Best Practice

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• Best Practice Research Clinical Obstetrics and
  Gynaecology
• Vol. 21, No. 5, pp. 857868,
• 2007
• Andrew Bisits
• Conjoint Senior Lecture and Director of
  Obstetrics
• Faculty of Health, University of Newcastle,
  Australia

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• It has long been the desire of clinicians to have
  therapies that can interrupt premature labour and
  allow the delivery of more mature infants with
  lower morbidity and mortality, time to use
  antenatal corticosteroids and transfer to
  tertiary care centres for delivery.

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CURRENT TOCOLYTIC AGENTS IN USE
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• 1332 women
• There was a significant decrease in the number of
  women giving birth within 48 h of administration
  of the b2 agonist
• There were significant increases in maternal
  adverse effects
• chest pain\ dyspnoea\ tachycardia \palpitations \
  tremor \ headaches \ hypokalaemia \
  hyperglycaemia \ nausea/vomiting \ nasal
  stuffiness
• And in other studies there were maternal deaths

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• There were no effects on perinatal deaths,
  respiratory distress (RDS), cerebral palsy (CP),
  neonatal death, infant death and necrotizing
  enterocolitis (NEC). Only .one trial reported
  neonatal length of hospital stay
• There is no evidence of improved neonatal
  outcomes with ß2 agonists, but an association
  with severe .maternal morbidity and mortality
• .Increase in cephalic presentation at delivery
• .Reduced incidence of caesarean section
• The most marked effect was in multiparous women.

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• MgSO4 has historically been most used in North
  America, with only sparse and poor quality
  evidence supporting its use.
• Reviewed 23 trials with gt 2000 women but only
  nine trials were rated as high quality.
• All trials and the nine high quality trials
  showed no effect on PTD lt 48 h after the
  administration of MgSO4 compared with placebo, no
  therapy or other tocolytics
• All trials showed an increase in fetal and
  paediatric .death, which was unexpected

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• No beneficial effect was seen for neonatal
  morbidity,
• including RDS, NEC or proven infection and
  reduction of CP.
• Crowther et al concluded that there was no
  evidence supporting the use of MgSO4 as a
  tocolytic agent.
• King repeating in 2004 that there was clear
  evidence from RCTs that its use as a tocolytic
  should be abandoned as there was an association
  with a higher .risk of perinatal death

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• 34 women, Panter
• Indomethacin,
• No increases in perinatal mortality or morbidity,
  namely NEC, bronchopulmonary dysplasia (BPD),
  interventricular haemorrhage (IVH) and
  periventricular leucomalacia (PVL).
• There was no evidence of any benefits from
  indomethacin . However, it can also be concluded
  that there were no detrimental effects.

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• Macones
• indomethacin to be an effective tocolytic in
  delaying PTD for gt48 h, 7-10 days, 37 weeks, and
  decreasing low birthweight .
• There may be an increased rate of IVH and NEC,
  but it is not possible to pool the results for
  neonatal outcomes. Premature closure of the
  ductus arteriosus occurs in 10-50 of fetuses
• exposed to indomethacin. It is more prevalent in
  later gestations (gt32 weeks) and if additional
  maternal treatment is longer than 48 h. These
  effects can be reversible but pathological
  effects on fetal myocardial function have been
  reported (endocardial ischaemia, papillary muscle
  dysfunction, cardiac failure and death).

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NSAIDs cont.

• From several researches(Suarez Loe etc.) ?
  the authors stated
• We cautiously conclude that use of indomethacin
  at less than 34 weeks of gestation for tocolysis
  does not appear to increase the risk of adverse
  neonatal outcomes.

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NSAIDs cont.

• Sulindac
• 95 women (46 given sulindac and 49 placebo
  controls)
• There were no outcome
• but there was a reduction in amniotic fluid
  index (AFI) and deepest pocket of liquor at 14
  days.
• The possibility of cyclooxygenase-2 (COX-2)
  inhibitors as possible tocolytic agents has been
  investigated by several teams but the withdrawal
  of rofecoxib has prevented a thorough evaluation.

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Nitric oxide donors

• The possibility of glyceryl trinitrate or nitric
  oxide (NO) .donors as tocolytics had great appeal
• OGrady et al,who reported a 100 successful
  tocolysis.
• Duckitt and Thornton 466 women
• NO donors did reduce the risk of delivering
  before 37 weeks
• but did not delay delivery prior to 32 or 34
  completed weeks, nor improve neonatal outcome,
• they were significantly more likely to cause
  headache
• They concluded there was insufficient evidence to
  support NO donors for tocolysis.

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Nitric oxide donors

• Bisits et al 233 women
• Comparing IV b2 agonists with glyceryl trinitrate
  (GTN) dermal patches.
• GTN being less efficacious
• Fewer side effects were noted with GTN.

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• From 1980
• Papatsonis et alcompare oral nifedipine or IV
  ritodrine
• Nifedipine was associated with lower rates of
  admission rates to NICU RDS ICH and
  neonatal jaundice
• Nifedipine was associated with significant
  increase in mean gestational age at birth and a
  higher mean birth weight.

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• King et al
• CCBs are more effective than ß2 agonists with
  less maternal side effects and reduced neonatal
  morbidity.
• Most trials have used oral treatments for
  maintenance up to 34-37 weeks. The results show
  decreased delivery within 7 days , decreased
  delivery before 34 weeks , reduced adverse
  maternal drug reaction , reduced RDS . NEC IVH
  admition to NICU neonatal jaundice
• Concerns have been raised regarding maternal
  cardiovascular side effects resulting from
  nifedipine therapy.

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• It has also been argued that nifedipine is not
  associated with severe hypotensionm other than
  that attributed to the underlying maternal
  condition because the maternal
• hypotension far outlasted the known half-life of
  oral nifedipine.

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• Atosiban(1-deamino-2-D-Tyro(OEt)-4-Thr-8-Orn
  oxytocin) is a competitive oxytocin receptor
  antagonist.
• Goodwin et al 112 women
• Only a small number of women at lt28 weeks were
  recruited. A significant decrease in uterine
  contraction frequency
• was seen over a 2-h period in the atosiban
  subjects.
• Romero et al recruited 551 patientscompare
  atosiban with placebo The percentages of patients
  remaining undelivered at 24 h, 48 h and 7 days
  were significantly higher in the atosiban group
  than in the control group.
• Atosiban was less effective at lt28 weeks and the
  incidence of fetal deaths was higher at lt24 weeks.

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• Moutquin et al reported a RCT of 363 women who
  received atosiban and 379 a b mimetic (ritodrine,
  salbutamol or terbutaline).31 There were no
  significant differences for delivery at 48 h or 7
  days. There were reduced maternal side effects
  (particularly cardiovascular) in the atosiban
  group but no differences in neonatal/infant
  outcomes. Significantly fewer women required
  alternative therapy in the atosiban group.

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• Papatsonis et al 1695 women
• Compared with placebo, atosiban did not reduce
  the incidence of preterm birth or improve
  neonatal outcome.
• There are lots of researches about Atosiban .and
  the results are different

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• Fetal fibronectin
• Ultrasound measurement of cervical length
• (Their combined results were better in predicting
  PTD.)

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• Atosiban is a combined vasopressin V1A/oxytocin
  receptor antagonist. Recently, a highly selective
  oxytocin receptor antagonist (barusiban) has been
  described.
• Barusiban would appear in theoretical and in vivo
  studies to be more effective than atosiban.

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• WASHINGTON CLARK HILL
• Department of Obstetrics and
• Gynecology, University of South Florida,
• 2004

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• Any treatment of preterm labor in the multiple
  gestation must include the administration of
  corticosteroids. The meta-analysis conducted by
  Crowley showed that the use of antenatal
  corticosteroids reduced significantly the
  incidence and severity of neonatal respiratory
  distress syndrome.35 Antenatal corticosteroids
  also reduce the incidence of intraventricular
  hemorrhage, necrotizing
• enterocolitis and neonatal mortality.

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• Vicenc Cararach
• European Journal of Obstetrics Gynecology and
• Reproductive Biology
• 2006
• Badalona, Spain
• Catalonia, Spain

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• Ritodrine provides more effective tocolysis
  within the first 48 h of preterm labor than
  nifedipine.
• Although nifedipine was initially less effective
  than ritodrine in the first 2 days, similar
  perinatal results were
• obtained with a significantly lower rate of
  secondary effects than with ritodrine treatment.

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• Nifedipine and atosiban should be considered as
  first-line tocolytic agents instead of b
  agonists, based on equal or superior efficacy and
  superior adverse events profiles.

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• Katie M. Groom
• 2007
• Auckland, New Zealand

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• Antibiotics may be beneficial in some women for
  preventing preterm birth but in others they may
  be associated with an increased risk and
  therefore should only be used with caution.
  Progesterone is likely to be the best potential
  drug at present for prevention of preterm birth.

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• EDWARD HAYES
• 2007
• Jefferson University, Obstetrics and Gynecology,
  Philadelphia, Pennsylvania
• American Journal of Obstetrics and Gynecology,
  Volume 195, Issue 6

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• Based on 25 clinical trials (total n1870
  patients),
• Nifedipine is the most cost-effective tocolytic
  and should be used as first-line therapy for
  tocolysis in the U.S.

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• S.G. Oei
• University of Technology, Eindhoven
• Netherlands
• European Journal of Obstetrics Gynecology and
• Reproductive Biology 126 (2006) 137145

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• Firstly, calcium channel blockers should not be
  combined with intravenous b-agonists.
• Secondly, intravenous nicardipine or high oral
  doses of
• nifedipine (gt150 mg/day) should be avoided in
  cases of
• cardiovascular compromised pregnant women and/or
  multiple gestations.
• In all cases, blood pressure should be monitored
  and cardiotocography recorded during the
  administration of immediate release tablets and
  chewing the tablets should be avoided.

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• Comparing nifedipine with placebo