Could new potential treatment mean safer IVF?


"Dozen babies born using 'safer' IVF treatment," reads today’s headline in The Independent. This headline was based on a new study providing proof of concept that the natural hormone kisspeptin-54 could...

“Dozen babies born using 'safer' IVF treatment,” reads today’s headline in The Independent.

This headline was based on a new study providing proof of concept that the natural hormone kisspeptin-54 could be used to stimulate egg maturation in women requiring in vitro fertilisation (IVF).

The modified IVF treatment on trial, which is hoped to be safer than standard IVF, led to 12 healthy babies being born from 53 women undergoing a single IVF treatment.

One of the main hopes is that using kisspeptin-54 could lead to a safer version of IVF by reducing the need to use human chorionic gonadotropin (hCG), which has a small risk of causing ovarian hyperstimulation syndrome (OHSS). This can be potentially fatal. However, this study was much too small to prove kisspeptin-54 was safer. Much larger trials are required to prove this, and are the logical next step for this early stage research.

The study looked mainly at different doses of kisspeptin-54, but did not compare it with current IVF treatment. It will be vital for future clinical trials to include a control group, so that the effectiveness and safety of the new IVF treatment can be directly compared to the existing treatment, to see which is better overall.

Where did the story come from?

The study was carried out by researchers from Imperial College London and Hammersmith Hospital, and was funded by the Medical Research Council, Wellcome Trust and National Institute for Health Research.

The study was published in The Journal of Clinical Investigation, a peer-reviewed medical journal.

The media’s reporting of this story has been generally accurate, with the BBC including important quotes at the end of their piece, illustrating some of the research's key limitations. The Independent’s coverage did not highlight the limitations inherent in the study, and instead focused on the potential positives of the finding, leaving readers with a less balanced account.

What kind of research was this?

This was a randomised clinical trial (RCT) investigating whether a new hormone could be used in the early stages of IVF to potentially improve its safety.

IVF is one of several techniques available to help couples with fertility problems have a baby. During IVF, eggs are surgically removed from the woman's ovaries and fertilised with sperm in a laboratory. The fertilised egg is grown for a few days in the lab, and the best one or two embryos are then returned to the woman's womb to implant, grow and develop.

IVF starts with women being given hormones to suppress their natural monthly cycle. They are then given fertility-stimulating hormones to increase the number of immature eggs produced in the ovaries. These are too immature to be collected, so a second hormone is injected, typically human chorionic gonadotropin (hCG), to stimulate these eggs to mature. These matured eggs can then be collected for fertilisation in the laboratory.

However, hCG tends to linger in the body and is associated with a small risk of the ovaries being stimulated too much, causing the condition OHSS. The researchers wanted to see if there was a safer way of stimulating women’s ovaries to produce mature eggs for the IVF process, but without the increased risk of OHSS.

In previous research, the group had come across a naturally occurring hormone called kisspeptin-54, which when faulty makes a person infertile, as they cannot go through puberty. They thought there was a chance it might stimulate egg maturation over a shorter period of time, lessening the chance of the ovaries being overstimulated, theoretically reducing the risk of OHSS. They designed a clinical trial to investigate whether it was possible to use kisspeptin-54 instead of hCG in the IVF process, specifically to stimulate egg maturation.

What did the research involve?

The researchers randomly allocated 53 women who had opted for IVF to different doses of kisspeptin-54 treatment. They wanted to see whether it could partially replace the hormone normally used to stimulate the maturation of eggs during IVF.

All of the women were given follicle-stimulating hormone (FSH) to stimulate the ovaries to produce lots of immature eggs. They were also given gonadotropin releasing hormone (GnRH) antagonist injections to prevent the eggs from leaving the ovaries too early. They were then given different doses of kisspeptin-54 to trigger egg maturation. When at least three ovarian follicles (immature eggs) of 18 mm or greater diameter were visible on an ultrasound scan, the women were given an injection of kisspeptin-54 to trigger egg maturation.

The women were recruited from a list of women requiring IVF treatment at Hammersmith Hospital, London. The inclusion criteria were specific and included:

  • age 18-34 years
  • early follicular phase level of serum FSH ?12 mIU/ml
  • serum anti-Mullerian hormone of 10-40 pmol/l (1.4-5.6 ng/ml)
  • both ovaries intact, regular menstrual cycles of 24-35 days duration
  • body mass index (BMI)18-29 kg/m2 (this includes women of a healthy weight and overweight, but not those who are obese or underweight)

Women were excluded if they:

  • had moderate or severe endometriosis
  • had poor response to, or more than one previous cycle of, IVF treatment
  • had clinical or biochemical hyperandrogenemia (an excess of androgens)
  • had polycystic ovarian syndrome

The researchers primarily wanted to know whether a single treatment of kisspeptin produced egg maturation. They assessed this by looking at the number of mature eggs, and the percentage of all eggs collected that were mature. Secondary outcomes included the later stages of IVF, such as fertilisation rates, successful implantation rates, pregnancy rates and healthy births.

Importantly, there was no control group of women who received normal IVF with gonadotropins to act as a comparison, so only the relative effects of the different doses of kisspeptin were under investigation. The study did not compare the effect of the experimental kisspeptin IVF treatment with regular IVF treatment.

What were the basic results?

Egg maturation was observed in response to each tested dose of kisspeptin-54, and the average (mean) number of mature eggs per woman broadly increased in a dose-dependent manner.

Fertilisation of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of patients treated with kisspeptin-54.

Clinical pregnancy rates using the technique were 23% (12/53) overall. 10 of the 53 women gave birth to healthy babies (12 babies in total, as two women had twins) following the kisspeptin IVF. Two women who initially became pregnant had a miscarriage.

In terms of safety and side effects, kisspeptin was reported to be well tolerated by all of the women. Five negative events were recorded in the group, but these were related to established complications of IVF, rather than the new hormone treatment. Two patients experienced an ectopic pregnancy, one had a heterotopic pregnancy (where an ectopic pregnancy and a viable intrauterine pregnancy occur at the same time) and two had miscarriages.

How did the researchers interpret the results?

They said the study "demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing IVF therapy. Subsequent fertilisation of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy.”


This study provided a “proof of concept” that the naturally occurring hormone kisspeptin-54 can be used to stimulate egg maturation in women requiring IVF. The modified IVF – which is hoped to be safer than standard IVF – led to 12 healthy babies being born from 10 mums. Out of the 53 women undergoing a single IVF treatment, this gave a 19% success rate.

Researchers hoped that using kisspeptin-54 could lead to a safer version of IVF by reducing the risk of OHSS. Although theoretically plausible, this study was much too small to prove that the new technique was safer; much larger trials will be required to prove this. What this study does prove is that it is possible to achieve IVF success to stimulate egg maturation by using kisspeptin-54.

Another factor limiting the interpretation of the results is the fact that there was no control group. The study did not compare the effect of the experimental kisspeptin-54 treatment with regular IVF treatment. Therefore, the study told us about the relative effects of the different doses of kisspeptin, rather than how they stacked up against the current IVF treatment. This is something fully acknowledged by the research authors, but much less clear in the media's reporting.

Future studies will need to examine not only whether the new treatment is safe, but also whether it leads to the similar success rates in terms of fertilisation and healthy births as the current technique.

The BBC carries a quote indicating that the next clinical trials will take place in women with polycystic ovary syndrome (PCOS), who are more vulnerable to overstimulation. This will be a useful way to investigate the potential safety benefits of this technique in this higher risk group.

Article Metadata Date Published: Thu, 23 Nov 2017
Author: Zana Technologies GmbH
NHS Choices