ECTOPIC PREGNANCY

Summary
Ectopic pregnancy occurs when an embryo attaches outside of the uterus, most commonly in
the fallopian tubes. It is frequently associated with pelvic inflammatory disease (PID), which may
lead to stenosis of the fallopian tubes. This prevents the fertilized egg from passing through to
the uterus, instead causing it to attach to the tube itself. In addition to signs of pregnancy,
symptoms include abdominal pain and vaginal bleeding. The first diagnostic step is to confirm
the pregnancy with a β-hCG test, which should be followed by a transvaginal ultrasound to
determine the location of the pregnancy and the fetal heartbeat. Uncomplicated ectopic
pregnancies often resolve spontaneously and are usually difficult to diagnose. Patients are
typically hemodynamically stable with low, declining hCG concentrations (< 5000 IU/L).
Complicated cases may involve tubal abortion or rupture, which can lead to intraabdominal
bleeding and shock. Whereas uncomplicated cases are treated conservatively (e.g.,
methotrexate or expectant management), complicated ectopic pregnancy requires surgical
removal. In cases of abdominal pain in women of reproductive age, it is therefore important to
rule out ruptured ectopic pregnancy.

ETIOLOGY
Localization
1. Fallopian tube (96% of cases): ampulla >> isthmus > fimbriae > interstitial pregnancy :
e.g., cornual pregnancy
2. Ovary (3% of cases)
3. Abdomen (1% of cases)
4. Cervix (very rare)

RISK FACTORS
● Anatomic alteration of the fallopian tubes is the main cause of ectopic pregnancy. It may
be due to:
A history of PID
Previous ectopic pregnancy
Past surgeries involving the fallopian tubes
Endometriosis
Exposure to DES (diethylstilbestrol) in utero [Diethylstilbestrol crosses the placenta,
causing tubal and uterine abnormalities, among many other conditions.]
Bicornuate uterus [Risk factor for interstitial pregnancy]
● Non‑anatomical risk factors
Intrauterine device (IUD) [Pregnancies that occur despite IUD contraception tend to
attach more frequently outside of the uterus.]
History of infertility [Infertility is often caused by tubal abnormalities, which also increase
the risk of ectopic pregnancy.]
Hormone therapy [Hormone therapy may cause hormonal dysregulations, which are
thought to slow down the transport of fertilized eggs, increasing the likelihood of ectopic
pregnancy.]
CLINICAL FEATURES
General symptoms of ectopic pregnancy
Patients usually present with signs and symptoms 4–6 weeks after their last menstrual period.

Lower abdominal pain and guarding

Vaginal bleeding​ [Occurs often and may be mistaken for (delayed) menstruation.]
Signs of pregnancy​: amenorrhea, nausea, breast tenderness, frequent urination
Tenderness in the area of the ectopic pregnancy
Cervical motion tenderness [Extreme pain with bimanual pelvic exam. Usually associated with
pelvic inflammatory disease.],​ closed cervix
Enlarged uterus
Interstitial pregnancies tend to present late, at 7–12 weeks of gestation, because of myometrial
distensibility.

Right lower quadrant pain may indicate appendicitis! Cervical motion tenderness may be a sign
of PID!

Tubal rupture
Acute course with ​sudden​ and s ​ evere lower abdominal pain​ (acute abdomen) [Bleeding into
the abdominal cavity can irritate the peritoneum. Besides pain, it can also cause shoulder pain
and hiccups (phrenic nerve irritation)]
Signs of hemorrhagic shock: e.g., tachycardia, hypotension, syncope
More common in interstitial pregnancy

DIAGNOSTICS
Positive pregnancy test: ↑ β-hCG
Serum test: β-hCG verifiable from the 8th day after ovulation
Follow-up measurements are required to monitor the increase of β‑hCG levels over time. [In a
normal pregnancy, β-hCG doubles approx. every 2 days in the first trimester.]

Transvaginal ultrasound (TVUS)

Best initial imaging test​ for determining the localization of the pregnancy and finding a
heartbeat
Ultrasound findings in ectopic pregnancy (see also ultrasound findings in normal pregnancy)
Empty uterine cavity​ in combination with a thickened endometrial lining
Tubal ring sign​: echogenic ring that surrounds an unruptured ectopic pregnancy [It has a very
high positive predictive value for ectopic pregnancy]
Possibly free fluid within the pouch of Douglas [An intraperitoneal space that lies between the
uterus and the rectum in females (rectouterine pouch) and between the bladder and rectum in
males (rectovesical pouch). The pouch of Douglas is the lowest point of the peritoneal cavity
and is therefore a common site of fluid collection and/or intraperitoneal metastases.]
Interstitial pregnancy
-Gestational sac appears separately, < 1 cm from the lateral edge of the uterine wall
-Thin myometrial layer (< 5 mm) surrounding sac seen on ultrasound

Endometrial biopsy ​[Only performed in certain cases of pregnancy of unknown location] :

shows decidualization of the endometrium [Physiologic change in endometrial stromal cells in
the postovulatory period to prepare the endometrium for pregnancy] without chorionic villi or
fetal parts

Every woman of reproductive age with abdominal pain should undergo a pregnancy test!

TREATMENT
Management may be conservative or surgical, depending on the severity of the condition.
Unstable patients require immediate hemodynamic support.

Conservative management
Indications
Uncomplicated ectopic pregnancies​ [Uncomplicated ectopic pregnancies often resolve
spontaneously, but require medical therapy in select cases]
Hemodynamic stability
β-hCG ≤ 5000 mlU/mL
No renal, hepatic, or hematologic diseases
No fetal heartbeat and ectopic mass size < 4 cm

Treatment of choice: ​methotrexate (MTX)​ [Inhibits folate-dependent steps in DNA synthesis to

terminate the rapidly dividing ectopic pregnancy]
-Outcome comparable to surgery
-A decrease in β-hCG levels should occur within a week of MTX administration.

Anti-D immunoglobulin (RhoGAM) [An antibody against the rhesus D antigen that is used as
prophylaxis against hemolytic disease of the fetus and newborn in Rh(D) negative mothers.]
Alternative: expectant management [Only if ultrasound shows no uterine or extrauterine mass
and β-hCG levels are already declining]

Surgery
Indications
Hemodynamic instability, impending rupture
Risk factors for rupture [Both high β-hCG levels of > 5000 mlU/mL and > 8 weeks since the last
menstrual period are important risk factors for rupture]
Contraindications for MTX treatment: e.g., renal insufficiency
If conservative treatment is unsuccessful

Laparoscopic removal
Salpingostomy (tube‑conserving operation)
-Risk of persistent ectopic pregnancy
-Patients with unruptured tubal pregnancy who do not meet the criteria for conservative
treatment

Salpingectomy (not function-preserving)

-Ruptured tube, heavy bleeding, large ectopic mass
-If the patient does not desire future pregnancies → bilateral salpingectomy

HYDATIDIFORM MOLE
Definition
-Classified as ​complete​ or ​partial​ moles
-Benign trophoblastic disease
-Proliferates within the uterus without myometrial infiltration or hematogenic dissemination
-May develop malignant traits and become an ​invasive mole
*No histologic signs of malignancy in the primary tumor
*Trophoblasts infiltrate the myometrium and gain access to the vascular system.
*Hematogenic dissemination leads to metastatic growth in different organs (brain, lungs, liver)

ETIOLOGY
Risk factors
-Prior molar pregnancy
-History of miscarriage
-Patients ≤ 15 and ≥ 35 years

Complete mole
-Does not contain any fetal or embryonic parts
-Caused by fertilization of an ​empty egg​ that does not carry any chromosomes → The
(physiological) haploid chromosome set contributed by the sperm is subsequently duplicated.
-In rare cases, the formation of a complete mole may also result from simultaneous fertilization
of an empty egg by two sperms.
-Fetal karyotypes
46XX​: more common (∼ 90% of cases)
46XY​: less common (∼ 10% of cases)
A 46YY karyotype has never been observed because it is nonviable

Partial mole
-Contains fetal or embryonic parts in addition to trophoblastic tissue
-Caused by fertilization of an egg containing a haploid set of chromosomes with two sperms
(each of them containing a haploid set of chromosomes as well)
-Fetal karyotypes: ​69XXX, 69XXY, 69XYY
Complete mole is the result of paternal disomy!
Partial mole is the result of triploidy!

Pathophysiology
Hydropic degeneration of chorionic villi​ with concomitant ​proliferation of cytotrophoblasts
and ​syncytiotrophoblasts​ → death of the embryo
*Invasive mole: trophoblasts invade the myometrium → increased risk of bleeding and
hematogenous spread [Metastases without histological signs of malignancy]

CLINICAL FEATURES
Complete mole
-Vaginal bleeding during the first trimester
-Uterus size greater than normal for gestational age
-Passage of vesicles that may resemble a bunch of grapes through the vagina
-Endocrine symptoms
*​Preeclampsia​ (before the 20th week of gestation)
*​Hyperemesis gravidarum
*Ovarian theca lutein cysts: bilateral, large, cystic, adnexal masses that are tender to the touch
[HCG replaces LH in its stimulatory function during pregnancy. However, the elevated
concentrations of HCG in GTD cause an overstimulation of the corpus luteum.]
*Hyperthyroidism [Very high amounts of β-hCG may lead to hyperthyroidism because β-hCG
structurally resembles TSH. Its thyrotropic activity also seems to play a role in preeclampsia and
hyperemesis gravidarum.]

Partial mole
-Less severe symptoms due to β-HCG levels that are lower than in complete moles
-Vaginal bleeding
-Pelvic tenderness

DIAGNOSTICS
Laboratory tests: β-HCG level measurement (initial test of choice),​ which should reveal
β-HCG that is markedly elevated (higher than expected for the gestational age)

Transvaginal ultrasound
Complete hydatidiform mole
-Theca lutein cysts
-Echogenic​ mass interspersed with many hypoechogenic cystic spaces that represent hydropic
villi (referred to as “swiss cheese,” “bunch of grapes,” or “snowstorm”)
No amniotic fluid
Lack of fetal heart tones

Partial hydatidiform mole

Fetal parts​ may be visualized.
Fetal heart tones may be detectable.
Amniotic fluid is present.
Increased placental thickness

Uterine evacuation​ (for definite diagnosis and treatment): histopathological examination of

evacuated uterine specimen (also see “Treatment” below)
Chest x-ray​: in case of dyspnea or chest pain
Some moles may not produce HCG at all!

TREATMENT
-Uterine evacuation by ​dilation​ and ​suction curettage​: Complete moles have a 20% risk of
becoming invasive and a 2% risk of developing into choriocarcinoma. Therefore, complete
evacuation of the uterine cavity is the mainstay of treatment.

-Monitor β-HCG levels​ until in reference range (usually 8–12 weeks)

-Chemotherapy​ (usually ​methotrexate)​ if unresolved, as indicated by any of the following:

β-HCG values do not decrease.
Histological features of malignant GTD are present.
If metastases are present on chest x-ray.

Prognosis
Most patients achieve normal reproductive function after recovery.