For two years, a group of world-class scientists has launched their idea for a new biotech company to investors: a start-up focused on promising therapy for preeclampsia, a serious complication of pregnancy that can become life-threatening. It was a cutting edge science, backed by a Nobel Prize winner, a Harvard kidney specialist, a prominent chemist and a biologist with personal experience and experience.
In the end, they gave up – not for science, not for preeclampsia – but for investors.
"We've talked to so many different venture capitalists and other companies, scientists and doctors will get excited," said Melissa Moore, a University of Massachusetts Medical School scientist who started working on pre-eclampsia after suffering in 2003 and was put to bed for more than a month, only to give birth seven weeks early for a girl who weighed less than four pounds. "But as soon as their lawyers have heard" sick, pregnant women, "nothing happened," Moore said. "There is such a sense of responsibility".
The experience of Moore and his colleagues highlights a persistent problem in medical research. About 10% of women of reproductive age get pregnant every year in the United States, but much less research is done in pregnancy rather than in much less common conditions. The effect of medicines on pregnant women and their fetuses is rarely studied. The basic understanding of pregnancy itself is full of gaping scientific holes, mysteries that include the way the placenta is formed and what exactly controls the timing of birth. Some pregnancy experts call the placenta, a necessary organ for all human reproduction, the Rodney Dangerfield of the human body because it has "no respect".
The default assumption has long been – and, to a large extent, it is still – that it is essential to protect pregnant women from research, rather than ensuring that they benefit from its rapid progress. But the concerted pressure of scientists and supporters is slowly starting to change the politics and culture of research.
In January an updated federal policy came into effect governing protections for human research subjects, officially removing pregnant women from being classified as "vulnerable to coercion or undue influence" alongside children and "mentally disabled" people.
"We all joked about the brain of pregnancy, but I was still able to make decisions for myself and my fetus," said Sonja Rasmussen, pediatrician and clinical geneticist at the University of Florida.
Separately, last year a federal task force recommended that the participation of pregnant women in drug trials that offered benefits to the fetus no longer required the approval of the child's father.
"Once the baby is born, only the consent of a parent is needed," said Catherine Spong, head of maternal-fetal medicine at the University of Texas Southwestern Medical Center, who presided over the task force. "Given the autonomy of pregnant women and the evolution of the family structure, we should really align it with parental consent for pediatrics".
Activists have successfully pushed for more women to be included in medical research in the 1990s, but pregnant and lactating women have largely been left behind. Now, another round of activism started ten years ago is pushing new ideas about pregnancy. The high rates of maternal mortality in the United States have intensified the attention, and there is a growing awareness that conditions during pregnancy can influence the risk of developing chronic conditions in old age.
Some researchers observe that pregnant women are increasingly being studied in full – and not just as the environment in which a fetus develops. Recent evidence suggests that pregnancy complications could predict women's susceptibility to dementia or heart disease decades later.
"Probably most people think that pregnancy is a time-limited experience, and therefore, since it lasts only nine months, we do not need to invest much resources in it – because it will soon be over," said Diana Bianchi , Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. "But this is really a misleading idea: pregnancy is a stress test for a woman, and there are these two opportunities, both to understand what lies ahead for the pregnant woman, but also by doing research that guarantees a healthy pregnancy, we are contributing to the long-term health of the nation. "
The medical attitude toward pregnancy was modeled more than half a century ago by the thalidomide crisis, when the women who took the medicine for morning sickness had children with birth defects. The incident helped launch the modern era of drug regulation in the United States, with requirements to demonstrate the effectiveness and safety of drugs before they could be approved for sale. Pregnant women, however, are generally excluded from such research.
One study found that the risks to human pregnancy were "undetermined" in 98 percent of prescribed drugs approved between 2000 and 2010. An analysis of historical data showed that it took nearly three decades to obtain information from more precise risk. This is despite the fact that of the 6 million women in the United States who are pregnant every year, 90 percent take at least one drug.
Anne Drapkin Lyerly, bioethicist and midwife at the University of North Carolina at Chapel Hill, said that there is a well-established rule to leave pregnant women out of clinical trials, reinforced by policies that classified them as "vulnerable" and norms institutions that made it easier to avoid considering the potential risks and benefits of the whole.
"If you want to exclude a pregnant woman from research, all you have to do is check the box, it's not included, no explanation," Lyerly said. "If you want to include it, there's a lot of paperwork and decisions and you have to justify your decision."
Taking women out of the vulnerable category is a long way to change their access to drug trials or to change the incentives that pharmaceutical companies need to include, but supporters say it's a long-awaited start. Last year, the US Food and Drug Administration also published a guideline on when to include women in clinical trials, exposing that there is a "critical public health need" for more information on how to use drugs in safe way in pregnant women.
"If you do not do these studies, then you do not have the data to base your decision, but you're still making decisions," Spong said. "You are providing assistance in the absence of data."
During the 2009 influenza pandemic, Rasmussen recalled that he had deliberated with other experts whether the Centers for Disease Control and Prevention should recommend that Tamiflu be given to pregnant women – which he did.
"It's one of the things I'm most proud of in my career: we looked at it and weighed the risks and benefits rather than the instinctive," We can not allow pregnant women to have this because the data they are limited & # 39; " Rasmussen said.
Another teaching moment for the medical community came last year when an anti-HIV drug called dolutegravir was reported as potentially causing birth defects through a study that monitored the use of the drug in Botswana. .
"The dolutegravir finding was something that directed the entire HIV research community towards pregnancy research, even people who do not work with pregnant women, and raised questions about how to think about women," he said. Lyerly.
For people who are pregnant or hoping to conceive, the unknowns go far beyond what women can safely assume. The National Institutes of Health, which monitors its research funding on nearly 300 health categories, ranging from Batten's rare illness to ubiquitous allergies, has begun to erupt its expenses for pregnancy, maternal health and breastfeeding in 2017.
Stephanie Hinze, 37, from Atlanta, suffers from spina bifida and has used a wheelchair since she was 8 years old. When she and her husband decided to conceive, there was little information they could rely on – except for an informal network of other women with disabilities who had already had children. Concerns included whether it was safe to carry a child; fertility questions; if he was gaining weight at the right speed, since the doctor's offices were not equipped with accessible ladders; and what to do when he could not hear the baby moving due to a decrease in the lack of sensitivity in the abdomen.
Hinze, who has two children, one of whom is adopted, is now pregnant for the second time. She says she was lucky – her first pregnancy went well and her team of doctors was supportive, in contrast to the anecdotes she heard from others. But with each step, they were solving new puzzles.
"My doctor, while he was large and very receptive, did not know what to expect.While things happened during pregnancy, he said," Let's face this problem and find out. "Hinze said," You do not want to go in and your doctor does not he is quite sure what the solution will be to what is happening. "
NIH last year collaborated with the CDC a Survey on how disabled women experience pregnancy. The questions they are hoping to answer include: are they more likely to develop complications? Does disability affect women's ability to breastfeed? What is their basic pregnancy experience?
"We do not know," said Alison Cernich, director of the National Center for Medical Research on Rehabilitation, describing the evidence gap on disability and pregnancy that attributes to a "quadruple" of barriers for women: women's health is Often overlooked, many disabled women belong to ethnic groups who do not receive optimal treatment due to injury, many disabled people live in poverty and disabilities are often stigmatized.
Even the basic science of pregnancy is taking a closer look, as NIH has financed so far $ 76 million in research projects to study the human placenta, the temporary organ that supplies oxygen and nutrients to the fetus. The recent discovery that it is possible to grow a miniature version of the placenta in a laboratory environment can help scientists understand the fundamental questions about how it develops, in part in response to secretions from the uterus.
"Even in the 21st century, we do not know what there is in the secretions, we do not know their composition, on which all the future of the human species depends," said Graham Burton, a professor of reproductive physiology at the scene. University of Cambridge.
The placenta is necessary for a successful pregnancy, but it also affects the health of the pregnant woman. Preeclampsia, which causes maternal hypertension, is caused in part by the proteins released by the placenta that influence the function of blood vessels in the mother. There is no treatment for preeclampsia, which ends only when the woman delivers the child – and the placenta.
Surendra Sharma, a professor of pediatrics at Brown University, is trying to uncover the science behind an alarming observation made by other researchers: women with preeclampsia seem to be at greater risk of dementia decades later. Curiously, he discovered that there are proteins misfolded in the placenta by women with preeclampsia, similar to those found in the brains of patients with Alzheimer's. Women with preeclampsia are also at increased risk for heart disease and stroke.
The idea that treatment of preeclampsia can help both mothers and children adds urgency to the search for Moore and colleagues, who have been disappointed but not discouraged by the lack of enthusiasm of investors.
"It was really exciting to see how drug developers seemed concerned about the indication of pregnancy, but on the other hand, I do not think it's insurmountable," said Craig Mello, Nobel Prize winner and co-the founder of the flamboyant start-up.
At the end of last year, Moore and colleagues demonstrated the promise of therapy in treating a baboon version of preeclampsia. They hope to develop the drug through an unconventional non-profit model.
The experience of Moore is rooted in basic biology, a profound understanding of a molecule called RNA that performs a large number of basic functions in cells, including rotational instructions written in the genetic code in proteins and regulation of the genome. When Moore was pregnant and suffering from preeclampsia, she first met with S. Ananth Karumanchi, a Harvard doctor who had discovered a protein that was overwhelming in women with preeclampsia – and they began to talk about the use of RNA to reduce the level of proteins. The translation of this insight into an effective drug depends critically on a chemist from the UMass medical school, Anastasia Khvorova.
As a newcomer to the field of pregnancy, the team is not discouraged by history.
"One of the reasons we did not have many drugs for pregnant women is that the risk is considered too high – and that's really unfortunate," said Karumanchi, who recently moved to the Cedars-Sinai Medical Center in Los Angeles. "I think doing nothing for these pregnant women is not an option".