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Cervical Ectopic Pregnancy
Diagnosis With Endovaginal Ultrasound Examination and Successful Treatment With Methotrexate
Lawrence M. Leeman, MD, MPH;
Claire L. Wendland, MD
Arch Fam Med. 2000;9:72-77.
ABSTRACT
Cervical ectopic pregnancy is the implantation of a pregnancy in the endocervical canal. Diagnosis and treatment of cervical ectopic pregnancy has changed dramatically in the last 15 years. Before 1980, the diagnosis commonly was made when dilation and curettage for presumed incomplete abortion resulted in unexpected hemorrhage. Emergency hysterectomy usually ensued. Cervical ectopic pregnancy is now commonly diagnosed on a first-trimester ultrasound examination. The family physician practicing obstetrics must consider the diagnosis of cervical ectopic pregnancy in women with first-trimester vaginal bleeding or pelvic pain to permit early diagnosis and fertility-saving treatment. A case report of diagnosis and successful medical management of a cervical ectopic pregnancy is presented. The literature on the epidemiology, causes, diagnosis, and treatment of cervical ectopic pregnancy is reviewed.
INTRODUCTION
A 42-year-old Native American woman classified as gravida 2 para 1 presented with a 1-day history of vaginal bleeding and pelvic cramping. Two weeks prior results of a urine pregnancy test were positive. She did not recall the date of her last menstrual period. Physical examination revealed a bloody mucoid discharge from the cervix, a uterus typical of an 8-week pregnancy, unremarkable adnexa, and a benign abdominal examination. The patient declined an endovaginal ultrasound examination, and transabdominal pelvic ultrasound examination showed an empty uterus and a 2 x 2-cm cyst in the right ovary. The patient's quantitative beta human chorionic gonadotropin ( -HCG) level was found to be 5800 IU/L several hours after she left the clinic. The patient was asked to return for another quantitative -HCG level and endovaginal ultrasound examination.
On arrival at the hospital the next day, the patient had heavier bleeding and increased pelvic cramping. Endovaginal ultrasound examination revealed a saclike structure with a well-defined trophoblastic rim very low in the uterus at the level of the cervix, with internal echoes suggestive of a fetal pole but with no fetal heartbeat. The second quantitative -HCG level was 5412 IU/L. A diagnosis of cervical ectopic pregnancy was made and the patient was referred for an obsteteric/gynecology consultation to an obstetrician/gynecologist at our referral hospital 40 minutes away.
Speculum examination by the consultant showed a bulky bluish cervix with a 5-cm fluctuant purple mass on the left posterior lip. Gentle bimanual examination demonstrated a uterus typical of a 6-week pregnancy, moderate left-sided adnexal tenderness, and no palpable adnexal mass. Repeated endovaginal ultrasound examination showed persistence of the gestational sac in the cervix and a 9-mm oblong structure in the sac suggestive of a fetal pole but without cardiac activity (Figure 1). The diagnosis of cervical ectopic pregnancy was confirmed and therapeutic options were discussed with the patient.
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Figure 1. Long view of uterus demonstrates gestational sac in cervix with empty corpus of the uterus.
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The patient wanted to preserve fertility and avoid a hysterectomy. A literature review and phone consultation with specialists at 2 regional university hospitals yielded reports of successful treatment with intramuscular methotrexate. The patient agreed to this treatment option and was given a single intramuscular dose of methotrexate at 50 mg/m2 body surface area.1 She was admitted for several days' observation owing to the risk of sudden hemorrhage. A Foley catheter with a 30-mL balloon was kept at the bedside for emergency cervical tamponade. Her course was notable only for increased bleeding 1 day after receiving methotrexate without substantial change in pelvic examination findings or hematocrit level.
Her outpatient follow-up examination showed a gradual decrease in her quantitative -HCG level, which was 2560 IU/L 7 days after treatment with methotrexate, 390 IU/L after 17 days, and 164 IU/L 24 days after treatment. The patient presented 28 days after treatment with severe cramping. An endovaginal ultrasound examination showed persistence of the gestational sac with some low-level echoes but no discernible fetal pole or heartbeat (Figure 2). Her physical examination showed a soft abdomen without rebound or guarding, mild lower abdominal tenderness, and no palpable cervical or abdominal mass. She was not bleeding at the time. Her cramping gradually resolved.
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Figure 2. Sagittal view shows persistence of gestational sac with internal echoes consistent with fetal pole (28 days after treatment).
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Two months after treatment, her quantitative -HCG level was undetectable. Three months after treatment, an endovaginal ultrasound examination revealed persistence of the gestational sac in the cervix; however, products of conception were no longer present in the sac (Figure 3). A colposcopy performed 5 months after treatment for slight dysplasia showed no evidence of residual cervical mass. A final endovaginal ultrasound examination 6 months after treatment revealed a normal-appearing cervix without gestational sac. She is currently using oral contraception and has no plans to attempt conception.
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Figure 3. Sagittal view shows persistence of gestational sac with fetal pole no longer seen (3 months after treatment).
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HISTORICAL OVERVIEW OF CERVICAL PREGNANCY
Cervical pregnancy was first described in 1817 and first named as such in 1860. In a 1911 case report, Rubin2 established diagnostic criteria for cervical pregnancy: close attachment of placenta to the cervix, cervical glands present opposite the implantation site, placental location below uterine vessel insertion or below anterior and posterior reflections of the visceral peritoneum of the uterus, and no fetal elements in the uterine corpus.
Prior to the late 1980s, clinical diagnosis of cervical pregnancy was usually made when curettage for presumed incomplete spontaneous abortion resulted in uncontrollable hemorrhage. Most women required emergent hysterectomy and transfusion of large volumes of blood. In a 1945 review of the world literature at that time,3 6 of 28 women with cervical pregnancies died.
The advent of real-time transvaginal ultrasound examination and readily available -HCG assays allowed earlier diagnosis; a review of 120 cases since 19784 revealed that the proportion of cases diagnosed preoperatively rose from 35% between 1978 and 1982 to 87.5% between 1991 and 1994. Early diagnosis has in turn allowed fertility-sparing treatment options.
CAUSES OF CERVICAL ECTOPIC PREGNANCY
The causes of cervical ectopic pregnancies remain unknown. The incidence has been calculated as between 1 in 1000 to 1 in 18,000 live births,5-6 or less than 1% of ectopic pregnancies.7 The rarity of the condition has prevented any retrospective studies with adequate numbers to determine potential risk factors. Accelerated migration of the fertilized ovum through the uterus, change in the ability of the endometrial lining to accept implantation, and damage to the endocervical canal may all be contributing factors.
Several studies have shown a high incidence of prior dilation and curettage among women with cervical pregnancies.6, 8 Curettage may damage the endometrial lining and prevent implantation of the fertilized ovum. Endometrial inflammation from use of an intrauterine device and pelvic inflammatory disease may explain an apparent increased incidence of cervical ectopic pregnancy in patients with these risk factors.9 Although any of these factors may increase the relative risk of cervical pregnancy, the absolute risk must remain small as intrauterine devices, pelvic inflammatory disease, and sharp curettage are all common, while cervical ectopic pregnancies remain rare. Several recent case reports have also suggested an increased incidence of cervical ectopic pregnancies in women undergoing in vitro fertilization.10-11
An actual increase in the incidence of cervical ectopic pregnancy may be attributable to an increased prevalence of women with a history of uterine curettage and the use of interventional treatments for infertility. Alternatively, the incidence of cervical ectopic pregnancy may seem to be increased owing to the early diagnosis by endovaginal ultrasound examination of cervical pregnancies, some of which would have spontaneously aborted. Clarification of the roles of various risk factors will require a large retrospective study with an appropriately matched control population.
CLINICAL DIAGNOSIS
Women with cervical pregnancy classically present with painless first-trimester vaginal bleeding, although several case reports (including ours) describe patients with cramping pain. Clinical signs that should suggest cervical pregnancy include a soft cervix that is disproportionately enlarged compared with the uterus, a partially open external os, and profuse hemorrhage on manipulation of the cervix. A visible cervical lesion, often described as blue or purple and distended or edematous in appearance, may be noted.12-13 None of these signs is either diagnostic or invariably present, however, and if the suspicion of cervical pregnancy arises, radiological evaluation is mandatory.
RADIOLOGICAL DIAGNOSIS
The widespread use of endovaginal ultrasonography in the last decade has facilitated the detection of cervical pregnancy at an early gestational age. Accurate diagnosis of cervical pregnancy requires that the sonographer be familiar with the distinctions between cervical pregnancy, cervical abortion, and early intrauterine pregnancy.
In 1978, Raskin14 suggested that the diagnosis by ultrasound examination of cervical pregnancy required 4 factors: enlargement of the cervix, uterine enlargement, diffuse amorphous intrauterine echoes, and absence of intrauterine pregnancy. In 1993, Timor-Tritsch et al15 proposed more stringent criteria: the placenta and entire chorionic sac containing the live pregnancy must be below the internal os and the cervical canal must be dilated and barrel shaped.
Diagnosis can be difficult in early pregnancies without fetal cardiac activity. These cervical pregnancies must be distinguished from a cervical abortion, which has been defined as a "spontaneous abortion of an intrauterine pregnancy into the cervical canal where the abortus is retained by a resistant external os, thereby ballooning out the cervical canal."16 The gestational sac of a cervical abortion is often described as crenated.17 The gestational sac in a cervical pregnancy will be round or oval and will usually demonstrate some evidence of a fetus or yolk sac. The internal os will invariably be dilated in a cervical abortion and is completely closed in a cervical pregnancy. The endometrial cavity in a cervical abortion will often show a dense echogenic mass representing a mixture of blood and products of conception, while in the cervical pregnancy only a prominent endometrial echo caused by decidual reaction will be seen.16 Cervical abortion, unlike true cervical pregnancy, is suggested by the body of the uterus being larger than in the nongravid state owing to the recent loss of the intrauterine sac. If the diagnosis is in doubt, serial ultrasound examinations performed over a few days should distinguish the cervical abortion by the transience of the sac.16
In 1996, Jurkovic et al18 proposed 2 additional diagnostic criteria to distinguish cervical ectopic pregnancy from an aborting intrauterine pregnancy residing in the cervix. The "sliding sign" is detected on endovaginal ultrasound examination: when the sonographer applies gentle pressure on the cervix with the probe, the gestational sac of an abortus slides against the endocervical canal. This sliding motion will not be found in an implanted cervical pregnancy. The second criterion is demonstration of peritrophoblastic blood flow from an active vascular supply to the conceptus, which requires use of color Doppler ultrasonography. The nonviable sac transiently passing through the cervix will not have any peritrophoblastic flow, as it is separated from its vascular supply. The use of color Doppler ultrasonography is controversial; Benson and Doubilet,19 in an editorial accompanying the article by Jurkovic et al,18 felt that there was little diagnostic information gained from the technique, owing to overlap in Doppler findings between cervical ectopic pregnancy and miscarriage in progress. Magnetic resonance imaging imaging of cervical ectopic pregnancy was first reported in 1989 and may perhaps be useful when diagnosis is difficult.20 To our knowledge, routine use of magnetic resonance imaging in cervical ectopic pregnancy has not been demonstrated to be of clinical benefit.
In our case report, the cervical gestational sac was present on ultrasound examination for at least 3 months despite the drop in -HCG level. A review by Brown et al21 of ectopic pregnancies treated by methotrexate showed that persistent sonographic findings were common. He did not consider sonographic persistence as indicative of treatment failure and advocated against routine follow-up of the ectopic pregnancy that is clinically resolving with falling -HCG levels; his case series, however, included no cervical ectopic pregnancies. If other cervical pregnancy case reports confirm our finding of a persistent sac despite clinical resolution, then it is essential for physicians not to feel the need to intervene based on ultrasound examination persistence. One case report described surgical intervention owing to the belief that ultrasound examination persistence was a treatment failure, although the patient's -HCG level had fallen to zero.22 The unfortunate result of this intervention was an emergency hysterectomy.
TREATMENT OPTIONS FOR CERVICAL PREGNANCY
Options for treatment of cervical ectopic pregnancy depend on the fetal gestational age and the woman's desire to maintain fertility. Some treatment options, due to their technical difficulty, may also be available only in restricted settings. One possible treatment algorithm is shown in Figure 4.
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Figure 4. Suggested treatment algorithm: cervical ectopic pregnancy.
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Treatment choices may be divided conceptually into 5 categories: tamponade, reduction of blood supply, excision of trophoblastic tissue, intra-amniotic feticide, and systemic chemotherapy. A brief review of each category is given in Table 1. It is worth noting that in most reported cases of cervical pregnancy, treatments from more than 1 category were used.
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Treatment of Cervical Ectopic Pregnancy
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TAMPONADE
In older reports, cervical or vaginal packing was most commonly used to apply direct pressure on the bleeding site. Use of a Foley catheter, placed gently past the external os followed by the inflation of the balloon, has proven to be more effective in achieving hemostasis than packing.4 The Foley catheter should have a 30-mL balloon, which can be inflated to as much as 100 mL if necessary. Tamponade is commonly used after other techniques (such as cervical curettage) result in hemorrhage.
REDUCTION OF BLOOD SUPPLY
Reduction in blood supply to the cervical pregnancy may be used in preparation for surgical therapy such as curettage, or in combination with chemotherapy. Methods include cervical cerclage, vaginal ligation of the cervical arteries, uterine artery ligation, internal iliac artery ligation, and angiographic embolization of the cervical, uterine, or internal iliac arteries. Local vasoconstrictive agents (ie, intracervical vasopressin) have also been used to minimize bleeding. These procedures can be considered attempts at conservative therapy, in that subsequent pregnancy is possible. Angiographic embolization has recently been used primarily as "rescue" therapy when profuse bleeding follows other conservative measures such as chemotherapy.17
SURGICAL EXCISION OF TROPHOBLAST
The 2 classic techniques for removing cervical pregnancies are curettage and hysterectomy. Curettage risks hemorrhage, but before the introduction of chemotherapy, it was the only treatment available that might retain the patient's fertility. Curettage has therefore often been combined with other mechanical techniques (cervical artery ligation followed by curettage followed by balloon tamponade, for instance) to reduce the risk of hemorrhage. Curettage in this setting results in hysterectomy in about one fifth of patients.4, 18 In recent reports, curettage has also been used to remove sonographically evident but nonviable pregnancy tissue after chemotherapy. This approach, as previously discussed, can cause hemorrhage requiring additional surgery and can cause infertility.
Primary hysterectomy may still be appropriate in the following settings: intractable hemorrhage; second-trimester or third-trimester diagnosis of cervical pregnancy; and possibly to avoid transfusion or emergency surgery in a woman who does not desire fertility. Every published case of cervical pregnancy beyond 12 weeks' gestation by ultrasonographic measurement has ultimately resulted in hysterectomy,22 and hysterectomy might therefore be reasonably considered as primary therapy in these circumstances. For the rare cases of cervical pregnancy persisting to the age of extrauterine viability, hysterotomy delivery followed by hysterectomy is recommended.
FETICIDE BY INTRA-AMNIOTIC INJECTION
Intra-amniotic injection of potassium chloride or methotrexate under guidance of an ultrasound examination has been used successfully to treat cervical pregnancy. Intra-amniotic potassium chloride has sometimes been combined with systemic methotrexate. The major drawback of intra-amniotic injection techniques is the skill required. The amniotic sac must be kept intact to avoid substantial bleeding, which is best achieved by a transcervical or even transabdominal approach, avoiding the cervical canal itself. Three to 5 mL of 2 mEq/mL potassium chloride is injected after withdrawal of amniotic fluid to confirm needle location. Some centers have gained expertise in intra-amniotic injection of potassium chloride with selective reduction procedures for multiple pregnancies after assisted reproduction techniques, and in such settings intra-amniotic treatment of cervical gestations may be an excellent option.
Intra-amniotic methotrexate requires similar skill and technique. It seems to be most successful before 9 weeks' gestation,23 particularly in the absence of fetal cardiac activity. The usual dose is 1 to 1.5 mg/kg maternal body weight, and there is some risk of systemic adverse effects such as stomatitis or elevation of hepatic transaminases.
SYSTEMIC CHEMOTHERAPY
Although treatment with etoposide24 and other antineoplastic medications has been reported, the most commonly used systemic agent is methotrexate. Interest in methotrexate for treatment of cervical pregnancy did not become widespread until its use for other forms of ectopic pregnancy had become common. Reports and case series since 1990 have suggested a success rate of more than 80%18 in well-selected cases. Methotrexate seems to be most successful at early gestational ages, but successes have been reported even at -HCG levels higher than 40,000 IU/L and in the presence of fetal cardiac activity. Single-dose and multiple-dose regimens, with and without folinic acid rescue, have been reported. The data at present are too limited to compare the efficacy of the regimens. The shorter regimens, however, seem to minimize adverse effects such as bone marrow suppression and gastrointestinal disturbances. Transient elevation of hepatic transaminase levels can occur even with single-dose therapy.
FERTILITY AFTER CERVICAL ECTOPIC PREGNANCY
A review of all English-language case reports from 1911 to 1994 found 37 pregnancies in 29 women after conservative treatment of cervical pregnancy.7 Thirty-four of the pregnancies were intrauterine, 2 were tubal, and one was a repeated cervical. Three women underwent cerclage procedures for suspected cervical incompetence. Although the numbers are too small for statistical analysis, they seem to suggest a slightly increased incidence of ectopic pregnancy and premature delivery.
Women who had a cervical ectopic pregnancy treated with methotrexate should be counseled regarding potential effects on future pregnancies. Although the serum half-life of low-dose methotrexate is only 10 hours, the drug may be retained for many months in the kidneys and liver.25 A review of methotrexate's role as a teratogen demonstrated that the window of risk is primarily with use at 6 to 8 weeks' gestational age.26 Teratogenic effects have not been found in women who conceived after treatment with methotrexate for gestational trophoblastic tumors, but these women are routinely urged to avoid pregnancy for 6 to 12 months to facilitate detection of recurrent trophoblastic disease.27 Although there are little data to suggest danger in conceiving soon after treatment of the cervical ectopic pregnancy with methotrexate, many women may prefer to wait at least 6 months to minimize any potential for teratogenic effect. Early ultrasound examination in a subsequent pregnancy may be advisable to detect a recurrent ectopic pregnancy. Clinicians would be prudent to watch carefully for a possible increased risk of preterm labor or incompetent cervix, while reassuring patients that most pregnancies after a cervical ectopic will lead to term deliveries.
CONCLUSIONS
To our knowledge, the case described is the first report in the family practice literature of successful medical treatment of a cervical ectopic pregnancy. Cervical ectopic pregnancy remains an uncommon entity, but the increasing use of assisted reproductive technology and the widespread use of endovaginal ultrasound examination for early diagnosis may increase the incidence of detected cervical ectopic pregnancies. The development of medical and surgical treatments that allow the preservation of fertility when cervical pregnancy is diagnosed in early pregnancy requires that family physicians seeing pregnant women include this entity in the differential diagnosis of women presenting with bleeding and cramping. The family physician may collaborate in the treatment of cervical ectopic pregnancy, but consultation with obstetrician/gynecologists and radiologists is essential as surgical and interventional radiological modalities of treatment may be required.
AUTHOR INFORMATION
Accepted for publication May 28, 1999.
We thank Rae Zuni, RTR, for her assistance with obstetrical ultrasound examinations.
Reprints: Lawrence Leeman, MD, MPH, Family Practice Center, Third Floor, Department of Family and Community Medicine, University of New Mexico School of Medicine, 2400 Tucker NE, Albuquerque, NM 87131-5140.
From the Departments of Family and Community Medicine and Obstetrics and Gynecology, University of New Mexico, Albuquerque (Dr Leeman); and the Department of Anthropology, University of Massachusetts, Amherst, Mass (Dr Wendland).
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