Therapeutic management of cervical ectopic pregnancy

Abstract

Ectopic pregnancy is one of the most important risk factors for maternal morbidity and mortality in early pregnancy. Cervical ectopic pregnancy is the rarest localization of ectopic pregnancy, although it constitutes a high-risk situation. On the one hand, there is a high rate of incorrect diagnosis; on the other, the clinician might be faced with severe therapeutic complications – for example, life-threatening hemorrhage. There are a variety of therapeutic alternatives but no standard guidelines exist regarding the ideal treatment. In most cases, successful treatment is achieved by a combination of therapeutic options. Conservation of fertility has priority, while massive hemorrhage also needs to be prevented. In this article, we present pitfalls and current strategies for diagnosis and management in patients with cervical pregnancy by introducing a classical constellation in an affected patient.

Keywords::

• cervical ectopic pregnancy
• first-trimester bleeding
• hCG
• hemorrhage
• methotrexate
• nidation

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Release date: December 17, 2010; Expiration date: December 17, 2011

Learning objectives

• • Distinguish important risk factors for CEP

• • Diagnose CEP effectively

• • Evaluate outcomes of expectant management for ectopic pregnancy

• • Analyze the use of methotrexate for CEP

Financial & competing interests disclosure

EDITOR

Elisa ManzottiEditorial Director, Future Science Group, London, UK.

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD, Associate Professor

Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Friederike Hoellen, MD

Department of Obstetrics and Gynaecology, University Hospital of Schleswig-Holstein, Luebeck, Germany.

Disclosure: Friederike Hoellen, MD, has disclosed no relevant financial relationships.

Klaus Diedrich, MD

Department of Obstetrics and Gynaecology, University Hospital of Schleswig-Holstein, Luebeck, Germany.

Disclosure: Klaus Diedrich, MD, has disclosed no relevant financial relationships.

Christine Dittmer, MD

Department of Obstetrics and Gynaecology, University Hospital of Schleswig-Holstein, Luebeck, Germany.

Disclosure: Christine Dittmer, MD, has disclosed no relevant financial relationships.

Katharina Kelling, MD

Department of Obstetrics and Gynaecology, University Hospital of Schleswig-Holstein, Luebeck, Germany.

Disclosure: Katharina Kelling, MD, has disclosed no relevant financial relationships.

Michael K Bohlmann

Department of Obstetrics and Gynaecology, University Hospital of Schleswig-Holstein, Luebeck, Germany.

Disclosure: Michael K. Bohlmann, MD, has disclosed no relevant financial relationships.

During the last three decades, an increase of ectopic pregnancies (EPs) in developed countries was observed by a factor of three to four [1], with the incidence now being 11 in 1000. This rising incidence is attributed to an increase in defined risk factors; for example, pelvic inflammatory disease, smoking, previous pelvic surgery, previous EP, past and current use of intrauterine devices (IUDs) and infertility therapy.

Whereas there is an increase in EPs in general, cervical EP (CEP) remains the rarest localization of inadequate implantation [2]. The incidence of cervical pregnancies is less than 1% of all ectopic gestations, and ranges between one in 2500–18,000 pregnancies [2–4]. Despite its infrequency, clinicians should take this rare diagnosis into account whenever being confronted with unusual clinical findings in early pregnancy, as the risks for hysterectomy and severe lethal hemorrhage are highly increased compared with tubal EPs. The present case will put emphasis on the pitfalls of misdiagnosis and misinterpretation of CEPs, underlining important risk factors. Different diagnostic features and the modalities of appropriate therapeutic management are discussed.

Case report

A 36-year-old woman presented in the outpatient clinic with a 4-week history of persisting vaginal spotting and moderate, persistent, diffuse abdominal pain. Furthermore, she reported a cupreous IUD T-200, which had been inserted 5 years before, and a submucosal fibroid. Her menses had been regular without any particularities until 6 weeks before. Relevant history included a cesarean section 9 years before and a miscarriage treated by dilation and curettage. Furthermore, the patient was a smoker.

She was hemodynamically stable with a hemoglobin level of 14.1 g/dl. The serum human chorionic gonadotropin (hCG) level at first presentation was 158 mIU/ml and progesterone was 1.0 ng/ml. Vaginal examination revealed an inconspicuous inspection with a slightly enlarged plain cervical portion. Ultrasound imaging was performed by a specially certified obstetrician; it was completely inconspicuous without any pathology of the cervix. There was no intraperitoneal fluid. The uterus was slightly enlarged with two small intramural and partly submucosal fibroids of 20 × 20 mm showing an irregular structure of the tissue as in adenomyosis uteri, the endometrial layer was thin. The IUD was in place in the uterine cavity. Both ovaries presented as inconspicuous. The patient was discharged with a diagnosis of early pregnancy of unknown localization and spotting in association with a nonremovable IUD persistent for over 5 years. She wanted to continue the pregnancy despite the high probability of a nonintact constellation. A follow-up of hCG levels was performed weekly, showing hCG levels of 93, 94 and 99 mIU/ml. Progesterone levels were stable (<1 ng/ml). The patient opted for expectant management as she was asymptomatic in the course and preferred conservative therapy. A total of 4 weeks after the first presentation, the patient presented for hysteroscopic removal of the IUD with persisting spotting, a persistent hCG titer of 60 mIU/ml and slight abdominal pain. Ultrasound imaging was idem. The hemoglobin level had dropped to 13.7 g/dl. Hysteroscopy and laparoscopy were planned in order to rule out abdominal EP or tubal miscarriage. The IUD was removed intraoperatively. Hysteroscopy revealed an area of necrotic tissue situated beneath the cervicocorporal transition zone at the posterior side of the cervical portion of the uterus. Cervical curettage was performed. Instant staining of frozen sections of the friable, mouldered tissue was conducted, revealing necrotic decidual tissue. To control hemorrhage, further curettage of the CEP was conducted by a combined transvaginal and laparoscopic surgical approach. Laparoscopy showed severe peritoneal adhesions obliterating the entire pelvis minor, especially between the uterus and bowels. Some small areas of superficial endometriosis were identified in the Douglas cavity. There was no tubal or abdominal EP. Curettage of the cervical canal was completed and followed by excessive uterine hemorrhage. We stopped the bleeding by a tamponade. Sulprostone was applied intravenously over 8 h. The patient remained hemodynamically stable. A sulprostone-impregnated gauze bandage was placed intrauterine and vaginal to suppress bleeding. Sulprostone is an analog of prostaglandin E₂ and acts as an oxytocic. A total of 24 h later, the tamponade was extracted in the operating theatre with an anesthesiologist on standby. The tamponade was replaced by a blockade with a conventional bladder catheter for persistent bleeding.

After the operation, the patient’s hemoglobin level dropped to 10 g/dl 4-h postoperatively and 8 g/dl 24-h later. Vaginal bleeding ceased and the hemoglobin level was stable in daily controls. The catheter was removed on the third day after the operation and the patient was discharged without any vaginal bleeding. Serum levels of hCG and progesterone dropped adequately. A day after operation, the hCG titer had dropped to 10 mIU/ml, 2 days later it was 6.5 mIU/ml, and after 4 days it was below 6 mIU/ml. Final histopathological examination revealed necrotic decidual tissue and chorionic villi.

Discussion

Ectopic pregnancy remains one of the most important reasons for deaths in early pregnancy [101]. Between 2000 and 2002, 15 deaths in early pregnancy were recorded in the UK, of which 11 were attributed to EP (seven ruptured tubal pregnancies and four cornual pregnancies). The majority of these EP-related deaths were associated with substandard care. Mortality due to EP is 1.8 in 1000, which accounted for 9% of all pregnancy-related deaths in the USA between 1991 and 1993 [2].

Bouyer et al. investigated a population of 1800 surgically treated EPs between 1992 and 2001 [1]. There was no cervical pregnancy at all in this population of surgically treated EPs. This fact emphasizes the infrequency of cervical pregnancies on the one hand, and the possibility of conservative management of cervical pregnancy in selective cases on the other [5]. Owing to its rare incidence, it is impractical to perform a prospective, randomized controlled study to evaluate the diagnostic procedures and efficacy of the different therapeutic approaches for CEP [5].

The uterine cervix is predisposed for nidation because of its high vascularization. At the same time, this high grade of vascularization renders this site especially vulnerable to life-threatening uncontrollable bleeding. Another factor that contributes to the increased risk of severe bleeding in cervical pregnancy is the microscopic architecture and the function of the cervical part of the uterus. Only 20% of the cervix consists of smooth muscle, the fibrous tissue is not contractile and insusceptible to mechanical hemostatic manipulation and uterotonic agents [6]. Therefore, in the past, CEP pregnancy was traditionally treated by hysterectomy [7], with cervical pregnancy only diagnosed retrospectively by histopathological examination.

Risk factors

Cervical ectopic pregnancies have been attributed to several risk factors. The pathogenesis of a CEP has been defined by two different aspects: on the one hand, it has been hypothesized that transport of the blastocyst through the immature endometrium is too rapid for nidation. On the other, fertilization of the ovum in the endocervical canal may occur too late [6]. Thus, these risk factors consist of factors that may have destroyed the structure of the endometrium and compromised the nidation of the ovum in the uterine cavity. On the other hand, there are factors that promote the nidation of the ovum in the endocervical portion of the uterus, which usually contains columnar epithelium and is thus not convenient for implantation. Most of the CEPs can be contributed to an iatrogenic origin and are due to a combination of several factors. Among these are preceding manipulation of the endocervical canal; for example, cervical or miscarriage curettage, the presence of an IUD, endometriosis in the cervical portion of the uterus enabling nidation of the ovum, endomyometritis, anatomic abnormalities such as Asherman’s syndrome, fibroids, intrauterine adhesions, previous cesarean section and uterine surgery in general, assisted reproduction techniques, and a history of diethylstilbestrol exposure [4,6–10]. A history of uterine curettage is considered to be the main risk factor and can be found in up to 70%, or in some reports even more, of cervical pregnancies [2,11,12]. Cigarette smoking has been detected to be a moderate risk factor for EPs in general [13]. All these risk factors may lead to a disturbed maternoembyronal dialogue with a subsequent ectopic implantation of the blastocyst (Box 1).

Clinical findings

The classical symptom of CEP is vaginal bleeding, which may be accompanied by abdominal pain [4,6]. In contrast to other nontubal EPs, CEP may present with urinary problems owing to mechanical irritation or compression of the urethra in more advanced cases [4].

Vaginal examination usually reveals an enlarged, globular, extended cervix with the ostium externum uteri enlarged and opened, whereas the ostium internum uteri is closed. There may be severe bleeding after manipulation.

A new era in the diagnosis and treatment of cervical pregnancy began when Raskin et al. first published an ultrasound report of a cervical pregnancy and introduced transvaginal ultrasound imaging as the main diagnostic tool [14]. Ultrasound findings are an empty uterus, a Doppler blood flow around the sac, the so-called hourglass uterus or a dilated, barrel-shaped cervix [15], the absence of the sliding sack sign – which helps to distinguish CEP from miscarriage in progress [16] – and a gestational sac below the uterine arteries [3]. In particular, the differentiation between the cervical stage of a common miscarriage, an isthmicocervical pregnancy and a de facto early CEP by ultrasound imaging has to be emphasized. In fact, cervical pregnancy is often mistaken as an incomplete miscarriage, cervical or prolapsed fibroid, a low-implanted placenta, cervical cancer or trophoblastic tumor [13]. The curettage after a ‘common’ miscarriage in early pregnancy is a routine intervention, whereas in the case of the treatment of a CEP, the clinician is faced with a high-risk operation that should be meticulously prepared [4]. In contrast to isthmicocervical pregnancy, the CEP requires the ultrasound demonstration of a closed ostium internum uteri, which can be identified at the level of the insertion of the uterine arteries [4,17]. Furthermore, local endocervical tissue invasion by the trophoblast can be visualized by color Doppler ultrasound imaging. At a later stage, if a viable embryo is identified, the CEP might be misinterpreted as an intact intrauterine pregnancy with a low placentation. In case of a late-stage CEP, which presents with a nonviable embryo, the differential diagnosis of an incomplete or missed miscarriage has to be taken into account. In addition, in some cases MRI might be required for correct diagnosis (Table 1)[13].

Therapy

There are three options for the management of an EP in general: expectant – which is reserved to early EPs with low and declining serum hCG levels – medical or surgical. In fact, spontaneous resolution has been reported in up to 69% of cases [13]. However, the risk of spontaneous hemorrhage in these cases is very high as EPs account for 9% of all maternal deaths due to severe bleeding [18]. In a prospective study including 60 women with ectopic tubal pregnancy who fulfilled the inclusion criteria, expectant management was successful in 28 of the patients (47.7%). In 32 patients (53.3%), expectant management failed and a treatment procedure was required [19]. The authors recommended to apply expectant management only if the initial hCG level is under 2000 mIU/ml and decreases in the proceeding serum controls. In those cases, expectant management was successful in 60% of patients. The authors concluded that expectant management should be offered as a treatment option only in those women fulfilling the criteria for a good prognosis. In a case–control study including 67 patients with EP managed expectantly, the prognostic factors for successful expectant management of EP were defined. Multivariate analysis showed that both initial hCG titer and trend in hCG titers, but not sonographic visualization of an ectopic gestational sac, were independent predictors of a successful or failed expectant management [20]. Trio et al. recommend an initial hCG titer of under 1000 mIU/ml as a cut-off for expectant management, with successful outcome in 88% of patients.

Treatment options to preserve the uterus in the case of cervical pregnancy consist of tamponade, reduction of blood supply, excision of trophoblastic tissue, intra-amniotic fetocide and systemic chemotherapy [3]. In most cases, successful conservative therapy consists of a combination of these methods. Exclusive operative methods; for example, dilatation and curettage in combination with uterine artery ligation, embolization or cervical balloon tamponade, tend to have a high failure rate, with one study reporting a hysterectomy rate of 22% [21]. However, the therapeutic approach was not randomly chosen in this study. In the last decade, local injections of potassium chloride or methotrexate (MTX) have been favoured owing to their high success rates (close to 100% according to the literature) and low complications or side effects [22].

Farabow et al. pioneered the administration of the folinic acid antagonist MTX for the treatment of CEP in 1983 [23]. Systemic MTX application had been established for a long time in the treatment of tubal EP in single- and multiple-dose protocols, and has thus been adopted for the treatment of CEP. MTX treatment lacks in uniformity. There are high- and low-dose protocols, and the administration can be systemic, local or a combination of both. A high-dose regimen refers to protocols containing MTX of 1 mg/kg four times every other day or a single dose of 300 mg/m² with folinic acid rescue, or a total dose of over 150 mg throughout the whole course of chemotherapy. A low-dose regimen refers to a protocol consisting of a dose of under 150 mg. A local injection of the chemotherapeutic agent can be carried out either by intra-amniotic or intracervical administration. If embryonic cardiac activity is present, feticide can be performed by intracardiac injection of potassium chloride, intra-amniotic instillation of MTX or direct traumatic punctures [5]. A possible technique of local MTX administration is a single transvaginal ultrasound-guided intra-amniotic installation of 70 mg of MTX plus oral folic acid [24]. Moon et al. recently reported intra-amniotic MTX injection through the cervical canal using a Tuohy needle after failure of systemic treatment [25].

In 1998, Hung et al. conducted a meta-analysis of the current literature to estimate the benefit of conservative treatment with MTX of CEPs. A total of 52 cases of CEP were reviewed. MTX was applied systemically, locally or in combination, and in either high or low doses. Local application could be conducted either by intra-amniotic or intracervical injection. The dosage did not influence the outcome. Meanwhile, systemic MTX administration might be associated with severe side effects, especially in the case of high-dose protocols; for example, bone marrow depression, stomatitis, anorexia, nausea, vomiting, diarrhea, hepatic toxicity, pulmonary fibrosis, alopecia and photosensivity [26,27]. In general, these side effects are infrequent during short-term MTX administration. However, Ushakov et al. reported an occurrence of side effects in 15% of all cases [17]. An inefficient result was defined as a rise or persistence in the serum hCG levels after 7 days, uncontrollable vaginal bleeding and a persistent gestational mass requiring an additional therapeutic intervention [5]. In most cases, the intragestational injection of MTX is conducted by transvaginal ultrasound guidance [3].

Hung et al. defined four factors that contribute to an inefficient application of MTX: serum hCG levels above 10,000 mIU/ml, advanced pregnancy passing 9 weeks of gestation, embryonic cardiac activity and crown–rump length over 10 mm. It has to be emphasized that conservative management of CEP does not prevent severe iatrogenically induced complications. Medical treatment with MTX might lead to severe hemorrhage as well, which was reported in six of the 52 cases for up to 28 days after application. This long-term side-effect was attributed to the trophoblast decidua shedding from the atonic cervix. Another complication might be a placenta accreta if the trophoblast continues to proliferate.

Kung et al. reported an efficacy of 91% for systemic treatment with MTX in 62 CEPs. However, in these cases, systemic MTX was always used in combination with local therapy; for example, cervical curettage [28].

According to Thomas et al., alternatives for the treatment of CEP consist of three major principles: mechanical termination of the EP by curettage, systemic or local application of MTX, and hemostasis. Hemostasis can be achieved by different means: local injection of vasopressin and cerclage [9], cervical-stay sutures, tamponade by a Foley balloon or ligation, or embolization of the descending branches of the uterine arteries [7,29]. As cervical pregnancies are well vascularized, surgery might be associated with severe hemorrhage. Women with uncontrolled bleeding might need blood transfusions, postoperative intensive-care-unit treatment or even a hysterectomy [17]. Therefore, Agdi et al. recommend an intravenous line with a large-bore needle, four units of blood for possible transfusion, and a Foley catheter for accurate monitoring of intake and output. In women who wish to preserve their fertility and to avoid hysterectomy, insertion of an angiographic catheter to the uterine arteries could be necessary in order to perform an arterial embolization in the presence of uncontrolled bleeding [17]. Another means to reduce hemorrhage during resection of the cervical pregnancy consists of cervical cerclage before evacuation of the pregnancy. The cerclage should be applied close to the ostium internum uteri of the cervix to occlude the blood vessels supplying the cervix appropriately. These vessels are especially prone to severe bleedings, as they are engorged during pregnancy. Alternatively, the descending branches of the uterine vessels can be ligated vaginally [17]. In the cases of second- and third-trimester cervical pregnancy, primary hysterectomy is still recommended owing to the high risk of life-threatening hemorrhage [3]. However, in most cases successful treatment of CEP may be achieved through a combination of systemic and local MTX application and means of local hemostasis. Associated complications consist of infections, uterine infarction, sciatic nerve injury, and necrosis of the bladder or rectum (Table 2)[9,30].

Conclusion

As in the case presented in this article, the patient’s medical history and previously existing diseases give a vital piece of information. First of all, her previous operation to treat a miscarriage by dilatation and curettage probably contributed to a local cervical pathology. Second, she had undergone a cesarean section, which represents another risk factor for inadequate nidation. Third, the aforementioned IUD that had been in place for 5 years is considered a risk factor contributing to a dislocated embryonic implantation. Surgery revealed uterine adhesions. In addition, the patient was a smoker. Thus, retrospectively, there were five independent main risk factors for EP, and especially for CEP. In general, these factors may contribute to the development, but not necessarily lead to CEP in every case.

The delay of the correct diagnosis, which could only be confirmed by histopathological examination by intraoperative instant staining section, was due to the minor clinical evidence. Preoperative ultrasound examination did not reveal any distinct typical features for a CEP established by Raskin. Color Doppler ultrasound at the level of the cervical portion of the uterus was not performed, as there was no suspect area sonographically. The missing preoperative ultrasound findings emphasize the pitfalls of CEPs. Thus, correct diagnosis could only be made through explorative laparoscopy and histopathological examination. Other probable sites of EP, including cesarean scar pregnancy and aborted tubal pregnancy, in the obliterated pouch of Douglas could be ruled out by intraoperative confirmation by instant staining and histopathological examination. In addition, laparoscopy was performed in order to control expected severe bleeding. In this case, in comparison to the current literature, a conservative management could have been an alternative as there was no embryonic cardiac activity, serum hCG levels were below 10,000 mIU/ml, and crown–rump length was under 10 mm, respectively there was no gestational sac at all [5]. We opted for hysteroscopy and laparoscopy, as the site of the EP was unclear and the IUD had to be removed. In addition, vaginal spotting and elevated hCG levels had persisted for over 4 weeks.

Expert commentary

The present case emphasizes the important role of taking the rare diagnosis of a CEP into account whenever the clinician is faced with a combination of several specific risk factors on the one hand, and the lack of typical clinical evidence of EP at common sites on the other. In order to apply conservative treatment options, diagnosis must be made at the earliest stage possible. Consequently, early diagnosis enables the preservation of the uterus and thus fertility and it is the basis for a decrease in morbidity and mortality due to CEP [3]. In particular, the high risk of severe hemorrhage in the case of misdiagnosis or misinterpretation of advanced CEP has to be taken into consideration. With regard to the variety of treatment options and combinations of treatment options available, the optimal therapeutic approach remains to be established. The clinician has to take into account the individual setting in order to achieve the optimum therapeutic result, which requires safety and effectiveness at the same time [3].

Five-year view

In the past, misinterpretation of CEP was common and consequently led to inadequate treatment, which resulted in a loss of fertility; for example, hysterectomy causing life-threatening hemorrhage or even maternal death. A significant improvement in therapeutic management was achieved by amelioration of the diagnostic methods. A new era in diagnosis and treatment began when Raskin first published the ultrasound findings of a cervical pregnancy and introduced transvaginal ultrasound imaging as the main diagnostic tool [13,14]. On the other hand, it is especially difficult to establish standard guidelines for the management of CEP due to its infrequence and thus the impracticality of prospective randomized clinical studies. In recent years risk factors have increased; for example, the presence of an IUD, previous cesarean section and uterine surgery in general, and, particularly, a considerable increase in assisted reproduction techniques. The optimum therapeutic result requires safety and effectiveness at the same time; for example, preservation of fertility while preventing severe life-threatening hemorrhage [3]. Considerable improvements of conservative treatment options have been achieved, and remain to be further investigated regarding application regimens of MTX, the introduction of new therapeutic agents and defining preconditions for successful conservative treatment.

Thus, further studies should emphasize the investigation of methods preventing the emergence of CEP; methods of early diagnosis, such as the role of advanced imaging modalities, conservative noninvasive treatment options and the definition of clinical features rendering a CEP appropriate to specific conservative treatment options.

Table 1. Sonographic criteria for cervical ectopic pregnancy.

Anatomical structure	Sonographic features
Uterus	Empty
Cervix	‘Hour-glassed uterus’, dilated, barrel shaped
Gestational sac	Below the uterine arteries
Sliding sign	Absent (differential diagnosis: miscarriage in progress)
Ostium internum uteri	Closed
Ostium externum uteri	Open
Doppler blood flow	Increased around the gestational sac

Modified from [3].

Table 2. Treatment modalities and respective indications.

Treatment modality	Indication
Expectant	Initial serum hCG level <1000 (2000) mIU/ml Declining serum hCG levels Absence of severe hemorrhage Absence of severe abdominal pain
Systemic MTX	Serum hCG level <10,000 mIU/ml Early pregnancy <9 weeks of gestation No embryonic cardiac activity Crown–rump length <10 mm
Intra-amniotic MTX	Present embryonic cardiac activity
Embryonic intracardiac injection of potassium chloride	Present embryonic cardiac activity
Cervical curettage	Whenever conservative treatment modalities fail Precondition: adequate hemostasis
Cervical cerclage, cervical-stay sutures	Hemostasis before evacuation of the CEP
Ligation/embolization of the descending branches of uterine arteries	Preoperative hemostasis in cases of expected severe hemorrhage and wish to preserve fertility Precondition for embolization: preoperative insertion of an angiographic catheter
Local injection of vasopressin	Noninvasive hemostasis before evacuation of the CEP in cases of expected moderate hemorrhage
Foley balloon	Tamponade for noninvasive hemostasis
Hysterectomy	Terminated family planning Life-threatening hemorrhage Second- and third-trimester CEP

CEP: Cervical ectopic pregnancy; hCG: Human chorionic gonadotropin; MTX: Methotrexate.

Box 1. Risk factors for cervical ectopic pregnancy.

• • Diagnostic or miscarriage cervical curettage and dilatation (70% of all CEPs)

• • Presence of an IUD

• • Endometriosis in the cervical portion of the uterus

• • Endomyometritis

• • Asherman’s syndrome

• • Fibroids

• • Uterine adhesions

• • Previous cesarean section

• • Previous uterine surgery

• • Assisted reproduction techniques

• • History of diethylstilbestrol exposure

• • Cigarette smoking

• • Previous cervicitis (gonorrhea, chlamydia)

Key issues

• • Cervical ectopic pregnancy (CEP) is the rarest localization of ectopic pregnancy (EP).

• • There is a high rate of incorrect diagnosis in the case of CEP.

• • Severe hemorrhage is the main risk of CEP.

• • The most common misdiagnosis is the cervical stage of a ‘common’ miscarriage.

• • Exclusive operative methods tend to a high failure rate due to severe hemorrhage.

• • Successful treatment of CEP may be achieved by means of a combination of systemic and local methotrexate applications and local hemostasis.

• • Hemostasis is the main aim of the therapy to prevent hysterectomy.

• • Exclusive conservative treatment with methotrexate is reserved for cases presenting with defined preconditions.

References

• Bouyer J, Coste J, Fernandez H, Pouly JL, Job-Spira N. Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases. Hum. Reprod.17(12), 3224–3230 (2002).
   PubMed Web of Science ®Google Scholar
• Oliver R, Malik M, Coker A, Morris J. Management of extra-tubal and rare ectopic pregnancies: case series and review of current literature. Arch. Gynecol. Obstet.276(2), 125–131 (2007).
   PubMedGoogle Scholar
• Chetty M, Elson J. Treating non-tubal ectopic pregnancy. Best Pract. Res. Clin. Obstet. Gynaecol.23(4), 529–538 (2009).
   PubMed Web of Science ®Google Scholar
• Gun M, Mavrogiorgis M. Cervical ectopic pregnancy: a case report and literature review. Ultrasound Obstet. Gynaecol.19(3), 297–301 (2002).
   Google Scholar
• Hung TH, Shau WY, Hsieh TT, Hsu JJ, Soong YK, Jeng CJ. Prognostic factors for an unsatisfactory primary methotrexate treatment of cervical pregnancy: a quantitative review. Hum. Reprod.13(9), 2636–2642 (1998).
   PubMed Web of Science ®Google Scholar
• Kraemer B, Abele H, Hahn M, Wallwiener D, Rajab TK, Hornung R. Cervical ectopic pregnancy on the portio: conservative case management and clinical review. Fertil. Steril.90(5), 2011.e1–4 (2008).
   Google Scholar
• Thomas RL, Gingold BR, Gallagher MW. Cervical pregnancy. A report of two cases. J. Reprod. Med.36(6), 459–462 (1991).
   PubMed Web of Science ®Google Scholar
• Spitzer D, Steiner H, Graf A, Zajc M, Staudach A. Conservative treatment of cervical pregnancy by curettage and local prostaglandin injection. Hum. Reprod.12(4), 860–866 (1997).
   Google Scholar
• Fylstra DL, Coffey MD. Treatment of cervical pregnancy with cerclage, curettage and balloon tamponade. A report of three cases. J. Reprod. Med.46(1), 71–74 (2001).
   PubMed Web of Science ®Google Scholar
• Cupr Z, Pospisil J, Milickova E. [Ectopic pregnancy on the vaginal part of the uterus]. Zentralbl. Gynakol.95(39), 1385–1387 (1973).
   Google Scholar
• Parente JT, Ou CS, Levy J, Legatt E. Cervical pregnancy analysis: a review and report of five cases. Obstet. Gynecol.62(1), 79–82 (1983).
   PubMed Web of Science ®Google Scholar
• Pisarska MD, Carson SA. Incidence and risk factors for ectopic pregnancy. Clin. Obstet. Gynecol.42(1), 2–8; quiz 55–56 (1999).
   PubMed Web of Science ®Google Scholar
• Agdi M, Tulandi T. Surgical treatment of ectopic pregnancy. Best Pract. Res. Clin. Obstet. Gynaecol.23(4), 519–527 (2009).
   PubMed Web of Science ®Google Scholar
• Raskin MM. Diagnosis of cervical pregnancy by ultrasound: a case report. Am. J. Obstet. Gynecol.130(2), 234–235 (1978).
   PubMed Web of Science ®Google Scholar
• Cepni I, Ocal P, Erkan S, Erzik B. Conservative treatment of cervical ectopic pregnancy with transvaginal ultrasound-guided aspiration and single-dose methotrexate. Fertil. Steril.81(4), 1130–1132 (2004).
   PubMed Web of Science ®Google Scholar
• Monteagudo A, Minior VK, Stephenson C, Monda S, Timor-Tritsch IE. Non-surgical management of live ectopic pregnancy with ultrasound-guided local injection: a case series. Ultrasound Obstet. Gynaecol.25(3), 282–288 (2005).
   PubMed Web of Science ®Google Scholar
• Ushakov FB, Elchalal U, Aceman PJ, Schenker JG. Cervical pregnancy: past and future. Obstet. Gynecol. Surv.52(1), 45–59 (1997).
   PubMedGoogle Scholar
• Ehrenberg-Buchner S, Sandadi S, Moawad NS, Pinkerton JS, Hurd WW. Ectopic pregnancy: role of laparoscopic treatment. Clin. Obstet. Gynecol.52(3), 372–379 (2009).
   Google Scholar
• Shalev E, Peleg D, Tsabari A, Romano S, Bustan M. Spontaneous resolution of ectopic tubal pregnancy: natural history. Fertil. Steril.63(1), 15–19 (1995).
   PubMed Web of Science ®Google Scholar
• Trio D, Strobelt N, Picciolo C, Lapinski RH, Ghidini A. Prognostic factors for successful expectant management of ectopic pregnancy. Fertil. Steril.63(3), 469–472 (1995).
   Google Scholar
• Jurkovic D, Hacket E, Campbell S. Diagnosis and treatment of early cervical pregnancy: a review and a report of two cases treated conservatively. Ultrasound Obstet. Gynaecol.8(6), 373–380 (1996).
   PubMed Web of Science ®Google Scholar
• Benson CB, Doubilet PM. Strategies for conservative treatment of cervical ectopic pregnancy. Ultrasound Obstet. Gynaecol.8(6), 371–372 (1996).
   PubMedGoogle Scholar
• Farabow WS, Fulton JW, Fletcher V Jr, Velat CA, White JT. Cervical pregnancy treated with methotrexate. NC Med. J.44(3), 91–93 (1983).
   PubMedGoogle Scholar
• Hassiakos D, Bakas P, Creatsas G. Cervical pregnancy treated with transvaginal ultrasound-guided intra-amniotic instillation of methotrexate. Arch. Gynecol. Obstet.271(1), 69–72 (2005).
   PubMedGoogle Scholar
• Moon HS, Hyun JH, Kim KS, Kim HJ, Moon SE, Koo JS. Use of Tuohy needle for intraamniotic methotrexate injection through the cervical canal in a cervical pregnancy after failure of systemic methotrexate treatment. Am. J. Obstet. Gynecol.202(5), e4–e6 (2010).
   PubMed Web of Science ®Google Scholar
• Floridon C, Thomsen SG. Methotrexate treatment of ectopic pregnancy. Acta Obstet. Gynecol. Scand.73(10), 746–752 (1994).
   PubMed Web of Science ®Google Scholar
• Carson SA, Buster JE. Ectopic pregnancy. N. Engl. J. Med.329(16), 1174–1181 (1993).
   PubMedGoogle Scholar
• Kung FT, Chang SY. Efficacy of methotrexate treatment in viable and nonviable cervical pregnancies. Am. J. Obstet. Gynecol.181(6), 1438–1444 (1999).
   PubMed Web of Science ®Google Scholar
• Kung FT, Lin H, Hsu TY et al. Differential diagnosis of suspected cervical pregnancy and conservative treatment with the combination of laparoscopy-assisted uterine artery ligation and hysteroscopic endocervical resection. Fertil. Steril.81(6), 1642–1649 (2004).
   Google Scholar
• Cosin JA, Bean M, Grow D, Wiczyk H. The use of methotrexate and arterial embolization to avoid surgery in a case of cervical pregnancy. Fertil. Steril.67(6), 1169–1171 (1997).
   PubMed Web of Science ®Google Scholar

Website

• CMAC: CEMACH Why Mothers Die 2000–2002, Dezember 2005 www.cmace.org.uk/getdoc/7cbb498a-f176–4cb5-ab83–6549bb19a886/Maternal-and-Perinatal-Health.aspx
   Google Scholar

Therapeutic management of cervical ectopic pregnancy

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1. The activity supported the learning objectives.
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1. You are seeing a 35-year-old woman with a complaint of vaginal bleeding accompanied by abdominal pain. Her last menstrual period was 6 weeks ago, and her urine pregnancy test is positive.
You suspect a possible ectopic pregnancy. Which of the following variables is the most significant risk factor for CEP specifically?

• □ A A history of nulliparity

• □ B A history of uterine curettage

• □ C A history of uterine curettage

• □ D Use of a vaginal ring contraceptive

2. Which of the following statements regarding the clinical presentation of CEP is most accurate?

• □ A The classical symptom of CEP is vaginal bleeding

• □ B Abdominal pain is invariably present in CEP

• □ C Both the external and internal os are open

• □ D There are no distinct ultrasound findings

3. The patient is diagnosed with CEP and desires expectant management only. What can you tell her regarding this option?

• □ A Less than 10% of all cases of ectopic pregnancy resolve spontaneously

• □ B Expectant management is best reserved for women with a serum hCG of 2000 mIU/ml or less

• □ C The most important prognostic factor for expectant management is visualization of an ectopic gestational sac

• □ D The risk for spontaneous hemorrhage is not elevated in the expectant management of CEP

4. It is decided to treat the patient with methotrexate (MTX). What should you keep in mind regarding this therapeutic option?

• □ A The standard dose of MTX is 5 mg/kg orally 4 times daily

• □ B Local application of MTX is best performed via intracervical injection only

• □ C MTX is less efficient when the pregnancy is past 9 weeks of gestation and has a crown-rump length over 10 mm

• □ D MTX is not associated with severe hemorrhage in cases of CEP

Notes

CEP: Cervical ectopic pregnancy; IUD: Intrauterine device.