Birth weight discordance and adverse fetal and neonatal outcomes among triplets in the United States.

OBJECTIVE: To examine the association between intratriplet birth weight discordance, fetal and neonatal mortality, and smallness for gestational age. METHODS: The 1995-1997 Centers for Disease Control and Prevention's Matched Multiple Birth file was used for this analysis. Birth weight discordance was calculated as the difference in birth weight between the largest and the smallest triplet's weight and expressed as percentage of the largest triplet's weight. For the middle-weight triplet, we also used the largest triplet's weight as a reference in calculating percentage birth weight discordance, which was then grouped into quintiles. RESULTS: Among 15,511 triplet live births and fetal deaths (at least 20 weeks' gestation), 35% had less than 10% birth weight discordance, 19.3% had 10-15%, 16.4% had 15-21%, 15.2% had 21-29%, and 14.1% had 29% or more. After controlling for confounders, the risk of fetal death associated with quintile V was significantly higher than that associated with quintile I for smallest (odds ratio [OR] 10.88; 95% confidence interval [CI] 4.87, 26.56), middle (OR 22.6; 95% CI 11.05, 46.3), and largest (OR 2.41; 95% CI 1.01, 5.89) triplets. Smallest and middle triplets in quintile V were more likely than quintile I triplets to be born small for gestational age (OR 26.0; 95% CI 17.1, 39.9 for smallest, and OR 13.4; 95% CI 8.01, 22.3 for middle). Birth weight discordance quintile was not associated with smallness for geatational age among largest triplets nor consistently with neonatal mortality among smallest, middle, or largest triplets. CONCLUSION: Increasing birth weight discordance was associated with increased risk of fetal death and smallness for gestational age. A birth weight discordance threshold of at least 29% should alert obstetricians for appropriate decision making.

Vaccination with recombinant fusion proteins incorporating Toll-like receptor ligands induces rapid cellular and humoral immunity.

Recognition of specific pathogen associated molecular patterns (PAMPs) is mediated primarily by members of the Toll-like receptor (TLR) family. Stimulation through these receptors results in quantitative and qualitative changes in antigen presentation and cellular activation, thereby linking innate and adaptive immunity. Consequently, the incorporation of TLR-ligands into vaccines could result in more potent and efficacious vaccines. To test this hypothesis, we employed a recombinant fusion protein strategy using the TLR5 ligand flagellin fused to specific antigens to promote protective immunity. These purified recombinant fusion proteins demonstrated potent TLR5-specific NF-kappaB dependent activity in vitro. Immunization of mice with the recombinant-flagellin-OVA fusion protein STF2.OVA resulted in potent antigen-specific T and B cell responses that were equal to or better than responses induced by OVA emulsified in Complete Freund's adjuvant. These included rapid and consistent antigen-specific IgG(1) and IgG(2a) antibody responses that were detectable within 7 days of immunization, and the development of protective CD8 T cell responses. Moreover, the enhanced immunogenicity to OVA is dependant on the direct fusion to flagellin, as co-delivery of OVA with flagellin unlinked failed to augment antigen-specific responses in vivo. Similar results were obtained using a recombinant fusion protein comprised of flagellin and a novel polypetide sequence containing two immuno-protective epitopes derived from the Listeria monocytogenes antigens p60 and listeriolysin O. Animals immunized with this recombinant protein demonstrated significant antigen-specific CD8 T cell responses and protection upon challenge with virulent L. monocytogenes. We conclude that immunization with PAMP:antigen fusion proteins induce rapid and potent antigen-specific responses in the absence of supplemental adjuvants. Collectively our data demonstrate that PAMP:antigen fusion proteins offer significant promise for developing recombinant protein vaccines.