Berrin Günaydin, MD, PhD Gazi University Faculty of Medicine

1. Nonobstetric Surgery during Pregnancy: Are we ready? Berrin Günaydin, MD, PhD Gazi University Faculty of Medicine Department of Anesthesiology, Ankara, Turkey

2. Multidisciplinary approach is a must for non-obstetric surgery during pregnancy

3. Epidemiology Each year over 75000 (87000) pregnant women in USA undergo nonobstetric surgery Semin Perinatol 2002 Chestnut’s 2009 Each year 5700-76000 (115000) pregnant women in EU undergo nonobstetric surgery Minerva Anestesiol 2007 Chestnut’s 2009

4. Epidemiology Needfornonobstetricsurgery 0.75%-2% (0.3%-2.2%) Chestnut’s 2009 J Clin Anesth 2006 42% duringthe 1st trimester 35% duringthe 2nd trimester 23% duringthe 3rd trimester These operations are either directly (such as; cerclage) or indirectly (such as; appendectomy) related to pregnancy Semin Perinatol 2002

5. FETAL CONCERNSRisk of Teratogenicitiy • Organogenesis is between15-70 days after lastmenstrual period • Manifestations of teratogenicity • Death (abortion, fetal death and stillbirth in humans and fetal resorption in animals) • Structural abnormalities • Growth restriction • Functional deficiencies areusually associated with exposure during late pregnancy or after birth (4th intrauterine month to 2nd postnatal month) IARS 2006

6. Risk of Teratogenicity • During maintaining normal maternal physiology • local anesthetics • volatile anesthetics • induction agents (barbiturates, ketamine and propofol) • muscle relaxants (wide margin of safety because of limited placental transfer) • opioids are not teratogen in clinical concentrations • Evidencedoes not supportassociationbetweendiazepam & craniofacialdefects • N2O is a weak teratogen in rodents by inhibiting methionine synthase which alters DNA synthesis under certain conditions (at 50% concentrations for 24 hours) • No human data support increased risk for congenital anomalies J Clin Anesth 2006 IARS 2006 Minerva Anestesiol 2007

7. FETAL CONCERNSPreterm Labor • It is unclear whether nonobstetric surgery, manipulation of uterus or underlying condition is responsible from increased incidence of preterm delivery and abortion • 22% of 778 patients who underwent appendectomy between 24 to 36 weeks gestation delivered within first week after surgery Mazze &Kallen. A Swedish registry study of 778 cases. Obstet Gynecol 1991 • No increased risk of delivery one week after surgery • 2nd trimester procedures and those not involving uterine manipulation carry the lowest risk of preterm labor

8. FETAL CONCERNSPreterm Labor • Evidence doesn’t suggest that any anesthetic agent or technique influence the risk of preterm labor • Prophylactic tocolytics may be considered but are associated with side effects (it is unclear whether they affect the outcome due to their limited efficacy for prevention of preterm labor) • Selective administration at high risk patients (e.g. cervical cerclage) or after 24 weeks gestation • Additional surveillance is required for patients receiving potent analgesics postoperatively

9. FETAL CONCERNSNondrug Factors • Prolonged hypoxia and hypercarbia and severe hypoglycemia • Maternal stress and anxiety • Hyperthermia(teratogen in humans and animals) • congenital CNS anomalies associated with maternal fever >38.90C during 1st half of pregnancy • Ionizing radiations(teratogen in humans and animals) • No increase in anomalies/growth restriction from exposure <5-10rads

10. BehavioralTeratology • Anesthetics act by potentiation of GABAA receptors or antagonism of NMDA receptorsinduce widespread neuronal apoptosis during period of synaptogenesis • Result in hippocampal (cornu ammonis:CA & dentat gyrus:DG) synaptic function deficit and persistent memory/learning impairments • The implications for human fetus or infants is unknown Jevtovic-Todorvic et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in developing rat brain and persistent learning deficits. J Neurosci 2003

12. Role of ketamine on the apoptotic effect of isoflurane in ratsKartal S, Gunaydin B. • Effects of ketamine (NMDA receptor antagonist) on the isoflurane (GABA-A agonist) induced apoptotic neurodegeneration was investigated • Apoptotic neurodegeneration has been shown in hypocampus (CA-1 and dentat gyrus) which was mediated by caspase 3, 8 and 9 • Significantly more immunoreactive cells for caspase 3, 8 and 9 in group Iso+Ket were observed in the hypocampus • Isoflurane induced apoptosis in rats increased by ketamine

13. Caspase 8 Caspase 8 Caspase 9 CA-1 Caspase 3 DG

14. Uteroplasental Perfusion & Fetal Oxygenation Causes of decreased uteroplacental perfusion • Aortocaval compression • High spinal or epidural blockade • Hemorrhage • Hypovolemia • Hyperventilation • Deep levels of general anesthesia • High dose of ά adrenergic agents • Increased circulating catecholamines • Uterinehypertonus from ketamine >2mg/kg in early pregnancy or toxic doses of local anesthetics Causes of hypoxia • Difficult intubation • Esophageal intubation • Pulmonary aspiration • High levels of regional block • Systemic local anesthetic toxicity • Airway compromise from trauma

15. TIMING OF SURGERY • Elective surgery should not be performed during pregnancy • Surgery should be avoided during the 1st trimester • 2nd trimester is the optimal time • Urgent operationslike abdominal emergencies, malignancies, neurosurgical and cardiac conditions • In serious maternal illness, primary goal is to preserve mother’s life • Simultaneous C/S or prior to surgical procedure to avoid fetal risks associated with special patient positioning (sitting or prone position), prolonged anesthesia, major intraoperative blood loss, maternal hyperventilation, deliberate hypotension or cardiopulmonary bypass

16. FETAL MONITORING • Continuous FHR monitoring (using transabdominal doppler) feasible after 18 weeks of gestation • FHR variability manifests after 25 to 27 weeks of gestation • FHR patterns from drug effects (opiates, induction and inhalation agents) should be distinguished from fetal hypoxia • FHR monitoring allows optimization of intrauterine environment • Nonreassuring pattern may indicate need to improve maternal oxygenation, increase blood pressure, increase uterine displacement, change site of surgical retraction or begin tocolysis

17. FETAL MONITORING • According to ACOG opinion • “The decision to use intraoperative FHR monitoring should be individualized and each case warrants a team approach for safety of woman and her baby” • Plan should be in place for proceeding with urgent or emergent cesarean delivery in the event of persistent nonreassuaring FHR pattern

18. Anesthetic ManagementPreoperative care • Preanesthetic medications • Preoperative medication is traditionally withheld • Sedatives are usually avoided (if necessary, 0.5-2 mg midazolam and/or 25-50 µg fentanyl can be considered) • Glycopyrolate (Anticholinergic agent of choice) • Does not readily cross the placenta • Prophylaxis • H2 receptor antagonists • Metoclopramide (10 mg IV) • Cholinergic agonist peripherally • Dopamin receptor antagonist centrally • Increases lower esophageal sphincter tone (antiemetic effect) • Reduces gastric volume by increasing gastric peristalsis • Crosses placenta but no significant effect on the fetus • Clear nonparticulate antacids • Sodium bicitra ( oral 30 mL) • Reduces gastric acidity Kuczkowski KM. Arch Gynecol Obstet 2007

19. AnestheticManagement • Prevention of aortocaval compression • Positioning must ensure 15⁰ left lateral tilt (since changes in maternal position can have profound hemodynamic effects, either Trendelenburg or reverse Trendelenburg’s positions should be carried out slowly) J Clin Anesth 2006 • Maternal and fetal monitoring • ECG, heart rate, SpO2 and ETCO2 • Blood pressure (noninvasive or invasive) • Peripheral nerve stimulator • Temperature • FHR and uterine activity Chestnut’sObstetric Anesthesia Principles and Practice2009

20. Regional Anesthesia General Anesthesia Rapid sequence IV induction Denitrogenation (100% O2 for 5 min) Effective cricoid pressure Endotracheal intubation is mandatory In case of failed intubation, LMA can be used in the reverse Trendelenburg’s position for brief periods Alveolar hyperventilation, reduction of FRC and 30% reduction of MAC Decreased thiopental requirements AnestheticTechnique Both regional and general anesthesia techniques have been successfully used for nonobstetric surgery • Decreased protein binding due to low albumin • Increased sensitivity to peripheral neural blockade • More extensive blockade with epidural and spinal anesthesia J Clin Anesth 2006

21. Decreased plasma cholinesterase levels by 25% • Prolonged neuromuscular blockade with Sch is uncommon due to increased Vd • Thiopental history of safe use • (propofol added to list later) • Benzodiazepines are avoided during organogenesis • Narcotics may be related to intrauterine fetal asphyxia • Morphine and fentanyl have also history of safe use • N2Omay impair DNA synthesis and inhibit cell division • No evidence suggests reproductive toxicity with sevoflurane or desflurane in clinical concentrations • Vecuronium when Sch is contraindicated (prolonged duration) • Rocuronium alternative to SCh in high doses (longer duration of action) • Cis-atracurium less desirable for RSI (shorter duration due to Hoffman’s elimination in vivo) Chestnut’sObstetric Anesthesia Principles and Practice2009

22. ReversalAgents • Anticholinesterases have a theoretical concern because of increased uterine tone that may precipitate preterm labor • Transplacental transfer of anticholinesterase is predicted as limited due to molecular size & structure of neostigmine but it can have significant fetal effecs • Although atropine which readily crosses placenta may cause fetal tachycardia and loss FHR variability, it may be preferable to counteract fetal effects of neostigmine instead of glycopyrolate

24. PostoperativeCare • FHR and uterine activity should be monitored during recovery from anesthesia • Satisfactory maternal analgesia can be achieved with systemic narcotic PCA or PCEA when available • Regional analgesia provides better pain relief and less effect on FHR variability • Use of NSAI drugs is avoided (because of potential premature closure of DA and development of oligohydramnios)

25. SpecificSituations • Laparoscopy • Cardiac surgery requiring CPB • Neurosurgery • Malignancy- metastatic breast cancer requiring surgery

26. Type of surgery • Laparoscopic surgery The most common abdominal procedures • Appendectomy1/1500-2000 pregnanccy • Cholecystectomy1-8/10000 pregnancy • Cardiac surgery requiring bypass • Neurosurgery J Clin Anesth 2006

27. SAGES Committee Opinion • Obtain an obstetric consult preoperatively • Delay elective cases until 2nd trimester • Use lower ext pneumatic compression devices (pregnancy and pneumoperitoneum may induce a hypercoagulable state) • Follow maternal and fetal physiologic status intraoperatively (maternal ETCO2) Society of AmericanGastrointestinalEndoscopicSurgeons (SAGES) Guidelinesforlaparoscopicsurgeryduringpregnancy

28. SAGES Committee Opinion • Protect uterus with lead shield for intraoperative cholangiography • Use open technique to gain pneumoperitoneum • Tilt table left side down to move gravid uterus off vena cava • Minimize pneumoperitoneum to 8 to 12 mm Hg Society of AmericanGastrointestinalEndoscopicSurgeons (SAGES) Guidelinesforlaparoscopicsurgeryduringpregnancy

29. Appendectomy • The most common nonobstetric surgical emergency during pregnancy • Appears to occur more frequently in the 2nd and 3rd trimesters • The mortality of appendicitis complicating pregnancy is the mortality of delay

30. Laparoscopic Surgery During Pregnancy Adding pneumoperitoneum to an enlarged uterus • Limits diaphragm expansion • Increases peak airway pressure • Decreases FRC • Decreases thoracic cavity compliance • Increases ventilation-perfusion mismatching

31. Laparoscopic Surgery During Pregnancy • CO2 pneumoperitoneum hypercapnia and hypoxemia • Hyperventilation reduce uteroplacental blood flow • Reduced venous return and cardiac index significant hypotension • Intermittent pneumatic compression devices and thrombophylaxis are important

32. Cardiacsurgeryduringpregnancy • Incidence of heart disease in pregnancy 1%-4% • Decompensation may peak at 28 to 30 weeks • Maternal mortality rate 20% to 35% • Cardiac surgery indications are few • Severe valve disease • Malfunction of prosthetic valve • Major vessel disease • Traumatic aortic rupture • Pulmonary embolism • Heart tumor • Patent foramen ovale Clin Obstet Gynecol 2009

33. Cardiacsurgeryduringpregnancy • Fetal bradycardia is common during bypass • Hypothermia is associated with uterine irritability • Duration of CPB does not affect fetal outcome • Maternal temperature above 29.5⁰C is associated with better fetal survival • Highest maternal mortality occurs if surgery is performed at delivery or immediately postpartum Clin Obstet Gynecol 2009

34. CPB • Moderate hypothermia during bypass • Persistent fetal bradycardia • Warm cardiopulmonary bypass will improve • Increase pump flow, if FHR<80 bpm • Ensure adequate uteroplacental perfusion • Maintain pump flow 30-50% greater than usual • Maintain perfusion pressure at or above 60 mmHg • Avoid aortocaval compression • Optimize acid-base status, oxygenation, and ventilation Kuczkowski KM, CME Rev 2003

35. 24 year old parturient at 32 weeks’ gestation • 158 cm, 60 kg • Severe mitral stenosis • Open mitral commissurotomy • General anesthesia • Induction with propofol, fentanyl, pancuronium • Maintenance by TIVA • Continuous FHR monitorization • CPB under mild hypothermia (30-32ºC)

36. 10 min after aortic cross clamping, progressive decelerations in FHR tracing followed by asystole • After rewarming, heart was defibrillated and CPB was discontinued • Then, protamine was administered • Since no FHR, pregnancy termination was considered by obstetricians • However, 2 hours after patient was transferred to the ICU, normal and rhythmic FHR returned • Parturient vaginally delivered at term • Authors conclude that loss of fetal heart sounds during CPB should not always indicate fetal death

37. Neurosurgery During PregnancyNeurosurgical Approach • Controlled hypotension(Volatile anesthetic, nitroglycerin or nitroprusside) • Reduction in SBP of 25-30% or MBP< 70mmHg causes reduction in uteroplacental blood flow Nitroprusside • crosses placenta resulting in fetal hypotension • converted to cyanide (may cause significant toxicity & fetal death) • Discontinue if Infusion rate> 0.5 mg/kg/hour Maternal metabolic acidosis Resistance to the agent • Hypothermia - Fetal bradycardia • Hyperventilation Decreased placental O2 transfer & umbilical vessel vasoconstriction • Diuresis - Significant negative fluid shift for fetus

38. Case 2: Sequential operation (C/S followed anterior corpectomy & posterior spinal decompression) at 34 weeks’ of gestation • 38 yr old parturient who underwent radical mastectomy and chemotherapy 9 years ago due to invasive ductal Ca stage II/III • Admitted with paraplegia due to spine metastasis at 31 weeks • 1850 g healthy baby was delivered by C/S under general anesthesia • Rapid sequence IV induction with propofol and Sch (7.0 mm cuffed tube) • After delivery, anesthesia was maintained in 0.7 MAC isoflurane and remifentanil infusion

39. ClinicalSuggestions • All women between 12 to 50 years should have the last menstrual period documented • If pregnancy is diagnosed, surgery is postponed until 2nd trimester if possible • Elective surgery is postponed until after delivery, if not possible then 1st trimester should be avoided • 1st trimester: theoretical risk of teratogenicity is increased • 2nd trimester: optimal time to perform surgery • 3rd trimester: preterm labor and maternal risk is high J Clin Anesth 2006

40. Objectives for anesthetic management during non-obstetric surgery • Provide maternal safety • Avoid using teratogenic drugs • Maintain uteroplasental perfusion by preventing intrauterine fetal asphysia • Avoid preterm labor

41. Potential teratogens during pregnancy • Angiotensin converting enzim inhibitors • Alkol • Androjenler • Antitiroid drugs • Carbamazepin • Chemotherapeutic drugs • Cocaine • Coumadin • Dietilstilbesterol • Lead • Lithium • Mercury • Phenytoin • Radiation (>0.5Gy) • Streptomycine/Canamycine • Tetracycline • Trimetadion • Valproic acite • Vitamine A

43. ACOG Committee Opinion No: 474Nonobstetricsurgery during pregnancyACOG Committee on Obstetric PracticeObstet Gynecol.2011 Feb;117(2 Pt 1):420-1 The American College of Obstetricians and Gynecologists' Committee on Obstetric Practice acknowledges that the issue of nonobstetric surgery during pregnancy is an important concern for physicians who care for women. It is important for a physician to obtain an obstetric consultation before performing nonobstetric surgery and some invasive procedures (eg, cardiac catheterization or colonoscopy) because obstetricians are uniquely qualified to discuss aspects of maternal physiology and anatomy that may affect intraoperative maternal-fetal well-being. Ultimately, each case warrants a team approach (anesthesia and obstetric care providers, surgeons, pediatricians, and nurses) for optimal safety of the woman and the fetus

45. Arch Gynecol Obstet. 2007 Sep;276(3):201-9. Epub 2007 Mar 13. • Laparoscopic procedures during pregnancy and the risks of anesthesia: what does an obstetrician need to know? • Kuczkowski KM. • Source • Department of Anesthesiology, University of California San Diego (UCSD) Medical Center, 200 W. Arbor Drive, San Diego, CA 92103-8770, USA. kkuczkowski@ucsd.edu • Abstract • BACKGROUND: • Nonobstetric surgery may be necessary during any stage of gestation. • METHODS: • The purpose of this article is to review the current recommendations (using Medline search for the relevant publications) for the perioperative anesthetic management of pregnant women undergoing laparoscopy for indications unrelated to pregnancy. • RESULTS: • The current estimates of the incidence of nonobstetric surgery in pregnancy range from 1% to 2%. Laparoscopy is the most common surgical procedure performed in the first trimester of pregnancy, whereas appendectomy is the most common procedure performed during the remainder of pregnancy. • CONCLUSIONS: • In the past pregnancy was considered as an absolute contraindication to laparoscopy. However, recent years have brought an extensive experience with this technique during gestation.

47. ACOG Committee on Obstetric Practice acknowledges that the issue of nonobstetric surgery and anesthesia in pregnancy is an important concern for physicians who care for women. However, there are no data to allow us to make specific recommendations. Number 284, August 2003

48. Thank you -Teşekkürler... Dziekujemybardzo