Eli Westerlund

Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study

Objective To estimate the risk of pulmonary embolism and venous thromboembolism in pregnant women after in vitro fertilisation. Design Cross sectional study. Setting Sweden. Participants 23 498 women who had given birth after in vitro fertilisation between 1990 and 2008 and 116 960 individually matched women with natural pregnancies. Main outcome measures Risk of pulmonary embolism and venous thromboembolism (identified by linkage to the Swedish national patient register) during the whole pregnancy and by trimester. Results Venous thromboembolism occurred in 4.2/1000 women (n=99) after in vitro fertilisation compared with 2.5/1000 (n=291) in women with natural pregnancies (hazard ratio 1.77, 95% confidence interval 1.41 to 2.23). The risk of venous thromboembolism was increased during the whole pregnancy (P<0.001) and differed between the trimesters (P=0.002). The risk was particularly increased during the first trimester, at 1.5/1000 after in vitro fertilisation versus 0.3/1000 (hazard ratio 4.22, 2.46 to 7.26). The proportion of women experiencing pulmonary embolism during the first trimester was 3.0/10 000 after in vitro fertilisation versus 0.4/10 000 (hazard ratio 6.97, 2.21 to 21.96). Conclusions In vitro fertilisation is associated with an increased risk of pulmonary embolism and venous thromboembolism during the first trimester. The risk of pulmonary embolism is low in absolute terms but because the condition is a leading cause of maternal mortality and clinical suspicion is critical for diagnosis, an awareness of this risk is important. Trial registration ClinicalTrials.gov NCT01524393.

Endogenous Estrogens Lower Plasma PCSK9 and LDL Cholesterol But Not Lp(a) or Bile Acid Synthesis in Women

Objective—Cholesterol and lipoprotein metabolism display pronounced gender differences. Premenopausal women have lower LDL and higher HDL cholesterol, whereas men display higher synthetic rates of bile acids and cholesterol. The effects of the administration of exogenous hormones to humans and animals indicate that these gender differences can often be explained by estrogens. We evaluated how increased levels of endogenous estrogens modulate cholesterol and lipoprotein metabolism in women. Methods and Results—We studied healthy women during initiation of in vitro fertilization using blood samples obtained when endogenous estrogens were low and high. Cholesterol in VLDL and LDL, but not in HDL, was reduced 20% when estrogens were high. Apolipoprotein B levels decreased 13%. Apolipoprotein A-I and triglyceride levels increased 8% and 37%, respectively, whereas lipoprotein(a) levels were unchanged. Circulating PCSK9, a suppressor of LDL receptors, was reduced 14% when estrogens were high. Serum markers of bile acid and cholesterol synthesis were unaltered. Growth hormone levels increased 3-fold when estrogens were high, whereas insulin-like growth factor-1 and fibroblast growth factor-21 concentrations were unaltered. Conclusion—In women, Apolipoprotein B-containing particles and circulating PCSK9 are reduced when endogenous estrogens are high, indicating that endogenous estrogens induce hepatic LDL receptors partly through a posttranscriptional mechanism. However, estrogens do not stimulate bile acid or cholesterol synthesis.

Detection of a procoagulable state during controlled ovarian hyperstimulation for in vitro fertilization with global assays of haemostasis.

INTRODUCTION Controlled ovarian hyperstimulation during in vitro fertilization (IVF) causes profound increments in serum estradiol which may influence haemostasis and the ovarian hyperstimulation syndrome. In the present study we investigated the effect of the standard IVF-stimulation protocol on coagulation and fibrinolysis as assessed by different global haemostatic assays. MATERIALS AND METHODS Blood samples were drawn from 31 women during the down-regulation phase when estradiol secretion is inhibited, and before egg retrieval, i.e. when estradiol levels are at supraphysiological levels, in the following called high level stimulation phase. Haemostasis was assessed during both treatment phases with 1) the calibrated automated thrombogram which measures thrombin generation, 2) overall haemostasis potential which measures fibrin formation and degradation and 3) fibrin gel permeability measurements which measures the quality of the fibrin network. RESULTS Estradiol increased from <150pg/mL to 5889pg/mL (range 1620-19500pg/mL). We found both increased thrombin generation as measured by the calibrated automated thrombogram (p<0.001) and an increase in overall haemostasis potential (p<0.001) from time of down-regulation to high level stimulation. CONCLUSIONS The assays used indicated procoagulable changes in haemostasis during in vitro fertilization. Further studies should evaluate their potential in the prediction of thrombosis and hyperstimulation.

Changes in von Willebrand factor and ADAMTS13 during IVF.

During IVF, circulating estradiol concentrations are strongly increased, and this may have direct effects on hemostasis. Elevated von Willebrand factor levels represent an important risk factor for arterial and venous thrombosis. ADAMTS13, also known as von Willebrand factor-cleaving protease, has an important regulatory function of von Willebrand factor but has not been studied during IVF. Blood was sampled from 31 women at maximal downregulation of estradiol synthesis using gonadotropin-releasing hormone analogues and during high-level stimulation of estradiol synthesis using follicle-stimulating hormone during the first phase of IVF. Von Willebrand factor antigen, von Willebrand factor ristocetin cofactor activity, factor VIII and ADAMTS13 antigen and activity levels in plasma were determined at the time of downregulation and at high-level stimulation. Estradiol increased from a mean of 154 pg/ml at downregulation to 5889 pg/ml at high-level stimulation (range 1620–19 500 pg/ml). Factor VIII increased from 0.96 ± 0.34 to 1.26 ± 0.41 kIU/l (P < 0.001). Von Willebrand factor antigen and activity increased from 0.75 ± 0.22 to 1.06 ± 0.40 kIU/l (P < 0.001) and from 0.83 ± 0.26 to 1.24 ± 0.48 kIU/l (P < 0.001), respectively. ADAMTS13 antigen decreased from 72.2 ± 13.5 to 67.9 ± 9.9% (P < 0.05, P = 0.01) and ADAMTS13 activity from 88.6 ± 18.3 to 80.8 ± 15.7% (P < 0.01). The increments in estradiol and factor VIII during IVF were paralleled by an increase in von Willebrand factor antigen and activity, and a decrease in circulating ADAMTS13 antigen and activity, respectively. This could in part explain why these patients have an increased risk of thrombotic events.

Detection of pulmonary embolism using repeated MRI acquisitions without respiratory gating: a preliminary study

Background Pulmonary embolism (PE) is a severe medical condition with non-specific clinical findings. Computed tomography angiography (CTA) using iodinated contrast agents is the golden standard for diagnosis, but many patients have contraindications for CTA. Purpose To investigate the diagnostic accuracy of repeated acquisitions of magnetic resonance imaging (MRI), without respiratory gating or breath holding, in diagnosing PE using CTA as the reference standard. Material and Methods Thirty-three patients with clinically suspected PE underwent MRI within 48 h after diagnostic CTA. A control group of 37 healthy participants underwent MRI and was matched with an equal number of negative CTA exams. The MRI protocol was based on free-breathing steady-state free precession producing 4.5 mm slices in axial, sagittal, and coronal planes. Instead of respiratory or cardiac gating five repetitive slices were obtained in each anatomical position to compensate for movement and artifacts. Clinical assessment including d-dimer and Well’s score was performed prior to imaging. One radiologist reviewed the CTA exams and two radiologists reviewed the MRI scans. Results All 70 MRI exams were of diagnostic quality and the total acquisition time for each MRI scan was 9 min 34 s. On CTA, 29 patients were diagnosed with PE and the MRI readers detected 26 and 27 of those, respectively. Specificity was 100% for both readers. Sensitivity was 90% and 93%, respectively. Inter-reader agreement using Cohen’s kappa was 0.97. Conclusion Our unenhanced MRI protocol shows a high sensitivity and specificity for PE, but further studies are required before considering it as a safe diagnostic test.

How to train radiology residents to diagnose pulmonary embolism using a dedicated MRI protocol

Background In recent years, magnetic resonance imaging (MRI) has been suggested as an alternative to computed tomography angiography (CTA) to diagnose pulmonary embolism (PE). In previous studies, only senior radiologists have been evaluated as reviewers. Purpose To investigate if radiology residents can be trained to review MRI regarding PE and to determine the learning curve effects. Material and Methods Four residents independently went through a training program consisting of 70 participants that had undergone steady-state free precession MRI. The individuals were randomized into ten training sessions. For each exam, the review time and presence or absence of embolus was recorded. After completing each session, the residents received feedback on diagnostic accuracy compared to a consensus reading by two specialists. The residents were also presented with the corresponding CTA. Results The review time was nearly halved (P = 0.0002) during the training program. Comparing the first three sessions with the last three sessions for all residents, the review time decreased from 5:22 min to 2:51 min. The inter-reader agreement improved for all residents during the training program reaching a clinically acceptable level after seven sessions. Conclusion Our study suggests that radiology residents can be trained to independently review MRI investigations regarding PE within a short training program. Similar training programs could be more extensively used as effective teaching method for residents.

Diagnosing upper extremity deep vein thrombosis with non-contrast-enhanced Magnetic Resonance Direct Thrombus Imaging: A pilot study

Diagnosing upper extremity deep vein thrombosis (UEDVT) can be challenging. Compression ultrasonography is often inconclusive because of overlying anatomic structures that hamper compressing veins. Contrast venography is invasive and has a risk of contrast allergy. Magnetic Resonance Direct Thrombus Imaging (MRDTI) and Three Dimensional Turbo Spin-echo Spectral Attenuated Inversion Recovery (3D TSE-SPAIR) are both non-contrast-enhanced Magnetic Resonance Imaging (MRI) sequences that can visualize a thrombus directly by the visualization of methemoglobin, which is formed in a fresh blood clot. MRDTI has been proven to be accurate in diagnosing deep venous thrombosis (DVT) of the leg. The primary aim of this pilot study was to test the feasibility of diagnosing UEDVT with these MRI techniques. MRDTI and 3D TSE-SPAIR were performed in 3 pilot patients who were already diagnosed with UEDVT by ultrasonography or contrast venography. In all patients, UEDVT diagnosis could be confirmed by MRDTI and 3D TSE-SPAIR in all vein segments. In conclusion, this study showed that non-contrast MRDTI and 3D TSE-SPAIR sequences may be feasible tests to diagnose UEDVT. However diagnostic accuracy and management studies have to be performed before these techniques can be routinely used in clinical practice.

Diffusion-weighted imaging in acute pulmonary embolism: a feasibility study

Background Magnetic resonance imaging (MRI) can be an alternative method to computed tomography angiography (CTA) for pulmonary embolism. Purpose To evaluate the feasibility of diffusion-weighted imaging (DWI) detecting acute pulmonary embolism (PE) in free-breathing humans. Material and Methods Twenty patients with PE verified by CTA and 20 controls were investigated with MRI (1.5 Aera, Siemens Healthcare). All sequences were performed in the transversal plane using free-breathing without gating. The protocol consisted of a two-dimensional steady-state free precession (SSFP) and a single-shot DWI echo-planar imaging sequence with a voxel resolution of 2 × 2 × 5 mm. Three b values were used: 50, 400, and 800 s/mm2. Images were analyzed in two orders: an open source analysis (OSA); and a blinded only DWI analysis (BDA) simulating clinical work. Results OSA of corresponding images showed 370 findings on CTA (i.e. one elongated emboli could be represented in multiple images). SSFP identified 237 of those (64%). DWI with b values of 50, 400, and 800 identified 327 (88%), 245 (66%), and 138 (37%), respectively. In BDA we found 160 true emboli (according to CTA) on b50, 78 on b400, and 54 on b800. Fifty-two of these findings at the subsegmental level could be correlated to PE on CTA but were not visible on SSFP. Conclusions DWI has a high sensitivity for detecting PE but suffers from poor specificity. It could potentially be used as an eye catcher, i.e. where to look for PE in other MRI sequences.