​Protecting Preemies from Intestinal Injury

Isabelle De Plaen, MD, in the lab.

Imagine a new mom whose preterm baby – who was fine initially– suddenly won’t tolerate his feeds anymore and seems very sick. Nothing happens as planned – the feedings come back up, the baby appears in pain and has bloody stools. What is most worrisome is that he is now pale and no longer active. The mom, understandably, is upset – frightened, troubled, confused. Her baby who only hours ordays before was healthy is now extremely ill.

Newborns who are very preterm are at risk of developing serious and potentially life-threatening conditions that only rarely occur in full term infants. Among these is necrotizing enterocolitis (NEC), the most common and difficult intestinal disease in preemies. Indeed, NEC affects approximately 7 to 10 percent of very low birth weight infants (weighting less than 3.3 pounds). In NEC, the intestinal tissues die off, leading to passage of bacterial products through the intestinal wall into the bloodstream, which causes the baby to go into shock.

Infants with NEC experience a variety of health issues and cannot eat by mouth for extended periods of time. Surgeons may need to remove dead intestinal tissues, resulting in the inability of these babies to digest food normally, which in turn necessitates long-term intravenous nutrition. Although the condition can resolve, some babies succumb. Those who survive could suffer from significant and lasting effects including poor growth, neurological or neurodevelopmental deficits, and visual or hearing impairments. There is currently no cure for NEC, and the therapeutic options are limited.

Isabelle De Plaen, MD, has been studying NEC at the bedside and in the lab for her entire career. As a neonatologist, she has cared for infants with NEC and their families. “These parents,” she says, “feel helpless to make things better for their newborns. Our goal is to prevent NEC from ever happening.”

Her laboratory recently showed evidence that insufficient intestinal microvasculature – a fine network of blood vessels – may be critical in the development of NEC. She has hypothesized that maintaining low levels of oxygen during fetal development is essential for proper formation of the tiny blood vessels feeding the intestinal tissue. During premature birth the growth of these incompletely formed intestinal blood vessels slows down, increasing the susceptibility of the intestines to NEC.

In a new study published in Pediatric Research, the De Plaen lab tested a novel agent called DMOG, which increases the stability of a signaling molecule called hypoxia inducible factor-1 (HIF-1), which is triggered by low oxygen levels. They found that mice treated with DMOG produce higher levels of VEGF, a key vascular growth-promoting factor, in their intestines. Furthermore, DMOG treated mice maintain intestinal blood vessel growth and are protected against intestinal injury when exposed to an experimental NEC model.

“Several factors may affect the growth of the intestinal tiny blood vessels in the developing fetus,” says De Plaen. “The problem is that we don’t know exactly what roles these factors play, and without that knowledge it is difficult to design models for improving outcomes in babies with NEC. It is critical for us to continue these studies so as to find ways to best stimulate molecular pathways that promote intestinal vascular development. Also, we want to prevent conditions that would interfere with vascular development, so that intestinal tiny vessel development is maintained in premature infants and NEC does not happen.”

De Plaen is encouraged by but realistic about the findings. She explains, “Despite many years of research, there are still no significant advances in therapy for NEC. The goal of our research is to identify key molecules or pathways that cause or prevent the disease. This is why we continue to do research, because we know it’s badly needed. By comparison, inflammatory bowel disease – an adult condition – now has an effective treatment, all due to animal-based research. This gives me hope that the same can be said of NEC in the near future.”

She continues, “I am grateful to be surrounded by such talented researcher associates including Drs. Xiaocai Yan and Elizabeth Managlia, whose work is key to this research. In addition, I want to acknowledge Dr. Rakhee Bowker, a former neonatology fellow who is now Assistant Professor and a neonatologist at Rush University, and who was instrumental in the recently published study in Pediatric Research. Finally, I am grateful for the friendship and advice of my former mentor, Dr. Wei Hsueh, and of my long time collaborator, Dr. Xiao-Di Tan.”

When asked about success stories with former patients, De Plaen’s face lights up. “Our parents like to send us news about how well NEC graduates are doing. We had a very preterm baby whose family moved out of the U.S. They came back to visit recently, and this once sick baby is now a happy and thriving young person. It is extremely gratifying to receive updates like that,” she says.

Isabelle De Plaen, MD, is an attending physician in the Division of Neonatology (Neonatal Intensive Care Unit) at Lurie Children’s, Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine, and a member of the Center for Intestinal and Liver Inflammation Research​ at Stanley Manne Children’s Research Institute.