prescription drug use among pregnant women in opioid maintenance treatment

Prescription drug use among pregnant women inopioid Maintenance Treatment

Ingunn Olea Lund1, Svetlana Skurtveit1,2, Anders Engeland2,3, Kari Furu2,4, Edle Ravndal1 &Marte Handal2

SERAF—Norwegian Centre for Addiction Research, University of Oslo, Oslo, Norway,1 Department of Pharmacoepidemiology, Norwegian institute of PublicHealth, Oslo, Norway,2 Department of Public Health and Primary Health Care, University of Bergen, Oslo, Norway3 and Department of Pharmacy, University ofTromsø, Tromsø, Norway4

ABSTRACT

Aims This study describes the use of prescribed drugs among women in opioid maintenance treatment (OMT)prior to, and during, pregnancy. Design This cohort study was based on data from two nationwide databases:the Medical Birth Registry of Norway and the Norwegian Prescription Database. Setting Norway, 2004–2010.Participants OMT drugs were dispensed to 138 women with 159 pregnancies. Measurements All prescriptiondrugs dispensed to women in OMT three months prior to, and during, pregnancy were studied. Amounts of benzodi-azepines, z-hypnotics and opioid analgesics dispensed during pregnancy were studied and bivariate analysis was usedto study neonatal outcomes of OMT pregnancies with and without such co-medication. Findings The prevalence ofprescription drug use by pregnant OMT women was high both during the three-month period prior to (69%), andduring (81%), pregnancy. The proportion of pregnant women that was dispensed anti-infectives (48%) and/or drugsacting on the nervous system (45%) during any time in pregnancy was especially high. In 21%, 15% and 13% of thepregnancies the women were dispensed benzodiazepine anxiolytics, opioid analgesics or benzodiazepine hypnoticsrespectively. Only 5% of the OMT women were dispensed antidepressants. Malformations were significantly morecommon among children born to mothers in OMT that received co-medication with opioids, benzodiazepines orz-hypnotics. Conclusions A higher proportion of women in opioid maintenance treatment in Norway use prescrip-tion drugs prior to, and during, pregnancy than pregnant women in the general population. Co-medication with drugswith abuse potential may increase the risk of adverse pregnancy outcomes and this need to be further addressed.

Keywords Antidepressants, benzodiazepines, co-medication, maternal outcomes, neonatal outcomes, opioids,opioid maintenance treatment, pregnancy, prescription drugs.

Correspondence to: Ingunn Olea Lund, SERAF—Norwegian Centre for Addiction Research, Postboks 1039 Blindern, 0315 Oslo, Norway.E-mail: [email protected] 25 August 2011; initial review completed 8 October 2011; final version accepted 3 August 2012

INTRODUCTION

Opioid dependence in pregnant women is a major publichealth issue associated with high costs to society and at apersonal level for women and their children [1,2]. OpioidMaintenance treatment (OMT) is considered the besttreatment option for most pregnant women with opioiddependence [3]; several studies have reported that suchtreatment improves pregnancy outcomes [4–8]. OMTduring pregnancy is not without risks, however—adversepregnancy and neonatal outcomes have been described[9–11].

With a high prevalence of psychiatric and somaticproblems [7,12,13], this patient group may be in need

of additional prescription medication. Co-occurringdisorders are common in pregnant OMT women. Theprevalence of depression is especially high—estimatedto 35–73% [7,8,14,15]. Hence, the use of prescriptiondrugs for depression and other conditions is expectedto be high. However, use of drugs during pregnancy isgenerally complicated because of the limited knowledgewith regard to beneficial and possible adverse effectsfor both the mother and the fetus. This is even morecomplicated for the vulnerable patient group thatpregnant OMT women constitute. Knowledge on poten-tial risks from co-medication with other prescriptiondrugs in pregnant OMT women is scarce and existingresearch is based on interviews and questionnaires

RESEARCH REPORT doi:10.1111/j.1360-0443.2012.04049.x

© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction Addiction

[7,13]. Such self-reported information may be incom-plete and biased.

Owing to limited knowledge about co-medication inpregnant OMT women some women may not receivethe medications they need because physicians fear thatco-medication may further increase the risk of adversepregnancy and neonatal outcomes. However, somewomen may receive co-medication that may be harmful,such as benzodiazepines, which may increase the risksof adverse neonatal outcomes [16–18]. Malformations,such as cleft lip and cleft palate, have been reported[18,19]. Z-hypnotics have similar mechanisms of actionsas benzodiazepines and limited human research has beenconducted on use during pregnancy [18]. Treatment ofpain in OMT patients is challenging because some anal-gesics, like opioids, may predispose to relapse to drug-seeking behavior and over-medication may occur [20].However, the opioid dose which is sufficient to avoid with-drawal symptoms does not contribute to pain relief andeffective pain treatment is therefore required [20]. Bothover- and under-medication endangers the treatment sta-bility and may cause a relapse to illegal substance use.The risk of drug-seeking behavior may increase if womenare prescribed additional medicines with abuse potentialfrom others than the medical doctor prescribing OMT.Additional opioids may also increase the risk of negativeneonatal outcomes [18].

There is a need for a methodological approach thatwill offer detailed information on co-medication amongstpregnant OMT women during pregnancy. Population-based registries of births and dispensed prescribed drugsin Norway offer a unique opportunity to perform prospec-tive studies on prescription drug use in a nationwidecohort of pregnant OMT women.

The main aims of the present study were to describeprescription drug use among women in OMT prior topregnancy and during the first, second and third trim-ester of pregnancy, and to describe in more detail the useof prescribed opioids analgesics, benzodiazepines andz-hypnotics among OMT women. In addition, we wantedto describe maternal and neonatal outcomes followingOMT with and without co-medication with these drugsduring pregnancy.

METHOD

Data sources

The Medical Birth Registry of Norway

The Medical Birth Registry of Norway contains informa-tion on all births in Norway [21]. The registry is based oncompulsory notification on every birth or late abortionfrom 12 weeks of gestation. The medical birth registrycontains information on complications during preg-

nancy and delivery, and length of pregnancy, as well asinformation on the infant, including birth defects andother perinatal problems [21]. A standard antenatal formis completed during prenatal care and the midwife entersadditional data recorded at the time of birth. Follow-updata are added until discharge of hospital births. Latespontaneous abortion was defined as termination ofpregnancy after 12 weeks, but before 22 completed weeksof gestation; stillbirth as birth of a dead fetus after 22completed weeks of gestation; and preterm birth as livebirth after at least 22, but before 37 completed weeks ofgestation. Major malformations were recorded accordingto European Registration of Congenital Anomalies andTwins (EUROCAT) [22]. Neonatal abstinence is describedin the Norwegian Medical Birth Registry as irritabilityand neurological symptoms in neonates born to womenknown to abuse narcotics, alcohol or prescription drugs.Hence, symptoms, not treatment, are registered. Thelength of pregnancy was determined by ultrasound [23]for most cases (97%) and a pregnancy start date wasestimated. Each pregnancy was divided into trimesters;weeks 1–12, weeks 13–26, week 27–birth.

The Norwegian Prescription Database

The Norwegian Prescription Database includes all pre-scribed drugs dispensed in Norway since 1 January 2004.It covers the entire Norwegian population of 4.9 million[21]. The prescription database contains information onall prescribed drugs in Norway dispensed at pharmaciesto individual patients outside hospitals and in-patienttreatment facilities. Data on use among institutionalizedpatients in hospitals and other institutions are also col-lected, though as the data is aggregated at institutionallevel, it is not included in our study. For each prescription,dispensing date and detailed information on the drug isregistered. The indication for prescribing is not registered,but, when present, the code of reimbursement isrecorded, which may function as a proxy of diagnosis.

Linkage of registry data

Data in the Medical Birth Registry of Norway was linkedto the Norwegian Prescription Database based on the per-sonal identity number that is assigned to each person inNorway at birth or immigration.

Setting

The national OMT program in Norway is operatedthrough regional centers that coordinates all OMT admis-sions. The program is a high threshold one with strictadmission criteria and high social control [24]. Prescrip-tion of methadone and buprenorphine in Norway may beprescribed by a medical doctor in specialist health-care

2 Ingunn Olea Lund et al.


services or by a general practitioner. If prescribed by ageneral practitioner, he or she should collaborate closelywith the specialist health-care services to make sure thatthe patient receives the care they need for optimal physi-cal, psychological, social and occupational functioning[25].

There is, in principle, zero tolerance to the use ofillegal drugs and alcohol during pregnancy in OMTwomen. If voluntary measures to help pregnant OMTwomen to stop using illegal drugs during pregnancydo not help, treatment providers are obliged by law totake action and women may be detained in in-patienttreatment during the entire, or parts of, the pregnancy[26].

Study population

Pregnancies

All singleton pregnancies registered in the Medical BirthRegistry beginning from 30 March 2004 and ending nolater than 31 December 2010 (349 020 pregnancies)were included. There may be more pregnancy and neo-natal complications in twin pregnancies so they were,therefore, excluded. Pregnancies where the mother’sidentity was unknown or she was living outside ofNorway at the time of birth were excluded. After allexclusions the number of pregnancies was 345 703.

To be defined as an OMT patient the pregnant womanhad to be dispensed methadone mixture [AnatomicalTherapeutic Chemical (ATC) classification system codeN07BC02], buprenorphine sublingual tablets (Subutex®/ATC code N07BC01) or buprenorphine–naloxone com-bined sublingual tablets (Subuxone®/N07BC51) from apharmacy at least once during pregnancy. Women thatreceived methadone drugs with the reimbursement codefor palliative treatment of malignant disease wereexcluded from the study. Methadone tablets or capsulescan be used in Norway in pain therapy, but this did notapply for any of the women in our study [27]. With theserequirements, our study consisted of 159 pregnancies in138 women in OMT treatment. According to numbersreported to the Norwegian Directorate of Health ofwomen in OMT giving birth during the study period, thestudy covers three quarters of all births from women inOMT in Norway.

Drugs

All drugs in Norway are classified according to the ATCclassification system [28]. The amount of drug dispensedis measured as defined daily doses (DDDs), a quantitybased on the assigned average dose per day on the medi-cations main indication for adults [28]. All ATC groupswere studied as an expression of comorbidity. In addi-

tion, some drugs acting on the nervous system (ATCgroup N) were studied more closely than other druggroups. Table 1 shows the DDDs for the different genericsubstances classified as benzodiazepine anti-epileptics,benzodiazepine anxiolytics, benzodiazepine hypnotics,z-hypnotics, and weak and strong opioids that werestudied in more detail. Drugs for opioid maintenancetreatment (methadone, buprenorphine and buprenor-phine combination) are excluded, both when describinguse of prescription drugs in general and when describingdrugs acting on the nervous system in more detail. Useof benzodiazepines refers to at least one prescription ofbenzodiazepine: anxiolytics, hypnotics or anti-epileptics(Table 1). Opioid analgesics were identified by the ATCcode N02A [28]. Opioid analgesics are usually catego-rized into two groups: week or strong opioids. Codeine,tramadol and dextropropoxyphene combinations arecategorized as weak opioid analgesics, whereas theremainider (ketobemidone, morphine, fentanyl,buprenorphine, hydromorhone, oxycodone, pethidine,dihydrocodeine, pentazocine) are classified as strongopioid analgesics.

Dispensing periods

Data on dispensed drugs from January 2004 to the end ofDecember 2010 were used to ensure the inclusion of alldrugs dispensed up to three months before pregnancy forall women in our sample whose pregnancies started from30 March 2004. The three months prior to pregnancywere included to enable us to evaluate a change in drugsdispensed as a result of pregnancy. Drugs dispensedduring this period may have been used by the women inthe early stages of pregnancy. The three-month time-frame was chosen to correspond to the duration of thethree trimesters of pregnancy.

Statistics

Period prevalence, means, medians, interquartile range(IQR) and confidence intervals (CI) are presented whereappropriate. CIs for proportions were calculated usingthe corrected version of the score [29]. The effect ofco-medication on pregnant OMT women on adverse preg-nancy and neonatal outcomes was studied by bivariateanalysis: t test and c2 test as appropriate. A cohort of159 pregnancies where approximately one third of thewomen received co-medication have low power to studythe effects of such medication in pregnant OMT women.As an example, an increase in the proportion of new-borns with abstinence from 50% to 61%, as observed inthis sample, has a power of 26% to be significant at analpha level of 0.05. Statistical analyses were conductedusing SPSS for Windows, version 18.0.

Pregnant women in OMT: prescription drug use 3


Ethics

The Norwegian Data Inspectorate was notified before theMedical Birth Registry and the Norwegian PrescriptionDatabase were linked, as required by the Norwegian lawfor national health registries. The linkage generatedanonymous files for research purposes.

RESULTS

Background characteristics of the OMT women

The mean age of the pregnant OMT women was 32 yearsand 64% had one or more children prior to the studyperiod. In total, 51% of the women were dispensed metha-done, 49% buprenorphine and 10% buprenorphine–naloxone combinations during pregnancy. All thewomen that used buprenorphine–naloxone combinationsswitched to buprenorphine.

Prescription drugs dispensed to pregnant OMT women

Apart from OMT drugs, 69% of the women were dispensedother drugs in the 3 months prior to, and 81% were dis-pensed prescription drugs during, pregnancy (Table 2).Use of anti-infectives for systemic use (48%) and prescrip-tion drugs acting on the nervous system (45%) were themost frequently used drugs during pregnancy.

Prescriptions of drugs acting on the nervous system

In total, 42 pregnant women [26.4% (95% CI 20–34)]used benzodiazepines (anti-epileptics, anxiolytics orhypnotics) during the entire pregnancy and 6 [4%,(2–8)] during the last trimester. In 21% and 13% of thepregnancies the women were dispensed benzodiazepineanxiolytics and benzodiazepine hypnotics respectively.All groups of benzodiazepines and z-hypnotics werereduced from the period prior to pregnancy to the thirdtrimester of pregnancy; benzodiazepine anti-epilepticsfrom 4% to 0%, benzodiazepine anxiolytics from 16%to 3%, benzodiazepine hypnotics from 2% to 1% andz-hypnotics from 9% to 3% (Table 3). Opioid analgesicswere used by 15% of the women during pregnancy(Table 3). Use was reduced from 11% in last 3 monthsprior to pregnancy to 3% during the last trimester. Anti-depressants were used by 5% of pregnant women duringpregnancy.

Benzodiazepines, z-hypnotics and opioids were notalways prescribed by the same physician that prescribedOMT during pregnancy; 17 of 30 women were pre-scribed opioid analgesics (N02A) from another physi-cian, 6 of 8 benzodiazepine anti-epileptics (N03AE01),20 of 42 benzodiazepine anxiolytics (N05B), 7 of 8benzodiazepine hypnotics (N05CD) and 11 of 16z-hypnotics (N05CF).

Table 1 Defined daily dose (DDD) of benzodiazepines, z-hypnotics and opioid analgesics used by pregnant women in opioid mainte-nance treatment in Norway (2004–2010).

ATC code DDD (oral administration)

BenzodiazepinesAnti-epileptics

Clonazepam N03AE01 8 mgAnxiolytics

Diazepam N05BA01 10 mgOxazepam N05BA04 50 mgAlprazolam N05BA12 1 mg

HypnoticsNitrazepam N05CD02 5 mgFlunitrazepam N05CD03 1 mg

Z-hypnoticsZopiclone N05CF01 7.5 mgZolpidem N05CF02 10 mgOpioid analgesicsOpioid analgesics (strong)

Morphine N02AA01 100 mgOxycodone N02AA05 30 mgBuprenorphine N02AE01 1.2 mga

Opioid analgesics (weak)Codeine N02AA59 b

ATC = Anatomical Therapeutic Chemical. aParenteral, sublingual and transdermal administration only. bAll codeine products are fixed combinationswith acetaminophen. For the product containing 400 mg paracetamol, one DDD will represent 120 mg codeine and 1600 mg paracetamol. For productscontaining 500 mg paracetamol, one DDD will represent 90 mg codeine and 1500 mg paracetamol.



Tabl

e2

Nu

mbe

r,pr

eval

ence

(%)a

nd

95

%co

nfid

ence

inte

rval

(CI)

ofpr

egn

anci

esin

opio

idm

ain

ten

ance

trea

tmen

tin

Nor

way

(20

04

–20

10

)wh

ere

the

wom

enw

ere

disp

ense

dpr

escr

ipti

ondr

ugs

thre

em

onth

spr

ior

to,a

nd

duri

ng,

preg

nan

cy(n

=1

59

).

Dru

ggr

oups

(ATC

grou

p)

Thre

em

onth

sbe

fore

topr

egna

ncy

Firs

ttr

imes

ter

Seco

ndtr

imes

ter

Thir

dtr

imes

ter

Ent

ire

preg

nanc

y(4

0w

eeks

)

n%

CI

[95

]n

%C

I[9

5]

n%

CI

[95

]n

%C

I[9

5]

n%

CI

[95

]

Alim

enta

rytr

act

and

met

abol

ism

(A)

64

[2–8

]2

11

3[9

–20

]1

28

[4–1

3]

74

[2–9

]3

01

9[1

3–2

6]

Blo

odan

dbl

ood

form

ing

orga

ns

(B)

74

[2–9

]1

06

[3–1

2]

13

8[5

–14

]9

6[3

–11

]2

11

3[9

–20

]C

ardi

ovas

cula

rsy

stem

(C)

74

[2–9

]7

4[2

–9]

21

[0–5

]6

4[2

–8]

13

8[5

–14

]D

erm

atol

ogic

als

(D)

12

8[4

–13

]9

6[3

–11

]8

5[2

–10

]7

4[2

–9]

18

11

[7–1

8]

Gen

itou

rin

ary

syst

eman

dse

xh

orm

ones

(G)

15

9[6

–15

]6

4[2

–8]

64

[2–8

]0

0[0

]1

28

[4–1

3]

Syst

emic

hor

mon

alpr

epar

atio

ns

excl

.sex

hor

mon

esan

din

sulin

’s(H

)1

06

[3–1

2]

43

[1–7

]9

6[3

–11

]7

4[2

–9]

11

7[4

–12

]A

nti

-in

fect

ives

for

syst

emic

use

(J)

36

23

[17

–30

]3

01

9[1

3–2

6]

40

25

[19

–33

]3

11

9[1

4–2

7]

77

48

[40

–56

]A

nti

neo

plas

tic

and

imm

un

omod

ula

tin

gag

ents

(L)

21

[0–5

]1

0[0

–4]

00

[0]

00

[0]

10

[0–4

]M

usc

oske

leta

lsys

tem

(M)

18

11

[7–1

8]

96

[3–1

1]

32

[0–6

]0

0[0

]1

28

[4–1

3]

Ner

vou

ssy

stem

(N)

excl

.dru

gsu

sed

inop

ioid

depe

nde

nce

71

45

[37

–53

]5

93

7[3

0–4

5]

41

26

[19

–33

]2

11

3[9

–20

]7

14

5[3

7–5

3]

An

tipa

rasi

tic

prod

uct

s,in

sect

icid

esan

dre

pelle

nts

(P)

43

[1–7

]2

1[0

–5]

00

[0]

00

[0]

21

[0–5

]R

espi

rato

rysy

stem

(R)

29

18

[13

–25

]2

11

3[9

–20

]2

01

3[8

–19

]1

96

[3–1

1]

40

25

[19

–33

]Se

nso

ryor

gan

san

dva

riou

s(S

+V

)7

4[2

–9]

43

[1–7

]2

1[0

–5]

64

[2–8

]1

17

[4–1

2]

Tota

l1

10

69

[61

–76

]9

66

0[5

2–6

8]

10

06

3[5

5–7

0]

74

47

[39

–55

]1

29

81

[74

–87

]

ATC

=A

nat

omic

alT

her

apeu

tic

Ch

emic

al.



Tabl

e3

Nu

mbe

r,pr

eval

ence

(%)

and

95

%co

nfid

ence

inte

rval

(CI)

ofpr

egn

anci

esin

Opi

oid

Mai

nte

nan

ceT

reat

men

tin

Nor

way

(20

04

–20

10

)w

her

eth

ew

omen

wer

edi

spen

sed

ase

lect

edgr

oup

ofpr

escr

ipti

ondr

ugs

acti

ng

onth

en

ervo

us

syst

emth

ree

mon

ths

prio

rto

,an

ddu

rin

g,pr

egn

ancy

(n=

15

9).

Dru

gsac

ting

onth

ene

rvou

ssy

stem

(ATC

-gro

upN

)

Thre

em

onth

spr

ior

topr

egna

ncy

Firs

ttr

imes

ter

Seco

ndtr

imes

ter

Thir

dtr

imes

ter

Ent

ire

preg

nanc

y(4

0w

eeks

)

n%

CI

[95

]n

%C

I[9

5]

n%

CI

[95

]n

%C

I[9

5]

n%

CI

[95

]

An

ti-e

pile

ptic

s(N

03

)1

59

[6–1

5]

13

8[5

–14

]9

6[3

–11

]3

2[0

–6]

17

11

[6–1

7]

Ben

zodi

azep

ine

deri

vativ

es(N

03

AE)

64

[2–8

]6

4[2

–8]

43

[1–7

]1

0[0

–4]

74

[2–9

]O

ther

s9

6[3

–11

]9

6[3

–11

]5

3[1

–8]

21

[0–5

]1

28

[4–1

3]

An

xiol

ytic

s(N

05

B)

26

16

[11

–23

]3

11

9[1

4–2

7]

16

10

[6–1

6]

43

[1–7

]3

42

1[1

5–2

9]

Hyp

not

ics

(N0

5C

)1

81

1[7

–18

]1

71

1[6

–17

]8

5[2

–10

]6

4[2

–8]

21

13

[9–2

0]

Ben

zodi

azep

ines

(N0

5C

D)

32

[0–6

]5

3[1

–8]

53

[1–8

]2

1[0

–5]

85

[2–1

0]

Z-hy

pnot

ics

(N0

5C

F)1

49

[5–1

5]

11

7[4

–12

]3

2[0

–6]

43

[1–7

]1

28

[4–1

3]

Mel

aton

in(N

05

CH

01

)1

1[0

–4]

10

[0–4

]0

0[0

]0

0[0

]1

0[0

–4]

Opi

oid

anal

gesi

cs(N

02

A)a

17

11

[6–1

7]

96

[3–1

1]

12

8[4

–13

]5

3[1

–8]

19

15

[8–1

8]

Stro

ng

opio

idan

alge

sics

10

6[3

–12

]5

3[1

–8]

64

[2–8

]3

2[0

–6]

10

6[3

–12

]W

eak

opio

idan

alge

sics

74

[2–9

]4

3[1

–7]

53

[1–8

]1

0[0

–4]

96

[3–1

1]

An

tide

pres

san

ts(N

06

A)

12

8[4

–13

]7

4[2

–9]

32

[0–6

]1

0[0

–4]

85

[2–1

0]

Non

-sel

ectiv

em

onoa

min

ere

-upt

ake

inh

ibit

ors

(N0

6A

A)

43

[1–7

]3

2[0

–6]

21

[0–5

]1

0[0

–4]

32

[0–6

]Se

lect

ive

sero

ton

inre

-upt

ake

inh

ibit

ors

(N0

6A

B)

64

[2–8

]2

1[0

–5]

10

[0–4

]0

0[0

]3

2[0

–6]

Oth

eran

tide

pres

san

ts2

1[0

–5]

21

[0–5

]0

0[0

]0

0[0

]2

1[0

–5]

ATC

=A

nat

omic

alT

her

apeu

tic

Ch

emic

al.

a Wh

enco

ndu

ctin

gth

ean

alys

isof

use

ofst

ron

gan

dw

eak

opio

idan

alge

sics

,on

epe

rson

was

excl

ude

dbe

cau

seth

eam

oun

tof

the

stro

ng

opio

idbu

pren

orph

ine

(ATC

code

N0

2A

E01

;in

dica

tion

:pa

in)

was

soh

igh

that

itw

asex

pect

edth

atth

ean

alge

sic

dru

gw

asu

sed

assu

bsti

tuti

ontr

eatm

ent

befo

reth

epa

tien

tst

arte

du

sin

gbu

pren

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Amount of benzodiazepines, opioid analgesicsand z-hypnotics

A median amount of 40 DDD may correspond to use of50 mg of oxazepam (1 DDD) as oral treatment for 40 days(Table 4). The observed median amount of benzodi-azepine hypnotics (145 DDD) and z-hypnotics (80 DDD)was higher. The median amount of strong opioid analge-sics was 85 DDDs. This may, for example, correspond to100 mg of morphine (1 DDD) as oral treatment for 85days.

Neonatal and maternal outcomes

Major malformations were significantly more commonamong children born to women in OMT that receivedco-medication with opioids, benzodiazepines or z-hypnotics (Table 5).

DISCUSSION

The proportion of women in OMT in Norway thatwere dispensed prescription drugs was higher, bothprior to (69% versus 39%), and during, all trimesters ofpregnancy (47–63% versus 29–39%) compared withpregnant women in the general population [30]. Anti-infectives and drugs acting on the nervous system werethe most frequently used drugs by women in OMT.

Benzodiazepines (anti-epileptics, anxiolytics or hyp-notics) were the most commonly used prescriptiondrugs acting on the nervous system in pregnant OMTwomen. Benzodiazepines may contribute to longer with-drawal treatment in neonates with abstinence symptoms[16,31]. Some [18], but not all [32], studies suggest thatthe use of benzodiazepines during pregnancy mayincrease the risk of major malformations. It is an issueof concern that one quarter were dispensed benzodi-

azepines at some point during pregnancy. However, it is apositive trend that use of all groups of benzodiazepineswas reduced from prior to pregnancy to the last trimesterof pregnancy. The amount of benzodiazepine anxiolyticsused by the OMT women suggested short-term treatment,whereas the amount of benzodiazepine hypnotics andz-hypnotics indicated longer duration of treatment.Use of benzodiazepines during pregnancy was slightlyhigher in the present study than self-reported use (18%)in a Norwegian cohort of pregnant OMT women [33],whereas international studies report higher (29–56%)prevalence [34,35]. Among the general population ofpregnant women in Norway, only 1% or less used anykind of anxiolytics or hypnotics in any trimester [30].Any benzodiazepines obtained from an illegal market arenot captured. However, recent research suggest that useof illegally-obtained prescription drugs during pregnancyamong women in OMT in Norway is low [13,33].

Compared with pregnant women in the general popu-lation, a markedly higher proportion of pregnant OMTwomen received opioid analgesics [30]. Strong opioidanalgesics were as commonly dispensed as weak opioidanalgesics. Almost all pregnant women in the generalpopulation that were dispensed opioid analgesics receivedweak opioid analgesics [23]. OMT patients require higherdoses of opioid analgesics for pain, owing to higher toler-ance, compared with the normal population [36]. A highprevalence of psychiatric problems may also contributeto a reduction of the pain threshold [7,37].

A large proportion of women in OMT were prescribedbenzodiazepines/z-hypnotics and opioid analgesics fromother physician/s than the one prescribing their OMTmedication during the 12-month period of the study.If the OMT prescribing physician is not the onlyprescriber there may be less control over which prescrip-tion drugs and doses a woman receives. High doses of

Table 4 Amount in defined daily doses (DDD) of benzodiazepines, z-hypnotics and opioid analgesics dispensed during the entirepregnancy to pregnant women in opioid maintenance treatment in Norway (2004–2010).

n

DDDd

Median MeanInterquartilerange (IQR)

BenzodiazepinesAnti-epileptic benzodiazepine derivatives (N03AE) 7 20 52 10–100Anxiolytics (N05B) 34 40 105 10–139Hypnotics (N05CD) 8 145 189 49–303Z-hypnotics (N05CF) 12 80 191 38–265Opioid analgesicsa

Strongb 10 85 107 27–197Weakc 9 7 12 5–16

aSee comment ‘b’ under Table 3. bBuprenorphine used for treatment of pain; morphine and oxycodone were the strong opioids dispensed. cCodeine wasthe only weak opioid dispensed. dThe DDDs for the different drugs are shown in Table 1.



benzodiazepines is a widespread problem among OMTpatients and the levels some of the women in the presentstudy received may suggest abuse and dependence [38].It is preferable that only one physician prescribes allthe prescription drugs a woman receives. However, itis a cause for concern that some physicians who shouldbe aware of the increased risk of negative outcomes,prescribe both OMT and benzodiazepines [25].

A significant increase in prevalence in major malfor-mation was detected in the co-medicated women. Thismay suggest that co-medication with opioids, benzodi-azepines or z-hypnotics contributes directly to increasedrisk of major malformations [18]. Alternatively, womenwho receive such co-medication are sicker and otherfactors than co-medication alone contribute.

Use of antidepressants was low throughout preg-nancy compared with OMT patients in general inNorway, where one in five receive antidepressant drugsduring a year [39]. One quarter of opioid-dependentwomen in a multinational study received antidepres-sants during pregnancy [40]. More than one third ofpregnant women in a Norwegian cohort of pregnantwomen in OMT reported depressive symptoms duringthe last month of pregnancy [8]. The small proportionof antidepressants prescribed may be due to increasedawareness among physicians of the potential dangers to

the fetus [41]. It may also indicate that pregnant OMTwomen are undertreated for depression. Use was aboutthe same as among pregnant women in the generalpopulation [30].

Considering the high comorbidity among pregnantopioid-dependent women, especially anxiety and depres-sion [8], it is noteworthy that a high number of women inthis cohort received benzodiazepines during pregnancy,whereas few received antidepressants. One explanationmay be that women, to a lesser extent, ask for antidepres-sants because antidepressants do not offer the same drugfeeling as benzodiazepines. Physicians treating pregnantOMT women should keep this in mind when they assessaffective disorders to make sure the women receive theproper diagnosis. For women that already receive benzo-diazepines it is recommended that the doses are graduallyreduced until abstinence is achieved [25,42]. Non-pharmacological treatment should be offered both duringand after this process [25]. The potential dangers of nottreating depression in pregnant OMT women can be fataland should be considered against the potential risks ofpharmacological treatment [43,44].

When comparing the results from our study withuse of prescription drugs among pregnant women inthe general population, it is important to rememberthat these groups differ on a range of characteristic

Table 5 Neonatal and maternal perinatal outcomes in pregnant women in Opioid Maintenance Treatment (OMT) in Norway (2004–2010) and their neonates.

All pregnant OMT women

Women without opioid,benzodiazepine orz-hypnotic co-medication

Women with opioid,benzodiazepine orz-hypnotic co-medication

Neonatal outcomesMeasures of fetal growth Number of

birthsMean (SD) Number of

birthsMean (SD) Number of

birthsMean (SD)

Gestational age, days 159 271 (31) 106 272 (31) 53 270 (31)Birth weight, g 156 3153 (666) 104 3210 (629) 52 3041 (727)Birth length, cm 144 48 (3.9) 98 49 (3.9) 46 48 (3.9)Head circumference, cm 150 34 (1.6) 101 34 (1.5) 49 34 (1.6)

Fetal survival and related measures % % %Stillbirtha 155 1.3 103 1.9 52 0.0Preterm birthb 155 7.7 103 5.8 52 12Apgar score < 8 after 1 minute 154 12 103 11 51 14Apgar score < 9 after 5 minutes 155 14 103 15 52 14Abstinence 128 54 82 50 46 61Major malformationsc,d,e 128 7.8 82 3.7 46 15*

Maternal outcomesSpontaneous abortionsf 159 0.6 106 0.9 53 0.0Cesarean sectionc 126 18 81 15 45 18

aStillbirths—delivery of a dead fetus after 22 completed weeks of gestation. bPreterm birth—delivery of a live newborn after 22 but before 37 completedweeks of gestation. cMajor malformations and cesarean sections only reported until 2009. dEUROCAT definitions of major malformations [22]. eMajormalformations registered among neonates in the present study were hydrocephalus, ventricular septal defect, club foot, hypospadias torticollis, musclemacrocephaly, gastroschisis, trisomy 21, pulmonary infundibular stenosis. fSpontaneous abortions—termination of pregnancy after 12 but before 22completed weeks of gestation. *Significantly (P > 0.05) higher prevalence of major malformations in children whose mothers were co-medicated withopioids, benzodiazepines or z-hypnotics.



besides OMT that might have affected medication use—socioeconomic status, smoking and comorbidity.

Limitations

Drugs dispensed at hospitals and other institutions arenot registered at an individual level. Patients who aredispensed drugs at pharmacies may be more stable andless prone to use drugs with abuse potential than patientsthat are dispensed OMT drugs at OMT centers. Hence, itmay be that our study underestimates the prevalence ofprescription drug use. Data on indication is not registeredin studies based on prescription databases and the dis-pensed drugs are not necessarily consumed by the recipi-ents. Some drugs may be taken sporadically upon theappearance of symptoms which could re-occur long afterthe dispensing date. The medication may be re-sold onthe illegal market and some women may have boughtprescriptions drugs from the illegal market [45].

To compare the effects of co-medication on adversepregnancy and neonatal outcomes we used bivariateanalysis, which means that we did not adjust for potentialconfounders.

Strengths

The study covers a national cohort of outpatient preg-nant OMT women in Norway. The data is not based onself-reports or interviews, hence recall biases are elimi-nated. The unique personal identity number andpopulation-based registries on birth, deaths, emigrationsand prescriptions provide high quality linkages betweenthe high quality registries in Norway.

CONCLUSION

Pregnant OMT women use more prescription drugs thanpregnant women in the general population [30]. Anti-infectives and drugs acting on the nervous system werethe most commonly used prescription drugs among preg-nant OMT women. The use of prescription drugs withabuse potential were reduced as pregnancy proceeded.The low use of antidepressants may indicate that womenin OMT in Norway are undertreated for depression.Co-medication may increase the risk of adverse preg-nancy outcomes and this needs to be further addressed.The findings provide invaluable knowledge for physiciansworking with this patient group and may form the basisfor developing clinical guidelines for co-medication inpregnant OMT women.

Declarations of interest

None.

Acknowledgements

Thanks to Gabrielle Welle-Strand, Norwegian Centrefor Addiction Research and Norwegian Directorate ofHealth, and Hendree Jones, RTI International and JohnsHopkins Medicine for invaluable help in reading andcommenting on the manuscript.

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