Hospital Medicine

Ectopic Pregnancy for the Hospitalist

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I. What every physician needs to know.

Ectopic pregnancy is any pregnancy that occurs outside the uterine cavity. The fallopian tubes account for 97% of all ectopic pregnancies, with the ampulla representing 55% and the isthmus 25%. Rarely, the pregnancy occurs in the abdominal cavity, cervix or ovary. Ectopic pregnancies account for 2% of all pregnancies.

Hemorrhage from the ectopic pregnancy is still the leading cause of maternal death in the first trimester.

The ectopic pregnancy results from damage to the normal fallopian tube anatomy. The most common gestational age is between 6–10 weeks. Spontaneous resolution of the pregnancy can occur but the risk of tubal rupture and hemorrhage remain high.

Current management attempts to preserve the fallopian tube from surgical resection and preserve reproductive function. Early diagnosis and treatment is therefore essential in reducing maternal mortality and preserving future fertility.

A. History Part I: Pattern Recognition:

Most women with an ectopic pregnancy present with vaginal bleeding and abdominal pain 5–9 weeks after amenorrhea. They frequently report normal changes of pregnancy including nausea and breast tenderness. Symptoms of hypovolemic shock or shoulder pain because of diaphragmatic irritation can occur if the ectopic has ruptured leading to gross hemorrhage. Risk factor assessment is an essential part to the evaluation of a woman with these symptoms.

B. History Part 2: Prevalence:

The rate of ectopic pregnancies is still increasing and has risen from 0.5% of all pregnancies in 1970 to 2% in 1992. Rupture of the pregnancy accounts for 1% to 15% of all maternal deaths. There is a trend towards decreasing hospitalizations but increasing incidence of ectopic pregnancies, as risk factors are also increasing and more management is done in the outpatient setting.

Young women of reproductive age are the most likely to have an ectopic pregnancy. Unfortunately, more than half of all women present without any known risk factors. Any woman who is capable of becoming pregnant is capable of having an ectopic pregnancy.

Risk factors include:

  • Previous ectopic pregnancy

  • Tubal surgery

  • Diethylstilbestrol (DES) exposure

  • Tobacco use

  • Genital infections like gonorrhea or chlamydia

  • Current intrauterine device (IUD) use

  • Infertility

  • Use of in vitro fertilization

Contraceptive use decreases the risk of ectopic pregnancies because of less chance of becoming pregnant. However, patients with an IUD have a higher risk for an ectopic pregnancy if they are pregnant. Patients with a history of an ectopic pregnancy have a 15% chance of a second ectopic pregnancy. Patients with a history of two ectopic pregnancies have a 30% chance of a third event.

C. History Part 3: Competing diagnoses that can mimic ectopic pregnancy.

Differential diagnosis includes gynecologic and gastrointestinal sources.

Gynecologic processes include ovarian torsion, pelvic inflammatory disease, ruptured cyst or miscarriage.

Gastrointestinal causes include acute appendicitis, inflammatory bowel disease and diverticulitis.

Urinary calculi should also be considered.

D. Physical Examination Findings.

On pelvic examination, a slightly enlarged uterus might be palpated. Vaginal bleeding and pelvic pain with cervical manipulation are highly suggestive of an ectopic. However, up to 30% of patients have no vaginal bleeding. A palpable adnexal mass is seen in 10% of patients.

Patients who have severe abdominal tenderness with rebound tenderness and guarding indicative of an acute abdomen should be considered to have a ruptured ectopic pregnancy.

E. What diagnostic tests should be performed?

All women who present with a history of amenorrhea and new vaginal bleeding need a urine pregnancy test. If the pregnancy test is positive, then a quantitative beta subunit of human chorionic gonadotropin (β-hCG) and a transvaginal ultrasound (TVUS) need to be obtained.

Only 45% of the time does a woman present with the classic triad of pelvic pain, bleeding and an adnexal mass.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

β-hCG levels increase by 53% every day in a normal intrauterine pregnancy and peak at a level greater than 100 000 IU/L at 9–11 weeks’ gestation. The plateau lasts for a few days and then declines around 20 weeks. A β-hCG level can be detected as early as 8 days in a pregnancy. In a normal pregnancy, an increase of at least 66% over 48 hours has been a cutoff point for viability. The rise in β-hCG is much slower in an ectopic pregnancy. However, 21% of ectopic pregnancies demonstrate a doubling of β-hCG identical to an intrauterine pregnancy.

A falling β-hCG level is indicative of a nonviable pregnancy. Therefore, serial β-hCG levels are attained to help evaluate for an ectopic. The discriminatory threshold is the β-hCG level where a gestational sac can be seen on an ultrasound (US). The discriminatory threshold is a level of 1500 IU/L for a TVUS, and 6500 IU/L for a transabdominal US.

Therefore, if a patient has a β-hCG level greater than 1500 IU/L but no evidence of a gestational sac on TVUS, then there is a high likelihood for an ectopic pregnancy.

If the β-hCG is below 1500 IU/L and there is no evidence of a uterine gestational sac, then the patient could still have an ectopic pregnancy or a viable pregnancy.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

An US is very accurate in differentiating between normal and abnormal pregnancies in the first trimester. An US showing an intrauterine pregnancy with a gestational sac plus yolk sac or other embryonic sign effectively rules out an ectopic pregnancy. In more than 75% of emergency department patients, an initial US scan can establish a diagnosis.

A TVUS can reveal an intrauterine pregnancy if the β-hCG is above 1500 IU/L. If the exam shows a complex adnexal mass, then an extrauterine pregnancy has occurred. If the TVUS fails to show either, then it is repeated in 48 hours along with the β-hCG level. If the TVUS still fails to show an intra- or extrauterine pregnancy but the β-hCG is increased or plateaued, then ectopic pregnancy is diagnosed.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

A normal serum progesterone level in a viable pregnancy is greater than 25 ng/mL (79.5 nmol/L). A nonviable pregnancy usually has a level less than 5 ng/mL (15.9 nmol/L). However, a progesterone level usually takes several days to process and is therefore not clinically relevant.

III. Default Management.

Management of an ectopic pregnancy is based on the presentation of the patient, the β-hCG levels and US findings.

Surgery, either with a laparotomy or laparoscopy, with either a tube-sparing salpingostomy versus salpingectomy, is the treatment of choice in the following conditions:

  • Hemodynamically unstable patient

  • Patient with poor compliance or follow-up

  • Patient with contraindications to methotrexate (MTX) therapy

  • Pretreatment β-hCG less than 5000 IU/L

  • Absence of fetal cardiac activity on US

  • Coexisting intrauterine pregnancy (heterotopic)

Medical therapy is done providing intramuscular MTX as a single dose or multiple dose regimen. MTX is a folic acid antagonist that inhibits deoxyribonucleic acid (DNA) synthesis in actively dividing cells. Overall, MTX has a 94% success rate in appropriate patients. The drug's effectiveness is inversely proportional to the β-hCG levels. MTX at 1 mg/kg or 50 mg/m2 can be given as a single intramuscular dose.

A multiple-dose regimen was more effective in older studies, but is associated with increased cost, requires folinic acid rescue therapy and has more side effects. Newer literature also casts doubt on its benefit. For most women, a single, low dose MTX injection is sufficient with close follow-up.

A baseline complete blood cell count and complete medical profile need to be obtained prior to giving MTX. MTX is contraindicated in patients with hepatic, renal and hematologic diseases, patients with active lung disease and peptic ulcer disease.

A. Immediate management.

Prompt consultation with an OB/GYN is warranted once the diagnosis is made.

B. Physical Examination Tips to Guide Management.

A pelvic exam can reveal an adnexal mass, but as noted above, this is noted in only about 10% of patients with ectopic pregnancy.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

All patients treated with MTX should be followed closely with serial β-hCG levels.

Repeat TVUS may show a worsening appearance with increased hemorrhage a week after MTX. An increase in mass size may be seen up to 3 months after treatment. Therefore, a repeat TVUS should only be obtained if a patient presents with increasing symptoms suggestive of rupture.

A repeat β-hCG should be obtained 7 days after administration of MTX. If there has not been a 25% reduction in the level, then a second dose of MTX should be given. Only 1% of patients require a second dose. The β-hCG levels should then be measured weekly until undetectable. The β-hCG levels decline to less than 15 IU/L around 33.6 days post treatment.

If the β-hCG levels fail to fall by more than 25% from the previous week's level, then consideration for repeat MTX should be considered. If 3 doses of MTX have been given and the β-hCG level has plateaued, then surgical intervention is considered.

D. Long-term management.

Patients should be counseled on the increased risk of a repeat ectopic pregnancy if future conception is planned. Because the ectopic pregnancy resulted from an abnormality within the fallopian tube, the patients are also at increased risk of future infertility.

E. Common Pitfalls and Side-Effects of Management.

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IV. Management with Co-Morbidities.

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A. Renal Insufficiency.

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B. Liver Insufficiency.

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C. Systolic and Diastolic Heart Failure.

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D. Coronary Artery Disease or Peripheral Vascular Disease.

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E. Diabetes or other Endocrine issues.

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F. Malignancy.

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G. Immunosuppression (HIV, chronic steroids, etc).

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H. Primary Lung Disease (COPD, Asthma, ILD).

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I. Gastrointestinal or Nutrition Issues.

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J. Hematologic or Coagulation Issues.

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K. Dementia or Psychiatric Illness/Treatment.

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A. Sign-out considerations While Hospitalized.

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B. Anticipated Length of Stay.

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C. When is the Patient Ready for Discharge.

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D. Arranging for Clinic Follow-up.

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1. When should clinic follow up be arranged and with whom.

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2. What tests should be conducted prior to discharge to enable best clinic first visit.

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3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

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E. Placement Considerations.

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F. Prognosis and Patient Counseling.

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A. Core Indicator Standards and Documentation.

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B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

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VII. What's the Evidence?

Berry, J,, Davey, M,, Hon, MS,, Behrens, R. "A 5-year experience of the changing management of ectopic pregnancy". J Obstet Gynaecol. vol. 25. 2016. pp. 1-4.

Hajenius, PJ,, Mol, F,, Mol, BW,, Bossuyt, PM,, Ankum, WM,, van der Veen, F.. "Interventions for tubal ectopic pregnancy.". Cochrane Database Syst Rev.. vol. 24. 2007.

Song, T,, Kim, MK,, Kim, ML,, Jung, YW,, Yun, BS,, Seong, SJ. "Single-dose versus two-dose administration of methotrexate for the treatment of ectopic pregnancy: a randomized controlled trial.". Hum Reprod. vol. 31. 2016. pp. 332-8.

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