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Team solves mystery of babies' growth: Ottawa reseachers find key to simple test, possible gene therapy
By Sharon KirkeyThe Ottawa Citizen
Tuesday, July 19, 2005
Canadian researchers believe they have unravelled one of the biggest mysteries of why some fetuses don't grow normally -- a discovery that could lead in a year to a simple blood test to detect babies at risk of being born too small.
Fetal growth restriction is the second leading cause of death in newborns in the developed world, behind premature birth. About three per cent of babies are affected.
"It's a significant number and they are way over represented in the intensive care units," says Dr. Andree Gruslin, a maternal-fetal medicine specialist at the Ottawa Hospital.
Growth-restricted babies are born with scrawny limbs, tiny muscles and loose, dry skin. They're five times more likely to die in the weeks after birth than normal babies, and those who survive are at increased risk of heart disease, diabetes and other complications when they become adults.
Some weigh as little as 450 grams (0.99 pounds) and many of the babies can't be carried to term. Dr. Gruslin once followed a woman who suffered eight miscarriages before finally having a baby that grew normally.
"These were real losses. This woman was losing pregnancies at 24 weeks, 28 weeks," says Dr. Gruslin, an associate scientist at the Ottawa Hospital Research Institute.
"Perinatal losses are extremely traumatic and when they're repeated, they're horrible. There's also a feeling of what have I done? Have I caused this? What is wrong with me? So (there's) a lot of guilt as well, and a lot of anxiety."
It was already known that the placenta, which provides oxygen and nutrients to the baby, needs to grow properly to support the fetus. The organ breathes for the baby and acts as a kidney and liver.
"We know that babies that are born too small also have very small placentas," says Dr. Gruslin. "We thought, if we could understand what controls growth of the placenta, then we could understand what controls growth of the baby."
Her team's study is published today in the journal Proceedings of the National Academy of Sciences.
They looked at a molecule called insulin-like growth factor II, or IGF-2. Previous studies in mice had shown that, if the gene that makes the protein is knocked out, the babies are born extremely small and with small placentas.
But for IGF-2 to work, it needs to be cut into smaller pieces so that it can be processed. The Ottawa team went looking for the scissors.
Some of the collaborators already knew that a particular enzyme found in the ovaries and testes could cut the IGF-2 protein. In the new study, they found the same enzyme in the placenta.
When IGF-2 was cut and made fully active, it allowed placental cells to invade the mother's uterus.
"If that doesn't happen, then you have miscarriages and fetuses that are growth restricted," Dr. Gruslin says.
The team compared blood samples from eight women who had normal babies with seven whose babies were born small. The mothers of the small babies had a lot more IGF-2 that wasn't processed, meaning the enzyme wasn't working properly.
"The wonderful thing that could come out of this, and this is obviously years and years away, is gene therapy for these infants," Dr. Gruslin says.
More immediately, the researchers are working on a blood test that could detect the defective enzyme as early as the first trimester of pregnancy. Those babies could then be closely monitored and delivered early if they're at risk of dying in the womb.
What typically happens now, is the problem isn't detected until the woman's uterus is measured with a measuring tape during a routine prenatal visit. "But it's not 100 per cent, it's not very sensitive and so a lot of cases are missed. And a lot of cases come and it's too late," Dr. Gruslin says. "We don't have an extremely good way of picking them up."
Carole Aylwin of Gatineau was 17 weeks pregnant when tests showed her baby wasn't growing normally. Three weeks later, doctors discovered more problems with fetal blood flow, and that the placenta was thick and dense.
"At that time they started to tell us the outcome most probably was going to be negative," she says.
Her son, whom they named Gabriel, was delivered stillborn last October when Ms. Aylwin was six months pregnant. "You're never prepared for that kind of experience," she said.
Ms. Aylwin is now 13 weeks pregnant. So far the baby appears to be developing normally.
Note: Reprinted with permission of the Ottawa Citizen