Assessment and treatment of

people with fertility problem NICE guideline, 2013

Aboubakr Elnashar

Benha university, Egypt

Aboubakr Elnashar

Fertility incidence

1 in 7 couples

Main causes: unexplained infertility: 25% ovulatory disorders: 25% tubal damage: 20% male factors: 30% uterine or peritoneal: 10% combined male and female: 40% Uterine or endometrial factors, gamete or embryo

defects, and pelvic conditions such as endometriosis may also play a role.

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Terms

Full cycle:

one episode of ovarian stimulation and transfer

of any resultant embryos fresh or frozen.

Infertility:

reproductive age woman

one year unprotected sexual intercourse

absence of known cause of infertility

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Unexplained infertility

Do not offer oral ovarian stimulation agents (such as clomifene citrate, or letrozole).

{no increase the chances of a pregnancy or a live birth}.

Offer IVF after 2 years

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Intrauterine insemination

unexplained infertility

mild endometriosis or

‘mild male factor:

Do not routinely offer IUI, either with or without ovarian stimulation

Advise: try to conceive for a total of 2 years (include 1 year before their fertility investigations) then IVF

Aboubakr Elnashar

Unstimulated IUI indication:

1. unable to, or would find it very difficult to, have vaginal intercourse

{physical disability or

psychosexual problem} .

If not conceived after 6 ovulatory cycles, offer a further 6 cycles of unstimulated IUI before IVF is considered

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Criteria for referral for IVF

under 40 ys:

not conceived after

2 years of regular unprotected intercourse or

6 cycles of IUI: 3 full cycles of IVF.

40–42 years:

offer 1 full cycle of IVF, provided the following 3 criteria are fulfilled:

never previously had IVF treatment

no evidence of low ovarian reserve

discussion of the additional implications of IVF and pregnancy at this age.

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Number of fresh or frozen embryo transfer

<37 years:

First full IVF cycle:

single embryo transfer.

Second full IVF cycle:

single embryo transfer if 1 or more top-quality embryos are available.

Consider using 2 embryos if no top-quality embryos are available.

Third full IVF cycle:

transfer no more than 2 embryos.

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37–39 years:

First and second full IVF cycles:

Single embryo transfer if there are 1 or more top-quality embryos.

Consider double embryo transfer if there are no top-quality embryos.

Third full IVF cycle:

transfer no more than 2 embryos.

40–42 years

double embryo transfer.

So: SET except

1. After 40

2. 3rd cycle

3. 2nd cycle if no goood quality E

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Principles of care

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Providing information

See the couples together.

Verbal information should be supplemented with written information or audio-visual media

Frequent counseling after every investigation and step.

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Chance of conception counseling

Psychological effects of infertility: reduced lipido and coital frequency.

sexual intercourse every 2 to 3 days optimises the chance of pregnancy.

>80% <40yrs with regular intercourse will conceive within 1 year

90% in two yrs.

Aboubakr Elnashar

Smoking

Reduce female fertility

Passive smoking is likely to affect their chance of

conceiving

An association between smoking and reduced

semen quality (although the impact of this on male

fertility is uncertain), and that stopping smoking will

improve their general health

Aboubakr Elnashar

Caffeinated beverages

No association between coffee, tee or colas

with fertility.

Maternal caffeine consumption has adverse

effects on the success rates of ART.

also alcohol and smoking

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BMI: Females:

>30: longer to conceive.

>30 who are not ovulating: losing weight increase

chance of conception

Men

>30: reduced fertility,

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<19

irregular menstruation or are not menstruating

increasing body weight improve chance of conception.

Tight underwear

: elevated scrotal temperature and reduced semen

quality,

loose-fitting underwear

improves fertility: uncertain.

Aboubakr Elnashar

Folic acid supplementation

before conception and up to 12 w reduces the risk of NTD.

Dose: 0.4 mg per day.

5 mg per day

previous NTD

anti-epileptics

diabetics.

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Investigation of fertility problems and

management strategies

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Semen analysis

vol: 1.5 ml or more

pH: 7.2 or more

Concentration: 15 million spermatozoa/ ml or more

total sperm number: 39 million spermatozoa per ejaculate or more

total motility: (PR+NP): 40% or more or

PR: 32% or more

vitality: 58% or more live spermatozoa

Normal forms: 4% or more.

based on strict morphological criteria.

Aboubakr Elnashar

Semen analysis: WHO, 2010

:

:

Lower reference limit Parameter

1.5 ml Volume

7.2 pH

15 million/ml Concentration

39 million/ejaculate Total sperm number

40% or PR: 32%

Total motility: (PR+NP)

58% live spermatozoa Vitality

4% (strict criteria). Normal forms

Aboubakr Elnashar

Other consensus threshold values

pH ≥7.2

Peroxidase-positive leukocytes (106 per ml)

<1.0

MAR test (motile spermatozoa with bound

particles, %) <50

Immunobead test (motile spermatozoa with bound

beads, %) <50

Seminal zinc (ųmol/ejaculate) ≥2.4

Seminal fructose (ųmol/ejaculate) ≥13

Seminal neutral glucosidase (mU/ejaculate) ≥20

Aboubakr Elnashar

o Antisperm antibodies

should not be offered

{no evidence of effective treatment}.

If first semen analysis is abnormal:

repeat 3 months later

{allow time for the cycle of spermatozoa formation to be completed}

a single-sample analysis will falsely identify about 10% of men as abnormal, but repeating the test reduces this to 2%

if a gross spermatozoa deficiency (azoospermia or severe oligozoospermia):

repeat as soon as possible

Post-coital testing:

not recommend {no predictive value on pregnancy rate}

Aboubakr Elnashar

Ovarian reserve testing

Woman's age an initial predictor of overall chance of success

Predictors of ovarian response to gonadotrophin stimulation in IVF:

1. Total antral follicle count less than or equal to 4 for a low response >16 for a high response 2. AMH less than or equal to 5.4 pmol/l (0.8ng/ml) for a low response

and greater than or equal to 25.0 pmol/l (3.5ng/ml)for a high

response. Conevrsion ratio:7 3. FSH >8.9 IU/l for a low response and <4 IU/l for a high response

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High

response

Low

response

16 4 Total AFC

4 0.5 AMH ng/ml

4 8.9 FSH IU/L

Aboubakr Elnashar

Do not use

1. ovarian volume

2. ovarian blood flow

3. inhibin B

4. oestradiol (E2)

Aboubakr Elnashar

Regularity of menstrual cycles

Regular monthly menstrual cycles: likely to be ovulating

Measure serum progesterone in the mid-luteal phase of their cycle (day 21 of a 28-day cycle) to confirm ovulation even if they have regular menstrual cycles

Aboubakr Elnashar

Investigations 1. Midluteal progesterone

in regular and irregular cycles

{confirm ovulation} In irregular prolonged cycles

Depending upon the timing of menstrual periods, conducted later in the cycle (for example day 28 of a 35-day cycle) and repeated weekly thereafter until the next menstrual cycle starts

2. Basal FSH and LH

Only in

irregular prolonged cycles

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3. Prolactin

Only in

ovulatory disorder

galactorrhoea or

pituitary tumour

4. TSH:

only if

symptoms of thyroid disease

Endometrial biopsy

To evaluate the luteal phase: No

{no evidence that medical tt of luteal phase defect improves pregnancy rates]

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Medical and surgical management of

male factor fertility problems

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male factor infertility

hypogonadotrophic hypogonadism: gonadotrophin drugs {effective}

idiopathic semen abnormalities:

No anti-oestrogens, gonadotrophins, androgens, or bromocriptine {not effective]

leucocytes in semen:

No antibiotic treatment unless there is an identified infection {no evidence that this improves pregnancy rates]

Aboubakr Elnashar

Obstructive azoospermia:

surgical correction of epididymal blockage, IF EXPERIENCE [likely to restore patency of the duct and improve fertility}.

Varicoceles

No varicocelectomy.

{does not improve pregnancy rates}

Aboubakr Elnashar

Ovulation disorders

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WHO classification

Group I: hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism).

Group II: hypothalamic-pituitary-ovarian dysfunction (predominately pcos).

Group III: ovarian failure.

Aboubakr Elnashar

WHO Group I

increasing body weight if they have a BMI <19

Moderating exercise levels if they undertake high levels of exercise.

pulsatile administration of gonadotrophin-releasing hormone or

gonadotrophins with LH activity to induce ovulation.

Aboubakr Elnashar

WHO Group II

BMI of 30 or over: lose weight.

{alone may restore ovulation, improve their response to ovulation induction agents, and have a positive impact on pregnancy outcomes]

Then one of the following treatments, taking into account potential adverse effects, ease and mode of use, the woman's BMI, and monitoring needed:

clomifene citrate or

metformin or a

combination.

Aboubakr Elnashar

o clomifene citrate:

ultrasound monitoring during at least the first cycle of treatment to ensure that they are taking a dose that minimises the risk of multiple pregnancy.

Do not continue for longer than 6 months.

o Metformin

side effects: nausea, vomiting and other gastrointestinal disturbances

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Resistant to clomifene citrate:

consider one of the following second-line

treatments, depending on clinical

circumstances and the woman's preference:

1. laparoscopic ovarian drilling or

2. combined treatment with clomifene citrate

and metformin if not already offered as first-

line treatment or

3. gonadotrophins.

Aboubakr Elnashar

Hyperprolactinaemic amenorrhoea

dopamine agonists such as bromocriptine.

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Monitoring ovulation induction during

gonadotrophin therapy

Ovarian ultrasound monitoring:

measure follicular size and number

{reduce the risk of multiple pregnancy and

ovarian hyperstimulation}.

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Tubal and uterine surgery

Aboubakr Elnashar

o mild tubal disease:

tubal surgery (Tubal microsurgery and laparoscopic tubal surgery)

may be more effective than no treatment.

In centres where appropriate expertise is available it may be considered as a treatment option.

Hydrosalpinges

salpingectomy, preferably by laparoscopy, before IVF treatment {improves the chance of a live birth}.

Aboubakr Elnashar

o proximal tubal obstruction

selective salpingography plus tubal catheterisation, or

hysteroscopic tubal cannulation, may be treatment options {improve the chance of pregnancy]

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Uterine surgery

Women with amenorrhoea who are found to have intrauterine adhesions should be offered hysteroscopic adhesiolysis [restore menstruation and improve the chance of pregnancy]

Aboubakr Elnashar

Medical and surgical management of endometriosis

Aboubakr Elnashar

Medical management (ovarian suppression) of endometriosis

Does not enhance fertility and should not be offered.

Surgical ablation

minimal or mild endometriosis who undergo laparoscopy should be offered surgical ablation or resection of endometriosis plus laparoscopic adhesiolysis {improves the chance of pregnancy]

Aboubakr Elnashar

ovarian endometriomas

laparoscopic cystectomy {improves the chance of pregnancy}

Moderate or severe endometriosis

surgical treatment {improves the chance of pregnancy]

Post-operative medical treatment does not improve pregnancy and is not recommended.

Aboubakr Elnashar

Prediction of IVF success

1. Female age

Success falls with rising female age

2. Number of previous treatment cycles

Chance of a live birth following IVF treatment falls as the number of unsuccessful cycles increases.

3. Previous pregnancy history

IVF treatment is more effective in women who have previously been pregnant.

Aboubakr Elnashar

4. BMI

should ideally be in the range 19–30 before commencing assisted reproduction, and that a female BMI outside this range is likely to reduce the success of assisted reproduction procedures.

5. Lifestyle factors

i. more than 1 unit of alcohol per day

ii. maternal and paternal smoking, and

iii. maternal caffeine consumption can adversely affect IVF success rates.

Aboubakr Elnashar

Procedures used during IVF treatment

Aboubakr Elnashar

Pre-treatment in IVF

oral contraceptive pill or a progestogen:

does not affect the chances of having a live birth.

Consider pre-treatment in order to schedule IVF

treatment for women who are not undergoing long

down-regulation protocols.

Aboubakr Elnashar

Down regulation and other regimens to avoid

premature luteinising hormone surges in IVF

Use either GnRH agonist down-regulation or

GNRH antagonists as part of gonadotrophin-

stimulated IVF treatment cycles.

Only offer GnRH agonists to women who have

a low risk of ovarian hyperstimulation

syndrome.

When using GnRH agonists as part of IVF

treatment, use a long down-regulation

protocol.

Aboubakr Elnashar

Controlled ovarian stimulation in IVF

Use either urinary or recombinant gonadotrophins for ovarian stimulation as part of IVF treatment.

use an individualised starting dose of follicle-stimulating hormone, based on factors that predict success, such as:

1. age

2. BMI

3. presence of polycystic ovaries

4. ovarian reserve

Aboubakr Elnashar

do not use a dosage of FSH of more than 450 IU/day.

Do not offer women 'natural cycle' IVF treatment.

Do not use

growth hormone or

dehydroepiandrosterone (DHEA) as adjuvant treatment in IVF protocols.

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Triggering ovulation in IVF

HCG (urinary or recombinant) to trigger ovulation in IVF treatment.

protocols for preventing, diagnosing and managing OHSS.

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Oocyte retrieval in IVF

Follicle flushing

does not increase the numbers of oocytes retrieved

or pregnancy rates, and increases the duration of

oocyte retrieval and associated pain.

Assisted hatching

not recommended because it has not been shown

to improve pregnancy rates.

Aboubakr Elnashar

Embryo transfer strategies in IVF

Ultrasound-guided

improves pregnancy rates.

Endometrium thickness

less than 5 mm unlikely to result in a pregnancy and is therefore not recommended.

Bed rest

more than 20 minutes' duration following embryo transfer does not improve the outcome of IVF treatment.

Embryo quality evaluation

at both cleavage and blastocyst stages,

The likelihood of a live birth after replacement of frozen–thawed embryos is similar for embryos replaced during natural cycles and hormone-supplemented cycles.

Aboubakr Elnashar

Luteal phase support after IVF

Progesterone for luteal phase support after IVF

treatment.

No HCG for luteal phase support after IVF treatment

[increased likelihood of ovarian hyperstimulation

syndrome]

The evidence does not support continuing any form of

treatment for luteal phase support beyond 8 weeks'

gestation.

Aboubakr Elnashar

Intracytoplasmic sperm injection

Indications for ICSI:

1. severe deficits in sperm quality

2. Azospermia

3. previous IVF treatment cycle resulted in failed or very poor fertilisation.

ICSI versus IVF

Improves fertilisation rates,

but once fertilisation is achieved the pregnancy rate is no better than with IVF.

Aboubakr Elnashar

Thanks

Aboubakr Elnashar