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Dryden, C. and Young, D. and Hepburn, M. and Mactier, H. (2009) Maternal methadone use
in pregnancy: factors associated with the development of neonatal abstinence syndrome and
implications for healthcare resources. British Journal of Obstetrics and Gynaecology, 116 (5). pp.
665-671. ISSN 0306-5456
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Dryden, C. and Young, D. and Hepburn, M. and Mactier, H. (2009) Maternal methadone use in
pregnancy: factors associated with the development of neonatal abstinence syndrome and
implications for healthcare resources. British Journal of Obstetrics and Gynaecology, 116 (5).
pp. 665-671. ISSN 0306-5456
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Maternal methadone use in pregnancy: factors
associated with the development of neonatal
abstinence syndrome and implications for
C Dryden,aD Young,bM Hepburn,c,dH Mactiera,d
aNeonatal Unit, Princess Royal Maternity, Glasgow, UKbDepartment of Statistics and Modelling Science, University of Strathclyde,
Glasgow, UKcDepartment of Obstetrics and Gynaecology, Princess Royal Maternity, Glasgow, UKdDivision of Developmental Medicine,
University of Glasgow, Glasgow, UK
Correspondence: Dr H Mactier, Neonatal Unit, Princess Royal Maternity, 16 Alexandra Parade, Glasgow G31 2ER, UK.
Objectives The objectives of this study were to investigate factors
associated with the development of neonatal abstinence syndrome
(NAS) and to assess the implications for healthcare resources of
infants born to drug misusing women.
Design Retrospective cohort study from 1 January 2004 to 31
Setting Inner city maternity hospital providing dedicated
multidisciplinary care to drug misusing women.
Population Four hundred and fifty singleton pregnancies of drug
misusing women prescribed substitute methadone in pregnancy.
Methods Case note review.
Main outcome measures Development of NAS and duration of
infant hospital stay.
Results 45.5% of infants developed NAS requiring
pharmacological treatment. The odds ratio of the infant
developing NAS was independently related to prescribed maternal
methadone dose rather than associated polydrug misuse.
Breastfeeding was associated with reduced odds of requiring
treatment for NAS (OR 0.55, 95% CI 0.34 0.88). Preterm birth
did not influence the odds of the infant receiving treatment for
NAS. 48.4% infants were admitted to the neonatal unit (NNU)
40% of these primarily for treatment of NAS. The median total
hospital stay for all infants was 10 days (interquartile range 7 17
days). Infants born to methadone prescribed drug misusing
mothers represented 2.9% of hospital births, but used 18.2% of
NNU cot days.
Conclusions Higher maternal methadone dose is associated with
a higher incidence of NAS. Pregnant drug misusing women should
be encouraged and supported to breastfeed. Their infants are
extremely vulnerable and draw heavily on healthcare resources.
Keywords Breastfeeding, health resources, methadone, neonatal
Maternal drug misuse is related to socio economic depriva
tion, and infants born to drug misusing mothers are recog
nised to be at risk of preterm delivery, poor intrauterine
(NAS).1These problems persist even when drug misusing
mothers are managed in specialist units.2Substitute prescrib
ing of methadone stabilises lifestyle and reduces risk taking
behaviour as well as the incidence of preterm birth and intra
uterine growth restriction3–6but is commonly associated with
NAS.6–9Preterm infants may be less likely than term infants to
exhibit signs of NAS resulting from opiate or opioid expo
sure.10–12There is conflicting evidence with regard to optimal
maternal methadone dose in pregnancy, with some studies
showing an association between maternal methadone dose
and the risk of NAS and some studies showing no such rela
tionship.9,13–19Durationof staymaybelonger forinfants born
to polydrug misusing mothers,20and since higher doses of
ing methadone during pregnancy may not be justified.13
Australian and European data have demonstrated large con
using women,2,8but there are few data to quantify this within
the UK healthcare setting.20–22
We present data from infants born over a 3 year period to
service within a large inner city maternity hospital in the UK.
Local service provision
Princess Royal Maternity provides an established obstetrically
led, community based city wide multidisciplinary service for
women with social problems including substance misuse.23
The majority of drug misusing women attending this service
use opiates and benzodiazepines. Antenatal care includes sub
stitute prescribing (predominantly with methadone) and is
provided in collaboration with social work and addiction
services.24In common with standard addiction management,
all women are prescribed sufficient methadone to eliminate
physical withdrawals. Urine is routinely screened at booking
to confirm the presence of illicit drugs. Thereafter, to foster
a sense of trust and responsibility and to keep women engaged
with services, additional urine drugs screens are performed as
infrequently as possible in the outpatient setting. A second
routine urine sample is collected immediately post delivery,
and additional urine screens generally only during periods of
hospitalisation to confirm grounds for discharge of difficult
women suspected to be using illicit drugs. Social stability is
monitored, taking into account factors such as antenatal
clinic attendance, general appearance and/or evidence of
intoxication and self reported drug use. All women are
referred to the clinic addiction worker at booking and
assessed to determine the level of social work input required.
Postnatally, women are cared for on a dedicated ward by
familiar midwifery staff who also provide community review
after discharge. Infants are nursed by their mother’s bedside
unless any specific indication for admission to the neonatal
unit (NNU) is present. Breastfeeding is encouraged for all
women unless HIV positive. Management of infants is guided
by local protocol including a modified version of the Lipsitz
Tool.25Lipsitz scores of ‡5 on two occasions prompt consid
eration of pharmacological treatment, particularly if the
infant is feeding poorly and/or unusually difficult to console.
First line treatment for infants exposed to opiates/opioids is
oral morphine solution21,26with phenobarbitone as second
line, particularly in cases of polydrug misuse.27–29Pharmaco
logical treatment for NAS is not an indication per se for
admission to the NNU, and mother and baby can remain
together in the postnatal ward until day 10; thereafter, healthy
mothers are discharged home and infants continuing to
require pharmacological treatment are admitted to the
NNU. Once oral morphine solution has been weaned, infants
may be considered for discharge on phenobarbitone. For
practical reasons, including the stability of the oral morphine
solution available during the time of this review, and the
difficulty of supervising 4 hourly administration of oral mor
phine solution, it is not our practice to discharge infants on
oral morphine solution.
This was a retrospective cohort study of singleton infants born
to drug misusing women prescribed substitute methadone
and delivered at Princess Royal Maternity in Glasgow over the
3 year period from 1 January 2004 to 31 December 2006.
Mothers were identified on admission to the postnatal
ward and information extracted from case notes after dis
charge. Completeness of data was ensured by cross checking
ward admission diaries, controlled drug books, hospital dis
charge and paediatric outpatient clinic records. Details of
maternal methadone prescription and additional illicit drug
misuse were obtained from case notes, hospital prescription
charts and urine toxicology as detailed above. Social depriva
tion was measured by postcode derived Carstairs deprivation
scores.30NAS was defined as signs of withdrawal that had
been considered severe enough to require pharmacological
treatment according to local protocol (vide supra). Data were
anonymised prior to analysis. The local research ethics com
mittee approved this anonymised retrospective study.
Univariate analyses were performed to investigate possible
predictors of NAS. Significant predictors were then entered
into a multivariate logistic regression model, and backwards
selection was performed to determine independent variables
associated with NAS. All analyses were performed using
Minitab (version 15) at a significance level of 5%. Methadone
was categorised according to daily dose into four groups(1 29,
30 59, 60 89 and ‡90 mg).
Four hundred and fifty singleton infants were delivered to 450
methadone prescribed drug misusing women over the 3 year
period. Two further women delivered two live sets of twins;
their data are not included. Six infants were stillborn (at 25,
32, 34, 34, 35 and 37 weeks of gestation, respectively). The
postnatal courses of the remaining 444 infants were reviewed.
Data were complete for 437 infants (98.4%) and 440 mothers
(97.8%). The remaining case notes could not be traced,
although basic demographic data including birthweight,
gestation and duration of hospital stay were obtained from
hospital electronic records for all deliveries.
Maternal characteristics and pattern of drug
Maternal characteristics are detailed in Table 1. The median
maternal age at delivery was 28 years (range 15 41 years), and
the median parity was 1. 18.2% of women had a history of
depression, two thirds of whom were on antidepressants. The
vast majority regularly smoked tobacco; by contrast, recog
nised excessive alcohol consumption during pregnancy was
relatively uncommon. Ninety percent of mothers were offered
and accepted antenatal hepatitis C screening; almost one
third had evidence of hepatitis C virus in the blood (poly
merase chain reaction [PCR] positive). One mother was HIV
positive, diagnosed prior to pregnancy. Social deprivation was
prevalent with 77.8% of the women assigned Carstairs scores
6 or 7. The median daily prescribed dose of methadone at
delivery was 50 mg (range 5 150 mg). There was no associ
ation between prescribed dose of methadone and antidepres
sant use. Combining self reported drug misuse and results of
urine toxicology, at least 80% of the women used illicit drugs
during their pregnancy (Table 1). The drugs most frequently
used were benzodiazepines and heroin. Cannabis misuse was
relatively common, and a significant minority of women also
used cocaine. Amphetamine use was uncommon.
Infant characteristics are outlined in Table 2. The median
gestational age was 38 weeks. 20.3% of infants were born
before 37 weeks of gestation compared with 9.4% for the
hospital as a whole (chi square, P < 0.001). Twenty three
percent of infants weighed less than the ninth centile includ
ing 7.4% weighing less than the second centile. Head circum
ferences were correspondingly low. 68.9% of infants were
born by spontaneous vertex delivery (SVD) compared with
58.1% for the hospital as a whole (chi square, P < 0.001) and
fewer required instrumental vaginal delivery (6.3 versus
12.3%, chi square, P < 0.001). Sixteen infants were born
before arrival at hospital. Seven (1.6%) infants had significant
congenital anomalies. All but two infants survived to dis
charge; one male infant died aged 7 days of complications
of prematurity and another infant with multiple anomalies
died of renal failure. One term infant died suddenly at home
aged 25 days; this death was unexplained after postmortem
examination. Breastfeeding was initiated in 27.7% of infants,
and a further 19 infants received mother’s own expressed
breast milk. 11.3% of the total cohort was still breastfeeding,
at least in part, at discharge.
Neonatal abstinence syndrome
45.5% infants received pharmacological treatment for NAS.
Median age at commencement of treatment was 3 days (range
1 13 days), and this was not related to the pattern of maternal
drug misuse. Duration of oral morphine therapy ranged from
1 to 44 days (median 11 days), and this was not different
among infants exposed to selective serotonin reuptake inhib
itors (SSRIs) in utero (n = 32). Of the infants who required
second line treatment (n = 42), just over half (22) were dis
charged home on phenobarbitone, eight of these to foster
Table 1. Maternal characteristics (n
Tobacco smokers, n (%)
Known excess alcohol consumption, n (%)
Hepatitis C serology, n (%)
Hepatitis C antibody positive*
Hepatitis C PCR positive**
History of depression, n (%)
On antidepressant treatment at time of booking***
Illicit drug use, n (%)
28 (15 41)
1 (0 7)
*86% of women tested.
**85% of women tested.
***Categorised as per British National Formulary.
Table 2. Infant characteristics (n
MeanSD Median IQR
Gestational age (weeks) 37.8
Mode of delivery, n (%)
IQR, interquartile range.
care. A further three infants who had been discharged home
without treatment were commenced on phenobarbitone in
the outpatient clinic at 3, 5 and 8 weeks of age, respectively.
Total duration of phenobarbitone therapy ranged from 2 to
140 (median 25) days. Ninety three percent of the infants
who required phenobarbitone had been exposed to polydrug
misuse in utero.
Factors associated with development of NAS
Maternal use of benzodiazepines in addition to prescribed
methadone significantly increased the likelihood of NAS
requiring treatment (OR 1.73, 95% CI 1.17 2.55; P = 0.006)
(Table 3), but there was a strong positive correlation between
prescribed maternal methadone dose and polydrug misuse
(P < 0.001). After multivariate logistic regression analysis,
only prescribed maternal methadone dose independently
influenced the likelihood of an infant receiving treatment
for NAS (P < 0.001). This is illustrated in Figure 1. Breast
feeding for ‡72 hours significantly reduced the odds of receiv
ing treatment for NAS (OR 0.55, 95% CI 0.34 0.88; P =
0.013). Neither gestational age (OR 1.00, 95% CI 0.93 1.08;
P = 0.954) nor prescription of SSRI (OR 1.3, 95% CI 0.63 2.7;
P = 0.479) affected the odds of an infant receiving treatment
48.4% infants were admitted to the NNU where duration of
stay ranged from 1 to 108 (median 13) days (Table 4). Rea
sons for admission included prematurity (15.8%), respiratory
distress (12.6%) and a variety of social reasons (13%). Forty
percent of admissions were primarily for continuing treat
ment of NAS, almost exclusively term infants. Premature
infants and infants with respiratory distress remained in the
NNU for a median of 20 and 16 days, respectively, reflecting
their increased medical needs. Nonadmitted term infants
remained in hospital with their mothers for a median of 7
days (interquartile range 6 9 days). Duration of hospital stay
was longer for infants born to polydrug misusing women
(median of 11days [interquartile range 7 19 days]) compared
with infants born to mothers who took only prescribed meth
adone (median 8 days [interquartile range 6 10 days]) (P <
0.001). Infants born to drug misusing mothers represented
2.9% of hospital births but occupied 18.2% of the total
NNU cot days for the period.
Table 3. Factors predictive of receiving pharmacological
treatment for NAS
Variablen OR95% CIP value
Gestation (weeks) (analysed as
30 59 vs 1 29 mg
60 89 vs 1 29 mg
?90 vs 1 29 mg
Mother only used methadone
Methadone plus other drugs
Mother on SSRI
Breastfed ?72 hours*
30 59 vs 1 29 mg
60 89 vs 1 29 mg
?90 vs 1 29 mg
Breastfed ?72 hours*
444 1.00 0.93 1.080.954
166 vs 98 1.58 0.94 2.66
135 vs 98 1.78 1.04 3.04
43 vs 98 5.09 2.32 11.18 ,0.001
27 0.40 0.16 0.96
272 1.73 1.17 2.550.006
76 1.33 0.81 2.170.264
1.30 0.63 2.70
0.52 0.33 0.83
166 vs 98 1.57 0.93 2.65
135 vs 98 1.72 1.00 2.96
43 vs 98 4.82 2.18 10.64 ,0.001
99 0.55 0.34 0.88
*Includes preterm infants receiving mother’s own expressed
Figure 1. Relationship between maternal methadone dose and develop
ment of NAS.
Table 4. Infant lengths of stay
n NNU stay
Infants admitted to the
NNU (all gestations)
Term infants admitted to
Infants not admitted to
10 (7 17)
18 (13 26)13 (6 22)
147 12 (5 20) 17 (12 26)
229Not applicable 7 (6 9)
IQR, interquartile range.
Discharge and follow up
Almost all women were allocated a named social worker dur
ing pregnancy, and all families were assessed by the social
work department prior to discharge. Forty two (9.5%) infants
were discharged to foster care, and a further 15 were dis
charged to the care of family members on a voluntary basis.
Outpatient appointments were offered to 182 infants, of
whom 51.1% failed to attend on two or more occasions.
Our data concur with some previous reports illustrating the
vulnerability of infants born to drug misusing mothers. Even
with specialist multidisciplinary antenatal care31and good
maternal compliance during pregnancy, these infants are of
low birthweight and at increased risk of preterm delivery.2,6,8
The stillbirth rate of 1.3% was almost double that seen in the
hospital as a whole, although the incidence of congenital
abnormality was not increased.32Undoubtedly, the effects
of drug misuse upon the unborn child are confounded by
social deprivation and maternal health and lifestyle. We
assessed social deprivation using a scoring system based on
four standard variables taken from census data including
adult male unemployment, lack of car ownership, low social
class and overcrowding:30three quarters of our population of
mothers lived in areas classified as the lowest two Carstairs
categories (6 and 7) compared with 50% for the hospital as
a whole. The vast majority of mothers regularly smoked cig
arettes, and 4.7% were recognised to have consumed excessive
amounts of alcohol during pregnancy. It is impossible to
estimate the relative contributions of drug misuse, cigarette
smoking, alcohol consumption, poverty and maternal ill
health upon fetal growth.
The increased frequency of SVD is consistent with the
observations of Kelly et al.2and may be explained in part by
smaller birthweight and head circumference but may also
reflect reluctance of labouring drug misusing mothers to
admit themselves early to hospital. It is our experience that
many of these women prefer to manage early labour them
selves at home, often with illicit top up drugs. This would also
explain the increased likelihood of delivery occurring before
arrival at the maternity hospital.
The reported incidence of NAS is dependent on local pol
icies for diagnosis and/or treatment as well as the pattern of
maternal drug use, hence the marked variation (16 91%)
reported between centres.2,3,7,8,27,28In a recent survey, only
55% of NNUs had a written policy for management of
NAS.33We defined NAS by a requirement for pharmacolog
ical treatment, commenced according to a reasonably strict
local policy incorporating the Lipsitz scoring system as rec
ommended by the American Academy of Pediatrics.34While
we concede that some interindividual differences exist with
regard to commencement of pharmacological treatment, we
believe that our policy minimises this. Our data agree closely
with Dashe et al.9who reported treatment rates of 44% in
a subgroup of infants born to women receiving 20 39 mg
methadone per day. Cigarette smoking may have contributed
to the development of NASin some infants, but this cannot be
quantified.35Within this cohort, maternal SSRI prescription
did not affect either the odds of developing NAS or the sever
ity of the condition as measured by duration of treatment.36
Previous studies investigating the influence of prescribed
maternal methadone dose upon the development of NAS
have yielded conflicting results.9,13–19The largest of these
studies included 100 infants.15Other studies have spanned
more than a decade and been confounded by cocaine and
heroin use.9Within our cohort of 444 infants, we observed
a strong positive association between prescribed maternal
methadone dose and the development of NAS. The trend
towards higher rates of illicit drug misuse among women
prescribed higher doses of methadone was contrary to that
observed by Berghella et al.15but consistent with the findings
of Dashe et al.9The latter study did not, however, separate the
effects of increasing methadone and supplemental heroin
upon the odds of the infant developing NAS. Within our
study cohort, polydrug misuse, although likely in women pre
scribed higher doses of methadone, was not an independent
predictor of NAS.
Two studies have reported lower rates of NAS among pre
term infants compared with term infants, postulated to be
due to developmental immaturity or reduced total drug
exposure during the intrauterine period.10,12Brown et al.11
reported greater levels of irritability in preterm infants
exposed to cocaine in utero. In our large cohort, we observed
no relationship between the gestation and the development of
Breastfeeding ‡72 hours was independently associated with
a halving of the odds of the infant receiving pharmacological
treatment for NAS. This is consistent with previous
reports,37,38but the magnitude of the effect has not previously
been quantified. The act of breastfeeding soothes agitated
infants,39and drugs taken by the mother are excreted in vary
ing amounts in breast milk, thus ameliorating the effects of
withdrawal.38,40The benefits of breast milk extend to preterm
infants unable to suckle.37Breastfeeding rates in our group
were low but must be seen against a breastfeeding rate for the
hospital as a whole of 34% by day 5. It is our impression that
the majority of our drug misusing mothers who choose not to
breastfeed do so as a result of deeply engrained social preju
dice and not because of polydrug misuse. With the exception
of the small group of women who are HIV positive, we rec
ommend that all drug misusing mothers should be encour
aged to breastfeed their infants. Rooming in helps to facilitate
We believe that a prolonged postnatal stay is important to
observe for signs of NAS and also to support breastfeeding
and provide the intense parenting support required by many
of the mothers. An extended postnatal stay also facilitates
comprehensive social work assessment prior to discharge
and organisation of support in the community when
required. It is expensive at an estimated cost of £540 per
mother/baby postnatal day42but compares favourably with
NNU (non intensive) costs of £676 per infant per day.42The
median cost of accommodating a term infant who did not
require admission to NNU was £3780, whereas for admitted
term infants, the median cost from birth to hospital discharge
was £10,812. Consistent with the increased odds of develop
ing NAS, duration of hospital stay was longer in infants born
to polydrug misusing mothers compared with those taking
only methadone.20Our cohort represented 2.9% of hospital
births but used almost one fifth of the neonatal cot days
during the period of the study.
Over half the infants given appointments for the outpatient
clinic defaulted on two or more occasions, reflective of the
complex lifestyle of many drug misusing parents. Poor atten
dance at clinics has been reported by other workers and
underpins the need for provision of appropriate support serv
ices in the community.43We have now adopted a more selec
tive follow up policy, with stringent efforts to communicate
directly with the health visitor and GP. This is facilitated by
a community liaison midwife and by copying all correspon
dence to the Social Work Department.
Development of NAS is related to prescribed maternal meth
adone dose and may be ameliorated by breastfeeding. Preg
nant drug misusing women should be maintained on the
lowest dose of methadone compatible with stability and
encouraged and supported to breastfeed their infants. Infants
bornto drug misusing women are highly vulnerable anddraw
heavily on healthcare resources.
Disclosure of interest
Contribution to authorship
C.D. collected and analysed data and completed the first draft of the
manuscript. D.Y. performed statistical analyses and commented
upon the manuscript. M.H. assisted with provision of maternal data
and reviewed the manuscript. H.M. suggested the review, collected
and analysed data and reviewed the manuscript.
Details of ethics approval
The local research ethics committee approved this anonymised ret
We would like to thank the secretarial and medical records staff at
Princess Royal Maternity for their assistance in tracking case notes,
and we acknowledge the assistance of the midwifery and clerical staff
in the Women’s Reproductive Health Service. We would also like to
thank Susan McKechnie and colleagues of NHS Greater Glasgow and
Clyde for providing costing information. j
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