News and views

Viable eggs and successful pregnancy in a woman of 46 years

There have been many headlines over the past 30 years announcing childbirth in postmenopausal women. The biology-defying practice became almost commonplace at the University of Southern California in the 1990s from where the gynaecologists Paulson and Sauer described their first series of over-50 fertility patients in The Lancet in 1993 – 21 transfers in 14 couples resulting in seven live births, a rate of 33%. ¹ These, of course, were all egg donation treatments, and what this and other reports would confirm beyond doubt was that success would depend not on the age of the recipient, but on the age of the donor. A later review by Paulson showed that cumulative pregnancy rates in egg donation cycles were the same whatever the age of the recipient; crucial was the hormonal synchronisation between donor and recipient and the viability of the egg. However, a further review of his own cases from 1991 to 2001 (77 women aged over 50) revealed relatively high rates of gestational diabetes (20%) and pre-eclampsia (35%) – between two and three times higher than in 40-year-old women. ² The problems with postmenopausal pregnancy thus seem more a question of obstetrics than gynaecology.

An opinion from the Ethics Committee of the American Society for Reproductive Medicine in 2013 (itself an update of the first opinion in 2004) concluded that ‘egg donation after age 50 is not such a significant departure from other currently accepted fertility treatments as to be considered ethically inappropriate in postmenopausal women’, but that ‘providing donor oocytes or embryos for transfer to any woman over 55 years of age, even when she has no underlying medical problems, should be discouraged’. ³

Now, a report in the ASRM’s own journal Fertility and Sterility suggests that, even well into her 40s and with an ovarian reserve running on empty, a woman may yet give birth without having to resort to egg donation. The report describes the case of a nulliparous 46-year-old who became pregnant with in vitro fertilisation (IVF) using her own eggs, despite a rock-bottom level of Anti-Müllerian hormone and hopeless fertility record. Yet following ovarian stimulation seven oocytes were retrieved, of which four became reasonably viable embryos. Following transfer, the pregnancy progressed without complications, with a singleton delivery at 32 weeks (later described as ‘thriving’). This, say the authors, is the first report of successful live birth from IVF in a 46-year-old woman using autologous oocytes following gonadotropin stimulation – thereby making her the world’s oldest successful IVF patient.

Infertile women in their mid-forties have only three options for pregnancy: IVF using their own oocytes, egg donation or adoption. The two latter procedures are by far the most likely to succeed, even though many women would still prefer a biologically related child. However, the chances of successful pregnancy with one’s own eggs – whether conceived spontaneously or with IVF – are somewhere between slim and impossible for a woman in her 40s, largely because of declining ovarian reserve and the chromosomal status of the embryo, which deteriorates with advancing age. According to the latest US IVF data (for 2011), live birth rates among women aged 44 and over are just 1.1%.

Even in 1993, the New York embryologist Santiago Munne ⁴ had discovered higher than expected rates of chromosomal abnormality in IVF embryos, and these, he suggested, may well be the cause of failed implantation. The prevalence of aneuploidy (and of chromosomal misarrangements, as in trisomy 21) was also found to increase with advancing age, such that as many as 60% of embryos in women over 40 may be chromosomally abnormal. It is for these reasons that preimplantation genetic screening is now often recommended in women over 40 having IVF – to detect any chromosomal defect and ensure that only euploid embryos are selected for transfer. That in itself does not guarantee pregnancy, but at least it gives a woman’s own eggs a better chance.

Abortions increase in women in their 30 s and 40 s

The latest figures from the UK’s Department of Health show that the number of abortions in women in their late 30 s and 40 s continues to rise, in contrast to a declining rate in all other age groups. Since 2001, the rate has risen by 15.5% in women aged 30 to 34 and by 6% in the over-35 s. ¹

Commenting on the figures, the British Pregnancy Advisory Service (BPAS) said that ‘among women in their 30 s and 40 s, unplanned and unwanted pregnancy may result from poorer access to contraception services for older women as well as the mistaken belief that their fertility is waning’. ² According to reports, the BPAS suggested that many women in this age group are under the false impression that they do not need contraception, believing that by this age the only way they can become pregnant is through IVF.

The BPAS also proposed that many in their 30 s and 40 s will have already completed their families, noting that abortions in women who are already mothers have continued to rise, from 47% in 2003 to 53% in 2013.

In a statement, the BPAS chief executive Ann Furedi said:

One in three women will have an abortion, and these figures show clearly that women need good access to contraception and abortion services at every stage of their reproductive lifetimes. We should stop politicising abortion and accept that it is a standard part of women’s healthcare. Much effort has been put into improving contraception services for younger women, but women don’t stop having sex when they hit 25. We need to construct services that meet the needs of older women.

The UK’s lost decade of good menopause advice

A generation of specialists, general practitioner (GPs) and nurses could have been making recommendations based on outdated advice, according to the British Menopause Society in launching a new education campaign for health professionals. The campaign, says the BMS, aims to boost the education of women and their carers about the specific needs of women during the menopause and in the following decades.

Behind the campaign lies a decade of confusion and misinformation following publication of the first Women’s Health Initiative and Million Women Study. Since then, writes the BMS, ‘there has not only been a large-scale withdrawal of doctors prescribing HRT, but also a lack of prioritization in care professionals addressing the needs of women after the menopause’. Confusion is worse than it might be, adds the BMS, ‘because information about HRT from UK regulators such as the MHRA has also not been updated’.

The BMS proposes:

HRT, if required and given to the right women at the right time for the correct duration, may have significant long term benefits sustainable for years after stopping HRT. Only fully up to date doctors and nurses will be able to do this (This was what the BMS recommended to the Department of Health in 2011. ¹ )

The campaign – known as ‘Mind the Gap’ – thus encourages women to visit their GP at the time of the menopause for up-to-date information on quality of life, fitness and longevity. Thus, the BMS along with its patient partner Women’s Health Concern have planned a nationwide campaign of accredited educational meetings and seminars for doctors and nurses, and evening meetings for patients.

Edward Morris, Chairman of the BMS, said at the launch of the campaign:

The gap that we need to close is a 10-year gap of knowledge on how to look after women during the decades after the menopause. It is time to end the taboo of talking about the menopause with the worries around the mixed messages about HRT. It is time to move towards a holistic and integrated approach to modern health care after the menopause where those giving advice are fully educated, up to date and able to support women through the decisions they make.

As if on cue, the International Menopause Society is promoting the use of a menopause toolkit designed for GPs treating women patients over the age of 40. Led by Susan Davis, a research team from Monash University in Australia combined existing research on menopause, diagnostic algorithms and clinical experience to develop the toolkit, which works through a patient’s medical history and risk factors to arrive at the best treatment. The Practitioner Toolkit for the Managing the Menopause is available for free download from the IMS’s journal Climacteric. ²

Metformin has wider implications than diabetes

The antiglycaemic drug metformin, widely prescribed as first-line treatment of type 2 diabetes mellitus, appears to slow ageing and have lifespan-extending properties – at least in a study of worms. ¹ Precisely how this is achieved remains unclear, but, using the techniques of proteomics, researchers from Belgium have discovered a signalling cascade in which metformin is able to extend lifespan by increasing the production of reactive oxygen species. These oxygen cells are usually toxic, damaging cell proteins and DNA, but, say the researchers, in small doses can actually be beneficial – a clear example of ‘hormesis’, by which a low dose of a usually toxic molecule has a reverse effect from the higher dose.

‘As long as the amount of harmful oxygen molecules released in the cell remains small,’ said researcher Wouter De Haes from Leuven, ‘it has a positive long-term effect on the cell. Cells use the reactive oxygen particles to their advantage before they can do any damage’. This study identified the antioxidant responsible for translating oxidative stress into a downstream prolongevity signal.

Metformin, apparently, causes a slight increase in the number of reactive oxygen molecules, which in turn made the worm cells stronger and extended their healthy lifespan. This was achieved through a process of hormesis in a signalling cascade in which the metformin-induced production of reactive oxygen species increased overall life expectancy.

As background to the study, the researchers noted that it has long been thought that harmful reactive oxygen molecules were paradoxically the very cause of ageing. Indeed, the food and cosmetics industries have continually emphasised the anti-ageing effects of products containing antioxidants, such as skin creams, fruit and vegetables, red wine and dark chocolate.

But, said the researchers, while antioxidants do in fact neutralise harmful reactive oxygen molecules in the cell, they actually negate metformin’s anti-ageing effects because the drug relies entirely on these molecules to work.

The researchers studied metformin’s mechanism in the tiny roundworm Caenorhabditis elegans, an ideal species for studying ageing because it has a lifespan of only three weeks. ‘As they age, the worms get smaller, wrinkle up and become less mobile’, said De Haes. ‘But worms treated with metformin show very limited size loss and no wrinkling. They not only age slower, but they also stay healthier longer’.

Of course, what happens in the worm may not necessarily happen in the human, but it does seem clear that metformin acts on a pathway common to several ageing-related disorders and appears to mimic dietary restriction in its effects. Nevertheless, and despite its widespread use, the detailed mode of action of metformin is largely unknown. This latest study appears to have identified the molecule able to translate the reactive oxygen species into a longevity cue.