Original article 267
Effects of anticoagulant therapy on pregnancy outcomes in patients with thrombophilia and previous poor obstetric history Ilknur Mutlua, Mehmet Firat Mutlub, Aydan Biria, Berk Bulutc, Mehmet Erdema and Ahmet Erdema This study investigates the effects of anticoagulant therapy on pregnancy outcomes in 204 patients with thrombophilia and previous poor obstetric outcomes. Patients with poor obstetric history (pre-eclampsia, intrauterine growth retardation, fetal death, placental abruption, recurrent pregnancy loss) and having hereditary thrombophilia were included in this study. Poor obstetric outcomes were observed more frequently in patients who had not taken anticogulant therapy compared with treated group. Live birth rate, gestational age at birth and Apgar scores were significantly higher in the treated group when compared with the untreated group. There were no significant differences in terms of birthweight, mode of delivery and admission rates to the neonatal intensive care unit (NICU). Low-molecular-weight heparin (LMWH) plus acetylsalicylic acid (ASA) had higher gestational age at birth, Apgar scores, live birth rate and a lower abortion rates when compared with controls; in contrast, no significant difference was observed in terms of birthweight, mode of delivery, obstetric complications and admission rates to NICU. There were no significant differences between control group and both LMWH only and ASA only groups in terms of gestational age at birth, Apgar scores, birthweight, mode of delivery,
Introduction Hereditary thrombophilias are a heterogeneous group of disorders associated with various degrees of increase in the risks of thrombotic events. Deficiencies of protein S, protein C and antithrombin III, Factor V Leiden (FVL) mutation, mutation in the gene encoding prothrombin and methylene tetrahydrofolate reductase (MTHFR) mutations C677T and A1298 are highlighted as the probable causes of hereditary thrombophilias. As well as being associated with an increased risk of venous thromboembolism in pregnancy, these disorders are also linked with a number of obstetric problems such as preeclampsia, intrauterine growth retardation (IUGR), intrauterine fetal death (IUFD), placental abruption and recurrent pregnancy loss [1–8]. Although the prevention of obstetric complications in pregnant women with previous adverse perinatal outcomes accompanied by thrombophilias has been widely discussed, the issue remains controversial because of our limited knowledge on the clinical impact of different thrombophilias and the small number of sufficiently large trials. Uteroplacental thrombosis is observed in pregnancies complicated by IUGR, preeclampsia, placental abruption 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
obstetric complications and admission rates to NICU. Only LMWH group had higher live birth rate as compared with control group. The use of only ASA did not seem to affect the perinatal complication rates and outcomes. In conclusion, anticoagulant therapy with both LMWH and ASA seems to provide better obstetric outcomes in pregnant women with thrombophilia and previous poor obstetric outcomes. Blood Coagul Fibrinolysis 26:267–273 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Blood Coagulation and Fibrinolysis 2015, 26:267–273 Keywords: acetylsalicylic acid, anticoagulant therapy, low-molecular-weight heparin, thrombophilia a Department of Obstetrics & Gynecology, Gazi University Faculty of Medicine, Ankara, bDepartment of Obstetrics & Gynecology, HRS Women Hospital, Ankara and cDepartment of Obstetrics & Gynecology, Okmeydani Research and Training Hospital, Istanbul, Turkey
Correspondence to Mehmet Firat Mutlu, MD, HRS Women Hospital Gunes Street No:14 06690 Kavaklıdere, Ankara, Turkey Tel: +90 532 325 77 90; e-mail: [email protected] Received 25 April 2014 Revised 1 July 2014 Accepted 27 July 2014
and fetal loss with thrombophilia. Consequently, anticoagulant prophylaxis has been offered to women to prevent recurrence of pregnancy complications, which are thought to be associated with hereditary thrombophilias. Anticoagulation therapy reduces thrombosis formation by decreasing vascular injury and thrombin generation. In the current literature, there are limited studies describing the effectiveness of anticoagulant therapy in pregnancies with thrombophilia [9–16]. However, the data are unsatisfactory because of the variability of study designs, low numbers of patients involved in studies, inclusion criteria, varying definitions of poor pregnancy outcomes and choices of medication. For this reason, we aim to determine the effects of anticoagulant therapy on pregnancy outcomes in patients with thrombophilia and previous poor obstetric outcomes.
Material and methods Patient selection
Our study included patients who applied to Gazi University Medical School Department of Obstetrics and Gynecology between 2006 and 2009. Their medical records were reviewed retrospectively and patients with DOI:10.1097/MBC.0000000000000219
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
268 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 3
a previous history of at least one of the following disorders were sorted in the study: preeclampsia, IUGR, IUFD, placental abruption and recurrent pregnancy loss. Among these, a total of 204 patients had been screened for antithrombin III, protein S and protein C deficiencies, APCR, factor V Leiden, prothrombin G20210A, methylene tetrahydrofolate reductase gene mutations, factor VIII, PT, aPTT and fasting homocysteine levels before their latest pregnancy. Consequently, our study group is composed of those patients who had poor obstetric history, a prior testing for probable indicators of hereditary thrombophilia and had never taken any anticoagulant treatment previously. The latest pregnancies of patients were taken into account for the study. The study protocol was approved by our Faculty Ethics Committee and informed consent was waived because of the retrospective nature of this study. Obstetrical complications set as inclusion criteria were preeclampsia, IUGR, IUFD, placental abruption and recurrent pregnancy loss. Preeclampsia was defined as blood pressure over 140/90 mmHg and proteinuria more than 300 mg, both detected after 20th gestational week. Placental abruption was defined as a clinical triad composed of uterine hypercontractility or hyperactivity, fetal distress, overt or obscure uterine bleeding. Fetal weight under the fifth percentile according to gestational age was accepted as IUGR. IUFD was described as fetal demise after 20th gestational week and recurrent pregnancy loss was defined as three or more pregnancy losses before 20th gestational week. None of the patients included in the study had chronic diseases, autoimmune disorders, infectious diseases, hormonal imbalances, uterine abnormalities and abnormal fetal or parental karyotypes that would cause adverse perinatal outcomes. Cases with IUGR or IUFD who had fetal congenital abnormalities, congenital infections and chromosomal abnormalities were excluded from the study. Data on age, gravidity, parity, abortions, previous obstetrical complications, live births, stillbirths and neonatal deaths were obtained from patient records. Serum levels of vitamin B12, vitamin B6, folic acid and homocysteine levels were within normal limits. Patients who had MTHFR mutation received 5-mg folic acid and multivitamin supplement throughout pregnancy and the rest received folic acid for the first 12 weeks of gestation. Patients were grouped according to whether they received anticoagulant therapy in their latest pregnancy. In the treatment group, treatment was initiated as soon as the patients were diagnosed with pregnancy. Treatment group was further divided into subgroups as acetylsalicylic acid (ASA) (80 mg/day), low-molecular-weight heparin (LMWH) (4000 IU/day) and LMWH (4000 IU/ day) þ ASA (80 mg/day)-receiving groups. These subgroups were compared with each other for delivery weeks
on latest pregnancy, birthweights, APGAR scores, live birth rates, stillbirths, neonatal deaths, abortion rates, obstetric complications, modes of delivery and newborn intensive care admission rates.
Methods Antithrombin III activity, protein C activity, active protein C resistance, protein S activity, factor VIII, prothrombin and active partial thromboplastin time were measured in 10 ml peripheral venous blood taken in ethylenediaminetetracetic acid (EDTA)-containing tubes. Homocysteine levels were measured by ‘Microplate Enzyme Immunoassay’ (ELISA) method (DRG Diagnostics, Springfield, New Jersey, USA). FVL, prothrombin G20210A, MTHFR C677T and A1298C mutations were studied by the PCR method in 10 ml peripheral venous blood samples taken in EDTA-containing tubes. Statistical studies
Statistical Package for Social Sciences (SPSS 20) software was used for statistical analyses (SPSS Inc, Chicago, Illinois, USA). Values are calculated as mean standard standard deviation. Student’s t test, chi-square test, Fisher’s exact test, Mann–Whitney U test and Kruskal– Wallis test were used. P values smaller than 0.05 were accepted as statistically significant.
Results Patients involved in the study who had at least one type of hereditary thrombophilia and poor obstetric history had an average age of 31.4 5.2 years, gravidity 3.6 1.1, parity 0.7 0.8, mean number of abortions 1.8 1.2; 65.4% percentage of the patients had no living child, whereas 30.7% had only one child and 3.5% of the patients had two children. Only one had three living children (0.4%). Mean number of intrauterine fetal deaths was 0.15 0.41. When the subgroups formed according to the treatment status were compared with each other, they had no differences in demographics (Table 1). In previous pregnancies, 7.4% of patients (n ¼ 15) had experienced preeclampsia, 5.4% (n ¼ 11) had IUGR, 13.7% of cases (n ¼ 28) had IUFD, 71.1% (n ¼ 145) had been diagnosed with recurrent pregnancy loss (RPL) and 2.5% (n ¼ 5) had placental abruption. One hundred and fifty-four patients had MTHFR mutation (75.5%), 13 cases (6.4%) were diagnosed with Table 1
Demographics of treatment and nontreatment groups
Age Gravidity Parity Abortions Intrauterine ex
Treatment (n ¼ 145)
Nontreatment (n ¼ 59)
P value
31.1 5.3 3.6 1,1 0.6 0.7 1.8 1.3 0.17 0.44
32.1 5.0 3.5 1.0 0.6 0.7 1.7 0.9 0.11 0.3
NS NS NS NS NS
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Anticoagulation in thrombophilic pregnants Mutlu et al. 269
a heterozygous FVL mutation and four patients (2%) had heterozygous mutant prothrombin gene. Two patients (1%) had protein S deficiency. A total of 31 patients (15.2%) were combined mutation carriers. Fourteen patients had MTHFR þ FVL heterozygous mutation, six cases had MTHFR þ prothrombin heterozygous mutant genes, six of the cases had homozygous MTHFR þ heterozygous FVL mutation, two patients had FVL þ PT heterozygous mutant genes and three patients had MTHFR þ FVL þ PT heterozygous mutant genes. None of the cases had antiphospholipid antibodies (Table 2). Patients were split into two groups according to whether they received anticoagulant therapy during their latest pregnancy. There were 145 patients who received therapy and 59 patients who did not. Two groups were compared with each other for weeks at delivery, birthweights, APGAR scores on 1st and 5th minutes, live births, stillbirths, neonatal deaths, abortion rates, modes of delivery, neonatal intensive care requirement and obstetrical complications (preeclampsia, IUGR, placental abruption). In the treatment group, weeks at delivery and APGAR scores at 1st and 5th minutes were significantly higher. When groups were compared for perinatal outcomes, treatment group had a significantly higher rate of live births, whereas nontreatment group had a higher abortion rate. Stillbirths, neonatal deaths, neonatal intensive care requirements, modes of delivery, perinatal complications were not different in two groups (Table 3). Treatment group was compared with nontreatment group after merging perinatal complications and abortions and treatment group had a rate of 81.9% in uneventful pregnancies versus 50% in the nontreatment group. This was a statistically significant difference (P < 0.001). Patients were subdivided into four groups according to whether they receive therapy and the kind of therapy they receive. The group treated solely with ASA contained 23 patients, whereas the group treated only with LMWH had 45 members and the group treated with combined ASA and LMWH consisted of 77 patients. Nontreatment group had 59 patients. The subgroups were compared with the nontreatment group. Therapyreceiving subgroups were not different from each other in delivery weeks, birthweights, APGAR scores in 1 and Table 2
5 min. When subgroups were compared with the nontreatment group separately for weeks at delivery, birthweight, APGAR scores at 1st and 5th minutes, nontreatment group was different from LMWH þ ASA group in weeks at delivery (P ¼ 0.04) and APGAR scores at 1st and 5th minutes (P < 0.001). There were no differences between nontreatment group and only LMWH and only ASA groups (Table 4). The subgroups were investigated for differences in perinatal complications and outcomes. The probability of an uneventful pregnancy was 69.6% in only ASA receiving group, whereas only LMWH group had a rate of 82.2% and the combined therapy group had a rate of 85.7%. These differences were not found to be significant. The rate of abortion was 13% in ASA group, 6.7% in LMWH group and 3.9% in LMWH þ ASA group. Live birth rates were 78.3, 93.3, and 93.5%, respectively in ASA, LMWH and ASA þ LMWH groups. There were no significant differences among the groups (P > 0.05). When subgroups were compared with each other two by two, LMWH þ ASA-receiving group had significantly fewer perinatal complications than solely ASA treatment group (P ¼ 0.044). Nontreatment group was compared separately with each subgroup. There was no significant difference between nontreatment group and ASA group in perinatal outcomes. However, LMWH and LMWH þ ASA groups were significantly different from nontreatment group (P < 0.001) (Table 4). Modes of delivery were compared in treatment and nontreatment groups. In treatment group, 32.6% of patients delivered vaginally, whereas in nontreatment group, this rate was 32.4% and there was no significant difference (P > 0.05). Treatment-receiving subgroups had no significant differences among themselves in mode of delivery. When the data of the latest pregnancies of the patients in treatment group were compared with the same patients’ past pregnancies during which they did not receive any treatment, live birth rate increases from 33.8% prior to therapy to 91% after the therapy. Abortion rate decreased to 6.2% from 46.9%, IUFD rate decreased to 1.4% from 14.5% and neonatal death rate decreased to 1.4% from 4.8% after the therapy. The percentage of patients with a previous stillbirth who had a live birth in the latest
Hereditary thrombophilias accompanying obstetrical pathologies MTHFR mutation, n (%)
Preeclampsia IUGR IUFD RPL Placental abruption
10 10 21 92 1
(66.7) (90.9) (53.6) (76.5) (20%)
FVL heterozygous, n (%) 3 0 3 6 1
(20) (0) (10.7) (4.1) (20%)
Prothrombin gene mutation heterozygous, n (%) 0 0 0 4 0
(0) (0) (0) (28) (0%)
Protein S deficiency, n (%) 0 0 0 4 0
(0) (0) (0) (2.8) (0%)
Combined, n (%) 2 1 4 22 2
FVL, Factor V Leiden; IUFD, intrauterine fetal death; IUGR, intrauterine growth retardation; MTHFR, methylene tetrahydrofolate; RPL, recurrent pregnancy loss.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
(13.3) (9.1) (14.3) (15.2) (40%)
270 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 3
Comparison of treatment and nontreatment groups for perinatal outcomes and modes of delivery
Table 3
Delivery week Birthweight APGAR 1 min APGAR 5 min Stillbirths Neonatal death Abortions Live birth Vaginal delivery Neonatal intensive care requirement Perinatal complications (Preeclampsia, IUGR, IUFD, placental abruption)
Treatment (n ¼ 145)
Nontreatment (n ¼ 59)
P value
37.7 2.4 3105 635 8.6 1.2 9.7 1.2 2 (1.4%) 2 (1.4%) 9 (6.3%) 132 (91%) 44 (32.6%) 18 (13.2%)
35.7 5.6 2773 1014 7.4 2.8 8.5 3.1 0 (0%) 0 (0%) 24 (40%) 35 (60%) 12 (32.4%) 8 (22.2%)
Effects of anticoagulant therapy on pregnancy outcomes in patients with thrombophilia and previous poor obstetric history Ilknur Mutlua, Mehmet Firat Mutlub, Aydan Biria, Berk Bulutc, Mehmet Erdema and Ahmet Erdema This study investigates the effects of anticoagulant therapy on pregnancy outcomes in 204 patients with thrombophilia and previous poor obstetric outcomes. Patients with poor obstetric history (pre-eclampsia, intrauterine growth retardation, fetal death, placental abruption, recurrent pregnancy loss) and having hereditary thrombophilia were included in this study. Poor obstetric outcomes were observed more frequently in patients who had not taken anticogulant therapy compared with treated group. Live birth rate, gestational age at birth and Apgar scores were significantly higher in the treated group when compared with the untreated group. There were no significant differences in terms of birthweight, mode of delivery and admission rates to the neonatal intensive care unit (NICU). Low-molecular-weight heparin (LMWH) plus acetylsalicylic acid (ASA) had higher gestational age at birth, Apgar scores, live birth rate and a lower abortion rates when compared with controls; in contrast, no significant difference was observed in terms of birthweight, mode of delivery, obstetric complications and admission rates to NICU. There were no significant differences between control group and both LMWH only and ASA only groups in terms of gestational age at birth, Apgar scores, birthweight, mode of delivery,
Introduction Hereditary thrombophilias are a heterogeneous group of disorders associated with various degrees of increase in the risks of thrombotic events. Deficiencies of protein S, protein C and antithrombin III, Factor V Leiden (FVL) mutation, mutation in the gene encoding prothrombin and methylene tetrahydrofolate reductase (MTHFR) mutations C677T and A1298 are highlighted as the probable causes of hereditary thrombophilias. As well as being associated with an increased risk of venous thromboembolism in pregnancy, these disorders are also linked with a number of obstetric problems such as preeclampsia, intrauterine growth retardation (IUGR), intrauterine fetal death (IUFD), placental abruption and recurrent pregnancy loss [1–8]. Although the prevention of obstetric complications in pregnant women with previous adverse perinatal outcomes accompanied by thrombophilias has been widely discussed, the issue remains controversial because of our limited knowledge on the clinical impact of different thrombophilias and the small number of sufficiently large trials. Uteroplacental thrombosis is observed in pregnancies complicated by IUGR, preeclampsia, placental abruption 0957-5235 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
obstetric complications and admission rates to NICU. Only LMWH group had higher live birth rate as compared with control group. The use of only ASA did not seem to affect the perinatal complication rates and outcomes. In conclusion, anticoagulant therapy with both LMWH and ASA seems to provide better obstetric outcomes in pregnant women with thrombophilia and previous poor obstetric outcomes. Blood Coagul Fibrinolysis 26:267–273 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Blood Coagulation and Fibrinolysis 2015, 26:267–273 Keywords: acetylsalicylic acid, anticoagulant therapy, low-molecular-weight heparin, thrombophilia a Department of Obstetrics & Gynecology, Gazi University Faculty of Medicine, Ankara, bDepartment of Obstetrics & Gynecology, HRS Women Hospital, Ankara and cDepartment of Obstetrics & Gynecology, Okmeydani Research and Training Hospital, Istanbul, Turkey
Correspondence to Mehmet Firat Mutlu, MD, HRS Women Hospital Gunes Street No:14 06690 Kavaklıdere, Ankara, Turkey Tel: +90 532 325 77 90; e-mail: [email protected] Received 25 April 2014 Revised 1 July 2014 Accepted 27 July 2014
and fetal loss with thrombophilia. Consequently, anticoagulant prophylaxis has been offered to women to prevent recurrence of pregnancy complications, which are thought to be associated with hereditary thrombophilias. Anticoagulation therapy reduces thrombosis formation by decreasing vascular injury and thrombin generation. In the current literature, there are limited studies describing the effectiveness of anticoagulant therapy in pregnancies with thrombophilia [9–16]. However, the data are unsatisfactory because of the variability of study designs, low numbers of patients involved in studies, inclusion criteria, varying definitions of poor pregnancy outcomes and choices of medication. For this reason, we aim to determine the effects of anticoagulant therapy on pregnancy outcomes in patients with thrombophilia and previous poor obstetric outcomes.
Material and methods Patient selection
Our study included patients who applied to Gazi University Medical School Department of Obstetrics and Gynecology between 2006 and 2009. Their medical records were reviewed retrospectively and patients with DOI:10.1097/MBC.0000000000000219
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
268 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 3
a previous history of at least one of the following disorders were sorted in the study: preeclampsia, IUGR, IUFD, placental abruption and recurrent pregnancy loss. Among these, a total of 204 patients had been screened for antithrombin III, protein S and protein C deficiencies, APCR, factor V Leiden, prothrombin G20210A, methylene tetrahydrofolate reductase gene mutations, factor VIII, PT, aPTT and fasting homocysteine levels before their latest pregnancy. Consequently, our study group is composed of those patients who had poor obstetric history, a prior testing for probable indicators of hereditary thrombophilia and had never taken any anticoagulant treatment previously. The latest pregnancies of patients were taken into account for the study. The study protocol was approved by our Faculty Ethics Committee and informed consent was waived because of the retrospective nature of this study. Obstetrical complications set as inclusion criteria were preeclampsia, IUGR, IUFD, placental abruption and recurrent pregnancy loss. Preeclampsia was defined as blood pressure over 140/90 mmHg and proteinuria more than 300 mg, both detected after 20th gestational week. Placental abruption was defined as a clinical triad composed of uterine hypercontractility or hyperactivity, fetal distress, overt or obscure uterine bleeding. Fetal weight under the fifth percentile according to gestational age was accepted as IUGR. IUFD was described as fetal demise after 20th gestational week and recurrent pregnancy loss was defined as three or more pregnancy losses before 20th gestational week. None of the patients included in the study had chronic diseases, autoimmune disorders, infectious diseases, hormonal imbalances, uterine abnormalities and abnormal fetal or parental karyotypes that would cause adverse perinatal outcomes. Cases with IUGR or IUFD who had fetal congenital abnormalities, congenital infections and chromosomal abnormalities were excluded from the study. Data on age, gravidity, parity, abortions, previous obstetrical complications, live births, stillbirths and neonatal deaths were obtained from patient records. Serum levels of vitamin B12, vitamin B6, folic acid and homocysteine levels were within normal limits. Patients who had MTHFR mutation received 5-mg folic acid and multivitamin supplement throughout pregnancy and the rest received folic acid for the first 12 weeks of gestation. Patients were grouped according to whether they received anticoagulant therapy in their latest pregnancy. In the treatment group, treatment was initiated as soon as the patients were diagnosed with pregnancy. Treatment group was further divided into subgroups as acetylsalicylic acid (ASA) (80 mg/day), low-molecular-weight heparin (LMWH) (4000 IU/day) and LMWH (4000 IU/ day) þ ASA (80 mg/day)-receiving groups. These subgroups were compared with each other for delivery weeks
on latest pregnancy, birthweights, APGAR scores, live birth rates, stillbirths, neonatal deaths, abortion rates, obstetric complications, modes of delivery and newborn intensive care admission rates.
Methods Antithrombin III activity, protein C activity, active protein C resistance, protein S activity, factor VIII, prothrombin and active partial thromboplastin time were measured in 10 ml peripheral venous blood taken in ethylenediaminetetracetic acid (EDTA)-containing tubes. Homocysteine levels were measured by ‘Microplate Enzyme Immunoassay’ (ELISA) method (DRG Diagnostics, Springfield, New Jersey, USA). FVL, prothrombin G20210A, MTHFR C677T and A1298C mutations were studied by the PCR method in 10 ml peripheral venous blood samples taken in EDTA-containing tubes. Statistical studies
Statistical Package for Social Sciences (SPSS 20) software was used for statistical analyses (SPSS Inc, Chicago, Illinois, USA). Values are calculated as mean standard standard deviation. Student’s t test, chi-square test, Fisher’s exact test, Mann–Whitney U test and Kruskal– Wallis test were used. P values smaller than 0.05 were accepted as statistically significant.
Results Patients involved in the study who had at least one type of hereditary thrombophilia and poor obstetric history had an average age of 31.4 5.2 years, gravidity 3.6 1.1, parity 0.7 0.8, mean number of abortions 1.8 1.2; 65.4% percentage of the patients had no living child, whereas 30.7% had only one child and 3.5% of the patients had two children. Only one had three living children (0.4%). Mean number of intrauterine fetal deaths was 0.15 0.41. When the subgroups formed according to the treatment status were compared with each other, they had no differences in demographics (Table 1). In previous pregnancies, 7.4% of patients (n ¼ 15) had experienced preeclampsia, 5.4% (n ¼ 11) had IUGR, 13.7% of cases (n ¼ 28) had IUFD, 71.1% (n ¼ 145) had been diagnosed with recurrent pregnancy loss (RPL) and 2.5% (n ¼ 5) had placental abruption. One hundred and fifty-four patients had MTHFR mutation (75.5%), 13 cases (6.4%) were diagnosed with Table 1
Demographics of treatment and nontreatment groups
Age Gravidity Parity Abortions Intrauterine ex
Treatment (n ¼ 145)
Nontreatment (n ¼ 59)
P value
31.1 5.3 3.6 1,1 0.6 0.7 1.8 1.3 0.17 0.44
32.1 5.0 3.5 1.0 0.6 0.7 1.7 0.9 0.11 0.3
NS NS NS NS NS
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Anticoagulation in thrombophilic pregnants Mutlu et al. 269
a heterozygous FVL mutation and four patients (2%) had heterozygous mutant prothrombin gene. Two patients (1%) had protein S deficiency. A total of 31 patients (15.2%) were combined mutation carriers. Fourteen patients had MTHFR þ FVL heterozygous mutation, six cases had MTHFR þ prothrombin heterozygous mutant genes, six of the cases had homozygous MTHFR þ heterozygous FVL mutation, two patients had FVL þ PT heterozygous mutant genes and three patients had MTHFR þ FVL þ PT heterozygous mutant genes. None of the cases had antiphospholipid antibodies (Table 2). Patients were split into two groups according to whether they received anticoagulant therapy during their latest pregnancy. There were 145 patients who received therapy and 59 patients who did not. Two groups were compared with each other for weeks at delivery, birthweights, APGAR scores on 1st and 5th minutes, live births, stillbirths, neonatal deaths, abortion rates, modes of delivery, neonatal intensive care requirement and obstetrical complications (preeclampsia, IUGR, placental abruption). In the treatment group, weeks at delivery and APGAR scores at 1st and 5th minutes were significantly higher. When groups were compared for perinatal outcomes, treatment group had a significantly higher rate of live births, whereas nontreatment group had a higher abortion rate. Stillbirths, neonatal deaths, neonatal intensive care requirements, modes of delivery, perinatal complications were not different in two groups (Table 3). Treatment group was compared with nontreatment group after merging perinatal complications and abortions and treatment group had a rate of 81.9% in uneventful pregnancies versus 50% in the nontreatment group. This was a statistically significant difference (P < 0.001). Patients were subdivided into four groups according to whether they receive therapy and the kind of therapy they receive. The group treated solely with ASA contained 23 patients, whereas the group treated only with LMWH had 45 members and the group treated with combined ASA and LMWH consisted of 77 patients. Nontreatment group had 59 patients. The subgroups were compared with the nontreatment group. Therapyreceiving subgroups were not different from each other in delivery weeks, birthweights, APGAR scores in 1 and Table 2
5 min. When subgroups were compared with the nontreatment group separately for weeks at delivery, birthweight, APGAR scores at 1st and 5th minutes, nontreatment group was different from LMWH þ ASA group in weeks at delivery (P ¼ 0.04) and APGAR scores at 1st and 5th minutes (P < 0.001). There were no differences between nontreatment group and only LMWH and only ASA groups (Table 4). The subgroups were investigated for differences in perinatal complications and outcomes. The probability of an uneventful pregnancy was 69.6% in only ASA receiving group, whereas only LMWH group had a rate of 82.2% and the combined therapy group had a rate of 85.7%. These differences were not found to be significant. The rate of abortion was 13% in ASA group, 6.7% in LMWH group and 3.9% in LMWH þ ASA group. Live birth rates were 78.3, 93.3, and 93.5%, respectively in ASA, LMWH and ASA þ LMWH groups. There were no significant differences among the groups (P > 0.05). When subgroups were compared with each other two by two, LMWH þ ASA-receiving group had significantly fewer perinatal complications than solely ASA treatment group (P ¼ 0.044). Nontreatment group was compared separately with each subgroup. There was no significant difference between nontreatment group and ASA group in perinatal outcomes. However, LMWH and LMWH þ ASA groups were significantly different from nontreatment group (P < 0.001) (Table 4). Modes of delivery were compared in treatment and nontreatment groups. In treatment group, 32.6% of patients delivered vaginally, whereas in nontreatment group, this rate was 32.4% and there was no significant difference (P > 0.05). Treatment-receiving subgroups had no significant differences among themselves in mode of delivery. When the data of the latest pregnancies of the patients in treatment group were compared with the same patients’ past pregnancies during which they did not receive any treatment, live birth rate increases from 33.8% prior to therapy to 91% after the therapy. Abortion rate decreased to 6.2% from 46.9%, IUFD rate decreased to 1.4% from 14.5% and neonatal death rate decreased to 1.4% from 4.8% after the therapy. The percentage of patients with a previous stillbirth who had a live birth in the latest
Hereditary thrombophilias accompanying obstetrical pathologies MTHFR mutation, n (%)
Preeclampsia IUGR IUFD RPL Placental abruption
10 10 21 92 1
(66.7) (90.9) (53.6) (76.5) (20%)
FVL heterozygous, n (%) 3 0 3 6 1
(20) (0) (10.7) (4.1) (20%)
Prothrombin gene mutation heterozygous, n (%) 0 0 0 4 0
(0) (0) (0) (28) (0%)
Protein S deficiency, n (%) 0 0 0 4 0
(0) (0) (0) (2.8) (0%)
Combined, n (%) 2 1 4 22 2
FVL, Factor V Leiden; IUFD, intrauterine fetal death; IUGR, intrauterine growth retardation; MTHFR, methylene tetrahydrofolate; RPL, recurrent pregnancy loss.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
(13.3) (9.1) (14.3) (15.2) (40%)
270 Blood Coagulation and Fibrinolysis 2015, Vol 26 No 3
Comparison of treatment and nontreatment groups for perinatal outcomes and modes of delivery
Table 3
Delivery week Birthweight APGAR 1 min APGAR 5 min Stillbirths Neonatal death Abortions Live birth Vaginal delivery Neonatal intensive care requirement Perinatal complications (Preeclampsia, IUGR, IUFD, placental abruption)
Treatment (n ¼ 145)
Nontreatment (n ¼ 59)
P value
37.7 2.4 3105 635 8.6 1.2 9.7 1.2 2 (1.4%) 2 (1.4%) 9 (6.3%) 132 (91%) 44 (32.6%) 18 (13.2%)
35.7 5.6 2773 1014 7.4 2.8 8.5 3.1 0 (0%) 0 (0%) 24 (40%) 35 (60%) 12 (32.4%) 8 (22.2%)
