Předčasný porod-management předčasného odtoku plodové vody (PPROM)
UPDATE ON PREMATURITY - PeaceHealth … · PPROM accounts for 20 ... Counsel your patients on this,...
Transcript of UPDATE ON PREMATURITY - PeaceHealth … · PPROM accounts for 20 ... Counsel your patients on this,...
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UPDATE ON PREMATURITY Charlotte Clausen, MD September 13th, 2013
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Disclosures • I have nothing to disclose
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Objectives • To assess the risk factors for preterm labor and birth • To define the tools we have to evaluate the risk of preterm
labor and birth • To apply the appropriate treatment to those diagnosed
with preterm labor to optimize outcome
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“A great deal of intelligence can be invested in ignorance when the need for illusion is deep”.Saul Bellow
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Scope of the problem • Preterm birth (PTB)
• Birth prior to 37w0d gestation • 12.18% in United States
• Largest contributor to infant mortality • Morbidity of PTB primarily in < 32w • Rising due to more multiple gestation, late PTB
• 75% occur between 34-36w gestation
• Societal cost of PTB $26.2 billion
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PTB rate
Very PTB rate
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SCOPE OF THE PROBLEM • 1:5 infants with developmental delay were born preterm.
• 1:3 infants with vision impairment were born preterm
• ~50% of infants with CP were born preterm • Long term, LBW infants are at an increased risk cardiovascular diseases, such as MI,stroke, Htn, and increased risk for diabetes, and cancer as adults.
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Pathogenesis •~70 - 80% of PTBs occur spontaneously
• Preterm labor accounts for 40 to 50% of all PTBs •PPROM accounts for 20 - 30% of all PTBs
•~ 20 - 30% of PTBs are due to intervention for maternal or fetal problems.
•4 primary processes are: •Activation of the maternal or fetal hypothalamic-pituitary-adrenal
axis. • Infection •Decidual hemorrhage. •Pathologic uterine distention.
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Prevention • Primary prevention: aimed at all pregnant women • Secondary prevention: aimed at reducing risk in women
with prior preterm birth. • Tertiary prevention: aimed at preterm infants. • IN THE VAST MAJORITY OF CASES IT IS BEYOND THE CAPABILITITES OF OBSTETRIC MEDICINE TO PREVENT PTB.
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Risk Factors Historical
• Prior preterm birth • Prior PPROM • Prior multiple D&E’s • Previous cervical surgery • Uterine anomalies • DES exposure • Significant myomata • Pre-existing medical conditions • Stress • Smoking or drug use* • African-American
*modifiable
Current pregnancy • Multifetal gestation* • Short inter-pregnancy interval* • Poor weight gain • Invasive testing • Polyhydramnios • Oligohydramnios • Maternal anemia* • Asymptomatic bacturia • Pyelonephritis* • Peronidontal disease • Abdominal surgery • Antepartum bleeding • Short cervix • Congenital anomalies • No prenatal care*
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Interpregnancy Interval • Highest risk for PTB with intervals of less than 6 months
• Rates lowest at 18-23 months, then gradually rise
• When maternal age and SES adjusted for: • Progressive increase as interval decreased < 18mo
• < 6mo: PTB OR 1.40, LBW OR 1.26, SGA OR 1.2 • > 60mo: PTB OR 1.20, LBW OR 1.43, SGA OR 1.29
• Greater contributor to PTB in Native Americans, Puerto-Ricans, African-Americans
• Overall contribution short IP interval makes to PTB rate is small, but it is CONTROLLABLE
• Counsel your patients on this, and encourage delivery spacing/family planning
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Multiple Gestation • 60% twins deliver preterm • Increase largely due to assisted reproduction • 2 to 3 percent of all births
• 15-20% of births under 37 weeks
• Nearly 1/4 of births under 32 weeks
• Uterine overdistention, fetal signaling • Reduction
• Responsible ART • Limiting number of embryos transferred
• Selective reduction of higher-order multiple gestations
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Weight/nutrition • Both low and high BMI associated with increased risk
PTB • Inconsistent evidence of benefit with nutritional
supplementation in patients with PTB • Obese patients often have indicated PTB
• Weight loss prior to pregnancy may improve medical co-morbidities
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Substance abuse • Smoking
• Modest does-dependent relationship between smoking and PTB • Greater than 10 cigarettes/d PTB OR 1.7 • Contribution of smoking-related complications such as abruption,
previa, PPROM, IUGR • Brief counseling sessions with pregnancy-specific discussion has
been shown to decrease smoking rates • 16% reduction in rate of PTB with smoking cessation programs
• Cocaine most common substance in subjects with PTL and positive urine tox screen
• Smoking and cocaine are bad for so many reasons, so just advocate for cessation
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Asymptomatic Bacteriuria • Antibiotic treatment of asymptomatic bacteriuria is
effective in: • Reducing incidence of pyelonephritis • Reducing incidence PTB and LBW infants*
• Regular screening of women w high risk ASB • Sickle cell trait, diabetes, recurrent UTI, renal d/o
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Peridontal Disease • Associated with variety of adverse pregnancy outcomes
• Independent risk factor for PTB
• Mechanisms • Seeding of the placenta by oral flora • Systemic inflammation • Could also be marker for exaggerated inflammatory response with
PTB as a result
• RCT of 1800 subjects treated prior to 24w • No reduction in PTB w tx (gingival scaling, root planing, oral
hygiene instruction)
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Bacterial vaginosis • Screening and treatment of low risk women has not
demonstrated benefit • 2007 metanalysis showed increased risk of PTB with tx. OR
2.16(1.56-3.0)
• High risk groups • 2011 meta-analysis showed decreased risk PTB <37 weeks if
treated <22 weeks with clindamycin • 2013 Cochrane review
• 21 trials of 7847 women • Effective at eradicating infection, but no <PTB in high-risk patients OR
0.78(0.62-1.17)
• ACOG, USPSTF and CDC recommend no routine screening.
• Treat if symptomatic
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Stress • Biologic plausibility in that stress can increase
corticotropin-releasing hormone which enhances prostaglandin production
• Hard to study because it is hard to define stress, confounders, acute vs chronic stress and timing in pregnancy
• Social support in pregnancy has not decrease PTB in these women
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Risk PTB in subsequent pregnancies 1st birth 2nd birth Risk PTB (%)
Not preterm 4-9
Preterm 17-22
Not preterm Not preterm 2-5
Preterm Not preterm 5-13
Not preterm Preterm 11-22
Preterm Preterm 28-42
Bakketeig et al. in Elder MG et al. Preterm Labor, 1987.
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PROGESTERONE
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Progesterone: Meis trial Progesterone Placebo RR
<37w 36.3% 54.9% 0.66
<35w 20.6% 30.7% 0.67
<32w 11.4% 19.6% 0.58
• 459 subjects • Documented h/o spontaneous
PTB • 250 mg 17α-
hydroxyprogesterone caproate IM or placebo
• Start 16-20w, continued weekly to 36w
• Progesterone-exposed infants had less perinatal morbidity • Lower NEC, IVH, need for
supplemental O2
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Progesterone: da Fonseca trial
Progesterone Placebo RR
<37w 13.8% 28.5% 0.66
<34w 2.7% 18.5% 0.67
• 142 subjects • History of PTB(90%),
uterine abnormality(6%), or cervical incompetence(5%)
• 100mg progesterone vaginal suppository
• Start at 24w, continue nightly to 34w
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Progesterone: O’Brien trial Progeste
rone Placebo OR
<37w 41.7 40.7 1.08
<35w 22.7 26.5 0.9
<32w 10% 11.3% 0.9
• 659 subjects • h/o PTB 20-35 weeks • No twins
• 90 mg progesterone vaginal gel
• Start 18-22.9w, every morning until 37w
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Meta-analyses • 5 different meta-analyses
• Reduction in PTB rates • 20-40% reduction in PTB with progesterone • NNT to prevent one PTB: 10
• Reduction in NEC and RDS in neonates • Decrease neonatal death
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Progesterone • 2% reduction in overall PTB rate if all eligible pts receive
progesterone • Regimens
• 17 alpha-hydroxyprogesterone caproate 250 mg/ml IM once a week starting at 16-20 weeks until 36 weeks
• 100 mg vaginal suppository of micronized progesterone nightly starting at 16-20 weeks until 34-36 weeks: cost 1 USD per suppository
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Cervical shortening • Cannot measure before 14
weeks • Transvaginal better than
transabdominal • Watch for dynamic change • <25mm is considered short • The shorter the length, the
greater the risk
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Cervical length measurements • Cervical length is not significantly affected by parity. • Cervical length normally declines slightly between 20 and 32 weeks
and more substantially after 32 weeks. Between 22 and 32 weeks gestation the length of the cervix is described by a normal bell shaped curve: • 5th centile at 20 mm • 10th centile at 25 mm • 50th centile at 35 mm • 90th centile at 45 mm • Median cervical length is 40 mm before 22 weeks, 35 mm at 22 to 32
weeks, and 30 mm after 32 weeks • It is important to remember that cervical shortening precedes preterm
birth by several weeks (3-8 weeks) in most cases, rather than imminent PTB.
• Great negative predictive value
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Progesterone + short cervix • Fonseca 2007
• RCT 250 subjects • No exclusion for prior PTB (15%) or twins (10%)
• 200mg capsules micronized progesterone to those with TVCL 15mm • Start at between 20-25w, nightly until 33w6d • Outcome PTB before 34w
• 19.2% progesterone v 34.4% placebo, RR 0.56 • Hassan 2011
• RCT 458 women • 90 mg vaginal progesterone gel to those with TVCL 10-20mm • Del <33 weeks 9% vs 16%, RR 0.55(0.33-0.92) • Still significant with hx PTB excluded
• Grobman 2012 • IM progesterone for CL <30mm • Nulliparous pts • PTB <37 weeks 25.1% vs 24.2%
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CERCLAGE
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Cerclage with hx PTB: Owen trial • 1014 subjects w prior PTB < 34w
• 301 with cervix < 25mm randomized, with outcomes
• Primary outcome PTB < 35w • Surveillance between 16w-21.9w • Every 2w unless 25-29mm, in which case every week • If <25mm, randomized to McDonald cerclage
• Antibiotics and tocolytics not standardized
• Results • PTB <35 weeks no significant difference RR 0.71(0.58-1.04) • <24 weeks RR 0.44 (0.21-0.92) 6.1% vs 14% • <37 weeks RR 0.75 (0.60-0.93) • Perinatal death RR 0.54 (0.29-0.99)
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Cerclage with hx PTB: Berghella meta-analysis • Included 5 RCTs of cerclage and short cervix(<25mm) • Hx of prior PTB, 502 women • Primary outcome PTB prior to 35w • 30% reduction in PTB(28% vs 41%) RR 0.7(0.55-0.89) • 36% reduction in composite perinatal mortality and
morbidity(16% vs 25%) RR 0.64 (0.45-0.91)
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Cerclage for short cervix Berghella meta-analysis • 4 RCT of cerclage for short cervix(n=607) • Individual patient data compiled
• Combination of low- and high-risk subjects • Differing cervical length cutoffs for intervention
• Primary outcome PTB <35 weeks • All singletons RR 0.74(0.57-0.96) • No hx of PTB RR 0.84(0.60-1.17) • Hx PTB RR 0.61(0.40-0.92) • Hx prior 2nd tri loss RR 0.57(0.33-0.99) • Twins RR 2.15(1.15-4.01)
• If no hx PTB, start with progesterone, then move to cerclage for dilation or progressive shortening.
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ACOG Bulletin
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Where progesterone use is unclear • Multiple gestation
• IM has not been shown to prolong gestation in twins or triplets • Vaginal showed ns decrease in PTB <33 weeks in twins
• Significant decrease in neonatal morbidity and mortality 23.9% vs 39.7% • History of singleton PTB with current multiples
• +FFN • With cerclage
• No large studies to show additional benefit • Post-hoc of Berghella study showed benefit for del <28 weeks
• Arrested preterm labor • Maybe? • Small trial, 70 subjects with vaginal progesterone showed
prolonged latency, but no ss decrease in neonatal outcomes • Not currently recommended
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ACTIVITY MODIFICATION?
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Work • Minimal relationship between work and PTB
• In some series, duration standing or total hours worked correlated with increased risk PTB
• No relationship in other studies
• Effects of reducing occupational fatigue have not been evaluated
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Play • No evidence that bedrest decreases the incidence of PTB
• In low risk population, physical activity associated with a reduced risk for PTB
• Coitus leads to increased uterine activity, but not PTB
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Bedrest • Has not been shown to decrease the incidence of PTB
• Cochrane review 2004- no evidence for strict bedrest. 1 RCT • Even in short cervix
• Grobman WA. • Fox NS
• After acute PTL • Yost NP- mainly showed no difference in HBR vs Home
• Has negative psychosocial effects • Increased risk for thromboembolic event, bone
demineralization, muscle deconditioning, depression
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Bedrest • Green journal article discussing ethical concerns
• Autonomy, Informed consent • Beneficence • Justice
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Preterm labor: Diagnosis • One of the most common reasons for hospitalization of
pregnant women. • Using clinical criteria alone: - menstrual like
camps,constant low back pain, uterine contractions, bloody show - • 30% of patient diagnosed with preterm labor resolve
spontaneously. • 50% of patients hospitalized for PTL deliver at term.
• Uterine contractions: threshold not identified. • Digital cervical examination (80% effacement, and or
cervical dilation > 2 cm dilation, regular painful contractions associated with cervical changes).
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Initial evaluation
BIOCHEMICAL ASSAYS AND ULTRASOUND EVALUATIONS OF THE CERVIX ARE NOT SUBSTITUTES FOR SOUND CLINICAL JUDGEMENT.
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Fetal fibronectin • Well over 500 publications on the use of fFN in the
management of PTL. • In 2008 over 40,000 fFN were performed each month in
the US. • Used in 2 ways:
• To predict the risk of PTB in symptomatic patients. • To identify asymptomatic women who are most likely to deliver
preterm.
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Use of ffn in symptomatic women • Systematic review of 32 cohort studies:
• PPV for predicting PTB within 7 days of the test is between 20% and 50%
• NPV for delivery within 7 days, within 14 days, and at < 37 weeks gestation were 99.5%, 99.2%, and 84>% respectively.
• Sample collection: • Intact fetal membranes • Cervical dilation < 3 cm • Gestational age 22-34 weeks • Use a sterile speculum exam • No lubricants, hx of coitus, vaginal bleeding or SVE • > 50 ng/mL is considered (+)
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Combining cervical length and ffn • Triage based upon cervical length:
• Cervical length > 30 mm: • No fFN is needed. • Exclude acute precipitating events. • Cervix not dilating or effacing. • D/C home.
• Cervical length 20 to 30 mm: • Send for fFN if (+) treat the patient actively.
• Cervical length < 20 mm: • These patients are at risk for PTB regardless of the results of the
fFN.
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NICHD Neonatal Research Network (NRN): Extremely Preterm Birth Outcome Data Gestational Age (Best Obstetric Estimate in
Completed Weeks): 24 weeks
Birth Weight: 650 grams
Sex: Female
Singleton Birth: Yes
Antenatal Corticosteroids: Yes
Outcomes Outcomes for All Infants Outcomes for Mechanically Ventilated Infants
Survival 66% 68% Survival Without Profound Neurodevelopmental Impairment
52% 55%
Survival Without Moderate to Severe Neurodevelopmental Impairment
38% 40%
Death 34% 32% Death or Profound Neurodevelopmental Impairment
48% 45%
Death or Moderate to Severe Neurodevelopmental Impairment
62% 60%
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Treatment of preterm labor • Hospitalize if under 34 weeks gestation • Transport of the mother if necessary • Tocolytic drugs for up to 48 hours • Appropriate antibiotics for GBS chemoprophylaxis • Antenatal glucocorticoids. • MgSO4 for neuroprotection. • Appropriate antibiotics to women with positive urine
culture results, GC or chlamydia.
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Choice of tocolytics:
• Beta-mimetics. • Magnesium sulfate. • Calcium channel blockers. • Prostaglandin synthetase inhibitors.
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Beta-mimetics Dosage and administration
Contraindications Maternal side effects
Fetal and neonatal side effects
Terbutaline, .25 mg subcutaneously every 20 min to 3 hrs (hold for pulse > 120 bpm)
Cardiac arrhythmias, tachy sensitive cardiac disease FDA Warning for use >48-72 hours
Cardiac or cardiopulmonary, arrhythmias, pulmonary edema, myocardial ischemia, hypotension, tachycardia
Fetal tachycardia, hyperinsulinemia, hyperglycemia, myocardial and septal hypertrophy, myocardial ischemia
Ritodrine initial dose of 50-100 mcg/min, increase 50 mcgevery 10 min until uc’s stopor side effects, max dose 350mcg/min
Poorly controlled hyperthyroid disease Poorly controlled DM
Hyperglycemia, hyperinsulinemia, hypokalemia, antidiuresis, abnormal thyroid function. Physiologic tremor plapitations, hallucinations, N&V
Neonatal tachycardia, hypoglycemia, hypocalcemia, hyperbilirubinemia, hypotension, IVH
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Magnesium Sulfate Dosage and administration
Contraindications Maternal side effects
Fetal and neonatal side effects
4 - 6 grams bolus for 20 minutes then 2 - 3 grams/hour
Myasthenia gravis FDA warning for use >5-7 days for fetal effects
Flushing, lethargy, headache, muscle weakness, diplopia, dry mouth, pulmonary edema, cardiac arrest
Lethargy, hypotonia, respiratory depression, demineralization with prolonged use
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Calcium channel blockers
Dosage and administration
Contraindications Maternal side effects
Fetal and neonatal side effects
NIFEDIPINE: 30 mg loading dose, then 10 - 20 mg every 4 to 6 hours
Cardiac disease, caution with renal disease, maternal hypotension (90/50), avoid concomitant use with magnesium sulfate
Flushing, headaches, dizziness, nausea, transient hypotension
None noted as yet
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Prostaglandin Syntestase Inhibitors
Dosage and administration
Contraindications Maternal side effects
Fetal and neonatal side effects
INDOMETHACIN: loading dose of 50 mg rectally or 50 - 100 mg orally, then 25 - 50 mg orally every 6 hours for 48 hours
Significant hepatic or renal impairment, platelet dysfunction
Nausea, heartburn
Constriction of ductus arteriosus, pulmonary hypertension, reversible decrease in renal function with oligohydramnios, IVH, hyperbilirubinemia, NEC
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Antibiotics • Is there a role for adjunctive antibiotics?
• Evidence than empiric treatment with broad spectrum antibiotics is not only less effective than placebo in prolonging gestation, but is also associated with long term abnormal CNS development.
• Treat for GBS prophylaxis while awaiting for culture results, discontinue treatment if GBS culture is negative.
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Antenatal steroids • 24-34 weeks • Reductions in
• Respiratory distress syndrome OR 0.55 • Intraventricular hemorrhage OR 0.54 • Necrotizing enterocolitis OR 0.46 • Neonatal mortality OR 0.69 • Neurologic handicap
Crowley P. Cochrane Database 2;2002.
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Antenatal steroids • 34-36 6/7 weeks
• Shanks A. • BMZ in those with documented lung immaturity between 34-37 weeks • Increased level of test for FLM: 28.4 vs 9.8%, too small to draw
conclusions about clinical outcomes • Brazilian RCT showed no difference • Concern with neurologic effect on more mature fetal brain
• Await results of ALPS(antenatal late preterm steroids)
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Antenatal steroids • “Rescue dose”
• 3 RCT’s • 1 no benefit, 2 benefit in <RDS • No data on long-term outcome • Small number of patients
• Australian study • Single dose decreased RDS
• ACOG • Consider if 7 days have passed since 1st dose and <34 weeks
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MgSO4 For “Neuroprotection” • Australasian Collaborative Trial of Magnesium Sulfate (ACTOMgSO4) published in 2003.
• PREMAG study from France published in 2007
• MFM Network study published in 2008 (BEAM).
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MgSO4 For “Neuroprotection”: Crowther et al JAMA, 2003;290: 2669
• (ACTOMgSO4) published in 2003. • 1,060 preterm laboring women at < 30 weeks gestation expected to
deliver within 24 hours.
• Randomly assigned to receive MgSO4 (4 g over 30 minutes, followed by 1g/hr up to 24 hrs maximum) or saline placebo.
• CP was 6.8% vs 8.2%: RR: 0.83(0.54 - 1.27)
• Pediatric mortality 13.8% vs 17.1%: RR: 0.83(0.64 -1.09)
• Composite outcome of death or CP 19.8% vs 24% : RR: 0.83(0.66 -1.03)
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MgSO4 For “Neuroprotection” Marret et al Gynecol Obstet Fertil 2008; 36: 278
• PREMAG study from France published in 2007. • 573 preterm laboring women at < 33 weeks gestation with
delivery planned or anticipated within 24 hours • Randomly assigned to receive a single dose of MgSO4 (4 g
bolus infusion) or saline placebo with NO maintenance. • Infants were followed for 2 years after discharge. • Primary outcome was white matter injury detected on
neonatal cranial ultrasound. • Secondary outcomes were “cerebral palsy or death” severe
motor dysfunction or death” • CP or death OR 0.65, (0.42-1.03) 16.1% vs 20.2% • Severe motor function or death 0.62 (0.41-0.93)
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MgSO4 For “Neuroprotection” Rouse et al: N Engl J Med 2008; 358: 895
• MFMU Network study published in 2008. • Multicenter placebo controlled trial of MgSO4 for the prevention of CP
• 2,241 preterm laboring women at 24 to 31 weeks gestation at risk of imminent delivery.
• Randomly assigned to receive MgSO4 (6 g bolus infusion, followed by 2g/hr infusion for 12 hours) or saline placebo.
• Primary outcome was the composite outcome of “stillbirth or infant death by one year of corrected age or moderate or severe Cp at or beyond 2 years of corrected age” 11.3 vs 11.9%
• Rate of moderate or severe CP was 1.9% vs 3.5%: RR: 0.55; 95% CI 0.32 - 0.95. Only < 28 weeks showed a significant reduction.
• The risk of death was similar in both groups 9.5 % vs 8.5%RR 1.12; 95% CI 0.85 - 1.47
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MgSO4 For “Neuroprotection” Doyle et al: Cochrane Database Syst Rev 2009, CD004661
• 4 studies explicitly designed to assess neuroprotective effect of MgSo4(4,446 children)
• Primary outcomes were fetal or infant death by age 1, neurological impairment, major neurological disability, and the composite outcome of “ death or an adverse neurological outcome” by age 2.
• Results: • Significant reduction in “death or CP” RR 0.85(0.74 - 0.98) • No significant effect on stillbirth or pediatric mortality rates RR 0.95(0.80
- 1.12) • Risk of any CP RR 0.71(0.55 - 0.91) • CP 3.7% vs 5.4% • Moderate /severe CP RR 0.64(0.44 - 0.92)
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MgSO4 For “Neuroprotection” • Treat 63 women threatening to deliver prior to 32 weeks gestation to prevent 1 case of moderate to severe CP.
• Treat 29 women to prevent 1 case of moderate to severe CP if restricted to delivery under 28 weeks gestation.
• Compare to 100 women with preeclampsia treated to prevent 1 case of eclampsia.
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MgSO4 For “Neuroprotection” • PROTOCOL:
• 24 to 32 weeks gestation for both preterm labor and PPROM
• Imminent risk of preterm birth within 24 hours. • 4 gram dose in 20 to 30 minutes
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After initial stabilization • Progesterone? No evidence • Bedrest? • Is there a role for maintenance treatment after completing
acute treatment? • Meta-analysis fails to demonstrate any benefit of maintenance
tocolysis in terms of gestational age at birth, pregnancy prolongation, or birth weight.
• Is tocolysis warranted for recurrent preterm labor?