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Two-drug approach might shorten painful labor, reduce Caesarean sections
Jim Barlow,
Life Sciences Editor
217-333-5802; jebarlow@illinois.edu
2/2/04
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CHAMPAIGN, Ill.
— The nationwide rise in induced labor and Caesarean deliveries
could be eased by an experimental dual drug approach that not only safely
jump-starts labor but also remodels the cervix to allow for speedy natural
delivery, scientists report.
A combination of RU 486 (mifepristone) and relaxin successfully hastened
labor and promoted healthy delivery of pups in rats altered so that
their reproductive systems mimicked the human reproductive system, researchers
at the University of Illinois at Urbana-Champaign report in the January
issue of the American Journal of Obstetrics and Gynecology.
Relaxin, a naturally occurring reproductive hormone, was the key to
the natural delivery, said O. David Sherwood, a professor of molecular
and integrative physiology. “Although the study was done with
rats, it was designed with the idea that RU 486 and relaxin could be
used at delivery in the human being. The results are compelling.”
Shuangping Zhao, a postdoctoral researcher in Sherwood’s laboratory,
said that RU 486, an antiprogresterone, given alone induced labor in
the rats but the cervix did not grow, leading to prolonged delivery
and pup deaths. When relaxin was given subcutaneously, the cervix grew
and softened (ripened), reducing delivery time and promoting healthy
pups.
“If relaxin works in the human,” she said, “it will
likely not only shorten the duration of painful labor, but also reduce
the incidence of Caesarean sections. This would be very beneficial for
women and reduce health-care costs.”
Genentech experimented without success administering relaxin in the
vagina as a topical treatment in the 1990s, hoping it would penetrate
the epithelial cells, enter the bloodstream and reach target cells in
the cervix. The investigators in the trials, done in Australia and Great
Britain, noted that relaxin failed to enter the bloodstream and suggested
that the lack of absorption was the reason the treatments failed.
Sherwood, also a professor in the College
of Medicine, has studied relaxin’s reproductive role in rats,
mice and pigs for 30 years. His laboratory has developed techniques
to measure relaxin in the blood and investigate its activity during
pregnancy.
“We believe the method of delivery is the key,” he said.
“In every species in which we’ve given relaxin subcutaneously
so that it enters the blood, we’ve seen marked cervical growth
and softening. Relaxin’s effects on the cervix have not been examined
in the human being after being administered in a way that assures it
reaches the target.”
Relaxin production increases as birth approaches in many species, but
in humans it declines, and blood levels are extremely low in the third
trimester when relaxin is needed the most, Sherwood said. The experimental
rats used in the study were treated with antibodies to block relaxin’s
actions in the late stages of pregnancy to reflect the lack of hormonal
activity of the human female.
“Using relaxin and RU 486 offers promise of not only enabling
delivery that is rapid and safe, but also relatively natural,”
Sherwood said. “Following their administration during the antepartum
period, both relaxin and RU 486 increase cervical extensibility but
only relaxin promotes dramatic growth of the cervix,” the authors
wrote.
RU 486, which was approved for use in the United States in 2000, has
been used for many years in other countries to terminate pregnancies
early. Since the late 1990s, several clinical investigators have reported
that RU 486 can be used to induce delivery at term pregnancy. It has
been found to effectively induce labor and delivery within three days
of administration, but “with no clear reduction in the incidence
of Caesarean section relative to other methods used to induce labor,”
Sherwood said.
Induced labor has risen from 9 percent to more than 20 percent of U.S.
childbirths since 1989. A paper in the American Journal of Obstetrics
and Gynecology in 2002 noted that more than 40 percent of births in
community hospitals are induced in the absence of medical necessity.
Caesarean sections now account for about 25 percent of all births, mostly
because of fetal stress resulting from a failure of the cervix to soften
and expand.
Labor currently is most often induced with oxytocin, prostaglandins
or both. However, the result often is a swift onset of contractions,
and the cervix does not always ripen for delivery, leading to Caesarean
operations. Other undesirable health side effects also are common in
many women with these and related compounds that are often utilized.
Sherwood and Zhao said that they envision relaxin being administered
by means of a small infusion pump that is placed beneath the skin at
or near the time that labor is induced with RU 486. “We believe
that relaxin would be ideal for short-term timely use,” Sherwood
said. “It would simply fill a late-term deficiency and would be
safe.”
A regulatory hurdle, however, exists. Relaxin is not approved for use
in humans. BAS Medical, a private company in California, recently purchased
the rights to recombinant human relaxin. “It remains to be determined
if BAS Medical will choose to explore the use of relaxin as an agent
to facilitate delivery,” Sherwood said.
The researchers propose that relaxin could replace the use of dinoprostone
(prostaglandin E2), which is now the only FDA-approved agent to soften
the cervix in humans. Dinoprostone often causes uterine hyperstimulation,
requiring the presence of a skilled attendant, and sometimes leads to
uterine rupture.
Sherwood’s lab and others have shown that relaxin reduces the
density and organization of collagen fibers, which may explain the softening
effect on the cervix. However, little is known about the mechanisms
whereby it promotes growth of the cervix.
Sherwood and colleagues have found that relaxin dramatically increases
the accumulation of cells within the cervix during the second half of
pregnancy in rats. Recent unpublished results from Sherwood’s
laboratory demonstrate that relaxin both promotes cell proliferation
and curtails cell death in the cervix, with the effects being most dramatic
during the two days before delivery.
The research was funded by grants from the National Institutes of Health
to both Sherwood and Zhao and by a Lalor Foundation postdoctoral fellowship
to Zhao.
