Abstract
Cerebral palsy (CP) is the most common cause of severe physical disability in childhood. The precise etiological factor for the development of the majority of cases of CP has not been identified, however, prematurity is considered to be the leading identifiable risk factor.
During the last decade, intrauterine infection/inflamation has been identified as the most common cause of preterm delivery and neonatal complications. When microorganisms or their products gain access to the fetus they stimulate the production of cytokines and a systemic response termed FIRS (Fetal Inflammatory Response Syndrome). Subsequently, FIRS was implicated as a cause of fetal or neonatal injury that leads to CP and chronic lung disease.
Several authors found an increase in the risk for CP in infants born to mothers with clinical chorioamnionitis, especially in preterm neonates. A relationship between CP and intra-amniotic inflammation was demonstrated, intrauterine infection may lead to activation of the cytokine network which in turn can cause white matter brain damage and preterm delivery, as well as the future development of CP. This white matter insult is identified clinically as periventricular leucomalacia (PVL) which is associated with the subsequent development of impaired neurological outcomes of variable severity including CP.
References
1 Arias F, P Tomich: Etiology and outcome of low birth weight and preterm infants. Obstet Gynecol60 (1982) 277Search in Google Scholar
2 Back SA, SA Rivkees: Emerging concepts in periventricular white matter injury. Semin Perinatol28 (2004) 405Search in Google Scholar
3 Bale JF Jr, JR Murph: Congenital infections and the nervous system. Pediatr Clin North Am39 (1992) 669Search in Google Scholar
4 Bashiri A, S Horowitz, M Huleihel, R Hackmon, D Dukler, M Mazor: Elevated concentrations of interleukin-6 in intra-amniotic infection with Ureaplasma urealyticum in asymptomatic women during genetic amniocentesis. Acta Obstet Gynecol Scand78 (1999) 379Search in Google Scholar
5 Benirschke K: Routes and types of infection in the fetus and the newborn. Am J Dis Child28 (1965) 71410.1001/archpedi.1960.02070030716003Search in Google Scholar
6 Benirschke K, SH Clifford: Intrauterine bacterial infection of the newborn infant: frozen sections of the cord as an aid to early detection. J Pediatr54 (1959) 11Search in Google Scholar
7 Berry SM, R Gomez, N Athayde, F Ghezzi, M Mazor, BH Yoon, SS Edwin, R Romero: The role of granulocyte colony stimulating factor in the neutrophilia observed in the fetal inflammatory response syndrome. Am J Obstet Gynecol178 (1998) S202Search in Google Scholar
8 Blackwell S, R Romero, T Chaiworapongsa, YM Kim, E Bujold, J Espinoza, N Camacho, S Hassan, BH Yoon, JS Refuerzo: Maternal and fetal inflammatory responses in unexplained fetal death. J Matern Fetal Neonatal Med14 (2003) 151Search in Google Scholar
9 Blanc W: Infection amniotique et neonatal. Gynaecologia136 (1956) 10110.1159/000308314Search in Google Scholar
10 Blanc W: Pathways of fetal and early neonatal infection: Viral placentitis, bacterial and fungal chorioamnionitis. J Pediatr59 (1964) 47310.1016/S0022-3476(61)80232-1Search in Google Scholar
11 Blickstein I: Cerebral palsy in multifoetal pregnancies. Dev Med Child Neurol44 (2002) 35210.1017/S0012162201002195Search in Google Scholar PubMed
12 Brown AS, ES Susser: In utero infection and adult schizophrenia. Ment Retard Dev Disabil Res Rev8 (2002) 51Search in Google Scholar
13 Cassell GH, RO Davis, KB Waites, MB Brown, PA Marriott, S Stagno, JK Davis: Isolation of Mycoplasma hominis and Ureaplasma urealyticum from amniotic fluid at 16–20 weeks of gestation: potential effect on outcome of pregnancy. Sex Transm Dis10 (1983) 294Search in Google Scholar
14 Cummins SK, KB Nelson, JK Grether, EM Velie: Cerebral palsy in four northern California counties, births 1983 through 1985. J Pediatr123 (1993) 230Search in Google Scholar
15 D'Alquen D, BW Kramer, S Seidenspinner, A Marx, D Berg, P Groneck, CP Speer: Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis. Pediatr Res57 (2005) 263Search in Google Scholar
16 Dammann O, EN Allred, N Veelken: Increased risk of spastic displegia among very low birth weight children after preterm labor or prelabor rupture of membranes. J Pediatr132 (1998) 531Search in Google Scholar
17 Duggan PJ, EF Maalouf, TL Watts, MH Sullivan, SJ Counsell, J Allsop, L Al-Nakib, MA Rutherford, M Battin, I Roberts, AD Edwards: Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet358 (2001) 1699Search in Google Scholar
18 Eastman NJ, M DeLeon: The etiology of cerebral palsy. Am J Obstet Gynecol69 (1955) 950Search in Google Scholar
19 Fatemi SH, J Earle, R Kanodia, D Kist, ES Emamian, PH Patterson, L Shi, R Sidwell: Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol22 (2002) 25Search in Google Scholar
20 Garnier Y, AB Coumans, A Jensen, TH Hasaart, R Berger: Infection-related perinatal brain injury: the pathogenic role of impaired fetal cardiovascular control. J Soc Gynecol Investig10 (2003) 450Search in Google Scholar
21 Gibson CS, AH MacLennan, WM Hague, EA Hann, K Priest, A Chan, GA Dekker, South Australian Cerebral Palsy Research Group: Associations between inherited thrombophilias, gestational age, and cerebral palsy. Am J Obstet Gynecol193 (2005) 1437Search in Google Scholar
22 Gomez R, F Ghezzi, R Romero, H Munoz, JE Tolosa, I Rojas: Premature labor and intra-amniotic infection: clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol22 (1995) 281Search in Google Scholar
23 Gomez R, R Romero, F Ghezzi, BH Yoon, M Mazor, SM Berry: The fetal inflammatory response syndrome. Am J Obstet Gynecol179 (1998) 194Search in Google Scholar
24 Goncalves LF, T Chaiworapongsa, R Romero: Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev8 (2002) 3Search in Google Scholar
25 Gray DJ, HB Robinson, J Malone, RB Jr Thomson: Adverse outcome in pregnancy following amniotic fluid isolation of Ureaplasma urealyticum. Prenat Diagn12 (1992) 111Search in Google Scholar
26 Grether JK, KB Nelson, E Walsh, RE Willoughby, RW Redline: Intrauterine exposure to infection and risk of cerebral palsy in very preterm infants. Arch Pediatr Adolesc Med157 (2003) 26Search in Google Scholar
27 Horowitz S, M Mazor, R Romero, J Horowitz, M Glezerman: Infection of the amniotic cavity with Ureaplasma urealyticum in the midtrimester of pregnancy. J Reprod Med40 (1995) 375Search in Google Scholar
28 Hutton JL, PO Pharoah: Effects of cognitive, motor, and sensory disabilities on survival in cerebral palsy. Arch Dis Child86 (2002) 84Search in Google Scholar
29 Jacobsson B, G Hagberg: Antenatal risk factors for cerebral palsy. Best Pract Res Clin Obstet Gynaecol18 (2004) 425Search in Google Scholar
30 Jacobsson B, G Hagberg, B Hagberg, L Ladfors, A Niklasson, H Hagberg: Cerebral palsy in preterm infants: a population based analysis of antenatal risk factors. Am J Obstet Gynecol182 (Suppl) (2000) S29Search in Google Scholar
31 Kallapur SG, I Nitsos, TJ Moss, BW Kramer, JP Newnham, M Ikegami, AH Jobe: Chronic endotoxin exposure does not cause sustained structural abnormalities in the fetal sheep lungs. Am J Physiol Lung Cell Mol Physiol288 (2005) 966Search in Google Scholar
32 Koman LA, BP Smith, JS Shilt: Cerebral palsy. Lancet363 (2004) 619Search in Google Scholar
33 Krymko H, A Bashiri, A Smolin, E Sheiner, J Bar-David, I Shoham-Vardi, H Vardi, M Mazor: Risk factors for recurrent preterm delivery. Eur J Obstet Gynecol Reprod Biol113 (2004) 160Search in Google Scholar
34 Kuban KC, A Leviton: Cerebral palsy. N Engl J Med330 (1994) 188Search in Google Scholar
35 Leviton A: Preterm birth and cerebral palsy: Is tumor necrosis factor the missing link? Dev Med Child Neurol35 (1993) 55310.1111/j.1469-8749.1993.tb11688.xSearch in Google Scholar PubMed
36 Leviton A, N Paneth: White matter damage in preterm newborns: an epidemiologic perspective. Early Hum Dev53 (1990) 407Search in Google Scholar
37 MacLennan A: A template for defining a causal relationship between acute intrapartum events and cerebral palsy: international consensus statement. International Cerebral Palsy Task Force. BMJ319 (1999) 105410.1136/bmj.319.7216.1054Search in Google Scholar PubMed PubMed Central
38 Mallard C, AK Welin, D Peebles, H Hagberg, I Kjellmer: White matter injury following systemic endotoxemia or asphyxia in the fetal sheep. Neurochem Res28 (2003) 215Search in Google Scholar
39 Markenson GR, RK Martin, M Tillotson-Criss, KS Foley, RS Jr Stewart, M Yancey: The use of the polymerase chain reaction to detect bacteria in amniotic fluid in pregnancies complicated by preterm labor. Am J Obstet Gynecol177 (1997) 1471Search in Google Scholar
40 Moss TJ, I Nitsos, M Ikegami, AH Jobe, JP Newnham: Experimental intrauterine Ureaplasma infection in sheep. Am J Obstet Gynecol192 (2005) 1179Search in Google Scholar
41 Nelson KB, JH Ellenberg: Antecedents of cerebral palsy. Univariate analysis of risks. Am J Dis Child139 (1985) 1031Search in Google Scholar
42 Nelson KB, JH Ellenberg: Antecedents of cerebral palsy. Multivariate analysis of risk. N Engl J Med315 (1986) 81Search in Google Scholar
43 Nelson KB, JK Lynch: Stroke in newborn infants. The Lancet Neurology3 (2004) 150Search in Google Scholar
44 O'Callaghan E, P Sham, N Takei, G Glover, RM Murray: Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet337 (1991) 1248Search in Google Scholar
45 Offenbacher S, V Katz, G Fertik, J Collins, D Boyd, G Maynor, R McKaig, J Beck: Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol67 (1996) 1103Search in Google Scholar
46 Ohlsson A, M Vearncombe: Congenital and nosocomial sepsis in infants born in a regional perinatal unit: cause, outcome, and white blood cell response. Am J Obstet Gynecol156 (1987) 407Search in Google Scholar
47 O'Shea TM, KL Klinepeter, RG Dillard: Prenatal events and the risk of cerebral palsy in very low birth weight infants. Am J Epidemiol147 (1998) 362Search in Google Scholar
48 O'Shea TM, JS Preisser, KL Klinepeter, RG Dillard: Trends in mortality and cerebral palsy in a geographically based cohort of very low birth weight neonates born between 1982 to 1994. Pediatrics101 (1998) 642Search in Google Scholar
49 Pacora P, T Chaiworapongsa, E Maymon, YM Kim, R Gomez, BH Yoon, F Ghezzi, SM Berry, F Qureshi, SM Jacques, JC Kim, N Kadar, R Romero: Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med11 (2002) 18Search in Google Scholar
50 Peebles DM, S Miller, JP Newman, R Scott, MA Hanson: The effect of systemic administration of lipopolysaccharide on cerebral haemodynamics and oxygenation in the 0.65 gestation ovine fetus in utero. BJOG110 (2003) 735Search in Google Scholar
51 Romero R, T Chaiworapongsa, J Espinoza: Micronutrients and intrauterine infection, preterm birth and the Fetal Inflammatory Response Syndrome. J Nutr133 (2003) 5SSearch in Google Scholar
52 Romero R, T Chaiworapongsa, J Espinoza, R Gomez, BH Yoon, S Edwin, M Mazor, E Maymon, S Berry. Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the membrance. Am J Obstet Gynecol187 (2002) 1125Search in Google Scholar
53 Romero R, J Espinoza, LF Goncalves, R Gomez, L Medina, M Silva, T Chaiworapongsa, BH Yoon, F Ghezzi, W Lee, M Treadwell, SM Berry, E Maymon, M Mazor, G DeVore. Fetal cardiac dysfunction in preterm premature rupture of membranes. J Matern Fetal Neonatal Med16 (2004) 146Search in Google Scholar
54 Romero R, R Gomez, F Ghezzi, BH Yoon, M Mazor, SS Edwin, SM Berry. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol179 (1998) 186Search in Google Scholar
55 Romero R, E Maymon, P Pacora, R Gomez, M Mazor, BH Yoon, SM Berry. Further observations on the fetal inflammatory response syndrome: a Potential homeostatic role for the soluble receptors of tumor necrosis factor alpha. Am J Obstet Gynecol183 (2000) 1070Search in Google Scholar
56 Romero R, M Mazor: Infection and preterm labor. Clin Obstet Gynecol31 (1988) 553Search in Google Scholar
57 Romero R, H Munoz, R Gomez, DM Sherer, F Ghezzi, A Ghidini, O Alfi, G Devore, L Randolph: Two thirds of spontaneous abortion/fetal deaths after genetic amniocentesis are the result of a pre-existing sub-clinical inflammatory process of the amniotic cavity. Am J Obstet Gynecol172 (1995) 261Search in Google Scholar
58 Romero R, M Sirtori, E Oyarzun, C Avila, M Mazor, R Callahan, V Sabo, AP Athanassiadis, JC Hobbins: Infection and labor. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol161 (1989) 817Search in Google Scholar
59 Sharief MK, EJ Thompson: In vivo relationship of tumor necrosis factor-alpha to blood-brain barrier damage in patients with active multiple sclerosis. J Neuroimmunol38 (1992) 27Search in Google Scholar
60 Shim SS, R Romero, JS Hong, CW Park, JK Jun, BI Kim, BH Yoon: Clinical significance of intra-amniotic inflammation in patients with preterm premature rupture of membranes. Am J Obstet Gynecol191 (2004) 1339Search in Google Scholar
61 Stanley FJ, L Watson: The cerebral palsies in Western Australia: trends, 1968 to 1981. Am J Obstet Gynecol158 (1988) 89Search in Google Scholar
62 Thompson PJ, A Greenough, HR Gamsu, KH Nicolaides, J Philpott-Howard: Congenital bacterial sepsis in very preterm infants. J Med Microbiol36 (1992) 117Search in Google Scholar
63 Toti P, C De Felice, M Stumpo, K Schurfeld, L Di Leo, R Vatti, G Bianciardi, G Buonocore, TA Seemayer, P Luzi: Acute thymic involution in fetuses and neonates with chorioamnionitis. Hum Pathol31 (2000) 1121Search in Google Scholar
64 Yoon BH, JW Chang, R Romero. Isolation of Ureaplasma urealyticum from the amniotic cavity and adverse outcome in preterm labor. Obstet Gynecol92 (1998) 77Search in Google Scholar
65 Yoon BH, JK Jun, R Romero, KH Park, R Gomez, JH Choi, IO Kim: Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-α), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol177 (1997) 19Search in Google Scholar
66 Yoon BH, SY Oh, R Romero, SS Shim, SY Han, JS Park, JK Jun: 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 Gynecol185 (2001) 1162Search in Google Scholar
67 Yoon BH, CW Park, T Chaiworapongsa: Intrauterine infection and the development of cerebral palsy. BJOG110 (Suppl 20) (2003) 12410.1046/j.1471-0528.2003.00063.xSearch in Google Scholar
68 Yoon BH, R Romero, JH Lim, SS Shim, JS Hong, JY Shim, JK Jun: The clinical significance of detecting Ureaplasma urealyticum by the polymerase chain reaction in the amniotic fluid of patients with preterm labor Am J Obstet Gynecol189 (2003) 919Search in Google Scholar
69 Yoon BH, R Romero, JS Park, JW Chang, YA Kim, JC Kim, KS Kim: 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 Gynecol179 (1998) 1254Search in Google Scholar
70 Yoon BH, R Romero, JS Park, CJ Kim, SH Kim, JH Choi, TR Han: Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol182 (2000) 675Search in Google Scholar
71 Yoon BH, R Romero, JS Park, M Kim, SY Oh, CJ Kim, JK Jun: 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 Gynecol183 (2000) 1124Search in Google Scholar
72 Yoon BH, R Romero, SH Yang, JK Jun, IO Kim, JH Choi, HC Syn: Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol174 (1996) 1433Search in Google Scholar
73 Watts DH, MA Krohn, SL Hillier, DA Eschenbach: The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol79 (1992) 351Search in Google Scholar
74 Wharton KN, H Pinar, BS Stonestreet, R Tucker, KR McLean, M Wallach, BR Vohr: Severe umbilical cord inflammation – a predictor of periventricular leukomalacia in very low birth weight infants. Early Hum Dev77 (2004) 77Search in Google Scholar
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