Infertility & Assisted Reproduction

Infertility is often taught as a list of tests followed by a list of treatments, which makes it seem arbitrary. It is neither.

The organising tool is that conception has exactly four requirements, and infertility means one of them has failed. Is there an egg? Is there sperm? Is there a path between them? Is there a place to implant?

Every investigation in this chapter answers exactly one of those questions, and every treatment either restores a missing requirement or bypasses it.

Ovulation tracking asks about the egg. Semen analysis asks about the sperm. Tubal patency testing asks about the path. Imaging of the cavity asks about the place. Nothing else is needed for a first assessment, and anything that does not answer one of the four is not a first-line test.

In vitro fertilisation is best understood not as a treatment for a disease but as a way of bypassing the path, which is why it works for tubal disease, for severe male factor and for unexplained infertility alike.

1. Definitions and When to Start

Infertility is the failure to conceive after twelve months of regular unprotected intercourse. Primary infertility means the woman has never conceived; secondary means she has conceived before, whatever the outcome of that pregnancy.

The twelve-month threshold exists because most fertile couples conceive within it, so waiting longer delays treatment for those who need it while investigating earlier subjects many to unnecessary tests.

Investigation begins earlier in defined circumstances: a woman aged 35 or over, known oligomenorrhoea or amenorrhoea, previous pelvic surgery or pelvic inflammatory disease, known endometriosis, or a male partner with a known abnormality.

The single strongest determinant of a couple's prognosis is female age, because both the number and the quality of oocytes decline, and quality declines faster than number.

Aneuploidy rates rise steeply with maternal age, which is why miscarriage becomes commoner as well as conception becoming harder, and why a 42-year-old with normal investigations still has a poor prognosis.

Both partners are assessed together from the outset. Assessing the woman first and the man only after her results return is a common and wasteful sequence, because male factor contributes in around a third to a half of couples.

2. Is There an Egg?

Ovulation is confirmed most simply by a regular menstrual cycle, which makes ovulatory dysfunction unlikely, and confirmed biochemically by a mid-luteal progesterone measured about seven days before the expected period.

Timing that sample matters more than the value. A progesterone taken on day 21 of a 35-day cycle is taken before ovulation and will be low in a woman who is ovulating perfectly well.

Anovulation is classified by the World Health Organization into three groups, and the classification determines treatment.

Group I responds to restoring weight or to pulsatile gonadotropin-releasing hormone; group II responds to ovulation induction; group III does not respond to any ovarian stimulation and requires donor oocytes, because the ovary has no follicles left to stimulate.

That last point is the practical value of the classification: it identifies the women for whom stimulation is futile before it is attempted.

Hyperprolactinaemia is a separate and eminently treatable cause, suppressing gonadotropin-releasing hormone pulsatility, and responding to a dopamine agonist. Thyroid dysfunction should be corrected before anything else is attempted.

3. Ovarian Reserve

Ovarian reserve testing estimates how many oocytes remain, and it is used to predict response to stimulation rather than to predict natural conception.

Anti-Mullerian hormone is the most useful marker. It is produced by granulosa cells of small growing follicles, so it reflects the size of the remaining pool, and it is stable across the cycle, which means it can be measured on any day.

Antral follicle count on transvaginal ultrasound gives similar information and correlates well.

Day 3 follicle stimulating hormone is the older test and is less reliable, because it rises only late, when reserve is already substantially depleted, and it fluctuates between cycles.

A low anti-Mullerian hormone predicts a poor response to stimulation but does not mean a woman cannot conceive naturally, and this distinction is regularly misunderstood by patients and examiners alike. It measures quantity, not quality, and quality is determined by age.

4. Is There Sperm?

Semen analysis is the single most informative test in the male, and it is performed after two to seven days of abstinence, with a repeat several weeks later before drawing conclusions, because counts vary considerably.

The terminology is examined precisely: oligozoospermia means reduced count, asthenozoospermia reduced motility, teratozoospermia abnormal morphology, azoospermia no sperm at all, and aspermia no ejaculate.

Azoospermia divides into obstructive and non-obstructive, and the distinction determines everything.

In obstructive azoospermia the testis produces sperm normally, so testicular volume and follicle stimulating hormone are normal, and sperm can be retrieved surgically. Congenital bilateral absence of the vas deferens is a classic cause and is associated with cystic fibrosis mutations.

In non-obstructive azoospermia the testis is failing, so testicular volume is reduced and follicle stimulating hormone is raised, because the pituitary is responding to absent feedback from a failing seminiferous epithelium.

Klinefelter syndrome and Y chromosome microdeletions are important causes, and karyotyping is indicated in severe male factor infertility because it changes counselling and identifies conditions transmissible to offspring.

Varicocele is common and its treatment remains debated, though repair is generally offered when it is clinically palpable with abnormal semen parameters.

5. Is There a Path?

Tubal factor is a major cause in India, largely because pelvic inflammatory disease and genital tuberculosis are common.

Genital tuberculosis is a distinctly Indian contribution to this subject and damages both the tubes and the endometrium, which is why it can cause infertility that persists even after tubal patency is restored.

Hysterosalpingography is the standard first-line test, using contrast under fluoroscopy to demonstrate the cavity and tubal spill. It is performed in the follicular phase to avoid disturbing an early pregnancy.

Laparoscopy with dye insufflation is more accurate and allows treatment of adhesions and endometriosis at the same time, but it is invasive and is reserved for women in whom pelvic pathology is suspected.

Endometriosis reduces fertility by several mechanisms at once: adhesions distorting the anatomy, an inflammatory peritoneal environment hostile to gametes, and impaired ovarian reserve where endometriomas have been present or removed.

Surgery for endometriosis improves fertility, but excision of an endometrioma removes normal ovarian tissue with it, so the decision must weigh the benefit against loss of reserve.

A hydrosalpinx should be removed or occluded before in vitro fertilisation, because the fluid refluxes into the cavity and substantially reduces implantation rates. This is one of the clearest examples of a preparatory step improving outcome.

6. Is There a Place?

Uterine causes are less common than the other three but are readily treatable when found.

Submucosal fibroids distort the cavity and reduce implantation, and their removal improves outcomes, whereas subserosal and small intramural fibroids generally do not require treatment for fertility.

Intrauterine adhesions, Asherman syndrome, follow vigorous curettage, particularly after postpartum or post-abortal instrumentation, and present with amenorrhoea or scanty periods after such a procedure.

Congenital uterine anomalies, particularly a septate uterus, are associated with miscarriage more than with failure to conceive, and hysteroscopic resection of a septum improves outcomes.

Saline infusion sonohysterography and hysteroscopy assess the cavity, and hysteroscopy has the advantage of allowing treatment at the same sitting.

Unexplained infertility is diagnosed when all four questions have been answered normally, and it accounts for a substantial minority of couples. It is a statement about the limits of testing rather than about the absence of a problem.

7. Treatment: Restoring or Bypassing

Treatment follows a ladder, and the correct rung depends on which requirement has failed.

Ovulation induction is used for anovulation, principally group II. Letrozole, an aromatase inhibitor, has largely replaced clomiphene as first line in polycystic ovary syndrome because it produces higher live birth rates.

Clomiphene is a selective oestrogen receptor modulator acting at the hypothalamus, blocking negative feedback so that gonadotropin secretion rises. Its antioestrogenic effect on cervical mucus and endometrium is a recognised drawback, and letrozole avoids it.

Gonadotropins are used where oral agents fail, and require careful monitoring because they carry the risks of multiple pregnancy and hyperstimulation.

Intrauterine insemination places prepared sperm directly into the cavity, bypassing the cervix, and is used for mild male factor, cervical factor and unexplained infertility, usually with ovarian stimulation. It requires at least one patent tube.

In vitro fertilisation bypasses the tube altogether, and its indications follow from that: tubal disease, severe male factor, endometriosis, failed simpler treatments and unexplained infertility.

Intracytoplasmic sperm injection injects a single sperm directly into the oocyte and is the treatment for severe male factor, since it reduces the requirement from millions of motile sperm to one viable one.

Preimplantation genetic testing examines embryos before transfer and is used for known monogenic disorders, chromosomal rearrangements and recurrent loss.

8. Complications of Treatment

Ovarian hyperstimulation syndrome is the most important iatrogenic complication in this subject.

Stimulated ovaries release vasoactive substances, principally vascular endothelial growth factor, which increase capillary permeability. Fluid shifts from the intravascular space into the peritoneal and pleural cavities.

The consequences follow directly from that shift: ascites, pleural effusion, haemoconcentration, oliguria, and a genuine risk of thromboembolism because the blood is concentrated and the patient is immobile.

The paradox to understand is that the patient is oedematous and fluid overloaded in appearance while being intravascularly depleted. Treating the ascites with a diuretic worsens the haemoconcentration and increases thrombotic risk.

Management is supportive with fluid, thromboprophylaxis and drainage of tense ascites. Risk factors are young age, polycystic ovaries, high anti-Mullerian hormone and a large number of follicles, and it is triggered or worsened by human chorionic gonadotropin, including that of an early pregnancy.

Prevention includes using an antagonist protocol with a gonadotropin-releasing hormone agonist trigger, and freezing all embryos for later transfer so that pregnancy does not sustain the syndrome.

Multiple pregnancy is the other major complication, and it carries far higher risks of prematurity and its consequences than the singleton pregnancies these treatments aim to produce. Elective single embryo transfer is the principal means of avoiding it.

9. Recurrent Pregnancy Loss and Fertility Preservation

Recurrent pregnancy loss is conventionally defined as two or more consecutive losses, and it is a different problem from infertility because conception is occurring.

The commonest single cause of any individual miscarriage is fetal aneuploidy, which is sporadic rather than recurrent, so a proportion of women with recurrent loss have simply been unlucky and have no identifiable abnormality.

The identifiable causes divide by mechanism. Parental balanced translocation is found in a small minority and is detected by karyotyping both partners. Uterine anomalies, particularly a septum, and intrauterine adhesions act mechanically.

Antiphospholipid syndrome is the most important treatable cause, diagnosed by persistently positive lupus anticoagulant, anticardiolipin or anti-beta-2-glycoprotein antibodies on two occasions at least twelve weeks apart, alongside the clinical criteria.

It matters because treatment works: aspirin with low molecular weight heparin substantially improves live birth rates, which is not true of most other interventions offered in this setting.

Uncontrolled diabetes and thyroid disease are corrected. Inherited thrombophilias are far less clearly implicated than antiphospholipid syndrome, and treating them is not established.

Fertility preservation matters increasingly because cancer treatment is more survivable. Oocyte and embryo cryopreservation are offered before gonadotoxic chemotherapy or pelvic radiotherapy, and ovarian tissue cryopreservation is used where treatment cannot be delayed, including in prepubertal girls.

10. The Law in India

India regulates this field by two statutes passed together in December 2021, and their provisions are examined directly.

The Assisted Reproductive Technology (Regulation) Act, 2021 requires every clinic and gamete bank to register with a national registry, sets standards for practice, and regulates gamete donation and the eligibility of those seeking treatment.

The Surrogacy (Regulation) Act, 2021 permits only altruistic surrogacy and prohibits commercial surrogacy, so the surrogate may receive medical expenses and insurance but no other payment.

The eligibility criteria are specific. The intending couple must be married, and the woman must be between 23 and 50 and the man between 26 and 55. A widow or divorcee between 35 and 45 may also access surrogacy.

The surrogate must be a married woman aged between 25 and 35 with at least one child of her own, must be a close relative of the intending couple, and may act as a surrogate only once in her lifetime.

A 2024 amendment permits the use of one donor gamete where a District Medical Board certifies medical necessity, but the child must remain genetically related to at least one intending parent, so using both donor egg and donor sperm remains prohibited.

11. Worked Examples

Example 1. A couple have been trying for 14 months. The woman has regular 28-day cycles and a mid-luteal progesterone confirming ovulation. Semen analysis shows azoospermia. Testicular volume is normal and follicle stimulating hormone is normal.

Normal testicular volume with a normal follicle stimulating hormone indicates that spermatogenesis is intact, so this is obstructive rather than non-obstructive azoospermia.

Sperm can therefore be retrieved surgically and used for intracytoplasmic sperm injection. Congenital bilateral absence of the vas deferens should be excluded, along with associated cystic fibrosis mutations, because that affects genetic counselling for the couple.

Example 2. A 28-year-old woman with polycystic ovary syndrome undergoes gonadotropin stimulation and develops abdominal distension, ascites, a haematocrit of 52 per cent and reduced urine output.

This is ovarian hyperstimulation syndrome. Vascular endothelial growth factor has increased capillary permeability, shifting fluid out of the intravascular compartment into the peritoneal cavity.

She looks fluid overloaded but is intravascularly depleted, so treatment is intravenous fluid rather than diuretics, with thromboprophylaxis because haemoconcentration and immobility together create a real thrombotic risk. Tense ascites is drained. A diuretic here would be actively harmful.

Example 3. A woman with bilateral hydrosalpinges is listed for in vitro fertilisation.

The hydrosalpinges should be removed or occluded before the cycle proceeds. Hydrosalpinx fluid refluxes into the uterine cavity and substantially reduces implantation and live birth rates.

Salpingectomy or proximal tubal occlusion restores implantation rates to those expected without hydrosalpinx, which makes this one of the clearest examples in reproductive medicine of a preparatory operation improving the outcome of a subsequent treatment.

Summary

• Conception has four requirements: an egg, sperm, a path and a place.
• Every test answers one of the four; anything else is not first line.
• In vitro fertilisation bypasses the path, which explains its broad indications.
• Infertility is failure to conceive after 12 months of regular unprotected intercourse.
• Investigate earlier at age 35 or over, or with known pathology.
• Female age is the strongest determinant of prognosis.
• Aneuploidy rises with age, so miscarriage rises as well as conception falling.
• Assess both partners together from the outset.
• Mid-luteal progesterone must be timed to the cycle, not to day 21.
• Group I anovulation is hypothalamic, group II is dysfunction, group III is ovarian failure.
• Group III does not respond to stimulation and needs donor oocytes.
• Hyperprolactinaemia and thyroid disease are treatable causes to exclude first.
• Anti-Mullerian hormone reflects the remaining follicle pool and is cycle-independent.
• It predicts response to stimulation, not natural conception, and measures quantity not quality.
• Day 3 follicle stimulating hormone rises only late and is less reliable.
• Semen analysis is repeated before conclusions are drawn.
• Obstructive azoospermia has normal volume and normal follicle stimulating hormone.
• Non-obstructive azoospermia has small testes and raised follicle stimulating hormone.
• Karyotype in severe male factor to detect Klinefelter and Y microdeletions.
• Genital tuberculosis damages both tube and endometrium in India.
• Hysterosalpingography is first line; laparoscopy is more accurate but invasive.
• Endometriosis impairs fertility by adhesions, inflammation and reduced reserve.
• Endometrioma excision costs ovarian tissue, so the decision is a trade-off.
• A hydrosalpinx must be removed or occluded before in vitro fertilisation.
• Submucosal fibroids reduce implantation; subserosal ones generally do not.
• Asherman syndrome follows vigorous curettage.
• A septate uterus causes miscarriage more than failure to conceive.
• Unexplained infertility means the tests were normal, not that nothing is wrong.
• Letrozole has replaced clomiphene as first line in polycystic ovary syndrome.
• Clomiphene has antioestrogenic effects on mucus and endometrium.
• Intrauterine insemination requires at least one patent tube.
• Intracytoplasmic sperm injection reduces the requirement to one viable sperm.
• Hyperstimulation shifts fluid out of the intravascular space.
• The patient looks overloaded but is intravascularly depleted; diuretics harm.
• Freezing all embryos prevents pregnancy sustaining the syndrome.
• Elective single embryo transfer is the main defence against multiple pregnancy.
• Recurrent loss is two or more consecutive miscarriages.
• Aneuploidy causes most individual losses but is sporadic, not recurrent.
• Antiphospholipid syndrome is the most important treatable cause.
• Aspirin with heparin substantially improves live birth in antiphospholipid syndrome.
• Inherited thrombophilias are far less clearly implicated and treatment is unproven.
• Oocyte, embryo or ovarian tissue cryopreservation precedes gonadotoxic treatment.
• Only altruistic surrogacy is permitted in India.
• The surrogate must be a married close relative aged 25 to 35 with one child, once only.
• A 2024 amendment allows one donor gamete on medical board certification.