Authors: Shahed Steiner, MD and Katrin Takenaka, MD, MEd; McGovern Medical School at the University of Texas Health Science Center at Houston

Edited by: Eric Blazar, MD, Rowan University, 

Updated: 2019

Case Study

A 29-year-old female presents to the emergency department (ED) with sudden onset right lower quadrant abdominal pain that has been worsening in severity over the past day. Her last menstrual period was 7 weeks ago although she does report some recent vaginal spotting. She is sexually active with multiple partners, inconsistently uses the progestin-only pill for contraception, and has been treated for pelvic inflammatory disease (PID) in the past. 

Her vital signs include T 99F, BP 116/75, HR 86, RR 18. She is in moderate distress due to pain. On abdominal exam, she has right lower quadrant tenderness to palpation as well as rebound.  Pelvic exam reveals a scant amount of blood in the vaginal vault, a slightly enlarged uterus, cervical motion tenderness, and right adnexal tenderness. 

Objectives

1. Describe risk factors associated with ectopic pregnancy
2. Discuss the role of testing in the diagnosis of ectopic pregnancy
3. Explain the treatment options for ectopic pregnancy
4. Review diagnostic and treatment algorithms in order to make appropriate dispositions for patients with suspected or confirmed ectopic pregnancy
   

Introduction

Ectopic pregnancy (EP) is a “can’t miss diagnosis” and the leading cause of maternal death in the first trimester. It results from the fertilized ovum implantation outside of the endometrium of the uterus. Although ectopics are most commonly found in the fallopian tubes, they can also occur in the ovary, cervix, myometrial interstitium, and peritoneal cavity. This potentially life-threatening condition occurs in up to 2% of all pregnancies. 

Despite improved diagnostics capabilities, abdominal pain in a fertile aged female carries a wide differential diagnosis.  Other conditions with similar presentations include urinary tract infection, appendicitis, spontaneous abortion, early pregnancy, PID, ovarian cyst and/or torsion, and tubo-ovarian abscess. 

Women with anatomic abnormalities, congenital or acquired, may impair the fertilized ovum’s ability to implant in the uterus are at risk for EP, including those with previous tubal surgery (even tubal ligation), prior ectopic pregnancy, intrauterine device use, and prior PID. Additional risk factors include infertility or infertility treatments, advanced maternal age, smoking, multiple sexual partners, and prior abdominal/pelvic surgeries. While risk factors are important to consider, a lack thereof does not rule out EP.  About half of patients with EP have no known risk factors.

When a female patient of child-bearing age presents with any combination of abdominal pain and vaginal bleeding, EP must be considered as early diagnosis and treatment are essential to decrease maternal mortality and preserve future fertility.

Initial Actions and Primary Survey

The initial evaluation of a patient with a suspected EP should focus on the rapid assessment of vital signs and the ABCs. The patient should be placed on monitors, and intravenous (IV) access should be obtained. Depending on the patient’s hemodynamic status, IV fluids or blood products may be necessary.  In those with evidence of hemorrhagic shock, O negative blood may need to be transfused and massive transfusion protocols initiated. Narcotic analgesia should be administered as needed for pain control.

Initial bloodwork for these patients should include a complete blood count, type and screen, and β-hCG. Although a urine qualitative β-hCG is often faster, there is a risk of false negatives. Thus in a patient with concerning signs and symptoms, a serum quantitative β-hCG should also be ordered. For some patients, a basic metabolic panel and coagulation studies may also be indicated. 

Similar to its use in trauma, a Focused Abdominal Sonography in Trauma (FAST) bedside ultrasound can help rapidly identify free fluid/hemoperitoneum in patients suspected of having a ruptured EP. The combination of a FAST positive for free fluid and positive pregnancy test should be treated as a ruptured ectopic pregnancy until proven otherwise.

Presentation

Symptoms of an EP develop as the growing fetus distorts surrounding tissues or rupture of the EP results in peritoneal irritation.  Typically this occurs at 6-8 weeks after the patient’s last menstrual period (LMP). Because presenting signs and symptoms vary, the diagnosis can be challenging. The classic triad of vaginal bleeding, abdominal pain, and amenorrhea is neither sensitive nor specific for an EP. Some women with EP may actually have no or minimal symptoms. Although abdominal pain is reported in 97-98%, the quality and severity of pain are highly variable. Vaginal bleeding occurs in 56-79% but may be minimal even in critically ill patients. The diagnosis of EP should also be considered in women presenting with syncope or unexplained hypotension. 

Unless they have experienced significant blood loss, most patients with EP have normal vital signs. However, all patients with suspected EP should be considered potentially unstable, and provisions should be made in anticipation of the development of hemodynamic instability. Tenderness on pelvic exam is the most common physical exam finding; however, few patients will have a palpable pelvic mass. It is important to remember that cervical motion tenderness can be a sign of peritoneal irritation. Additionally EP cannot be ruled out by history and physical examination alone.

Diagnostic Testing

All women of childbearing age presenting with abdominal or pelvic pain and/or vaginal bleeding should have a urine pregnancy test performed upon arrival in the ED. As mentioned above, if concerning signs and symptoms are present, a serum β-hCG  should be ordered due to the risk of false negatives with urine pregnancy tests. Hemodynamically unstable patients in the first trimester with a positive pregnancy test should be assumed to have an EP and immediate OB-GYN consultation obtained.

β-hCG is a hormone produced by trophoblasts.  In normal first trimester intrauterine pregnancies (IUPs), it doubles every 48-72 hours. The discriminatory zone is the lowest β-hCG at which an IUP should be visible on ultrasound (6000-6500 mIU/mL transabdominally, 1000-2000 mIU/mL transvaginally). However, EP (even ruptured ones) may occur in patients with β-hCG < 100 mIU/mL. The decision to ultrasound a pregnant patient with abdominal pain and/or vaginal bleeding should not be based on the β-hCG level as it cannot be used to predict the presence of an EP or an IUP. However, it can be useful to help interpret ultrasound findings and make disposition decisions. 

As stated earlier, bedside FAST can identify free fluid in the abdomen/pelvis, raising the concern for ruptured EP. Ultrasound can also be used to visualize the presence or absence of an IUP. Unless a concern for heterotopic pregnancy exists (i.e., concurrent EP and IUP), the presence of an IUP rules out EP. Although heterotopic pregnancies are rare overall (1/10,000-30,000 natural conceptions), assisted reproductive technology rates may be as high as 1/100. 

The earliest ultrasound finding of an IUP is the double decidual sac, occurring at 4.5-5 weeks post-LMP. At 5-6 weeks, a yolk sac can usually be visualized and guarantees the presence of an IUP. A fetal pole and embryonic cardiac activity are usually seen by 6-7 weeks.  Ultrasound findings conclusive of an EP include an extrauterine yolk sac or embryo. The presence of an adnexal mass or tubal ring sign without an IUP is concerning for EP.

Ultrasound images of normal early IUPs and ectopics can be found at:

• https://radiopaedia.org/articles/early-pregnancy?lang=us 
• https://radiopaedia.org/articles/ectopic-pregnancy?lang=us 

The more complex diagnostic dilemma arises when neither an IUP nor an adnexal mass is appreciated on ultrasound because early pregnancy, abnormal IUP/spontaneous abortion, and EP remain possible. In this case, a β-hCG above the discriminatory zone increases the likelihood of an EP. For hemodynamically stable patients without significant abdominal pain, further outpatient monitoring of serial β-hCGs +/- repeat ultrasonography may be needed to cinch the diagnosis.

Although rarely used since ultrasound became readily available, culdocentesis is a bedside procedure that can be performed to detect intraperitoneal blood in unstable patients with suspected EP. After a needle is advanced through the posterior vaginal wall into the peritoneal space, obtaining more than 2 ml of nonclotting blood suggests the presence of hemoperitoneum and ruptured EP.

Treatment

Management options for patients with suspected or confirmed EP include expectant management, medical therapy, or operative intervention.  In general, these management decisions should be made in conjunction with OB-GYN. Rh-negative pregnant women with vaginal bleeding or suspected EP should receive 50 or 300 μg of anti-D immunoglobulin (RhoGAM) to prevent maternal alloimmunization. 

Patients who are hemodynamically unstable or have signs of a ruptured EP should be resuscitated in the same manner as others with acute hemorrhage with IV fluids and/or blood products. OB-GYN should be consulted expeditiously as these patients will require surgical intervention. 

Stable patients with EP may be managed medically with methotrexate. Medical management may preserve future fertility better than surgery. This agent interferes with DNA synthesis and replication of fetal cells, resulting in involution of the pregnancy. 36% of patients fail single dose therapy and require a second dose if β-hCG levels are not declining as expected.

Methotrexate may be considered in hemodynamically stable patients: 

• Without evidence of rupture 
• With β-hCG < 5000 mIU/mL
• With gestations < 4 cm
• Without fetal cardiac activity 

Contraindications include: 

• inability to return for follow-up 
• immunodeficiency 
• renal, liver, or pulmonary disease 
• peptic ulcer disease 
• blood dyscrasias 
• breastfeeding

Abdominal pain is not uncommon 2-3 days after methotrexate administration and must be differentiated from pain associated with ruptured EP. Patients who cannot receive or fail methotrexate therapy require laparoscopy. 

Patients with pregnancy of unknown location (i.e., neither confirmed IUP nor confirmed EP) and β-hCG above the discriminatory zone should receive OB-GYN consultation for suspected EP. Those with β-hCG below the discriminatory zone and without a strong suspicion for EP may be managed expectantly with 48 hour follow up for repeat β-hCG +/- repeat ultrasonography. All patients with concern for EP who are discharged from the ED should receive instructions to return for evaluation if worsening pain, vaginal bleeding, dizziness, syncope, or weakness develops.

Pearls and Pitfalls

• Patients with EP have variable presentations, and the classic presentation of abdominal pain, vaginal bleeding, and amenorrhea is uncommon. 
• While risk factors for EP are important to consider, a lack thereof does not rule out EP.
• All patients with suspected EP should be considered potentially unstable, and provisions should be made in anticipation of the development of hemodynamic instability (e.g., frequent vital sign monitoring, IV access). 
• Urine pregnancy tests can produce false negatives. Thus patients with concerning signs and symptoms require serum β-hCG measurement. 
• The discriminatory zone for ultrasound detection of an IUP is 6000-6500 mIU/mL transabdominally and 1000-2000 mIU/mL transvaginally. However, EP (even ruptured ones) may occur in patients with β-hCG < 100 mIU/mL. 
• In patients without concern for heterotopic pregnancy, the presence of an IUP effectively rules out EP. 
• Management decisions for patients with suspected or confirmed EP should usually be made in conjunction with OB-GYN.
• Surgical intervention is required for patients who are hemodynamically unstable, have a ruptured EP, or cannot receive or have failed methotrexate therapy. 
• Patients with pregnancy of unknown location and β-hCG above the discriminatory zone should receive OB-GYN consultation. Those with β-hCG below the discriminatory zone and without a strong suspicion for EP may be managed expectantly with 48 hour follow up for repeat β-hCG +/- repeat ultrasonography
  

Case Study

The patient’s β-hCG was 5000 mIU/mL. Although transvaginal ultrasound did not reveal an IUP, an adnexal mass containing a yolk sac was visualized. The patient was Rh-positive and, therefore, did not require RhoGAM. After OB-GYN consultation, the decision was made to administer methotrexate since the patient was hemodynamically stable, had no evidence of ruptured EP, and had no contraindications to medical management. The patient was discharged home with “ectopic return precautions.” After close follow up with OB-GYN, serial β-hCG levels were found to be decreasing appropriately.

References

ACEP Clinical Policies Committee and Clinical Policies Subcommittee on Early Pregnancy. Clinical Policy: Critical issues in the initial evaluation and management of patients presenting to the emergency department in early pregnancy. Ann Emerg Med. 2003; 41:123-133. (PMID: 12514693)

Adhikari S, Blaivas M, Lyon M. Diagnosis and management of ectopic pregnancy using bedside transvaginal ultrasonography in the ED: a 2-year experience. Am J Emerg Med. 2007; 48:591-596. (PMID: 17606080)

Alkatout I, Honemeyer U, Strauss A, Tinelli A, Malvasi A, Jonat W, et al. Clinical diagnosis and treatment of ectopic pregnancy. Obstet Gynecol Surv. 2013; 68:571-581. PMID: 23921671)

Ankum W, Mol B, Van der Veen F, Bossuyt P. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril. 1996; 65:1093-1099. (PMID: 8641479)

Barnhart K. Clinical practice: ectopic pregnancy. N Engl J Med. 2009; 361:379-387. (PMID:  19625718)

Bhatt S, Ghazale H, Dogra V. Sonographic evaluation of ectopic pregnancy. Radiol Clin North Am. 2007; 45:549-560. (PMID: 17601508)

Branney S, Wolfe R, Moore E, Albert N, HeinigM, Mestek M, et al. Quantitative sensitivity of ultrasound in detecting free intraperitoneal fluid. J Trauma. 1995; 39:375-380. (PMID: 7674411)

Deutchman M, Tubay A, Turok D. First trimester bleeding. Am Fam Physician. 2009; 79:985-992. (PMID: 19514696)

Gurel S. Ectopic pregnancy. Ultrasound Clin. 2008; 3:331-343.

Jain K. Gynecologic causes of acute pelvic pain: ultrasound imaging. Ultrasound Clin. 2008; 3:1-12.

Hendriks E, MacNaughton H, MacKenzie MC. First trimester bleeding: evaluation and management. Am Fam Physician. 2019; 99;166-174. (PMID: 30702252)

Lee R, Dupuis C, Chen B, Smith A, Kim YH. Diagnosing ectopic pregnancy in the emergency setting. Ultrasonography. 2018; 37: 78-87. (PMID: 29061036)

Levine D. Ectopic Pregnancy. Radiology. 2007; 245:385-397. (PMID: 17940301)

Lin E, Bhatt S, Dogra V. Diagnostic clues to ectopic pregnancy. Radiographics. 2008; 28:1661-1671. (PMID: 18936028)

Mukul L, Teal S. Current management of ectopic pregnancy. Obstet Gynecol Clin North Am. 2007; 34:403-409. (PMID: 17921007)

Promes S, Nobay F. Pitfalls in first-trimester bleeding. Emerg Med Clin North Am. 2010; 28:219-234. (PMID: 19945608)

Robertson JJ, Long B, Koyfman A. Emergency medicine myths: ectopic pregnancy evaluation, risk factors, and presentation. J Emerg Med. 2017; 53: 819-828. (PMID: 29110976)

Seeber BB. Ectopic Pregnancy. In T. Falcone, & W. Hurd, Clinical Reproductive Medicine and Surgery (1st ed.). Philadelphia, PA: Mosby Elsevier, 2007.

Stein JC, Wang R, Adler N, Boscardin J, Jacoby VL, Won G, et al. Emergency physician ultrasonography for evaluating patients at risk for ectopic pregnancy: a meta-analysis. Ann Emerg Med. 2010; 56: 674-683. (PMID: 20828874)

Tay J, Moore J, Walker J. Ectopic Pregnancy. West J Med. 2000; 173:131-134. (PMID: 10924442)