This will be my second post in a row to point out problems with the practice of conventional medicine, specifically when it comes to potential harm from widespread suboptimal use of antibiotics. So I hope that any naysayers out there will henceforth refrain from using straw man arguments involving claims of our ignoring certain topics and only focusing on so-called alternative medicine. We know that conventional medicine isn’t perfect. Far from it, in fact. Still, I would rather trust my life, and the lives of my family, with science-based medicine than with modern day fairy tales based on the arbitrary prescientific claims we so often discuss here on SBM.

Making the news last week was a study in The BMJ revealing a possible link between the use of a certain popular class of antibiotics during pregnancy and major birth defects, particularly cardiovascular anomalies. Before I get into the details, I think it’s important to first point out two things. One is that this is a retrospective cohort study. It’s a pretty large retrospective cohort study, but it still can’t answer the question of causality with certainty. But it certainly can raise our level of concern and even potentially help to guide clinical decision making.

The other thing is that this didn’t come out of left field. Though the data has been somewhat mixed, concern regarding the use of macrolide antibiotics during pregnancy is far from new. To give just one example, based on concerns of association with cardiac defects, Sweden issued a warning in 2005. The approach has varied in other countries. In the United States, for example, neither the American College of Obstetricians and Gynecologists or the American Academy of Pediatrics warn against their use in pregnancy.

In the study, researchers reviewed anonymized public medical records on over a million British children born between 1990 and 2016, finding just over 100,000 whose mothers were prescribed either a macrolide or a penicillin at any time during their pregnancy. They excluded children with chromosomal abnormalities or whose mothers took drugs known to cause birth defects. Including the penicillin cohort was an effort to minimize potential confounding by the effect of infections during pregnancy, because the two antibiotic classes are often used to treat the same types of infections and penicillins have a long track record of safety during pregnancy. The researchers also attempted to account for a number of other potential confounding variables, such as maternal age, alcohol/drug use, and diabetes.

There were two negative control cohort populations used in the study as well. These included roughly 82,000 children born to mothers who were prescribed a penicillin or macrolide prior to conception and a group of 53,000 or so siblings of children who were exposed to these antibiotics prenatally. The primary outcomes they were on the lookout for were the diagnosis of any major malformation or one of four neurodevelopmental disorders: cerebral palsy, epilepsy, ADHD, and autism.

The authors found that roughly a third of mothers received at least one course of antibiotics during pregnancy, with penicillins and macrolides accounting for 69% and 10% respectively. Among children exposed to macrolides in the first trimester, there were 27.7 major malformations per 1,000 live births. Children exposed during the 2nd or 3rd trimester were found to have a rate of 19.5 major malformations per 1,000 live births. Prenatal penicillin exposure at any point during pregnancy was associated with roughly 17.5 major malformations per 1,000 live births.

If real, this reveals a significant increase in these malformations when mothers take a macrolide in the first trimester. The association was particularly robust when looking specifically at cardiovascular malformations. The study found that for every 1,000 women who receive a macrolide instead of a penicillin, there would be 4 additional children born with a heart defect. Genital malformations were also found to be associated with macrolides compared to the penicillin cohort, with about 1.7 extra cases per 1,000 live births. There was no association with increased risk of any of the neurodevelopmental disorders.

It’s important to sort out whether or not these medications are safe for a developing fetus. Previous studies have shown that about a quarter of pregnant women receive an antibiotic at some point during pregnancy. This study found it to be a bit higher at about 30%. And macrolide antibiotics are frequently what pregnant women get. They are frequently what everyone gets. Odds are, in fact, that most of the people reading this post have been prescribed a macrolide at some point in their lives.

In 2017, nearly 45 million prescriptions for a macrolide were written in the outpatient setting in the United States, making it the second most common behind the penicillins. The vast majority of macrolide prescriptions, around 43 million or so, come in the form of the more recently developed (approved in 1988) azithromycin (Zithromax, Z-Pak). As any student or resident who has rounded with me for any significant amount of time can attest to, it is by far my least favorite antibiotic.

Don’t get me wrong, azithromycin is a great antibiotic that is very effective in a number of clinical scenarios, but it is terrible for the same reasons that it is great. It’s cheap, conveniently dosed once per day and for a shorter course than penicillins for common indications, and more broad in its coverage than them as well. And because I’m a pediatrician, I have to also point out that it tastes decent in its liquid formulation. Add to this the catchy trade name, and you’ve got a recipe for improved patient adherence to your treatment recommendation.

Unfortunately, you also have a perfect set up for overprescribing. Of the roughly 43 million prescriptions for it, which is actually down from closer to 60 million per year a decade ago, most are suboptimal. Doctors have become cavalier with use of this antibiotic more so than any other, frequently prescribing it for what are clearly self-limited viral respiratory infections but are labelled as ear infections, sinusitis, bronchitis, “strep throat”, or pneumonia. Azithromycin is also the antibiotic most often asked for by name by patients and parents. The marketing was very, very effective.

Part of what makes me so grumpy about this antibiotic, in addition to the fact that it is so often prescribed when an illness is clearly caused by a virus, is that prescribing it reveals a fundamental knowledge gap in many medical professionals. The most common bacterial pathogen known to cause ear infections, sinusitis, and pneumonia is pneumococcus. That’s one of the bugs that we have developed highly successful vaccines against, preventing many life threatening cases of pneumonia, bloodstream infections, and meningitis across the lifespan. But it’s still a common cause of human infections, and it is highly resistant to azithromycin. I’m talking a coin flip’s chance or worse of it working.

So in summary, this study is raising serious concern that a very commonly prescribed antibiotic, which provides little to no benefit for a large percentage of the patients it is prescribed for, might increase the risk of serious birth defects in children whose mother’s take it early in pregnancy. That being said, there are proper indications for using a macrolide. Severe penicillin allergy, for example, is a common reason. Also chlamydia infections, tuberculosis, and atypical pneumonia in some instances. And poorly treated maternal infections can cause harm to her fetus as well. So I don’t want to completely throw the baby out with the bathwater here.

The bottom line is that there is legitimate reason to be cautious about macrolide use during pregnancy. Of course, it would be great if we stopped treating viruses with antibiotics, but that is a steep hill to climb at this point. There is, however, lower hanging fruit. More than 90% of people who think that they are allergic to penicillins probably aren’t. For a variety of reasons, not just avoiding macrolide antibiotics during pregnancy, there really should be a more concerted effort put into delisting penicillin allergies. It isn’t hard to do.


Posted by Clay Jones

Clay Jones, M.D. is a pediatrician and a regular contributor to the Science-Based Medicine blog. He primarily cares for healthy newborns and hospitalized children, and devotes his full time to educating pediatric residents and medical students. Dr. Jones first became aware of and interested in the incursion of pseudoscience into his chosen profession while completing his pediatric residency at Vanderbilt Children’s Hospital a decade ago. He has since focused his efforts on teaching the application of critical thinking and scientific skepticism to the practice of pediatric medicine. Dr. Jones has no conflicts of interest to disclose and no ties to the pharmaceutical industry. He can be found on Twitter as @SBMPediatrics and is the co-host of The Prism Podcast with fellow SBM contributor Grant Ritchey. The comments expressed by Dr. Jones are his own and do not represent the views or opinions of Newton-Wellesley Hospital or its administration.