February 15, 2018

expert reaction to study looking at asthma, preventer and reliever inhalers, and fertility

Women with asthma who only use short-acting asthma relievers take longer to become pregnant than other women, reports new research published in the European Respiratory Journal.

Prof. Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“This is an interesting study, and I wouldn’t argue with its recommendations on the use of asthma medications by women planning pregnancy.  I’m happy to see that the authors are planning further studies of fertility in women with asthma.

“As a statistician, and not a clinician, I shouldn’t be making clinical recommendations anyway, but I can look at the strength of the evidence from this study.  In my view, despite the large number of women in the study, and despite the fact that the researchers used appropriate statistical methods to produce their findings, the evidence is not entirely clear.  That’s for two sets of reasons.  First, this is an observational study.  The research report points out that the group of women with asthma differed from those who did not have asthma in many ways – for example they were younger, weighed more (for their height), were more likely to smoke, and were less well off.  Perhaps any differences in fertility were caused by some other difference between the groups, and not by asthma medication at all.  The researchers allowed statistically for several such factors, and indeed these statistical adjustments made the differences in fertility rather clearer – but it remains possible that the observed differences in fertility were actually caused by some other factor that the researchers could not allow for.  Perhaps their planned further work will throw more light on this.

“The second set of reasons is that, statistically, the differences in fertility between the women taking short-acting asthma relievers, and other women, were not particularly clear-cut.  Again that’s not the researchers’ fault – it’s just that any differences in fertility, depending on asthma treatment, appear not to be very large, so that even a study with over 5,000 women could not estimate them very closely.  The reduction in the monthly chance of getting pregnant, in women taking only short-acting asthma relievers compared to those who did not have asthma, is not particularly large.  It’s not even entirely clear, statistically, that any reduction in fertility in these women was really greater than any reduction in fertility in the women taking longer-acting asthma medication – though that’s not a reason to ignore the researchers’ recommendation that women with asthma planning a pregnancy should continue to take their long-acting preventer medication.  Also, though the researchers found that the women taking only short-term relievers were more likely to take over a year to get pregnant, this effect was not big enough to rule out the possibility that it was simply due to chance.  (That is, it was not statistically significant.)  So this research points in interesting and important directions, but can’t provide an entirely clear picture.

“The women in this study were all expecting their first babies.  Therefore the study tells us nothing directly about any possible effects of asthma medication on women aiming to become pregnant for the second or subsequent time, as the research report makes clear.

“There are a couple of technical statistical points.  First, the original version of the press release said that women taking short-acting medications were 40% more likely have taken a year to conceive, compared to women who did not have asthma.  I understand that this has now been corrected to 30%, but this is a change on the odds scale, and the change in probability would be smaller as a percentage.  (I can’t say exactly how much smaller without knowing the probability that a woman without asthma would take more than a year to get pregnant, and the research report does not reveal that figure.)  Second, in the research report itself, it is stated that a fecundability odds ratio (FOR) greater than 1 corresponds to a reduction in fecundability (the chance of getting pregnant in a cycle), and hence to a longer time to pregnancy, and an FOR less than 1 corresponds to a shorter time to pregnancy.  Again, I understand this is a typo, and that it should say that an FOR less than 1 corresponds to a longer time to pregnancy, and an FOR of more than 1 to a shorter time to pregnancy.”

Prof. Ying Cheong, Professor of Reproductive Medicine, University of Southampton, said:

“Grzeskowiak et al reports that women with asthma have reduced fertility, but those who take short acting asthma medication (e.g. beta-agonist) were worse off than those women who take long acting asthma medication (e.g. steroids).  One major weakness of the study was that the data obtained were self reported e.g. diagnosis of asthma, time to pregnancy etc., and as such can be inaccurate, and hence, subjected to certain amount of bias.

“Nevertheless the results reported are extremely interesting and makes clinical and biological sense.  The embryo (early pregnancy) is very sensitive to its environment, whether this is to changes in oxygenation or inflammation levels within the womb or other physical factors, and it does not surprise me that a condition such as asthma, and its associated treatment(s) will impact on the growth, development and longer term outcomes of the baby.  To further unravel this mystery, research needs to focus on the womb environment, and study how and when the womb environment becomes hostile, and apply remedy if necessary.  Asthma is a common condition, and women who have asthma should ensure they are on the appropriate medication, for general health, but also to optimise reproduction.”

Prof. Tony Fox, Professor of Pharmaceutical Medicine, King’s College London, said:

“The investigators should consider whether patients using symptomatic short-acting bronchodilators are actually treating their asthma less well than those patients using inhaled corticosteroids to prevent asthma attacks from happening in the first place.  The latter, by reducing their attacks, might have better general health than those who treat their attacks when they occur.  It could be that this general improvement in health, by not having asthma attacks, is what influences the improvement in fertility, and not some negative effect of the short-term bronchodilators that are only used after an asthma attack has already started.”

Prof. Aziz Sheikh, Director, Asthma UK Centre for Applied Research, The University of Edinburgh, said:

“This large, multi-country prospective observational study has found that asthma managed only with short-acting bronchodilators is associated with reduced fertility, but this is not the case in those with asthma who are also taking inhaled corticosteroids.  This seems plausible given that regular use of inhaled corticosteroids improves asthma control and so the authors’ key conclusion that women trying to conceive should ensure good compliance with their preventer therapies in order to optimise asthma control is sound clinical advice.

“In terms of progressing the science, there is a need for the evidence base to be strengthened through more formal approaches to diagnosing asthma and assessing asthma severity and control, lung function, inhaler technique and compliance, as well as studying a fuller range of confounders, in order to develop a clearer appreciation of whether this represents a causal relationship or not.”

* ‘Asthma treatment impacts time to pregnancy: evidence from the international SCOPE study’ by Luke E. Grzeskowiak et al. published in the European Respiratory Journal on Thursday 15 February 2018. 

Declared interests

Prof. Kevin McConway: “Member of the SMC’s advisory board.”

Prof. Ying Cheong: “I am a director of Vivoplex Medical Ltd, a device company specialising in miniaturised sensors in detecting abnormal womb environment.”

Prof. Aziz Sheikh: “No conflicts.”

None others received.