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London – Treatment with a macrolide antibiotic in the 1st trimester of pregnancy was in an analysis of electronic medical records in the British Medical Journal (BMJ 2020; 368: m659) associated with an increased rate of malformations especially of the cardiovascular system.
The macrolides azithromycin, clarithromycin and erythromycin are among the safest antibiotics. They are therefore one of the preferred means during pregnancy, if penicillins are out of the question. And antibiotics are often prescribed to pregnant women, although caution is generally advised during pregnancy.
In an analysis by the Clinical Practice Research Datalink (CPRD), the electronic medical records, the proportion of mothers who were prescribed antibiotics at least once during pregnancy was 31%.
The most common prescriptions were penicillins, which are considered safe for children. Macrolides are among the reserve medications. However, your security is controversial. There are particular concerns about clarithromycin, which has disrupted the embryonic development of rats in animal studies. Teratogenic potential has also been described for azithromycin. Erythromycin is classified more favorably because the placental passage is relatively low.
Heng Fan from University College London and co-workers have now specifically looked for an accumulation of malformations in children whose mothers had been prescribed a macrolide in pregnancy in an analysis of the CPRD. First, the researchers compared the data from 104,605 children whose mothers were prescribed either a macrolide or a penicillin.
In fact, severe malformations were observed more often in children whose mothers received macrolide during pregnancy than in children of women who received penicillin. This was most evident in the 1st trimester. The development of the organs falls into this phase. Embryogenesis is particularly susceptible to teratogenic damage.
Fan determined a prevalence of 27.7 per 1,000 live births after exposure to a macrolide compared to 17.7 per 1,000 live births after exposure to a penicillin. The adjusted risk ratio was 1.55 and was significant with a 95% confidence interval of 1.19 to 2.03. The risk of cardiovascular malformation (10.6 versus 6.6 per 1,000 live births) was most pronounced, with a risk ratio of 1.62 (1.05 to 2.51).
With exposure in the 2nd or 3rd trimester, the risk was significantly lower. In the children exposed with a macrolide, the prevalence was 19.5 per 1,000 live births. In the control group exposed to penicillin, 17.3 severe malformations occurred in 1,000 live births. The adjusted risk ratio of 1.13 (0.94 to 1.36) was not significant.
Fan also determined an increased risk of genital malformations (4.7 versus 3.1 per 1,000 live births, risk ratio 1.58; 1.14-2.19). Hypospadias were the most common. There was no evidence of an increased risk of cerebral palsy, attention deficit hyperactivity disorder (ADHD) or autism.
When considering the individual macrolides, an increased risk (adjusted risk ration 1.50; 1.13 to 1.99) could only be demonstrated for erythromycin. This was probably due to the fact that the other two macrolides were used only rarely due to the known concerns. After all, the results contradict the prevailing view that erythromycin is harmless.
The researchers carried out 2 negative controls. Malformations in children whose mothers had been prescribed antibiotics prior to pregnancy, which could not have harmed the children, were examined in the first. This was to rule out the fact that increased morbidity in women (and not the use of antibiotics) was responsible for the increased risk of malformation.
The siblings were examined in a second analysis. This should preclude a genetic predisposition as an explanation. An increased risk of malformation was not found in either of the two negative controls.
The absolute risk of malformation is low. Fan estimates that using a macrolide instead of a penicillin in the first trimester could lead to 4.1 additional serious malformations (95% confidence interval 0.4 to 9.4) – if the association is based on a causality.
This can never be proven with certainty in an epidemiological study. Together with the information from animal studies, the risk must be taken seriously. An arrhythmogenic effect, which is a known complication of macrolides in adults, can be used as a mechanism. © warmth / aerzteblatt.de