Skip to main content Accessibility help
×
Hostname: page-component-546b4f848f-hhr79 Total loading time: 0 Render date: 2023-06-01T05:55:50.551Z Has data issue: false Feature Flags: { "useRatesEcommerce": true } hasContentIssue false

Section 4 - Problems Associated with Infection

Published online by Cambridge University Press:  15 November 2017

David James
Affiliation:
University of Nottingham
Philip Steer
Affiliation:
Imperial College London
Carl Weiner
Affiliation:
University of Kansas
Bernard Gonik
Affiliation:
Wayne State University, Detroit
Stephen Robson
Affiliation:
University of Newcastle
Get access

Summary

Intra-amniotic infection/inflammation (IAI) is a frequent and important cause of spontaneous preterm labor and delivery. Indeed, it is the only pathologic process for which both a causal link with spontaneous preterm birth has been established and a molecular pathophysiology defined. Fetal infection/inflammation has been implicated in the genesis of fetal and neonatal injury leading to cerebral palsy (CP) and chronic lung disease. Pathologic intra-amniotic inflammation can occur in the absence of detectable microorganisms, upon analysis by cultivation and/or molecular microbiologic techniques. This condition is known as sterile intra-amniotic inflammation and has been observed in patients with preterm labor and intact membranes, preterm prelabor rupture of the membranes (PPROM), and a short cervix. A mild sterile inflammatory process also participates in spontaneous labor at term, but this is considered to be an example of physiologic inflammation similar to that implicated in other important events in reproductive physiology, such as ovulation and implantation.

Type
Chapter
Information
High-Risk Pregnancy
Management Options
, pp. 579 - 602
Publisher: Cambridge University Press
First published in: 2017

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Further Reading

Conde-Agudelo, A, Romero, R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and meta-analysis. Am J Obstet Gynecol 2009; 200: 595609.CrossRefGoogle Scholar
DiGiulio, DB, Callahan, BJ, McMurdie, PJ, et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci U S A 2015; 112: 11060–5.CrossRefGoogle ScholarPubMed
Dong, Y, Yu, Z, Sun, Y, et al. Chronic fetal hypoxia produces selective brain injury associated with altered nitric oxide synthases. Am J Obstet Gynecol 2011; 204: e16–28.CrossRefGoogle ScholarPubMed
Gomez, R, Romero, R, Ghezzi, F, et al. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998; 179: 194202.CrossRefGoogle ScholarPubMed
Gomez, R, Romero, R, Nien, JK, et al. Antibiotic administration to patients with preterm premature rupture of membranes does not eradicate intra-amniotic infection. J Matern Fetal Neonatal Med 2007; 20: 167–73.CrossRefGoogle Scholar
Gomez-Lopez, N, Romero, R, Xu, Y, et al. A role for the inflammasome in spontaneous preterm labor with acute histologic chorioamnionitis. Reprod Sci 2017; 24: 1382–401.
Gonçalves, LF, Chaiworapongsa, T, Romero, R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 2002; 8: 313.CrossRefGoogle ScholarPubMed
Guo, R, Hou, W, Dong, Y, et al. Brain injury caused by chronic fetal hypoxemia is mediated by inflammatory cascade activation. Reprod Sci 2010; 17: 540–8.Google ScholarPubMed
Kenyon, SL, Taylor, DJ, Tarnow-Mordi, W. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE Collaborative Group. Lancet 2001; 357: 979–88.Google ScholarPubMed
Kenyon, S, Pike, K, Jones, DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet 2008; 372: 1310–18.Google ScholarPubMed
Kim, J, Choi, IY, Dong, Y, et al. Chronic fetal hypoxia affects axonal maturation in guinea pigs during development: A longitudinal diffusion tensor imaging and T2 mapping study. J Magn Reson Imaging 2015; 42: 658–65.CrossRefGoogle ScholarPubMed
Kim, CJ, Romero, R, Chaemsaithong, P, et al. Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. Am J Obstet Gynecol 2015; 213 (4 Suppl): S2952.
Leviton, A, Paneth, N. White matter damage in preterm newborns: an epidemiologic perspective. Early Hum Dev 1990; 24: 122.CrossRefGoogle Scholar
Nien, JK, Yoon, BH, Espinoza, J, et al. A rapid MMP-8 bedside test for the detection of intra-amniotic inflammation identifies patients at risk for imminent preterm delivery. Am J Obstet Gynecol 2006; 195: 1025–30.CrossRefGoogle ScholarPubMed
Romero, R, Brody, DT, Oyarzun, E, et al. Infection and labor. III. Interleukin-1: A signal for the onset of parturition. Am J Obstet Gynecol 1989; 160: 1117–23.Google ScholarPubMed
Romero, R, Dey, SK, Fisher, SJ Preterm labor: one syndrome, many causes. Science 2014; 345: 760–5.
Romero, R, Miranda, J, Chaiworapongsa, T, et al. A novel molecular microbiologic technique for the rapid diagnosis of microbial invasion of the amniotic cavity and intra-amniotic infection in preterm labor with intact membranes. Am J Reprod Immunol 2014; 71: 330–58.
Romero, R, Miranda, J, Chaiworapongsa, T, et al. Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Reprod Immunol 2014; 72: 458–74.
Romero, R, Xu, Y, Plazyo, O, et al. A role for the inflammasome in spontaneous labor at term. Am J Reprod Immunol 2018; 79: e12440.

References

Naeye, RL, Ross, SM. Amniotic fluid infection syndrome. Clin Obstet Gynecol 1982; 9: 593607.
Minkoff, H. Prematurity: infection as an etiologic factor. Obstet Gynecol 1983; 62: 137–44.
Romero, R, Mazor, M. Infection and preterm labor. Clin Obstet Gynecol 1988; 31: 553–84.
Ledger, WJ. Infection and premature labor. Am J Perinatol 1989; 6: 234–6.
Romero, R, Sirtori, M, Oyarzun, E, et al. Infection and labor. V. Prevalence, microbiology, and clinical significance of intra-amniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol 1989; 161: 817–24.
Gibbs, RS, Romero, R, Hillier, SL, et al. A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992; 166: 1515–28.
Goldenberg, RL, Hauth, JC, Andrews, WW. Intrauterine infection and preterm delivery. N Engl J Med 2000; 342: 1500–7.
Goncalves, LF, Chaiworapongsa, T, Romero, R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 2002; 8: 313.
Romero, R, Mazor, M, Munoz, H, et al. The preterm labor syndrome. Ann N Y Acad Sci 1994; 734: 414–29.
Romero, R, Dey, SK, Fisher, SJ Preterm labor: one syndrome, many causes. Science 2014; 345: 760–5.
Romero, R, Gomez, R, Ghezzi, F, et al. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 1998; 179: 186–93.
Gomez, R, Romero, R, Ghezzi, F, et al. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998; 179: 194202.
Yoon, BH, Romero, R, Park, JS, et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000; 182: 675–81.
Yoon, BH, Romero, R, Kim, KS, et al. A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1999; 181: 773–9.
Romero, R, Miranda, J, Chaiworapongsa, T, et al. A novel molecular microbiologic technique for the rapid diagnosis of microbial invasion of the amniotic cavity and intra-amniotic infection in preterm labor with intact membranes. Am J Reprod Immunol 2014; 71: 330–58.
Romero, R, Miranda, J, Chaiworapongsa, T, et al. Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Reprod Immunol 2014; 72: 458–74.
Romero, R, Miranda, J, Chaiworapongsa, T, et al. Sterile intra-amniotic inflammation in asymptomatic patients with a sonographic short cervix: prevalence and clinical significance. J Matern Fetal Neonatal Med 2014 Sep 24: 117.
Romero, R, Miranda, J, Chaemsaithong, P, et al. Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med 2015; 28: 1394–409.
Romero, R, Grivel, JC, Tarca, AL, et al. Evidence of perturbations of the cytokine network in preterm labor. Am J Obstet Gynecol 2015; 213: 836.e1–18.
Musilova, I, Kutová, R, Pliskova, L, et al. Intraamniotic inflammation in women with preterm prelabor rupture of membranes. PLoS One 2015; 10 (7): e0133929.
Maddipati, KR, Romero, R, Chaiworapongsa, T, et al. Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals up-regulation of leukotriene B4. FASEB J 2016; 30: 3296–307.
Musilova, I, Bestvina, T, Hudeckova, M, et al. Vaginal fluid interleukin-6 concentrations as a point-of-care test is of value in women with preterm prelabor rupture of membranes. Am J Obstet Gynecol 2016; 215: 619.e1–12.
Romero, R, Miranda, J, Kusanovic, JP, et al. Clinical chorioamnionitis at term I: microbiology of the amniotic cavity using cultivation and molecular techniques. J Perinat Med 2015; 43: 1936.
Romero, R, Chaemsaithong, P, Korzeniewski, SJ, et al. Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response. J Perinat Med 2016; 44: 522.
Romero, R, Chaemsaithong, P, Korzeniewski, SJ, et al. Clinical chorioamnionitis at term III: how well do clinical criteria perform in the identification of proven intra-amniotic infection? J Perinat Med 2016; 44: 2332.
Romero, R, Chaemsaithong, P, Docheva, N, et al. Clinical chorioamnionitis at term IV: the maternal plasma cytokine profile. J Perinat Med 2016; 44: 7798.
Romero, R, Chaemsaithong, P, Docheva, N, et al. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response. J Perinat Med 2016; 44: 5376.
Romero, R, Chaemsaithong, P, Docheva, N, et al. Clinical chorioamnionitis at term VI: acute chorioamnionitis and funisitis according to the presence or absence of microorganisms and inflammation in the amniotic cavity. J Perinat Med 2016; 44: 3351.
Chaiyasit, N, Romero, R, Chaemsaithong, P, et al. Clinical chorioamnionitis at term VIII: a rapid MMP-8 test for the identification of intra-amniotic inflammation. J Perinat Med 2017; 45: 539–50.
Musilova, I, Andrys, C, Drahosova, M, et al. Cervical fluid interleukin 6 and intra-amniotic complications of preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med 2018; 31: 827–36.
Romero, R, Xu, Y, Plazyo, O, et al. A role for the inflammasome in spontaneous labor at term. Am J Reprod Immunol 2018; 79: e12440.
Rock, KL, Kataoka, H, Lai, JJ Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol 2013; 9: 1323.
Duewell, P, Kono, H, Rayner, KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464: 1357–61.
Blanc, WA. Amniotic and neonatal infection: quick cytodiagnosis. Gynaecologia 1953; 136: 100–10.
Benirschke, K. Routes and types of infection in the fetus and the newborn. Am J Dis Child 1960; 99: 714–21.
Blanc, WA. Pathways of fetal and early neonatal infection: viral placentitis, bacterial and fungal chorioamnionitis. J Pediatr 1961; 59: 473–96.
Driscoll, S. Pathology and the developing fetus. Pediatr Clin North Am 1965; 12: 493514.
Romero, R, Gomez-Lopez, N, Winters, AD, et al. Evidence that intra-amniotic infections are often the result of an ascending invasion: a molecular microbiological study. J Perinat Med 2019; 47: 915–31. https://doi.org/10.1515/jpm-2019-0297.
Benirschke, K, Clifford, SH. Intrauterine bacterial infection of the newborn infant: frozen sections of the cord as an aid to early detection. J Pediatr 1959; 54: 1118.
Romero, R, Shamma, F, Avila, C, et al. Infection and labor. VI. Prevalence, microbiology, and clinical significance of intra-amniotic infection in twin gestations with preterm labor. Am J Obstet Gynecol 1990; 163: 757–61.
Galask, RP, Varner, MW, Petzold, CR, Wilbur, SL. Bacterial attachment to the chorioamniotic membranes. Am J Obstet Gynecol 1984; 148: 915–28.
Romero, R, Kadar, N, Hobbins, JC, Duff, GW. Infection and labor: the detection of endotoxin in amniotic fluid. Am J Obstet Gynecol 1987; 157: 815–19.
Newnham, JP, Moss, TJ, Kramer, BW, et al. The fetal maturational and inflammatory responses to different routes of endotoxin infusion in sheep. Am J Obstet Gynecol 2002; 186: 1062–8.
Thompson, PJ, Greenough, A, Gamsu, HR, et al. Congenital bacterial sepsis in very preterm infants. J Med Microbiol 1992; 36: 117–20.
Carroll, SG, Papaioannou, S, Ntumazah, IL, et al. Lower genital tract swabs in the prediction of intrauterine infection in preterm prelabour rupture of the membranes. Br J Obstet Gynaecol 1996; 103: 54–9.
Goldenberg, RL, Andrews, WW, Goepfert, AR, et al. The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol 2008; 198: 43–5.
Hillier, SL, Krohn, MA, Kiviat, NB, et al. Microbiologic causes and neonatal outcomes associated with chorioamnion infection. Am J Obstet Gynecol 1991; 165: 955–61.
Yoon, BH, Romero, R, Park, JS, et al. Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol 1998; 179: 1254–60.
Hitti, J, Riley, DE, Krohn, MA, et al. Broad-spectrum bacterial rDNA polymerase chain reaction assay for detecting amniotic fluid infection among women in premature labor. Clin Infect Dis 1997; 24: 1228–32.
Alanen, A. Polymerase chain reaction in the detection of microbes in amniotic fluid. Ann Med 1998; 30: 288–95.
Jalava, J, Mantymaa, ML, Ekblad, U, et al. Bacterial 16S rDNA polymerase chain reaction in the detection of intra-amniotic infection. Br J Obstet Gynaecol 1996; 103: 664–9.
Gardella, C, Riley, DE, Hitti, J, et al. Identification and sequencing of bacterial rDNAs in culture-negative amniotic fluid from women in premature labor. Am J Perinatol 2004; 21: 319–23.
Cassell, GH, Andrews, WW, Hauth, JC, Cutter, G. Chorioamnion colonization: correlation with gestational age in women delivered following spontaneous labor versus indicated delivery. Am J Obstet Gynecol 1993; 168: 425.
Andrews, WW, Shah, SR, Goldenberg, RL, et al. Association of post-cesarean delivery endometritis with colonization of the chorioamnion by Ureaplasma urealyticum. Obstet Gynecol 1995; 85: 509–14.
Watts, DH, Krohn, MA, Hillier, SL, Eschenbach, DA. The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol 1992; 79: 351–7.
Yoon, BH, Kim, YA, Romero, R, et al. Association of oligohydramnios in women with preterm premature rupture of membranes with an inflammatory response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol 1999; 181: 784–8.
Romero, R, Quintero, R, Oyarzun, E, et al. Intra-amniotic infection and the onset of labor in preterm premature rupture of the membranes. Am J Obstet Gynecol 1988; 159: 661–6.
Gomez, R, Romero, R, Nien, JK, et al. Antibiotic administration to patients with preterm premature rupture of membranes does not eradicate intra-amniotic infection. J Matern Fetal Neonatal Med 2007; 20: 167–73.
Romero, R, Gonzalez, R, Sepulveda, W, et al. Infection and labor. VIII. Microbial invasion of the amniotic cavity in patients with suspected cervical incompetence: prevalence and clinical significance. Am J Obstet Gynecol 1992; 167: 1086–91.
Lee, KY, Jun, HA, Kim, HB, Kang, SW. Interleukin-6, but not relaxin, predicts outcome of rescue cerclage in women with cervical incompetence. Am J Obstet Gynecol 2004; 191: 784–9.
Lee, SE, Romero, R, Park, CW, et al. The frequency and significance of intra-amniotic inflammation in patients with cervical insufficiency. Am J Obstet Gynecol 2008; 198: 633–8.
Andersen, HF, Nugent, CE, Wanty, SD, Hayashi, RH. Prediction of risk for preterm delivery by ultrasonographic measurement of cervical length. Am J Obstet Gynecol 1990; 163: 859–67.
Iams, JD, Goldenberg, RL, Meis, PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med 1996; 334: 567–72.
Heath, VC, Southall, TR, Souka, AP, et al. Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol 1998; 12: 312–17.
Hassan, SS, Romero, R, Berry, SM, et al. Patients with an ultrasonographic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol 2000; 182: 1458–67.
Hassan, S, Romero, R, Hendler, I, et al. A sonographic short cervix as the only clinical manifestation of intra-amniotic infection. J Perinat Med 2006; 34: 1319.
Kiefer, DG, Keeler, SM, Rust, OA, et al. Is midtrimester short cervix a sign of intraamniotic inflammation? Am J Obstet Gynecol 2009; 200: 374–5.
Mazor, M, Hershkovitz, R, Ghezzi, F, et al. Intra-amniotic infection in patients with preterm labor and twin pregnancies. Acta Obstet Gynecol Scand 1996; 75: 624–7.
Romero, R, Salafia, CM, Athanassiadis, AP, et al. The relationship between acute inflammatory lesions of the preterm placenta and amniotic fluid microbiology. Am J Obstet Gynecol 1992; 166: 1382–8.
Hillier, SL, Witkin, SS, Krohn, MA, et al. The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection. Obstet Gynecol 1993; 81: 941–8.
Pacora, P, Chaiworapongsa, T, Maymon, E, et al. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med 2002; 11: 1825.
Hillier, SL, Martius, J, Krohn, M, et al. A case–control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med 1988; 319: 972–8.
Andrews, WW, Hauth, JC, Goldenberg, RL, et al. Amniotic fluid interleukin-6: correlation with upper genital tract microbial colonization and gestational age in women delivered after spontaneous labor versus indicated delivery. Am J Obstet Gynecol 1995; 173: 606–12.
Steel, JH, Malatos, S, Kennea, N, et al. Bacteria and inflammatory cells in fetal membranes do not always cause preterm labor. Pediatr Res 2005; 57: 404–11.
Kim, MJ, Romero, R, Gervasi, MT, et al. Widespread microbial invasion of the chorioamniotic membranes is a consequence and not a cause of intra-amniotic infection. Lab Invest 2009; 89: 924–36.
Kim, CJ, Romero, R, Chaemsaithong, P, et al. Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. Am J Obstet Gynecol 2015; 213 (4 Suppl): S2952.
Cassell, GH, Davis, RO, Waites, KB, et al. Isolation of Mycoplasma hominis and Ureaplasma urealyticum from amniotic fluid at 16–20 weeks of gestation: Potential effect on outcome of pregnancy. Sex Transm Dis 1983; 10: 294302.
Gray, DJ, Robinson, HB, Malone, J, Thomson, RB. Adverse outcome in pregnancy following amniotic fluid isolation of Ureaplasma urealyticum. Prenat Diagn 1992; 12: 111–17.
Horowitz, S, Mazor, M, Romero, R, et al. Infection of the amniotic cavity with Ureaplasma urealyticum in the midtrimester of pregnancy. J Reprod Med 1995; 40: 375–9.
Berg, TG, Philpot, KL, Welsh, MS, et al. Ureaplasma/Mycoplasma-infected amniotic fluid: pregnancy outcome in treated and nontreated patients. J Perinatol 1999; 19: 275–7.
Romero, R, Avila, C, Santhanam, U, Sehgal, PB. Amniotic fluid interleukin 6 in preterm labor: association with infection. J Clin Invest 1990; 85: 1392–400.
Yoon, BH, Romero, R, Kim, CJ, et al. Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 1995; 172: 960–70.
Romero, R, Munoz, H, Gomez, R, et al. Two thirds of spontaneous abortion/fetal death after genetic amniocentesis are the result of a pre-existing sub-clinical inflammatory process of the amniotic cavity. Am J Obstet Gynecol 1995; 172: 261.
Wenstrom, KD, Andrews, WW, Tamura, T, et al. Elevated amniotic fluid interleukin-6 levels at genetic amniocentesis predict subsequent pregnancy loss. Am J Obstet Gynecol 1996; 175: 830–3.
Bujold, E, Tetu, A, Laforest, G, et al. “Silent” intra-amniotic inflammation precedes early spontaneous preterm labor. Sage Journal, Society of Reproductive Investigation, Montreal (Canada) 2016; 126A.
Soucy-Giguere, L, Vachon-Marceau, C, Tétu, A, et al. Subclinical intra-amniotic inflammation in the midtrimester and the subsequent development of abnormal gross motor skills in infants born either term or preterm. Abstract 115. Presented at the 37th Annual Pregnancy Meeting of the Society for Maternal-Fetal Medicine, Jan 23 –28, 2017, Las Vegas, Nevada. Am J Obstet Gynecol 2017; 216 (Supplement 1): S801.
Weiner, CP, Stone, P, Dong, Y. Lack of intra-amniotic inflammation (IAI) during the mid-second trimester of women with spontaneous preterm birth (PTB). Society for Maternal Fetal Medicine, Chicago, IL, February 2010.
Romero, R, Kadar, N, Miranda, J, et al. The diagnostic performance of the mass restricted (MR) score in the identification of microbial invasion of the amniotic cavity or intra-amniotic inflammation is not superior to amniotic fluid interleukin-6. J Matern Fetal Neonatal Med 2014; 27: 757–69.
Chaiworapongsa, T, Romero, R, Tolosa, JE, et al. Elevated monocyte chemotactic protein-1 in amniotic fluid is a risk factor for pregnancy loss. J Matern Fetal Neonatal Med 2002; 12: 159–64.
Yoon, BH, Oh, SY, Romero, R, et al. An elevated amniotic fluid matrix metalloproteinase-8 level at the time of mid-trimester genetic amniocentesis is a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol 2001; 185: 1162–7.
Wenstrom, KD, Andrews, WW, Hauth, JC, et al. Elevated second- trimester amniotic fluid interleukin-6 levels predict preterm delivery. Am J Obstet Gynecol 1998; 178: 546550.
Ghidini, A, Eglinton, GS, Spong, CY, et al. Elevated mid-trimester amniotic fluid tumor necrosis alpha levels: a predictor of preterm delivery. Am J Obstet Gynecol 1996; 174: 307.
Spong, CY, Ghidini, A, Sherer, DM, et al. Angiogenin: a marker for preterm delivery in midtrimester amniotic fluid. Am J Obstet Gynecol 1997; 176: 415–18.
Ghezzi, F, Franchi, M, Raio, L, et al. Elevated amniotic fluid C-reactive protein at the time of genetic amniocentesis is a marker for preterm delivery. Am J Obstet Gynecol 2002; 186: 268–73.
Goldenberg, RL, Andrews, WW, Mercer, BM, et al. The preterm prediction study: granulocyte colony-stimulating factor and spontaneous preterm birth. National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Am J Obstet Gynecol 2000; 182: 625–30.
Cox, SM, King, MR, Casey, ML, MacDonald, PC. Interleukin-1 beta, -1 alpha, and -6 and prostaglandins in vaginal/cervical fluids of pregnant women before and during labor. J Clin Endocrinol Metab 1993; 77: 805–15.
MacDonald, PC, Casey, ML. The accumulation of prostaglandins (PG) in amniotic fluid is an aftereffect of labor and not indicative of a role for PGE2 or PGF2 alpha in the initiation of human parturition. J Clin Endocrinol Metab 1993; 76: 1332–9.
Romero, R, Yoon, BH, Gonzalez, R, et al. The clinical significance of microbial invasion of the amniotic cavity with mycoplasmas in patients with preterm PROM. J Soc Gynecol Invest 1993; 70: S4.
Romero, R, Roslansky, P, Oyarzun, E, et al. Labor and infection. II. Bacterial endotoxin in amniotic fluid and its relationship to the onset of preterm labor. Am J Obstet Gynecol 1988; 158: 1044–9.
Mor, G, Aldo, P, Alvero, AB The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol 2017; 17: 469–82. doi:10.1038/nri.2017.64.
Romero, R, Oyarzun, E, Mazor, M, et al. Meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight. Obstet Gynecol 1989; 73: 576–82.
Lee, J, Romero, R, Kim, SM, et al. A new anti-microbial combination prolongs the latency period, reduces acute histologic chorioamnionitis as well as funisitis, and improves neonatal outcomes in preterm PROM. J Matern Fetal Neonatal Med 2016; 29: 707–20.
Kenyon, SL, Taylor, DJ, Tarnow-Mordi, W. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE Collaborative Group. Lancet 2001; 357: 979–88.
Lee, J, Romero, R, Kim, SM, Chaemsaithong, P, Yoon, BH A new antibiotic regimen treats and prevents intra-amniotic inflammation/infection in patients with preterm PROM. J Matern Fetal Neonatal Med 2016; 29: 2727–37.
Romero, R, Sibai, B, Caritis, S, et al. Antibiotic treatment of preterm labor with intact membranes: a multicenter, randomized, double-blinded, placebo-controlled trial. Am J Obstet Gynecol 1993; 169: 764–74.
Cox, SM, Bohman, VR, Sherman, ML, Leveno, KJ. Randomized investigation of antimicrobials for the prevention of preterm birth. Am J Obstet Gynecol 1996; 174: 206–10.
King, J, Flenady, V. Antibiotics for preterm labour with intact membranes. Cochrane Database Syst Rev 2000; (2): CD000246.
Kenyon, SL, Taylor, DJ, Tarnow-Mordi, W. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. ORACLE Collaborative Group. Lancet 2001; 357: 989–94.
Kogure, K, Simidu, U, Taga, N. A tentative direct microscopic method for counting living marine bacteria. Can J Microbiol 1979; 25: 415–20.
Relman, DA, Schmidt, TM, MacDermott, RP, Falkow, S. Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 1992; 327: 293301.
Markenson, GR, Martin, RK, Tillotson-Criss, M, et al. The use of the polymerase chain reaction to detect bacteria in amniotic fluid in pregnancies complicated by preterm labor. Am J Obstet Gynecol 1997; 177: 1471–7.
DiGiulio, DB, Romero, R, Amogan, HP, et al. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PLoS ONE 2008; 3: e3056.
Oyarzun, E, Yamamoto, M, Kato, S, et al. Specific detection of 16 micro-organisms in amniotic fluid by polymerase chain reaction and its correlation with preterm delivery occurrence. Am J Obstet Gynecol 1998; 179: 1115–19.
Yoon, BH, Romero, R, Kim, M, et al. Clinical implications of detection of Ureaplasma urealyticum in the amniotic cavity with the polymerase chain reaction. Am J Obstet Gynecol 2000; 183: 1130–7.
Blanchard, A, Hamrick, W, Duffy, L, et al. Use of the polymerase chain reaction for detection of Mycoplasma fermentans and Mycoplasma genitalium in the urogenital tract and amniotic fluid. Clin Infect Dis 2003; 17 (Suppl 1): S272–9.
Yoon, BH, Romero, R, Lim, JH, et al. The clinical significance of detecting Ureaplasma urealyticum by the polymerase chain reaction in the amniotic fluid of patients with preterm labor. Am J Obstet Gynecol 2003; 189: 919–24.
Gerber, S, Vial, Y, Hohlfeld, P, Witkin, SS. Detection of Ureaplasma urealyticum in second-trimester amniotic fluid by polymerase chain reaction correlates with subsequent preterm labor and delivery. J Infect Dis 2003; 187: 518–21.
Markenson, GR, Adams, LA, Hoffman, DE, Reece, MT. Prevalence of Mycoplasma bacteria in amniotic fluid at the time of genetic amniocentesis using the polymerase chain reaction. J Reprod Med 2003; 48: 775–9.
Nguyen, DP, Gerber, S, Hohlfeld, P, et al. Mycoplasma hominis in mid-trimester amniotic fluid: relation to pregnancy outcome. J Perinat Med 2004; 32: 323–26.
Perni, SC, Vardhana, S, Korneeva, I, et al. Mycoplasma hominis and Ureaplasma urealyticum in midtrimester amniotic fluid: association with amniotic fluid cytokine levels and pregnancy outcome. Am J Obstet Gynecol 2004; 191: 1382–6.
Wenstrom, KD, Andrews, WW, Bowles, NE, et al. Intrauterine viral infection at the time of second trimester genetic amniocentesis. Obstet Gynecol 1998; 92: 420–4.
DiGiulio, DB, Callahan, BJ, McMurdie, PJ, et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci U S A 2015; 112: 11060–5.
Romero, R, Hassan, SS, Gajer, P, et al. The vaginal microbiota of pregnant women who subsequently have spontaneous preterm labor and delivery and those with a normal delivery at term. Microbiome 2014; 2: 18.
Aagaard, K, Ma, J, Antony, KM, et al. The placenta harbors a unique microbiome. Sci Transl Med 2014; 6: 237ra65. doi:10.1126/scitranslmed.3008599.
Lauder, AP, Roche, AM, Sherrill-Mix, S, et al. Comparison of placenta samples with contamination controls does not provide evidence for a distinct placenta microbiota. Microbiome 2016; 4: 29.
Theis, KR, Romero, R, Winters, AD, et al. Does the human placenta delivered at term have a microbiota? Results of cultivation, quantitative real-time PCR, 16S rRNA gene sequencing, and metagenomics. Am J Obstet Gynecol 2019; 220: 267.e1267.e39.
Wiqvist, N, Lindblom, B, Wikland, M, Wilhelmsson, L. Prostaglandins and uterine contractility. Acta Obstet Gynecol Scand Suppl 1983; 113: 23–9.
Bennett, PR, Elder, MG, Myatt, L. The effects of lipoxygenase metabolites of arachidonic acid on human myometrial contractility. Prostaglandins 1987; 33: 837–44.
Ellwood, DA, Mitchell, MD, Anderson, AB, Turnbull, AC. The in vitro production of prostanoids by the human cervix during pregnancy: preliminary observations. Br J Obstet Gynaecol 1980; 87: 210–14.
Karim, SM, Filshie, GM. Therapeutic abortion using prostaglandin F2 alpha. Lancet 1970; 1: 157–9.
Ekman, GA, Forman, K, Marsal, U, et al. Intravaginal versus intracervical applications of prostaglandin E2 in viscous gel of cervical priming and induction of labor at term in patients with unfavorable cervical state. Am J Obstet Gynecol 1983; 47: 657–61.
Harper, MJ, Skarnes, RC. Inhibition of abortion and fetal death produced by endotoxin or prostaglandin F2α. Prostaglandins 1972; 2: 295309.
Giri, SN, Stabenfeld, GH, Moseley, TA, et al. Role of eicosanoids in abortion and its prevention by treatment with flunixin meglumine in cows during the first trimester of pregnancy. J Vet Med 1991; A38: 445–59.
Keirse, MJ. Endogenous prostaglandins in human parturition. In Kerise, MA, Gravenhorst, J (eds), Human Parturition. The Hague: Martinus Nijhoff, 1979, p. 101.
Romero, R, Emamian, M, Quintero, R, et al. Amniotic fluid prostaglandin levels and intra-amniotic infections. Lancet 1986; 1: 1380.
MacDonald, PC, Schultz, FM, Duenhoelter, JH, et al. Initiation of human parturition. I. Mechanism of action of arachidonic acid. Obstet Gynecol 1974; 44: 629–36.
Romero, R, Emamian, M, Wan, M, et al. Prostaglandin concentrations in amniotic fluid of women with intra-amniotic infection and preterm labor. Am J Obstet Gynecol 1987; 157: 1461–7.
Shiki, Y, Shimoya, K, Tokugawa, Y, et al. Changes of lipocalin-type prostaglandin D synthase level during pregnancy. J Obstet Gynaecol Res 2004; 30: 6570.
Mitchell, MD, Chang, MC, Chaiworapongsa, T, et al. Identification of 9alpha, 11beta-prostaglandin F2 in human amniotic fluid and characterization of its production by human gestational tissues. J Clin Endocrinol Metab 2005; 90: 4244–8.
Romero, R, Wu, YK, Mazor, M, et al. Amniotic fluid 5-hydroxyeicosatetraenoic acid in preterm labor. Prostaglandins 1988; 36: 179–89.
Romero, R, Wu, YK, Mazor, M, et al. Amniotic fluid arachidonate lipoxygenase metabolites in preterm labor. Prostaglandins Leukot Essent Fatty Acids 1989; 36: 6975.
Lopez-Bernal, A, Hansell, DJ, Canete Soler, R, et al. Prostaglandin, chorioamnionitis and preterm labour. Br J Obstet Gynaecol 1987; 94: 1156–8.
Falco, G, Hansson, G. Leukotriene C4 stimulates TXA2 formation in isolated sensitized guinea pig lungs. Biochem Pharmacol 1981; 30: 2491–3.
Romero, R, Durum, SK, Dinarello CA, , et al. Interleukin-1: a signal for the initiation of labor in chorioamnionitis. J Soc Gynecol Investig 1986; Abstract p71.
Romero, R, Wu, YK, Brody, DT, et al. Human decidua: a source of interleukin-1. Obstet Gynecol 1989; 73: 3134.
Romero, R, Brody, DT, Oyarzun, E, et al. Infection and labor. III. Interleukin-1: a signal for the onset of parturition. Am J Obstet Gynecol 1989; 160: 1117–23.
Romero, R, Mazor, M, Manogue, K, et al. Human decidua: a source of cachectin-tumor necrosis factor. Eur J Obstet Gynecol Reprod Biol 1991; 41: 123–7.
Romero, R, Manogue, KR, Mitchell, MD, et al. Infection and labor. IV. Cachectin-tumor necrosis factor in the amniotic fluid of women with intraamniotic infection and preterm labor. Am J Obstet Gynecol 1989; 161: 336–41.
Romero, R, Mazor, M, Sepulveda, W, et al. Tumor necrosis factor in preterm and term labor. Am J Obstet Gynecol 1992; 166: 1576–87.
Romero, R, Mazor, M, Brandt, F, et al. Interleukin-1 alpha and interleukin-1 beta in preterm and term human parturition. Am J Reprod Immunol 1992; 27: 117–23.
Romero, R, Mazor, M, Tartakovsky, B. Systemic administration of interleukin-1 induces preterm parturition in mice. Am J Obstet Gynecol 1991; 165: 969–71.
Silver, RM, Lohner, S, Chen, CL. Tumor necrosis factor-alpha mediates LPS-induced abortion: evidence from the LPS-resistant murine strain C3H/HeJ. J Soc Gynecol Investig 1993; Abstract p218.
Romero, R, Tartakovsky, B. The natural interleukin-1 receptor antagonist prevents interleukin-1–induced preterm delivery in mice. Am J Obstet Gynecol 1992; 167: 1041–5.
Gomez, R, Ghezzi, F, Romero, R, et al. Two thirds of human fetuses with microbial invasion of the amniotic cavity have a detectable systemic cytokine response before birth. Am J Obstet Gynecol 1997; 176: 514.
Tilg, H, Moschen, AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772–83.
Catalano, PM, Hoegh, M, Minium, J, et al. Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism. Diabetologia 2006; 49: 1677–85.
Silswal, N, Singh, AK, Aruna, B, et al. Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB–dependent pathway. Biochem Biophys Res Comm 2005; 334: 1092–101.
Ognjanovic, S, Bryant-Greenwood, GD. Pre-B-cell colony-enhancing factor, a novel cytokine of human fetal membranes. Am J Obstet Gynecol 2002; 187: 1051–8.
Gainsford, T, Willson, TA, Metcalf, D, et al. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci U S A 1996; 93: 14564–8.
Lord, GM, Matarese, G, Howard, JK, et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998; 394: 897901.
Mazaki-Tovi, S, Romero, R, Vaisbuch, E, et al. Dysregulation of maternal serum adiponectin in preterm labor. J Matern Fetal Neonatal Med 2009; 22: 887904.
Mazaki-Tovi, S, Romero, R, Vaisbuch, E, et al. Adiponectin in amniotic fluid in normal pregnancy, spontaneous labor at term, and preterm labor: a novel association with intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2010; 23: 120–30.
Mazaki-Tovi, S, Romero, R, Kusanovic, JP, et al. Visfatin/Pre-B cell colony-enhancing factor in amniotic fluid in normal pregnancy, spontaneous labor at term, preterm labor and prelabor rupture of membranes: an association with subclinical intrauterine infection in preterm parturition. J Perinat Med 2008; 36: 485–96.
Mazaki-Tovi, S, Romero, R, Vaisbuch, E, et al. Maternal plasma visfatin in preterm labor. J Matern Fetal Neonatal Med 2009; 22: 693704
Kusanovic, JP, Romero, R, Mazaki-Tovi, S, et al. Resistin in amniotic fluid and its association with intra-amniotic infection and inflammation. J Matern Fetal Neonatal Med 2008; 21: 902–16.
Hanna, N, Hanna, I, Hleb, M, et al. Gestational age-dependent expression of IL-10 and its receptor in human placental tissues and isolated cytotrophoblasts. J Immunol 2000; 164: 5721–8.
Yoshida, H, Yoshiyuki, M. Regulation of immune responses by interleukin-27. Immunol Rev 2008; 226: 234–47.
Hanna, N, Bonifacio, L, Weinberger, B, et al. Evidence for interleukin-10–mediated inhibition of cyclo-oxygenase-2 expression and prostaglandin production in preterm human placenta. Am J Reprod Immunol 2006; 55: 1927.
Gotsch, F, Romero, R, Kusanovic, JP, et al. The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: a role for interleukin-10. J Matern Fetal Neonatal Med 2008; 21: 529–47.
Robertson, SA, Skinner, RJ, Care, AS. Essential role for IL-10 in resistance to lipopolysaccharide-induced preterm labor in mice. J Immunol 2006; 177: 4888–96.
Murphy, SP, Fast, LD, Hanna, NN, Sharma, S. Uterine NK cells mediate inflammation-induced fetal demise in IL-10-null mice. J Immunol 2005; 175: 4084–90.
Annells, MF, Hart, PH, Mullighan, CG, et al. Interleukins-1, -4, -6, -10, tumor necrosis factor, transforming growth factor-beta, FAS, and mannose-binding protein C gene polymorphisms in Australian women: risk of preterm birth. Am J Obstet Gynecol 2004; 191: 2056–67.
Sadowsky, DW, Novy, MJ, Witkin, SS, Gravett, MG. Dexamethasone or interleukin-10 blocks interleukin-1beta-induced uterine contractions in pregnant rhesus monkeys. Am J Obstet Gynecol 2003; 188: 252–63.
Terrone, DA, Rinehart, BK, Granger, JP, et al. Interleukin-10 administration and bacterial endotoxin-induced preterm birth in a rat model. Obstet Gynecol 2001; 98: 476–80.
Janeway, C, Travers, P, Walport, M, Schlomchik, M. Innate immunity. In Janeway, C, Travers, P, Walport, M, Schlomchik, M (eds), Immunobiology. New York, NY: Garland Science, 2005, pp. 37102.
Hargreaves, DC, Medzhitov, R. Innate sensors of microbial infection. J Clin Immunol 2005; 25: 503–10.
Pasare, C, Medzhitov, R. Toll-like receptors: linking innate and adaptive immunity. Microbes Infect 2004; 6: 1382–7.
Kim, YM, Romero, R, Chaiworapongsa, T, et al. Toll-like receptor-2 and -4 in the chorioamniotic membranes in spontaneous labor at term and in preterm parturition that are associated with chorioamnionitis. Am J Obstet Gynecol 2004; 191: 1346–55.
Holmlund, U, Cebers, G, Dahlfors, AR, et al. Expression and regulation of the pattern recognition receptors Toll-like receptor-2 and Toll-like receptor-4 in the human placenta. Immunology 2002; 107: 145151.
Kumazaki, K, Nakayama, M, Yanagihara, I, et al. Immunohistochemical distribution of Toll-like receptor 4 in term and preterm human placentas from normal and complicated pregnancy including chorioamnionitis. Hum Pathol 2004; 35: 4754.
Kim, YM, Romero, R, Oh, SY, et al. Toll-like receptor 4: a potential link between “danger signals,” the innate immune system, and preeclampsia? Am J Obstet Gynecol 2005; 193: 921–7.
Abrahams, VM, Bole-Aldo, P, Kim, YM, et al. Divergent trophoblast responses to bacterial products mediated by TLRs. J Immunol 2004; 173: 4286–96.
Abrahams, VM, Visintin, I, Aldo, PB, et al. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol 2005; 175: 80969104.
Patni, S, Wynen, LP, Seager, AL, et al. Expression and activity of Toll-like receptors 1–9 in the human term placenta and changes associated with labor at term. Biol Reprod 2009; 80: 243–8.
Alexopoulou, L, Holt, AC, Medzhitov, R, Flavell, RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413: 732–8.
Abrahams, VM, Schaefer, TM, Fahey, JV, et al. Expression and secretion of antiviral factors by trophoblast cells following stimulation by the TLR-3 agonist, Poly(I: C). Hum Reprod 2006; 21: 2432–9.
Patni, S, Flynn, P, Wynen, LP, et al. An introduction to Toll-like receptors and their possible role in the initiation of labour. BJOG 2007; 114: 1326–34.
Elovitz, MA, Wang, Z, Chien, EK, et al. A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4. Am J Pathol 2003; 163: 2103–11.
Wang, H, Hirsch, E. Bacterially-induced preterm labor and regulation of prostaglandin-metabolizing enzyme expression in mice: the role of Toll-like receptor 4. Biol Reprod 2003; 69: 1957–63.
Ilievski, V, Lu, SJ, Hirsch, E. Activation of Toll-like receptors 2 or 3 and preterm delivery in the mouse. Reprod Sci 2007; 14: 315–20.
Lorenz, E, Hallman, M, Marttila, R, et al. Association between the Asp299Gly polymorphisms in the Toll-like receptor 4 and premature births in the Finnish population. Pediatr Res 2002; 52: 373–6.
Athayde, N, Edwin, SS, Romero, R, et al. A role for matrix metalloproteinase-9 in spontaneous rupture of the fetal membranes. Am J Obstet Gynecol 1998; 179: 1248–53.
Maymon, E, Romero, R, Pacora, P, et al. Matrilysin (matrix metalloproteinase 7) in parturition, premature rupture of membranes, and intrauterine infection. Am J Obstet Gynecol 2000; 182: 1545–53.
Maymon, E, Romero, R, Pacora, P, et al. Human neutrophil collagenase (matrix metalloproteinase 8) in parturition, premature rupture of the membranes, and intrauterine infection. Am J Obstet Gynecol 2000; 183: 94–9.
Maymon, E, Romero, R, Pacora, P, et al. Evidence for the participation of interstitial collagenase (matrix metalloproteinase 1) in preterm premature rupture of membranes. Am J Obstet Gynecol 2000; 183: 914–20.
Maymon, E, Romero, R, Pacora, P, et al. Evidence of in vivo differential bioavailability of the active forms of matrix metalloproteinases 9 and 2 in parturition, spontaneous rupture of membranes, and intra-amniotic infection. Am J Obstet Gynecol 2000; 183: 887–94.
Maymon, E, Romero, R, Pacora, P, et al. A role for the 72 kDa gelatinase (MMP-2) and its inhibitor (TIMP-2) in human parturition, premature rupture of membranes and intraamniotic infection. J Perinat Med 2001; 29: 308–16.
Fortunato, SJ, Menon, R, Bryant, C, Lombardi, SJ. Programmed cell death (apoptosis) as a possible pathway to metalloproteinase activation and fetal membrane degradation in premature rupture of membranes. Am J Obstet Gynecol 2000; 182: 1468–76.
Buhimschi, IA, Kramer, WB, Buhimschi, CS, et al. Reduction-oxidation (redox) state regulation of matrix metalloproteinase activity in human fetal membranes. Am J Obstet Gynecol 2000; 182: 458–64.
Ferrand, PE, Parry, S, Sammel, M, et al. A polymorphism in the matrix metalloproteinase-9 promoter is associated with increased risk of preterm premature rupture of membranes in African Americans. Mol Hum Reprod 2002; 8: 494501.
Fujimoto, T, Parry, S, Urbanek, M, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 (MMP-1) promoter influences amnion cell MMP-1 expression and risk for preterm premature rupture of the fetal membranes. J Biol Chem 2002; 277: 6296–302.
Wang, H, Parry, S, Macones, G, et al. Functionally significant SNP MMP8 promoter haplotypes and preterm premature rupture of membranes (PPROM). Hum Mol Genet 2004; 13: 2659–69.
Wang, H, Ogawa, M, Wood, JR, et al. Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes. Hum Mol Genet 2008; 17: 1087–96.
Yoon, BH, Romero, R, Moon, JB, et al. Clinical significance of intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Obstet Gynecol 2001; 185: 1130–6.
Shim, SS, Romero, R, Hong, JS, et al. Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 2004; 191: 1339–45.
Maymon, E, Romero, R, Chaiworapongsa, T, et al. Amniotic fluid matrix metalloproteinase-8 in preterm labor with intact membranes. Am J Obstet Gynecol 2001; 185: 1149–55.
Nien, JK, Yoon, BH, Espinoza, J, et al. A rapid MMP-8 bedside test for the detection of intra-amniotic inflammation identifies patients at risk for imminent preterm delivery. Am J Obstet Gynecol 2006; 195: 1025–30.
Kim, KW, Romero, R, Park, HS, et al. A rapid matrix metalloproteinase-8 bedside test for the detection of intra-amniotic inflammation in women with preterm premature rupture of membranes. Am J Obstet Gynecol 2007; 197: 292–95.
Park, CW, Lee, SM, Park, JS, et al. The antenatal identification of funisitis with a rapid MMP-8 bedside test. J Perinat Med 2008; 36: 497502.
Chen, GY, Nunez, G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 2010; 10: 826–37.
Matzinger, P. An innate sense of danger. Semin Immunol 1998; 10: 399415.
Lotze, MT, Deisseroth, A, Rubartelli, A. Damage associated molecular pattern molecules. Clin Immunol 2007; 124: 14.
Oppenheim, JJ, Yang, D. Alarmins: chemotactic activators of immune responses. Curr Opin Immunol 2005; 17: 359–65.
Romero, R, Mazor, M, Brandt, F, et al. Interleukin-1 alpha and interleukin-1 beta in preterm and term human parturition. Am J Reprod Immunol 1992; 27: 117–23.
Friel, LA, Romero, R, Edwin, S, et al. The calcium binding protein, S100B, is increased in the amniotic fluid of women with intra-amniotic infection/inflammation and preterm labor with intact or ruptured membranes. J Perinat Med 2007; 35: 385–93.
Chaiworapongsa, T, Erez, O, Kusanovic, JP, et al. Amniotic fluid heat shock protein 70 concentration in histologic chorioamnionitis, term and preterm parturition. J Matern Fetal Neonatal Med 2008; 21: 449–61.
Romero, R, Chaiworapongsa, T, Alpay Savasan, Z, et al. Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1. J Matern Fetal Neonatal Med 2011; 24: 1444–55.
Romero, R, Chaiworapongsa, T, Savasan, ZA, et al. Clinical chorioamnionitis is characterized by changes in the expression of the alarmin HMGB1 and one of its receptors, sRAGE. J Matern Fetal Neonatal Med 2012; 25: 558–67.
Wang, H, Bloom, O, Zhang, M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999; 285: 248–51.
Lotze, MT, Tracey, KJ High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5: 331–42.
Gomez-Lopez, N, Romero, R, Plazyo, O, et al. Intra-amniotic administration of HMGB1 induces spontaneous preterm labor and birth. Am J Reprod Immunol 2016; 75: 37.
Hori, O, Brett, J, Slattery, T, et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 1995; 270: 25752–61.
Park, JS, Gamboni-Robertson, F, He, Q, et al. High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 2006; 290: C91724.
Andersson, U, Wang, H, Palmblad, K, et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 2000; 192: 565–70.
Park, JS, Arcaroli, J, Yum, HK, et al. Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol 2003; 284: C8709.
Orlova, VV, Choi, EY, Xie, C, et al. A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J 2007; 26: 1129–39.
Messmer, D, Yang, H, Telusma, G, et al. High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. J Immunol 2004; 173: 307–13.
Fiuza, C, Bustin, M, Talwar, S, et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 2003; 101: 2652–60.
Plazyo, O, Romero, R, Unkel, R, et al. HMGB1 induces an inflammatory response in the chorioamniotic membranes that is partially mediated by the inflammasome. Biol Reprod 2016; 95: 130.
Martinon, F, Burns, K, Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002; 10: 417–26.
Petrilli, V, Papin, S, Tschopp, J. The inflammasome. Curr Biol 2005; 15: R581.
Ogura, Y, Sutterwala, FS, Flavell, RA The inflammasome: first line of the immune response to cell stress. Cell 2006; 126: 659–62.
Mariathasan, S, Monack, DM Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 2007; 7: 3140.
Stutz, A, Golenbock, DT, Latz, E. Inflammasomes: too big to miss. J Clin Invest 2009; 119: 3502–11.
Franchi, L, Eigenbrod, T, Munoz-Planillo, R, Nunez, G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 2009; 10: 241–7.
Jha S, Ting JP. Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases. J Immunol 2009; 183: 7623–9.
Schroder, K, Tschopp, J. The inflammasomes. Cell 2010; 140: 821–32.
Franchi, L, Munoz-Planillo, R, Reimer, T, Eigenbrod, T, Nunez, G. Inflammasomes as microbial sensors. Eur J Immunol 2010; 40: 611–15.
Gross, O, Thomas, CJ, Guarda, G, Tschopp, J. The inflammasome: an integrated view. Immunol Rev 2011; 243: 136–51.
Lamkanfi, M, Dixit, VM Modulation of inflammasome pathways by bacterial and viral pathogens. J Immunol 2011; 187: 597602.
Horvath, GL, Schrum, JE, De Nardo, CM, Latz, E. Intracellular sensing of microbes and danger signals by the inflammasomes. Immunol Rev 2011; 243: 119–35.
van de Veerdonk, FL, Netea, MG, Dinarello, CA, Joosten, LA Inflammasome activation and IL-1beta and IL-18 processing during infection. Trends Immunol 2011; 32: 110–16.
Franchi, L, Munoz-Planillo, R, Nunez, G. Sensing and reacting to microbes through the inflammasomes. Nat Immunol 2012; 13: 325–32.
Franchi, L, Immunology, Nunez G. Orchestrating inflammasomes. Science 2012; 337: 1299–300.
Henao-Mejia, J, Elinav, E, Strowig, T, Flavell, RA Inflammasomes: far beyond inflammation. Nat Immunol 2012; 13: 321–4.
Latz, E, Xiao, TS, Stutz, A. Activation and regulation of the inflammasomes. Nat Rev Immunol 2013; 13: 397411.
Lamkanfi, M, Dixit, VM Mechanisms and functions of inflammasomes. Cell 2014; 157: 1013–22.
Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 2015; 21: 677–87.
Black, RA, Kronheim, SR, Merriam, JE, March, CJ, Hopp, TP A pre-aspartate-specific protease from human leukocytes that cleaves pro-interleukin-1 beta. J Biol Chem 1989; 264: 5323–6.
Kostura, MJ, Tocci, MJ, Limjuco, G, et al. Identification of a monocyte specific pre-interleukin 1 beta convertase activity. Proc Natl Acad Sci U S A 1989; 86: 5227–31.
Thornberry, NA, Bull, HG, Calaycay, JR, et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 1992; 356: 768–74.
Cerretti, DP, Kozlosky, CJ, Mosley, B, et al. Molecular cloning of the interleukin-1 beta converting enzyme. Science 1992; 256: 97100.
Gu, Y, Kuida, K, Tsutsui, H, et al. Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science 1997; 275: 206–9.
Ghayur, T, Banerjee, S, Hugunin, M, et al. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature 1997; 386: 619–23.
Dinarello, CA Interleukin-1 beta, interleukin-18, and the interleukin-1 beta converting enzyme. Ann N Y Acad Sci 1998; 856: 111.
Fantuzzi, G, Dinarello, CA Interleukin-18 and interleukin-1 beta: two cytokine substrates for ICE (caspase-1). J Clin Immunol 1999; 19: 111.
Netea, MG, van de Veerdonk, FL, van der Meer, JW, Dinarello, CA, Joosten, LA Inflammasome-independent regulation of IL-1-family cytokines. Annu Rev Immunol 2015; 33: 4977.
Pineles BL, Romero R, Montenegro D, et al. “The inflammasome” in human parturition. Reprod Sci 2007; 14: 59A.
Gomez-Lopez, N, Motomura, K, Miller, D, et al. Inflammasomes: their role in normal and complicated pregnancies. J Immunol 2019; 203: 2757–69. https://doi.org/10.4049/jimmunol.1900901.
Gotsch, F, Romero, R, Chaiworapongsa, T, et al. Evidence of the involvement of caspase-1 under physiologic and pathologic cellular stress during human pregnancy: a link between the inflammasome and parturition. J Matern Fetal Neonatal Med 2008; 21: 605–16.
Romero, R, Brody, DT, Oyarzun, E, et al. Infection and labor. III. Interleukin-1: a signal for the onset of parturition. Am J Obstet Gynecol 1989; 160: 1117–23.
Pacora, P, Romero, R, Maymon, E, et al. Participation of the novel cytokine interleukin 18 in the host response to intra-amniotic infection. Am J Obstet Gynecol 2000; 183: 1138–43.
Gomez-Lopez, N, Romero, R, Xu, Y, et al. A role for the inflammasome in spontaneous preterm labor with acute histologic chorioamnionitis. Reprod Sci 2017; 24: 1382–401.
Gomez-Lopez, N, Romero, R, Xu, Y, et al. A role for the inflammasome in spontaneous labor at term with acute histologic chorioamnionitis. Reprod Sci 2017; 24: 934–53.
Blanc, WA Amniotic infection syndrome; pathogenesis, morphology, and significance in circumnatal mortality. Clin Obstet Gynecol 1959; 2: 705–34.
Russell, P. Inflammatory lesions of the human placenta: Clinical significance of acute chorioamnionitis. Am J Diagn Gynecol Obstet 1979; 2: 127–37.
Blanc, WA Pathology of the placenta and cord in ascending and in haematogenous infection. Ciba Found Symp 1979: 1738.
Redline, RW, Faye-Petersen, O, Heller, D, et al. Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2003; 6: 435–48.
Redline, RW Placental inflammation. Semin Neonatol 2004; 9: 265–74.
Fox, H, Sebire, NJ Infections and inflammatory lesions of the placenta. In Pathology of the placenta, 3rd edn. Edinburgh: Elsevier Saunders, 2007, pp. 303–54.
Benirschke, K, Burton, G, Baergen, R. Infectious diseases. In Pathology of the Human Placenta, 6th edn. Berlin: Springer, 2012, pp. 557656.
Park, JY, Romero, R, Lee, J, et al. An elevated amniotic fluid prostaglandin F2α concentration is associated with intra-amniotic inflammation/infection, and clinical and histologic chorioamnionitis, as well as impending preterm delivery in patients with preterm labor and intact membranes. J Matern Fetal Neonatal Med 2016; 29: 2563–72.
Romero, R, Chaemsaithong, P, Chaiyasit, N, et al. CXCL10 and IL-6: markers of two different forms of intra-amniotic inflammation in preterm labor. Am J Reprod Immunol 2017; 78(1). doi:10.1111/aji.12685.
Oh, KJ, Kim, SM, Hong, JS, et al. Twenty-four percent of patients with clinical chorioamnionitis in preterm gestations have no evidence of either culture-proven intraamniotic infection or intraamniotic inflammation. Am J Obstet Gynecol 2017; 216: 604.e1–11.
Gomez-Lopez, N, Romero, R, Xu, Y, et al. Inflammasome assembly in the chorioamniotic membranes during spontaneous labor at term. Am J Reprod Immunol 2017; 77(5). doi:10.1111/aji.12648.
Lappas, M. Caspase-1 activation is increased with human labour in foetal membranes and myometrium and mediates infection-induced interleukin-1β secretion. Am J Reprod Immunol 2014; 71: 189201.
Gomez-Lopez, N, Romero, R, Panaitescu, B, et al. Inflammasome activation during spontaneous preterm labor with intra-amniotic infection or sterile intra-amniotic inflammation. Am J Reprod Immunol 2018; 80: e13049. https://doi.org/10.1111/aji.13049.
Theis, KR, Romero, R, Motomura, K, et al. Microbial burden and inflammasome activation in amniotic fluid of patients with preterm prelabor rupture of membranes. J Perinat Med 2020; 48: 115–31. https://doi.org/10.1515/jpm-2019-0398.
Yoon, BH, Romero, R, Park, JS, et al. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. Am J Obstet Gynecol 2000; 183: 1124–9.
Guo, R, Hou, W, Dong, Y, et al. Brain injury caused by chronic fetal hypoxemia is mediated by inflammatory cascade activation. Reprod Sci 2010; 17: 540–8.
Gomez, R, Berry, S, Yoon, BH, et al. The hematologic profile of the fetus with systemic inflammatory response syndrome. Am J Obstet Gynecol 1998; 178: S202.
Berry, SM, Romero, R, Gomez, R, et al. Premature parturition is characterized by in utero activation of the fetal immune system. Am J Obstet Gynecol 1995; 173: 1315–20.
Ferber, A, Minior, VK, Bornstein, E, Divon, MY. Fetal “nonreassuring status” is associated with elevation of nucleated red blood cell counts and interleukin-6. Am J Obstet Gynecol 2005; 192: 1427–9.
Yoon, BH, Romero, R, Shim, J, et al. “Atypical” chronic lung disease of the newborn is linked to fetal systemic inflammation. Am J Obstet Gynecol 2002; 187: S129.
Ghezzi, F, Gomez, R, Romero, R, et al. Elevated interleukin-8 concentrations in amniotic fluid of mothers whose neonates subsequently develop bronchopulmonary dysplasia. Eur J Obstet Gynecol Reprod Biol 1998; 78: 510.
Yoon, BH, Romero, R, Jun, JK, et al. Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1997; 177: 825–30.
Romero, R, Espinoza, J, Goncalves, LF, et al. Fetal cardiac dysfunction in preterm premature rupture of membranes. J Matern Fetal Neonatal Med 2004; 16: 146–57.
Garnier, Y, Coumans, AB, Jensen, A, et al. Infection-related perinatal brain injury: the pathogenic role of impaired fetal cardiovascular control. J Soc Gynecol Invest 2003; 10: 450–9.
Yoon, BH, Romero, R, Jun, JK, et al. An increase in fetal plasma cortisol but not dehydroepiandrosterone sulfate is followed by the onset of preterm labor in patients with preterm premature rupture of the membranes. Am J Obstet Gynecol 1998; 179: 1107–14.
Seckl, JR, Cleasby, M, Nyirenda, MJ. Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming. Kidney Int 2000; 57: 1412–17.
Nathanielsz, PW, Berghorn, KA, Derks, JB, et al. Life before birth: effects of cortisol on future cardiovascular and metabolic function. Acta Paediatr 2003; 92: 766–72.
Kim, YM, Romero, R, Chaiworapongsa, T, et al. Dermatitis as a component of the fetal inflammatory response syndrome is associated with activation of Toll-like receptors in epidermal keratinocytes. Histopathology 2006; 49: 506–14.
De Felice, C, Toti, P, Santopietro, R, et al. Small thymus in very low birth weight infants born to mothers with subclinical chorioamnionitis. J Pediatr 1999; 135: 384–6.
Di Naro, E, Cromi, A, Ghezzi, F, et al. Fetal thymic involution: a sonographic marker of the fetal inflammatory response syndrome. Am J Obstet Gynecol 2006; 194: 153–9.
Yinon, Y, Zalel, Y, Weisz, B, et al. Fetal thymus size as a predictor of chorioamnionitis in women with preterm premature rupture of membranes. Ultrasound Obstet Gynecol 2007; 29: 639–43.
Kuban, JD, Allred, EN, Leviton, A. Thymus involution and cerebral white matter damage in extremely low gestational age neonates. Biol Neonate 2006; 90: 252–7.
Paneth, N, Kiely, J. The frequency of cerebral palsy: a review of population studies in industrialized nations since 1950. In Stanely, F, Alberman, E (eds). The Epidemiology of the Cerebral Palsies. Oxford: Blackwell Scientific, 1984, pp. 4656.
Stanley, FJ, Watson, L. Trends in perinatal mortality and cerebral palsy in Western Australia, 1967 to 1985. BMJ 1992; 304: 1658–63.
Leviton, A, Paneth, N. White matter damage in preterm newborns: an epidemiologic perspective. Early Hum Dev 1990; 24: 122.
Hagberg, B, Hagberg, G, Beckung, E, Uvebrant, P. Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991. Acta Paediatr 2001; 90: 271–7.
Bejar, R, Wozniak, P, Allard, M, et al. Antenatal origin of neurologic damage in newborn infants. I. Preterm infants. Am J Obstet Gynecol 1988; 159: 357–63.
Fazzi, E, Lanzi, G, Gerardo, A, et al. Correlation between clinical and ultrasound findings in preterm infants with cystic periventricular leukomalacia. Ital J Neurol Sci 1991; 12: 199203.
Murphy, DJ, Sellers, S, MacKenzie, IZ, et al. Case–control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995; 346: 1449–54.
Yoon, BH, Jun, JK, Romero, R, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997; 177: 1926.
Grether, JK, Nelson, KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997; 278: 207–11.
Eastman, NJ, Deleon, M. The etiology of cerebral palsy. Am J Obstet Gynecol 1955; 69: 950–61.
Nelson, KB, Ellenberg, JH. Epidemiology of cerebral palsy. Adv Neurol 1978; 19: 421–35.
Graham, M, Levene, MI, Trounce, JQ, Rutter, N. Prediction of cerebral palsy in very low birthweight infants: prospective ultrasound study. Lancet 1987; 2: 593–6.
Han, TR, Bang, MS, Lim, JY, et al. Risk factors of cerebral palsy in preterm infants. Am J Phys Med Rehabil 2002; 81: 297303.
Yoon, BH, Romero, R, Yang, SH, et al. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 1996; 174: 1433–40.
Verma, U, Tejani, N, Klein, S, et al. Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate. Am J Obstet Gynecol 1997; 176: 275–81.
Yoon, BH, Kim, CJ, Romero, R, et al. Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits. Am J Obstet Gynecol 1997; 177: 797802.
Debillon, T, Gras-Leguen, C, Verielle, V, et al. Intrauterine infection induces programmed cell death in rabbit periventricular white matter. Pediatr Res 2000; 47: 736–42.
Hagberg, H, Peebles, D, Mallard, C. Models of white matter injury: comparison of infectious, hypoxic–ischemic, and excitotoxic insults. Ment Retard Dev Disabil Res Rev 2002; 8: 30–8.
Dong, Y, Yu, Z, Sun, Y, et al. Chronic fetal hypoxia produces selective brain injury associated with altered nitric oxide synthases. Am J Obstet Gynecol 2011; 204: 254.e16–28.
Kim, J, Choi, IY, Dong, Y, et al. Chronic fetal hypoxia affects axonal maturation in guinea pigs during development: a longitudinal diffusion tensor imaging and T2 mapping study. J Magn Reson Imaging 2015; 42: 658–65.
Leviton, A. Preterm birth and cerebral palsy: is tumor necrosis factor the missing link? Dev Med Child Neurol 1993; 35: 553–8.
Iida, K, Takashima, S, Takeuchi, Y. Etiologies and distribution of neonatal leukomalacia. Pediatr Neurol 1992; 8: 205–9.
van der Poll, T, Buller, HR, ten Cate, H, et al. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990; 322: 1622–7.
Camussi, G, Bussolino, F, Salvidio, G, Baglioni, C. Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor. J Exp Med 1987; 166: 1390–404.
Selmaj, KW, Raine, CS. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 1988; 23: 339–46.
Yoon, BH, Romero, R, Kim, CJ, et al. High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 1997; 177: 406–11.
Sharief, MK, Thompson, EJ. In vivo relationship of tumor necrosis factor-alpha to blood–brain barrier damage in patients with active multiple sclerosis. J Neuroimmunol 1992; 38: 2733.
Fidel, P, Ghezzi, F, Romero, R, et al. The effect of antibiotic therapy on intrauterine infection-induced preterm parturition in rabbits. J Matern Fetal Neonatal Med 2003; 14: 5764.
Kenyon, S, Pike, K, Jones, DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet 2008; 372: 1310–18.
Gravett, MG, Adams, KM, Sadowsky, DW, et al. Immunomodulators plus antibiotics delay preterm delivery after experimental intraamniotic infection in a nonhuman primate model. Am J Obstet Gynecol 2007; 197: 518.e1–8.
Nelson, KB, Grether, JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995; 95: 263–9.
Schendel, DE, Berg, CJ, Yeargin-Allsopp, M, et al. Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA 1996; 276: 1805–10.
Matsuda, Y, Kouno, S, Hiroyama, Y, et al. Intrauterine infection, magnesium sulfate exposure and cerebral palsy in infants born between 26 and 30 weeks of gestation. Eur J Obstet Gynecol Reprod Biol 2000; 91: 159–64.
Rouse, DJ, Hirtz, DG, Thom, E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008; 359: 895905.
Conde-Agudelo, A, Romero, R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and meta-analysis. Am J Obstet Gynecol 2009; 200: 595609.
Doyle, LW, Crowther, CA, Middleton, P, et al. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009; (1): CD004661.
Leigh, J, Garite, TJ. Amniocentesis and the management of premature labor. Obstet Gynecol 1986; 67: 500–6.
Weeks, JW, Reynolds, L, Taylor, D, et al. Umbilical cord blood interleukin-6 levels and neonatal morbidity. Obstet Gynecol 1997; 90: 815–18.
Kashlan, F, Smulian, J, Shen-Schwarz, S, et al. Umbilical vein interleukin 6 and tumor necrosis factor alpha plasma concentrations in the very preterm infant. Pediatr Infect Dis J 2000; 19: 238–43.
Dollner, H, Vatten, L, Halgunset, J, et al. Histologic chorioamnionitis and umbilical serum levels of pro-inflammatory cytokines and cytokine inhibitors. BJOG 2002; 109: 534–9.
Yoon, BH, Romero, R, Shim, JY, et al. C-reactive protein in umbilical cord blood: a simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis. J Matern Fetal Neonatal Med 2003; 14: 8590.
Rogers, BB, Alexander, JM, Head, J, et al. Umbilical vein interleukin-6 levels correlate with the severity of placental inflammation and gestational age. Hum Pathol 2002; 33: 335–40.
Pankuch, GA, Appelbaum, PC, Lorenz, RP, et al. Placental microbiology and histology and the pathogenesis of chorioamnionitis. Obstet Gynecol 1984; 64: 802–6.
Grafe, MR. The correlation of prenatal brain damage with placental pathology. J Neuropathol Exp Neurol 1994; 53: 407–15.
Tauscher, MK, Berg, D, Brockmann, M, et al. Association of histologic chorioamnionitis, increased levels of cord blood cytokines, and intracerebral hemorrhage in preterm neonates. Biol Neonate 2003; 83: 166–70.