4. • Implantation bleeding.
• Pregnancy of unknown location (PUL).
• Miscarriage.
• Ectopic pregnancy.
• Gestational trophoblastic disease (GTD).
• Genital tract pathology (e.g. polyp, ruptured
varicose veins and malignancy).
Causes of bleeding in early pregnancy
Dr Mostafa Darweish
4
5. • Despite improvements in diagnosis and management,
ruptured ectopic pregnancy continues to be a significant
cause of pregnancy-related mortality and morbidity.
• In 2011–2013, ruptured ectopic pregnancy accounted for
2.7% of all pregnancy-related deaths and was the leading
cause of hemorrhage-related mortality.
• Every sexually active, reproductive-aged woman who
presents with abdominal pain or vaginal bleeding should
be screened for pregnancy, regardless of whether she is
currently using contraception.
Ectopic Pregnancy
Dr Mostafa Darweish
5
9. β-hCG levels : Sub-optimal:
= 3 measurements showing:
-Suboptimal increase OR
-Suboptimal decrease OR
-Flactuating OR
-Plateauing.
-When the rise or the fall in β-hCG is sub-optimal the
cause may be:
-Persisting PUL.
-ECTOPIC pregnancy .
Dr Mostafa Darweish
9
10. • If β-hCG is above the (DZ) and no “true"
gestational sac is seen inside the uterus by TVS,
ectopic pregnancy is highly likely.
• If a gestational sac is clearly identified within the
uterine cavity, it is unlikely that an ectopic
pregnancy coexist (heterotopic pregnancy).
• However, it should be considered in all women
presenting after IVF.
β-hCG levels : Sub-optimal
Dr Mostafa Darweish
10
11. • Ectopic pregnancy
• The initial serum β-hCG level is a key
prognostic indicator for the success of
management in cases tubal ectopic
pregnancies.
• TVS is the diagnostic tool of choice ectopic
pregnancy.
• Laparoscopy is no longer the gold standard
for diagnosis. Dr Mostafa Darweish
11
12. • TYPES OF ECTOPIC PREGNANCY:
• The majority (~95%) of ectopic pregnancies occur
in the Fallopian tube (tubal ectopic pregnancy).
• An ectopic pregnancy may occur in "a non-tubal"
location, in conjunction with an IU pregnancy, or
even bilaterally.
• Uncommon types include heterotopic, cesarean
scar, cervical, ovarian, rudimentary uterine horn,
and abdominal pregnancy. Dr Mostafa Darweish
12
13. • Tubal ectopic
• TVS diagnostic criteria on:
• The following may be visualized:
• (1) An “inhomogeneous” adnexal mass.
• (2) An empty extra-uterine sac with a
hyper-echoic ring.
• (3) A yolk sac and/or fetal pole with or without
cardiac activity in an extra-uterine sac.
Dr Mostafa Darweish
13
14. • US
Tubal ectopic:
• An inhomogeneous mass may represent either
an early developing ectopic (before a gestational
sac is visualized) or a failing ectopic pregnancy.
Dr Mostafa Darweish
14
15. DIAGNOSIS OF ASYMPTOMATIC TUBAL PREGNANCY
Not all of ectopic pregnancies can be visualized
initially on TVS and indeed, some are never
visualized at all.
• Possible ectopic pregnancy.
• Probable ectopic pregnancy.
• Ectopic pregnancy.
Dr Mostafa Darweish 15
16. • Treatment Options For Tubal Ectopic Pregnancy:
• 1-Expectant management:
• At least 15% of ectopic pregnancy resolves spontaneously
without any intervention.
• Repeat β-hCG tests: between 2 and 7 days.
• A rapidly decreasing β-hCG level predicts a favourable outcome.
• Followed up until the serum β-hCG level was < 10 mIU/ml.
Surgical Management:
Indications for surgical treatment include:
Hemodynamic instability.
Failed medical (pharmacological) therapy.
Coexisting heterotopic pregnancy.
Patient not able to comply with follow-up.
Dr Mostafa Darweish
16
17. • 2-Pharmacological Management:
• Systemic methotrexate is the most commonly used drug
for treatment of tubal ectopic pregnancy.
• “Anti-metabolite" chemotherapeutic agent.
• Folic acid antagonist.
• Therefore, it inhibits DNA synthesis and cell
reproduction, primarily in actively proliferating cells
such as malignant cells, trophoblasts, and fetal cells.
• Adverse reactions to MTX include stomatitis and
conjunctivitis.
• Gastritis, enteritis, dermatitis, pneumonitis, alopecia,
elevated liver enzymes, and bone marrow suppression.
Dr Mostafa Darweish
17
18. • Indications of "MTX" treatment:
• Systemic methotrexate has been used to treat
gestational trophoblastic disease since 1956 with
excellent results and was first used to treat
ectopic pregnancy in 1982.
• "MTX" is indicated for treating asymptomatic
patients having ‘persisting PUL’ or tubal ectopic
pregnancy with special criteria.
• MTX has been reported to be successful in
treating interstitial, abdominal, and cervical
pregnancies, which have high substantial surgical
risk. Dr Mostafa Darweish
18
20. • A Good Candidate For Methotrexate:
• The patient prefers medical option, willing to attend
follow-up for up to 6 weeks, not breast-feeding,
haemodynamically stable, and having no severe medical
conditions including renal or hepatic disease,…..
CRITERIA OF ECTOPIC PREGNANCY ( for MTX
treatment):
Minimal clinical symptoms.
No evidence of tubal rupture.
Mass : < 3.5 cm.
No cardiac pulsation.
β-hCG level is < 3,000 mIU/mL ( 1500: 3000).
No contraindications to Methotrexate.
Patient will be available for follow-up.Dr Mostafa Darweish
20
21. • MTX
• There are many well-documented cases of women with
IU pregnancies treated for suspected ectopic pregnancy
with MTX.
• MTX should, therefore, never be given at the first visit,
unless the diagnosis of ectopic pregnancy is absolutely
clear and a viable ‘IU pregnancy’ has been excluded.
RCOG
• If the concept of the β-hCG discriminatory level is to be
used as a diagnostic aid in women at risk of ectopic
pregnancy, the value should be conservatively high
(e.g., as high as 3,500 mIU/mL) to avoid the potential
for misdiagnosis and possible interruption of an
intrauterine pregnancy. Dr Mostafa Darweish
21
23. • The Single Dose Protocol
• Request:
• Serum β-HCG level, blood type, CBC, renal
function tests, liver function tests.
• "MTX" is rapidly cleared from the body by the
kidneys, and in women with renal insufficiency,
a single dose of MTX can lead to death or severe
complications, including bone marrow
suppression, acute adult RDS and bowel
ischemia.
• NB. dialysis does not provide normal renal clearance.
Dr Mostafa Darweish
23
24. • Single-dose protocol
• MTX can be given IV, IM, or orally or by direct
local injection into the ectopic pregnancy sac
transvaginally or laparoscopically.
• IM administration is most common.
• Approximately 15 to 20% of women will require
a second dose of MTX and fewer than1% of
patients need more than two doses. Dr Mostafa Darweish
24
25. • Single-dose protocol
• “Day 1" is the day that MTX is administered.
• The dose of MTX used to treat ectopic pregnancy is 50
mg per square meter of body surface area "50 mg/m2”
• Frequently, an increase in β-hCG level may be observed
in the first several days after therapy (due to continued
production of β-hCG by the syncytiotrophoblast).
• Additionally, 60% of patients experience
increased pelvic pain (may be due to tubal
abortion or haematoma formation causing tubal
distension). Dr Mostafa Darweish
25
26. • Single-dose protocol
• *On Day 7
• Administer a second dose of MTX if the serum β-hCG
concentration has not declined by at least ‘25%’ from
the day 1 level.
• After day 7, β-hCG testing is repeated weekly.
• If there is a ≥15% β-hCG decline from days 7 to 14, check
β-hCG weekly until the level is undetectable.
• NB. The β-hCG concentration usually declines to <15
mIU/mL by 35 days post-injection, but may take as long
as 109 days. Dr Mostafa Darweish
26
27. • Single-dose protocol
• *On Day 14,
• If there is a <15% β-hCG decline from days 7 to 14,
a third dose is given IM.
• Give a maximum of three doses of MTX.
• If hCG levels plateau or increase during follow-up,
consider administering methotrexate for treatment of a
persistent ectopic pregnancy.
• If the β-hCG falls <15% between weekly
measurements after a third dose, surgery is
indicated . Dr Mostafa Darweish
27
28. • The two-dose regimen was first proposed in 2007 in an
effort to combine the efficacy of the multiple-dose
protocol with the favorable adverse effect profile of the
single-dose regimen.
• The two-dose regimen adheres to the same hCG
monitoring schedule as the single-dose regimen, but a
second dose of methotrexate is administered on day 4 of
treatment.
• If hCG levels plateau or increase during follow-up,
consider administering methotrexate for treatment of a
persistent ectopic pregnancy.
Two-dose protocol
Dr Mostafa Darweish
28
29. • III- Fixed Multiple-Dose Protocol :
• The multiple-dose MTX regimen involves up to 8
days of treatment with alternating administration
of MTX and folinic acid, which is given as a rescue
dose to minimize the adverse effects of the
methotrexate. Dr Mostafa Darweish
29
30. • III- Fixed Multiple-Dose Protocol :
• Administer ‘MTX’ 1 mg/kg IM on days 1, 3, 5, 7; alternate
with folinic acid 0.1 mg/kg IM on days 2, 4, 6, 8.
• Measure β-hCG levels on ‘MTX’ dose days and continue
until β-hCG has decreased by 15% from its previous
measurement.
• If the decrease is greater than 15%, discontinue
administration of ‘MTX’ and measure hCG levels weekly
until reaching non-pregnant levels (may ultimately need
one, two, three, or four doses)
• If hCG levels plateau or increase during follow-up,
consider administering methotrexate for treatment of a
persistent ectopic pregnancy. Dr Mostafa Darweish
30
31. • Single-Dose Versus Two-Dose:
• A systematic review and meta-analysis of three
randomized controlled trials showed a
comparable risk of adverse effects for the two-
dose and single-dose protocols.
• A systematic review and meta-analysis of three
randomized controlled trials .
• Single-Dose Versus Two-Dose.
• Single-Dose Versus Multiple-Dose.
Choice of MTX protocol
Dr Mostafa Darweish
31
32. • Single-Dose Versus Two-Dose:
• The two-dose regimen was associated with
greater success among women with high initial
β-hCG levels.
• A statistically significant higher success rate was
reported for the two-dose regimen versus the
single-dose regimen in patients with initial serum
hCG levels between 3,600 mIU/mL and 5,500
mIU/mL Dr Mostafa Darweish
32
33. • Relative contraindications for the use of MTX do
not serve as absolute cut-offs but rather as
indicators of potentially reduced effectiveness.
• For example, a high initial hCG level is considered
a relative contraindication.
• Systematic review evidence shows a failure rate of
14.3% or higher with MTX when pretreatment
hCG levels are > 5,000 mIU/mL compared with a
3.7% failure rate for hCG levels < 5,000 mIU/mL.
Dr Mostafa Darweish
33
34. • Single-Dose Versus Two-Dose
• Resolution of serum β-HCG levels after medical
management is usually complete in 2–4 weeks
but can take up to 8 weeks.
• The resolution of hCG levels is significantly faster
in patients successfully treated with the two-
dose methotrexate regimen compared with the
single-dose regimen. Dr Mostafa Darweish
34
35. • Single-Dose Versus Multiple-Dose
• Observational studies that compared the single-
dose and multiple-dose regimens have indicated
that although the multiple-dose regimen is
statistically more effective the single-dose
regimen is associated with a decreased risk of
side effects. Dr Mostafa Darweish
35
36. • The choice of methotrexate protocol should be
guided by the initial β-hCG level and discussion
with the patient regarding the benefits and risks
of each approach.
• In general, the single-dose protocol may be most
appropriate for patients with a relatively low initial β-
hCG level or a plateau in β- hCG values, and the two-
dose regimen may be considered as an alternative to
the single-dose regimen, particularly in women with an
initial high β-hCG value.
Choice of MTX protocols
Dr Mostafa Darweish
36
