‘Stretch for Your Goals and Your Ideas:’ Q&A With N. Scott Adzick, MD

The Association for Clinical and Translational Science (ACTS) awarded N. Scott Adzick, MD, Surgeon-in-Chief at Children’s Hospital of Philadelphia, the 2021 ACTS Distinguished Investigator Award for Translation from Proof-of-Concept to Widespread Clinical Practice

Editor’s Note: The Association for Clinical and Translational Science (ACTS) awarded N. Scott Adzick, MD, Surgeon-in-Chief at Children’s Hospital of Philadelphia, the 2021 ACTS Distinguished Investigator Award for Translation from Proof-of-Concept to Widespread Clinical Practice. The award recognizes Dr. Adzick’s pivotal role in transforming fetal surgery from the theoretical to a well-established practice. We had a conversation with Dr. Adzick about how his early studies laid the groundwork for performing fetal surgery at CHOP’s Center for Fetal Diagnosis and Treatment (CFDT), now the largest and most comprehensive fetal program in the world. He also shared words of encouragement and motivation for early career scientists with novel ideas.

What motivates you to pursue groundbreaking prenatal treatments for birth defects?

N. Scott Adzick, Surgeon-in-Chief at Children’s Hospital of Philadelphia

I hope to serve as a creative force to overcome the unsolved problems of pediatric surgery. This goal is particularly true for babies with birth defects, most of which are now diagnosed before birth, who come to our world-class Center for Fetal Diagnosis and Treatment (CFDT). To quote my predecessor Dr. C. Everett Koop, the first Surgeon-in-Chief at CHOP for 32 years, “When you operate and save the life of a child, you save a lifetime.”

I arrived at CHOP as Surgeon-in-Chief in 1995 from the University of California, San Francisco, where the first fetal surgery techniques were developed. CHOP was at the nexus of clinical advances, and I could foresee the crucial role of translational research to advance pediatric surgery. Maternal-fetal ultrasound had come to the fore, and for the first time, we could accurately diagnose birth defects before birth.

The field of fetal surgery arose out of clinical frustration in taking care of babies who were born with devastating birth defects that lead to death or severe disability. We had the idea that in carefully selected clinical circumstances, we could surgically treat birth defects before birth, which was admittedly a crazy idea at the time.

But I could just see it in my mind’s eye, and I came to CHOP to do the research work to develop various animal models of birth defects and then craft surgical techniques to repair them before birth. Translational research is part of what we do so well at the Research Institute: We attack unsolved pediatric surgical problems, and we use translational research to overcome those problems.

Can you give an example of one of those fetal surgical problems that CHOP and its Research Institute helped to solve, from the lab to the clinic?

One example that I think this award focused on was the spina bifida problem. Spina bifida occurs when the neural tube fails to develop around the spinal cord by four to six weeks gestation. I was taught a long time ago at Harvard Medical School that the outcome for the baby depends on how high on the spine the spina bifida defect occurred, and predictably would lead to hydrocephalus requiring a shunt to drain fluid from the brain, brain damage, and paralysis. We thought that those outcomes were cast in stone, but due to a variety of research endeavors that we did, we showed that the in utero environment — particularly neurotoxic amniotic fluid — was causing the damage to the exposed nerves.

We subsequently learned that if you repaired the spina bifida before birth in fetal sheep, they did not have hindlimb paralysis — they could walk, and they could go up and down stairs, just like normal little lambs. Their neuromotor ability wasn’t completely normal, but it was remarkable. That publication came out in Nature Medicine in 1995, the same year I came to CHOP and started the Center for Diagnosis and Treatment, which is now the largest fetal treatment program in the world.

Our work evolved, and we collaborated with CHOP’s Department of Radiology on the first use of fetal MRI, in addition to ultrasound, so we could better diagnose birth defects. That advancement was particularly important for identifying central and peripheral nervous system problems like spina bifda. After doing all this experimental work, and with precise prenatal diagnosis and careful patient selection, we performed the first successful fetal surgical repair of spina bifida which we published in The Lancet in 1998.

Meanwhile, we had ongoing studies in fetal sheep that showed that hydrocephalus occurs with spina bifida due to hindbrain herniation. Hindbrain herniation is a common finding for babies with spina bifida in which the lower back part of the brain (the hindbrain) comes down (herniates) into the top of the spinal canal.

We showed that if you repaired the spina bifida before birth and sealed the leak of cerebrospinal fluid that bathes the brain and spinal cord before birth, you not only protect the nerves that control the legs, the bowel, and the bladder, but also the hindbrain herniation reverses. Accordingly, hydrocephalus is much less of a problem in babies with spina bifida who are treated before birth, and they have much less need for shunts, better bladder function, and better neuromotor development. That experimental work in fetal sheep was all done in the Abramson Research Center here at CHOP and then applied clinically.

Your team’s research built evidence supporting the launch of the randomized prospective clinical trial called the Management of Myelomeningocele Study – the MOMS trial. Tell us about how your proof-of-concept work became widespread clinical practice.

We really needed to put this technique of fetal surgery for spina bifida to the test in patients. We did that with two other centers, UCSF and Vanderbilt, through the MOMs Trial. That trial was very difficult to craft. Carrying out a clinical trial that compares medicines is difficult. Performing a clinical trial that compares surgeries is really difficult. Accomplishing a clinical trial that compares fetal surgery to postnatal surgery is extraordinarily difficult.

We received National Institutes of Health funding, and along with CHOP support, the MOMS trial showed incontrovertibly that the fetal surgery approach for spina bifida lead to better outcomes than waiting until the baby’s birth and then closing the spina bifida thereafter. We published our findings 10 years ago in the New England Journal of Medicine. We recently published results from the “MOMS2: Follow-up of the Management of Myelomeningocele Study” in Pediatrics and in JAMA Pediatrics that showed significant physical and neurodevelopmental benefits in school-age children who received corrective surgery in the womb for MMC.

Our research led to proliferation of fetal surgery programs throughout the world — Zurich, London, Belgium, Poland, Asia, and in the United States and Canada. We’ve trained amazing leaders of fetal diagnosis and treatment centers to perform fetal surgery for spina bifida and other prenatally diagnosed birth defects. We also established the North American Fetal Therapy Network (NAFTNet) in 2004, which is now a consortium of 36 fetal treatment centers in the U.S. and Canada, to share data and protocols so that we can continue to find ways to give unborn patients better treatment.

My colleagues in the CFDT and I have performed more than 2,000 fetal surgeries and cared for more than 27,000 expectant mothers who have come to CHOP from all 50 states and more than 70 countries. Fetal surgery for spina bifida, congenital diaphragmatic hernia, Twin-Twin Transfusion Syndrome, lung lesions, sacrococcygeal teratoma, and lower urinary tract obstruction are now life-changing options for unborn patients and their families.

What does being named the recipient of the 2021 ACTS Distinguished Investigator Award for Translation from Proof-of-Concept to Widespread Clinical Practice mean to you?

Any success or awards that I have received are due to the incredible multidisciplinary team that we have created at the Center for Fetal Diagnosis and Treatment. In 1995, CHOP was a good clinical place with 34 pediatric surgical specialists and no NIH grant support. Now, we have 125 pediatric surgical specialists in our Department of Surgery. Each of its eight divisions have NIH funding. We have 40 endowed chairs, and that is because CHOP’s exceptional platform attracts donors and attracts talent.

I am honored to receive this award from ACTS, which feels like a culmination of work that began several decades ago and now has helped so many families. It’s immensely gratifying to see an idea that at one time seemed purely theoretical become widespread practice, offering an improved future for so many children.

What advice do you have for new investigators who have a theoretical idea that they envision could one day improve the future for children’s health and quality of life?

One of my teachers at Harvard Medical School and Boston Children’s Hospital, the brilliant Dr. Judah Folkman who influenced me beginning at age 17, taught me:

“As long as there is an unconquered disease, an injury that cannot be repaired, or a method of prevention that remains beyond reach, we have an obligation to conduct research. Research represents hope, and for many patients and families, hope is the best thing we have to offer. We pursue our investigations so that one day we can offer more than hope, we can offer health.”

My advice to young investigators: Stretch for your goals and your ideas. You must persist even seemingly to point of obstinance!