1. Methadone Maintenance Treatment During Pregnancy and Perinatal Outcomes CLEARY BJ 1,2,3 ; DONNELLY JM 2 ; STRAWBRIDGE JD 3 ; GALLAGHER PJ 3 ; FAHEY T 4 ; WHITE MJ 2 ; MURPHY DJ 1,2 1 Department of Obstetrics and Gynaecology, Trinity College Dublin 2 Coombe Women and Infants University Hospital, Dublin 8 3 School of Pharmacy, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2 4 HRB Centre for Primary Care Research, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2

2. Disclosure Statement None of the study authors have any conflicts of interest to declare This research was funded by an unrestricted educational grant from the charity Friends of the Coombe and the School of Pharmacy, Royal College of Surgeons in Ireland

3. Background Methadone maintenance- current treatment of choice for pregnant opiate-dependent women Few studies have compared perinatal outcomes in methadone-exposed and non-exposed pregnancies Neonatal abstinence syndrome (NAS) develops in 40-90% of neonates exposed to methadone in utero Results of studies of relationship between methadone dose and NAS have been equivocal

4. Aims Compare the likelihood of adverse perinatal outcomes in methadone exposed and unexposed pregnancies Explore the determinants of the occurence of neonatal abstinence syndrome (NAS) in methadone-exposed neonates

5. Methods Retrospective cohort study Based on electronic records of 61043 singleton pregnancies delivered Jan 2000 and Dec 2007 Methadone exposure at delivery Exposure recorded by a midwife during pregnancy before perinatal outcomes known –At booking interview –At admission to delivery suite if unbooked Other sources of exposure ascertainment: –Controlled drug registers –Hospital prescription records Research protocol approved by REC

6. Methods Main Study Variables & Outcomes Maternal sociodemographic, medical and obstetric characteristics Methadone dose at delivery Perinatal outcomes Congenital anomalies- EUROCAT classification NAS diagnosis- objective scoring system (Finnegan)

7. Methods Statistical Analysis Univariable and multivariable logistic regression Odds ratios and 95% confidence intervals for the association between: –methadone exposure and maternal/perinatal outcomes adjusted for differences in maternal characteristics between exposed and unexposed –risk factors and the occurrence of NAS adjusted for neonatal and maternal characteristics that differ between NAS and non-NAS groups Mixed effects logistic regression used to adjust for lack of independence in perinatal outcomes

8. Results Maternal Characteristics Methadone used at delivery in 618 (1%) pregnancies Factors associated with methadone use: –Age 20-29y –Unemployment OR 15.4, 95% CI 11.2-21.1 –Irish nationality OR 4.7, 95% CI 3.3-6.8 –Single marital statusOR 42.5, 95% CI 28.7-62.9 –Unplanned pregnancyOR 4.6, 95% CI 3.8-5.4 –Public patientOR 209, 95% CI 29-1485 –Smoking in pregnancy OR 53.1, 95% CI 38.2-73.8 Hepatitis C and HIV more common in methadone- exposed

9. Results Perinatal Outcomes Methadone exposure associated with adverse perinatal outcomes: –Preterm birth (<37/40)aOR 3.1, 95% CI 2.3-4.1 –Very preterm birth (<32/40)aOR 2.5, 95% CI 1.4-4.3 –SGA (<10 th centile)aOR 2.2, 95% CI 1.8-2.6 –Apgar score <3 (1 min.)aOR 1.9, 95% CI 1.1-3.4 –Apgar score <7 (5 min.)aOR 2.1, 95% CI 1.2-3.5 –Neonatal unit admissionaOR 6.2, 95% CI 5.1-7.4 Perinatal death: 2.4% (15/618) vs. 0.8% (491/60412)

10. Results Perinatal Outcomes * Includes Pierre Robin Sequence Anomaly Subgroup Exposed n=19/618 (3.1%) Non-exposed n=647/60412 (1.1%) Nervous system 2 (0.3)105 (0.2) Eye 0 (0)8 (0) Ear, face and neck 1 (0.2)43 (0.1) Congenital heart disease 4 (0.6)103 (0.2) Respiratory 0 (0)11 (0) Oro-facial clefts 3 (0.5)54 (0.1) Digestive system 0 (0)45 (0.1) Abdominal wall defects 0 (0)33 (0.1) Urinary 1 (0.2)46 (0.1) Genital 0 (0)72 (0.1) Limb 4 (0.6)129 (0.2) Musculo-skeletal 0 (0)23 (0) Other malformations 0 (0)6 (0) Teratogenic syndromes with malformations 0 (0)4 (0) Genetic syndromes and microdeletions* 4 (0.6)12 (0) Major Anomalies Categorised Into EUROCAT Subgroups

11. Results Perinatal Outcomes Pierre Robin Sequence –Exposed: 4 cases in 618 (1 in 155) –Non-exposed: 8 cases in 60412 (1 in 7,552) Methadone exposure associated with major congenital anomalies: –aOR 1.9, 95% CI 1.1-3.4

12. Results Neonatal Abstinence Syndrome A diagnosis of NAS was recorded for 236 (40.1%) methadone exposed neonates NAS was more likely with increasing methadone dose at delivery –>50mg vs. ≤50mg aOR 2.1, 95%CI 1.5-3.0

14. Limitations Retrospective study using routinely collected data from one centre Residual confounding may explain some of adverse perinatal outcomes Incomplete ascertainment of congenital anomalies Unblinded assessment of NAS Maternal urine toxicology results not available

15. Implications Dedicated, well-resourced, multi-disciplinary care required for these women & their infants as they are at increased risk of very preterm birth, low Apgar scores and other adverse perinatal outcomes Findings relating to congenital malformations need to be evaluated in other populations Robust prospective studies of large cohorts of opioid-dependent pregnant women required to assess all the determinants of NAS and provide further information on perinatal and longer-term outcomes

16. Acknowledgements Thanks to: Funders –Friends of the Coombe –School of Pharmacy, RCSI Supervisors Midwives and other staff who collected the data Emma McNamee who extracted the data

17. Thank You !