Research links macrolide antibiotics in pregnancy with birth defects

Children of mothers prescribed macrolide antibiotics during the first trimester are at an associated increased risk of major birth defects, particularly cardiovascular malformations, compared with children of mothers prescribed penicillin or no antibiotics.
 
Such were the findings of new research published in The BMJ.
 
These findings show, according to researchers, that macrolides should be used with caution during pregnancy and, if feasible, alternative antibiotics should be prescribed until further research is available.
 
Researchers analysed data from 104,605 children born in the UK from 1990 to 2016, with a median follow-up of 5.8 years after birth.
 
After taking account of potentially influential factors, the researchers found macrolide prescribing during the first trimester was associated with an increased risk of any major malformation compared with penicillin (28 versus 18 per 1000), and specifically cardiovascular malformations (11 versus seven per 1000).
 
These increased risks were not observed in children of mothers whose macrolides were prescribed in the second or third trimester.
 
However, macrolide prescribing was associated with a slightly increased risk of genital malformations, such as hypospadias, in any trimester (five versus three per 1000).
 
No statistically significant associations were found for other system-specific malformations, or for any of the four neurodevelopmental disorders for which the researchers were looking.
 
Dr Alex Polyakov is a senior lecturer in the Department of Obstetrics and Gynaecology at the University of Melbourne and a consultant obstetrician, gynaecologist and fertility specialist at the Reproductive Biology Unit at the Royal Women’s Hospital in Melbourne.
 
He told newsGP the absolute risk of major malformations from taking macrolide antibiotics in pregnancy is ‘small’.
 
In this study, he said the background risk of malformations was 1.7% – the same risk for women who had taken penicillin during pregnancy.
 
Meanwhile, the use of macrolides was associated with an increased absolute risk of about 2.2%.
 
This effect was stronger if macrolides were used in the beginning of pregnancy, before 13 weeks’ gestation, where the risk rose to 2.8%.
 
‘With macrolides, the risk was higher [than for penicillin] by about 60% but, at the same time, the absolute risk is really quite small; you’re looking at 1.7% versus 2.5%,’ Dr Polyakov said.
 
However, he said it is still a ‘significant and clinically important finding’.
 
Macrolide antibiotics include erythromycin, azithromycin and clarithromycin. They are commonly prescribed for patients with penicillin allergies.
 
According to the Therapeutic Goods Administration (TGA), erythromycin is currently category A for pregnancy, while azithromycin is category B1 and clarithromycin is category B3.
 
The TGA describes category A medications in pregnancy as, 
 
‘Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed’.
 
Dr Alex Polyakov believes that the current category A classification of erythromycin needs to be re-evaluated.

In light of this new study’s findings, Dr Polyakov questions whether that classification needs revision.
 
‘I think based on all available evidence so far, the current classification [of category] A needs to be re-evaluated,’ he said.
 
Whether that will happen is another story.
 
‘Probably not based on one study, but there are other studies that raised concerns in the past,’ he said.
 
Dr Polyakov said this study adds weight to the notion that all medications should be used with caution in pregnancy.
 
‘Certainly from a GP’s perspective, I would say that these antibiotics should probably be avoided, especially in the first trimester, but that is in fact true for all medication,’ he said.
 
‘I would say the first trimester is the crucial trimester, that’s when the organogenesis takes place, and therefore any medical interventions need to be cautiously administered and considered.’
 
However, Dr Polyakov said that if a pregnant women presents to her GP with concerns about having taken a macrolide antibiotic such as erythromycin before she knew she was pregnant, reassurance can be offered.
 
‘If someone doesn’t know that they’re pregnant and they’ve taken erythromycin, it doesn’t mean that any extra care is required and I don’t think it’s a major, major problem,’ he said.
 
Another key message from this research, Dr Polyakov said, is the added reassurance of the safety of penicillin in pregnancy.
 
‘Penicillin has never been shown to be a problem in any of the studies,’ he said.
 
‘That’s the case in this study. They looked at penicillin versus nothing, and the rates of malformations were exactly the same.’
 
While Dr Polyakov said these findings are significant, Dr Gino Pecoraro, Associate Professor of Obstetrics and Gynaecology at the University of Queensland, is concerned about how they may be interpreted.
 
‘These observational-type studies are not sufficiently powered to prove causation and can unnecessarily fuel anxiety in pregnant women and sometimes even lead to denial of what can be important treatment options,’ he said.
 
‘Until further research clarifies this question, women and doctors should observe what has always been best practice when it comes to the prescription of medication, including antibiotics, during pregnancy.

‘The benefits of using a drug should be weighed against the risks to the mother and developing baby of not providing treatment, and where a safer and available alternative exists that drug should be preferred.’
 
But this study may influence which antibiotic to prescribe for bacterial infections during pregnancy, according to Professor David Ellwood, the Dean of Medicine and Professor of Obstetrics and Gynaecology at Griffith University.
 
‘[W]here there may be choices in the type of antibiotic used, information from studies such as this can be helpful in guiding clinical practice,’ he said.
 
‘Until further evidence is available, it would seem prudent to avoid where possible the use of macrolides in the first trimester of pregnancy, and to exercise caution in their use in later gestations, carefully balancing the benefits with these possible risks of causing harm to the fetus.’
 
Dr Mark Blaskovich, a senior research officer at the Centre for Superbug Solutions at the University of Queensland Institute for Molecular Bioscience, and co-founder of the Community for Open Antimicrobial Drug Discovery, raised another key point.
 
He noted the study only included children whose mothers were prescribed an antibiotic for a respiratory tract infection.
 
‘These are one of the most common causes of unnecessary antibiotic use, as they are usually caused by viruses,’ he said.

‘It highlights that antibiotics should only be taken when needed – they are not harmless and do have side effects. You don’t see healthy people taking anti-cancer drugs “just in case”, but for some reason it is acceptable for antibiotics.’
 
Dr Polyakov echoed that sentiment, saying the takeaway message from this research is in line with general advice on using antibiotics in pregnancy.
 
‘The bottom line, and the advice that is always valid, is to say that you only use antibiotics if they are truly required,’ he said.
 
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antibiotics birth defects cardiovascular malformations pregnancy