Taiwan is only 81 miles off the coast of mainland China and was expected to be hard hit by the coronavirus, due to its proximity and the number of flights between the island nation and its massive neighbor to the west.

Yet it has so far managed to prevent the coronavirus from heavily impacting its 23 million citizens, despite hundreds of thousands of them working and residing in China.

According to the Johns Hopkins Coronavirus COVID-19 Global Cases map, as of Tuesday there were only 42 cases and one death in Taiwan, far behind China, with more than 80,000 cases and more than 2,900 deaths. The country also lags far behind its other Asian neighbors and ranks 17^th in the world for the number of global cases. As of this writing, South Korea was second, with 5,186 cases; followed by Iran with 2,336 and Italy with 2,036 people infected with the virus.

The United States currently stands at 107 known cases and six deaths.

The viral outbreak in China occurred just before the Lunar New Year, during which time millions of Chinese and Taiwanese were expected to travel for the holidays.

So what steps did Taiwan take to protect its people? And could those steps be replicated here at home?

Stanford Health Policy’s Jason Wang, MD, PhD, an associate professor of pediatrics at Stanford Medicine who also has a PhD in policy analysis, credits his native Taiwan with using new technology and a robust pandemic prevention plan put into place at the 2003 SARS outbreak.

“The Taiwan government established the National Health Command Center (NHCC) after SARS and it’s become part of a disaster management center that focuses on large-outbreak responses and acts as the operational command point for direct communications,” said Wang, a pediatrician and the director of the Center for Policy, Outcomes, and Prevention at Stanford. The NHCC also established the Central Epidemic Command Center, which was activated in early January.

“And Taiwan rapidly produced and implemented a list of at least 124 action items in the past five weeks to protect public health,” Wang said. “The policies and actions go beyond border control because they recognized that that wasn’t enough.”

Wang outlines the measures Taiwan took in the last six weeks in an article published Tuesday in the Journal of the American Medical Association.

“Given the continual spread of COVID-19 around the world, understanding the action items that were implemented quickly in Taiwan, and the effectiveness of these actions in preventing a large-scale epidemic, may be instructive for other countries,” Wang and his co-authors wrote.

Within the last five weeks, Wang said, the Taiwan epidemic command center rapidly implemented those 124 action items, including border control from the air and sea, case identification using new data and technology, quarantine of suspicious cases, educating the public while fighting misinformation, negotiating with other countries — and formulating policies for schools and businesses to follow.

Big Data Analytics

The authors note that Taiwan integrated its national health insurance database with its immigration and customs database to begin the creation of big data for analytics. That allowed them case identification by generating real-time alerts during a clinical visit based on travel history and clinical symptoms.

Taipei also used Quick Response (QR) code scanning and online reporting of travel history and health symptoms to classify travelers’ infectious risks based on flight origin and travel history in the last 14 days. People who had not traveled to high-risk areas were sent a health declaration border pass via SMS for faster immigration clearance; those who had traveled to high-risk areas were quarantined at home and tracked through their mobile phones to ensure that they stayed home during the incubation period.

The country also instituted a toll-free hotline for citizens to report suspicious symptoms in themselves or others. As the disease progressed, the government called on major cities to establish their own hotlines so that the main hotline would not become jammed.

Some might say that because Taiwan is such a small country — about 19 times smaller than Texas — it is easier to mobilize during emergencies. Yet Taiwan is particularly challenged by its proximity to China and the fact that 850,000 of its citizens reside on the mainland; another 400,000 work there. Taiwan had 2.71 million visitors from China last year.

So when the WHO was notified on Dec. 31, 2019, of a pneumonia of unknown cause in Wuhan, China, Taiwanese officials began to board planes and assess passengers on direct flights from Wuhan for fever and pneumonia symptoms before passengers could deplane.

As early as Jan. 5, notification was expanded to include any individual who had traveled to Wuhan in the past 14 days and had a fever or symptoms of upper respiratory tract infection at the point of entry. Suspected cases were screened for 26 viruses, including SARS and MERS. Passengers displaying symptoms were quarantined at home and assessed whether medical attention at a hospital was necessary.

What the U.S. Could Learn

One of Wang’s co-authors, Robert H. Brook, M.D., ScD., of the David Geffen School of Medicine at the University of California, Los Angeles, said Washington could learn a great deal from Taiwan’s so-far successful management of the virus.

“In Taiwan, diverse political parties were willing to work together to produce an immediate response to the danger,” said Brook, also of the nonprofit RAND Corporation. “Transparency was critical and frequent communication to the public from a trusted official was paramount to reducing public panic.”

The other co-author of their study is Chun Y. Ng, MBA, MPH, of The New School for Leadership in Health Care, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan.

Brook said Taiwan got out ahead of the epidemic by setting up a physical command center to facilitate rapid communications. The command center set the price of masks and used government funds and military personnel to increase mask production. By Jan. 20, the Taiwan CDC announced that it had a stockpile of 44 million surgical masks, 1.9 million N95 masks and 1,100 negative pressure isolation rooms.

“In a country as complex as the United States,” Brook said, “there needs to be a sharing of intelligence on a real-time basis among states and the federal government so that action is not delayed by going through formal channels.”

Please contact Beth Duff-Brown for media requests. 

A new study by Stanford economists shows that giving fathers flexibility to take time off work in the months after their children are born improves the postpartum health and mental well-being of mothers.

In the study, slated for release by the National Bureau of Economic Research on June 3, Petra Persson and Maya Rossin-Slater examined the effects of a reform in Sweden that introduced more flexibility into the parental leave system. The 2012 law removed a prior restriction preventing a child’s mother and father from taking paid leave at the same time. And it allowed fathers to use up to 30 days of paid leave on an intermittent basis within a year of their child’s birth while the mothers were still on leave.

The policy change resulted in some clear benefits toward the mother’s health, including reductions in childbirth-related complications and postpartum anxiety, according to their empirical analysis.

“A lot of the discussion around how to support mothers is about mothers being able to take leave, but we often don’t think about the other part of the equation — fathers,” says Rossin-Slater, an assistant professor of health research and policy.

“Our study underscores that the father’s presence in the household shortly after childbirth can have important consequences for the new mother's physical and mental health,” says Persson, an assistant professor of economics.

Rossin-Slater and Persson are both faculty fellows at the Stanford Institute for Economic Policy Research.

Among their main findings of effects following the reform: Mothers are 14 percent less likely to need a specialist or be admitted to a hospital for childbirth-related complications — such as mastitis or other infections — within the first six months of childbirth. And they are 11 percent less likely to get an antibiotic prescription within that first half-year of their baby’s life.

There is also an overall 26 percent drop in the likelihood of any anti-anxiety prescriptions during that six-month postpartum period — with reductions in prescriptions being most pronounced during the first three months after childbirth.

What’s more, the study found that the average new father used paid leave for only a few days following the reform — far less than the maximum 30 days allowed — indicating how strong of a difference a couple of days of extra support for the mother could make.

“The key here is that families are granted the flexibility to decide, on a day-to-day basis, exactly when to have the dad stay home,” said Persson. “If, for example, the mom gets early symptoms of mastitis while breastfeeding, the dad can take one or two days off from work so that the mom can rest, which may avoid complications from the infection or the need for antibiotics.”

These indirect benefits from giving fathers workplace flexibility are not trivial matters when you consider the health issues mothers often face after childbirth and after they get home from the hospital, says Rossin-Slater, who is also a faculty member of Stanford Health Policy.

Infections and childbirth complications lead to one out of 100 women getting readmitted to the hospital within 30 days in the United States, according to the study.

Meanwhile, postpartum depression occurs for about one out of nine women, and maternal mortality has also been a rising trend over the past 25 years in the U.S.

The study comes as a growing number of lawmakers in the United States vocalize support for paid family leave but have failed to pass federal legislation.

Washington, D.C., and six states have adopted various paid family leave laws, but the U.S. remains the only industrialized nation in the world that does not have a national mandate guaranteeing a certain amount of paid parental leave.

Some federal lawmakers are working on family leave measures and have proposed such legislation over the past few years — including The Family Act, The New Parents Act — but none of them have ever gained enough traction to proceed in Congress.

This new study can help broaden the policy discussions, the researchers say.

The larger context around paid family leave policies is often framed today as a way to help narrow the gender wage gap by giving women more workplace flexibility and fewer career setbacks.

This study, however, shines a light on maternal health costs and how a policy on paid family leave — that includes workplace flexibility for the father — offers more benefits than previously thought, Rossin-Slater says.

“It's important to think not only about giving families access to some leave, but also about letting them have agency over how they use it,” she says.

And when it comes to concerns that fathers might use paid parental leave to goof off instead of spending the time as intended, the researchers say their study should assuage those worries.

“It's not like fathers are going to end up using a whole month to just stay home and watch TV. We don't find any evidence of that,” Rossin-Slater says. “Instead they only use a limited number of days precisely when the timing for that seems most beneficial for the family.”

“For all these reasons,” Persson says, “giving households flexibility in how to use paternity leave makes a lot of sense.”

People today can generally expect to live longer and, in some parts of the world, healthier lives. The substantial increases in life expectancy underlying these global demographic shifts represent a human triumph over disease, hunger, and deprivation, but also pose difficult challenges across multiple sectors. Population aging will have dramatic effects on labor supply, patterns of work and retirement, family and social structures, healthcare services, savings, and, of course, pension systems and other social support programs used by older adults. Individuals, communities, and nations around the world must adapt quickly to the demographic reality facing us and design new approaches to financing the many needs that come with longer lives.

This imperative is the focus of a newly published special issue of The Journal of the Economics of Ageing, entitled Financing Longevity: The Economics of Pensions, Health and Long-term Care. The special issue collects articles originally written for and discussed at a conference that was dedicated to the same topic and held at Stanford in April 2017 to mark the tenth anniversary of APARC’s Asia Health Policy Program (AHPP). The conference convened top experts in health economics and policy to examine empirical and theoretical research on a range of problems pertinent to the economics of aging from the perspective of sustainable financing for long lives. The economics of the demographic transition is one of the research areas that Karen Eggleston, APARC’s deputy director and AHPP director, studies. She co-edited the special issue with Anita Mukherjee, a Stanford graduate now assistant professor in the Department of Risk and Insurance at the Wisconsin School of Business, University of Wisconsin-Madison.

The Financing Longevity conference was organized by The Next World Program, a Consortium composed of partners from Harvard University, Fudan University, Stanford University, and the World Demographic and Aging Forum, and was cosponsored by AHPP, the Stanford Institute for Economic Policy Research, and the Stanford Center on the Demography and Economics of Aging.

The contributions that originated from the conference and are collected in the Journal’s special issue cover comparative research on more than 30 European countries and 17 Latin American countries, as well as studies on Australia, the United States, India, China, and Japan. They analyze a variety of questions pertinent to financing longevity, including how pension structures may exacerbate existing social inequalities; how formal and informal insurance interact in securing long-term care needs; the ways in which the elderly cope with caregiving and cognitive decline; and what new approaches might help extend old-age financial security to those working outside the formal sector, which is a major concern in low-income countries.

Another challenge of utmost importance is the global pension crisis, caused due to committed payments that far exceed the saved resources. It is a problem that Eggleston and Mukherjee highlight in their introduction to the special issue. By 2050, they note, the pension gap facing the world’s eight largest pension systems is expected to reach nearly US $400 trillion. The problem cannot be ignored, as “the financial security of people leading longer lives is in serious jeopardy.” Indeed four of the eight research papers in the special issue shed light on pensions and inequality in income support for older adults. The other four research papers focus on health and its interaction with labor force participation, savings, and long-term care.

The issue also features two special contributions. The first is an interview with Olivia S. Mitchell, a professor at the University of Pennsylvania’s Wharton School and worldwide expert on pensions and ageing. Mitchell explains the areas offering the most promise and excitement in her field; discusses ways to encourage delayed retirement and spur more saving; and suggests several priority areas for future research. The latter include applying behavioral insights to questions about retirement planning, improving financial literacy, and advancing innovations to help people imagine themselves at older ages and save more for their future selves.

The second unique contribution is a perspective on the challenges of financing longevity in Japan, based on the keynote address delivered at the 2017 Stanford conference by Mr. Hirotaka Unami, then senior Director for policy planning and research of the Minister’s secretariat of the Japan Ministry of Finance and currently deputy director general with the Ministry’s Budget Bureau.

In Japan, decades of improving life expectancy and falling birth rates have produced a rapidly aging and now shrinking population. Data released by Japan’s Statistics Bureau ahead of Children's Day on May 5, 2019 reveal that Japan’s child population (those younger than 15) ranks lowest among countries with a total population exceeding 40 million. In his piece, Unami focuses on the difficult tradeoffs Japan faces in responding to the increase in oldest-old population (people aged 75 and over) and the overall population decline. Japan aspires to do so through policies that are designed to restore financial sustainability for the country’s social security system, including the medical care and long-term care insurance systems.

Unami argues that Japan must simultaneously pursue a combination of increased tax revenues, reduced benefit growth, and accelerated economic growth. He notes that these three-pronged efforts require action in five areas: review Japan’s pension policies; reduce the scope of insurance coverage in low-risk areas; increase the effectiveness of health service providers; increase a beneficiary’s burden according to their means; and enhance policies for preventive health care for the elderly.

The aging of our world’s population is a defining issue of our time and there is pressing need for research to inform policies intended to improve the financial well-being of present and future generations. The articles collected in the Financing Longevity special issue and the ongoing work by APARC’s Asia Health Policy Program point to multiple areas ripe for such future research.

View the complete special issue >>

Learn more about Dr. Karen Eggleston’s work in the area of innovation for healthy aging >>

The United States is the only country in the 35-member Organization for Economic Cooperation and Development that offers no paid leave to new mothers. The U.S. also has relatively poor infant health ratings, particularly for preterm births and infant mortality.

So why has the federal government been so reluctant to join other industrialized nations in paying new mothers to stay at home so they can nurture and nourish these new citizens?

“There’s opposition from business interests arguing that any type of mandate on employers imposes too large costs, especially for small businesses,” said Stanford Health Policy’s Maya Rossin-Slater. “There’s not much empirical evidence supporting this argument, but I think the strong political opposition from business supporters may be a central reason for a lack of action on the federal level.”

In a policy brief published March 28 in Health Affairs, Rossin-Slater, an assistant professor of health research and policy, lays out the evidence that suggests the introduction of paid family leave (PFL) for up to one year in duration may yield significant child and maternal health benefits, both in the short and long term. Her co-author on the brief is Lindsey Uniat, a predoctoral research fellow at the Stanford Institute for Economic Policy Research.

“Existing research suggests that when leave is paid, take-up rates are higher among low-income and disadvantaged families than when it is unpaid, which enables more families to benefit,” they wrote.

Some of the short- and long-term health benefits include decreased incidence of low birthweight and preterm births, increased breast-feeding, reduced rates of hospitalizations among infants and improved maternal health.

Family and Medical Leave Act

The federal Family and Medical Leave Act (FMLA) of 1993 provides 12 weeks of unpaid, job-protected leave with continued health insurance coverage to attend to a newborn or adopted child, a family member, or an employee’s own serious health condition. There are strict eligibility requirements for the FMLA, such as needing to have worked at least 1,250 hours for an employer with 50 or more employees during the 12 months before the start of the leave.

The most recent data, according to the authors, indicate that only about 60 percent of private-sector workers are eligible for FMLA, and 46 percent of those eligible report not being able to afford taking unpaid time off work.

Six states and the District of Columbia have passed paid family leave policies, and the issue has been receiving attention at both state and federal levels in recent years. California, Hawaii, New Jersey, New York and Rhode Island, as well as Puerto Rico, have State Disability Insurance (SDI), which provides partial wage-replaced leave for workers with temporary disabilities and for mothers preparing for and recovering from childbirth. These policies offer up to six weeks of leave postpartum for vaginal deliveries and eight weeks for C-section deliveries.

“The majority of existing research on the health effects of PFL focuses on children’s outcomes,” the authors write. Earlier work on the impacts of unpaid leave provided through the FMLA shows that it led to small increases in birthweight and large reductions in infant mortality rates.

However, these health benefits were apparent only for children of relatively advantaged mothers, the authors wrote, which is consistent with prior evidence that such mothers were most likely to be eligible for, and able to afford to use, unpaid leave.

“In contrast, mothers and children from less advantaged backgrounds particularly benefit from access to paid leave,” they said, noting that one study showed that the introduction of paid maternity leave through the SDI system in five states led to a reduction in the share of low birthweight and preterm births, especially for unmarried and black mothers.

Rossin-Slater and Uniat believe paid family leave may affect population health through multiple channels:

• Children of parents who take leave may receive more parental care, breast-feeding and immunizations if parents are able to stay home longer after birth;
• Child health may improve from the extra resources that parents get form PFL benefits, such as more nutritious food;
• Infant and long-term health outcomes may improve if PFL access lowers maternal stress during pregnancy, perhaps due to increased financial and job security;
• Taking time off from work without the financial strain may improve the parental bond with the infant — leading to long-term health benefits for the child.

The Labor Market

Finally, existing research indicates that paid family leave may benefit the labor market by leading to fewer high-school dropouts, thus an increase in children’s future wages.

“Several policy takeaways are evidence from the research to date,” the authors wrote. “Paid leave, in contrast to unpaid leave, increases leave usage and duration, especially among disadvantaged parents who are least able to afford unpaid time off.”

More research is needed, they said, to understand how paid family leave legislation could impact employers.

“We know little about how employers deal with work interruptions due to employees’ taking leave or whether employers respond to PFL mandates by changing their own benefits packages, hiring practices, or other aspects of jobs,” they said.

Something as simple as, "Are you taking your medications?" could conceivably prolong a life.

The study, detailed in a new working paper released this week by the National Bureau of Economic Research, was co-authored by Petra Persson, an assistant professor of economics; Maria Polyakova, an assistant professor of health economics at Stanford School of Medicine and core faculty at Stanford Health Policy; and Yiqun Chen, a doctoral student in health economics at Stanford School of Medicine. Persson and Polyakova are both faculty fellows at the Stanford Institute for Economic Policy Research (SIEPR).

Their study tackles the issue of health inequality and specifically examines the effects of having access to informal health expertise by having a doctor or nurse in the family. It finds that those with relatives in the health profession are 10 percent more likely to live beyond age 80. They are also significantly less likely to have chronic lifestyle-related conditions, such as heart attacks, heart failure and diabetes.

Younger relatives within the extended family also see gains: They are more likely to have been vaccinated, and they have fewer hospital admissions and a lower prevalence of drug or alcohol addiction.

In addition, the closer the relatives are to their familial medical source – either geographically or within the family tree – the more pronounced the impact of the health benefits, according to the findings.

The researchers used data from Sweden, where lotteries were used in the early 2000s to break ties among equally qualified applicants for admission into medical schools. The researchers then compared the health of the family members of lottery winners against lottery losers – a setup similar to a randomized control trial.

The strong findings of health benefits funneled from a familial sphere of medical knowledge suggest it would be worth ramping up access to health expertise in our health care system, the researchers say.

A doctor, for instance, could prescribe statins – a type of drug known to lower the risk of heart attacks – but whether the patient continues taking it from day to day is a decision made at home.

“Our work shows that there is a lot of value in trying to improve people’s decisions about their investment in their own health,” Persson says.

“If the government and health care system, including public and private insurers, could mimic what goes on inside families, then we could reduce health inequality by as much as 18 percent,” she says, referring to a main finding of the study.

Intra-family transmissions of health-related expertise might encompass frequent nagging to adhere to prescribed medications, get vaccinations or refrain from smoking during pregnancy, and “these behavioral changes are – from a society’s perspective – simple and cheap,” the study states.

Disparity despite access

The study also reveals limitations to the impact of equal access to medical care, underscoring the importance of other health efforts.

The researchers compared mortality data of Sweden – where there is universal access to health care – to the United States. They found the overall mortality was lower in Sweden but the level of health inequality largely mirrored that of the United States. In Sweden, despite its extensive social safety net, the rich also live longer and the poor die younger. Specifically, among people alive at age 55, more than 40 percent of individuals at the bottom of the income distribution in Sweden will have died by age 80 – as opposed to fewer than 25 percent for those at the top of the distribution.

“This health inequality appears to be extremely stubborn,” Persson says. “We can throw a universal health insurance system at it and yet substantial inequality persists. So, is there anything else that can help us close that health gap between rich and poor?”

According to their latest research, yes.

Health effects from having a medical professional in the family were substantial and occurred across the income spectrum, according to the study. And because the effects from the exposure to medical expertise was often even stronger for those at the lower half of the income distribution, the researchers estimated that information-driven behaviors could make a significant difference in getting rid of health disparities.

Closer ties, less churn

The study did not examine the complexity of family dynamics or specific actions that led to the positive health effects, but the researchers hypothesize that the mere presence of a medical professional in the family translates somehow to either a heightened health culture or, at least, having a coach of sorts to encourage healthy, good-patient behavior.

Although general public health campaigns (e.g., “Get Your Flu Shot Today!”) may not carry the same level of influence as intimate dinner-table discussions or persistent prodding among family members, there could be other ways society can improve its exposure to medical expertise to lead to healthier, longer lives, the researchers say.

Community health worker or nurse outreach programs can perhaps lead to more targeted, personalized communication efforts, they say. Digital nudges delivered through mobile phone apps could potentially make healthy dents.

Reminders of preventive care can also come by way of closer patient-doctor relationships and more consistent, longer-term ties to the same doctor.

“The idea of continuity of care and developing a true relationship with your doctor, who becomes someone who pays attention to you as an individual and sees you and your family over a long period of time, is well known,” Polyakova says. “Today, it’s what they might call old-fashioned primary care, where the whole family goes to the same doctor for many years. Many countries, the U.S. included, appear to be moving increasingly away from this model, and our results suggest that we might want to do the reverse.”

The finding of how a closer family connection or closer proximity leads to even stronger health outcomes helps substantiate the potential difference a closer bond between any doctor and patient could make – improvements that would be hard to glean from rushed and infrequent medical appointments, Persson and Polyakova say.

Communication-focused health initiatives don’t have to come with hefty price tags either, they say.

“We pour a lot of resources into getting even fancier machines inside hospitals, but the things that are making a difference here are not that expensive,” Persson says of their findings. “These are cheap, easily scalable preventative investments that are translating to gains in longevity, which is remarkable.”

Sweden’s medical school lotteries

Using large-scale data from Sweden, the researchers focused on quantifying the role of informal exposure to health expertise via a medical professional in the family while avoiding results that would be muddled with other differences between individuals with and without a doctor in the family.

The researchers used two different approaches. First, they took advantage of the fact that in some years, lotteries were used to break ties among equally qualified applicants to Sweden’s medical schools. This allowed the researchers to use medical school application records and track the health of family members of applicants who won and lost the lottery.

The researchers looked at more than 30 years of continuous health and tax records spanning four generations of family members, and examined health-related outcomes of the extended family members of newly trained doctors and nurses – including their siblings, parents, grandparents, children, aunts, uncles, cousins and in-laws.

Second, researchers sought to double-check whether higher income and higher social status associated with the medical profession had anything to do with the positive health benefits they found.

One of the ways they did this was to draw a comparison to lawyers, a similarly paid profession. The parents of doctors, they found, were 16 percent more likely to be alive than the parents of lawyers 20 years after their children matriculated. The parents of doctors also faced lower prospects of lifestyle-related chronic diseases.

In addition to the higher likelihood of their parents living past age 80 and the lower likelihood of heart diseases, the relatives of health professionals showed higher levels of preventive behaviors, including purchases of heart and blood-thinning medications, and vaccinations for HPV, or human papillomavirus. Younger family members also had fewer hospital admissions and addiction cases.

“People with health professionals in the family essentially make preventative investments that everyone should be doing,” Persson says.

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).