Introduction
Macrolide antibiotics are commonly used to treat respiratory problems
and certain sexually transmitted diseases.1-3 They are
generally considered to have a good safety profile, but there have been
conflicting findings about their potential to prolong the QT interval in
ECG tests of the heart.1- 4 Azithromycin, an analogue
of erythromycin, is considered to have a better safety profile than
erythromycin and clarithromycin.1,4 It has a
slow-acting anti-malarial property; and owing to growing resistance to
sulphadoxine-pyrimethamine (SP), its combination with chloroquine has
been proposed as an alternative to the current WHO recommended
intermittent preventive treatment of malaria in pregnancy with
SP.5-7 Currently, the potential use of azithromycin -
chloroquine combination in COVID -19 treatment is being
tested.8
Macrolides are widely used during pregnancy, but evidence of their
teratogenic potential is limited and inconsistent. Animal studies have
generally found limited evidence of teratogenicity of macrolides.
However, ever since the thalidomide disaster in the 1960s, animal
studies are not considered adequate to predict risk in
humans.9 Pregnant women are excluded from human trials
to determine drug efficacy and safety for ethical
reasons.9 Safety information needed by pregnant women
and their clinicians to guide risk and benefit analysis must, therefore,
come from post-marketing pharmaco-epidemiological studies.
There has been a growing debate about the potential association of
macrolides (especially erythromycin) with congenital heart defects
(CHD). In 2003, a Swedish Birth Registry study reported that first
trimester use of macrolides (mainly erythromycin) was associated with
increased risk for CHD (OR 1.79; 95%CI 1.3 - 2.8).10Subsequent updates of this study in 2005 and 2013 found similar results.11,12 A recent UK study has also corroborated this
result, reporting an increased risk of CHD (adjusted relative risk 1.62;
95%CI 1.05 - 2.51).13 Other studies have found no
significant association between macrolides and CHD14 -
28 , including a 2019 meta-analysis.29 Most studies
did not have an adequate sample size and power to investigate specific
CHD. Most teratogens are specific to the defects they
cause30 and analysing congenital anomalies (CA) in
large groups may result in missed associations of the exposure with
specific defects.
We investigate here the teratogenic potential of five macrolide
antibiotics, as part of a wider study of antibiotics using the large
European EUROmediCAT database
(http://www.euromedicat.eu/currentresearchanddata/data), derived
from registries belonging to the EUROCAT network for Surveillance of
Congenital Anomalies
(https://eu-rd-platform.jrc.ec.europa.eu/eurocat/eurocat-network_en).
We also conduct a meta-analysis of the literature for CHD, including our
own results.