Preterm birth (PTB), or the delivery prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. Although twin studies estimate that maternal genetic contributions account for approximately 30% of the incidence of PTB, and other studies reported fetal gene polymorphism association, to date no consistent associations have been identified. In this study, we performed the largest reported genome-wide association study analysis on 1,349 cases of PTB and 12,595 ancestry-matched controls from the focusing on genomic fetal signals. We tested over 2 million single nucleotide polymorphisms (SNPs) for associations with PTB across five subpopulations: African (AFR), the Americas (AMR), European, South Asian, and East Asian. We identified only two intergenic loci associated with PTB at a genome-wide level of significance: rs17591250 (P = 4.55E-09) on chromosome 1 in the AFR population and rs1979081 (P = 3.72E-08) on chromosome 8 in the AMR group. We have queried several existing replication cohorts and found no support of these associations. We conclude that the fetal genetic contribution to PTB is unlikely due to single common genetic variant, but could be explained by interactions of multiple common variants, or of rare variants affected by environmental influences, all not detectable using a GWAS alone.

Although earlier studies have shown that antiviral treatment regimens using valganciclovir (VGCV) improved hearing function in some infants with congenital cytomegalovirus (CMV) infection; its efficacy on the severity of hearing dysfunction is unclear. We conducted a prospective study among 26 infants with congenital CMV infections from 2009 to 2018. Oral VGCV (32 mg/kg/day) was administered for 6 weeks (November 2009 to June 2015; n = 20) or 6 months (July 2015 to March 2018, n = 6). Hearing function was evaluated by measuring the auditory brainstem response before VGCV treatment and at 6 months. Hearing dysfunction, defined as a V-wave threshold >40 dB, was categorized into: most severe, ≥91 dB; severe, 61–90 dB; and moderate, 41–60 dB. Hearing improvement was defined as a decrease of ≥20 dB from the pretreatment V-wave threshold. Of 52 ears in 26 infants with congenital CMV infection, 29 (56%) had hearing dysfunction, and of 29 ears, 16 (55%) improved after VGCV treatment. Although, 16 (84%) of 19 ears with moderate or severe hearing dysfunction improved after treatment (p < 0.001), 10 ears with the most severe form did not. In conclusion, VGCV treatment is effective in improving moderate and severe hearing dysfunction in infants with congenital CMV infection.

Our aims were to determine the clinical impact of oral valganciclovir (VGCV) in infants aged ≤2 months with congenital cytomegalovirus (CMV) disease and evaluate the efficacy of VGCV when initiated beyond the neonatal period. The multicenter, single-arm, open-label clinical trial was conducted in Japan. Twenty-five infants aged ≤2 months with congenital CMV disease involving the central nervous system were enrolled and treated with VGCV for 6 months. The primary endpoint was the change in the whole blood CMV load before and after treatment. The secondary endpoint was the change in the auditory brainstem response (ABR) before and after treatment. Changes in ABR were assessed between the younger and older age groups (≤ and >30 days at treatment initiation). Of the 25 patients, one was excluded owing to epilepsy before VGCV administration. The median change in the CMV DNA level in whole blood was −246.0 IU/mL. The best ear and total ear assessments based on ABR were categorized as (improved + unchanged) after treatment for 100% and 93.8%, respectively. No differences in hearing efficacy were observed between the younger and older age groups. Oral VGCV is a potential therapeutic option for treating infants aged ≤2 months with congenital CMV disease.

Preterm sepsis is characterized by systemic bacterial invasion and inflammatory response. Its pathogenesis is unclear due to lack of proper animal models. Heme oxygenase-1 (HO-1) can affect physiologic and pathologic conditions through its anti-inflammatory, antioxidative, and anti-apoptotic properties. Since HO-1 is developmentally regulated, it may play a role in the pathogenesis of preterm sepsis. For this study, sepsis was induced using the non-surgical “cecal slurry” (CS) model. CS was given intraperitoneally at various doses to 4-day-old newborn mice to determine dose-dependent effects. The LD40 was then given and changes in bodyweight, bacterial colonization of organs, hematology, serum biochemistry, and immunomodulatory gene expression were determined. We found a dose-dependent mortality with an LD40 of 2.0 mg/g. Significant bacterial colonization and hematological changes (leukocytopenia, thrombocytopenia, and lymphocytopenia) and increased gene expression of pro-inflammatory cytokines, pattern-recognition receptors, and other genes related to immune responses were also observed. Twenty-four hours post-sepsis induction, bodyweight loss was associated with mortality and organ damage. Finally, to elucidate a protective role of HO-1, 30-μmol heme/kg was given subcutaneously 24 h pre-sepsis induction. HO activity in livers and spleens significantly increased 64% and 50% over age-matched controls 24 h post-heme administration. Importantly, heme significantly reduced mortality from 40.9% to 6.3% (P <0.005) and gene expression of pro-inflammatory cytokines (Ccl5, Cxcl10, IL-1b, and Ifng). We conclude that the CS model can be used as a model to study preterm sepsis. Because induction of HO-1 significantly reduced mortality, we speculate that HO-1 may confer protection against sepsis in preterm infants.