Jun Kumakiri1 , Rie Ozaki1 , Satoru Takeda1 , Antonio Malvasi2, 3 and Andrea Tinelli4, 5, 6, 7
Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Department of Obstetrics and Gynecology, Santa Maria Hospital, G.V.M. Care and Research, Bari, Italy
International Translational Medicine and Biomodelling Research Group, Department of Applied Mathematics, Moscow Institute of Physics and Technology (State University), Moscow Region, Russia
Department of Obstetrics and Gynecology, Vito Fazzi Hospital, Lecce, Italy
Laboratory of Human Physiology, The International Translational Medicine and Biomodelling Research Group, Department of Informatics and Applied Mathematics, Moscow Institute of Physics and Technology (State University), Dolgoprudny, Moscow Region, Russia
Institute of Physics and Technology (State University), Moscow, Russia
Division of Experimental Endoscopic Surgery, Imaging, Technology and Minimally Invasive Therapy, Department of Obstetrics & Gynecology, Vito Fazzi Hospital, Lecce, Italy
Jun Kumakiri (Corresponding author)
Ectopic pregnancy is defined as a pregnancy in which the fertilized ovum is implanted outside the endometrial cavity. Ectopic pregnancy is one of the leading causes of maternal death during the first trimester of pregnancy, and it is related to 10 % of all maternal deaths . However, in recent years, since the development of high-resolution ultrasonography and the availability of techniques for the rapid measurement of serum human chorionic gonadotropin (hCG) concentrations has improved early detection of tubal pregnancy, ectopic pregnancy-related deaths have decreased. Most (93–98 %) ectopic pregnancies are located within the fallopian tube (Fig. 4.1). Of these, 13 % are isthmic, 75 % ampullary, and 12 % fimbrial . Major risk factors of tubal pregnancy include previous chlamydia infection, adnexal adhesions owing to previous surgery, and smoking. In addition, ectopic pregnancy including tubal pregnancy has increased because of the recent technical progress and prevalence of artificial reproductive technology.
A transvaginal pelvic ultrasonographic scanning of a left tubal pregnancy
Some investigators postulate that the etiology is likely to be a combination of impaired embryo-tubal transport and alterations in the tubal environment allowing early implantation . While the characteristics of ectopic pregnancy in humans are well known, they are not yet understood in animals. Because tubal pregnancy does not occur in laboratory, domestic, or farm animals but is limited to primates, no animal model of the condition exists . Several factors related to ovum implantation are reported as being different between humans and animals. For example, it was suggested that a mechanism in rabbits that prevents oviductal implantation is lacking in human fallopian tubes .
Ectopic pregnancy is potentially life threatening. If the fallopian tube ruptures before the woman is diagnosed and treated, massive intra-abdominal hemorrhage can occur (Fig. 4.2), leading to death. We summarize here the clinical presentation, diagnosis, and surgical and medical treatments of ectopic pregnancy.
The image represents a fallopian tube rupture with a massive hemorrhage collecting in the Douglas pouch
Ectopic pregnancy has increased in recent decades, with the rate of diagnosis increasing sixfold between 1970 and 1992 in the United States [6–9], although it seemed to be stabilizing in the late 1990s . The reason for this increase is the increased prevalence of risk factors of ectopic pregnancy. For example, sexually transmitted disease, mainly chlamydia infection, has been spreading worldwide. The increasing prevalence of assisted reproductive technology also accounts for some of the increase in ectopic pregnancies. Epidemiologic data vary depending on the country studied. Approximately 2 % of all pregnancies in Europe and the United States are ectopic [1, 11]. Investigators have reported annual ectopic pregnancy rates of 20.70 per 1000 reported pregnancies and 1.03 per 1000 women aged 15–44 years . The incidence of ectopic pregnancy in the United Kingdom was reported as 11.1 per 1000 pregnancies , which is similar to that in other countries, including Norway (14.9 per 1000)  and Australia (16.2 per 1000) in 1994 , while that in California was 11.2 per 1000 pregnancies during 1991–2000 . The data from 1991 to 1999 in the United States estimated an ectopic pregnancy mortality rate of 31.9 per 100,000 ectopic pregnancies . However, the mortality rate of ectopic pregnancy has decreased annually. In the United States, 876 deaths in the United States were attributed to ectopic pregnancy between 1980 and 2007. The mortality rate decreased from 1.15 to 0.50 deaths per 100,000 live births between 1980–1984 and 2003–2007 . In addition, during 2003–2007, the mortality rate was 6.8 times higher for African Americans than for whites and 3.5 times higher for women older than 35 years than for those younger than 25 years. The majority of ectopic pregnancies occur in the fallopian tube, with 40–80 % of these occurring in the ampulla, 10–28 % in the isthmus, 7–17.4 % in the fimbriae, and 2–13 % in the interstitial (cornual) region [2, 17, 18] (Fig. 4.3).
Locations of tubal pregnancies. (a) Fimbria, (b) ampulla, (c) isthmus, (d) interstitial portion
The exact etiology of tubal pregnancy is unclear. However, it is hypothesized that tubal pregnancy is caused by a combination of the embryo remaining in the fallopian tube (Fig. 4.4) owing to an impaired embryo-tubal transport system and alterations in the tubal environment that allow early implantation . The contraction of the smooth muscle of the fallopian tube plays a key role in the embryo transport system [3, 20] and is modulated by several factors, including adrenergic neurons , sex steroid hormones, prostaglandins [22–24], nitric oxide [25, 26], prostacyclin , and cAMP . A tubal pregnancy may occur when the embryo transport system is impaired for any reason. Another key factor is activity of the cilia within the fallopian tube dominantly influences embryo-tubal transport , which is impaired in tubal pregnancy, as evidenced by a large reduction in the number of ciliated cells .
A transvaginal pelvic section of extrauterine right tubal pregnancy at 5 weeks, showing a small anechoic round image
The etiology of tubal pregnancy has been studied from the viewpoint of molecular mechanisms, and several proteins have been implicated in its development. Sex steroid hormone receptors play a key role in the activity of the fallopian tubes, and progesterone receptor levels are significantly reduced and estrogen receptor α is absent in the fallopian tubes of women with tubal pregnancies [30–32]. Leukemia inhibitory factor (LIF), which has roles in extravillous trophoblast adhesion and invasion and which is present in ectopic implantation sites, may be associated with the development of tubal pregnancy: LIF-stimulated blastocyst adhesion to fallopian tube epithelial cells was significantly reduced after LIF inhibitor treatment, and LIF promoted placental explant outgrowth, whereas co-treatment with LIF inhibitor blocked such outgrowth . The interleukins (ILs), which are dominant inflammatory proteins, are also implicated. A study using quantitative competitive polymerase chain reaction (PCR) to analyze segments of fallopian tube adjacent to an ectopic pregnancy and from women undergoing tubal ligation as controls demonstrated that IL-1β mRNA expression was decreased and IL-1 receptor antagonist (IL-1ra) and IL-1 receptor type 1 mRNA expression was increased in the fallopian tubes with ectopic pregnancies in comparison with the control tubes . The authors concluded that a lower IL-1β to IL-1ra ratio and a higher expression of the IL-1 receptor in the fallopian tubes may be associated with tubal pregnancy. An immunohistochemistry study revealed that the expression levels of IL-6 and IL-8 were significantly upregulated, particularly near the implantation site, in fallopian tubes with tubal gestation . Vascular endothelial growth factor (VEGF), which is a key generator of angiogenesis, contributes to the establishment of a viable pregnancy and participates in the processes of implantation. In the fallopian tube, VEGF is localized in the epithelial cells, smooth muscle cells, and blood vessel cells in a region-specific manner [36, 37]. The VEGF-A and VEGF receptor mRNAs are significantly increased in the implantation site compared with non-implantation sites of fallopian tubes  and are associated with trophoblastic invasion into the tubal wall . Indeed, circulating levels of VEGF-A have been found to increase in women with an ectopic pregnancy .
4.4 Risk Factors
Risk factors for ectopic pregnancy include pelvic inflammatory disease (Fig. 4.5a), previous surgery, age over 35 years, in vitro fertilization, and smoking. A matched case–control study conducted in women with planned pregnancies including 900 women diagnosed with ectopic pregnancy and 889 women with intrauterine pregnancy as the control group found a significant positive risk of ectopic pregnancy for previous adnexal surgery [odds ratio (OR) = 3.99], uncertainty of previous pelvic inflammatory disease (OR = 6.8), a history of infertility including tubal infertility (OR = 3.62), non-tubal infertility (OR = 3.34), and in vitro fertilization treatment (OR = 5.96). In contrast, previous use of condoms was a negatively significantly associated with ectopic pregnancy (OR = 0.27) . Knowledge of risk factors for tubal pregnancy could be helpful for an early and accurate diagnosis, resulting in appropriate and immediate management including surgery and medical therapy. Table 4.1 shows risk factors of tubal pregnancy.
(a) The image collects aspects of pelvic inflammatory disease (PID), showed by diffuse adhesions in the Douglas pouch, between uterus, bowel, adnexa, and large ligaments, by Fitz-Hugh-Curtis syndrome (adhesions between the liver and diaphragm) and by ultrasonographic images of pelvis with free fluid in the Douglas pouch and adhesions. (b) Bilateral hydrosalpinx caused by previous Chlamydia trachomatis infection. (c) Right tubal ampullary pregnancy with adhesions caused by Chlamydia trachomatis infection
Risk factors for ectopic pregnancy
Previous ectopic pregnancy
Previous tubal surgery (including female sterilization)
Genital infection and pelvic inflammatory disease (caused by Chlamydia trachomatis and gonorrhea)
Assisted reproductive technology
Infertility (tubal disease, unexplained infertility)
Intrauterine contraceptive device
Multiple sexual partners
Smoking (including past exposure)
Pelvic surgery (including ovarian cystectomy and caesarian section)
Abdominal surgery (including appendectomy and bowel surgery)
Early age of intercourse (<18 years)
4.5 Chlamydia Infection
Chlamydia trachomatis is the most common bacterial sexually transmitted infection throughout the world. The infection rate estimated to be 89 million cases per year worldwide . Untreated urogenital Chlamydia trachomatisinfection may give rise to complications including pelvic inflammatory disease (Fig. 4.5b), ectopic pregnancy (Fig. 4.5c), and tubal pathology [43, 44]. Furthermore, tubal pregnancy is more common in women who have experienced pelvic inflammatory disease. Although the exact mechanism by which C. trachomatis infection leads to tubal pregnancy remains unknown, the chlamydial heat shock protein is associated with arrest of the chlamydial developmental cycle and persistence of infection. The antigens, a group of highly conserved membrane proteins found in both prokaryotes and eukaryotes, cause a tubal inflammatory response leading to tubal blockage or a predisposition to tubal implantation . Repeated infections with C. trachomatis are thought to increase tubal damage .
4.6 History of Surgery
Prior tubal surgery (Fig. 4.6) (salpingostomy, neosalpingostomy, fimbrioplasty, tubal reanastomosis, and lysis of peri-adnexal adhesions) increases the risk for developing a tubal pregnancy, which depends on the degree of damage and the extent of anatomic alteration . A retrospective cohort study carried out between January 2003 and September 2011 of 618 patients admitted to a hospital with tubal pregnancy and who had received surgical treatment reported 2-year cumulative recurrent tubal pregnancy rates of 8.1 % for salpingectomy, 6.3 % for salpingostomy, and 16.7 % for tubal anastomosis. Taking the patients who underwent salpingectomy as the reference group, the patients who underwent tubal anastomosis had a significantly higher risk of recurrent tubal pregnancy (hazard ratio = 2.280; 95 % confidence interval [CI], 1.121–4.636) in univariate analysis . The perforation that complicates appendicitis can lead to intra-abdominal infection and scarring, which can secondarily result in obstruction of the fallopian tubes and subsequent infertility . A meta-analysis revealed a significant effect of appendectomy on ectopic pregnancy based on a pooled estimate from four studies (OR = 1.78, p < 0.0001) .
Laparoscopic images of prior pelvic peri-tubal surgery, with lysis of peri-adnexal adhesions
Advanced maternal age is one of the risk factors of tubal pregnancy, with the incidence of increasing from 1.4 % of all pregnancies in women aged 21 years to 6.9 % in women aged ≥44 years [51, 52]. A physiologic explanation for the association of tubal pregnancy and advanced maternal age at conception remains unclear, but hypotheses include an increase in chromosomal abnormalities in trophoblastic tissue and age-related changes in tubal function that delay ovum transport, resulting in tubal implantation .
4.8 Assisted Reproductive Technology
Assisted reproductive technology (ART) is suggested to increase the risk of tubal pregnancy (Fig. 4.7). The rate of tubal pregnancy following in vitro fertilization (IVF)–embryo transfer (ET) is three- to five-fold higher than that in the general population . The prevalence of ectopic pregnancy following ART ranges between 2.1 and 8.6 % of all pregnancies and can reach up to 11 % in female patients with a history of tubal factor infertility . The risk of tubal pregnancy following IVF-ET suggests that tubal damage has a predominant role in the same pathogenesis of naturally occurring tubal pregnancies (Fig. 4.8) . E-cadherin is a useful marker of endometrial receptivity; a study demonstrated strong immunochemical staining for E-cadherin in cytotrophoblast cells of chorionic villi in post-IVF tubal pregnancies but negative or weak staining in spontaneous tubal pregnancies. The authors hypothesized that the differential expression of E-cadherin, a potent adhesion molecule, resulted in tubal pregnancy owing to less than optimal, temporal, and spatial conditions during the IVF cycle . Furthermore, the technique of ET itself may be a potential cause, as the number of embryos that are transferred during IVF treatment has been reported as a risk of tubal pregnancy .
The figure represents an intrauterine insemination
An early tubal pregnancy following IVF-ET at 4 weeks detected by transvaginal pelvic scanning
Multiple studies have demonstrated a strong association between cigarette smoking and ectopic pregnancy. A French population-based study  showed a significant positive association of smoking with ectopic pregnancy in women who smoked compared with those who had never smoked (adjusted OR = 3.9), and the risk associated with smoking increased in a dose-dependent manner (adjusted OR = 5.9 for >20 cigarettes/day). Smoking increases transcription of prokineticin receptor 1 (PROKR1), a G-protein-coupled receptor  that is known for its angiogenic properties, control of smooth muscle contractility, and regulation of genes important for intrauterine implantation. Its expression is altered in fallopian tubes from women with tubal pregnancy, where implantation has already occurred. An in vitro study analyzed changes in gene expression using the Illumina Human HT-12 array in an oviductal epithelial cell line (OE-E6/E7) and in explants of human fallopian tubes from nonpregnant women exposed to physiologically relevant concentrations of cotinine, the principle metabolite of nicotine . Cotinine-sensitive genes identified through this process were then localized and quantified in fallopian tube biopsies from nonpregnant smokers and nonsmokers using immunohistochemistry and TaqMan reverse transcription–PCR. The principal cotinine-induced change in gene expression detected by the array analysis in both explants and the cell line was significant downregulation of the proapoptotic gene BAD. Consistent with the array data, smoking was associated with decreased levels of BAD transcript and increased levels of BCL2 transcript (p < 0.05) in fallopian tube biopsies. The authors suggested that smoking may alter tubal epithelial cell turnover and is associated with structural as well as functional changes that may contribute to the development of ectopic pregnancy.
4.10 Other Risk Factors
The use of an intrauterine device (IUD) (Fig. 4.9) is known to increase the risk of tubal pregnancy. A retrospective nested case–control study  showed a significant positive association of IUD use with tubal pregnancy (OR = 4.39). Another study reported that previous use of IUDs was associated with a slight risk of ectopic pregnancy and the risk increased with the duration of previous use . The adjusted risk of ectopic pregnancy of prior spontaneous abortions was particularly high in women with three or more previous spontaneous abortions. In addition, there was an association between previous induced abortions and ectopic pregnancy, with an adjusted OR of 1.9 for women with two or more prior induced abortions . A study evaluating the association between the risk of ectopic pregnancy and the use of common contraceptives during the previous and current conception showed that the incidence of ectopic pregnancy may be higher in women using a contraceptive method that failed than in those not using a contraceptive . Endometriosis and its treatment (Fig. 4.10) have also been correlated to the development of tubal pregnancy [41, 55, 63]. The formation of pelvic and tubal adhesions caused by endometriosis could result in abnormal tubal function.
Ultrasound image of the intrauterine device. The FD-1 (Fuji Latex Co., Ltd., Tokyo, Japan) is a commonly used intrauterine device in Japan (a). A coronal T2-weighted image reveals the FD-1 inserted in the uterine corpus (b). Axial transvaginal ultrasonography shows the hyperechoic shadow (arrowheads) of the FD-1 within the uterine corpus (c)
Right tubal ampullary pregnancies (arrowheads) with severe adhesions caused by pelvic endometriosis
4.11 Clinical Presentation
Early in gestation (approximately 5 weeks), women with ectopic pregnancy are usually asymptomatic. With advancing gestation (>6 weeks), atypical symptoms, including genital bleeding and abdominal pain, may be present. Although more than 50 % of women with tubal pregnancy may present with vaginal bleeding, the symptom is not considered typical and the amount of genital bleeding is usually small. Vaginal bleeding is sometimes mistaken for normal menstrual bleeding or earlier chemical miscarriage. The genital bleeding results from the decidualization of thickened endometrium that is not stabilized owing to an inadequate amount of progesterone from the corpus luteum. Abdominal pain associated with tubal pregnancy ranges from mild to severe, according to the condition of the ectopic mass. The pain is related to tubal distention (Fig. 4.11) caused by the proliferating chorionic villi and hemorrhage into the lumen. When the abortion of the ectopic mass occurs in the fallopian tube, moderate to severe abdominal pain may be present owing to peritoneal irritation caused by hemoperitoneum. On pelvic examination, adnexal tenderness at the concurrent location of a unilateral tubal mass is often noted; however, the tubal mass is rarely palpable. In addition, bimanual examination should be done carefully and gently because manual pressure occasionally results in rupture of the fragile ectopic mass (Fig. 4.12). In contrast, although clinical symptoms are useful for an earlier auxiliary diagnosis, a recent study reported that one-third of women with ectopic pregnancy have no clinical signs and 9 % have no symptoms [64, 65]. The tubal mass sometimes, but not always, ruptures during the clinical course, usually after 7 weeks of gestation (Fig. 4.13). The rupture may occur because of the limitations of the growing ectopic mass imposed by the tubal lumen. When a rupture is present, severe abdominal distention and marked tenderness may be present due to peritoneal irritation caused by massive hemoperitoneum (Fig. 4.14). When these physical signs are obvious and the woman has a tendency of hypotension and tachycardia, immediate fluid reinfusion should be selected for maintaining a sufficient volume flow through the circulation and surgical management to arrest the hemorrhage.
The figure represents an overdistention of left unruptured tubal pregnancy evoking abdominal pain, ranging from mild to severe
The image shows a tubal rupture of the fragile ectopic mass with massive bleeding
A laparoscopic image showing a tubal rupture of an ectopic mass at 7 weeks of pregnancy, with blood collection into the Douglas pouch
Patient with ruptured tubal pregnancy. Computed tomography revealing isodense areas of severe hemoperitoneum around the uterus (a) and the spleen and liver (b). The dilated left tubal isthmus (arrowheads) can be seen (a, b). Laparoscopy revealing massive hemoperitoneum in the pelvis (c) and continuous bleeding from ruptured tubal isthmus (d)
The accuracy of diagnosing tubal pregnancy has been greatly improved by technical advances in diagnostic tools and techniques. However, discriminating earlier spontaneous pregnancy is inevitable. Differentiating spontaneous abortion from tubal pregnancy is also necessary. In addition, early diagnosis of tubal pregnancy is important to prevent maternal mortality due to massive hemorrhage of a ruptured tubal pregnancy.
Ultrasonography is the first diagnostic tool used when a tubal pregnancy is suspected. Ultrasonography technology has been markedly advanced in recent years, and high-resolution images can help in earlier detection of ectopic masses (Fig. 4.15). Transvaginal ultrasonography (TVS) for diagnosis of tubal pregnancy is considered superior (Fig. 4.16) to transabdominal ultrasonography (TAS). The first step in diagnosing tubal pregnancy is differentiating it from spontaneous pregnancy and miscarriage by visibility and viability of an intrauterine gestational sac using TVS (Fig. 4.17). If the gestational sac is not visible on TVS after 5 weeks of gestation, other findings should be carefully evaluated when a tubal pregnancy is suspected. However, in some cases of tubal pregnancy, a pseudo-sac appears in the intrauterine cavity, leading to a misdiagnosis of spontaneous pregnancy on TVS [66, 67]. In addition, although spontaneous heterotopic pregnancy is considered very rare with an incidence of 1 in 30,000 pregnancies, the incidence of heterotopic pregnancy following ART is increased and has been reported to occur in approximately 0.8 % of pregnancies following infertility treatment (Fig. 4.18) . It is known that previous surgery is one of the risk factors of heterotopic tubal pregnancy. A literature review estimated by 80 women with heterotopic pregnancy demonstrated that 51 women (63.8 %) had the previous surgery including salpingectomy for previous tubal pregnancy (Fig. 4.19) . An anechoic free fluid in the pouch of Douglas on TVS (Fig. 4.20) is generally detected in not only intrauterine but also ectopic gestations . The presence of echogenic fluid has been found in 28–56 % of women with tubal pregnancy [70, 71]. The echogenic appearance reflects the condition of tubal pregnancy and correlates well with the surgical findings of hemoperitoneum . The presence of fluid in the Morrison’s pouch observed via TAS indicates that severe hemoperitoneum may have occurred by rupture of the tubal pregnancy (Fig. 4.21). The most common finding of adnexal ectopic mass is visible as an inhomogeneous or a non-cystic adnexal mass (Fig. 4.22) sometimes known as the blob sign in approximately 60 % of cases . A prospective study on over 5000 consecutive women including 120 tubal pregnancies demonstrated that 73.9 % of tubal masses were visualized on TVS when the patient first attended the clinic . A meta-analysis of 10 studies showed TVS could be used to detect the mass of a tubal pregnancy with a specificity, positive predictive value, sensitivity, and negative predictive value of 98.9 %, 96.3 %, 84.4 %, and 94.8 %, respectively .
A laparoscopic earlier detection of a right tubal ectopic pregnancy
A transvaginal pelvic ultrasonography diagnosing an early left tubal pregnancy, at 5 weeks of pregnancy
Left tubal ampullary pregnancy. Ultrasonography revealing a low echoic cystic mass (red arrowheads) on left adnexal area (a). Color Doppler ultrasonography revealing blood flows (white arrowhead) in a fetus-like lesion inside the cystic mass (b). Echo-free space (blue arrowheads) detected around the uterus caused by hemoperitoneum (c). Laparoscopic image of the left tubal ampullary pregnancy (yellow arrowheads) confirmed by ultrasound imaging (d)
Simultaneous tubal-splenic pregnancy after assisted reproductive technology. Although the pregnancy was found in the right tubal ampulla after salpingectomy at 6 weeks of gestation, the patient serum human chorionic gonadotropin level increased at 8 weeks of gestation. Upper abdominal computed tomography revealing a cystic lesion accompanied by edema at the inferior pole of the spleen (a). Ultrasonography revealing a gestational sac and fetus with a beating heart in the inferior pole within the spleen (b) (See Refaat et al. )
Heterotopic pregnancy after assisted reproductive technology. Laparoscopy showing the heterotopic pregnancy with a ruptured ectopic mass, located in the stump of the ipsilateral tube, persisted after a previous salpingectomy (a, b). After the removal of ectopic tissue, the stump was closed using absorbable strings (c, d)
An ultrasonographic transvaginal scan showing an anechoic free fluid in the pouch of Douglas generally detected in not only intrauterine but also ectopic gestations
The figure represents a sudden rupture of the tubal pregnancy; it is usually cause of severe hemoperitoneum
A ultrasonographic transvaginal scanning showing the most common finding of adnexal ectopic mass: an inhomogeneous or a non-cystic adnexal mass (in the orange ring). The patient had a right early tubal pregnancy
4.12.2 Human Chorionic Gonadotropin
Human chorionic gonadotropin (hCG) is a useful marker for diagnosing tubal pregnancy. The quantitative measurement of hCG is accurately correlated to TVS findings . Serial hCG measurements are also useful for pregnancy of unknown location (PUL) when an intrauterine gestational sac cannot be visualized using ultrasonography, e.g., earlier stage of pregnancy, spontaneous abortion, or ectopic pregnancy. Many physicians consider that a slower rise in hCG indicates an abnormal pregnancy . Silva et al.  reported that the initial rise of hCG among 200 women with an ectopic pregnancy was slower (75 % increase in 2 days) than that reported for women with a viable intrauterine pregnancy. In addition, the authors found that the initial decline in hCG was slower (27 % decline in 2 days) than the mean reported for completed spontaneous abortion. Doubling of hCG concentration over 2 days is often used to predict a normal pregnancy [79, 80]. Seeber  considered that a miscarriage or ectopic pregnancy is not in doubt in cases of PUL in which the hCG concentrations do not rise at least 53 % within 2 days after the initial measurements, based on the studies of Barnhart et al. [76, 81]. The reason the author adopted the predictable limit of the subsequent hCG rise was that the limit with a 99 % CI intends that <1 % of viable pregnancies indicated an hCG rise even slower than that. However, clinicians need to know that the hCG concentrations of some women with ectopic pregnancy behave irregularly. Silva et al.  reported that 20.8 % of women with an ectopic pregnancy presented with a rise in hCG concentrations similar to the minimal rise for women with an intrauterine pregnancy and 8 % of women presented with a fall in hCG values similar to women with a spontaneous abortion. Therefore, although measuring hCG concentrations for a suspected tubal pregnancy is essential, a comprehensive diagnosis in combination with assessment of clinical presentations and appearance of ultrasonography should be conducted. It was reported that the combination of hCG measurement and TVS could detect ectopic pregnancy with 97 % sensitivity and 95 % specificity, avoiding the need for further invasive tests including a dilatation and curettage . It is suggested that a definition of a discriminatory zone to identify the optimal hCG concentration at which a normal pregnancy can be visible on ultrasound is important for individual institutions or clinicians. When the hCG concentration exceeds the discriminatory zone and an intrauterine pregnancy is not confirmed by ultrasonography, the pregnancy is not viable but is a suspected PUL including ectopic pregnancy. It is important to be careful in setting the range of discriminatory zone, because setting it too high or too low may lead to delayed diagnosis of ectopic pregnancy or excessive and unnecessary interventions for a normal pregnancy. The discriminatory zone ranges between 1500 and 2000 mIU/mL according to guidelines from the American College of Obstetricians and Gynecologists (ACOG) . Detection of discriminatory zone may differ according to the type of hCG immunoassay method. Desai et al.  studied how a lack of hCG assay harmonization may affect the interpretation of serum hCG concentrations with respect to the discriminatory zone. They used seven hCG reagent platforms to evaluate 80 serum samples containing various concentrations of hCG. They concluded that the hCG concentration within a discriminatory zone of 1500–3500 IU/L can be used for all but one commonly used hCG reagent platform.
4.12.3 Other Serum Markers
The markers are classified with respect to the biological conditions of ectopic pregnancy, including endometrial function and angiogenesis for implantation and corpus luteum function and trophoblast functions for embryonic viability [84–86]. Serum progesterone concentrations are stable at 8–10 weeks of gestation . Serum progesterone has been widely studied as a marker of viability of early pregnancy. However, a meta-analysis evaluated 26 studies concluded that though less than 5 ng/mL of serum progesterone concentration had good prediction for non-viability of PUL, it has no ability to discriminate tubal pregnancy from PUL . It is suggested that a single serum progesterone concentration could be used only to assess the risk of ectopic pregnancy in a PUL but not to differentiate ectopic pregnancy from spontaneous abortion. However, the measurement of serum progesterone concentrations combined with other serum markers may be occasionally helpful for the discrimination between tubal pregnancy and spontaneous abortion. In a retrospective case–control study including 50 of women with ectopic pregnancy and 50 of women with abortion, serum progesterone and anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt1) serum levels were measured. Although the area under curves for progesterone and sFlt-1 was low at 0.756 (cutoff point; 6 ng/mL, sensitivity = 60 %, specificity = 72.7 %) and 0.842 (cutoff point; 93 pg/mL, sensitivity = 84.5 %, specificity = 86.3 %), the combination of both markers allowed us to increase the AUC to 0.910 . Table 4.2 shows other diagnostic serum markers for tubal pregnancy.
Serum biomarkers of tubal ectopic pregnancy
Related to embryo
Placental micro RNAs
Cell free fetal DNA
Corpus luteal function
Relaxin and renin
Related to implantation
Other tissue function
Smooth muscle heavy-chain myosin and myoglobin
hCG human chorionic gonadotropin, PAPP-A pregnancy-associated plasma protein-A, SP1 pregnancy-specific beta glycoprotein-1, hPL human placental lactogen, ADAM-12 a disintegrin and metalloprotease-12, AFP alpha-fetoprotein, VEGF vascular endothelial growth factor, PIGF placental-like growth factor, LIF leukemia inhibitory factor, Muc-1 mucin-1, CK creatine kinase
A prospective study assessing the association between ultrasound images and serum concentrations of VEGF in tubal ampullary pregnancies in 55 patients demonstrated, via multiple logistic regression analysis, a significant association between ultrasound images of an ectopic gestational sac in the ampulla containing an embryo or fetus with fetal heartbeat and serum VEGF values . The authors suggested that serum VEGF facilitates a deeper invasion of trophoblastic tissue into the tubal wall and is related to embryonic cardiac activity.
MicroRNAs (miRNAs) are non-coding RNA molecules that regulate gene expression at the posttranscriptional level. Although miRNAs have been discovered only recently, they play a key role in diverse biological processes, including development, cell proliferation, differentiation, and apoptosis. Approximately 3 % of human genes encode miRNAs, and miRNAs fine-tune the expression of as much as 30 % of human protein-coding genes . Recently, miRNAs have been scrutinized as candidates for diagnostic and prognostic biomarkers and predictors of drug response because they have also been implicated in a number of diseases. Pregnancy-associated circulating miRNAs have been proposed as potential biomarkers for the diagnosis of pregnancy-associated complications as well as ectopic pregnancy [92–95]. In a retrospective case–control analysis of 89 women with a diagnosis of viable intrauterine pregnancy, spontaneous abortion, or ectopic pregnancy , concentrations of serum hCG, progesterone, miR-517a, miR-519d, and miR-525-3p were significantly lower in women with ectopic pregnancy and spontaneous abortion than in women with viable intrauterine pregnancy. In contrast, the concentration of miR-323-3p was significantly increased in women with ectopic pregnancy in comparison with women with viable intrauterine pregnancy and spontaneous abortion. A stepwise analysis that used hCG first, added progesterone, and then added miR-323-3p revealed a 96.3 % sensitivity and a 72.6 % specificity for the diagnosis of ectopic pregnancy.
4.12.4 Other Diagnostic Managements
If serum hCG concentrations do not rise normally and women are diagnosed with a PUL, endometrial curettage is recommended . Determining the presence or absence of chorionic villi by endometrial curettage is helpful to distinguish between spontaneous abortion and tubal pregnancy. Women whose hCG concentrations do not decrease by at least 15 % in the 12 h after curettage or whose samples do not include chorionic villi are diagnosed with ectopic pregnancy . However, the absence of chorionic villi does not definitively indicate an ectopic pregnancy, because chorionic villi will also be absent in patients with complete spontaneous miscarriage of an intrauterine pregnancy . In addition, dilatation and curettage for diagnosing ectopic pregnancy is an invasive technique with a risk of adverse events .
Pelvic magnetic resonance imaging (MRI) can be helpful for detecting tubal pregnancy (Fig. 4.23). MRI is an excellent procedure to confirm or better define suspected tubal pregnancy when TVS fails to reveal the focus of adnexal abnormal implantation or to distinguish ectopic pregnancy from incomplete miscarriage. The advantage of MRI for diagnosing tubal pregnancy is an identifiability of fresh blood owing to its excellent tissue contrast as well as accurate localization of the abnormal implantation site . A retrospective study evaluating characteristics obtained by pelvic MRI demonstrated that a well-demarcated and thick-walled cystic mass presumed to be a gestational sac lateral or adjacent to the uterus could be detected in all 27 patients with tubal pregnancy . The contents of the gestational sac-like structures in the 27 cases could be divided into three types: 26 % of cases (7/27) exhibited nonspecific liquid with a hypointense signal on T1-weighted images (WIs) and a hyperintense signal on T2-WIs with no enhanced solid components, 56 % of cases (15/27) exhibited papillary solid components representing embryo tissues with an isointense signal on T2-WI and marked enhancement, and 19 % of cases (5/27) exhibited hyperintense signal on both T1- and T2-WIs, indicating fresh blood or a fluid–fluid level resulting from blood degradation without a visible solid component. In addition, the study demonstrated that MRI features, including dilatation of the affected fallopian tube associated with a hyperintense clot and hemoperitoneum associated with signal intensities higher than that of urine in the bladder on T1-WIs or clear fluid with hypointense signal on T1-WIs and hyperintense signal on T2-WIs in the pelvic cavity, were useful for diagnosing tubal pregnancy.
Magnetic resonance imaging (MRI) of left tubal isthmus pregnancy at 5 weeks of gestation. A cystic gestational sac-like mass on the left side of the uterus shown on axial (a) and coronal (b) T2-weighted images as high-intensity areas (red arrowheads). The low-intensity area of the T1-weighted image indicates nonhemorrhagic content in the cystic mass (blue arrowheads) (c). Laparoscopic appearance of the tubal isthmus pregnancy (yellow arrowheads) detected by the MRI (d)
Recently, the outcomes of tubal pregnancy, which had been a fatal condition in the first quarter of the twentieth century, have been dramatically improved by the developments of not only early diagnostic methods but also medical treatments. Both surgical and medication therapy are used. Salpingectomy is chosen as a radical surgery for tubal pregnancy (Figs. 4.24 and 4.25), and salpingostomy when the patient desires fertility-sparing surgery. In addition, laparoscopic surgery is the gold-standard surgical approach because it is less invasive than laparotomy. Medical treatment using methotrexate is used in some women with tubal pregnancy. A high recovery rate after methotrexate therapy can be predicted for selected women.
A laparoscopic left salpingectomy chosen as a radical surgery for ruptured tubal pregnancy and hemoperitoneum
The figure represents a dramatic rupture of right tubal pregnancy with embryo expulsion in the pelvis
4.14 Expectant Management
Expectant management is occasionally applicable for symptomatic and clinically stable women with tubal pregnancy. Women with early tubal pregnancies with lower hCG levels are the best candidates for observation. Approximately 20–30 % of ectopic pregnancies are associated with decreasing hCG levels at the time of presentation . According to ACOG guidelines, if the initial hCG level is <200 mU/mL, 88 % of patients experience spontaneous resolution, and lower spontaneous resolution rates can be anticipated with higher hCG levels . In 107 women with tubal pregnancies, success was achieved in 75 women (70 %) undergoing expectant management . The success of expectant management was 96 % (32/33 cases) in women with initial serum β-hCG ≤175 IU/L, 66 % (40/60) in women with β-hCG 175–1500 IU/L, and only 21 % (3/14) in women with β-hCG >1500 IU/L. The study also demonstrated that the success rate of expectant management was associated with low progesterone levels (<10 nmol/L), gestational age ≤42 days, and pregnancy measuring >15 mm in diameter. A prospective observational study was carried out to validate the efficacy and safety of a clinical protocol for expectant management of selected women diagnosed with tubal pregnancy . Selection criteria for expectant management were clinical stability with no or minimal abdominal pain, no evidence of significant hemoperitoneum on ultrasonography, ectopic pregnancy measuring <30 mm in mean diameter with no evidence of embryonic cardiac activity, serum β-hCG < 1500 IU/L, and the woman’s consent. Of 146 women with tubal pregnancies who received expectant management, 104 (71.2 %) resolved spontaneously and two (1.4 %) were lost to follow-up; in the remaining 40 (27.4 %), expectant management was unsuccessful. In another study conducted to establish clearance curves for serum hCG levels, 161 women diagnosed with a nonviable tubal pregnancy underwent successful expectant management . The study reported a mean initial serum hCG level of 488 (range 41–4883) IU/L and a median serum β-hCG clearance time of 19 (range 5–582) days. The average half-life of β-hCG was 82.5 h in patients with steadily declining serum hCG levels compared with 106.7 h in patients with primarily plateauing hCG levels in the declining phase. A recent multicenter randomized controlled trial  found that expectant management for women that are hemodynamically stable, with an ectopic pregnancy visible on transvaginal sonography, and with a plateauing serum hCG concentration <1500 IU/L or with a PUL and a plateauing serum hCG concentration <2000 IU/L, is an alternative to medical treatment with single-dose methotrexate treatment. The study demonstrated that there was no significant difference in primary treatment success rate of single-dose MTX versus expectant management, 31/41 (76 %) and 19/32 (59 %), respectively (relative risk;1.3, 95 % confidence interval; 0.9–1.8).
4.15 Surgical Management
4.15.1 Laparoscopic Approach
Laparoscopic surgery is the best possible treatment for tubal pregnancy (Fig. 4.26), and the laparoscopic approach has already been standardized. Laparoscopic surgery is minimally invasive, resulting in a shorter duration of hospital stay, lower blood loss, and lower pain after surgery. Two randomized studies comparing outcomes between laparotomy and laparoscopic surgery in the 1990s showed that laparoscopic surgery was superior to laparotomy [106, 107]. In addition, there was no significant difference in the tubal patency and intrauterine pregnancy or incidence of repeat tubal pregnancy after surgery. A randomized controlled study compared adhesion formation between salpingostomy via laparoscopy and laparotomy for ectopic pregnancy . The study demonstrated that women who underwent laparotomy developed significantly more adhesions on the operated side than did women who underwent laparoscopy. Another advantage of laparoscopic surgery is that the abdominal appearance can be minutely inspected via a closed laparoscopic view. The first abdominal incision for a laparoscopic approach is usually made at the umbilicus, and two to three additional incisions are made for intra-abdominal manipulations. In recent years, the invasiveness of the laparoscopic approach for tubal pregnancy has decreased with the use of reduced port surgery [109–114], including single-port laparoscopic surgery (Fig. 4.27); however, the duration of the procedures tends to be longer. Therefore, further randomized studies comparing these procedures should be conducted to confirm their benefits.
A laparoscopic conservative management of an early left tubal pregnancy
Single-incision laparoscopic surgery for tubal pregnancy. Multiple devices for laparoscopic surgery are inserted through a single umbilical incision using SILS-portTM (Covidien, MA, USA) (a). A left fallopian tube with an ectopic mass is removed using a vessel-sealing device during single-incision laparoscopic salpingectomy (b). The ectopic mass is gently removed from the tubal lumen using forceps via a linear incision during single-incision laparoscopic salpingostomy (c). The tubal mucosa and serosa are closed by sutures using SILS-stitchTM(Covidien) during single-incision laparoscopic salpingostomy (d)
4.16 Surgical Procedures
Salpingectomy is a radical surgery for tubal pregnancy involving complete, or sometimes partial, resection of the fallopian tube containing an ectopic mass. Indications for salpingectomy include a ruptured ectopic pregnancy, a tubal ectopic mass diameter >5 cm, and a repeat tubal pregnancy after conservative management. The resection of an affected fallopian tube starts with an incision from the mesosalpinx between the fimbria and ovary using a monopolar or bipolar power device, and the tube is finally detached by cutting the uterine attachment site. Laparoscopic loop ligation was used as a classical procedure because of the convenience. However, the persisting remnant interstitial or fimbrial portions may result in an ipsilateral ectopic pregnancy [115–117]. Therefore, the fallopian tube should be completely resected all the way around. Recently, vessel-sealing devices (Fig. 4.27b), which can reduce blood loss and shorten the surgery duration, have been used instead of mono- and bipolar power devices for resection of the affected fallopian tube (Fig. 4.28). A laparoscopic disposable bag is useful to extracorporeally remove the resected fallopian tube to prevent residency of the ectopic tissue in the abdominal cavity.
Laparoscopic procedures for tubal pregnancy. (a) Using vessel-sealing device for salpingectomy. (b) Incision on the tubal serosa using laparoscopic scissors during salpingostomy. (c) Removal of intra-tubal ectopic tissue using a forceps. (d) Closing by suture on tubal serosa
Salpingostomy for tubal pregnancy is chosen for women who wish to retain fertility after the surgery. Injection of 2–4 IU vasopressin (diluted 1:100 in saline) into the mesosalpinx around the affected tube can reduce blood loss and prevent thermal damage caused by extensive coagulation during surgery. The tubal serosa of the superior edge of the mass is gently grasped, and an incision point is made on the tubal serosa using a monopolar needle or laparoscopic scissors (Fig. 4.29). Subsequently, 3–4 cm of tubal serosa and muscle are sharply and linearly dissected along the long axis of the tube using scissors. After complete fenestration of the tubal lumen, intra-tubal ectopic tissue is carefully removed using a forceps (Fig. 4.30). The most important issue in performing salpingostomy is to prevent the risk of persistent ectopic pregnancy. Therefore, the ectopic mass containing trophoblast tissue should be completely extracted from the fallopian tube. After the mass is removed from the fallopian tube, the inner lumen of the tube must be adequately irrigated with saline, and the milking of the fallopian tube should be performed with minimal tubal trauma to protect the salpingian mucosa. In a comparative observational study conducted on 102 patients with ampullary tubal pregnancy, stripping was performed in 56 women using unique fallopian tube stripping forceps devised for tubal milking, and salpingostomy was performed in 46 women. Although there was no significant difference in bleeding, surgical duration, or persistent ectopic pregnancy rate, the persistent ectopic pregnancy rate tended to be lower in women who underwent the stripping performed using the unique fallopian tube stripping forceps . The cleavage site of the tubal muscular layer is confirmed by chromotubation with indigo carmine dye injected through the uterine manipulator (Fig. 4.30). Closing by suture is preferred because this may prevent postsurgical adhesion formation (Fig. 4.30); however, whether to suture the tubal incised serosa after tissue removal is controversial [119, 120]. A randomized study comparing outcomes between women who underwent salpingostomy without and with suturing showed, respectively, a 90 and 94 % tubal patency rate of the treated side, and evaluation of second-look laparoscopy 3 months after the initial surgery revealed peritubal adhesions in 33 % of the women without suturing and in 29 % of the women with suturing . In addition, there was no significant difference in the incidence of tubal fistula or cumulative pregnancy rate after surgery between the two groups. The patency of the treated tube was favorable in approximately 90 % of women who underwent salpingostomy for tubal pregnancy .
Laparoscopic salpingostomy for tubal pregnancy. Vasopressin diluted in saline is injected into the mesosalpinx around the affected tube (a). An incision point is made on the tubal serosa using a monopolar needle (b). The tubal serosa and muscle are sharply and linearly dissected along the long axis of the tube using scissors (c). Intra-tubal ectopic tissue is carefully removed using forceps (d)
Laparoscopic salpingostomy for tubal pregnancy. The cleavage site of the tubal muscular layer is confirmed by chromopertubation using indigo carmine dye (e). The tubal muscular and serosal layers are closed by continuous suture using 3-0 absorbable strings (f–h)
4.16.3 Persistent Ectopic Pregnancy
The incidence of persistent ectopic pregnancy after salpingostomy is reported as 5–20 % . It has been reported that a postoperative day 1 hCG decrease of <50 % from the initial preoperative hCG level was significantly associated with the development of persistent ectopic pregnancy after conservative surgical management for tubal pregnancy (Fig. 4.31) (relative risk = 3.51) . In addition, no case of persistent ectopic pregnancy developed when the postoperative day 1 hCG declined more than 76 %. Two randomized controlled trials have shown that the risk of persistent trophoblastic tissue is higher after laparoscopy than after laparotomy [124, 125]. However, a recent retrospective cohort study has shown that only nine of 334 patients (2.7 %) who underwent laparoscopic salpingostomy developed persistent ectopic pregnancy and were treated with systemic methotrexate after surgery . An observational study evaluating 46 women with tubal pregnancy showed that only one women (2.1 %) developed persistent ectopic pregnancy after laparoscopic salpingostomy . These results indicated that advances in laparoscopic techniques may decrease the incidence of persistent ectopic pregnancy. It is suggested that several factors may increase the risk of persistent ectopic pregnancy after conservative surgery, including preoperative high hCG level, treatment for a ruptured tube, extraction of tissue containing a fetal heartbeat, an isthmus pregnancy, and the diameter of the tubal ectopic mass. A retrospective cohort study  demonstrated that among 1306 women with an ectopic pregnancy managed exclusively by means of laparoscopic conservative surgery, 86 (6.6 %) required further treatment for persistent ectopic pregnancy. The study found a statistically significant risk of failure in patients with preoperative serum hCG levels ≥1960 IU/L (OR = 1.8; 95 % CI, 1.1–2.8, p = 0.02). In another study , 47 of 134 women (35.9 %) who underwent successful linear salpingostomy developed persistent ectopic pregnancy after the initial surgery and 18 of 134 women had no patency in the treated tube evaluated by hysterosalpingography or second-look laparotomy. The study demonstrated that the serum hCG level in women who underwent unsuccessful procedures was significantly higher than that of the women whose procedures were successful, and the procedures in all women with serum hCG >10,000 IU/L failed; salpingostomy may also fail for women with a fetal heartbeat in the ectopic mass because these women had higher preoperative hCG levels. Some authors recommended that laparoscopic salpingostomy should not be attempted when the maximum diameter of the ectopic pregnancy lesion is more than 4–6 cm [128–130]. It was reported that the use of prophylactic methotrexate during or after surgery decreases the risk of persistent ectopic pregnancy. A randomized study evaluated the incidence of persistent ectopic pregnancy in women who underwent linear salpingostomy in comparison with women who received a single injected dose of methotrexate after surgery . The study revealed that the incidence of persistent ectopic pregnancy was significantly lower in women injected with methotrexate after surgery (1.9 %) than in women without injection (14.5 %). In addition, the relative risk of developing persistent ectopic pregnancy after prophylactic methotrexate was 0.13. An observational study evaluating the incidence of persistent ectopic pregnancy in women who had 50 mg methotrexate locally injected into the tubal wall immediately following laparoscopic linear salpingostomy for tubal pregnancy ; none of the women who received a local methotrexate injection developed persistent ectopic pregnancy, but 17.5 % of the women in the control group did.
A transvaginal pelvic scan detecting a persistent ectopic pregnancy after laparoscopic salpingostomy
4.16.4 Salpingectomy Versus Salpingostomy
If the tube is ruptured or appears extensively damaged, salpingectomy may be preferred. However, there is debate over whether surgical treatment for tubal pregnancy should be a conservative salpingostomy or radical salpingectomy in women who desire a future pregnancy. Table 4.3 shows recent studies comparing outcomes of salpingostomy with salpingectomy [133–135]. An observational population-based study  assessed reproductive outcomes after an ectopic pregnancy based on the type of treatment used and reported that the 24-month cumulative rate of intrauterine pregnancy was 67 % after salpingectomy, 76 % after salpingostomy, and 76 % after medical treatment. In multivariate analysis, the intrauterine pregnancy rate was significantly higher after conservative treatment compared with that after salpingectomy (hazard ratio 0.784). However, two recent multicenter randomized studies denied the superiority of fertility outcomes after salpingostomy [134, 135]. The European Surgery in Ectopic Pregnancy (ESEP) study group  reported no significant difference in the cumulative pregnancy rate after salpingostomy (60.7 %) and after salpingectomy (56.2 %), and persistent ectopic pregnancy occurred more frequently in the salpingostomy group (7 %) than in the salpingectomy group (<1 %) (relative risk 15.0). In contrast, there was no significant difference in the incidence of repeat ectopic pregnancy between the two groups (8 % vs. 5 %). However, if a woman who has undergone salpingectomy due to previous tubal pregnancy would be occurred repeat contralateral pregnancy, the choice of salpingectomy for residual tube is not exactly for the feasibility of her future fertility. Therefore, further studies concerning to betterment of surgical treatment for fertility for women with repeat tubal pregnancy should be conducted.
Recent studies comparing salpingostomy to salpingectomy for tubal ectopic pregnancy
No. of patients
Surgical inclusion criteria
Persistent tubal pregnancy
Repeat tubal pregnancy
Cumulative pregnancy rate
de Bennetot et al. 
Observational population based-study
1064 salpingostomy, 646; salpingectomy, 299; Medical treatment, 119
Including symptomatic patients, ruptured tube and hCG >5000 IU/L
Salpingotomy and salpingectomy, 18.5 %; medical treatment, 25.5 %
At 24 months salpingostomy, 76 %; salpingectomy, 67 %; medical treatment, 76 % p = 0.74
Fernandez et al.  (The DEMETER study)
129 salpingostomy + MTX, 66;
With hemodynamically stable, unrupured tube, and healthy contralateral tube
Salpingostomy + MTX, 4 (8 %); salpingectomy, 6 (12 %) p = 0.96
At 24 months salpingostomy + MTX, 70 %; salpingectomy, 64 % p= 0.77, HR; 1.06, 95 % CI; 0.69–1.63
Mol et al.  (The ESEP study)
446 salpingotomy, 215; salpingectomy, 231
With hemodynamically stable, unrupured tube, and healthy contralateral tube
Salpingotomy, 14 (7 %); salpingectomy, 1 (<1 %), p = 0.01
Salpingotomy, 18 (8 %); salpingectomy, 12 (5 %), p = 0.19
At 36 months salpingotomy, 62.3 %; salpingectomy, 56.2 %, p = 0.49, HR; 1.10, 95 % CI; 0.83–1.46
NA not applicable, RCT randomized controlled trial, MTX methotrexate, HR hazard ratio, CI confidence interval
4.16.5 Medication Therapy with Methotrexate
Methotrexate has been used as a unique medication therapy for tubal pregnancy, and its safety and efficacy for this purpose have already been proven. The use of methotrexate therapy was established in the late 1980s and has become widely accepted as a primary treatment for ectopic pregnancy, especially when an early diagnosis is made. In addition, methotrexate administration is often useful to prevent persistent ectopic pregnancy after surgery.
4.17 Mechanism of Action
Methotrexate, a folic acid antagonist that binds to the catalytic site of dihydrofolate reductase (DHFR), was the first agent to produce remission in leukemia and the first to result in the cure of a solid tumor, specifically choriocarcinoma. Folic acid is an essential component in the synthesis of DNA precursors such as purines and thymidylate . Methotrexate and other folate analogs inactivate the enzyme DHFR, which leads to the depletion of tetrahydrofolate cofactors, which are required for DNA and RNA synthesis. In order to trap the folic acid analogs intracellularly, folylpolyglutamate synthetase adds extra glutamate residues onto the molecule. These residues do not cross cell membranes easily, and as such, this mechanism is efficient in increasing the intracellular concentration of the drug, thus prolonging the action of the medication within the cells. It is likely that this mechanism accounts for the feasibility of single-dose administration of the drug. Folate is reduced to tetrahydrofolate by DHFR by the addition of single-carbon groups, which are then subsequently transferred in the synthesis of DNA and RNA. Tetrahydrofolate is converted to dihydrofolate when it donates a methyl group to dUMP in the production of thymidylate. In order to keep the reaction propagating, dihydrofolate must again be reduced by DHFR to tetrahydrofolate in order to continue donating methyl groups for subsequent reactions. When DHFR is inhibited by folic acid analogs, the dihydrofolate polyglutamates build up in the cell and act as toxic substrates. When this occurs, the one-carbon transfer reactions are halted, as is the synthesis of DNA and RNA.
Folinic acid, the 5-formyl derivative of tetrahydrofolic acid, is readily metabolized in vitro by tetrahydrofolic acid and, like folic acid, also functions as a vitamin. It activates regardless of the action of DHFR and thus resolves the reduction of DHFR action caused by methotrexate, but the mechanism of this action remains unclear. Therefore, folinic acid (leucovorin) prevents some otherwise prohibitive side effects and allows for the administration of higher or multiple methotrexate doses for tubal pregnancy (leucovorin rescue). Methotrexate is rapidly cleared from the body by the kidneys, with 90 % of an intravenous dose excreted unchanged within 24 h.
4.18 Preparation of Methotrexate Treatment
Methotrexate should be administered only when a definitive pretreatment diagnosis of tubal pregnancy has been made lest women with undiagnosed miscarriage experience unnecessary side effects and costs. In addition, methotrexate carries a risk of congenital anomalies if it is administered during the first trimester of gestation. Administration of methotrexate is an option for women who do not have a ruptured tube, are hemodynamically stable, have no severe abdominal pain or signs of massive hemoperitoneum, and are reliable for continuation of follow-up until the resolution of the condition. Contraindications for methotrexate treatment are postulated by the ACOG guidelines . Before treatment, adequate medical history and blood tests are essential to exclude absolute contraindications. Because methotrexate is hepatotoxic and is filtered by the kidneys, it should not be administered to women with liver or kidney disease. Patients should not be treated with methotrexate when laboratory data, such as liver transaminase levels, are outside of the normal range; other absolute contraindications include anemia, a creatinine level greater than 1.3–1.5 mg/dL, a white blood cell count <3000/μL, or a platelet count <100,000/μL . Folic acid intake interferes with methotrexate efficacy and should be avoided . A chest radiograph is needed to rule out pulmonary disease because methotrexate has been implicated as a cause of serious lung toxicity . Relative contraindications are proposed by clinical failure of methotrexate treatment. The practice Committee of the American Society for Reproductive Medicine  suggested that predictive factors related to treatment failure are identified before treatment, including the presence of an ectopic mass >4 cm in diameter, visible fetal cardiac motion on ultrasound, and a serum hCG level >5000 mIU/mL, as relative contraindications. It was reported that women treated with a single-dose regimen for tubal pregnancy with an initial hCG concentration >5000 mIU/mL had a higher failure rate than did women with a lower hCG concentration (OR = 5.5; 95 % CI, 3.0–9.8) . An ectopic mass with a diameter <3–4 cm by ultrasound is also commonly used as a patient selection criterion, although this has not been fully agreed on by some clinicians as a predictor of successful treatment. In addition, pregnancy after administration of methotrexate should be avoided for more than 3 months .
4.19 Protocols of Methotrexate Treatment
The two methotrexate protocols commonly used for ectopic pregnancy are multiple-dose and single-dose administrations. The multiple-dose protocol, which originates from early experience with methotrexate treatment for trophoblastic disease, was first used to treat ectopic pregnancy . For the multiple-dose protocol, methotrexate is intramuscularly administered at a dose of 1 mg/kg per day on days 1, 3, 5, and 7 of treatment . Leucovorin is given at a dose of 0.1 mg/kg intramuscularly on days 2, 4, 6, and 8 to prevent cell toxicity from an overdose of methotrexate. Women receive up to four doses until their serum hCG level decreases by at least 15 % on two consecutive measurements, 2 days apart. All women need to be followed up until their hCG level is no longer detectable in serum. If the hCG level is confirmed to be increased or plateaued after four doses administered on day 7, an additional dose can be given 2 days later. However, surgical management may be preferable for such a condition.
Under the single-dose protocol, methotrexate is intramuscularly administered at a dose of 50 mg/m2 body surface area . Leucovorin rescue is not required because of the low dose. The advantage of this protocol is the simplified administration and less need for follow-up. However, if hCG values do not decrease by at least 15 % from the initial value between days 4 and 7 after initial administration, a second dose is administered after 1 week. Similar to the multiple-dose protocol, women are followed up until their hCG level is no longer detectable in serum.
Figures 4.32 and 4.33 show schemes of the two regimens.
The methotrexate protocol commonly used for ectopic pregnancy by single-dose administration. hCG human chorionic gonadotropin, MTX methotrexate
The methotrexate protocol used for ectopic pregnancy by multiple-dose administrations. hCG human chorionic gonadotropin, MTX methotrexate, LEU leucovorin
4.20 Clinical Course and Side Effects of Methotrexate Treatment
Awareness of the clinical course after methotrexate treatment for ectopic pregnancy is indispensable for clinicians to immediately manage treatment failure and tubal rupture. Transient pain, the so-called separate pain, may occur between 3 and 7 days after treatment begins in some patients , but it normally is relieved within 4–12 h of onset. When severe and persistent pain is confirmed, surgical management should be considered with suspected rupture of the tubal ectopic mass. Signs suggesting treatment failure or possible rupture include hemodynamic instability, increasing abdominal pain regardless of trends in hCG levels, and rapidly increasing hCG concentrations (>53 % over 2 days) after four doses in the multiple-dose regimen or after two doses in the single-dose regimen . Although methotrexate-related toxicity may include leukopenia, thrombocytopenia, pancytopenia, nausea, vomiting, stomatitis, mucositis, and liver and lung toxicity, these side effects are very uncommon. A previous retrospective study demonstrated that 2 % of 50 patients developed stomatitis, all of which resolved spontaneously . In addition, a literature review showed that the single-dose regimen was associated with fewer side effects (OR = 0.44) compared with the multiple-dose regimen .
4.21 Clinical Efficacy of Methotrexate Treatment
Table 4.4 shows recent studies comparing single-dose with multidose regimen [147–150]. A meta-analysis  of 26 articles including 1327 cases of women diagnosed with ectopic pregnancy treated with methotrexate reported an overall success rate of 89 % for women treated with methotrexate for an ectopic pregnancy, including single-dose and multiple-dose regimens. The presence of embryonic cardiac activity noted on ultrasound was significantly associated with treatment failure (OR 9.09; 95 % CI, 3.76–21.95). A total of 36.2 % of women experienced side effects, including nausea, diarrhea, mouth sores, or an increase in liver transaminases. The presence of abdominal pain was reported in 28.3 % of women. The overall success rate in 1067 women managed with the single-dose regimen was 88.1 % and that in the 260 women managed with the multiple-dose regimen was 92.7 %. Of the women who received the single-dose regimen, 14.5 % received more than one dose of methotrexate and 1 % received three or more doses. Of the women treated with the multiple-dose regimen, 53.5 % received four or more doses and 6.8 % received more than five doses. The single-dose regimen for ectopic pregnancy was significantly associated with a higher failure rate compared with the multiple-dose regimen; however, women treated with the single-dose regimen had significantly fewer side effects. Two randomized studies demonstrated that the success rate of the single-dose regimen was the same as that of the multiple-dose regimen [149, 150]. Another randomized study compared the success rate of the single-dose regimen with that of the multiple-dose regimen in 108 patients presenting with unruptured ectopic pregnancies with hemodynamic stability, tubal mass <3.5 cm in diameter, absence of fetal cardiac activity, and hCG <15,000 mlU/mL and found no significant difference between the two groups (88.9 % vs. 92.6 %) . Although the number of doses of methotrexate in the multiple-dose group was higher, no significant difference between the two groups was found in the incidence of complications. Another randomized study evaluated 120 women with unruptured tubal pregnancy who met the criteria for hemodynamic stability, serum hCG levels reaching a plateau or increasing by <50 % in 48-h intervals, and an adnexal mass ≤3.5 cm in diameter and found no significant difference in the success rates between the single-dose and multiple-dose regimens (80.6 % vs. 89.7 %, p= 0.21) . The mean number of days until the hCG level dropped <5 mU/mL was significantly longer in the single-dose group than in the multiple-dose group (22.3 ± 7.6 vs. 18.3 ± 10.7 days, p = 0.03). However, the incidence of side effects was significantly higher in the multiple-dose group (48.3 % vs. 27.7 %, p = 0.02). The authors concluded that the multiple-dose methotrexate regimen for unruptured tubal pregnancy is not more effective than a single-dose regimen.
Studies compared single-dose with multidose regimen for tubal ectopic pregnancy
No. of patients
Barnhart et al. 
Single-dose regimen, 1067; multidose regime, 260
Single-dose, 88.1 %; multidose, 92.7 % p = 0.035
Lipscomb et al. 
Retrospective cohort study
Single-dose regimen, 546; multidose regimen, 97
Ectopic mass, < 3.5–4 cm; absence of fetal cardiac activity
Single-dose, 90 %; multidose, 95 % p = 0.18
Alleyassin et al. 
Single-dose regimen, 54; multidose regimen, 54
Ectopic mass, < 3.5 cm; absence of fetal cardiac activity serum hCG < 15,000 mIU/mL
Single-dose, 88.9 %; multidose, 92.6 % p = 0.07, OR; 0.64, 95 % CI; 0.17–2.4
Guvendag Guven et al. 
Single-dose regimen, 62; multidose regimen, 58
Hemodynamically stable ectopic mass, <3.5 cm; absence of fetal cardiac activity serum hCG with plateau or increasing ≦50 % in 48-h interval
Single-dose, 80.6 %; multidose, 89.7 % p = 0.21, OR; 0.90, 95 % CI; 0.77–1.05
NA not applicable, RCT randomized controlled trial, OR odds ratio, CI confidence interval
4.22 Efficacy of Local Injection of Methotrexate
Although the population in studies of local injection is limited, some clinicians described that local injection of methotrexate is acceptable for women who have a tubal pregnancy with a high serum hCG concentration, large conceptus size, and the presence of fetal cardiac activity. A retrospective study including 12 women with ectopic pregnancy and fetal cardiac activity treated by combined local and systemic injection of methotrexate reported a success rate of 91.6 % . A study evaluating the efficacy of a systemic multiple-dose regimen combined with ultrasound-guided local injection of methotrexate in 82 women with tubal pregnancies showed that the success rate in women who received combined therapy was higher than that in women who received only systemic treatment (93.3 % vs. 73.0 %, p = 0 .05) . The proportion of women in the systemic treatment group who received more than two injections of methotrexate was significantly greater than that in the combination treatment group (48.6 % vs. 15.6 %, p = 0.002). The local injection of methotrexate is sometimes useful for women relative contraindications for methotrexate treatment; however, technical difficulties with this technique remain.
4.23 Surgery Versus Methotrexate Treatment
Several randomized controlled studies comparing methotrexate treatment with laparoscopic surgery for tubal pregnancy [153–157] demonstrated that methotrexate treatment is equal to laparoscopic surgery in selected women. In addition, it has also been reported that fertility after both treatments does not differ. A randomized controlled trial of comparison 34 women who received systemic methotrexate with 40 who underwent laparoscopic salpingostomy found that the cumulative spontaneous intrauterine pregnancy rates at 18 months were with not significantly different: 36 % and 43 %, respectively . A recent randomized study comparing outcomes of single-dose methotrexate treatment for tubal pregnancy with laparoscopic surgery in 106 women with hemodynamic stability, a gestational sac diameter <3.6 cm, and plasma hCG <2000 IU/L  found no significant difference in the success rates and subsequent spontaneous intrauterine pregnancy rate between the two groups (74 % with methotrexate treatment vs. 87 % after surgery and 73 % with methotrexate treatment vs. 62 % after surgery, respectively). In contrast, systemic methotrexate therapy was reported to have a more negative impact on patients’ health-related quality of life than laparoscopic surgery. A randomized controlled trial including 79 hemodynamically stable women with unruptured tubal pregnancy without signs of active bleeding compared patients’ health-related quality of life after systemic methotrexate therapy and after laparoscopic salpingostomy . The authors found that health-related quality of life, assessed using the Medical Outcomes Study Short-Form 20, was more severely impaired after methotrexate treatment than after laparoscopic salpingostomy. Physical functioning, role functioning, social functioning, mental health, health perceptions, and pain were all worse in the methotrexate treatment group than in the surgery group.
Although tubal pregnancy is a common gynecologic condition and the risk factors have been evaluated, the specific etiology is not yet fully clear. Therefore, further study is needed to elucidate the etiology of tubal pregnancy for better prevention and for the development of novel diagnostic procedures and therapy. Accurate earlier diagnosis for tubal pregnancy is mandatory to facilitate prompt management to prevent maternal fatal outcomes.
At present, although it seems that surgical and medical treatments have already been established, it is suggested that more minimally invasive (Figs. 4.34, 4.35, 4.36, and 4.37), as well as cost-effective, therapies and treatments could be developed in an effort to avoid deterioration in the health-related quality of life of patients.
Schematic laparoscopic treatment of a tubal pregnancy. First step: tubal incision by monopolar instrument (croquet needle)
Schematic laparoscopic treatment of a tubal pregnancy. Second step: extrauterine pregnancy removal
Schematic laparoscopic treatment of a tubal pregnancy. Third step: intra-tubarian suction of residual fragments of extrauterine pregnancy
Schematic laparoscopic treatment of a tubal pregnancy. Fourth step: anastomotic and hemostatic suturing of the incised fallopian tube
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