TABLE 2.

Summary of clinical studies (in chronological order) examining polar lipid supplementation and associated changes in cognitive development¹

Reference	Intervention	Methodology	Outcome
Gurnida et al. 2012 (22)	CML (gangliosides)	Double-blind, randomized, controlled, parallel group trial; term infants from ages 2–8 to 24 wk. The treatment group (n = 29) was fed ganglioside-supplemented formula (to increase GD3 content by 2–3 mg/100 g), the control group (n = 30) was fed standard formula, and the reference group (n = 32) was breastfed. All infants were exclusively breastfed up to the point of intervention. Cognitive development (using the Griffiths scales) was tested before (ages 2–8 wk) and after intervention (age 24 wk).	Ganglioside supplementation resulted in improved scores for Hand and Eye coordination IQ, Performance IQ, and General IQ on the Griffiths scales. Scores for the treatment group and breastfed reference group did not differ significantly.
Cheatham et al. 2012 (174)	Phosphatidylcholine (750 mg/day)—maternal supplementation	Double-blind, randomized controlled trial (n = 140 pregnant women) supplemented from 18 weeks of gestation through 90 d postpartum. Phosphatidylcholine supplementation (750 mg) vs. placebo (corn oil). Infants’ (n = 99) cognitive development (Mullen Scales of Early Learning, language development, and visual spatial and episodic memory) tested at ages 10 and 12 mo.	No difference in infant cognitive development at either time point.
Tanaka et al. 2013 (177)	SM-fortified milk	Double-blind, randomized controlled trial, low-birth-weight infants (<1.5 kg; n = 24) supplemented with fortified milk [SM = 20% of all phospholipids (n = 12) vs. 13% in the control group (n = 12)] for first 12 mo of life. Assessed plasma phospholipids, VEPs, Fagan, BSID-II, attention and memory tests at 3, 6, 9, 12, and 18 mo of corrected age.	SM-fortified group reported an increased percentage of SM in total phospholipids at 4, 6, and 8 wk. In addition, the SM-fortified group had better Behaviour Rating Scale of the BSID-II, Fagan test, VEP latency, and sustained attention scores at 18 mo compared with control.
Ross et al. 2013 (175)	Phosphatidylcholine (6300 mg/d)— maternal supplementation and 100 mg/d for infants	Double-blind, randomized, placebo-controlled trial (n = 100). Phosphatidylcholine supplementation (6300 mg/d for mothers) vs. placebo (corn oil) from second trimester of pregnancy until third postnatal month; 100 mg/d for infants from birth to 52 wk. Infants’ cerebral evoked responses to auditory stimuli were assessed at ages 5 and 13 wk.	No adverse effects of phosphatidylcholine supplementation were observed on maternal health and delivery, birth, or infant development. At postnatal week 5, P50 response was suppressed in phosphatidylcholine-treated infants; there was no difference at 13 wk.
Timby et al. 2014 (176)	Bovine MFGM [4% of total (wt:wt) protein content] supplemented, low-energy, low-protein experimental formula.	Prospective, double-blind, randomized controlled trial (n = 160). MFGM supplemented, low-energy, low-protein experimental formula vs. standard formula from 2 mo to 6 mo of age. Infant cognitive development was assessed using BSID-III.	At age 12 mo, cognitive score for the experimental group was higher than that for the standard group. There were no significant differences in other measures (linear growth, weight gain, body mass index, etc.).
Ross et al. 2015 (13)	Phosphatidylcholine (6300 mg/d), maternal supplementation	Double-blind, randomized, placebo-controlled trial (n = 49). As for Ross et al. 2013 (175). Infant behavior was measured at 40 mo using the Child Behavior Checklist (n = 23 treatment group; n = 26 placebo group).	At 40 mo, parents rated children receiving treatment as having fewer attention problems and less social withdrawal compared to placebo.
Huang et al. 2017 (173)	CML: standard CML formula and a ganglioside-enhanced CML formula (4 mg/serving; 8 mg/d)	Multicenter, 3-group, parallel randomized controlled trial—the CLIMB (Complex Lipids In Mothers and Babies) study. Three groups—standard maternal milk formulation, CML-enhanced maternal milk formulation, and no maternal milk formulation but provided standard pregnancy advice. Postnatal follow-up at 6 wk and 12 mo: cognitive development assessed with BSID-I.	Trial is ongoing.

¹BSID-I, -II, and -III, Bayley Scales of Infant Development, First Edition, Second Edition, and Third Edition, respectively; CML, complex milk lipids; IQ, intelligence quotient; MFGM, milk fat globule membrane; P50, P50 auditory evoked potential; SM, sphingomyelin; VEP, visual evoked potential.