Pregnancy of unknown locationEctopic pregnancy not

yet diagnosed

By Ahmad Saber Soliman

Assistant lecturer Benha University Hospital

Objectives of studying PUL

• Approach the diagnostic dilemma of evaluating a patient with a possible ectopic pregnancy

• Diagnosis of failed pregnancy.

•Understand the value of various diagnostic tests

• Reducing follow up cost by developing adequate clinically applicable algorithms.

4.Probable intrauterine pregnancy Intrauterine echogenic sac-like structure

5.Definite IUP Intrauterine gestational sac with yolk sac and/or embryo (with or without cardiac activity)

Consensus Nomenclature. (Barnhart et al., 2011)

3.PUL

1.Definite ectopic pregnancy Extrauterine gestational sac with yolk sac and/or embryo (with or without cardiac activity)

2.Probable EP homogeneous adnexal mass or extrauterine sac-like structure

Definite risk

No risk

High risk

Low risk

Unknown risk

Definition No signs of either intra- or extra-uterine pregnancy or retained products of conception in a woman with a +ve pregnancy test.

Up to 35% In specialised scanning units, the overall incidence of pregnancy of unknown location is as low as 8–10%.

Empty uterine cavity Free adnexaPreg.

test

Diagnostic modalities

• Serum progesterone • Novel biomarkers for early detection

of ectopic pregnancy

• TVUS• Serum β-hCG

PUL

Ectopic pregnan

cy

Failing PULIUP

60-90% 10-40%

Rarely, false-positive result may be due to a placental site tumour or ovarian

neoplasm secreting hCG .

Ultrasonography2D - Colour Doppler - 3D

• Initially: TAUS 2-5 MHz

• 2nd TVUS is the gold standard in scanning 5-12MHz

TVUS no, no, no ,

Initial TAUS no IUP no free fluid no associated pathology

GS of an IUP grows approximately 1 mm per day and is visible on US when it reaches 3 mm or

greater.Up to 15 %percent of cases with an indeterminate initial scan, ectopic pregnancy is evident on follow-up US

Early US findings of Pregnancy

Endometrial thicknessThe best cutoff point of ET as a possible predictor for IUP was

10mm.However, Measurement of ET is not recommended as a single clinical test for intrauterine pregnancy prediction in women with pregnancy of unknown location. (Ellaithy etal.,2013)

For each millimeter increase in endometrial thickness, the odds increased by 27% that the patient would have a normal IUP. No normal IUP had an endometrial thickness < 8 mm. (Moschos 2008)

Endometrial fluid collectionMay be

True intrauterine gestational sac

PseudosacOr

Findings suggestive of IUP

Gestational sacAppears as either Intradecidual sign Or double decidual sign  

Intradecidual sign

(A) Coronal TVUS of the uterus reveals an intrauterine gestational sac (straight arrow),decidua capsularis (curved arrow), decidua parietalis (arrowhead), and effaced endometrial cavity (asterisks). (B) Corresponding line diagram.

Double decidual sac sign .

Findings suggestive of EP

Characters of pseudo sac :

1.does not have an echogenic rim

2.located in the middle of the uterine cavity rather embedded in the decidua

3. change in shape during the

scan

4.may be complex

Pseudosac

Benson et al. J Ultrasound Med 2013;32:389-393.

Echogenic ECC is seen to one side of central endometrial echo (arrows).

Fluid collection is seen, without echogenic rim around it.

Eccentric position

Characters

1. thinner wall

2. do not in a line with the endometrial canal

3. are generally located in the peripheral endometrium at the myometrial junction

4. can be multiple

Nonspecific findings Decidual cysts are small cysts within the endometrium that can be seen in either intrauterine or ectopic pregnancies

Application of color flow Doppler

color Doppler mapping of trophobastic flow (TF) and peri-endometrial flow.

Ring of fire

The primary contribution of Doppler in women with pregnancy of unknown location is that it occasionally identifies an adnexal mass that was not detected on grey scale US

Trophoblastic tissue has high velocity systolic flow and low impedance diastolic flow, characteristics that are highlighted with Doppler.

color flow Doppler does not differentiate a tubal pregnancy from a corpus luteum, since a "ring of fire" appearance

Bimanual scanning technique can be used to determine whether the mass is separate from the ovary

Is it ectopic pregnancy or it is a corpus luteum of a pregnancy of unknown location?

Ovarian cysts rapidly change in appearance.

The corpus luteum is usually equal to or less echogenic than the ovary, while the tubal ring of an ectopic pregnancy is usually more echogenic than ovarian parenchyma.

ENDOMETRIAL FINDINGS DIAGNOSTIC OF IUP

On TVUS, the yolk sac is typically seen by approximately 5.5 weeks of gestation and/or when the mean gestational sac diameter is ≥8 mm

visualization of an embryo on TVUS is a mean gestational sac diameter of 18 mm.

Yolk sac

Embryo

Serum β-hCGSingle measurement Serial measurements

As regard IUP

Kadar et al., 1981 first to describe the minimal rate of rise for IUP to be 66% over 48 hours

More recently Bamhart 2004

report 53% rate of rise

In clinical practice more conservative cut-off level of 35% had been sugessted

For TAUS it is ≥ 6500 U/L For TVUS ≥ 1500 U/L

Of limited value in PUL?1-Many ectopics have low β-hCG Levels

2-β-hCG falsely reassure the doctor

Failing pregnancy

A decline of 21-35% at 48 hrs depending on the initial hCG Barmhart et al., 2004.

A decrease ˃13% or hCG ratio <.87 had been shown to have sensitivity of 92.71 and specificity of 96.7 for prediction of failing PUL Condous et al., 2006

As regard EP

No single way to characterize the patter of serum hCG behaviour

Pattern of

increase mimics IUP in 21% of cases and pattern of

decrease mimics spontenous abortion in 8% of cases (silva et al., 2006 )

Recent evidence suggests an even higher threshold that 99 % of gestational sacs were with a discriminatory level of 3510 IU/mL. (Connolly et al., 2013)

Threshold level •ß-hCG = 400 –500 mIU/mL (1st IRP)

Lowest ß-hCG level at which a normal intrauterine pregnancy can be detected Discriminatory level •ß-hCG = 1000-1500 mIU/mL (1st IRP)

The level of ß-hCG above which all normal intrauterine pregnancies should be seen

Threshold level vsDiscriminatory level

Dependencies Transducer frequency uterine position operator experience/ability

1st, 3rd, or 4th International Standard –2nd I.S.~ ½ that of others

A β-hCG ratio below 0.87 (or a β-hCG decrease >15%) has a 92.7% sensitivity and a 96.7% specificity for the prediction of a failing pregnancy (Condous et al 2006, Bignardi et al 2008).

β-hCG ratios (β-hCG 48 h/β-hCG 0 h)

Sensitivity of detection of EP is up to 83% when

• hCG not rise quick enough to be IUP

i.e : hCG rise by <35 %• Not fall quick enough to be

failing pregnancy i.e : hCG 21-35%

(Seeber et al ., 2006)

Probable Ectopic pregnancy

Serum progesterone can be a useful adjunct when ultrasound suggests pregnancy of unknown location. Level B

Serum progesterone

Serum progesterone levels

Condous et al., 2005 Concluded a cateorization of PULs according to initial

serum hCG and P into:Low risk

P < 1o nmol/LhCG <25 IU/LFailing IUP

High risk P 10-50 nmol/LhCG ˃ 25 IU/LPropable ectopic pregnancy

Serum P ˃ 50nmol/LProbable IUP

Meta-analysis of 26 studies showed that single progesterone has a good discriminative capacity to distinguish between pregnancy failure and a viable IUP however, discriminative capacity insufficient to diagnose ectopic pregnancy with certainty . (Mol et al., 1998)

Women with PULs with progesterone ≤10 nmol/L at presentation are at low risk of requiring medical intervention and may not benefit from attending routine follow-up visits. 2009 ISUOG.

Serum progesterone level is a good viability test but not helpful for localizing pregnacy

According to Day et al., 2009

Intervention rate with serum P ≤10 nmol and hCG level ≤450IU/L is 1.3%

Hemodynamic

state???

60 nmol/L˃≤10 nmol/L

53% 53%

Hemodynamic

state???

60 nmol/L˃≤10 nmol/L

53% 53%

There is no role for uterine curettage in the contemporary diagnostic workup of women with a pregnancy of unknown location. (LEVEL A)

Novel Biomarkers

Markers of implantation Hyperglycosylated hCG Activin A Pregnancy-associated plasma protein-A Human Chorionic Gonadotropin Pregnancy-specific beta glycoprotein 1 Human placental lactogen A Disintegrin and Metalloprotease-12 Nucleic Acid Markers

Markers of Corpus Luteal Function Progesterone Inhibin A

Markers of Angiogenesis Vascular Endothelial Growth Factor Placental like growth factor

Markers of Endometrial Function Leukemic Inhibitory Factor Glycodelin Mucin-1 Adrenomedullin

Markers of Inflammation and Muscle Damagecreatine kinasesmooth muscle heavy chain myosin, Myoglobin CA-125, and TNF-alpha

Markers of implantation Hyperglycosylated hCG Activin A Pregnancy-associated plasma protein-A Human Chorionic Gonadotropin Pregnancy-specific beta glycoprotein 1 Human placental lactogen A Disintegrin and Metalloprotease-12 Nucleic Acid Markers

Markers of Corpus Luteal FunctionProgesterone Inhibin A

Markers of AngiogenesisVascular Endothelial Growth Factor Placental like growth factor

Markers of Endometrial Function Leukemic Inhibitory Factor Glycodelin Mucin-1 Adrenomedullin

Markers of Inflammation and Muscle Damage

Creatine kinase,smooth muscle heavy chain myosin, Myoglobin CA-125, and TNF-alpha

Q: Is pain only is an indication of surgical intervention?

One take home message

Early diagnosis of cases of ectopic pregnancy means that surgical treatment is not always indicated

However subsequent fertility not differs after different treatment approaches

Thanks

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