1. What every clinician should know
Epidemiology of ectopic pregnancy
Ectopic pregnancy, the implantation of a fertilized ovum outside the uterine cavity, has been increasing in number. The true incidence of ectopic pregnancy is difficult to estimate because many women are treated in an outpatient setting. The latest information from MMWR Surveillance Summaries claims that it accounts for 2% of all pregnancies in the United States. The prevalence of ectopic pregnancy among women presenting to an emergency department with first-trimester vaginal bleeding, abdominal pain, or both has been reported to be as high as18%. Ectopic pregnancy accounts for 6% of all pregnancy-related deaths and is the leading cause of maternal death in the first trimester.
Nearly all ectopic pregnancies (97%) are implanted within the fallopian tube, and a common factor for the development of such ectopics is the presence of a pathological fallopian tube. Causes of such pathology include genital tract infection caused by gonorrhea and Chlamydia, tubal surgery including tubal sterilization, previous ectopic pregnancy, and in-utero exposure to diethylstilbestrol. Other risk factors for tubal ectopic pregnancy include conception with an IUD in place, conception while using a progesterone only contraceptive method, a history of infertility, the use of assisted reproductive technologies, and smoking.
One third of pregnancies that occur after sterilization failure are ectopic implantations, and such pregnancies account for 10% of all ectopic pregnancies. Additionally, one third of pregnancies after a prior ectopic pregnancy are repeat ectopic implantations.
Ectopic implantation can also occur outside of the fallopian tube, within the cervix, ovary, abdomen, uterine cornua, and cesarean scars. These extra-tubal implantations may not be associated with tubal pathology or the expected preexisting risk factors for tubal ectopic implantation.
2. Diagnosis and differential diagnosis
Traditionally, the diagnosis of ectopic pregnancy has been based on the clinical signs and physical symptoms of tubal rupture in a sexually active women with a positive pregnancy test: acute onset of severe abdominal pain; acute abdomen; and orthostatic hypotension. However, if ectopic pregnancy is diagnosed before rupture, conservative nonsurgical treatment is an option. By measuring serial human chorionic gonadotropin (hCG) levels and using serial ultrasonography, ectopic pregnancy can be diagnosed before rupture.
At least one half of women in whom an ectopic pregnancy is diagnosed have no identifiable risk factors or initial definitive physical findings. Early diagnosis is aided by a high index of suspicion. Every sexually active reproductive-aged woman who presents with abdominal pain or vaginal bleeding should be screened for pregnancy, and if present should be presumed to have an ectopic implantation until proven otherwise.
Transvaginal ultrasonography should be considered for all women with suspected early gestational pathology (positive pregnancy test with abdominal pain and/or vaginal bleeding).
An early pregnancy transvaginal ultrasound examination can result in one of the following three diagnoses or a nondiagnostic result:
An intrauterine pregnancy, living or failing
Rarely a hetrotopic pregnancy (one intrauterine and one extrauterine pregnancy)
An extrauterine gestation- ectopic pregnancy
A nondiagnostic result- further evaluation
A nondiagnostic ultrasound result is common and the one that presents the greatest clinical dilemma requiring further evaluation. Accurate gestational age calculation, rather than an absolute level of hCG, is the best determinant of when a normal pregnancy should be seen within the uterus with transvaginal ultrasonography.
If the precise gestational age is known, as in the case of women conceiving with ovulation induction or embryo transfer, the failure to detect a gestational sac within the uterus by 24 days or later after conception is presumptive evidence of an abnormal pregnancy. Without such precise gestational dating, the serum level of hCG must be used in order to interpret a non-diagnostic ultrasonogram.
If a woman has an initial nondiagnostic ultrasound examination result, an equivocal or normal serum progesterone level, and an appropriately increasing hCG level, and she remains clinically stable, a transvaginal ultrasound examination should be repeated when the hCG reaches the discriminatory zone.
Serum Human Chorionic Gonadotropin (hCG)
The “discriminatory zone” of hCG is between 1,500–2,000 mIU/ml (International Reference Preparation), which when reached is associated with the appearance, on transvaginal ultrasonography, of a normal singleton intrauterine gestation. If the hCG level is higher than the discriminatory zone, and the transvaginal ultrasound examination result is non-diagnostic, ectopic pregnancy is likely.
There is one instance where the discriminatory zone is not helpful: multifetal gestation. Multifetal (twins, etc.) gestations have a higher hCG level than singletons at any given gestational age and may lead to hCG levels well above 2,000 mIU/ml before ultrasound recognition of an intrauterine pregnancy. Therefore, if a multifetal gestation is likely, the discriminatory zone should be reevaluated.
Serial Serum HCG levels: with 99% sensitivity in early pregnancy, an increase in serum hCG of less than 53% in 48 hours confirms an abnormal/ failing pregnancy, but does not predict the location of the failing pregnancy (ectopic or intrauterine).
Serum Progesterone level determination may help confirm an abnormal/failing pregnancy.
Serum progesterone values are independent of hCG levels. An abnormal progesterone level is consistent with an abnormal, failing pregnancy but again, does not identify the site of the pregnancy (failed intrauterine or ectopic pregnancy)
A serum progesterone level less than 5 ng/ml has a specificity of 100% in confirming an abnormal pregnancy.
Normal intrauterine pregnancies usually have a serum progesterone level above 20 ng/ml. Levels between 5 and 20 are nondiagnostic.
Diagnosis of abnormal pregnancy (not necessarily ectopic): A non-diagnostic ultrasound examination result with a serum progesterone level less than 5 ng/ml and an inappropriate increase in hCG are each associated with an abnormal/failed pregnancy.
Endometrial Biopsy can be used to differentiate between an abnormal/ failed intrauterine pregnancy and ectopic pregnancy.
If intrauterine chorionic villi are noted on biopsy then the abnormal/failing pregnancy was intrauterine. If no intrauterine chorionic villi are found on endometrial biopsy then an ectopic pregnancy is confirmed
Ruptured ectopic pregnancy: once a woman with an ectopic pregnancy has signs of rupture with a hemoperitoneum, surgical management is necessary, with removal by laparoscopy or laparotomy.
Tubal ectopic pregnancies are amendable to salpingectomy, linear salpingostomy or fimbrial expression.
Location-specific treatments have been recommended for ectopic implantation occurring outside of the fallopian tube, within the cervix, ovary, abdomen, uterine cornua, or cesarean scars (see references).
Unruptured early diagnosis ectopic pregnancy: Regardless of location, however, when diagnosed early, prior to symptoms of rupture, many ectopic pregnancies can be successfully treated conservatively.
Methotrexate therapy can be considered for those women with a confirmed ectopic pregnancy who are hemodynamically stable who meet the following criteria:
Ectopic pregnancy on U/S smaller than 3.5 cm in diameter,
No evidence of a living embryo (yolk sac or cardiac activity),
A pretreatment hCG less than 5000 mIU/ml.
Three protocols are published for the administration of methotrexate to treat ectopic pregnancy:
Single dose – one dose of methotrexate, 50 mg per unit of body surface area.
Two dose – two doses of methotrexate, 50 mg per unit of body surface area on days 0 and 4 of treatment.
Fixed multi-dose – methotrexate, 1 mg per kilograms of body weight alternating daily with folinic acid, 0.1 mg per kilogram of body weight.
The single 50 mg/m2 dose regimen is the simplest and has been shown by some to be as effective as the fixed multi-dose regimen, eliminating the need for folinic acid rescue to minimize side effects.However, a recent meta-analysis has shown the fixed multi-dose regimen to be more effective, especially in treating women with more advanced gestations and those with embryonic cardiac activity.
The success of methotrexate therapy is monitored by following anticipated progressively falling serial serum hCG levels (see references for specific protocols) to exclude the possibility of a persistent ectopic pregnancy requiring an alternate recue therapy.
An initial post-therapy rise is serum hCG is common, but less than a 15% fall in the hCG level from post treatment days 4 until 7 post-therapy indicated treatment failure. After a 15% day 4 until 7 fall, weekly hCG measurements and clinical monitoring is appropriate, and a progresively falling hCG should be followed until it reaches a non-pregnant level. Failure of an appropriately falling hCG indicates initial treatment failure and rescue therapy is needed, either with additional methotrexate dosing or surgery.
The same hCG falling criteria to predict treatment success should be followed with any of the metotrezate treatment protocols.
Clinical observations should always accompany any conservative ectopic pregnancy management because and ectopic pregnancy can rupture leading to a hemoperitoneum even in the presence of a falling hCG level.
Late diagnosis of ectopic pregnancy can be life threatening. Ectopic pregnancy is the leading cause of maternal death in the first trimester and accounts for 6% of all pregnancy-related deaths.
Early diagnosis and treatment is necessary to spare maternal mortality and minimize maternal morbidity. However, ectopic pregnancy, in general is a threat to a woman’s future fertility. One third of pregnancies following a prior ectopic are repeat ectopics, and once a woman has had two ectopic pregnancies, her future chance of delivering a baby is only 4%.
The surgical management of ectopic pregnancies bears the overall risks of an operation. Risk of anesthesia including death, risk of blood loss, untoward injury to other intra-abdominal and pelvic organs and infection, including wound infections.
Methotrexate morbidity usually is dose and treatment duration dependent. Because methotrexate affects rapidly dividing tissues, gastrointestinal side effects, such as nausea, vomiting, and stomatitis, are the most common.
Women treated with methotrexate should be advised not to use alcohol and nonsteroidal anti-inflammatory drugs (NSAIDs).
Elevation of liver enzymes usually is seen only with multi-dose regimens and resolves after discontinuing methotrexate use or increasing the rescue dose of folinic acid. Alopecia is a rare side effect with the doses used to treat ectopic pregnancy.
Women should report any fever or respiratory symptoms because pneumonitis has been reported. It is not unusual for women treated with methotrexate to experience abdominal pain 2–3 days after administration, presumably from the cytotoxic effect of the drug on the trophoblast tissue, causing tubal abortion. In the absence of signs and symptoms of overt tubal rupture and significant hemoperitoneum, this pain usually can be managed expectantly by monitoring a woman’s hemoglobin level and intraperitoneal fluid amount with transvaginal ultrasound.
5. Prognosis and outcome
Persistent ectopic (the persistent presence of trophoblastic tissue producing hCG with the potential for rupture and hemoperitoneum) is the result of failed primary management, either surgical or medical, with a need for additional rescue therapy.
Persistent ectopic pregnancy is diagnosed by monitoring serial post-treatment hCG levels.
A biochemically diagnosed persistent ectopic without signs of rupture almost always responds to a single (additional) dose of methotrexate.
Ruptured persistent ectopics need surgical intervention.
Ectopic pregnancy is a potential threat to a woman’s future fertility.
With tubal ectopic pregnancy, regardless of treatment, a woman’s future fertility is dependent upon the anatomy of her contralateral fallopian tube, and if normal her future fertility is not compromised.
However, after multiple ectopic pregnancies, future child-delivering potential is futile.
6. What is the evidence for specific management and treatment recommendations
Fylstra, DL. “Ectopic pregnancy not within the (distal) fallopian tube: etiology, diagnosis and treatment: accepted for publication”. Am J Obstet Gynecol. 2012. (A review of the etiology, diagnosis, and location-specific treatments of ectopic pregnancies not located within the fallopian tube.)
“ACOG Practice Bulletin. Number 94. Medical management of ectopic pregnancy”. Obstet Gynecol. vol. 111. 2009. pp. 1479-85. (Detailed guidance for the appropriate use of methotrexate in treating non-ruptured ectopic pregnancy.)
Fylstra, DL, Soper, DE. “Ectopic Pregnancy”. Operative Obstetrics. 2002. pp. 355-8. (Book chapter extensive review of ectopic pregnancy.)
Barnhart, KT, Sammel, MD, Gracia, CR, Chittams, J, Hummel, AC, Shaunik, A. “Risk factors for ectopic pregnancy in women with symptomatic first-trimester pregnancies”. Fertil Steril. vol. 86. 2006. pp. 36-43. (Outlines the expectation of ectopic pregnancy in women with symptoms of gestational pathology.)
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. vol. 104. 2004. pp. 50-5. (Documentation of the minimum acceptable 48 hour serial rise of serum hCG when following women with gestational pathology that ultimately predicts a living, intrauterine pregnancy.)
Barnhart, KT, Gosman, G, Ashby, R, Sammel, M. “The medical management of ectopic pregnancy: a meta-analysis comparing “single dose” and “multidose” regimens”. Obstet Gynecol. vol. 101. 2003. pp. 778-84. (Success of multidose methotrexate when treating those ectopic pregnancies more likely to fail single dose therapy.)
Barnhart, K, Hummel, AC, Sammel, MD, Menon, S, Jain, J, Chakhtoura, N. “Use of “2-dose” regimen of methotrexate to treat ectopic pregnancy”. Fertil Steril. vol. 87. 2007. pp. 250-6. (A novel dose regimen using an automatic second methotrexate dose 4 days after the initial dose, independent of serial hCG monitoring.)
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