麻豆传媒

AT FIFTY-FIVE years old, Angelina Calabro gave birth to her one and only child, a much-loved daughter called Carmelina. What sets Calabro apart from the handful of other women who give birth this late in life is that she did not set out to get pregnant using reproductive technology. She conceived entirely naturally and unexpectedly.

鈥淲e were incredulous,鈥� she told Australian newspaper The Age 鈥淚 turned around to look behind me when the doctor told me, I asked him if he was talking to me.鈥� Carmelina is now 11 years old and her parents are retired.

It is much publicised stories like this that give women in their fifth, sixth or even seventh decade the idea that it might not be too late to have children after all. In rich countries, many women today don鈥檛 even start to think about having children until well into their thirties, if then. It seems that now we are in control of our reproductive capabilities, education and careers are the priority for many women.

Another factor could be that men are baulking at the prospect of having babies. Without a partner, relatively few women are prepared to go it alone. Whatever the reasons, many women have become the living embodiment of that 1980s T-shirt: 鈥淥h my god! I forgot to have a baby!鈥�

An estimated 1 in 5 British women in their mid-forties are now childless either through choice or because of a lack of opportunity, twice as many as 15 years ago. The trends are similar in the US and Australia. Meanwhile, women who are having children are leaving it later and later, with the average age of first-time mothers now standing at 27 in the UK, up from 24 in 1970.

And this average does not tell the whole story. The most dramatic changes have been in older age groups. In the US, the number of women giving birth for the first time between age 35 and 39 rose by 36 per cent between 1991 and 2001. For women aged 40 to 44, there was a staggering 70 per cent increase. In 2002, 263 babies 鈥� first or otherwise 鈥� were born to women between 50 and 54 years old. So will improvements in fertility treatments and pregnancy management allow women to delay childbirth ever later? And is this trend a cause for concern or celebration?

For now, the outlook is not brilliant for someone just starting to contemplate the patter of tiny feet at 40-something. Under the age of 30 a woman has around a 40 per cent chance of getting pregnant in a year, but by age 45 that figure plummets to a mere 10 per cent. And getting pregnant is only the first hurdle: as eggs age, the risk of miscarriage soars from 10 per cent at 20 years old to well over 50 per cent above 45.

Still, if your eggs are still healthy enough at 42 or 43 for you to get pregnant and stay pregnant, you have a pretty good chance of a safe delivery, although not as good as your younger sisters. The number of stillbirths, for instance, rises from 1.1 per 1000 births in women under 35 to 4 per 1000 in women over 40. 鈥淪tillbirths that come out of the clear blue are just devastating,鈥� says Linda Heffner, an expert on maternal and fetal medicine at Boston University Medical Center.

The 40-something is also more likely to be obese or have high-blood pressure or other chronic disorders. These increase the risk of problems such as gestational diabetes, which can lead to an unhealthily large baby, and pre-eclampsia 鈥� pregnancy-related high blood pressure. Pre-eclampsia can cause strokes, seizures, kidney and liver damage and occasionally death. It can also restrict a baby鈥檚 growth and lead to premature birth.

These risks rise rapidly for older mothers, according to a study by Richard Paulson of the University of Southern California in Los Angeles of women aged 50 to 63 who used donor eggs and IVF. While the conception and miscarriage rates were identical to those for younger women using the same methods, mild pre-eclampsia developed in a quarter of the 55 pregnancies, even though the women had all passed a fitness test. A further 10 per cent developed severe pre-eclampsia. For those over 55 years old, pre-eclampsia rates shot up to 60 per cent.

Gestational diabetes showed similar patterns, with a fifth of women needing to alter their diets or take insulin. Four of the 10 women over 55 suffered gestational diabetes.

What about the risks to the children? In the USC study, 10 pregnancies ended in miscarriage, but the 45 babies born were all within the normal range for weight and generally healthy. Nonetheless, if you start looking at larger studies, clear trends emerge.

Compared with 20 to 29 year olds, women who give birth over 40 are two to three times more likely to have a premature baby and/or a low-birthweight one (under 2.5 kilograms), with the risk increasing with age. And although many small babies will survive, the smallest ones often suffer a host of medical problems at birth, such as respiratory distress. The effects can last a lifetime: such children tend to have poorer academic records and lower IQs as adults.

鈥淚f you haven鈥檛 met someone at 33, you could freeze your eggs. That would be really good news鈥�

The biggest worry for older mums is the huge increase in the risk of having a baby with chromosomal disorders. The most common is Down鈥檚 syndrome, the risk of which increases from 1 in 1500 at 20 years old to 1 in 30 at 45.

Without the huge advances in medicine in the past century, however, the risks facing older mothers and their children would be far higher. For instance, there has been a fall in the number of children born with Down鈥檚 syndrome despite the rising age of mothers, thanks to steady advances in prenatal screening in recent decades.

鈥淭esting turns upside-down who鈥檚 at risk,鈥� says David Nyberg, a radiologist in Scottsdale, Arizona, who helped run one trial of Down鈥檚 screening. 鈥淭he unaware 20-year-old who doesn鈥檛 undergo screening ends up at higher risk than the aware 40-year-old who does and gets a good result.鈥�

Prenatal testing will undoubtedly improve further (see 鈥淎 window on the womb鈥�), but an abnormal result will always leave prospective parents facing the heart-wrenching decision of whether to terminate the pregnancy. Women who undergo IVF, however, can avoid this dilemma, because pre-implantation genetic diagnosis (PGD) can now be used to screen out embryos with many chromosomal disorders.

Besides preventing disorders such as Down鈥檚, the hope is that advances in PGD will improve IVF birth rates, especially for older women, by distinguishing between healthy embryos and those doomed to fail. For the moment, though, the evidence is mixed (麻豆传媒, 28 May 2005, p 11).

IVF has already helped millions of women with fertility problems to have children. Yet as with natural conception, the success rates plummet for older women. One study found 28 per cent of women who started IVF at 40 ended up with a baby, compared with 10 per cent at 43 and none at all at 46.

One way around this is to use donor eggs from a younger woman. Donor eggs are in short supply, though, and do not help couples set on having their own genetic offspring. In the not-too-distant future it might become possible to generate eggs from other adult cells (see 鈥淭he egg and sperm race鈥�). A more immediate prospect is for women to freeze their eggs when they are young.

鈥淭hat will be really good news. If you haven鈥檛 met anyone at 33, you could decide to freeze your eggs,鈥� says Heffner. With young eggs in the freezer, one of the biggest causes of the mismatch between an older woman鈥檚 reproductive capabilities and her maternal desires would go out the window.

The first pregnancy involving a frozen egg was reported by an Australian team in 1986, yet while freezing embryos and sperm has become routine, freezing eggs has proved far trickier. The problem might be their large size and relatively impermeable shell and cell membrane, which means it takes a long time for cryoprotective chemicals that prevent the formation of damaging ice crystals to diffuse into the egg. Since these chemicals are toxic to the egg at body temperatures, the egg gets damaged during the very process that is intended to protect it.

Freezing and thawing can also damage the cellular machinery that ensures the egg ends up with the correct number of chromosomes. Studies in mice in the 1980s suggested that this could cause high levels of chromosomal abnormalities, leading to an unofficial moratorium on egg freezing.

But improvements in freezing methods have largely alleviated these fears, and there has been a resurgence of interest in freezing eggs, with private clinics already offering the procedure for a fee. Many groups worldwide are experimenting with methods that further reduce damage to the egg, such as vitrification, which involves cooling eggs so rapidly that the water becomes super viscous, forming a glass-like gel rather than ice crystals.

The published figures for the number of pregnancies from frozen eggs are disappointing 鈥� just 80 children born from 4300 frozen eggs. But the actual number of births is now closer to 500, says Michael Tucker of Georgia Reproductive Specialists in Atlanta. 鈥淲e can improve on survival rates but nevertheless, the technology has come of age.鈥�

鈥淎 lot of people have been claiming great results,鈥� agrees Roger Gosden, director of reproductive biology at the Weill Medical College of Cornell University in New York. 鈥淭he practice of egg freezing will grow steadily, matching the success rate of the technology. Once there is a breakthrough and someone manages to get a success rate that matches fresh eggs, it will become quite irresistible to many centres,鈥� he predicts. Some teams appear to be getting close, with one group in Japan claiming a success rate from frozen eggs nearly as high as that for fresh eggs at a conference earlier this year.

鈥淭he practice of egg freezing will grow steadily as the success rate of the technology improves鈥�

How irresistible it will be to women planning to delay children depends on how deep their pockets are. One private clinic in the US charges well over $10,000 to collect and store the eggs, just for the first year. Freezing eggs also means undergoing the pain and risks of egg collection: the hormones women have to inject can have serious side effects. New techniques that reduce or avoid the need for these hormones could soon make the procedure much safer, however (see 鈥淪ex is for fun, IVF is for children鈥�).

The combination of egg freezing and PGD promises to greatly increase older women鈥檚 chances of getting pregnant and staying pregnant. Yet while the problem of ageing eggs looks solvable, the problem of ageing bodies is far harder to address.

There is some room for progress. Calculations by Heffner鈥檚 team, for instance, suggest that in women over 35, weekly monitoring of the fetus from week 37, with induction of labour if necessary, could reduce the risk of stillbirth, saving the lives of 4 fetuses per 1000 pregnancies (Obstetrics and Gynecology, vol 104, p 56). Although this has yet to be proven, many obstetricians are already embracing the practice.

However, none of the fertility experts contacted by 麻豆传媒 is optimistic about the prospects of reducing older women鈥檚 chances of developing pre-eclampsia. 鈥淧regnancy is all about blood flow, including the blood vessels鈥� ability to adapt to the 50 per cent increase in blood volume that occurs in pregnancy,鈥� says Paulson. Declining cardiovascular fitness may ultimately set the limit on the age at which women will be able attempt pregnancy. 鈥淚f you have high blood pressure and you get pregnant, we鈥檒l take care of you. If you have high blood pressure, are post-menopausal and want to get into a donor egg programme, you won鈥檛 pass the screening test,鈥� points out Heffner. Many clinics simply turn away women older than 52, the average age of the menopause.

Paulson is generally upbeat about the prospects for over-50s. 鈥淲e know women in their 50s who can handle a marathon, so they can handle a pregnancy,鈥� he says. 鈥淎nd having a pregnancy is worth some degree of risk.鈥� But he too stresses the importance of cardiovascular fitness.

鈥淲e know women in their fifties who can handle a marathon, so they can handle a pregnancy鈥�

Clearly, waiting until you retire to have children will not be a realistic option for most women any time soon. At the same time, the trend for women to have children later shows few signs of abating. 鈥淭he women coming to see me are getting older and older. Maybe they don鈥檛 understand their own reproductive physiology,鈥� says Rita Alesi, head counsellor at Monash IVF in Melbourne. 鈥淥r maybe they hear the media excitement about a woman in her fifties giving birth, and it makes them more aware of what is possible.鈥�

Of course, most people don鈥檛 plan their lives with military precision. When you have children is often determined by chance events, such as meeting the right person or failing to use contraception. Nevertheless, is there a case to be made for governments to encourage women to have children earlier by, for example, a generous parental leave policy or free childcare?

While the health risks for older women and their children are higher, this needs to be seen in perspective: the risks are tiny compared with those facing young women in poor countries, and even in rich countries factors such as smoking during pregnancy may have a greater impact than maternal age. And some studies suggest that mature parents are better parents. 鈥淪ome people leave it a bit late, but in general, delaying children until you are more mature socially, psychologically and economically, is a good thing,鈥� says Susan Harlap, who studies birth risks associated with older parents at the Mailman School of Public Health in New York. 鈥淒espite the increased risks, the vast majority of offspring born to older mothers are normal.鈥�

One worry is that children will be disadvantaged by ageing parents dying. But as Heffner points out: 鈥淲e live a lot longer. If you are healthy, is there really any difference having a child today at 50 when you can expect to live into your eighties, to having child at 30 when life spans were only to the mid-fifties?鈥� Nonetheless, she thinks that societies should put an age limit on motherhood.

鈥淪ome leave it a bit late, but in general delaying children until you are more mature is a good thing鈥�

Even if governments do try to intervene, it鈥檚 not apparent if the trend for having children later could be reversed. The demand for new technologies looks unstoppable. As a sign of things to come, take Denmark. According to an unpublished projection by Tom谩s Sobotka of the Vienna Institute of Demography, more than 6 per cent of all births to Danish women born in the 1970s will be a result of assisted reproduction.

The impact of egg freezing and PGD could be almost as revolutionary as the Pill, allowing women to routinely delay having their own children until they are well into their forties. Beyond this point, though, ageing bodies will limit what can be achieved.