Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2013

Exploration of the effects of intra-amniotic delivery of anti-inflammatory drugs on human fetal membranes in an ex-vivo two-compartment model (#157)

Demelza J Ireland 1 , Lisa F Stinson 1 , Adrian K Charles 1 , John P Newnham 1 , Jeff A Keelan 1
  1. School of Women's and Infants' Health, University of Western Australia, Crawley, WA, Australia

Background and rationale: Anti-inflammatory agents may be useful in treating intrauterine inflammation, the major cause of preterm labour and birth (PTB) prior to 32 weeks’ gestation.  The aim of this study was to compare the efficacy of a range of anti-inflammatory drugs using an ex-vivo model mimicking intra-amniotic (IA) drug delivery in human preterm fetal membranes.

Methods: Extra-placental membranes collected from preterm placentas (30-34 weeks’ gestation) delivered vaginally or by C-Section after spontaneous onset of labour (excluding preeclampsia and gestational diabetes) were retrospectively defined as with/without inflammation (+INF/-INF) by histopathology. Membranes were secured over Transwell inserts and placed in 6-well culture plates. After 12 h equilibration, N-acetyl cysteine [NAC; 10 mM], SB239063 [20 µM], TPCA-1 [7 µM], NEMO binding domain inhibitor [NBD; 10 µM] and (5Z)-7-Oxozeaenol [OxZ; 3 µM]) were added to the amniotic compartment. Accumulation of IL-10, IL-6, TNF-α, MCP-1 and PGE2 were measured in fetal and maternal conditioned media after 12 h incubation at 37oC. Twins with distinct membranes were processed as separate placentas (2/3).

Results: Eight singleton and three twin pregnancies have been recruited to date. Maternal age, gravidity/parity, gestational age, sex and birthweight were consistent across groups.  Five from 11 deliveries were +INF, with Ureaplasma urealyticum identified in 2/5, Staphylococcus aureus in 1/5 and clinical chorioamnionitis in 1/5. Of the five drugs tested, OxZ (TAK1 inhibitor) and TPCA-1 (IKKβ inhibitor) were most effective at inhibiting amniotic accumulation of cytokines and PGE2, with inhibitory effects of 50-70%. TAK1 and TPCA-1 had greatest effect on amniotic production of PGE2 and MCP-1 in –INF membranes and IL-6 and TNF-α in +INF membranes. SB239063 had some effect whilst NAC and NBD were minimally effective.

Conclusions: Preliminary data from this ongoing study suggests IA administration of NF-κB and TAK1 inhibitors could be effective treatments for intrauterine inflammation and prevention of preterm birth.