Hormone level may set birth weight

CAMBRIDGE, England, June 26 (UPI) -- A baby's all-important birth weight, which has a strong bearing on the child's survival and health, may be determined in the first 10 weeks of pregnancy and influenced by the father's genes, two independent studies indicate.

The findings may lead to earlier identification -- and safeguarding -- of women at risk of stillbirth and other birth complications. They also may fire up debate over a theory that implicates a battle of the sex genes in fetal development.

Both studies -- one of mice, and one of 4,288 women and their newborns -- address the critical question of why some full-term babies are born dangerously small, weighing less than 5.5 pounds. Such tiny stature increases their risk of death as newborns, abnormal physical or mental development and, later in life, coronary heart disease, type-2 diabetes and respiratory problems.

The research did not include premature infants or those whose low birth weight results from the mother's abuse of alcohol or drugs.

"In humans, there are solid epidemiological data showing a direct correlation between low birth weight and cardiovascular disease later in life. This is in addition to the better known immediate consequences of low birth weight in terms of medical problems in the newborn," said Dr. Benjamin Tycko, associate professor of pathology at Columbia University in New York, who analyzed the studies in an accompanying commentary.

His own recently published findings revealed the role of another gene in maintaining optimal size of the placenta, an organ critically important to proper embryonic development that provides the growing fetus with a means to receive nourishment and eliminate wastes.

"Understanding the control of placental function by genetic and (environmental) factors will likely have broad significance for human health." Tycko told United Press International.

In the study of pregnant women, Dr. Gordon Smith, professor of obstetrics and gynecology at Cambridge University in England, and his team found that too little of a molecule called PAPP-A produced during the first trimester of pregnancy may underlie low birth weight. PAPP-A is associated with the development of the placenta.

"The single most striking finding is that the outcome of the pregnancy at 40 weeks can be predicted by a test performed in the first few weeks post-conception," Smith told UPI. "Poor outcome may already be determined when a woman first attends for prenatal care."

The results support a hypothesis he postulated in a 1998 New England Journal of Medicine study of 4,229 pregnant women: slow first-trimester fetal growth may be associated with low birth weight and premature delivery.

"Obstetricians can already diagnose poorly growing babies," Smith said. "However, the key is identifying high-risk women at whom these tests should be directed. That is the relevance of the current study."

Because the findings indicate low birth weight is being determined before the fetus makes any significant caloric demands, they suggest the link between birth weight and later disease may not be related to the mother's diet during pregnancy, he added.

Building on previous work, the second study -- by Miguel Constancia of the Laboratory of Developmental Genetics and Imprinting at the Babraham Institute in Cambridge and his colleagues -- pointed to control of fetal growth by a newly recognized phenomenon called genetic imprinting.

Normal development requires genes to be inherited from both parents, who exert equal influence over much of their offspring's genetic makeup. A few specific regions of the genome, however, are subject to a mechanism called genetic imprinting that permits only one parent to take full control. The type of inherited trait thus "imprinted" depends upon whether it came from the mother or the father.

Constancia and colleagues found the paternal copy of the imprinted gene, called insulin-like growth factor 2 or IGF2, thought to play a key role in fetal growth, is turned on in both the fetus and the placenta. The findings provide the first direct evidence that imprinted genes can control the supply of maternal nutrients to the fetus, scientists said.

The results support the genetic "conflict" theory, which holds that more of the father-contributed IGF2 means a bigger placenta, which means more nutrients for the fetus, a big and healthy baby, and a greater chance of dad's genes making it into the next generation. On the other hand, mom "counters" through her own imprinted genes that control the size of the baby, preventing her from investing all her energy in one birth and allowing her to reproduce more than once so as many of her genes as possible leave their mark on her progeny.

"People have strong opinions (about the theory), and this will be an ongoing debate," Tycko told UPI.

In a technical tour de force, Constancia and colleagues removed the growth factor gene from a mouse placenta, enabling them to analyze the effect of the male imprinted gene on the organ. They found the placenta in the gene-less rodents was smaller, with fewer nutrients crossing over to the fetus, which tended to weigh less than normal.

"What is so remarkable is that this demonstrates control by paternal genes in a system we might imagine to be handled by the mother. It also shows that the supply and the demand of nutrients are under the control of the same gene," said Dr. Wolf Reik, group leader at Babraham.

"Our study is one of the very first to address the role of imprinted genes specifically in the placenta, an organ that is very important in the evolution of imprinting," Constancia told UPI. It is too early to know to what degree the mouse results apply to humans, he cautioned.

In their study, Smith and his team compared blood tests performed six to 10 weeks after conception to the weight of the baby six months later.

"The aim of the study was to determine whether low levels of PAPP-A were associated with poor fetal growth," Smith said. The investigators found mothers with low amounts of the placenta-produced hormone were more likely to deliver infants weighing less than five-and-a-half pounds.

"As the level of PAPP-A increased from the lowest 1 percent of values to the highest 1 percent of values, the risk of a low birth weight baby at term decreased by 80 percent," Smith said. Some of the women delivering normal-weight babies also had lower-than-average PAPP-A levels, so further studies are needed, he cautioned.

Smith's ultimate goal is "to be able to identify women who are at greater risk of adverse pregnancy outcome," Smith said. "This would allow these women to receive optimum monitoring and to allow genuinely low-risk women to enjoy pregnancy as a physiological experience."

The research is published in the June 27 issue of the British journal Nature.