Preterm labor with intact membranes
        Main and The Obgyn Clinic of Hvidovre (danish)
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            Induction of Labour
            PROM (Premature Rupture of Membranes)
            PPROM (Preterm Premature Rupture of Membranes )
        Definition: Labor before 37 weeks of gestation < 259 days and > 20 weeks.
        Occurs approximately in 5-10% of pregnancies.
        Extremely preterm before 28 weeks of gestation (1%).

        Prognosis: Regular persistent uterine contraction (lasting 30 seconds or longer) and with a maximum of 5 minutes interval in 20 minutes with progression in cervical effacement and/or dilatation.

        Treatment: If no contraindication, tocolysis is indicated to postpone labor for up to 48 hours to get optimal effect of steroid Betamethasone 2 doses of 12 mg /ml 24 hours apart from 23-0 weeks up to 32 or 34 completed weeks.

        Initial Evaluation: History and physical examination including specular sterile vaginal examination and cervical ultrasound if needed with documented cervical status. Further digital examination should be avoided unless patient is in active labor.

        Cardiotocography
          Ultrasound
          • Fetal presentation and number
          • Placenta localization
          • Fetal weight and abnormalities survey if not performed previously
          • Biophysical profile especially amniotic fluid index and fetal breathing. Fetal breathing less likely to occur if the women are in true labor.
          • Cervical assessment by ultrasound ³ 2,5 (1,5) cm unlikely to be in case of premature labor.
          • Fibronectin useful as negative predictive value is high.

        Urinanalysis and culture Vaginal culture (inside introitus) Serum electrolytes, creatinine and glucose, glucosuria and ketonuria

        Antibiotics:
        Although a prolongation in time to delivery and a trend towards a reduction in neonatal sepsis antibiotics cannot be recommended with intact membranes because of raised concerns about increase perinatal mortality for those who received antibiotics.

        Contraindication to Tocolysis:
        Abnormal vaginal bleeding - abruption
        Severe hypertension

        Chorioamnionitis Fetal distress Fetal abnormality and demise

        TOCOLYSIS
        Acute

        Acute tocolysis: Glycerolnitrate (Nitroglycerin) or Terbutaline. Myometrial relaxation within seconds after Nitroglycerin and the duration is 2-3 min.

        Indication:
        1. Fetal distress caused by hypercontractility or before section if fetal heart rate is abnormal on contraction.
        2. Caesarean section if difficulties are anticipated such as transverse lie (Spray Sublingual at skin incision).
        3. Difficult delivery of the head in breech.
        4. Inversion of the uterus
        5. Internal version after twin A or difficulties during cesarean section.
        6. Shoulder dystocia if Zavanelli maneuver is applied.

        Dose:
        Sublingual Nitroglycerin 0.25 mg or
        Sublingual spray 0.4 mg/dose in case of anesthesia (can be repeated 2 times).
        Alternative to Nitroglycerin is Terbutaline 0.25 mg IV.

        Tocolysis in premature labor
        There is still no clear evidence that tocolytic drugs improve outcome following labor but should be considered to gain a few days from course of steroids or in-utero transfer. If a tocolytic agent is used, Ritodrine no longer seems the best choice.
        Alternative such as Atosiban or Nifedipine appears to have comparable effectiveness in terms of delivery for up to seven days and are associated with fewer maternal adverse effects and less risk of rare serious adverse effect. Nifedepine is not licensed as a tocolytic agent. Indomethacin, calcium channel blockers (Nifedepine) and Atosiban (Tractocile) should be considered first line according to British guidelines. B-mimetics (Ritodrine and Terbutaline) has many side effects and therefore is not so often used nowadays.
        Magnesium Sulfate: The effect is like placebo.

        In very early gestation multiple tocolytic agents have been suggested by some.

        Atosiban Guidelines
        Atosiban (Tractocile):
        Selective oxytocin antagonist small placental transfer seems to be as effective as B-mimetic but questionable before 26 weeks and in twins. The side effects and diabetogenic is lesser than B-mimetics and should be used in case of severe adverse effects of B-mimetics and in case of gestational diabetes and hyperthyroidism.

        Side Effect - seldom:
        Headache, nausea, vomiting, increase temperature, palpitation, hypotension, hyperglycemia, seldom itching, rash and sleeping disturbances.

        Observation:
        Blood pressure, ketonuria, and hourly the first 3 hours and after each micturition thereafter.

        Procedure:

        Stage Procedure Rate Doses
        1. 1 Bolus 0,9 ml (7,5 mg/ml) Within 1 minute 6,75 mg
        2. 2 Saturation-infusion (0,75 mg/ml) 24 ml/hour in 3 hours 18 mg/hour
        3. 3 Maintenance-infusion (0,75 mg/ml) 8 ml/hour for up to 8 hours 6 mg/hour
          Bolus-injection: 0,9 ml Tractocile ampoule (7,5 mg/ml).
          Saturation- and maintenance infusion: 100 ml NaCl. Remove 10 ml and replace with 2 ampoules of 5 ml Tractocile (7,5 mg/ml).

        Calcium Channel Blockers:
        Inhibits smooth muscle contraction by impeding the flow of calcium across the muscle cell membrane and reduce uterine vascular resistance.

        Administration:
        10 mg oral (Sublingual can cause acute hypotension) Nifedipine (Adelat) every 15 min until effect or max 1 time some start with loading dose of 30 mg followed by 20 mg po q 4 hour depending of uterine activity. Maintenance 10 mg q 8 hours up to 48 hours). Slow release Nifedipine 60-160 mg/day.
        Halflive 2-3 hours and action up to 6 hours.

        Contraindication:
        Nifedipine and magnesium together can cause hypotension and affect the heart.
        Cardiac disease. Heart failure (risk for AMI and severe hypotension) and severe liver disease.

        Side Effect:
        Headache, blushing, nausea, dizziness, cranial Hypertension, hypotension and tachycardia.

        Observation:
        Blood pressure: Pulse and ketonuria at start. Blood pressure and pulse every ½ hours, the first 3 hours. Ketonuria every 3-4 hours (after micturition).

        Indomethacin
        Seems to be as effective as B-mimetic Up to 100 mg suppositories followed after 8 hours by 25 mg supp every 8 hours for max of 48 hours. If longer, echocardiography evaluation should be performed with signs of tricuspidal evaluation

        Fetal side effects
        Possible only after longer than 2 days treatment Ductus constriction, tricuspid regurgitations, pulmonary hypertension and persistent fetal circulation. Oligohydramnios, renal improvement

        Recent metanalysis demonstrated an increased risk of perrventricular leucomalacia and necroting interocolittis.

        Specific contraindications:
        Cardiac disease, gastrointestinal bleeding, hepatitis,
        Diabetes, impaired renal function and oligohydramnios
        Not recommended more than 24 hours after 32 weeks (increased cardiac sensitivity).

        B-mimetics
        seldom used because of sideeffects and atosiban and nifidepine appear preferable as they have or fewer adverse effects and seem to have comparable effectivenes.

        Magnesium sulfate:
        The litterature does not support on effect.

        Rules of Thumb for the Prognosis in Preterm Infants
        Rules of Thumb for the Prognosis in Preterm Infants (Sandbjerg)
        Gestational age 24 25 26 27 28 29 32
        Survival 40% 50% 60% 70% 80% 90% >97%
        Normal among survivors 40% 50% 60% 70% 80% 90% >97%
        Celeston & surfactant The prognose 1-2 weeks better than gestational age
        <85% of median weight The prognose 1 week worser than gestational age
        <75% of median weight The prognose 2 weeks than gestational age

        From 23-24 weeks survival increase 3% for each day (Finnstroem 1999)

        References:
        (1) King J, Flenady V. Antibiotics for preterm with intact membranes. Cochrane Database of Systematic Reviews. Issue 2, 2000.

        (2) King JF, Flenady VJ, Papatsonis DNM, Dekker Ga, Carbonne B. Calcium channel blockers for inhibiting preterm . Cochrane Database Syst Rev 2002(3).

        (3) Tocolytic drugs for women in preterm. Royal College of Obstetricians and Gynecologists. Clinical Guideline No. 1(B). October 2002.

        (4) Simhan HN, Caritis SN. Prevention of Pretence Delivery NEJM 2007;357:477-87

        (5) www.uptodate 2007


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