Predicting women at risk of preeclampsia before clinical symptoms

Many of my female friends became pregnant with their first child in their late 30s or early 40s, which increased their risk of common complications such as high blood pressure, gestational diabetes and preeclampsia.

Affecting over 8 million women worldwide, preeclampsia can lead to serious, even fatal, complications for both the mother and baby. The clinical symptoms of preeclampsia typically start at 20 weeks of pregnancy and include high blood pressure and signs of kidney or liver damage.

“Once these clinical symptoms appear, irreparable harm to the mother or the fetus may have already occurred,” said Stanford immunologist Brice Gaudilliere, MD, PhD.  “The only available diagnostic blood test for preeclampsia is a proteomic test that measures a ratio of two proteins. While this test is good at ruling out preeclampsia once clinical symptoms have occurred, it has a poor positive predictive value.”

Now, Stanford researchers are working to develop a diagnostic blood test that can accurately predict preeclampsia prior to the onset of clinical symptoms.

A new study conducted at Stanford was led by senior authors Gaudilliere, statistical innovator Nima Aghaeepour, PhD, and clinical trial specialist Martin Angst, MD, and co-first authors and postdoctoral fellows Xiaoyuan Han, PhD, and Sajjad Ghaemi, PhD. Their results were recently published in Frontiers in Immunology.

They analyzed blood samples from 11 women who developed preeclampsia and 12 women with normal blood pressure during pregnancy. These samples were obtained at two timepoints, allowing the scientists to measure how immune cells behaved over time during pregnancy.

“Unlike prior studies that typically assessed just a few select immune cell types in the blood at a single timepoint during pregnancy, our study focused on immune cell dynamics,” Gaudilliere explained. “We utilized a powerful method called mass cytometry, which measured the distribution and functional behavior of virtually all immune cell types present in the blood samples.”

The team identified a set of eight immune cell responses that accurately predicted which of the women would develop preeclampsia — typically 13 weeks before clinical diagnosis.

At the top of their list was a signaling protein called STAT5. They observed higher activity of STAT5 in CD4+ T-cells, which help regulate the immune system, at the beginning of pregnancy for all but one patient who developed preeclampsia.

“Pregnancy is an amazing immunological phenomenon where the mother’s immune system ‘tolerates’ the fetus, a foreign entity, for nine months,” said Angst. “Our findings are consistent with past studies that found preeclampsia to be associated with increased inflammation and decreased immune tolerance towards the fetus.”

Although their results are encouraging, more research is needed before translating them to the clinic.

The authors explained that mass cytometry is a great tool to find the “needle in the haystack.” It allowed them to survey the entire immune system and identify the key elements that could predict preeclampsia, but it is an exploratory platform not suitable for the clinic, they said.

“Now that we have identified the elements of a diagnostic immunoassay, we can use conventional instruments such as those used in the clinic to measure them in a patient’s blood sample.” Aghaeepour said.

First though, the team needs to validate their findings in a large, multi-center study. They are also using machine learning to develop a “multiomics” model that integrates these mass cytometry measurements with other biological analysis approaches. And they are investigating how to objectively define different subtypes of preeclampsia.

Their goal is to accurately diagnose preeclampsia before the onset of clinical symptoms.

 “Diagnosing preeclampsia early would help ensure that patients at highest risk have access to health care facilities, are evaluated more frequently by obstetricians specialized in high-risk pregnancies and receive treatment,” said Gaudilliere.

Women with preeclampsia can receive care through the obstetric clinic at Lucile Packard Children’s Hospital Stanford.

Photo by Pilirodriquez

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Advertisements

On the importance of including pregnant women in clinical trials: A Q&A

hands-2568594_1920
Photo by StockSnap

As a research scientist, I’ve negotiated the complex nature of getting approval to image human subjects. So I know firsthand that it is common to exclude pregnant women from clinical trials. Although this practice is well-intentioned, it is also misguided — according to an opinion piece recently published in JAMA. To learn more, I spoke with one of the authors, Heather Byers, MD, a clinical assistant professor in pediatrics at Stanford.

Why are pregnant women excluded from clinical trials?

“Historically, women in general were excluded from clinical trials because men were thought to be a more homogenous group without hormonal cycles and other sex-based variables that might impact the medical conditions under study.

In addition, pregnant women are still classified as a ‘vulnerable’ population for all research studies, so investigators must take additional steps to enroll them to ensure minimum risk.

Also, the lack of data about what pregnant women can safely be exposed to leads to more uncertainty. So many investigators choose to exclude them, even if they might benefit from the study intervention.”

Why is this a problem?

“Excluding them is a problem because women don’t stop getting sick or stop having chronic medical conditions just because they are pregnant. The average woman is exposed to four medications during her pregnancy and over 80 percent of medications haven’t been studied in a like population. This forces pregnant women to take medications on an “off-label” basis — meaning, the medications weren’t studied or approved for use in pregnant women — because there’s no other option. Pregnant women deserve better. It’s a matter of justice.”

What are the barriers and how can we overcome them?

“First, we advocate reclassifying pregnant women from ‘vulnerable’ to ‘scientifically complex.’ Pregnancy doesn’t alter a woman’s capacity for autonomous decision-making. Indeed, a pregnant woman frequently makes complex medical decisions for herself and her fetus that reflect her family’s values.

Another barrier for medical investigators is the perceived legal risk regarding a potential adverse outcome in the fetus or mother. As we discuss in the JAMA Viewpoint, this barrier could be addressed by standardizing the informed consent process.

Finally, federal regulations don’t define ‘acceptable risk’ to the woman or fetus and this uncertainty is perceived as a risk in itself. But in some cases, pregnant women may accept the uncertainty and risk.

For example, it was imperative to reduce mother-to-child transmission of HIV. So obstetricians reluctantly included pregnant women with HIV in their study of antiretroviral treatments, since the risk of the drugs were thought to be low and the potential benefit high. And the effectiveness of this study helped transform the AIDS epidemic.”

Is progress being made?

“Although progress has been slow, there has been an increased effort to enroll pregnant women. Several high-profile clinical trials involving pregnant women recently completed and institutions like the National Institutes of Health are working to change their polices. For example, the NIH Task Force on Research Specific to Pregnant Women and Lactating Women recently issued a report that summarizes the current gaps in knowledge and provides recommendations for continued progress.”

How did you become involved?

“I first became interested in this subject as a medical student during my rotation at NIH with Pamela Stratton, MD, one of the obstetricians involved in the study of antiretrovirals to prevent vertical transmission of HIV.

Later, as an obstetrics resident, I was frustrated by the lack of information to share with my patients regarding the risk and clinical impact of various medications, vaccines and medical conditions in pregnancy. Every anecdotal story  — such as my patient who was hospitalized in intensive care for months with influenza because she’d been too afraid to get the flu vaccine earlier in her pregnancy — is one too many. The fear of uncertain risk can be dangerous. There should be a better way.

One thing that has changed is the rise of social media and patient support group accessibility. Although this should not replace the controlled setting of a clinical trial, partnerships between motivated patient advocacy groups and medical investigators can be a powerful tool for obtaining information about risk and benefits going forward.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Fertility quiz: How well do you know your body?

2364734203_937bfdfe48_z_Flickr_ScottMaxwell
Photo by Scott Maxwell

Remember all the rumors that you heard about sexuality and fertility as a teen (or even a 20-something or a 30-something)? It’s hard to sort out fact from fiction.

According to the Institute for Reproductive Health (IRH) at the Georgetown University Medical Center, an accurate understanding of sexuality and fertility is surprisingly low around the world. That’s why IRH has created an online quiz to probe fertility awareness, called “Know Your Bod,” which poses the challenge: “You live with your body everyday. Do you really know it? Find out.”

The online quiz asks ten questions including the true-or-false query, “A woman will get pregnant only if she has sex on the same day she ovulates?” After you select an answer, the quiz provides a simple educational summary that explains the correct answer. At the end, it shows your score and how you compare to the general population.

The quiz was officially introduced this week at the International Conference on Family Planning in Indonesia. It was developed as part of IRH’s Fertility Awareness for Community Transformation Project, which strives to increase fertility awareness and the use of family planning.

Victoria Jennings, PhD, director of IRH, explained in a recent Georgetown press release:

Accurate understanding and awareness about human fertility is surprisingly low around the world, regardless of age, sex or education level. If we could lift the taboos and improve fertility awareness, would people be informed and empowered to make better sexual and reproductive health decisions? At IRH, we believe the answer to this question is ‘yes.’

So why not take the challenge? How well do you know your bod?

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Reducing cesarean delivery rates, without jeopardizing safety

166471938_0c0f8ca48b_b_Flickr_SalimFadhley_560x375

Approximately one-third of all babies born in the United States are currently delivered by cesarean section, according to the Centers for Disease Control and Prevention. Although cesarean delivery can be life saving for both the mother and child, the rapid increase in the cesarean birth rate between 1996 and 2011 raised significant concern that cesarean delivery is being overused.

This concern has led to initiatives to lower the c-section rates, including a new plan funded by the Oakland-based California HealthCare Foundation (CHCF) to lower California’s c-section rate for low-risk mothers to 23.9% in the next five years — in alignment with the Healthy People 2020’s national target.

A recent KQED Science article describes these efforts to reduce the state’s c-section rates. The story also explores the controversial issue that a healthy pregnant woman’s likelihood of having a cesarean birth varies depending on the hospital, based on a recent analysis of maternity care. For instance, the assessment report found that Lucille Packard Children’s Hospital Stanford has a c-section rate of 23.0 percent and the Coastal Communities Hospital in Santa Ana has a rate of 42.9 percent.

Deirdre Lyell, MD, professor of obstetrics and gynecology, clarified the issue in a recent email:

Nationally and internationally, there is concern that cesarean rates as a whole are too high. CHCF and others have shown a wide rage in cesarean rates by hospital around the country, and even within hospitals among individual physicians. Hospitals with very high rates should examine the underlying reasons. However, the “ideal rate” depends on the characteristics of the patient population, and it would be inappropriate to apply one goal to all women. For example, a pregnant, non-obese 25-year old who has had a prior vaginal delivery has a better likelihood of delivering her baby vaginally than does a pregnant, obese 45-year old first time mom.

At Stanford, we follow the “Safe Prevention of the Primary Cesarean Delivery” guidelines outlined by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine. We care for a higher-risk maternal and higher-risk fetal population, and share with our patients a common goal for delivery: a safe mom and a safe baby, while not performing cesareans unnecessarily. Avoidance of the first cesarean helps reduce the potential risks in the future.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Infections During Pregnancy May Increase Autism Risk

B&W photograph of pregnant woman sitting on couch
Photograph courtesy of Stuart Handy via a Creative Commons license.

Every day our brains help us make sense of the world around us, interpreting the things we see, hear, taste, touch, smell and experience. But if someone’s brain has trouble processing this incoming information, it can be hard to communicate, understand or learn.

Autism spectrum disorders (ASD) are characterized by difficulties in social interaction, verbal and nonverbal communication, and repetitive behaviors. These disorders include autism, Asperger syndrome and Pervasive Developmental Disorder-Not Otherwise Specified.

About 1 in 88 children have been identified with an autism spectrum disorder and over 2 million people are affected in the United States, according to the Centers for Disease Control and Prevention. Government statistics also suggest that the proportion of people with autism spectrum disorders have increased 10 to 17 percent annually in recent years. This is in part due to wider awareness and better screening, but the continued increase is not fully understood.

The cause of ASD is also not fully known, but current research indicates that it is likely due to a complex combination of genetic predisposition and environmental risk factors that influence early brain development. Significant environmental risk factors include the advance age of either parent at the time of conception, maternal illness during pregnancy, extreme prematurity, and very low birth weight.

Over 40 years ago, epidemiological studies determined that the risk of having a child with ASD is increased when the mother has an infection early in the pregnancy. Since a wide range of bacterial and viral infections can increase the risk, studies suggest that activation of the mother’s general immune system is responsible. However, scientists do not completely understand how the activated immune system can disrupt normal brain development to cause ASD.

Research at the University of California Davis Center for Neuroscience provides new insight. Recently published in the Journal of Neuroscience, their studies identify a new biological mechanism that links maternal immune activation to neurodevelopmental disorders.

Kimberley McAllister, a senior author of the study, explained in a press release, “This is the first evidence that neurons in the developing brain of newborn offspring are altered by maternal immune activation. Until now, very little has been known about how maternal immune activation leads to autism spectrum disorder and schizophrenia-like pathophysiology and behaviors in the offspring.”

The researchers studied pregnant mice with immune systems that were activated halfway through gestation compared to pregnant control mice without activated immune systems. They found that the mice exposed to a viral infection had offspring with dramatically elevated levels of immune molecules called major histocompatibility complex 1 (MHC1) on their brain surface.

In the affected newborn mice, these high levels of MCH1 disrupted the development of neural cells in the brain. Specifically, the increase in MCH1 interfered with the neurons’ ability to form the synapses that allow neurons to pass electrical or chemical signals to other cells; consequently these offspring had less than half as many synapses than the control offspring. When MCH1 were returned to normal levels in the neurons of maternal immune-activated offspring, the synapses density returned to normal.

However, MCH1 doesn’t work alone. In a series of additional experiments, the researchers identified the new biological signaling pathway that regulates synapses development caused by maternal immune activation. This signaling pathway requires calcineurin, myocyte enhancer factor-2 and MCH1 to limit synapses density.

A better understanding of the underlying biological mechanisms will hopefully lead to the development of improved prenatal health screening, diagnostic tests and eventually therapies for neurodevelopmental disorders.

Of course, not every child of a bacterially or virally infected mother develops a neurodevelopmental disorder like autism. The effect of maternal immune activation depends on a complex interaction involving the strength of the infection and genetic predisposition.

This is a repost of my KQED Science blog.