Two studies in tomorrow's issue of Nature may help explain why some babies are born so slight, and might one day help doctors predict low birth weight from the earliest days of pregnancy.
In the first study, Gordon Smith and his colleagues at the University of Cambridge in England looked at the link between birth weight and a molecule called pregnancy associated plasma protein-A (PAPP-A). This substance is already included in a battery of tests doctors use to detect fetal genetic disorders such as Down syndrome.
Looking at more than 4,000 women who'd previously given birth, Smith's group found those with lower levels of PAPP-A early in pregnancy were much more likely to deliver low birth weight babies (under 2,500 grams, or roughly 5.5 pounds).
Mothers with the most protein in their blood were up to 80 percent less likely to have a dangerously light infant than those with the least.
Since all the babies were born full-term and were otherwise healthy, the findings could not be explained by prematurity or pregnancy complications. Both PAPP-A and a second pregnancy molecule, beta-HCG, were inversely associated with earlier labor. In other words, as blood levels of the two substances increased, the chances of delivery on that day fell.
The differences were apparent in the first 10 weeks after conception, suggesting that a baby's birth weight may already be determined by the time a woman starts seeking prenatal care, Smith says.
How PAPP-A might influence fetal development isn't entirely clear. However, the second study points to a promising possibility.
The substance, which is expressed in placental cells called trophoblasts, frees up two key growth proteins called IGF-1 and IGF-2 (short for insulin-like growth factor), which are present in the placenta and the fetus. Higher concentrations of these growth factors leads to larger offspring, so in theory more PAPP-A should, too.
Miguel Constancia, a geneticist at the Babraham Institute in Cambridge, and his colleagues in England and Canada deleted the gene for IGF-2 from the sperm of male mice, which then mated with genetically normal females.
The resulting placentas were missing the growth gene, and were about a quarter lighter, on average, than normal. Pups born from the mutant placentas weighed about 70 percent as much as their litter-mates.
The defect didn't affect the runts' ability to gain weight after birth, though, and by 21 days they'd all but caught up to the other pups.
Constancia's group also found that the mutant placentas were less efficient than usual at transferring nutrients along to the mouse fetuses. Although the placentas initially tried to compensate for this inefficiency by pumping more amino acids from the mothers to their offspring, they couldn't sustain the pace and the developing pups were undernourished.
"What our study really shows is that IGF-2 is a major modulator of placental growth. It's very important to have a normal transfer of nutrients to the fetus," he says.
The findings may have implications for at least some cases of low birth weight in people, although most result from multiple pregnancies, smoking during pregnancy, and other factors that aren't genetic. However, Constancia says it's too soon to tell what the contribution of IGF-2 will be for human fetal development.
"It could be a very good genetic cause for some low birth weight in humans, but it would be a small proportion of cases," he says.
Yet Smith says that if all women were in the top 10 percent of blood PAPP-A, as many as 35 percent to 40 percent of low birth weight deliveries might be avoided. Still, the protein is unlikely to prove a useful screening test.
For starters, many women in his study had low PAPP-A readings but delivered normal-weight babies, so the test is, at best, not specific enough. "It's not sufficiently strong to be diagnostically predictable," says Smith, who hopes to combine the test with other measures to make it more reliable.
Perhaps more important, he says, scientists currently have no interventions that have been shown to prevent low birth weight. "Supplementing the diet can help only in cases of extreme starvation," he explains.
What To Do
Visit the American College of Obstetricians and Gynecologists to learn more about a healthy pregnancy. To learn more about early child development, try the American Academy of Pediatrics.