Birth after 35 - the older mother.

This is a report of a meeting of the Forum on Maternity and the Newborn of the Royal Society of Medicine, held on Thursday 21st February 2008.

Chairs: Mr Eugene Oteng-Ntim, President, Forum on the Maternity and the Newborn, and Chandrima Biswas, obstetric specialist registrar.

A shorter version of this report is to be published on line by the RCM Midwives Magazine.

The science and signs of the biological clock.
William Ledger (WL), Professor of Obstetrics and Gynaecology and Head of the Academic Unit of Reproductive and Developmental Medicine, University of Sheffield (Co-author).

Many women put off planning their first pregnancy until their late thirties or early forties, and by that age fertility treatment has little to offer if they cannot conceive naturally. Although the chances of IVF working for younger women are increasing year on year, there has been little progress for the older patient (see Figures).

Figure A:

older IVF



Chance of livebirth after a single cycle of IVF. UK HFEA data, early 1990s, Templeton & Parslow 1996

Figure B:

Single cycle



Chance of livebirth after a single cycle of IVF, Oxford Fertility Unit, 2000

The ideal age for a woman to have children is between twenty and thirty-five; I speak biology, not sociology. But in the past twenty years the average age for women in the UK becoming pregnant has shifted from 25 to 34, a huge rate of change in demographic terms; recently late conceptions increased from 10.7 to 11.3 per 1000 (6% in one year). One may guess at the causes of this, but importantly people do not understand its implications. There is no appreciation of the health risks of pregnancy in older women, including increased risks of breast cancer, premature birth and fetal abnormality. Similarly the health risks to offspring of having an older father (heart disease, some cancers, schizophrenia) are not understood.

Although adult men make about 30 million sperm daily, women never make a single new egg once they are born. They have 7 million primordial follicles at 5-7 months of their fetal lives, but only 2 million survive to birth, and there is further attrition throughout life.

Follicles



Not only the quantity but the quality of the eggs also declines with increasing age; chromosomal abnormalities develop resulting in miscarriage , Down's syndrome and so on.

Quality



How can we measure ovarian reserve?
I am interested in the use of a blood test taken on the second day of the menstrual cycle. Inhibins are secreted in the ovaries in the early phase of follicle development; inhibin B is a product of the granulosa cells, and identifying low levels of this throughout the menstrual cycle up to ovulation indicates poor quantity and quality of eggs for IVF. Good inhibin B levels promise eggs in sufficient quantity and more embryos.

Inhibins



Measurement of follicle stimulating hormone (FSH) alone would not have shown the difference. An early fall in inhibin levels indicates the onset of the menopause earlier than a rise in FSH. Anti-Mullerian hormone (AMH), another granulosa cell product, is an even better indicator than inhibin B, and is now a useful predictor of IVF outcome. It may be useful to combine these markers to derive an ovarian reserve index (ORI), derived mathematically from unstimulated day 2 or 3 inhibin B, AMH and FSH. This optional test is offered to women of age 30 – 45 who are planning to defer having children. They must have regular periods (27 - 35 day cycle), must not be using the oral contraceptive pill or other hormonal medications and must have had at least 3 periods following childbirth. Polycystic ovary syndrome (PCOS), endometriosis, and other medical disorders and medications contraindicate the test.

The ORI reflects the remaining number of follicles in the ovaries, establishes an individual's ORI in relation to her age group, and with repetition establishes a trend. It is not a complete 'fertility test', since it takes no account of male, uterine, and tubal factors. We warn older women of the risks of deferring pregnancy even if they have normal ORIs.

As more women defer childbirth the problems of the biological clock become more acute. Nowadays 40 years is the new twenty ; but women are living to age 85, while their fertility is still failing at age 40 as it was hundreds of years ago when women died aged 45.

Consequences of being an older mother in pregnancy.
Dr Katrina Erskine (KE), Consultant Obstetrician and Physician, Homerton University Hospital (Co-author).

Compared to women aged under 35 years the older woman is more likely to be in a stable relationship, to be more mature, and to have better financial resources. I shall be discussing a number of problems to which they are more prone by reason of their age; these include in no particular order stress incontinence, abnormal weight gain, obesity, antepartum haemorrhage, premature rupture of the membranes, malpresentation, fetopelvic disproportion, instrumental delivery, sphincter rupture, Caesarean section, late stillbirth and reduced energy. And grandparents are likely to be more briefly there for the babies. For the older woman I can be seen as the bad news doctor!

More women are delaying childbirth to their late 30s; they tend to be of higher socio-economic status in developed countries. Being less fertile, they are more likely to need fertility assistance. They are 1.5-2 times more likely to have multiple births, have an increased risk of stillbirth, are more likely to have a chronic disease, and are more likely to have pregnancy complications in both developed and developing countries.

There are serious issues around fertility treatment. After adjusting for age and parity, women receiving fertility treatment face a number of increased risks. The odds ratio (OR: the ratio of the odds of an event occurring in one group to the odds of it occurring in another group) for pre-eclampsia is 1.9 , and significantly higher when ovum donation has been used. The OR for placenta praevia is 3.9, for placental abruption 1.8, caesarian section (CS) 2.1, and preterm delivery  1.7. 10% of women having fertility treatment by ovum donation will have postpartum haemorrhages requiring hysterectomy, a statistic rarely mentioned by the professionals.

Pregnancy with dichorionic twins carries a fourfold increase in perinatal mortality and significantly increased risks of pre-eclampsia, preterm delivery, CS and cerebral palsy.

Essential hypertension is more common among older mothers, and here too there are increased risks of pre-eclampsia, utero-placental dysfunction and abruption with possible stillbirth. If more than one anti-hypertensive is required and there is significant proteinuria by 20 weeks the risks are even greater. Also some anti-hypertensive drugs have teratogenic effects.

The increased risks which diabetics run include miscarriage, fetal abnormality, macrosomia and babies small for gestational age (SGA), and stillbirth. They more frequently require CS, and their condition is liable to be affected by pregnancy.

When in labour the older mother may expect longer first and second stages, and an increased requirement for oxytocin in both stages. Older women are more likely to need delivery by CS: OR 5.42 for elective CS , 2.67 for emergency CS. They have an increased risk of postpartum haemorrhage , and admission of their babies for neonatal care is more likely. Advanced maternal age has an independent risk of stillbirth, approximately doubling, possibly due to the increased incidence of pregnancy-induced hypertension or gestational diabetes.There is an increase in stillbirth at 37 to 41 weeks, usually unexplained; increased surveillance should be carefully considered in older women after 37 weeks.

As professionals we should be informing younger childless women of the risks of leaving childbearing until later. Older women are often unaware of the increased risks they face; we need to discuss their pregnancy intentions, their reducing fertility, and the pregnancy complications and the risks of assisted conception, including multiple birth.

The older mother: a blessing, a fear or a fuss?
Ms Lowri Turner (LT), Journalist.

I am a woman who left pregnancy late; my babies were born from age 35 to 42. I have polycystic ovaries, had problems conceiving but eventually conceived naturally. Older women who read and otherwise attend to the media are now panicking, having learned of all the problems of pregnancy in their age group and that they have left it too late. Research has concentrated on the diminishing reserve of our ovaries and has omitted studying positive aspects. However I cannot believe that the young women who are binge drinking and smoking are in the best condition to have their babies either. Back then my lifestyle was much the same, and my parents would have been horrified, even embarrassed, to think that I was wasting an education and a career by getting pregnant at that age. If a gynaecologist had asked me then to consider my fertility I would have felt insulted - none of his/her business. We don't want to be defined by our fertility or gender. Men  can and do ignore the biological realities; we're not allowed to do that but we want to. The government may ordain maternity leave, but do we want it? We would prefer to get back  to work, and arrange child care - not ideal for our babies to be sure.    

  We older women feel our age and are adopting healthier lifestyles, but the messages are scaring and punishing. And there's nothing to read about the problems which older fathers face; it has come as news to me that their babies may miscarry or if born have a greater risk of becoming schizophrenic.

One of the pressures on older women to conceive is divorce and remarriage; we regard fertility treatment as a magic wand, and it has come as a shock to me to learn of its dangers. Even at our age the medical profession patronises us; we're not given credit for mature decision-making, but it is we who are taking folic acid and have up to a point informed ourselves of the risks we run. We still need information, but do not deserve to be scolded or stigmatised. The problem of equating our needs with the capabilities of our bodies remains.

The Older Mother from the perspective of the anti-ageing culture.
David Alpert (DA), Founder of the International Institute for Anti-Ageing, London

Anti- ageing medicine is not to be confused with aesthetics medicine. It looks at ways to improve the health span - extending the healthy years and reducing the risk and incidence of age related disease as chronological age advances. The biological age is that at which the body is functioning, and is preferably less than the chronological age. We can illustrate the anti-ageing model with this pyramid:

anti-ageing


Achieving a reduction in biological age requires work on the factors listed. The environment of the individual and his DNA are basic. We study nutrition; exercise - the nearest we have to an anti-ageing pill; nutritional and hormonal supplements and some advanced therapies. And the benefits of positive mental attitude for anti-ageing are now becoming very apparent. A study reported from Cambridge University (Khaw K.T. 2008) has shown that an active 74 year-old non-smoker with a low alcohol consumption who eats five daily servings of fruit and vegetables has the same risk of dying as a 60 year old who has none of these advantages; 14 years have been added to a life. This is anti-ageing behaviour.

Professor Ledger and Dr. Erskine have described the degree to which the average age of conception has increased in recent years, the liability of the older group to develop the diseases of ageing – diabetes, hypertension, obesity – and the difficulties they face with conception, assisted or otherwise.

Between the years of 1997 and 2006 the incidence of chlamydia increased by 166% and of gonorrhoea by 46%; consider the contribution of sexually transmitted diseases to infertility. The pollution of the environment by heavy metals, plastics, pesticides and industrial chemicals has a like effect.

Factors contributing to male infertility, aside from the well known tight underwear, include bathing in hot water, smoking marijuana, the use of laptop computers and cell phones, and cigarette smoking. Coffee on the other hand has been shown to improve male fertility.

Smoking before pregnancy or during breastfeeding reduces the fertility of both male and female offspring, while higher intake of beef by their mothers has a similar effect on the males.

The high intake of carbohydrates increases ovulatory infertility; where fats are concerned the greatest single factor having a negative effect on fertility is trans fat (found in most margarines, many fast foods and commercially baked products, they may be even more unhealthy than saturated fats, boosting LDL cholesterol and triglycerides). The converse is true of unsaturated fats. The higher the proportion of plant rather than animal protein in the diet the better for fertility; the benefits of moderate exercise, full fat dairy products, and zinc are well documented. Unfortunately the past 50 years have seen the loss of substantial amounts of beneficial elements in vegetables, fruit and meat.

Any hormonal treatment is best balanced to achieve homoeostasis, using bioidentical products in physiological dosage.

Finally the negative effects of stress, overt or sub-clinical, on fertility are not to be ignored.

Vitamin A has an important role in healthy cell differentiation, DNA repair and apoptosis (a form of programmed cell death in multicellular organisms), yet women are being advised to avoid it in pregnancy; when giving subfertile women nutritional advice, we must separate the wheat from the chaff.

Reference: Khaw KT, Wareham N, Bingham S, Welch A, Luben R, et al. 2008. Combined impact of health behaviours and mortality in men and women: The EPIC-Norfolk Prospective Population Study PLoS Medicine 5:1 e12 doi:10.1371/journal.pmed.0050012

Discussion:

WL: Media reports of successful pregnancies in older women exaggerate the ease with which these are achieved; they don't tell us that these women have received donor eggs from much younger women, and that even so the success rate is about one in five at age 40, and one in ten at age 45. Of course it is not biologically sensible to seek pregnancy above age 45, and we discourage this in our unit. LT: We older women decide to plan pregnancy for strong personal reasons, not on a selfish whim. And if we have no partner we discover that the men are all dating much younger women. When these much older women have their babies and do well, I admire their courage. (WL agrees). KE: It is not for us as professionals to lay down the law on decisions around pregnancy planning; we detail the ways in which we can help, the advantages and disadvantages of these, and the risks of both pregnancy and IVF . But it is our duty to explain to younger women that there are dangers in leaving it too late.

WL replying to Professor Wendy Savage: There are risks in teenage pregnancy even when corrected for social class.

WL: There have only been about 300 successful pregnancies using frozen eggs worldwide, and we await advances in this technology. To produced the eggs a perfectly healthy woman has to go through much of IVF; then the success rate per frozen egg is only 6%, and if a woman delays until age 50 she has nowhere else to turn. I would discourage egg freezing for young women unless they are about to be rendered sterile as they would be by chemotherapy for cancer.

Asked whether attention to diet and the regular ingestion of trace elements can enhance fertility, DA pointed out that the fertility curve varied among women but that coexisting disease such as diabetes will inhibit fertility. WL agreed with DA that DNA and genetic factors influence fertility within families; furthermore, smoking brings forward the menopause by about two years with a corresponding limitation of fertility, an effect no longer apparent after two years when smoking is discontinued.

WL emphasised the conditions other than ageing which can affect fertility, such as damage from sexually transmitted disease, blocked fallopian tubes, fibroids, endometriosis, and of course male subfertility.

A midwife and counsellor reported the distress of older infertile women, who tend to idolise pregnancy “although in fact it's not all that it's cracked up to be”. KE: They are particularly prone to depression ensuing upon the exhaustion of early motherhood.

An obstetrician and gynaecologist adverted to the substantial list of pathology to which older women are prone, with pelvic pain prominent. He ascribes much of this to damage of the neural complexes round the vaginal vault during traumatic first births, especially when large babies are delivered with difficulty, instrumentally or otherwise. He also pinpointed straining at stool, common to many constipated women. By the time a woman with this problem reaches age 35 a lot of damage can have been caused, possibly with impaired motility in the uterus and tubes, poor pelvic floor support, and pelvic pain. Here we can see a role for improved diet.

KE: The issues of age affect older women in addition to those of multiparity.

DA: Any possible surge in population fertility following disasters such as wars could be a psychological/behavioural effect; the associated caloric restriction is only likely to reduce sex drive.

WL: KE may regard deferring pregnancy as a feminist issue, but I also see reluctance to commit to fatherhood in the life of a busy partner. LT: Some men see pregnancy as restricting not only the sexual activity permitted by contraception, but also other diversions such as travel and sport. And while the older mother is confined to home, breastfeeding and other baby care, her partner is now free to carry on working now that the limitations of pregnancy and birth are behind him. Too often neither partner is completely content with the pregnancy situation. A delegate pointed out that although equal, men and women experience this differently, having to give up different activities but with equal reluctance, and being older both are more set in their ways.

Responding to a question from a doula, DA agreed that psychology has its effects on biology, in the case of the anxiety of the older woman to expedite pregnancy as the biological clock ticks.

WL: A good clinic will place counselling at the centre of its work; the stresses inherent in the IVF situation put great pressure on relationships, which not seldom break down during the process or even after the successful birth of a baby.

WL: There is a risk of decreased semen quality in the male offspring of fathers who have DNA deletions of the azoospermia factor in the AZF region and who are resorting to IVF with ICSI ; these men do not seem to be discouraged from persisting although they have received this warning. Otherwise it is known that numbers of the children resulting from IVF have themselves had healthy babies.

LT: My experience in the workplace has been of the managers – in my case editors, men or women – who have an entirely negative attitude to pregnancy and maternity leave. The effect of this on older women returning to fight for their jobs after the exhaustion of early motherhood can be imagined. Now such a woman returning to work has the problem of combining the job with family life; this becomes even more problematical if she feels the need to hurry the second baby along and now has to juggle so much to keep all the balls in the air. The press continues to spin a negative view of older motherhood, even suggesting that it is irrational. Unfortunately the diversity panels which big business has set up to establish family friendly policies tend to have members who are mostly male, and perhaps a young woman who has no interest in pregnancy or an older woman embittered by childlessness, with disappointing results. A gynaecologist gave an account of the attitude of some established nurses to the pending appointment of new staff; they expressed the hope that none of the candidates would be employed on a part time basis, seriously implying that they would not have the necessary dedication to their work. LT: It has been shown that motherhood sharpens the focus of women at work, improving their efficiency.

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