DOI: 10.1111/j.1471-0528.2006.00927.

x
www.blackwellpublishing.com/bjog
Maternal medicine

Drug prescription patterns before, during and

after pregnancy for chronic, occasional and
pregnancy-related drugs in the Netherlands
MK Bakker,a J Jentink,b F Vroom,b PB Van Den Berg,b HEK De Walle,a LTW De Jong-Van Den Bergb
a EUROCAT Northern Netherlands, Department of Medical Genetics, University Medical Center Groningen, University of Groningen, Groningen,

The Netherlands b Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, University Institute for Drug Exploration
(GUIDE), University of Groningen, Groningen, The Netherlands
Correspondence: Prof Dr LTW De Jong-Van Den Berg, Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy,
University Institute for Drug Exploration (GUIDE), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen,
The Netherlands. Email [email protected]

Accepted 10 February 2006.

Objective To compare the prescription of drugs in women over Results About 79.1% of the women received at least one
a period from 2 years before until 3 months after pregnancy, prescription during pregnancy. The prescription rate for most
regarding the type of drugs used and the fetal risk. drugs for chronic diseases and for occasional use decreased during
pregnancy, whereas, as expected, the prescription rate for
Design A cohort study based on pharmacy records of women
pregnancy-related drugs increased. During the first trimester of
giving birth to a child between 1994 and 2003.
pregnancy, 1.7% of all drugs prescribed for chronic conditions and
Setting The study was performed with data from the InterAction 2.3% of the occasional drugs were classified as harmful.
database, containing prescription-drug-dispensing data from
Conclusions The increase in prescription rate during pregnancy is
community pharmacies.
caused by an increase in prescription rate of drugs for pregnancy-
Population The study population included 5412 women for whom related symptoms. The prescription of harmful drugs is more
complete pharmacy records were available. commonly associated with drugs for occasional use rather than
with drugs for chronic conditions. Therefore, a more cautious
Methods Drugs were classified into three categories: (1) drugs for
prescribing of drugs to healthy women in the fertile age is
chronic conditions, (2) drugs for occasional use and (3) drugs for
necessary.
pregnancy-related symptoms and also classified according to the
Australian classification system. Keywords Drug utilisation, fetal risk classification, pregnancy,
prescription rate, register based.
Main outcome measures The prescription rate was calculated as
the number of women per 100 women who received one or more
prescriptions for a given drug within a specified time period.

Please cite this paper as: Bakker M, Jentink J, Vroom F, Van Den Berg P, De Walle H, De Jong-Van Den Berg L. Drug prescription patterns before, during and after
pregnancy for chronic, occasional and pregnancy-related drugs in the Netherlands. BJOG 2006; 113:559–568.

such as vitamins, iron and analgesics. Most studies found an

Introduction
increasing trend in drug use during pregnancy.2–7
Since the teratogenic risk of most drugs is still undetermined, Drug use cannot be always avoided during pregnancy. For
it is important to monitor drug use regularly among pregnant women with certain chronic medical conditions such as epi-
women. Drug-utilisation studies reveal that most women use lepsy, diabetes, inflammatory bowel disease and asthma, the
drugs during pregnancy, with estimations varying from 441 to use of drugs is essential, and benefits for mother and child
99%.2 However, comparison is difficult because of differences may well outweigh the teratogenic risk of the drug.8,9 Other
in study design. Interviews or prescription databases may be nonchronic diseases related or unrelated to the pregnancy
used for collecting drug-use data, and the type of drugs stud- may require medical treatment. Most studies do not distin-
ied may or may not include over-the-counter (OTC) drugs guish between the different reasons for which the drugs are

ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology 559

 Bakker et al.

prescribed. Therefore, it is not clear to what extent changes in periods of 13 weeks (trimesters). The 12 trimesters were num-
drug use among pregnant women can be explained by bered as can be seen in Figure 1.
chronic, occasional or pregnancy-related drug use. We ordered drugs that were commonly prescribed into
The aim of this study was to compare the prescription of three mutually exclusive categories: (1) drugs for chronic
drugs in pregnant women, with respect to the type of drugs conditions, (2) drugs for occasional and short-time use and
and the fetal risk before, during and after pregnancy. (3) drugs for pregnancy-related symptoms. Drugs and drug
groups belonging to these three categories are listed in
Table 1. Drugs for chronic conditions are not necessarily
Methods
taken on a chronic basis but can also be taken during episodes
This study was performed with the InterAction database when the disease surfaces. The drugs were also classified based
(IADB), which contains data on prescriptions dispensed on the Australian risk classification for pregnancy (Table 2).15
from community pharmacies in the Netherlands. The IADB Categories D and X were combined because for both catego-
includes all prescription drugs from an estimated popula- ries, the use of drugs during pregnancy is clearly contraindi-
tion of 220 000 from 1994 to 1999 and was expanded to cated and only one drug was classified as X (isotretinoine,
approximately 450 000 since 1999.10,11 Registration is irre- D10BA01). The three B categories were combined for statis-
spective of health insurance and is considered representative tical purposes. Drugs that were not classified according to the
for the general population. Each prescription record con- Australian classification system were categorised as B because
tains information about the drug, date of dispensing, quan- their fetal risk was obviously unknown.
tity dispensed, dose regimen and the prescribing physician. Per trimester, we counted the number of specific drugs
The indication for the prescription is not known. All the prescribed to individual women, excluding contraceptives.
drugs are coded according to Anatomical Therapeutic Chem- If a specific drug was prescribed twice during a trimester, it
ical (ATC) classification.12 Each patient has a unique (anon- was counted only once. In addition, prescriptions covering
ymous) identifier; date of birth and gender of patients are more than one trimester were counted only in the trimester in
known. Due to a high patient–pharmacy commitment in which they were dispensed. The prescription rate was calcu-
the Netherlands and sophisticated pharmacy software, the lated as the number of women per 100 women who received
medication records for each patient are virtually complete.13 one or more prescriptions for a given drug or drug class
The IADB does not include OTC drugs and drugs dispensed within one trimester or otherwise specified time period.
during hospitalisations. Prescription rates were tested in SPSS 12.0.2 for Windows
To identify mothers, all children born between 1 January (Chicago, USA) over the 3-year study period and the preg-
1994 and 1 January 2004 were selected from the database. For nancy period, using the chi-square test for trend.
each child within the IADB, the female person 15–50 years
older than the child with the same address code was consid-
ered to be the mother, providing there were no other female Results
persons 15–50 years older with the same address code. Using
The mean age at birth of the 5412 mothers included was 29.6
this method, 65% of the mothers could be identified. Valida-
years (range 15–49 years). During the 3-year study period, they
tion of this method is described in detail by Schirm et al.14
received a total of 78 944 drugs, excluding contraceptives, of
Because only the child’s birth date is known, the theoretical
conception date was determined as the date of birth minus
273 days (i.e. 9 months). Between 1 January 1994 and 1 Jan-
uary 2004, 10 261 women were identified, with a total of
13 894 pregnancies. To rule out the influence of previous
pregnancies, we included only the first pregnancy, as regis-
tered in the database, for which complete pharmacy records
were available in the IADB from 2 years before the theoretical
conception date until 3 months after delivery. According to
these criteria, 5501 women were included. To avoid misclas-
sification of medication use, we subsequently excluded
women who gave birth to twins (n = 87) or triplets (n = 2)
because the gestation period in twin and triplet pregnancies is Figure 1. Prescription rate for all prescriptions and the mean number of
drugs dispensed among women with at least one prescription. Trimester
more likely to be shorter than in singleton pregnancies. Thus,
–8 to –5 represents the second year before pregnancy, trimester –4 to
for the final analysis, pharmacy data for 5412 women were –1 represents the first year before pregnancy. The period between the
used. To allow direct comparisons of prescription rates over dotted lines (trimester 1–3) is the pregnancy period, and trimester 4 is
time, the whole study period of 3 years was divided into 12 the period after pregnancy.

560 ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology

 Drug prescription patterns in pregnancy

Table 1. Categorisation of drugs and drug groups included in this study, according to their ATC code

Categories ATC code

Category I: Drugs for chronic conditions

Drugs used in diabetes A10
Corticosteroids, dermatological preparations D07
Corticosteroids for systemic use H02
Thyroid therapy H03
Anti-inflammatory and antirheumatic products M01
Antimigraine medication N02C
Antiepileptics N03A
Antipsychotics N05A, excl. N05AB04
Antidepressants N06A
Antiasthmatics R03
Category II: Drugs for occasional and short-time use
Antispasmodic and anticholinergic agents and propulsives A03, excl. A03FA01
Antidiarrhoeals, intestinal anti-inflammatory/anti-infective agents A07
Antifungals for dermatological use D01
Emollients and protectives D02
Antibiotics and chemotherapeutics for dermatological use D06
Antiacne preparations D10
Antibacterials for systemic use J01
Analgesics and antipyretics N02B
Anxiolytics N05B
Hypnotics and sedatives N05C
Antiparasitic products, insecticides and repellents P
Antihistamines for systemic use R06, excl. R06AD and R06AE
Ear, eye, nose and throat preparations S02, S03, S01, R01, R02A, R05
Category III: Pregnancy-related drugs
Antacids A02A
Antiemetics A03FA01, A04A, N05AB04, R06AD, R06AE
Laxatives A06
Iron preparations B03A
Folic acid and derivatives B03B
Gynaecological anti-infectives and antiseptics G01
Gonadotrophins and other ovulation stimulants G03G

The drug categories are mutually exclusive.

which 12 407 drugs were dispensed during pregnancy. Over- tion, while during the pregnancy period, 470 different drugs
all, 5236 women (96.7%) received at least one prescription were prescribed. The drugs categorised in Table 1 accounted
drug during the 3-year study period and 4280 (79.1%) for 57.3% of all the different drugs prescribed and for
received at least one prescription drug during their preg- 81.9% of all prescriptions during the 3-year study period. For
nancy. Figure 1 presents the prescription rates per trimester the pregnancy period, these were 65.7 and 89.1%, respectively.
for all drugs, excluding contraceptives. In the 2 years before The prescription rates per trimester for the drugs listed in
pregnancy, the prescription rate was constant, approximately Table 1 are reported in Appendix 1. A graphical reproduction
43 per 100 women. The average number of drugs per trimes- of the prescription patterns for certain drug groups of the
ter among women who were prescribed drugs was two (range three categories is shown in Figures 2–4.
1–17). The prescription rate increased from 43.6 per 100 A clear decrease in prescription rate in pregnancy was seen
women in the first trimester to 49.3 and 60.8 per 100 women for antidepressants and antipsychotics (N06A/N05A), anti-
in the second and third trimester of pregnancy. During preg- migraine drugs (N02C; Figure 2), anti-inflammatory and
nancy, the mean number of prescription drugs per trimester antirheumatic drugs (M01). The prescription rates for anti-
among women who were prescribed drugs was approximately epileptics (N03A; Figure 2), antiasthmatics (R03) were nearly
the same as before pregnancy (1.9). constant during pregnancy. There seems to be an increase in
During the 3-year study period, 865 different drugs prescription rate for insulins (A10; Figure 2), but this was not
(based on ATC code) were prescribed to our study popula- statistically significant.

ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology 561

 Bakker et al.

Table 2. Risk classification based on the Australian risk classification15 and as used in this study

Category Description Fetal risk classification in this study

A Drugs that have been taken by a large number of pregnant women and Safe
women of childbearing age, without any proven increase in the
frequency of malformations or other direct or indirect harmful effects
on the fetus having been observed.
B Drugs that have been taken by only a limited number of pregnant women Undetermined
and women of childbearing age, without an increase in the frequency of
malformation or other direct or indirect harmful effects on the human fetus
having been observed. Studies in animals have not shown evidence of an
increased occurrence of fetal damage or have shown evidence of an
increased occurrence of fetal damage, of which the significance is
considered uncertain in humans.
C Drugs that, owing to their pharmacological effects, have caused or may be Potentially harmful
suspected of causing harmful effects on the human fetus or neonate,
without causing malformations. These effects may be reversible.
D/X Drugs that have caused or suspected to have caused or may be expected Harmful
to cause an increased incidence of human fetal malformations or
irreversible damage. These drugs may also have adverse pharmacological effects.

The prescription rates of drugs for occasional use generally (A02A; Figure 4) and gynaecological anti-infectives (G01;
showed a decrease during pregnancy, followed by an increase Figure 4) were most prescribed in the second and third tri-
after delivery. For antibiotics (J01; Figure 3), there was mester in pregnancy. The prescription of laxatives (A06) was
a decrease in prescription rate in the first trimester in preg- highest after pregnancy. Ovulation stimulants (G03G) were
nancy but an increasing pattern in the second and third tri- most prescribed before pregnancy, with a prescription rate of
mester. For antispasmodic and anticholinergic agents (A03) 4.2 per 100 women.
and for antihistamines for systemic use (R06), there was a Figures 5–7 show the distribution of the fetal risk classifi-
decrease in prescription rate during pregnancy. For analgesics cation of the prescribed drugs. In these figures, we included
(N02B, Figure 3), hypnotics and anxiolytics (N05C/N05B) only the drugs that were ordered in the three categories ac-
and for ear, eye, nose and throat preparations (S02, S03, cording to Table 1. The corresponding numbers can be found
S01, R01, R02A, R05; Figure 3), there was a decreasing trend in Appendix 2. As previously described, there was a clear
during the 3-year period but constant rates during pregnancy. decrease in the total number of prescribed drugs for chronic
As expected, the prescription patterns of drugs for pregnancy- conditions (Figure 5) and for occasional and short-time use
related symptoms showed an increase during pregnancy. For (Figure 6) during pregnancy. This decrease was in contrast
folic acid and derivatives (B03B) and for antiemetics (A03FA01, with the number of prescribed drugs for pregnancy-related
A04A, R06AD, R06AE; Figure 4), the highest rates can be seen
in the first trimester. Iron preparations (B03A), antacids

Figure 3. Prescription patterns for certain drugs for occasional and short-
Figure 2. Prescription patterns for certain drugs for chronic conditions time use in the period from 2 years before pregnancy until 3 months after
in the period from 2 years before pregnancy until 3 months after delivery. delivery. The dots represent the prescription rate per trimester for the
The dots represent the prescription rate per trimester for the specific drug specific drug class. The period between dotted lines is the pregnancy
class. The period between dotted lines is the pregnancy period. Catego- period. Categorisation of drug groups according to Table 1: antibacterials
risation of drug groups according to Table 1: drugs used in diabetes (A10), for systemic use (J01), analgesics and antipyretics (N02B) and ear, eye,
antimigraine medication (N02C) and antiepileptics (N03A). nose and throat preparations (S02, S03, S01, R01, R02A, R05).

562 ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology

 Drug prescription patterns in pregnancy

Figure 4. Prescription patterns for certain drugs for pregnancy-related

symptoms in the period from 2 years before pregnancy until 3 months after Figure 6. Total number of prescription drugs for occasional and short-
delivery. The dots represent the prescription rate per trimester for the time use (only the prescribed drugs that were categorised as drugs for
specific drug class. The period between dotted lines is the pregnancy occasional and short-time use as presented in Table 1 were counted)
period. Categorisation of drug groups according to Table 1: antacids per trimester and the distribution of these drugs according to the
(A02A), gynaecological anti-infectives and antiseptics (G01) and pregnancy risk classification.
antiemetics (A03FA01, A04A, N05AB04, R06AD and R06AE).

increased to over 70% in the second and third trimester.

symptoms, which showed a large increase during pregnancy,
The proportion of harmful drugs decreased to 0.4% in the
as shown in Figure 7. When taking all categories together,
third trimester. The majority of the drugs prescribed for preg-
81.7% of all drugs prescribed during pregnancy were classified
nancy-related symptoms in the first trimester were classified
as A, 10.9% as B, 6.3% as C and 1.1% as D or X. For the drugs
as safe, 2.1% as potentially harmful and 2.9% as harmful.
prescribed during the first trimester, these percentages were
In the second and third trimester of pregnancy, 97.6% of
70.9, 16.5, 10.2 and 2.4, respectively. However, when we
the drugs prescribed for pregnancy-related symptoms were
investigated the distribution of the prescribed drugs per cat-
classified as A, 1% as C and 0.2% as D or X.
egory (chronic, occasional or pregnancy related), large differ-
ences are observed.
In the first trimester, only 50.4% of the prescribed drugs for
Discussion
chronic diseases were considered safe (A), 30.8% were poten-
tially harmful (C) and 1.7% were classified as harmful (D or A clear change in drug prescription patterns is visible among
X). During pregnancy, the proportion of class A drugs pregnant women in the Netherlands. Drugs for chronic con-
increased to 67% in the third trimester and the proportion ditions and for occasional and short-time use were prescribed
of drugs classified as C decreased to less than 15%. The pro- less during pregnancy, while at the same time, an increased
portion of harmful drugs was constant (1.9% in the third prescribing of drugs for pregnancy-related symptoms was
trimester). After pregnancy, the proportion of potentially seen. For all three categories, the proportion of drugs classi-
harmful and harmful drugs increased to 45%. When we inves- fied as safe increased during pregnancy compared with the
tigated the prescribed drugs for occasional and short-time period before and after pregnancy.
use, 60.8% of the drugs in the first trimester were classified The prescription rate covering the 3-year study period was
as safe, 7.8% as potentially harmful and 2.3% as harmful. very high, with 97 per 100 women receiving at least one pre-
During pregnancy, the proportion of drugs classified as A scription drug. The high prescription rate may reflect the

Figure 5. Total number of prescription drugs for chronic conditions Figure 7. Total number of prescription drugs for pregnancy-related
(only the prescribed drugs that were categorised as drugs for occasional symptoms (only the prescribed drugs that were categorised as drugs for
and short-time use as presented in Table 1were counted) per trimester occasional and short-time use as presented in Table 1 were counted) per
and the distribution of these drugs according to the pregnancy risk trimester and the distribution of these drugs according to the
classification. pregnancy risk classification.

ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology 563

 Bakker et al.

origin of our study population. To be included in the pre- caused by infections of the breast and uterus. Because anti-
scription database, a person had to purchase at least one pre- biotics are also frequently prescribed outside pregnancy, we
scription drug at a participating pharmacy since 1994. In our decided to categorise antibiotics as drugs for occasional and
population, the prescription rate during pregnancy, including short-time use.
vitamins and iron, was 79%. This percentage is somewhat The proportion of class A drugs prescribed during preg-
higher than found in a Dutch cohort of women with a low- nancy is somewhat lower than the proportion found in an
risk pregnancy (76.5% of the women attending a gynaecol- other study conducted with the IADB (81.7 versus 86%).6
ogist and 57.4% of the women attending a midwife used This difference can be explained because we restricted our
medications during pregnancy), but in the latter study, iron analysis to the drugs that were ordered into the three cate-
supplements were excluded.16 The prescription rate in this gories (65.7% of all drugs). In the previous study of the
study was high compared with register-based studies in IADB, all drugs were included. The proportion of category
Denmark (44.2%, excluding iron and vitamins),1 Finland A drugs in our study is much higher than found in a Danish
(46.2%)17 and USA (64%, excluding vitamins and miner- study, where 40.9% of all prescriptions during pregnancy
als).18 Higher prescription rates during pregnancy were found were classified as safe (A).22 We found that 2.4% of all drugs
in the South West of France (99%, including iron and vita- prescribed in the first trimester were harmful drugs. The
mins)2 and in Germany (96.4 and 85.2%, including and harmful drugs prescribed in the first trimester for pregnancy-
excluding vitamins, respectively).4 Several explanations can related symptoms were ovulation-stimulating drugs, and for
be given for the differences in prescription rates. The Danish chronic conditions, antiepileptics. Doxycycline, a tetracycline
study used a database that did not include prescribed drugs antibiotic, was responsible for the high percentage of harmful
that were not refunded, such as benzodiazepines, many anal- drugs for occasional use in the first trimester. Doxycycline
gesics and antacids, explaining the lower prescription rates. may affect the bone and tooth development of the developing
Cultural prescribing differences might also play a role in these fetus and is therefore contraindicated in pregnancy.
variations. The strength of our study was that for all women included
Except for drugs used in diabetes, most drugs for chronic in this study, complete data were available on drugs pre-
conditions were prescribed less during pregnancy. In the scribed in the period from 2 years before pregnancy until 3
trimester after pregnancy, the prescription rate increased but months after delivery. Because we applied a cohort design
not to the pre-pregnancy level. Low prescription rates shortly comparing the prescription rates during pregnancy with the
after pregnancy are most likely a result of breastfeeding. For prescription rates before pregnancy in the same population,
some drugs, such as antidepressants and antipsychotics and selection bias is minimised. Some drug-utilisation studies
antiepileptics, the decrease in prescription rate started before compare drug use among pregnant women with drug use
pregnancy. This decrease may indicate precautionary meas- among nonpregnant women of comparable age. This might
ures by women planning pregnancy, as the safety of these introduce bias, since factors related to pregnancy and drug
drugs is not established. Several studies have associated the use might be disproportionately present in the two groups. A
use of antidepressants with adverse pregnancy outcomes such Finnish study showed that more nonpregnant women had
as spontaneous abortions, low birthweight and gestational a chronic disease such as epilepsy, rheumatoid diseases, dia-
age.19,20 From our data, it is not possible to infer whether betes, hypertension, ulcerative colitis and psychotic and men-
the decreases are physician driven or woman driven. As the tal disorders when compared with pregnant women of
indication for prescription is not known, the possible adverse comparable age.17
effects of stopping some of these medications is not known. By distinguishing drugs based on their indication, we could
The prescription rate of antimigraine medication decreased demonstrate that the increase in prescription rate during
in the second and third trimester of pregnancy, which might pregnancy is caused by an enhanced prescribing of drugs
be a consequence of less migraine attacks during pregnancy for pregnancy-related symptoms. Most other drug-utilisation
or the use of other analgesics such as paracetamol. Anti- studies that investigated drug-use patterns among pregnant
inflammatory and antirheumatic drugs were also rarely pre- women make no distinction between the indications for
scribed in pregnancy: the use of these drugs is contraindicated drug use.
in pregnancy and moreover, rheumatic disease activity im- Although our study was conducted with data from a
proves in most women during pregnancy.21 population-based prescription database, only women with
The prescription of most drugs for occasional and short- a liveborn child are included. Women with a spontaneous
time use decreased during pregnancy. The increase in the or induced abortion and women whose pregnancy resulted
prescriptions for antibiotics in the second and third trimester in a stillbirth or whose child did not survive until the first
can be explained by urinary tract infections, a complication in prescription were not included.
pregnancy for which treatment is recommended. The high Since we have no information on the actual length of
prescription rate of antibiotics after pregnancy is most likely the gestation period, the time of conception was estimated

564 ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology

 Drug prescription patterns in pregnancy

as 273 days (39 weeks) before birth. The use of a standard women to identify problems. In addition, this individual-level
gestational period, mostly 270 days, is common in studies exposure data can serve as a reference for future risk-assessment
using administrative data.4,17,18 A recent study, comparing studies and provide relevant information for education
administrative data with data from a birth registry, showed programmes of health professionals as well as for prevention.
that gestational age assumptions can result in a small pro- Although drug use during pregnancy is mostly studied in
portion of misclassification. The extent of potential drug- relation to the occurrence of congenital anomalies at birth,
exposure misclassification was larger for category X drugs in other adverse long-term effects in the offspring, such as devel-
the first trimester of pregnancy.23 We believe that administra- opmental delay, may also be associated with maternal drug
tive datasets with estimated gestational age can be useful in use in the second and third trimester. In a cohort study in
research on prescription of drugs during pregnancy. How- the South West of England, frequent paracetamol use in late
ever, in studies evaluating the risk of drugs on birth outcome, pregnancy was associated with an increased risk of wheezing
precise timing of drug exposure is essential and then admin- in the offspring at 30–42 months.26 If maternal drug use can
istrative datasets alone are insufficient. be linked to the prescription of drugs to their children,
In our study, ovulation-stimulating drugs were prescribed prescription databases may also be used to screen for certain
in the first trimester of pregnancy, an indication that mis- long-term drug effects.
classification has occurred. Prescription of other harmful In conclusion, this register-based study shows that the
drugs in the first trimester can also be explained by unaware- majority of the Dutch women use drugs during pregnancy.
ness of the pregnancy. Although almost 80% of the preg- The increase in prescription rate during pregnancy is caused
nancies in the Netherlands are planned, a woman mostly by an increase in prescription rate for drugs used for pregnancy-
does not recognise her pregnancy until the third week after related symptoms, whereas the prescription rate for drugs for
conception. chronic diseases and for occasional and short-time use
The prescription rate as defined in this study reflects the declines during pregnancy. Also, the prescription of harmful
prescribing behaviour of physicians and cannot be translated drugs decreases during pregnancy. However, 2.3% of all drugs
directly into exposure rates. Drugs prescribed for a longer prescribed for occasional and short-time use in the first tri-
period of time can lead to an underestimation of exposure mester were classified as harmful. Therefore, the results of this
in the subsequent trimesters. Also, particularly in pregnancy, study argue in favour for a cautious prescribing of drugs to
prescribed drugs are not always taken, leading to overestima- healthy women in the fertile age, in which the prescription of
tion of drug exposure. In a Danish study, only 43% of all harmful drugs should be avoided as much as possible.
drugs dispensed to pregnant women were reported to be
taken. Compliance was high for drugs used in chronic dis-
eases but low for drugs used for local or short-time treat- Acknowledgement
ment.24 Furthermore, the prescription database does not
include drugs administered in hospitals and OTC drugs. We thank M Naunton of the Department of Social Pharmacy,
For some drugs, underestimation of exposure may be consid- Pharmacoepidemiology and Pharmacotherapy for his thought-
erable. The prescription rate of analgesics and antipyretics, for ful comments on a previous version of this article. j
instance, is very low, with approximately 1.5 per 100 women
during pregnancy. The number of women who used analge-
References
sics during pregnancy is probably much higher because anal-
gesics are freely available in the Netherlands. In a recent study 1 Olesen C, Steffensen FH, Nielsen GL, de Jong-van den Berg, Olsen J,
Sorensen HT. Drug use in first pregnancy and lactation: a population-
in the USA, where data on maternal drug use were evaluated
based survey among Danish women. The EUROMAP group. Eur J Clin
from two case–control studies of birth defects, at least 65% Pharmacol 1999;55:139–44.
of the women took paracetamol at some point during preg- 2 Lacroix I, Damase-Michel C, Lapeyre-Mestre M, Montastruc JL.
nancy.25 Other pregnancy-related drugs such as antacids, lax- Prescription of drugs during pregnancy in France. Lancet
atives, folic acid and some antiemetics are also available as 2000;356:1735–6.
3 Donati S, Baglio G, Spinelli A, Grandolfo ME. Drug use in pregnancy
OTC drugs in the Netherlands.
among Italian women. Eur J Clin Pharmacol 2000;56:323–8.
Although not all drugs prescribed to the study population 4 Egen-Lappe V, Hasford J. Drug prescription in pregnancy: analysis
were ordered into the three categories, we believe that this of a large statutory sickness fund population. Eur J Clin Pharmacol
study is representative for drugs prescribed to pregnant 2004;60:659–66.
women. The drugs included in the three categories accounted 5 Nordeng H, Eskild A, Nesheim BI, Jacobsen G. Drug use in pregnancy
among parous Scandinavian women. N J Epidem 2001;11:97–103.
for almost 90% of all prescriptions in the pregnancy period.
6 Schirm E, Meijer WM, Tobi H, de Jong-van den Berg LT. Drug use by
Drugs not included in the analyses were rarely prescribed. pregnant women and comparable non-pregnant women in The
The use of population-based prescription databases is an Netherlands with reference to the Australian classification system.
important tool to monitor the use of drugs among pregnant Eur J Obstet Gynecol Reprod Biol 2004;114:182–8.

ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology 565

 Bakker et al.

7 de Jong-van den Berg LT, van den Berg PB, Haaijer-Ruskamp FM, Dukes 17 Malm H, Martikainen J, Klaukka T, Neuvonen PJ. Prescription drugs
MN, Wesseling H. Investigating drug use in pregnancy. Methodological during pregnancy and lactation—a Finnish register-based study. Eur J
problems and perspectives. Pharm Weekbl Sci 1991;13:32–8. Clin Pharmacol 2003;59:127–33.
8 Wiebe S. Managing women with epilepsy. Guideline producers now 18 Andrade SE, Gurwitz JH, Davis RL, Chan KA, Finkelstein JA, Fortman K,
need to pay attention to implementation. BMJ 2000;320:3–4. et al. Prescription drug use in pregnancy. Am J Obstet Gynecol
9 Moore TR. Diabetes in pregnancy. In: Creasy RK, Resnik R, editors. 2004;191:398–407.
Maternal-Fetal Medicine. Philadelphia, PA: Saunders; 1999. p. 964–95. 19 Chun-Fai-Chan B, Koren G, Fayez I, Kalra S, Voyer-Lavigne S, Boshier A,
10 Tobi H, van den Berg PB, De Jong-van den Berg LTW. The Interaction et al. Pregnancy outcome of women exposed to bupropion during
Database: synergy of science and practice in pharmacy. In: Brause RW, pregnancy: a prospective comparative study. Am J Obstet Gynecol
Hanisch E, editors. Medical Data Analysis. Berlin, Germany: Springer- 2005;192:932–6.
Verlag; 2000. p. 206–11. 20 Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal anti-
11 Schirm E, Monster TB, de Vries R, van den Berg PB, de Jong-van den depressant exposure. Am J Psychiatry 2002;159:2055–61.
Berg LT, Tobi H. How to estimate the population that is covered by 21 Ostensen M, Villiger PM. Immunology of pregnancy—pregnancy as
community pharmacies? An evaluation of two methods using drug a remission inducing agent in rheumatoid arthritis. Transpl Immunol
utilisation information. Pharmacoepidemiol Drug Saf 2004;13:173–9. 2002;9:155–60.
12 WHO Collaborating Centre for Drugs Statistics Methodology. ATC/ 22 Olesen C, Sorensen HT, de Jong-van den Berg, Olsen J, Steffensen FH.
DDD Index 2004 [www.whocc.no/atcddd/]. Accessed 2 December Prescribing during pregnancy and lactation with reference to the Swedish
2004. classification system. A population-based study among Danish women.
13 Leufkens HGM, Urquhart J. Automated pharmacy record linkage in the The Euromap Group. Acta Obstet Gynecol Scand 1999;78:686–92.
Netherlands. In: Strom BL, editor. Pharmacoepidemiology. Chichester, 23 Raebel MA, Ellis JL, Andrade SE. Evaluation of gestational age and admis-
UK: John Wiley & Sons; 2000. p. 347–60. sion date assumptions used to determine prenatal drug exposure from
14 Schirm E, Tobi H, de Jong-van den Berg LT. Identifying parents in phar- administrative data. Pharmacoepidemiol Drug Saf 2005;14:829–36.
macy data: a tool for the continuous monitoring of drug exposure to 24 Olesen C, Sondergaard C, Thrane N, Nielsen GL, de Jong-van den Berg,
unborn children. J Clin Epidemiol 2004; 57:737–41. Olsen J. Do pregnant women report use of dispensed medications?
15 Medicines in Pregnancy Working Party of the Australian Drug Evalu- Epidemiology 2001;12:497–501.
ation Committee. Prescribing medicines in pregnancy. An Australian 25 Werler MM, Mitchell AA, Hernandez-Diaz S, Honein MA. Use of over-
categorisation of risk of drug use in pregnancy, 4th edn. 1999 the-counter medications during pregnancy. Am J Obstet Gynecol
[www.tga.gov.au/docs/html/medpreg.htm] Accessed 12 January 2005;193:771–7.
2003. 26 Shaheen SO, Newson RB, Sherriff A, Henderson AJ, Heron JE, Burney
16 de Jong PC, Nijdam WS, Zielhuis GA, Eskes TK. Medication during low- PG, et al. Paracetamol use in pregnancy and wheezing in early child-
risk pregnancy. Eur J Obstet Gynecol Reprod Biol 1991;41:191–6. hood. Thorax 2002;57:958–63.

566 ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology

 Drug prescription patterns in pregnancy

Appendix 1. Prescription rate per 100 women per trimester* and the results of the chi-square test for trend for all drugs and for the drugs
ordered into the three categories

Trimester x2 test for trend

Total period Pregnancy

28 27 26 25 24 23 22 21 1 2 3 4 x2 P Slope x2 P Slope

All drugs 43.0 43.4 43.3 44.0 44.2 43.0 43.2 43.3 43.6 49.3 60.8 68.0 873.218 0.000 / 320.495 0.000 /
I: Drugs for chronic diseases
Drugs used in diabetes (A10) 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.5 0.5 0.5 0.6 0.4 2.126 0.145 1.695 0.193
Corticosteroids, dermatological (D07) 4.7 5.1 4.7 5.1 5.1 4.9 5.2 2.7 3.9 3.6 3.4 4.7 29.701 0.000 \ 1.400 0.237
Corticosteroids, systemic (H02) 0.8 0.7 0.8 0.8 0.8 0.7 0.9 0.7 0.4 0.4 0.4 0.6 14.823 0.000 \ 0.000 1.000
Thyroid therapy (H03) 0.7 0.7 0.7 0.8 0.8 0.8 1.0 0.9 0.9 0.9 0.9 1.0 4.930 0.026 / 0.000 1.000
Anti-inflammatory and antirheumatic 6.2 6.4 7.1 7.2 7.4 7.1 7.4 6.7 2.2 0.7 0.3 5.0 407.643 0.000 \ 86.643 0.000 \
drugs (M01)
Antimigraine medication (N02C) 0.8 1.0 0.9 1.0 1.0 0.9 1.0 0.8 0.3 0.0 0.0 0.6 72.332 0.000 \ 25.607 0.000 \
Antiepileptics (N03A) 0.3 0.4 0.3 0.3 0.3 0.4 0.3 0.2 0.3 0.3 0.2 0.3 1.844 0.174 0.150 0.698
Antipsychotics and antidepressants 3.0 3.0 2.9 3.1 3.0 2.9 3.2 2.6 1.9 1.0 0.9 2.1 107.641 0.000 \ 17.374 0.000 \
(N05A, excl. N05AB04; N06A)
Antiasthmatics (R03) 2.4 2.9 2.7 2.9 2.9 2.6 2.6 2.6 2.4 2.4 2.3 2.1 9.788 0.002 \ 0.145 0.704
II: Drugs for short-time and occasional use
Antispasmodic and anticholinergic agents and 1.6 1.4 1.5 1.5 1.5 1.6 1.3 1.4 0.9 0.3 0.4 0.7 89.387 0.000 \ 15.780 0.000 \
propulsives (A03, excl. A03FA01)
Antidiarrhoeals, intestinal 0.6 0.7 0.7 0.7 0.7 0.6 0.7 0.6 0.6 0.5 0.6 1.9 16.933 0.000 / 0.017 0.897
anti-inflammatory/anti-infective
agents (A07)
Antifungals for dermatological use (D01) 2.6 2.3 2.4 2.7 2.1 2.4 2.4 2.1 2.6 2.9 3.2 4.7 44.349 0.000 / 3.579 0.059
Emollients and protectives (D02) 2.0 2.3 1.9 2.0 2.1 1.6 2.0 1.7 2.1 2.3 2.2 2.7 4.457 0.035 / 0.276 0.599
Antibiotics and chemotherapeutics for 1.3 1.4 1.1 1.1 1.0 1.0 1.0 1.0 0.8 0.7 0.6 1.2 16.963 0.000 \ 0.644 0.422
dermatological use (D06)
Antiacne preparations (D10) 1.3 1.4 1.1 1.1 1.0 1.0 1.0 1.0 0.8 0.7 0.6 1.2 9.940 0.002 \ 6.557 0.010 \
Antibacterials for systemic use (J01) 8.2 8.0 8.5 8.2 9.0 8.2 7.9 8.1 6.3 7.3 8.8 13.3 19.427 0.000 / 24.448 0.000 /
Analgesics and antipyretics (N02B) 2.4 2.5 2.7 2.1 2.1 2.1 2.0 2.1 1.4 1.1 1.1 1.6 69.431 0.000 \ 1.743 0.187
Anxiolytics, hypnotics and sedatives 2.7 2.9 2.5 2.9 3.2 3.0 2.9 2.6 1.2 0.9 1.5 2.4 66.673 0.000 \ 1.797 0.180
(N05B, N05C)
Antiparasitic products, insecticides 0.7 0.7 0.6 1.0 0.9 0.8 0.9 0.7 0.2 0.1 0.3 0.7 22.614 0.000 \ 1.074 0.300
and repellents (P)
Antihistamines for systemic use 2.2 2.2 1.7 1.9 1.8 2.3 2.2 1.8 1.0 0.4 0.3 1.2 109.604 0.000 \ 20.800 0.000 \
(R06, excl. R06AD and R06AE)
Ear, eye, nose and throat preparations 6.9 6.7 6.9 7.6 6.9 6.5 6.9 6.4 5.2 5.2 4.8 5.2 63.942 0.000 \ 1.111 0.292
(S02, S03, S01, R01, R02A, R05)
III: Drugs for pregnancy-related symptoms
Antacids (A02A) 1.1 0.9 0.6 0.5 0.5 0.4 0.5 0.6 2.1 8.5 16.7 0.5 1533.455 0.000 / 692.835 0.000 /
Antiemetics (A03FA01, A04A, 1.3 1.4 1.6 1.4 1.0 1.3 1.3 1.4 5.8 2.0 1.1 0.8 24.677 0.000 / 208.959 0.000 \
N05AB04, R06AD, R06AE)
Laxatives (A06) 1.5 1.8 1.3 1.3 1.3 1.5 1.2 1.5 2.4 2.9 2.8 6.9 334.565 0.000 / 2.018 0.155
Iron preparations (B03A) 3.2 2.4 1.8 1.5 1.2 1.1 1.2 1.3 5.2 21.0 31.5 30.4 6638.584 0.000 / 1208.418 0.000 /
Folic acid and derivatives (B03B) 1.2 1.5 1.6 2.0 2.4 3.1 4.1 6.1 8.6 3.5 4.7 5.2 460.647 0.000 / 79.302 0.000 \
Gynaecological anti-infectives and 2.6 2.5 2.8 2.7 2.5 2.5 2.7 2.7 3.6 6.5 7.2 2.6 168.624 0.000 / 67.139 0.000 /
antiseptics (G01)
Gonadotrophins and other ovulation 0.9 1.0 1.3 1.5 1.9 2.5 2.8 4.2 2.4 0.1 0.1 0.0 25.649 0.000 \ 168.553 0.000 \
stimulants (G03G)

*Trimester 28 to 25 represents the second year before pregnancy, trimester 24 to 21 represents the first year before pregnancy. Trimester 1–3 is
the pregnancy period and trimester 4 is the period after pregnancy.

ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology 567

 Bakker et al.

Appendix 2. Total number of prescription drugs per trimester* and the distribution of these drugs according to the risk classification (only
the prescribed drugs that were categorised into drugs for chronic conditions, drugs for occasional use and drugs for pregnancy-related
symptoms were included)

Trimester

28 27 26 25 24 23 22 21 1 2 3 4

Drugs for chronic diseases

Total number of prescription drugs 1052 1133 1120 1174 1174 1131 1162 1062 701 536 520 919
Proportion (%) classified as
A 36.7 38.0 36.2 35.7 36.8 35.9 37.5 36.7 50.4 62.9 67.5 41.8
B 14.5 15.5 14.0 15.5 14.3 15.5 14.1 15.2 17.1 17.4 16.0 13.7
C 46.7 44.5 48.0 47.1 47.4 46.8 47.0 47.1 30.8 17.5 14.6 42.3
D (1X) 2.1 1.9 1.8 1.7 1.4 1.9 1.4 1.0 1.7 2.2 1.9 2.2
Drugs for short-time and occasional use
Total number of prescription drugs 1632 1628 1587 1651 1636 1553 1573 1497 1166 1109 1186 1805
Proportion (%) classified as
A 47.9 45.9 48.3 47.6 46.5 45.7 45.5 49.9 60.8 75.1 72.2 58.1
B 32.2 34.3 32.0 33.6 32.4 34.3 35.5 31.5 29.1 18.8 19.4 31.2
C 12.5 13.0 11.8 11.8 12.9 13.1 12.1 12.6 7.8 5.5 8.0 8.6
D (1X) 7.4 6.7 7.9 7.1 8.2 6.9 6.9 5.9 2.3 0.5 0.4 2.1
Drugs for pregnancy-related symptoms
Total number of prescription drugs 593 573 588 570 594 659 748 975 1433 1913 2612 2051
Proportion (%) classified as
A 83.0 80.6 77.7 76.7 75.1 73.0 72.1 72.4 89.2 97.6 97.6 95.3
B 11.6 14.7 17.3 18.8 18.7 20.3 21.0 18.5 5.9 1.2 1.3 3.7
C 3.4 3.5 2.7 2.6 1.9 1.8 2.1 1.5 2.1 1.0 1.0 1.0
D (1X) 2.0 1.2 2.2 1.9 4.4 4.9 4.8 7.6 2.9 0.2 0.1 0.0

*Trimester 28 to 25 represents the second year before pregnancy, trimester 24 to 21 represents the first year before pregnancy. Trimester 1–3
is the pregnancy period and trimester 4 is the period after pregnancy.

568 ª RCOG 2006 BJOG An International Journal of Obstetrics and Gynaecology