Association Between Enteral Supplementation With High-Dose Docosahexaenoic Acid and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-analysis

Abstract

Importance: High-dose docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid, may affect the risk of bronchopulmonary dysplasia (BPD). However, high-level summative evidence supporting such clinical association in very preterm infants is lacking.

Objective: To examine the association between enteral supplementation with high-dose DHA during the neonatal period and the risk of BPD in preterm infants born at less than 29 weeks' gestation.

Data sources: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, medRxiv, and ClinicalTrials.gov were searched from inception to August 1, 2022, for eligible articles with no language restrictions.

Study selection: Randomized clinical trials (RCTs) were eligible for inclusion (1) if their interventions involved direct administration of a minimum DHA supplementation of 40 mg/kg/d or breast milk or formula feeding of at least 0.4% of total fatty acids, and (2) if they reported data on either BPD, death, BPD severity, or a combined outcome of BPD and death.

Data extraction and synthesis: Two investigators completed independent review of titles and abstracts, full text screening, data extraction, and quality assessment using the Cochrane Risk of Bias 2.0. Risk ratios (RRs) with 95% CIs were pooled using random-effect meta-analyses.

Main outcomes and measures: Primary outcome was BPD using trial-specific definitions, which was further stratified for RCTs that used a more stringent BPD definition based on systematic pulse oximetry assessment at 36 weeks' postmenstrual age. Other outcomes were BPD, death, BPD severity, or combined BPD and death.

Results: Among the 2760 studies screened, 4 RCTs were included, which involved 2304 infants (1223 boys [53.1%]; mean [SD] gestational age, 26.5 [1.6] weeks). Enteral supplementation with high-dose DHA was associated with neither BPD (4 studies [n = 2186 infants]; RR, 1.07 [95% CI, 0.86-1.34]; P = .53; I2 = 72%) nor BPD or death (4 studies [n = 2299 infants]; RR, 1.04 [95% CI, 0.91-1.18]; P = .59; I2 = 61%). However, an inverse association with BPD was found in RCTs that used a more stringent BPD definition (2 studies [n = 1686 infants]; RR, 1.20 [95% CI, 1.01-1.42]; P = .04; I2 = 48%). Additionally, DHA was inversely associated with moderate-to-severe BPD (3 studies [n = 1892 infants]; RR, 1.16 [95% CI, 1.04-1.29]; P = .008; I2 = 0%).

Conclusions and relevance: Results of this study showed that enteral supplementation with high-dose DHA in the neonatal period was not associated overall with BPD, but an inverse association was found in the included RCTs that used a more stringent BPD definition. These findings suggest that high-dose DHA supplementation should not be recommended to prevent BPD in very preterm infants.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Marc reported being the principal investigator of one of the randomized clinical trials included in this review, which received funding from the Canadian Institutes of Health Research (CIHR) and in-kind support from DSM Nutritional Products. Dr Makrides reported being an author on 2 publications included in this review; receiving grants from the National Health and Medical Research Council outside the submitted work; and holding a patent in the US, Canada, Australia, and Malaysia for South Australian Health and Medical Research Institute licensed to Nu-Mega/Clover Corporation, “Methods and compositions for promoting the neurological development of an infant.” No other disclosures were reported.

Figures

Figure 1.. Flow Diagram of the Selection Process

DHA indicates docosahexaenoic acid; RCT, randomized clinical trial.

Figure 2.. Meta-analysis Comparing High-Dose Docosahexaenoic Acid Supplementation With a Control on Bronchopulmonary Dysplasia (BPD) and Death

In panels B and C, death was analyzed up to 36 weeks' postmenstrual age (PMA) except in Hellström et al, where death was analyzed up to 40 weeks' PMA. PMA indicates postmenstrual age; RR, risk ratio.

Figure 3.. Meta-analysis Comparing High-Dose Docosahexaenoic Acid Supplementation With a Control on Bronchopulmonary Dysplasia (BPD) Severity

The BPD severity was classified according to criteria from the National Institute of Child Health and Human Development in Collins et al and Marc et al. A definition was not specified in Hellström et al. PMA indicates postmenstrual age; RR, risk ratio.