Impact of Maternal Pomegranate Juice on Brain Injury in Infants With Intrauterine Growth Restriction (IUGR) (POM-1)

Impact of Maternal Pomegranate Juice on Brain Injury in Infants With Intrauterine Growth Restriction (IUGR)

Impact of Maternal Pomegranate Juice on Brain Injury in Infants With Intrauterine Growth Restriction (IUGR)

Infants with intrauterine growth restriction are known to be at increased risk for long term neurodevelopmental delay into adulthood. The main mechanism for this is likely decreased blood flow to the brain secondary to altered placental blood flow. Antioxidants may serve to protect the developing brain from this process. Animal studies have shown that pomegranate juice protects the fetal brain from injury in a model of stroke. This clinical trial is intended to evaluate if giving mothers pomegranate juice during the last several weeks of pregnancy can help protect intrauterine growth restricted babies' brains.

This study is divided into two separate phases. Phase I evaluated if the antioxidants produced from pomegranate juice cross the placenta in normal healthy pregnancies. Twenty women were enrolled, 10 who will take 8 oz of pomegranate juice daily and then 10 others who will take 8 oz of placebo juice without pomegranate daily. Blood samples were first collected from the woman at the time enrollment and then from both the woman and the cord blood at the time of delivery. These blood samples were analyzed to measure the levels of antioxidant metabolites from the pomegranate juice. This phase was deigned to confirm placental transfer of antioxidant pomegranate metabolites. The results confirmed placenta transfer of pomegranate metabolites. Further, placental tissues from 12 patients (4 in the pomegranate group and 8 in the control group) were collected for analysis of oxidative stress. The preliminary in vivo results were extended to oxidative stress and cell death assays in vitro. Placental explants and cultured primary human trophoblasts were exposed to pomegranate juice or glucose (control) under defined oxygen tensions and chemical stimuli. We found decreased oxidative stress in term human placentas from women who labored after prenatal ingestion of pomegranate juice compared with apple juice as control. Moreover, pomegranate juice reduced in vitro oxidative stress, apoptosis, and global cell death in term villous explants and primary trophoblast cultures exposed to hypoxia, the hypoxia mimetic cobalt chloride, and the kinase inhibitor staurosporine. Punicalagin, but not ellagic acid, both prominent polyphenols in pomegranate juice, reduced oxidative stress and stimulus-induced apoptosis in cultured syncytiotrophoblasts. Phase II focuses on pregnancies with intrauterine growth restriction. If they meet entry criteria, then woman will be enrolled and randomized into 1 of 2 groups. Treatment group: Expecting mothers in this group will start a daily regimen of 8 oz glass of pomegranate juice. They will keep a daily diary documenting their compliance. They will continue this daily intake up until delivery of their infant. Placebo group: These women will start a daily regimen of an 8 oz of pomegranate free juice placebo that matches taste, calories, and appearance to regular pomegranate juice but lacks polyphenols. They will also keep a diary of daily intake to help ensure compliance similar to the treatment group. They too will continue to take the placebos up until the time they deliver. Both groups: All women will be followed up on a weekly basis to assess compliance. A detailed diet history will be collected from the women at the time of enrollment, midway through the 3rd trimester and at the time of delivery. Furthermore, all women will have a detailed social history collected at the time of enrollment. Upon delivery, cord blood will be collected and sent for ellagic acid, a polyphenic component. All placental material will be sent for formal pathological exam and analyzed for markers of placental injury. If clinically stable, the infants will receive MRI evaluations to evaluate for possible brain injury.

Juice that matches the makeup of pomegranate in regards to sugar, vitamin C, etc. The only difference is that it lacks pomegranate juice.

Qualitative MRI injury- white matter injury (WMI) and gray matter injury (GMI) Brain Metrics on MR imaging Diffusion- apparent diffusion coefficient (ADC) and fractional anisotropy (FA) Spectroscopy- lactate and NAA levels in the basal ganglia Advanced MRI development indices - brain volumes, surface based morphology (SBM, folding indices)

Placental: immunoassays: HSP90, lipid hydroperoxide, nitrotyrosine assay, paraoxonase 1 expression, superoxide dismutases

Phase I: Inclusion Criteria: Healthy expecting mothers two weeks from their expected due dates No evidence of IUGR No evidence of fetal problems Phase II: Inclusion Criteria: Expecting mother with a fetal diagnosis of intrauterine growth restriction (IUGR) defined by estimated fetal weight <10th percentile for gestational age 24 - 34 weeks gestation Exclusion Criteria: Major congenital abnormalities Known fetal chromosomal disorder Maternal illicit drug use Maternal IV and Hepatitis C infection Premature rupture of membranes

Matthews LG, Smyser CD, Cherkerzian S, Alexopoulos D, Kenley J, Tuuli MG, Nelson DM, Inder TE. Maternal pomegranate juice intake and brain structure and function in infants with intrauterine growth restriction: A randomized controlled pilot study. PLoS One. 2019 Aug 21;14(8):e0219596. doi: 10.1371/journal.pone.0219596. eCollection 2019.