15.12 — Infertility and Assisted Reproduction

Human reproduction is remarkably inefficient. In a couple with no fertility problem at all, having well-timed intercourse, the chance of conception in any one cycle is around 20 to 25 percent.

Which means that not conceiving in a given month is the normal outcome, and a substantial part of the distress in early attempts comes from not knowing that.

Cumulatively: around 60 percent conceive within 6 months, 85 percent within a year, and 92 percent within two years.

So a year of trying without success identifies roughly the 15 percent who need looking at — and half of those will conceive in the following year without any treatment.

Definitions and when to investigate

Infertility: no conception after 12 months of regular unprotected intercourse.

Investigate earlier — after 6 months — if the woman is over 35, or if there is a known reason to expect a problem: irregular or absent periods, previous pelvic infection or surgery, endometriosis, undescended testis, chemotherapy, or known genital tract abnormality.

Primary infertility — never conceived. Secondary — previously conceived, whatever the outcome.

Affects around 1 in 7 couples.

Where the problem lies

And the distribution is worth stating because investigation has historically been skewed.

Male factor: 30 to 40 percent, alone or contributing.Ovulation disorders: 25 percent.Tubal damage: 20 percent.Endometriosis: 10 to 15 percent.Unexplained: 25 percent.

They overlap, so the figures exceed 100 percent.

Both partners are investigated from the start. A semen analysis is cheap, non-invasive and immediate (Chapter 15.2), and investigating the woman first as a default is a documented and correctable pattern.

The three questions

Investigation answers three things, and everything else follows.

Is she ovulating?

A regular cycle of 21 to 35 days is strong evidence of ovulation.

Confirmed by a progesterone level 7 days before the expected period — mid-luteal — which is day 21 in a 28-day cycle and day 28 in a 35-day cycle (Chapter 15.4). Timing it wrong is a common source of falsely reassuring or falsely alarming results.

Are the tubes open?

Hysterosalpingography — dye injected through the cervix and imaged with X-ray. And it has a small therapeutic effect: pregnancy rates rise slightly in the months afterwards, apparently from flushing the tubes, particularly with oil-based contrast.

Hysterosalpingo-contrast ultrasound — the same principle with ultrasound rather than X-ray.

Laparoscopy with dye — the most accurate, and it also identifies endometriosis and adhesions (Chapter 15.3). Invasive, so reserved for those with a reason to suspect pelvic pathology.

Is the semen normal? (Chapter 15.2).

And ovarian reserve is assessed alongside, by anti-Müllerian hormone (AMH) and antral follicle count on ultrasound.

AMH deserves a clear caveat, because it is heavily marketed as a "fertility test".

It measures the size of the remaining follicle pool, which predicts how a woman will respond to IVF stimulation. It does not predict natural fertility well, and it does not tell an individual woman how long she has. Women with low AMH conceive naturally; women with high AMH do not always.

Selling AMH testing to healthy women as a guide to family planning runs well ahead of what the test can do, and professional bodies have said so.

The main causes and what is done

Ovulation disorders

Polycystic ovary syndrome — the commonest cause (Chapter 12.6).

Treatment: weight loss of 5 to 10 percent frequently restores ovulation — a large effect from a modest change. Letrozole is now first-line for ovulation induction, ahead of clomifene, having been shown to produce higher live birth rates. Metformin where insulin resistance is prominent.

Hypothalamic amenorrhoea — from low energy availability, excessive exercise or stress (Chapter 15.4). Treatment is correcting the cause, and it works, though it requires addressing behaviour that the person may be reluctant to change.

High prolactin — treated with a dopamine agonist, which frequently restores ovulation within weeks (Chapter 12.2).

Thyroid disease — both directions affect fertility, and correction is straightforward.

Premature ovarian insufficiency (Chapter 15.10) — the one with limited options, and donor eggs are the main route.

Tubal damage

The leading cause is pelvic inflammatory disease, most often chlamydia (Chapter 15.3), and the risk rises with each episode — around 12 percent after one, 25 percent after two, 50 percent after three.

Which makes chlamydia screening in young people a fertility intervention with a calculable benefit, and one that is frequently framed only as infection control.

Other causes: previous surgery, endometriosis, and previous ectopic pregnancy.

Surgical repair is possible for limited damage, and IVF bypasses the tubes entirely and is generally more effective.

Hydrosalpinx — a blocked, fluid-filled tube — halves IVF success rates, apparently because the fluid leaks into the uterus and is toxic to embryos. Removing or clipping the tube before IVF restores the success rate, which is a specific and important point.

Endometriosis

Reduces fertility by mechanisms that are not fully understood — adhesions distorting anatomy, inflammation affecting egg and sperm quality, and impaired implantation (Chapter 15.3).

Surgical treatment of mild disease modestly improves natural conception rates. For advanced disease, IVF is usually the more effective route.

Male factor

Chapter 15.2 covered the causes and the modifiable factors.

And the treatment landscape is narrow. Varicocele repair, hormonal treatment where there is a specific deficiency, and correcting the modifiable factors.

For most male factor infertility the effective treatment is ICSI (below), which bypasses the problem rather than correcting it.

Unexplained infertility

Around a quarter of couples, and it is a genuinely unsatisfying diagnosis — it means the standard tests are normal, not that nothing is wrong.

And a substantial proportion conceive without treatment, which is why expectant management for 6 to 12 months is often reasonable before intervention, particularly in younger women.

Age

The single most important variable, and the one least amenable to treatment.

Female fertility declines gradually from the late twenties, more steeply from 35, and sharply from 38 to 40.

Two things decline together: the number of eggs and their quality.

And the quality decline is the harder problem. The proportion of eggs with chromosomal abnormalities rises steeply (Chapter 15.4) — from around 20 to 30 percent in the early thirties to over 50 percent at 40 and over 80 percent by 44.

Which is why both conception rates fall and miscarriage rates rise with age, and why IVF cannot compensate: it can retrieve more eggs and it cannot make an older egg younger.

Live birth rates per IVF cycle using a woman's own eggs, by age — approximate and varying by clinic and country:

Age	Live birth per cycle started
Under 35	30–40%
35–37	25–30%
38–39	18–22%
40–42	10–12%
43–44	4–5%
Over 44	1–2%

And the striking comparison: with donor eggs from a young donor, success rates are 40 to 50 percent per transfer regardless of the recipient's age.

Which establishes that it is egg quality rather than uterine ageing that drives the decline — the uterus works fine at 45.

Male fertility declines more gradually, with increasing time to conception, higher miscarriage rates, and increasing new mutations (Chapter 15.10).

Assisted reproduction

Ovulation induction — tablets to stimulate ovulation in a woman who is not ovulating. Letrozole or clomifene, with ultrasound monitoring to avoid multiple follicles.

Intrauterine insemination (IUI) — prepared sperm placed directly in the uterus around ovulation.

Used for mild male factor, unexplained infertility, cervical problems, and same-sex couples or single women using donor sperm.

Success around 10 to 15 percent per cycle, and it is substantially less effective than IVF.

IVF

The steps, and each has a reason.

1. Downregulation or antagonist — suppressing the natural cycle so that ovulation does not occur before the eggs are collected.

2. Stimulation — high-dose FSH for 8 to 14 days, overriding the natural selection of a single follicle (Chapter 15.4) so that a cohort develops together. Monitored by ultrasound and blood tests.

3. Trigger — hCG or a GnRH agonist, mimicking the LH surge and maturing the eggs. Timed precisely, because collection must occur about 36 hours later, before ovulation.

4. Egg collection — a needle passed through the vaginal wall into each follicle under ultrasound guidance, with sedation. Typically 8 to 15 eggs.

5. Fertilisation — either conventional IVF, mixing eggs and sperm, or ICSI, injecting a single sperm directly into each egg (Chapter 4.3).

ICSI was developed for severe male factor infertility and is now used in around two thirds of cycles worldwide — considerably more than male factor accounts for. The evidence that it improves outcomes in non-male-factor cases is weak, and its overuse is a recognised issue.

6. Culture — embryos grown for 3 to 5 days. Blastocyst transfer at day 5 allows better selection, because embryos that are going to arrest usually do so by then.

7. Transfer — one embryo, in almost all cases.

And single embryo transfer is one of the most important changes in the field. Multiple pregnancy is by far the largest risk of IVF — to the mother, and to the babies through prematurity. Transferring one embryo and freezing the rest gives cumulative success rates equal to transferring two, without the multiple pregnancy rate.

8. Luteal support — progesterone, because the natural corpus luteum function is disrupted by the process.

9. Pregnancy test at 2 weeks.

The add-ons

And this section matters, because it is where money is spent for little return.

Fertility clinics offer a large number of additional treatments — endometrial scratch, embryo glue, assisted hatching, immune therapies, time-lapse imaging, preimplantation genetic testing for aneuploidy.

Regulators in several countries have introduced traffic-light rating systems for these, and the great majority are rated as having no or insufficient evidence of improving live birth rates.

Some carry risk. Nearly all carry cost.

The practical advice: ask what the evidence is for any add-on, and ask specifically whether it improves live birth rate rather than any intermediate measure. Couples in this situation are exceptionally vulnerable to being sold hope, and the asymmetry of information is severe.

Preimplantation genetic testing deserves separating.

PGT-M, testing for a specific known inherited condition — genuinely valuable for couples at risk of a serious genetic disease.

PGT-A, screening all embryos for chromosome number — widely marketed and much more contested. Trials have not consistently shown improved live birth rates per cycle started, and there is a risk of discarding embryos that are mosaic and would have produced a healthy child.

Risks

Ovarian hyperstimulation syndrome — the main complication of stimulation.

The ovaries become enlarged and vascular permeability increases, so fluid shifts out of the circulation into the abdomen and chest.

Mild in around 20 to 30 percent; severe in under 1 percent, with abdominal distension, breathlessness, haemoconcentration, clot risk and kidney impairment.

And it has become much less common, because of two changes: using a GnRH antagonist protocol with a GnRH agonist trigger instead of hCG, and freezing all embryos for later transfer rather than transferring fresh — since pregnancy itself worsens the syndrome.

Multiple pregnancy — addressed by single embryo transfer.

Ectopic pregnancy — slightly increased.

And the emotional cost is substantial and frequently underestimated. Rates of anxiety and depression during treatment are high, and the cycle of hope and disappointment is genuinely difficult. Counselling should be offered as standard and often is not taken up.

Fertility preservation

Egg freezing (oocyte vitrification) — the technique improved dramatically with vitrification, which flash-freezes and avoids ice crystal damage.

Medical indications — before chemotherapy, radiotherapy or surgery that will damage the ovaries.

And this should be offered before cancer treatment in anyone of reproductive age, which is a step that is occasionally omitted in the urgency and matters enormously later.

Social egg freezing — and the numbers should be given honestly.

Success depends overwhelmingly on age at freezing. Eggs frozen under 35 give substantially better outcomes than those frozen at 38 or later.

And the number matters: around 15 to 20 mature eggs frozen under 35 gives a reasonable chance — perhaps 70 percent — of at least one live birth. Fewer eggs, or older eggs, gives considerably less.

A substantial proportion of women who freeze eggs never use them, either because they conceive naturally or because circumstances change.

Sperm freezing — simple, cheap and effective, and it should be offered before any treatment that may impair fertility (Chapter 15.1).

Ovarian tissue freezing — removing and freezing ovarian cortex, then re-implanting it after treatment. Over 200 live births reported, and it is the only option for prepubertal girls.

Donor conception and surrogacy

Donor sperm, eggs or embryos — used for severe male factor, premature ovarian insufficiency, genetic conditions, same-sex couples and single people.

And a change worth knowing: donor anonymity has been removed in many countries, so donor-conceived people can access identifying information about the donor at 18.

The evidence supports early disclosure to donor-conceived children — those told young report better outcomes than those who find out later or accidentally, and the widespread availability of consumer DNA testing has made secrecy effectively impossible (Chapter 2.10).

Surrogacy — legal frameworks vary enormously between countries, from prohibition to commercial arrangements, and cross-border surrogacy raises real questions about exploitation, the surrogate's rights and the child's legal status. The medical procedure is straightforward; the ethical and legal context is not, and it should not be presented as though it were.

What helps, without a clinic

And this is worth ending on, because a proportion of couples labelled infertile are not.

Timing. The fertile window is the 5 days before ovulation and the day of it (Chapter 4.3), and intercourse every 2 to 3 days throughout the cycle achieves the same result without the burden of tracking.

Stopping smoking — reduces fertility in both sexes and reduces IVF success rates.

Weight. Both obesity and being significantly underweight reduce fertility, and correction improves it measurably.

Reducing alcohol.

Folic acid before conception (Chapter 4.4).

And time. Half of couples with unexplained infertility conceive in the second year without treatment, which is the most under-stated fact in this chapter.

What the next page fixes

Chapter 15.13 closes this Part with sexual health — the infections, how they present, what they do if untreated, and what actually prevents them.