J. Perinat. Med. 41 (2013) 301–307 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.

1515/jpm-2012-0091

Pharmacovigilance in pregnancy: adverse drug reactions

associated with fetal disorders

Carmen Wettach1, Janine Thomann1, Conclusions: The results suggest that the nervous system
Claudia Lambrigger-Steiner1, Thierry Buclin2, drug group bears an especially high risk for malformations.
Jules Desmeules3 and Ursula von Mandach1,* The most commonly identified drug exposures can help
1 focus pharmacoepidemiologic efforts in drug-induced birth
Department of Obstetrics and Gynecology, Perinatal
defects.
Pharmacology, Zurich University Hospital, Zurich,
Switzerland
2
Division of Clinical Pharmacology and Toxicology, Keywords: Drug use; fetal disorders; pharmacovigilance;
Department of Internal Medicine, University Hospital pregnancy; safety; teratovigilance.
Lausanne, Switzerland
3
Division of Clinical Pharmacology and Toxicology,
Department of Internal Medicine, Geneva University Introduction
Hospitals, Geneva, Switzerland
Despite lingering safety questions, pregnant women may
intentionally or inadvertently be exposed to various prescrip-
tion drugs for pregnancy and non-pregnancy indications.
Abstract
Current utilization studies that ascertain the most commonly
Objective: To provide the first update on drug safety profiles used drugs in pregnancy are important for establishing priori-
and adverse drug reactions (ADRs) associated with fetal dis- ties in birth-defects research with major public health impli-
orders from the Swiss national ADR database. cations [11].
Methods: We conducted a retrospective study using data Studies conducted among pregnant women in the USA and
from 202 pharmacovigilance reports on drug-associated fetal in some European countries show exposure to high rates of
disorders from the Swiss national ADR database from 1990 to prescription medications, including exposure to medications
2009. Evaluated aspects included administrative information with known teratogenic potential [1, 2, 7, 10, 16]. Engeland et
on the report, drug exposure, and disorders. al. [7] found that among more than 100,000 pregnant women
Results: The ADR reporting frequency on the topic of fetal in Norway in 2004–2006, approximately 57% received a
disorders has increased during the last 20 years, from only 1 prescription medication. Studies from France and Germany
report in 1991 to a maximum of 31 reports in 2008. Nervous showed an even higher rate of more than 85% [6, 15].
system drugs were the most frequently reported drug group However, at the time of marketing, there exist little data
(40.2%) above all antidepressants and antiepileptics. The on the safety of a drug used in pregnancy and adverse drug
highest level of overall drug intake could be observed for the reactions (ADRs) on the fetus. Initial data on a drug’s safety
1st trimester (85.4%), especially for the first 6 weeks of preg- profile concerning its use during pregnancy are provided prior
nancy. The most frequently reported types of fetal disorders to marketing by reproductive toxicity studies in animals. Such
were malformations (68.8%), especially those of the muscu- studies are quite reliable for the detection of a drug’s terato-
loskeletal and circulatory systems. A positive association was genic potential because only few drugs that did not show a
discovered between antiepileptics and malformations in gen- teratogenic effect in animals are later found to be teratogenic
eral and in particular of the circulatory system and the eye, in humans. However, because of differences in the species’
ear, face, and neck. pharmacokinetic profiles, findings about toxic doses in animals
can only limitedly be extrapolated to humans. Furthermore,
clinical trials in drug development generally exclude pregnant
women for ethical reasons.
*Corresponding author: These factors increase the importance of ongoing risk
Prof. Dr. Pharm. Ursula von Mandach assessment in the postmarketing phase. In fact, postmar-
Department of Obstetrics and Gynecology
keting observational studies have revealed associations
Perinatal Pharmacology
between many commonly used drugs and various birth
Zurich University Hospital
Zurich defects [3, 4, 26].
Switzerland The aim of this study was to provide the first update on
Tel.: +41 44 255 51 36 the existing postmarketing pharmacovigilance data on drug-
Fax: +41 44 255 44 30 associated fetal disorders from the Swiss national ADR
E-mail: [email protected] database.

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302 Wettach et al., Pharmacovigilance in pregnancy

Materials and methods To characterize the study group, the following details from the
VigiFlow ADR reports were collected: the report year, the sender,
Data source the sender ’s report number, the report’s seriousness (serious, not
serious), the reason for seriousness (death, life threatening, hospi-
The Swiss national ADR database, called VigiFlow, contains ADR talization, disabling, congenital anomaly, other), the number and
reports from the entirety of Switzerland’s approximately 7 million types of suspected drugs, the active substance with its Anatomical
inhabitants. It is held by the national pharmacovigilance center Therapeutic Chemical (ATC) code, the concomitant drugs, the route
run by the Swiss Agency for Therapeutic Products (Swissmedic), of administration, the reason for drug intake, the date of drug intake,
which is the central supervisory authority for therapeutic products the date of the last menstrual period, the reported fetal disorders as
in Switzerland. Swissmedic is a public service organization of the well as possible neonatal disorders.
federal government and has its headquarters in Berne. Most of the
reports are spontaneous (97%); others are sourcing from clinical Analysis
studies. Reports on observed ADRs are sent by health-care profes-
sionals to one of the regional pharmacovigilance centers (RPVCs) The gestational age at the time of drug exposure was calculated
located in Zurich, Basel, Berne, Lausanne, Geneva, and Lugano. The from the first day of the mother ’s last menstrual period [weeks post
RPVCs register, classify, and evaluate the reports and enter them menstruation (p.m.), month or trimester].
directly into VigiFlow. Moreover, reports on ADRs are collected Fetal disorders were divided into four subcategories: growth retar-
by the pharmaceutical companies and sent directly to Swissmedic, dation, malformations, chromosomal abnormalities, and other fetal
which enters the incoming reports into VigiFlow. Every report disorders. The subcategory “malformations” was further categorized
entering VigiFlow is evaluated by a clinical reviewer and checked according to chapter Q of the International Statistical Classification
for quality and completeness. Swissmedic is closely involved in the of Diseases, 10th Revision, system with respect to the affected organ
World Health Organization (WHO) program for drug monitoring and system.
its classification system. For the classification of ADR reports, sever- The reports’ quality was assessed by four criteria: ATC code of the
al international standards, documents, and guidelines are used [5, 13, suspected drug, route of administration, chronology of drug intake,
21–23] (Table 1). All ADR reports in VigiFlow are directly submitted and listed ADR. A report’s quality was categorized as sufficient if all
to WHO’s ADR database in Uppsala, Sweden (VigiBase). VigiFlow four criteria were provided.
is compatible with the International Conference on Harmonisation The primary end point was drug exposure (type and number of
Guideline E2B and complies with international standards [25]. It drugs, gestational age) in relation to observed fetal disorders (focus-
contains administrative and identification information (e.g., ID num- ing on malformations). Secondary end points were parameters char-
ber, primary source and sender, and seriousness) as well as informa- acterizing the quality of reports (year, sender).
tion on the case report (patient characteristics and information on
suspected and concomitant drugs and ADRs).
Statistics

Study group For statistics, the statistical program PASW, version 18, was used.
For discrete data, relative frequencies were computed. Continuous
The Swiss national ADR database VigiFlow was searched for all parameters were described by mean, standard deviation (SD), me-
ADR reports from January 1, 1990, until December 31, 2009, cat- dian, and interquartile range (IQR). Associations between drugs and
egorized in the System Organ Class (SOC) category No. 1500 (fetal disorders were confirmed by the likelihood ratio test and the t-test
disorders) of the WHO-Adverse Reaction Terminology (ART) sys- (two-tailed).
tem. This category consists of predefined terms of abnormal fetal
conditions or development occurring during pregnancy or present at
birth as well as other negative pregnancy outcomes such as induced Results
abortion. Cases of drug exposure during pregnancy without negative
fetal outcome are also included in this category. To restrict the study
The primary search resulted in 1727 cases, of which 1503
group to relevant cases of fetal disorders, only reports with sufficient
cases were ruled out by the exclusion criteria. Of the resulting
information on at least one negative fetal outcome of the SOC1500
category were included. The exclusion criteria were no information 224 cases, 16 were excluded as they were incorrectly classi-
on a negative outcome at all, no negative outcome of the SOC1500 fied. Another six cases were excluded because they were dou-
category, or fetal death, intrauterine death, miscarriage, stillbirth, ble reports. The final study group, as defined by the inclusion
abortion, missed abortion, spontaneous incomplete abortion, or criteria, therefore included a total of 202 ADR reports from
induced abortion as the only reported outcome. the Swiss national ADR database from January 1, 1990 until

Table 1 Classifications used in VigiFlow.

Reactions/events (ADRs) WHO-Adverse Reaction Terminology (WHO-ART) [21]

Drugs WHO-Drug Dictionary (WHO-DD), with information about active ingredients and ATC codes [22]
Medical history/indications WHO International Classification of Diseases, 10th Revision (WHO-ICD-10) [23]
Seriousness International assessment criteria, according to ICH E2A and E2D [13]
Causality WHO classification. Further specification in collaboration with the RPVCs: certain, probable, possible,
unlikely, unclassifiable
ADRs = Adverse drug reactions, ATC = Anatomical Therapeutic Chemical, ICH = International Conference on Harmonisation, RPVC = Regional
pharmacovigilance center, WHO = World Health Organization.

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 Wettach et al., Pharmacovigilance in pregnancy 303

40

35

30
Number of reports

25

20

15

10

0
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Year

Figure 1 Frequency of reports (n) per year in the study group.

December 31, 2009, with sufficient information on at least intake (6.4%) followed by the missing route of administration
one negative fetal outcome of the SOC1500 category. (3.6%). Within the study group, 78.7% of the reports were
Reports about fetal disorders have increased considerably classified as “serious” and 21.3% as “not serious”. The most
during the last 20 years (Figure 1). Starting from 1991 with frequent special reasons for a report to be classified as serious
only one case, the number of reported cases significantly were “congenital anomaly” (28.3%) and “death” (16.4%).
increased in 2006, reaching a maximum in 2008 with 31
reports about fetal disorders. The overall reporting frequency Drug exposure
in VigiFlow shows that in the general population also, the
number of ADR reports sent per year has increased during the A total of 361 suspected drugs were reported in the study
last 20 years (Figure 2). group. Most women reported only one suspected drug
Most ADR reports were sent by the Swiss Teratogen (58.9%). Two drugs were taken by 22.3% of the women,
Information Service (38.6%) followed by the RPVCs (37.6%) three drugs were taken by 10.4% of the women, and four or
and the pharmaceutical companies (21.8%); other senders more drugs were taken by 8.5% of the women. The maximum
played only a minimal role (2.0%) (Figure 3). number of suspected drugs reported in a case was nine (mean:
Sufficient quality (as defined above) was provided for 1.79; SD: 1.31; median: 1.00; IQR: 1).
315 of the reported drugs (87.3%). The most frequent reason Drugs acting on the nervous system (anatomical main
for insufficient quality was the missing chronology of drug group N) were most frequently reported, whereas drugs from

10,000
9000
8000
Number of reports

7000
6000
5000
4000
3000
2000
1000
0
>2000 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Year

Figure 2 Overall frequency of reports (n) per year in VigiFlow.

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304 Wettach et al., Pharmacovigilance in pregnancy

40 trimesters. Most drugs were consumed in the 1st trimester

(85.4%), followed by the 2nd trimester (44.1%) and the 3rd
35 trimester (36.5%). The drug intake per week of pregnancy
30 could be assessed for 284 drugs. It shows a high intake in
the 1st trimester, mainly during the first 6 weeks p.m. (range:
% of total reports

25 57.7%–67.6%). In week 7, the drug intake was 50.0% and

20
decreased further afterwards (Figure 4).

15
Disorders
10
Among fetal disorders, malformations were most frequently
5 reported (68.8%) followed by growth retardation (18.3%)
and other fetal disorders (17.8%). Chromosomal abnormali-
0
Other Pharm. companies RPVCs STIS ties were reported in 6.9% of the cases (Figure 5). In cases of
Main groups of senders malformation, the most frequently afflicted organ system was
the musculoskeletal system (35.3%), followed by the circula-
Figure 3 Frequency of reports (%) according to the sender. tory system (25.2%). Malformations of the eye, ear, face, and
STIS = Swiss Teratogen Information Service, RPVC = Regional phar- neck (15.1%), malformations of the urinary system (13.7%),
macovigilance center. of the nervous system (12.9%), of genital organs (7.9%), as
well as “other malformations” (7.9%), cleft lips and cleft
other anatomical main groups did not differ significantly from palates (7.2%), and malformations of the digestive system
each other in frequency (Table 2). The six most frequently (6.5%) were reported less often (Figure 6).
reported therapeutic subgroups were psychoanaleptics (N06, Statistically significant associations between drugs and
13%), psycholeptics (N05, 12.5%), antiepileptics (N03, disorders were confirmed for antibacterials for systemic use
8.6%), antivirals for systemic use (J05, 5.5%), antiacne prep- (J01) and chromosomal abnormalities and fetal death, respec-
arations (D10, 5%), and antibacterials for systemic use (J01, tively, as well as for antiepileptics (N03) and malformations
4.7%). From the pharmacological subgroups, antidepres- (in general and particularly of the circulatory system and the
sants (N06A, 12.5%), antiepileptics (N03A, 8.6%), anxio- eye, ear, face, and neck) and neonatal disorders, respectively
lytics (N05B, 6.1%), direct-acting antivirals (J05A, 5.5%), (Table 3).
antipsychotics (N05A, 5.3%), and antiacne preparations for
topical use (D10A, 3.9%) were most frequently reported. The
three most frequently reported chemical subgroups were from Discussion
the nervous system: selective serotonin reuptake inhibitors
(SSRIs) (N06AB, 6.9%), benzodiazepines (N05BA, 6.1%), The first study about ADR reports in Switzerland focusing
and antidepressants excluding SSRIs (N06AX, 4.7%). on the WHO-ART SOC category No. 1500 (fetal disorders)
The drug intake per trimester could be assessed for 329 includes all reports of the existing (since 1990) Swiss national
of the reported 361 drugs; 25.8% were taken in all three ADR database.

Table 2 Frequency of anatomical main groups.

Anatomical main groups. Frequency, n (%) 95% CI

Lower Upper

A Alimentary tract and metabolism 31 (8.6) 5.5 11.4

B Blood and blood-forming organs 10 (2.8) 1.1 4.4
C Cardiovascular system 21 (5.8) 3.6 8.3
D Dermatologicals 28 (7.8) 5 10.5
G Genitourinary system and sex hormones 15 (4.2) 2.2 6.4
H Systemic hormonal preparations (excluding sex hormones and insulins) 10 (2.8) 1.1 4.7
J Antiinfectives for systemic use 41 (11.4) 8.3 14.7
L Antineoplastic and immunomodulating agents 24 (6.6) 4.2 9.7
M Musculoskeletal system 10 (2.8) 1.4 4.7
N Nervous system 145 (40.2) 35.5 45.2
P Antiparasitic products, insecticides and repellents 9 (2.5) 1.1 4.2
R Respiratory system 14 (3.9) 2.2 6.1
V Various 2 (0.6) 0 1.4
Unknown 1 (0.3) 0 0.8
Total 361 (100) 100 100
CI = Confidence interval.

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 Wettach et al., Pharmacovigilance in pregnancy 305

80

70

60

50

% of drugs
40

30

20

10

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Weeks of pregnancy (p.m.)

Figure 4 Drug intake per week of gestation.

content could be classified as sufficient. Information about the

Malformations
time of drug exposure was missing entirely for only 6.4% of
the drugs, demonstrating a good overall quality of reports.
Growth retardation
In almost 60% of the cases, only one suspected drug was
reported. This simplifies the evaluation of the cases regarding
Other fetal disorders the association between drug and ADR. The finding that an
association between drugs and fetal disorders was most fre-
Chromosomal
abnormalities quently reported for drugs acting on the nervous system (N)
(40.2% of all drugs) has to be interpreted carefully. It does
0 10 20 30 40 50 60 70 80
not necessarily mean that these drugs are the most dangerous
% of reports
ones. If these data are compared with the overall reporting
Figure 5 Type of fetal disorder (frequency, %) in reports.
frequency in VigiFlow, it becomes obvious that drugs act-
ing on the nervous system (N) are also the most frequently
reported anatomical main group throughout the general popu-
We have been able to show that the number of reports on lation. Drugs acting on the nervous system (N) are widely
the topic of fetal disorders has increased considerably. This used and, more importantly, are the drug group of primary
may be a result of the development and improvement of the interest concerning ADRs. These factors should be borne in
reporting system in Switzerland, which is now working much mind when drawing conclusions from these data.
more efficiently than 20 years ago rather than of an increase The fact that 25% of the drugs were taken during the whole
in the appearance of fetal disorders over the years. This inter- pregnancy indicates a high percentage of long-term therapies
pretation is supported by the overall reporting frequency in during pregnancy. More drugs were taken in the 1st trimester
VigiFlow, which shows that not only in the study group but (85.4%) than in the 2nd (44.1%) and the 3rd (36.5%) trimesters.
also in general the number of ADR reports sent per year has Our data are in contradiction with those of other authors who
increased during the last 20 years. Not only the number but have found an increase in the number of exposed women and
also the quality of the reports has increased with the years. the number of prescribed drugs during pregnancy [6, 14]. One
For 87% of the reported suspected drugs, the informational explanation could be that in the other studies only prescribed

Musculoskeletal system
Circulatory system
Eye, ear, face and neck
Urinary system
Nervous system
Genital organs
Other malformations
Cleft lip/cleft palate
Digestive system
Respiratory system
0 5 10 15 20 25 30 35 40
% of cases with malformations

Figure 6 Type of malformations (frequency, %) in the subclass “malformations”.

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306 Wettach et al., Pharmacovigilance in pregnancy

Table 3 Drugs and corresponding disorders.

ATC therapeutic subgroups

D10 J01 J05 N03 N05 N06 Other drugs

Fetal disorders
Growth retardation
Malformations +
Eye, ear, face, and neck +
Circulatory system +
Chromosomal abnormalities +
Other fetal disorders
Fetal death +
Neonatal disorders +
Other disorders +
Likelihood ratio test and t-test with significance level of 5%+positive association (P < 0.05).
ATC = Anatomical Therapeutic Chemical, J01 = Antibacterials for systemic use, N03 = Antiepileptic drugs, “other drugs” = ATC therapeutic sub-
groups other than D10, J01, J05, N03, N05, and N06.

drugs were assessed while in this study any kind of drug Our results have demonstrated the important relationship
intake (including self-medication and medication errors) was between drugs acting on the nervous system and malforma-
evaluated. Furthermore, in this study only cases with a nega- tions of the circulatory system as well as the relationship
tive fetal outcome, which occurred more frequently after drug between nervous system drugs and malformations of the eye,
intake in the 1st trimester, were analyzed. ear, and neck. It is hoped that this study will lead to further
Malformations were the most frequently reported subcat- prospective pharmacoepidemiological and pharmacovigi-
egory of fetal disorders. The circulatory and the musculo- lance studies confirming these results.
skeletal systems were the most frequently affected organs,
suggesting a higher susceptibility compared with other organ
systems. Our data are in line with data from other sources Acknowledgments
such as from EUROCAT, 2000–2008 [8], or from Sachsen-
Anhalt, Germany, 2008 [9]. We thank Rudolf Stoller and Rosemarie Sift Carter from the Swiss
The association between antiepileptics (N03) and mal- Agency for Therapeutic Products Swissmedic, Berne, Switzerland,
for their support.
formations is widely described in the literature, suggesting
that antiepileptic drugs (AEDs) (especially valproate but
also other AEDs such as phenobarbitone, phenytoin, and References
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