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The Subtle Symptoms of an Ectopic Pregnancy

Ectopic pregnancy is relatively rare, yet it accounts for 10% of all maternal deaths in the U.S.

Olivia is a 37-year-old healthy female who presented to the emergency department (ED) with pelvic pain and vaginal spotting. She has had a hormonal intrauterine device (IUD) in place for four years, yet continues to have regular menses. Her last regular menses was 3 weeks ago, and she has had light spotting and midline pelvic cramping ever since. The night prior to Olivia's presentation in the ED, the pain acutely worsened (but had since waned). Acetaminophen provided her moderate relief; she was pain-free at time of evaluation. She denied experiencing other symptoms, notably fever, vomiting, dysuria, vaginal discharge, and flank pain. Olivia voiced concern that there could be something wrong with her IUD.

Medical History
Olivia reported being monogamous with a male partner. Her medical history revealed that Olivia was G4P2Ab2 (meaning, pregnant 4 times, having birthed 2 children and lost 2 pregnancies).

Physical Examination
At triage, Olivia's vital signs were as follows: BP 109/58 mm Hg; P 61 beats/min; RR 16; T 97.8 F; and SpO2 99% on room air. She appeared well and said she felt comfortable. Her physical examination was unremarkable, other than a report of mild midline suprapubic tenderness. A pelvic examination revealed a small amount of dark blood in Olivia's vaginal vault, IUD strings at the cervical os, and mild bilateral adnexal tenderness without masses or fullness.

Initial diagnostic studies performed included complete blood cell count, urinalysis, urine hCG, chlamydia/gonorrhea swabs, and pelvic ultrasound.

The CBC and urinalysis were unremarkable. The urine hGC, however, was positive and the pelvic ultrasound revealed a 2.7 cm x 3.4 cm x 2.5 cm mixed echogenicity adnexal structure adjacent to the right ovary. The IUD was visualized in the uterus and there were no findings consistent with an intrauterine pregnancy.

Upon these findings, gynecology was consulted and additional diagnostics were obtained. The tests ordered included quantitative hCG, Rh, basic metabolic panel (BMP), and liver function tests (LFTs).

Pregnancy of Unknown Location
Often, after an initial workup in the ED, providers are left with a diagnosis of pregnancy of unknown location (PUL). This is defined as the absence of pregnancy localization (either intra- or extra-uterine) by pelvic ultrasonography in patients who have a serum beta hCG less than 1,000 IU/L to 1,500 IU/L, a range known as the discriminatory zone (the hCG level at or above one would expect to visualize pregnancy on ultrasonography).1

Any woman classified as having a PUL must be followed closely until a final outcome can be determined. Outcomes include intrauterine pregnancy (IUP), pregnancy failure, or ectopic pregnancy. Current guidelines recommend following the patient's serial beta hGC levels at 48-hour intervals on an outpatient basis.

A 50% to 66% rise in hCG levels in a 48-hours period is consistent with likely IUP, while a 21% to 35% decline is more consistent with pregnancy failure.3 A static or irregularly rising or falling hCG level raises concerns for an ectopic location of the pregnancy. Serial ultrasonography and examinations are also indicated based on clinical status and hCG laboratory values.

Ruling Out Ectopic Pregnancy
Ectopic pregnancy (EP) occurs in approximately 1% of all pregnancies.1 An ectopic pregnancy is defined as a pregnancy that is located anywhere outside of the endometrial cavity of the uterus. The most common location is one of the fallopian tubes, but an EP can also occur at an ovary, or in the cervix or abdominal cavity.2 Since none of these sites are able to support a growing embryo, there is always a chance of rupture and associated hemorrhage.

A ruptured ectopic pregnancy is one of the leading causes of pregnancy-related mortality in the U.S., accounting for between 10% to 15% of all maternal deaths. It is, therefore, a true medical emergency and a very important differential diagnosis for emergency medicine providers. 

Making a definite diagnosis of EP in a stable patient can become a prolonged process, but it begins with clinical suspicion. Higher suspicion should occur among women with risk factors.

Risk factors that provide strong evidence for association with EP include:2

·  Pelvic inflammatory disease;

·  Previous ectopic pregnancy;

·  Endometriosis;

·  Previous tubal surgery;

·  Previous pelvic surgery;

·  Infertility treatments;

·  Uterotubal anomalies;

·  History of in utero exposure to diethylstilbestrol; and

·  Cigarette smoking.

Risk factors that offer weaker evidence for association with EP include:2

·  Multiple sexual partners;

·  Early age at first intercourse; and

·  Vaginal douching.

The patient in this case was not high-risk for ectopic pregnancy based on the risk factors listed above, so the initial workup aimed at ruling out common causes of irregular vaginal bleeding and pelvic pain in a patient with an IUD, such as pregnancy, ovarian pathology, hormonal IUD side effects or expulsion, dysfunctional uterine bleeding, or mittelschmerz.

Managing Ectopic Pregnancy
Management options for EP depend on many factors and can include surgical, medical, or expectant modalities.

For patients that are hemodynamically unstable, emergent surgical management is indicated. Other indications for surgical management include: ectopic masses >3.5cm, fetal cardiac motion, higher beta hCG levels, known or suspected rupture, or patient preference. Surgical procedures generally include salpingectomy or salpingostomy, either via laparoscopy or laparotomy.2

Medical management of EP offers the advantages of lower cost, preservation of tubal function, and avoidance of surgery. Many chemical agents have been studied for the medical treatment of ectopic pregnancy. To date, the mainstay of medical treatment is the folic acid antagonist, methotrexate, in either one or two dose regimens.2

Patients with EP whose blood type is Rh negative should be treated with Rho(D) immune globulin in order to prevent Rh incompatibility, which can cause complications for future pregnancies. These complicating conditions range from mild-to-moderate infantile anemia and/or hyperbilirubinemia to severe conditions such as kernicterus, hydrops fetalis, or even death in utero from massive antibody-induced hemolytic anemia.4

Several studies have found that approximately 68% to 77% of ectopic pregnancies resolve without any surgical or medical interventions, making expectant management a potential option. This management modality should be reserved for stable patients with small ectopic pregnancies and falling beta hCG levels who can be trusted to closely follow up with outpatient providers.2

Regardless of which approach is utilized to manage ectopic pregnancy, the patient should have serial beta hCG levels followed until undetectable, out of concern for potential heterotopic pregnancy or treatment failure [2]. 

Olivia's Diagnosis
Olivia's quantitative hCG result was 830 and Rh was negative, while the BMP and LFTs were unremarkable. These findings are consistent with pregnancy of unknown location. Once it had been determined that Olivia was pregnant, an ultrasound raised the concern of implantation in the adnexa and the diagnosis of likely ectopic pregnancy was determined.

The gynecology consult service was called into the ED, and members of that team administered Methotrexate to Olivia before performing a Karmen biopsy-for both diagnostic and potentially therapeutic purposes.

Additionally, members of the gynecology consult team removed Olivia's IUD. Rho(D) immune globulin was administered intramuscularly. After a period of observation with stable vital signs, Olivia was discharged to her home with strict warnings to return to the ED if symptoms returned and to follow up with the gynecology clinic within 2 days.  

Olivia soon followed up with the gynecology clinic to have her serial quantitative hCG levels tested. At that visit, Olivia learned that her Karmen biopsy revealed endometrial cells without chorionic villi, consistent with ectopic pregnancy, and the swab that had been taken to test for both chlamydia and gonorrhea were negative.

Olivia's quantitative hCG levels required approximately one month from administration of methotrexate to reach zero. At this time, she elected to resume the hormonal IUD as her method of contraception.

Analysis of This Case
Intrauterine devices are often mistakenly associated with ectopic pregnancy, although there is no evidence to suggest that modern-day IUDs increase the risk of this condition.2 In fact, because the IUD is such a reliable and reversible contraception method, they decrease the overall risk of pregnancy, including the risk of ectopic pregnancy. Consider, for example, the hormonal IUDs that are currently available, which boast low failure rates of 0.1 to 0.6 per 100 woman-years (WY), and even lower rates of ectopic pregnancy (0.02 to 0.2 per 100 WY).5 In fact, the hormonal IUD boasts one of the lowest rates of ectopic pregnancy among other birth control methods (other than complete abstinence). 

It is important to note that despite these reassuring statistics and the fact that IUD use does not increase the absolute risk of ectopic pregnancy, if an IUD should fail and result in pregnancy, the implantation is slightly more likely to occur in an ectopic location.2,6

Although we considered EP as an initial differential diagnosis for a woman with a hormonal IUD who had reported weeks of cramping and spotting with a sudden, acute worsening of pain, our initial clinical suspicion for this was not as high as other possible diagnoses. The leading differential diagnoses for Olivia's case were ovarian cyst rupture, ovarian torsion, mittelschmerz, IUD expulsion, IUD-related side effects, or dysfunctional uterine bleeding. Pregnancy (including intrauterine, ectopic, and spontaneous abortion), tubo-ovarian abscess, and sexually transmitted infection were also considered as possible differential diagnoses.

Janelle Bludorn is a physician assistant in the emergency department at UNC Health Care and an assistant professor at the University of North Carolina at Chapel Hill School of Medicine. This is a case she encountered in her previous practice at Massachusetts General Hospital emergency department in Boston. 

References

1. Varma R, Gupta J. Tubal ectopic pregnancy. BMJ Clinical Evidence. 2012:1406.

2. Tenore JL. Ectopic pregnancy. Am Fam Physician. 2000;61(4):1080-1088. 

3. Kirk E, Bottomley C, Bourne T. Diagnosing ectopic pregnancy and current concepts in the management of pregnancy of unknown location. Hum. Reprod. Update. 2014;20(2):250-261.

4. Fung K, Eason E, Crane J, Armson A, De La Ronde S, Farine D, et al. Prevention of Rh alloimmunization. J Obstet Gynaecol Can. 2003;25(9):765-773.

5. Heinemann K, Reed S, Moehner S, Do Minh T. Comparative contraceptive effectiveness of levonorgestrel-releasing and copper intrauterine devices: the European Active Surveillance Study for Intrauterine Devices. Contraception. 2015;91(4):280-283.

6. Li C, Zhao WH, Meng CX, Ping H, Qin GJ, Cao SJ, et al. Contraceptive use and the risk of ectopic pregnancy: a multi-center case-control study. PLoS ONE. 2014;9(12).

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