Prenatal and natal (i.e., perinatal) occurrences are the most common causes of cerebral palsy. Among prenatal causes are intrauterine trauma, such as tearing of the placenta, maternal infection during pregnancy, in utero brain injury, and restricted or abnormal intrauterine growth. Natal causes of cerebral palsy include perinatal stroke and asphyxia at birth. Children born prematurely are at an elevated level of risk for cerebral palsy due to factors that precede or result from premature births (e.g., brain injury and limited in utero development, respectively).
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Cerebral palsy (CP) affects 2/1000 live-born children. Multiple antenatal factors, including preterm delivery, low birth weight, infection/inflammation, multiple gestation, and other pregnancy complications, are mostly associated with CP in both the preterm and term infant, with birth asphyxia playing a minor role. Owing to the increasing survival of the very preterm and very low birth weight infant secondary to improvements in neonatal and obstetric care, the incidence of CP may be increasing. The focus of this paper is to explore antenatal antecedents as etiologies of CP and the impact of obstetric care on the prevention of CP.
[Clark, S. M., Ghulmiyyah, L. M. &Hankins, G. D. (2008). Antenatal antecedents and the impact of obstetric care in the etiology of cerebral palsy. Clinical Obstetrics and Gynecology, 51(4), 775-86.]
[ Abstract ]
Causative factors in cerebral palsy (CP) vary to some degree according to gestational age group and clinical CP subtype. Such catastrophes of birth as placental abruption, cord prolapse, and uterine rupture sharply heighten risk of CP. These conditions are fortunately uncommon, and are sometimes not survived; individually and collectively they account for only a small proportion of CP. Among other factors associated with increased risk of CP are prematurity, intrauterine exposure to infection or maternal fever in labor, ischemic stroke, congenital malformations, atypical intrauterine growth (restricted or excessive for gestational age), and complications of multiple gestations. Although any 1 factor, if severe, may be sufficient to cause CP, more often it is the presence of multiple risk factors that overwhelms defense mechanisms and leads to CP. The contribution of genetic vulnerabilities that interact with environmental stressors is an emerging aspect of our understanding of causative factors in CP.
[Nelson, K. B. (2008). Causative factors in cerebral palsy. Clinical Obstetrics and Gynecology, 51(4), 749-62.]
[ Abstract ]
Abstract Aims: To evaluate the association between the presence of bacterial pathogens in the amniotic cavity at the time of preterm delivery and neuromotor outcome at two years adjusted age in preterm infants born at </=33 weeks' gestation. Methods: The cohort included 114 preterm infants, born at 23-33 weeks' gestation to mothers with amniotic cavity cultures taken during cesarean delivery who were subsequently evaluated at 24.0+/-1.1 months corrected age with the Bayley Scales of Infant Development II and a standardized neurologic examination. Results: A group of 67 infants with negative amniotic cavity cultures was compared to 47 infants with positive amniotic cavity cultures (Ureaplasma urealyticum (Uu) in 32 cases and other bacteria in 15 cases). Patients with positive amniotic cavity cultures had a significantly higher risk for an adverse psychomotor development index (PDI) score (OR 3.1, CI 1.3-7.1), an abnormal neurologic outcome (OR 4.8, CI 1.7-13.8), and a higher probability for diagnosis of cerebral palsy (OR 4.8, CI 1.4-16.4) at two years compared to patients with negative culture results. Isolation of Uu at birth was associated with a particular adverse outcome of preterm infants. Conclusions: Isolation of pathogens from the amniotic cavity at birth is significantly associated with abnormal PDI and adverse neuromotor outcome in preterm infants, irrespective of gestational age and birthweight.
[Berger, A., Witt, A., Haiden, N., Kaider, A., Klebermasz, K., Fuiko, R., Langgartner, M. & Pollak, A. (2008). Intrauterine infection with Ureaplasma species is associated with adverse neuromotor outcome at 1 and 2 years adjusteed age in preterm infants. Journal of Perinatal Medicine [e-publication ahead of print].]
[ Abstract ]
Cerebral white matter injury during prenatal maternal infection characterized as periventricular leukomalacia is the main substrate for cerebral palsy (CP) in premature infants. Previously, we reported that maternal LPS exposure causes oligodendrocyte (OL)-injury/hypomyelination in the developing brain which can be attenuated by an antioxidant agent, N-acetyl cysteine (NAC). Herein, we elucidated the role of peroxisomes in LPS-induced neuroinflammation and cerebral white matter injury. Peroxisomes are important for detoxification of reactive oxidative species (ROS) and metabolism of myelin-lipids in OLs. Maternal LPS exposure induced selective depletion of developing OLs in the fetal brain which was associated with ROS generation, glutathione depletion and peroxisomal dysfunction. Likewise, hypomyelination in the postnatal brain was associated with decrease in peroxisomes and OLs after maternal LPS exposure. Conversely, NAC abolished these LPS-induced effects in the developing brain. CP brains imitated these observed changes in peroxisomal/myelin proteins in the postnatal brain after maternal LPS exposure. In vitro studies revealed that pro-inflammatory cytokines cause OL-injury via peroxisomal dysfunction and ROS generation. NAC or WY14643 (peroxisome proliferators activated receptor (PPAR)-alpha agonist) reverses these effects of pro-inflammatory cytokines in the wild-type OLs, but not in PPAR-alpha(-/-) OLs. Similarly treated B12 oligodenroglial cells co-transfected with PPAR-alpha siRNAs/pTK-PPREx3-Luc, and LPS exposed PPAR-alpha(-/-) pregnant mice treated with NAC or WY14643 further suggested that PPAR-alpha activity mediates NAC-induced protective effects. Collectively, these data provide unprecedented evidence that LPS-induced peroxisomal dysfunction exacerbates cerebral white matter injury and its attenuation by NAC via a PPAR-alpha dependent mechanism expands therapeutic avenues for CP and related demyelinating diseases.
[Paintlia, M. K., Paintlia, A. S., Contreras, M. A., Singh, I. & Singh, A. K. (2008). Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: Attenuation by N-acetyl cysteine. Experimental Neurology, 210(2), 560-76.]
[ Abstract ]
Intra-amniotic infection (IAI), or chorioamnionitis, complicates up to 10% of all pregnancies and up to 2% of labors at term. There is a significant risk of complications for the mother and the neonate following IAI, including sepsis and pneumonia. In addition, there is a correlation between IAI and premature rupture of membranes, preterm premature rupture of membranes, preterm labor, and preterm birth. Research in the last decade has also revealed a complex and significant association between IAI and cerebral palsy and other central nervous system damage in both the preterm and term fetus. Timely diagnosis and treatment of IAI can significantly reduce the risk of both maternal and neonatal complications.
[Fahey, J. O. (2008). Clinical management of intra-amniotic infection and chorioamnionitis: A review of the literature. Journal of Midwifery & Women's Health, 53(3), 227-35.]
[ Abstract ]
OBJECTIVE: To determine the perinatal risk factors of long-term neurologic impairment for preterm infants. METHODS: A case-control study was conducted with 60 neurologically impaired and 60 healthy children, all born prematurely. RESULTS: There was no relation between neurologic impairment and maternal pregnancy complications or prenatal steroid administration, bacteriologic content of cervical smear, fetal presentation, fetal heart rate, or mode of delivery. Cerebral palsy was associated with early neurologic signs, perinatal asphyxia, neonatal septicemia, abnormal brain ultrasound findings, prolonged interval between rupture of membranes and delivery, and multiple placental lesions. Children with minimal cerebral dysfunction were more frequently first born. Multiple placental lesions, neonatal septicemia, abnormal brain ultrasound findings, and perinatal asphyxia were independently correlated with long-term neurologic impairment. CONCLUSION: Perinatal infection, perinatal asphyxia, and abnormal brain ultrasound findings seem to be risk factors for cerebral palsy whereas primigravidity seems to be correlated with minimal cerebral dysfunction.
[Skrablin, S., Maurac, I., Banovic, V. & Bosnjak-Nadj, K. (2008). Perinatal factors associated with the neurologic impairment of children born preterm. International Journal of Gynaecology and Obstetrics, 102(1), 12-18.]
[ Abstract ]
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.
[Romero, R., Gotsch, F., Pineles, B. & Kusanovic, J. P. (2007). Inflammation in pregnancy: Its roles in reproductive physiology, obstetrical complications, and fetal injury. Nutrition Reviews, 65(12 Pt. 2), S194-202.]
[ Abstract ]
PURPOSE: The etiology of congenital cerebral palsy is unclear. Recent studies have suggested that maternal infection is involved. Indirect, but supportive, evidence for an infectious hypothesis would be provided by the finding of space-time clustering. METHODS: We analyzed all 906 cases born during the period 1991-2003 using a population-based registry from Northern England. We applied the K-function method for testing global space-time clustering and used residential addresses at the time of birth. The Knox method was used to determine the spatio-temporal range over which global clustering occurred. Tests were repeated using nearest neighbor thresholds to allow for variable population density. Additionally, Kulldorff's scan statistic identified specific space-time clusters. RESULTS: There was statistically significant evidence of global space-time clustering (p <or= 0.05). Clustering occurred over a range of close distances, but was most pronounced for cases born within 1-4 months of one another. A specific space-time cluster was identified during 1994. CONCLUSIONS: The application of spatial statistics for the study of cerebral palsy is novel. There is tentative evidence for the involvement of spatially and temporally varying environmental etiological factors. These findings may support a role for infections or similar agents. However, the role of chance cannot be excluded.
[McNally, R. J. & Colver, A. F. (2008). Space-time clustering analyses of occurrence of cerebral palsy in Northern England for births 1991 to 2003. Annals of Epidemiology, 18(2), 108-12.]
[ Abstract ]
Periventricular leukomalacia (PVL), the dominant form of brain injury in premature infants, is characterized by white matter injury (WMI) and is associated with cerebral palsy. The pathogenesis of PVL is complex and likely involves ischemia/reperfusion, free radical formation, excitotoxicity, impaired regulation of cerebral blood flow, a procoagulant state, and inflammatory mechanisms associated with maternal and/or fetal infection. Using an established animal model of human PVL, we investigated whether activated protein C (APC), an anti-coagulant factor with anti-inflammatory, anti-apoptotic, anti-oxidant, and cytoprotective activities, could reduce endotoxin-induced WMI in the developing rat brain. Intraperitoneal injections of lipopolysaccharide (LPS) (0.5 mg/kg body weight) were given at embryonic days 18 (E18) and 19 (E19) to pregnant Sprague-Dawley rats; control rats were injected with sterile saline. A single intravenous injection of recombinant human (rh) APC (0.2 mg /kg body weight) was given to pregnant rats following the second LPS dose on embryonic day 19 (E19). Reduced cell death in white matter and hypomyelination were shown on TUNEL and myelin basic protein (MBP) staining, respectively, on late postnatal days (P7) in APC-treated groups. There were significantly fewer TUNEL+nuclei in the periventricular WM in the APC+LPS group than in the untreated LPS group. Compared to the APC+LPS and control group, MBP expression was weak in the LPS group on P7, indicating endotoxin-induced hypomyelination in the developing rat brain. APC attenuated the LPS-induced protein expression of inflammatory cytokines, tumor necrosis factor-alpha, and interleukin-6, as evaluated by ELISA in neonatal rat brains. A single intraperitoneal injection of rhAPC (0.2 mg/kg body weight) to neonatal rats on P1 also had similar protective and anti-inflammatory effects against maternally administered LPS. Collectively, these data support the hypothesis that APC may provide protection against an endotoxin-evoked inflammatory response and WMI in the developing rat brain. Moreover, our results suggest that the possible use of APC in treatment of preterm infants and pregnant women with maternal or placental infection may minimize the risk of PVL and cerebral palsy.
[Yesilirmak, D. C., Kumral, A., Baskin, H., Ergur, B. U., Aykan, S., Genc, S., Genc, K., Yilmaz, O., Tugyan, K., Giray, O., Duman, N. & Ozkan, H. (2007). Activated protein C reduces endotoxin-induced white matter injury in the developing rat brain. Brain Research, 1164, 14-23.]
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OBJECTIVES: This study was undertaken to determine the perinatal predictors of cerebral palsy in extremely low birthweight infants (<1000 g). STUDY DESIGN: A case control study of infants with birthweight of less than 1000 g (19 with cerebral palsy and 38 controls) who survived beyond 18-22 months of corrected age was performed. Outcome variables included maternal demographics, obstetric complications, and neonatal outcome (gestational age at delivery, birthweight, Apgar scores, intrauterine growth restriction, respiratory distress syndrome, intraventricular hemorrhage, and neonatal sepsis). Data analysis consisted of t tests, chi2, and analysis of variance when appropriate. RESULTS: There were no significant differences between cerebral palsy and control groups with regard to mode of delivery, Apgar scores, preeclampsia, antenatal vaginal bleeding, or the use of magnesium sulfate. However, male gender (odds ratio 3.70; 95% CI 1.05-12.5), primigravid status (odds ratio 5.52; 95% CI 1.67-18.3), early neonatal sepsis (odds ratio 12.9; 95% CI 2.94-57.2) and chorioamnionitis, both clinical and histologic (odds ratio 3.71; 95% CI 1.16-11.9) were significantly associated with the development of cerebral palsy. The strong association between cerebral palsy and chorioamnionitis, as well as early neonatal sepsis, remain significant after adjustment for primigravid status and male gender. CONCLUSION: In extremely low birthweight infants, cerebral palsy was strongly associated with chorioamnionitis, early neonatal sepsis, male gender, and primigravid status.
[Constantine, M. M., How, H. Y., Coppage, K, Maxwell, R. A. & Sibai, B. M. (2007). Does peripartum infection increase the incidence of cerebral palsy in extremely low birthweight infants? American Journal of Obstetrics and Gynecology, 196(5), e6-8.]
[ Abstract ]
The etiology of cerebral palsy and other related perinatal brain injuries is poorly understood. Infections of the central nervous system are rare but important causes of neurodisability. Recent evidence suggests that infections and other inflammatory conditions apparently limited to the placenta are also associated with an increased risk of neurologic impairment. A major hypothesis to explain this connection is that cytokines, activated inflammatory cells, and other mediators of the innate immune response are released into the fetal circulation where they can directly or indirectly affect the development or integrity of the central nervous system. This review surveys the organisms, mediators, and placental lesions that have been associated with perinatal brain injury.
[Redline, R. W. (2007). Infections and other inflammatory conditions. Seminars in Diagnostic Pathology, 24(1), 5-13.]
[ Abstract ]
OBJECTIVE: The objective of this study was to determine the interaction between histologic chorioamnionitis and unexplained neonatal cerebral palsy among low-birth-weight infants. METHODS: 105 preterm infants delivered under 1500 g between 2000-2004 were studied. The clinical data, the neonatal neuroimaging, the laboratory results finds and the histopathologic features of fetal parts (placenta, umbilical cord and membranes) were evaluated. RESULTS: During the study period cerebral palsy were detected in 7.6% (8/105) of the newborns. The frequency of silent histologic chorioamnionitis was 39.7% (31 cases). The rate of caesarean section was 80.9% (72/89 deliveries), and elective operation was made in 51 cases (70.1%). In a logistic regression analysis controlling for confounding factors, compared with data on uninfected infants, histologic chorioamnionitis was significantly associated with risk of unexplained cerebral palsy (p = 0.006). There was also significant interaction between the maternal genital infections and chorioamnionitis (p = 0.024), and the maternal infections and positive smear of neonatal gastric aspirates (p = 0.033). There was no significant association between of intrapartum distress, the maternal genital infections, the prematurity and the maternal complications (hypertension, preeclampsia, diabetes mellitus, IUGR). Neither mechanic nor hypoxic ischaemic encephalopathy were demonstrated. CONCLUSION: Intrauterine exposure to maternal infection was associated with a marked increase in risk for cerebral palsy in infants of birth weight less than 1500 g.
[Horvath, B., Grasselly, M., Turay, A., Hegedus, A. & Oreg, Z. (2006). Histologic chorioamnionitis is associated with cerebral palsy [Hungarian]. Orvosi Hetilap, 147(5), 211-6.]
[ 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/inflammation 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.
[Bashiri, A., Burstein, E. & Mazor, M. (2006). Cerebral palsy and fetal inflammatory response syndrome: A review. Journal of Perinatal Medicine, 34(1), 5-12.]
[ Abstract ]
The second highest risk group for developing a cerebral stroke is the perinatal period, generally defined as 20 weeks of gestation through 28th postnatal day of age. In this commentary, a brief overview of ischemic perinatal strokes is presented. Ischemic perinatal stroke (IPS) occurs at a rate of 1 : 2300 to 1 : 5000 births, accounting for 30% of children with hemiplegic cerebral palsy (CP). Thus, IPS is the most common known cause for CP [1-3]. Although they occur frequently, much remains to be studied about perinatal strokes in general and the ischemic variety in particular.
[Raju, T. N. (2008). Ischemic perinatal stroke: Challenge and opportunities. International Journal of Stroke, 3(3), 169-72.]
[ Abstract ]
BACKGROUND: Carbon monoxide (CO) poisoning in pregnancy is a relatively rare occurrence, but it can result in fetal mortality and neurologic complications in fetuses who survive to term. CASE: We describe the course of an infant who was acutely exposed to CO at 20 weeks of gestation. CONCLUSIONS: We conclude that despite maternal well-being, CO intoxication at critical periods of human brain development can lead to hypoxic-ischemic lesions in the globus pallidus and that dystonic cerebral palsy may develop in the infant during long-term follow-up. 2007 Wiley-Liss, Inc.
[Alehan, F., Erol, I & Onay, O. S. (2007). Cerebral palsy due to nonlethal maternal carbon monoxide intoxication. Birth Defects Research. Part A, Clinical and Molecular Teratology, 79(8), 614-6.]
[ Abstract ]
Prenatal risk factors causing cerebral palsy (CP), here defined as a non-progressive motor abnormality of tone or posture, are much more numerous than once believed, when a great deal of brain injury was attributed to factors surrounding delivery. Scientific advances in genetics and biochemistry, as well as clinical technical advances in, for example, amniotic fluid examination or fetal neuroimaging, has permitted us to find a multiplicity of new etiologies causing neonatal encephalopathy, most of which were formerly attributed to perinatal hypoxia-ischemia. This article reviews an expanded list of etiologies, including asphyxia, which has been found to cause only 6-10% of CP in full term infants, and periventricular leukomalacia, which is associated with 30-50% of CP in premature births. We also review a few of the genetic causes of CP, which lead to metabolic encephalopathies in come cases, to congenital anomalies in others, and sometimes to both. We discuss maternal gestational or intrapartum infections which may affect the fetus by direct in utero contagion or by other less direct means. Inborn metabolic errors affecting the fetus, such as diabetes, are touched on, as are the effects of maternal medications or recreational drugs on the fetus. Finally, we briefly cite the curious phenomenon occurring in multiple births, namely the potential of CP in the surviving infant or infants were the others have died in utero.
[Pascual, J. M. & Koenigsberger. M. R. (2003). Cerebral palsy: Prenatal risk factors [Spanish]. Revista de Neurologia, 37(3), 275-80.]
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