Review of Medications used in Preterm Labour

1. Review of Medications used in Preterm Labour Hilary Rowe BSc(Pharm) 2009-10 VIHA pharmacy Resident June 3rd and 4th 2010

2. Objectives • For each medication discussed: • Describe the mechanism of action • Know the Loading and Maintenance dose for medications used at VGH • Name 3 side effects of each medication for mom • Name 2 risks of each medication for the fetus • Know how long to use each medication • List what stages of gestation each medication is safe

3. Tocolytic Medications • Tocolytic: A medication used to suppress uterine contractions • Preterm Labour: Progressive dilatation of the cervix with uterine contractions between 20+0 and 36+6 weeks gestation • Goals of Therapy: • Provide time for safe transport of the mother • Prolong pregnancy when there are self-limiting conditions that can cause labor

4. Tocolytic Medications • Goals of Therapy Continued: • Delay delivery by >48 hrs so glucocorticoids (eg. betamethasone) given to mother have time to work • Glucocorticoids reduce the risk of • Neonatal death • Respiratory distress syndrome • Intraventricular hemorrhage • Necrotizing enterocolitis

5. Mechanisms of Action • Generation or alteration of intracellular messengers • B-agonists, Nitric oxide donors, Magnesium sulfate, Calcium channel blockers • Inhibiting the synthesis or blocking the action of known myometrial (muscle of the uterus) stimulants • Oxytocin antagonists or Prostaglandin synthesis inhibitors

7. Indomethacin (COX inhibitor) • M of A: Non-steroidal anti-inflammatory • Prostaglandins enhance formation of myometrial gap junctions • Increase intracellular calcium by ↑ transmembrane influx & release of calcium from the sarcoplasmic reticulum

8. Indomethacin • Loading and Maintenance dose • Initial Dose: 100mg rectal suppository • Maintenance Dose: 25-50mg orally or rectally q4-6 hr for 24-48 hrs • Place in Therapy • First choice providing patient is suitable • BCPHP recommends this choice

9. Indomethacin • Side effects for mom • Headache, nausea, dizziness & dyspepsia • GI bleeding and inhibition of platelet aggregation • Nephritis • Fluid retention & HF • infection may be masked (antipyretic effects) • Avoid if asthma or allergy to aspirin • Stages of gestation medication is safe • Use if < 32 weeks • Use in gestational age >32 weeks is associated with premature closure of the ductusarteriosus

10. Indomethacin • Risks of medication for the fetus • Therapy > 48 hours may cause oligohydramnious and platelet dysfunction • Premature closure of the ductusarteriosus is related to both gestational age and length of therapy • Increase in the incidence • Neonatal pulmonary hypertension • Intraventricularhemorrhage • Necrotizing enterocolitis • Duration of Use • Strictly limited to 48hrs

11. Nifedipine (Calcium Channel Blocker) • M of A: Acts as a smooth muscle relaxant • Directly blocks influx of calcium through cell membrane & release of intracellular calcium from sarcoplasmic reticulum • ↓ in calcium inhibits myosin light chain kinase muscle relaxation

12. Nifedipine • Loading and Maintenance dose • Initial dose: • Nifedipine 10mg PO q15min until contractions stop (4 doses max, or 40mg in 1 hour) • Maintenance dose: • 8 hours after loading dose;Nifedipine XL 30mg PO q12h (max daily dose 120mg)

13. Nifedipine • Side effects of medication for mom • Tachycardia, rarely palpitations, flushing • Transient hypotension, weakness & dizziness • Peripheral edema • Stages of gestation medication is safe • All weeks

14. Nifedipine • Risks of each medication for the fetus • Possible reductions in uterine and umbilical blood flow (not proven in human studies) • Duration of Use • No limit unless: • 48 hours after the first dose of corticosteroids has been administered to patient • Significant side effects occur • Delivery is imminent

15. Nifedipine • Place in Therapy • Not in BCPHP Guidelines (2005) • Compared to older agents has a better side effect profile • First line if >32 weeks gestation

16. Nitroglycerin Patch (Nitric Oxide Donor) • M of A: Nitric Oxide is involved in maintaining normal uterine tone during gestation • Nitroglycerin is a nitric oxide donor that ↑cGMP synthesis inactivates myosin light chain kinase smooth muscle relaxation

17. Nitroglycerin Patches • Loading and Maintenance Dose: • 500 mL normal saline IV over 30 minutes • Apply nitroglycerin patch (0.4 mg/hour) transdermally • If after 1 hour there is continued cervical changes and/or contractions are more frequent than 4 in 20 minutes, apply 2nd nitroglycerin patch • If after 1 hour following 2nd patch there is additional cervical changes and/or contractions are more frequent than 4 in 20 minutes contact physician • Replace patch(es) in 24 hrs x once only

18. Nitroglycerin Patches • Stage of gestation medication is safe • All • Side effects of medication for mom • ↓ blood pressure, dizziness, headache • Tachycardia & flushing

19. Nitroglycerin Patches • Risks of medication for the fetus • Maternal hypotension could ↓ uterine and placental blood flow (no adverse effects reported) • Duration of Use • Remove all patches after 48hrs from initial patch application • There is little evidence: small (n=153) RCT • Use in <32 weeks gestation showed a reduction in neonatal morbidity and mortality as a result of decreasing birth before 28 weeks • Not commonly used

20. Salbutamol & Terbutaline (Beta agonists) • M of A: Beta-agonists bind beta-2 adrenergic receptors and ↑ cAMP inactivates myosin light-chain kinase diminished myometrial contractility

21. Salbutamol & Terbutaline • Terbutaline IV or SC (not available in Canada) • Salbutamol IV, PO or Inhaler available in Canada but there are no dosing guidelines available • Side effects of medication for mom • Tremor, palpitations, shortness of breath • Chest discomfort, anxiety • Hyperglycemia, hypokalemia • Incidence of side effects are ~77% • Medication is poorly tolerated

22. Salbutamol & Terbutaline • Stages of gestation medication is safe • Throughout gestation • Risks of medication for the fetus: • Tachycardia • Hypoglycemia from fetal hyperinsulinemia due to prolonged maternal hyperglycemia • Place in Therapy • Rarely used in Canada, commonly used in the US

23. Magnesium Sulphate M of A: Magnesium inhibits smooth muscle contractions by reducing calcium binding and distribution in the myometrium by competing for calcium binding sites.

24. Magnesium Sulphate • Loading and Maintenance dose • Initial dose: 4 to 6g IV over 15 to 30 minutes • Maintenance dose: 2 to 6g per hour (until adequate tocolysis) • Side effects of medication for mom • ↓ or absent deep tendon reflexes = 1st toxicity sign • Respiratory & myocardial depression • Flushing & nausea or vomiting • Blurred or double vision • Lethargy

25. Magnesium Sulphate • Stages of gestation medication is safe • All • Risks of medication for the fetus • Lethargy • Hypotonicity • Low APGAR scores • Antenatal: decreased variability of the fetal heart rate, altered cerebral blood flow, a depressed biophysical profile

26. Magnesium Sulphate • A systematic review including four randomized trials (n = 334 fetuses/newborns) comparing Magnesium with no treatment or placebo • No evidence of a clinically important tocolytic effect for magnesium sulfate was found • Therapy did not significantly reduce the risk of birth within 48 hours, 7 days or 37 weeks • No reduction in neonatal respiratory distress, IVH or newborn death • Place in Therapy • No longer used

27. Atosiban (Oxytocin Antagonist) • M of A: A selective oxytocin-vasopressin receptor antagonist. • Oxytocin stimulates contractions through a mechanism that causes release of calcium into the cytoplasm • Oxytocin receptor antagonists compete with oxytocin for binding to oxytocin receptors in the myometrium and endometrium prevention of ↑ in intracellular free calcium

28. Atosiban • Loading and Maintenance dose • Initial Dose: IV bolus of 6.75 mg followed by a 300 mcg/min infusion for three hours • Maintenance Dose: 100 mcg/min for up to 45 hours • Side effects of medication for mom Hypersensitivity and injection site reactions • Stages of gestation medication is safe • >28 weeks of gestation (higher mortality < 28 weeks)

29. Atosiban • Risks of medication for the fetus • In one study a higher rate of fetal-infant death was noted – deaths were associated with infection and extreme prematurity (relationship to atosiban cannot be excluded) • Duration of Use • Up to 45 hours • Place in Therapy • Not approved in Canada or the US

30. Antibiotics • Infection contributes to pre-term labour • A Cochrane review evaluated broad-spectrum prophylactic antibiotics in addition to tocolysis for inhibiting PTL up to 36 weeks in women with intact membranes • Use of antibiotics did not prolong pregnancy or result in significant reductions in delivery < 48 hours from initiating treatment • A significant reduction in maternal infection (chorioamnionitis, endometritis) with use of prophylactic antibiotics was found

31. Antibiotics Evidence Continued • Subgroup analysis by type of antibiotic showed antibiotics against anaerobes was associated with a significant reduction in the number of women delivering within seven days of enrollment and fewer admissions to the neonatal intensive care unit • Some caution with metronidazole as it has been found to shorten duration of pregnancy

32. Thank You Any questions ???

33. References Simhan HN and Caritis SN. NEJM. Prevention of Preterm Delivery Aug 2, 2007; 357(5):477-487. Simhan HN and Caritis SN. Inhibition of acute preterm labor [Internet]. Up to date; [Updated 2010 February 3; cited 2010 May]. Available from: http://uptodateonline.com/online/content/topic.do?topicKey=pregcomp/11591&selectedTitle=1%7E150&source=search_result. Lam FL and Gill PG. B-Agonist Tocolytic Therapy. ObstetGynecolClin N Am. 2005; 23: 457-84. British Columbia Reproductive Care Program. Obstetric Guideline 2A Preterm Labour. 2005 March.: 1-18.