Ectopic pregnancy: Forget the “classic presentation” if you want to catch it sooner

,

Applied Evidence

Ectopic pregnancy: Forget the “classic presentation” if you want to catch it sooner

J Fam Pract. 2006 May;55(5):388-395

By

Kalyanakrishnan Ramakrishnan, MD

A new algorithm to improve detection.

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References

1. Stovall TG, Kellerman AL, Ling FW, Buster JE. Emergency department diagnosis of ectopic pregnancy. Ann Emerg Med 1990;19:1098-1103.

2. Fylstra DL. Tubal pregnancy: a review of current diagnosis and treatment. Obstet Gynecol Surv 1998;53:320-328.

3. Ankum WM, Mol BW, Van der Veen F, Bossuyt PM. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril 1996;65:1093-1099.

4. Mol BW, Ankum WM, Bossuyt PM, Van der Veen F. Contraception and the risk of ectopic pregnancy: a meta-analysis. Contraception 1995;52:337-341.

5. Bouyer J, Coste J, Shojaei T, et al. Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case-control, population-based study in France. Am J Epidemiology 2003;157:185-194.

6. Carr RJ, Evans P. Ectopic pregnancy. Prim Care 2000;27:169-183.

7. Barnhart K, Esposito M, Coutifaris C. An update on the medical treatment of ectopic pregnancy. Obstet Gynecol Clin North Am 2000;27:653-667, viii.

8. Buckley RG, King KJ, Disney JD, Ambroz PK, Gorman JD, Klausen JH. Derivation of a clinical prediction model for the emergency department diagnosis of ectopic pregnancy. Acad Emerg Med 1998;5:951-960.

9. Cacciatore B, Tiitinen A, Stenman U, Ylostalo P. Normal early pregnancy: serum hCG levels and vaginal ultrasonography findings. Br J Obstet Gynecol 1990;97:899-903.

10. Brown DL, Doubilet PM. Transvaginal sonography for diagnosing ectopic pregnancy: positivity criteria and performance characteristics. J Ultrasound Med 1994;13:259-266.

11. Nyberg DA, Hughes MP, Mack LA, Wang KY. Extrauterine findings of ectopic pregnancy at transvaginal US: importance of echogenic fluid. Radiology 1991;178:823-826.

12. Pellerito JS, Taylor KJ, Quedens-Case C, et al. Ectopic pregnancy: evaluation with endovaginal color flow imaging. Radiology 1992;183:407-411.

13. Mol BW, Hajenius PJ, Engelsbel S, et al. Serum human chorionic gonadotropin measurement in the diagnosis of ectopic pregnancy when transvaginal sonography is inconclusive. Fertil Steril 1998;70:972-981.

14. Kaplan BC, Dart RG, Moskos M, et al. Ectopic pregnancy: prospective study with improved diagnostic accuracy. Ann Emerg Med 1996;28:10-17.

15. Braffman BH, Coleman BG, Ramchandani P, et al. Emergency department screening for ectopic pregnancy: a prospective US study. Radiology 1994;190:797-802.

16. Mateer JR, Aiman EJ, Brown MH, Olson DW. Ultrasonographic examination by emergency physicians of patients at risk for ectopic pregnancy. Acad Emerg Med 1995;2:867-873.

17. Dart RG, Mitterando J, Dart LM. Rate of change of serial beta-human chorionic gonadotropin values as a predictor of ectopic pregnancy in patients with indeterminate transvaginal ultrasound findings. Ann Emerg Med 1999;34:703-710.

18. Dart RG, Kaplan B, Varaklis K. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emerg Med 1999;33:283-290.

19. Carson SA, Buster JE. Ectopic pregnancy. N Engl J Med 1993;329:1174-1181.

20. Kadar N, Caldwell BV, Romero R. A method of screening for ectopic pregnancy and its indications. Obstet Gynecol 1981;58:162-166.

21. Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W. Symptomatic patients with an early viable intrauterine pregnancy: hCG curves redefined. Obstet Gynecol 2004;104:50-55.

22. Kadar N, DeVore G, Romero R. Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy. Obstet Gynecol 1981;58:156-161.

23. Brennan DF. Ectopic pregnancy—Part I: Clinical and laboratory diagnosis. Acad Emerg Med 1995;2:1081-1089.

24. Mol BWJ, Lijmer JL, Ankum WM, Van der Veen F, Bossuyt PM. The accuracy of single serum progesterone measurement in the diagnosis of ectopic pregnancy: a meta-analysis. Hum Reprod 1998;13:3220-3227.

25. Buckley RG, King KJ, Disney JD, Riffenburgh RH, Gorman JD, Klausen JH. Serum progesterone testing to predict ectopic pregnancy in symptomatic first-trimester patients. Ann Emerg Med 2000;36:95-100.

26. Barnhart KT, Gracia CR, Reindl B, Wheeler JE. Usefulness of pipelle endometrial biopsy in the diagnosis of women at risk for ectopic pregnancy. Am J Obstet Gynecol 2003;188:906-909.

27. Birkhahn RH, Gaeta TJ, Paraschiv D, et al. Serum levels of myoglobin, creatine phosphokinase, and smooth muscle heavy-chain myosin in patients with ectopic pregnancy. Ann Emerg Med 2001;38:628-632.

28. Daniel Y, Geva E, Lerner-Geva L, et al. Levels of vascular endothelial growth factor are elevated in ectopic pregnancy: is this a novel marker? Fertil Steril 1999;72:1013-1017.

29. Bree RL, Edwards M, Bohm-Velez M, Beyler S, Roberts J, Mendelson EB. Transvaginal sonography in the evaluation of normal early pregnancy: correlation with hCG level. AJR Am J Roentgenol 1989;153:75-79.

30. Barnhart K, Mennuti MT, Benjamin I, Jacobson S, Goodman D, Coutifaris C. Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet Gynecol 1994;84:1010-1015.

31. Hill LM, Kislak S, Martin JG. Transvaginal sonographic detection of the pseudogestational sac associated with ectopic pregnancy. Obstet Gynecol 1990;75:986-988.

32. Dart R, Burke G, Dart L. Subclassification of indeterminate pelvic ultrasonography: prospective evaluation of the risk of ectopic pregnancy. Ann Emerg Med 2002;39:382-388.

33. Spandorfer SD, Barnhart KT. Endometrial stripe thickness as a predictor of ectopic pregnancy. Fertil Steril 1996;66:474-477.

34. Mol BW, Hajenius PJ, Engelsbel S, et al. Are gestational age and endometrial thickness alternatives for serum human chorionic gonadotropin as criteria for the diagnosis of ectopic pregnancy? Fertil Steril 1999;72:643-645.

35. Dart RG, Dart L, Mitchell P, Berty C. The predictive value of endometrial stripe thickness in patients with suspected ectopic pregnancy who have an empty uterus at ultrasonography. Acad Emerg Med 1999;6:602-608.

36. Kirchler H, Seebacher S, Alge AA, Muller-Holzner E, Fessler S, Kolle D. Early diagnosis of tubal pregnancy: changes in tubal blood flow evaluated by endovaginal color Doppler sonography. Obstet Gynecol 1993;82(4 Pt 1):561-565.

37. Kataoka ML, Togashi K, Kobayashi H, Inoue T, Fujii S, Konishi J. Evaluation of ectopic pregnancy by magnetic resonance imaging. Hum Reprod 1999;14:2644-2650.

38. Cacciatore B, Stenman U, Ylosato P. Diagnosis of ectopic pregnancy by vaginal ultrasonography in combination with a discriminatory serum hCG level of 1000 IU/l (IRP). Br J Obstet Gynecol 1990;97:904-908.

39. Mol BWJ, Van der Veen F, Bossuyt PM. Implementation of probabilistic decision rules improves the predictive values of algorithms in the diagnostic management of ectopic pregnancy. Hum Reprod 1999;14:2855-2862.

40. Gracia CR, Barnhart KT. Diagnosing ectopic pregnancy: decision analysis comparing six strategies. Obstet Gynecol 2001;97:464-470.

Practice recommendations

Less than half of the patients with ectopic pregnancy present with the classic triad of a history of amenorrhea, abdominal pain, and irregular vaginal bleeding (C).
Definite cervical motion tenderness and peritoneal signs are the most sensitive and specific examination findings for ectopic pregnancy—91% and 95%, respectively (A).
Beta-human chorionic gonadotropin (β-hCG) levels can be used in combination with ultrasound findings to improve the accuracy of the diagnosis of ectopic pregnancy (A).
Women with initial nondiagnostic transvaginal ultrasound should be followed with serial β-hCGs (B).

Despite advanced detection methods, ectopic pregnancy may be missed in 40% to 50% of patients on an initial visit.¹ Most women with ectopic pregnancy have no risk factors (TABLE 1),^2-5 and the classic triad of a history of amenorrhea, abdominal pain, and irregular vaginal bleeding is absent in more than half of cases.

Early diagnosis not only decreases maternal mortality and morbidity; it also helps preserve future reproductive capacity—only one third of women with ectopic pregnancy have subsequent live births.²

FAST TRACK

Most women with ectopic pregnancy have adnexal and lower abdominal tenderness, with cervical motion tenderness and peritoneal signs the most specific

Management strategies for patients with ectopic pregnancy have evolved rapidly, with ambulatory medical therapy becoming an option for more patients.⁶ Using a practical decision protocol, we discuss the physical findings that most reliably suggest ectopic pregnancy, describe sensible use of laboratory and imaging studies, and explain what to do when results are equivocal. In part 2 of this article (coming in the June 2006 Journal of Family Practice), we provide a decision protocol for management of ectopic pregnancy.

TABLE 1
Risk factors for ectopic pregnancy

DEGREE OF RISK	FACTOR	ODDS RATIO (95% CONFIDENCE INTERVALS)
		ANKUM ET AL³	MOL ET AL⁴	BOUYER ET AL⁵
High	Previous tubal surgery	21 (9.3–47)		4.0 (2.6–6.1)
	Tubal ligation		9.3 (4.9–18)
	Previous ectopic pregnancy	8.3 (6.0–11.5)
	In utero DES exposure	5.6 (2.4–13)
	Current IUD use		4.2–45*
	Tubal pathology/abnormality	3.5–25*
Moderate	Infertility	2.5–21*		2.7 (1.8–4.2)
	History of PID	2.5 (2.1–3.0)		3.4 (2.4–5.0)
	Previous chlamydial or gonococcal infection	2.8–3.7*
	Current smoking	2.3 (2.0–2.8)		3.9 (2.6–5.9)
	Spontaneous abortions ≥3			3.0 (1.3–6.9)
	Induced abortions (medical±surgical)			2.8 (1.1–7.2)
	Lifetime sexual partners >1	2.1 (1.4–4.8)
Low	Age first intercourse <18 years	1.6 (1.1–2.5)
	Previous pelvic/abdominal surgery	0.93–3.8*
	Vaginal douching	1.1–3.1*
DES, diethylstilbestrol; PID, pelvic inflammatory disease; IUD, intrauterine device
* Range; summary odds ratio not calculated owing to significant heterogeneity between studies.

Evaluation

Clinical features of ectopic pregnancy highly variable

No single clinical feature accurately indicates ectopic pregnancy. Less than half of women with ectopic pregnancy exhibit the classic triad of a history of amenorrhea, abdominal pain, and irregular vaginal bleeding.¹ And, unfortunately, these features are seen commonly in patients with both viable (50%) and nonviable (25%) intrauterine pregnancies, as well as in threatened abortion, cervical irritation, infection, and trauma.⁷

Set a low threshold for suspicion. For any woman of childbearing age with abdominal pain and vaginal bleeding, consider pregnancy and take steps to rule out ectopic pregnancy. Abdominal pain and vaginal bleeding are highly sensitive for ectopic pregnancy but are not specific for the disorder (TABLE 2).^8-17 Pain located in the hypogastrium or iliac fossa may be mild to severe. Vaginal bleeding, present in 50% to 80% of patients with ectopic pregnancy, can be mistaken for a normal menstrual period.^2,6 Pregnancy-associated symptoms of nausea and vomiting, breast tenderness, and fatigue may be present.

FAST TRACK

With transvaginal ultrasound, the gestational sac of a normal single intrauterine pregnancy should be visible at a β-hCG level over 1000–1500 mIU/mL

Lower abdominal and adnexal tenderness can be elicited in most women with ectopic pregnancy. Cervical motion tenderness, peritoneal signs, and adnexal masses are most specific for ectopic pregnancy, but are not sensitive.⁸ An adnexal mass is palpable in less than 10% of cases; when it is detected, one third of patients will have a contralateral ectopic pregnancy on ultrasonography.¹⁸ Symptoms of hemodynamic compromise (orthostasis, hypotension, shock) are becoming uncommon with earlier diagnosis of ectopic pregnancy, facilitated by improved detection methods.

TABLE 2
Significance of features associated with ectopic pregnancy

FEATURES	SN (%)	SP (%)	LR+	LR–
Clinical features⁸
Any risk factors	23	83	1.4	0.9
Estimated gestational age <70 days	95	27	1.3	0.2
Vaginal bleeding	69	26	0.9	1.2
Abdominal pain	97	15	1.1	0.2
Abdominal tenderness	85	50	1.7	0.3
Peritoneal signs	23	95	4.6	0.8
Cervical motion tenderness	33	91	3.7	0.7
Adnexal tenderness	69	62	1.8	0.5
Adnexal mass	5	96	1.3	1.0
Transvaginal ultrasound
No intrauterine gestational sac⁹	100	89	9.1	<0.1
Adnexal mass¹⁰
Separate from ovary	93	99	93	0.1
Cardiac activity	20	100	∞	0.8
Yolk sac or embryo	37	100	∞	0.6
Tubal ring/yolk sac or embryo	65	99	65	0.4
Fluid in pouch of Douglas¹¹
Any	63	69	2.0	0.5
Echogenic	56	96	14.0	0.5
Color-flow Doppler¹²	95	98	47.5	0.1
β-hCG combined with transvaginal ultrasound
Empty uterus
≥1000 mIU/mL^10,13,14	43–96	86–100	3.0–∞	0.04–0.66
≥1500 mIU/mL^13,15	40–99	84–96	6.3–9.9	0.01–0.63
≥2000 mIU/mL^13,16	38–48	80–98	2.3–25.3	0.63–0.68
Adnexal mass*
≥1000 mIU/mL¹³	73	85	4.7	0.32
≥1500 mIU/mL^13,15	46–64	92–96	5.9–16.5	0.38–0.58
≥2000 mIU/mL¹³	55	96	14.2	0.47
β-hCG rise in 48 hours (empty uterus)^†
>66%¹⁷	—	—	1.1	—
<66%¹⁷	—	—	7.4	—
>50%¹³	—	—	2.8	—
<50%¹³	—	—	3.3	—
β-hCG fall in 48 hours (empty uterus)^†
>50%^13,17	—	—	0.8–1.4	—
<50%^13,17	—	—	0–0.1	—
* Mass or fluid in cul de sac for β-hCG ≥1500 mIU/mL and ≥2000 mIU/mL.
† Strata-specific likelihood ratios reported, sensitivity and specificity not applicable.
Sn, sensitivity; Sp, specificity; LR, likelihood ratio; β-hCG, beta-human chorionic gonadotropin.

Laboratory tests

In an early normal pregnancy, the beta-human chorionic gonadotropin (β-hCG) level doubles every 1.8 to 3 days, rising to 1000 mIU/mL IRP (International Reference Preparation, measured by radioimmunoassay) by 5 weeks, to 2500 mIU/mL by 6 weeks, and to 13,000 mIU/mL (±3000) by 7 weeks. A single quantitative β-hCG level is not always helpful, as it can range from less than 100 mIU/mL to greater than 50,000 mIU/mL with both ruptured and unruptured ectopic pregnancies.¹⁹