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A century ago, childbirth in the United States was anything but routine. On average, complications of pregnancy took the lives of 8 women for every 1,000 births.

Today in the U.S., fewer than 20 women die per 100,000 births—a dramatic turnaround largely attributed to significant improvements in public health and major advances in obstetric medicine.

The Stanford School of Medicine recruited its first professor of obstetrics in 1912, and in the century since has been at the forefront of improving the lives of expectant mothers and newborns. With the addition of Lucile Packard Children’s Hospital in 1991, Stanford quickly became a nationally recognized leader in obstetric research and training.

“In just 20 years, Packard researchers have literally changed the treatment of preterm labor in this country,” says Maurice Druzin, MD, the Charles B. and Ann L. Johnson Professor and vice chair of obstetrics and gynecology.

Druzin joined the faculty in July 1991, shortly after Packard Children’s opened its doors. Among the handful of obstetrics residents at the new Hospital was Yasser El-Sayed, MD, now a professor of obstetrics and gynecology and associate chief of maternal-fetal medicine.

“Packard’s broad range of expertise attracted very high–risk patients from across the country,” recalls El-Sayed. “That was crucial, because it created a population base large enough for us to develop clinical trials of new treatments and procedures.”

Today, obstetric specialists at Packard Children’s remain closely involved in interdisciplinary research to develop new protocols and strategies for diagnosing, treating, and preventing reproductive and neonatal problems. Experts across the Hospital and medical campus are focused on ways to refine medication and treatment for preterm labor, and are pursuing genomic investigations that may help identify at-risk conditions or problems in fetal development.

“We have fostered a track record of excellence in clinical investigation and translational medicine,” says El-Sayed. “Research is an important part of our commitment and helps Packard expand its clinical care and outreach.”

Innovative Clinical Studies

Four years ago, El-Sayed and Deirdre Lyell, MD, associate professor of obstetrics and gynecology, began conducting trials of the drug nifedipine, a muscle relaxant routinely given to pregnant women in early labor to reduce contractions and prevent premature birth. Although widely prescribed, nifedipine had never been tested in a placebo-controlled study.

In 2008, Lyell and her colleagues recruited 70 women at Packard Children’s who were in early labor. Some were randomly given nifedipine, others a sugar pill.

“We found that nifedipine was no more effective than the placebo at delaying delivery,” says Lyell, lead author of the study, which the American College of Obstetrics and Gynecology named one of the outstanding research papers of 2008.

“We demonstrated that pregnant women were being exposed to many drugs unnecessarily,” adds El-Sayed. “I’m confident that our clinical trial made a big change in how nifedipine is administered in this country.”

In 2010, Lyell was named director of a new program at Packard Children’s established to study placental disorders and to streamline the care of pregnant women whose placentas are abnormally attached.

“The placenta normally separates from the uterus after delivery, but when it can’t, the risk to the woman increases substantially,” explains Lyell. For example, a small percentage of pregnant women are diagnosed with placenta accreta, a condition in which the placenta grows too deeply into the uterine wall. Placenta accreta can result in vaginal bleeding and premature delivery, and is a leading cause of death for women during childbirth. Treatment often requires postpartum removal of the uterus.

Research shows that cesarean deliveries significantly increase the risk of placenta accreta. A woman who has had accreta and one cesarean has as much as a 25 percent risk of accreta in her next pregnancy.

“Because of the nationwide increase in cesareans, there is now a higher incidence of accreta in the U.S.,” says Lyell. “We’re conducting research on why women who’ve had cesareans are more susceptible to placental disorders, and are working to identify surgical techniques at cesarean which might reduce the future development of accreta.” Lyell was recently awarded a prestigious Harman Faculty Scholar Award to continue her research in placenta accreta.

Depression during pregnancy is another focus of Lyell’s research. “There should be universal screening of pregnant women for depression,” she says. “In many cases, the condition isn’t even noted in their medical charts.”

Because expectant mothers are often reluctant to take antidepressants, Lyell and her colleagues have been conducting clinical trials of alternative treatments.

In 2010, she and Druzin co-authored a study, led by Rachel Manber, PhD, a professor of psychiatry, showing that acupuncture could be a viable alternative for pregnant women with depression.
Collaborative Genetic Research

Researchers at Stanford are also working to address serious complications of pregnancy using state-of-the-art techniques, such as medical genetics.

Anna Penn, MD, PhD, an assistant professor of pediatrics, leads the Stanford Placental Working Group, a multidisciplinary team of scientists and doctors focused on understanding the contribution of placental pathology to preterm birth. For example, roughly half of premature births at Packard each year are the result of preeclampsia, a condition that causes high blood pressure in pregnant women. Severe preeclampsia can lead to seizures and other serious health problems for the mother. One goal of the Placental Working Group is to shed light on this disorder by comparing DNA samples from hundreds of placentas donated by normal, preterm, and preeclampsia patients at Packard Children’s.

These donations will form the foundation of a Placental Tissue Bank that can support many lines of investigation at Stanford.

Meanwhile, Nihar Nayak, PhD, DVM, an assistant professor of obstetrics and gynecology, is conducting basic and translational research in abnormal placental implantation leading to different diseases of pregnancy, particularly preeclampsia. Nayak studies factors that affect angiogenesis, the process of creating new blood vessels, a critical step for normal placental development. Recently, Druzin, El-Sayed, Nayak, and colleagues at the School of Medicine co-authored a study that identified a potential new biomarker for preeclampsia screening.

Nayak and his research team have also developed a novel method for tracking placental gene expression throughout pregnancy, a significant step forward for studies on placental gene functions.

In other research, El-Sayed, Lyell, and Druzin recently co-authored a study comparing pregnancy outcomes among white and mixed Asian/white couples. The study, based on data collected from more than 9,000 couples whose babies were delivered at Packard Children’s from 2000 to 2006, found that pregnant women have a higher risk of gestational diabetes if one parent is Asian and the other is white. “With the rich diversity of the San Francisco Bay Area, this is an important contribution to our understanding of the role of ethnicity in pregnancy outcomes,” says Druzin.

Across campus, Stephen Quake, PhD, a professor of bioengineering and of physics, has developed a noninvasive prenatal test for Down syndrome and other genetic disorders. Standard screening procedures, such as amniocentesis, are risky, because they require inserting a needle into the uterus to get a sample of placental DNA. Quake’s technique isolates fetal DNA in the mother’s blood, eliminating the need to puncture the placenta and thus minimizing the risk of miscarriage.

“People are sometimes fearful about genetic testing,” says Mary Norton, MD, professor of obstetrics and gynecology and of pediatrics. An expert in maternal-fetal genetics, Norton was recruited to Packard Children’s in 2008 as director of perinatal research.

“In our studies, we found that with invasive procedures, such as amniocentesis, pregnant women were more selective,” Norton says. “They only wanted to be tested for serious or potentially fatal diseases.”

Advancing Care Nationwide

To broaden the opportunities for high-impact research beyond the medical campus, Norton and her colleagues submitted an application on behalf of Stanford for membership in the Maternal-Fetal Medicine Units (MFMU) Network, a consortium of 14 university-based clinical centers across the U.S. Established in 1986 as the national hub for clinical research in obstetrics, the Network coordinates nationwide trials and large-scale population studies involving thousands of pregnant women and newborns across the country.

Earlier this year, the National Institutes of Health approved the application, making Stanford the first and only MFMU center in California.

Today, Norton and El-Sayed are leading two MFMU studies, both of which are currently recruiting pregnant women throughout the U.S. One is a placebo-controlled clinical trial to determine if giving steroids to women who deliver early reduces respiratory complications in babies who are just slightly premature.

The other study is a randomized trial of a new diagnostic device called ST segment analysis (STAN) that continuously monitors the fetal heart rate with more sophisticated technology than what is currently standard. STAN was designed to reduce the chance of fetal brain damage due to lack of oxygen and to provide a more accurate assessment of a baby’s heart rate, resulting in fewer unnecessary cesareans.

“You need a proven track record of clinical trials to be accepted in the MFMU Network,” Druzin says. “It’s prestigious, and reflects our commitment to advancing the field of obstetrics.”

Simulation-Based Training

"Obstetrics is a team sport,” observes Kay Daniels, MD, clinical professor of obstetrics and gynecology.

At Packard Children’s, that team includes labor and delivery nurses, neonatal pediatricians, obstetricians, obstetric anesthesiologists, and other specialists, nurses, and staff.

To address the high-risk nature of obstetric medicine, Daniels and her colleagues have created a simulation–based training program called OBSim. This pioneering program allows doctors, nurses, residents, and interns to experience difficult deliveries in a hospital-like setting.

Using live actors and mannequins, OBSim staff create realistic scenarios designed to teach obstetric personnel how to handle unexpected situations in the delivery room that may threaten the health of a mother and her baby.

“There is a unique time pressure to obstetrical care,” says Daniels, co-director of the OBSim program. “If something catastrophic happens, you have 5 or 10 minutes to deal with it. That’s where OBSim helps by improving communication.”

The program was launched in 2004 as part of Packard’s Center for Advanced Pediatric and Perinatal Education (CAPE), the world’s first simulation-based training center devoted to training medical professionals in the care of fetal, neonatal, and obstetric patients. “A gift from an anonymous donor allowed us to build a simulation training center across the street from Packard Children’s,” says CAPE director Lou Halamek, MD, associate professor of pediatrics and, by courtesy, of obstetrics and gynecology.

The 400-square-foot simulation room is designed to replicate a variety of hospital settings. For OBSim, a bed, monitors, and other medical equipment are arranged to simulate a delivery room. Staff direct each scenario from a control room, which is separated from the simulation room by a one-way mirror. TV monitors in the control room display live video from cameras set up throughout the mock delivery room. Each scenario is videotaped so that participants can review their performance.

When a mannequin of a pregnant woman is used in a scenario, a mock voice of the woman is played through speakers in the simulation room. At other times, a staff person plays the part of the mother. In one scenario, she holds a mannequin of a fetus in such a way that its shoulders are stuck in the uterus at the time of delivery—a condition known as shoulder dystocia.

“OBSim allows us to learn more about the roles each of us play in patient care,” says Julie Arafeh, RN, MSN, director of training and research at CAPE. “For example, we created a scenario in which there was a sudden drop in fetal heart rate. For anesthesiologists, this could mean that the mom is having an adverse response to her epidural, which could require a change in how much anesthetic is delivered. The obstetrician might think there is a placental problem and consider moving the mom to the operating room for delivery. For the nurses, we say, whatever happens, we’re ready.”

OBSim is also used to assess strengths and weaknesses in a real hospital environment. In 2008, Packard nurses participated in a drill that simulated a woman with postpartum hemorrhage. In the scenario, the woman was bleeding profusely, and a nurse was instructed to get medication quickly from a computerized system called Pyxis—standard equipment at Packard and many other hospitals.

“Pyxis confers a certain amount of safety,” explains Daniels. “For example, if you request a medication that the patient is allergic to, Pyxis won’t let you remove it until you enter the patient’s name and get biometric authorization by placing your finger on the screen. But if the mom is bleeding 700 cc of blood per minute, you need to move quickly.”

When Daniels and her colleagues reviewed the video of the Pyxis drill, they discovered that it took the nurse more than two minutes to get all of the required medications, because each one had to be entered individually. “We contacted the company that manufactures Pyxis, and they agreed to improve the biometrics,” Daniels says. “Then we worked with our pharmacy to create a kit that allowed all the medications to be removed at once. The next time we ran the drill, it took the nurse only 29 seconds to retrieve the appropriate medication.”

Postpartum hemorrhage occurs in about 4 percent of births, so this newly streamlined system could save the lives of many women. “Maternal mortality from hemorrhage and other causes is rising in the U.S., and that’s unacceptable,” says Steven Lipman, MD, clinical associate professor of anesthesiology and co-director of the OBSim Program.

“To be involved with OBSim has been exciting, intellectually stimulating, and gratifying,” he adds. “By working together, we’ve broken down barriers and created an esprit de corps that has changed the culture at Packard. Now we’re doing group multidisciplinary rounds every day for each patient. Everyone has a chance to help make a plan of treatment. That’s a direct result of OBSim.”

Training the Next Generation

In addition to preeminence in obstetric research, Packard and Stanford have developed an innovative training and education program for future obstetricians.

Packard Children’s is one of the few institutions in California that uses an “open model” in which private doctors work alongside medical school faculty. About half of the pregnant women admitted to Packard come under the care of private practitioners.

“It’s a wonderful blend,” says Druzin. “Residents and interns learn from highly regarded faculty at the medical school and from skilled doctors in private practice. It’s the best possible education, and has resulted in one of the top OB/GYN training and residency programs in the country.”

Today, the Stanford School of Medicine accepts five residents annually to a four-year training program in general obstetrics and gynecology. An additional three-year fellowship in maternal-fetal medicine, accepting just one individual annually, provides training in high-risk obstetrics. The program leads to subspecialist certification, and positions graduates for careers in academic medicine.

Specialty training and high-quality research go hand in hand, notes El-Sayed. “Our vision at Packard is to conduct clinical studies that affect the care of pregnant women worldwide,” he says. “To do that, we need to support fellows and faculty through unrestricted research grants. Obstetric research has always been under-funded. If donors are thinking about helping children, remember, it all starts with pregnancy.”