Nathanielsz

Further proof that the fetus monitors its developing systems and "decides" when it is ready to be born comes from studies of rhesus monkeys conducted by pregnancy researchers at Cornell's College of Veterinary Medicine and Mt. Sinai Medical School and reported in the journal Nature Medicine (April 1996).

The finding is said to help explain the causes of premature labor and may lead to better care of women who go past their normal due dates.

"The possibility that, in normal human pregnancy, it is the fetal brain that controls the duration of pregnancy is an exciting one," said Dr. Peter W. Nathanielsz, leader of the androgen study and director of the Laboratory for Pregnancy and Newborn Research in the College of Veterinary Medicine.

When unborn rhesus monkeys receive additional amounts of the steroid hormone androgen, which is normally produced by their adrenal glands, that sets off a chemical chain reaction through the placenta to the mother's blood, resulting in premature labor and live delivery of healthy babies, the researchers demonstrated.

Earlier studies by the Cornell researchers had shown a similar link in pregnant sheep, although with a different hormone produced by the fetus, and they now believe that androgen is the chemical messenger in human births.

"These studies demonstrate remarkable parallels between the regulation of the onset of labor and delivery in sheep and in primates," Nathanielsz said. "We now believe that the precise timing of normal delivery in pregnant women is likely to be under the control of increased fetal adrenal activity."

Nathanielsz, who is the James Law Professor of Reproductive Physiology in the College of Veterinary Medicine, described how the fetal sheep brain monitors intrauterine conditions and signals the onset of labor in the medical literature in 1991 and in the popular book Life Before Birth, The Challenges of Fetal Development. In the case of sheep, which is a widely used model of pregnancy, a small group of nerve cells in the fetal brain was found to play a central role in signaling the start of birth. The cell group, called the paraventricular nuclei, controls the function of the fetal lamb's adrenal gland by initiating signals that stimulate the fetal adrenal to produce more of the hormone cortisol.

Cortisol then circulates in the fetal lamb's blood to the placenta where it "instructs" the placenta to produce more estrogen. The estrogen stimulates maternal systems that cause both the uterus to contract and the cervix to dilate, allowing delivery of the young.

"It's an elegantly designed system that allows the fetal brain to regulate the duration of pregnancy and to match the baby's own maturation to the time of its own delivery," Nathanielsz said. "But the question remains: Do similar mechanisms occur in human pregnancy? It would be surprising if fetal sheep were capable of such excellent control over their destiny while primates, including humans, do not utilize some similar mechanism."

So the researchers turned to a primate species, searching for the chemical signal that prompts estrogen to rise in the mother's blood at the end of pregnancy.

"While cortisol from the fetal adrenal in sheep instructs the placenta to produce more estrogen (from progesterone produced by the placenta), primates needed to adopt a different strategy," the reproductive physiologist said. The placenta in primates produces estrogen directly from androgen, the steroid hormone produced in large amounts at the end of pregnancy, he explained.

The physiologists repeated the sheep experiments with pregnant rhesus monkeys substituting androstenedione, a powerful androgen known to be rapidly converted to estrogen by the monkey placenta. They hoped to answer two questions: Will the fetus deliver early if extra androgen causes the placenta to produce more estrogen? And, if estrogen production is increased in the placenta following the infusion of androgen, will this increase in estrogen produce live delivery with all the essential steps that normal delivery involves?

The answers: Yes and yes. Within two days, monkeys receiving androstenedione showed labor- and delivery-type activity (including the typical short periods of intense, contraction-like activity each night for several days) and live young were delivered -- prematurely -- within seven days. Control monkeys, which entered the study at the same point of gestation but received only an inert fluid without androstenedione, waited 17 days for labor-type uterine contractions to begin and delivered after the 20th day.

This birth-signal mechanism makes excellent biological sense, Nathanielsz said. "It would be of great survival value if the fetal brain can act as a 'computer,' taking messages from several vital developing systems, such as lungs, kidneys and other parts of the brain, to compute the level of maturation and act accordingly."

But when something goes wrong in the computing and message-sending, results can be tragic. Fifty percent of human neonatal deaths and 75 percent of long-term neurological handicaps are the direct result of being born too small or too soon.

"Premature birth extracts an enormous toll from society," Nathanielsz said. "It is absolutely essential that we learn how these natural systems work and how to help when they don't."