Buprenorphine During Pregnancy: Maternal and Infant Outcomes

1. Buprenorphine During Pregnancy: Maternal and Infant Outcomes Alane B. O’Connor DNP, FNP Faculty, Maine Dartmouth Family Medicine Residency Adjunct Instructor, Dartmouth Medical School

2. Disclosures • I do not have any real or apparent conflict(s) of interest that may have a direct bearing on the subject matter of this education program. • Use of buprenorphine while breastfeeding is off label.

3. Outline • Brief introduction to buprenorphine, scope of opioid addiction problem, particularly during pregnancy. • Latest data on use of buprenorphine during pregnancy. • Breastfeeding rates at MDFMR; potential impact of breastfeeding on neonatal abstinence syndrome. • Challenges of monitoring/caring for infants born to mothers taking more than one substance that can cause a withdrawal syndrome.

4. Buprenorphine • FDA approved (2002) medication for the treatment of opioid dependence. • Partial agonist for mu opioid receptor; high affinity, low activity. • Monotherapy during pregnancy; dissolved sublingually. • MAT recommended for opioid dependence during pregnancy, fetal risk of intoxication/withdrawal. • Methadone is standard of care during pregnancy. • If methadone is refused or unavailable, buprenorphine is an alternative (US SAMHSA). • Infants exposed to opioids during pregnancy are at risk for neonatal abstinence syndrome (NAS). • Finnegan scoring system. • Irritability, tremors, poor feeding/sleeping, GI distress, respiratory complications.

5. The scope of the problem • 11% of women of childbearing age used illicit drugs in the past month. • 4.5% of all pregnant women. • Pregnant teens at greatest risk (16% ). • May be as high as 25%. • Maine leads the US (8x national average) in per capita rate of residents seeking treatment for addiction to painkillers. • Maine: 165 DABs in 2005, 667 DABs in 2011. • More Mainers die of drug overdose than in automobile accidents.

6. Our program at MDFMR • First delivery December 2007; more than 70 deliveries since. • Prenatal, intrapartum, postpartum care for mom; care for infants in hospital and after birth. • Integrated care model. • Offer medical care, MAT with buprenorphine and psychological care in one setting. • Research approved by MaineGeneral IRB.

7. Challenges of studying opioid dependent pregnant women. • Ethical considerations of studying drug dependent pregnant women. • Limited data available about buprenorphine during pregnancy. • Measuring opioid use: • urine toxicology; • self-report. • Polysubstance use. • Paying for negative urine drug screens. • Impact of poverty, poor nutrition, lack of access to prenatal care on outcomes.

8. Previous data are limited… • Few randomly controlled trials. • 3 randomized controlled studies (2 of 3 had fewer than 10 women). • MOTHER : • 175 opioid dependent pregnant women in 8 sites (58 delivered on buprenorphine). • Double-blind, double-dummy, flexible-dosing, randomized, controlled study comparing buprenorphine to methadone. • Prospective studies (US, Europe). • Only 1 with more than 100 women delivering on buprenorphine. • Case reports and retrospective chart reviews. • O’Connor A, Alto W, Musgrave K, et al. Observational study of buprenorphine treatment of opioid-dependent pregnant women in a family medicine residency: Reports on maternal and infant outcomes. Journal of the American Board of Family Medicine. 2011;24(2):194-201.

9. Methadone vs. Buprenorphine: Maternal Outcomes • MOTHER: • No significant differences in 6 maternal outcomes : • Weight gain. • Number of OB visits. • Incidence of cesarean section. • Abnormal presentation of fetus. • Use of analgesia during delivery. • Positive urine drug screen at delivery. • Maternal methadone exposure associated with: • Increased incidence of non-serious medical events (variations HR, BP).

10. Methadone vs. Buprenorphine: Fetal Outcomes • MOTHER: • Fetuses (32-35 wks): methadone condition showed more motor activity suppression, shorter duration movements than buprenorphine condition. • Fetuses (31-33 wks): higher incidence of non-reactive non-stress tests for methadone group vs. buprenorphine group. • Long term implications unknown.

11. Methadone vs. Buprenorphine: Infant Outcomes • MOTHER: • When compared to buprenorphine, infants exposed to methadone had: • More severe NAS: Peak NAS score 12.8 vs. 11.0; • Longer duration NAS treatment: 9.9 days vs. 4.1 days; • Longer overall hospitalization: 17.5 days vs. 10.0 days; • Required more morphine for NAS treatment:10.4 mg vs. 1.1 mg. • No significant difference in number of infants treated for NAS (57% methadone vs. 47% buprenorphine).

12. Treatment options • Treatment of opioid dependent pregnant women must be individualized. • Comprehensive: medical (OB, pediatric), psychological care, social services, public health nursing, etc. • Risk-benefits of methadone, buprenorphine. • Previous recovery attempts, successes. • Patient preference (informed consent). • Polysubstance use. • Inpatient vs. outpatient buprenorphine initiation. • Pregnancy, substance abuse outcomes improved when care provided in same setting. • Buprenorphine first line therapy?

13. Breastfeeding and Buprenorphine • Very limited previous literature. • Appears safe. • US DHHS “not contraindicated,” “use professional judgment.” • Likely minimal infant exposure. • Concentration breast milk similar to maternal serum levels but poor bioavailability. • Relative ingestion per kg of infant body weight less than 1% of dose per kg weight mother.

14. Breastfeeding and Buprenorphine • Lack of professional recommendations leads to inconsistencies across institutions: • Negative urine toxicology at admission? • No evidence of illicit drug use in third trimester? • Maternal intoxication at birth (pump and dump first feed only)? • “Abuse of narcotics” not contraindication to breastfeeding? • Decision should be on case by case basis after weighing benefits and risks if mother is not able to remain abstinent?

15. ABM recommendations • Breastfeeding okay if: • Engaged in substance abuse treatment; • Received consistent prenatal care; • Abstained from illicit substance use in 90 days prior to delivery. • Breastfeeding NOT okay if: • Not engaged (or planning to engage) in substance abuse treatment; • Relapsed in the 30 days prior to delivery. • ???: • Relapsed in the 30 to 90 days prior to delivery; • Recently entered treatment; • Maintained sobriety only in an inpatient setting.

16. Breastfeeding and Buprenorphine • Historically, opioid dependent pregnant women have low rates of breastfeeding. • 3 previous studies with breastfeeding rates: • 50% (Fischer et al., 2006); • 45% (Wachman et al., 2010); • 21% (Lejeune et al., 2006). • At MDFMR, 78% breastfed at delivery, 65% still breastfeeding at 2 months. • Significantly more likely to breastfeed at delivery (p<.001) than those previously studied.

17. Why more likely to breastfeed? • Born at Baby Friendly Hospital? • Only 45% at BMC, also Baby Friendly. • Women in Maine more likely to breastfeed? • 73.5% compared to US rate 74.6%. • Unique integrated medical behavioral health model? • Maybe. Reduces barriers to breastfeeding hypothesized by other authors. • Superb support of nurses/lactation consultants. • Less restrictive policy than other institutions.

18. Breastfeeding and NAS • 52 maternal-infant pairs: • 41 breastfeeding, 11 non-breastfeeding. • Method by choice, except 1 maternal-infant pair. • No differences in exposure to other substances that may cause withdrawal syndrome: illicit substances, tobacco, antidepressants. • Breastfeeding infants: • Less likely to require NAS treatment (27% vs. 45%, p=.204). • Less severe NAS (9.5 vs. 10.4, p=.390). • Experienced NAS resolution earlier (68.6 hrs vs. 82.0 hrs, p=.359). • No difference in infant length of hospitalization. • But not significant (small number of non-breastfed infants = larger standard error than expected).

19. Breastfeeding and NAS • No previous literature to compare to: • One poster (Brown et al., 2011): • 49% (36/73) of women on buprenorphine breastfeeding. • 36% of breastfeeding infants required NAS treatment vs. 68% of non-breastfed infants, (p=.007). • No information about polysubstance use. • Breastfeeding can be abruptly discontinued. • Difficult to distinguish potential breastfeeding effects from non-pharmacologic NAS interventions that accompany breastfeeding (e.g., swaddling, enhanced skin-to-skin contact).

20. Polysubstance use and infant withdrawal • Finnegan scoring system only validated for use in opioid withdrawal. • Many substances can cause a withdrawal syndrome in infants. • High rates of polysubstance use (75%) including illicit opioids, amphetamines, cocaine, marijuana, bath salts. • Challenges properly assessing this use. • Majority of women in treatment for opioid dependence (64%) have one or more psychiatric diagnosis beyond opioid dependence. • Majority of women (81%) use tobacco during pregnancy. • Complications of selecting NAS treatment medication.

21. Substance abuse, depression and pregnancy • High rate of concurrent substance abuse and mental health diagnoses. • Depressed pregnant women who are not treated at risk for poor outcomes. • Decision is based on risk-benefit assessment. • No randomized, controlled trials assessing efficacy and safety of antidepressant drugs during pregnancy. • 30% of infants exposed to SSRIs in 3rd trimester experience withdrawal syndrome: • Irritability, tremor, constant crying, shivering, GI disturbances, increased tonus, eating/sleeping difficulties, and convulsions.

22. Buprenorphine and antidepressants • 52 maternal-infant pairs: • 6 exposed to antidepressants third trimester, 46 not exposed. • 3 sertraline, 1 each on bupropion, trazodone, amitriptyline. • No differences in exposure to other substances that may cause withdrawal syndrome: illicit substances, tobacco, maternal dose**. • Infants exposed to antidepressants in utero more likely to be preterm (3/6 vs. 4/46, p=0.026). • Impact of concurrent use?

23. Buprenorphine and antidepressants • 52 maternal-infant pairs (cont’d): • No difference in NAS severity (p=.737). • No difference in NAS treatment rate (p=.608) • No significant difference in length of hospitalization (p=.218) though longer in those exposed to both (9 days vs. 6.9 days). • Time to NAS resolution significantly longer in infants exposed to both buprenorphine and antidepressants (101 hrs vs. 68 hrs) (p=.034). • Why? Shared metabolic pathway in the liver? Variations in placental transfer of substances? • Longer NAS resolution not related to being preterm.

24. Buprenorphine and antidepressants

25. Further work… • Ideally more RCTs. • Larger samples to investigate relationship between breastfeeding and NAS as well as concurrent use of buprenorphine and antidepressants. • Integrated assessment tool that can reliably differentiate between prenatal exposure to opioids vs. variety of other substances that cause withdrawal syndromes. • Standardized, evidenced based treatment protocol for NAS including pharmacologic approaches.

26. Discussion…