The distribution of CA 125 in the reproductive tract of pregnant and non-pregnant women

Investigation of serum and tissue homogenates obtained from first, second and third trimester pregnancies, and from non-pregnant women, has provided further insight into the possible origin of the CA 125 antigen. Serum CA 125 levels were higher in the first trimester (median 53.6 U/ml, range 15.6-268.3 U/ml) than in non-pregnant women (median 19.3 U/ml, range 7.2-27.0 U/ml) and later in pregnancy (second trimester: median 18.5 U/ml, range 12.0-25.1 U/ml, third trimester: median 19.2 U/ml, range 16.8-43.8 U/ml) (P less than 0.05) but were two orders of magnitude less than in second trimester amniotic fluid (median 4825 U/ml, range 3200-9300 U/ml). Fetal serum CA 125 activity was consistently less than 20 U/ml. The highest tissue levels of CA 125 were detected in first trimester decidual homogenate (median 4547 U/100 mg, range 340.4-20 851 U/100 mg) and were greater than in non-pregnant endometrium (median 388 U/100 mg, range 100.9-3341 U/100 mg) (P less than 0.01) and term decidua (median 116 U/100 mg, range 32.7-449.9 U/100 mg) (P less than 0.01). These observations suggest that CA 125 is synthesized by normal endometrium and decidua and that increased CA 125 activity during pregnancy is of decidual origin.     

Maternal serum Ca125 and Ca15-3 antigen levels in normal and pathological pregnancy

OBJECTIVE: To evaluate the value of maternal serum CA125 and CA15-3 concentrations for discriminating pathological from normal pregnancies. METHODS: Serum samples from 120 women, in whom pregnancy outcome was pathological, i.e. spontaneous abortion, fetal death, intrauterine growth retardation, chromosomal and structural abnormalities, and (pre)eclampsia, were assessed for CA125 and CA15-3 and compared with levels found in 350 women with a normal pregnancy outcome matched for age and duration of pregnancy. RESULTS: Maternal CA125 serum values were significantly higher in the first and the third trimester of pregnancy (median 23.0 and 21.0 U/ml; p < 0.00001 and p < 0.001, respectively), compared to those in the second trimester (median 14.0 U/ml), but not significantly different from those obtained in pathological pregnancies. Maternal serum CA15-3 values were significantly higher during the third trimester (median 26.0 U/ml) compared to the first and second trimester of pregnancy (median 14.0 and 15.0 U/ml; p < 0.0001); CA15-3 serum levels in normal and pathological pregnancies showed no significant difference. CONCLUSION: Maternal serum levels of CA125 are higher during the first and third trimester of pregnancy. CA15-3 maternal serum levels are higher during the third trimester compared to the first and second trimester. Maternal CA125 and CA15-3 serum levels showed no relation with a pathological outcome of pregnancy.     

Maternal CA 125 serum level in intrauterine pregnancy and abortion in the first trimester

OBJECTIVE: Maternal CA 125 levels are supposed to rise in pregnancies complicated by vaginal bleedings in dependence to the extent of decidual disruption which is directly related to the outcome of pregnancy. MATERIAL AND METHODS: The prognostic value of maternal CA 125 serum measurement was investigated in 239 women with a first trimester intact pregnancy, imminent, incomplete, complete or missed abortion. RESULTS: 43.9% of the CA 125 serum levels were without normal range (> 20 U/ml). Mean CA 125 serum levels were higher in patients with incomplete (52.4 +/- 67.4 U/ml), complete (34.3 +/- 46.1 U/ml), and imminent abortion (33.0 +/- 45.8 U/ml) as compared with normal pregnancies (28.9 +/- 28.8 U/ml) and missed abortion (23.5 +/- 21.5 U/ml). CA 125 levels in first trimester pregnancies tended to be higher in patients with vaginal bleedings than in patients without bleeding (40.5 U/ml +/- 55.0 vs. 28.9 U/ml +/- 28.8; p = 0.65). CONCLUSIONS: For clinical use CA 125 serum measurement is not relevant. First trimester CA 125 measurement can not serve as an accurate predictor of pregnancy outcome due to the wide overlap of ranges.     

Ontogeny of CA 125 antigen in pregnancy: immunoradiometric determination in amniotic fluid and immunohistochemical localization in fetal membranes

CA 125 antigen was measured in amniotic fluid, maternal blood, cord blood, and fetal urine by a commercially available immunoradiometric assay kit. The amniotic fluid was obtained from 99 normal pregnancies at various gestational ages. The mean antigen levels were 29,676, 3350, and 1680 U/ml in amniotic fluid of the first, second, and third trimesters, respectively. In maternal blood, 12.5% of pregnant women in the first trimester of pregnancy showed elevated levels of CA 125 (65 to 100 U/ml). Late in gestation, CA 125 levels in cord blood and fetal urine were always less than 65 U/ml. Immunohistochemical study of CA 125 in fetal membranes, placenta, and decidua showed the presence of antigen only in the amnion. These results suggest that CA 125 is shed into amniotic fluid directly from the amniotic membrane.     

Serum CA125 at 11-14 weeks of gestation in women with morphologically normal ovaries

In a number of pregnant women ovarian cysts are found incidentally during the routine first trimester scan. These cysts may pose diagnostic difficulties, and the measurement of serum CA125 levels can be used to aid management. In this study we measured maternal serum CA125 levels in 188 women with uncomplicated pregnancies between 11–14 weeks of gestation. All women had morphologically normal ovaries observed on ultrasound examination. The median serum CA125 levels were 23.4 U/mL (range 2.2–166.3 U/mL, 95% reference interval 5.28–70.15) and did not change significantly with gestation. We conclude that CA125 levels are increased at 11–14 weeks of gestation and cut off values which are used to assess the nature of ovarian cysts in nonpregnant women cannot be applied to pregnant women at this gestation.     

CA 125 in tissues and amniotic fluid during pregnancy

CA 125 was assayed in amniotic fluid and tissue extracts by immunoradiometric assay, and immunohistochemical studies were performed on paraffin-embedded sections of endometrium, decidua, and fetal membranes with the monoclonal antibody OC 125 used as primary antibody. The concentration of CA 125 in amniotic fluid changes during pregnancy so that levels of 800 to 1000 U/ml are found before 12 weeks. Thereafter, levels of 4000 to 10,000 U/ml are detected routinely. As term approaches, amniotic fluid CA 125 concentrations fall to a range of 1000 to 2000 U/ml. Levels of CA 125 in tissue extracts of secretory endometrium and decidua were 65,000 and 29,500 U/gm of tissue, respectively. CA 125 was readily detected on the apical surfaces of glandular epithelium and in the secretions of endometrial glands obtained throughout the menstrual cycle. It was also detected in the lumina of decidualized glands throughout pregnancy. No antigen was detectable within glandular epithelial cells. We have previously reported high concentrations of CA 125 in chorionic tissue extracts (42,000 U/gm) and low concentrations in amniotic tissue extracts (275 U/gm). In contrast to those findings, immunohistochemical techniques detected CA 125 within the intercellular canaliculi that surround amniotic epithelial cells but not in chorion. We conclude that the likely source of amniotic fluid CA 125 is the decidua and that it gains access to the amniotic fluid via the intercellular canalicular system that traverses the amniotic epithelium.     

Evaluation of CA125 as a circulating tumor marker for ovarian cancer

CA125 usefulness was evaluated using sera from healthy persons, pregnant women, and patients with ovarian and other tumors. Since serum CA125 levels significantly depended on sex and age in healthy persons, the original cut-off levels were 40 and 25 U/ml in terms of sex and age. Changes in CA125 levels within 40 U/ml were observed during the menstruation cycle. Elevation of CA125 levels was also observed during the first trimester of pregnancy, but these levels fell below 50 U/ml as pregnancy progressed. Immunostaining of the endometrium with OC125 suggested that ovarian function may play an important role in production of CA125 in early pregnancy and menstruating young women. Elevated levels of CA125 were detected in 33/34 (97%) cases with surgically demonstrated ovarian cancer. The clinical usefulness of CA125 for monitoring the course of ovarian cancer was reconfirmed. Practical application of CA125 proved to be useful for the early detection of ovarian cancer and confirmation of the complete disappearance of any tumor.     

Maternal serum CA125 levels in early intrauterine and tubal pregnancies

Summary Using an immunoradiometric assay, serum CA125 levels were measured in 13 women with a normal pregnancy, 9 with a spontaneous abortion, 3 with a hydatidiform mole, and 15 with a tubal pregnancy. Serum CA125 levels were high in patients with a normal pregnancy (154±169 U/ml; mean±S.D.), a spontaneous abortion (244±258 U/ml), or a hydatidiform mole (54±16 U/ml). In contrast, CA125 levels in patients with a tubal pregnancy (33±25 U/ml) were low, and almost all of those without uterine bleeding (25±9 U/ml) were within the normal range for non-pregnant women (<35 U/ml). The difference between serum CA125 levels with intrauterine pregnancy and with tubal pregnancy may be ascribed to the difference of the amount of decidual tissues at the site of trophoblastic invasion.     

Prognostic value of repeated serum CA 125 measurements in first trimester pregnancy.

OBJECTIVE: To assess the diagnostic value of maternal CA 125 in patients with symptomatic first trimester pregnancy and to evaluate the prognostic significance of CA 125 versus beta-hCG in early pregnancies with intact fetal heartbeat, complicated by vaginal bleeding. STUDY DESIGN: Two prospective open-label studies with longitudinal follow-up in the second trial. SETTING: Academic Department of Obstetrics and Gynecology, University of Cologne. PATIENTS: Study 1: 168 patients presenting between gestational weeks 6 and 12 with: extrauterine pregnancy, 29; missed abortion, 50; incomplete spontaneous abortion, 38; imminent abortion, 33; and normal pregnancy (no history of endometriosis or ovarian mass), 18. Study 2: Fifty consecutive patients with vaginal bleeding during gestational weeks 6-12 all of whom having demostrable fetal heartbeat. Eighteen patients finally aborted whereas the remainder had normally continuing pregnancy until term. MAIN OUTCOME MEASURE: Study 1: Single serum determinations of CA 125 and beta-hCG were correlated with the different disorders observed. Study 2: Two sequential measurements of serum CA 125 and beta-hCG performed within a 5-7 days interval were related to the outcome of pregnancy as indicated by changes of the ultrasound presentation, miscarriage, future hospitalization, or delivery. RESULTS: Study 1: Patients with vaginal bleeding generally had higher median CA 125 values (38 IU/ml; range 1.3-540) compared to non-bleeding patients (17.8 IU/ml; range 1.0-157). No statistically significant differences in regard to median serum CA 125 levels between symptomatic and normal pregnancies occurred: normal pregnancy, 25.5 IU/ml (range 3.2-97); ectopic pregnancy, 26 IU/ml (range 1.3-157); missed abortion, 19.1IU/ml (range 1-242); threatened abortion, 48 IU/ml (range 5.2-540); spontaneous abortion, 40 IU/ml (range 5.4-442). Study 2: Initial CA 125 levels did not differ significantly between both groups of patients with 27/32 non-aborters and 13/18 aborters showing concentrations below 65 IU/ml. After 5-7 days, CA 125 in all patients who eventually aborted remained high or increased whereas non-aborters all had constantly low or steeply declining CA 125 measures. beta-hCG increased in all non-aborters but also in 13/18 aborters during the 5-7 day interval. CONCLUSION: Single serum measurements of CA 125 in symptomatic first trimester pregnant patients failed to discriminate spontaneous abortion, ectopic or normal pregnancies. However, sequential determinations of maternal CA 125 measurements appear to be a highly sensitive prognostic marker in patients with viable pregnancy at risk for abortion.     

The prognostic significance of maternal serum CA125 measurement in threatened abortion.

The prognostic predictive value of maternal serum CA125 measurement was investigated in 25 cases of threatened abortion. The women were non-smoker, had a ultrasonographically verified viable single fetus, and the gestational ages ranged from 7 to 12 weeks. Twenty-five healty pregnant women, with the same characteristics were used as the control group. The overall abortion rate was found to be 20% (5/25) in the study group. In serial measurements the mean serum CA125 level of the patients with an unfavorable pregnancy outcome was significantly higher than that of the patients with a favorable outcome. When the cut-off level of maternal serum CA125 was taken as > 65 U/ml in the first and > 60 U/ml in the second measurements of the study group, the risk of termination of the pregnancy by spontaneous abortion was 83.3% in the patients with elevated serum CA125 levels. No statistically significant difference was observed with respect to the duration of vaginal bleeding between the aborters and the patients with a favorable outcome. Nevertheless, when vaginal bleeding had been present for 3 days or more and there was high maternal serum CA125 activity, the abortion risk was found to be 100% (3/3). These findings suggest that the maternal serum CA125 measurement in threatened abortion can be useful to determine the extent of decidual destruction which is directly related to the outcome of pregnancy.     

Fibrinopeptide A during normal pregnancy

Fibrinopeptide A (FPA) is the first peptide released from fibrinogen upon thrombin action. Plasma FPA is cleared rapidly with a first order kinetics and therefore its level reflects the rate of thrombin cleavage of fibrinogen. A prospective study was undertaken to establish normal values of FPA during pregnancy. The mean FPA for the pregnant group (n = 136) was 2.8 ng/ml (SD = 3.3) while it was 1.24 ng/ml (SD = 0.4) for a nonpregnant control group of healthy women (n = 30). The median FPA for the pregnant group was 2.2 ng/ml and 1.4 ng/ml for the nonpregnant group (Wilcoxon test P less than 0.0001). Plasma FPA levels increased with gestational age. The median value was 1.5 ng/ml in the first trimester (n = 18), 1.8 ng/ml in the second trimester (n = 40), and 2.5 ng/ml in the third trimester (n = 78). Plasma FPA concentrations in the third trimester were significantly higher than in the first and second trimester. These findings suggest increased thrombin activity and fibrin generation during the course of normal pregnancy.     

Indoleamine-dioxygenase is expressed in human decidua at the time maternal tolerance is established

The semi-allogeneic fetus has to be tolerated by the maternal immune system. In mice, it has been shown that inhibiting indoleamine-dioxygenase (IDO) leads to fetal rejection, suggesting a central significance for IDO in establishing maternal tolerance. Consequently, we have analyzed IDO expression in human endometrium and decidua to determine whether it may be of significance in human reproduction. Endometrial (n=60) and decidual (n=68; first and second trimester) tissue samples and isolated cells were analyzed for IDO mRNA and protein expression by real-time PCR, Western blot and immunohistochemistry. IDO expression in the decidua of proven fertile women (n=34) was compared to women presenting with their first pregnancy (n=22) and women with a history of miscarriages (n=12). Expression of IDO was localized in glandular epithelial cells and scattered stromal leukocytes. Expression started at the mid-luteal phase in the menstrual cycle and was high until the second trimester of pregnancy. However, glandular expression of IDO decreased during the second trimester, whereas expression in villous trophoblast started at this time. There were no significant differences in decidual IDO expression between proven fertile women and women presenting with their first pregnancy or women with a history of miscarriages. From the expression pattern we conclude that IDO may play a central role in human pregnancies for the establishment of maternal tolerance of fetal antigens. Thereby, IDO expression may be needed in each pregnancy independently from prior pregnancies, and a history of miscarriage may not reflect a general deficiency in IDO expression.     

Syncytiotrophoblastic fragments in first-trimester decidual veins: evidence of placental perfusion by the maternal circulation early in pregnancy.

OBJECTIVE: To determine whether maternal placental perfusion occurs in the first trimester, this study compared veins in endometrium with those in decidua. We hypothesize that veins draining the placenta become dilated and contain syncytiotrophoblastic fragments. STUDY DESIGN: Normal late-secretory endometrial biopsy specimens (n = 10) were compared with elective abortion decidua at 7 to 11 weeks (n = 100). Tissue sections were processed by routine staining and immunohistochemical studies. The cross sections of veins and glands were counted in 25 decidual biopsy specimens, and the number of syncytiotrophoblastic fragments in veins or glands was determined. Statistical significance by chi(2) or linear regression analysis was P <.05. RESULTS: All sets of decidua had dilated veins; no secretory endometrium did. Intravenous syncytiotrophoblastic fragments were seen in 91 of 100 sets of decidua. There were more syncytial elements in veins (572/6845, 8.4%) than in glands (13/23,310, 0.06%) (P <.001). CONCLUSION: Decidual veins were distended and contained syncytiotrophoblastic fragments, consistent with maternal intervillous perfusion in the first trimester.     

Mechanism and clinical significance of elevated CA 125 levels in the sera of pregnant women

To clarify the mechanism of CA 125 elevation in maternal sera, serum levels of CA 125 and CA 19-9 were measured in 122 apparently healthy pregnant women (fifth to fortieth week of gestation) and 50 postpartum women (26 term deliveries and 24 second-trimester induced abortions). Serum levels of CA 125 showed an initial increase by the tenth week and then decreased to less than 35 U/ml, remaining below this level until delivery. However, within 1 hour after term delivery or second-trimester induced abortion, the CA 125 levels showed a second increase and decreased rapidly thereafter. In contrast, serum levels of CA 19-9 did not change significantly during these periods. Combined with our previous finding that the decidua contains abundant CA 125 but little CA 19-9, these results indicate that the elevated CA 125 levels in maternal sera originate from the decidual cells affected by chorionic invasion or the placental separation.     

Serum CA 125 as a tumor marker and the expression of c-erbB-2 oncogene in tubal malignancies

Serum CA 125 levels were evaluated in 26 patients with fallopian tube malignancies. CA 125 was elevated preoperatively in seven samples (median 178 U ml⁻¹ range 41–19021 U ml⁻¹), and postoperatively in eight of nine (89%) samples collected from patients with residual disease (median 109 U ml⁻¹ range 10–1883 U ml⁻¹) but only in one of seven (14%) samples from patients without residual disease (median 14, range 5–170 U ml⁻¹) ( P < 0.001). Changes in the serum CA 125 level during chemotherapy correlated with the clinical course of disease in 13 of 14 patients with a pre-chemotherapy serum CA 125 level> 35 U ml⁻¹. Nine patients with clinical remissions showed decreasing serum CA 125 levels, one with clinically stable disease showed decreasing levels and four with disease progression showed increasing levels. Serum CA 125 levels were measured in four patients before second-look laparotomy. Two of three with positive findings at laparotomy had elevated serum CA 125 levels whilst the third had a normal level. One patient with negative findings at second-look surgery had a normal CA 125 level. Disease relapse was associated with elevated serum CA 125 levels in nine of 10 patients (median 108 U ml⁻¹, range 27–38200 U ml⁻¹). Using immunohistochemical staining, none of the tumors showed positive cytoplasmic staining for c-erbB-2 (NEU) oncogene. This report shows that CA 125 is a reliable tumor marker for monitoring patients with cancer of the fallopian tube during active treatment and follow-up.     

CA125 antigen levels in obstetric and gynecologic patients

An immunoradiometric assay using a monoclonal antibody detects an antigenic determinant (CA125) that is present in more than 80% of epithelial ovarian cancers. CA125 levels are elevated in the sera of 16% of women in the first trimester of pregnancy and is found in very high concentration in amniotic fluid. In 988 nonpregnant patients with benign gynecologic disorders, CA125 was greater than 65 U/mL in 1% on a single determination and in 0.5% with two determinations. Given the low rate of positivity in benign gynecologic disease, the CA125 assay may deserve further evaluation for the early detection of ovarian carcinoma.     

The comparison of vessels in elective and spontaneous abortion decidua in first trimester pregnancies: importance of vascular changes in early pregnancy losses

BACKGROUND: To determine whether adequate trophoblastic migration and maternal placental perfusion occurs in cases of early pregnancy loss, we compared vessels in elective abortion decidua with those in spontaneous abortion decidua. METHODS: Elective abortion decidua at 5-11 weeks (n = 40) were compared with spontaneous abortion decidua at 5-12 weeks (n = 25). Also normal late secretory endometrial biopsy specimens (n = 10) were examined. The cross-sections of veins and arteries were counted in 25 elective and 15 spontaneous abortion materials. The number of the veins that contain trophoblastic fragments and the number of the spiral arteries converted by trophoblasts were determined. Statistical significance by Mann-Whitney U and Spearman's correlation test was p < 0.05. RESULTS: All sets of decidua had dilated veins, but no secretory endometrium did. The ratio of converted spiral arteries to nonconverted arteries was much more in elective abortion decidua (113/938, 12.04%) than in spontaneous abortion decidua (11/511, 2.15%) (p < 0.001). CONCLUSIONS: The presence of converted arteries, dilated veins, and intravenous trophoblastic fragments in decidual specimens were evidence of intervillous circulation and placental perfusion by maternal circulation in the first trimester. Also the insufficient conversion of the arteries in spontaneous abortions might be responsible for many cases of early pregnancy loss.     

Measurement of CEA, TPA, neopterin, CA125, CA153 and CA199 in sera of pregnant women, umbilical cord blood and amniotic fluid

The following tumor markers were determined in body fluids associated with pregnancy: carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), neopterin, CA125, CA153 and CA199. CEA levels (cut-off 5.0 ng/ml) were not elevated during gestation, whereas TPA was above cut-off (85 U/l) in 98 out of 107 cases (range 40-408 U/l). TPA was significantly higher during the 3rd trimester of pregnancy than during the 1st and 2nd trimesters. 38.3% of CA125 measurements were slightly above the chosen cut-off of 35 U/ml, and the mean concentration was 33.5 +/- 16.2 U/ml. During delivery, 14 out of 21 values (67%) were elevated. Only 9.4% of CA153 values were elevated. CA199 and neopterin were also hardly ever above cut-off. In general, there was a wide scattering of individual values. With the exception of CA153 (neopterin not determined), high concentrations of CEA (maximum: 207 ng/ml), TPA (maximum: 1,565 U/ml), CA125 (maximum: 2,371 U/ml) and also CA199 (maximum: 1,533 U/ml) were found in amniotic fluid. The distribution in mixed cord blood was similar but with more moderate elevations and a lower incidence of levels above cut-off. Thus, none of these antigens is tumor specific. The term 'tumor-associated antigen' instead of 'tumor marker' is more appropriate. CEA, TPA, CA125 and CA199, but not CA153, are oncofetal antigens.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum CA 125 levels in early pregnancy and subsequent spontaneous abortion

CA 125 has been found in high concentrations in human amniotic fluid throughout gestation, with significant quantities seen in the decidua and chorion. Because disruption of the epithelial basement membrane of the fetal membrane or the decidua could theoretically lead to a rise in maternal CA 125 levels, this increase may be a predictor of subsequent spontaneous abortion of the fetus. A study was initiated to investigate whether a sudden rise in the serum CA 125 level might predict spontaneous first-trimester abortions. CA 125 levels of 101 pregnant women were evaluated 18-22 days from conception and 6 weeks from conception (a frequent time for spontaneous abortion) to determine whether there is a sudden increase (from baseline or early trimester levels) during the middle or late first trimester immediately before or at the time of abortion. The results indicated that although there was a definite correlation found between elevation of CA 125 and spontaneous abortion, the higher levels occurred early in the first trimester whereas the majority of abortions did not occur until much later, after fetal viability was established. Six of ten women with CA 125 levels of 150 U/mL or greater aborted, compared with four of 92 women with CA 125 levels less than 150 U/mL. One of 11 women pregnant after in vitro fertilization had a CA 125 level above 150 U/mL, and she aborted.     

Evaluation of serum CA 125 level as a tumor marker in borderline tumors of the ovary

Serum CA 125 was evaluated as a tumor marker in 85 patients with borderline ovarian tumors. Serum CA 125 levels were elevated preoperatively in 18 of 20 (90%) samples (median 66, range 5–272 U ml⁻¹). Preoperative serum CA 125 levels did not correlate to FIGO stage. Preoperative serum CA 125 levels were elevated in seven of nine (78%) with serous tumors (median 131, range 5–272 U ml⁻¹) and in all 11 with mucinous tumors (median 62, range 41–157 U ml⁻¹). There was no significant difference in the CA 125 levels between these two histologic types. Postoperative serum CA 125 levels, measured 3–6 weeks after primary laparotomy, were significantly lower than the preoperative ones ( P < 0.001). No difference in the postoperative CA 125 levels was found between those with and those without residual disease after surgery. Postoperative serum CA 125 levels were elevated in eight of 60 (13%) without residual tumor. None of these had relapsed at the time of analysis (26–87 months after surgery). Serum CA 125 levels tended to correlate with disease evolution during chemotherapy. Two with disease remissions had falling levels, one with stable disease had falling level and one with disease progression had rising level. Serum CA 125 samples were obtained before second-look laparotomy in seven patients. Two with negative findings at second-look had normal levels. Of five with positive findings at laparotomy only two had elevated serum CA 125 levels. Disease relapse was associated with elevated serum CA 125 levels in only one of six patients.