Drug used in association with RU 486
Second Study Links Misoprostol to Developmental Malformations

By Randall K. O'Bannon, Ph.D.
NRL Director of Education and Research

For the second time in less than a month, a study appearing in a major medical journal has linked the prostaglandin misoprostol, when used by itself to induce an abortion, with certain congenital malformations problems in babies who survived the attempted abortion.

As reported last month (see NRL News, 6/8/98, p. 11) an article in the May 30 issue of the international medical journal The Lancet systematically identified and categorized the pattern of congenital malformations in babies attributable to misoprostol when it "failed" to induce an abortion. A report in the June 25, 1998, New England Journal of Medicine (NEJM), also discovered a pattern of malformation associated with the use of misoprostol by pregnant women in Brazil.

Properly used, misoprostol (sold under the brand name Cytotec) is an effective anti-ulcer drug. Currently, however, it is being used "off label" for a purpose not indicated on the label in conjunction with RU 486 to chemically induce abortions in women up to seven weeks pregnant. The two-drug abortion technique works this way.

Forty-eight hours after taking the RU 486 pills, a woman takes misoprostol to stimulate powerful uterine contractions to expel the emaciated baby. Used alone, RU 486 is only 60-80% " effective" in aborting the baby. The use of misoprostol raises that "effectiveness" level to 90-95% for women seven weeks pregnant or less.

Because of its powerful properties, misoprostol may also induce an abortion on its own. However, it is "unsuccessful" up to 80% of the time. This means that unless the mother undergoes a surgical abortion, the child is carried to term. Nonetheless, it is sometimes used by women in countries where abortion is illegal to surreptitiously induce abortions.

Brazil is one of those countries in which the laws protect unborn babies. But misoprostol is legal. Available over the counter, an estimated 57% to 75% of women who attempt abortions in Brazil use misoprostol. Brazil therefore provides researchers with almost a case study in the deleterious effects on children born after "failed"misoprostol abortions.

The NEJM study paired 96 infants diagnosed with Möbius syndrome (full or partial facial paralysis with or without other neurologic signs or accompanying limb malformations) in seven Brazilian hospitals, with 96 infants diagnosed with neural tube defects (meningocele, meningomyelocele, anencephaly, encephalocele) for the period January 1990 through May 1996 at the same hospitals. Researchers discovered that 49%, or nearly half, of the mothers of those children with Möbius syndrome had taken misoprostol early on in their pregnancy in an attempted abortion, while that was true of only 3% of those mothers of the children with the diagnosed neural tube defects. Based on this data, researchers concluded, "In this study of Brazilian infants, we found a strong association between Möbius syndrome and prenatal use of misoprostol by their mothers."

Given the basic chemical activity of the drug, the researchers wrote, "It is biologically plausible that exposure to misoprostol might cause Möbius syndrome." The researchers speculated that the syndrome may be due to disruption of blood flow of the subclavian artery during the fourth to sixth weeks of embryonic development. The subclavian artery supplies oxygenated blood to the skull, brain, and meninges, in addition to other areas of the upper body. Exposure to misoprostol during the first two months of pregnancy, the authors wrote, "could cause an ischemic event," or obstruction of blood flow, in the embryonic brain stem, causing the syndrome. "Whatever the pathophysiology [the mechanism initiating the syndrome]," the researchers stated, "our results suggest that the window of susceptibility is wider than previously thought."

This study differed from the earlier one reported in The Lancet in that researchers first identified those with certain congenital malformations and then looked for information on any prior misoprostol usage, rather than the other way around. This was done intentionally to avoid any selection bias by researchers already prepared to see a connection from reading earlier studies. (This also explains why researchers did not focus on limb defects or deficiencies, which were apparent in The Lancet study.)

If anything, the researchers say, their study may underreport the incidence of malformations associated with the use of misoprostol when it "fails" to abort. Because of the status of abortion law in Brazil,mothers may have been reluctant to admit they had used misoprostol to try to abort their babies. In addition, because the children with Möbius syndrome ranged anywhere from a half month to six and a half years old, some mothers may have actually forgotten details of their pregnancies.

Some of the misoprostol dosages the women reported taking were high (18 pills, in one case), but most were in a normal range (between 2 and 3 pills), similar to the one-time dose employed in the second stage of an abortion that uses RU 486 and the prostaglandin, misoprostol as the second drug.

While Americans are unlikely to turn to misoprostol as a chemical abortion method by itself, its use in conjunction with methotrexate (a powerful anti-cancer drug with its own teratological dangers) or RU 486 (which may also cause congenital malformations) is likely to precipitate similar problems. While methotrexate and RU 486 are more "effective" abortifacients when used in conjunction with misoprostol (inducing abortions between 90% and 96% of the time), they are not universally effective, meaning some babies survive. When they do, research tells us they may be born with partial facial paralysis, club feet, or missing fingers or toes.

The NEJM researchers said it best with their own closing: "Administration of misoprostol during pregnancy should be strongly discouraged, given the drug's low efficacy and its likelihood of causing fetal malformation."