E-mail: elnashar53@hotmail.com

ABOUBAKR ELNASHAR

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. 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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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 ABOUBAKR ELNASHAR

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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low concentrations of serum inhibin A is useful in

predicting ßHCG-positive preclinical `biochemical'

pregnancies (Treetampinich et al, 2000).

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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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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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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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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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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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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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7. HCG

•Serum & urinary

•Single & paired measurements

•Different cutoff values

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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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

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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