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Blackwell Science, Ltd

Oxford, UK

BCPBritish Journal of Clinical Pharmacology

0306-5251Blackwell Publishing 2003

55Original Article

Maternal use of amoxicillin and pregnancy outcomeP. Jepsen
et al.

Correspondence:

Peter Jepsen, Department of Clinical Epidemiology, Aarhus
University, Vennelyst Boulevard 6, DK-8000 Aarhus C, Denmark. E-mail:
pj@soci.au.dk

Received 13 June 2002; accepted 5 September 2002.

A population-based study of maternal use of amoxicillin and pregnancy
outcome in Denmark

Peter Jepsen, Mette V. Skriver, Andrea Floyd, Loren Lipworth,

1,2

Henrik C. Schnheyder

3

&
Henrik T. Srensen

Department of Clinical Epidemiology, Aarhus University Hospital and Aalborg University Hospital, Aarhus, Denmark,

1

International Epidemiology
Institute, Rockville, MD and

2

Department of Preventive Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine,
Nashville, TN, USA, and

3

Department of Clinical Microbiology, Aalborg Hospital, Aalborg, Denmark

Aims

Amoxicillin is a widely used penicillin, but data on its safety in pregnancy are
limited. We examined the association between amoxicillin exposure during preg-
nancy and birth weight, preterm delivery, congenital malformations, perinatal death,
and spontaneous abortion.

Methods

We identied all primiparous women with a live birth, or a stillbirth after
the 28

th

gestational week, from 1 January 199131 December 2000 in the County
of North Jutland, Denmark. Data on prescriptions for amoxicillin and outcome were
obtained from population-based registries. Using a follow-up and a casecontrol
design, we compared pregnancy outcomes between women who had been pre-
scribed amoxicillin during pregnancy and those who had not, adjusting for available
potentially confounding factors.

Results

We identied 401 primiparous women who redeemed a prescription for
amoxicillin during their pregnancy. The control group consisted of 10 237 primip-
arous women who did not redeem any prescriptions from 3 months before preg-
nancy until the end of pregnancy. The adjusted mean birth weight of children born
to amoxicillin-exposed mothers was 57 g [95% condence interval (CI) 9, 105]
higher than that of children born to controls. Odds ratios among amoxicillin-
exposed relative to controls were: low birth weight 0.63 (95% CI 0.26, 1.53),
preterm delivery 0.77 (95% CI 0.49, 1.21), congenital malformation 1.16 (95% CI
0.54, 2.50), and spontaneous abortion 0.89 (95% CI 0.66, 1.18). We did not observe
any cases of perinatal death in the amoxicillin-exposed women.

Conclusions

We did not nd any increased risk of adverse pregnancy outcome
associated with amoxicillin exposure during pregnancy, but additional studies are
warranted.

Keywords:

amoxicillin, epidemiology, malformations, perinatal mortality, pregnancy,
preterm delivery, safety, spontaneous abortion

Introduction

In Denmark, 28.7% of all prescriptions redeemed by
pregnant women are for antibiotics, of which large pro-
portions are broad-spectrum penicillins [1]. Amoxicillin
is the most commonly used drug in this class of antibi-
otics [2], so any adverse effect of amoxicillin on preg-
nancy outcome could have considerable public health
implications. While several studies have evaluated the
effect of other penicillin drugs on pregnancy outcome
[37], the only available data on the safety of amoxicillin
in pregnancy derive from a single randomized trial
including 252 pregnant women with probable gonor-
rhoea, who were treated with either amoxicillin, ceftri-
axone, or spectinomycin [8, 9].
Thus, we have conducted a population-based study to
examine the association between amoxicillin exposure
during pregnancy and birth weight, preterm delivery,

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217

congenital malformations, perinatal death, and spontane-
ous abortion.

Methods

This study was conducted in the County of North
Jutland, Denmark, which has approximately 490 000
inhabitants. It was carried out in accordance with the
guidelines of the regional science ethics committee for
use of clinical and registry data.

Exposure data
The North Jutland Pharmaco-Epidemiological Prescription
Database

The National Health Service provides tax-
supported health care for all inhabitants of the country.
Apart from guaranteeing free access to general practitio-
ners, hospitals, and public clinics, the insurance pro-
gramme reimburses 5075% of the costs of selected
antibiotics, including amoxicillin. The pharmacies in the
County of North Jutland are equipped with a comput-
erized accounting system used primarily to secure reim-
bursement from the National Health Service. When
prescriptions are redeemed, data are also sent from the
accounting system to the North Jutland Pharmaco-
Epidemiological Prescription Database, which contains
data on all redeemed prescriptions since 1 January 1991.
These data include the date, the type of drug redeemed
(according to the Anatomical Therapeutical Chemical
(ATC) classication system), and the customers personal
identication number, which incorporates information
on gender and age.

Outcome data
The Danish Medical Birth Registry

This registry con-
tains data on all live births in Denmark since 1 January
1973. The midwives and doctors responsible for the
deliveries record data on all births, including birth
weight, gestational age, gender, as well as the mothers
personal identication number and smoking status.

The County Hospital Discharge Registry

We identied
all congenital malformations, perinatal deaths (stillbirth
after the 28th gestational week or death within the rst
week after birth), and spontaneous abortions through the
County Hospital Discharge Registry. This registry was
established in 1980 and transfers data to the National
Registry of Patients, where 99.4% of all discharges from
Danish somatic hospitals are recorded [10]. Recorded
information includes personal identication number,
dates of admission and discharge, surgical procedures per-
formed, and up to 20 discharge diagnoses. Discharge
diagnoses were classied according to the Danish version
of the International Classication of Diseases, 8th revi-
sion until the end of 1993, and according to the 10th
revision thereafter. The children were followed in the
County Hospital Discharge Registry until 1 September
2001. The codes for congenital malformations in ICD-8
and ICD-10 were 740.00759.99 and Q0.00Q99.9,
respectively, but congenital dislocation of the hip and
undescended testes were excluded due to poor validity
of these diagnoses [11]. The ICD-8 and ICD-10 codes
for spontaneous abortion were 634.61, 643.89, 645.1,
and O02, and O03, respectively.

Record linkage

Records from the North Jutland
Pharmaco-Epidemiological Prescription Database were
linked with the Danish Medical Birth Registry and the
County Hospital Discharge Registry using the mothers
personal identication number issued by the Central
Ofce of Civil Registration. However, the childs per-
sonal identication number was used to identify congen-
ital malformations in the County Hospital Discharge
Registry.

Study design
Cohort analysis

The association between amoxicillin
exposure and birth weight, preterm delivery, congenital
malformations, and perinatal death was examined in a
cohort of primiparous women with either a live birth or
a stillbirth after the 28th gestational week between
1 January 1991 and 31 December 2000. We had to
restrict the cohort to primiparous women, because pre-
scriptions to children up to 15 years of age were recorded
in the mothers name in the Danish National Health
Service until 1 April 1996. The exposed group consisted
of those who redeemed a prescription for amoxicillin
during pregnancy, and these women were further divided
by trimester of exposure, based on prescription date
recorded in the Pharmaco-Epidemiological Prescription
Database and on gestational age as reported to the Danish
Medical Birth Registry. The control group consisted of
all those who did not redeem any prescriptions in the
time period from 3 months before pregnancy to delivery.

Casecontrol analysis

We used a casecontrol design to
study the association between amoxicillin exposure and
spontaneous abortion. Through the County Hospital
Discharge Registry, cases were identied as all women
whose rst pregnancy between 1 January 1991 and
31 December 2000 resulted in hospitalization with spon-
taneous abortion. None of these women had given birth
or had an abortion between 1980 and 1991. Use of
amoxicillin in pregnancy was determined as having
redeemed a prescription for amoxicillin less than

P. Jepsen

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3 months prior to the date of admission with a diagnosis
of spontaneous abortion. The control group consisted of
women whose rst pregnancy between 1 January 1991
and 31 December 2000 resulted in a live birth or a
stillbirth after the 28th gestational week, and who had
not given birth or had an abortion between 1980 and
1991. In this group, use of amoxicillin was determined
as use of amoxicillin less than 3 months before the 12

th

gestational week.

Statistical analysis
Cohort analysis

We used multiple regression analysis to
estimate the difference in birth weight between children
of women exposed to amoxicillin and controls. The
model was adjusted for maternal age (

<

25, 2530, and

>

30 years), gestational age (2833, 3436, and

37 weeks), and maternal smoking status (smoker, non-
smoker), using design variables.
We used logistic regression analyses to estimate the
association between use of amoxicillin and low birth
weight (

2500 g), preterm delivery (

<

37 weeks), con-
genital malformations, and perinatal death. The analyses
were adjusted for maternal age and smoking, and these
variables were coded as described above. The analysis of
low birth weight was restricted to full-term deliveries
(

37 weeks), and only prescriptions for amoxicillin
redeemed in the rst trimester were included in the
analysis of congenital malformations.

Casecontrol analysis

The risk of spontaneous abortion
in women exposed to amoxicillin during pregnancy rel-
ative to controls was estimated using a logistic regression
model adjusted for maternal age divided into three
categories (

<

25, 2530, and

>

30 years) using design
variables.

Results

Cohort analysis

We identied 401 primiparous women who redeemed a
prescription for amoxicillin during pregnancy, and 147
of them redeemed their prescription during the rst
trimester. The control group consisted of 10 237 primi-
parous women who did not redeem any prescriptions
from 3 months before conception until delivery. In the
group of women exposed to amoxicillin at any time
during pregnancy, average birth weight was 3498 g, 5.0%
had a preterm delivery, and 4.0% gave birth to a child
with a congenital malformation. The corresponding
numbers in the control group were 3429 g, 6.3%, and
4.1% (Table 1). There were no cases of perinatal death in
the exposed group, so this outcome was not examined
in logistic regression analysis.
According to the multiple regression analysis, adjusted
mean birth weight of children born to mothers in the
exposed group was 57 g [95% condence interval (CI)
9, 105] higher than that of children born to controls.
In adjusted logistic regression analyses, risk of low
birth weight [odds ratio (OR) 0.63, 95% CI 0.26, 1.53]
and preterm delivery (OR 0.77; 95% CI 0.49, 1.21) was
nonsignicantly reduced, while risk of congenital mal-
formations (OR 1.16; 95% CI 0.54, 2.50) was close to
unity among children born to mothers in the exposed
group compared with those born to controls (Table 2).

Table 1

Characteristics of the study cohort.

Exposed to amoxicillin
in the rst trimester
Exposed to amoxicillin
during pregnancy Controls

Number of women 147 401 10 237
Number of prescriptions 150 445
Mean age (range) 27.4 (1842) 27.0 (1642) 26.8 (1345)
Proportion of smokers (%) 35.4 33.4 25.9

Gestational age (weeks)



37 139 381 9 588
3436 8 18 450
2833 0 2 199
Mean birth weight (range) 3518 (22704665) 3498 (18154675) 3 429 (5166230)
Number of low birth weight* (%) 2 (1.4) 5 (1.3) 183 (1.9)
Number of preterm deliveries (%) 9 (6.1) 20 (5.0) 649 (6.3)
Number of malformations (%) 7 (4.8) 16 (4.0) 416 (4.1)
Number of perinatal deaths (%) 0 (0) 0 (0) 60 (0.6)
*Restricted to full term deliveries (

37 weeks).

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Casecontrol analysis

In the analysis of spontaneous abortion, we found that
52 (1.2%) of the women in the case group redeemed a
prescription for amoxicillin compared with 437 (1.3%)
of the controls. After adjustment for maternal age, the
OR for spontaneous abortion was 0.89 (95% CI 0.66,
1.18) (Table 2).

Discussion

In this study, which we believe is the rst follow-up
study of the safety of amoxicillin in pregnancy, we found
that women who redeemed a prescription for amoxicillin
during pregnancy tended to give birth to babies with
higher birth weight, but were not at increased risk for
adverse pregnancy outcomes such as preterm delivery,
congenital malformations, or spontaneous abortion.
Use of the prescription database, which has no more
than 0.2% coding errors [12], ensured virtually complete
registration of redeemed prescriptions. Furthermore,
since patients are required to pay part of the cost of
prescribed amoxicillin, the use of prescriptions that were
actually redeemed is likely to have reduced misclassi-
cation due to noncompliance. However, it is still pos-
sible that not all amoxicillin was actually taken [13].
In-hospital use of amoxicillin is an additional source of
misclassication as it is not recorded in the prescription
database. Any misclassication of amoxicillin use will lead
to a conservative bias.
We may have overestimated the effect of amoxicillin
on pregnancy outcome, because women in the amoxicil-
lin group could have redeemed prescriptions for other
drugs than amoxicillin during pregnancy, whereas the
controls did not redeem any prescriptions during
pregnancy.
Registration of births and stillbirths was of high qual-
ity. The predictive value and completeness of diagnoses
of congenital malformations in the County Hospital Dis-
charge Registry have been estimated at 90% (unpublished
data), but we do not believe that either predictive value
or completeness could be associated with use of amox-
icillin. However, we were not able to identify malformed
fetuses detected at prenatal examinations and conse-
quently aborted, and we do not know whether these
malformations were associated with exposure to amox-
icillin. Lack of completeness and of data from prenatal
examinations may explain the slightly lower occurrence
of congenital malformations in this study (4.1% among
controls) compared with the 4.8% (after subtraction of
congenital dislocation of the hip and undescended testes)
reported in a Hungarian study [14].
If amoxicillin does cause congenital malformations, it
would probably cause only a few specic malformations,
and it would take a large number of these specic mal-
formations to produce a statistically signicant increase
in congenital malformations overall [15]. We had the
power to detect only a 2.5-fold increased risk of con-
genital malformations overall.
With respect to spontaneous abortion, we were able
to identify only spontaneous abortions which resulted in
hospitalization. Thus, we cannot report on the association
between amoxicillin exposure and early spontaneous
abortion that did not require hospitalization.
We assumed that all spontaneous abortions occurred at
12 weeks of gestation, because we did not know the
exact gestational age at the time of the abortion. If it
occurred before week 12 of gestation, we could have
included prescriptions redeemed before conception.
Conversely, if the spontaneous abortion occurred after
week 12 of gestation, we may have missed prescriptions
redeemed early in pregnancy. Thus, we may have mis-
classied amoxicillin exposure, resulting in a conservative
bias.
Smoking is a risk factor of spontaneous abortion [16],
but we were unable to adjust for smoking in our case
control analysis, because we did not know the smoking
status of women with a spontaneous abortion. However,

Table 2

Probability of pregnancy outcomes in the amoxicillin group relative to controls.

Exposure to amoxicillin
Crude odds ratio 95% CI Adjusted odds ratio 95% CI
Cohort analysis

Low birth weight* 0.68 0.281.67 0.63

0.261.53
Preterm delivery 0.78 0.491.22 0.77

0.491.21
Congenital malformations 1.18 0.552.54 1.16

0.542.50

Casecontrol analysis

Spontaneous abortion 0.92 0.691.23 0.89

0.661.18
*Restricted to full-term deliveries (

37 weeks).

Adjusted for smoking and maternal age.

Adjusted for maternal age.

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we did nd a higher proportion of smokers among
women exposed to amoxicillin in our cohort analysis
(33.4%

vs

25.9% among controls), suggesting that smok-
ing is unlikely to explain the slightly protective effect of
amoxicillin on spontaneous abortion.
Our nding of a higher birth weight among children
born to mothers exposed to amoxicillin is consistent with
ndings from other studies of antibiotics in pregnancy [3,
4], but the opposite has also been reported [5]. However,
we believe that the magnitude of the weight difference
found in this study (57 g) was too small to have any
prognostic impact. One explanation for our nding
could be that antibiotic treatment during pregnancy pre-
vents infections that would otherwise cause lower birth
weight. However, confounding by socio-economic sta-
tus, whereby women of low socio-economic status,
which may be associated with low birth weight [17], did
not receive appropriate antibiotic treatment, cannot be
ruled out.
A previous randomized trial, including 252 pregnant
women with probable gonorrhoea, found similar risk of
congenital malformations among those who were treated
with amoxicillin and in those treated with ceftriaxone or
spectinomycin [8]. To our knowledge, there are no stud-
ies to date of the association between amoxicillin and
either low birth weight, perinatal death, or spontaneous
abortion. Augmentin is a combination of amoxicillin and
clavulanic acid, and a Hungarian casecontrol study
including 52 (0.75%) augmentin-exposed women among
6935 who had offspring with congenital malformations
reported a nonsignicantly increased odds ratio for con-
genital malformations overall of 1.4 compared with
10 238 controls [7]. The risks of cleft lip or palate (OR
2.1; 95% CI 0.6, 7.1), poly/syndactyly (OR 2.5; 95% CI
0.4, 16.3), cardiovascular malformations (OR 2.6; 95%
CI 1.1, 6.0), malformations of diaphragm (OR 7.0; 95%
CI 0.4, 135.5), and hypospadias (OR 4.3; 95% CI 1.2,
15.4) were increased after exposure to augmentin at any
time during pregnancy, and not only during the critical
period for congenital malformations. As the data on aug-
mentin exposure were based on questionnaires, recall bias
might have contributed to the ndings [18]. Pivampicil-
lin and ampicillin are closely related to amoxicillin, and
another Hungarian study of ampicillin use in 61 016
pregnant women, based on the same casecontrol dataset,
did not report increased risk of serious congenital mal-
formations [6]. Similarly, a Danish study of 199 women
who received pivampicillin in the rst trimester did not
nd any increased risk of malformations, preterm deliv-
ery, or low birth weight [4].
In conclusion, amoxicillin use during pregnancy does
not appear to increase the risk of adverse pregnancy
outcome, but even this large study cannot rule out an
effect.

This study has received nancial support from the Western Danish
Research Forum for Health Sciences.

References

1 Olesen C, Steffensen FH, Nielsen GL, de Jong-van den Berg
Olsen J, Srensen HT. Drug use in rst pregnancy and
lactation: a population-based survey among Danish women.
The EUROMAP Group.

Eur J Clin Pharmacol

1999;

55

: 139
144.
2 The Danish Medicines Agency.

Medicinal Products Statistics
19941998.

Albertslund: Schult Information, 1999.
3 Larsen H, Nielsen GL, Mller M, Ebbesen F, Schnheyder
HC, Srensen HT. Birth outcome and risk of neonatal
hypoglycaemia following

in utero

exposure to pivmecillinam:
a population-based cohort study with 414 exposed
pregnancies.

Scand J Infect Dis

2001;

33

: 439444.
4 Larsen H, Nielsen GL, Srensen HT, Mller M, Olsen J,
Schnheyder HC. A follow-up study of birth outcome in
users of pivampicillin during pregnancy.

Acta Obstet Gynecol
Scand

2000;

79

: 379383.
5 Czeizel AE, Rockenbauer M, Olsen J. Use of antibiotics
during pregnancy.

Eur J Obstet Gynecol Reprod Biol

1998;

81

:
18.
6 Czeizel AE, Rockenbauer M, Srensen HT, Olsen J. A
population-based casecontrol teratologic study of ampicillin
treatment during pregnancy.

Am J Obstet Gynecol

2001;

185

:
140147.
7 Czeizel AE, Rockenbauer M, Srensen HT, Olsen J.
Augmentin treatment during pregnancy and the prevalence
of congenital abnormalities: a population-based casecontrol
teratologic study.

Eur J Obstet Gynecol Reprod Biol

2001;

97

:
188192.
8 Cavenee MR, Farris JR, Spalding TR, Barnes DL, Castaneda
YS, Wendel GD Jr. Treatment of gonorrhea in pregnancy.

Obstet Gynecol

1993;

81

: 3338.
9 Friedman JM, Polifka JE.

The Effects of Drugs on the Fetus and
Nursing Infant

, 1st edn. Baltimore and London: The Johns
Hopkins University Press, 1996.
10 Andersen TF, Madsen M, Jrgensen J, Mellemkjr L, Olsen
JH. The Danish National Hospital Register. A valuable source
of data for modern health sciences.

Dan Med Bull

1999;

46

:
263268.
11 Nielsen GL, Srensen HT, Larsen H, Pedersen L. Risk of
adverse birth outcome and miscarriage in pregnant users of
non-steroidal anti-inammatory drugs: population based
observational study and casecontrol study.

BMJ

2001;

322

:
266270.
12 Olsen JH, Srensen HT, Friis S

et al.

Cancer risk in users
of calcium channel blockers.

Hypertension

1997;

29

: 1091
1094.
13 Olesen C, Sndergaard C, Thrane N, Nielsen GL, de Jong-
van den Berg L, Olsen J. Do pregnant women report use of
dispensed medications?

Epidemiology

2001;

12

: 497501.
14 Czeizel AE, Intody Z, Modell B. What proportion of
congenital abnormalities can be prevented?

BMJ

1993;

306

:
499503.
15 Mitchell AA. Special considerations in studies of drug-
induced birth defects. In

Pharmacoepidemiology

, 2nd edn, ed.
Strom BL. Chichester: Wiley, 1994: 595607.

Maternal use of amoxicillin and pregnancy outcome

2003 Blackwell Science Ltd

Br J Clin Pharmacol

,



55

, 216221

221

16 Ness RB, Grisso JA, Hirschinger N

et al.

Cocaine and
tobacco use and the risk of spontaneous abortion.

N Engl J
Med

1999;

340

: 333339.
17 Olsen J, Frische G. Social differences in reproductive health.
A study on birth weight, stillbirths and congenital
malformations in Denmark.

Scand J Soc Med

1993; 21: 9097.
18 Rockenbauer M, Olsen J, Czeizel AE, Pedersen L, Srensen
HT. Recall bias in a casecontrol surveillance system on the
use of medicine during pregnancy. Epidemiology 2001; 12:
461466.