Discussion
In this large EUROmediCAT study, we did not find evidence of a strong
association between CHD and macrolide exposure, and meta-analysis of our
study combined with all previous literature confirmed an overall lack of
a strong association. However, we did find evidence regarding a
threefold or more raised risk of AVSD specifically, significantly
associated with three types of macrolide, robust across analyses with
different control groups and exposure comparison groups. AVSD accounts
for 2% of CHD cases in EUROCAT data, so it is not surprising this does
not affect the overall CHD finding. AVSD are common in babies with Down
syndrome, but none of the exposed AVSD cases had Down syndrome. The
majority of negative studies regarding macrolides and
CHD,14 - 26 as well as those that found an
association,10 -13 did not have enough power to
investigate specific subgroups of CHD. We found only one study (Crideret al. 2009)17 that has investigated the
association between AVSD and erythromycin and found an elevated risk,
although not statistically significant (AOR 2.2, CI: 0.8 - 6.1). This
was a case-control study which obtained exposure information
retrospectively by interview a considerable time after exposure, thus
possibly underestimating ORs.
As elaborated by Källén et al .,11 there is
compelling evidence from animal and human studies that suggests
macrolides could have a link with some CHDs. At clinical concentrations,
macrolides can inhibit a specific cardiac potassium current (IKr)
channel, expressed by hERG (human ether a-go-go related gene). This can
then lead to a prolonged QT interval, causing a type of ventricular
tachycardia called torsades de pointes(TdP).4,39 In a developing rat embryo, particularly
during the period before the heart is inverted (corresponding to weeks 5
- 9 of human pregnancy), TdP can result in pressure changes and
misdirection of blood flow in the developing cardiovascular system, that
can in turn lead to hypoxia and re-oxygenation damage resulting in
septal and other vessel defects.41-44
Determining the cause of birth defects is complex, as a single birth
defect may have multiple causes, just as multiple birth defects can have
a single cause. However, our current AVSD finding has met many of the
widely accepted Bradford Hill criteria of causation,45including the large effect size, observed pattern specific to
macrolides, existence of prior hypothesis regarding CHD and a plausible
biological mechanism.
In other exploratory analysis, we have found robust elevated risk of
diaphragmatic hernia, orofacial clefts, syndactyly, and hydrocephalus,
associated with first trimester use of erythromycin, clarithromycin,
azithromycin, and clindamycin respectively. None of these associations
have been previously reported. However, multiple testing may have
produced some spuriously significant results, and independent
confirmation is necessary.
We could not confirm previous associations of macrolides with genital
anomalies,21 erythromycin with
anencephaly17 or limb deficiency,17and azithromycin with orofacial clefts.16 Since our
2016 literature search, a new study found an association of urinary
system defects with erythromycin (AOR 2.12, CI: 1.08 –
4.17),25 which our data and other studies did not
support.12,21,46-48
Our investigation of spiramycin did not find an association with any of
the CAs studied, but this was the least frequent exposure and we had
limited statistical power. We found only one study from the literature
that investigated spiramycin, finding no increased
risk.27 Further studies are needed on the teratogenic
potential of this antibiotic.
Apart from CA, other adverse outcomes related to macrolide use during
pregnancy have been reported, such as miscarriage 49and fetal growth restriction in animal studies of clarithromycin and
azithromycin.50-52
Safety advice about the use of macrolides during pregnancy varies across
different countries. In the United Kingdom, the Medicines and Healthcare
products Regulatory Agency advises alternatives to clarithromycin and
azithromycin should be prescribed during pregnancy.53In Sweden, the report of Källén et al .,11 in
2005 that suggested elevated risk of CHD related to erythromycin led to
warning against its use in the first trimester.53 In
the USA, the previous Food and Drug Agency pregnancy classification
system classified erythromycin, azithromycin and clindamycin as category
B (animal studies found no risk and there are no adequately controlled
human studies), and clarithromycin as category C (animal studies show
adverse effects, but there are no adequately controlled human studies
and benefit may warrant use despite potential risks). In light of the
findings from the current study, regulatory authorities should revise
the safety advice on macrolide use during the first trimester of
pregnancy to reflect the potential risk of adverse outcomes. As the
world considers the potential use of azithromycin - chloroquine
combination in the treatment of COVID -19,8 particular
attention should be given to the potential teratogenic and other
negative effects of azithromycin use during the first trimester of
pregnancy.