Early diagnosis of an ectopic pregnancy is critically important in terms of outcome. When an ectopic pregnancy is detected early in development, especially prior to rupture or damage to surrounding tissue, major morbidity is decreased and the treatment options are enhanced.
There is no uniformly accepted diagnostic protocol for the determination of an ectopic pregnancy. Different gynecologists seem to have protocols that "work for them." These are often modifications of the published flow diagrams found in the major textbooks. Some of the common themes are discussed here.
A universal characteristic of a good "early diagnosis" protocol is a "high index of suspicion." Even in the absence of known risk factors, ectopic pregnancy may occur as often as 1-2% of pregnancies. If there are multiple risk factors, the risk may be 25% of pregnancies.
Sensitive blood hCG assays allow very early diagnosis of pregnancy. Typically these assays have a sensitivity of 1-5 mIU/mL so they can detect the occurrence of pregnancy (not location) about 7-8 days after fertilization (a few days prior to a missed menstrual flow). If the hCG assay is negative (generally less than 5 mIU/mL) then complications from an ectopic pregnancy are generally thought to be ruled out. Exceptions may occur in unusual circumstances, such as when one of my patients was treated for an ectopic pregnancy with medication (methotrexate) and she ruptured a blood vessel from the ectopic pregnancy site after her hCG dropped from a few thousand mIU/mL to negative (less than 5 mIU/mL). Caution should always prevail.
Other blood concentrations of pregnancy related polypeptides or steroid hormones have been used for the early detection of ectopic pregnancy. Included are progesterone, early pregnancy factor (EPF), pregnancy specific beta-1 glycoprotein (SP1), and placental protein 5 (PP 5). These other factors have not been adequately characterized to allow widespread routine use in ectopic pregnancy detection.
The second most common hormone (hCG is the most common) followed in pregnancy is progesterone. Unfortunately, there is a wide overlap between circulating progesterone concentrations in normal intrauterine pregnancy and ectopic pregnancy. Generally, a progesterone concentration of greater than 25 ng/mL is highly correlated (greater than 95% level of confidence) with a normal intrauterine pregnancy while a concentration of less than 5 ng/mL is highly correlated (almost 100% level of confidence) with an abnormal and nonviable pregnancy. Concentrations between 10 and 20 ng/mL (the most common concentrations) are of little differential value. Of concern for those who use 5 ng/mL as an indicator of fetal nonviability are the reports of several women with documented very low progesterone concentrations (typically thought to be inconsistent with a viable intrauterine pregnancy) who have gone on to deliver normal babies at term. These reports force one to reconsider the value of the progesterone concentrations, and include:
- women with the congenital abnormality known as abetalipoproteinemia have cells that are unable to take up and use VLDL-cholesterol. VLDL-cholesterol is a primary source for cellular cholesterol. Since cholesterol is required for the synthesis of progesterone these women have very low circulating progesterone concentrations. There are reports of women with abetalipoproteinemia who have documented low progesterone concentrations throughout pregnancy and have carried their pregnancy to term
- fetuses with a rare deficiency in one of the enzymes required for progesterone production, such as "3-beta hydroxysteroid dehydrogenase" or the "cholesterol side chain cleavage complex," may be delivered at term despite the inability of these fetuses (and presumably also their placentas) to produce adequate progesterone. Prenatal diagnosis of these conditions has never been early enough to actually document low progesterone throughout pregnancy (at least from the time of placental takeover of progesterone production)
- an In Vitro Fertilization patient from a well known NYC program with a diagnosis of unexplained infertility discontinued her prescribed progesterone when she noted vaginal bleeding at 4-5 weeks gestation (and assumed that she was not pregnant). Bloodwork documented a progesterone concentration of less than 2.0 ng/mL at 5-6 weeks gestation, she did not return to progesterone supplementation and she delivered a normal fetus at term. It is generally accepted that a progesterone concentration of less than 7 ng/ml at the time of hCG rescue (the usual nadir in progesterone concentration which occurs at about 4 weeks gestation) is ominous and predicts spontaneous abortion.
Serial circulating hCG concentrations are often used to gain insight into the normalcy of an existing pregnancy. A period of intense research characterized the rate of rise of hCG in normal pregnancy as at least 66% and more often 100% in a 2 day period during the first 6 weeks of pregnancy. If there is a rate of rise of less than 66% in hCG over a 2 day period of time (in early pregnancy) then this suggests an abnormally growing intrauterine pregnancy or an ectopic pregnancy. Again, there are several reports of women (up to 10%) who have abnormal rates of rise in hCG and who go on to deliver babies at term.
It would be ideal to have an "ectopic pregnancy hormone" to check whenever the concern for an ectopic arose. There is active research is this field, but thus far there are no clinically useful direct tests for ectopic pregnancy. If such a test becomes available, this would revolutionize the diagnosis of these potentially fatal complications of pregnancy.
If the concern for an ectopic pregnancy is raised by either the woman's history of risk factors, pelvic or adnexal pain in early pregnancy, or an abnormal doubling of the hCG titers then additional diagnostic intervention is appropriate.
Transvaginal ultrasonography is a sensitive radiologic test and should be able to detect an intrauterine gestational sac at an hCG concentration of about 1500 mIU/mL (using the 1st International Reference Preparation), which normally occurs at about 5 weeks "estimated gestational age" (EGA). The absence of a gestational sac with an hCG concentration of greater than 1500 mIU/mL suggests either an abnormally developing intrauterine pregnancy or an ectopic pregnancy. Exceptions do occur. Multiple gestations have two placentae each producing its own hCG so the concentration of 1500 mIU/mL will occur several days prior to a singleton gestation at the same EGA. Also, pregnancies with large placentae may produce hCG concentrations that are greater than expected for their EGA.
In the absence of pain, evidence of hemoperitoneum (rupture) or cardiovascular instability a conservative approach is most appropriate if the status and location of the pregnancy is unclear and the couple desires the pregnancy. When it becomes clear that there is an abnormal or ectopic pregnancy or if the woman becomes less stable then active treatment must be quickly reevaluated and selected.
If the woman is stable hemodynamically and an abnormal or ectopic pregnancy is diagnosed then one can consider a dilatation and curettage (D+C) to evacuate the uterine cavity in hope of finding or eliminating the abnormal pregnancy. If a D+C is performed and products of conception (placental villi) are identified or the hCG titers start to fall, then an incomplete or missed abortion is diagnosed. If no villi are identified, then an ectopic pregnancy is very likely (occasionally one will not be able to disrupt an early small intrauterine pregnancy even with a thorough D+C). One can consider checking an hCG concentration to confirm that the level is not decreasing after the D+C and then consider active management of the likely ectopic pregnancy.
Available Case Reports: