Rajiv B. Gala
History of present illness
A 37-year-old female, gravida 2, para 1, presents to the emer- gency department with mild, left lower quadrant pain and vaginal spotting that started 2 hours prior to admission. Her last menstrual period was six weeks prior to presentation.
A home pregnancy test was positive one week ago. The patient denies any fevers, chills, shortness of breath, or dizziness while walking. Her appetite has been normal and her last bowel movement was one day ago. She describes the pain as dull, colicky, and rated it at 3 out of 10 on the pain scale.
Her past medical history is significant for a tubo-ovarian abscess treated four months ago. Her past surgical history is negative. She has been married for four years and uses no contraception. She has no known drug allergies. Her only medication is a daily prenatal vitamin.
Physical examination
General appearance:Well-developed, well-nourished woman who is in mild discomfort but alert and oriented Vital signs:
Temperature: 37.0°C Pulse: 92 beats/min
Blood pressure: 110/72 mmHg Respiratory rate: 16 beats/min Oxygen saturation: 100% on room air Height: 65 inches
Weight: 130 lb BMI: 21.6 kg/m2
Abdomen:Thin, soft, nontender, nondistended, no guarding, no rebound
External genitalia:Unremarkable
Vagina:Scant dark blood in posterior fornix
Cervix:Parous, closed, no active bleeding or passage of tissue
Uterus:Anteverted, mobile, normal size, mild tenderness on bimanual examination
Adnexa:Fullness in LLQ, mild discomfort with palpation Laboratory studies:
Urine pregnancy test: Positive Beta-hCG: 3241 mIU/mL Blood group and Rh: B positive Indirect Coombs: Negative WBCs: 12 800/μL
Hb: 11.9 g/dL Ht: 36.2%
Imaging:Transvaginal ultrasound shows uterus normal with endometrial thickness 6 mm, 3.4 cm left corpus luteum cyst with another mass adjacent to the ovary, no freefluid (Fig. 33.1)
How would you manage this patient?
The patient has a small unruptured ectopic pregnancy.
The combination of beta-human chorionic gonadotropin (beta-hCG) above the discriminatory zone, absence of a visible intrauterine pregnancy, and presence of a suspicious adnexal mass makes ectopic pregnancy highly likely. Since the patient is hemodynamically stable, it is unlikely that the ectopic has ruptured and she is a candidate for either medical or surgical management.
The patient was thoroughly counseled on the risks and benefits of the different treatment options. Preservation of future fertility was a major priority for her and she decided to proceed with medical management using methotrexate. She received a single dose of 50 mg/m2. The patient’s serum beta- hCG levels dropped appropriately and became undetectable four weeks after her dose and she did not require any further treatment.
Small unruptured ectopic pregnancy
A pregnancy is ectopic when it implants anywhere other than the endometrial lining of the uterine cavity. While ectopic pregnancies most commonly occur in the ampullary portion of the fallopian tube, other less common sites of implantation include the ovary, cervix, interstitial portion of the fallopian tube, or the abdomen. Ectopic pregnancies are the leading cause of maternal death in thefirst trimester, primarily from severe hemorrhage after tubal rupture. Despite the fivefold increase in ectopic pregnancy rates from 1970 to 1992 [1], improved diagnosis and treatment has resulted in a 10-fold decline in the case fatality rate.
The classic triad of ectopic pregnancy symptoms is irregu- lar vaginal bleeding, abdominal pain, and amenorrhea. Prior to rupture, the pain may be described as colicky, diffuse, or localized. Once the ectopic pregnancy ruptures, patients typic- ally report sharp, diffuse pain likely from peritoneal irritation caused by the bleeding. Unfortunately, the classic symptoms are nonspecific and can be found with other disease processes in the differential diagnosis: ovarian torsion, hemorrhagic Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
corpus luteum cyst, salpingitis, or a threatened or spontaneous abortion. Consideration of ectopic pregnancy risk factors is important for a more timely and accurate diagnosis. The most common risk factors for ectopic pregnancy are a prior ectopic pregnancy, tubal surgery, prior pelvic inflammatory disease, smoking, and the use of assisted reproductive technology. It is not unusual for ectopic pregnancy to occur in patients without known risk factors. This patient’s recent episode of pelvic inflammatory disease with tubo-ovarian abscess puts her at high risk.
Once an ectopic pregnancy is suspected and the patient is confirmed to be hemodynamically stable, a systematic approach using high resolution ultrasonography and serial serum beta-hCG measurements can be used to confirm the diagnosis. In normal pregnancies, the serum beta-hCG rises in a log-linear fashion until around 70 days after the last menstrual period. A normal intrauterine pregnancy should demonstrate a 53–66% increase in serum beta-hCG levels every 48 hours [2]. An inadequately rising serum beta-hCG only indicates an abnormal pregnancy, not its specific location.
Pregnancies with inappropriately rising levels can be abnormal intrauterine pregnancies and are not necessarily ectopic gesta- tions. Serum progesterone levels have been studied to aid in the diagnosis of ectopic pregnancies when the serum beta-hCG was inconclusive. The primary utility of serum progesterone levels is to help differentiate normal from abnormal pregnan- cies. A progesterone level of less than 5 ng/mL is consistent with an abnormal pregnancy and a value of greater than 20 ng/
mL has a 95% sensitivity to identify a normal pregnancy.
Serum progesterone levels have the same limitations as serial beta-hCG assays for determining location.
Transvaginal ultrasonography is highly effective at identifying intrauterine pregnancies. In normal intrauterine pregnancies, a gestational sac is usually visible by five weeks after the last menstrual period, a yolk sac appears betweenfive and six weeks, and a fetal pole with cardiac activity is first
detected around six weeks. When the date of the last menstrual period is uncertain, the serum beta-hCG levels can help define expected sonographicfindings. The beta-hCG levels at which these landmarks typically occur can vary from institution to institution because of differences in ultrasound equipment and beta-hCG assays, and discriminatory levels should be determined for each institution. For most institutions, the serum beta-hCG discriminatory value is between 1500 and 2500 mIU/mL. The serum beta-hCG discriminatory value is higher when performing transabdominal ultrasonography.
Inability to visualize a gestational sac above these values makes the likelihood of normal intrauterine pregnancy exceedingly small and should increase the suspicion for an ectopic preg- nancy. Other ultrasoundfindings that can be seen with ectopic pregnancies include:
Pseudogestational sac–one layer collection of sloughing decidua in the midline of the uterine cavity.
Halo sign–thin hypoechoic area caused by subserosal edema in the fallopian tubes (Fig. 33.2).
Ring offire–placental bloodflow within the periphery of a complex adnexal mass.
While the diagnosis of ectopic pregnancy was straightfor- ward in this case, there are many times when the combin- ation of beta-hCG level and ultrasound findings is not definitive. If the patient is hemodynamically stable and the pregnancy is desired, it is reasonable to repeat the serum beta-hCG and ultrasound in 48 hours to monitor for change, as there are scenarios such as multiple gestations where the ultrasound findings can lag behind the beta-hCG level. If the pregnancy was not desired or there is thought to be a very high likelihood of an ectopic pregnancy, uterine curet- tage can be performed. If trophoblastic tissue is obtained, an ectopic pregnancy has been effectively ruled out. If no tro- phoblastic tissue is obtained, ectopic pregnancy is extremely likely, and further treatment is indicated. Obtaining a
Fig. 33.1 Ultrasound image of left adnexa. 3.4 cm left corpus luteum cyst with another mass adjacent to the ovary.
definitive diagnosis can avert the use of methotrexate in nearly 40% of cases [3].
When patients are hemodynamically stable, a small unrup- tured ectopic pregnancy can be managed either medically or surgically. Expectant management with spontaneous resorption of an ectopic pregnancy should only be considered when the serum beta-hCG is less than 200 mIU/mL. Most patients prefer medical therapy using methotrexate. With methotrexate, rates of overall tubal preservation, tubal patency, repeat ectopic pregnancies, and future pregnancies are equiva- lent to surgical management [4]. Methotrexate works by inhibiting the binding of dihydrofolic acid to the enzyme dihydrofolate reductase, thereby arresting DNA, RNA, and protein synthesis. Since methotrexate targets rapidly dividing cells, side effects are mostly related to the gastrointestinal tract and bone marrow (ulcerative stomatitis, severe diarrhea, thrombocytopenia, and severe anemia). There are two intra- muscular methotrexate protocols that have been well studied with similar success rates of between 67 and 93% (Table 33.1) [5]. The single-dose methotrexate protocol is the most widely used, in part due to patient convenience. Prior to
administration of methotrexate, a serum beta-hCG level, com- plete blood count, complete metabolic panel, blood type and Rh status, and liver function tests should be obtained. The patient is then administered 50 mg/m2 body surface area of intramuscular methotrexate. Beta-hCG levels will usually con- tinue to rise until day 4 after administration. A serum beta- hCG level should be obtained for comparison on days 4 and 7 following methotrexate administration. A decline by 15% or more between days 4 and 7 indicates an appropriate initial response, and patients should then have weekly serum beta- hCG levels drawn until they are undetectable. If there is less than a 15% decline between any weekly measurements, the patient is failing treatment and should receive an additional dose of methotrexate following the original protocol. An alter- native multidose methotrexate protocol involves 1 mg/kg of methotrexate followed by a dose of leucovorin 24 hours later.
If there is not a 15% drop in serial serum beta-hCG concen- trations from days 0–1 or days 1–3, an additional methotrex- ate/leucovorin combination is given up to a maximum of four doses (Table 33.1[6]). Proponents of the multidose protocol justify the more intense post-therapy monitoring because
Fig. 33.2 Left corpus luteum cyst with adjacent ectopic pregnancy displaying halo sign.
Table 33.1 Methotrexate treatment protocol for ectopic pregnancy*
Single-dose protocol Multidose protocol
Medication doses:
Methotrexate
Leucovorin 50 mg/m2BSA 1.0 mg/kg
0.1 mg/kg Serum beta-hCG
collections Days 1 (baseline), 4, 7 Days 0 (baseline), 1, 3, 5, 7
Need for repeat
medication If serum beta-hCG does not fall by 15% from day 4 to 7
If serum beta-hCG does not fall by 15% in 1 week
If serum beta-hCG does not fall by 15% between days 0 and 1
If serum beta-hCG does not fall by 15% between days 1 and 3 (after repeat doses)
Adapted from American College of Obstetricians and Gynecologists [6].
beta-hCG, beta-human chorionic gonadotropin; BSA, body surface area.
Case 33: A pregnant 37-year-old woman with lower left quadrant pain
series suggest a better cure rate. Unfortunately, there has not been an adequately powered randomized trial comparing single and multidose therapy to confirm this difference.
Surgical treatment options include both laparoscopy and laparotomy, although laparoscopic treatment is preferred since there are shorter hospital stays, reduced blood loss, and shorter operating times. The two options for ectopic removal are salpingectomy (removal of the fallopian tube) or salpingost- omy (preserving the fallopian tube). In the face of a normal contralateral fallopian tube, both techniques have similar sub- sequent intrauterine pregnancy rates. Salpingectomy would be preferred over salpingostomy if future fertility is not desired or there was complete tubal rupture. Compliance with serial serum beta-hCG after salpingostomy is important to monitor for incomplete eradication of trophoblastic tissue, as seen in 3–20% cases.
In this case, both treatment options were reviewed with the patient, as she was an appropriate candidate for either. She was a good candidate for medical therapy because she was asymptomatic and motivated enough to remain compliant with post-therapy surveillance. In addition, her chance of success was equivalent between medical and surgical options because the tubal diameter was less than 3.5 cm, no extrauterine fetal cardiac activity was present, and the serum beta-hCG was less than 5000 mIU/mL. Absolute contraindications to medical therapy include breast-feeding, alcoholism or liver disease, active pulmonary disease, peptic ulcer disease, and hepatic,
renal, or hematologic dysfunction [6]. All patients receiving medical therapy need to be counseled on the high likelihood of increased abdominal pain during the first few days after treatment. This pain is thought to be due to tubal distension caused by tubal abortion or hematoma formation. Typically acetaminophen is adequate for pain relief. An oral narcotic can be given if necessary, but, if substantial pain relief is needed, the patient should be evaluated for possible tubal rupture. The patient should be advised not to use folic acid supplements, nonsteroidal anti-inflammatory drugs, or alcohol while being treated with methotrexate. She should also avoid sunlight exposure, vigorous physical activity, and sexual activity.
Key teaching points
The classic triad of symptoms for a patient with an ectopic pregnancy is irregular vaginal bleeding, abdominal pain, and amenorrhea.
A uterine curettage in the face of a presumed ectopic pregnancy can confirm an abnormal uterine pregnancy in nearly 40% of cases.
Hemodynamically stable patients with a small unruptured ectopic pregnancy can be managed medically with methotrexate or surgically via laparoscopy or laparotomy.
Failure of medical therapy is defined as tubal rupture with massive intra-abdominal hemorrhage or lack of resolution after four doses of methotrexate.
References
1. Centers for Disease Control and Prevention. Ectopic pregnancy–United States, 1990–1992.MMWR1995;44:
46–8.
2. Barnhart KT, Sammel MD, Rinaudo PF, et al. Symptomatic patients with an early viable intrauterine pregnancy:
hCG curves redefined.Obstet Gynecol 2004;104:50–5.
3. Shaunik A, Kulp J, Appleby DH, Sammel MD, Barnhart KT. Utility of dilation and curettage in the diagnosis of pregnancy of unknown location.Am J Obstet Gynecol2011;204(2):130.e1–6.
4. Hajenius PJ, Mol F, Mol BWJ, et al.
Interventions for tubal ectopic pregnancy.Cochrane Database Syst Rev 2007, Issue 1. Art. No.: CD000324. DOI:
10.1002/14651858. CD000324.pub2.
5. Lipscomb GH, Givens VM, Meyer NL, et al. Comparison of multidose and single-dose methotrexate protocols for the treatment of ectopic pregnancy.Am J Obstet Gynecol2005;192:1844–7;
discussion 187–8.
6. American College of Obstetricians and Gynecologists. Medical management of ectopic pregnancy. Practice Bulletin No.
94.Obstet Gynecol2008;111:1479–85.