The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis

Whether or not pregnant women with a previous episode of venous thromboembolism (VTE) should receive antithrombotic prophylaxis is a matter of debate. In order to estimate the rate of recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE) during pregnancy and puerperium we retrospectively investigated a cohort of 1104 women with previous VTE; after a single DVT or isolated PE, 88 of them became pregnant at least once without receiving antithrombotic prophylaxis. Overall, 155 pregnancies and 120 puerperium periods without prophylaxis were recorded. There were nine recurrences during pregnancy and 10 during puerperium, with a rate of 5.8% [95% confidence interval (CI) 3.0-10.6] and 8.3% (95%CI 4.5-14.6) respectively. In pregnancy, the rate of recurrence was 7.5% (95%CI 4.0-13.7) if the first VTE was unprovoked, related to pregnancy or to oral contraceptive use, whereas no recurrence occurred if the first VTE was related to other transient risk factors. In puerperium, the rate of recurrence was 15.5% (95%CI 7.7-28.7) in women with a pregnancy-related first VTE, with a risk 3.9-times higher than in the remaining women. Inherited thrombophilia was not associated with a statistically significant increase in risk of recurrence in pregnancy or in puerperium, yet the rate of recurrence in puerperium was 14.2% (95%CI 5.7-31.4) in overall carriers of factor V Leiden and 30% (95%CI 10.7-60.3) in carriers with a pregnancy-related first VTE, with a risk 6.8 times higher than in women without thrombophilia and with a non pregnancy-related first VTE.     

Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives

Epidemiological studies have shown that women who use third-generation oral contraceptives (OC) containing desogestrel, gestodene or norgestimate have a higher risk of venous thrombosis than women who use second-generation OC containing levonorgestrel. It is also known that a mutation in factor V (factor V_Leiden), which results in resistance to activated protein C (APC) and which is the most common cause of hereditary thrombophilia, potentiates the prothrombotic effect of OC.
Effects of APC on thrombin generation in the plasma of women using OC were compared to the response to APC in non-OC users and in individuals that were hetero-zygous or homozygous for factor V_Leiden. The response towards APC was evaluated on basis of the ratio (APC-sr) of the time integrals of thrombin formation determined in the presence and absence of APC.
Compared with women not using OC, women who used OC exhibited a significantly decreased sensitivity to APC ( P  < 0.001), independent of the kind of OC used. Women who used third-generation monophasic OC were significantly less sensitive to APC than women using second-generation OC ( P  < 0.001) and had APC-sr that did not significantly differ from heterozygous female carriers of factor V_Leiden who did not use OC. Women who were heterozygous for factor V_Leiden and used OC had APC-sr in the range of homozygous carriers of factor V_Leiden. Two women who started OC therapy had significantly elevated APC-sr within 3 d.
Acquired APC resistance may explain the epidemiol-ogical observation of increased risk for venous thrombosis in OC users, especially in women using third-generation OC.     

Risk-based secondary prevention of obstetric antiphospholipid syndrome

Treatment of pregnant women with antiphospholipid syndrome (APS) should be set apart from that from thrombotic APS patients. Patients with a history of pregnancy morbidity but no vascular thrombosis are usually treated with a prophylactic dose of heparin plus low-dose aspirin; whereas, those with previous vascular thrombosis alone or associated with previous pregnancy morbidity, are commonly treated with a therapeutic dose of heparin generally combined with low-dose aspirin. However, in about 20% of pregnant APS women these regimens fail. In this context, we conducted a case-control study on a large multicentre cohort of conventionally treated pregnancies to verify whether specific laboratory profiles and/or clinical characteristics are predictive of unsuccessful pregnancy outcome during conventional treatments. Multivariate analysis showed that pregnancy failure during conventional therapies was independently associated with a history of both thrombosis and pregnancy morbidity, the presence of systemic lupus erythematosus (SLE) or other systemic autoimmune diseases and triple antiphospholipid antibody positivity. With the aim to discover the most effective and safe treatments in high-risk pregnant APS women a large-scale multicentre study focusing on the effect of treatments on pregnancy outcome in women with APS and further risk factors for pregnancy failure has been designed.     

Catastrophic antiphospholipid syndrome during pregnancy and puerperium: maternal and fetal characteristics of 15 cases

BACKGROUND: The catastrophic variant of the antiphospholipid syndrome (APS) is a life-threatening form of presentation of this syndrome that can be triggered by several factors. AIM: To describe the characteristics of patients who developed catastrophic APS triggered during pregnancy and puerperium. METHODS: A review of the first 255 cases collected in the website-based "CAPS Registry" was undertaken. Three new and unpublished cases of catastrophic APS developed during pregnancy and puerperium were added. RESULTS: Fifteen cases were identified. The mean (range) age was 27 (17-38) years. Most patients had a previous unsuccessful obstetric history. In 7 of 14 (50%) cases with available medical history, the catastrophic APS appeared during pregnancy, in 6 (43%) during the puerperium and in 1 (7%) after curettage for a fetal death. The main clinical and serological characteristics were similar to those patients with catastrophic APS triggered by other factors, except for a history of a higher prevalence of previous abortions (p<0.01). Several specific features were found, including the HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome in 8 (53%) patients, placental infarctions in 4 (27%) patients, and pelvic vein thrombosis and myometrium thrombotic microangiopathy in 1 (7%) patient each. Mortality rate was high for the mothers (46%), and for the babies (54%). CONCLUSIONS: It is important to consider the possibility of the development of catastrophic APS in those patients with signs of HELLP syndrome and multiorgan failure during pregnancy or puerperium, especially in those patients with previous history of abortions and/or thrombosis.     

Clinical study of venous thromboembolism during pregnancy and puerperium

We encountered 16 cases of venous thromboembolism (VTE) in women during pregnancy and/or puerperium over the past 15 years at our perinatal center, representing 0.14% of all patients who delivered babies. The present study was undertaken to analyze the risk factors, clinical course and outcomes in these 16 cases. The ages of the patients varied from 29 to 39 years. Four women had pulmonary embolism (PE), 3 of which after caesarean section (C/S) at 35 to 40 weeks, and one case after ovarian cystectomy at 13 weeks of gestation. Twelve cases had deep venous thrombosis (DVT), 4 of which during pregnancy, and the remaining 8 cases after C/S. Four patients who had DVT during a normal course of pregnancy had severe thrombophilia: antiphospholipid antibody syndrome, a history of thrombosis and antithrombin (AT) deficiency. They were treated with heparin with or without AT and had healthy babies via successful vaginal deliveries. The common risk factors in 3 cases of PE with C/S was prolonged bed rest due to threatened premature delivery with total placenta previa, uterine myoma and Ehlers-Danlos syndrome. Other risk factors were massive bleeding, and positive lupus anticoagulant. However, the case of the ovarian cystectomy had only one risk factor, which was obesity. This patient died but the remaining patients recovered with treatment. Because of the low incidence of thrombosis in the Japanese population, prophylactic anticoagulant therapy has not routinely been given to patients undergoing obstetrical operations. However, proper management including prophylactic anticoagulant therapy might be considered for risk patients, depending on the risk factors.     

Acquired resistance to activated protein C in breast cancer patients

In 56 women with a lymph-node-positive breast carcinoma and 28 matched healthy control subjects, the sensitivity to activated protein C (APC-sr) was determined with an APC resistance test that quantifies the effect of APC on thrombin generation initiated via the extrinsic coagulation pathway. Carriers of the Factor V Leiden mutation were excluded from the study. Significant resistance to APC was found in the breast cancer patients: median APC-sr 2.02 vs 1.03 in the healthy control subjects (P < 0.001). No difference in APC-sr was found between patients with metastases and without metastases. In patients with metastases, protein S levels were significantly elevated compared with patients without metastases and healthy control subjects: 108.0%vs 96.0% and 94.5% (P = 0.008 and P = 0.007). The APC-sr correlated with protein S in the control subjects and in patients without metastases but not in patients with metastases. The disturbance of the haemostatic balance probed by the tissue-factor-based APC resistance test might contribute to the cancer-related hypercoagulability.     

Anticoagulation during pregnancy

Venous thromboembolism (VTE) occurs infrequently but is a leading cause of illness and death during pregnancy and the puerperium. In the general population the incidence of pregnancy-associated VTE is approximately 1 in 1500 deliveries. The risk of VTE is five times higher in a pregnant than in a nonpregnant woman. Postpartum the VTE risk is even higher. Women with congenital abnormalities or persistent presence of antiphospholipid antibodies have an increased risk of VTE during pregnancy and the puerperium. Women with previous VTE have an approximately 3.5-fold increased risk of recurrent VTE during pregnancy. Heparin does not cross the placenta and is therefore the anticoagulant of choice. In case of acute thrombosis during pregnancy, treatment is performed in the same manner as for nonpregnant patients. There is an ongoing debate whether pregnant women with previous venous thrombosis should routinely receive prophylactic anticoagulation. Patients who have hereditary antithrombin deficiency, antiphospholipid antibodies, a combined abnormality, or a history of a severe thrombotic event (pulmonary embolism or extended deep vein thrombosis) should be advised to use prophylactic heparin during pregnancy, starting during the first trimester. Postpartum prophylaxis should be given to all women with an increased risk for VTE. A large body of evidence has been presented that hypercoagulability may cause recurrent abortions, stillbirth, and preeclampsia. There is no doubt that the antiphospholipid syndrome is strongly associated with fetal loss. The combination of heparin and aspirin significantly decreases the fetal loss rate during pregnancy and thus this is the treatment of choice in this patient group. Several studies indicate that women with recurrent miscarriage may benefit from heparin administration during pregnancy, however, data from controlled trials have not yet been published. In women with artificial heart valves, maternal and fetal complications are frequent despite anticoagulation, but oral anticoagulants can reduce the risk for maternal complications.     

Development of resistance to activated protein C during pregnancy

Summary. We measured activated protein C (APC) anticoagulant activity in 20 healthy women at 14-20, 28 and 36 weeks gestation, and at 1 d post-partum. Significant reductions in the mean APC sensitivity ratio (APC-SR) were observed at all stages of pregnancy studied compared with the mean APC-SR obtained for baseline measurements carried out at > 8 weeks post-partum. APC resistance was seen in 8/19 (42%) and in 11/20 (55%) women at 14-20 and 28 weeks gestation respectively. The development of resistance to APC may contribute to the increased risk of thrombosis during pregnancy.     

The risk of maternal venous thromboembolism disease. Synopsis and definition of high-risk groups

Risk factors for venous thromboembolic disease, during pregnancy and post-partum, can be identified in as much as 75% of pregnant women, who present such an accident. Different risk factors are usually associated in the same women. Risk factors can be attribuated to the pregnant women (age over 35 years, overweight, varicose veins, smoking, previous deep venous thrombosis and/or pulmonary embolism) or to the conditions of the pregnancy (multiparity, immobilisation, hypertension and pre-eclampsia, cesarean delivery). Inherited or acquired biological thrombophilia enhance the risk of thrombosis but the magnitude of this effect in ante-partum, puerperium or post-partum depends on the nature of the abnormality. The analysis of all these risk factors and their cumulative effect enable classifying pregnant women into groups with very high risk, high risk or moderate risk for venous thromboembolism and to propose an adapted strategy to prevent the occurrence of such accidents.     

Ulcerative colitis and pregnancy

The relationship between ulcerative colitis (UC) and pregnancy was studied in 83 cases (124 deliveries). The results were as follows: 1) In women with UC, there was no significant difference in fertility compared with the general population. 2) The existence of UC and treatment of UC during pregnant period had no significant adverse effects for the course of pregnancy. 3) In the 17 out of 36 pregnancies with inactive UC at the onset of pregnancy suffered relapses. Relapse rate in same patients in the pregnant period was significant higher than that in the non-pregnant period. 4) First attack of UC developing in 12 cases during pregnancies or the puerperium, the onset being commonly in the first trimester. UC developing during pregnancy was especially severe in other patients. We concluded that the relapse rate of UC is high during pregnant period, however, the course of pregnancy is not affected with UC.     

In vivo insulin action in type 1 (insulin-dependent) diabetic pregnant women as assessed by the insulin clamp technique

To determine the influence of pregnancy on insulin sensitivity in patients with type 1 diabetes mellitus in more detail, a hyperinsulinemic euglycemic clamp study was performed in six pregnant type 1 diabetic women and eight nonpregnant women with type 1 diabetes mellitus. All of the pregnant women were studied three times: in early pregnancy (mean, week 13), late pregnancy (mean, week 34), and within a week after delivery. Insulin was infused in a constant rate of 1.0 mU/kg X min, which resulted in steady state serum free insulin levels (I) of 44 +/- 3 (+/- SEM), 56.6 +/- 6, and 55 +/- 8 microU/ml in the pregnant diabetic women and 52 +/- 4 microU/ml in the nonpregnant women. Mean glucose disposal (M) was 5.6 +/- 0.3 mg/kg X min early in pregnancy and 3.4 +/- 0.5 mg/kg X min late in pregnancy (P less than 0.02). However, in the early postpartum period, M was again higher (7.2 +/- 0.7 mg/kg X min; P less than 0.02) and similar to values in early pregnancy and nonpregnant diabetic women (7.2 +/- 0.6 mg/kg X min). When tissue sensitivity to insulin was expressed as the M to I ratio, similar results were obtained (nonpregnant women, early stage of gestation, and postpartum vs. late stage of gestation: 0.13 +/- 0.01, 0.13 +/- 0.01, and 0.15 +/- 0.03 mg/kg X min per microU/ml vs. 0.06 +/- 0.1 mg/kg X min per microU/ml; P less than 0.03 in all). There tended to be an inverse relationship between serum levels of human placental lactogen and the M to I ratio during pregnancy (r = -0.74; P = 0.09). However, we found no association between changes in the impairment of insulin action and serum estradiol, progesterone, or cortisol levels. In conclusion, pregnant type 1 diabetic women have insulin resistance in peripheral tissues in the late stage of gestation. Insulin sensitivity returns to values found in nonpregnant diabetic women within the first week after delivery.     

Epidemiology and risk factors for venous thrombosis

Venous thrombosis, including deep vein thrombosis (DVT) and pulmonary embolism (PE), occurs at an annual incidence of about 1 per 1,000 adults. Rates increase sharply after about age 45 years, and are slightly higher in men than women in older age. Major risk factors for thrombosis, other than age, include exogenous factors such as surgery, hospitalization, immobility, trauma, pregnancy, and the puerperium and hormone use, and endogenous factors such as cancer, obesity, and inherited and acquired disorders of hypercoagulation. This review focuses on epidemiology of venous thrombosis and the general implications of this in patient management.     

Arg506–Gln mutation in factor V and risk of thrombosis during pregnancy

Seventy women with thrombosis in pregnancy were investigated for the presence of APC resistance and the associated Arg⁵⁰⁶–Gln mutation in coagulation factor V. The mutation was found in 46% of the investigated women. Carriers of the mutation were more prone to develop thrombosis in the first pregnancy (OR (odds ratio) = 3.41; P  < 0.05) and had a higher probability of recurrence (OR = 3.86; P  < 0.05) compared to non-carriers. The incidence of miscarriage was not related to the mutation but its probability increased in women with thrombosis in a second or subsequent pregnancy ( P  < 0.025). Negative dynamics of APC response during pregnancy was observed in 20/22 women; eight of them developed APC resistance de novo . The suppression of APC response was independent of the mutation.     

Pregnancy and deep vein thrombosis

The diagnosis, treatment, and prevention of deep vein thrombosis (DVT) during pregnancy remain problematic. This article reviews the pathophysiology of pregnancy-related DVT and suggests diagnostic strategies, highlighting the pitfalls specific to this patient population. The treatment of DVT in pregnant patients is difficult because unfractionated heparin and low-molecular-weight heparins, the cornerstones of initial therapy, may have significant maternal side effects and warfarin can cause embryopathy and other adverse fetal effects. As well, there are limited data regarding the efficacy of anticoagulant therapy in the treatment and prophylaxis of DVT during pregnancy. This article briefly reviews the areas of controversy and provides recommendations for the treatment of acute DVT and thromboprophylaxis in pregnant patients.     

Iron status of pregnant Filipino women as measured by serum ferritin.

Iron status of pregnant women at different stages of pregnancy was evaluated by comparing values for hemoglobin (Hb), red cell indices, serum iron (SI), transferrin saturation (TS) and serum ferritin (SF) values with those of a group of non-pregnant women of comparable age and socio-economic status. Mean SF values on the second and third trimesters (9.3 +/- 2.60 ng/ml and 7.1 +/- 2.19 ng/ml) were significantly lower compared to that in the first trimester (22.6 +/- 2.20 ng/ml). These levels were also lower than that found in the non-pregnant controls. The trend was the same for TS. Hemoglobin levels of the pregnant subjects were significantly lower than those of the non-pregnant women. Prevalence of iron deficiency based on SF < 12.0 ng/ml and TS < 16.0% was highest at term and lowest during the first trimester indicating a decrease in iron stores as pregnancy progressed. Sensitivity for each of the iron parameters was computed, and it was found that for the diagnosis of iron deficiency in pregnant women, SF has a greater sensitivity than TS, SI, MCV and MCH.     

Control del embarazo en pacientes con lupus eritematoso sistémico y síndrome antifosfolípido. Parte 1: Infertilidad,preservación ovárica y valoración preconcepcional. Documento de consenso de la Sociedad Española de Ginecología y Obstetricia (SEGO), Sociedad Española de Medicina Interna (SEMI) y Sociedad Española de Reumatología (SER)

ObjectivePregnancy and puerperium are considered a risk situation in women with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Therefore, specialized assessment is essential both preconception and during pregnancy and the puerperium. Likewise, it is very important that different specialists in autoimmune diseases and high-risk pregnancies participate in the follow-up of these patients in a coordinated manner. The Spanish Society of Gynaecology and Obstetrics, the Spanish Society of Internal Medicine, and the Spanish Society of Rheumatology have set up a working group for the preparation of three consensus documents.MethodsThe stages of the work were: distribution of work in three groups corresponding to the three periods related to pregnancy (preconception, during pregnancy and childbirth and puerperium), identification of key areas, exhaustive review of the literature and formulation of recommendations.ResultsThis first document includes the 48 recommendations that address aspects related to infertility, the need for and treatments for gonadal preservation and preconception assessment.ConclusionsThese multidisciplinary recommendations are considered decision-making tools for clinicians involved in the care of patients with SLE/APS during pregnancy.     

Association of HELLP syndrome with primary antiphospholipid syndrome—a case report

Authors present the first Hungarian case of a young pregnant woman with the association of antiphospholipid syndrome (APS) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. After the onset of severe preeclampsia, the pregnancy was terminated but the patient’s condition continued to worsen. New symptoms of APS, including deep vein thrombosis and ischemic nervus opticus lesion, developed in the patient followed by the onset of acute respiratory distress syndrome, which required respiratory therapy. Intensive treatment with plasmapheresis, high-dose intravenous immunoglobulin, high-dose corticosteroids, cyclophosphamide, and anticoagulants eventually led to full recovery. There have been only few scattered reports in the literature on the association of HELLP syndrome and APS, which was successfully managed with the combination of various immunosuppressive and immunomodulatory treatment modalities.     

Antiphospholipid antibody syndrome

Opinion statement Antiphospholipid antibody syndrome (APS) is a recently defined autoimmune disorder characterized by recurrent vascular thromboses or recurrent pregnancy morbidity; these features are linked to the presence in blood of autoantibodies against negatively charged phospholipids or phospholipid-binding proteins. Thrombosis can occur in any tissue, in veins, arteries, or the microvasculature. Pregnancy morbidity in APS includes miscarriages or premature birth. Criteria that define the major clinical and laboratory features of APS were published in 1999. In patients with antiphospholipid antibodies and prior thrombosis or pregnancy morbidity, there is a high risk of recurrence that persists as long as antiphospholipid antibodies occur in blood. This risk for recurrence of thrombosis or pregnancy morbidity is greatly reduced by preventive anticoagulant therapy. Patients presenting with thrombosis in APS are initially managed in much the same way as are patients with vascular thrombosis owing to other causes. However, in patients with APS, high-intensity anticoagulation is usually needed to prevent recurrences of thrombosis. Thrombosis in APS is often multifactorial, as with non-APS thrombosis. Therefore, in all patients with APS, other reversible risk factors for thrombosis should be sought. The pregnancy outcome of women with APS who have had prior miscarriages is greatly improved by treatment during pregnancy with a combination of heparin and low-dose aspirin.     

Prevention of venous thromboembolism in pregnancy

Pulmonary thromboembolism, rising from deep venous thrombosis (DVT), is a major cause of maternal death in the developed World. DVT is a significant source of morbidity in pregnancy and the puerperium with long-term sequelae such as post-thrombotic syndrome. The major risk factors for venous thromboembolism (VTE) are: increasing age, particularly over 35 years; operative vaginal delivery; Caesarean section, especially emergency Caesarean section in labour; high body mass index; previous VTE, especially if idiopathic or thrombophilia-associated; thrombophilia; and a family history of thrombosis suggestive of an underlying thrombophilia. Thromboprophylaxis centres largely on the use of low-molecular-weight heparin (LMWH). LMWHs, such as enoxaparin and dalteparin, have substantial clinical and practical advantages compared with unfractionated heparin, particularly in terms of improved safety with a significantly lower incidence of heparin-induced osteoporosis and thrombocytopenia. Such agents should be used in women with significant risk factors for VTE both antenatally and post-partum.     

Physiologic multivalvular regurgitation during pregnancy: a longitudinal Doppler echocardiographic study

Valvular function, assessed by Doppler technique, has not been extensively investigated during normal pregnancy. To prospectively study this feature, 18 normal pregnant women were followed during their pregnancies and puerperium, with serial clinical and pulsed-continuous Doppler echocardiographic examinations. In four gestational periods and the puerperium, we analysed: (a) ventricular and atrial dimensions, as well as valve annular diameters; (b) prevalence and characteristics of trivial valvular regurgitations. During pregnancy, slight but significant increases of the four cardiac chamber dimensions and valve annular diameters were observed, except for the aortic ring. The prevalence of physiologic valvular regurgitation in early pregnancy (mitral, 0%; tricuspid, 38.9%; pulmonary, 22.2%; aortic, 0%), was similar to a control group of 18 healthy non-pregnant women. As pregnancy evolved, there was a progressive and significant increase of multivalvular regurgitation, maximal at full-term (mitral, 27.8%; tricuspid, 94.4%; pulmonary, 94.4%, P < 0.05 vs. early pregnancy). Aortic regurgitation was not detected in any stage of pregnancy. In the puerperium, mitral regurgitation resolved, but tricuspid and pulmonary regurgitation were still significantly prevalent (83.3% and 66.7%, respectively, P < 0.05 vs. early pregnancy). It is concluded that physiologic multivalvular regurgitation is frequent in pregnancy, mainly involving right-sided valves in late gestational periods, occasionally persisting in the early puerperium. Chamber enlargement, valve annular dilatation, and increased prevalence of trivial valve regurgitation are time-related events during normal pregnancy, resulting from a reversible cardiac remodeling process induced by physiologic volume overload. These aspects should be considered for a correct interpretation of Doppler echocardiographic findings in pregnant women with suspected heart disease.