Infertility and Subfertility
Infertility is defined by the WHO as failure to achieve pregnancy after 12 months or more of regular unprotected sexual intercourse, while subfertility describes reduced fertility with a prolonged time to conception. Causes may involve female factors, male factors, both partners, or no identifiable cause.
This updated UKMLA guide to infertility and subfertility is based primarily on NICE NG257, which covers causes, risk factors, referral criteria, investigations, management, assisted reproductive technology (ART), and complications.
Note: For clarity and to reduce repetition in this article:
- Females = women, trans men, and non-binary people with female reproductive organs
- Males = men, trans women, and non-binary people with male reproductive organs
Definition
WHO definition (more widely used): failure to achieve pregnancy after 12 months or more of regular unprotected sexual intercourse.
- Primary infertility: in couples who have never achieved pregnancy
- Secondary infertility: in couples who have achieved pregnancy at least once before (with the same or different sexual partner)
NICE defines infertility as the period of time people have been trying to conceive without success, after which formal investigation is justified and possible treatment implemented.
Subfertility: describes any form of reduced fertility, characterised by a prolonged time taken to achieve pregnancy despite regular unprotected sexual intercourse.
Epidemiology
Infertility is common, it affects ~1 in 7 heterosexual couples in the UK.
Causes
Main causes of infertility in the UK:
- Male factors (30%)
- Ovulatory disorders (25%)
- Tubal damage (20%)
- Uterine or peritoneal disorder (10%)
- No identifiable cause (25%)
~40% of infertility cases are due to factors affecting both the male and female partners.
Female Infertility
| Category | Causes |
|---|---|
| Ovulatory disorders | Ovulatory disorders are categorised into 3 groups (WHO):
Other conditions that can cause ovulatory disorders:
|
| Tubal damage |
|
| Uterine or peritoneal factors | Uterine factors:
Peritoneal factors:
|
Male Infertility
| Category | Causes |
|---|---|
| Testicular failure | Most cases of testicular failure are unknown
Acquired causes include:
Certain endocrine disorders are associated with low testosterone levels (e.g. hyperprolactinaemia, Kallmann syndrome) |
| Obstructive azoospermia | Absence of spermatozoa in the ejaculate, due to an obstruction in the genital tract
Causes include:
|
| Ejaculatory and erectile dysfunction | Erectile dysfunction: persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance
Ejaculatory disorders include:
|
| Abnormal sperm function and quality | Causes include:
|
Risk Factors
Female Infertility
- Age (the physiological maximum potential for reproduction starts declining significantly at ~32 y/o and declines rapidly after 37 y/o)
- STIsSexually transmitted infections (esp. chlamydia and gonorrhoea)
- Obesity and low body weight
- Lifestyle factors
- Smoking
- Stress
- Exposure to pesticides, nitrous oxide, metals (lead, cadmium, manganese), solvents, formaldehyde and other occupational and environmental hazards
- Drugs (e.g. NSAIDs, chemotherapy, metoclopramide, methyldopa, sertraline, fluoxetine, and antipsychotics, recreational drugs)
Male Infertility
- Age (>55 y/o may affect sperm motility)
- STIs
- Obesity
- Lifestyle factors
- Smoking
- Excessive alcohol intake
- Stress
- Tight underwear (elevated scrotal temperature reduces semen quality)
- Exposure to pesticides, nitrous oxide, metals (lead, cadmium, manganese), solvents, formaldehyde and other occupational and environmental hazards
- Drugs
- Sulfasalazine – affects spermatogenesis
- 5-alpha reductase inhibitors – can cause sexual dysfunction
- Hormone treatment (esp. testosterone supplementation, anabolic steroid) – can inhibit spermatogenesis and impair fertility
- Certain antipsychotics, antidepressants, antihypertensives – can cause retrograde ejaculation and orgasmic dysfunction
- Recreational drugs
Patient Education
Initial advice to people concerned about delays in conception:
| Aspect | Description / advice |
|---|---|
| Chance of conception | For females aged <40 y/o in a heterosexual couple, who are not using contraception and have regular vaginal intercourse, the approximate pregnancy rates are:
|
| Frequency and timing of sexual intercourse | Regular vaginal sexual intercourse every 2-3 days to optimise the chance of pregnancy |
Advice on factors that can affect fertility:
| Aspect | Description / advice |
|---|---|
| Alcohol consumption | For females who are planning to become pregnant:
For males:
|
| Smoking | Smoking reduces fertility, lowers the chance of conception, and can impair semen quality.
Advise smoking cessation to improve fertility and overall health (see the Smoking Cessation article for more information) |
| Caffeine consumption | There is no consistent evidence of an association between consumption of caffeinated beverages (e.g. tea, coffee, energy drinks, colas) and fertility problems |
| Extremes of body weight | Extremes of body weight could negatively impact fertility, including:
|
When to Refer / Investigate
The following applies to those who present with the inability to conceive
| Scenario | Referral timing |
|---|---|
| No suspected or known clinical cause of infertility | Refer both partners for further investigations if NOT conceived after 1 year of unprotected vaginal sexual intercourse |
| Female ≥36 y/o | Refer to specialist upon presentation (do NOT wait further) – to discuss options for attempting conception, further assessment and appropriate treatment |
| Either partner has suspected or known clinical cause of infertility, or history of predisposing factors for infertility | |
| Person is using artificial insemination to conceive, with no suspected or known clinical cause of infertility | Refer for further investigations if NOT conceived after 6 cycles
If the partner’s sperm is being used, also investigate their partner |
| Planned treatment may result in infertility (e.g. treatment for cancer) | Expedite fertility specialist referral |
For those who do not yet meet the referral criteria above (e.g. <36 y/o woman presenting after 6 months of trying to conceive), provide appropriate patient education as outlined above and arrange suitable follow-up.
Assessment, Investigation and Diagnosis
In most cases, assessment and investigation in both male and female partners are necessary.
Males
Initial work-up:
- 1st line test: semen analysis (compare to WHO reference values
- Semen volume: 1.4 ml or more
- pH: 7.2 or more
- Sperm concentration: 16 million spermatozoa per ml or more
- Total sperm number: 39 million spermatozoa per ejaculate or more
- Total motility (percentage of progressive motility and non-progressive motility): 42% or more motile
- Progressive motility: 30% or more
- Vitality: 54% or more live spermatozoa)
- Sperm morphology (percentage of normal forms): 4% or more
- If the semen analysis is abnormal → repeat semen analysis
- Ideally, 3 months after the initial test, to allow time for the cycle of spermatozoa formation to be completed
- Exception: repeat the test ASAP if there is gross spermatozoa deficiency (azospermia or severe oligozoospermia)
- If both semen analyses are abnormal:
- Physical examination of the scrotum and testes, and
- Consider measuring serum testosterone and gonadotropin levels
Key categories of sperm abnormality (in accordance with the WHO reference values
):
- Azoospermia = absence of sperm in the ejaculate
- Obstructive azoospermia = normal FSH, normal testis size, dilated epididymis
- Non-obstructive azoospermia = elevated FSH, testicular atrophy
- Oligozoospermia = low sperm concentration
- Asthenozoospermia = reduced progressive motility
- Teratozoospermia = low % of morphologically normal sperm
Other tests:
| Test | Indications |
|---|---|
| CFTRCystic fibrosis transmembrane conductance regulator genetic mutation testing | Presence of:
|
| Y chromosome microdeletion testing | Presence of:
|
| Karyotyping | Idiopathic azoospermia
Consider in those with a persistent sperm concentration <5 million per mL |
Do not offer routine testing for antisperm antibodies.
Do not carry out testing for sperm DNA integrity (fragmentation).
Females
Tests to Confirm Ovulation
Test of choice: serum progesterone level
Timing to measure depends on the person’s menstrual cycle regularity:
- Regular cycles: measure at mid-luteal phase (7 days before the expected next menstrual period) (e.g. day 21 of a 28-day cycle, or day 28 of a 35-day cycle)
- Irregular cycles:
- Measure ~7 days before the expected next menstrual period
- Repeat measurement weekly until the next menstrual cycle starts
Do not use basal body temperature charts to confirm ovulation because they are not reliable in predicting ovulation.
Ovarian Reserve Testing
Use maternal age as an initial predictor of the overall chance of becoming pregnant through spontaneous conception or with IVF
Measure AMHAnti-Müllerian hormone levels or AFCAntral follicle count to predict ovarian response and likelihood of live birth following assisted conception
Do not use anti-Müllerian hormone (AMH) measurement as a predictor of clinical pregnancy through spontaneous conception.
Do not use FSH measurement as a predictor of ovarian response or outcome of assisted conception.
Tubal / Uterine Abnormalities Testing
Choice of test depends on whether the patient has comorbidities Comorbidities refer to those that may predispose one to tubal abnormalities, such as:
:
- No comorbidities → hysterosalpingography to screen for tubal occlusion
- Alternative: hysterosalpingo-contrast ultrasound
- Presence of comorbidities → laparoscopy and dye to assess both tubal and pelvic pathologies simultaneously
Only offer hysteroscopy if a uterine / endometrial abnormality is clinically suspected (e.g. adhesions, polyps, submucosal fibroids)
The 3 investigations listed above may sound similar, but they assess different structures and have distinct roles:
- Hysterosalpingography (less invasive) = X-ray + contrast dye passed through the cervix to assess whether the fallopian tubes are patent and outline the uterine cavity (primary role = test for tubal patency)
- Laparoscopy + dye (invasive) = a 2-component procedure
- Laparoscopy: a camera is inserted through small abdominal incisions to inspect the abdominopelvic cavity directly
- Dye test: dye is passed through the cervix into the uterus, then through the fallopian tubes, and the surgeon observes whether the dye spills from the fimbrial ends of the tubes into the pelvis (if there is no / reduced spill → possible tubal blockage)
- Hysteroscopy = a camera is passed through the cervix into the uterus to directly inspect the endometrial cavity for intrauterine pathology. Does not assess tubal patency or the pelvis
Other Tests
The following tests are NOT routinely performed:
- Serum gonadotrophin levels (LH and FSH) – only in the presence of irregular menstrual cycles
- Serum prolactin measurement – only for those with ovulatory disorder, galactorrhoea, pituitary tumour
- TFT – only if there are symptoms of thyroid disease
- Coeliac testing (see the Coeliac Disease article for more information) – consider in cases of unexplained subfertility
Do not routinely use post-coital testing of cervical mucus in the investigation of fertility problems because it has no predictive value on pregnancy rate.
Management of Infertility Causes
Disclaimer:
Infertility management is a vast topic, as there are many underlying causes and each has its own dedicated treatment approach.
This section provides a simplified overview based on the management options specifically covered in the NICE guideline. It does NOT cover the management of every single cause of infertility.
Male Factor Infertility
Management largely depends on the underlying cause:
| Cause of male factor infertility | Recommended management |
|---|---|
| Hypogonadotropic hypogonadism (e.g. Kallmann syndrome) | Gonadotrophin therapy |
| Varicocele | Consider radiological or surgical treatment (e.g. varicocelectomy) if the patient has reduced semen parameters and is trying to conceive spontaneously |
| Azoospermia (absence of sperm in the ejaculate) | Obstructive azoospermia → surgical correction / surgical sperm retrieval
Non-obstructive azoospermia → surgical sperm retrieval |
| Ejaculatory failure | Management depends on the underlying cause |
Do NOT offer gonadotropin or anti-oestrogen therapy in those with impaired semen parameters but no evidence of hypogonadotrophic hypogonadism.
Do not offer androgens to treat semen abnormalities.
Female Factor Infertility
Management largely depends on the underlying cause:
| Cause of female factor infertility | Recommended management |
|---|---|
| Hypogonadotropic hypogonadism (e.g. Kallmann syndrome, functional hypothalamic amenorrhoea) | Gonadotropin therapy (LH activity or GnRH)
For those with functional hypothalamic amenorrhoea, also advise:
|
| PCOSPolycystic ovary syndrome |
Disclaimer on PCOS management guidelines
Optimise preconception health and lifestyle (to be implemented prior to and alongside medical treatments):
Interventions:
|
| Hyperprolactinaemia-associated ovulatory disorder | Offer cabergoline (dopamine agonist) |
| Tubal disease | Mild tubal disease → consider tubal surgery
Proximal tubal obstruction → consider fallopian tube catheterisation (hysteroscopic or radiological guidance) |
| Hydrosalpinges (if undergoing IVF) | Laparoscopic salpingectomy or tubal occlusion before IVF |
| Intrauterine adhesions (Asherman syndrome) | Hysteroscopic adhesiolysis |
| Endometriosis | Initial management: discuss either of the following options:
If expectant management and surgical treatment failed or are not appropriate:
Do NOT offer hormonal treatment (i.e. COCP, progestogens, GnRH agonist) – they do NOT improve spontaneous pregnancy rates. |
For those who are offered ovulation induction (gonadotrophins or clomiphene):
- Use ovarian ultrasound monitoring to measure follicular size and number
- To reduce risk of multiple pregnancy and ovarian hyperstimulation syndrome (see ART section below for more information)
Unexplained Fertility Problems
For individuals with unexplained fertility problems, advise them to have regular unprotected vaginal intercourse for 2 years before considering treatment.
Treatment options:
- Intrauterine insemination with ovarian stimulation (gonadotrophins)
- IVFIn vitro fertilisation
Do not offer ovarian stimulation as a stand-alone treatment for unexplained fertility problems.
Assisted Reproductive Technology (ART)
Overview:
| Assisted reproductive technology | Description |
|---|---|
| Intrauterine insemination (IUI) | Prepared sperm is placed directly into the uterine cavity around ovulation to increase the chance of fertilisation (in vivo) |
| In vitro fertilisation (IVF) | Eggs are collected and fertilised with sperm in the laboratory (in vitro)
The embryo is then transferred into the uterus |
| Intracytoplasmic sperm injection (ICSI) | A specialised form of IVF in which a single sperm is injected directly into an egg to aid fertilisation
The main difference is at the fertilisation stage:
|
| Donor insemination | Donor sperm is used instead of partner sperm
Usually performed via IUI, sometimes as part of IVF |
| Oocyte donation | Donor egg is used, usually part of IVF |
| Fertility preservation | Eggs, sperm, or embryos are collected, frozen and stored for future use (IUI / IVF) |
Indications to Offer ART
Unstimulated Intrauterine Insemination (IUI)
Indications to offer unstimulated IUI (exact wording: NICE recommends offering IUI before considering IVFIn vitro fertilisation in the following situations):
- People who are unable to have vaginal intercourse due to a physical disability or psychosexual problem
- Physical disability include conditions that affect mobility, positioning, pain, coordination of ability to have intercourse safely (e.g. motor neuron disease, spinal cord injury, multiple sclerosis, cerebral palsy)
- Psychosexual problems include vaginismus, severe dyspareunia, erectile dysfunction, sexual anxiety
- Males with azoospermia, where surgical sperm retrieval is not suitable or has been unsuccessful, and who wish to use donor sperm treatment
- People using donor insemination who have not conceived after 6 cycles
Unstimulated IUI relies on the woman’s spontaneous ovulation without any fertility medications. The timing of ovulation can be determined by measuring the endogenous LH surge. IUI is then performed shortly after the LH surge.
Stimulated IUI may be used in some specialist settings, which involves administering medications (e.g. clomiphene citrate, letrozole, gonadotropin), early in the menstrual cycle to promote follicular growth. However, this is not the main focus of the current NICE recommendations.
In Vitro Fertilisation (IVF)
Offer IVF if the female is <42 y/o PLUS any of the following:
- Treatment for an identified cause of infertility has been unsuccessful or is not suitable
- Unexplained infertility, with no conception after 2 years of regular unprotected vaginal intercourse +/- intrauterine insemination
- No conception after 12 cycles of artificial insemination, of which at least 6 cycles should be intrauterine insemination
Disclaimer:
The decision to offer IVF is often complex and individualised. It takes into account the patient’s wishes, clinical circumstances, age, fertility factors, likelihood of success, risks, and local service/funding criteria. The points listed above are simplified criteria for when IVF may be considered / when a patient may be eligible for assessment, rather than an automatic guarantee that IVF will be offered.
Basic steps of IVF:
- Pre-treatment assessment: fertility history, investigations, ovarian reserve assessment (e.g. AMH / AFC), semen analysis, and treatment planning
- Controlled ovarian stimulation: hormonal medication (e.g. gonadotrophins) is used to stimulate the ovaries to develop multiple follicles/eggs in one cycle (rather than the usual single egg)
- Prevention of premature ovulation: additional medication (e.g. GnRH antagonist) may be used to prevent ovulation occurring too early during stimulation
- Monitoring response: ultrasound scans +/- blood tests are used to assess follicle growth and adjust treatment if needed
- Triggering final oocyte maturation: when follicles are ready, a “trigger” medication (typically hCG, or GnRH agonist) is given to complete egg maturation before collection
- Egg collection (oocyte retrieval): eggs are collected from the ovaries using a transvaginal ultrasound-guided procedure
- Fertilisation in the laboratory: eggs are fertilised with sperm:
- Standard IVF = eggs + sperm incubated together
- ICSI = a single sperm injected into an egg
- Embryo culture: fertilised eggs develop into embryos in the lab over several days
- Embryo transfer: a selected embryo is transferred into the uterus
- Luteal support: progesterone is commonly given after egg collection / transfer to support implantation and the early luteal phase
- Pregnancy test: performed later to assess treatment success
Intracytoplasmic Sperm Injection (ICSI)
Offer ICSI using surgically retrieved sperm or frozen–thawed oocytes.
Consider IVFIn vitro fertilisation with ICSI if:
- The male partner has abnormal semen parameters, or
- Previous IVFIn vitro fertilisation cycles have resulted in failed fertilisation or a very low fertilisation rate
- Note that this refers to failure at the fertilisation stage, rather than any unsuccessful IVFIn vitro fertilisation cycle
- ICSI may improve fertilisation when sperm–egg interaction is the issue, but it does not necessarily improve outcomes if failure occurred for other reasons (e.g. poor oocyte quality, poor embryo development, implantation failure, miscarriage)
Note that ICSI is a fertilisation method used within an IVFIn vitro fertilisation cycle, not a standalone treatment done independently of IVFIn vitro fertilisation. So when ICSI is being considered, it is generally in the context of a couple already undergoing assisted conception with IVFIn vitro fertilisation.
Donor Insemination
Indications:
- Azoospermia (obstructive and non-obstructive)
- Severe deficits in sperm quality, and do not wish to undergo IVFIn vitro fertilisation with ICSIIntracytoplasmic sperm injection
Consider donor insemination in:
- High risk of passing a genetic disorder to the child (autosomal dominant and X-linked conditions like hereditary cancer syndromes, Marfan syndrome, Huntington’s disease)
- High risk of transmitting infectious disease via the semen to the female partner or child (e.g.. HIV)
- Severe rhesus isoimmunisation
Donor insemination is only suitable when the female partner is ovulating and has patent, functional fallopian tubes. These factors should be assessed before treatment.
Donor insemination is mainly used when infertility is related to the male partner.
Oocyte Donation
Indications:
- Premature ovarian insufficiency (premature ovarian failure)
- Gonadal dysgenesis (e.g. Turner syndrome)
- Certain cases of failed IVF
Consider if there is a high risk of passing a genetic disorder to the child
Fertility Preservation
Consider fertility preservation for patients who are about to undergo treatment likely to impair fertility (e.g. gonadotoxic treatment), such as: [Ref]
- Chemotherapy, particularly higher-risk agents
- Platinum agents (e.g. cisplatin, carboplatin)
- Alkylating agents (e.g. busulfan, cyclophosphamide)
- Radiation therapy involving the gonads / hypothalamus / pituitary / uterus
- Haematopoietic stem cell transplantation (including conditioning / induction regimens)
- Surgery affecting reproductive organs (e.g. orchiectomy, oophorectomy)
Complications of ART
Shared Complications
The single most significant risk is multiple gestation / births (e.g. twins and triplets)
ART also increases the risk of developing other obstetric complications (4Ps): [Ref]
- Placenta praevia (odds ratio 6.0)
- Pre-eclampsia
- Placental abruption
- Vasa praevia
- Stillbirth
- Caesarean delivery
OHSS (Ovarian Hyperstimulation Syndrome)
OHSS is an uncommon but serious iatrogenic complication associated with controlled ovarian stimulation during IVF
| Cause | OHSS can occur whenever ovarian stimulation is used, including:
|
| Pathophysiology |
|
| Risk factors |
|
| Clinical manifestation | Onset can be early (<9 days of stimulation) or late (>9 days)
Mild OHSS
Severe OHSS can lead to life-threatening complications
|
| Diagnosis | Clinical |
| Management |
|
References
NICE guideline Fertility problems: assessment and treatment
Related Articles
Polycystic Ovary Syndrome (PCOS)
Pelvic Inflammatory Disease (PID)
Menopause and Premature Ovarian Insufficiency