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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 4  |  Page : 1258-1263

Role of CA-125 and ultrasound in early prediction of outcome of threatened miscarriage


1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Obstetrics and Gynecology, Mit Ghamer General Hospital, Mit Ghamer, Egypt

Date of Submission03-Feb-2020
Date of Decision02-Mar-2020
Date of Acceptance07-Mar-2020
Date of Web Publication24-Dec-2020

Correspondence Address:
Marwa M Omar
Mit Ghamer, Dkahlia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_23_20

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  Abstract 


Objective
The aim was to study the role of serum cancer antigen 125 (CA-125) and ultrasound in early prediction of outcome of threatened miscarriage.
Background
Threatened abortion is a clinically descriptive term applied to women who are less than 24 weeks of gestation having vaginal spotting or bleeding, closed cervical, and possibly mild uterine cramps.
Patients and methods
A prospective case–control study was conducted on 80 pregnant women at 6–12 weeks attending the Department of Obstetrics and Gynecology of El-Menoufia University Hospital Mit-Ghamer General Hospital during the period from January 2017 to February 2018. A total of 40 women had symptoms of threatened miscarriage and 40 had apparently healthy pregnancy as controls. Serum CA-125 was assayed by Cobas410 full auto motion method, and they were followed up till 20 weeks of gestational age.
Results
A total of 80 pregnant women were recruited in the study and were divided into two groups: group I (40 with threatened miscarriage) and group II (40 controls). Serum CA-125 was significant higher in group I, and it was significantly higher in women who developed miscarriage than those who continued their pregnancy till 20 weeks. Using receiver operating characteristic curve analysis, optimal cutoff criteria of CA-125 of greater than 30.3 IU/ml for prediction of occurrence of miscarriage in patients with threatened miscarriage would be established with sensitivity of 100% and specificity 98.6%.
Conclusion
Maternal serum CA-125, as well as ultrasound seems to be a promising biomarker for the early prediction of pregnancy outcome in threatened miscarriage.

Keywords: abortion, cancer antigen 125, miscarriage, threatened, ultrasound


How to cite this article:
Anter ME, Shabana AA, Ellakwa HE, Hamza HA, Omar MM. Role of CA-125 and ultrasound in early prediction of outcome of threatened miscarriage. Menoufia Med J 2020;33:1258-63

How to cite this URL:
Anter ME, Shabana AA, Ellakwa HE, Hamza HA, Omar MM. Role of CA-125 and ultrasound in early prediction of outcome of threatened miscarriage. Menoufia Med J [serial online] 2020 [cited 2021 Apr 18];33:1258-63. Available from: http://www.mmj.eg.net/text.asp?2020/33/4/1258/304497




  Introduction Top


Threatened abortion is a clinical dilemma for the obstetrician regarding the outcome of pregnancy. Threatened abortion is a clinically descriptive term applied to women who are less than 24 weeks of gestation having vaginal spotting or bleeding, closed cervical os, and possibly mild uterine cramps. It may progress to a term viable pregnancy or may result in incomplete, complete, missed, or septic abortion[1].

Up to 15% of recognized pregnancies miscarry, and as many as one in four women will experience a miscarriage at some point in her lifetime[2].

Ultrasonography, serial serum quantitative assessment of β-subunit of human chorionic gonadotropins (β-hCG), serum cancer antigen 125 (CA-125), and serum progesterone values measured alone or in various combinations have proven helpful in ascertaining if a live intrauterine pregnancy is present. Maternal serum biochemistry has also been proposed as a predictor[3].

CA-125 or carbohydrate antigen 125 (CA-125), also known as mucin 16, is a glycoprotein, with high molecular weight that can be detected in endocervix, endometrium ovaries, and epithelia of tubes and amnion. CA-125 antigen in sera of pregnant women is derived from the decidual cells following their invasion by trophoblastic cells[4].

Gestational age was calculated by modified Naegele's rule. Last menstrual period-derived gestational age was compared with ultrasound-derived gestational age using crown rump length (CRL), and marked discrepancy of one or more weeks led to exclusion of participants from study[5].

Mean gestational sac diameter (MGSD) was assessed by averaging three dimensions (longitudinal, anteroposterior, and transverse). Sac was measured from inside of the sac to the inside of the decidual reaction, excluding the latter in the measurement[5].

The yolk sac diameter (YSD) can be an important measurement in early pregnancy. The first trimester, absence of the yolk sac, or an unusually large yolk sac may be markers for possible impending pregnancy loss[6].

CRL was measured in sagittal plane of the embryo avoiding inclusion of YS. This was recorded as an average of three measurements. CRL greater than 9 mm in transabdominal scan (TAS) who fail to demonstrate heart beat was judged nonviable and CRL less than 9 mm without a visible heart beat returned for repeat ultrasonography after 1 week[5].

The aim of this work was to study the role of serum CA-125 and ultrasound in early prediction of outcome of threatened miscarriage.


  Patients and Methods Top


This hospital-based prospective case–control study was conducted in El-Menoufia University Hospital and Mit-Ghamer General Hospital from January 2017 to February2018

An informed written consent was obtained from participants. Approval of the Ethical Committee of the Department of Obstetrics and Gynecology was obtained before commencement of the study. All the participants' names were hidden and replaced by code numbers to maintain privacy of the participants.

A total of 80 women pregnant at 6–12 weeks (calculated by last menstrual period with regular cycles) were recruited in the study. A total of 40 women were diagnosed clinically as threatened abortion. These were miscarriage cases with vaginal bleeding or spotting, as well as abdominal pain and positive fetal life by ultrasonography. The other 40 showed no past or present history of bleeding in the current pregnancy.

Inclusion criteria were maternal age (20–40 years), gestational age (6–12 weeks), and patients in their first trimester of a singleton spontaneous pregnancy presenting with vaginal bleeding or spotting, and a visible gestational sac of a living embryo, verified by cardiac activity.

Exclusion criteria were history of general medical disease, for example, diabetes or thyroid disease; presence of local (gynecological) disease, for example, fibroid or adnexal masses verified by normal appearance of the uterus and ovaries by ultrasound; patients with history of recurrent miscarriages; presence of uterine malformation as septate uterus; and history of any maternal disease that would cause an increase in CA-125 level such as chronic pelvic infection and endometriosis.

General examination and local examination were done to assess the state of cervix and vaginal bleeding. To confirm viability, gestational age was measured by gestational sac diameter, YSD, and crown rump length; ascertained closed cervix; and exclusion of uterine malformation and uterine lesions. Evaluation of maternal serum CA-125 was done through obtaining 5 ml of venous blood from each patient on the same day of ultrasound examination. Follow-up of patients was carried out until 20 weeks, and patients were subdivided into two groups: group A will continue their pregnancy, and group B will abort. Then comparison between two groups are done regarding ultrasonography and serum CA-125.

The collected data were presented as mean and standard deviation, minimum, and maximum for numerical variables, whereas qualitative variables were presented as frequency and percent. Comparison between groups was done by independent samples (t) test for numerical variables and χ2 or Mann–Whitney (U) test. Correlation between variables was estimated by bivariate Pearson's correlation coefficient (r), whereas sensitivity and specificity and best cutoff values were calculated through receiver operation characteristics curve. P value less than 0.05 was considered significant. All statistical analysis was done by Statistical Package for the Social Sciences version 18 (SPSS Inc., Chicago, Illinois, USA) and MedCalc Statistical Software version 15.8 (https://www.medcalc.org, 2015; MedCalc Software bvba, Ostend, Belgium).


  Results Top


This study included 80 women who attended the outpatient clinic of Obstetrics and Gynecology Department, El-Menoufia University Hospital, and Mit-Ghamer General Hospital, with manifestations of first trimester threatened miscarriage. Regarding the incidence of abortion, 10 of them (12.5%) already had abortion before 20 weeks of gestation, whereas 70 women (87.5%) continued their pregnancy after the 20 week of gestation [Table 1].
Table 1: Abortion distribution between studied groups

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Regarding sensitivity of different studied variables in prediction of threatened abortion, the best was CA-125, with a sensitivity of 100% and specificity of 98.6% at a cutoff value greater than 30 IU/ml [Table 2], and multivariate logistic regression for threatened abortion showed YSD was only independent predicator for threatened abortion [Table 3].
Table 2: Validity of CA-125 as a predictor of complete abortion

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Table 3: Multivariate logistic regression for threatening abortion

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We classified the threatened abortion group into two subgroups according to gestational age, the first subgroup was less than 8 weeks and the second subgroup was 8–12 weeks. In the first subgroup, all parameters were significantly higher, except gestational sac diameter, whereas in the second subgroup, only YSD was significant [Table 4].
Table 4: Gestational age, yolk sac diameter, and crown rump length distribution among different gestational age category

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Regarding CA-125 levels, there was a statistically significant increase of CA-125 in group A (aborted) when compared with group B (continued) (50.51 ± 18.76 vs 13.97 ± 5.42, respectively) [Table 5].
Table 5: Relation between CA-125 and abortion

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  Discussion Top


Pregnancy loss is a common medical problem in reproductive-age women, with ∼25% of all women attempting pregnancy experiencing at least one spontaneous abortion. Medically, all pregnancy losses before 20 weeks of gestation are termed as abortion[7],[8]. More than 50% of human pregnancies are aborted before term. The majority are unrecognized occurring before or with the expected next menses. Approximately 10–12% of all clinically diagnosed pregnancies are lost as first trimester or early second trimester. The rate of fetal death after 14 weeks of gestation is much lower than the rate of pre embryonic and embryonic loss[9]. Sporadic abortion is the commonest adverse outcome in human reproduction. In most sporadic spontaneous abortions, an etiology is unknown. Spontaneous abortions or miscarriages were expected to occur in 15–25% of all pregnancies[10]. CA-125, also known as mucin 16 or MUC16, is a member of the mucin family glycoproteins. CA-125 has been found in the application as a tumor marker or biomarker, where its level may be increased in the serum of some patients with specific types of cancers, or other benign conditions and rises in the circulation after the absorption by peritoneal lymphatics[11].

As the pregnancy proceeds, a functional obstruction occurs owing to the fusion of decidua capsularis and decidua parietalis in tuba uterine, and serum CA125 levels decrease[12].

Some studies detected that the abortion risk is increased in pregnant women with higher CA-125 levels. The present study was designed as a prospective study to evaluate the role of CA-125 as a biochemical marker and ultrasound parameters (crown rump length, gestational sac diameter, and YSD) in prediction of abortion in patients with threatened abortion. It included 80 females who presented by vaginal bleeding with closed cervix at gestational age of 6 to 12 weeks. They all underwent full history taking, clinical examination, laboratory examination, and ultrasound investigations. In the present study, there was no statistically significant difference between studied groups regarding age and parity. These results are comparable to those reported by Maged and AlMostafa[13], where there was no significant difference among the three study groups regarding age, parity, BMI, gestational age at study, or number of previous abortions. In addition, it was reported that no statistically significant differences were found between both groups regarding maternal age, parity, or the number of previous miscarriages. In the present work, the incidence of abortion before 20 weeks of gestation was 12.5%, and this is comparable to the value of 20% reported by Al Mohamady et al.[14]. Of the 40 pregnancies, nine (22.5%) cases had aborted during follow-up. The possible explanation for higher rate of abortion in the present work when compared with their study is that they included all pregnant women with singleton pregnancy, whereas we included only women with threatened abortion. On the contrary, the results of the present work are comparable to those reported by Kouk et al.[15], where 36 (25.9%) of the 139 women who experienced a threatened miscarriage progressed to a complete miscarriage within 16 weeks of gestation. However, the percentage of the complete threatened abortion in the present study is much lower than that of the 1992 study conducted in Singapore, which reported that 55.3% of women who experienced a threatened miscarriage in the first trimester progressed to a complete miscarriage at any time during their pregnancy[16]. The shorter follow-up duration in the present work, and possibly improvements in the management of threatened miscarriage over the years, may account for this discrepancy.

Women with healthy pregnancy and 50 women with threatened abortion were evaluated for the level of CA-125 and were followed up regarding the outcome. The mean level of CA-125 in finally aborted patients was 58.17 ± 7.25 IU/ml and in normal pregnant women, who continue to term, was 26.61 ± 1.76 IU/ml. The CA-125 level in threatened women, whose pregnancy continued and did not abort, was 30.89 IU/ml. They concluded that measurement of serum CA-125 may be an inexpensive, easily available, sensitive, and specific predictor of outcome in threatened abortion, which results in the loss of pregnancy.

In addition, Maged and AlMostafa[13] in their study reported that CA125, beta hCG, and progesterone are good biochemical markers for the prediction of outcome in women with threatened abortion. This study involved 250 women in their first trimester who were divided into three groups: group I (65 women) in whom threatened abortion ended in abortion, group II (85 women) with threatened abortion who completed their pregnancy, and group III (100 women) with normal pregnancy. There was a statistically significant difference between group 1 and the other two groups regarding CA-125. The sensitivity and specificity of CA 125 at cutoff of 80 IU/ml were 80.2% and 78.3%, respectively. In agreement with the results of the present work, Al Mohamady et al.[14] reported that the level of serum CA-125 for the threatened miscarriage (miscarried) group was 54.28 ± 11.4 IU/ml, whereas for the threatened miscarriage (continued) group, it was 18.81 ± 8.02 IU/ml. The difference was statistically significant (P < 0.001). They added, using a receiver operation characteristics curve for CA-125 in predicting the outcome of pregnancy in threatened miscarriage cases, that the cut-off limit of 31.2 IU/ml of CA-125 level achieved sensitivity of 96.2% and specificity of 100%. CA-125 level above 31.2 IU/ml predicted occurrence of miscarriage with an overall accuracy of 99.4%. The CA-125 and β-hCG association showed a higher prognostic value (sensitivity 78.9%·and specificity 96.5%) in assessing pregnancy outcome than CA 125 or β-hCG alone (sensitivity 78.9 and 57.9%, respectively, and specificity 75.8 and 86.20%, respectively). The lower sensitivity in their work when compared with the present study can be attributed to different inclusion criteria, as only women with threatened abortions were included in the present study. On the contrary, these results are in contradiction to the study by Mahdi[17], who in their study for estimation of CA-125 level in first trimester threatened abortion concluded that CA-125 cannot be used as a predictor of outcome of early pregnancy complicated by vaginal bleeding. This may be owing to the small number of patients in their study.

A used cutoff value of 66.5 IU/ml showed a sensitivity of 55%, and a cutoff value of 65 IU/ml showed a sensitivity of 50% for this level, as reported by Fiegler et al.[18], Schmidt et al.[19], respectively. However, a cut-off value of 125 IU/ml showed a 100% sensitivity and specificity. Regarding crown rump length, it ranged from 0.60 to 6.90 cm, and there was no significant difference between group A and B (2.72 ± 0.68 vs 2.49 ± 0.76, respectively). Azogui et al.[20], on the contrary, showed that gestational sac diameter ranged from 2.20 to 6.50 cm, and there was a statistically significant increase in group A when compared with group B (3.57 ± 0.49 vs 3.10 ± 0.27 cm respectively). In addition, fetal heart rate (FHR) ranged from 110 to 182 beat/min, and there was a statistically significant increase in group A (continued) when compared with group B (aborted) (157.37 ± 13.18 vs 121.45 ± 7.08, respectively). These results are comparable to those reported by Maged and AlMostafa[13], who reported that FHR and CRL are good ultrasonographic markers for the prediction of outcome in women with threatened abortion. However, the results were unlike Maged and AlMostafa[13] and Al Mohamady et al.[14], who reported that there was no significant difference between groups regarding crown rump length, and these results were confirmed in the present work. In addition, they reported that the mean GSD was significantly lower in the group that miscarried compared with the group that continued (P = 0.023). The mean FHR was 156.9 ± 20 bpm for the continued group and 122 ± 9 for the aborted group, which showed a statistically significant difference (P < 0.001). These results are consistent with the present study. These results are also in agreement with the study Falco et al.[21] who evaluated the outcome and prognostic criteria of pregnancies with first-trimester bleeding and a gestational sac less than or equal to 16 mm. They found that of 50 patients, 32 (64%) underwent miscarriage; the size of GSD showed a high level of statistical significance. Results of the present work (as CRL) are also inconsistent with Reljic[22] who studied 310 singleton pregnancies with live fetuses, presenting with threatened miscarriage before 13 weeks of gestation. He reported that in fetuses with CRL less than 18 mm, there was a significant positive association between deficit in the CRL for gestation and the incidence of subsequent spontaneous miscarriage. The smaller number of women in our study may explain this difference. Regarding FHR, results of the present study are in agreement with Doubilet and Benson[23]. However, when the embryonic heart rate is within the normal range for gestation, the outcome remains uncertain, as in another study done by Tannirandorn et al.[24]. In the present study, there was a statistically significant increase of hematoma and pain in patients with abortion in comparison with those who continued their pregnancy. These results are comparable to those reported by Al Mohamady et al.[14], who reported that there was a significant difference between women who miscarried and women who continued their pregnancy regarding the presence of subchorionic hematoma (P = 0.002).


  Conclusion Top


Maternal serum CA-125, as well as ultrasound, seems to be a promising biomarker for the early prediction of pregnancy outcome in threatened miscarriage.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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12.
Menczer J, Ben-Shem E, Golan A, Levy T. The significance of normal pretreatment levels of CA125 (<35 U/ml) in epithelial ovarian carcinoma. Rambam Maimonides Med J. 2015; 6:e0005.  Back to cited text no. 12
    
13.
Maged AM, AlMostafa W. Biochemical and ultrasonographic predictors of outcome in threatened abortion. Middle East Fertil Soc J 2013; 18:177–181.  Back to cited text no. 13
    
14.
Al Mohamady M, Fattah GA, 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 Fertil Steril. 2016; 9:506.  Back to cited text no. 14
    
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21.
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23.
Doubilet PM, Benson CB. Outcome of first-trimester pregnancies with slow embryonic heart rate at 6-7 weeks gestation and normal heart rate by 8 weeks at US. Radiology 2011; 236:643–646.  Back to cited text no. 23
    
24.
Tannirandorn Y, Sangsawang S, Manotaya S, Uerpairojkit B, Samritpradit P, Charoenvidhya D. Fetal loss in threatened abortion after embryonic/fetal heart activity. Int J Gynecol Obstet 2003; 81:263–266.  Back to cited text no. 24
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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