The fetal inflammatory response syndrome (FIRS) is a condition characterized by systemic inflammation and an elevation of fetal plasma interleukin-6. This syndrome has been observed in fetuses with preterm labor with intact membranes, preterm prelabor rupture of the membranes, and also fetal viral infections such as cytomegalovirus. FIRS is a risk factor for short-term perinatal morbidity and mortality after adjustment for gestational age at delivery and also for the development of long-term sequelae such as bronchopulmonary dysplasia and brain injury. Multiorgan involvement in FIRS has been demonstrated in the hematopoietic system, thymus, adrenal glands, skin, kidneys, heart, lung, and brain. This article reviews the fetal systemic inflammatory response as a mechanism of disease. Potential interventions to control an exaggerated inflammatory response in utero are also described.

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We conducted a systematic review and meta-analysis to characterize the relationship between smoking and miscarriage. We searched the PubMed database (1956-August 31, 2011) using keywords and conducted manual reference searches of included articles and reports of the US Surgeon General. The full text of 1,706 articles was reviewed, and 98 articles that examined the association between active or passive smoking and miscarriage were included in the meta-analysis. Data were abstracted by 2 reviewers. Any active smoking was associated with increased risk of miscarriage (summary relative risk ratio = 1.23, 95% confidence interval (CI): 1.16, 1.30; n = 50 studies), and this risk was greater when the smoking exposure was specifically defined as during the pregnancy in which miscarriage risk was measured (summary relative risk ratio = 1.32, 95% CI: 1.21, 1.44; n = 25 studies). The risk of miscarriage increased with the amount smoked (1% increase in relative risk per cigarette smoked per day). Secondhand smoke exposure during pregnancy increased the risk of miscarriage by 11% (95% CI: 0.95, 1.31; n = 17 studies). Biases in study publication, design, and analysis did not significantly affect the results. This finding strengthens the evidence that women should not smoke while pregnant, and all women of reproductive age should be warned that smoking increases the risk of miscarriage.

Fetal development and growth occur in a sterile amniotic cavity while first exposure to microorganisms happens at birth. However, at least 25% of all preterm births, the leading cause of perinatal morbidity and mortality worldwide, occur in mothers with microbial invasion of the amniotic cavity. Microbial attack of the fetus takes place in approximately 10% of pregnancies with intra-amniotic infection, and the human fetus is capable of deploying an inflammatory response (cellular and humoral) in the mid-trimester of pregnancy. The onset of premature labor in the context of infection is mediated by pro-inflammatory cytokines, such as interleukin (IL)-1beta and tumor necrosis factor alpha (TNF-alpha), as these cytokines are produced by intrauterine tissues in response to microbial products, can stimulate prostaglandin production, and induce labor in animals. Moreover, knockout experiments suggest that infection is less likely to lead to premature labor when the IL-1 and TNF signaling pathways are disrupted. A fetal inflammatory systemic response occurs in a fraction of fetuses exposed to microorganisms in utero, and is associated with the impending onset of labor as well as multisystem organ involvement. Neonates born with funisitis, the histologic marker of such inflammation, are at increased risk for neurologic handicap and cerebral palsy. Evidence has begun to accumulate that gene-environment interactions determine the likelihood of preterm labor and delivery and, probably, the risk of fetal injury. Fetal inflammation has emerged as a major mechanism of disease responsible for complications in the perinatal period (in utero and in the first 28 days of life), as well as in infancy. Moreover, reprogramming of the fetal immune response may predispose to diseases in adulthood.