1. C ARING FOR INFANTS WITH SHORT - AND LONG - TERM EFFECTS OF IN - UTERO OPIOID EXPOSURE Bonny Whalen, MD Medical Director / Newborn Pediatrician CHaD/DHMC Newborn Nursery June 5, 2013

2. OBJECTIVES Demonstrate an understanding of short- and long-term effects of in-utero opioid exposure on the developing fetus / neonate Discuss the importance of multi-disciplinary, family-centered care for these infants in the newborn period Help families best prepare for the birth of their at-risk infant including how to provide calm, nurturing environments, limiting visitors, etc.

3. I LLICIT D RUG U SE IN U.S. W OMEN ~ 11% illicit drug use in past month in women 15-44 yr 15-17 yr: 13%18-25 yr: 16.8%26-44 yr: 7.6% 4.4% illicit drug use in past month in known pregnancy 15-17 yr: 16.2%18-25 yr: 7.4%26-44 yr: 1.9% Most commonly reported illicit drugs used by women: 1. Marijuana 2. Psychotherapeutics (e.g., opioids) 2009 & 2010 National Surveys on Drug Use and Health https://nsduhweb.rti.org/

4. Growth restriction Prematurity Developmental abnormalities / long-term effects? Opioid system mediates developmental events Farid WO, et al. Curr Neuropharmacol. 2008. Motor delays? Cognitive delays? ADHD? Review of available studies reveals no adverse effects on development for opiate-exposed infants Jones HE, et al. Early Hum Dev. 2009. CharacteristicHeroinMTDBUPMTD vs BUP Delivery < 37 wk (%)29.8%26.3%21.8%*NS Birthweight2601 g3050 g*2900 g*NS IUGR27.7%10.5%*9.3%*NS * P < 0.05 for heroin vs. substitution agent Binder T and Vavrinkova B. Neuroendocrinol Lett. 2008. I N - UTERO OPIATE EXPOSURE AND ITS EFFECTS

5. N EONATAL A BSTINENCE S YNDROME (NAS) CNS hyperirritability Autonomic hyperfunction GI dysfunction

6. CNS HYPERIRRITABILITY High-pitched crying Sleeplessness Hyperactive moro reflex Tremors Increased muscle tone Myoclonic jerks Seizures http://newborns.stanford.edu/PhotoGallery/Jittery3.html

7. AUTONOMIC HYPERFUNCTION Metabolic / Vasomotor / Respiratory Disturbances Fever Sweating Yawning Mottling Nasal stuffiness Sneezing Nasal flaring Tachypnea Retractions

8. GI DYSFUNCTION Excessive sucking Poor feeding Regurgitation Projectile vomiting Loose stools Watery stools

9. NAS: W HAT TO E XPECT Lejeune et al. Drug Alcohol Depend. 2006. Sigman et al. J Peds. 2010 2/3 - 3/4 infants develop some degree of NAS Symptoms from long-acting opioids start on DOL 2 May see symptoms earlier if: Mom missed dose the day prior Baby has early rapid withdrawal phase of buprenorphine Mom using other substances / meds / nicotine Symptoms usually peak DOL 3-4 May depend on med, mom’s other meds, baby’s metabolism... ≥ 1/2 infants require Rx for NAS No relationship b/w dose of substitution agent and NAS severity or duration of Rx

10. M INIMUM R ECOMMEND M ONITORING T IMES FOR OPIOID - EXPOSED INFANTS 2 days Short-acting opioids e.g., morphine, oxycodone, Percocet 4 days Heroin Long-acting opioids e.g., buprenorphine, methadone

11. Study OutcomesMTD (N = 73) BUP (N = 58) P % infants treated for NAS 57%47%0.26 Peak NAS score 12.8±0.611.0±0.60.04 Total amount of morphine needed for Rx 10.4 mg1.1 mg<0.0091 Duration of Rx for NAS 9.9 d4.1 d<0.0031 Length of stay 17.5 d10 d<0.0091 METHADONE VS. BUPRENORPHINE Jones et al. N Engl J Med. 2010; 363:2320-2331. Multi-center RCT (n = 7) comparing MTD vs. BUP Rx in 175 pregnant women with opioid dependency (89 MTD, 86 BUP) Double-blind, double-dummy, flexible-dosing Comparison of 131 neonates whose mothers were followed to end of pregnancy 33% BUP vs. 18% MTD discontinued Rx (P > 0.02) - Most commonly due to maternal dissatisfaction with Rx Unclear if pts with more severe dependence more likely to leave BUP group, therefore skewing towards better outcomes in BUP neonates; however post-hoc analyses remained significant when excluded moms on ≥ 100 mg methadone

12. S IGNIFICANT P REDICTORS RELATED TO NAS Need for Rx for NAS Maternal cigarette smoking Higher birthweight Higher peak NAS score prior to Rx Lower maternal weight Maternal SSRI use Higher birthweight Lower gestational age Vaginal delivery Longer duration of Rx Maternal use of SSRIs, antidepressants, or antipsychotics Higher dose of morphine required for Rx Maternal use of SSRIs, antidepressants, or antipsychotics SSRIs independently Lower # days of maternal receipt of study medication Greater # of cigarettes smoked 24 hr prior to delivery Kaltenbach, et al. Addiction. 2012;107:45-52.

13. S IGNIFICANT D IFFERENCES IN NAS P ROFILES Methadone-exposed Higher incidence of: Undisturbed tremors Hyperactive Moro Greater mean severity score: Total NAS score Disturbed tremors Undisturbed tremors Hyperactive Moro Excessive irritability Failure to thrive Shorter time to Rx initiation 36 hr (compared with 59 hr for buprenorphine) Buprenoropine-exposed Higher incidence of: Nasal stuffiness Sneezing Loose stools Greater mean severity score: Sneezing Gaalema, et al. Addiction. 2012;107:53-62. Limitation = Data from neonates requiring Rx were excluded from analyses once Rx was initiated → may underestimate measures of incidence / severity

14. H OW TO A SSESS FOR NAS: F INNEGAN SCORING TOOL

15. Signs / symptomsPercentage Tremors90 Restlessness85 Hyperactive reflexes51 Regurgitation45 Increased muscle tone45 High pitched cry33 Sneezing31 Frantic sucking of fists25 Inability to sleep24 Stretching22 Nasal stuffiness18 Respiratory distress12 Vomiting9 Frequent yawning9 Sweating8 Excoriation of knees, toes and nose7 Mottling5 Diarrhea3 Fever3 Pallor3 Lacrimation2 Generalized convulsion2 Developed to: 1.monitor full spectrum of abstinence sx due to narcotic withdrawal 2.monitor response to Rx Determined prevalence of 20 most common sx seen in infants with narcotic withdrawal Ranked sx based on potential for greatest harm to infant Finnegan LP, at al. Int J Clin Pharmacol Biopharm. 1975. DEVELOPMENT OF THE FINNEGAN SCORING TOOL

16. Assigned score of “5” to sx with greatest potential to harm infant and “1” to sx with least pathological significance Scored q 1 hr in 1 st 24 hr, q 2 hr x 24 hr, then q 4 hr corresponding to “Nursery feedings” Good inter-rater reliability Finnegan LP, et al. Int J Clin Pharmacol Biopharm. 1975 Modified in 1986 - Score q 4 hr - Allow to feed q 2-3 hr

17. LIMITATIONS OF FINNEGAN TOOL Designed for term infants At times, difficult to interpret sx of ‘normal newborn’ vs NAS Study of 102 non-addicted infants DOL 1-3: Median score = 2 Variability increased on DOL 1-2 DOL 1: 95 th percentile = 5.5 DOL 2: 95 th percentile = 7 Zimmermann-Baer et al. Addiction. 2010. Can be prone to subjectivity Not to be used for a “one point in time” quick assessment Lacks specificity DDx: hunger, nicotine or benzo withdrawal, SSRI toxicity vs withdrawal, hypoglycemia, infection, CNS injury, hypocalcemia, hyperthyroidism

18. CO-MORBIDITIES Nicotine withdrawal Tobacco use in pregnancy ~85% Lejeune et al. Drug Alcohol Depend. 2006. Zimmermann-Baer et al. Addiction. 2010. SSRI withdrawal / toxicity 13% maternal SSRI use in pregnancy Zimmermann-Baer et al. Addiction. 2010. Other substance / med toxicity 12% benzodiazepine Rx in pregnancy Zimmermann-Baer et al. Addiction. 2010. Difficulties feeding Increased weight loss

19. NAS SCORING TIPS Teach parents how NAS scoring is performed Teach parents how to help monitor infant e.g., watch for decreased sleep, yawning, sneezing, excessive sucking Score within 2 hr of birth, then q 3 - 4 hr Score baby when awake to elicit reflexes & behaviors Do not awaken unless asleep for > 3 hr Allow infant to calm first e.g., allow infant to feed before scoring, place skin-to-skin with mother especially important for muscle tone & RR Score all symptoms that occur within interval If score ≥ 8, score NAS q 2 hr until < 8 x 24 hr

20. SUPPORTIVE CARE FOR NEWBORNS Rooming-in Allows family to respond to infant at early feeding / stress cues, empowers family to care for their infant independently, and provides opportunity for calmer environment for infant Decreased need for NAS Rx Shorter length of stay More likely to be discharged into custody of mother Abrahams R et al. Can Fam Physician. 2007.

21. SUPPORTIVE CARE FOR NEWBORNS Feed baby at early feeding cues, till content Frequent skin-to-skin contact Use calming techniques C-position Swaddling Gentle jiggling Slow, rhythmic up & down movements * Clap baby’s bottom with cupped hand * Shooshing Non-nutritive sucking *May not work for some babies

22. SUPPORTIVE CARE FOR NEWBORNS Provide undisturbed periods of sleep / rest Cluster care Decrease environmental stimuli Low lights Quiet room Limit visitors / # caregivers Avoid “excessive handling” of baby Introduce stimuli as baby able to tolerate Infant touch / massage

23. BREASTFEEDING AND OPIATE REPLACEMENT Rx Methadone and buprenorphine considered safe Breastfed infants may experience decreased NAS severity Farid et al. Curr Neuropharmacol. 2008. Ensure no active illicit drug use - see ABM guidelines Provide lactation support Promote calm, organized environment Frequent, ad lib feedings Provide emotional support Teach ways to help baby if NAS present Skin-to-skin Hand expression / breast massage during feeding Organize baby’s suck on finger first if suck disorganized Feed small amount of colostrum first C-hold in cross cradle / football positions May require caloric supplementation for increased metabolic needs

24. ABM’ S BREASTFEEDING GUIDELINES Consistent prenatal care Abstinent from illicit drug use or licit drug abuse for 90 days prior to delivery & able to maintain sobriety in outpt setting Women engaged in substance abuse Rx who have provided consent to discuss progress with Rx & postpartum plans with substance abuse Rx counselor Negative urine toxicology testing at delivery No medical contraindications e.g., HIV, contraindicated antipscyh med The Academy of Breastfeeding Medicine Protocol Committee. ABM Clinical Protocol #21: Guidelines for breastfeeding and the drug-dependent woman. Breastfeeding Medicine. 2009;4:225-228.

25. DRUG OF ABUSE SCREENING Obtain specimens within 24 - 48 hr of delivery to help: Anticipate timing and type of withdrawal symptoms Inform DCF / DCYF of exposure, when clinically indicated Make recommendations re: safety of breastfeeding Urine drug of abuse screen Urine confirmatory testing Meconium drug of abuse screen

26. WHEN TO CONSIDER RX / ICN TRANSFER Apnea Seizures 3 consecutive scores (or average of) ≥ 8 2 consecutive scores (or average of) ≥ 12 Inability to feed orally due to NAS sx

27. PHARMACOLOGIC RX FOR NAS Capture Phase Oral morphine *§ q 4 hr, dose increased until NAS sx controlled Phenobarbital added if difficult to capture or wean Maintenance Phase Find smallest dose that adequately controls baby’s sx Goal of Rx = NAS scores < 8 Weaning Phase Begin wean when scores < 8 x 48 hr & baby clinically stable Wean by 10% daily when following present: NAS scores < 8 Baby clinically stable * Agent of choice at DHMC, alternative agents sometimes preferred at other institutions (e.g., methadone) § 2010 Cochrane Systematic Review on Opiate Rx for opiate withdrawal in newborn infants: “There is insufficient data to determine safety or efficacy of any specific opiate compared to another opiate.”

28. CARE COORDINATION Clinical Resource Coordinator Assist in identifying and arranging postnatal supports VNA, Good Beginnings, breast pump rental, etc. Identify Primary Care Physician (PCP) Social Worker Perform initial assessment of mother and newborn Assist in identifying and arranging postnatal supports Review risk for postpartum depression / stress & identify coping mechanisms / supports Mandated report to DCF/DCYF, when clinically indicated Consider offering that mother make report herself Review how report will help engage parenting/family supports

29. KEEPING CHILDREN AND FAMILY SAFE ACT As a condition of federal funds under Child Abuse Prevention and Treatment Act, each state must develop policies & procedures to address needs of infants born and identified as being affected by illegal substance abuse or withdrawal symptoms resulting from prenatal drug exposure Notify CPS of substance-exposed newborns Develop plan of safe care for infant Law specifies that reports of prenatal substance exposure shall not be construed to be child abuse or require prosecution for any illegal action

30. DHMC MANDATED REPORTING GUIDELINES Mother continuing to use any of following substances during pregnancy, subsequent to documented teaching on potential dangers of substance(s) and resources offered for cessation: Alcohol Controlled medication not prescribed to the mother Illicit substance Mother who admits to prenatal use of illicit substance and use not previously disclosed Baby tests positive for any of above substances Baby with Fetal Alcohol Syndrome or Adverse Effects

31. DISCHARGE READINESS No apnea or respiratory compromise Stable vital signs Baby has completed appropriate observation period No active concerns for significant sx of NAS Feeding well with appropriate weight pattern Parents demonstrate appropriate response to / care of baby Home environment assessed as safe Referrals to community resources in place

32. COMMUNITY RESOURCES Information and Referral NH Resource 211 802-652-4636 VT Resource 211 866-444-4211 Support/Home-based programs (e.g., VNA, Good Beginnings, Parenting Programs) Health and Mental Health / Treatment Programs Child Protective Services Domestic/Family Violence Housing Emergency Financial Assistance Legal Assistance Transportation Long-term follow-up programs / interventions (e.g., Early Intervention)

33. GOING HOME … Communication with community supports Identify known family challenges (domestic violence, mental health issues, homelessness) Identify known family strengths and informal supports Update state CPS agency, as clinically indicated Known family challenges and strengths Issues in the home which may pose risk for baby Results of drug of abuse screening Community supports recommended / accepted Communication with baby’s PCP & 1 st visit made Update on medical course, social issues, community resources offered / accepted

34. P RENATAL PREPARATION Maintain abstinence Engage social supports Encourage breastfeeding (with abstinence) Decrease / stop smoking Educate families regarding what to anticipate Likelihood of NAS symptoms / what sx look like Need to stay in hospital for at least 4 days for monitoring Possibility of needing Rx / duration of Rx if needed Providing calm environments for baby / calming techniques Limiting visitors, rooming-in, skin-to-skin, swaddling, etc. Drug of abuse screening Need for mandated reporting / referral to DCF/DCYF

35. R ESOURCES FOR PROVIDERS “Parenting and Substance Abuse: Developmental Approaches to Intervention” - Book that explores issues of the substance exposed dyad pre- and post- partum Edited by Nancy Suchman, Marjukka Pajulo and Linda Mayes (Oxford University Press, 2013). “Highs and Lows” - Book about women and addiction. http://www.camh.ca/en/education/about/camh_publications/Pag es/highs_lows.aspx

36. QUESTIONS?