PHARMACOEPIDEMIOLOGYAND PRESCRIPTION

Dispensing of benzodiazepines and benzodiazepine-related drugsto pregnant women: a population-based cohort study

Brit Solvor Riska & Svetlana Skurtveit & Kari Furu &

Anders Engeland & Marte Handal

Received: 26 May 2014 /Accepted: 20 August 2014 /Published online: 11 September 2014# Springer-Verlag Berlin Heidelberg 2014

AbstractPurpose The study aimed to describe the dispensing of ben-zodiazepines and benzodiazepine-related drugs (z-hypnotics)to pregnant women and to study the characteristics of thesewomen and the extent of co-medication.Methods A population-based cohort study was conductedbased on the linkage of nationwide registries: the MedicalBirth Registry of Norway and the Norwegian PrescriptionDatabase. The data covers dispensed drugs to women3 months prior to, during and after pregnancy. The studypopulation consisted of 345,703 singleton pregnancies duringa period starting 1 April 2004 or later and ending before 1January 2011.Results In 5,135 (1.5 %) of the pregnancies, the womenwere dispensed a benzodiazepine or z-hypnotic at leastonce. Of these, 68.5 % filled just one prescription forthe duration of the pregnancy. Prevalence was lower inpregnancy than before and after pregnancy. The mediantotal amount of benzodiazepines and/or z-hypnotics

dispensed during pregnancy was 15 defined daily doses(DDDs), while the 25 % receiving the largest amountsgot 40 DDDs or more. Five hundred eleven women, the10 % that were prescribed the largest amounts duringpregnancy, received a median amount of 220 DDDs.Women receiving these drugs were older, more oftensmokers, without a partner and suffering from chronicdisease. Of the medicated pregnant women, 19.6 % and19.3 % were also prescribed an opioid and antidepres-sant, respectively.Conclusions The use of benzodiazepines and z-hypnoticdrugs during pregnancy was not very prevalent inNorway. However, our findings imply that there is asubstantial number of pregnancies where these drugs aredispensed often and/or in large quantities and where co-medication occurred.

Keywords Pharmacoepidemiology . Benzodiazepine .

Benzodiazepine-related drugs . Z-hypnotic . Pregnancy .

Co-medication

Introduction

Pregnant women frequently report both anxiety anddifferent kinds of sleep disorders during pregnancy [1,2]. Prescribing physicians must balance maternal needfor treatment with potential foetal risk of medication.Physicians are advised to make a careful considerationof the drug’s necessity unless prescribing drugs wherelarge data have indicated no malformative norfeto/neonatal toxicity [3]. Knowledge about the risk ofuse of benzodiazepines and benzodiazepine-related drugs(z-hypnotics) during pregnancy and breastfeeding isscarce. Use of benzodiazepines and z-hypnotics in highdoses, or taken for extended periods, has resulted in

Electronic supplementary material The online version of this article(doi:10.1007/s00228-014-1744-4) contains supplementary material,which is available to authorized users.

B. S. Riska (*)Faculty of Medicine, University of Oslo, P.O. 1078, Blindern,0316 Oslo, Norwaye-mail: b.s.riska@studmed.uio.no

S. Skurtveit :K. Furu :A. Engeland :M. HandalDepartment of Pharmacoepidemiology, Norwegian Institute ofPublic Health, P.O. Box 4404, Nydalen, 0403 Oslo, Norway

S. SkurtveitNorwegian Centre for Addiction Research, University of Oslo, Oslo,Norway

A. EngelandDepartment of Global Public Health and Primary Care, University ofBergen, Bergen, Norway

Eur J Clin Pharmacol (2014) 70:1367–1374DOI 10.1007/s00228-014-1744-4

adverse outcomes in neonates and in breastfed babies [4, 5].Lethargy and loss of weight has been reported, and the use ofthese drugs in breastfeeding women is not recommended [6].Alternative treatment for anxiety and sleep disorders existsand is recommended [7]. However, when needed, benzodiaz-epines are the drug of choice. They should be given at thelowest effective dose and for a minimum amount of time [8].

In a study by Engeland et al. [9], of all prescribed drugs topregnant women in Norway during 2004–2006, the preva-lence of anxiolytics and hypnotics during pregnancy (includ-ing a 3-month period before and after pregnancy) was inves-tigated as a group and 3.3 % of the women were dispensedthese drugs. In a study of 10,174 pregnant women in a Frenchregion, 3 % were prescribed a benzodiazepine during preg-nancy and 1 %, another hypnotic or anxiolytic [10]. This wasregistry data from the health insurance service database.Andrade et al. [11] also reported from registry data including129,616 women giving birth in US hospitals, where 3,137pregnant women (2.4%) had used a sedative hypnotic, musclerelaxant or antiepileptic drug during pregnancy. According toDaw et al. [12], reporting data from population-based admin-istrative databases in Canada, benzodiazepines were pre-scribed in 3.2 % of the pregnancies. In a recent study byLupatelli et al. [13] using web-based questionnaires, with9,459 responding pregnant women from Europe, theAmericas and Australia, 2.2 % reported to have used apsycholeptic sometime during pregnancy.

There has been a changing prescription pattern of benzo-diazepines and z-hypnotics in the general population duringthe past 10-year period that might have influenced the pre-scribing to pregnant women [14]. There is lack of knowledgeon type and amount of drug used and on changes in use duringthe time around the pregnancy. Co-medication with differentpsycholeptic drugs during pregnancy, as has been shown tooccur in several different study populations [15–18], has onlyto a limited extent been investigated in pregnant women.

We hypothesised that the women filling prescriptions ofbenzodiazepines and z-hypnotics were on average older andmore burdened with disease than the pregnant women whodid not. Further, we hypothesised that most women only filledone prescription and that the amounts prescribed were small.We assumed that some of the pregnant women filled prescrip-tions for far larger amounts and/or dispensed the drugs morefrequently and that women who were co-medicated also usedlarger doses of benzodiazepines and z-hypnotics.

The aim of this study was to study the characteristics of thepregnant women in Norway receiving benzodiazepines and z-hypnotics and to describe in detail the prescription patterns ofthese drugs in the 3-month period before pregnancy, duringpregnancy and the 3 months following pregnancy. Further, wewanted to explore the extent of co-medication with the othertypes of psycholeptic drugs most frequently used during preg-nancy, opioids and antidepressants.

Materials and methods

Data sources

The Norwegian Prescription Database (NorPD) is a da-tabase that captures information on all dispensed drugsin Norway since 1 January 2004, covering the wholepopulation [19]. It contains information on all pre-scribed drugs dispensed to individuals in ambulatorycare. Drugs dispensed at hospitals and other institutionsare also registered in the database but at an institutionallevel; these are therefore not included in this study.Drugs are classified as in the Anatomical TherapeuticChemical (ATC) classification system [20]. For eachprescription to a pregnant woman, we have includedher age, dispensing date and drug information, includingATC classification and amount dispensed in units ofdefined daily doses (DDDs).

The Medical Birth Registry of Norway (MBRN) is apopulation-based registry containing information on allbirths and late abortions, from 12 weeks of gestationonward, in Norway since 1967 [21]. Report of a birthor miscarriage beyond week 12 is mandatory. MBRNincludes identification of the mother in terms of herpersonal identity number, demographic information, themother's health before and during pregnancy and thelength of the pregnancy. A standard antenatal form iscompleted at visits to a general practitioner or a mid-wife during pregnancy and is brought by the mother tothe place of birth. The midwife uses the antenatal formand additional data recorded at the time of birth whenreporting to the MBRN [22].

For this study, the two databases were linked by using thepersonal identity number assigned to all Norwegians at birthor immigration to give information on use of prescribed drugsamong pregnant women.

Study population, pregnancies

All singleton pregnancies registered in the MBRN be-ginning 1 April 2004 or later and ending before 1January 2011 were included (n=346,342). Only preg-nancies where the mother had a valid personal identitynumber, and where her place of residency was Norwayat the time of delivery, were included (excluding n=323). Some pregnancies where birth weight was veryunlikely in light of pregnancy duration were excluded(n=316). The duration of pregnancy was mainly esti-mated by ultrasound examination (97 %). Otherwise, thestart of pregnancy was set to the first day of the lastmenstruation period. If the woman had several pregnan-cies during the period, every pregnancy was included.This gave us a study population of 345,703 pregnancies

1368 Eur J Clin Pharmacol (2014) 70:1367–1374

in 265,203 mothers. Since the MBRN only registerspregnancies from 12 weeks of gestation, all pregnanciesin our study population reached the second trimester,but 2,927 pregnancies did not last until the third trimes-ter; these were not included in the prevalence calcula-tions for that trimester.

Drugs

The benzodiazepines we have studied are antiepileptics(ATC-group N03AE), anxiolytics (N05BA) and hyp-n o t i c s a n d s e d a t i v e s (N05CD ) ( eTa b l e 1 ) .Benzodiazepine-related drugs (z-hypnotics) in ATC-group N05CF were also included. For simplicity andclarity, we have chosen to use the term z-hypnoticsinstead of ‘benzodiazepine-related drugs’ throughoutthe rest of the text. In addition, we have studied co-medication with prescribed drugs shown in earlier drugutilization studies to be frequently used together withthe study drugs; opioids (N02A) and antidepressants(N06A) [23]. For simplicity, we have, in some placesin the article, applied the term ‘use of drugs’, but it isimportant to recognise that the study is based on dataon dispensed drugs from pharmacies to individuals andnot on actual use.

Dispensing periods

Drugs dispensed 90 days or less before conception, during thepregnancy or no more than 90 days after delivery were

included. Each pregnancy was divided into trimesters (week0–12, 13–26 and 27 onwards).

Analysis strategy and statistical analysis

Period prevalence was estimated in two ways: (a) bydividing the number of patients who had filled at leastone prescription of the studied drugs and (b) by divid-ing the number of patients who had filled at least twoprescriptions of the studied drugs during the period ofinterest by the total number of pregnant women in thesame period.

We used the stock register to identify the pack with thesmallest amount on the market during the study period(eTable 1).

If a woman filled a prescription of both a study drug andeither an antidepressant or an opioid during a defined timeperiod, this was defined as co-medication. Two different timeperiods were studied: the entire pregnancy and the thirdtrimester.

Medians and interquartile ranges (25–75 %) and confi-dence intervals are presented when appropriate.

SPSS 17.0 for Windows was used to generate the descrip-tive statistics.

Ethics

Linkage between the two registries generated anonymous filesfor research purposes, as regulated by Norwegian law forhealth registers.

Table 1 Baseline characteristics of study population. Pregnancies where the mother was prescribed none or ≥1 benzodiazepine and/or z-hypnotic drugbefore, during or after pregnancy (n=334,818 and n=10,885, respectively) (Norway 2004–2010)

No prescription ≥1 prescription

Age distribution of mothers, % (CI) <20 2.3 (2.3–2.5) 1.7 (1.5–1.9)

20–24 14.6 (14.5–14.7) 13.6 (13.0–14.2)

25–29 31.4 (31.2–31.6) 25.7 (24.9–26.5)

30–34 33.2 (33.0–33.6) 32.5 (31.6–33.4)

35–39 15.7 (15.6–15.8) 21.2 (20.4–21.6)

>40 2.8 (2.7–2.9) 5.2 (4.8–5.6)

Marital status of mother: married or cohabiting, % (CI) 92.3 (92.2–92.4) 82.4 (81.7–83.1)

Parity of pregnancy: first-time mothersa, % (CI) 42.1 (41.9–42.3) 41.9 (41.0–42.8)

Mother has had one or more previous spontaneous abortion before week 12b, % (CI) 18.1 (18.0–18.2) 23.0 (22.2–23.8)

Chronic disease in motherc at start, during or end of pregnancy, % (CI) 10.9 (10.8–11.0) 17.9 (17.2–18.6)

Smoking mother, at the beginning and/or end of pregnancyd, % (CI) 14.4 (14.3–14.5) 30.4 (29.5–31.3)

CI confidence intervala Primiparous, first-time pregnanciesbMissing data in each group 10.3 and 11.1 %, respectivelyc Having one or more of the following chronic conditions: asthma at start of pregnancy, chronic hypertension, chronic kidney disease, relapsing urinarytract infection, heart disease, rheumatoid arthritis, epilepsy, diabetes mellitus at start of or during pregnancy, thyroid conditiond Sometimes or daily. Missing data in each group of pregnant women 17.3 and 17.9 %, respectively

Eur J Clin Pharmacol (2014) 70:1367–1374 1369

Tab

le2

Num

berandpercentage

(%)of

pregnancieswith

maternalreceiptof

benzodiazepine

derivatives

orz-hypnoticdrugsandtheam

ounts(D

DDs)dispensedbefore,duringandafterpregnancy(n=

345,703,Norway

2004–2010)

Drug

Dispensingperiod

Pregnancies,n(%

,CI)

Pregnancieswith

≥2prescriptio

ns,

n(%

,CI)

Num

berof

prescriptio

nsa ,

median(IQR)

DDDs,median(IQR)

Totalb

enzodiazepinederivativ

esandz-hypnotics

Before(3

months)

6,095(1.76,1.72–1.80)

2,031(0.59,0.56–0.61)

1(1–2)

20(10–40)

1sttrimester

3,335(0.96,0.93–0.99)

1,027(0.30,0.28–0.32)

1(1–2)

20(10–40)

2ndtrim

ester

1,338(0.39,0.37–0.41)

505(0.15,0.14–0.16)

1(1–2)

20(10–50)

3rdtrim

ester

1,736(0.51,0.49–0.53)

487(0.14,0.13–0.15)

1(1–2)

13(7–30)

After

(3months)

2,895(0.84,0.81–0.87)

1,031(0.30,0.28–0.32)

1(1–2)

19(9–33)

Entirepregnancy

5,135(1.49,1.44–1.52)

1,617(0.47,0.45–0.49)

1(1–2)

15(8–37)

b,c

Benzodiazepinederivativ

esd

Any

type

Before(3

months)

3,168(0.92,0,89–0,95)

1,079(0.31,0.29–0.33)

1(1–2)

13(8–30)

1sttrimester

1,961(0.57,0.54–0.60)

638(0.18,0.17–0.19)

1(1–2)

13(8–30)

2ndtrim

ester

965(0.28,0.26–0.30)

359(0.10,0.09–0.11)

1(1–2)

13(8–40)

3rdtrim

ester

1,149(0.34,0.32–0.36)

315(0.09,0.08–0.10)

1(1–2)

10(5–23)

After

(3months)

1,825(0.53,0.51–0.55)

592(0.17,0.16–0.18)

1(1–2)

13(6–25)

Entirepregnancy

3,191(0.92,0.89–0.95)

1,019(0.29,0.27–0.31)

1(1–2)

10(5–30)

Antiepileptics(clonazepam)

Before(3

months)

129(0.04,0.03–0.05)

59(0.02,0.02–0.02)

1(1–3)

19(9–38)

1sttrimester

113(0.03,0.02–0.04)

37(0.01,0.01–0.01)

1(1–2)

19(9–38)

2ndtrim

ester

75(0.02,0.02–0.02)

31(0.01,0.01–0.01)

1(1–2)

25(9–47)

3rdtrim

ester

56(0.02,0.02–0.02)

16(0.00)

1(1–2)

19(9–26)

After

(3months)

72(0.02,0.02–0.02)

28(0.01,0.01–0.01)

1(1–2)

19(9–28)

Entirepregnancy

156(0.05,0.04–0.06)

84(0.02,0.02–0.02)

2(1–3)

26(9–56)

Anxiolytics

Before(3

months)

2,924(0.85,0.82–0.88)

966(0.28,0.26–0.30)

1(1–2)

12(6–25)

1sttrimester

1,791(0.52,0.50–0.54)

543(0.16,0.15–0.17)

1(1–2)

13(6–25)

2ndtrim

ester

847(0.25,0.23–0.27)

302(0.09,0.08–0.10)

1(1–2)

13(5–37)

3rdtrim

ester

964(0.28,0.26–0.30)

263(0.08,0.07–0.09)

1(1–2)

10(5–20)

After

(3months)

1,640(0.47,0.45–0.49)

522(0.15,0.14–0.16)

1(1–2)

10(5–23)

Entirepregnancy

2,858(0.83,0.80–0.86)

850(0.25,0.23–0.27)

1(1–1)

10(10–25)

Hypnotics

Before(3

months)

279(0.08,0.07–0.09)

110(0.03,0.02–0.04)

1(1–2)

50(20–100)

1sttrimester

188(0.05,0.04–0.06)

83(0.02,0.02–0.02)

1(1–2)

50(20–100)

2ndtrim

ester

96(0.03,0.02–0.04)

38(0.01,0.01–0.01)

1(1–2)

50(20–100)

3rdtrim

ester

165(0.05,0.04–0.06)

41(0.01,0.01–0.01)

1(1–2)

20(20–40)

After

(3months)

203(0.06,0.05–0.07)

56(0.02,0.02–0.02)

1(1–2)

20(20–50)

Entirepregnancy

368(0.11,0.10–0.12)

123(0.04,0.03–0.05)

1(1–1)

20(20–70)

1370 Eur J Clin Pharmacol (2014) 70:1367–1374

Results

Characteristics of the medicated women

The women who were dispensed a benzodiazepine or z-hypnotic drug were older than those who were not dispensedsuch drugs (Table 1) and fewer had a partner at the time ofpregnancy. More of them had previously experienced an earlyspontaneous abortion, were suffering from chronic disease orsmoked during pregnancy.

Prevalence of use and amounts dispensed

In 3,191 (0.9 %) and 2,459 (0.7 %) pregnancies, the womenreceived a benzodiazepine or z-hypnotic drug during pregnan-cy (Table 2), respectively. In a total number of 5,135 pregnan-cies (1.5 %), the women received a benzodiazepine or a z-hypnotic at least once, and in 1,617 (0.5 %), twice or more.The proportion of women who were dispensed any of therelevant drugs decreased from the 3-month period beforeconception compared to all the trimesters and increased againafter birth. None of the drug groups did the proportion of usersreturn to the level of pre-pregnancy. The decline in pregnancywas evident in each drug group. Before pregnancy, z-hypnotics were dispensed more often than benzodiazepines,but the prevalence of z-hypnotic use was lower during preg-nancy (Table 2).

The median number of prescription in all trimesters wasone for all substances in all trimesters (Table 2). The mediantotal amount of benzodiazepines and/or z-hypnotics dispensedduring pregnancy was 15 DDDs, while the 25% receiving thelargest amounts got 40 DDDs or more.

Five hundred eleven women composed the 10 % that wereprescribed the largest total amounts of benzodiazepines and/orz-hypnotic during pregnancy. Among these, the median was220 DDDs.

During the study period from 2004 to 2011, there were nochanges observed in the prevalence of dispensed benzodiaze-pines or z-hypnotics to the pregnant women (data not shown).

Prevalence of co-medication with opioids or antidepressants

Of the women who were dispensed either a benzodiaz-epine or a z-hypnotic any time during pregnancy, 1,006(19.6 %) were also dispensed an opioid during pregnan-cy and 994 (19.3 %) of the women were co-medicatedwith an antidepressant (Table 3). The median totalamounts of benzodiazepines and/or z-hypnotic drugsdispensed during pregnancy were 25 DDDs for thewomen co-medicated with an opioid and 30 DDDs forthe women co-medicated with an antidepressant.T

able2

(contin

ued)

Drug

Dispensingperiod

Pregnancies,n(%

,CI)

Pregnancieswith

≥2prescriptio

ns,

n(%

,CI)

Num

berof

prescriptio

nsa ,

median(IQR)

DDDs,median(IQR)

Z-hypnotics

Hypnotics

Before(3

months)

3,545(1.03,1.00–1.06)

931(0.27,0.25–0.29)

1(1–2)

30(10–40)

1sttrimester

1,712(0.50,0.48–0.52)

355(0.10,0.09–0.11)

1(1–1)

30(10–40)

2ndtrim

ester

479(0.14,0.13–0.15)

159(0.05,0.04–0.06)

1(1–2)

30(10–60)

3rdtrim

ester

686(0.20,0.19–0.21)

172(0.05,0.04–0.06)

1(1–2)

20(7–35)

After

(3months)

1,420(0.41,0.39–0,43)

406(0.12,0.11–0.13)

1(1–2)

20(10–33)

Entirepregnancy

2,459(0.71,0.68–0.74)

580(0.17,0.16–0.18)

1(1–1)

20(10–35)

n=345,703:So

mewom

anmay

contributewith

morethan

onepregnancyandthus

countseveraltim

esinthedata.P

regnancies

areregistered

intheNorwegianMedicalBirthregistry

from

gestationweek

12.N

otallp

regnancies

reachedthe3rdtrim

ester,in

thisperiod

n=342,776

DDDdefineddaily

dose,C

Iconfidence

interval,IQRinterquartile

range(25–75

%)

aIn

pregnancieswhere

numberof

prescriptio

nsfortherespectiv

eperiod

was

≥1bMedianDDD/day

during

pregnancy=0.06

cIn

uppertenthpercentile:medianDDDduring

pregnancy=220.MedianDDD/day

during

pregnancy=0.82

dSo

mewom

enmight

have

received

prescriptio

nsforseveraltypes

ofbenzodiazepinesduring

onepregnancyandthus

contributein

morethan

onesubgroup

Eur J Clin Pharmacol (2014) 70:1367–1374 1371

Prevalence of use in more than one trimester

In the 5,135 pregnancies where the mothers were dispensed abenzodiazepine or a z-hypnotic drug, 3,518 (68.5 %) filledjust one prescription for the duration of the pregnancy, 897(17.5 %) filled at least one prescription in more than onetrimester, while the remaining 720 (14.0 %) filled severalprescriptions but within the same trimester. Among the wom-en in pregnancies where co-medication with an opioid orantidepressant occurred, the prevalence of filling at least oneprescription for a benzodiazepine or a z-hypnotic drug duringseveral trimesters were 278 (27.6 %) of 1,006 and 307(30.9 %) of 994, respectively.

Discussion

During 2004–2010, 1.5 % of pregnant women in Norwaywere dispensed a benzodiazepine or a z-hypnotic at least once.Around 70 % of these filled just one prescription for theduration of the pregnancy. The pregnant women who weredispensed these drugs were older, more likely not married orcohabiting, more likely to have had a miscarriage, suffer fromchronic diseases or conditions and were more likely to smoke.Prevalence of use was lower during pregnancy than before butincreased after delivery. Co-medication with an opioid oc-curred in approximately one fifth of the pregnancies wherethe mother filled a prescription for a benzodiazepine or z-hypnotic drug; an equal portion was co-medicated with anantidepressant. The women who were co-medicated moreoften filled prescriptions in several trimesters and were dis-pensed larger amounts of benzodiazepines/z-hypnotics.

In the drug use in pregnancy (DUP) study published in1993 [24], the data from 22 countries showed an overallprevalence of use of benzodiazepines among pregnant womento be 3 %: 0.9 % in Sweden, 0.7 % in Denmark and 3.7 % inNorway. This last number contrasts with what we found in ourdata where 0.9 % were dispensed a benzodiazepine. However,the studied population, time period and the methods of the twostudies are very different, and a direct comparison is difficult.The DUP data were from a selection of maternity wards meantto represent the general delivery practice of a country; our datawere from ambulatory care outside institutions such as mater-nity wards and cover the whole population. But, it is possiblethat the discrepancy partly represents a real decline in use from1988–1990 to 2004–2011. We did not observe any change inprevalence during the period of our study. In Montreal,Canada, 3.9 % (4,245 of 109,344) of pregnant women in theyears 1998–2002 filled at least one prescription for a benzo-diazepine during pregnancy [25]. Andrade et al. [11] docu-mented the use of prescription drugs among pregnant womenin the US in 1996–2000 and found a prevalence of use ofsedative hypnotics during pregnancy at 1.3 %. Overall, prev-alence is low, but there are variations between countries andover time, suggesting that the use is amenable to change.

Considering the amount dispensed, most women receivedlow doses of benzodiazepines/z-hypnotics. That the 10% of thewomen receiving the largest amount of the drugs combineddispensed a median amount of 220 DDDs indicates that there isa substantial group where use of benzodiazepines/z-hypnoticsin pregnancy is frequent. Details on amount have not beenstudied in any of the other articles we have found on the subject.

Almost one fifth of the pregnant women who were dispenseda benzodiazepine/z-hypnotic drug were co-medicated with opi-oids and/or antidepressants. These women filled both several

Table 3 Co-medication of either a benzodiazepine or z-hypnotic and either an opioid or an antidepressant, during pregnancy and in the 3rd trimester, andamounts (DDDs) of benzodiazepine/z-hypnotic dispensed, in a total population of 345,703 pregnancies

Pregnancies, Number of prescription ofbenzodiazepines/z-hypnotics,

DDDs of benzodiazepines/z-hypnotics,

Dispensingperiod

n (%, CI) median (IQR) median (IQR)

Benzodiazepine/ z-hypnotic andopioids

Duringpregnancy

1,006 (0.29, 0.27–0.31) 1 (1–3) 25 (10–75)a

During 3rdtrimester

257 (0.07, 0.06–0.08) 1 (1–3) 20 (10–60)

Benzodiazepine/z-hypnotic andantidepressants

Duringpregnancy

993 (0.29, 0.27–0.31) 1 (1–3) 30 (10–68)b

During 3rdtrimester

197 (0.06, 0.05–0.07) 1 (1–3) 20 (9–60)

DDD, Defined Daily Dose

CI confidence interval, IQR interquartile range (25–75 %)aDDD per day, median (IQR) 0.10 (0.04–0.29)b DDD per day, median (IQR) 0.10 (0.04–0.25)

1372 Eur J Clin Pharmacol (2014) 70:1367–1374

prescriptions for a benzodiazepine/z-hypnotic drug and weredispensed larger amounts than the women who were only dis-pensed a benzodiazepine/z-hypnotic drug. While only 0.3 % ofthe pregnant women in total used a benzodiazepine/z-hypnoticdrug in several trimesters, this was the case for almost a third ofthe pregnant women who were co-medicated with an opioid oran antidepressant. That is, the women who used several types ofthe studied drugs used larger doses and in more periods. It ispossible that drug exposure to this extent could in some wayinfluence the developing nervous system of the foetus.

The medicated women in our study were older than thewomen who were not dispensed drugs. This concurs withwhat is seen in the general population, the use of these drugsincreases with age [14]. Marchetti et al. [24] also found thatprevalence of use of benzodiazepine in the Nordic countrieswas highest in the oldest group of pregnant women (>35) andthat it was more common among smokers than non-smokers.Equally, smoking was also more common among the medi-cated mothers in our data, and a larger proportion also hadchronic conditions or disorders.

A major strength of our study is the use of two nationwideregistries ensuring the inclusion of nearly all singleton preg-nancies in the whole Norwegian population over 7 years. Theonly pregnancies not included are the ones that did not reach12 weeks of gestation since these are not registered in theMBRN. As our results show that benzodiazepine/z-hypnoticusers report early abortions more frequently, our calculatedprevalence in the first trimester may be an underestimate. Thequality of the linkage of the two databases was ensured by theuse of the unique personal identity number, and the obstetricinstitutions and the pharmacies’ duty to report ensure thecoverage of the databases. No changes were made to theregistries in the period studied, ensuring the data’s reliability.

Our data are dispensed drugs in ambulatory care. Validity ischallenged by the fact that consumption of the drugs might nottake place in the same period as the prescription was dis-pensed. Use might be postponed to a later period or somemight not be consumed at all. In a recent validity study, theNorPD data on dispensed benzodiazepines were compared toself-reported data on benzodiazepine use by pregnant womenin the Norwegian Mother and Child Cohort study [26]. Thestudy showed that prescription data provides valid informa-tion on exposure to benzodiazepine antiepileptics; however,validity is lower for anxiolytic and hypnotic benzodiazepines(sensitivity 53 % and 33 % and specificity 99 % and 100 %,respectively). Our data does not cover drugs dispensed whenpatients are staying in institutions. While in institutions, preg-nant womenmaymore frequently be consumers of these typesof drugs, making our numbers underestimates. Still, prescrip-tions made in institutions and filled at a pharmacy after dis-charge or after a visit to an outpatient clinic are included.Some of these drugs may also be bought or sold on the illegalmarket.

In some cases, theremay be a strong clinical indication for useof benzodiazepines/z-hypnotics during pregnancy. Today’s rec-ommendations from The Norwegian Directorate of Health statethat there is little experience with the use of these drugs duringpregnancy; they should preferably be avoided but use may beconsidered for short periods [27]. The lower prevalence of dis-pensing seen in our data compared with studies from earlierperiods may reflect that prescribers have becomemore restrictivein accordance with these guidelines.

In conclusion, the use of benzodiazepines and z-hypnoticdrugs during pregnancy was not very prevalent in Norway inthese years and lower than reported from earlier time periods.There was a reduction in the use of these drugs during preg-nancy; the decline was more pronounced for z-hypnotics thanfor benzodiazepines. However, our findings imply that there isa substantial number of pregnancies where these drugs aredispensed often and/or in large quantities. A part of the med-icated pregnant women were also prescribed an opioid orantidepressant. Further research should perhaps focus on thewomen who receive the largest amounts during pregnancyand those that combine these drugs with other psycholeptics.

Conflict of interest The authors declare that they have no conflict ofinterest.

References

1. Sahota PK, Jain SS, Dhand R (2003) Sleep disorders in pregnancy.Curr opin pulm med 9(6):477–483

2. Rubertsson C, Hellstrom J, Cross M, Sydsjo G (2014) Anxiety inearly pregnancy: prevalence and contributing factors. Arch wommental health. doi:10.1007/s00737-013-0409-0

3. EMA (2008) Guideline on risk assessment of medicinal products onhuman reproduction and lactation: from data to labelling. EuropeanMedicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003307.pdf.Accessed 17 July 2014.

4. Wikner BN, Stiller CO, Bergman U, Asker C, Kallen B (2007) Use ofbenzodiazepines and benzodiazepine receptor agonists during pregnan-cy: neonatal outcome and congenitalmalformations. PharmacoepidemiolDrug Saf 16(11):1203–1210. doi:10.1002/pds.1457

5. Fass (2013) Fakta för förskrivare (Facts for prescribers).Läkemedelsindustriföreningens Service AB. http://www.fass.se/LIF/h e a l t h c a r e f a c t s ; j s e s s i o n i d = e 6 b U 6 3 h _JvcfYv86OU0S8hJE6Nihi6MGJVamYV2RNIqtaeZaTNrb!1437283995?docId=18338&userType=0. Accessed 13 August 2014.

6. Bennett PN, Working Group WHO (eds) (1988) Drugs and humanlactation. Elsevier, Amsterdam, New York, Oxford

7. Tamanna S, Geraci SA (2013) Major sleep disorders among women:(women's health series). South Med J 106(8):470–478. doi:10.1097/SMJ.0b013e3182a15af5

8. Garbis H, McElhatton PR (2007) 2.11 - Psychotropic drugs. In:Schaefer C, Peters P, Miller RK (Eds.) Drugs During Pregnancyand Lactation (Second Edition)ed. Academic , pp288-320

9. Engeland A, Bramness JG, Daltveit AK, Ronning M, Skurtveit S,Furu K (2008) Prescription drug use among fathers and mothersbefore and during pregnancy. A population-based cohort study of

Eur J Clin Pharmacol (2014) 70:1367–1374 1373

106,000 pregnancies in Norway 2004–2006. Br J Clin Pharmacol65(5):653–660. doi:10.1111/j.1365-2125.2008.03102.x

10. Lacroix I, Hurault C, Sarramon MF, Guitard C, Berrebi A, Grau M,Albouy-Cossard C, Bourrel R, Elefant E, Montastruc JL, Damase-Michel C (2009) Prescription of drugs during pregnancy: a studyusing EFEMERIS, the new French database. Eur J Clin Pharmacol65(8):839–846. doi:10.1007/s00228-009-0647-2

11. Andrade SE, Gurwitz JH, Davis RL, Chan KA, Finkelstein JA, FortmanK, McPhillips H, Raebel MA, Roblin D, Smith DH, Yood MU, MorseAN, Platt R (2004) Prescription drug use in pregnancy. Am J ObstetGynecol 191(2):398–407. doi:10.1016/j.ajog.2004.04.025

12. Daw JR, Mintzes B, Law MR, Hanley GE, Morgan SG (2012)Prescription drug use in pregnancy: a retrospective, population-based study in British Columbia, Canada (2001–2006). ClinTher34(1):239–249. doi:10.1016/j.clinthera

13. Lupattelli A, Spigset O, Twigg MJ, Zagorodnikova K, Mardby AC,Moretti ME, Drozd M, Panchaud A, Hameen-Anttila K, Rieutord A,Gjergja Juraski R, Odalovic M, Kennedy D, Rudolf G, Juch H,Passier A, Bjornsdottir I, Nordeng H (2014) Medication use inpregnancy: a cross-sectional, multinational web-based study. BMJopen 4(2):e004365. doi:10.1136/bmjopen-2013-004365

14. NorPD (2014) Statistics from the Norwegian Prescription Database.Norwegian Prescription Database. http://www.reseptregisteret.no/.Accessed 13 August 2014.

15. Neutel CI, Skurtveit S, Berg C, Sakshaug S (2013) Multiple pre-scribers in older frequent opioid users—does it mean abuse? Journalof population therapeutics and clinical pharmacology=Journal de latherapeutique des populations et de la pharamcologie clinique 20 (3):e397-405

16. Mellbye A, Svendsen K, Borchgrevink PC, Skurtveit S, FredheimOM (2012) Concomitant medication among persistent opioid userswith chronic non-malignant pain. Acta Anaesthesiol Scand 56(10):1267–1276. doi:10.1111/j.1399-6576.2012.02766.x

17. Handal M, Engeland A, Ronning M, Skurtveit S, Furu K (2011) Useof prescribed opioid analgesics and co-medication with benzodiaze-pines in women before, during, and after pregnancy: a population-based cohort study. Eur J Clin Pharmacol 67(9):953–960. doi:10.1007/s00228-011-1030-7

18. Hausken AM, Furu K, Tverdal A, Skurtveit S (2010) Mental distressand subsequent use of anxiolytic drugs—a prospective population-based cohort study of 16,000 individuals. Scandinavian J PublicHealth 38(5):465–473. doi:10.1177/1403494810370229

19. Furu K, Wettermark B, Andersen M, Martikainen JE, AlmarsdottirAB, Sorensen HT (2010) The Nordic countries as a cohort forpharmacoepidemiological research. Basic Clin Pharmacol Toxicol106(2):86–94. doi:10.1111/j.1742-7843.2009.00494.x

20. WHO Collaborating Centre for Drug Statistics Methodology (2011)ATC classification index with DDDs 2012. Organization, WorldHealth

21. Irgens LM (2002) Medical birth registry—an essential resource inperinatal medical research. Tidsskrift for den Norske laegeforening :tidsskrift for praktisk medicin, ny raekke 122(26):2546–2549

22. Irgens LM (2000) The Medical Birth Registry of Norway.Epidemiological research and surveillance throughout 30 years.Acta Obstet Gynecol Scand 79(6):435–439

23. Skurtveit S, Selmer R, Roth C, Hernandez-Diaz S, Handal M (2014)Prenatal exposure to antidepressants and language competence at agethree: results from a large population-based pregnancy cohort inNorway. BJOG Int J Obstet Gynaecol. doi:10.1111/1471-0528.12821

24. Marchetti F, Romero M, Bonati M, Tognoni G (1993) Use of psy-chotropic drugs during pregnancy. A report of the international co-operative drug use in pregnancy (DUP) study. Collaborative Groupon Drug Use in Pregnancy (CGDUP). Eur J Clin Pharmacol 45(6):495–501

25. Kulaga S, Zargarzadeh AH, Berard A (2009) Prescriptions filledduring pregnancy for drugs with the potential of fetal harm. BJOG:an International Journal of Obstetrics and Gynaecology 116(13):1788–1795. doi:10.111/j.1471-0528.2009.02377.x

26. Skurtveit S, Selmer R, Odsbu I, Handal M (2014) Self-reported data onmedicine use in theNorwegianMother andChild cohort study comparedto data from the Norwegian Prescription Database. Submitted

27. NDH (2013) Nasjonal faglig veileder vanedannende legemidler-rekvirering og forsvarlighet: graviditet. The Norwegian Directorateof Health. http://helsedirektoratet.no/sites/vanedannende-legemidler/utfordrende-situasjoner-og-tilstander/graviditet/Sider/default.aspx.Accessed 14 August 2014.

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