Three methods are described for using methotrexate to medically treat ectopic pregnancies: single dose, two dose, and fixed multi dose regimens. Success rates range from 71.2-94.2% depending on gestational age and initial hCG level. Follow up hCG levels must decrease by at least 15% between measurements for the treatment to be considered successful, otherwise additional doses may be administered or surgery pursued. Precautions must be taken regarding liver, kidney, and bone marrow function both before and after methotrexate administration due to potential side effects.

1. SAMUEL BEZABIH
MESKEREM 2004
SAMUEL BEZABIH (MD)

2. ECTOPIC PREGNANCY
An ectopic or
extrauterine
pregnancy is one in
which the blastocyst
implants anywhere
other than the
endometrial lining of
the uterine cavity
• Tubal EP >95% EP
Ampullary-Isthmic-Fimbrial-
Interstitial ( in descending order of
freq.)
• Ovarian- 3%
• cevical <1%
• CS scar <1%
• Abdominal -1%
• Hetrotopic
• Bilateral ectopic
SAMUEL BEZABIH (MD)

3. SAMUEL BEZABIH (MD)

4. Incidence
• The prevalence of EP among women
presenting to an emergency department with
1st trimester vaginal bleeding, abdominal pain,
or both reported to be as high as 18% .
• It is the leading cause of maternal death in the
first trimester .
=>6% of all pregnancy-related deaths;
SAMUEL BEZABIH (MD)

5. Risk Factors
• Previous EP( 15-20% recurrence in either the same or other
tube)
• Salpingitis- (50% risk)
• Peritubal adhesions 2⁰ to
– infections (postabortal, peurperial)
– appendicitis,
– endometriosis
• Tubal surgery-( ligation, reanastomosis, TS for EP/
infertility
• IUDs
– if pregnancy Occurs it has high likelihood of being ectopic
– Risk-1.02/10,000WY,( less than half of the risk posed on
women who use no contraceptive)
SAMUEL BEZABIH (MD)

6. Risk factors
• Progestin only contraception( POPs , injectables)
=>4-6% of pregnancy in users are EP
• History of infertility
• ART
• Developmental abnormalities of the tube
( eg diverticula, hypoplasia…) mainly ass. With
intrauterine DES exposure
• Increased maternal age
SAMUEL BEZABIH (MD)

7. SAMUEL BEZABIH (MD)

8. Contraceptives Vs EP
• The incidence or absolute risk of EP is reduced with all
methods of contraception.
• For any method, the EP rate (pregnancy rate X the
proportion of pregnancies with ectopic implantation) is
lower than for women using no contraception (2.6
EP/1,000 woman-years).
• Vasectomy and OCPs- the lowest EP absolute
incidence (0.0005/ 1000WY)
• IUDs and BTL- relatively higher incidence
– IUD risk- 1.02/10,000WY, less than half of the risk posed
on women who use no contraceptive
– BTL- a 10 year risk of 7.2/ 1000 procedures ( ~1/3rd of the
sterilization failures (18.5pregnancies / 1000procedures)
SAMUEL BEZABIH (MD)

9. Natural history of EP
Because of unfavorable environment, early interruption
is inevitable
• Possibilities include:
1. Tubal abortion:
• complete or incomplete.
• Common way in ampullary & infundibular
• May be resorbed or implant on peritoneum / viscera
and develop as 20 abdominal pregnancy
2. Tubal rupture:
• common in interstitial & isthmic pregnancies
3. Tubal perforation
4. Continuation of pregnancy- rarest

10. Rupture of EP
• Mostly spontaneous, but can also be caused by trauma as
in bimanual pelvic examination or coitus
• Timing of tubal rupture is partially dependent on pregnancy
location
– Isthmic (narrow space=>the earliest rupture, in 6- 8wks)
– Ampullary (in ~8-12 wks)
– Interstitial * (in 12-16 wks))
• After rupture embryo may
- be resorbed
- remain as amass in abdominal Cavity or culde sac
- implant in abdominal cavity
* may cause fatal bleeding from uterine and ovarian arteries
SAMUEL BEZABIH (MD)

11. Acute VS Chronic EPs
• Acute Eps
– Healthy, rapidly growing trophoblastic tissue
– High level of serum hCG
– No early bleeding late Dx
– carry the highest risk of tubal rupture compared
with chronic
• Chronic Eps
– Abnormal trophoblastic cells that die early
– Early bleedingearly Dx
– Low /static serum hCG
SAMUEL BEZABIH (MD)

12. DDx of EP
– Normal pregnancy
– Abortion ( incomplete, threatened..)
– Ovarian cyst rupture
– ovarian torsion
– AGE
– Appendicitis
– salpingitis
– Molar pregnancy
SAMUEL BEZABIH (MD)

13. Dx-Signs and symptoms
• Clinical symptoms of an EP usually appear 6
to 10 weeks after the LNMP
– Abdominal Pain
– Vaginal Bleeding
– Amenorrhoea
– Uterine changes of pregnancy
– Adnexal mass
– Abdominal Tenderness
– Hemodynamic instability
– Syncope
SAMUEL BEZABIH (MD)

14. EP Dx- Ruptured vs unruptured
Unruptured EP
• Symptoms of early
pregnancy
irregular spotting or
bleeding, N,V ,swelling of
breasts, bluish discoloration
of vagina and cervix,
softening of cervix, slight
uterine enlargement,
increased urinary
frequency)
• Abdominal & pelvic pain
Ruptured EP
– Collapse,weakness,syncope
– Fast, weakpulse (>110/min)
– Hypotension
– Hypovolaemia
– Acute abdominal pain and
– Abdominal distension(SD)
– Rebound tenderness
– Anemia
SAMUEL BEZABIH (MD)

15. DX- TVUS
• TV US should be considered for all women
with suspected early gestational pathology.
• An initial TVUS is used to visualize
– An intrauterine pregnancy or
– a definite extrauterine gestation
– or it can be nondiagnostic/NDUS (nothing seen to
confirm a gestation inside or outside the uterus)
SAMUEL BEZABIH (MD)

16. EP-DX
EP is likely with TVUS findings of
– Empty ux** ( EP or dead Intrauterine fetus/complete
abortion) plus
• Adnexal mass separate from ovary and uterus (may be corpus
leutum cyst)
• Tubal ring/gestational sac with yolk sac/embryo( (Definitive)
• Dilated tube with cul-de-sac fluid(rapture)
**Intra uterine gestational sac rules out EP (Neverthless, there
is Increased chance of hetrotropic pregnancy in ART cases)
•
SAMUEL BEZABIH (MD)

17. EP-DX
• The woman with a NDUS examination result
requires further evaluation, including
measurement of serum hCG and progesterone
levels The
• "Discriminatory Zone" of hCG is that level of
hCG which when reached is associated with
the appearance, on TVUS, of a normal
singleton intrauterine gestation
– generalized 1,500-2,000 mIU/mL (International
Reference Preparation.
SAMUEL BEZABIH (MD)

18. DX-Serum progestrone
• Serum progesterone level (SPL) determination may
help confirm DX of EP.
• Serum progesterone values are independent of hCG
levels, and an abnormal progesterone level is
consistent with an abnormal, failing pregnancy but
does not identify the site of the pregnancy (failed
intrauterine or ectopic pregnancy).
– <5 ng/mL - an abnormal pregnancy (100% specific ).
– >20 ng/mL=> usually normal intrauterine pregnancies,
– 5 -20 ng/mL are considered equivocal.
• Most ectopic pregnancies are associated with a serum
progesterone level between 10 ng/mL and 20 ng/mL,
limiting the clinical utility of this assessment.
SAMUEL BEZABIH (MD)

19. Dx-NDUS
What to do with NDUS finding?
1. If HCG > discriminatory level
– Do D&C to detect presence of villi
• villi found*  Iux pregnancy
• No villi (arias stella Rxn)  EP pregnancy
2. If HCG < discriminatory level
– Follow HCG titer( doubling time)**
• Normal increase Do US whenhCG reaches DZ
• Sub-normal doubling  EP/ abnormal iux preg
*villi can be identified by floating the uterine contents in saline
and searching for characteristic bubble like structures joined
by strands of tissue
**hCG ↑ rate <53% in 48 hrs => abnormal pregnancy (99% sensitivity in early pregnancy)
SAMUEL BEZABIH (MD)

20. DX
• In NDUS or SPL consistent with failed pregnancy serial
hCG levels must be used to evaluate an ongoing
pregnancy.
• hCG ↑ rate <53% in 48 hrs => abnormal pregnancy
(99% sensitivity in early pregnancy)
• Therefore, a NDUS examination result with a serum
progesterone level < 5 ng/mL and an inappropriate
increase in hCG are each associated with an abnormal
pregnancy.
• If necessary, endometrial sampling can be used to
differentiate between a failed intrauterine pregnancy
and ectopic pregnancy by confirming the presence or
absence of intrauterine chorionic villi.
SAMUEL BEZABIH (MD)

21. Dx- NDUS
Repeat TVUS examination when the hCG reaches
the discriminatory zone if :
– an initial US examination has non diagnostic result,
– serum progesterone level is equivocal or normal, and
– hCG level increases appropriately, and
– the patient is clinically stable,
• The same diagnostic possibilities then should be
considered.
SAMUEL BEZABIH (MD)

22. Endometrial Sampling
There are a number of endometrial changes
associated with EP that include
– decidual reactions found in 42 % of samples,
– secretory endometrium in 22 %, and
– proliferative endometrium in 12 % (Lopez, 1994).
• Trophoblasts are not seen.
• Barnhart and associates (2002) recommend that
absence of trophoblastic tissue be confirmed
by curettage before methotrexate treatment is
given.
SAMUEL BEZABIH (MD)

23. Arias – Stella reaction
ASR- Nuclear enlargement, irregularity and
hyperchromesia and cytoplasmic vacuolation of
endometrial cells
– Described by Arias-stella (1954)
• May also be seen in normal pregnancy or
spontaneous abortion
• Cause – poorly understood, two hypothesis
– Exaggerated proliferative and secretory response to
elevated hormones of pregnancy???
– Involutional/ regressive endometrial changes in
response to declining hormonal levels???
SAMUEL BEZABIH (MD)

24. The Arias-Stella reaction of the endometrium. The glands are closely packed and
hypersecretory with large, hyperchromatic nuclei suggesting malignancy.
SAMUEL BEZABIH (MD)

25. EP- Dxtic Procedures
• TV Color Doppler sonography- “Ring of Fire” of an ectopic
pregnancy placental blood flow around the periphery
of the pregnancy. This finding, however, may also be seen
with corpus luteum cysts
• Laparascopy- ahead of D&C for desired pregnancy
• Laparatomy -for unstable pt with presumed DX of EP
• Culdocentesis- (largely replaced by TV US)
– positive(along with symptoms)- aspiration of non clotting
blood(5cc)
– negative-serous fluid
– non-diagnostic- little clotting blood
Nonclotting blood indicates active intraperitoneal bleeding.
Determine the hematocrit: A Hct>15% is most consistent with hemorrhage from a
ruptured EP or actively bleeding ruptured corpus luteum while a hematocrit
less than 8 %t is more consistent with blood tinged fluid from a ruptured
ovarian cyst or pelvic inflammation. UPTODATE
SAMUEL BEZABIH (MD)

26. SAMUEL BEZABIH (MD)

27. SAMUEL BEZABIH (MD)

28. Rx of EP
I.Expectant Mgt (EM)
Waiting for possible Tubal abortion,
separation and resolution
 candidates -asymptomatic, compliant pt.
– with low HCG(<200mu/ml) and
– low chance of rupture
SAMUEL BEZABIH (MD)

29. Medical Mg’t
• Early detection of EP can lead to successful
management without surgery.
• Methotrexate, a folic acid antagonist, can be used
successfully to treat early, non ruptured EP.
• The overall success of treatment of EP in
observational studies ranges from 71.2% to 94.2%
• Success of medical rx of EP depends on the
– treatment regimen used,
– gestational age, and
– hCG level (If hCG levels are higher than 5,000 mIU/mL,
multiple doses may be appropriate*)
SAMUEL BEZABIH (MD)

30. Medical Mg’t-ACOG 2008
*several observational studies reported a
failure rate of >14.3% with single-dose
methotrexate when pretreatment hCG levels
are > 5,000 mIU/mL, compared with a 3.7%
failure rate for hCG levels <5,000 mIU/mL
SAMUEL BEZABIH (MD)

31. Medical Mg’t
Methotrexate rx can be considered for those
women with
– confirmed, or high clinical suspicion of, ectopic
pregnancy
– hemodynamic stability
– un ruptured mass.
– compliance for follow-up surveillance.
• Methotrexate affects all rapidly dividing tissues
within the body, including bone marrow, the GI
mucosa, and the respiratory epithelium.
• Hepatotoxic , cleared by renal system
SAMUEL BEZABIH (MD)

32. Methotrexate for EP
• Before administering metho-trexate, a woman should
have a confirmed normal serum creatinine level,
normal liver transaminases, and no bone marrow
dysfunction indicated by significant anemia,
leucopenia, or thrombocytopenia
• Typically, these laboratory tests are repeated 1 week
after administering methotrexate to evaluate any
possible impact on renal, hepatic, and hematologic
function. (pre and post treatment LFT, RFT, CBC )
• Rx response- elimination of trophoblastic activity
(revealed by serum HCG level)
SAMUEL BEZABIH (MD)

33. Medical Mgt of EP
Absolute contraindications
– breast feeding,
– Immunodeficiency,
– Alcoholism ,alcoholic liver disease ,any CLD,
– previous blood dyscrasyasis( BM hypoplasia,
thrombocytopenia,leukopenia, significant anemia)
– metothrexate hypersensitivity,
– pulmonary disease,
– PUD,
– renal,hepatic, hematologic dysfunction -
SAMUEL BEZABIH (MD)

34. Medical mg’t
Relative CI:
– adnexal mass >3.5cm,
– fetal heart motion ( high failure rate)
SAMUEL BEZABIH (MD)

35. Medical mg’t- systemic methotrexate
Regimen-
Three protocols are published for methotrexate
treatment of ectopic pregnancy
I. singledose,
II. two dose, and
III. fixed multidose
SAMUEL BEZABIH (MD)

36. Medical mg’t- systemic methotrexate
single dose=> 50mg/m2 IM stat
Follow up
– Check HCG on days 4&7
• ( 15% ↓se is expected b/n days 4&7)
– Then check weekly until comes to non pregnant level
– If HCG decreases by < 15%, repeat 2nd dose of
50mg/m2 and check HCG on days 4&7.
– This can be repeated as necessary
– If HCG level increases/plateaus on follow up consider
repeating MTX SAMUEL BEZABIH (MD)

37. Medical Rx of E
Two dose*MTX 50mg/m2 IM on day 0 and 4
Followup
– Measure HCG on days 4 & 7
– If HCG decrease by > 15%- weekly measurement till
non-pregnant levels reach
– If HCG level decreases by< 15% - repeat the same
dose on days 7 &11 measuring HCG concomitantly
– if HCG decreases by>15% b/n days 7 and 11, continue
weekly followup, if not opt for surgical management)
* A recent prospective study evaluating a two-dose regimen
found high patient satisfaction, few side effects, and 87%
treatment success
SAMUEL BEZABIH (MD)

38. Medical Rx of EP
Fixed multi dose*=>
1mg/kg IM on days 1,3,5,7 + folinic acid 0.1mg/kg IM on days 2,4 6, 8
Followup :
– Measure HCG on MTX days until its level is 15% below
the previous value,
– then weekly until reaching prepregnant level
*a recent meta-analysis has shown the fixed multidose regimen
to be more effective, especially in treating women with more
advanced gestations and those with embryonic cardiac
activity
SAMUEL BEZABIH (MD)

39. SAMUEL BEZABIH (MD)
Medical Treatment Protocols for Ectopic Pregnancy ACOG 2012
The single-dose and multidose methotrexate protocols are associated with
overall resolution rates for ectopic pregnancy that approximate 90 %

40. Medical Rx of EP
• Methotrexate also can be used after surgical
management of an ectopic pregnancy.
• Treatment failure (persistent ectopic pregnancy)
ranges
– 2% to 11% after laparotomy and salpingostomy,
– 5% to 20% after laparoscopic salpingostomy .
• A non-ruptured, persistent EP after
salpingostomy diagnosed by monitoring serial
hCG levels almost uniformly resolves with a
single dose of methotrexate.
SAMUEL BEZABIH (MD)

41. Methotrexate-Direct Injection into EP
• In efforts to minimize systemic side effects of
methotrexate, local injection into the gestational
sac under sonographic or laparoscopic guidance
has been evaluated.
• Pharmacokinetic studies with 1 mg/kg of
methotrexate injected either into the sac under
sonographic guidance or by traditional IM
injection showed similar success rates.
• However, fewer drug-related side effects were
seen with local injection (Fernandez, 1995).
SAMUEL BEZABIH (MD)

42. Other Regimens for Med Rx
Mifeprostone + Meth
• It seems logical that the addition of 600 mg of mifepristone
orally to single-dose methotrexate might improve efficacy
and speed resolution of unruptured EPs.
• In a randomized trial of 212 cases, however, Rozenberg and
coworkers (2003) documented no differences in success
rates.
Hyperosmolar Glucose.
• In a small prospective trial, Yeko and colleagues (1995)
reported that direct injection of 50-% glucose into the
ectopic mass using laparoscopic guidance was 94%
successful in women with an unruptured ectopic whose
serum β-hCG level was <2500 IU/L.
• Gjelland and coworkers (1995) reported that treatment
success was significantly better in a similar population in
which sonographic-rather than laparoscopic-guided
injection was used. SAMUEL BEZABIH (MD)

43. Med mg’t
• Available studies comparing MTX to traditional surgical
management report similar subsequent tubal patency
and tubal preservation ,fertility rates ,repeat ectopic p,
• Arguments against its use include its toxicity,
=> marrow suppression, dermatitis, and stomatitis, as
well as potential for treatment failure and tubal
rupture.
• Chronic ectopics, with decreasing but persistent -hCG
titers, pose a management dilemma. Some will resolve
on their own, whereas others will require surgery.
• Unfortunately, at present it is impossible to predict
which patients will fail expectant management.
SAMUEL BEZABIH (MD)

44. Surgical m’gt
Surgical mgt-
• salpingostomy
• salpingotomy
• Salpingectomy
• Segmental resection and anastomosis
• Oopheroctomy ( for ovarian EP)
• Hysterectomy for interstitial& cervical EP with
excessive bleeding
• Abdominal pregnancy- deliver and leave placenta
to avoid hemorrhage
SAMUEL BEZABIH (MD)

45. Surgical management
• Milking to effect tubal abortionMilking the
tube to effect a tubal abortion has been
advocated; if the pregnancy is fimbrial,
• this technique may be effective. However,
when milking was compared with linear
salpingostomy
• for ampullary ectopic pregnancies, milking
was associated with a twofold increase in the
recurrent ectopic pregnancy rate (NOVAC)
SAMUEL BEZABIH (MD)

46. Medical Vs Surgical Mgt
• Several studies compared medical and laparascopic rx
of EP
Overall
• women who are hemodynamically stable and in whom
there is a small tubal diameter, no fetal cardiac activity,
and serum β-hCG concentrations <5000 IU/L have
similar outcomes with medical or surgical
management.
• Despite lower success rates with medical therapy for
women with larger tubal size, higher serum β-hCG
levels, and fetal cardiac activity, medical management
can be offered to the motivated woman who
understands the risks of emergency surgery in the
event of treatment failure.
SAMUEL BEZABIH (MD)

47. Studdiford ‘s Dxtic Criteria for 10 abdominal
ectopic pregnancy1942:
– Both tubes and ovaries must be in normal
condition with no evidence of recent or remote
injury.
– No evidence of uteroperitoneal fistula should be
found.
– The pregnancy must be related exclusively to the
peritoneal surface and be early enough to
eliminate the possibility that it is a secondary
implantation following a primary implantation in
the tube.
Primary ABDOMINAL ECTOPIC PREGNANCY
SAMUEL BEZABIH (MD)

48. Ovarian Ectopic Pregnancy -
Spiegelberg’s Dxtic criteria for an intrafollicular
pregnancy
1. the tube, including the fimbria ovarica, is intact
and is clearly separate from the ovary;
2. the gestational sac definitely occupies the
normal position of the ovary;
3. the sac is connected to the Ux by the
uteroovarian ligament; and
4. ovarian tissue is unquestionably demonstrated in
the wall of the sac.
SAMUEL BEZABIH (MD)

49. CERVICAL ECTOPIC PREGNANCY DX
Rubin’s criteria 1911:
– Cervical glands must be opposite the placental
attachment.
– Placental attachment to the cervix must be
situated below the entrance of the uterine vessels
or below the peritoneal reflection of the anterior
and posterior surfaces of the uterus.
– Fetal elements must be absent from the corpus
uteri.
SAMUEL BEZABIH (MD)

50. Non-tubal EP mg’t
Abdominal (1⁰ or 2⁰ ,~0.003% of all pregnancies)
remove the fetus by tying the cord close to the
placenta and leave the placenta in place to avoid
bleeding
Cervical
suction , hysterectomy for severe bleeding
Ovarian
cystectomy/ opheroctomy+ some times
salpingectomy on the affected side
SAMUEL BEZABIH (MD)