{"paper_id":"27f86f94-f195-4382-9ef6-3c1353681725","body_text":"First-trimester bleeding is one of the most\ncommon obstetric complications, occurring in\n25% of all pregnancies ( 1 ). More than 80 percent\nof abortions occur in the first 12 weeks of\npregnancy and at least half result from chromosomal\nanomalies. After the first trimester, both\nthe abortion rate and the incidence of chromosomal\nanomalies decrease ( 2 ). The clinical diagnosis\nof threatened miscarriage is presumed\nwhen bloody vaginal discharge or bleeding appears\nthrough a closed cervical os during the\nfirst half of pregnancy ( 3 ). Ultrasonography, serial\nserum quantitative assessment of B-subunit\nof human chorionic gonadotropins (B-hCG),\nserum cancer antigen -125 (CA-125) and serum\nprogesterone values measured alone or in various\ncombinations, have proven helpful in ascertaining\nif a live intrauterine pregnancy is present\n( 2 ). Maternal serum biochemistry has also\nbeen proposed as a predictor. La Marca et al. ( 4 )\nreported that the presence of low concentrations\nof hCG in women with threatened abortion suggests\na negative outcome for the pregnancy.\nProgesterone concentrations show a narrow\nvariation in the first trimester. The lowest serum\nprogesterone concentration associated with\na viable first trimester pregnancy is 5.1 ng/ml\nand a single serum progesterone measurement\nof at least 25 ng/ml carries a 97% likelihood for\nviable intrauterine pregnancy, being more sensitive\nthan two serial hCG measurements ( 5 ).\nIn this study we examined the diagnostic accuracy\nof serum CA-125 and progesterone levels in\nthe prediction of the outcome of pregnancy in patients\nwith threatened miscarriage, as well as the\ncorrelation between these chemical markers and\nultrasound markers.\n\nprospective comparative case-control study\nwas set up to determine the accuracy of biochemical\nmarkers in the prediction of the pregnancy outcome,\nas well as their correlation with each other\nand with the ultrasound markers of pregnancy\noutcome. The hospital ethical committee approval\nwas attained before beginning the study. A total of\n105 patients with clinical diagnosis of first trimester\nmiscarriage were recruited in this study. They\nattended the outpatient clinic or the causality department\nof Obstetrics and Gynecology, in Kasr\nEl-Aini Hospital, Giza, Egypt during the period\nfrom March 2013 to October 2013. Ethical committee\napproval of the Department of Obstetrics\nand Gynecology of Cairo University was obtained\nwas obtained. All participants gave an informed\nconsent and had preoperative clinical evaluation.\nFive patients did not complete their follow up program\nwith us, and hence were considered as drop\nout cases leaving 100 patients who were eligible\nfor analysis.\nWe included the patients that were diagnosed by\n1st trimester threatened miscarriage. The patients\nhad a singleton spontaneous pregnancy and were\npresenting with vaginal bleeding or spotting. The\npregnancy was confirmed by a visible gestational\nsac of a living embryo, verified by cardiac activity\nvisualized on real time ultrasound. The maternal\nage should range between 20-40 years and the\ngestational age should range between 7-13 weeks\n(calculated from the 1st day of the last normal\nmenstrual period, preceded by 3 regular menstrual\ncycles, and correlating with ultrasound measurements).\nWe excluded patients with history of general\nmedical disease e.g. diabetes or thyroid disease,\npresence of local (gynecological) disease e.g.\nfibroid or adnexal masses verified by normal\nappearance of the uterus and ovaries by ultrasound,\npresence of uterine malformations e.g\nhypoplastic uterus or septate uterus. Patients\nwith history of recurrent miscarriages were\nexcluded from the study; also we excluded patients\nwith history of any maternal disease that\nwould cause an increase in CA-125 level such\nas chronic pelvic infection and endometriosis.\nWe excluded abnormal findings in the dating\nscan as blighted ovum or missed miscarriage.\nAll the patients underwent vaginal examination\nto assess if there is any cervical dilatation as well\nas the amount of bleeding. They all underwent ultrasonographic\nand biochemical studies.\nEach participant in the study underwent preliminary\nultrasound examination. The same experienced\noperator performed the ultrasound examinations.\nUltrasound scanning was performed to all patients using Accuvix (Medison, Korea) scanner\n4-7 MHz endovaginal probe. The scan was done to\nassess the gestational age and fetal viability as well\nas to exclude any uterine malformations.\nUltrasound parameters also included gestational\nsac diameter (GSD), fetal crown-rump length\n(CRL diameter), fetal heart rate (FHR) and the\npresence/absence of sub-chorionic hematoma\n(collection between the uterine wall and the chorionic\nmembrane).\nAll venous samples (5 ml) were allowed to\nclot, and sera were separated by centrifugation\nat room temperature at 3,000 rpm for 10 minutes.\nSera were stored at -80˚C until they were\nanalyzed at the end of the study. Quantification\nof CA-125, and progesterone was performed\nusing the direct chemiluminometric technology\nusing kits (ADVIA Centaur) supplied by (Bayer\nHealth Care Diagnostics, USA). The test was\nperformed according to the manufacturer’s instructions.\nFollow up of all patients was carried out until\n20 weeks of pregnancy to detect the patients\nwho would miscarry and those who would proceed\ninto the second trimester. Then, comparison\nwas done between the two study groups,\nmiscarried and continued groups, for ultrasound\nfinding data, progesterone level and CA-125\nlevel.\nData were statistically described in terms of\nrange, mean ± SD, median, frequencies (number\nof cases) and percentages when appropriate.\nComparison of numerical variables between the\nstudy groups was done using one-way ANOVA\ntest with posthoc multiple 2-group comparisons.\nFor comparing categorical data, Chi square (χ2)\ntest was performed. Exact test was used instead\nwhen the expected frequency is less than\n5. Accuracy was represented using the terms\nof sensitivity, and specificity. Receiver operator\ncharacteristic (ROC) analysis was used to\ndetermine the optimum cut off value for the\nstudied diagnostic markers. P values less than\n0.05 was considered statistically significant. All\nstatistical calculations were done using computer\nprograms Microsoft Excel 2007 (Microsoft\nCorporation, USA) and SPSS (SPSS Inc., USA)\nversion 15 for Microsoft Windows.\n\nA total of 100 pregnant patients with vaginal\nbleeding between 7 and 13 weeks’ gestation\nin which a singleton embryo with cardiac activity\nwas initially documented completed the study.\nTwenty cases ended by miscarriage (20%, group\n1) and 80 cases (80%, group 2) continued till 20\nweeks of gestation.\nNo statistically significant differences were\nfound between both groups as regards maternal\nage, parity, the number of previous miscarriages,\nand CRL. The mean GSD was significantly\nlower in the group that miscarried compared to\nthe group that continued (P=0.023,  Table 1 ).\nThe mean FHR was 156.9 ± 20 bpm for the continued\ngroup and 122 ± 9 for the aborted group,\nwhich showed a statistically significant difference\n(P<0.001).\nOn comparison between study cases presented\nby sub chronic hematoma in relation to\nstudy parameters, CA-125 level was significantly\nhigher in the group that showed hematoma\nas compared with the group without hematoma\n(52.857 ± 29.219 vs. 23.501 ± 13.295,\nP<0.001). Also, serum progesterone level was\nsignificantly lower in the group that showed\nhematoma as compared with the group without\nhematoma (14.67 ± 7.09 vs. 23.507 ± 9.39,\nP=0.017).\nThe level of serum CA-125 for the threatened\nmiscarriage (miscarried) group was 54.28\n± 11.4 IU/ml; while for the threatened miscarriage\n(continued) group it was 18.81 ± 8.02 IU/\nml. The difference was statistically significant\n(P<0.001). The level of serum progesterone for\nthe threatened miscarriage (miscarried) group\nwas 8.7 ± 1.85 ng/ml; while for the threatened\nmiscarriage (continued) group it was 26.3 ± 7.2\nng/ml, which showed a statistically significant\ndifference (P<0.001,  Table 1 ).\nUsing a ROC curve for CA-125 in predicting\nthe outcome of pregnancy in threatened miscarriage\ncases, the cut-off limit of 31.2 IU/ml of\nCA-125 level achieved sensitivity of 96.2% and specificity of 100%. CA-125 level above 31.2\nIU/ml predicted occurrence of miscarriage with\nan overall accuracy of 99.4%.\nUsing a ROC curve for progesterone level in\npredicting the outcome of pregnancy in threatened\nmiscarriage cases, the cut-off limit of 11.5\nng/ml of progesterone level achieved sensitivity\nof 97.5 % and specificity of 100%. A progesterone\nlevel of <11.5 ng/ml predicted the occurrence\nof miscarriage with an overall accuracy\nof 99.8%.\nCA-125 level showed a strong significant negative\ncorrelation with progesterone level (r=-0.716,\nP<0.001), and a significant negative correlation\nwith the FHR (r=-0.414, P<0.001). Serum progesterone\nlevel showed a correlation with GSD\n(r=0.521, P<0.001), CRL (r= 0.407, P<0.001) and\nFHR (r= 0.363, P<0.001,  Table 2 ).\nUltrasonographic and biochemical markers in the miscarried and continued pregnancy groups\n*; Significant difference (P<0.05), GSD; Gestational sac diameter, CRL; Crown-rump length, FHR; Fetal heart rate,\nSCH; Subchorionic hematoma and CA-125; Cancer antigen-125.\nCorrelation between CA-125 and progesterone levels to the other study parameters\n*; Significant difference (P<0.05), CRL; Crown-rump length, GSD, Gestational sac diameter, FHR; Fetal\nheart rate and CA-125; Cancer antigen-125.\n\nThe present study aimed to evaluate the prognostic\nvalue of serum progesterone level and serum\nCA-125 level at the time of initial presentation\nwith pregnancy outcome in patients with first\ntrimester threatened miscarriage.\nAs regards GSD, the GSD of the group that\ncontinued pregnancy was significantly higher\nthan that of the group that miscarried. These\nresults are also in agreement with the study by\nFalco et al. ( 6 ) who evaluated the outcome and\nprognostic criteria of pregnancies with first-trimester\nbleeding and a gestational sac ≤16 mm.\nThey found that of 50 patients, 32 (64%) underwent\nmiscarriage. The size of GSD a high level\nof statistical significance.\nHowever, these results are not in agreement with\nthe study by Oh et al. ( 7 ) who found that the mean\ndiameter of the gestational sac at 28-42 days from\nthe last menstrual period among normal pregnancies\ndid not differ significantly from that in those\nthat subsequently miscarried (2.6 vs. 2.7 mm).\nThis difference can be attributed to the difference\nin the range of gestational age at which ultrasound\nwas done, 4-6 weeks in their study and 7-13 weeks\nin our study.\nIn this study, the CRL was not significantly different\nbetween the group that continued pregnancy\nand the group ended by miscarriage (P=0.06),\nwhich was inconsistent with Reljic ( 8 ) who studied\n310 singleton pregnancies with live fetuses,\npresenting with threatened miscarriage before 13\nweeks of gestation. He reported that in fetuses\nwith CRL<18 mm, there was a significant positive\nassociation between deficit in the CRL for gestation\nand the incidence of subsequent spontaneous\nmiscarriage. The smaller number of women in our\nstudy may explain this difference.\nIn this study, there was a significant difference\nbetween women who miscarried and women who\ncontinued regarding the presence of sub-chorionic\nhematoma (SCH) (P=0.002). These results are in\nagreement with many studies that showed that SCH\nwas associated with high incidence of 1st trimester\nmiscarriage ( 9 ,  10 ). However, our results are not in\nquite agreement with Pearlstone and Baxi’s findings\n( 9 ). They reviewed the English literature on\nSCH. Fourteen studies were reviewed. The incidence\nof SCH varied greatly among studies from\n4 to 48 per cent. They concluded that small SCH\ntend to be more common in the first trimester and\nappear to pose no added risk to the ongoing pregnancy\nbut this could be challenged by how small\nthe hematoma needed to be so that to have no adverse\neffects. Also we didn’t correlate the size and\nsite of the hematoma with the outcome, which is a\nlimitation of our study.\nIn this study, the FHR was significantly different\nbetween the two groups (the miscarried and the\ncontinued groups). Our results are in agreement\nwith Doubilet and Benson’s findings ( 11 ). However,\nwhen the embryonic heart rate is within the\nnormal range for gestation, the outcome remains\nuncertain, as in another study done by Tannirandorn\net al. ( 12 ).\nThe concentrations of CA-125 in the pregnant\nwomen who subsequently miscarried were higher\nthan those who did not, thus suggesting that the\nserumCA-125 levels are not so important in maintaining\nsuccessful pregnancy ( 13 ). CA-125 might\nhave a role in the preparation of the endometrium\nfor successful implantation ( 14 ). More trophoblastic\ndamage is associated with higher levels of\nCA125 and lactate dehydrogenase (LDH) ( 15 ).\nCA-125 can be used as a prognostic factor to the\noutcome of pregnancy as it might be related to the\nextent of trophoblastic destruction.\nIn the present study, serum CA-125 levels\nshowed a significant difference between the group\nof women that continued and the group of women\nthat miscarried (P<0.001). These results are consistent\nwith other studies ( 14 - 16 ). There was a\nhighly significant increase in serum CA-125 level\nin women who miscarried. They stated that serum\nCA-125 level might be developed as a cheap, sensitive\nand specific predictor of outcome in cases of\nthreatened miscarriage, whereas Mahdi ( 16 ) found\nthat there was no statistically significant difference\nin CA-125 level of patients who miscarried compared\nwith those women that continued pregnancies\nin spite of its higher level. Their study showed\nthat serum CA-125 level are not predictive of\nspontaneous miscarriage in the first trimester and\nfailed to discriminate among threatened miscarriages\nand normal pregnancies.\nSeveral cut-off values were suggested in other\nstudies in order to predict pregnancy outcome in\nearly viable pregnancies complicated by vaginal bleeding or to discriminate between viable and\nnon-viable gestations at the time of vaginal bleeding.\nIn this study, a cut-off limit of 31.2 IU/ml of\nCA-125 level was suggested, with a sensitivity of\n96.2% and specificity of 100%. Fiegler et al. ( 17 )\nused a cut-off value of 66.5 IU/ml with a sensitivity\nof 55%. Schmidt et al. ( 18 ) used 65 IU/ml as a\ncut-off value and reported a sensitivity of 50% for\nthis level. Azougi et al. ( 19 ) used a 125 IU/ml as a\ncut-off value and reported a 100% sensitivity and\nspecificity.\nThe present study evaluated the possible role of\nserum progesterone measurement in the prognosis\nof first trimester miscarriage. According to the statistical\nanalysis, there was a significant difference\nbetween the group of women that continued and\nthe group of women that miscarried (P<0.001).\nThis was in accordance with the study of Edwar et\nal. ( 20 ) who studied 78 pregnant women presented\nby vaginal bleeding, 44 continued till 13th week of\npregnancy and 34 ended with spontaneous miscarriage.\nSerum progesterone level was 5.7 ± 10.9 in\ncontinuing pregnancy and 6.7 ± 4.8 in spontaneous\nabortion. The difference in progesterone level was\nhighly significant.\n\nThe use of certain maternal serum markers (CA-\n125 and progesterone) in the first trimester represent\nnon invasive, early and fast methods that can\nbe considered as a good predictor for the outcome\nof pregnancy in cases with threatened abortion,\nLarger clinical trials are still needed to support this\nrecommendation.","source_license":"CC-BY-4.0","license_restricted":false}