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Safer therapy in the treatment of preterm birth

Supervisor: Dino Giussani

 

Preterm birth occurs in ca. 10% of pregnancies and is a major cause of infant mortality. Babies born preterm miss the rise in fetal plasma cortisol at the end of gestation, which enables fetal organs to be mature enough to sustain life after birth, including the lungs.  Consequently, expectant mothers threatened with preterm labour are injected with synthetic glucocorticoids to accelerate fetal lung maturation. This therapy is hugely successful in obstetric medicine, markedly decreasing infant morbidity and mortality.

Despite this, there are alarming unwanted effects of antenatal steroid therapy. These include increasing the risk of cardiovascular disease in later life, including hypertension, endothelial and cardiac dysfunction as well as insulin resistance. Therefore there is an urgent need to fine-tune current clinical practice to maintain beneficial, but prevent unwanted effects of antenatal steroid therapy.  We have now discovered that the adverse effects of steroids on the developing cardiovascular system are secondary to oxidative stress.  This suggests that combined glucocorticoid and antioxidant therapy may be safer for the developing offspring.

This PhD project will test the hypothesis that combined antenatal glucocorticoid and antioxidant therapy will maintain maturational effects on the fetal lung but prevents adverse effects of glucocorticoids on the developing cardiovascular system. 

The PhD project will test the hypothesis using chick embryos as this is the only established animal model to isolate the direct effects of therapy on the fetal organs independent of effects on the maternal and/or placental physiology.

The work will adopt an integrative approach combining in vivo cardiovascular physiology with work at the isolated organ (Langendorff, Myography and Pulmonary compliance), cellular (Stereology), mitochondrial (oxygen consumption) and molecular (Western blot, miRNA) levels.

Relevant references

Niu et al. J Physiol. 2013 Oct 15;591(Pt 20):5083-93.
Tijsseling et al. Pediatr Res. 2013 Dec;74(6):639-45.
Herrera et al. PLoS One. 2010 Feb 17;5(2):e9250.

 

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