February 2, 2018

expert reaction to study looking at ibuprofen exposure of foetal ovarian tissue in the lab, and survival and number of egg cells

Researchers publishing in Human Reproduction examine whether ibuprofen use during the first trimester of pregnancy interferes with the development of the human fetal ovary.

Prof. Richard Anderson, Head of Section of Obstetrics and Gynaecology, MRC Centre for Reproductive Health, University of Edinburgh, said:

“There are concerns that common painkillers like paracetamol and ibuprofen might have effects on the developing baby when taken during pregnancy.  This study explores the possibility that ibuprofen, which is taken by many pregnant women, might have effects on the early development of her baby’s ovaries.  As all the eggs that a woman’s ovary will have are formed before she is born, any effects at this time might have implications for her later fertility, and perhaps even the age she goes through the menopause.

“This study is based on experiments in the lab, and shows that treatment of fetal ovaries with ibuprofen for 2-7 days affects survival of the egg cells at that time.  These seem concerning results, though how much these experiments in the lab match what might happen when ibuprofen is taken by a pregnant woman are unclear.  They do however emphasise the need to only take approved medicines during pregnancy, and for as short as time as necessary.”

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

“Leverrier-Penna et al performed experimental human ovarian cultures with tissue obtained from 7-12 weeks foetuses obtained from 185 individuals who underwent termination of pregnancy, and exposed the cultures continuously for 2 ,4 and 7 days to ibuprofen of concentrations 1-100 micromols.

“They found significant loss of cell numbers in the ovarian cultures in the 7 day, 10 micromols cultures.

“This research is of good quality and represents important scientific advancement.  The organotypic cultures used is an excellent model to study the impact and exposure of substances on tissue.  The drawback of course, is that this is an in vitro system, trying to mimic what happens in vivo.  As such, whilst the concentrations in the culture were carefully controlled, in reality, developing ovaries are unlikely to be immersed continuously in ibuprofen in the body the same way as they are in the laboratory, with the pharmacokinetics and pharmacodynamics in the body being much more varied and complex depending on a whole host of biological factors.  Normally, when the drug dose is increased, the detrimental impact also increases, but in this case, why the worst impact on cell numbers were seen in the 10micromols cultures but not the 100micromols culture warrants further investigation.

“In my opinion, the work is of excellent quality and represents important scientific advancement.  We now need longitudinal epidemiological data to further confirm these observations as to whether exposure in early pregnancy relates to reduce fertility.  Generally speaking, ibuprofen should be used in pregnancy sparingly but the current evidence should not be used to ‘scare-monger’ women into not using this rather effective simple analgesics at all.”

Dr Dan Hawcutt, Senior Lecturer in Paediatric Clinical Pharmacology, University of Liverpool, said:

“This is a very interesting piece of research, and my interpretation of it is that it shows an area where more research is needed, and by itself it is not concrete proof of a problem.  As the authors state, this work relies on cell culture techniques, and with all such work there is a question about whether this accurately replicates the situation in real life.

“There is natural variation between individual in terms of how many eggs they are born with, with the average number being approximately 2 million.  There is therefore a considerable excess of eggs in the developing ovary at birth, and most eggs do not get released as part of the normal cycle of ovulation.  It may therefore be that even if this effect is genuine, the number of ‘extra’ eggs women are born with compensates for this.

“This report may concern mothers with daughters who have used ibuprofen early in pregnancy, but it is too soon to tell if this is a finding that will affect a child’s future fertility.

“For women who are pregnant, the use of any medicine should ideally be discussed with a suitable healthcare professional to work out your own personal potential risks and benefits.”

Dr Christoph Lees, Clinical Reader in Obstetrics, Imperial College London, said:

“The findings of this interesting ex vivo study suggest that ibuprofen may adversely affect the development of fetal ovaries, by causing the ovarian germ cells to die.  These are the cells that later in life may be fertilized to form embryos.

“It’s important to note that the study did not take place under normal physiological conditions and we must be careful about drawing conclusions about how short term ingestion of ibuprofen in the real world affects the development of fetal ovaries.  Particularly so as the authors didn’t show a dose dependent effect of ibuprofen in ovarian cell death – in fact, bizarrely, the highest does of ibuprofen had the least effect.  This is something the authors have not drawn attention to or explained sufficiently, but is potentially very important in interpreting the messages from the study.

“Nevertheless, there is growing evidence that therapeutic doses of non steroidal drugs should be avoided in pregnancy due to the their effects on developing kidneys and lungs.  This study, despite some unresolved methodological issues, certainly makes an important contribution to this body of evidence.”

Dr Michelle Bellingham, Society for Endocrinology member and lecturer at the Institute of Biodiversity Animal Health and Comparative Medicine, University of Glasgow, said:

“I think the study is very interesting and builds on other work which has indicated that painkillers during pregnancy may be detrimental to the reproductive health of the offspring.  While it’s always difficult to determine cause and effect from these types of experiments where cultured cells are used in comparison to a whole human (which would not be feasible), the study has considered the dose of the drug that the developing ovary may receive, and is well powered (185 samples).  The authors clearly indicate the limitations of study, mainly that they cannot address the long-term effect of this drug on the ovary, but emphasise that further research at the population level is required to understand the effects better.”

* ‘Ibuprofen is deleterious for the development of first trimester human fetal ovary ex vivo’ by S. Leverrier-Penna et al. published in Human Reproduction on Friday 2 February 2018.

Declared interests

Prof. Richard Anderson: “A colleague is an author.”

Dr Dan Hawcutt: “I have no conflicts of interest to declare.  I am a paediatric pharmacologist, so my comments and expertise will be from the child’s perspective.  I am employed by the University of Liverpool, and do not know any of the authors of this study.  I have no grant income in this area.”

Dr Michelle Bellingham: “I know the group peripherally but I have no direct conflict of interest to declare.”

None others received.