1. The document discusses pregnancy of unknown location (PUL), where the pregnancy is not located intrauterinely or extrauterinely based on initial tests. 2. It evaluates various diagnostic modalities for PUL including serum progesterone, ultrasound, and serum hCG levels which can help determine if the pregnancy is intrauterine, ectopic, or failing. 3. Serial serum hCG measurements and ultrasound are important to accurately diagnose and manage PULs.

1. Pregnancy of unknown location
Ectopic pregnancy not yet diagnosed
By
Ahmad Saber Soliman
Assistant lecturer
Benha University Hospital

3. 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. 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.ProbableEP homogeneous adnexal mass or extrauterine sac-like structure
Definite risk
No risk
High risk
Low risk
Unknown risk

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

6. Diagnostic modalities
• Serum progesterone
• Novel biomarkers for early detection
of ectopic pregnancy
• TVUS
• Serum β-hCG

7. PUL
Ectopic pregnancyFailing PULIUP
60-90 % 10-40 %
Rarely, false-positive result may be due to a placental site tumour or ovarian
neoplasm secreting hCG .

8. Ultrasonography
2D - Colour Doppler - 3D
• Initially: TAUS 2-5 MHz
• 2nd TVUS is the gold standard in scanning 5-12MHz

9. 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

10. Early US findings of Pregnancy

11. Endometrial thickness
The 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)

12. Endometrial fluid collection
May be
True intrauterine
gestational sac
PseudosacOr

13. Findings suggestive of IUP
Gestational sac
Appears as either Intradecidual sign Or double decidual sign
Intradecidual sign

14. (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.

16. 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

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

18. Echogenic ECC is seen to one side of central
endometrial echo (arrows).
Fluid collection is seen, without echogenic
rim around it.

19. 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

21. 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

22. 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

23. 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 .

24. 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.

25. 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

27. Serum β-hCG
Single 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)

28. 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 vs Discriminatory level
Dependencies
 Transducer frequency
 uterine position
 operator experience/ability
1st, 3rd, or 4th International Standard
–2nd I.S.~ ½ that of others

29. 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)

30. 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

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

32. Serum progesterone levels

33. Condous et al., 2005 Concluded a cateorization of PULs according to
initial serum hCG and P into:
Low risk
P < 1o nmol/L
hCG <25 IU/L
Failing IUP
High risk
P 10-50 nmol/L
hCG ˃ 25 IU/L
Propable ectopic pregnancy
Serum P ˃ 50nmol/L
Probable 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)

34. 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.

35. 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 hCGlevel ≤450IU/L is 1.3%

36. Hemodynamic
state ???
˃60 nmol/L ≤10 nmol/L
53% <53%

38. Hemodynamic
state ???
˃60 nmol/L ≤10 nmol/L
53% <53%

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

40. Novel
Biomarkers

41. 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 Damage
creatine kinase
smooth muscle heavy chain myosin, Myoglobin
CA-125, and TNF-alpha

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

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

47. Thanks

52. `