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Clarithromycin in Early Pregnancy and the Risk of
Miscarriage and Malformation: A Register Based
Nationwide Cohort Study
Jon Trærup Andersen
1,2
*, Morten Petersen
1,2
, Espen Jimenez-Solem
1,2
, Kasper Broedbaek
1,2
, Nadia
Lyhne Andersen
3
, Christian Torp-Pedersen
4,5
, Niels Keiding
5
, Henrik Enghusen Poulsen
1,2,5
1Laboratory of Clinical Pharmacology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, 2Department of Clinical Pharmacology, Bispebjerg
Hospital, Copenhagen, Denmark,, 3Mental Health Centre Copenhagen, Copenhagen, Denmark, 4Department of Cardiology, Gentofte University Hospital, Hellerup,
Denmark, 5Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
Abstract
Background:
The antibiotic clarithromycin has been associated with fetal loss in animals and a study has found a doubling
in the frequency of miscarriages among women using clarithromycin in pregnancy. The aim of the study was to investigate
whether clarithromycin use in early pregnancy was associated with an increased risk for miscarriages and major
malformations.
Methods:
We conducted a nationwide cohort study including all women in Denmark with a known conception between
1997 and 2007. The Fertility Database was used to identify all women giving birth and the National Hospital Register was
used to identify all women with a record of miscarriage or induced abortion. Prescription data was obtained from the
National Prescription Register. The primary outcome was the number of miscarriages and offspring with major congenital
malformations among users of clarithromycin compared to non-users.
Results:
We identified 931 504 pregnancies (705 837 live births, 77 553 miscarriages, and 148 114 induced abortions). 401
women redeemed a prescription of clarithromycin in the first trimester of which 40 (10.0%) experienced a miscarriage and
among the live born nine (3.6%) had offspring with malformations. The hazard ratio (HR) of having a miscarriage after
exposure to clarithromycin was 1.56 (CI95% 1.14–2.13). There was no increased hazard of having a miscarriage when being
exposed to penicillin or erythromycin. There was no increased prevalence (OR = 1.03 (CI95% 0.52–2.00)) of having offspring
with malformations after exposure to clarithromycin.
Conclusions:
We found an increased hazard of miscarriage but no increased prevalance of having offspring with
malformations among women redeeming a prescription of clarithromycin in early pregnancy. This is supported by previous
studies in animals and humans. However, further research is required to explore the possible effect of treatment indication
on the associations found.
Citation: Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen NL, et al. (2013) Clarithromycin in Early Pregnancy and the Risk of Miscarriage and
Malformation: A Register Based Nationwide Cohort Study. PLoS ONE 8(1): e53327. doi:10.1371/journal.pone.0053327
Editor: Colin Simpson, The University of Edinburgh, United Kingdom
Received May 14, 2012; Accepted November 29, 2012; Published January 2, 2013
Copyright: ß2013 Andersen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study is supported by grants from the Danish Agency for Science, Technology and Innovation (http://en.fi.dk/), and the P. Carl Petersen Foundation
(http://www.pcarlp-fond.dk/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: All authors have declared that no competing interests exist.
* E-mail: jta@rh.dk
Introduction
Clarithromycin is a macrolide antibiotic used to treat common
infections including respiratory tract infections, skin infections and
helicobacter pylori infections. Only limited data are available
concerning the effect of clarithromycin on the human fetus when
used in pregnancy.
Animal studies have shown that clarithromycin can induce fetal
loss in rabbits and monkeys when used in very low dosages and in
high dosages, respectively. [1] One observational study concerning
pregnant women showed a doubling of the number of miscarriages
in women exposed to clarithromycin in early pregnancy compared
to a match control group. [2] There is limited knowledge
concerning the risk of congenital malformations among women
exposed to clarithromycin during pregnancy.
Based on the current knowledge clarithromycin is not
recommended for use in pregnancy. However, since use of
clarithromycin is used in very common conditions and only half of
pregnancies are planned a substantial number of women risk
exposure to clarithromycin in early pregnancy. [3].
We therefore conducted a nationwide cohort study testing the
hypothesis that use of clarithromycin in the first trimester is
associated with miscarriage. Furthermore, we investigated whether
there is an association between use of clarithromycin in the first
trimester and major congenital malformations.
PLOS ONE | www.plosone.org 1 January 2013 | Volume 8 | Issue 1 | e53327
Methods
We identified all registered pregnancies in Denmark with
a conception between 1 January 1997 and 31 March 2007
(n = 934 480). We excluded 2976 pregnancies due to coding
errors.
From the Danish Fertility Database all live births with
a conception date in the study period were identified. Using the
National Hospital Register we identified all registered cases of
miscarriages and provoked abortions (O02, O03, O04, O05 or
O06 according to the International Classification of Diseases 10
th
Danish revision). Information on major malformations was
obtained from the National Hospital Register. All major mal-
formations and subgrouping are according to the European
Surveillance of Congenital Anomalies (EUROCAT) classification
system guide 1.3. [4]
The Danish Fertility Database consists of individual-level data
on the mother and father, including a unique identification
number, age, previous births and abortions, as well as birth weight
and length, death and cause of death, sex and gestational age of
the offspring. The time of conception is based on ultrasound
estimates or information of the date of last menstruation. More
than 99.5% of births in Denmark since 1978 are registered in the
Danish Fertility Database. [5,6] The National Hospital Register
contains information on all hospitalizations in the country,
including admittance data and discharge diagnosis. [7,8] It holds
more than 99% of discharge records from all Danish hospitals. [9]
Since 1997, information on gestational length has been added to
diagnoses of provoked abortion and miscarriage.
Information on prescription medication use was collected from
the National Prescription Register (the Register of Medicinal
Product Statistics). [10,11] Exposure was defined as redemption of
a prescription of a drug containing clarithromycin (Anatomical
Therapeutic Chemical Classification (ATC) J01FA09) for systemic
use.
The register contains individual-level data on all prescribed
drugs dispensed at all pharmacies in Denmark since 1995.
Pharmacies are required by law to register prescriptions and this
activity is coupled with reimbursement of expenses from the state,
which ensures highly accurate prescription data. Completeness has
previously been estimated to be 97.5%. [12] The register has no
information on indication of treatment or over-the-counter drugs.
The infection treated with clarithromycin, could itself induce
miscarriages. To test for this possible confounding by indication
we compared the hazard of miscarriage for redeeming a pre-
scription of clarithromycin with the hazard of miscarriage when
redeeming a prescription of phenoxymethylpenicillin (ATC
J01CE02) for systemic use or erythromycin (ATC J01FA01) for
systemic use in the first trimester. Clarithromycin is furthermore
used in treatment of helicobacter pylori infections in combination
with proton-pump inhibitors (PPI) (ATC A02BC) and amoxicillin
(ATC J01CA04). We therefore tested whether redemption of
prescriptions on these drugs in the first trimester was associated
with miscarriages. Furthermore we compared the risk of mis-
carriage of women exposed to clarithromycin directly against the
risk of women exposed to the four above mentioned drugs.
To exclude the importance of other characteristics of women
using clarithromycin during pregnancy, we compared the result
with the hazard of dispensing clarithromycin in the 12 weeks
before pregnancy.
Statistics
All data management and analyses were performed using SAS
software, version 9.2 (SAS Institute Inc., Cary, NC, USA).
Cox proportional hazard regression models with first trimester
exposure to clarithromycin as a time dependent variable and time
from conception to miscarriage as outcome. Time to birth or
induced abortion was considered as censoring variables. Prescrip-
tions redeemed after miscarriage or censoring was not included in
the analyses.
A priori, an unadjusted model was planned in addition to
a model adjusted for maternal age (five categories, ,20, 20–24,
25–29, 30–34 and $35 years), the number of previous
miscarriages (four categories, 0, 1, 2, $3 miscarriages), income
(categorized as quartiles) and education (four categories).
Two logistic regression models were used to estimate the ratio of
malformations among women redeeming a prescription of
clarithromycin in the first trimester compared to unexposed.
The first model was unadjusted and the second adjusted for
maternal age (five categories, ,20, 20–24, 25–29, 30–34 and $35
years), the number of previous births (four categories, 0, 1, 2, $3),
income (categorized as quartiles) and education (four categories).
Data on maternal age, previous registered miscarriages, pre-
vious births and income had less than 1% missing values. If
information on highest achieved educational level was missing,
data from the following year was used. Data on educational level
was missing for 3.4% of the records.
For all analyses, a two-sided value of p,0.05 was considered
statistically significant, and all hazard ratios and odds ratios are
presented with 95% confidence intervals.
Ethics
All data were linked in computers held by Statistics Denmark
and were made available with encrypted personal information.
This ensured that no individuals could be identified. In Denmark
The Act on Processing of Personal Data does not require ethical
permission or obtained written informed consent for anonymised
retrospective register studies. The Danish Data Protection Agency
approved the study (No. 2008-41-2517).
We report our findings according to strengthening the reporting
of observational studies in epidemiology (STROBE). [13].
Results
We included 931 504 pregnancies identified within the study
period. 77 553 (8.3%) miscarriages, 148 114 (15.9%) induced
abortions and 705 837 (75.8%) live births.
Women redeeming a prescription of clarithromycin in the study
period were older (p = 0.003) and had a lower educational level
(,0.0001) compared to unexposed women.
Miscarriage
In the 401 pregnancies exposed to clarithromycin in the first
trimester, 40 (10.0%) of the pregnancy outcomes were recorded as
miscarriages, compared to 77 513 (8.3%) in the unexposed group.
We found a hazard ratio of 1.66 (CI95% 1.22–2.26) of having
a miscarriage when being exposed to clarithromycin. Adjusting for
age, number of previous miscarriages, educational level and
income the hazard was 1.56 (CI95% 1.14–2.13).
Major Congenital Malformations
Among the 401 women exposed to clarithromycin in the first
trimester 253 resulted in live births. Among these, nine children
were diagnosed with a major malformation (3.6%) compared to 24
808 (3.5%) among children born by unexposed mothers (table 1).
We found an unadjusted odds ratio of 1.01 (CI95% 0.52–1.97) of
having a child diagnosed with a major malformation when
exposed to clarithromycin in the first trimester compared to
Clarithromycin, Miscarriage and Malformation
PLOS ONE | www.plosone.org 2 January 2013 | Volume 8 | Issue 1 | e53327
unexposed women, and an adjusted odds ratio of 1.03 (CI95%
0.53–2.00). There was no significant difference in the number of
major malformation according to the EUROCAT grouping
system between women exposed to clarithromycin and unexposed
women (table 2).
Other Analyses
To investigate if the increased hazard of having a miscarriage
when exposed to clarithromycin could be confounded by
indication, we tested for the hazard of some drugs typically used
for respiratory infections in Denmark. We found no increased
hazard of having a miscarriage after redeeming a prescription, in
the first trimester, of erythromycin (HR =1.00 (CI95% 0.92–1.10))
or phenoxymethylpenicillin (HR = 1.02 (CI95% 0.98–1.07)).
Furthermore, we investigated if use of PPI or amoxicillin, both
used as first line treatment in combination with clarithromycin in
helicobacter pylori infection, were associated with miscarriages.
We found no increased HR for PPI or amoxicillin (table 3,
figure 1). Furthermore we estimated the hazard of miscarriage in
women exposed to clarithromycin compared directly to women
exposed to the drugs used in same conditions as clarithromycin.
We found that women exposed to clarithromycin had an adjusted
hazard of 1.51 (CI95% 1.09–2.12) of having a miscarriage
compared directly to the hazard of miscarriage in women exposed
to phenoxymethylpenicillin, and 1.45 (CI95% 1.04–2.03) com-
pared directly to the hazard of miscarriage in women exposed to
erythromycin (figure 2). Women exposed clarithromycin had an
adjusted hazard of 1.69 (CI95% 1.19–2.39) of having a miscarriage
compared directly to women exposed to PPIs and an adjusted
hazard of 1.88 (CI95% 1.34–2.65) compared directly to women
exposed to amoxicillin (figure 2).
There was no increased hazard of having a miscarriage when
being exposed to clarithromycin in the 12 weeks before conception
(HR = 0.90 (CI95% 0.77–1.06)).
Discussion
We found an increased hazard of having a miscarriage when
redeeming a prescription of clarithromycin in the first trimester of
pregnancy. We did not find an association between exposure to
clarithromycin and major congenital malformations.
The findings of this study strengthen other available data. In an
animal study an increased number of fetal losses among rabbits
given an intravenous dose 17 times lower than the maximum
proposed human dose. [1] In monkeys, clarithromycin plasma
levels three times the human serum level, resulted in embryonic
loss. [1] An observational study showed that women treated with
clarithromycin in the first trimester had a doubling of the number
of miscarriages compared to a control group. Although the finding
was statistical significant compared to the control group the
authors noted that the number of miscarriages in the exposed
group was within the expected range and they conclude that
clarithromycin can be taken safely in pregnancy. [2]
To assess the robustness of our findings we analysed the hazard
of having a miscarriage when redeeming a prescription of
phenoxymethylpenicillin and erythromycin. These are two anti-
biotics commonly used in Denmark to treat respiratory infections.
We did not find increased hazard ratios of miscarriages in these
groups indicating that infections requiring these treatments are not
Table 1. Basic characteristics.
All pregnant women
Clarithromycin use n = 401 No clarithromycin use n = 931 103
Age (years)
,20 15 (3.7%) 30 811 (3.1%)
20–24 50 (12.5%) 120 727 (13.0%)
25–29 97 (24.2%) 296 369 (31.8%)
30–34 139 (34.7%) 308 991 (33.2%)
$35 100 (25.0%) 174 205 (18.7%)
Education
Low 199 (50.5%) 343 774 (37.8%)
Medium 103 (26.1%) 270 084 (29.7%)
High 69 (17.5%) 264 207 (29.1%)
No information 23 (5.8%) 31 157 (3.4%)
Income
Lowest quartile 105 (26.2%) 232 706 (25.0%)
Low quartile 116 (28.9%) 232 639(25.0%)
Medium quartile 96 (23.9%) 232 765 (25.0%)
High quartile 84 (21.0%) 232 993 (25.0%)
Number of previous miscarriages
0 321 (80.2%) 770 664 (82.3%)
1 62 (15.5%) 129 360 (13.9%)
2 13 (3.2%) 24 315 (2.6%)
$3 5 (1.3%) 6764 (0.7%)
doi:10.1371/journal.pone.0053327.t001
Clarithromycin, Miscarriage and Malformation
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associated with miscarriages nor do the drugs induce miscarriages
themselves. It has previously been shown that the transplacental
transfer of clarithromycin is two times that of erythromycin.
[14,15] This could potentially explain why we find an increased
hazard for clarithromycin but not for erythromycin. Furthermore,
we analyzed the hazard of having a miscarriage when redeeming
Table 2. Exposure to clarithromycin in the first trimester.
Type of major malformation
Number of offspring diagnosed
with a major malformation Odds ratio (CI95%)
Exposed
N = 253
Unexposed N = 705
584 Unadjusted adjusted
Congenital malformations of the nervous system 0 (0.0) 886 (0.1) – –
Neural Tube Defects 0 (0.0) 292 (0.0)
Congenital malformations of the eye 0 (0.0) 950 (0.1) – –
Congenital malformations of the ear, face and neck 0 (0.0) 439 (0.1) – –
Congenital malformations of the heart 2 (0.8) 5286 (0.8) 1.06 (0.26–4.25) 1.04 (0.26–4.17)
Oro-facial clefts 0 (0.0) 1295 (0.2) – –
Congenital malformations of the digestive system 0 (0.0) 1277 (0.2) – –
Congenital malformations of the internal urinary system 0 (0.0) 1819 (0.3) – –
Congenital malformations of the external genital organs 2 (0.8) 2077 (0.3) 2.70 (0.67–10.86) 2.86 (0.71–11.51)
Congenital malformations of the limbs 5 (2.0) 7509 (1.1) 1.88 (0.77–4.55) 1.97 (0.81–4.78)
Congenital malformations of the musculoskeletal system 0 (0.0) 1179 (0.2) – –
Chromosomal abnormalities 0 (0.0) 983 (0.1) – –
Teratogenic syndromes with malformations 0 (0.0) 63 (0.0) – –
Genetic syndromes and microdeletions 0 (0.0) 529 (0.1) – –
Other malformations 0 (0.0) 1131 (0.2) – –
Congenital malformations of the respiratory system 0 (0.0) 638 (0.1) – –
Abdominal wall defects 0 (0.0) 178 (0.0) – –
All major congenital malformations 9 (3.6) 24 808 (3.5) 1.01 (0.52–1.97) 1.03 (0.53–2.00)
CI95%, 95% confidence intervals.
doi:10.1371/journal.pone.0053327.t002
Figure 1. The hazard ratio of having a miscarriage when redeeming a prescription of a drug in the first trimester of pregnancy. All
hazards are adjusted for age, parity, educational level, and income. *Proton pump inhibitors.
doi:10.1371/journal.pone.0053327.g001
Clarithromycin, Miscarriage and Malformation
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a prescription of PPIs or amoxicillin. Both drugs are used in the
treatment of helicobacter pylori infections in combination with
clarithromycin. We did not find an increased hazard of mis-
carriage when redeeming prescriptions on these drugs, which
indicates that PPIs and amoxicillin and infections treated with
these drugs are not, associated with miscarriages. The hazards of
phenoxymethylpenicillin, erythromycin, PPIs and amoxicillin
suggest that the primary result regarding clarithromycin and
miscarriages are not a product of confounding by indication.
To address the importance of other characteristics of women
using clarithromycin, we compared the result with dispensing of
clarithromycin much earlier than the pregnancy period but found
no increased prevalence with dispensing in the 12 weeks before
pregnancy. This indicates that the increased hazard of having
a miscarriage is not explained by unaccounted characteristics of
exposed women.
We did not find an association between first trimester exposure
to clarithromycin and major congenital malformations. All though
this is a small study with limited power, the result is supported by
three other studies. [2,16,17] A higher rate of heart defects has
been observed among rat offspring when the mother was given
clarithromycin during pregnancy compared to unexposed con-
trols. [1] Likewise, studies on mice demonstrated a higher rate of
offspring with cleft palate when given clarithromycin compared to
controls. [1] None of the clarithromycin exposed in our study were
given a diagnosis of oro-facial cleft and we did not find an
increased odds ratio of being diagnosed with a heart defect when
Figure 2. The hazard ratio of having a miscarriage when redeeming a prescription of clarithromycin in the first trimester of
pregnancy directly compared to the hazard of women redeeming prescriptions of different drugs used in similar conditions. All
hazards are adjusted for age, parity, educational level, and income. *Proton pump inhibitors.
doi:10.1371/journal.pone.0053327.g002
Table 3. Sensitivity analyses. Adjusted hazard ratios of having a miscarriage when redeeming a prescription in the first trimester
compared to unexposed.
Number of
exposed
Number of
unexposed Hazard ratio unadjusted Hazard ratio adjusted
Erythromycin 6492 925 012 1.04 (0.95–1.14) 1.03 (0.94–1.13)
Phenoxymethylpenicillin 33 469 898 035 1.01 (0.97–1.06) 1.00 (0.96–1.04)
Proton pump inhibitors 3577 927 927 1.09 (0.96–1.24) 1.03 (0.91–1.18)
Amoxicillin 4584 926 920 0.96 (0.86–1.08) 0.92 (0.82–1.04)
doi:10.1371/journal.pone.0053327.t003
Clarithromycin, Miscarriage and Malformation
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exposed to clarithromycin in the first trimester compared to
unexposed.
The main limitation of the present study is the lack of
information concerning treatment indication and we can therefore
not completely rule out that our results are confounded by
indications. Furthermore, we do not have information on the
prescribed dosage and therefore the analyses are restricted to
treatment or no treatment. Even though the women went to the
pharmacy, redeemed the prescription and paid for the drug we do
not know whether or not they were exposed. If they were not
exposed, our results would be biased towards underestimating the
effect. Furthermore there is a risk of bias due to unaccounted
confounders; even though we analysed the risk miscarriage of
women exposed to clarithromycin before pregnancy we cannot
completely rule out that women exposed to clarithromycin might
differ from unexposed women in aspects causally related to the
outcome. This could include obesity, alcohol consumption,
smoking and antiphospholipid syndrome.
Another limitation is the low number of women exposed to
clarithromycin in the study period. Analyses of risk of different
subgroups of major congenital malformations should therefore be
interpreted with caution.
We only have information on the date the miscarriage was
recognized by the women and unfortunately not the exact time
when the fetus perished in the uterus. If the exposure to
clarithromycin was before the actual miscarriage, but after the
fetus perished, the analyses could be biased.
We used registers to define the outcomes and they may be
subject to misclassification. If women experience a miscarriage
without contacting a hospital the number of registered mis-
carriages would be underestimated. This underreporting has been
estimated to 30% [18] and is probably due to miscarriages early in
pregnancy. We find no indications of a difference in the reporting
of miscarriages between the two groups. If the increased hazard of
miscarriages in women treated for an infection during the first
trimester should be due to better reporting we would expect to find
the same increase in the women treated with erythromycin,
penicillin and amoxicillin, which we did not (table 3). The quality
of the malformation diagnoses has been validated and found to
have a predictive value of 88% for having a congenital malforma-
tion, with a completeness of 90% and misclassification, if any, was
most probably random. [19].
This study covers nationwide data and includes all registered
birth, provoked abortions and miscarriages in the study period.
We thereby minimize selection bias, and ensure high completeness
of data independent of social-, economic-, and educational level,
age and race.
The registers have previously been validated and found to be
accurately recorded. More than 99.5% of all birth in Denmark
have been recorded in the Danish Fertility Database [5,6] and
more than 99% of all discharge diagnoses have been registered in
the National Hospital Register. [20].
Exposure is based on information from the National Pre-
scription Register which holds records on all redeemed prescrip-
tions which means that the drugs have been collected at the
pharmacy and paid for. Completeness has been estimated to 98%.
[12].
This study demonstrates that treatment with clarithromycin in
the first trimester of pregnancy was associated with a 50% increase
(hazard ratio) of miscarriage compared to no treatment and
a similarly increased risk compared to penicillin and erythromycin.
We did not find an association between clarithromycin and major
congenital malformations. The results are similar to other studies
addressing the same issue both in human and animals. However,
further research is required to explore the possible effect of
treatment indication on the associations found.
Author Contributions
Conceived and designed the experiments: JTA NK MP ES. Performed the
experiments: JTA ES. Analyzed the data: JTA MP ES KB NA CTP HP
NK. Contributed reagents/materials/analysis tools: JTA KB NA CTP HP.
Wrote the paper: JTA.
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