Methadone Maintenance Treatment During Pregnancy and Perinatal Outcomes CLEARY BJ1,2,3; DONNELLY JM2; STRAWBRIDGE JD3; GALLAGHER PJ3; FAHEY T4; WHITE MJ2; MURPHY DJ1,2

 

1Department of Obstetrics and Gynaecology, Trinity College Dublin2Coombe Women and Infants University Hospital, Dublin 83School of Pharmacy, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 24HRB Centre for Primary Care Research, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 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

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

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

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

MethodsMain 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)

MethodsStatistical 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

ResultsMaternal 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 status OR 42.5, 95% CI 28.7-62.9– Unplanned pregnancy OR 4.6, 95% CI 3.8-5.4– Public patient OR 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

ResultsPerinatal 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 (<10th 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 admission aOR 6.2, 95% CI 5.1-7.4

• Perinatal death: 2.4% (15/618) vs. 0.8% (491/60412)

ResultsPerinatal Outcomes

* Includes Pierre Robin Sequence

Anomaly SubgroupExposed

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

ResultsPerinatal 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

ResultsNeonatal 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

24%19/80

33%73/219

47%117/247

48%26/54

73%11/15

18%12/68

29%53/183

39%75/192

25%8/32

50%4/8

02

04

06

08

0

%NAS

<21mg 21-50mg 51-80mg 81-100mg >100mg

Methadone Dose Band

All methadone-exposed neonatesExcluding neonates with positive urine toxicology

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

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

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

Thank You !