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Antenatal Betamethasone for Women at Risk for Late Preterm Delivery

Cynthia Gyamfi-Bannerman, Elizabeth A. Thom, Sean C. Blackwell, Alan T.N. Tita, Uma M. Reddy, George R. Saade, Dwight J. Rouse, David S. McKenna, Erin A.S. Clark, John M. Thorp, Edward K. Chien, Alan M. Peaceman, Ronald S. Gibbs, Geeta K. Swamy

New England Journal of Medicine, 2016; 160204050010006 DOI: 10.1056/NEJMoa1516783

Editor’s comment: Prof. Dan Farine: Corticosteroids for late preterm birth – Are you British or American?
The Society of Maternal Fetal Medicine (SMFM) has published new guidelines on administration of corticosteroids for late preterm pregnancies in order to reduce neonatal morbidity and specifically pulmonary complications. These recommendations are based mainly on the large RCT performed in the American MFM Network that was recently published in the NEJM (1). This study was large and properly designed and conducted in some of the better American Tertiary centers. It clearly showed that there was an improved outcome with a reduction of the poor outcomes from 14% to 11%. Interestingly in 60% of cases there was an administration of only one dose and not of the full course which leads to an unanswered question – is a single dose sufficient to achieve these outcomes?

While this study has very clear results showing a benefit of corticosteroids on short term outcomes; this study was not designed to look at long term effects. The unanswered question is if the benefits to the 3% of pregnancies that had significant short term improvements justify the exposure of 100% of these pregnancies to corticosteroids? I do not think that we currently have a good answer to this question. Corticosteroids have an effect on many different systems and could possibly alter the fetus in several different ways including: brain development, the pituitary adrenal axis, metabolic effects and possible modulation of the immune system. There is data showing that the volume of the hypocampal area (involved in memory function) is reduced by about 40%. We have shown about 20 years ago in a NEJM paper that chronic administration of corticosteroids resulted in smaller babies (2). Nunham from Perth had similar data pertaining mainly to possible lung and brain effects and Murphy in the MAC study showed that repeated doses of steroids may lead to smaller head measurements (3). Last year, in an evaluation of a study that showed benefits of corticosteroid administration prior to elective CS three British researchers published in the JAMA a paper raising such concerns on the long term effects of corticosteroids and the fact that the current long term data is derived from series of therapy in early preterm births where the major benefits of the therapy may outweigh its risks (5).

The British concerns were probably influenced by the ORACLE II study (6) that showed that antibiotics administration in women with preterm labor did not improve the short term outcomes but resulted in significant increase in cerebral palsy. These may a reason for the British guidelines on progesterone for preterm birth to be quite different from most of the other guidelines (7). While most guidelines (American, Canadian European etc.) strongly recommended the use of progesterone in some populations at risk for PTL the British guidelines insisted that their use should be limited to a research setting until long term outcome are available. The recently published OPPTIMUM study (8) demonstrated that there was no long term benefits and even casted shadow on the short term outcomes.

The new SMFM guidelines emphasize the clear-cut benefits demonstrated in a large and properly performed RCT. However, they preferred not to wait for a long term follow-up of this cohort. We believe that a caution may have to be exercised before the SMFM guidelines are adopted and we encourage the American MFM network to follow the babies in this study so these concerns could be resolved.

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Commentaries by Editor Prof. Jim Thornton