Maternal pomegranate juice intake and brain structure and function in infants with intrauterine growth restriction: A randomized controlled pilot study

Lillian G Matthews, Christopher D Smyser, Sara Cherkerzian, Dimitrios Alexopoulos, Jeanette Kenley, Methodius G Tuuli, D Michael Nelson, Terrie E Inder, Lillian G Matthews, Christopher D Smyser, Sara Cherkerzian, Dimitrios Alexopoulos, Jeanette Kenley, Methodius G Tuuli, D Michael Nelson, Terrie E Inder

Abstract

Polyphenol-rich pomegranate juice has been shown to have benefit as a neuroprotectant in animal models of neonatal hypoxic-ischemia. No published studies have investigated maternal polyphenol administration as a potential neuroprotectant in at-risk newborns, such as those with intrauterine growth restriction (IUGR). This was a randomized, placebo-controlled, double-blind pilot study to investigate the impact of maternal pomegranate juice intake in pregnancies with IUGR, on newborn brain structure and function at term-equivalent age (TEA). Mothers with IUGR at 24-34 weeks' gestation were recruited from Barnes-Jewish Hospital obstetrical clinic. Consented mothers were randomized to treatment (8 oz. pomegranate juice) or placebo (8 oz. polyphenol-free juice) and continued to take juice daily from enrollment until delivery (mean 20.1 and 27.1 days, respectively). Infants underwent brain MRI at TEA (36-41 weeks' gestation). Brain measures were compared between groups including: brain injury score, brain metrics, brain volumes, diffusion tensor imaging and resting state functional connectivity. Statistical analyses were undertaken as modified intention-to-treat (including randomized participants who received their allocated intervention and whose infants received brain MRI) and per-protocol (including participants who strictly adhered to the protocol, based on metabolite status). Seventy-seven mothers were randomized to treatment (n = 40) or placebo (n = 37). Of these, 28 and 27 infants, respectively, underwent term-equivalent MRI. There were no group differences in brain injury, metrics or volumes. However, treatment subjects displayed reduced diffusivity within the anterior and posterior limbs of the internal capsule compared with placebo. Resting state functional connectivity demonstrated increased correlation and covariance within several networks in treatment subjects, with alterations most apparent in the visual network in per-protocol analyses. Direct effects on health were not found. In conclusion, maternal pomegranate juice intake in pregnancies with known IUGR was associated with altered white matter organization and functional connectivity in the infant brain, suggesting differences in brain structure and function following in utero pomegranate juice exposure, warranting continued investigation. Clinical trial registration. NCT00788866, registered November 11, 2008, initial participant enrollment August 21, 2012.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Participant flowchart.
Fig 1. Participant flowchart.
Fig 2. Relationships between maternal pomegranate juice…
Fig 2. Relationships between maternal pomegranate juice intake and infant DTI measures.
(Top) Treatment vs. placebo (modified intention-to-treat analysis). (Bottom) Metabolite-positive treatment vs. metabolite-negative placebo (per-protocol analysis). The point estimates represent the difference between groups in white matter DTI measures based on analyses run using generalized linear models (GLM) adjusted for postmenstrual age at scan. The error bars represent the 95% confidence intervals. ALIC–anterior limb of internal capsule; CC–corpus callosum; CNBD–cingulum bundle; CSOV–centrum semiovale; FA–fractional anisotropy; Frontal–frontal lobe; OR–optic radiation; MD–mean diffusivity; PLIC–posterior limb of internal capsule; RD–radial diffusivity. Left/Right indicate measures for bilateral white matter tracts.
Fig 3. Relationships between maternal pomegranate juice…
Fig 3. Relationships between maternal pomegranate juice intake and infant fcMRI measures (correlations).
Group mean Fisher’s z-transformed correlation coefficient matrices are shown representing all ROI pairs. The block structure along the diagonal seen in both groups corresponds to resting state networks. Warm hues within diagonal blocks reflect positively correlated ROIs within RSN, while cool hues reflect negatively correlated ROIs within RSNs. (Top, A-C) Treatment vs. placebo (modified intention-to-treat analysis). (A) Infants in treatment (pomegranate juice) group and (B) infants in placebo group at term-equivalent. (C) Shows the difference between groups (treatment minus placebo). (Bottom, D-F) Metabolite-positive treatment vs. metabolite-negative placebo (per-protocol analysis). (D) Infants in metabolite-positive treatment group and (E) infants in metabolite-negative placebo group at term-equivalent. (F) Shows the difference between groups (metabolite-positive treatment minus metabolite-negative placebo). Note metabolite-positive treatment > metabolite-negative placebo correlation in subcortical and visual network. CER—cerebellar; CO—cingulo-opercular; DAN–dorsal attention network; DMN–default mode network; FP–frontal parietal network; LAN–language area network; Metab–metabolite; Neg–negative; POM–pomegranate; Pos–positive; SAL–salience network; SMN–sensorimotor network; SUB–subcortical grey matter; VAN–ventral attention network; VIS–visual network.
Fig 4. Relationships between maternal pomegranate juice…
Fig 4. Relationships between maternal pomegranate juice intake and infant fcMRI measures (covariance).
Group mean covariance matrices are shown representing all ROI pairs. The block structure along the diagonal seen in both groups corresponds to resting state networks. Warm hues within diagonal blocks reflect positively correlated ROIs within RSN, while cool hues reflect negatively correlated ROIs within RSNs. (Top, A-C) Treatment vs. placebo (modified intention-to-treat analysis). (A) Infants in treatment (pomegranate juice) group and (B) infants in placebo group at term-equivalent. (C) Shows the difference between groups (treatment minus placebo). Note treatment > placebo covariance within subcortical and visual networks. (Bottom, D-F) Metabolite-positive treatment vs. metabolite-negative placebo (per-protocol analysis). (D) Infants in metabolite-positive treatment group and (E) infants in metabolite-negative placebo group at term-equivalent. (F) Shows the difference between groups (metabolite-positive treatment minus metabolite-negative placebo). Note metabolite-positive treatment > metabolite-negative placebo covariance within subcortical and visual networks. CER—cerebellar; CO—cingulo-opercular; DAN–dorsal attention network; DMN–default mode network; FP–frontal parietal network; LAN–language area network; Metab–metabolite; Neg–negative; POM–pomegranate; Pos–positive; SAL–salience network; SMN–sensorimotor network; SUB–subcortical grey matter; VAN–ventral attention network; VIS–visual network.

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