Preeclampsia is a serious complication of pregnancy that affects 5 to 10 percent of all pregnancies — over 8 million a year worldwide — and claims the lives of 76,000 mothers and half a million babies each year.

The condition causes hypertension and abnormal protein in the urine, and has few effective preventive or therapeutic strategies. The clinical abnormalities usually resolve completely after delivery, but recent research shows that women who have had preeclampsia have higher rates of heart disease later in life, for reasons that are poorly understood.

That’s where Mark Hlatky, Virginia Winn, and their Stanford Medicine research team come in. They were recently awarded a 4-year, $6 million NIH grant from the National Heart, Lung and Blood Institute to study the links between preeclampsia and the subsequent risk of atherosclerotic cardiovascular disease (ASCVD) as women grow older.

“The goal of this study is to improve cardiovascular health in women, by learning how pregnancy affects heart disease later in life,” said Hlatky, a Stanford Health Policy fellow. “We hope that shedding new light on these links can lead to better prevention and treatment.”

The interdisciplinary study called EPOCH — Effect of Preeclampsia On Cardiovascular Health — could eventually help millions of women and their clinicians worldwide.

“Since about 85 percent of women become pregnant at some point during their lives, and heart disease is the leading cause of death in women, determining how pregnancy complications might increase the risk of heart disease later in life could be very important,” said Hlatky, a professor of health research and policy and of cardiovascular medicine. “If there is a specific biomarker ‘signature’ of heart disease risk in women who have had preeclampsia, it would open up new possibilities for risk assessment and better treatment to prevent heart attacks and strokes.”

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Hlatky and his co-principal investigator, Stanford high-risk obstetrician Winn, note that a history of preeclampsia doubles the woman’s risk of future heart disease and stroke, and triples her risk of hypertension. And these adverse consequences occur at younger ages than in women who never developed the condition during pregnancy.

"The dramatic physiologic changes that happen during pregnancy are indeed remarkable," said Winn, the Arline and Pete Harman faculty scholar in the Department of Obstetrics and Gynecology. "This study highlights how complications that occur in pregnancy impact women's health beyond pregnancy." 

The pathogenic links between preeclampsia early in life and ASCVD late in life have been difficult to investigate because the process develops over decades, the authors said. And few clinicians are aware of the link between the condition and late ASCVD risk and there are no validated biomarkers for this process.

Preliminary data that contributed to the application of the project was a direct result of Winn’s endowed Arline and Pete Harman Faculty Scholar award and funding from the Stanford Maternal and Child Health Research Institute and the Stanford Cardiovascular Institute.

The 4-year grant will support a multi-disciplinary research team in taking a life-course approach. The EPOCH study will enroll three cohorts of women at distinct points in the natural history of the disorder: during pregnancy in their reproductive years; during the long, asymptomatic period in mid-life; and the ultimate development of ASCVD in later life.

“It’s very difficult to study the effects of early life events on the development of diseases late in life, since they are separated by 40 years or more,” Hlatky said. “We don’t have reliable health records in the United States from 40 or more years ago, so it’s a challenge for American researchers.” This is why, he said, the EPOCH study includes researchers from Denmark, which has a national health system, complete medical data of their citizens since the 1970’s, and a national biobank that will allow study of later life events.

The first cohort of women will include some of those who are already part of the Stanford March of Dimes Prematurity Research Center. The center, led by David Stevenson began recruiting women in 2011 to study pregnancy from the first trimester through delivery. The study has collected a wide array of “omics” measures at multiple time points: metabolomics, proteomics, cell-free RNA, the microbiome and immune cells for analysis, as well as collection of amniotic fluid, cord blood, and the placenta. The pregnancy cohort will enroll additional women who are cared for at Lucile Packard Children’s Hospital for treatment of preeclampsia, about 100 in all, plus a matched group with uncomplicated pregnancies.

This is where it gets pretty technical — but also pretty cool

The researchers will collect high-dimensional “omic” biomarker data to assess the pathophysiology of preeclampsia and its relationship to cardiovascular function and disease. They’ll assess cell signaling pathways using single-cell immune profiling (CyTOF) methods in the lab of Brice Gaudilliere, an assistant professor of anesthesia.

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They will then analyze the cell-free RNA profiles using methods developed by co-investigator Stephen Quake, a professor of bioengineering and applied physics, and co-president of the Chan Zuckerberg Biohub. They will assess metabolomics using novel methods also developed at Stanford by co-investigator Michael Snyder,  professor and chair of genetics.

Stanford data scientists, including co-investigators, Robert Tibshirani and Nima Aghaeepour, have been at the forefront of developing and applying novel statistical and bioinformatic approaches, which the team will use to analyze the torrents of data that can now be collected by modern “omics” technologies from individual clinical research subjects.

“The EPOCH study is truly interdisciplinary — we are bringing together faculty from eight different departments to study a major problem in women’s health.”

The second, mid-life cohort will be recruited from women who had a pregnancy complicated by preeclampsia. Marcia Stefanick, professor of medicine in the Stanford Prevention Research Center, will use the Stanford Medicine Research Data Repository (STARR), which contains electronic records from more than 1.6 million patients since 1995, to identify eligible women. Stefanick and the EPOCH team will recruit 200 pre-menopausal women who had either a pregnancy complicated by preeclampsia or an uncomplicated pregnancy.

The third, late-life cohort of women will be identified in the Danish National Biobank by Stanford visiting professor Mads Melbye. Samples will be retrieved from women who had preeclampsia early in life and ASCD later in life, as well as a set of matched control subjects, and analyzed in Stanford laboratories.

“We’re not quite sure whether the physiologic challenges of pregnancy that result in preeclampsia simply reveal underlying cardiovascular risk, or causes change that leads to the increased risk in later life,” Winn said. “The EPOCH study will identify unique aspects of preeclampsia that links it to later ASCVD, opening potential novel approaches to improve women’s health.”

The EPOCH study brings together investigators from eight departments. Additional faculty include Gary Shaw and Seda Tierney (Pediatrics), Martin Angst (Anesthesia), Nicholas Leeper (Surgery) and Heather Boyd (Danish Biobank).

Research by Stanford Health Policy’s Michelle Mello looks at what happens when a group of hospitals started systematically acknowledging adverse outcomes in care by apologizing and proactively offering compensation where substandard care caused serious harm. 

Hospitals have traditionally “crouched in a deny-and-defend posture when things go wrong in medical care,” said Mello, a professor of law at Stanford Law School and a professor of health research and policy. The new approach, called “a communication-and-resolution program,” or CRP, is being adopted by an increasing number of health-care facilities.

“None of the hospitals experienced worsening liability or trends after CRP implementation, which suggests that transparency, apology, and proactive compensation can be pursued without adverse financial consequences,” Mello and her co-authors write in the study published Monday in Health Affairs. However, despite the growing consensus that CRPs are the right thing to do, concerns over liability risks remain.”

Stanford Health Policy asked Mello some questions about the research:

Could this new approach to resolving patient conflict be a thing of the future?

Hospitals that adopt CRPs believe they will help improve patient safety and are consistent with the ethical obligation to disclose medical errors; they also hope they will reduce liability costs. However, there is a lot of uncertainty about their effects on costs. On the one hand, being honest with patients could avoid the anger that prompts patients to sue, and compensating injured patients early on saves on litigation expenses. On the other hand, in the traditional system, very few patients injured by substandard care ever get compensated. Offering up admissions of error and early compensation could mean a lot more patients receive payment, raising total costs. Uncertainty about this issue continues to be a barrier to widespread adoption of the CRP approach.

What were the key findings in your study?

We evaluated the liability effects of CRP implementation at four Massachusetts hospitals by examining before-and-after trends in malpractice claims, volume, cost, and time to resolution. We then compared those to trends among similar hospitals in the state that did not adopt CRPs. We found that CRP implementation was associated with improved trends in the rate of new claims and legal defense costs at the two big hospitals that implemented these programs — favorable developments that were not seen at comparison hospitals with no communication-and-resolution programs in place. CRP implementation was not associated with significant changes upward or downward in trends of new claims receiving compensation, compensation costs, total liability costs, or average compensation per paid claim, nor was it associated with a significant change in time to resolution.

So then why are the findings important?

The study helps resolve uncertainty about the liability effects of admitting and compensating medical errors, especially since the study design was much stronger than that of previous studies. We found that the CRP approach does not expand liability risk and may, in fact, improve some liability outcomes. Therefore, hospitals can “do the right thing” — be honest about errors, apologize, and compensate patients who are injured by negligence — without adverse financial consequences.

Who began the CRP approach and what is the average payment proactively made to patients who did not receive proper care?

The approach dates to the late 1990s and was first publicized by a Veterans Affairs hospital in Kentucky and then by the University of Michigan Health System, both of which reported very positive outcomes.  Stanford was also an early adopter.

The model calls for patients to be compensated at about what the hospital estimates their claim would be worth in traditional litigation. In our study in Massachusetts, the median payment to patients was $75,000. That’s a lot lower than the median payment in the tort system, but the mix of injuries is different. In traditional litigation, 85 percent of claims involve very serious injuries or deaths, because smaller claims aren’t attractive to plaintiff attorneys. They just go uncompensated. In CRPs, it’s easier for patients with moderate-severity injuries to have access to justice.

Stanford Health Policy's Paul Wise held a conversation with Dr. Jim Yong Kim, president of the World Bank Group about improving the health of the poorest communities around the world. The two old friends talked about their work and the keys to accomplishing big goals during the Conversation in Global Health event. Wise is a core faculty member at Stanford Health Policy and the Center for Innovation in Global Health, as well as a senior fellow at the Freeman Spogli Institute for International Studies.

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A cutting-edge treatment for blood cancer in children with promising short-term remission rates has nevertheless come under intense scrutiny due to its unprecedented cost.

Acute lymphoblastic leukemia (ALL) is the most commonly diagnosed pediatric cancer. Though treatment advances have driven five-year survival rates above 90 percent, relapse is common and ALL remains a leading cause of death from childhood cancer. Those surviving relapse typically require hematopoietic stem cell transplant (HSCT) to remain in remission.

The Food and Drug Administration last year approved tisagenlecleucel as the first anti-CD19 CAR T-cell therapy for relapsed or refractory pediatric ALL. While tisagenlecleucel-induced remission rates are encouraging compared with those of established therapies — more than 80 percent compared with less than 50 percent — a one-time infusion costs $475,000.

That makes it one of  the most expensive oncologic therapies out there, even though no studies exist to show how the therapy maintains remission in the long term.

So Stanford Health Policy’s John K. Lin, Jeremy Goldhaber-Fiebert and Douglas K. Owens, in collaboration with Kara Davis, an assistant professor of pediatrics at Stanford’s Lucile Packard Children’s Hospital, set out to determine whether the treatment is cost-effective. 

Their study was recently published in the Journal of Clinical Oncology.

“CAR-T cells are an exciting new therapy to help us cure more patients with ALL,” said Davis. “They use a patient’s own immune system to precisely target their leukemia and remission rates are impressive for patients with relapsed disease.”

The researchers note, however, it remains unknown whether tisagenlecleucel is sufficient to cure relapsed or refractory disease without a transplant.

Not only is it a very expensive treatment, it also has expensive and serious side effects, such as cytokine release syndrome, which can cause symptoms ranging from fevers and muscle aches to lethal drops in blood pressure and difficulty breathing, requiring ICU-level care.

“Given [its] high cost and broad applicability in other malignancies, a pressing question for policymakers, payers, and clinicians is whether the therapy’s cost represents reasonable value,” the authors wrote.

In order to evaluate the economic value of tisagenlecleucel, the authors created a computer simulation that modeled children with relapsed or refractory ALL. Since the durability of the therapy’s effects are unknown, they evaluated the therapy at different levels of long-term effectiveness.

Through their analyses, the authors found that at the simulation’s most optimistic projections, patients receiving tisagenlecleucel would, on average, live over a decade longer than those receiving alternative therapies. At these projections, the therapy would be cost-effective. However, at more modest long-term outcomes, its clinical and economic benefits declined.

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“The durability of CAR-T cell therapy is the main question. For many children with relapsed or refractory ALL, their disease is fatal — if the therapy results in sustained remissions, it would represent an important advance,” said lead author Lin, who is a VA Health Services Research and Development Fellow at Stanford Health Policy.

In the end, the researchers concluded that at tisagenlecleucel’s current price, its economic value is “uncertain,” as the true cost-effectiveness depends on its long-term performance, which has yet to be determined. They noted that substantial price reductions would improve its cost-effectiveness even if its long-term performance is relatively modest.

“A commonly asked question for many expensive, novel therapies is why can’t prices be lowered at least until we know how well they work,” said Goldhaber-Fiebert. 

The “Catch-22” here is that long-term effectiveness data are needed to justify a drug’s price, but current uncertainty about its effectiveness, along with its high price, means developing the data to justify its price occurs much more slowly.

“CAR-T is an individually tailored treatment that has thus far been produced for a relatively small number of patients,” Goldhaber-Fiebert said. “Its current production costs may well be very high, and certainly the companies that have spent heavily on its research and development are interested in achieving returns on their investments.”

When the effectiveness of a therapy is uncertain, some pharmaceutical companies and health policy experts have proposed something called outcomes-based payment, which is essentially a “money-back guarantee” if the therapy doesn’t work as intended.

Novartis, which developed tisagenlecleucel, has a money-back guarantee; if the patient does not achieve initial remission within the first month, they are not responsible for the payment of the therapy.

“However, we find that because most children have an initial remission, this does not materially improve cost-effectiveness,” Lin said.

He suggested that if the money-back guarantee were extended to see whether the patient relapses within a year, such a guarantee would improve the treatment’s cost-effectiveness.

The other co-authors of the study are James I. Barnes, Alex Q.L. Robinson, Benjamin J. Lerman, Brian C. Boursiquot and Yuan Jin Tan.

The United States is in the grip of an opioid epidemic, which is affecting millions of Americans and claiming thousands of lives. Many trace their opioid dependence back to their doctor’s office, the drugs prescribed for pain after an injury, surgery, or dental procedure. Were these painkillers over prescribed? Did drug manufacturers exaggerate opioids’ effectiveness while deliberately underplaying their danger? Did drug distributors and retailers take necessary steps to ensure that pills weren’t falling in to the wrong hands?  

In this Q&A, Stanford Law Professors Michelle Mello, an expert in health law and core faculty member at Stanford Health Policy, and Nora Freeman Engstrom, an expert in tort law and complex litigation, explain the scope of the opioid problem and discuss the latest cases and legal challenges.

Just how big of a problem is the opioid crisis in the United States? Can you describe the problem’s scope and seriousness? 

Engstrom: The opioid problem is monstrous. Some 2.4 million Americans have an opioid use disorder, and the epidemic has already claimed 300,000 American lives, including 42,000 in 2016 alone. Worse, if the problem isn’t addressed, death tolls will rise: opioids are on track to claim the lives of another half-million Americans within the next decade. That’s like wiping out the entire city of Atlanta. The economic cost is also astronomical. The Council of Economic Advisors has estimated that, in 2015, “the economic cost of the opioid crisis was $504.0 billion, or 2.8 percent of GDP.”

Mello: If there’s one picture that brings home the shocking toll, it’s this one, showing trends in U.S. deaths based on data from the Centers for Disease Control and Prevention.  Nearly all of the “Poisoning” deaths shown here are opioid related. In terms of what’s killing Americans, opioids dwarf car crashes and guns.

Opioid lawsuits are now making news . Some of the actions are criminal, pursued by the states and federal government. Others of those suits are being initiated by cities, counties, and even states. What do those latter suits allege and what damages are the public plaintiffs trying to recover?

Engstrom: In the past four years, roughly 400 cities, counties, and states have initiated lawsuits seeking recovery for their additional public spending traceable to the opioid epidemic. The governmental entities claim they have been injured because defendants—typically, opioid manufacturers, distributors, and big retail pharmacies—have pumped opioids into the hands of their citizens and, in so doing, increased their spending for governmental services. Everything from policing, education, foster care, the provision of health care, even the operation of coroner’s officers, have all been made more expensive because, as compared to a healthy citizenry, an opioid-addicted populace is far less productive and needs much more by way of government help. Facing these spiraling costs, the governmental plaintiffs contend that the opioid defendants—who, they contend, caused and profited from this crisis—should foot the bill.

So, the typical defendants in these cases are opioid manufacturers, distributors, and big retail pharmacies. What is it that the plaintiffs are alleging these defendants did wrong?

Mello: There are some variations state to state, but for manufacturers, plaintiffs are typically claiming that they made false statements to prescribers and others that the drugs were safer and less addictive than alternatives, even when mounting evidence showed otherwise; that they failed to warn physicians and patients about the risks; and that the products were defectively designed—for example, because manufacturers didn’t make the pills tamper-resistant. For distributors and retailers, the claims are that these defendants failed to monitor, detect, investigate, and report suspicious orders of prescription drugs, even though reasonably prudent suppliers would have done so and the federal Controlled Substances Act requires suppliers to maintain effective controls against diversion of controlled substances to illicit markets.

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There are a billion guns in the world today. Those firearms took the lives of about 251,000 people in 195 countries in 2016, according to new research. 

That’s a lot of guns and fatalities, mostly by homicide, suicide and accidents with firearms.

About 35 percent of those gun deaths were by Americans committing suicide.

In the most comprehensive investigation of its kind, the findings, published this week in the Journal of the American Medical Association (JAMA), show 64 percent of firearm-related deaths were homicides, 27 percent were suicides and 9 percent were unintentional deaths.

And in all but one year of the 27-year study period — 1994 due to the Rwandan genocide — firearm deaths were more common along sidewalks than on the battlefields.

“This constitutes a major public health problem for humanity,” said Stanford Health Policy’s David Studdert, a professor of medicine and professor of law.

In an accompanying editorial alongside the research by a consortium of public health experts, the Global Burden of Disease 2016 Injury Collaborators, Studdert and his co-authors write:

“Injuries and deaths from firearms are increasingly part of modern consciousness, particularly in some countries. In the United States, gun-related massacres at schools, places of worship, workplaces, night clubs, and recreational venues have seared images of innocent victims in the minds of the populace. In the United States and elsewhere, acts of terrorism committed with firearms and other lethal means have changed the way people live, work, travel, and play.”

But Studdert and his co-authors — firearms and public health experts Frederick P. Rivara at the University of Washington and Garden J. Wintemute at the University of California, Davis — argue that the deaths from these headline-generating mass shootings and terrorist attacks are only a fraction of the public health burden of firearm-related murders and suicides.

“Mass shootings and terrorism perpetrated with guns are the most visible forms of firearm violence,” Studdert told SHP. “But most firearm deaths are private tragedies. They are homicides and suicides that occur behind closed doors, leaving families and communities devastated.”

The global burden of firearm mortality is highly concentrated, according to the research. In 2016, six countries in the Americas — Brazil, the United States, Mexico, Columbia, Venezuela and Guatemala — accounted for slightlymore than 50 percent of all deaths.

An estimated 32 percent of the deaths occurred in just two countries, Brazil and the United States, with Brazil accounting for one-fourth of all firearm homicides and the United States 35 percent of all firearm suicides.

“For individuals living in the United States, where the national policy debate has focused largely on interpersonal violence, the study provides a reminder of the importance of firearm suicide. In 2016, there were 2 firearm suicides for every firearm homicide, a margin that has widened over the past decade as suicide rates have increased and homicide rates have been relatively flat. Older white non-Hispanic men are at greatest risk of firearm suicide. Research and prevention efforts in the United States should proceed from a more inclusive definition of firearm violence.”

The authors believe more robust methods for estimating the number and distribution of firearms — as well as a better understanding of access — are critically important in determining which policies and prevention strategies are most effective and how best to implement them.

Studdert and his fellow researchers said research on firearm violence and public health has been impeded by the Dickey Amendment, the 1996 bill that mandated “none of the funds made available for injury prevention and control  at the Centers for Disease Control and Prevention may be used to advocate or promote gun control.”

“In the absence of this funding, several private foundations have stepped in to fill the void," they wrote. "However, real progress in addressing the vast public health problem that the Global Burden of Injury Collaborators document will depend on sustained action from governments in both research and policy.”

Federal health advisors say women can now consider three options when it's time for their cervical cancer screening tests. The influential group, the U.S. Preventive Services Task Force (USPSTF), has expanded its recommendations for this potentially life-saving exam.

The new recommendations were published in the latest issue of JAMA.

Pap smears have saved many lives since they became available decades ago. Inspecting samples of cervical tissue for pre-cancerous changes is effective at catching possible cancer, and is still the go-to test for women aged 21 to 29, according to the USPSTF guidelines. But there's another option. 

"Most cervical cancer is caused by what's called the human papilloma virus, or HPV," says Stanford Health Policy's Dr. Douglas Owens, a professor of medicine at Stanford Medicine and vice-chair of the USPSTF. "And we now have tests for HPV and that's an important step forward."

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