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Researchers, publishing in the Journal of the American College of Cardiology, reported that adolescents who were born through assisted reproductive technologies had higher blood pressure than those who were conceived naturally.
Dr Jacques Cohen, Product Developer of Althea Science and Director of ART Institute of Washington, said:
“This is a small study with important observations, but possibly over-extended conclusions.
“Regardless of any criticism, the findings deserve follow-up in a much larger and better controlled study population using acceptable prospective criteria such as subject and data blinding of the assessors. The assessors in this small study knew who the experimental group children were. The data evaluators also knew the origin of the study and control groups.
“Follow-up studies of assisted reproduction procedures always need to distinguish between the parental etiology, pharmacological effects of the drugs preceding the laboratory portion of assisted reproduction, and the laboratory technologies. Eluding that any findings are caused by only one or the other without evidence, shows a potential for bias. All these aspects are instrumental in determining the validity of health outcomes of children born from assisted reproduction.”
“There are over 200 confounders in assisted reproduction. These were not controlled here. For instance – were these children conceived in one clinic? What was the cause of infertility? What were the ages of both parents?”
“The power calculation seems erroneous. Only 37 subjects were needed? Increased paternal age is associated with increased gene mutations in naturally derived offspring. Paternal age is advanced in many IVF procedures. Paternal age was unfortunately not accounted for in this study.
“It is well known that egg health diminishes with maternal age. Women visiting IVF clinics in the USA in 2014 were 10 years older than women who conceived for the first time naturally.
“The potential pharmacological effects on the mother and her eggs during the recruitment of multiple eggs preceding the IVF procedure should be considered. In the paper it is alluded that this made no difference. The authors do not demonstrate this using a convincing analysis. They refer to a 2012 (https://www.ncbi.nlm.nih.gov/pubmed/22434595) paper. In that paper simple confounder analysis such as paternal age was not performed. In the 2012 paper* a comparison was made with 16 children conceived by only hormonal stimulation. This analysis was under-powered.
“Regardless any conclusions, etiology of infertility is different between the control group, and the assisted reproduction group. This is a problem of any such study. How to determine it is the chicken and not the egg?”
Dr Adam Watkins, Assistant Professor in Reproductive Biology University of Nottingham, said:
“This is a very interesting study that adds to a growing body of literature indicating that ART techniques such as IVF and ICSI may affect the cardiovascular health of the children generated.
“There’s a large body of data from various animals model studies which show that the early embryo is very sensitive to changes in the immediate environment, including research that finds impacts on offspring cardiovascular health.
“Studies on human embryo sensitivity are understandably fewer in number therefore this study highlights the need for additional follow up studies on the cardiovascular effects of ART on offspring.
“Limitations of this study include that it’s a relatively small study, looking at only 54 people in the ART group and these all come from a single community in a single country. Therefore we have to be cautious about relating the findings from this study to the over 6 million worldwide born through IVF.
“A strength of this study is that they’ve looked at children again five years on and continued to see the same effects, but as the numbers are small, it is difficult to extrapolate up to the entire population.”
Prof Tim Chico, Professor of Cardiovascular Medicine and Honorary Consultant Cardiologist, University of Sheffield, said:
“This study adds to previous evidence from mouse studies that suggests that people who were conceived using IVF may be predisposed to some alterations in blood vessel function. The study compares people who were conceived using assisted reproduction technologies (often IVF) with controls, but although it attempted to match these groups the number of people studied was too small to be sure about the findings. It is quite possible the differences in blood vessel function between these groups was caused by factors other than the assisted conception. These findings do justify a much larger study that would allow us to work out whether IVF and related techniques do increase the risk of cardiovascular disease.
“The abnormal blood vessel function seen in this study can be caused by lack of physical activity, an unhealthy diet, excess alcohol, and smoking, so even if assisted conception does affect blood vessels, their risk of developing cardiovascular disease will be determined more by these factors than the assisted conception.”
Dr Channa Jayasena, Clinical Senior Lecturer and Consultant in Reproductive Endocrinology and Andrology, Imperial College London, said:
“This is a thought-provoking and well conducted study. IVF is a tremendous treatment for infertility, and is overall very safe. But, this study suggests that mild increases in blood pressure can be seen in teenagers born following IVF. Hormones regulate the function of blood vessels, so could conceivably mediate any effects of IVF on blood pressure. High reproductive hormones during IVF could conceivably affect the egg, so development of the embryo and the blood vessels.
“The study is very small, so we need to see if the same findings applies to other offspring from IVF. Furthermore, we know that IVF children are on average born into more affluent families which might make them less likely to be obese and less likely to smoke. So, it is not a foregone conclusion that ‘IVF children’ will be overall more or less healthy than average.”
Prof Alastair Sutcliffe, Professor of General Paediatrics, UCL, said:
“The study does not give enough evidence for concern around the safety of IVF and a healthy lifestyle (or not) will be far more deterministic of those risks than IVF conception.
“Some work by Ceelen et al in the Netherlands inferred there may be a problem with higher risk of heart disease in the adolescent years, but both her work and that of the Swiss group were of modest size with inadequate controls.
Regarding health of those born via IVF more generally:
“Indeed parents using IVF have a higher mean age and older parents are at higher rates of conceiving children with certain disorders, for example men as older fathers are more likely to have children with autism and achondroplasia but those increased risks are still small, women are more likely to have children with Downs Syndrome for example but these are not effects of conception method per se but more that these couples did conceive when older.
“IVF conceived individuals are generally healthy but at higher risk of Beckwith Weidmann Syndrome diagnosed at birth and also at higher risk of diseases associated with prematurity if born premature.
Otherwise their health to date (e.g. with cancer risk) is no different than the population as a whole.”
“Currently, the MRC has funded Sutcliffe et al’s work using the dataset involving 77,000 children in England and Wales whose health outcomes will be studied by linking to other NHS datasets. This will address any health concerns in a meaningful and unbiased manner.”
Prof Tom Fleming, Emeritus Professor in Developmental Biology, University of Southampton, said:
“This new dataset is consistent with previous research showing evidence of cardiovascular and metabolic dysfunction in IVF children compared with the naturally conceived population. This has been shown in animal models as well as studies on IVF children directly. Because IVF as a clinical treatment for infertility has only been around for 40 years, the bulk of children born have not reach adulthood and middle age when cardiovascular conditions would normally become apparent, so more evidence may become available in future years.
“Animal models indicate this is not a reflection of being infertile but more likely caused by the treatment itself. Whether the changes occurring in IVF offspring would enter the diagnosis of disease state is not clear, changes may be statistically significant yet within the range of normal health, time will tell.
“From a biological perspective, the early embryo is known to be sensitive to environmental conditions that may alter how it develops, affecting later gene expression and physiological condition, and may lead to changes such as hypertension. This vulnerability of the early embryo and risk of IVF has been recognised in recent Lancet articles (eg, see Fleming TP et al Lancet (2018) Origins of lifetime health around the time of conception: causes and consequences. Lancet, 391:1842-1852).”
* ‘Association of Assisted Reproductive Technologies With Arterial Hypertension During Adolescence’ by Theo Meister et al. was published in Journal of the American College of Cardiology on Monday 3rd September.
All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/tag/IVF/
Declared interests
Dr Adam Watkins: No declarations of interest
Prof Tim Chico: No declarations of interest
Dr Channa Jayasena: No declarations of interest