Eva-Marie Jacobsen

High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease

Most patients diagnosed with primary chronic cold agglutinin disease (CAD) have a clonal lymphoproliferative bone marrow disorder. Treatment with rituximab is the only well-documented effective therapy, leading to 45%-60% partial responses (PR). Complete responses (CR) are rare, and median response duration is only 11 months. In a prospective multicenter trial, 29 patients received rituximab 375 mg/m(2) on days 1, 29, 57 and 85; and fludarabine orally, 40 mg/m(2) on days 1-5, 29-34, 57-61 and 85-89. Twenty-two patients (76%) responded, 6 (21%) achieving CR and 16 (55%) PR. Among 10 patients nonresponsive to rituximab monotherapy, 1 achieved CR and 6 PR. Median increase in hemoglobin level was 3.1 g/dL among the responders and 4.0 g/dL in those who achieved CR. Lower quartile of response duration was not reached after 33 months. Estimated median response duration was more than 66 months. Grade 3-4 hematologic toxicity occurred in 12 patients (41%). In conclusion, fludarabine and rituximab combination therapy is very efficient in patients with CAD. Toxicity may be a concern, and benefits should be carefully weighed against risks in very old and comorbid patients. It remains to be established whether the combination should be first-line or an efficient second-line therapy in CAD patients requiring treatment.

The association of antiphospholipid antibodies with pregnancy-related first time venous thrombosis - a population-based case-control study

In this population-based case-control study we explored the association of antiphospholipid antibodies with pregnancy-related venous thrombosis. From 1990 through 2003 615 pregnant women were identified at 18 hospitals in Norway with a diagnosis of first time VT. In 2006, 531 of 559 eligible cases and 1092 of 1229 eligible controls were invited for further investigations. The final study population comprised 313 cases and 353 controls, who completed a comprehensive questionnaire and donated a single blood sample, 3-16 years after index pregnancy. We report the results on lupus anticoagulant, anticardiolipin antibodies, and anti-ss(2) glycoprotein-1 antibodies alone, in combination, and with the contribution of the factor V Leiden and the prothrombin gene G20210A polymorphisms. Cut-off values for APAs were chosen according to current international consensus. 29 (9.3%) of the cases and 24 (6.8%) of the controls had at least one positive test for APAs (OR 1.4; 95% CI 0.8-2.5). Nine cases (2.8%) and no controls had more than one positive test (multi-positivity) for APAs. After excluding women with factor V Leiden or prothrombin polymorphisms, still 6 cases were multi-positive for APAs. We conclude that multi-positivity, but not single-positivity, for APAs was weakly associated with a history of ante- and postnatal VT.

Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms.

Background:  Pregnancy is associated with a 10‐fold increased risk of venous thrombosis (VT), with different risk profiles for the antenatal and postnatal periods. The purpose of this study was to assess the risk of pregnancy‐related VT associated with the factor (F)V Leiden and prothrombin gene G20210A polymorphisms.

Women's experiences in relation to stillbirth and risk factors for long-term post-traumatic stress symptoms: a retrospective study

Objectives (1) To investigate the experiences of women with a previous stillbirth and their appraisal of the care they received at the hospital. (2) To assess the long-term level of post-traumatic stress symptoms (PTSS) in this group and identify risk factors for this outcome. Design A retrospective study. Setting Two university hospitals. Participants The study population comprised 379 women with a verified diagnosis of stillbirth (≥23 gestational weeks or birth weight ≥500 g) in a singleton or twin pregnancy 5–18 years previously. 101 women completed a comprehensive questionnaire in two parts. Primary and secondary outcome measures The womens experiences and appraisal of the care provided by healthcare professionals before, during and after stillbirth. PTSS at follow-up was assessed using the Impact of Event Scale (IES). Results The great majority saw (98%) and held (82%) their baby. Most women felt that healthcare professionals were supportive during the delivery (85.6%) and showed respect towards their baby (94.9%). The majority (91.1%) had received some form of short-term follow-up. One-third showed clinically significant long-term PTSS (IES ≥ 20). Independent risk factors were younger age (OR 6.60, 95% CI 1.99 to 21.83), induced abortion prior to stillbirth (OR 5.78, 95% CI 1.56 to 21.38) and higher parity (OR 3.46, 95% CI 1.19 to 10.07) at the time of stillbirth. Having held the baby (OR 0.17, 95% CI 0.05 to 0.56) was associated with less PTSS. Conclusions The great majority saw and held their baby and were satisfied with the support from healthcare professionals. One in three women presented with a clinically significant level of PTSS 5–18 years after stillbirth. Having held the baby was protective, whereas prior induced abortion was a risk factor for a high level of PTSS. Trial registration The study was registered at http://www.clinicaltrials.gov, with registration number NCT 00856076.

Classification of stillbirths and risk factors by cause of death – a case‐control study

To investigate risk factors for stillbirths by cause, using the Causes of Death and Associated Conditions (CODAC) classification system for perinatal deaths.

A new, clinically oriented, unifying and simple placental classification system

OBJECTIVE At present there is no internationally accepted, clinically easy understandable, comprehensive morphological placental classification. This hampers international benchmarking and comparisons, and clinical research. STUDY DESIGN Internationally published criteria on morphological placental pathology were collected, standardized and focused into a comprehensive diagnosis category system. The idea was to create a clinically relevant placental pathology scheme related to major pathological processes. A system of nine main diagnostic categories (normal placenta included) was constructed. Pathologists and obstetricians discussed the mutual understanding of the wording in the reporting. The previously published diagnostic criteria were merged, structured and standardized. Through an interobserver correlation study on 315 placentas from intrauterine deaths and 31 controls (placentas from live births) the microscopic criteria in this classification system were tested on user-friendliness and reproducibility. RESULTS The clinical feedback has been very positive, focusing on the understandability and usefulness in patient follow-up. The interobserver agreement in the microscopic correlation study was in general good. The differences in agreement mainly reflected the degree of preciseness of the microscopic criteria, exemplified by excellent correlation in diagnosing acute chorioamnionitis. Maternal and fetal circulatory disorders need grading criteria and studies are needed to get more insight and clinical correlations of villitis and maturation disorders. CONCLUSION The clinically oriented, unifying and simple placental pathology classification system may work as a platform for standardization and international benchmarking. Further research is needed to define diagnostic criteria in staging and grading of some main diagnostic categories.

Incidence and risk factors of fetal death in Norway: a case-control study

Objective. To estimate incidence and risk factors for intrauterine fetal death (IUFD) in a Norwegian study‐population applying two different control groups. Design. Case‐control study. Setting. Two university hospitals in Oslo, Norway, January 1990 through December 2003. Sample. The cases: 377 women with IUFD. Controls: 1) all women delivering at the study‐hospitals in the period (facility‐based), and 2) 1 215 women with live births at one study‐hospital in the period (selected). Methods. Information from cases and selected controls was collected from medical records. Data on facility‐based controls were provided by the Medical Birth Registry of Norway. Data were analyzed using chi‐squared test and logistic regression. Main outcome measures. Incidence of IUFD and adjusted odds ratios of risk factors. Results. The incidence was 4.1/1 000 deliveries. Small‐for‐gestational age (SGA) and placental abruption were the strongest risk factors for IUFD. Hypertensive disorders were of low risk if not associated with SGA. Low to moderate risk factors were pre‐pregnancy diabetes mellitus, thyroid disease, placenta previa, gestational diabetes, smoking and twin pregnancy. Advanced maternal age was significant when compared with facility‐based controls. Risk estimates pointed in the same direction independent of control‐group. Hypertension appeared overestimated when using facility‐based controls, whereas advanced age was underestimated in the analysis among selected controls. Conclusion. SGA has a strong association with IUFD, and the risk of hypertensive disorders is mediated through SGA. The other risk factors, except placental abruption, are of low prevalence and of limited importance in the prevention of a relatively low incidence, although dramatic, event like IUFD.

The association of antiphospholipid antibodies with intrauterine fetal death: A case–control study

INTRODUCTION Over the past few decades it has been recognized that antiphospholipid antibodies are associated with pregnancy loss. Other placenta-mediated pregnancy complications have also been associated with the presence of antiphospholipid antibodies. Most studies have measured antiphospholipid antibodies near the time of the event investigated. OBJECTIVES To investigate the association of antiphospholipid antibodies and a history of intrauterine fetal death (IUFD) in a case-control design. MATERIALS AND METHODS A case-control study of 105 women with a history of IUFD after 22 gestational weeks and 262 controls with live births. The prevalence of lupus anticoagulant, anticardiolipin- and anti-β2-glycoprotein 1 antibodies were measured 3-18years after the event of IUFD. RESULTS Total 9.5% of women with a history of IUFD and 5.0% of controls had at least one positive test for antiphospholipid antibodies (OR 2.0; 95% confidence interval (CI) 0.9-4.8). Women with a history of IUFD were significantly more often positive for lupus anticoagulant compared to controls (OR 4.3; 95% CI 1.0-18.4). The association of lupus anticoagulant with a history of IUFD was confined to women positive for other antiphospholipid antibodies in addition to lupus anticoagulant. Being positive for anti-β2-glycoprotein 1 or anticardiolipin antibodies alone was not significantly associated with a history of IUFD. CONCLUSIONS Women with a history of IUFD after 22 gestational weeks were more often lupus anticoagulant positive. The association was confined to women with multiple positivity for antiphospholipid antibodies, although firm conclusions on the importance of multiple positivity cannot be made from this study.

Long-term impact of intrauterine fetal death on quality of life and depression: a case–control study

BackgroundIntrauterine fetal death (IUFD) is a serious incidence that has been shown to impact mothers’ psychological well-being in the short-term. Long-term quality of life (QOL) and depression after IUFD is not known. This study aimed to determine the association between intrauterine fetal death and long-term QOL, well-being, and depression.MethodsAnalyses were performed on collected data among 106 women with a history of intrauterine fetal death (IUFD) and 262 women with live births, 5–18 years after the event. Univariable and multivariable linear and logistic regression models were used to quantify the association between previous fetal death and long-term QOL, well-being and depression. QOL was assessed using the QOL Index (QLI), symptoms of depression using the Center for Epidemiological Studies Depression Scale (CES-D), and subjective well-being using the General Health Questionnaire 20 (GHQ-20).ResultsMore of the cases had characteristics associated with lower socioeconomic status and did not rate their health as good as did the controls. The QLI health and functioning subscale score was slightly but significantly lower in the cases than in the controls (22.3. vs 23.5, P = .023). The CES-D depressed affect subscale score (2.0 vs 1.0, P = 0.004) and the CES-D global score (7.4 vs 5.0, P = .017) were higher in the cases. Subjective well-being did not differ between groups (20.6 vs 19.4, P = .094). After adjusting for demographic and health-related variables, IUFD was not associated with global QOL (P = .674), subjective well-being (P = .700), or global depression score (adjusted odds ratio = 0.77, 95% confidence interval 0.37–1.57).ConclusionsWomen with previous IUFD, of which the majority have received short-term interventions, share the same level of long-term QOL, well-being and global depression as women with live births only, when adjusted for possible confounders.Trial registrationThe study was registered at http://www.clinicaltrials.gov, with registration number NCT 00856076.

Adaptation of trustworthy guidelines developed using the GRADE methodology: a novel five-step process.

BACKGROUND Adaptation of guidelines for use at the national or local level can facilitate their implementation. We developed and evaluated an adaptation process in adherence with standards for trustworthy guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, aiming for efficiency and transparency. This article is the first in a series describing our adaptation of Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for a Norwegian setting. METHODS Informed by the ADAPTE framework, we developed a five-step adaptation process customized to guidelines developed using GRADE: (1) planning, (2) initial assessment of the recommendations, (3) modification, (4) publication, and (5) evaluation. We developed a taxonomy for describing how and why recommendations from the parent guideline were modified and applied a mixed-methods case study design for evaluation of the process. RESULTS We published the adapted guideline in November 2013 in a novel multilayered format. The taxonomy for adaptation facilitated transparency of the modification process for both the guideline developers and the end users. We excluded 30 and modified 131 of the 333 original recommendations according to the taxonomy and developed eight new recommendations. Unforeseen obstacles related to acquiring a licensing agreement and procuring a publisher resulted in a 9-month delay. We propose modifications of the adaptation process to overcome these obstacles in the future. CONCLUSIONS This case study demonstrates the feasibility of a novel guideline adaptation process. Replication is needed to further validate the usefulness of the process in increasing the organizational and methodologic efficiency of guideline adaptation.