Early Pregnancy Loss and Ectopic Pregnancy
BS. Nguyễn Hồng Anh
KEY POINTS
1 Spontaneous pregnancy loss is common, occurring in up to 20% of recognized
conceptions.
2 Following an ectopic pregnancy, approximately 15% of women will have a
subsequent ectopic pregnancy.
3 Laparoscopy is the preferred approach for surgical management of ectopic
pregnancies.
4 Single-dose methotrexate appears to be the treatment of choice if medical therapy is
indicated and selected.
5 Surgical management and medical therapy have similar future reproductive
outcomes.
An abnormal gestation can be either intrauterine or extrauterine. Abnormal
intrauterine pregnancy often results in pregnancy loss early in gestation. Such
losses can be related to a number of factors such as age, previous pregnancy loss,
and maternal smoking (Table 32-1). Extrauterine or ectopic pregnancy occurs
when the fertilized ovum becomes implanted in tissue other than the
endometrium. Although 70% of ectopic gestations are located in the ampullary
segment of the fallopian tube, such pregnancies may occur in other sites (Fig. 32-
1) (1). With abnormal intrauterine and extrauterine gestation, early recognition is
key to diagnosis and management. Establishing a woman’s goals for her
pregnancy may alter management. Providers often incorrectly assume that all
spontaneous abortions or abnormal pregnancies were intended pregnancies, when
it is established that approximately 50% of pregnancies are unintended and may
be undesired (2). As with all pregnancies, management must be highly dependent
on each woman’s pregnancy goals and her perceptions of the different risks.
ABNORMAL INTRAUTERINE PREGNANCY
Spontaneous Abortion
Spontaneous abortion is a pathologic process resulting in unintentional
termination of the pregnancy prior to 20 weeks’ gestation. [1] About 8% to 20%
of known pregnancies terminate in spontaneous abortion (3,4). About 80% of
spontaneous pregnancy losses occur in the first trimester; the incidence
decreases with each gestational week (5,6). A large multicenter trial indicated
the risk of loss in a pregnancy with documented fetal cardiac activity at 10 to 13
weeks gestation had a spontaneous abortion rate of 0.96% before 24 weeks
gestation (7). In women who had one prior spontaneous abortion, the rate of
spontaneous abortion in a subsequent pregnancy ranges from 13% to 20%; in
women who had three consecutive losses, the rate is 33% to 43% (8,9). Patients
should be reassured that, in most cases, spontaneous abortion does not recur. Risk
factors for spontaneous abortion include increasing maternal age, closely spaced
pregnancies (less than 3 to 6 months apart), history of previous spontaneous
abortion, maternal diabetes, and maternal smoking during pregnancy (10–14).
Age is a dose-dependent risk factor for miscarriage; in women less than 36 years
of age, when fetal cardiac activity is confirmed by ultrasound, the risk of
spontaneous abortion is less than 4.5%. For women older than 36, the risk of
spontaneous abortion rises to 10%, and above 40 years may approach 30% (15).
Spontaneous abortion can be differentiated into various categories, based on
examination findings and ultrasound findings. The following sections review each
of these categories in detail.
Table 32-1 Potential Causes of Spontaneous Pregnancy Loss
Increased maternal age
Previous spontaneous abortion
Maternal smoking
Maternal systemic disease (diabetes mellitus, infection, thrombophilia, etc.)
Maternal alcohol consumption (moderate to high)
Increasing gravidity
Amphetamine use
Chromosomal or other embryologic abnormalities
1914Anembryonic gestation
Uterine anomalies
Intrauterine device in place
Placental anomalies
Severe maternal trauma
Extremes of maternal weight
Missed Abortion
Missed abortion is defined as a nonviable intrauterine pregnancy in the presence
of a closed cervix and minimal abdominal cramping or vaginal bleeding.
Transvaginal ultrasound evaluation is key to diagnosing a missed abortion and
guidelines are available to aid in diagnosis (Table 32-2). These criteria are
guidelines. They are more conservative than the studies and data used to develop
these guidelines with the goal of eliminating the risk of intervening in what may
have been a viable intrauterine pregnancy. These guidelines should be used in
combination with clinical judgment and the patient’s desires and wishes in
deciding next steps in management.
Missed abortion can be subdivided into anembryonic gestation and embryonic
demise. Anembryonic gestation is a pregnancy where the embryo failed to
develop. This is confirmed when the mean gestational sac diameter measured by
transvaginal ultrasound is greater than 25 mm and no embryonic pole is present.
When an embryo is present with crown–rump length greater than 7 mm and no
cardiac activity, this is classified as embryonic demise and the pregnancy is
nonviable (16)
1915FIGURE 32-1 Common sites of ectopic pregnancy. (Adapted from Seeber BE, Barnhart
KT. Suspected ectopic pregnancy. Obstet Gynecol 2006;107:399–413 and Bouyer J,
Coste J, Fernandez H, et al. Sites of ectopic pregnancy: A 10 year population-based
study of 1800 cases. Hum Reprod 2002;17:3224–3230.)
Threatened Abortion
Threatened abortion is defined as any vaginal bleeding before 20 weeks of
gestation. It occurs in at least 20% of all pregnancies (17). This is distinct
from missed abortion by ultrasound documentation of an intrauterine
embryo or fetus with cardiac activity. The bleeding is usually light and may be
associated with mild lower abdominal or cramping pain (16). The differential
diagnosis in these patients includes consideration of possible cervical polyps,
vaginitis, cervical carcinoma, gestational trophoblastic disease, ectopic
pregnancy, trauma, and foreign body. On physical examination, the abdomen
usually is not tender, and the cervix is closed. Bleeding can be seen coming from
the os and usually there is no cervical motion or adnexal tenderness.
In the vast majority of cases, threatened abortion does not result in a
pregnancy loss, but may be associated with poor outcomes later in
pregnancy. In a review of over 4,500 women presenting with first trimester
vaginal bleeding, 12% with bleeding had a miscarriage which was similar to the
rate in pregnancies with no bleeding (18). There is no effective therapy for a
threatened abortion. Bed rest and progesterone treatment, although often
advocated, have been demonstrated to be ineffective and carry their own risks
1916(19). Women with first trimester vaginal bleeding with continuing pregnancies
have nearly three times the risk of preterm birth between 28 and 31 weeks as
women without bleeding and a 50% higher likelihood of preterm birth between 32
and 36 weeks (20). First trimester bleeding may be associated with higher risk of
intrauterine growth restriction, preterm premature rupture of membranes, and
placental abruption (21).
Inevitable Abortion
With an inevitable abortion, the cervical os is open and effaced prior to 20
weeks, but no tissue has passed. Most patients have crampy lower abdominal
pain and some have cervical motion or adnexal tenderness. When the cervical os
has dilated or excessive bleeding is present, the patient should be offered medical
or surgical management. Blood type and Rh determination and a complete blood
count should be obtained if there is any concern about the amount of bleeding.
Rho(D) immune globulin (RhoGAM) should be given if the patient’s blood is
Rh negative. It is acceptable to give a dose of 50 lg until 12 completed weeks;
if this dose is not available, the standard 300 lg dose may be given (22).
Incomplete Abortion
An incomplete abortion is a partial expulsion of the pregnancy tissue. Lower
abdominal cramping is invariably present and the pain may be described as
resembling labor. On physical examination, the cervix is dilated and effaced,
bleeding is present and products of conception may be visible in the cervical
canal. Often clots are admixed with products of conception. If the bleeding is
profuse the patient should be examined promptly for tissue protruding from the
cervical os; removal of this tissue with a ring forceps may reduce the bleeding. A
vasovagal bradycardia may occur and responds to removal of the tissue. A
complete blood count, maternal blood type, and Rh determination should be
obtained; Rh-negative patients should receive RhoGAM. If the patient is
febrile, broad-spectrum antibiotic therapy should be administered.
Management of Spontaneous Abortion
All discussions of management of early pregnancy should start with asking the
woman about her pregnancy intentions and reproductive planning. Providers often
incorrectly assume that all spontaneous abortions were intended pregnancies,
when it is established that approximately 50% of pregnancies are unintended and
may be undesired (2). Establishing a woman’s goals for her pregnancy may alter
management. In women with stable vital signs and mild vaginal bleeding, three
management options exist: expectant management, medical treatment, and suction
1917curettage.
For expectant management, although there is a wide range (25% to 76%) of
success cited in the literature, it may be a desirable option for a stable and
carefully counseled patient (23,24). Success of expectant management varies
based on the type of miscarriage and patients should be counseled accordingly.
Incomplete, missed, and anembryonic abortions have a 91%, 76%, and 66%
success rates respectively (25). Women should be counseled that it may take up to
4 to 8 weeks for the pregnancy to pass in any of these situations (26). Expectant
management is associated with an increase in unscheduled surgical evacuations,
bleeding and blood transfusions but no difference in infection rates (26,27).
Medical management with misoprostol is often successful in avoiding a
surgical procedure. Misoprostol can be used vaginally, orally, sublingually, or
bucally and the dose typically ranges from 400 to 800 μg. The American College
of Obstetricians and Gynecologists recommends medical treatment of missed
abortions with 800 μg of misoprostol placed vaginally with efficacy up to 84% in
achieving complete abortion (28,29). It is acceptable to use 600 μg sublingually.
For incomplete abortion, the misoprostol dose can be reduced to 600 μg orally or
400 μg sublingually, with efficacy greater than 90% (30,31).
Studies have investigated the benefit of adding mifepristone to the medical
regimen in the hopes of improving success rates as the use of mifepristone with
misoprostol has been well-documented in the effective treatment of medical
abortion terminations. A study of 300 women with early pregnancy loss
demonstrated improved success of misoprostol when women are pretreated with
200 mg of mifepristone 24 hours prior. Approximately 83% of the women in the
group pre-treated with mifepristone experienced treatment success without
intervention by the first follow-up visit compared with only 67% in the
misoprostol only group. There were no significant differences in adverse events,
bleeding intensity, pain, or satisfaction between the two groups (32).
Suction curettage should be performed in women who desire surgical
management or who have excessive bleeding, unstable vital signs, or in whom
reliable follow-up is a concern.
ECTOPIC GESTATION
Incidence
The incidence of ectopic pregnancy has historically been underestimated.
Previous reports mainly had used hospital records and many ectopic pregnancies
are treated on an outpatient basis either in surgery centers or in outpatient clinics
with methotrexate (33). Reports using insurance claims databases have estimated
the overall rate of ectopic pregnancy to be between 1% and 2%. In one study
1918using the insurance claims database of private insurance the rate of ectopic was
0.64%, with significant differences by age group. The rate of ectopic pregnancy
increases with age, with 0.3% of pregnancies among 15- to 19-year-old women
and 1% of pregnancies among 24- to 44-year-old women (34). This study found
that up to 16% of women who present with first trimester bleeding, pain, or both,
will ultimately be diagnosed with ectopic pregnancy (35). While uncommon,
ectopic pregnancy accounts for approximately 2.7% of all maternal deaths and
increases the risk of recurrence in future pregnancies (35). Studies have shown a
decreasing mortality rate in ectopic pregnancy, attributed to improved early
diagnosis and treatment. Similar to most causes of maternal mortality, the
mortality from ectopic pregnancy varies by race, with African American women
having 6.8 times the risk of mortality from ectopic pregnancy than Caucasian
American women (36).
Etiology and Risk Factors
Ectopic pregnancy results from various factors that interrupt the successful
migration of the conceptus to the endometrium. Up to half of women who present
with an ectopic pregnancy have no identifiable risk factor, therefore a high index
of suspicion is critical. Any condition that delays or interferes with the passage of
an embryo through the fallopian tube increases the risk of ectopic pregnancy. [2]
The most important risk factor for an ectopic pregnancy is a prior ectopic
pregnancy with a recurrent risk of 10% to 15% after first ectopic pregnancy
and 30% after second ectopic pregnancy (37). Other risk factors include a
history of tubal surgery including tubal ligation, assisted reproductive technology,
and history of pelvic inflammatory disease (PID). Anything that causes
inflammation of the fallopian tube or disruption of tubal motility increases the
risk of ectopic pregnancy. Inflammation of fallopian tube is present in up to 90%
of ectopic pregnancies with causes including PID, tubal endometriosis, and
salpingitis isthmica nodosa. Many other risk factors, including smoking and
multiple lifetime sexual partners, are weakly associated with ectopic pregnancy.
Intrauterine devices (IUDs) are an effective contraceptive method, with an annual
failure rate of <0.1%. While the overall risk of pregnancy is incredibly low in
women using this type of contraception, those rare pregnancies that do occur are
more likely to be ectopic (38).
Prior Ectopic Pregnancy
A previous history of ectopic pregnancy is the strongest risk factor for another
occurrence. The increased recurrence exists because of the previous factors that
led to the initial ectopic combined with the potential damage to the fallopian tube
1919from the prior ectopic pregnancy and its treatment. The rates for intrauterine
pregnancy (40%) and ectopic pregnancy (15%, range 4% to 28%) are
similar after tubal removal or conservation (39). Tubal patency appears to be
variably affected by medical treatment with methotrexate. In one study of 121
women who received methotrexate treatment, hysterosalpingograms (HSGs) done
3 months after treatment revealed 72% of women had bilateral tubal patency, 19%
had unilateral tubal patency, and 3% had bilateral tubal obstruction. Of the
women who had bilateral tubal patency on HSG, over 90% had a subsequent
pregnancy, 78% without reproductive assistance. Given that 97% of women in the
study had no change in their fertility, an HSG is not indicated or cost-effective
after methotrexate treatment (40).
Tubal Surgery
It is clear that tubal surgery is associated with an increased risk for ectopic
pregnancy, what is unclear is whether the increased risk results from the
surgical procedure or from the underlying problem. Although tubal
sterilization remains one of the most effective forms of contraception and
pregnancy is unlikely, failures do occur; when they do, they are more likely to
result in ectopic gestation. A large Cochrane review published in 2016 found that
depending on the technique, the failure rate of tubal sterilization ranges from
36.5/1,000 procedures (Filshie clip) to 7.5/1,000 procedures (postpartum
salpingectomy and unipolar coagulation) (41). The 10-year cumulative
incidence of tubal pregnancy after any sterilization procedure is 7.3 per
1,000 procedures (42). The risk depends on the sterilization technique and the
woman’s age at the time of sterilization: postpartum partial salpingectomy and
unipolar coagulation have the lowest rates of ectopic pregnancy (1.5 and 1.8 per
1,000 procedures), while bipolar coagulation techniques had the highest incidence
(17.1 per 1,000 procedures). Spring clip and band application techniques have 10-
year ectopic rates similar to the general incidence, 8.5 and 7.3 per 1,000
procedures, respectively (42). Women younger than 28 years at the time of
sterilization are more likely to have a failure than women over 34 years.
Sterilization reversal increases risk for ectopic pregnancy. The exact risk
depends on the method of sterilization, site of tubal occlusion, residual tube
length, coexisting disease, and surgical technique. In general, the risk of any
pregnancy after a reanastomosis of a cauterized tube is up to 8% for laparoscopic
procedures based on recent studies (43). There is insufficient evidence for a rate
of ectopic pregnancy after hysteroscopic sterilization, but retrospective data and
models show overall pregnancy rates are higher than with laparoscopic
sterilization (44,45).
1920Pelvic Infection
The relationship of pelvic infection, tubal obstruction and ectopic pregnancy is
well-documented. In a study of 2,500 women with suspected PID who underwent
diagnostic laparoscopy, the incidence of ectopic pregnancy in the subsequent
pregnancy for those with laparoscopically confirmed disease was 9.1% compared
with 1.4% in the women with normal laparoscopy (46). In a study of 415 women
with laparoscopically proven PID, the incidence of tubal obstruction increased
with successive episodes of PID: 13% after one episode, 35% after two, and
75% after three (47). Chlamydia is an important pathogen causing tubal
damage and subsequent tubal pregnancy. Chlamydia was cultured from 7%
to 30% of patients with tubal pregnancy (48). Conception is three times as
likely to be tubal in women with anti–Chlamydia trachomatis titers higher than
1:64 than in those women whose titers were negative (49). Women at risk for
chlamydia infections should be diligently tested, treated when infection is present,
and counseled about the risk of ectopic pregnancy.
Infertility
The incidence of ectopic pregnancy increases with age and parity, and there is a
significant increase in nulliparous women undergoing infertility treatment
(38,39,50). Additional risks for infertile women are associated with specific
treatments, including reversal of sterilization, ovulation induction, and in vitro
fertilization (IVF). Various studies examining risk factors for ectopic pregnancy
found that infertility increased the odds of tubal pregnancy at least four times and
perhaps as much as 40 times, depending on etiology of infertility (51).
Smoking
Alterations of tubal motility, ciliary activity, and blastocyst implantation are
associated with nicotine intake. Cigarette smoking is associated with an increased
risk for tubal pregnancy in a dose-dependent fashion. Two classic case-control
studies demonstrated this relationship; compared with nonsmokers, smokers of
more than 20 cigarettes a day had a relative risk of 3.5, and smokers of up to 10
cigarettes a day had a relative risk of 2.3 (1,52).
Contraceptive Use
By reducing the overall likelihood of pregnancy, all contraceptive use reduces the
overall risk of ectopic pregnancy. There is concern that because of the various
mechanisms of action of contraceptives, if a pregnancy were to occur, it might be
more likely to be ectopic. In a meta-analysis of 13 studies examining the
relationship between contraception and the risk of ectopic pregnancy, there was
no increased risk in users of oral contraceptives or barrier methods compared with
1921pregnant controls (53). There is no demonstrated increased risk in users of depomedroxyprogesterone injections, emergency contraceptive pills or etonogestrel
implants (54,55). Hormonal and copper-containing IUDs are highly effective at
preventing intrauterine and extrauterine pregnancies, with failure rates of 0.2% in
the first year of use and 0.7% in the first 5 years of use (56). In the rare case that
women conceive with an IUD in place the pregnancy is more likely to be
ectopic.
Diagnosis
The diagnosis of ectopic pregnancy is complicated by the wide spectrum of
clinical presentations from asymptomatic cases to acute abdomen and
hemodynamic shock. Until the location of the pregnancy is confirmed, the
diagnosis remains a pregnancy of unknown location. The differential diagnosis of
a pregnancy of unknown location includes early viable intrauterine pregnancy,
early nonviable intrauterine pregnancy, stable ectopic pregnancy and unstable
ectopic pregnancy. Making the diagnosis involves combining history and physical
examination with clinical findings including laboratory and ultrasound data.
While the management of a ruptured ectopic pregnancy is directed at the
primary goal of achieving hemostasis, the management of a pregnancy of
unknown location in a stable patient is varied and depends on many patient and
pregnancy-specific factors. It is critical to maintain a high degree of suspicion of
ectopic pregnancy with pregnancies of unknown location, especially in areas of
high prevalence. History and physical examination identify patients at risk,
improving the probability of detection of ectopic pregnancy before rupture occurs.
History
The patient’s history can be helpful in identifying patients at risk for ectopic
pregnancies. Pertinent points in the history include the patient’s age, menstrual
history, previous pregnancy, infertility history, current contraceptive status, risk
factor assessment, and current symptoms.
The classic symptom triad of ectopic pregnancy is pain, amenorrhea, and
vaginal bleeding. This symptom group is present in about 50% of patients
and is more typical in patients with a ruptured ectopic pregnancy. Abdominal
pain is the most common presenting symptom, but the severity and nature of the
pain vary widely. There is no pathognomonic pain for an ectopic pregnancy. Pain
may be unilateral or bilateral and may occur in the upper or lower abdomen. The
pain may be dull, sharp, or crampy and either continuous or intermittent. With
rupture, the patient may experience transient relief of the pain, as stretching of the
tubal serosa ceases. Shoulder and back pain, thought to result from peritoneal
1922irritation of the diaphragm may indicate intra-abdominal hemorrhage.
Physical Examination
The physical examination should include measurements of vital signs and
examination of the abdomen and pelvis. Frequently, the findings before rupture
and hemorrhage are nonspecific and vital signs are normal. The abdomen may be
nontender or mildly tender, with or without rebound. The uterus may be slightly
enlarged with findings similar to a normal pregnancy (57). Cervical motion
tenderness may or may not be present. An adnexal mass may be palpable in up
to 50% of cases, but the mass varies markedly in size, consistency, and
tenderness. A palpable mass may be the corpus luteum and not the ectopic
pregnancy. With rupture and intra-abdominal hemorrhage, the patient develops
tachycardia followed by hypotension. Bowel sounds are decreased or absent. The
abdomen is distended with marked tenderness and rebound tenderness. Cervical
motion tenderness is present. Frequently, the findings of the pelvic examination
are inadequate as a result of pain and guarding. History and physical examination
may or may not provide useful diagnostic information. Additional tests are
frequently required to differentiate between early viable intrauterine pregnancy,
abnormal intrauterine pregnancy, and suspected ectopic.
Laboratory Assessment
Quantitative β-human chorionic gonadotropin (β-hCG) measurements are the
diagnostic cornerstone for ectopic pregnancy. Urine pregnancy tests can detect β-
hCG at ≥20 mIU/mL while serum pregnancy tests can detect levels >5 mIU/mL.
a-hCG levels cannot be used to predict gestational age (58). a-hCG levels
peak at approximately 10 weeks gestation and the average peak level is
approximately 100,000 with a wide normal range of variation. There is the
possibility of a phantom β-hCG, in which the presence of heterophile antibodies
or proteolytic enzymes causes a low level false-positive serum β-hCG result.
These antibodies are large glycoproteins and are not excreted in the urine,
resulting in a negative urine pregnancy test. In the patient with a-hCG levels
less than 1,000 mIU/mL, a urine pregnancy test should be performed and
confirmatory positive results obtained before instituting treatment (59).
Single Human Chorionic Gonadotropin Level
A single a-hCG measurement has limited usefulness in the evaluation of a
pregnancy of unknown location because there is considerable overlap in
values between normal and abnormal pregnancies at a given gestational age.
a-hCG levels do not correlate with pregnancy site (60). Many patients with
pregnancy of unknown location are uncertain about their menstrual dates. A
1923single β-hCG level may be useful if negative to exclude the diagnosis of ectopic
pregnancy. A single β-hCG level may facilitate the interpretation of
ultrasonography when an intrauterine gestation is not visualized. An a-hCG level
greater than the ultrasound discriminatory zone indicates a possible
extrauterine pregnancy; however caution must be used with previously
defined discrimination zones, as recent research indicates that a much higher
a-hCG level should be used for ruling out a normal intrauterine pregnancy
(16,61). Determination of serial β-hCG levels are usually needed to differentiate
an ectopic pregnancy from an intrauterine pregnancy failure. Further tests are
required for patients in whom ultrasonography examination results are
inconclusive and β-hCG levels are below the discriminatory zone.
Serial Human Chorionic Gonadotropin Level
Serial a-hCG levels are usually required when the results of the initial
ultrasonography examination are indeterminate (i.e., when there is no
evidence of an intrauterine gestation or extrauterine findings consistent with
an ectopic pregnancy). Traditionally the β-hCG level was expected to rise at
least 66% over 48 hours with an 85% confidence interval, with 15% of normal
pregnancies falling outside of this range. About the same number of ectopic
pregnancies will have a greater than 66% rise (62). Data indicate that a more
conservative cut-off of 53% gives a 99% confidence interval with less than 1% of
viable intrauterine pregnancies having a slower rise (63). This data was based on
a homogeneous patient population and women with unknown dating (i.e., unclear
last menstrual period) were excluded from the study. A more conservative cut-off
of greater than or equal to 35% was found in a larger study of over 1,000
ethnically and racially diverse women to adequately predict a viable intrauterine
pregnancy and decrease the chance of misclassifying a pregnancy (64). This large
study showed that having at least three serial values is helpful, especially if the
starting β-hCG level is low. Follow-up research suggests that the expected rise in
β-hCG is dependent upon starting β-hCG level. If the initial a-hCG level is less
than 1,500, 1,500 to 3,000, or greater than 3,000 mIU/mL, then the predicted
rise at 48 hours is 49%, 40%, and 33%, respectively (65). Based on these data
the traditional 66% should no longer be used in diagnosing ectopic pregnancies.
A cut-off of 53% or even lower to 35% may be more appropriate and
decrease the risk of intervening in what may be a viable intrauterine
pregnancy. β-hCG levels alone usually are not enough to make a diagnosis in a
pregnancy of unknown location. The entire clinical picture including history,
physical examination, and ultrasound findings, combined with β-hCG levels, are
needed to make an accurate diagnosis.
If there is a plateau or decline in β-hCG levels, this is usually indicative of a
1924nonviable pregnancy, either intrauterine or extrauterine. The decline in β-hCG
levels can be helpful in diagnosing a pregnancy of unknown location. Ectopic
pregnancies will plateau or have a slower rate of decline than spontaneous
abortions. Several studies have evaluated the expected decline to develop clinical
guidelines. Data support that most spontaneous abortions are expected to decrease
21% to 35% 2 days after presentation and 60% to 84% at 7 days. The drop
depends on the starting β-hCG level with faster decline noted with higher starting
values of β-hCG (63). An updated model suggested that the range of the drop
should be 35% to 50% at 2 days and 66% to 87% at 7 days from the first
laboratory test (66). A large study did show that if there is an 85% drop within 4
days or a 95% drop in 7 days the risk of ectopic pregnancy appears to be 0 (67).
These expected rates of decline can aid in detecting those women at risk for an
ectopic pregnancy and warrant closer follow-up or even intervention, but should
be combined with clinical judgment and not be used as absolutes in patient
management.
Serum Progesterone
Earlier studies suggested that serum progesterone level could be used to diagnose
ectopic pregnancies and identify viable intrauterine pregnancies. However, the
level of progesterone in all pregnancies can vary greatly. There are progesterone
thresholds that can aid in the evaluation of patient with pregnancy of unknown
location. Progesterone levels greater than or equal to 25 ng/mL are associated
with viable intrauterine pregnancies as only 1% to 2% of ectopic pregnancies will
have levels this high (68). If the ectopic pregnancy does have a level above this
threshold it is usually associated with cardiac activity and identifiable on
ultrasound. Serum progesterone levels <5 mg/mL are associated with pregnancy
failure. Less than 1% of viable intrauterine pregnancies are below this cut-off
(69,70).
Other Endocrine Markers
In an effort to improve early detection of ectopic pregnancy various endocrine
and protein markers have been evaluated. Useful biomarkers have not been
identified for clinical use but further studies are underway.
Ultrasonography
Transvaginal ultrasound is the imaging modality of choice for evaluating the
pelvic structures and the location of a newly diagnosed pregnancy (71,72).
Transabdominal ultrasonography permits visualization of the pelvis and
abdominal cavity and should be included as part of the complete ectopic
pregnancy evaluation to detect adnexal masses and hemoperitoneum.
1925The earliest ultrasound finding of an intrauterine pregnancy is the
gestational sac that characteristically has a round, thick echogenic ring
surrounding a sonolucent center. As the pregnancy progresses this sac becomes
eccentrically located within the endometrial cavity. Although the gestational sac
is the first sign of a definitive intrauterine pregnancy it can be mimicked by an
intrauterine fluid collection called a pseudogestational sac. Pseudosacs occur in
8% to 29% of patients with ectopic pregnancy (73,74). This ultrasonographic
lucency, centrally located, probably represents bleeding into the endometrial
cavity by the decidual cast. Clots within this lucency may mimic a fetal pole.
Historically, identification of the double decidual sac sign (DDSS) is the best
method of differentiating true sacs from pseudosacs. The double sac, believed to
be the decidua capsularis and parietalis, is seen as two concentric echogenic rings
separated by a hypoechogenic space. Although useful, this approach has some
limitations in sensitivity and specificity—the DDSS sensitivity ranges from 64%
to 95% (75). Pseudosacs may occasionally appear as the DDSS; intrauterine sacs
of failed pregnancies may appear as pseudosacs. The DDSS is best observed on
transabdominal ultrasound as this is frequently missed with transvaginal
ultrasound (16). However, if abdominal ultrasound reveals a DDSS with an
empty-appearing gestational sac, a transvaginal ultrasound should be performed
as a yolk sac is often visible in this view and is a definitive diagnosis of
intrauterine pregnancy.
The appearance of a yolk sac within the gestational sac is diagnostic of an
intrauterine pregnancy, while the gestational sac alone is not sufficient
because of the risk of misdiagnosis (76). Diagnosing an ectopic pregnancy on
transvaginal ultrasound may or may not be straightforward. In the absence of an
intrauterine pregnancy, if an adnexal gestational sac with a yolk sac or an embryo
is present this is diagnostic of an ectopic pregnancy. However, this finding is the
least sensitive sign of ectopic pregnancy, occurring in only 10% to 17% of cases
(77).
The recognition of other characteristics of ectopic pregnancy improves
ultrasonographic sensitivity. Adnexal rings (fluid sacs with thick echogenic rings)
are visualized in less than 50% of ectopic pregnancies (77,78). The adnexal ring
may not always be apparent because bleeding around the sac results in the
appearance of a nonspecific adnexal mass. Complex or solid adnexal masses are
frequently associated with ectopic pregnancy; however, the mass may
represent a corpus luteum, endometrioma, hydrosalpinx, ovarian neoplasm
(e.g., dermoid cyst), or pedunculated fibroid (5,78). The presence of free culde-sac fluid is frequently associated with ectopic pregnancy but is not considered
evidence of rupture (79). The presence of intra-abdominal free fluid should raise
concern about tubal rupture.
1926Historically ultrasound findings were correlated with a “discriminatory
zone”—the level of β-hCG where an intrauterine pregnancy should be visualized.
Discriminatory zones for transvaginal ultrasonography are reported at levels
from 1,000 to 2,000 mIU/mL and vary by institution (15,73,75,77,78,80).
Studies have suggested raising the discriminatory zone to 3,510 mIU/mL in
order to avoid false results for an abnormal pregnancy (61). Discriminatory
zones vary according to the expertise of the examiner, capability of the
equipment, and pregnancy-related characteristics such as multiples.
Although there are guidelines for a discriminatory zone for intrauterine
pregnancy, there is no such zone for ectopic pregnancy. Levels of β-hCG do
not correlate with the size of ectopic pregnancy. Regardless of how high the β-
hCG level may be, nonvisualization of the pregnancy outside the uterus does not
exclude ectopic pregnancy. An ectopic pregnancy may be present anywhere in the
abdominal cavity, making ultrasonographic visualization difficult.
Dilation and Curettage
Uterine curettage is performed when the pregnancy is confirmed to be
nonviable or is not desired and the location of the pregnancy cannot be
determined by ultrasonography. The decision to evacuate the uterus in the
presence of a positive pregnancy test must be made with caution to avoid the
unintentional disruption of a viable intrauterine pregnancy. Although suction
curettage traditionally was performed in the operating room, it can be
accomplished under local anesthesia on an outpatient basis. Endometrial sampling
methods (e.g., a Novak curettage or Pipelle endometrial sampling device) are
accurate in diagnosing abnormal uterine bleeding but their reliability for detecting
intrauterine chorionic villi is low and these devices should not be used in the
evaluation of a possible ectopic pregnancy (81,82).
It is essential to confirm the presence of trophoblastic tissue as rapidly as
possible so that therapy may be instituted. There are many ways this tissue can
be evaluated depending on setting of procedure. Traditionally these specimens
were sent to pathology for formal evaluation. In this case, the presence of
chorionic villi may be assessed rapidly with frozen section analysis, which avoids
the waiting period of at least 48 hours for permanent histologic evaluation.
Immunocytochemical staining techniques can be used to differentiate
intermediate trophoblasts from decidual tissue (83).
More often these simple procedures are performed in an outpatient setting and
the ability to immediately evaluate the tissue allows for rapid diagnosis of an
intrauterine pregnancy. Surgeons experienced in evaluating tissue immediately
after aspiration are at least as accurate as pathologists especially with accurately
identifying the presence of the products of conception (84).
1927After tissue is obtained by curettage, it can be added to saline, in which it will
float. Decidual tissue does not float. Chorionic villi are usually identified by their
characteristic lacy frond appearance, as demonstrated in Figure 32-2 above.
FIGURE 32-2 When floated in saline, chorionic villi are often readily distinguishable as
lacy fronds of tissue. (From Stovall TG, Ling FW. Extrauterine Pregnancy: Clinical
Diagnosis and Management. New York: McGraw-Hill, 1993:186, with permission.)
It is important to identify a gestational sac. Rare villi may be present in uterine
aspirations in the presence of interstitial pregnancies, therefore identifying the
gestational sac is required. Heterotopic pregnancies are rare but are increasing
with advancements in artificial reproductive technologies. If suspicion for a
heterotopic pregnancy is high the presence of villi and a gestational sac still
1928warrants further investigation.
If chorionic villi are not confirmed β-hCG levels should be monitored. After
evacuation of an abnormal intrauterine pregnancy, the β-hCG level decreases by
greater than 15% within 12 to 24 hours (50). It has been suggested that a fall of
≥50% within 24 hours following manual vacuum aspiration is predictive of an
abnormal intrauterine pregnancy (85). A borderline fall may represent interassay
variability. A repeat level should be obtained in 24 to 48 hours to confirm the
decline. If the uterus is evacuated and the pregnancy is extrauterine, the β-hCG
level will plateau or continue to increase, indicating the presence of extrauterine
trophoblastic tissue.
Culdocentesis
Culdocentesis was historically widely used as a diagnostic technique for ectopic
pregnancy. With the use of β-hCG testing and transvaginal ultrasonography,
culdocentesis is rarely indicated and is considered obsolete in the evaluation of
ectopic pregnancies (86).
Laparoscopy
Traditionally laparoscopy was the gold standard for the diagnosis of ectopic
pregnancy. At the time of laparoscopy, the fallopian tubes are easily visualized
and evaluated, but the diagnosis of ectopic pregnancy is missed in 3% to 4% of
patients who have very small ectopic gestations. The ectopic gestation is seen
distorting the normal tubal architecture. With earlier diagnosis, the possibility
increases that a small ectopic pregnancy may not be visualized. Pelvic adhesions
or previous tubal damage may compromise assessment of the tube. False-positive
results occur when tubal dilation or discoloration is misinterpreted as an ectopic
pregnancy, in which case the tube can be incised unnecessarily and damaged.
With the advances in ultrasound technology, more ectopic pregnancies are being
diagnosed earlier allowing for medical interventions and reducing the need for
surgical management, thus laparoscopy is no longer considered the gold standard
for diagnosis.
Diagnostic Algorithm
The presenting symptoms and physical findings of patients with unruptured
ectopic pregnancies are similar to those of patients with normal intrauterine
pregnancies (87). History, risk factor assessment, and physical examination are
the initial steps in the management of suspected ectopic pregnancy. Patients in a
hemodynamically unstable condition should undergo immediate surgical
intervention. Patients with a stable, relatively asymptomatic condition may be
assessed as outpatients.
1929There are several potential benefits if the diagnosis of ectopic pregnancy can be
confirmed without laparoscopy. First, the anesthetic and surgical risks of
laparoscopy are avoided; second, medical therapy becomes a treatment option.
Because many ectopic pregnancies occur in histologically normal tubes,
resolution without surgery may spare the tube from additional trauma and
improve subsequent fertility. Previously, an algorithm for the diagnosis of
ectopic pregnancy without laparoscopy proved to be 100% accurate in a
randomized clinical trial (88,89).
This screening algorithm combined the results of history and physical
examination, serial β-hCG levels, vaginal ultrasonography, and dilation and
curettage (Fig. 32-3). Serial β-hCG levels are used to assess pregnancy viability,
correlated with transvaginal ultrasonography findings and measured serially after
a suction curettage. For patients in a stable condition, a treatment decision is
never based on a single β-hCG level. After the initial evaluation, the patient is
seen again at 48 hours for a repeat β-hCG level. At this time, transvaginal
ultrasonography often is repeated so the findings can be correlated with the two β-
hCG levels. The algorithm has been updated to account for changes in the new
recommendations for a discriminatory zone and expected changes in the β-hCG
level with a viable intrauterine pregnancy.
In this algorithm, transvaginal ultrasonography is used as follows:
1. The identification of an intrauterine gestational sac with yolk sac excludes
the presence of an extrauterine pregnancy. If the patient has a β-hCG level
of more than 3,510 mIU/mL, and no intrauterine gestational sac is identified,
the patient is considered to have an extrauterine pregnancy and can be treated
without further testing.
2. Adnexal gestational sac with a yolk sac or embryo, when seen, definitively
confirms the diagnosis of ectopic pregnancy.
3. A tubal mass as small as 1 cm can be identified and characterized.
Suction curettage is used to differentiate nonviable intrauterine
pregnancies from ectopic gestations (less than 53%, or even as low as 35%,
rise in a-hCG level over 48 hours, an a-hCG level of less than 3,510 mIU/mL,
and indeterminate ultrasonography findings). Performance of this procedure
avoids unnecessary use of methotrexate in patients with abnormal intrauterine
pregnancy that can be diagnosed only by evacuating the uterus. An unlikely
potential problem with suction curettage is missing either an early nonviable
intrauterine pregnancy or combined intrauterine and extrauterine pregnancies.
Treatment
1930Ectopic pregnancy can be effectively treated medically or surgically.
Traditionally, exploratory laparotomy with unilateral salpingectomy was used for
diagnosis and treatment for ectopic pregnancies. With techniques available that
allow for early detection, including serum quantitative β-hCG levels and
ultrasound, more conservative treatment options are available. Minimally invasive
surgical techniques and medical management with methotrexate are the
commonly used treatment options for ectopic pregnancies. The treatment
approach depends on the clinical circumstances, the site of the ectopic
pregnancy and the available resources.
Surgical Treatment
Operative management is the most widely used treatment for ectopic pregnancy.
The surgical approach (laparotomy vs. laparoscopy) and procedure
(salpingectomy vs. salpingostomy) used to treat ectopic pregnancies depend on
the clinical circumstances, available resources, and provider skill level. Each
approach and procedure has associated risks and benefits and the treatment
employed must be individualized to best meet the needs of the patient and
provider.
Laparotomy Versus Laparoscopy
Treatment of an ectopic pregnancy can be accomplished by laparoscopy or
laparotomy. The hemodynamic stability of the patient, size and location of the
ectopic mass, and the surgeon’s expertise all contribute to determining the
appropriate surgical approach. Laparotomy is indicated when the patient
becomes hemodynamically unstable and an expedited abdominal entry is
required. A ruptured ectopic pregnancy does not necessarily require
laparotomy. If the hemoperitoneum cannot be evacuated in a timely manner,
laparotomy should be considered. Surgeon’s experience with laparoscopy and the
availability of laparoscopic equipment will determine the surgical approach.
In most cases, [3] laparoscopy is superior to laparotomy for management
of ectopic pregnancy. The indications for laparotomy include abdominal
pregnancy, extensive abdominal or pelvic adhesive disease, and any other
condition making laparoscopy difficult or unsafe. In a case control study of 50
patients comparing the use of laparoscopy and laparotomy for ectopic pregnancy
management, hospital stay was significantly shorter (1.3 ± 0.8 vs. 3.0 ± 1.1 days),
operative time was shorter (78 ± 26 vs. 104 ± 27 minutes), and convalescence was
shorter (9 ± 8 vs. 26 ± 16 days) in the laparoscopy group (90).
Laparoscopic management was associated with significant cost savings
when compared with laparotomy ($4,368 ± $277 vs. $5,090 ± $168). Using a
prospective analysis, 105 patients with tubal pregnancy were stratified with regard
1931to age and risk factors and randomized to undergo either laparoscopic
management or laparotomy (91). Subsequently, 73 patients underwent secondlook laparoscopy to assess the degree of adhesion formation. Patients treated by
laparotomy had significantly more adhesions at the surgical site than those treated
by laparoscopy, but tubal patency rates were similar. A Cochrane review
confirmed these findings and laparoscopic salpingostomy was associated with
decreased cost, operative time, blood loss, and hospital stay when compared to
salpingostomy at the time of a laparotomy (92).
An alternative to laparoscopy is the use of a mini-laparotomy incision. This
approach has the advantage of not requiring laparoscopic equipment and utilizes a
smaller incision that should result in decreased postoperative pain and shorter
recovery times for patients. A randomized control trial comparing
minilaparotomy to laparotomy showed decreased complication rates and reduced
costs associated with the mini-laparotomy incision with similar success rates in
the treatment of the ectopic pregnancy (92,93).
FIGURE 32-3 Non-laparoscopic algorithm for diagnosis of ectopic pregnancy. β-hCG,
human chorionic gonadotropin; IUP, intrauterine pregnancy; D&C, dilation and curettage.
Salpingectomy Versus Salpingostomy
Multiple studies have been conducted to compare management of ectopic
pregnancy with a salpingostomy or salpingectomy. The decision to choose one
technique over the other depends on the patient’s fertility goals, clinical picture,
and the condition of the affected and contralateral fallopian tubes.
Linear salpingostomy can be considered when the patient has an unruptured
ectopic pregnancy, wishes to retain her potential for future fertility, and the
affected fallopian tube appears otherwise normal. This is particularly important to
consider if the contralateral tube appears damaged or has been previously
removed.
In a salpingostomy, the products of conception are removed through an incision
made into the tube on its antimesenteric border. The procedure can be
accomplished with needle-tip cautery, laser, scalpel, or scissors. It can be done
with operative laparoscopic techniques or via a laparotomy. Contraindications to a
salpingostomy include ruptured fallopian tube, use of extensive cautery to obtain
hemostasis, severely damaged tube and recurrent ectopic pregnancy in the same
tube. The main risk of salpingostomy is a persistent ectopic pregnancy resulting
from failure to remove the entire pregnancy. This was reported in 8% of cases in a
recent large open-label study (94). Patients with high starting β-hCG levels, early
gestations, and small ectopic pregnancies (<2 cm) are at greater risk of having a
persistent pregnancy after a salpingostomy (95). Because of this risk, after
salpingostomy, weekly β-hCG levels should be followed to ensure complete
resolution of the ectopic pregnancy. β-hCG levels that persist or plateau can
usually be treated successfully with a single dose of methotrexate (31).
Historically, milking the tube to effect a tubal abortion was advocated; if the
pregnancy is located within the fimbriae, this technique may be effective.
However, when milking was compared with linear salpingostomy for ectopic
pregnancies within the ampulla, milking was associated with a twofold increase in
the recurrent ectopic pregnancy rate, thus this process is generally not
recommended (96).
Reproductive Outcome
Reproductive outcome after ectopic pregnancy is evaluated by determining tubal
patency by HSGs, the subsequent intrauterine pregnancy rate, and the recurrent
ectopic pregnancy rate. Pregnancy rates are similar in patients treated by either
laparoscopy or laparotomy, though a minimally invasive procedure is preferred
due to lower overall risks and faster recovery. Tubal patency on the ipsilateral
1935side after conservative laparoscopic management is about 84% (97). In a
study of 143 patients followed after undergoing laparoscopic procedures for
ectopic pregnancy, the overall intrauterine pregnancy rates after
laparoscopic salpingostomy (60%) and laparoscopic salpingectomy (54%)
were not significantly different (98). However, if the patient had evidence of
tubal damage, pregnancy rates (42%) were significantly lower than in those
women who did not have tubal damage (79%). In another study, the reproductive
outcome of 188 patients followed for a mean of 7.2 years (range 3 to 15 years)
was reported after conservation by laparotomy for ectopic pregnancy (99). In
randomized controlled trials comparing salpingectomy and salpingostomy, there
was no overall difference in future intrauterine pregnancy rates or repeat ectopic
pregnancy. However, in cohort studies, salpingostomy is associated with higher
rate of repeat ectopic pregnancy (10% vs. 4% with salpingectomy, OR 2.27), but
is associated with a slightly higher rate of intrauterine pregnancy (RR 1.24, CI
1.08–1.42) (100).
Medical Treatment
The drug most frequently used for medical management of ectopic
pregnancy is methotrexate, although other agents have been studied, including
potassium chloride (KCl), hyperosmolar glucose, prostaglandins, and RU-486.
These agents may be given systemically (intravenously, intramuscularly, or
orally) or locally (laparoscopic direct injection, ultrasound-guided injection, or
retrograde salpingography). Other agents besides methotrexate are not
recommended for the treatment of ectopic pregnancy because their safety and
efficacy are not well-documented.
Methotrexate
Methotrexate is a folic acid analog that inhibits dehydrofolate reductase and
thereby prevents synthesis of DNA. Methotrexate affects actively growing cells
including trophoblastic tissues, malignant cells, bone marrow, intestinal mucosa
and respiratory epithelium (101). It is used extensively in the treatment of
gestational trophoblastic disease (see Chapter 41). Initially, methotrexate was
used for the treatment of trophoblastic tissue left in situ after exploration for an
abdominal pregnancy (102). In 1982, Tanaka et al. treated an unruptured
interstitial gestation with a 15-day course of intramuscular methotrexate and
began treatment of ectopic pregnancies with this medication (103). Multiple
studies have documented the safety and efficacy of methotrexate therapy for the
management of ectopic pregnancies; this is the first-line treatment for many
providers. Approximately 35% of patients with ectopic pregnancies are
candidates for primary therapy with methotrexate (104). Methotrexate may be
1936given for the treatment of persistent ectopic pregnancies that fail surgical
management.
Candidates for Methotrexate
Medical management of ectopic pregnancies with methotrexate is safe and
effective, however, not all patients are candidates for this medical therapy.
Methotrexate therapy can be considered for patients with confirmed, or high
suspicion for ectopic pregnancy who are hemodynamically stable with no
evidence of rupture. Table 32-3 documents the absolute contraindications to
methotrexate therapy including breastfeeding, hepatic, renal, or hematologic
disorders and known sensitivity to methotrexate. Relative contraindications to
methotrexate therapy include gestational sac greater than 4 cm and embryonic
cardiac motion on transvaginal ultrasound (Table 32-3). Prior to the
administration of methotrexate, a patient should have a complete blood count,
blood type, liver function tests, electrolyte panel including creatinine, and a chest
x-ray if there is any history of pulmonary disease. These studies are usually
repeated 1 week after administration of methotrexate to evaluate for any potential
complications from the therapy (105).
Table 32-3 Contraindications to Medical Therapy
Absolute Contraindications
Intrauterine pregnancy
Hemodynamically unstable
Ruptured ectopic pregnancy
Breastfeeding
Immunodeficiency
Moderate to severe anemia, leukopenia or thrombocytopenia
Known sensitivity to methotrexate
Active pulmonary disease
Active peptic ulcer disease
Clinically important hepatic or renal dysfunction
Relative Contraindications
1937Ectopic pregnancy >4 cm in size by transvaginal ultrasound
Embryonic cardiac motion detected on transvaginal ultrasound
Unable to comply with medical management follow-up
High initial β-hCG concentration (>5,000 mIU/mL)
Refusal to accept blood transfusion
Adapted from The Practice Committee of the ASRM, Medical Treatment of Ectopic
Pregnancy, 2013.
Methotrexate Dosing Regimens
Methotrexate is typically given via intramuscular injection but can be
administered orally or by intravenous infusion. There are three published
regimens for administration of methotrexate: single-dose regimen, a two-dose
regimen, and a multidose regimen. Methotrexate traditionally was administered
using a multidose regimen, but single dosing protocols have improved patient
compliance and have similar success rates of approximately 90% (92,106). The
single-dose protocol also has fewer side effects, however an additional dose of
methotrexate may be required in up to 25% of women who receive this treatment
(92,106). This second dose is more often required in women with higher starting
β-hCG levels.
Methotrexate Single-Dose Regimens
Single-dose regimens were designed to increase patient compliance and simplify
the administration of methotrexate. This regimen is well studied and safe and
effective in the treatment of ectopic pregnancies. The single-dose regimen is
detailed in Table 32-4.
Table 32-4 Methotrexate Treatment Regimens
Single-Dose Regimen
Administer MTX 50 mg/m2 on day 0
Measure β-hCG level on days 4 and 7
If levels drop by 15%, monitor β-hCG weekly until nonpregnant level
If levels do not drop by 15%, repeat dose of MTX and measure β-hCG on days 4
and 7
1938Multidose Regimen
Administer MTX 1 mg/kg IM days 1, 3, 5, 7
Administer leucovorin 0.1 mg/kg IM days 2, 4, 6, 8
Measure β-hCG levels on days 1, 3, 5, 7 until 15% decrease between two
measurements
Once β-hCG levels drop 15%, stop MTX and monitor β-hCG weekly until
nonpregnant level
Two-Dose Regimen
Administer MTX 50 mg/m2 on days 0 and 4
Measure β-hCG level on days 4 and 7
If levels drop by 15%, monitor β-hCG weekly until nonpregnant level
If levels do not drop by 15%, repeat dose of MTX on days 7 and 11 and measure
β-hCG on days 11 and 14. If levels drop 15%, monitor β-hCG weekly until
nonpregnant level
MTX, methotrexate; IM, intramuscular; β-hCG, β-human chorionic gonadotropin.
Adapted from The Practice Committee of the ASRM, Medical Treatment of Ectopic
Pregnancy, 2013.
Approximately 15% to 20% of patients in the single-dose regimen will require
a second dose of methotrexate because of persistent β-hCG levels (106,107). The
β-hCG level at the time of treatment appears to predict the subsequent success
rate of single-dose therapy. Patients with β-hCG levels greater than 5,000
mIU/mL have a 14.3% chance of treatment failure compared to only 3.7% for
women with levels less than 5,000 mIU/mL. [4] Compared with the multidose
protocol, single-dose methotrexate is less expensive, patient acceptance is
greater because less monitoring is required during treatment, and the
treatment results and prospects for future fertility are comparable (108).
Multidose Regimen
The multidose regimen is outlined in Table 32-4. Patients receive 1 mg/kg of
methotrexate intramuscularly or intravenously on days 1, 3, 5, and 7 with
leucovorin 0.1 mg/kg administered on days 2, 4, 6, and 8. As a result of the repeat
dosing of methotrexate, side effects are more common. The leucovorin helps
reduce these side effects and increases patients’ tolerance of the treatment. A
1939patient may not require all four doses of methotrexate and her β-hCG levels
should be monitored on days 1, 3, 5, and 7. If the β-hCG level drops 15% between
two measurements, the regimen can be stopped and weekly β-hCG monitoring
initiated. If the methotrexate is discontinued early, the patient should receive
leucovorin after her final dose of methotrexate to help reduce potential side
effects. If a patient’s β-hCG level plateaus or increases, a second round of
methotrexate and leucovorin can be given 1 week later. Earlier studies indicated
approximately 19% will require all four doses, and 17% of women will require
only one dose with this regimen (109,110). A meta-analysis showed 10% of
women require only one dose, while nearly 54% will require all four doses
(106).
Methotrexate Two-Dose Regimen
The two-dose regimen was described as a cross between the single- and multidose
regimens. Because only 54% require all four doses of the multidose regimen and
15% to 25% will require a second dose in the single-dose regimen, it is
reasonable to consider a two-dose regimen of methotrexate. The protocol is
outlined in Table 32-4 and involves the administration of methotrexate on day 0
and day 4 with monitoring of β-hCG levels on days 4 and 7. If there is less than a
15% drop between the two measures, a repeat administration of methotrexate is
given on days 7 and 11 and β-hCG levels drawn accordingly. A single study
showed an 87% success rate with low complication rates and high patient
satisfaction (111).
Effectiveness of Methotrexate
The overall effectiveness of methotrexate therapy ranges from 78% to 96% (112).
Although the previously mentioned meta-analysis of 26 observational studies
including 1,300 women revealed a slightly improved rate of success with
multidose therapy, another meta-analysis including two randomized controlled
trials showed no difference in success rates between the two regimens. However,
the β-hCG levels in both of those studies were less than 3,000 mIU/mL
(106,113,114). Systematic reviews have demonstrated an overall failure rate of at
least 14.3% when initial β-hCG is greater than 5,000 mIU/mL compared with a
failure rate of less than 4% when the β-hCG is less than 5,000 mIU/mL (108).
When comparing methotrexate to laparoscopic salpingostomy, the multidose
regimen has similar success rates. The single-dose regimen has lower initial
success rates. However, after women receive additional doses as needed, the
success rates are comparable between laparoscopic salpingostomy and singledose methotrexate protocols (106).
Table 32-5 Initiation of Methotrexate: Physician Checklist and Patient Instructions
1940Physician Checklist
Obtain β-hCG level
Check CBC with differential, liver function tests, creatinine, blood type, and
antibody screen
Administer RhoGAM if patient is Rh-negative
Identify unruptured ectopic pregnancy smaller than 4 cm (relative contraindication)
Obtain informed consent
Prescribe FeSO4 325 mg PO bid if hematocrit is less than 30%
Schedule follow-up appointment on days 4 and 7
Patient Instructions
Refrain from alcohol use, multivitamins containing folic acid, NSAID use and sexual
intercourse until β-hCG level is negative
Call your physician if:
You experience prolonged or heavy vaginal bleeding
The pain is prolonged or severe (lower abdomen and pelvic pain is normal during
the first 10–14 days of treatment)
About 4% to 5% of women experience unsuccessful methotrexate treatment and require
surgery. β-hCG, human chorionic gonadotropin; SGOT, serum glutamic-oxaloacetic
transaminase; BUN, blood urea nitrogen; CBC, complete blood count; RhoGAM, Rho(D)
immune globulin; NSAIDs, nonsteroidal anti-inflammatory drugs; WBC, white blood cell;
PO, by mouth; bid, twice daily.
Initiating Methotrexate
Outlined in Table 32-5 is a checklist that should be followed by the physician
before initiating methotrexate. It includes instructions that are helpful to the
patient.
Patient Follow-Up
After intramuscular administration of methotrexate, regardless of the dose
regimen used, patients are monitored on an outpatient basis with weekly β-
hCG levels. These levels need to be monitored until the β-hCG reaches
nonpregnant levels. It is possible that tubal rupture may occur even if β-hCG
levels are falling. Signs of a tubal rupture include severe pain, hemodynamic
1941instability, and a drop in hematocrit. Patients who report severe or prolonged pain
should be evaluated by measuring hematocrit levels and performing transvaginal
ultrasonography. The ultrasound findings during follow-up, although usually not
helpful, can be used to provide reassurance that the tube is not ruptured (115).
Cul-de-sac fluid is a common finding and the amount of fluid may increase if a
tubal abortion occurs. It is not necessary to intervene surgically, unless the patient
has a precipitous drop in hematocrit levels or she becomes hemodynamically
unstable.
Side Effects
Side effects of methotrexate therapy are dose and frequency dependent. The
most commonly reported side effects are the gastrointestinal symptoms of
nausea, vomiting, stomatitis, and abdominal pain. The frequency of reported
side effects ranges from 30% to 40% (106). As a result of these potential effects,
women are cautioned against using alcohol and nonsteroidal anti-inflammatory
medications during treatment with methotrexate. Other side effects include bone
marrow suppression, hemorrhagic enteritis, alopecia, dermatitis, elevated liver
enzyme levels, and pneumonitis (116). These side effects are usually mild and
self-limited; few life-threatening side effects are reported. The risk of all side
effects does appear to be higher for multidose regimens. For those patients on
prolonged therapy, leucovorin can reduce the incidence of these side effects and is
included in the “multidose” regimen. Long-term follow-up of women treated with
methotrexate for gestational trophoblastic disease shows no increase in congenital
malformations, spontaneous abortions, or tumors recurring after chemotherapy
(117). Treatment of ectopic pregnancy differs from that of gestational
trophoblastic disease in that a smaller total dose of methotrexate is required and
shorter treatment duration is used. Although surgical management of ectopic
pregnancy remains the mainstay of treatment worldwide, methotrexate treatment
is appropriate in those patients who meet the treatment criteria.
Reproductive Outcome
Reproductive function after methotrexate treatment can be assessed on the basis
of repeat ectopic pregnancy rates, tubal patency, and pregnancy outcome. The risk
of subsequent ectopic pregnancy is approximately 10% following either
methotrexate or salpingostomy (118,119). The tubal patency rates are reported to
be higher than 80% in those patients treated with either single-dose or multidose
regimens with no difference in rates compared with women treated with
salpingostomy. A randomized trial comparing methotrexate to laparoscopic
salpingostomy showed no difference in tubal patency rates among the two groups,
although in this trial patency rates were lower than previously reported at 66% in
1942the salpingostomy group (120). Subsequent spontaneous intrauterine pregnancy
rates are similar between those women treated with methotrexate versus
salpingostomy, with rates ranging from 36% to 64% (121,122). A Cochrane
review comparing interventions for ectopic pregnancy showed no difference in
subsequent risk of a repeat ectopic pregnancy and future intrauterine pregnancy
rates comparing surgically and medically treated patients. Studies evaluating
ovarian reserve after treatment with methotrexate for an ectopic showed no
impact on future ovarian reserve (123,124). [5] Comparison of laparoscopically
treated patients with methotrexate-treated patients indicates that the two
methods have similar reproductive outcomes (92).
Types of Ectopic Pregnancy
Spontaneous Resolution of Pregnancies of Unknown Location
Some ectopic pregnancies resolve by resorption or by tubal abortion,
obviating the need for medical or surgical therapy. The proportion of ectopic
pregnancies that resolve spontaneously and the factors that make this more likely
are unknown. There are no specific criteria for predicting successful spontaneous
resolution of an ectopic pregnancy. A falling β-hCG level is the most common
indicator used, but tubal rupture can occur even with falling β-hCG levels. One
recent study found that a ratio of β-hCG level at 48 hours compared with initial
hCG level of <0.87 predicted a failing pregnancy of unknown location, better than
absolute serum β-hCG levels at both of those time periods (125). Patients with
low initial levels of β-hCG are generally the best candidates for expectant
management, and there is a reported 88% success rate of spontaneous remission
with an initial β-hCG level less than 200 mIU/mL (126,127). These patients
should be followed with serial β-hCG levels, with a plan to initiate active
management if levels plateau or rise or signs suggestive of tubal rupture occur.
Persistent Trophoblastic Tissue
Persistent ectopic pregnancy occurs when a patient underwent conservative
surgery (e.g., salpingostomy, fimbrial expression) and viable trophoblastic
tissue remains. Histologically, several criteria exist: there is no identifiable
embryo, the implantation usually is medial to the previous tubal incision and
residual chorionic villi are confined to the tubal muscularis. Peritoneal
trophoblastic tissue implants may be responsible for persistence. Diagnosis is
made when β-hCG levels plateau after conservative surgery. Risk factors for
persistent ectopic pregnancy include the type of surgical procedure, the initial β-
hCG level, the duration of amenorrhea, and the size of the ectopic pregnancy,
with smaller, earlier pregnancies treated by salpingostomy carrying the highest
1943risk (128). Patients treated with laparoscopic salpingostomy have a higher rate of
persistent ectopic pregnancies compared to those treated with salpingostomy at
the time of a laparotomy, with an incidence of persistence after laparoscopic
linear salpingostomy ranging from 4% to 15% (39,92,94).
Management. Persistent ectopic pregnancy can be treated surgically or
medically; surgical therapy consists of either repeat salpingostomy or, more
commonly, salpingectomy. Methotrexate offers an alternative to patients who are
hemodynamically stable at the time of diagnosis. Methotrexate may be the
treatment of choice because the persistent trophoblastic tissue may not be
confined to the tube and, therefore, not readily identifiable during repeat surgical
exploration (128).
Nontubal Ectopic Pregnancy
The majority of ectopic pregnancies diagnosed are found in the ampulla portion
of the fallopian tube and the majority (93%) found within some part of the
fallopian tube. Increasingly, more ectopic pregnancies are found in other locations
within the abdomen and pelvis. These nontubal ectopic pregnancies are rare but
are important to consider as they are associated with more adverse events caused
by difficulty and delay in diagnosis and treatment.
Cervical Pregnancy
Diagnosis. Pregnancy implanted within the cervix is the rarest of all ectopic
pregnancies, accounting for less than 1% of all ectopic pregnancies (1). The
cause of cervical ectopic pregnancies is unknown and the rare occurrence
prevents identification of known risk factors. The diagnosis may not be suspected
until the patient is undergoing suction curettage for a presumed incomplete
abortion and hemorrhage occurs. In some cases, bleeding is light, whereas in
others there is hemorrhage. These types of ectopic pregnancies are diagnosed and
distinguished from ongoing spontaneous abortion mainly with ultrasound
findings, and serial β-hCG measurements. Distinguishing a cervical ectopic
pregnancy from an incomplete process is often difficult, and many cervical
ectopic pregnancies may be misdiagnosed (129). Suggested criteria can be found
in Table 32-6. Other potential diagnoses that must be differentiated from cervical
pregnancy include cervical carcinoma, cervical or prolapsed submucosal
leiomyomas, trophoblastic tumor, placenta previa, and low-lying placenta. An
MRI may be helpful in distinguishing between some of these entities if the
ultrasound and β-hCG measurements are not clear.
Table 32-6 Ultrasound Criteria for Cervical Pregnancy
19441. Gestational sac or placental tissue visualized within the cervix
2. Cardiac motion noted below the level of the internal os
3. No intrauterine pregnancy
4. Hourglass uterine shape with ballooned cervical canal
5. No movement of the sac with pressure from transvaginal probe (i.e., no “sliding
sign” that is typically seen with incomplete abortions)
6. Closed internal os
Adapted from Kung FT, Lin H, Hsu TY, et al. Differential diagnosis of cervical ectopic
pregnancy and conservative treatment with the combination of laparoscopy-assisted uterine
artery ligation and hysteroscopic endocervical resection. Fertil Steril 2004;81:1642–1649.
Management. Options for management of cervical ectopic pregnancies
include medical treatment with methotrexate and surgical dilation and
curettage. The ideal regimen for medical management is unknown and success is
reported with both the single- and multidose regimens. More advanced gestations,
especially with fetal cardiac activity, may require a combination of multidose
methotrexate and intra-amniotic/intra-fetal injection of KCl for fetal demise.
These injections require skill to avoid rupture of membranes during the
procedure. A retrospective study of 62 women with cervical ectopic pregnancies
treated in China found that viable pregnancies treated with methotrexate had a
higher rate of surgical intervention (43%) than nonviable pregnancies (13%)
(130). As this was a retrospective chart review, the authors do not comment on
whether some of the additional procedures were planned or if they were a result
of methotrexate failure. As with tubal ectopic pregnancies, medical management
is appropriate only for those patients who are hemodynamically stable (129).
Preventative surgical management of cervical ectopic pregnancy has been
described. If the patient and physician elect to proceed with surgical management,
the preoperative preparation should include blood typing and cross-matching,
establishment of intravenous access, and detailed informed consent. This consent
should include the possibility of hemorrhage that may require transfusion or
hysterectomy. In a small study of 6 patients with cervical ectopic in China, all
patients were treated with uterine artery embolism (UAE) followed by
hysteroscopic endocervical resection (129). Treatment was successful in all six
cases without any adjunctive methotrexate treatment and with minimal blood loss
(mean 125 mL, range 50 to 250 mL). While this study is small, it suggests the
safety of minimally invasive techniques. Patients should be counseled that the
1945fertility effects of undergoing even a temporary UAE are not yet clear.
When a cervical ectopic pregnancy presents with bleeding or if bleeding occurs
as part of treatment, various techniques can be used including uterine packing,
UAE, lateral cervical suture placement to ligate the lateral cervical vessels,
placement of a cerclage, and insertion of an intracervical 30-mL Foley catheter
for cervical tamponade. When none of these methods is successful, hysterectomy
is required.
Ovarian Pregnancy
Diagnosis. A pregnancy confined to the ovary accounts for up to 3% of all
ectopic pregnancies and is the most common type of nontubal ectopic
pregnancy (1,131). Though the clinical presentation of bleeding, abdominal pain,
and positive pregnancy test is similar, ovarian pregnancy is not associated with
PID, infertility, or tubal disease like other ectopic pregnancies (132). The
pathology diagnostic criteria were described in 1878 by Spiegelberg, listed in
Table 32-7 (133). Ultrasound criteria are difficult as findings are typically a
cystic ovarian mass, with a differential of corpus luteum cyst, hemorrhagic cyst,
and tubal ectopic pregnancy.
Management. The treatment of ovarian pregnancy has changed. Whereas
oophorectomy was advocated in the past, ovarian cystectomy and/or wedge
resection is utilized with success and successful treatment with methotrexate has
been reported (134–136).
Abdominal Pregnancy
Abdominal pregnancies are one of the rarest types of ectopic pregnancy,
representing 1% to 1.4% of ectopic pregnancies (1,131). They are typically
classified as primary or secondary. Pathology criteria for primary abdominal
ectopic pregnancy have been established by Studdiford (see Table 32-8) and
include normal tubes and ovaries, no evidence of uteroplacental fistula (137).
Secondary abdominal pregnancies are more common, thought to result from tubal
abortion or rupture or, less often, from subsequent implantation within the
abdomen after uterine rupture. Risk factors for abdominal pregnancy include PID,
multiparity, endometriosis, assisted reproductive techniques, and tubal damage.
The most common area of implantation within the abdomen is the posterior culde-sac, and pregnancies have been confirmed in the mesosalpinx, omentum and
bowel, liver, spleen, abdominal wall, and within broad ligament (131).
Abdominal pregnancy is associated with high morbidity and mortality, with
the risk for death seven to eight times greater than from tubal ectopic
pregnancy and 50 times greater than from intrauterine pregnancy, most
likely resulting from later diagnosis.
1946Table 32-7 Criteria for Ovarian Pregnancy Diagnosis
1. The fallopian tube on the affected side must be intact
2. The fetal sac must occupy the position of the ovary
3. The ovary must be connected to the uterus by the ovarian ligament
4. Ovarian tissue must be located in the sac wall
From Spiegelberg O. Casusistik der ovarialschwangerschaft. Arch Gynaecol 1878;13:73.
Table 32-8 Studdiford’s Criteria for Diagnosis of Primary Abdominal Pregnancy
1. Presence of normal tubes and ovaries with no evidence of recent or past pregnancy
2. No evidence of uteroplacental fistula
3. The presence of a pregnancy related exclusively to the peritoneal surface and early
enough to eliminate the possibility of secondary implantation after primary tubal
nidation
Adapted from Anderson PM, Opfer EK, Busch JM, et al. An early abdominal wall
ectopic pregnancy successfully treated with ultrasound guided intralesional methotrexate:
A case report. Obstet Gynecol Int 2009; Article ID 247452.
Diagnosis. Ultrasound detects only approximately half of all abdominal ectopic
pregnancies. Ultrasound features that have been suggested include gestational sac
surrounded by loops of bowel, normal-appearing fallopian tubes, and ovaries
(138). Differential includes intrauterine pregnancy with retroflexion or distorted
by fibroids. When diagnosis is highly suspected, MRI may be helpful in assessing
degree of vascular attachment to other abdominopelvic tissues. Abdominal
ectopic pregnancies are one of the few ectopic pregnancies that may proceed out
of the first trimester. In advanced abdominal pregnancy, the clinical presentation
may include painful fetal movement, fetal movements high in the abdomen or
sudden cessation of movements. Physical examination may disclose persistent
abnormal fetal positioning, abdominal tenderness, a displaced uterine cervix, easy
palpation of fetal parts, and palpation of the uterus separate from the gestation.
The diagnosis may be suspected when there are no uterine contractions after
oxytocin infusion.
Management. Because the pregnancy can continue to term, the potential
maternal morbidity and mortality are very high. As a result, surgical intervention
1947is recommended when an abdominal pregnancy is diagnosed. At surgery, the
placenta can be removed if its vascular supply can be identified and ligated, but
hemorrhage can occur, requiring abdominal packing that is left in place and
removed after 24 to 48 hours. Options for management of hemorrhage include
artery embolization. If the vascular supply cannot be identified, the cord is ligated
near the placental base, and the placenta is left in place. Placental involution can
be monitored using serial ultrasonography and assessment of β-hCG levels.
Potential complications of leaving the placenta in place include bowel
obstruction, fistula formation and sepsis as the tissue degenerates. There are
concerns regarding the use of methotrexate treatment in abdominal pregnancies.
Specifically, there is theoretically an increased risk of infection and sepsis
resulting from the rapid tissue necrosis that occur following methotrexate
administration. There are reports of successful treatment of abdominal
pregnancies with methotrexate in patients not considered to be optimal surgical
candidates (136,139). There are scattered reports of term abdominal pregnancies.
When this occurs, perinatal morbidity and mortality are high, usually as a result
of growth restriction and congenital anomalies such as fetal pulmonary
hypoplasia, pressure deformities, and facial and limb asymmetry (140).
Interstitial Pregnancy
Diagnosis. Interstitial pregnancies represent about 2.4% of ectopic
pregnancies (1). This section of the fallopian tube is relatively thick with an
increased capacity to expand prior to rupture. This ability along with increased
vascularity of this area may allow these types of ectopic pregnancies to remain
asymptomatic for 7 to 16 weeks of gestation (141). However, late presentations
are rare; most patients typically present between 6 and 8 weeks of gestation (141).
Differential diagnosis includes angular pregnancy, a viable pregnancy that
implants within the uterine angle, medial to the ostia. Typically angular
pregnancies are asymptomatic unless they end in miscarriages, which occurs
approximately 38% of the time (141). In laparoscopy, these can be distinguished
as a true interstitial pregnancy appears lateral to the round ligament.
Interstitial pregnancies represent a disproportionately large percentage of
fatalities from ectopic pregnancy with a 2.5% mortality rate (142).
Management. These pregnancies were classically treated with laparotomy with
cornual resection. Early detection allows for a more conservative management
approach in hemodynamically stable patients without evidence of rupture.
Medical management with methotrexate is well described, with the single- and
multidose regimens. Approximately 10% to 20% of patients treated medically
will ultimately require surgery and close follow-up is warranted as with all
medically managed ectopic pregnancies (141).
1948Although cornual wedge resection by laparotomy is an acceptable surgical
option, minimally invasive techniques exist, including cornual excision,
minicornual excision and cornuostomy. Laparoscopic approaches are more
widely used and are dependent on surgical skill. Transcervical suction evacuation
under laparoscopic or ultrasound guidance has been reported (136,141). The
appropriate surgical technique and approach depends on the individual patient
presentation and the surgeon’s expertise.
Cesarean Scar Ectopic Pregnancy
A pregnancy implanted within the uterine myometrium at the site of a healed
cesarean scar is called a cesarean scar pregnancy (CSP). Historically, CSP has
been an extremely rare occurrence. However, as cesarean deliveries are becoming
more common, incidence has been slowly increasing with estimations among
women with prior cesarean deliveries to be up to 1:500 pregnancies (136,143).
Because of small numbers, it has not been determined if the number of cesarean
deliveries or type of cesarean delivery (e.g., classical or Pfannenstiel incisions)
affect risk of CSP.
Diagnosis. Ultrasound is the initial diagnostic tool for CSP, with signs
suggestive of CSP including: (1) gestational sac located at the level of the prior
scar; (2) surrounding Doppler flow with minimal separation from bladder; (3)
outward bulging of the gestational sac within the scar; and (4) negative “sliding
organs sign” where the gestational sac does not move with gentle pressure from
transvaginal ultrasound (143). CSPs have been separated into two types based on
prognosis; type 1 progressing toward uterine cavity; type 2 progressing toward
the bladder.
Management. As CSP is quite rare and can present differently based on
location and type, there is no management that has proved superior. Early
treatment is recommended, as CSP can progress into placental accreta or even
uterine rupture if left untreated. Management options include medical
management with systemic or local injection of either methotrexate or KCl,
surgical management with dilation and curettage with or without hysteroscopy,
UAE, or some combination of these approaches. Medical management should
only be offered to hemodynamically stable patients. Success rates for
methotrexate doses systemically, locally, and combined systemic/local have been
reported as 56%, 60%, and 77%, respectively. These cases had a hemorrhage rate
of 7% and hysterectomy rate of 3% (143). For surgical management, dilation and
curettage under ultrasound guidance had a reported success rate of 76% with a
30% hemorrhage risk and 3% hysterectomy risk (143). Hysteroscopic resection
was used with a 62% risk of persistent trophoblastic disease and should be
performed in combination with dilation and curettage. A combination of
1949methotrexate followed by dilation and curettage has been reported with success
rates up to 86%, hemorrhage risk of 14%, and hysterectomy risk of 4%. UAE can
be performed prior to dilation and curettage or even prior to methotrexate therapy
to reduce hemorrhage risk. If UAE is not done prophylactically, it can be done in
the case of hemorrhage after other treatment options. In some cases, methotrexate
was injected into uterine arteries prior to UAE. If used alone, UAE has a reported
success rate of 81% with risk of hemorrhage 5%, and risk of hysterectomy 4%
(143).
Heterotopic Pregnancy
Heterotopic pregnancy occurs when intrauterine and ectopic pregnancies
coexist. The reported incidence is 1:30,000 (35). The diagnosis is often delayed
as an intrauterine pregnancy is seen during ultrasonography examination and an
extrauterine pregnancy may be overlooked. Patients undergoing ovulation
induction with assisted reproductive technology are at risk of ovarian
hyperstimulation syndrome (OHSS), which can cause similar ultrasound findings
including enlarged ovaries and free fluid in the abdomen and is important to
consider in differential diagnosis (144). Serial β-hCG levels are not helpful
because the intrauterine pregnancy causes the β-hCG level to rise appropriately.
Heterotopic pregnancy is much more common with assisted reproductive
technology than spontaneous conception, with possible etiologies including
multiple embryo transfers and previous tubal damage (144,145).
Management. The ectopic pregnancy is treated surgically if the intrauterine
pregnancy is desired. When the ectopic pregnancy is removed, the intrauterine
pregnancy continues in most patients. The rate of spontaneous abortion is higher
with approximately one in three ending in miscarriage (145,146). It may be
possible to treat the ectopic pregnancy using nonchemotherapeutic medical
treatment, such as KCl, by transvaginal or laparoscopically directed injection;
however, a reported 55% may require additional surgical treatment (147).
Multiple Ectopic Pregnancies
Twin or multiple ectopic gestations occur less frequently than heterotopic
gestations and may appear in a variety of locations and combinations.
Multiple ectopic pregnancies are thought to be rare, but with the advent of
assisted reproductive technologies the incidence appears to be rising. A
review of bilateral tubal pregnancies reported 242 cases between 1918 and 2007,
with 42 cases in the past 10 years alone. Fifty percent of these twin tubal
pregnancies were associated with assisted reproductive technologies (148).
Another review of 163 cases of tubal ectopic pregnancies had a reported rate of
twin tubal pregnancies of 2.4% (149). Although most reports are confined to twin
1950tubal gestations, ovarian, interstitial, and abdominal twin pregnancies have been
reported. Management is similar to that of other types of ectopic pregnancy and is
somewhat dependent on the location of the pregnancy.
Pregnancy After Hysterectomy
The most unusual form of ectopic pregnancy is one that occurs after vaginal or
abdominal hysterectomy (150,151). Such a pregnancy may occur after
supracervical hysterectomy because the patient has a cervical canal that may
provide intraperitoneal access (149). Pregnancy may occur in the perioperative
period with implantation of the already fertilized ovum in the fallopian tube.
Pregnancy after total hysterectomy probably occurs secondary to a vaginal
mucosal defect that allows sperm into the abdominal cavity. Only case reports are
available and management options include surgical removal and systemic
methotrexate, depending on location of pregnancy and patient characteristics.
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