Neurodevelopment of Preterm Infants at 24 Months After Neonatal Supplementation of a Prebiotic Mix: A Randomized Trial.

OBJECTIVES: Fetal brain maturation is disrupted by preterm birth. Inflammation during the neonatal period may further harm neurodevelopmental outcomes. The present study aimed to determine the effect of short-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides/pectin-derived acidic oligosaccharides (scGOS/lcFOS/pAOS) on neurodevelopmental outcomes measured by Bayley Scales of Infant and Toddler Development in preterm infants at 24 months. METHODS: In this randomized controlled trial, scGOS/lcFOS/pAOS or placebo was supplemented between days 3 and 30 of life. Serum samples at day 1, 7, and 14 were analyzed for cytokine levels. Stool samples at day 1, 7, 14, and 30 were measured for bacterial count and bifidobacteria percentage. At 24 months corrected age infants were followed up by a blinded pediatric psychologist for the Bayley Scales of Infant and Toddler Development II or III. RESULTS: Seventy-seven of one hundred one (76%) eligible infants participated in the follow-up study. Neurodevelopmental outcomes were not different in the scGOS/lcFOS/pAOS and placebo group. Infections during the neonatal period, lower percentages of bifidobacteria at day 7 (F = 3.8, P = 0.05) and day 14 (F = 5.0, P = 0.02) and higher levels of Interleukine (IL)-1ß (F = 4.0, P = 0.04) and IL-8 (F = 8.0, P = 0.01) at day 7 are associated with lower mental developmental index. Lower psychomotor outcomes are associated with IL-2 (F = 4.0, P = 0.05), IL-4 (F = 6.0, P = 0.02) at birth, and interferon gamma at day 7 (F = 4.4, P = 0.04). CONCLUSIONS: scGOS/lcFOS/pAOS showed no significant improvement of neurodevelopmental outcomes at 24 months in preterm infants. Infections, lower bifidobacteria counts, and higher serum cytokine levels during the neonatal period were associated with lower neurodevelopmental outcomes at 24 months of age indicating the relevance of microbiome and immune responses in neurodevelopmental processes.

Response on Pneumococcal Vaccine in Preterm Infants After Neutral and Acidic Oligosaccharides Supplementation.

BACKGROUND: Supplementation of oligosaccharides in premature infants was shown to influence the immune system. We determined the effect of combined short-chain galacto-oligosaccharides (scGOS), long-chain fructo-oligosaccharides (lcFOS) and pectin-derived acidic oligosaccharides (pAOS) on antibody concentrations after pneumococcal conjugate vaccination in very preterm infants. METHODS: Very preterm infants with gestational age <32 weeks and/or birth weight <1500 g were randomized to receive enteral supplementation with scGOS/lcFOS/pAOS or placebo between days 3 and 30 of life. Blood samples were collected at birth, 5 and 12 months of age and compared with term samples from a Dutch cross-sectional population-based serosurveillance study. IgG antibody levels to pneumococcal capsular polysaccharides were determined by multiplex immunoassay. RESULTS: In total, 113 preterm infants were included with similar baseline and nutritional characteristics in both groups. After 3 primary pneumococcal vaccinations, the scGOS/lcFOS/pAOS-group had lower GMC antibody concentrations (µg/mL; serotype 4: 1.53, 6B:0.25, 9V: 1.19, 14: 2.39, 18C: 1.88, 19F: 7.42, 23F: 0.72) than the placebo group (serotype 4: 3.29, 6B: 0.79, 9V:2.64, 14: 4.52, 18C: 3.13, 19F: 14.64, 23F: 1.88; all P < 0.05), but comparable with those in the term control group (serotype 4: 0.97, 6B: 0.32, 9V: 1.67, 14: 3.24, 18C: 2.03, 19F: 5.06, 23F: 0.59; all P > 0.05). After the booster vaccination at 11 months, antibody levels were no longer different between the two preterm groups. CONCLUSION: Enteral supplementation of scGOS/lcFOS/pAOS has a regulatory effect on the response to conjugated polysaccharide pneumococcal vaccine with normalization of the enhanced responses in preterm infants toward levels similar to healthy term infants.

Lower transplacental antibody transport for measles, mumps, rubella and varicella zoster in very preterm infants.

BACKGROUND: Maternal antibodies, transported over the placenta during pregnancy, contribute to the protection of infants from infectious diseases during the first months of life. In term infants, this protection does not last until the first recommended measles-mumps-rubella vaccination at 14 months in the Netherlands, while these viruses still circulate. The aim of the study was to investigate the antibody concentration against measles, mumps, rubella and varicella (MMRV) in mothers and preterm infants or healthy term infants at birth. METHODS: Antibody concentrations specific for MMRV were measured in cord blood samples from preterm (gestational age <32 weeks and/or birth weight <1500 g) and term infants, and matched maternal serum samples, using a fluorescent bead-based multiplex immune-assay. RESULTS: Due to lower placental transfer ratios of antibodies against MMRV in 96 preterm infants (range 0.75-0.87) compared to 42 term infants (range 1.39-1.65), the preterm infants showed 1.7-2.5 times lower geometric mean concentrations at birth compared to term infants. Maternal antibody concentration is the most important determinant of infant antibody concentration against MMRV. CONCLUSIONS: Preterm infants benefit to a lesser extent from maternal antibodies against measles, mumps, rubella and varicella than term infants, posing them even earlier at risk for infectious diseases caused by these still circulating viruses.

Neonatal modulation of serum cytokine profiles by a specific mixture of anti-inflammatory neutral and acidic oligosaccharides in preterm infants.

Infections are common in preterm infants and cause differences in cytokine levels. Aim of this study was to measure cytokine levels in preterm infants during the first year of life and to determine the effect of feeding a specific non-digestible carbohydrate mixture (scGOS/lcFOS/pAOS). Furthermore, other perinatal factors in relation to these cytokine levels were analysed. In a randomized controlled trial, preterm infants (GA <32weeks and/or birth weight <1500 g) received a scGOS/lcFOS/pAOS mixture or a placebo (maltodextrin) between days 3 and 30 of life. Cytokine levels (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, IFN-γ, and TNF-α) were analysed at 5 time points during the study: before start of the study, at day 7, at day 14 and at 5 and 12 months after the start of the intervention. In total, 55 preterm infants in the scGOS/lcFOS/pAOS group and 58 in the placebo group were included. During the neonatal period cytokine levels increased, followed by a decrease at 5 months and 12 months. Enteral supplementation of the non-digestible oligosaccharides decreased cytokine levels at day 7 but not at day 14, indicating a temporarily anti-inflammatory effect. In the neonatal period, serious infection before sampling increased all cytokine levels. In conclusion, enteral supplementation of this specific non-digestible oligosaccharide mixture decreased cytokine levels in preterm infants at day 7 of life, although this effect disappeared thereafter.

Neutral and acidic oligosaccharides supplementation does not increase the vaccine antibody response in preterm infants in a randomized clinical trial.

BACKGROUND: In preterm infants, a decreased immunological response and lower serological effectiveness are observed after immunizations due to ineffectiveness of both humoral and cellular immune mechanisms. OBJECTIVE: To determine the effect of 80% neutral oligosaccharides [small-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (scGOS/lcFOS)] in combination with 20% pectin-derived acidic oligosaccharides (pAOS) on antibody concentrations after DTaP-IPV-Hib immunization in preterm infants. DESIGN: In this randomized clinical trial, preterm infants with gestational age <32 weeks and/or birth weight <1500 g received enteral supplementation with scGOS/lcFOS/pAOS or placebo (maltodextrin) between days 3 and 30 of life. Blood samples were collected at 5 and 12 months of age. RESULTS: In total, 113 infants were included. Baseline and nutritional characteristics were not different in both groups. Geometric mean titers were not different after prebiotic supplementation at 5 months, Ptx (37/44 EU/ml), FHA (78/96 EU/ml), Prn (78/80 EU/ml), Diphtheria (0.40/0.57 IU/ml), Tetanus (0.74/0.99 IU/ml) and Hib (0.35/0.63 µg/ml), and at 12 months Ptx (55/66 EU/ml), FHA (122/119 EU/ml), Prn (116/106 Eu/ml), Diphtheria (0.88/1.11 IU/ml), Tetanus (1.64/1.79 IU/ml) and Hib (2.91/2.55 µg/ml). CONCLUSIONS: Enteral supplementation of neutral (scGOS/lcFOS) and acidic oligosaccharides (pAOS) does not improve the immunization response in preterm infants. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN16211826 ISRCTN16211826.

Transplacental transport of IgG antibodies specific for pertussis, diphtheria, tetanus, haemophilus influenzae type b, and Neisseria meningitidis serogroup C is lower in preterm compared with term infants.

BACKGROUND: Maternal antibodies, transported through the placenta during pregnancy, contribute to the protection of infants from infectious diseases during the first months of life. The aim of this study was to measure the concentration of antibodies against several vaccine-preventable diseases in paired maternal and cord blood serum samples in preterm and term infants and to assess placental transfer ratios and infant antibody concentrations against vaccine-preventable diseases. METHODS: Antibody concentrations specific against pertussis proteins (pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae), diphtheria and tetanus toxins, and antibody concentrations specific against polysaccharides from Haemophilus influenzae type b and Neisseria meningitidis serogroup C were measured in cord blood samples from preterm (<32 weeks and 1500 g) and term infants and maternal serum samples, using a fluorescent bead-based multiplex immunoassay. RESULTS: A total of 96 preterm and 42 term infants and their mothers were included in the study. Placental transfer ratios of antibodies against all vaccine antigens were significantly lower in preterm infants (medians varied from 0.26 to 0.86) compared with term infants (medians, 0.74-1.89; all antibodies P < 0.05). Furthermore, polysaccharide-vaccine-specific antibodies showed lower transplacental transport ratios than protein-vaccine-specific antibodies. Maternal concentrations are the most important determinants of infant antibody concentrations against vaccine-preventable diseases. CONCLUSIONS: Preterm infants benefit to a lesser extent from maternal antibodies against vaccine-preventable diseases than term infants, posing them at higher risk for infectious diseases in the first months of life.

Neutral and acidic oligosaccharides in preterm infants: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Serious infectious morbidity is high in preterm infants. Enteral supplementation of prebiotics may reduce the incidence of serious infections, especially infections related to the gastrointestinal tract. OBJECTIVE: The objective was to determine the effect of enteral supplementation of a prebiotic mixture consisting of neutral oligosaccharides ((SC)GOS/(LC)FOS) and acidic oligosaccharides (AOS) on serious infectious morbidity in preterm infants. DESIGN: In a randomized controlled trial, preterm infants (gestational age <32 wk and/or birth weight <1500 g) received enteral supplementation of 80% (SC)GOS/(LC)FOS and 20% AOS (1.5 g . kg(-1) . d(-1)) or placebo (maltodextrin) between days 3 and 30 of life. Serious infectious morbidity was defined as a culture positive for sepsis, meningitis, pyelonephritis, or pneumonia. The analysis was performed by intention-to-treat and per-protocol, defined as > or =50% supplementation dose during the study period. RESULTS: In total, 113 preterm infants were included. Baseline and nutritional characteristics were not different between groups. In the intention-to-treat analysis, the incidence of > or =1 serious infection, > or =1 serious endogenous infection, or > or =2 serious infectious episodes was not significantly different in the (SC)GOS/(LC)FOS/AOS-supplemented and placebo groups. In the per-protocol analysis, there was a trend toward a lower incidence of > or =1 serious endogenous infection and > or =2 serious infectious episodes in the (SC)GOS/(LC)FOS/AOS-supplemented group than in the placebo group (P = 0.09 and P = 0.07, respectively). CONCLUSIONS: Enteral supplementation of (SC)GOS/(LC)FOS/AOS does not significantly reduce the risk of serious infectious morbidity in preterm infants. However, there was a trend toward a lower incidence of serious infectious morbidity, especially for infections with endogenous bacteria. This finding suggests a possible beneficial effect that should be evaluated in a larger study. This trial was registered at isrctn.org as ISRCTN16211826.