Two-drug approach might shorten painful labor, reduce Caesarean sections

02/02/04

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 University of Illinois 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 in the study.

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.

Source: Eurekalert & others

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