J Physiol 591.20 (2013) pp 4957–4958 4957

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Steroids and antioxidants:a neonatal cocktail for savingyour adult heart?

Laura BennetFetal and Neonatal Physiology Group,Department of Physiology, The University ofAuckland, 85 Park Road, Grafton, Auckland1023, New Zealand

Email: l.bennet@auckland.ac.nz

The paper by Niu et al. (2013) in this issueof The Journal of Physiology demonstratesthat neonatal rat pups exposed to a standardcourse of post-natal steroids go on todevelop impaired cardiac function in adultlife. The authors also make the strikingobservation that this impairment can beameliorated when steroids are given inconjunction with anti-oxidants.

Crucially this study reminds us ofsomething we all intellectually understand:no clinical treatment is without risk. Whenassessing treatment risks in newborn babieswe often neglect the fact that many risksmay occur much later in life. This is easyto do, after all adult health problems arenot really the focus of the neonatologistwho is trying to save a baby’s life. Yet,when it comes to post-natal steroids, andwhether to use them, clinicians are advisedthat there is no consensus on treatment,and that they should use their own clinicaljudgment to weigh-up the pros and consabout the need to prevent acute illnessversus the possibility of causing injury ordisease in later life (Watterberg, 2010).This is a tall order, given the dearth ofinformation on the potential long-termeffects of steroids. The current paper addsto the growing literature demonstratingthat post-natal steroids are associated withnumerous adverse outcomes that cliniciansshould be aware of. Importantly, the authorshighlight the fact that in the future there maybe relatively straightforward therapeuticstrategies which will help reduce or preventthese outcomes.

That a drug therapy given so early in lifecan lead to impaired cardiac structure andfunction later in life should not come asa surprise. There is now a wealth of datademonstrating that many adult diseases mayhave developmental origins. For example,fetal hypoxia and poor maternal nutrition

can lead to altered organ developmentand function, and these changes are inturn strongly associated with increasedrisk of insulin resistance, hypertension andobesity; key factors underpinning heartdisease and diabetes (McMillen & Robinson,2005). Strikingly, however, few studieshave evaluated whether the drugs we giveroutinely in clinic; standard therapies, mightalso have similar programming effects.

Few would argue that a drug as powerfulas a steroid is risk free, but when itcomes to fetuses and newborn babiesour love affair with the miraculouseffectiveness of steroids has, to a certainextent, coloured our perceptions aboutrisks (Jobe, 2004). It has also tempered,until recently, our apparent desire to looktoo closely at potential adverse outcomes,particularly when those outcomes mayoccur much later in life. Remarkably, wehave embraced the use of post-natal steroidsfor treating neonatal cardiorespiratoryproblems such as hypotension and broncho-pulmonary dysplasia without detailed pre-clinical or clinical risk/benefit analysis.Current research now shows us that thissomewhat unchecked enthusiasm has notserved the infants well, with standardcourses associated with impaired neuro-development (Wilson-Costello et al. 2009;Watterberg, 2010). The current paper showsthat the heart is also very much at risk.

Despite the increasing evidence ofadverse outcomes, and the absence ofa consensus about treatment protocols,steroids continue to be used, and willbe for the foreseeable future given thelack of suitable alternatives (Jobe, 2004;Watterberg, 2010). This leaves us withhow to manage the increasingly evidentside-effects. The paper by Niu et al. offersus important new ideas to potentiallystart addressing this. Intriguingly, whensteroids were given in conjunction with anti-oxidants, not only was neonatal survivalimproved, but impaired cardiac functionin adult life was markedly attenuated.Considerable work must now be done tovalidate these findings and to determineprecise mechanisms of action. However,the authors highlight nitric oxide as animportant pathway for investigation, anddiscuss previous key data from their researchgroup in support of this (Adler et al.2010).

Undeniably, this observation demonstratesthe fact that potential treatments can bedeveloped to reduce or prevent adverseoutcomes from our standard therapies. Todo this, however, requires that we commitourselves to a more robust assessment ofthe effects associated with these therapiesand not simply leave it up to individualclinicians to figure out how to balance shortand long-term risks (Watterberg, 2010).The same argument must also be made forante-natal treatments, for the fetus is asvulnerable as the newborn infant.

Finally, the paper provides one finaland very important reminder of wherethis perspective started: no treatment iswithout risk. While anti-oxidants givenin conjunction with steroids amelioratedthe adverse effects of steroids, when givenby themselves they too had a detrimentaleffect on cardiac function in adult life.These findings are very consistent withmany other trials to date, as discussedby the authors. Anti-oxidant treatmentshave been fashionable for many years,for a variety of conditions ranging frompre-eclampsia in pregnancy to Alzheimer’sdisease of the brain. The popular presstoo is full of exhortations to consumevast quantities of vitamins and eat foodshigh in anti-oxidants. If one believes thepress we will be healthier and live longer,but research suggests otherwise. A recentCochrane Database review concludes, forexample, that there is little or no evidencethat anti-oxidants are useful for eitherprimary or secondary prevention of diseaseand death (Bjelakovic et al. 2012).

The current study would stronglysupport the mounting consensus thatanti-oxidants in adulthood are not usefulfor reverting cardiac disease once it has beenestablished. However, treatment duringearly developmental windows may pre-vent the evolution of disease. Hence, oneshould not throw the baby out with thebathwater, for in neonatal rat pups atleast, an anti-oxidant-steroid cocktail mayprove to be just the tonic our adult heartsneed.

References

Adler A, Camm EJ, Hansell JA, Richter HG &Giussani DA (2010). Neonatology 98,73–83.

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society DOI: 10.1113/jphysiol.2013.263962

4958 Perspectives J Physiol 591.20

Bjelakovic G, Nikolova D, Gluud LL, SimonettiRG & Gluud C (2012). Cochrane Database SystRev 3, CD007176.

Jobe AH (2004). N Engl J Med 350,1349–1351.

McMillen IC & Robinson JS (2005). Physiol Rev85, 571–633.

Niu Y, Herrera EA, Evans RD & Giussani DA(2013). J Physiol 591, 5083–5093.

Watterberg KL (2010). Pediatrics 126, 800–808.

Wilson-Costello D, Walsh MC, Langer JC,Guillet R, Laptook AR, Stoll BJ, Shankaran S,Finer NN, Van Meurs KP, Engle WA& Das A (2009). Pediatrics 123,e430–437.

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society