Abstract
Preterm birth (PTB) at less than 37 weeks of gestation is the leading cause of neonatal morbidity and mortality. Intrauterine infection (IUI) due to microbial invasion of the amniotic cavity is the leading cause of early PTB (<32 weeks). Commensal genital tract Ureaplasma and Mycoplasma species, as well as Gram-positive and Gram-negative bacteria, have been associated with IUI-induced PTB. Bacterial activation of Toll-like receptors and other pattern recognition receptors initiates a cascade of inflammatory signaling via the NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling pathways, prematurely activating parturition. Antenatal antibiotic treatment has had limited success in preventing PTB or fetal inflammation. Administration of anti-inflammatory drugs with antibiotics could be a viable therapeutic option to prevent PTB and fetal complications in women at risk of IUI and inflammation. In this mini-review, we will discuss the potential for anti-inflammatory drugs in obstetric care, focusing on the class of drugs termed “cytokine suppressive anti-inflammatory drugs” or CSAIDs. These inhibitors work by specifically targeting the NF-κB and p38 MAPK inflammatory signaling pathways. Several CSAIDs are discussed, together with clinical and toxicological considerations associated with the administration of anti-inflammatory agents in pregnancy.
Highlights
Preterm birth (PTB), delivery prior to 37 weeks of gestation, is estimated to affect 5–15% of pregnancies worldwide (1) and remains the leading cause of morbidity and mortality of neonates (2) and the second largest direct cause of death in children under 5 years (3)
We propose that a combination of anti-inflammatory therapy and effective antibiotics will be required to combat intrauterine infection (IUI) and reduce the associated inflammatory responses leading to preterm labor (PTL) and adverse fetal sequelae
Based on our current appreciation of the importance of intrauterine infection (IUI) and inflammation in the etiology of Preterm birth (PTB), the identification and treatment of pregnant women at risk of IUI with effective cytokine signaling inhibitors holds great promise for the prevention of PTB and improvement of neonatal outcomes
Summary
Preterm birth (PTB), delivery prior to 37 weeks of gestation, is estimated to affect 5–15% of pregnancies worldwide (1) and remains the leading cause of morbidity and mortality of neonates (2) and the second largest direct cause of death in children under 5 years (3). CSAIDs: A NOVEL CLASS OF ANTI-INFLAMMATORY DRUGS As a class of compounds, CSAIDs target the NF-κB and p38 MAPK signaling pathways to inhibit cytokine-mediated events with demonstrated efficacy in a range of animal models (54–56) These agents are being examined for their potential to be more effective and selective than NSAIDs for the inhibition of inflammation-driven PTB, as they directly target signaling molecules leading to the activation of the NF-κB and p38 MAPK inflammatory cascades without interfering with the constitutive/homeostatic roles of prostanoids (Table 1 and Figure 1). NBDI was shown to inhibit LPS and Ureaplasma parvum-induced PGE2 production in ovine gestational membranes (38) but not γ-irradiation-killed E. coli-induced proinflammatory responses in ex vivo human fetal membranes (38); differences in binding affinity or endogenous protease activity in human fetal membranes may explain differential efficacy observed
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