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When does gold become tarnished?

Systematic reviews, especially with meta-analysis, are often considered scholarly works at the top of the pyramid (See the Oxford Centre for Evidence-Based Medicine for example.) This is because they typically combine randomized controlled trials (RCTs) that may be limited by small sample sizes, enabling stronger conclusions to be better derived.  Yet, this seemingly golden offering of scholarly literature may have its limitations. 

A systematic review by Boyd, Quigley, and Brocklehurst (2007) on donor breast milk for preterm infants compared to formula is a frequently quoted reference on the subject. The seven studies examined included five randomized controlled trials. The section of the review that receives the most ongoing attention in the literature is the combined effects of three of the studies by meta-analysis on the variable of confirmed necrotizing enterocolitis (NEC), a complication of high concern in premature infants. This analysis combined two RCTs and one observational study. Separately, the sample sizes for these studies ranged from 39 to 162; the combined sample size became 268.  Individual study results did not meet the minimal level of statistical significance of p=0.05. Combined evidence from these studies created a relative risk (RR) of 0.21, 95% CI of 0.06-0.76, p=0.017. The conclusion was that donor milk reduces NEC by about 79% compared to formula. At face value, this is an enticing result. Why the worry?

The concerns with this analysis are partially acknowledged by the authors. The articles used for this study are dated no later than the early 1980’s with data from the 1970’s and the beginning of the 1980’s. Babies included in the studies were 30-33 weeks of age and 1310-1954g, much larger than the premature infant surviving today in our neonatal intensive care units. These studies involved non-fortified milk and exclusive feeding of the control and treatment groups. This too is contrary to today’s practices as fortification is much more the standard practice now. 

One of the authors (Quigley) went on to perform an updated review. This review (Quigley, Henderson, Anthony, McGuire, 2007) is published in the Cochrane Database of Systematic Reviews, a much revered source of scholarly literature. Here five studies were combined in meta-analysis with the addition of a more recent study (Schanler, 2005) of sizeable impact. Unlike several of the other comparisons in this document, the heterogeneity is assessed to be low (I2 of 0.00%) and results favored donor breast milk, with a RR of 2.46, 95% CI 1.19-5.08, p=0.015. This confidence interval was much better than some of the singular studies that reported such wide variances as 0.11 to 60.38. Yet, more limitations exist in this review. Growth restricted preterm infants that are already at high risk for NEC were noted here as excluded.  Again, many of the studies came from the pool described in the article by Boyd and colleagues and infant size and age along with the fortification issue remain. Preparation of the donor milk may also have differed in the early studies compared to today. In summary, the golden scholarly product is tarnished. 

A final note is that evidence reviews cannot end with the statistical analysis. Donor milk costs $3.50 per ounce or more via standard milk banks.  Cost effectiveness needs to be evaluated in order to make this costly recommendation. Given the limitations of the literature and the cost involved, a local team of experts decided against widespread adoption of donor breast milk for premature infants. 


Boyd, C. A., Quigley, M. A., & Brocklehurst, P. (2007).  Donor breast milk versus infant formula for preterm infants:  Systematic review and meta-analysis.  Archives of Diseases in Childhood, Fetal and Neonatal Edition, 92, F169-F175.  doi:  10.1136/adc.2005.089490

Quigley, M., Henerson, G., Anthony, M. Y., McGuire, W.  (2008).  Formula milk versus donor breast milk for feeding preterm or low birth weight infants.  Cochrane Database of Systematic Review 2007, Issue 4.  Art. No.:  CD002971.  doi:  10.1002/14651858.CD002971, pub2

Submitted by: 
Kathy Russell-Babin, MSN, RN, ACNS-BC, NEA-BC
Sr. Manager, Institute for Evidence-Based Care
Meridian Health System


Posted by Lisa Morris Bonsall on 9/12/2012 8:13:30 AM with 0 comments

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