Luis Gomez

The Role of Inflammation and Infection in Preterm Birth

Much emphasis in recent decades has been devoted to inflammation and infection as a premier causal mechanism of preterm birth. This article explores the epidemiologic, clinical, and animal data that exist to support this conceptual paradigm as well as proposed mechanisms through which to potentially mitigate the adversity of prematurity. Truly successful interventions are not likely to occur until the pathogenesis of preterm birth and the role of inflammation in causing not only parturition but also fetal and neonatal injury is fully elucidated.

Evidence of a gene-environment interaction that predisposes to spontaneous preterm birth: a role for asymptomatic bacterial vaginosis and DNA variants in genes that control the inflammatory response

OBJECTIVE We determined whether an environmental exposure to bacterial vaginosis (BV) modified genetic susceptibilities for spontaneous preterm delivery within genes that regulate the inflammatory response. STUDY DESIGN Maternal DNA samples and vaginal smears for Gram staining were collected from 743 women (68 preterm births). We used a 1536-single nucleotide polymorphism (SNP) custom chip to study associations between genotype distributions and preterm birth. RESULTS For 8 SNPs in 3 genes (protein kinase C alpha, fms-like tyrosine kinase 1, and interleukin 6), the odds ratios for preterm birth ranged from 1.9-4.0 among women with susceptible genotypes who were BV positive. The odds ratios for preterm birth were 2.0-5.0 times greater among women who were BV positive than among women who were BV negative. The significance of these differences was demonstrated by logistic regression analyses for genotype/BV interaction. CONCLUSION These results demonstrate that the risk of preterm delivery that is associated with tag SNPs in genes that regulate the inflammatory response is modified by an environmental exposure such as bacterial vaginosis.

Trophoblast infection with Chlamydia pneumoniae and adverse pregnancy outcomes associated with placental dysfunction

OBJECTIVE We sought to determine whether Chlamydia pneumoniae impairs invasive trophoblast function and is associated with preeclampsia. STUDY DESIGN We conducted cell viability and invasion assays using primary extravillous trophoblast cells isolated from first-trimester placentas. We performed a case-control study to identify C pneumoniae in trophoblast cells dissected by laser capture microscopy from placentas in women with severe preeclampsia and control subjects who delivered at term. RESULTS Trophoblast cell viability and invasion through extracellular matrices were decreased after infection with C pneumoniae (both P < .05). C pneumoniae DNA was detected in trophoblast cells in 15/48 cases but only 3/30 controls (odds ratio, 4.1; P = .02). Positive and negative controls yielded expected results. CONCLUSION C pneumoniae infection can reduce trophoblast invasion into the uterine wall and is associated with preeclampsia. Further investigation of the mechanisms by which C pneumoniae induces trophoblast dysfunction, and the identification of therapies to prevent adverse outcomes attributed to trophoblast dysfunction, are warranted.

CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops.

Background Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome) is a rare autosomal recessive disorder, characterized by 1) neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2) severe chronic lymphedema, mainly lower limb. LCS was originally described in a Norwegian kindred in which a locus, LCS1, was mapped to a 6.6cM region on chromosome 15. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS. Methods Consanguineous parents of Mexican ancestry had a child with LCS who did not exhibit extended homozygosity in the LCS1 region. A subsequent pregnancy was electively terminated due to fetal hydrops. We performed whole-genome single nucleotide polymorphism genotyping to identify regions of homozygosity in these siblings, and sequenced promising candidate genes. Results Both siblings harbored a homozygous mutation in CCBE1, c.398 T>C, predicted to result in the missense change p.L133P. Regions containing known ‘cholestasis genes’ did not demonstrate homozygosity in the LCS patient. Conclusions Mutations in CCBE1 may yield a phenotype not only of lymphatic dysplasia, but also of LCS or fetal hydrops; however, the possibility that the sibling with LCS also carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded.