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2. Effects of pain medications on fetus and neonate ManizhehGharehbaghi. M.D. Professor of Pediatrics. Tabriz University of Medical Sciences

3. Obstetric pain medications • Appropriate to • Labor process • Current conditions as evaluated by obstetric provider • Has little impact on fetus as possible

4. Perception of pain is influenced by • Fear of pain • Increased susceptibility to pain because of generalized anxiety • Level of education • Age • parity

5. Classification of pain • Visceral • Originate from viscera • Is described as • Cramping • Dull • Steady • Somatic • Related to nonvisceral structures • Is described as • sharp • Intermittent • Well localized

6. Dilation phase (first stage) • Visceral pain predominates • Arises from • Mechanical distention of lower uterine segment • Cervical dilation

7. Descent phase (second stage) • Somatic pain • Attributed to • Distention and traction on pelvic structures surrounding vagina • Distention of pelvic floor and perineum

8. Very dynamic nature of labor pain requires adaptation of pain management • Pain can evolve rapidly over a short period of time • Changing in • Intensity • From visceral to somatic source • All medications are not effective for all types of pain

9. Techniques that modify pain • Non pharmacologic • Do not alter the actual transmission of pain sensation • Alter the person’s perception and response • Their effectiveness is hard to evaluate • Not have any adverse effect on the neonate • The safest and healthiest choices for mothers and babies • Pharmacologic

10. The worst effects of drugs on fetus is when medication has produced cerebral effect on the mother • Cross the lipid blood brain barrier • Cross the placental barrier • Drug’s pharmacokinetic • Pharmacodynamic properties • Dose • Mode of delivery • Pharmacokinetics, pharmacodynamics and fetus

11. Effects of drugs on fetus • Consider three pharmacologic characteristics when weighting whether or not a medication has a properties to enter the maternal circulation from its primary site of administration

12. How much of the drug is ionized • Determined by its PH • If a drug’s PH is physiologic(7.4), 50% of the drug is ionized and 50% non ionized • The ionized drug can’t cross membrane barrier • Local anesthetics are week bases( pKa=7.6- 9.1) • Local anesthetics with Pka 9.1are more ionized in physiologic PH and more will stay in the maternal circulation than those with Pka 7.6 • Non ionized portion can cross a membrane

13. If fetal PH is lower than the mother PH (acidosis), more drug converts to ionized form • Can’t return to the maternal circulation • If maternal exposure to the drug persists, more drug passes to fetus and accmulate • (fetal ion trapping phenomenon) • The deleterious effects of drug in the compromised fetus

14. Lipophilic properties vs. hydrophilic • More capable of crossing lipid rich membrane • Most obstetric medications are lipophilic with varying degrees • Lipophilic opiates • Fentanyl • Sufentanil is much more lipophilic • Epidural doses of sufentanil more readily leave the epidural space to enter the maternal circulation

15. Protein binding • Drug that binds with protein remains in maternal circulation • Unbound drug freely cross the membrane • Except Active transport, unbound nonionized portion of lipophilic drugs can cross membrane barrier to produce effect

16. Metabolism and elimination • Extensive metabolism into inactive metabolites in maternal circulation(little effect) • Succinylcholine to benign metabolites by pseudo cholinesterase • Has half life about 90 sec • Metabolize into active metabolite in maternal system then crosses into fetal system • Normeperidine the active metabolite of meperidine

17. Estimate Fetal medication exposure by UV/MV ratio • A ratio =1 means umbilical vein equal maternal vein • A low ratio means small amount has crossed the placenta • The non depolarizing muscle relaxants are highly ionized, hydrophilic compounds not cross barrier • UV/MV Ratio=0.1

18. Placental passage

19. Even if umbilical vein levels are significant, may not enough to produce neurobehavioral effect because of two protective barriers of fetus • 40-60%entering drug passes through the liver first and then travel IVC to heart and into circulation (metabolized) • Unique fetal circulation dilutes most of drug

20. Dose and mode of administration are important • The greatest to the least effect on maternal blood level • Intravenous ˃ paracervical ˃ IM ˃ Epidural ˃ Spinal

21. Systemic medications • There are two classes of commonly used drugs • Opioids • Pain relief • Sedatives • Relax • Reduce anexiety • Other drugs in emergent surgical conditions

22. Sedatives • Markedly diminished routine use of sedatives in acute phase of labor • Primary purpose • Rest during prolonged latent phase of labor • A sleep aid before starting induction • During C/S to anxious patient • Before induction of general anesthesia • Enough time passes between administration and delivery except in C/S

23. Benzodiazepines • Midazolam • Low UV/MV ratio • Dose not cross to fetus • Most common use in unplanned C/S • Causes maternal amnesia • Diazepam • High UV/MV ratio (1)within minutes • Reaches UV/MV=2 within hours • Active metabolites remain up to 8 days

24. Causes • hypotonia • Hypothermia • respiratory depression in neonate • Oral cleft malformations during first trimester? • Diazepam is limited to the management of maternal seizure

25. Barbitorates • Phenobarbital • is rarely used • Thiopental • Common anesthetic induction agent • Propofol • Is more frequently used • Neonatal effects are concerned

26. Phenothiazines • Early labor • Reducing anxiety • Promoting sleep • Phenergan • Antiemetic • Pain relief

27. opioids • Stimulate opioid receptors • Pure agonists • Morphine • Meperidine • Fentanyl • Act on some receptors and block others • Agonist-antagonist • Nalbuphine • Butorphanol • Block all receptors • Pure antagonist (naloxane)

28. Opioids don’t block pain transmission • Stimulate receptors to alter the perception of pain • Incomplete analgesics • More effective on visceral pain • During first stage of labor • Can cross the placenta • Metabolized from fetus before delivery

29. µ receptors • most complete analgesia • Pruritus, nausea, vomiting • Euphoria, dysphoria • Respiratory depression • k receptors • Less intense analgesia • Ceilling effect for analgesia and respiratory depression • Flattening of dose response

30. Depressive effects on the neonate • Sedation • Respiratory depression • Low oxygen saturation • Reserved for situations in which regional technique is not available or contraindicated

31. Commonly used opioids • Agonists • Morphine • Meperidine • Fentanyl • Sufentanyl • Alfentanyl • Remifentanyl • Agonist-antagonist • Nalbuphine • Butrphanol

32. Opioid agonists • Alfentanyl • is less effective • Doses 10µ /kg in mother cause severe neonatal respiratory suppression • Morphine • More depressive than other opioids • Depress uterine contractions

33. Fentanyl , sufentanil for anesthetic nerve block • alfentanil, remifentanil systemically • Liphophilic • Cross placenta • Metabolize to inactive metabolites • Uncommon depressive effects with intermittent IV boluses (beat to beat variability) • Remifentanil is so short acting • Suited to IV-PCA

34. Meperidine • Most commonly used systemically • Enhances effacement and dilation of cervix • Tachycardia and myocardial depression • Epidural or spinal injection produce block similar local anesthetics • Useful in allergy to local anesthetics • Duration of action 2-4 hrs • Half life 3-4.5 hrs • Metabolized to active metabolites by fetal liver and accumulate • With half life is 14-40 hrs

35. Opioid agonist-antagonists • Butorphanol (stadol) • Sedation in mother • Cross placenta • Degrade to inactive metabolites • Limited fetal effects • Butorphanol • reduces beat to beat variability • can produce sinusoidal pattern

36. Nalbuphine(nubain) • Nalbuphine can be used in small doses in lieu of naloxane • Side effect of pruritus • Caution in addicted mother • Causes withdrawal • Heavy use cause hyper & hypoventilation, fetal acidosis

37. Fetal Risks of Neuroaxial Block • Every negative maternal effect associated with negative fetal or neonatal effect? • Literature dose not support it • Poor sensitivity to distinguish between hypoxic or drug effects in neurologic adaptive capacity score (NACS)

38. Acid base balance • Best reflect intrauterine environment • No longer maternal hyperventilation with neuraxial block • Low PCO2 causes left shift in oxygen dissociation curve • Impaired placental transfer of oxygen • Compensatory Metabolic acidosis • Worsening acidosis & hypoxia

39. Improved acid –base balance • Less stress on the fetus • Amounts of meconium are less • Apgar score improved • Better intrauterine environment

40. Fetal heart rate • Bradycardia in 10-12% epidural • Within 15-45 min after initiation of neuroaxial analgesia • Decreased maternal epinephrine causes temporary imbalance between tocolytic and tocodynamic forces • Uterine hypertonus • Decreased uterine perfusion • Fetal bradycardia

41. Bradycardia Resolves with conservative therapy • Apgar score is fine • Loss of beat to beat variability • With large doses • Should be careful with timing and use in second stage

42. Breast feeding • Dose related detrimental effect in some studies • Maternal infant separation is minimized • No effect on lactation success