By PAM BELLUCK
June 5, 2012
Labels inside every box of morning-after pills, drugs widely used to prevent pregnancy after sex, say they may work by blocking fertilized eggs from implanting in a woman’s uterus. Respected medical authorities, including the National Institutes of Health and the Mayo Clinic. have said the same thing on their Web sites.
Such descriptions have become kindling in the fiery debate over abortion and contraception .
Based on the belief that a fertilized egg is a person, some religious groups and conservative politicians say disrupting a fertilized egg’s ability to attach to the uterus is abortion, “the moral equivalent of homicide,” as Dr. Donna Harrison, who directs research for the American Association of Pro-life Obstetricians and Gynecologists. put it. Mitt Romney recently called emergency contraceptives “abortive pills.” And two former Republican presidential candidates, Newt Gingrich and Rick Santorum, have made similar statements.
But an examination by The New York Times has found that the federally approved labels and medical Web sites do not reflect what the science shows. Studies have not established that emergency contraceptive pills prevent fertilized eggs from implanting in the womb, leading scientists say. Rather, the pills delay ovulation, the release of eggs from ovaries that occurs before eggs are fertilized, and some pills also thicken cervical mucus so sperm have trouble swimming.
Patricia Wall / The New York Times
It turns out that the politically charged debate over morning-after pills and abortion, a divisive issue in this election year, is probably rooted in outdated or incorrect scientific guesses about how the pills work. Because they block creation of fertilized eggs, they would not meet abortion opponents’ definition of abortion-inducing drugs. In contrast, RU-486. a medication prescribed for terminating pregnancies, destroys implanted embryos.
The notion that morning-after pills prevent eggs from implanting stems from the Food and Drug Administration’s decision during the drug-approval process to mention that possibility on the label — despite lack of scientific proof, scientists say, and objections by the manufacturer of Plan B. the pill on the market the longest. Leading scientists say studies since then provide strong evidence that Plan B does not prevent implantation, and no proof that a newer type of pill, Ella. does. Some abortion opponents said they remain unconvinced.
After The Times asked about this issue, A.D.A.M. the firm that writes medical entries for the National Institutes of Health Web site. deleted passages suggesting emergency contraceptives could disrupt implantation. The Times, which uses A.D.A.M.’s content on its health Web page, updated its site. The medical editor in chief of the Web site for the Mayo Clinic, Dr. Roger W. Harms, said “we are champing at the bit” to revise the entry if the Food and Drug Administration changes labels or other agencies make official pronouncements.
“These medications are there to prevent or delay ovulation,” said Dr. Petra M. Casey, an obstetrician-gynecologist at Mayo. “They don’t act after fertilization.”
Part of a handout included with packages of one of the medications, Plan B.
The F.D.A. declined to discuss decisions about the effect on implantation or to say whether it would consider revising labels. But Erica Jefferson, an F.D.A. spokeswoman, acknowledged: “The emerging data on Plan B suggest that it does not inhibit implantation. Less is known about Ella. However, some data suggest it also does not inhibit implantation.”
Scientists say the pills work up to five days after sex, primarily stalling an egg’s release until sperm can no longer fertilize it. Although many people think sperm and egg unite immediately after sex, sperm need time to position themselves.
Controversy over emergency contraception is figuring in the presidential race and debates over the Obama administration’s health care law. Some abortion opponents and religious groups are fighting the law because it requires insurers, including those for employees of Roman Catholic institutions that oppose birth control. to cover contraceptives, including morning-after pills. While some object to contraception generally, others focus on birth control methods that they believe cause abortions.
And some proponents of “personhood” initiatives, proposals being put forward in several states to define fertilized eggs as people, say the initiatives would bar the pills if they work after eggs are fertilized.
Doctors also say some patients who are not active on abortion issues want to resolve ethical questions about whether the pills affect a fertilized egg.
A Growing Market
While scientific and political disputes over emergency contraception may persist even if labels change, both sides consider the wording on labels central because it summarizes scientific consensus and shapes what medical authorities say.
“F.D.A. labeling is important to us, it’s very important,” said Jeanne Monahan, director of the Center for Human Dignity at the Family Research Council. a conservative group.
Diana Blithe, a biochemist who oversees contraception research for the National Institutes of Health, the federal agency for medical research, said the possibility of an effect on implantation should not be cited on the labels. “As a scientist, I would definitely take it off of emergency contraception,” she said.
Ninety-nine percent of the emergency contraception market in the United States consists of Plan B (approved in 1999 and now sold as Plan B One-Step) and its generic versions, Next Choice and levonorgestrel tablets. They are available without prescription for women ages 17 and older. The other pill, Ella, became available by prescription only in the United States in late 2010. Emergency contraceptive use has steadily increased, with about 12 million packages sold last year, according to IMS Health and the SymphonyIRI Group, health information and market research companies.
European medical authorities have not mentioned an effect on implantation on Ella’s label, and after months of scrutiny, Ella was approved for sale in overwhelmingly Catholic Italy, where laws would have barred it if it could be considered to induce abortion, said Erin Gainer, chief executive of Ella’s manufacturer, Paris-based HRA Pharma.
Some abortion opponents said that while emergency contraceptives’ primary function may be delaying ovulation, they doubted that scientists could exclude the possibility of implantation effects.
“I would be relieved if it doesn’t have this effect,” said Richard Doerflinger, associate director of the Secretariat of Pro-Life Activities for the United States Conference of Catholic Bishops. “So far what I see is an unresolved debate and some studies on both sides,” he said, adding that because of difficulties in ethically testing the drugs on women, “it’s not only unresolved, but it may be unresolvable.”
Several scientists acknowledged that absolute proof may be elusive; in science, as James Trussell, a longtime emergency contraception researcher at Princeton, said, “You can never prove the negative.” But he and others said the evidence from multiple studies was persuasive.
A Labeling Dispute
How did the statement about implantation end up on F.D.A.-approved labels?
Beginning with the 1999 approval process, the maker of Plan B — Barr Pharmaceuticals, later acquired by Teva Pharmaceuticals — asked the F.D.A. in writing not to list an implantation effect on the label. said people familiar with the requests who asked for anonymity because such discussions are considered confidential.
Anti-abortion activists were not yet publicly focusing on the issue.
“There were other drugs that I remember causing controversy,” said Dr. Jane E. Henney, the F.D.A. commissioner then. “This wasn’t one.”
Back then, scientific research concentrated on whether Plan B’s active ingredient, a synthetic progesterone. safely and
effectively prevented pregnancy, not on how it worked, said Dr. Kristina Gemzell-Danielsson, an obstetrics and gynecology professor at the Karolinska Institute in Sweden, who participated in World Health Organization studies leading to F.D.A. approval.
The F.D.A.’s own description was speculative, saying Plan B “could theoretically prevent pregnancy by interfering with a number of physiological processes” followed by a long list, including ovulation and implantation.
A New York Times review of hundreds of pages of approval process documents found no discussion of evidence supporting implantation effects.
Ms. Jefferson of the F.D.A. said it was often difficult when a drug is approved, and even afterward, to pinpoint how it works. Citing confidentiality rules, she would not discuss why the agency declined the company’s request to omit implantation.
Experts say implantation was likely placed on the label partly because daily birth control pills, some of which contain Plan B’s active ingredient, appear to alter the endometrium, the lining of the uterus into which fertilized eggs implant. Altering the endometrium has not been proven to interfere with implantation. But in any case, scientists say that unlike the accumulating doses of daily birth control pills, the one-shot dose in morning-after pills does not have time to affect the uterine lining.
“It takes time for an endometrium to change, for its cells to divide,” said Susan Wood, a biochemist who, shortly after Plan B’s approval became the F.D.A.’s top women’s health official and later resigned, frustrated with the delay in making the pill available without prescription.
Implantation also likely wound up on the label because of what Dr. Gemzell-Danielsson called wishful thinking by some scientists, who thought that if it could also block implantation, it would be even better at preventing pregnancy.
By 2002, studies produced evidence that Plan B did not interrupt implantation.
Abortion opponents were also becoming more vocal about emergency contraception. In 2005-6, when the F.D.A. reviewed Plan B, making it available without prescription for ages 17 and over, some opponents said it was an abortion-inducing drug. Plan B’s maker again asked that implantation be removed from the label.
Addressing the issue in a 2005 memorandum, Dr. Steven Galson, director of the F.D.A.’s Center for Drug Evaluation and Research, wrote that studies “conclusively demonstrate” that Plan B’s ability to block ovulation, is “responsible for most, if not all, instances in which emergency contraception prevents pregnancy.” But he also said that studies at that time could not exclude the possibility the pills impeded implantation “in a small percentage of women.” He declined a request to be interviewed.
By 2007, scientific consensus was building that morning-after pills did not block implantation. In one study using fertilized eggs that would have been discarded from fertility clinics, Dr. Gemzell-Danielsson found that adding Plan B in a dish did not prevent them from attaching to cells that line the uterus.
Later, in 2007, 2009 and 2010, researchers in Australia and Chile gave Plan B to women after determining with hormone tests which women had ovulated and which had not.
None who took the drug before ovulation became pregnant, underscoring how Plan B delays ovulation. Women who had ovulated became pregnant at the same rate as if they had taken no drug at all. In those cases, there were no difficulties with implantation, said one of the researchers, Gabriela Noé, at the Instituto Chileno de Medicina Reproductiva in Santiago. Dr. Blithe of the N.I.H. said, “No one can say that it works to inhibit implantation based on these data.”
The Evidence Grows
In 2009-10, during discussions about making Plan B available over the counter for all ages, the manufacturer, Teva Pharmaceuticals, again asked that implantation be deleted from the label. The F.D.A. again declined. Valerie Mulligan, Teva’s senior director of regulatory affairs, declined to discuss conversations about Plan B, but said, “There is quite a lot of evidence now that it doesn’t affect implantation.”
By this year, the International Federation of Gynecology and Obstetrics considered the research so strong that it issued a statement saying that pills with Plan B’s active ingredient “do not inhibit implantation.”
Research on Ella, approved in 2010, is less extensive, but the F.D.A. Dr. Blithe, and others say evidence increasingly suggests it does not derail implantation, citing, among other things, several studies in which women became pregnant when taking Ella after ovulating. The studies, focused on Ella’s effectiveness, were not designed to determine if it blocked implantation, but experts still consider them significant.
Dr. Trussell of Princeton said that if morning-after pills worked after eggs were fertilized, they would prevent pregnancy better than they do. The pregnancy prevention rates are probably lower than scientists and pill makers originally thought, he said — in some studies as low as 52 percent for Plan B and 62 percent for Ella.
By contrast, scientists say, research suggests that the only other officially approved form of emergency contraception, the copper intrauterine device (also a daily birth control method), can work to prevent pregnancy after an egg has been fertilized.
Despite the accumulating evidence, several abortion opponents said they remain unpersuaded. Dr. Harrison, director of research and public policy for the American Association of Pro-life Obstetricians and Gynecologists, said that the Plan B studies were led by “a good researcher,” but that she would prefer a study with more women and more documentation of when in their cycles they took Plan B. She added that if the studies done so far are correct, Plan B’s label should say it is ineffective after ovulation.
With Ella, Dr. Harrison cited a document from the European Medicines Agency (similar to the F.D.A.) and animal studies that she said suggest the lining of the uterus could be altered. Dr. Blithe said that the European document did not demonstrate that effect, and that the animal results were not analogous to human experience, partly because the doses were higher.
So far, in only one human study have researchers suggested that Ella’s active ingredient might thin the lining in doses higher than the dose in an Ella pill. But Dr. Blithe said that study, conducted by researchers at her agency, the N.I.H. produced results too unclear or insignificant to show that effect. Most human studies suggest otherwise, she said.
Dr. Harrison also cited similarities between Ella’s active ingredient and RU-486. But Dr. Anita L. Nelson, a professor of obstetrics and gynecology at University of California, Los Angeles, said RU-486’s ingredient is given in a dose up to 20 times higher than Ella’s ingredient and is taken when women are up to seven weeks pregnant, long after the egg has implanted.
Steps by government agencies or medical Web sites to revise language about implantation are already causing controversy. Recently, some abortion opponents criticized two agencies of the Department of Health and Human Services for online fact sheets that omit an implantation effect or say that science undermines it.
A department spokesman explained the fact sheets, saying “the public should have access to the most accurate and up-to-date scientific information available on matters of preventative health, including contraception.”
Critics said they wondered if scientists and government agencies were debunking an implantation effect because they support abortion rights. Jonathan Imbody, vice president of government relations for the Christian Medical Association. wrote on LifeNews.com. that the fact sheets contradict Plan B’s abortion-inducing nature and raise questions about “whether ideological considerations are driving these decisions.”