For every woman, the risk is always there after a baby comes. It's known as the third stage of labour, when the placenta peels away from the uterine wall to wend its way down the birth canal. It leaves behind a wound "the size of a small pizza," a tear about 20 centimetres across.
If all goes well, the uterus naturally contracts to close around blood vessels, as the umbilical cord is clamped and the placenta delivered. But if the uterus fails to contract, as it does in up to 15 per cent of cases, those vessels can flow like a tap. A woman can bleed out in an hour.
"In the developing world, where I work, you have a one-in-100 chance of dying in childbirth because of it," says Malcolm Potts, an obstetrician and scientist at the University of California at Berkeley.
Of the estimated 1,000 women who die from pregnancy-related causes in the world each day, postpartum hemorrhaging kills more than any other complication.
"One woman dies of PPH every seven minutes," Dr. Potts says.
In the industrialized world, it has been 75 years since drugs came along to jump-start contractions and stop postpartum bleeding, and the better part of a century since women regarded childbirth as a reason to write a will. But those medications require money, refrigeration, medical skill and equipment to be administered, making them unavailable to millions of women living where electricity remains a luxury.
Yet several years ago, doctors discovered a drug that could help save their lives, a simple 10-cent tablet that needs no cold storage or special devices to deliver. But the medicine, called misoprostol, also can induce labour and abortions, and it's mired in a triad of controversy - political, ethical and medical. Access to it for women delivering, 45 million of whom will give birth this year without a trained assistant, remains patchy.
Some countries see it as a moral danger. The Philippines has banned it. Experts at the World Health Organization see its use for postpartum bleeding in the community as a potential medical danger. But many on the front lines of safe motherhood - a few now embroiled in a very public dispute with the WHO - believe misoprostol is the best weapon there is to fight PPH in developing countries.
It could revolutionize obstetrics the way penicillin revolutionized treatment for infections. Dr. Malcolm Potts, who heads Berkeley's Bixby Center of Population Health and Sustainability.
The WHO worries that pregnant women, or those who care for them, will misuse misoprostol, which can have disastrous consequences if taken at the wrong time at the wrong dose. It insists that the drug needs further safety studies and may yet prove to have serious side effects.
Metin Gülmezoglu, medical officer in the WHO's department of reproductive health and research, put it this way: "In medicine, there are things that look like they may be so straightforward, and they turn out not to be ... and that can cause hundreds of thousands of deaths. That's what we're trying to avoid here."
Hazem El-Refaey, an Egyptian-born scientist, obstetrician and gynecologist now at the Chelsea and Westminster Hospital in London, pioneered the drug's use in obstetrics. But he suspects that politics undermine efforts to make misoprostol widely available.
"If you present it around the world as a life-saving drug for postpartum hemorrhaging, it will be available in every hut to treat postpartum hemorrhaging - and it will also be available in every hut for abortion," he says. "There is no other pill like it."
It also may be that no other pill has the power to force a global reckoning on the ties between a mother's well-being and a woman's reproductive rights.
In the lead-up to this week's G20 and G8 summits in Southern Ontario, where maternal health is a key focus, Stephen Harper's Conservative government worked to separate the two issues. Canada has pledged new money and rallied international commitment to improve the health of mothers worldwide, but Ottawa says it will not support any initiative that involves abortion. Recent polling by Nanos Research suggests that Canadians disagree; 67.7 per cent said women in countries receiving aid from Canada should have access to safe abortions.
Unsafe abortions account for 13 per cent of maternal deaths. Postpartum bleeding accounts for 25 per cent, meaning a largely preventable condition still stands as the lead cause of maternal mortality.
In many ways, the story of misoprostol exposes the minefields in maternal health, and why progress, even on the most lethal front, moves at a glacial pace.
THE ORPHAN DRUG
Misoprostol first hit the market as a gastric ulcer drug in the 1980s. Manufactured by the U.S.-based G.D. Searle & Co. under the brand name Cytotec, it was approved for that purpose in 85 countries. But like many drugs, it was found to have other uses.
Cytotec's packaging warned pregnant women against taking it, but by the early 1990s, women in Brazil were doing just that to induce safe abortions. "It spread like bushfire when women figured it out," Dr. Gülmezoglu says. "Then scientists and researchers picked it up."
Dr. El-Refaey was one of them. While working on his postdoctoral thesis at Aberdeen University in Scotland, he established the safe dose for an abortion, and found that the drug could be administered vaginally, as well as orally. He also showed that taking misoprostol as a follow-up to mifepristone, now standard practice, made the highly controversial abortion pill RU-486 more effective.
His studies convinced Dr. El-Refaey that misoprostol is unique. "To have so many purposes, at different doses, it's the most important development in women's health for decades."
The drug is a synthetic prostaglandin, which is a hormone-like messenger found in both sexes that acts on stomachs, kidneys, blood vessels and the uterus. While the online grapevine spread its use as an abortion drug, doctors discovered that misoprostol also could clear the uterus after a miscarriage, sparing women from invasive procedures, and induce labour.
"It became more and more widely used," says Beverly Winikoff, a New York public-health scientist who has researched misoprostol for 20 years.
It was cowboy medicine. Some people were putting it under the tongue, some were putting it in the rectum, some people were putting it into the vagina, at 200 micrograms, 400 micrograms, 600 micrograms. ... And on it went through the nineties. Beverly Winikoff
The manufacturer had no incentive to conduct trials to establish safe doses for obstetrics, says Dr. Winikoff, founder and president of Gynuity Health Projects, a non-profit research group that works to improve access to safe reproductive technologies. "It was 'Don't ask, don't tell,'" she says. "They could still profit and they didn't have to advertise or train doctors in its use."
So, as non-profit researchers figured out dosages, black markets blossomed, doctors and hospitals picked it up as a multipurpose, off-label obstetrics drug. But the data vacuum eventually proved deadly.
Inducing labour requires just 25 micrograms of misoprostol every four to six hours - a dose so small that a woman "only has to look at the drug" for contractions to start, Dr. Potts says. Yet the pill comes in tablets containing eight to 24 times that dose, which can rupture the uterus late in a pregnancy.
"Doctors were cutting it up with razor blades," Dr. Potts says, some of them simply eager to have babies born during office hours. There were abuses and mistakes. Overdoses killed women and babies around the world.
Lawsuits were filed, fingers pointed and in August, 2000, G.D. Searle (which was taken over by Pfizer Inc. two years later) sent a letter warning U.S. doctors how deadly Cytotec could be in pregnancy.
Some hospitals stopped using it, but many medical bodies disagreed. The American College of Obstetricians and Gynecologists, for instance, sent out a letter stressing evidence that showed misoprostol to be safe for abortions, inducing labour and after miscarriages, if taken correctly, and the WHO eventually added misoprostol, with medical supervision, for incomplete miscarriage, abortion and labour induction to its List of Essential Medicines.
While the controversy played out in the U.S., Dr. El-Refaey continued work on the drug. In the mid-1990s, he had moved to the University College London where, one day, he passed the portrait of John Chassar Moir, the famous British surgeon who changed childbirth forever with his 1935 discovery of ergometrine, the first drug used to contract the uterus and combat postpartum bleeding.
Dr. El-Refaey knew too well that Dr. Moir's advance had not reached poor regions, including his own. It was why he had chosen his specialty - hoping to make motherhood the happy experience he saw in the West. As he gazed at the portrait, it occurred to him that perhaps misoprostol could force contractions postpartum, perhaps it too had the power to stop a hemorrhage.
In 1996, he and colleagues published evidence of its use against PPH in The Lancet. Then he boarded a plane to see the WHO in Geneva.
Excitement flowed like a spring creek: a cheap and easy pill to combat the biggest mother killer of all time. Within a year, the WHO had co-ordinated a massive trial involving 18,500 women in nine countries to compare misoprostol for PPH against oxytocin, the gold-standard treatment in industrialized countries.
'THIS WAS THE NEW HOPE'
In 1998, Ndola Prata, a doctor and medical demographer from Africa, arrived at UC Berkeley to join the Bixby Center, convinced, like many, that misoprostol could be the perfect solution. "No one was looking for a drug to help these women and this was the new hope," she says.
Dr. Prata had spent the first part of her career in her native Angola, where death during childbirth is so routine that, "when a mother in Africa goes into delivery, she explains to her children that she's going on a journey and that she might not come back."
Few such women have access to hospitals, and aren't about to "get in a car and drive seven hours to the nearest clinic. … There are cultural barriers. After all, pregnancy is not a disease, it is a happy time and there are social ceremonies around a birth."
In Ethiopia, 94 per cent of women deliver at home, as do 80 per cent in Bangladesh and 60 per cent in Tanzania. But even medical professionals can be helpless without drugs at hand.
"I've seen women die of postpartum hemorrhaging in front of me," Dr. Prata says.
I still have nightmares, to be honest with you. You just watch them die. It would be better if I didn't know what to do, if I didn't know there was something I could do. Dr. Prata
When she heard misoprostol could combat PPH, she had only one question: "How can I bring this to the women who deliver at home, to the real world?"
In 2001, the Berkeley physicians, along with Dr. Potts's wife, Martha Campbell, a health-policy specialist, founded the non-profit aid group Venture Strategies for Health and Development, which later spun off Venture Strategies Innovations, to get misoprostol to women having babies.
After the drug came off patent in 2000, manufacturers in Brazil, Colombia, Peru, Mexico, China and Vietnam and 20 in India alone produced generic versions. But to import, market and distribute the drug legally as a PPH treatment, governments must register it for that purpose.
Reaching women who deliver at home, explains Dr. Prata, now medical director of Venture Strategies, requires community and media campaigns, and altering the packaging to include pictorial instructions that illiterate women can follow. None of this can be done if the drug is registered only as an ulcer treatment.
But persuading countries to see misoprostol as an obstetrical drug is tricky business. As Dr. El-Refaey notes, those in the developing world want to follow the lead of the West, and no Western country has approved misoprostol for PPH. Also, patients in countries like Canada have options - "other drugs, doctors, hospitals" - so its use in obstetrics remains off-label.
It took Dr. El-Refaey nearly seven years to persuade a drug company and Egyptian health officials to produce a low-dose tablet that could be used to induce labour safely. "Misoprostol is an orphan drug with no profit associated with its production - and money makes the world go round, so at the end of the day, who cares about making this drug at the right doses?" he asks. "At the end of the day, the voice of the poor is rarely heard."
To complicate matters, it so happens that the high dose needed to prevent and treat postpartum bleeding is similar to the dose needed to induce an abortion. For those morally opposed to terminating pregnancy, that makes the pill too bitter to swallow.
Dr. Potts recalls a meeting of doctors in Uganda, where a physician said, "We can't use this drug ... women will use it for abortions." Another doctor slammed his fist on the table and shouted, "They use aspirins for abortions!"
WONDER DRUG PROS AND CONS
In 2001, the large WHO-run trial found that, while misoprostol was effective against PPH, oxytocin was better - in 30 per cent of cases, women receiving misoprostol faced a higher risk of bleeding "a little or a lot." The agency deemed oxytocin the preferred treatment even though it must be refrigerated and delivered by injection.
That ruling, Dr. Potts says, is meaningless in many places. "It's become a very stupid argument about which drug is better - you cannot use injection drips and refrigerated drugs in a hospital in Nigeria."
More recently, Dr. Winikoff's Gynuity received $25-million from the Bill and Melinda Gates Foundation to research misoprostol as a treatment for PPH. This year, she co-wrote a study published in The Lancet that found the drug can stop heavy bleeding within 20 minutes for nine out of 10 women who receive it.
Several aid organizations now have community programs to distribute misoprostol to women delivering. But the WHO still has safety concerns. "There is no guarantee that it will be used after delivery," the agency's Dr. Gülmezoglu says. "We are worried that women or traditional birth attendants given these tablets at 30 weeks may be tempted" to use it earlier to induce labour, or to speed it up. "That can be catastrophic."
Such concerns are legitimate, says Dorothy Shaw, a clinical professor of obstetrics and gynecology at the University of British Columbia and past president of the International Federation of Gynecology and Obstetrics, particularly when those who need the drug may well be young and powerless.
She cites the example of a 14-year-old Ethiopian girl, married and pregnant before her pelvis has been fully formed. In such cases, she says, the girl may labour for days without progress because the baby is too large for her to deliver. "There's no saying someone wouldn't be tempted to administer this drug to move the labour along at an earlier stage," and that runs the risk of rupturing the uterus, killing mother and baby.
On the other hand, she says, "there have been quite a lot of publications" suggesting that, with proper counselling, these fears are not borne out. "The drug appears quite safe.… We aren't seeing it … to induce labour, or to make labour go faster or to abort. Even though those concerns are valid, we haven't seen evidence of it."
But Dr. Gülmezoglu, who has worked on misoprostol issues since the late 1990s, says that because the drug acts on the whole body, and is known to cause shivers and temperature spikes after delivery, the WHO suspects it may be life-threatening if used then.
Last September, the WHO published a review of 46 misoprostol trials involving more than 40,000 women. But the agency found it could draw no conclusions about its potentially serious risks.
Dr. Gülmezoglu argues that many of the studies done so far have been small, biased and flawed. "Some of them had no control group for comparison," he says, and they were conducted "like a health campaign." Aid workers "come into communities and say they have a wonder drug, that you aren't going to bleed any more. … Then six months later they ask them, 'Oh, how did you feel?' and the women say, 'Oh, I feel great.'
If they had done research properly, after seven or eight years, we wouldn't be in this position that we are now. Dr. Gülmezoglu
But Dr. Shaw questions the WHO stance. "Are we going to wait for the gold standard of evidence while women die?"
Dr. Gülmezoglu concedes that misoprostol is "better than nothing," and when nothing is available, the WHO recommends that a properly trained health worker administer it orally after delivery.
But this has sparked debate over who qualifies as a trained health worker, when birth attendants in poor settings tend to be relatives and neighbours.
"Our strategy to reduce maternal death," Dr. Gülmezoglu says, "is to train health workers, and to get more [women]to go to hospitals" - a goal that Dr. Potts considers "unachievable" in poor areas.
"Once they are skilled or trained, they want to leave and go and work in France or Canada, or they want to go to the cities where their children can have better opportunities and their husbands have jobs," he insists.
Venture Strategies now co-operates with local medical institutions to run 14 programs in Africa and Asia, giving misoprostol, with instructions, directly to pregnant women at their eight-month checkup. To date, 16 countries have registered the drug as a PPH treatment, and work continues to make it available there.
"In Africa, it will take 80 years for every woman to deliver with a skilled attendant," Dr. Prata says. "Do we wait until we have a midwife or a gynecologist for every woman? Women are dying.
"I don't need 100 studies to tell me that this drug can stop the bleeding."
AN ESSENTIAL MEDICINE?
In 2008, Dr. Winikoff's Gynuity and Venture Strategies applied to have misoprostol added to the WHO's List of Essential Medicines for the prevention and treatment of PPH in the community, a status that would give it instant international legitimacy.
The application, Dr. Prata says, had the support of the International Federation of Gynecology and Obstetrics, the International Confederation of Midwives, and American Pharmacopeia, which sets safe drug standards.
Although the WHO already ranks misoprostol as an essential medicine for labour inductions, abortions and incomplete miscarriages, it must be administered under medical supervision for these uses, rather than distributed locally. The WHO committee, which updates the list every two years, rejected the application, and the agency confirmed its position last year with a statement saying it "does not recommend distribution of misoprostol to community-level health workers or women and their families for routine or emergency use."
Dr. Potts suspects that the UN agency has been swayed in part by doctors reluctant to have women medicate themselves: "There are still groups of people in the world threatened by the notion that people can do for themselves things only doctors have done," he says. In a commentary published in The Lancet in February, he and others called the WHO position "contrived and unsubstantiated." They followed with another critical article in May.
This month, the WHO fired back in a bulletin posted online, countering the Berkeley group's attacks. Dr. Gülmezoglu noted that, unlike non-profit groups, the WHO is accountable to its member states. "Mothers are dying, but if we don't do the research first, we may be doing ineffective interventions and we may well be doing harm."
Dr. Gülmezoglu says the WHO plans to run a safety study on misoprostol for PPH in Uganda, and start a program to monitor its use in Ethiopia.
Dr. Winikoff, who is now working with the WHO, notes that doctors, not women, have been misusing the drug to disastrous ends. She remains optimistic that eventually, misoprostol will find its way to women who need it. "These things don't happen quickly; they can't. In some cases, they shouldn't."
Dr. Potts, however, hears the clock ticking. "Lets say that community-based distribution of misoprostol could save one woman every one or two hours. If the WHO delays this work by six months, then that is 1,500 to 3,000 deaths that might have been prevented. Obviously it takes time to get anything used on a large scale, and those deaths might not be averted immediately, but somewhere along the line, those women will die.
"Caution," he says, "can kill."