Monitoring

IVF cycleProf. Aboubakr

ElnasharBenha university Hospital,

Egypt

ABOUBAKR ELNASHAR

CONTENTSI. METHODS OF MONITORING

II. OBJECTIVES OF MONOTORING1. Prediction of ovarian response prior to COS

2. Monitor the effect of pituitary down-regulation.

3. Evaluate whether the dose of Gnt is adequate or not

4. Prevention of OHSS.

5. Find the optimal time to give hCG.

6. Avoid cycle cancellation

III. RECORDS OF MONITORING

CONCLUSION

3ABOUBAKR ELNASHAR

Monitoring

close continuous observation ",

monitoring an in IVF-ET cycle

close observation not only of

1. patient’s initial parameters

2. ovarian response to ovulation induction

3. events after completion of the therapy.

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I. METHODS OF MONITORING

I. US

1.2D TVUS2. Power Doppler imaging

3. 3D US.

II. Hormonal

1.E22. P

3. LH

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III. Combining US and E2

Controversial.

E2 measurement: unnecessary

Time consuming

Expensive

Anxiety of the couple

Inconvenient for the woman(Howard 1988; Rainhorn 1987; Tan 1992).

Minimal monitoring

no adverse effects on treatment outcome

no incidence of OHSS(Abdalla 1989; Roest 1995; Tan 1994)

Some IVF programs have abandoned the use of the

hormone assay completely (Kemeter 1989; Tan 1994; Vlaisavljevic 1992).

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Cochrane SR, Kwan et al, 2014

No significant difference in

number of oocytes retrieved

incidence of OHSS

No evidence from RCT to support cycle monitoring

by US plus E2 as more effective than cycle

monitoring by US only on PR and LBR.

A large well-designed RCT is needed

Until such a trial is considered feasible, cycle

monitoring by TV US plus E2 may need to be

retained as a precautionary good practice point.

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II. OBJECTIVES OF MONOTORING

1. Prediction of ovarian response prior to COS

2. Monitor the effect of pituitary down-regulation.

3. Evaluate whether the dose of Gnt is adequate or not

4. Prevention of OHSS.

5. Find the optimal time to give hCG.

6. Prevention of cycle cancellation

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1.Prediction of ovarian response to GntAim:

1. Identify poor responder

2. Identify risk of OHSS

Important:

To choose optimal starting dose of FSH.

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Methods:

AFC, FSH, AMH

AFC:

superior to basal FSH. (Ng et al, 2005)

≤6: longer duration

higher dose of Gnt

less oocytes retrieved.

increased risk of cycle cancellation before OR

≥16: High responder

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SELECTION OF PROTOCOL ACCORDING TO

OVARIAN ReserveReserve ‘Low’ ‘Average’ ‘High’

AFC <7 7-14 >14

AMH <1.1 ng/ml 1.1-3.5 >3.5

Starting FSH

dose IU

Amp

375

5

225

3

150

2

Protocol Antagonist

Microdose flare

Agonist stop

Natural

Modified

natural

GH

Long

protocol

Antagonist

Antagonist

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2. Monitoring the effect of pituitary down-

regulation.

Before starting follicular stimulation: confirm down regulation (Criteria of suppression):

Hormonal assay1. E2 < 50 ng/ml

2. LH < 5.0 IU/ml,

3. P4 < 1 ng/m ng/ml

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TVS:

1. No ovarian cysts

2. Number of small follicles (<8 mm) ≤ 4

3. Endometrial thickness <6 mm predicts down

regulation in 95% of cases

4. Ovarian artery resistance index: 0.9 have the

highest specificity and PPV

If not:

stimulation is postponed

assays repeated after 2—4 further days of down-

regulation.

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3. Evaluate whether the dose of GnT is

adequate or not.

1. TVS:

A. 1st US

D 6 stimulation

In normal responder

Number: 6-8 each ovary

With diameter: 11- 12 mm

D4 Stimulation

In PCO

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Day 6 of stimulation

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B. Follow up

Daily or Every other day depending on follicle size

How:Each follicle is measured in two perpendicular planes.

Then, the average of the four largest diameters is calculated.

mean of two, three or four diameters, measured in one or two planes.

Measure the internal diameter of the follicle in two

planes and the average diameter is then calculated.

Follicles usually grow by 2-3 mm/d.

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2. E2

In normal responders:

seldom changes the timing of hCG

does not increase PR or the risk of OHSS

(Lass et al, 2003)

E2 D6

300 -600 pg/ml

D6 E2 < 60 pg/ml: PR 7.8 %

If ok: continue the same dose.

If less than that: increase by one ampoule.

If greater than that: decrease the dose by ½ -1 amp

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Important in

1. If risk for OHSS.

2. Poor responder

E2 D5 stimulation: •<700 pmol/l: FSH dose is increased by 75-150 u

•US on stimulation D9 or 10.

This is a simple way of early discovery that the

starting dose has been sufficient.

3. US monitoring shows adequate follicular growth

but inadequate endometrial growth

{low E production/follicle due to a low endogenous LH

level}: add rec LH

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4. Prevention of OHSS.

Predicting of hyper-response

1. Previous history of OHSS

2. The presence of PCOS

3. Younger age

4. Lower BMI

5. High AMH

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1. US :

a. PCO pattern of response to GnRH before GnT

b. Number of follicles >20

Number of small & intermediate size (10-14 mm)

>15

No risk when immature follicles are < 15.

{Number of the immature follicles is more important

than the number of mature follicles in predicting

OHSS.

c. Doppler:

low intraovarian vascular resistance

Combination of E2 & US: best chance for prediction

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2. E2: High or rapid slope

<1000 pg/ml: No OHSS

>3000-4000 pg/ml: HCG should be withheld

<3500 pg/mL: No OHSS (Asch et al 2005)

3500-5999 pg/mL: 1.5%

6000 pg/mL: 38%

Cases with severe OHSS are seen with E2 <1500

pg/ml.

Small fraction of cases will be with excessive E2:

slope of rise of E2 is more accurate (considered if

the value is doubled).

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Do not trigger ovulation with the intention of fresh

ET in women who have:

E2>3500 pg/ml or

>20 follicles on US

(NICE, 2013)

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HCG when?

3 or more follicles of size ≥17-18 mm

Endometrial thickness at least 7 mmEstrogen levels coinciding with follicle diameter and number

(about 1,500-1,800pmol/Lper follicle ≥18mm)

If LH and progesterone levels increase early or

E2 level plateaus:

hCG can be administrated earlier.

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5. Find the optimal time to give hCG.

Ovulation when?

35-42 h after the onset of LH surge which triggers resumption of meiosis inside the oocyte

Optimal timing of hCG administration is necessary to

retrieve high quality oocytes.

Too early administration of hCG:

more immature oocytes.

Too late:

high progesterone levels:

negative effects on oocytes quality and

endometrial receptivity.

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The ovulation trigger is usually timed according to

1. Follicle size and number of follicles

2. E2 concentrations

should be correlated to the number of mature follicles

at the time of hCG administration.

As a guide, each mature follicle may produce

about 1000 pmol/L E2.

3. Endometrium thickness and morphology

4. LH and progesterone levels

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OR when?

35-36 hours after the hCG administration.

When most of the follicles are large enough to

suggest the presence of mature oocytes.

Optimal oocyte recovery and fertilization rates can

be obtained from follicles between 14 and 24 mm in

diameter.

Oocyte recovery rates start to decrease after the

follicles exceed 24 mm in diameter.

No difference in the oocyte quality obtained from

follicles between 18 and 22 mm in diameter: more

convenient and predictable planning of oocyte

collection.

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US signs of impaired implantation at the time of hCG

administration

1. Endometrial thickness of <7 mm

2. Endometrial volume <2 cm3

3. Endometrial thickness >14 mm?

4. Absence of multilayered endometrium

5. Uterine artery PI >3.0

6. Absence of subendometrial or reduction in the

endometrial vascularized area

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If Endometrial thickness ≤7

1. Prolong ovulation induction until endometrial

thickness of >7 mm is achieved.

2. If pregnancy is not achieved, in a subsequent

cycle the ovulation induction regimen is changed

to allow for a better endometrial development.

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6. Avoid Cycle cancellation

Define:

discontinuation of ovarian stimulation prematurely

without oocyte retrival.

Incidence

12% of all IVF cycles are cancelled before egg

collection.

Women's age Cancellation rate

Less than 35 7.7-10%

35-37 11.6-14.7%

38-40 14.6-19.5%

Over 40 19.1-24.6%ABOUBAKR ELNASHAR

The main reasons

1.No or poor egg production (83%)

2.Patient’s personal reasons (10%)3.Excessive response to ovarian stimulation and risk

of developing OHSS (5%)

4.Medical illness (1%). (SART 2005 and HFEA 2006 Reports).

AMH:

all cases that was cancelled due to poor response

had AMH < 0.4 ng/ml.(La Marca et al., 2006)

all cases that was cancelled due to high risk of OHSS

had AMH >7 ng/ml.

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Indications

1. Follicular growth is delayed:

ovarian stimulation over 10 days:

< 3 follicles > 16 mm & E2 < 600 pg/ml.

2.OHSS is suspected:

each ovary contains > 10 follicles 16 mm &

E2 > 3500 pg/ml

Ovary size > 80 mm

3. Basal LH is elevated:

LH > 10 IU/l or a premature LH surge occurs

4. Elevated serum P4:

>1.5 ng/ml is detected prior to ovulation induction.

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P elevation on HCG day:

Progesterone levels are estimated on

day 2 of the menstrual cycle before COS is

initiated

on the day of hCG.

A detrimental effect of PE on PR

General IVF population and poor

responders:

0.8-1.1 ng/ml

High responders:

1.9–3.0 ng/ml.

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For prevention:

Use of Low-dose hCG alone in the late COH stages

Flexible antagonist protocol

Use of mifepristonehCG administration when the levels of P>1.0

ng/mL.

Aspiration of a single leading follicle

use milder stimulation protocols

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Sandro Steef, 2016

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Serum LH

It has been observed that LH surge is unlikely to

occur before

Follicle diameter has reached 15 mm and/or

E2 level has reached 164 pg/mL.

LH levels should be measured daily once the follicle

reaches 15–16 mm to determine the LH surge and

the exact time of ovulation.

The LH surges that result in ovulation are extremely

variable in configuration, amplitude, and duration.

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LH Surge Can Be Detected by Measuring

1. Serum LH levels.

2. Metabolites of LH in urine using urinary LH detection

kits.

Urinary hormone metabolites accurately reflect LH and correspond to serum patterns and thus, a high predictive value for detecting ovulation. Detection of the LH surge by a urinary LH test may have false-negative results.

• When peak levels are 40 IU/L• When women have surges of 10 h in duration• When diluted urine is tested A study by Lloyd et al. showed that when LH kits alone were used to time IUI• 36 % of inseminations were timed incorrectly• 15 % of women had already ovulated

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III. Records of Monitoring

Specially designed charts allows us to see all the

relevant characteristics of the cycle at a glance.• Date and day of cycle

• Number of developing follicles in each ovary

• Dynamics of follicular growth

• Endometrial thickness

• Type of ovulation regimen

• Quantity of medication used

• Baseline hormone levels

• E2, if required, in the proliferative phase

• E2 and P4 on the day of hCG

• Any change in the dose and hormonal evaluation

done must also noted

• Date and time of administration of hCG

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CONCLUSIONTwo-dimensional ultrasound scanning of follicular

size is still the method of choice for monitoring IVF

cycles, irrespective of the protocol used for COH.

It is the most practical, and is still reliable enough

for monitoring ovarian stimulation with

gonadotropins.

Combining ultrasound monitoring of follicular size

with E2 is particularly valuable for monitoring poor

responders as well as those at risk for OHSS.

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