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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.
ABOUBAKR ELNASHAR
I. METHODS OF MONITORING
I. US
1.2D TVUS2. Power Doppler imaging
3. 3D US.
II. Hormonal
1.E22. P
3. LH
ABOUBAKR ELNASHAR
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).
ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
1.Prediction of ovarian response to GntAim:
1. Identify poor responder
2. Identify risk of OHSS
Important:
To choose optimal starting dose of FSH.
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
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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ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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).
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
Sandro Steef, 2016
ABOUBAKR ELNASHAR
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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.
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
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
ABOUBAKR ELNASHAR
ABOUBAKR ELNASHAR
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.
ABOUBAKR ELNASHAR
ABOUBAKR ELNASHAR
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