Central Medical Journal of Obstetrics and Gynecology

Cite this article: Sweed MS, Sammour HM, Bakr AA (2016) Serum CA-125 for Early Prediction of Miscarriage. Med J Obstet Gynecol 4(1): 1077.

*Corresponding authorsMohamed Samir Sweed, Department of Obstetrics and Gynecology, Ain-Shams University, Cairo, Egypt; Tel: 02 01001222047; Email:

Submitted: 21 January 2016

Accepted: 11 February 2016

Published: 18 February 2016

ISSN: 2333-6439

Copyright© 2016 Sweed et al.

OPEN ACCESS

Research Article

Serum CA-125 for Early Prediction of MiscarriageMohamed S. Sweed*, Hazem M. Sammour and Aya A. BakrDepartment of Obstetrics and Gynecology, Ain-Shams University, Cairo, Egypt

Keywords•CA-125•Threatened miscarriage•Abortion•Miscarriage

ABBREVIATIONSCA-125: Cancer Antigen-125; ROC Curve: Receiver-Operating

characteristic Curve

INTRODUCTIONMiscarriage is defined as pregnancy loss before 20 weeks,

or fetus less than 500 grams before the age of viability [1], with more than 4 fifth occurring in the first trimester [2]. Threatened miscarriage affects one fifth of women, with the uncertainty about its prognosis, many biochemical markers have been studied to predict its outcome [3]. However, the differentiation of normal and abnormal pregnancy remains a clinical challenge, with no conclusive biochemical marker used before sonographic diagnosis is established which might need several weeks of follow up [4].

Cancer Antigen-125 (CA-125) is a cell surface high molecular weight glycoprotein that has been found to be expressed by fetal chorion, amniotic fluid, and maternal deciduas in significant amounts [5]. This theoretically implies that any disruption of the deciduas or fetal membranes’ basement membrane would lead to a rise in maternal CA-125, and predict a subsequent miscarriage [6].

This study was conducted to assess the use of maternal serum CA-125 as a biochemical marker for the prediction of miscarriage.

MATERIALS AND METHODSThis prospective case-control study was conducted in

Ain-Shams University Maternity Hospital from January 2013 to January 2014. Approval of the ethical committee of the Department of Obstetrics and Gynecology was obtained before commencement of the study. 180 women pregnant at 6-12 weeks (calculated by last menstrual period (LMP), with regular cycles) were recruited in the study. 120 women were diagnosed as threatened miscarriage cases with vaginal bleeding or spotting and positive fetal life by ultra sonography. The other 60 showed no past or present history of bleeding in the current pregnancy. All women not meeting the inclusion and exclusion criteria were excluded, and an informed written consent was obtained from the participants.

The exclusion criteria included: missed abortion, blighted ovum, molar pregnancy, ectopic pregnancy, high-order pregnancy, ovarian tumors with pregnancy, history of pelvic inflammatory disease, history of pelvic tuberculosis, and history of ovarian hyerstimulation (conceived by ovulation induction and /or assisted reproduction). After careful and thorough history,

Abstract

Objective: To assess the predictive value of single measurement of maternal serum CA-125 for pregnancy outcome in threatened miscarriage.

Materials and methods: A prospective case-control study, conducted on 180 women pregnant at 6-12 weeks attending the outpatient clinic or the emergency room of Ain-Shams Maternity Hospital during the period from January 2013 to January 2014. 120 had symptoms of threatened miscarriage and 60 with apparently healthy pregnancy as their control. Serum CA-125 was assayed by chemiluminescent immunometric method and they were followed up till 20 weeks gestational age.

Results: 180 pregnant women were recruited in the study and were divided into two groups, group I (120 with threatened miscarriage) and group II (60 controls). Serum CA-125 was significant higher in group I, and also it was significantly higher in women who developed miscarriage than those who continued their pregnancy till 20 weeks. Using Receiver-operating characteristic (ROC) curve analysis, optimal cut-off criteria of CA-125 > 58 IU/ml for prediction of occurrence of miscarriage in patients with threatened miscarriage would be established with sensitivity of 78 % and specificity 97%.

Conclusion: Maternal serum CA-125 seems to be a promising biomarker for the early prediction of pregnancy outcome in threatened miscarriage.

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physical, and sonographic examination to confirm gestational age, fetal viability, intrauterine single gestation and absence of exclusion criteria, the participants were allocated to two groups, group I (120 women with threatened miscarriage) and group II (60 controls).

5 ml of venous blood were collected from each patient for measuring CA-125 serum level. After clotting of the blood sample the serum was separated from the cells by centrifugation within 2 hours of collection and removed using sterile pipette. All samples were stored refrigerated at 2-8 Cᵒ for one day. Serum levels of CA-125 were assayed by chemiluminescent immunometric method using Immulite 1000 systems. Kits used were Cobas e 601 supplied by Siemens Healthcare Diagnostics products Ltd. (Llanberis, Gwynedd, LL554EL, and UK). Measuring of all samples was analyzed in Biochemistry Department of Ain-Shams University Maternity Hospital.

Patients with threatened miscarriage were reassured and advised physical and mental rest at home. Follow-up monthly visits were arranged in the out-patient clinic till 20th weeks. During each visit, the patients were re-examined by ultrasound to re-evaluate their pregnancy state. Participants were instructed to come to the emergency room of the hospital if considerable vaginal bleeding occurred and the contact numbers of the investigators were given to them.

Sample size was calculated using EpiInfo® version 6.0, setting the type-1 error (α) at 0.05 and the power (1-β) at 0.8. Data from a previous study [7] showed that, among women with threatened abortion, the mean (± SD) serum CA-125 concentration was 30.89 ± 2.93 IU/ml (in women with ongoing pregnancy) and 58.17 ± 7.52 IU/ml (in women who aborted) (p=0.01). Calculation according to these values produced a sample size of 31 cases in each group. Assuming a drop-out rate of 10% (loss of contact during follow-up), a minimum of 35 cases should be included in each group. Statistical analysis was done on a personal computer using MedCalc© version 12.5 (MedCalc© Software bvba, Ostend, Belgium). Normality of numerical data distribution was tested using D’Agostino-Pearson test. Since these data were skewed, they were presented as median and inter-quartile range and intergroup differences were compared non-parametrically using the Mann-Whitney U test. Categorical data were presented as number and percentage. The Pearson chi square test was used to test between-group differences as regards nominal variables. Fisher’s exact test was used in place of the Pearson chi square test if > 20% of the cells in a contingency table had an expected count < 5. Between-group differences as regards ordinal variables were tested using the chi square test for trend. Receiver-operating characteristic (ROC) curve analysis was used to examine the value of continuous variables for prediction of binary outcomes. P < 0.05 was considered statistically significant.

RESULTS180 pregnant women were recruited in the study and

were divided into two groups, group I (120 with threatened miscarriage) and group II (60 controls). Age, parity and gestational age at time of recruitment showed no statistical difference between the 2 groups (Table 1). 30 (25%) of group I developed miscarriage while 90 (75%) continued their pregnancy till 20

weeks. In group II 6 (10%) patient only developed miscarriage and 54 (90%) continued their pregnancy. Serum CA-125 showed a statistically significant difference between group I and II (Table 2), and also it differed significantly between women who continued their pregnancy and those who developed miscarriage (Figure 1). The same difference was observed between women who completed their pregnancy till 20 weeks and those who developed miscarriage within each group (Tables 3 and 4).

Using Receiver-operating characteristic (ROC) curve analysis with sensitivity of 80% and specificity 100%, an optimal cut-off criterion of CA-125 > 40.16 IU/ml would be used for prediction of occurrence of miscarriage (Figure 2). While, optimal cut-off criteria of CA-125 > 58 IU/ml for prediction of occurrence of miscarriage in patients with threatened miscarriage (group I) would be established with sensitivity of 78 % and specificity 97% (Table 5). Also in group II, with sensitivity of 80% and specificity 100%, optimal cut-off criteria of CA1-25 > 28.45 IU/ml was found for prediction of occurrence of miscarriage (Table 6).

DISCUSSIONThreatened miscarriage might be a very distressing condition

for women, both physically and psychologically. Sometimes, bleeding due to threatened miscarriage may persist for days or weeks, making the prediction of the outcome of pregnancy very important to relieve the stress from both the patient and the physician. Ultrasonography together with several biochemical markers have been used to try to discriminate between normal and abnormal pregnancy.

Vaginal ultrasonography, serial measurements of β-HCG and progesterone titers have been used and proved to be helpful in predicting the presence of a healthy intra-uterine pregnancy [7]. However, their results turned out to be not a very satisfactory sensitive test in early pregnancy [8].

Table 1: Age, parity and gestational age at time of recruitment in the 2 groups.

Variable Group II(number=60)

Group I(number=120) P value

Age (years) 26.5 (20 – 34) 28 (23 – 33) 0.311

Parity

0.481P0 27 (45%) 50 (41.7%)

P1 8 (13.3%) 28 (23.3%)

P2 12 (20%) 27 (22.5%)

P3 or higher 13 (21.7%)15 (12.5%)

Gestational age at recruitment (weeks)

9 (8 – 11) 10 (8 – 11) 0.582

Data are presented as median (inter-quartile range) or number (%).

Table 2: Comparison of serum CA-125 level between the 2 groups.

Variable Group II (n=60) Group I (n=120) P value

CA-125 at recruitment (IU/ml)

25.45(23.45 – 26.3)

35.1(33.54 – 40.16) <0.001

Data are presented as median (inter-quartile range).

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Figure 1 Box plot showing CA-125 level in women who continued pregnancy and who developed miscarriage. Box represents inter-quartile range. Horizontal line across box represents median. Error bars represent minimum and maximum.

Table 3: Serum CA-125 in group I.

Threatened miscarriage (n=120)

Variable Continued pregnancy (n=90) Miscarriage (n=30) p-

valueCA-125

U/ml 34.7 (32.0 – 36.5) 50.9 (49.0 – 58.2) <0.001

Data are presented as median (inter-quartile range).

Table 4: Serum CA-125 level in group II.

Normal pregnancy (n=60)

Variable Continued pregnancy (n=54) Miscarriage (n=6) p-value

CA-125U/ml 25.3 (23.4 – 26.3) 28.0 (27.4 – 28.0) <0.001

Data are presented as median (inter-quartile range).

Figure 2 ROC curve for prediction of the occurrence of miscarriage using CA-125 level.

CA-125, being found to be expressed fetal membranes and maternal deciduas [5], has drawn attention as a possible useful biochemical marker for the prediction of pregnancy outcome in threatened miscarriage. Studying CA-125 as a possible marker for threatened miscarriage has lead to conflicting results. Several studies, in spite of finding its serum level higher in patients experiencing first trimester miscarriage, found these levels not statistically different from these in women who completed their pregnancies [8-12]. Some attributed this for single measurement of CA-125 when they found much more promising results using sequential measurement of CA-125 and found this to be a highly sensitive prognostic marker [12, 13]. Others found a single measurement of serum CA-125 to be valuable for women with symptoms of imminent abortion [7, 14]. Conversely, one study found serum CA-125 level significantly higher in women who completed their pregnancy [15].

A recent systematic review and meta-analysis suggested serum CA-125 to have ‘a high predictive value in identifying pregnancies that are ‘likely to continue’, it even suggested it to be clinically superior to the commonly used biochemical markers as β-HCG and progesterone in predicting the outcome of a pregnancy with healthy fetus [3]. The results of this study agree

Table 5: ROC curve for prediction of occurrence of miscarriage using CA-125 level in group I.

Estimate 95% CI P value

Area under the ROC curve (AUC) 0.975 0.940 to 0.993 <0.0001

Youden index J 0.923 0.869 to 0.962

Optimal cutoff criterion (IU/ml) >58 43.45 to 58.45

Sensitivity (%) 78.95 86.3 - 96.2

Specificity (%) 97.67 92.9 - 100.0

+LR N/A N/A

-LR 0.077 0.04 - 0.1

+PV (%) 93.75 97.0 – 95.2

-PV (%) 91.30 71.4 - 83.8Youden index (J) = (sensitivity + specificity) – 1; +LR = positive likelihood ratio; -LR = negative likelihood ratio; +PV = positive predictive value; -PV = negative predictive value; N/A = not applicable.

Table 6: ROC curve for prediction of occurrence of miscarriage using CA-125 level in group II.

Estimate 95% CI P value

Area under the ROC curve (AUC) 0.975 0.940 to 0.993 <0.0001

Youden index J 0.923 0.869 to 0.962

Optimal cutoff criterion (IU/ml) >28.45 26.4 to 28.45

Sensitivity (%) 92.31 86.3 - 96.2

Specificity (%) 100 92.9 - 100.0

+LR N/A N/A

-LR 0.077 0.04 - 0.1

+PV (%) 100 97.0 - 100.0

-PV (%) 83.3 71.4 - 91.8Youden index (J) = (sensitivity + specificity) – 1; +LR = positive likelihood ratio; -LR = negative likelihood ratio; +PV = positive predictive value; -PV = negative predictive value; N/A = not applicable.

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with this review in the value of CA-125 in the early prediction of pregnancy outcome in threatened miscarriage. Serum CA-125 showed significantly higher levels in women presenting with bleeding than those with normal pregnancy, and this supports the idea of CA-125 being released secondary to decidual disruption which was suggested by several other studies [16-18]. Also the findings of this study suggests that a single measurement of serum CA-125 is valuable in the prediction of miscarriage being significantly higher than in women with viable pregnancy even if experienced bleeding.

Few studies tried to calculate a discriminatory value for CA-125 to predict miscarriage. Using ROC curve analysis with sensitivity of 80% and specificity 100%, this study found optimal cut-off criteria of CA-125 > 40.16 IU/ml would be used for prediction of occurrence of miscarriage. While, in patients with threatened miscarriage, optimal cut-off criteria of CA-125 > 58 IU/ml would be used. These results were similar to those of two other studies [5, 14], while lower threshold level was suggested by a more recent study [19].

CONCLUSIONSerum CA-125 seems to be a promising biomarker for the early

prediction of miscarriage, still further studies are needed trying to combine its use with other biomarkers and ultrasonography for better accuracy and sensitivity.

REFERENCES1. Osmanagaoglu MA, Karahan SC, Aran T, Güven S, Turgut E, Mentese

A et al. The Diagnostic Value of β Human Chorionic Gonadotropin, Progesterone, and Ischemia-Modified Albumin and Their Combined Use in the Prediction of First Trimester Abortions. Int Scholarly Research Notices. 2014.

2. Rubio C, Simón C, Vidal F, Rodrigo L, Pehlivan T, Remohí J, Pellicer A . Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum Reprod. 2003; 18: 182-188.

3. Pillai RN, Konje JC, Tincello DG, Potdar N. Role of serum biomarkers in the prediction of outcome in women with threatened miscarriage: a systematic review and diagnostic accuracy meta-analysis. Hum Reprod Update. 2015.

4. Abdul-Hussein MM, Abdul-Rasheed OF, Al-Moayed HA . The Values of CA-125, Progesterone, ß-HCG and Estradiol in the Early Prediction of Ectopic Pregnancy. Oman Med J. 2012; 27: 124-128.

5. Katsikis I, Rousso D, Farmakiotis D, Kourtis A, Diamanti-Kandarakis E, Panidis D. Receiver operator characteristics and diagnostic value of progesterone and CA-125 in the prediction of ectopic and abortive

intrauterine gestations. Eur J Obstet Gynecol Reprod Biol. 2006; 125: 226-232.

6. Check JH, Nowroozi K, Winkel CA, Johnson T, Seefried L . Serum CA 125 levels in early pregnancy and subsequent spontaneous abortion. Obstet Gynecol. 1990; 75: 742-744.

7. Ayaty S, Roudsari FV, Tavassoly F. CA-125 in normal pregnancy and threatened abortion. Iran J of Reprod Med. 2007; 5: 57-60.

8. Mahdi B. Estimation of CA-125 Level in First Trimester Threatened Abortion. The Internet J of Gynecol and Obstet. 2009; 12.

9. Hornstein MD, Check JH, Hill JA . Serum CA 125 levels and spontaneous abortion. Am J Obstet Gynecol. 1995; 172: 695-699.

10. Foth D, Römer T. Maternal CA 125 serum level in intrauterine pregnancy and abortion in the first trimester. Zentralbl Gynakol. 2000; 122: 217-221.

11. Bon GG, Kenemans P, Verstraeten AA, Go S, Philipi PA, van Kamp GJ, et al. Maternal serum Ca125 and Ca15-3 antigen levels in normal and pathological pregnancy. Fetal Diagn Ther. 2001; 16: 166-172.

12. Schmidt T, Rein DT, Foth D, Eibach HW, Kurbacher CM, Mallmann P, et al. Prognostic value of repeated serum CA 125 measurements in first trimester pregnancy. Eur J Obstet Gynecol Reprod Biol. 2001; 97: 168-173.

13. Bhattacharya A, Pramanik SR, Saha R, Bhaswati das, Sen OM. Correlation of Serial Beta HCG Titre and CA125 Estimation In Predicting Early Pregnancy Failure. IOSR J of Pharm. 2015; 5: 16-20.

14. Fiegler P, Katz M, Kaminski K, Rudol G . Clinical value of a single serum CA-125 level in women with symptoms of imminent abortion during the first trimester of pregnancy. J Reprod Med. 2003; 48: 982-988.

15. Yamane Y, Takahashi K, Kitao M. Prognostic potential of serum CA125 and pregnant markers in threatened abortion. Nihon Sanka Fujinka Gakkai Zasshi. 1989; 41: 1999-2004.

16. Noci I, Biagiotti R, Periti E, Baronci D, Torricelli F, Cefalà L, et al. Maternal serum CA 125 levels in first trimester abortion. Eur J Obstet Gynecol Reprod Biol. 1995; 60: 35-36.

17. Scarpellini F, Mastrone M, Sbracia M, Scarpellini L . Serum CA 125 and first trimester abortion. Int J Gynaecol Obstet. 1995; 49: 259-264.

18. Madendag Y, Col-Madendag I, Kanat-Pektas M, Danisman N. Predictive power of serum CA-125 and LDH in the outcome of first trimester pregnancies with human chorionic gonadotropin levels below discriminatory zone. Arch Gynecol Obstet. 2009; 279: 661-666.

19. Al-Mohamady M, Abdel-Fattah G, Elkattan E, Bayoumy R, Hamed DA. Correlation of Serum CA-125 and Progesterone Levels with Ultrasound Markers in the Prediction of Pregnancy Outcome in Threatened Miscarriage. Int J of Fert and Sterility. 2016; 9: 506-511.

Sweed MS, Sammour HM, Bakr AA (2016) Serum CA-125 for Early Prediction of Miscarriage. Med J Obstet Gynecol 4(1): 1077.

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