NNEPQIN Guideline for the Management of Labor, Delivery and the Newborn in the Opioid Dependent Pregnancy. March 2014

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1 The following guidelines are intended only as a general educational resource for hospitals and clinicians, and are not intended to reflect or establish a standard of care or to replace individual clinician judgment and medical decision making for specific healthcare environments and patient situations. NNEPQIN Guideline for the Management of Labor, Delivery and the Newborn in the Opioid Dependent Pregnancy March 2014 The National Survey on Drug Use and Health estimates that 5 million Americans are using pain relievers for non-medical purposes. Of these, approximately 2 million people meet abuse or dependence criteria for prescription opiates. Between 2000 and 2009 it is estimated the incidence of opiate use in pregnancy has increased 5-fold and the incidence of Neonatal Abstinence Syndrome (NAS) has increased by 3 fold (1). Maternal Care: Opioid dependence is often related to other circumstances which can affect the health outcomes of mothers and their newborns, including poverty and deprivation, physical, emotional, and sexual abuse, inadequate nutrition, and psychiatric co-morbidity. Comprehensive womancentered treatment programs for opioid addicted pregnant women that address these problems will result in the best outcomes. Ideally, prenatal care should be integrated with substance abuse counseling, psychiatric treatment and social services (2). The objectives for treating opioid dependence in pregnancy are: Avoid withdrawal symptoms during pregnancy Avoid cravings and thus limit the exposure of the fetus to other illicit substances and high risk behavoirs Engage the mother in her ultimate recovery Methadone and burpenorphine are commonly used for maintenance of symptoms in prenatal patients. Methadone has long been considered the drug of choice for maintenance, due to long term neonatal outcome data supporting its use. Recently, buprenorphine has gained more

2 widespread use in pregnancy. The potential advantages of buprenorphine over methadone include a lower risk of overdose, fewer drug interactions, the ability to be treated on an outpatient basis, and evidence of less severe NAS (3). Potential disadvantages of buprenorphine include a higher dropout rate from therapy (4). Dosing is usually managed by an addiction specialist, and should be closely monitored by the obstetrical provider. Communication among care providers, with patient consent, is important in order to support proper dosing and coordinate care. The dose of medications should be adjusted to reduce symptoms of craving or withdrawal, while limiting over sedation. Rare fatal arrhythmias have been reported in patients taking methadone and this effect is noted to be dose-dependent. Prolongation of the QT interval is used as a surrogate marker for the risk of developing potentially fatal arrhythmias such as torsades de pointes. EKG monitoring should be performed with the initiation of methadone and when methadone doses exceed 100mg/day, and in patients with risk factors for QT prolongation, or symptoms that may be attributable to arrhythmia (5). EKG monitoring should also be initiated if medications known to prolong the QT interval (eg, ondanestron) are initiated by patients taking methadone. (6) Pain Management in Labor and Delivery: Several factors may influence the management of intrapartum or postpartum pain. Opioid dependent patients experience opioid tolerance. Chronic opioid use may result in an increased response to painful stimuli. Also, opiate maintenance medications occupy opiate receptors and may decrease the typical response to opiate pain-relievers used during peripartum care. As a result, opioid dependent patients often require higher doses of narcotics for pain relief. For example, among women using buprenorphine, there has been shown to be an average 47% increase in the amount of opiate pain reliever medications necessary after cesarean delivery (7). Women receiving opioid maintenance who are undergoing labor and delivery should receive pain relief as if they were not taking opioids (8). Daily doses of methadone and buprenorphine should be maintained during labor to prevent withdrawal. Intravenous short-acting nalbuphine (Nubain) and butorphanol (Stadol) are contraindicated as they contain partial opiate antagonist activity and may precipitate withdrawal. Epidural anesthesia is often effective for pain relief in labor. The postpartum use of acetaminophen and nonsteroidal anti-inflammatory medications should be encouraged, if not contraindicated for the individual patient.

3 Usually, there is little need for immediate postpartum opioid maintenance dosage adjustment. Additional dosing of long-acting opiates is not effective for pain relief, and puts the patient at risk of over-sedation. Patients experiencing pain postpartum may require additional short-acting opiate treatment. Patients should be monitored for over sedation. Consider administration of non-opiate medications when patients exhibiting symptoms of sedation are requesting additional treatment for pain. A comprehensive guideline for the evaluation and treatment of pregnant women and their newborns exposed to substances of abuse has been developed by the Vermont Child Health Improvement Program and is available at: (8) Postpartum Care: Ongoing education and support for the mother is essential to maintain alliance during hospitalization and for the duration of observation and possible treatment for the newborn. Efforts should be made to encourage rooming in and frequent skin to skin contact between mother and infant. Patients are at high risk for the development of postpartum depression, especially if infants are being treated for NAS. Mothers should be assessed and referred as needed. The treating addiction specialist should be notified on discharge from the inpatient setting to facilitate smooth transition back to outpatient treatment. Patients may need documentation of opioid medication administered as in-patients and/or prescribed for post-operative pain management. Newborn Care: The Neonatal Abstinence Syndrome (NAS) is characterized by hyperactivity and dysregulation of the central and autonomic nervous system. Signs include uncoordinated sucking reflexes, irritability and high-pitched cry. Hypertonia, emesis, watery stools, seizures and respiratory distress could also develop. NAS is most commonly associated with opiate exposure during pregnancy, but may result from antenatal exposure to other medications or substances such as nicotine, SSRIs or benzodiazepines. NAS symptoms have been described in 60-80% of infants exposed to heroin or methadone in utero (9). Approximately half of infants diagnosed with NAS will require pharmacologic treatment (4).

4 Each nursery that cares for infants with neonatal withdrawal should develop a protocol that defines indications and procedures for screening for maternal substance abuse. In addition, each nursery should develop and adhere to a standardized plan for the evaluation and comprehensive treatment of infants at risk for or showing signs of withdrawal (10). Newborn screening is performed by biochemical assessment of in utero substance exposure (10). Newborn urine toxicology screening must be performed soon after birth as many drugs are metabolized and eliminated rapidly by the newborn. Qualitative urine screening should be confirmed by quantitative screening due to risk of false positives. Urine screening may only reflect recent maternal drug abuse; therefore, additional testing is recommended. Newborn meconium analysis is more sensitive for detecting in utero exposure, but may result in delayed sampling and results. Umbilical cord tissue analysis approximates the sensitivity of meconium analysis, can improve turn-around time, and is efficacious at any gestational age. Indications for newborn screening for in utero substance exposure: The neonate is exhibiting signs or symptoms of withdrawal. Maternal urine toxicology is positive for substances not prescribed. Mother is suspected of using substances during the pregnancy. Placental abruption. Unexplained IUGR, or head measurement < 10 th percentile. Unexplained neonatal seizures, neonatal apnea, or congenital anomaly. NAS Assessment If there is a history of maternal use of substances associated with NAS, suspected use, or symptoms of withdrawal are present, a clinical assessment for NAS should be initiated and continued. An objective scoring system should be used to assist assessment (10). NNEPQIN recommends use of the modified Finnegan scoring system (Level C). The Finnegan was developed for assessment of narcotic withdrawal and has not been validated for use when other drug exposures are present (11). NAS Scoring (Finnegan scoring system, see appendix) Initiate NAS scoring 2 hours after birth and continue every 3-4 hours If score is greater than 8 begin scoring every 2 hours until the scores are less than 8 on 2 consecutive occasions. Begin pharmacological intervention if the patient has: 3 consecutive NAS scores equal to or greater than 8 --OR -- 2 consecutive NAS scores equal to or greater than 12

5 --OR Severe symptoms of NAS (e.g., apnea, seizures) NAS scoring should be done every 2 hours after the start of pharmacologic therapy until less than 8 and then every 3-4 hours for the duration of treatment if the score remains less than 8. If an infant scores 8 or above, scoring is performed q 2 hours until less than 8. When infants have been exposed to long acting opioids (methadone and buprenorphine) or to poly-drug use, in hospital observation for a minimum of 5 days is indicated. Infants exposed to short acting prescription opiates should be observed for a minimum of 2 days. Instruct families in NAS scoring and ask that they monitor baby s sleeping, sneezing, feeding, stooling, spitting up, excessive sucking, and yawning. Incorporate family s observations in NAS score. Calm infant before scoring using techniques such as assessing infant in skin-to-skin contact with the mother or another family member, or having infant suck on gloved finger or a pacifier. NAS Management (10, 12, 13, 14, 15, 16) Non-Pharmacologic Treatment should minimize stimulation and promote adequate rest and nutrition, and should include: Holding/ gentle rocking/swing/swaying head to toe direction Decreased stimulation (light and noise)/calm environment/slow movements Positioning with hands to face and flexed extremities/swaddling/nesting Skin-to-skin contact with parents or family members Encourage breastfeeding when medically appropriate Sucking on a pacifier or finger Providing uninterrupted periods of sleep Rooming in with mother Pharmacologic Treatment Various protocols for the medical treatment of NAS exist, and no specific protocol has been found to be superior. The optimal pharmacologic treatment of infants withdrawing from sedatives or hypnotics is unknown. Oral methadone or morphine are usually initiated, but clonidine, phenobarbital, and benzodiazepines have been investigated for the treatment of NAS. Each nursery should develop a protocol to be consistently used on their unit. The Vermont Child Health Improvement Program has published a complete guideline for the primary administration of methadone for NAS (16). NNEPQIN offers the following optional protocol for medical management of NAS: All infants requiring pharmacological treatment of NAS should undergo continuous cardio respiratory monitoring.

6 Limited evidence supports the initiation of oral morphine therapy for infants exhibiting signs of opiate withdrawal. Phenobarbital may be used as a secondary intervention if symptoms are not controlled with opiate therapy. Morphine Oral Solution (0.4 mg/ml) - suggested schedule: NAS Score Starting Dose mg/kg/dose PO every 3 hours mg/kg/dose PO every 3 hours 17 or greater 0.08 mg/kg/dose PO every 3 hours Escalating scores: If 3 consecutive NAS scores are greater than 8, or 2 consecutive NAS scores are greater than 12, increase dose to the level indicated by the new scores. When good control of symptoms is achieved (NAS scores are 4-8), maintain the same therapeutic dose for 48 hours before weaning. The recommended maximum total daily dose is 0.8 mg/kg/day (0.1 mg/kg/dose every 3 hours or 0.13 mg/kg/dose every 4 hours). Consider initiating Phenobarbital as adjunct treatment if infant has reached maximum total daily dose of morphine, is experiencing polysubstance withdrawal, or has been treated for 7 days with difficulty weaning. Phenobarbital Phenobarbital loading dose = 10 mg/kg/dose every 12 hours for total of two doses. Phenobarbital maintenance dose = 4 to 5 mg/kg/day. Start 12 hours after the second loading dose. Phenobarbital steady state will be reached at 5 half-lives (i.e., 7-10 days). If the infant s NAS scores remain greater than 8, the Phenobarbital level may be obtained after 7 days of treatment to help determine the next step of treatment. Optimal level is micrograms/ml. A rough dosing guide for adjusting Phenobarbital is that the difference between target and actual level is the dose in mg/kg to be given. Phenobarbital level may be obtained at any time if there is concern about toxicity. Weaning of Neonatal Morphine When NAS scores are less than 8 for 48 hours, wean by 10% of maximum dose every hours as tolerated. Use 10% of maximum dose to establish a weaning decrement and continue same dosing interval. DO NOT subsequently readjust doses for changes in weight. Discontinue oral morphine solution when the dose is less than or equal to 0.02 mg/kg/dose and NAS scores are less than 8 for hours. If withdrawal symptoms increase following weaning of the dose, increase back to the last effective dose, stabilize for 48 hours and begin to wean again.

7 If the infant is on Phenobarbital, wean the patient off morphine first before discontinuing Phenobarbital. Discontinue Phenobarbital 7 days after the last dose of morphine. Breast Feeding and Drug Exposure (17, 18) Institutions should have written information available to patients regarding breastfeeding policies. Using drugs of abuse (such as amphetamines, cocaine, heroin, marijuana and phencyclidine), or consumption of moderate to heavy amounts of alcohol, is a contraindication to breast feeding. Minimal levels of methadone or buprenorphine are detectable in breast milk. Women on methadone or buprenorphine maintenance therapy are encouraged to breastfeed their infants, providing they are HIV negative. Social and Legal Implications Support of the Family and Infant Encourage the mother and family to be with the infant as much as possible Parent(s)/caregivers are to be taught NAS scoring and how to help assess and care for their infant, including: To identify and appropriately respond to their infant s feeding and stress cues, such as feeding baby when hungry and until content. To interpret their infant s stress cues, for more or less interaction. To synchronize their care and behavior with that of the infant. To organize care and handling so that the infant is not overwhelmed with multiple stimuli. To utilize graduated interventions in quieting the fussy infant. To appreciate the infant s unique competencies and ability to interact with his/her environment. To stay with their infant at all times ( rooming in ). To hold their infant in skin-to-skin contact or swaddled in a blanket. Legal Implications According to federal law (The Child Abuse Prevention and Treatment Act), healthcare providers are required to report to state child protective service agencies all infants born and identified as affected by illegal substance abuse or experiencing withdrawal symptoms resulting from prenatal illegal drug exposure, and to develop a plan of safe care for the infant. The presence of other risk factors or information combined with a positive toxicology screen for an illegal substance may require that a report of child abuse or neglect be made to DCYF (Division for Children, Youth and Families) in any given case.

8 Appendix 1 Studies were reviewed and evaluated for quality according to the method outlined by the U.S. Preventative Services Task Force I Evidence obtained from at least one properly designed randomized controlled trial. II 1 Evidence obtained from well designed controlled trials without randomization. II 2 Evidence obtained from well designed cohort or case control analytic studies, preferably from more than one center or research group. II 3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments also could be regarded as this type of evidence. III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Based on the highest level of evidence found in the data, recommendations are provided and graded according to the following categories: Level A Recommendations are based on good and consistent scientific evidence. Level B Recommendations are based on limited or inconsistent scientific evidence. Level C Recommendations are based primarily on consensus and expert opinion.

9 Appendix 2 Modified Finnegan Scoring System References: 1. Stephen W. Patrick, MD, MPH, MS; et. al. Neonatal Abstinence Syndrome and Associated Health Care Expenditures in the United States, JAMA. 2012;307:1934 (Level II-2)

10 2. Opioid Abuse, Dependence and Addiction in Pregnancy, ACOG Committee Opinion, Number 524. May William A. Alto, MD; Alane B. O Connor, DNP, Management of women treated with buprenorphine during pregnancy. AJOG 2011 (Level III) 4. Jones, et al. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. N Engl J Med. 2010; 363: M.J. Krantz, et. al. QTc Interval Screening in Methadone Treatment. Annals of Internal Medicine 2009;150:387. (Level II-2) 6. FDA Drug Safety Communication: Abnormal heart rhythms may be associated with use of Zofran (ondansetron), September 15, Jones HE, Johnson RE, Milio L. Post-cesarean pain management of patients maintained on methadone or buprenorphine. Am J Addict.2006;15:258. (Level III) 8. Meyer, M, Mandell, T, et al. Vermont Guidelines for Obstetric Providers. Vermont Child Health Improvement Program (VCHIP) (Level III) 9. Doberczak TM, Kandall SR, Wilets I. Neonatal opiate abstinence syndrome in term and preterm infants. J Pediatr. 1991;118:933 (Level III) 10. Mark L. Hudak, Rosemarie C. Tan, Neonatal Drug Withdrawal. Pediatrics Feb 2012 (129) 540. (Level III) 11. Finnegan, L.P Neonatal abstinence syndrome: assessment and pharmacotherapy. In Nelson N, (ed) Current Therapy in Neonatal Perinatal Medicine. 2 ed. Ontario: BC Decker. (Level II-2) 12. Adapted from Boston Medical Center NAS Clinical Guideline # 13.20, Adapted from Guideline for Care of the Known or Suspected Drug (Illicit Substance) Exposed Newborn, Dartmouth Hitchcock Medical Center, Personal communication with Dr Bonny Whalen, August Adapted from Guidelines for Testing and Reporting Drug Exposed Newborns in Washington State (2011, June) pdf 15. Osborn D, Cole M. Jeffery H. Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database Systemic Review. 2010, October:10: CD (Level II-2) 16. Johnson, A, et al. Management of Neonatal Opioid Withdrawal. Vermont Child Health Improvement Program (VCHIP) (Level III) 17. American Academy of Pediatrics Policy Statement Breast Feeding and the Use of Human Milk Pediatrics 129 (3) March 2012, e827-e Hale, Thomas W. Medications and Mother s Milk, 13 th edition, 2008.