February 4, 2019

expert reaction to study looking at infertility treatment and pregnancy complications

Reactions to a study published in the Canadian Medical Association Journal which claims women who have undergone IVF treatment are more likely to experience severe pregnancy complications.

Prof Simon Fishel, Founder and President and Head of R&D, and Professor of Human Reproduction, CARE Fertility Group, said:

“In my view a better headline for the press release would have been ‘Patients undergoing infertility treatment may be at slightly higher risk of pregnancy complications’ – my point being it could well be an associated problem of some of the patient population, rather than the infertility treatment itself, which is responsible for the slightly higher risk.

“The research is a statistical comparison of databases – to that extent it has been performed well. But the conclusions are incomplete in that they continually state the infertility treatment per se seems to have a risk associated, whereas they have not proven it is not the patient cohort that is potentially at risk as distinct from the treatment. For example, we now know there are genetic mutations, in men as well as women, that expose women to risk of ‘small-for-date babies’, pre-eclampsia, VTE (thrombosis – even after delivery) – and such risks have been shown to be higher in the population of people seeking IVF.

“Also, it seems they excluded patients at risk of miscarriage in the control population – as mentioned there is a link here that could raise the incidence of issues in the general population. The authors do appear to give credence to this in their very last paragraph: “Further research should identify patient- and treatment-specific factors that might be modified to mitigate excess maternal risks.”

“The authors give their view on how this study fits in with existing evidence, which is that it is supportive of previous studies indicating the higher risk group is over 40 and with a multiple pregnancy.

“One other limitation is that they did not have comprehensive access to all the clinical histories and treatment provisions to the patients receiving more invasive infertility treatment – or that they didn’t or couldn’t account for this information. By using only headline features such as IVF or ICSI from a registry it does not give enough individual patient granularity (a general epidemiological problem).”

Prof Alastair Sutcliffe, Professor of General Paediatrics, University College London, said:

“Subfertility is defined as failure of spontaneous conception after 12 months of unprotected sexual intercourse.  It is associated with factors to do with the mother including anovulation, tubal disease, and endometriosis as well as factors to do with the father including defects in spermatogenesis.  In a third of couples, no obvious cause is found and the infertility is described as unexplained.  Regardless of cause, the NICE recommended treatment for prolonged unresolved infertility is assisted reproduction.

“This study uses existing data sets which are fairly complete to investigate an effect which was not the original reason for collecting the data, therefore reducing significantly the chances of bias.  In this Canadian study there has been an attempt to investigate via registry data any ill effects of fertility treatments per se on pregnancy complications and to ask are those established risks greater if the infertility treatment was more ‘invasive’, e.g. conventional IVF, rather than less so, e.g. the use of clomiphene and other ovulation induction without ‘full IVF’.  No epidemiological study can establish cause and effect, and this study is no exception – so we can’t know whether it was the IVF that caused the small increase in complications or whether other factors were responsible, such as the underlying reason the couple were subfertile in the first place.  The slight overall increased risk of complications after IVF therapies will not allow for residual confounding, although the authors try.  I am interested to see for example there is no reference to pulmonary embolus or stroke or other major cardiovascular complications which women treated with IVF are at higher risk of, suggesting their sample size was too small to detect these.  This study adds a suggestion that the degree of ‘invasiveness‘ of the nature of the fertility treatment is associated with the higher risk of complications.

“Should couples be put off IVF due to this study?  The answer is no.  As fertility treatments have advanced, they have become more refined so to speak with less use of supra physiological drug doses as a prime example.  This is a continuing refinement making IVF safer and safer.  The bottom line is that the subfertile couple are a skewed population per se and their health risks reflect that.  More research is of course always welcome.”

Prof Joyce Harper, Head of Research Department of Reproductive Health, Institute for Women’s Health, UCL, said:

“This is an important paper highlighting the need to follow up assisted reproductive technology pregnancies.  Continued studies like this are needed to obtain reliable data.  The risk of complications are slight but women going through these treatments need to be fully informed.  They also need to be told about the importance of maternal health before they embark on treatment.  We know the risks of multiple pregnancy and we need to encourage single embryo transfer, especially with the high success rates of using frozen embryos.”

Prof Marian Knight, NIHR Professor of Maternal and Child Population Health, National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, said:

“IVF or other assisted reproductive technologies have been shown in several previous studies to be associated with severe pregnancy complications – however, as the authors of this paper note, this increase in pregnancy complications is most likely to be a reflection of underlying maternal health conditions rather than the IVF itself.

“In this analysis, the authors use propensity score matching in an attempt to account for the underlying maternal conditions.  However, it is likely that there are still differences between the women in the IVF group and the comparison women which this analysis technique has been unable to account for.  More women in the IVF group, for example, had a multiple pregnancy – a known risk factor for severe haemorrhage – and the authors are unable to assess the severity of medical complications that women had.  It is therefore possible that the women in the IVF group had more severe pre-existing medical conditions, which could account for their higher risk of pregnancy complications.

“The most important message for women is that if they have a medical or mental health condition, they should consult their doctor or midwife before getting pregnant, whether by IVF or naturally, to make sure the medications they are taking are the safest for pregnancy.”

‘Infertility treatment and risk of severe maternal morbidity: a propensity score-matched cohort study’ by Natalie Dayan et al. was published in CMAJ (Canadian Medical Association Journal) at 05:15 UK time on Monday 4 February 2019.

Declared interests

Prof Alastair Sutcliffe: “No interests at present.”

Prof Joyce Harper: “Joyce Harper is writing a book on the science behind fertility called What Every Woman Should Know.”

Prof Marian Knight: “I conduct a range of studies focussing on severe maternal morbidity and lead the UK programme of surveillance and investigations into maternal deaths. I have no financial conflicts.”

None others received.