Chicks hatch clue on life-saving therapy for preterm babies

Scientists at the University of Cambridge have suggested that subtle changes to the drugs administered to mothers threatened with preterm birth or to premature babies could further improve clinical treatment and help increase their safety. While the current practice of using glucocorticoid therapy shows life-saving benefits for the preterm infant, the researchers say that combining them with antioxidants would overcome safety concerns.

One in ten babies are born prematurely and up to three-quarters of these are at significant risk of death or long-term illness because premature babies are born with immature lungs and at risk of dying from respiratory problems.

The clinical use of glucocorticoids both in mothers at risk of premature labour and in premature babies has become common practice in the last 40 years. The treatment is based on research which discovered the important role played by glucocorticoids in fetal development and that giving premature babies synthetic glucocorticoids could accelerate the development of their lungs and respiratory system; in essence saving their lives. Now, every mother at risk of preterm birth gets this treatment worldwide in developed societies.

“The evidence supporting the life-saving benefits of glucocorticoid treatment for premature babies is overwhelming. Without it, preterm babies would mostly die or suffer significantly from conditions associated with prematurity, leaving them with significant disability” states PhD student Noor Teulings.  “It is regarded as one of the best examples of successfully translating basic experimental science into efficient human clinical practice and it saves literally millions of preterm children every year”, says lead author Professor Dino Giussani from the Department of Physiology Development & Neuroscience and a member of the Reproduction SRI Steering Committee.

However, despite the very clear life-saving effects of antenatal glucocorticoid therapy to accelerate the lung maturation in the infant, new research from the Giussani laboratory in collaboration with Professors Sue Ozanne and Mike Murphy, also at Cambridge, has identified potential adverse side effects on the offspring’s developing cardiovascular systems. Since antenatal glucocorticoid therapy is administered to the mother, and the steroid drug can diffuse through all tissues, the adverse side effects on the developing cardiovascular system may be secondary to ill effects on the mother, the placenta and/or fetus.  To disentangle between these possibilities, the Giussani laboratory treated chicken embryos as they develop independent of the existence of a mother or a placenta.  In an ingenious paper published today in the FASEB Journal, Giussani and colleagues show that treating chicken embryos with human clinically relevant doses of glucocorticoids accelerated the maturation of the lungs but it also led to hearts developing with a lower number of cells which were prone to dysfunction.  The scientists also found the negative effects on the hearts to be due to oxidative stress.

“By simplifying the layers of complexity in mammals and employing the chicken embryo model, this study provides a significant conceptual advance to the field, isolating the direct effects of synthetic glucocorticoids on the developing cardiovascular system. We show that glucocorticoid treatment in the chicken embryo promotes significant cardiac remodelling and dysfunction via mechanisms involving a premature switch from tissue accretion to differentiation, increased oxidative stress and activated cellular senescence signalling pathways” added Professor Giussani.

Professor Giussani further stated that combined antenatal glucocorticoid with antioxidant therapy may be one way forward to get the best of both worlds: accelerate fetal lung maturation while combating the adverse side effects of oxidative stress on the developing heart.  “This would make current life-saving therapy for millions of children every year safer and therefore even better” concluded Giussani.

Image of chicks: Katie Skeffington

Reference

Teulings NEW, Garrud TAC, Niu Y, Skeffington KL, Beck C, Itani N, Conlon F, Botting KL, Nicholas LM, Ashmore TJ, Blackmore HL, Tong W, Camm EJ, Derks JB, Logan A, Murphy MP, Ozanne SE & Giussani DA.  Isolating adverse effects of glucocorticoids on the embryonic cardiovascular system. The FASEB J; 5 June 2020; DOI 10.1096/fj.202000697R.