In an effort to improve early detection of ectopic pregnancy, various endocrinologic and protein markers were studied. Estradiol levels increase slowly from conception until 6 weeks of gestation and then rise rapidly as placental production of estradiol increases (119). Estradiol levels are significantly lower in ectopic pregnancies when compared with viable pregnancies. However, there is considerable overlap between normal and abnormal pregnancies and between intrauterine and extrauterine pregnancies (120,121).
Maternal serum creatinine kinase was studied as a marker for ectopic pregnancy diagnosis (122). Maternal serum creatine kinase levels were significantly higher in all patients with tubal pregnancy when compared with those in patients who had missed abortions or normal intrauterine pregnancies. No correlation was found between the creatine kinase level and the clinical presentation of the patient, and there was no correlation with the hCG levels. Schwangerschafts protein 1 (SP1), also known as pregnancy-associated plasma protein C (PAPP-C) or pregnancy-specific β-glycoprotein (PSBS), is produced by the syncytiotrophoblast (120). The main advantage of SP1 level assessment may be in the diagnosis of conception after recent hCG administration. A level of 2 ng/L might be used for the diagnosis of pregnancy; however, it is doubtful that a diagnosis can be established before delay of menses. Although the level of SP1 increases late in all patients with a nonviable pregnancy, a single SP1 level assessment does not have prognostic value (123).
Relaxin is a protein hormone produced solely by the corpus luteum of pregnancy. It appears in the maternal serum at 4 to 5 weeks of gestation, peaks at about 10 weeks of gestation, and decreases until term (124). Relaxin levels are significantly lower in ectopic pregnancies and spontaneous abortions than in normal intrauterine pregnancies. Prorenin and active renin levels are significantly higher in viable intrauterine pregnancies than in either ectopic pregnancies or spontaneous abortions, with a single level of more than 33 pg/mL excluding the diagnosis of ectopic pregnancy (125). The clinical utility of relaxin, prorenin, and renin levels in diagnosing ectopic pregnancy is not yet determined.
CA125 is a glycoprotein, the origin of which is uncertain during pregnancy. Levels of CA125 rise during the first trimester and return to a nonpregnancy range during the second and third trimesters. After delivery, maternal serum concentrations increase (126,127). Levels of CA125 were studied in an effort to predict spontaneous abortion. Although a positive correlation was found between elevated CA125 levels 18 to 22 days after conception and spontaneous abortion, repeat measurements at 6 weeks of gestation did not correlate with outcome (128). Conﬂicting results were reported—one study showed a higher serum CA125 level in normal pregnancies than in ectopic pregnancies 2 to 4 weeks after a missed menses, whereas another study found higher CA125 levels for ectopic pregnancies compared with normal pregnancies (129,130).
Maternal serum α-fetoprotein (AFP) levels are elevated in ectopic pregnancies; however, the use of AFP measurements as a screening technique for ectopic pregnancy was not studied (131,132). A combination of AFP with three other markers—β-hCG, progesterone, and estradiol—has 98.5% specificity and 94.5% accuracy for the prediction of ectopic pregnancy (133,134). Serum placental growth factor may prove to be a diagnostic biomarker for ectopic pregnancy because it was shown to be undetectable in ectopic and nonviable pregnancies.