Supplementation with milk enriched with complex lipids during pregnancy: A double-blind randomized controlled trial.

BACKGROUND: Gangliosides are a class of sphingolipids that are present in the cell membranes of vertebrates. Gangliosides influence a broad range of cellular processes through effects on signal transduction, being found abundantly in the brain, and having a role in neurodevelopment. OBJECTIVE: We aimed to assess the effects of maternal daily consumption of ganglioside-enriched milk vs non-enriched milk and a non-supplemented group of pregnant women on maternal ganglioside levels and pregnancy outcomes. DESIGN: Double-blind parallel randomized controlled trial. METHODS: 1,500 women aged 20-40 years were recruited in Chongqing (China) between 11 and 14 weeks of a singleton pregnancy, and randomized into three groups: Control-received standard powdered milk formulation (≥4 mg gangliosides/day); Complex milk lipid-enhanced (CML-E) group-same formulation enriched with complex milk lipids (≥8 mg gangliosides/day) from milk fat globule membrane; Reference-received no milk. Serum ganglioside levels were measured in a randomly selected subsample of 250 women per group. RESULTS: CML-E milk was associated with marginally greater total gangliosides levels in maternal serum compared to Control (13.02 vs 12.69 µg/ml; p = 0.034) but not to Reference group. CML-E milk did not affect cord blood ganglioside levels. Among the 1500 women, CML-E milk consumption was associated with a lower rate of gestational diabetes mellitus than control milk [relative risk 0.80 (95% CI 0.64, 0.99)], but which was not different to the Reference group. CML-E milk supplementation had no other effects on maternal or newborn health. CONCLUSIONS: Maternal supplementation with milk fat globule membrane, as a source of gangliosides, was not associated with any adverse health outcomes, and did not increase serum gangliosides compared with the non-supplemented reference group. TRIAL REGISTRATION: Chinese Clinical Trial Register (ChiCTR-IOR-16007700). CLINICAL TRIAL REGISTRATION: ChiCTR-IOR-16007700; www.chictr.org.cn/showprojen.aspx?proj=12972.

Effect of supplementation of complex milk lipids in pregnancy on fetal growth: results from the Complex Lipids in Mothers and Babies (CLIMB) randomized controlled trial.

BACKGROUND: Gangliosides (GAs) are important for neuronal function and development of the brain, accumulating rapidly in the fetal brain during the last trimester of pregnancy. No study in humans has investigated whether maternal supplementation of GAs during pregnancy has an effect on fetal growth, particularly of the head circumference. OBJECTIVE: To evaluate the effect of maternal dietary supplementation of complex milk lipids (CML; gangliosides and phospholipids) from the milk fat globule membrane (MFGM) during pregnancy on fetal growth. DESIGN: Double-blind three-arm parallel randomized controlled trial of 1500 pregnant women from the Chongqing Municipality of China, recruited between 11 and 14 weeks of pregnancy. Intervention was in the form of supplementation with: control maternal milk formulation containing a minimum of 2 mg GA per serving (4 mg GA per day) versus a CML-enriched (CML-E) maternal milk formulation containing a minimum of 4 mg GA per serving (8 mg GA per day) versus no maternal milk supplementation, but with standard obstetric care including prenatal folic acid supplementation. Main outcomes and measures were ultrasonographically-derived estimates of fetal growth in head circumference (HC) & biparietal diameter (BPD) (primary outcomes); and abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW) (secondary outcomes) (Clinical trial registry: ChiCTR-IOR-16007700). RESULTS: Supplementation with CML-E milk had no effects on size at midpregnancy or growth trajectories in any of the fetal biometric dimensions. CONCLUSIONS: Supplementation of CML from the MFGM from the end of the first trimester did not have any effects on fetal growth. The absence of any adverse growth outcomes suggests that maternal MFGM supplementation during pregnancy is safe and using CML-E milk formula can be a method of providing an increased GA and phospholipid supply in early life, which has been associated with neurodevelopmental benefits. CLINICAL TRIAL REGISTRY: ChiCTR-IOR-16007700 (http://www.chictr.org.cn/enindex.aspx).

The CLIMB (Complex Lipids In Mothers and Babies) study: protocol for a multicentre, three-group, parallel randomised controlled trial to investigate the effect of supplementation of complex lipids in pregnancy, on maternal ganglioside status and subsequent cognitive outcomes in the offspring.

INTRODUCTION: Complex lipids are important constituents of the central nervous system. Studies have shown that supplementation with complex milk lipids (CML) in pregnancy may increase the level of fetal gangliosides (GA), with the potential to improve cognitive outcomes. METHODS AND ANALYSIS: We aim to recruit approximately 1500 pregnant women in the first trimester (11-14 weeks) and randomise them into one of the three treatment groups: standard maternal milk formulation, CML-enhanced maternal milk formulation or no maternal milk intervention with standard pregnancy advice (ie, the standard care). Maternal lifestyle and demographic data will be collected throughout the pregnancy, as well as biological samples (eg, blood, hair, urine, buccal smear, cord blood, cord and placenta samples). Data from standard obstetric care recorded in hospital maternity notes (eg, ultrasound reports, results of oral glucose tolerance test and pregnancy outcome data) will also be extracted. Postnatal follow-up will be at 6 weeks and 12 months of age, at which point infant cognitive development will be assessed (Bayley Scales of Infant Development I). ETHICS AND DISSEMINATION: This project was approved by the Ethics Committee of Chongqing Medical University. Dissemination of findings will take the form of publications in peer-reviewed journals and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-16007700; Pre-results.

Long-Term Supplementation with Beta Serum Concentrate (BSC), a Complex of Milk Lipids, during Post-Natal Brain Development Improves Memory in Rats.

We have previously reported that the supplementation of ganglioside-enriched complex-milk-lipids improves cognitive function and that a phospholipid-enriched complex-milk-lipid prevents age-related cognitive decline in rats. This current study evaluated the effects of post-natal supplementation of ganglioside- and phospholipid-enriched complex-milk-lipids beta serum concentrate (BSC) on cognitive function in young rats. The diet of male rats was supplemented with either gels formulated BSC (n = 16) or blank gels (n = 16) from post-natal day 10 to day 70. Memory and anxiety-like behaviors were evaluated using the Morris water maze, dark-light boxes, and elevated plus maze tests. Neuroplasticity and white matter were measured using immunohistochemical staining. The overall performance in seven-day acquisition trials was similar between the groups. Compared with the control group, BSC supplementation reduced the latency to the platform during day one of the acquisition tests. Supplementation improved memory by showing reduced latency and improved path efficiency to the platform quadrant, and smaller initial heading error from the platform zone. Supplemented rats showed an increase in striatal dopamine terminals and hippocampal glutamate receptors. Thus BSC supplementation during post-natal brain development improved learning and memory, independent from anxiety. The moderately enhanced neuroplasticity in dopamine and glutamate may be biological changes underlying the improved cognitive function.

'Iron-saturated' lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy.

Bovine lactoferrin (bLf), an iron-containing natural defence protein found in bodily secretions, has been reported to inhibit carcinogenesis and the growth of tumours. Here, we investigated whether natural bLf and iron-saturated forms of bLf differ in their ability to augment cancer chemotherapy. bLf was supplemented into the diet of C57BL/6 mice that were subsequently challenged subcutaneously with tumour cells, and treated by chemotherapy. Chemotherapy eradicated large (0.6 cm diameter) EL-4 lymphomas in mice that had been fed iron-saturated bLf (here designated Lf(+)) for 6 weeks prior to chemotherapy, but surprisingly not in mice that were fed lesser iron-saturated forms of bLf, including apo-bLf (4% iron saturated), natural bLf (approximately 15% iron saturated) and 50% iron-saturated bLf. Lf(+)-fed mice bearing either EL-4, Lewis lung carcinoma or B16 melanoma tumours completely rejected their tumours within 3 weeks following a single injection of either paclitaxel, doxorubicin, epirubicin or fluorouracil, whereas mice fed the control diet were resistant to chemotherapy. Lf(+) had to be fed to mice for more than 2 weeks prior to chemotherapy to be wholly effective in eradicating tumours from all mice, suggesting that it acts as a competence factor. It significantly reduced tumour vascularity and blood flow, and increased antitumour cytotoxicity, tumour apoptosis and the infiltration of tumours by leukocytes. Lf(+) bound to the intestinal epithelium and was preferentially taken up within Peyer's patches. It increased the production of Th1 and Th2 cytokines within the intestine and tumour, including TNF, IFN-gamma, as well as nitric oxide that have been reported to sensitize tumours to chemotherapy. Importantly, it restored both red and white peripheral blood cell numbers depleted by chemotherapy, potentially fortifying the mice against cancer. In summary, bLf is a potent natural adjuvant and fortifying agent for augmenting cancer chemotherapy, but needs to be saturated with iron to be effective.

The safety of New Zealand bovine colostrum: nutritional and physiological evaluation in rats.

The potential detrimental effects of two different oral doses of bovine colostrum were assessed in young rats according to OECD guidelines. Colostrum was supplemented at 3% and 10% into a normal rat chow. A control group received the rat chow with no supplementation. After 90 days there was no difference between colostrum-fed animals and the control group in body weight, food consumption, clinical signs, haematology and most parameters of blood chemistry including carbohydrate metabolism, liver function and kidney function. The only effects of statistical significance were a decrease in serum cholesterol concentration in the rats receiving 10% colostrum (p<0.025), and a 33% increase in serum triglyceride concentration in the rats receiving 3% colostrum (p<0.005) although this was not apparent in the 10% colostrum group. Further, histological examination of most organs and tissues confirmed that there were no apparent differences between the animals receiving colostrum compared to controls. Based on these results, it can be concluded that the young growing rats had no observed toxicological and histopathological abnormalities caused by colostrum at the levels of supplementation used.