Does ivermectin cause male infertility?

There has been a paper circulating on Twitter that people have used to back up claims that ivermectin results in male sterility. Is this true? Let’s look at the paper in question: Effect of ivermectin on male fertility and its interaction with P-glycoprotein inhibitor (verapamil) in rats. Eviron Toxicol Pharmacol 2008 Sep;26(2):206-11. doi: 10.1016/j.etap.2008.03.011.Epub 2008 Mar 29. https://pubmed.ncbi.nlm.nih.gov/21783912/

There are a number of steps to follow in order to assess value. I will outline them below with comments.

Is this article from a journal published by a reputable publisher? If you look at the article record on PubMed, on the right you will see full text links. There is a button for Elsevier. Elsevier is a giant in science publishing. Good so far!

Next up – let’s look at the paper itself. Yes that’s right, let’s look at the actual paper – NOT the abstract. You can’t make a judgement on abstract alone. Abstracts can give false impressions and leave out important information. Sometimes abstracts are incorrect. So, if you want to make a decision using this paper, get the full text and read it. I can’t emphasise this enough. If you want to look around for papers in order to make informed decisions, this is great. This is what healthcare staff want you to do! But you have to do the work. It is possible for you to get this paper for just a small fee. Go to your local public library and request it. This is called interlibrary loan.

Now you have the paper, what next? Well, we are going to do what is called a critical appraisal. It’s a process that anyone can do that helps unpick and understand the contents. It is basically a checklist for things to look out for and think about. This is an animal study (I know humans are animals, but still ..) so what we have to do is find a checklist for animal studies. These two webpages are from a paper[1] proposing a set of questions to answer [Table 1 Table 2]. I haven’t used this one yet as all the checklists I’ve used have been for human studies. So let’s begin!

1] “If the study was conducted in a manner that suggests little internal bias, will it be useful for the ‘next step’ because the population is relevant to ‘the next step?’” YES/N The paper authors state that there is a presumption that results of laboratory animal studies can be extrapolated to humans but this is not the case. The next step they say is to take it to other animal populations. So the question is – is it worthwhile going forward with this study and conduct another experiment in a different animal population?

This is a small early laboratory animal study in rats. Can I use it to make a health decision for myself or a family member? No. Let’s go back to the question we originally put: does ivermectin cause infertility in male humans? This paper will not answer that question. It is only asking if it causes infertility in male rats when used with verapamil. To answer this question, you need a paper that looks at side effects of ivermectin – a study about drug safety.

Safety of high-dose ivermectin: a systematic review and meta-analysis. [2] This title looks like a paper that could answer our question. There are lots of good starting points: the journal is indexed in Medline and it is a systematic review. Systematic reviews take studies found using a broad search strategy for a narrow question and analyse them together. Sometimes the studies the authors found are so similar, the individual results can be combined for statistical analysis – this is called meta-analysis. Systematic reviews still have to be critically appraised though and one tool I use is CASP. There are lots of hints as to where to look for the information in a paper and what to look for. If you have the full text, let’s do an appraisal.

1. Is there a clearly focussed question? Yes – look at the last sentence in the Introduction
2. Did the authors look for the right type of papers? – Ideally, RCTs should be used but in this case, it could be unethical. All types of studies were included that met the inclusion criteria.
3. Do you think that all important and relevant studies were included? Look at the Methods section. Relevant databases were searched, all languages included, reference papers sought and authors contacted. There is no ready access to the search strategy, which is a shame, but let’s say Yes and continue.
4. Did the authors do enough to assess the quality of the studies? There are two quality assessment sections – one for the meta-analysis which used only RCTs (a big plus) and the another for the other study types.
5. If the results have been combined, was it reasonable to do so? This means, was there a meta-analysis? Yes, there were two for different drug doses. Was it reasonable to do so? Yes. The authors state that there was low heterogeneity, which means the results were similar enough to be able to be combined.
6. What are the results? Adverse events were mild or moderate and not connected to the dosage but to the underlying condition the drug was being used to treat. There is a table of adverse effects and infertility is not there. The adverse effects listed are: eye, brain, skin and other (things like swelling and back pain),
7. How precise are the results? Looking at confidence intervals gives you an idea about how accurate the estimate is. The smaller the range, the better. The researchers are confident that if the analysis was repeated, similar results would appear. There are a range here – some are larger than others, depending on the condition.
8. Can the results be used in the local setting? This question is for health professionals. Are the populations in the study similar to mine?
9. Where all the important outcomes considered? For our purposes, yes! We want to know about infertility as a side effect.
10. Are the benefits worth the harm and costs? Ivermectin is a low cost drug and easily obtainable. But our question wasn’t about using it for treating parasitical infection.

Take-away: Ivermectin does NOT cause infertility in human males.

[1] Annette M. O’Connor, Jan M. Sargeant, Critical Appraisal of Studies Using Laboratory Animal Models, ILAR Journal, Volume 55, Issue 3, 2014, Pages 405–417, https://doi.org/10.1093/ilar/ilu038

[2] Navarro, Miriam, et al. “Safety of high-dose ivermectin: a systematic review and meta-analysis.” Journal of Antimicrobial Chemotherapy 75.4 (2020): 827-834. https://www.icpcovid.com/sites/default/files/2020-04/Safety%20of%20higher%20doses%20of%20Ivermectin%20JAC%202020.pdf