91av

Eugene, Oregon

IN A Leonardo da Vinci sketch of a pregnant womb, the unborn baby is depicted
as totally calm and peaceful. The infant seems to be savouring its last few days
of serenity, a gentle prisoner patiently awaiting the cataclysmic forces that
will eventually whisk it away to freedom. And for much of the twentieth century,
physiologists trying to solve the mystery of what triggers birth have shared da
Vinci’s view: the innocent fetus is at the mother’s mercy. Her body alone
decides when birth is to begin.

More recently, however, a very different picture of the baby’s role in the
birth process has emerged. The fetus, most researchers believe, is a virtual
autocrat, dictating when the mother’s muscles should start contracting. Now, a
team of fetal physiologists led by Caroline McMillen of the University of
Adelaide in Australia has an idea about what drives this little despot to pull
off so precocious a stunt.

Far from waiting serenely for the right moment to arrive, they argue that
during the last few weeks of pregnancy the fetus becomes increasingly stressed
as it rapidly outstrips its mother’s ability to supply nutrients and oxygen.
Eventually, it all gets too much. At that point, the baby’s brain unleashes a
flood of hormones that wash across the placenta, triggering a cascade of events
that ends with the baby’s expulsion. As McMillen sees it, birth is the fetus’s
way of saying: “I’ve had enough, let me out.”

The modern quest to understand parturition—as the process of giving
birth is known—owes its existence to studies of abnormal deliveries in
humans and sheep. In 1933, British obstetrician Percy Malpas reported on babies
afflicted with anencephaly, in which portions of the brain fail to develop. What
interested Malpas was that many babies with anencephaly are born weeks late,
hinting that something in the developed brain of a normal fetus is essential for
labour to start on time.

Then, in the 1950s, bizarre one-eyed lambs were born in the mountain meadows
of Idaho. Investigators traced the problem to pregnant ewes grazing on skunk
cabbage, a toxic plant that interfered with normal fetal development. Crucially,
these cyclopean fetuses outstayed their welcome in the womb by up to 100
days—150 days is full term for a sheep. In some cases, the one-eyed lambs
were twice the size of a normal newborn.

At one time, physicians assumed that the uterus’s finite capacity for
expansion played a large part in triggering birth. Over extend it, and like a
deflating balloon the uterus would spring back, ejecting the fetus in the
process. But as the cyclopean lambs showed, lack of womb space is not a big
issue.

But a vital clue to what might trigger birth comes from something else that
one-eyed lambs and anencephalic babies have in common besides their late
delivery. In normal adults and fetal animals, the hypothalamus, a group of
neurons at the base of the brain, supervises hormone production by the body’s
endocrine system. In cyclopic lambs and anencephalic babies, that same link
between the brain and the body’s hormone production centres was disrupted,
suggesting that it might play a role in the process of birth. Definitive proof
came in the 1960s, when Mont Liggins, a fetal physiologist at the National
Women’s Hospital in Auckland, operated on unborn fetal sheep. He surgically
destroyed either the pituitary gland (which lies close to the hypothalamus, and
receives its signals) or the adrenal glands (which lie above the kidneys),
stopping natural delivery. The lambs were eventually delivered by Caesarian
section.

It turned out that the sheep fetus calls the shots when it comes to delivery.
Beginning two to three weeks before time, the unborn lamb’s hypothalamus goes
into overdrive, stimulating the pituitary. The pituitary cells react by churning
out adrenocorticotrophic hormone or ACTH. The hormone reaches the fetus’s
adrenal glands via the bloodstream, triggering the production of cortisol.
Cortisol starts to shift the proceedings to the mother’s territory by making its
way through the baby’s bloodstream to the placenta, where it activates the
enzymes that make oestrogens. Oestrogens then move into the uterus, setting off
the chemical fireworks that underlie the involuntary muscle contractions of
labour.

Although it is difficult to prove that human babies use exactly the same
hormones to tell their mothers it’s time to grab the overnight bag and head for
the maternity wing, most of the evidence suggests that the two systems are
fundamentally similar, with a few minor variations.

Still, one major question remains unanswered: exactly what gets the fetal
hypothalamus going in the first place? Like the demise of the dinosaurs, it’s a
seductive riddle shrouded in speculation, controversy, and a host of competing
theories. Some researchers have argued that the unborn baby’s hypothalamus
simply reaches maturity, revving up as certain neurons or connections between
existing neurons fall into place. Then, there are those, like Peter Nathanielsz,
a fetal physiologist at Cornell University in Ithaca, New York, who doubt the
validity of the question in the first place. Perhaps there is no single trigger,
he says, and birth occurs with the confluence of factors that are set into
motion at conception, including the maturation of the lungs, heart, kidneys,
hypothalamus, adrenal glands and other organs that are needed for life outside
the womb. “The key to parturition,” says Nathanielsz, “is fertilisation.”

Layer cake

Meanwhile, a minority of birth researchers want to return a semblance of
control to the mother. They argue that hormones from the placenta, a sort of
layer cake of mother and fetal tissue, turn on the fetal hypothalamus.

McMillen, on the other hand, cedes full control to the fetus. And what makes
the unborn infant demand that its mother starts pushing, she suggests, is stress
induced by its hunger for glucose and other metabolic essentials.

One of the first clues that unborn fetuses might be as metabolically stressed
as a marathon runner approaching the finish line came in the late 1980s, when a
student in McMillen’s lab, Ieva Ozolins, investigated an apparent paradox in the
brain-body hormonal link. Cortisol levels increase whenever a healthy sheep or
person suffers some physiological or mental stress—say, a dip in a cold
pool, hunger, or the anticipation of pain. Cortisol’s job is to release fats and
amino acids from their storage sites in the body, providing the animal with the
raw materials it needs to deal with the stress.

And because you can have too much a good thing, cortisol also helps stop the
body from entering hormone overkill. When the cortisol reaches a certain level
in the blood it turns down the hypothalamus and the pituitary, switching off its
own supply at source. Unborn lambs, however, are an exception. In their last few
weeks of gestation, cortisol levels just keep going up, approaching levels as
high as in a very stressed adult sheep—say, one trapped in the same room
as a barking dog. The popular explanation for this strange state of affairs is
that the cortisol mysteriously and temporarily loses its control over the
hypothalamus and pituitary.

Ozolins found the complete opposite. When she injected even more cortisol
into fetal sheep, their pituitaries responded by turning down ACTH. Clearly,
cortisol could still make its presence felt, so there had to be another,
stronger pressure on the pituitary to keep it churning out ACTH, overriding
cortisol’s instructions.

McMillen began casting about the literature for clues that would help explain
what she and Ozolins were seeing. That’s when she came upon the work of Mary
Dallman, a physiologist at the University of California in San Francisco who was
studying how rats respond to long-term stress caused by being repeatedly
restrained for 30 minutes at a time.

As McMillen read, she realised that lambs in the last stages of pregnancy and
the stressed rats were in some ways remarkably similar—both had enlarged
adrenal glands, and high levels of ACTH even in the face of high cortisol. The
fetal sheep had to be suffering from chronic stress, she thought, and that’s
what triggers birth. “It seemed to me, there was no need for any other
explanation,” she says now, “it just fits so well.”

In some ways, McMillen is revisiting an old idea. Hippocrates
himself argued that birth was the result of an overgrown fetus breaking free
from a placenta no longer able to sustain it. But the eminent Greek had few
facts to back up this assertion and the idea faded into history. “What makes
McMillen’s approach really interesting is that it’s very mechanistic,” says
Charles Wood, a fetal physiologist at the University of Florida in Gainesville.
“She has actually looked at the neuroendocrine control of ACTH by the fetal
brain, and looked at changes in sensitivity to different stimuli.”

And there are other indications that stress triggers birth. For
instance, underfed pregnant sheep give birth up to a week early—a finding
mirrored by the shorter pregnancies among women in India who may not be getting
enough to eat. There are even hints that women in high stress jobs go into
labour earlier than women in less stressful positions.

But, whereas most researchers are happy to concede that stress can, in some
cases, lead to premature birth, McMillen goes one step further. She says that
stress also calls the shots in full term deliveries.

The argument runs like this. A fetus is forced to keep its blood glucose and
oxygen levels low to maintain a concentration gradient across the placenta that
allows nutrients to flow “downhill” from the mother to the fetus. And as
pregnancy progresses, the situation gets worse. In the second half of pregnancy,
fetal sheep undergo a rapid, 16-fold increase in mass, and their blood glucose
drops by more than 20 cent. By late gestation, blood glucose and oxygen levels
are around four times lower in the fetus than in its mother. This transfers
oxygen and glucose more rapidly to the ever-expanding tissues of the fetus. But
it also means the fetus has decreasing levels of these energy sources
circulating in its blood, putting it in a precarious situation.

“If we had [blood] levels of glucose or oxygen like the fetus has, we would
be in trouble,” says McMillen. “That’s the issue. Does the fetus wish to escape
its environment because it becomes aware that its environment is in some way no
longer able to sustain it?”

McMillen’s answer to that wholly rhetorical question is a resounding yes. She
points out that there is ample evidence that in the last few weeks of pregnancy,
as blood glucose falls in fetal sheep, at least one stress hormone, ACTH, goes
up. And, Ozolins and Joe Simonetta, a post-doc in McMillen’s lab, have found
that ACTH and cortisol soar in fetal sheep when they are short of oxygen or
glucose because their mothers have been breathing low-oxygen air, or been
starved for short periods, or injected with insulin. What’s more, when the
hypothalamus and pituitary are surgically disconnected in fetal lambs, a drop in
blood oxygen or glucose has no effect on ACTH. That shows that the hypothalamus
is registering the state of the fetus’s energy supplies, and signalling the
pituitary to produce lots more ACTH when shortages arise.

Furry balloons

But it also raises the question of how the fetal hypothalamus monitors the
body’s energy supplies in the first place. To answer this question, McMillen and
her student Kirsty Warnes turned their attention to a brain chemical called
neuropeptide Y, or NPY. Made by the hypothalamus, NPY is the most potent known
stimulant of appetite (see “Things Can Only Get Thinner”, 23 August 1997, p 22),
and it is regulated, at least in part, by a chemical called leptin that is made
in fat cells. When lab mice are starved, their NPY levels rise. When they eat,
their NPY levels fall. And when they are constantly dosed up with extra NPY, the
animals can’t stop eating and turn into little furry balloons. More
interestingly for McMillen, an injection of NPY into the hypothalamus also
activates that organ’s link with the adrenals, firing up cortisol
production.

If a reduction in the amount of nutrients available to the unborn lamb or
child was the driving force behind birth, NPY levels should rise in a fetus
during late gestation. As indeed they do. In the Journal of
Neuroendocrinology, McMillen and her team last month reported that NPY
levels in slices of hypothalamus taken from sheep fetuses increase four-fold in
the final 50 days of pregnancy.

Thus a picture emerges: as the fetus grows and the placenta is unable to keep
pace, it becomes hungry just as an adult would. Unlike an adult, however, the
fetus can’t run to the fridge. Unable to increase food intake or call off the
NPY dogs, it continues to churn out cortisol. This triggers the production of
more NPY—a fact McMillen only recently uncovered by injecting cortisol
into late-term fetal lambs. The fetus’s hormones spiral ever upwards with birth
its only escape.

But some researchers are not convinced. “Survival of our species depends upon
birth,” says John Challis a fetal physiologist at the University of Toronto.
“The idea that birth depends upon the creation of an adverse environment that is
not good for fetal growth, that is not good for fetal development, that is not
good for fetal neuronal structure, doesn’t make sense to me. Biology is smarter
than that.”

McMillen thinks that argument misses the point. The problem, she says, is
that the word “stress” sounds worse than it is. Stress, after all, is just an
animal’s healthy response to changes in its environment, the organism’s way of
making sure it can cope. It only becomes bad when the animal can’t do anything
about its environment—including escape it. As McMillen sees it, the fetus
in late gestation is rather like an adolescent undergoing a growth
spurt—in fact, it’s the same NPY rush that turns teenagers into ravenous
beasts. “You get these signals to the fetal hypothalamus, but [the fetus] can’t
eat,” she says. “It can’t do anything except stimulate the pituitary-adrenal
axis. And it keeps on stimulating it until it’s born and when it’s born the
newborn eats and off you go.”

Big payoff

Still, McMillen admits that there are some gaps in her model. She doubts, for
instance, that NPY is the sole trigger for the hormonal changes in the fetus
that lead to birth. Rather, she says, the fetal hypothalamus probably behaves as
it does in adults—like a computer that monitors temperature, oxygen,
glucose and other body conditions, and spits out signals based on its analysis
of the total picture. Sorting through this labyrinth is a task she has only just
begun. “If the question of what causes parturition were simple, it would have
been solved by now,” she says.

But if she is on the right track, the rewards will be great. “This is
potentially a big payoff area,” says Wood. “If someone could figure out what the
critical steps [to birth] are, that would be very, very significant to human
health.” Premature births are the leading cause of infant mortality in the
industrialised world. Doctors have no surefire way of stopping early labour once
it has begun. Understanding what nudges the fetus out of the uterus should make
it much easier to find reliable ways to stop labour before it has gained too
much momentum. Only then will a mother, with a little help from the
pharmaceuticals industry, be able to wrest back some control from her
all-powerful unborn baby.