Prediction of pregnancy outcome after ICSI

1. E-mail: elnashar53@hotmail.com
ABOUBAKR ELNASHAR

2. IMPORTANCE OF PREDICTION
1. The anxiety and uncertainty of pregnancy out
come following ICSI is one of main psychological
stresses for couples
(Theocaris et al., 2001).
2. The rate of multiple gestation is high (20-25%)
and closer follow-up started as early as possible is
beneficial
(Urbancesek et al., 2002).
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3. 3. Early pregnancy loss is common, which causes
anxiety in the couples involved
(Bergh et al., 1999).
4. The incidence of ectopic pregnancies varies from
double to nearly 5- fold compared with that in
spontaneous pregnancies
(Strandell et al., 1999).
5. It useful in providing counseling to IVF patients
regarding pregnancy prognosis and result in cost
savings
(Glatstein et al, 1995) .
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4. METHODS OF PREDICTION
Markers have been sought to distinguish between
viable and non-viable pregnancies before
verification of live intrauterine pregnancy TVS.
1. HCG
2. Inhibin
3. Progesterone
4. Pregnancy-associated plasma protein-A (PAPP-
A).
5. Placental protein 14 (PP14).
6. Placental isoferritin.
7. IL-2 sR
The clinical role of these measurements is not yet
fully established
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5. 1. Inhibin A
•The dimeric glycoproteins inhibin A (alpha- betaA)
and activin A (betaA-betaA)
(Lockwood et al, 1997).
The fetoplacental unit is the major source of these
glycoproteins. The corpus luteum of pregnancy is
the major source of the alpha monomer.
{The initially low levels and very rapid decline in
pregnancies with embryonic failure, inhibin A is a
monitor of early-pregnancy viability.
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6. low concentrations of serum inhibin A is useful in
predicting ßHCG-positive preclinical `biochemical'
pregnancies
(Treetampinich et al, 2000).
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7. Although serum inhibin A concentrations are more
accurate than hCG levels for predicting preclinical
abortion after IVF, they had no advantage in
forecasting ongoing or multiple ongoing
pregnancies
Routine assessment of serum inhibin A during
follow-up of IVF pregnancies is unjustified
(Huzman et al, 2004).
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8. 2. Progesterone
A single serum progesterone on day 12 post ET,
could highly differentiate between normal and
abnormal pregnancies
(Loannidis et al, 2005).
Median
(nmol/l)
Range
(nmol/l)
On-going pregnancies 430 390–500
Abnormal pregnancy 72 48–96
Failed to conceive 33 28–37
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9. 3. Pregnancy-associated plasma protein-A
(PAPP-A),
A macromolecular glycoprotein of placental origin,
was reported to be depressed in established
ectopic pregnancies
(Bischof et al, 1989).
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10. 4. Placental protein 14 (PP14)
In the pregnant group, serum PP14 were markedly
increased after ET, and a significant difference
between the pregnant group and the nonpregnant
group was observed 8 days following ET
(Suzuki et al, 2000).
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11. 5. Placental isoferritin
levels were significantly higher in normally
developing pregnancies (33±28 U/mL) than in
cases which eventually aborted spontaneously
during the first trimester (1±2 U/mL)
(Fisch et al, 1996).
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12. 6. IL-2 sR
levels were significantly higher in patients with an
early pregnancy loss compared with patients with a
normal term delivery (849.5 ± 69.6 versus 693.5 ±
31.2 pg/ml) and a cut-off point of IL-2 sR
>1000 pg/ml predicted a poor pregnancy outcome
(Fasouliotis et al, 2004). .
Elevated levels of IL-2 sR at day11 after embryo
transfer are associated with poor IVF pregnancy
outcome.
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13. 7. HCG
•Serum & urinary
•Single & paired measurements
•Different cutoff values
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14. Free HCG
The RIA with 1E5 free beta-subunit monoclonal
antibody to measure this component in blood
samples
(Cole et al, 1987).
A detectable serum hCG free beta-subunit level
(0.02-3.0 nmol/L) by 28 days post-ET may indicate
normal term pregnancy outcome.
Urinary HCG
A cutoff value for prediction of ongoing pregnancy is
25 IU/L on day 12 & 250 IU/L on day 19 of ET
(Fujiwara et al, 2002)
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15. Considerations relevant to ICSI that can influence
the interpretation of the HCG
1.The exact day of implantation is not known and will
vary between patients, consequently higher HCG
values for any particular day may just be from
embryos that implanted sooner
(Liu, et al., 1995).
Implantation in patients undergoing IVF or ICSI,
occurs generally within 10 days after ET,
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16. 2. Although the timing from fertilization to initial
appearance of HCG can be different between
assisted and unassisted pregnancies, the amount
and rate of increase perday of HCG levels are
similar
(Lenton et al., 1982).
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17. 3. Higher HCG values could be from the initial
implantation of multiple embryos that later reduced
to a single gestational sac at 4 weeks
(Dor et al., 1988).
4. The irregular and pulsatile secretion of HCG is of
minimum influences {the long half-life and the
continual increase of this hormone in circulation}
(Muyan et al., 1997).
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18. 5. HCG administration in the stimulation protocol
would have dropped to baseline value within 8-13
days and is therefore unlikely to confound reported
values of endogenous HCG that were measured
usually between 14 and 20 days after HCG
administration
(Stenman et al., 1997).
6. Male factor infertility and ICSI are associated with
relatively low HCG values in viable pregnancies
(Poikkeus et al, 2002). .
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19. Single measurement
A single determination of serum HCG concentration
is predictive of pregnancy outcome
(Sugantha et al., 2000), even as early as 11-12 days after
embryo transfer
(Bjercke et al., 1999).
Day 12:
Day 12 HCG
(IU/L)
Author
50 (Sugantha et al, 2000)
55 (Bjercke et al, 1999).
72 (Carmona et al, 2003).
.
76 (Poikkeus et al, 2002).
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20. Day 14
The positive predicative value of β-HCG
100 mIU/mL in distinguishing viable from nonviable
pregnancies was 0.83 (sensitivity 91%, specificity
71%)
(Lila et al.,1994)
The positive predictive value of β-HCG
< 400 mIU/mL in distinguishing singleton from
multiple gestations was 0.92 (sensitivity 86%,
specificity 82%).
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21. Day 15
A cut-off value of 150 mIU/ml, the sensitivity was
71% and the specificity was 77%
(Chen et al, 1997).
The positive predictive value (HCG15 > or = 150
mIU/ml indicating a normal pregnancy) was 89%,
while the negative predictive rate (HCG15 < 150
mIU/ml indicating an abnormal pregnancy) was
51%.
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22. Day 16
HCG >300 mIU/ml predicted an ongoing pregnancy
for day 5 transfer in 97%of pregnancies compared
with 92% for day 3 embryo transfers
(Papageorgiou et al, 2001).
HCG >400mIU/ml predicted multiple gestation in
70% of pregnancies with in day 5 group compared
with 63% for day 3.
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23. Paired measurement
Day 12 & day 19:
No significant differences were found when day 19
was compared with the predictive value of day 12
(Carmona et al, 2003).
A multiple marker strategy did not help distinguish
viable from nonviable pregnancies.
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24. Day 22/ Day 15
HCG22/HCG15 ratio > or = 15: a 90% chance of
normal pregnancy
(Chen et al, 1997)..
HCG22/HCG15 ratio < 15: 84% chance of an
abnormal pregnancy.
The ratio of HCG22 to HCG15 has a higher
diagnostic accuracy for prediction of pregnancy
outcome than either analysis alone.
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25. Theoretical Day 11
(Urbancsek et al, 2002).
A cut-off level of 50 IU/L predicts pregnancy outcome
with a sensitivity of 75% and a specificity of 81%,
hCG value >135 IU/L predicts a multiple ongoing
pregnancy with a sensitivity of 80% and a specificity
of 88%.
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26. HCG of any 2 days between day 8 & 18 post ET to calculate β-
HCG of theoretical day 11 post ET through the following
equations
 HCG1 is the initial HCG recording.
 HCG2 is the subsequent HCG recording.
 The doubling time is defined as the number of days required
for serum HCG concentration to double.
log2 × (time interval in days)
log ( HCG2 / HCG1 )
(11-day1) / doubling time
• Doubling time =
• HCGday11=HCG1 × 2
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27. Elnashar et al (2004) performed a study to
determine the most accurate cutoff value of
calculated day 11 B HCG in prediction of
pregnancy outcome after ICSI .
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28. Prediction of ongoing pregnancy using different -
hCG values on day 11 post ET.
Cut off
Values
50
mlU/ml
75
mlU/ml
100
mlU/ml
125
mlU/ml
150
mlU/ml
Sensitivity 92% 55% 40% 29% 22%
Specificity 25% 50% 62% 75% 75%
+ve P. V. 80% 78.9% 78% 80% 75%
-ve P. V. 50% 25% 23% 24% 22%
+ve LR 1.2 1.1 1.05 1.16 1.04
-ve LR 0.32 0.9 0.96 0.94 0.8
Accuracy 77% 54% 45% 40% 34%
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29. Prediction of multiple pregnancy using different -hCG
values on day 11 post ET.
Cut off
Values
50
mlU/ml
100
mlU/ml
150
mlU/m
l
200
mlU/m
l
250
mlU/ml
Sensitivity 100% 66% 33% 11% 11%
Specificity 23% 88% 94% 100% 100%
+ve P. V. 58% 85% 87% 100% 100%
-ve P. V. 100% 71% 59% 51% 51%
+ve LR 1.29 5.5 5.3 ∞ ∞
-ve LR 0 0.38 0.65 0.89 0.89
Accuracy 62% 77% 65% 54% 54%ABOUBAKR ELNASHAR

30. CONCLUSION
1) β-HCG measurement is an important predictor of
pregnancy outcome and multiple gestation after
ICSI.
2) Theoretical day 11 (post ET) β-HCG level showed
that the most accurate cutoff value for prediction of
ongoing pregnancy was 50mIU/ml, and for
prediction of multiple pregnancy was 100mIU/ml.
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31. ABOUBAKR ELNASHAR