in a delivery room or the neonatal intensive-care unit."

But finding the condition’s cause -- a gene that can also result in the birth of underweight babies who battle health problems all their lives -- may make it possible to screen pregnant women at risk and develop a treatment.

"If we can find out about the women at risk very early on, we can monitor a baby a lot more closely and possibly save the baby," said Dr. Gruslin, co-author of the report published in the current issue of the Proceedings of the National Academy of Sciences.

The Ottawa team is now setting up a study to run blood tests on roughly 2,000 pregnant women for signs of the underactive enzyme, to ensure the discovery can translate from research into clinical practice.

Known as fetal-growth restriction, the condition strikes 3 per cent of all pregnancies and is the second leading cause of infant deaths in industrialized countries, after premature birth.

Carole Aylwin and her husband Dominique Ratté knew nothing about fetal-growth restriction when last year they saw the troubling ultrasound images of their first child, 17 weeks into the pregnancy.

"At the hospital, [doctors] realized the baby was looking very small. At first, they thought they had mixed up the dates . . . that the baby was two weeks younger than they thought," Ms. Aylwin said.

But after ruling out a genetic problem with the baby and a maternal infection, the doctors realized during regular ultrasound scans that her placenta looked "weird" and "dense," she said, and the baby’s growth was discouraging. By the 24th week, Ms. Aylwin -- nearly six months pregnant -- and her husband learned their tiny baby could be severely handicapped if he or she survived at all.

"So then it was a matter of what would happen and when would it happen," said Ms. Aylwin, describing a nearly unbearable level of stress during what was to be such a happy time.

Last October, their baby was delivered stillborn at 26 weeks.

"All the time, you are asking how come this is happening," Ms. Aylwin said. "Knowing now that they have discovered this molecule that could offer a preventative treatment . . . would be a relief."

Dr. Gruslin teamed up with OHRI researchers Qing Qiu, Ajoy Basak, Majambu Mbikay and Benjamin Tsang to study the molecular biology behind the growth of placentas.

Earlier research had shown that a gene producing a protein known as insulin-like growth factor 2, or IGF2, was critical.

This growth factor invades the muscle cells of the uterus to allow blood and oxygen in to feed the fetus, and helps fetal cells divide and grow. Mice born without the IGF2 gene were very tiny and also grew abnormally small placentas.

But the Ottawa research showed that the normal form of this IGF2 protein has a very long chemical structure.

However, to function properly when helping to build the placenta, another molecule has to effectively cut it down into a smaller form.

That molecule, a so-called PC4 enzyme, is produced by a gene known to be active in the ovaries, the testes and now the placenta.

Dr. Gruslin said it acts like scissors, which cut down the growth-factor protein to a length that is crucial to a healthy pregnancy.

"We have found the scissors in some women are just not sharp enough, or they just don't have enough scissors," Dr. Gruslin explained.

The team tested its theory in a study that found seven pregnant women who suffered from fetal-growth restriction carried longer, or "uncut" forms of the IGF2 protein in their blood.

Eight women without the condition carried shorter forms of the protein.

"This is pointing to a gene that is not active enough in these women," Dr. Gruslin said of the women who suffer from fetal-growth restriction.

There are no immediate medical or genetic therapies to treat the condition and screening for it still remains in the research phase.

Dr. Gruslin has found some success with certain interventions, but she stresses that she can offer no scientific research to explain their effectiveness at this point.

In the case of the women who suffered eight consecutive miscarriages, for example, she prescribed a high-dose of folic acid and a baby Aspirin daily.

That woman has since given birth to a healthy child.

Now Ms. Aylwin who is once again pregnant, currently 14 weeks along, is trying a similar regimen. "They are following me closely," Ms. Aylwin said, "So far everything is fantastic."