Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

with underlying or associated medical condition

1st line – optimisation of medical management

Back
ACUTE
|
with underlying or associated medical condition
1st line – 

optimisation of medical management

It is important to address and optimise any underlying or associated medical disorder, such as diabetes or thyroid disease, and include weight loss where appropriate.[105]​​[106][107]​​ This should ideally occur before pregnancy is achieved. Pre-pregnancy counselling with obstetricians is encouraged, because medical conditions are increasingly complex and early involvement of a multidisciplinary care team is beneficial.

ONGOING

anovulatory

1st line – controlled ovarian stimulation

Back
ONGOING
|
anovulatory
|
hypothalamic or hypopituitary
1st line – 

controlled ovarian stimulation

Gonadotrophins are first-line options for patients with hypothalamic amenorrhoea.[1][14]​ For women with a non-functioning pituitary gland (e.g., with Kallman's syndrome), drugs such as clomifene are ineffective. The treatment of choice, therefore, is controlled ovarian stimulation with gonadotrophins.

Typical starting doses of gonadotrophins are dependent on female age, diagnosis, and prior stimulation history. Stimulation duration depends on response to medications.

Protocols vary, but a step-up regimen of gonadotrophins is standard, and this is sometimes accompanied by down-regulation and ovulation induction with human chorionic gonadotrophin (hCG).

These medications should only be used by experienced infertility practitioners because of the high risk of ovarian hyperstimulation syndrome and higher-order multiple gestations in uncontrolled situations.

Primary options

menotrophin: consult product literature for guidance on dose

OR

follitropin alfa: 75-225 IU subcutaneously once daily

More

and

lutropin alfa: 75 IU subcutaneously once daily

More

Consider – human chorionic gonadotrophin (hCG)

Back
ONGOING
|
anovulatory
|
hypothalamic or hypopituitary
Consider – 

human chorionic gonadotrophin (hCG)

Additional treatment recommended for SOME patients in selected patient group

Protocols vary, but a step-up regimen of gonadotrophins is standard and this is sometimes accompanied by down-regulation and ovulation induction with human chorionic gonadotrophin.

These medications should only be used by experienced infertility practitioners because of the high risk of ovarian hyper-stimulation syndrome and higher-order multiple gestations in uncontrolled situations.

Primary options

chorionic gonadotrophin: 5000 to 10,000 IU intramuscularly as a single dose

Plus – counselling

Back
ONGOING
|
anovulatory
|
hypothalamic or hypopituitary
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems,​​ but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

2nd line – IVF

Back
ONGOING
|
anovulatory
|
hypothalamic or hypopituitary
2nd line – 

IVF

IVF is a form of medically assisted reproduction and is an appropriate second-line treatment option for anovulatory infertility, if conception has not occurred within 6-12 ovulatory cycles, or if ovarian stimulation has proved difficult to control.[123]

During IVF, the ovaries are stimulated​ and the eggs are removed from the follicles by a minor surgical procedure. [ Cochrane Clinical Answers logo ] ​ Eggs and sperm are combined, creating embryos that are then transferred back to the uterus. [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] ​​ To reduce multiple gestation and its associated risks, guidelines recommend elective single embryo transfer as standard for most patients.[170][171] Double embryo transfer is associated with an increased risk of adverse obstetric and perinatal outcomes, even when the result is a singleton birth.[172]

In 2021, the live birth rate per egg retrieval cycle in the US was 50.7% in women aged <35 years using their own eggs.[173]​ There are international variations in success rates for assisted reproductive techniques. Local guidance documents should be consulted.[174][175]

Plus – counselling

Back
ONGOING
|
anovulatory
|
hypothalamic or hypopituitary
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems,​ but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

1st line – weight loss

Back
ONGOING
|
anovulatory
|
polycystic ovary syndrome (PCOS)
1st line – 

weight loss

Lifestyle and dietary advice is important in women who are overweight.[113][123]

The most important factor in achieving weight loss is to maintain a caloric deficit, by reducing caloric intake or increasing calorie expenditure through increased physical activity.

Weight loss is not recommended as first-line fertility treatment for normal-weight women with PCOS. In these women, letrozole should be first line.[123]

Plus – counselling

Back
ONGOING
|
anovulatory
|
polycystic ovary syndrome (PCOS)
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems, but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

Consider – metformin

Back
ONGOING
|
anovulatory
|
polycystic ovary syndrome (PCOS)
Consider – 

metformin

Additional treatment recommended for SOME patients in selected patient group

Patients with PCOS can also be treated with metformin.[1][123]​​​​​[128] In ovulation induction, there is no clear benefit over clomifene.[129] However, combination therapy with clomifene and metformin can be recommended to improve ovulation and pregnancy rates.[113] Some experts believe all women with PCOS may benefit, while others would give metformin only to women who are overweight/obese or who have proven insulin resistance.[113]​​[128]​​​​

Primary options

metformin: 1500-2000 mg orally (extended-release) once daily

1st line – controlled ovarian stimulation + consideration of ovarian drilling

Back
ONGOING
|
anovulatory
|
polycystic ovary syndrome (PCOS)
1st line – 

controlled ovarian stimulation + consideration of ovarian drilling

Controlled ovarian stimulation may be achieved with ovulation induction medications including a selective oestrogen receptor modulator (i.e., clomifene), an aromatase inhibitor (e.g., letrozole), highly purified gonadotrophins (also known as menotrophin), or recombinant follicle-stimulating hormone (FSH).[113]

Clomifene (a competitive antagonist of oestradiol) disrupts negative feedback and augments gonadotrophin-releasing hormone (GnRH) production.

Ovarian drilling may be undertaken in patients with clomifene-resistant PCOS prior to moving to gonadotrophin treatment. Although the observed reduction in multiple pregnancies might make this a more attractive procedure than gonadotrophin treatment, one systematic review found low quality evidence that ovarian drilling may decrease the live birth rate slightly compared with medical ovulation induction, and there are few data for the long-term outcomes of this destructive process.[123][130][131]​​ Unilateral laparoscopic ovarian drilling may be an alternative to conventional bilateral ovarian drilling, with similar reproductive outcomes in one meta-analysis, but further long-term studies are needed.[132]​ The woman's age, potential surgical risks in cohorts with high body mass index, and cost implications of laparoscopic ovarian drilling compared with other fertility options should be taken into account.

Letrozole (a competitive reversible inhibitor of testosterone aromatisation) decreases circulating oestrogen, affects the hypothalamic feedback, and induces greater levels of FSH. Letrozole has been recommended as the oral agent of choice in women with PCOS, with overall improved pregnancy and live birth rates, coupled with a lower observed multiple pregnancy rate, compared with clomifene.[113][124][125]​​​ In one systematic review, live birth rates were higher in women with PCOS treated with letrozole compared with clomifene; rates of ovarian hyperstimulation syndrome, miscarriage, and multiple pregnancy were similar.[126] [ Cochrane Clinical Answers logo ] ​​​

Data suggesting increased fetal abnormalities in pregnancies following the use of aromatase inhibitors have restricted their use to post-menopausal women in some countries; however, these data have been successfully challenged more recently. Multicentred randomised controlled trials, meta-analyses and systematic reviews have concluded that the risks of fetal congenital abnormalities in those using letrozole and clomifene were not increased (the expected anomaly rate in fertile women who did not have assisted conception is 5% to 8%).​​[119][120]​​​

Gonadotrophins are typically used after oral agents have failed. Typical starting doses of gonadotrophins are dependent on female age, diagnosis, and prior stimulation history; however, low doses are usually used. Stimulation duration depends on response to medications. Specific protocols may vary.

These medications should only be used by experienced infertility practitioners because of the high risk of ovarian hyper-stimulation syndrome and higher-order multiple gestations in uncontrolled situations.

Primary options

letrozole: 2.5 to 7.5 mg orally once daily for 5 days, starting on day 3 of cycle

More

OR

clomifene: 50-100 mg orally once daily for 5 days, starting on day 5 of cycle

Secondary options

menotrophin: consult product literature for guidance on dose

OR

follitropin alfa: 75-225 IU subcutaneously once daily

More

Plus – counselling

Back
ONGOING
|
anovulatory
|
polycystic ovary syndrome (PCOS)
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems,​ but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

Consider – metformin

Back
ONGOING
|
anovulatory
|
polycystic ovary syndrome (PCOS)
Consider – 

metformin

Additional treatment recommended for SOME patients in selected patient group

Patients with PCOS can also be treated with metformin. In ovulation induction, there is no clear benefit of sole metformin use over clomifene.[129] However, combination therapy of clomifene and metformin can be recommended to improve ovulation and pregnancy rates.[113] Some experts believe all women with PCOS may benefit, while others would give metformin only to women who are overweight/obese or who have proven insulin resistance.[113]​​[128]​​​

Primary options

metformin: 1500-2000 mg orally (extended-release) once daily

2nd line – IVF

Back
ONGOING
|
anovulatory
|
polycystic ovary syndrome (PCOS)
2nd line – 

IVF

IVF is an effective treatment option for anovulatory infertility with PCOS if conception has not occurred with sequential clomifene, letrozole, and/or gonadotrophin treatment.[123][133]​ Women should be counselled on the higher risks of ovarian hyper-stimulation syndrome (OHSS), which can be minimised with an antagonist cycle and elective freeze-all of embryos created.[134][135]

During IVF the ovaries are stimulated,​ and the eggs are removed from the follicles by a minor surgical procedure. [ Cochrane Clinical Answers logo ] ​ Eggs and sperm are combined creating embryos that are then transferred back to the uterus. [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] ​ To reduce multiple gestation and its associated risks, guidelines recommend elective single embryo transfer as standard for most patients.​​​​​​[170][171]​ Double embryo transfer is associated with an increased risk of adverse obstetric and perinatal outcomes, even when the result is a singleton birth.[172]

In 2021, the live birth rate per egg retrieval cycle in the US was 50.7% in women aged <35 years using their own eggs.[173]​ There are international variations in success rates for assisted reproductive techniques. Local guidance documents should be consulted.[174][175]

Plus – counselling

Back
ONGOING
|
anovulatory
|
polycystic ovary syndrome (PCOS)
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems, but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

1st line – controlled ovarian stimulation

Back
ONGOING
|
anovulatory
|
non-polycystic ovary syndrome (PCOS), non-hypothalamic/non-hypopituitary
1st line – 

controlled ovarian stimulation

Controlled ovarian stimulation may be achieved in these women with ovulation induction medications including a selective oestrogen receptor modulator (i.e., clomifene), an aromatase inhibitor (e.g., letrozole), highly purified gonadotrophins (also known as menotrophin), or recombinant follicle-stimulating hormone (FSH).

Clomifene (a competitive antagonist of oestradiol) disrupts negative feedback and augments gonadotrophin-releasing hormone production.

Letrozole (a competitive reversible inhibitor of testosterone aromatisation) decreases circulating oestrogen, affects the hypothalamic feedback and induces greater levels of FSH. Data suggesting increased fetal abnormalities in pregnancies following the use of aromatase inhibitors have restricted their use to post-menopausal women in some countries; however, these data have been successfully challenged.[119][120]​ 

Gonadotrophins are typically used after oral agents have failed. A typical starting dose of any gonadotrophin is dependent on female age, diagnosis, and prior stimulation history. The length of the stimulation is dependent on the response to medications. Specific protocols may vary.

These medications should only be used by experienced infertility practitioners because of the high risk of ovarian hyper-stimulation syndrome and higher-order multiple gestations in uncontrolled situations.

Primary options

clomifene: 50-100 mg orally once daily for 5 days, starting on day 5 of cycle

OR

letrozole: 2.5 to 7.5 mg orally once daily for 5 days, starting on day 3 of cycle

More

Secondary options

menotrophin: consult product literature for guidance on dose

OR

follitropin alfa: 75-225 international units subcutaneously once daily

More

Plus – counselling

Back
ONGOING
|
anovulatory
|
non-polycystic ovary syndrome (PCOS), non-hypothalamic/non-hypopituitary
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems,​ but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

2nd line – IVF

Back
ONGOING
|
anovulatory
|
non-polycystic ovary syndrome (PCOS), non-hypothalamic/non-hypopituitary
2nd line – 

IVF

IVF is a form of medically assisted reproduction and is an appropriate second-line treatment option for anovulatory infertility, if conception has not occurred within 6-12 ovulatory cycles, or if ovarian stimulation has proved difficult to control.[123]

During IVF, the ovaries are stimulated,​ and the eggs are removed from the follicles by a minor surgical procedure. [ Cochrane Clinical Answers logo ] ​ Eggs and sperm are combined creating embryos that are then transferred back to the uterus. [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] To reduce multiple gestation and its associated risks, guidelines recommend elective single embryo transfer as standard for most patients.​​​​​​[170][171]​​ Double embryo transfer is associated with an increased risk of adverse obstetric and perinatal outcomes, even when the result is a singleton birth.[172]

In 2021, the live birth rate per egg retrieval cycle in the US was 50.7% in women aged <35 years using their own eggs.[173]​ There are international variations in success rates for assisted reproductive techniques. Local guidance documents should be consulted.[174][175]

Plus – counselling

Back
ONGOING
|
anovulatory
|
non-polycystic ovary syndrome (PCOS), non-hypothalamic/non-hypopituitary
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems,​ but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

tubal

1st line – IVF

Back
ONGOING
|
tubal
1st line – 

IVF

IVF is the best option for patients with abnormal fallopian tubes. There is accruing evidence that the removal or clipping of ultrasound-evident hydrosalpinges prior to treatment can improve the outcome of IVF treatment, but there is a lack of data on long-term fertility outcomes and procedure- or pregnancy-related adverse effects.[138]​ The ovaries are stimulated​ and the eggs are removed from the follicles with minor surgery. [ Cochrane Clinical Answers logo ] ​ Eggs and sperm are combined creating embryos that are then transferred back to the uterus. [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] ​​ To reduce multiple gestation and its associated risks, guidelines recommend elective single embryo transfer as standard for most patients.[170][171]​ Double embryo transfer is associated with an increased risk of adverse obstetric and perinatal outcomes, even when the result is a singleton birth.[172]

In 2021, the live birth rate per egg retrieval cycle in the US was 50.7% in women aged <35 years using their own eggs.[173]​ There are international variations in success rates for assisted reproductive techniques. Local guidance documents should be consulted.[174][175]

Plus – counselling

Back
ONGOING
|
tubal
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems,​ but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

Consider – tubal reconstruction

Back
ONGOING
|
tubal
Consider – 

tubal reconstruction

Additional treatment recommended for SOME patients in selected patient group

The utility of tubal reconstruction has been highly debated in the infertility literature.[136]​ Variables predictive of success include younger female age, unilateral versus bilateral tubal disease, density of the adhesions, and thickness of the tubal wall.

There is accruing evidence that the removal or clipping of ultrasound-evident hydrosalpinges prior to treatment can improve the outcome of IVF treatment, but there is a lack of data on long-term fertility outcomes and procedure- or pregnancy-related adverse effects.[138]​​

Although pregnancy rates approximate 30%, ectopic pregnancy rates approximate 14%. As the pregnancy rates from IVF continue to improve, the value of surgical intervention (with increased surgical risk) has diminished.[137] Tubal surgery is not usually performed as the first-line treatment for infertility, having been largely superseded by IVF, unless there is a specific other indication; for example, pelvic pain.[137] The exception to this may be tubal anastomosis after voluntary sterilisation.

endometriosis- or adenomyosis-related

1st line – controlled ovarian stimulation ± intrauterine insemination

Back
ONGOING
|
endometriosis- or adenomyosis-related
1st line – 

controlled ovarian stimulation ± intrauterine insemination

Treatment for endometriosis-related infertility is multifaceted and is influenced by multiple factors, namely staging of endometriosis, duration of infertility, severity of symptoms, and female age. In women with mild endometriosis, controlled ovarian stimulation combined with intrauterine insemination (IUI) can be considered.[142]​ Endometriosis and adenomyosis frequently co-exist, and management options for adenomyosis-related infertility are similar in practice.

Controlled ovarian stimulation may be achieved with ovulation induction medications including a selective oestrogen receptor modulator (i.e., clomifene), an aromatase inhibitor (e.g., letrozole), highly purified gonadotrophins (also known as menotrophin), or recombinant follicle-stimulating hormone (FSH).

Clomifene (a competitive antagonist of oestradiol) disrupts negative feedback and augments gonadotrophin-releasing hormone production.

Letrozole (a competitive reversible inhibitor of testosterone aromatisation) decreases circulating oestrogen, affects the hypothalamic feedback, and induces greater levels of FSH. Data suggesting increased fetal abnormalities in pregnancies following the use of aromatase inhibitors have restricted their use to post-menopausal women in some countries; however, these data have been successfully challenged.[119][120]​ ​

A typical starting dose of any gonadotrophin is dependent on female age, diagnosis, and prior stimulation history. The length of the stimulation is dependent on the response to medications. Specific protocols may vary.

These medications should only be used by experienced infertility practitioners because of the high risk of ovarian hyper-stimulation syndrome and higher-order multiple gestations in uncontrolled situations.

The UK National Institute for Health and Care Excellence recommends against offering IUI, either with or without ovarian stimulation, to women with mild endometriosis, and considers IVF as the first-line treatment after 2 years' expectant management.[1]

Primary options

clomifene: 50-100 mg orally once daily for 5 days, starting on day 5 of cycle

OR

letrozole: 2.5 to 7.5 mg orally once daily for 5 days, starting on day 3 of cycle

More

Secondary options

menotrophin: consult product literature for guidance on dose

OR

follitropin alfa: 75-225 IU subcutaneously once daily

More

Plus – counselling

Back
ONGOING
|
endometriosis- or adenomyosis-related
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems, but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

2nd line – IVF

Back
ONGOING
|
endometriosis- or adenomyosis-related
2nd line – 

IVF

IVF has the highest success rate for the treatment of endometriosis-associated infertility, especially in those with moderate to severe disease.[145]​ The per cycle pregnancy rate after IVF for women with endometriosis is higher than after surgery alone.

However, IVF may not be an available treatment option for all women because the degree of pelvic damage may render normal ovarian tissue inaccessible for oocyte retrieval.

Endometriosis and adenomyosis frequently co-exist, and management options for adenomyosis-related infertility are similar in practice. However, women with concurrent adenomyosis and endometriosis have a significantly lower live birth rate with IVF than women with endometriosis alone.[150] Limited evidence from retrospective studies suggests that gonadotrophin-releasing hormone agonist pre-treatment may improve IVF outcomes in women with adenomyosis, but further studies are needed to confirm this.[151][152]​​[153]

Plus – counselling

Back
ONGOING
|
endometriosis- or adenomyosis-related
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems,​ but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

Consider – surgical ablation

Back
ONGOING
|
endometriosis- or adenomyosis-related
Consider – 

surgical ablation

Additional treatment recommended for SOME patients in selected patient group

For women with endometriosis, surgery may have a role in restoring pelvic anatomy and alleviating symptoms, potentially increasing chances of spontaneous pregnancy.[24][142]​ By contrast, surgery carries inherent risks and a recovery period, in addition to the potential reduction of ovarian reserve, if ovarian operation is involved. It is also unclear from the evidence whether surgery has any significant benefit on IVF outcome.[146][147]​ Meta-analyses of observational studies suggest that surgery might improve live birth and pregnancy rates per assisted reproductive technology (ART) cycle in women with deep infiltrating endometriosis compared with first-line ART without surgery.[147][148]​ However, randomised trials are lacking, and the European Society of Human Reproduction and Embryology recommends that the decision to offer surgery for deep endometriosis should mainly be guided by pain and patient preference.[142][149]

Further considerations must be made when weighing up surgical options, on cost implications and the potential delay in commencing assisted fertility treatment, which ultimately has the highest chance of achieving a successful pregnancy.[24] The optimal treatment, therefore, must be individualised, considering all risk factors and the woman’s preferences.

Ablation of the endometrial implants and lysis of adhesions may be recommended if there is a specific indication (other than infertility) for surgery. Implants may have been ablated in the course of diagnostic laparoscopy.

Uterine-sparing surgery may be considered for women with symptomatic adenomyosis, but it is controversial due to uncertain impact on reproductive outcomes and an increased risk of complications such as adhesions and uterine rupture.[151][154]​​[155]

age-related

1st line – counselling

Back
ONGOING
|
age-related
1st line – 

counselling

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems, but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

Consider – oocyte donation with donor IVF

Back
ONGOING
|
age-related
Consider – 

oocyte donation with donor IVF

Additional treatment recommended for SOME patients in selected patient group

Oocyte donation is a successful option for patients with diminished ovarian reserve or ovarian failure. This process requires IVF.[157] A healthy donor undergoes ovarian stimulation and the oocytes are retrieved. During this process the intended recipient uterus is synchronised with the donor. The oocytes are fertilised and transferred to the recipient, with success rates correlated closely to donor’s age.

1st line – controlled ovarian stimulation ± IVF

Back
ONGOING
|
age-related
1st line – 

controlled ovarian stimulation ± IVF

Controlled ovarian stimulation has also been used to optimise fertility outcomes. Success rates, however, are dependent on female age, and therefore ovarian stimulation may confer little benefit. Despite that, clinical improvements in assisted reproductive technology are evident in reports from the UK, in which birth rates are observed to steadily increase for all women up to the age of 43 years.[156]

Controlled ovarian stimulation may be achieved with ovulation induction medications including highly purified gonadotrophins (also known as menotrophin), a selective oestrogen receptor modulator (i.e., clomifene), an aromatase inhibitor (e.g., letrozole), or recombinant follicle-stimulating hormone (FSH).

In this population, gonadotrophins are the first-line options. Typical starting doses of gonadotrophins are dependent on female age, diagnosis, and prior stimulation history. Stimulation duration depends on response to medications. Specific protocols may vary.

Clomifene (a competitive antagonist of oestradiol) disrupts negative feedback and augments gonadotrophin-releasing hormone production.

Letrozole (a competitive reversible inhibitor of testosterone aromatisation) decreases circulating oestrogen, affects the hypothalamic feedback, and induces greater levels of FSH. Data suggesting increased fetal abnormalities in pregnancies following the use of aromatase inhibitors (AIs) have restricted their use to post-menopausal women in some countries; however, these data have been successfully challenged.[119][120]​ 

These medications should only be used by experienced infertility practitioners because of the high risk of ovarian hyper-stimulation syndrome and higher-order multiple gestations in uncontrolled situations.

Ovarian stimulation may also be done as part of an IVF process. During IVF, the ovaries are stimulated​ and the eggs are removed from the follicles by a minor surgical procedure. [ Cochrane Clinical Answers logo ] ​ Eggs and sperm are combined creating embryos that are then transferred back to the uterus. [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] To reduce multiple gestation and its associated risks, guidelines recommend elective single embryo transfer as standard for most patients.​​​​​​[170][171]​ Double embryo transfer is associated with an increased risk of adverse obstetric and perinatal outcomes, even when the result is a singleton birth.[172]

The live birth rate per cycle declines with age. For example, the following rates were reported in the US in 2021 for women using their own eggs: 50.7% for women aged <35 years; 36.3% for women aged 35-37 years; 23.3% for women aged 38-40 years; 7.9% for women over 40 years.[173]​ There are international variations in success rates for assisted reproductive techniques. Local guidance documents should be consulted.[174][175]

Primary options

menotrophin: consult product literature for guidance on dose

OR

follitropin alfa: 75-225 IU subcutaneously once daily

More

Secondary options

clomifene: 50-100 mg orally once daily for 5 days, starting on day 5 of cycle

OR

letrozole: 2.5 to 7.5 mg orally once daily for 5 days, starting on day 3 of cycle

More

damaged/missing uterus

1st line – surrogacy

Back
ONGOING
|
damaged/missing uterus
1st line – 

surrogacy

Surrogacy may be used if the uterus is damaged or missing (e.g., Mayer-Rokitansky-Kuster-Hauser syndrome affects 1 in 5000 women).[158][159]​ For some women, carrying a pregnancy may be hazardous to their health. The surrogate may act as an egg donor in addition, and pregnancy may be achieved by insemination with the commissioning partner’s sperm. Alternatively, embryos produced by IVF using the commissioning couple’s eggs and sperm can be transferred into the surrogate’s uterus to achieve pregnancy.

Plus – counselling

Back
ONGOING
|
damaged/missing uterus
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems,​ but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

endometrial polyps or uterine septum

1st line – consider surgery

Back
ONGOING
|
endometrial polyps or uterine septum
1st line – 

consider surgery

If endometrial polyps are detected during the infertility work-up, it is standard practice to remove them. Evidence suggests that hysteroscopic polypectomy may improve outcomes with natural conception and intrauterine insemination, irrespective of polyp size.[160][161][162]​ Polyp removal may also be considered for women planning IVF, but it is unclear whether polypectomy improves IVF outcomes, especially for polyps detected incidentally during IVF stimulation.[160]

Surgical correction of a uterine septum (hysteroscopic metroplasty) may also be considered in women with infertility, but the American Society for Reproductive Medicine guideline concludes that it is uncertain whether this improves live birth rate.[163][164][165]​​ Uterine septa are the most common congenital uterine anomaly and are associated with an increased risk of recurrent pregnancy loss and other adverse pregnancy outcomes such as preterm birth, malpresentation, and fetal growth restriction. However, the association between uterine septa and infertility is less clear, and treatment is controversial.[164][166]​​ One meta-analysis of observational studies suggests that septum removal reduces the rate of miscarriage and may improve live birth rate.[167]​ Conversely, one randomised controlled trial found no difference in live birth rate compared with expectant management in women with a history of infertility, pregnancy loss, or preterm birth, but the study was limited by a small sample size and a long recruitment period.[168]

Plus – treatment of underlying cause

Back
ONGOING
|
endometrial polyps or uterine septum
Plus – 

treatment of underlying cause

Treatment recommended for ALL patients in selected patient group

Further treatment is based on any other underlying cause of infertility (i.e., ovulatory dysfunction, tubal, endometriosis-/adenomyosis-related, age-related, or unexplained). See relevant patient group for more information on further management.

Plus – counselling

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endometrial polyps or uterine septum
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counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems,​ but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

unexplained

1st line – age-stratified expectant management

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unexplained
1st line – 

age-stratified expectant management

A diagnosis of unexplained infertility is reached in about 25% of couples, if clinical investigations fail to identify any male or female barriers to conception. In these couples, expectant management is an accepted approach, supported by evidence that it is effective in a well-selected group of patients.[1][139][169] It may be appropriate to consider intervention earlier in older women with unexplained subfertility.

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unexplained
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counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems, but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

2nd line – controlled ovarian stimulation and intrauterine insemination

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unexplained
2nd line – 

controlled ovarian stimulation and intrauterine insemination

Several guidelines on unexplained infertility recommend initial therapy with ovarian stimulation with oral agents and intrauterine insemination (IUI) followed by IVF, if initial treatment is unsuccessful.[2][139][169]​​ Compared with expectant management, ovarian stimulation (with oral agents or gonadotrophins) coupled with IUI is associated with superior pregnancy outcomes.ul.[2][139]

Although ovarian stimulation with IUI is less expensive than IVF, the trade off of multiple pregnancy, potential cycle cancellation, and cumulative costs of repeated treatments may make this option overall less attractive. The Canadian Fertility and Andrology Society also suggests a benefit of advancing therapy to IVF in terms of improved live birth rates per cycle and reduced multiple pregnancy, but notes that this approach is invasive and costly.[139] The UK National Institute for Health and Care Excellence guidance recommends IVF as first-line treatment for couples with unexplained infertility who have not conceived after 2 years of expectant management.[1]​ This strategy was associated with high pregnancy rate and shorter time to pregnancy compared with other treatment modalities with ovarian stimulation and IUI, especially if female age is above 38 years old.

​Oral ovarian stimulation agents should not be used alone for unexplained infertility.[1][139][169]

Controlled ovarian stimulation may be achieved with ovulation induction medications including a selective oestrogen receptor modulator (i.e., clomifene), an aromatase inhibitor (e.g., letrozole), highly purified gonadotrophins (also known as menotrophin), or recombinant follicle-stimulating hormone (FSH).[2][176]

Clomifene (a competitive antagonist of oestradiol) disrupts negative feedback and augments gonadotrophin-releasing hormone production.

Letrozole (a competitive reversible inhibitor of testosterone aromatisation) decreases circulating oestrogen, affects the hypothalamic feedback, and induces greater levels of FSH. Data suggesting increased fetal abnormalities in pregnancies following the use of aromatase inhibitors have restricted their use to post-menopausal women in some countries; however, these data have been successfully challenged.[119][120]

A typical starting dose of any gonadotrophin is dependent on female age, diagnosis, and prior stimulation history. The length of the stimulation is dependent on the response to medications. Specific protocols may vary.

These medications should only be used by experienced infertility practitioners because of the high risk of ovarian hyper-stimulation syndrome and higher-order multiple gestations in uncontrolled situations.

Primary options

clomifene: 50-100 mg orally once daily for 5 days, starting on day 5 of cycle

OR

letrozole: 2.5 to 7.5 mg orally once daily for 5 days, starting on day 3 of cycle

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Secondary options

menotrophin: consult product literature for guidance on dose

OR

follitropin alfa: 75-225 IU subcutaneously once daily

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unexplained
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems, but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

3rd line – IVF

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unexplained
3rd line – 

IVF

Several guidelines on unexplained infertility recommend initial therapy with ovarian stimulation with oral agents and intrauterine insemination (IUI) followed by IVF, if initial treatment is unsuccessful.[2][139][169] However, the UK National Institute for Health and Care Excellence guidance recommends IVF as first-line treatment for couples with unexplained infertility who have not conceived after 2 years of expectant management.[1]​ This strategy was associated with high pregnancy rate and shorter time to pregnancy compared with other treatment modalities with ovarian stimulation and IUI, especially if female age is above 38 years old.

During IVF, the ovaries are stimulated​ and the eggs are removed from the follicles by a minor surgical procedure. [ Cochrane Clinical Answers logo ] ​ Eggs and sperm are combined creating embryos that are then transferred back to the uterus. [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] To reduce multiple gestation and its associated risks, guidelines recommend elective single embryo transfer as standard for most patients.[170][171] Double embryo transfer is associated with an increased risk of adverse obstetric and perinatal outcomes, even when the result is a singleton birth.[172]

In 2021, the live birth rate per egg retrieval cycle in the US was 50.7% in women aged <35 years using their own eggs.[173]​ There are international variations in success rates for assisted reproductive techniques. Local guidance documents should be consulted.[174][175]​

Plus – counselling

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ONGOING
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unexplained
Plus – 

counselling

Treatment recommended for ALL patients in selected patient group

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems,​ but good evidence is lacking.[110][111]​​[112] [ Cochrane Clinical Answers logo ]

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