Ectopic pregnancy: a review
Poonam Rana, Imran Kazmi, Rajbala Singh, Muhammad Afzal, Fahad A. AlAbbasi, Ali Aseeri, Rajbir Singh, Ruqaiyah Khan & Firoz Anwar Archives of Gynecology and Obstetrics ISSN 0932-0067 Volume 288 Number 4 Arch Gynecol Obstet (2013) 288:747-757 DOI 10.1007/s00404-013-2929-2
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Author's personal copy Arch Gynecol Obstet (2013) 288:747–757 DOI 10.1007/s00404-013-2929-2
REPRODUCTIVE MEDICINE
Ectopic pregnancy: a review Poonam Rana • Imran Kazmi • Rajbala Singh • Muhammad Afzal • Fahad A. Al-Abbasi • Ali Aseeri Rajbir Singh • Ruqaiyah Khan • Firoz Anwar
•
Received: 24 December 2012 / Accepted: 22 May 2013 / Published online: 21 June 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Ectopic pregnancy (EP) presents a major health problem for women of child-bearing age. EP refers to the pregnancy occurring outside the uterine cavity that constitutes 1.2–1.4 % of all reported pregnancies. All identified risk factors are maternal: pelvic inflammatory disease, Chlamydia trachomatis infection, smoking, tubal surgery, induced conception cycle, and endometriosis. These developments have provided the atmosphere for trials using methotrexate as a non-surgical treatment for EP. The diagnosis measure of EP is serum human chorionic gonadotropin, urinary hCGRP/i-hCG, progesterone measurement, transvaginal ultrasound scan, computed tomography, vascular endothelial growth factor, CK, disintegrin and metalloprotease-12 and hysterosalpingography. The treatment option of EP involves surgical treatment by
P. Rana I. Kazmi R. Singh (&) M. Afzal (&) R. Khan F. Anwar (&) Siddhartha Institute of Pharmacy, Dehradun 248001, Uttarakhand, India e-mail:
[email protected] M. Afzal e-mail:
[email protected] F. Anwar e-mail:
[email protected]
laparotomy or laparoscopy, medical treatment is usually systemic or through local route, or by expectant treatment. Results It was concluded that review data reflect a decrease in surgical treatment and not an actual decline in EP occurrence so that further new avenues are needed to explore early detection of the EP. Keywords
b-hCG TVS Methotrexate Laparotomy
Abbreviations EP Ectopic pregnancy CEP Cervical ectopic pregnancy OEP Ovarian ectopic pregnancy CSEP Cesarean scar ectopic pregnancy IP Interstitial pregnancy PID Pelvic inflammatory disease PROKR Prokineticin receptor IVF In vitro fertilization ART Assisted reproductive technology b-hCG Serum human chorionic gonadotropin TVS Transvaginal ultrasound scan CT Computed tomography VEGF Vascular endothelial growth factor ADAM-12 Disintegrin and metalloprotease-12 Hsg Hysterosalpingography MTX Methotrexate PPV Positive predictive value
F. A. Al-Abbasi Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia A. Aseeri Lab Director, Jeddah Eye Hospital, Ministry of Health, Jeddah, Saudi Arabia R. Singh Alchemist Hospital, Panchkula, Haryana, India
Introduction Ectopic pregnancy (EP) or extra uterine pregnancy, accepted from the Greek word ‘‘ektopos’’ meaning out of place [1], refers to the blastocyst implantation outside the
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uterine cavity endometrium with over 95.5 % implanting in the fallopian tube [2–6]; where fetus or embryo is often absent or stops growing. The other most common implantation sites are ovarian (3.2 %) and abdominal (1.3 %) sites [7]. This is a major track and significant cause of morbidity and mortality with associated risks of tubal rupture and intra abdominal hemorrhage in women and can lead to substantial future reproductive morbidity, including subsequent ectopic pregnancy and infertility [8–12]. Hence, it is a medical emergency that requires immediate treatment [13]. The annual incidence of EP has increased over the past 30 years [14]. In the western world 4–10 % of pregnancyrelated deaths have been observed [15, 16], from this issue and now it is a growing problem in developing countries also [17]. Although advances in diagnostic methods have allowed for earlier diagnosis, it still remains a life threatening condition. Approximately, 75 % of deaths in the first trimester and 9 % of all pregnancy-related deaths are due to EP [12]. Around 10,000 EP are diagnosed annually in the UK. The incidence of EP in the UK (11.1/1,000 pregnancies) is similar to that in other countries, such as Norway (14.9/ 1,000) and Australia (16.2/1,000) [18–20] from 1994, the overall rate of EP and resulting mortality (0.35/1,000 EP in 2003–2005) has been static in the UK [20]. A French population study undertaken from 1992 to 2002 found that, over the duration of the study, the rate of reproductive failure EP increased by 17 %. Haifa et al. studied that there is an increasing trend in terms of EP in the eastern countries like Saudi Arabia [21]. Calderon et al. [22] reported an EP rate in California of 11.2 per 1,000 pregnancies during 1991–2000; Sewell and Cundiff [23] noted a rate in Maryland of 5.2 per 10,000 women aged 15–44 years between 1994 and 1999 (Fig. 1).
Types of ectopic pregnancy The fallopian tube is the dominant site [24] in the majority of cases of tubal ectopic pregnancy. 75–80 % of EPs occur in the ampullary portion, 10–15 % of EPs occur in the isthmic portion and about 5 % of EP is in the fimbrial end of the fallopian tube [25]. The tubal EP can be detected by TVS, and implies an intact fallopian tube with a pregnancy that is likely to be growing and visualized of an inhomogeneous mass that might well be a collapsed sac, which is less likely to contain active trophoblastic tissue [26]. Cervical ectopic pregnancy (CEP) is rare and represents only 0.15 % of all EP [27]. A cervical pregnancy before 1979 was almost always associated with hysterectomy for uncontrollable vaginal bleeding, and this made women sterile [28, 29]. It can be diagnosed by ultra sonography
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according to the criteria described by Hofmann and TimorTritsch. In true CEP, Doppler studies show characteristic patterns of trophoblast with high flow velocity and low impedance [30, 31]. Ovarian ectopic pregnancy (OEP) is one of the rarest variants, and incidence is estimated to be 0.15–3 % of all diagnosed OEP [32, 33]. Early diagnosis is necessary to avoid more serious complications and emergency invasive procedures [34]; moreover, Panda et al. [35] said that its preoperative diagnosis remains a challenge, and it cannot be early diagnosed. Medical therapy with MTX was not a possible option due to the occurrence of massive bleeding. In general, in case of hemoperitoneum most surgeons prefer to perform laparotomy. Few cases of laparoscopic treatment in women with hemoperitoneum have been reported by various researchers [36]. Cesarean scar ectopic pregnancy (CSEP) is another rarest form of EP with an incidence of 1:1,800 pregnancies [37] due to increased number of cesarean deliveries over the last 30 years [38]. It is widely spreading in society. Here, the gestational sac is implanted in the myometrium at the site of a previous cesarean section. Various complications, such as uterine rupture and massive hemorrhage, may be life threatening and impact negatively on future fertility in case of CSEP [38]. The etiology of cesarean scar pregnancy is unclear although previous cesarean section, myomectomy, adenomyosis, IVF, previous dilatation and curettage, along with manual removal of placenta have been linked as risk factors for such type of EP [39–41]. Interstitial pregnancy (IP) constitutes 2.5 % of all EP [2]. Correct diagnosis of IP can be quite difficult and it requires accurate ultrasound interpretation. The diagnosis relies heavily on ultrasound and potentially on laparoscopic evaluation [42]. It is performed by visualization of the interstitial line adjoining the gestational sac and the lateral aspect of the uterine cavity followed by continuation of the myometrial mantle around the ectopic sac [30]. A true cornual ectopic pregnancy is one in the rudimentary horn of a unicornuate uterus. It is one of the insolites, form of EP at 0.27 % of imports [43]. This term is often used in the medical literature with interstitial EP [44, 45]. The traditional treatment of interstitial pregnancy has been cornual resection or hysterectomy in cases of severely damaged uterus [42]. However, there are successful case reports of laparoscopic resection of cornual pregnancies [46]. Laparoscopic excision is safe but attention needs to be paid to the possibility of urinary tract anomalies which may be associated with unicornuate uteri [47]. Advanced cases in the second and third trimester, where the risk of rupture is high, requires an open approach to excision at laparotomy [48]. Abdominal ectopic pregnancy with 1.3 % of cases [2] is diagnosed at a rate of 1:10,000 births and is an extremely rare and serious form of extrauterine gestation [49]. It is
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Fig. 1 Summary of ectopic pregnancy (EP) Tubal EP (90-95%) Cervical EP (0.15%)
PREGNANCY (EP)
Expectant treatment Medical treatment (systemic or local
Ovarian EP (0.15%-3%)
route)
Caesarean scar EP (6%)
Surgical treatment (laparotomy or
Interstitial EP (2.5%)
laparoscopy)
Abdominal EP (1.3%) Heterotopic EP (1-3%)
Serum β-human chorionic gonadotropin (bhCG) test Urinary hCGRP/i-hCG ratio Light vaginal bleeding Progesterone measurement
Pelvic inflammatory disease (PID)
Transvaginal ultrasonography (TVS)
Age
Computed Tomography (CT) or MRI
Lower abdominal pain
Cigarette smoking
Vascular Endothelial Growth Factor (VEGF)
Sharp abdominal cramps
History of ART and IVF Creatine kinase (CK) Previous history of EP Contraception pills
Disintegrin and Metalloprotease-12 (ADAM-12)
Nausea and Vomiting
Pain on one side of the body Dizziness or weakness Pain in the shoulder, neck, rectum
Hysterosalpingography (Hsg)
described as primary or secondary abdominal ectopic pregnancy and usually results from an implantation following tubal rupture or abortion through the fimbricated end of the fallopian tube. The fetus continues to grow following attachment to an abdominal structure, using its blood source, which may be extensive. It usually attaches to the surface of the uterus, broad ligaments, or ovaries, but may also attach to the liver, spleen, or intestines [24, 50]. The traditional management involves a laparotomy with removal of the fetus with or without placental tissue [51]. One of the problems associated with the removal of abdominal pregnancies after the first trimester is that the risk of uncontrolled bleeding from the placental bed [52]. A heterotopic ectopic pregnancy is diagnosed when women have any of the above said EP in conjunction with an intra uterine pregnancy. It occurs with a rate \1:30,000 naturally occurring pregnancies, and 1:100 couples who conceive through assisted reproduction [53]. It is also more common (1–3 %) in in vitro fertilization and fertility treatments involve superovulatory drugs [54, 55]. A highresolution transvaginal ultrasound with color Doppler will be helpful to locate the trophoblastic tissue in the adnexa in a case of heterotopic EP [56]. Different sites for ectopic pregnancy are depicted in Fig. 2. Fig. 2 Different site for ectopic pregnancy
Risk factor EP is further common in women who have suffered with pelvic inflammatory disease (PID) and more than 50 % of
women who have been infected are unaware of the exposure of PID [57]. Moreover, it is due to difficulties in determining the effect of female genital chlamydial
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infection on reproductive outcome arise from flaws in specific study design and the lack of a reliable method for measuring a history of pelvic infection [58]. Current assumptions on the risks of subsequent pregnancy problems, following pelvic infection, are based on retrospective case control studies, the incidence of tubal damage increases after successive episodes of PID (i.e., 13 % after 1 episode, 35 % after 2, and 75 % after 3 episodes) [57, 59–62]. It has been proposed that an antibody response to the chlamydial heat shock protein (hsp-60) may cause a tubal inflammatory response leading to tubal blockage or a predisposition to tubal implantation [63]. Repeated infections with C. trachomatis are thought to increase tubal damage [64]. Age is the risk of EP increases with advancing maternal age, with age over 35 years being a significant risk factor [12]. Hypotheses for this association include the higher probability of exposure to most other risk factors with advancing age, increase in chromosomal abnormalities in trophoblastic tissue and age-related changes in tubal function delaying ovum transport, resulting in tubal implantation [65]. The incidence of EP showed a steady increase with the increase in maternal age at conception from 1.4 % of all pregnancies at the age of 21 years to 6.9 % of pregnancies in women aged 44 years or more [66, 67]. Cigarette smoking is the major cause of one-third of all cases of EP [68]. Most studies investigating the effect of smoke on the fallopian tube have been performed in rodents and relate to cigarette smoke’s effect on ciliary beat frequency and smooth muscle contraction [69–71]. Furthermore, the reason why smoking cause tubal ectopic pregnancy is not understood [71]. Tubal EP is thought to be a consequence of embryo retention within the fallopian tube due to impaired smooth muscle contractility and alterations in the tubal microenvironment. The cigarette smoking increases transcription of prokineticin receptor 1 (PROKR1), a G-protein-coupled receptor [65]. The PROKRs are receptors for PROK1, a molecule known for its angiogenic properties, control of smooth muscle contractility, and regulation of genes important for intrauterine implantation [72, 73]. Both PROKR1 and PROKR2 expression are altered in fallopian tube from women with EP, where implantation has already occurred [65]. EP is more common in women attending infertility clinics even in the absence of tubal disease. In addition, the use of assisted reproductive technology (ART) increases the rate of EP [74]. The rate of tubal EP following in vitro fertilization (IVF) still remains higher (approximately 2–5 %) than the rate of tubal EP with spontaneous pregnancy (1–2 %) [12, 75]. The reason for the increased incidence of tubal EP by IVF is unclear. The technique of embryo transfer is a potential cause but there is little
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evidence to support this. The risk of tubal EP has also been reported to increase with the number of embryos that are transferred during IVF treatment [76]. Women with a previous history of EP also have an increased risk, which increases further in proportion to the number of previous EP. In Shaw et al.’s [5] study, the OR for having an EP was 12.5 % after one previous EP and 76.6 % after two. Prior tubal surgery (salpingostomy, neosalpingostomy, fimbrioplasty, tubal reanastomosis, and lysis of peritubal or periovarian adhesions) has an increased risk for developing EP. This in turn depends on the degree of damage and the extent of anatomic alteration [57]. Some types of contraception, such as progestogen only contraception and the intrauterine contraceptive device are associated with an increased incidence of EP when there is contraceptive failure, without necessarily increasing the absolute risk of EP [77]. According to Patil et al. [57], case control examination of the risk of the EP has been linked with the fourfold elevation after OI with clomiphene citrate or injectable gonadotrophins therapy. Diagnosis Previously EP was diagnosed on clinical symptoms such as vaginal bleeding and lower abdominal pain but it imposed severe constraints on early detection [78]. Initial diagnosis of first-trimester hemorrhage presents an important challenge [79]. Recently, detection of EP is determined through serum human chorionic gonadotropin (b-hCG) levels and vaginal ultrasonography techniques [79–82]. Urinary hCGRP/i-hCG ratio measurement may be effective in the diagnosis of EP [83] as a single serum measurement of the b-hCG concentration may not show the location of the gestational sac [84, 85]. Demonstration of normal doubling of serum levels over 48 h supports a diagnosis of fetal viability but does not rule out EP. Failing levels on raising the level of b-hCG concentration to reach 50 % confirm non-viability suggesting EP [86, 87]. Progesterone measurement of the serum concentration of progesterone has been deciphered as a potential useful adjunct to serum b-hCG measurement. In contrast with b-hCG concentrations, serum progesterone levels are stable for first 8–10 weeks of gestation [5, 88]. Mol et al. [89] investigated that sensitivity ranged of progesterone from 44 to 100 %, depending on the threshold. Both high ([22 ng/ml) and low (B5 ng/ml) cutoff points have been assessed for their ability to correctly identify non-viable and ectopic pregnancies; serum progesterone levels B5 ng/ml could apparently be used to predict EP with 70–90 % sensitivity and 30–99 % specificity [90, 91]. Elson et al. [92] reported that if patients have serum progesterone measurements below 10 ng/ml (31.8 nmol/L)
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and b-hCG levels below 1,500 mIU/L are more likely to demonstrate spontaneous resolution of EP. Transvaginal ultrasound scan (TVS) is very popular from 1980, and by the mid 1990 sensitivity and specificity were calculated at 84.4 and 98.9 %, respectively. It remains the gold standard for diagnosis of EP [30, 93]. A b-hCG level that has elevated above the detestable threshold in the absence of sonographic signs of early pregnancy is considered concomitant conformation of an EP. With the evolution in ultrasound technology, the detestable threshold has dropped from 6,500 IU/L with a transabdominal approach to between 1,000 and 2,000 IU/L with transvaginal imaging [94]. The spectrum of sonographic findings in EP is broad. Identification of an extrauterine gestational sac containing a yolk sac (with or without an embryo) confirms the diagnosis for EP [95]. Pregnant women generally do not undergo computed tomography (CT) and MRI examination, due to radiation but should be ruled out in all young women complaining of the abdominal pain. CT findings of the ruptured EP are sporadic and extremely rare. In emergency situations, the role of CT imaging of the abdominal and pelvic cavity has been evaluated: it remains the first-line treatment in such situations, [96–98]. Usually, CT diagnosis is reported in the context of suspected cases when the patient is extremely unstable. The CT scans clearly identified the site of bleeding and helped to differentiate and characterize other various causes of acute abdominal pain [98, 99]. Sometimes, an MRI can be helpful as well; moreover, this is not a first-line examination. It is rather used for a better preoperative planning, or as a problem-solving tool in pregnant patients, or for imaging of fetal anatomy and pathology [100, 101]. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that acts as a modulator of vascular growth, remodeling, and permeability in the endometrium, decidua, and trophoblast, as well as during vascular development in the embryo, all of which are crucial processes related to normal implantation and placentation [102]. Serum values of VEGF were significantly increased in EP. Daponte et al. [79] described higher serum VEGF concentrations in women with EP (median 227.2 pg/ml) than with abnormal intrauterine pregnancy (median 107.2 pg/ml) (p \ 0.001) and it concluded that VEGF serum concentrations might be a useful marker for EP, and suggested 174 pg/ml as the cut-off value for EP diagnosis. On the other hand, some groups have found conflicting results on whether serum measurement of VEGF could be used for differentiation of EP [81, 103]. Existing evidence suggests elevated creatine kinase (CK) as a tool for diagnosis of EP. The trophoblast usually invades the muscle layer and maternal blood vessels are eroded, allowing muscle cell products such as CK to enter
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the circulation [104]; therefore, increased serum CK levels are normal during EP [104, 105]. Saha et al. [105] performed a study comprising 40 women; total serum CK levels were found to be significantly higher in the EP group as compared to the controls (p \ 0.001), suggesting that this test might be used as a indicator for EP. Similarly, Katsikis et al. [106] studied 40 women with EP; and concluded that women with EP had significantly higher CK concentrations compared to women with intrauterine abortive pregnancies and controls, suggesting that CK concentrations could be used to predict EP. Disintegrin and metalloprotease-12 (ADAM-12), a proteomics evaluation of serum from women with EP, is diagnosed with the presence of latter has both novel marker disintegrin and metalloprotease-12. It has both an adhesion and protease domain, plays a role in myoblast fusion [107] as well as giant cell macrophage and osteoclast formation in bone [108]. In humans, ADAM-12 is expressed in placenta, and potently provokes myogenesis. In first-trimester placentas, it is localized to the cytotrophoblasts as well as the apical side of the synctiotrophoblasts and to play a role in syncytial fusion in the trophoblast [109]. If ADAM-12 is involved in the normal implantation of pregnancy, and decreased levels are a harbinger of an abnormal pregnancy or the abnormal implantation of pregnancy, then decreased levels in ectopic pregnancy may be biologically plausible; the ADAM12 test would be more sensitive in the group of EP with lower b-hCG levels [110–112]. Hysterosalpingography (Hsg) is the radiographic evaluation of the uterine cavity and fallopian tubes after the administration of a radio opaque medium through the cervical canal. The Hsg was first practiced in 1910 and was considered to be the special radiologic procedure. A properly performed Hsg can decipher the contour of the uterine cavity and the width of the cervical canal. Further contrast medium injection will outline the cornua isthmic and ampullary portions of the tubes and will show the degree of spillage [113, 114]. There is a high probability that tubal obstruction really exist because of high specificity of Hsg, while the observation of tubal permeability shown after the examination does not exclude tubal pathology, since it does not assess its function. In addition, Hsg is a safe and inexpensive procedure [115, 116]; being the most cost effective method in the study of the fallopian tubes EP [117]. Medical management The treatment option of EP involves surgical treatment by laparotomy or laparoscopy, and medical treatment is usually systemic or through local route, or by expectant treatment [118, 119].
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Expectant treatment Expectant treatment can be applied in a selected subset of patients with self-limiting ectopic pregnancy; the proportion over treated must be accepted until a marker that identifies this subgroup of patients is found [120, 121]. Studies evaluating expectant management of ectopic pregnancy are primarily based on this concept of trophoblast in regression, and therefore exposed to the uncertainties of definite primary EP which are diagnosis [122]. According to the most recent guideline, published by the American College of Obstetricians and Gynecologists, there may be a role for expectant management when the b-hCG level is \200 mIU/ml and which is further in decline phase. It should only be offered when TVS remains non-diagnostic and b-hCG levels continue to decline. Tubal rupture has occurred with low or declining b-hCG levels. However, almost all EPs resolve spontaneously when the b-hCG level reaches 15 mIU/ml [123, 124]. Another multivariate analysis has shown that the favorable prognostic signs for successful expectant management of ectopic pregnancy are the following—absent or minimal clinical symptoms with no evidence of haemodynamic compromise: evidence of ectopic resolution by declining b-hCG levels preceding expectant treatment can be used for such dilation; low initial serum b-hCG: successful expectant management occurs in 98 % of cases for hCG \200 IU/L, in 73 % for b-hCG\500 IU/L and in 25 % for b-hCG \2,000 IU/L. Overall, if initial serum b-hCG \1,000 IU/L then successful expectant management might occur in most patients (88 %) with an ectopic pregnancy size of \4 cm, without a fetal heart beat on transvaginal sonography; followed by haemoperitoneum \50 ml. Evidence of ectopic resolution on scan is another way to diagnosis. A decrease in ectopic pregnancy size on day 7 had a sensitivity of 84 % and specificity of 100 % in predicting spontaneous resolution [122].
Medical treatment Medical treatment of EP is quite less expensive than surgery [125]. Many different agents have been used to treat ectopic pregnancies including systemic and local methotrexate (MTX), local potassium chloride, hyperosmolar glucose, prostaglandins, danazol, etoposide, and mifepristone (RU486) [126–128]. Current therapies focus primarily on MTX treatments. A better understanding of the pathogenesis of the disease could avoid the risk in women by providing better prediction and prevention [9, 65]. MTX was first used in diagnosed EP in the 1960 to aide safe surgical removal of the placenta from its abdominal implantation sites in second and third trimester cases [129].
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Patients treated with MTX should be monitored closely because as mentioned earlier, it causes severe abdominal pain and side effect too. The serum b-hCG concentration should be measured weekly. If the serum b-hCG concentration has not declined by at least 25 % in first week after MTX administration, a second dose should be given which is only required 15–20 % of patients [6]. Two common regimens are available for MTX, multidose (MTX 1.0 mg/kg i.m daily; days 0, 2, 4, and 6 alternated with folinic acid 0.1 mg/kg orally on days 1, 3, 5, 7) and single dose (MTX 0.4 to 1.0 mg/kg or 50 mg/m2 i.m. without folinic acid) [129]. The multidose regimen alternates an every other day dose of intramuscular MTX 1.0 mg/kg with an every other day dose of intramuscular leucovorin calcium 0.1 mg/kg, a folic acid antagonist antidote, up to four doses of each until the b-hCG level decreases by 15 % on two consecutive days. The single-dose regimen is an intramuscular injection of MTX, 50 mg/m2, based on the patient’s body surface, and does not include leucovorin rescue. If b-hCG levels do not decline by 15 % on days 4 and 7 after treatment, a second dose of MTX may be given after 1 week. About 20 % of women will need a second treatment cycle [130– 133]. Many side-effects associated with MTX treatment are nausea and vomiting, stomatitis, diarrhea, abdominal discomfort, pneumonitis, photosensitivity skin reaction, impaired liver function, reversible, severe neutropenia (rare), reversible alopecia (rare) [122]. Gabbur et al. reported that on its retrospective analysis of stable women with small unruptured EP treated with single-dose intramuscular MTX concluded that day 4 post treatment b-hCG levels do not predict successful treatment or need for surgery. Only day 7 b-hCG levels were associated with successful single-dose MTX treatment [134]. Barnhart et al. [135] investigated in their meta-analysis of both regimens (multi dose and single dose) and concluded that the multi-dose regimen was more effective than the single-dose regimen, with success rate reported as 93 % for the multi-dose regimen and 88 % for the single-dose regimen. Kirk et al. evaluated that the TVS is a non-surgical workup logarithm of patients with suspected EP. From 1993, a monitoring protocol has been developed based on serial serum b-hCG taken evaluated on day 1, 4, 7, and weekly until resolution. Efficacy of treatment is determined when there is a C15 % fall in serum b-hCG between days 4 and 7. This definition of treatment success has a positive predictive value (PPV) of 93 %, with a sensitivity of 93 % and a specificity of 84.2 % [136]. Barnhart et al. was attempted by the challenge to develop an optimum regimen that balances efficacy and safety on the one hand and convenience on the other hand, and he first described what is called the ‘‘double-dose protocol’’. In a study that included 101 patients, two doses
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of MTX were administered on days 0 and 4 without measuring b-hCG between doses. The authors reported a success rate of 76 % after two doses and 87 % after a further two doses [137]. Hossam et al. found that the double-dose protocol was an efficient and safe alternative to the single-dose regimen. It has the advantage of a shorter follow-up duration that improves patient compliance, treatment satisfaction, and costs [138].
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the salpingostomy site [145]. In high-risk cases, a single dose of MTX (1 mg/kg) can be administered postoperatively for prophylaxis [144, 145]. In one randomized controlled trial of laparoscopic surgery, prophylactic MTX lowered the rate of persistent ectopic pregnancy from 14.5 to 1.9 %. The major benefit was in the shorter duration of postoperative monitoring [144]. Since experience is limited, there is no single optimum treatment as on date. In the largest series, all of 19 patients with persistent ectopic pregnancies were successfully treated with single-dose systemic MTX (50 mg/m2) [143].
Surgical treatment Surgical treatment is the preferred treatment for EP when there is rupture, hypotension, anemia, diameter of the gestational sac greater than 4 cm on ultrasonography, or pain persisting beyond 24 h [139]. In America, the first abdominal surgery for EP was performed in 1759 by John Bard, and became increasingly attempted in the nineteenth century. Robert Lawson Tait, an eminent British surgeon, described treatment of ruptured EP by ligating bleeding vessels at laparotomy in 1884. This was a major advancement in development of effective surgical management of this condition [140]. Surgical treatment of EP should be reserved for those patients who have contraindications to medical treatment or to whom medical treatment has failed and those who are hemodynamically unstable. Two techniques are described to remove the EP from the fallopian tube—(1) salpingectomy: the pregnancy is removed en bloc with the tube, (2) salpingostomy: an incision is made on the fallopian tube over the swelling, the EP carefully removed with forceps or irrigation and the incision should be either closed or left to heal by secondary intention [125, 140]. The preferred method of surgical treatment of EP today is diagnostic laparoscopy with salpingostomy and tubal conservation [130, 141]. Laparotomy is indicated in the case of hemodynamic instability because it allows rapid access to pelvic structures [130]. The success rate of salpingostomy is 92 % and failure cases can be managed with MTX [142]. Serial b-hCG measurements should be taken until undetectable to be certain that there is no persistence of trophoblastic tissue. Sometimes a prophylactic dose of MTX is given with salpingosotomy [130]. Persistent EP occurs as a result of incomplete removal of trophoblastic tissue [143], the most common complication of laparoscopic salpingostomy, occurs at a frequency of 5–20 % [139, 144]. It is diagnosed during follow-up when b-hCG concentrations measured once a week plateau or rise. Factors increasing risk are small ectopic pregnancies (\2 cm diameter), early therapy (\42 days from last menstrual period), high concentrations of b-hCG ([3,000 IU/L) preoperatively, and implantation medial to
Discussion and conclusion Ectopic pregnancy in developing countries is a serious threat, just because of poor medical facility so that a significant morbidity rate and the potential for maternal death generally are seen. Many patients have no documented risk factors and no physical indications of EP, yet they suffer from the complication. On the other hand, in developed countries, it is now not so threatening as in past because they have advanced technique of diagnosis and women are much more aware of their health. Management is dictated by the clinical presentation, serum b-hCG levels and TVS findings. Expert consultation with radiologists and gynecologists is recommended whenever ectopic pregnancy is suspected. The use of MTX for treatment of early unruptured EP reported to be safe and effective. Surgical treatment is particularly appropriate for women who are hemodynamically unstable or unlikely to be compliant with post treatment monitoring and those who do not have immediate access to medical care. The choice of treatment should be guided by the patient’s preference, after a detailed discussion about monitoring, outcome, risks, and benefits of the approaches. The radiologists and gynecologists should have been firstly the identification of clinical features or biomarkers predictive of MTX success and the secondly is the use of additional medical treatments or novel adjuncts that reduce treatment failures. The current analysis of EP would suggest declining trends over time. However, this reflects a decrease in surgical treatment and not an actual decline in EP occurrence. Further, new avenues are needed to explore early detection and less side effect medication of the EP. Conflict of interest
None declared.
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