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Three Part Question

In [a preterm infant] does [blood transfusion] increase [the risk of NEC]?

Clinical Scenario

An otherwise well 3 week old infant born at 28 weeks gestation has a haemoglobin level of 68 g/l and is prescribed a blood transfusion. The departmental protocol states feeds should be withheld during the transfusion to decrease the risk of development of necrotising enterocolitis (NEC). What is the evidence that blood transfusion increases the risk of NEC?

Search Strategy

Pub Med (1975–2003)
Embase (1974–2003)
Cinahl (1982–2004)
Cochrane Library (Issue 3, 2003)
Sum Search
"transfusion" AND "necrotizing enterocolitis" (excluding exchange transfusion). LIMITS newborn. using clinical queries with methodology filters (category aetiology, emphasis: sensitivity).

Search Outcome

Pub Med (1975–2003) - 85 articles, of which two were relevant. using clinical queries - 34 articles, of which one was relevant (picked up previously)
Embase (1974–2003) - 111 articles, of which one relevant (already retrieved by Pub Med).
Cinahl (1982–2004) - 15 articles, none relevant.
Cochrane Library (Issue 3, 2003) - no systematic reviews
Sum Search - 29 articles, none relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bednarek et al 1998	Prospective analysis of blood transfusions and outcomes (including NEC) in 825 very low birth weight (<1500 g) infants in 6 neonatal units over 1 year, with adjustment for birth weight and illness severity. The 6 units were categorized into low, medium and high transfusion units based on the mean number of transfusions per infant	Prospective ecological study (level 2c)	Incidence of NEC	Adjusted OR (95% CI) for the: High transfusing units: 1.1 (0.5–2.2) Medium units: 1 (reference) Low transfusing units: 0.3 (0.1–0.08) p<0.05 The low transfusing NICU group showed a significantly lower incidence of NEC compared with the middle and high transfusing units.	Association difficult to interpret in ecological studies as the association found between transfusion and NEC is at the level of the units but was not studied at the individual neonate level. Findings may be related to other practices in the specific NICU (e.g. restricted transfusion policy) or reflect confounding by indication for transfusion (e.g. infants who have NEC may require more transfusions). Time interval between transfusion and NEC not available (any transfusion at any time before NEC was counted)
McGrady et al 1987	Case-control study of 33 neonates with NEC during an outbreak, and 40 controls matched on birth weight, duration of stay in the unit and approximate date of admission. Median birth weight of cases = 1360 grams, median gestational age = 32.5 weeks	Individual case-control study (level 3b)	Risk factors for NEC	Transfusion was highly and significantly associated with NEC, crude OR = 15.5 (95% CI = 2.59–92.51); RR = 8.98 (95% CI = 1.08–74.6) after adjustment for therapy with caffeine, theophylline and furosemide. There was no association with type or timing of feeding	This study was that of an outbreak of NEC and not the endemic form of NEC. Epidemic NEC may be importantly very different from endemic NEC

Comment(s)

In the two reported studies (Bednarek, McGrady) the indications for transfusion were not standardised, the time interval between transfusion and NEC was not available, and any transfusion at any time between birth and NEC was analysed. The results of the ecological study are difficult to interpret as the association found between transfusion and NEC was at the level of the NICU but was not studied at the individual neonate level. Bias in the published results of the two studies is possible, as the findings may be related to other practices in the specific neonatal intensive care unit (e.g. restricted transfusion policy). It may also reflect confounding by the indication for transfusion (e.g, infants who have NEC may require more transfusions). It could also be that the anaemia for which a blood transfusion was requested was an independent risk factor for NEC, or an early manifestation of NEC still developing, which then becomes recognised several hours later (during or after the transfusion). While anecdotal reports suggest that NEC has developed quickly after a blood transfusion, such information is not available in published studies. However, neonatal exchange transfusion (Jackson, Tan) and intrauterine transfusion (Musemeche) both via umbilical vessels, have been shown to be associated with an increased incidence of NEC. Further studies minimising bias and confounding are needed to prove or disprove an association between blood transfusion and the risk of NEC, but even then, association is not necessarily synonymous with causality. It should be possible to undertake randomised controlled studies on the effect of withholding feeds versus feeding during blood transfusions on the rate of NEC, although blinding would be impossible and the sample size required for adequate power would likely be extremely large.

Clinical Bottom Line

Low quality evidence has shown an association between neonatal blood transfusion and the development of NEC. Withholding enteral feeds for a few hours during a blood transfusion may have theoretical benefits, but there is no published evidence to support this practice. Despite a lack of direct evidence, we continue to withhold feeds during blood transfusion.

References

1. Bednarek FJ, Weisberger S, Richardson DK, et al. Variations in blood transfusions among newborn intensive care units. SNAP II Study Group. J of Pediatr 1998; 133 pp 601–7.
2. McGrady GA, Rettig PJ, Istre GR, et al. An outbreak of necrotizing enterocolitis. Association with transfusions of packed red blood cells. Am J Epidemiol 1987;126 pp 1165–72.
3. Jackson JC. Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics 1997; 99 ppE7.
4. Tan KL, Phua KB, Ang PL. The mortality of exchange transfusions. Med J Aust 1976; 1 pp 473–6.
5. Musemeche CA. Reynolds M. Necrotizing enterocolitis following intrauterine blood transfusion. J Pediatr Surg 1991;26 pp 1411–12.