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  1. 1. Magnesium Sulfate Neuroprotection GUIDELINES FOR REDUCTION OF Cerebral Palsy NOVEMBER 2010 CP results in Motor & Postural Dysfunction Commonly associated with Mental disability, and Abnormalities of Vision , Hearing , and Speech
  2. 2. ACOG COMMITTEE OPINION 455 MARCH 2010 <ul><li>Available evidence suggests that magnesium sulfate given before early preterm birth reduces the risk of cerebral palsy in surviving infants. </li></ul><ul><li>Physicians electing to use magnesium sulfate for fetal neuroprotection should develop specific guidelines regarding inclusion criteria, treatment regimens, and monitoring in accordance with one of the larger trials. </li></ul>
  3. 3. Riverside Neuroprotection MODIFIED BEAM TRIAL PROTCOL <ul><li>Neuroprotection protocol INITIATED for IMMINENT delivery FROM 23 0/7 – 33 6/7 weeks with @ least 2 hours Magnesium infusion prior to delivery for benefit. Exclude patients anticipated to deliver in < 2 hours or CI to MgSO4 ( eg. myasthenia gravis or severe sirs/sepsis ) </li></ul><ul><li>Delivery is considered imminent if clinically anticipated within ~ 12-24 hours. </li></ul><ul><li>1) Regular contractions ASSOCIATED with advanced cervical dilation ( 3-4 cm) with either preterm rupture of membranes OR intact membranes. </li></ul><ul><li>2) OR clinical suspicion for imminent delivery with isolated premature preterm rupture of membranes. </li></ul><ul><li>3) OR clinical suspicion of imminent delivery with antenatal bleeding </li></ul><ul><li>4) OR before an indicated preterm delivery </li></ul>
  4. 4. Riverside Neuroprotection Modification of the BEAM trial <ul><li>Neuroprotection PROTOCOL : 6 gram MgSo4 LOAD followed by 2 grams / hour for 12-24 hours until delivery. Discontinue MgS04 2g/hr maintenance if delivery is not anticipated to be imminent after the initial 12 hrs. </li></ul><ul><li>HOWEVER ; If after the initial 12 hours delivery is still anticipated within the subsequent 24 hours ( ie within 36 hours from protocol enrollment ) continue with 2 g / hr maintenance until delivery or 24 hours elapsed. Discontinue if delivery not imminent. </li></ul><ul><li>If MgSo4 2g/ hr maintenance has been previously discontinued WHEN subsequently delivery again appears imminent ( ie onset of labor OR delivery indicated ) </li></ul><ul><li>1) If more than 6 hours has elapsed since discontinuation of 2 g / hour MgSo4 maintenance ; RELOAD with MgSO4 6 grams and continue with MgSo4 2 grams / hour until delivery or 12 hours elapsed. </li></ul><ul><li>2) If 6 hours has not elapsed since discontinuation of previous 2 g / hr maintenance , Reload not recommended; only Re-Initiate 2 grams/ hour maintenance dosage and continue until delivery or 12 hours elapsed. </li></ul>
  5. 5. Biologic Plausibility MgSO4 Neuroprotection <ul><li>MgSO4 may exert a vasodilator effect in the fetal cerebral vessels mitigating hypoxia and/or ischemia induced brain damage. </li></ul><ul><li>MgSO4 exerts an anti-inflammatory effect resulting in decreased production of pro-inflammatory cytokines and free radicals which ultimately decreases cerebral cell death secondary to inflammation. </li></ul><ul><li>MgSO4 down regulates NMDA receptors for the neurotransmitter glutamate thereby decreasing Calcium entry into the cell and modulating a protective mitigation of excitatory action potential propagation. </li></ul>
  6. 6. Referenced by ACOG opinion 455 3 Largest RCT n = 4,184 <ul><li>N Engl J Med 2008;359:895 (BEAM TRIAL) ( < 34 weeks 6g/2g /12-24hrs) The rate of moderate to severe cerebral palsy was significantly lower in the magnesium group (1.9 versus 3.5 percent; RR 0.55; 95% CI 0.32-0.95) </li></ul><ul><li>N= 2,241 </li></ul><ul><li>JAMA 2003;290:2669 (ACTOMgSO4) ( < 30 weeks 4g/1g /24hrs) When gross motor function was considered the magnesium group had significantly lower rates of substantial gross motor dysfunction (3.4 vs 6.6 %) and the combined outcome of death or substantial gross motor dysfunction (17.0 vs 22.7 %). N=1,255 </li></ul><ul><li>BJOG 2007;114:310 (PREMAG) ( < 33 weeks 4g load only) Exposure to magnesium sulfate was protective against &quot;severe motor dysfunction or death&quot; (OR 0.62, 95% CI 0.41-0.93) </li></ul><ul><li>N= 688 </li></ul>ACOG COMMITTEE OPINION 455 MARCH 2010
  7. 7. Meta Analysis Conclusions <ul><li>Cochrane 2009 The neuroprotective role for antenatal magnesium sulphate therapy given to women at risk of preterm birth for the preterm fetus is now established. The number of women ( < 34 weeks ) needed to be treated to benefit one baby by avoiding cerebral palsy is 63 (95% confidence interval 43 to 155) n = 6,145 </li></ul><ul><li>Obstet Gynecol 2009;114:354 (NICHD) Fetal exposure to magnesium sulfate in women at risk of preterm delivery significantly reduces the risk of cerebral palsy without increasing the risk of death. n = 5,235 </li></ul><ul><li>AJOG 2009; 200:595 In conclusion, magnesium sulfate administered to women at risk of delivery before 34 weeks of gestation reduces the risk of cerebral palsy. n = 5,357 </li></ul><ul><li>Obstet Gynecol 2009;113:1327 Antenatal magnesium sulfate therapy given to women at risk of preterm birth is neuroprotective against motor disorders in childhood for the preterm fetus. n=4,446 </li></ul>
  8. 8. NNT Prevention Ratios <ul><li>(Cochrane) The number of women that would need to be treated to prevent one child from developing cerebral palsy less than 34 weeks was 63 </li></ul><ul><li>(NICHD) The number of women that would need to be treated to prevent one child from developing cerebral palsy in the 32-34 wk group was 56 </li></ul><ul><li>(NICHD) The number of women that would need to be treated to prevent one child from developing cerebral palsy in the less than 30 week group was 46 </li></ul><ul><li>(AJOG 2009;200:610) The number of women that would need to be treated to prevent one child from developing cerebral palsy in the less than 28 week group estimated to be 29 </li></ul><ul><li>Additional outcomes reviewed included: </li></ul><ul><li>In utero magnesium exposure did not significantly reduce the risk of -blindness </li></ul><ul><li>- deafness </li></ul><ul><li>- developmental delay </li></ul><ul><li>No significant adverse Neonatal effects such as increased risk of Apgar score less than seven at five minutes, intraventricular hemorrhage, periventricular leukomalacia, neonatal seizures, or need for ongoing respiratory support </li></ul>
  9. 9. Prematurity results in CP <ul><li>CP develops in as many as 15-20 % of surviving premature infants </li></ul><ul><li>The earlier the gestational age at delivery; The greater is the risk of developing CP. </li></ul><ul><li>CP risk % >>> 30 weeks >> 32-34 weeks with a plateau > 34 weeks unless chorioamnionitis or intrapartum hypoxia occurs. </li></ul><ul><li>CP as a result of prematurity is associated with the presence of Periventricular Leukomalacia (PVL is an anatomic lesion.) </li></ul><ul><li>In addition to perinatal inflammation, cerebral ischemia contributes to PVL and may result in CP in preterm infants. </li></ul><ul><li>Other conditions that primarily affect preterm infants and may lead to CP include severe intraventricular hemorrhage (IVH) and periventricular hemorrhagic infarction which may result in posthemorrhagic hydrocephalus which frequently leads to CP </li></ul>
  10. 10. Chorioamnionitis SYNERGISTICALLY Increases the risk of CP with Prematurity <ul><li>There are significant associations between clinical chorioamnionitis or histological chorioamnionitis and cerebral palsy, for clinical chorioamnionitis a pooled odds ratio of 2.42 (95% CI 1.52–3.84), and for histological chorioamnionitis a pooled odds ratio of 1.83 (95% confidence interval, 1.17–2.89). </li></ul><ul><li>This data is associated with an increased risks of 140% and 80% for neonates exposed to clinical chorioamnionitis or histological chorioamnionitis, to develop CP respectively. </li></ul><ul><li>PVL occurs more frequently in premature infants born to mothers with chorioamnionitis, premature or prolonged rupture of the membranes. In a meta-analysis, chorioamnionitis was associated with cystic PVL (relative risk 3.0) and cerebral palsy (relative risk 1.9) . Funisitis or neonatal sepsis also increases the risk of PVL </li></ul>Obstet Gynecol 2010;116:387–92 Clin Obstet Gynecol 1998 Dec;41(4):827-31 . Paediatr Perinat Epidemiol 1998 Jan;12(1):72-83
  11. 11. PVL <ul><li>PVL is more common in premature than term infants, and occurs more frequently with decreasing gestational age and size. The greatest period of risk for PVL is under 32 weeks of gestational age. </li></ul><ul><li>Prematurity increases vulnerability to PVL due to decreased cerebral vascular autoregulation and vasoconstriction. Autoregulation is further impaired by asphyxia, hypoxemia, infection, hypotension and hypocarbia. </li></ul><ul><li>The anatomy of the immature cerebral vasculature renders the premature infant especially vulnerable to periventricular white matter injury. Incomplete development of vessels that penetrate the deep and subcortical white matter and vessels that supply the area near the ventricles result in a zone around the ventricles with diminished vascularization. This area is particularly vulnerable to reduced blood flow in infants < 32 weeks. </li></ul>
  12. 12. < 5 % of CP results from Intrapartum Hypoxia Obstet Gynecol. 2006 Jun;107(6):1357-65. <ul><li>Data were available for analysis in 213 cases of CP. Major antenatal or pediatric cerebral palsy-related pathologies were identified in 98.1% of all these cases. An isolated acute intrapartum hypoxic event was defined as likely in only 2 of the 46 neonates born at term and none born preterm. </li></ul><ul><li>CONCLUSION: Cerebral palsy was seldom preceded by acute intrapartum hypoxia but antenatal cerebral palsy-related pathologies are often detectable. The objective American College of Obstetricians and Gynecologists/American Academy of Pediatrics criteria are useful to audit cerebral palsy causation and exclude primary intrapartum hypoxia </li></ul>