Planning Pregnancy and Birth in Women with Inherited Bleeding Disorders.

Inherited bleeding disorders are characterized by a diverse clinical phenotype within and across specific diagnoses. von Willebrand disease (VWD), hemophilia A, and hemophilia B comprise 95 to 97% of inherited bleeding disorders, with the remaining 3 to 5% attributed to rare bleeding disorders, including congenital fibrinogen disorders, factor deficiencies (affecting FII, FV, FV + FVIII, FVII, FX, FXI, and FXIII), and platelet function defects. The pregnancy, birth, and the puerperium may be adversely influenced in the setting of an inherited bleeding disorder depending on its type and clinical phenotype. Obstetric hemostatic challenges may sometimes also unmask the presence of a previously unknown inherited bleeding disorder. This review aims to address the approach to pregnancy and birth in the context of an inherited bleeding disorder and highlights the significance of multidisciplinary input into the care of these women.

Distinct maternal and fetal pregnancy outcomes in women with sickle cell disease can be predicted using routine clinical and laboratory data.

We aimed to identify risk factors for adverse outcomes in pregnancies of women with sickle cell disease (SCD) and develop risk prediction models. Models were derived from a retrospective cohort of pregnant women with SCD and constructed using generalised estimating equation logistic regression, with clustering by woman. Maternal event(s) consisted of acute anaemia; cardiac, pulmonary, hepatobiliary, musculoskeletal, skin, splenic, neurological or renal complications, multi-organ failure, venous thromboembolism, admission-requiring vaso-occlusive events (VOE), red cell transfusion, mortality or hypertensive disorder of pregnancy. Fetal events included preterm birth, small-for-gestational-age or perinatal mortality. Of 199 pregnancies, 71% and 45% resulted in adverse maternal and fetal outcomes respectively. Low first-trimester haemoglobin, admission-requiring VOE in the year before pregnancy, multiple transfusions before pregnancy, SCD genotype and previous cardiac complications predicted maternal risk. Younger age and SCD genotype allowed early prediction of fetal risk (model-F1). Adding maternal event(s) and high lactate dehydrogenase enabled re-assessment of fetal risk with advancing gestation (model-F2). Models were well calibrated and moderately discriminative for maternal outcome (c-statistic 0·81, cross-validated value 0·79) and fetal outcome (model-F1 c-statistic 0·68, cross-validated value 0·65; model-F2 c-statistic 0·72, cross-validated value 0·68). The models will allow early identification of women with SCD at high risk of adverse events, permitting early targeted interventions and ongoing fetal risk re-assessment enabling intensification of surveillance and optimisation of delivery timing.

Haemostatic and thrombo-embolic complications in pregnant women with COVID-19: a systematic review and critical analysis.

BACKGROUND: As pregnancy is a physiological prothrombotic state, pregnant women may be at increased risk of developing coagulopathic and/or thromboembolic complications associated with COVID-19. METHODS: Two biomedical databases were searched between September 2019 and June 2020 for case reports and series of pregnant women with a diagnosis of COVID-19 based either on a positive swab or high clinical suspicion where no swab had been performed. Additional registry cases known to the authors were included. Steps were taken to minimise duplicate patients. Information on coagulopathy based on abnormal coagulation test results or clinical evidence of disseminated intravascular coagulation (DIC), and on arterial or venous thrombosis, were extracted using a standard form. If available, detailed laboratory results and information on maternal outcomes were analysed. RESULTS: One thousand sixty-three women met the inclusion criteria, of which three (0.28, 95% CI 0.0 to 0.6) had arterial and/or venous thrombosis, seven (0.66, 95% CI 0.17 to 1.1) had DIC, and a further three (0.28, 95% CI 0.0 to 0.6) had coagulopathy without meeting the definition of DIC. Five hundred and thirty-seven women (56%) had been reported as having given birth and 426 (40%) as having an ongoing pregnancy. There were 17 (1.6, 95% CI 0.85 to 2.3) maternal deaths in which DIC was reported as a factor in two. CONCLUSIONS: Our data suggests that coagulopathy and thromboembolism are both increased in pregnancies affected by COVID-19. Detection of the former may be useful in the identification of women at risk of deterioration.

Modal instabilities in high power fiber laser oscillators.

Transverse mode competition and instabilities in high-power fiber oscillators have been studied experimentally by monitoring the dynamic power exchanges and characteristic frequencies of the transmitted fundamental mode (FM) and scattered high-order modes (HOMs) of the fiber laser cavity under CW and pulsed pumping. The FM and HOM power evolution indicates the presence of two competing effective laser cavities which result in rich output dynamics and full chaotic operation. The thermal and inversion related contributions to the observed instabilities have been identified by monitoring the associated characteristic instability frequencies under pulsed pumping. It is shown that in the transient regime, both inversion and thermal effects contribute successively to the observed power instabilities. Increasing the pump power leads to full chaotic response through an interplay between transverse and longitudinal mode instabilities.

Genetic polymorphism of KIR2DL4 in the Polish population.

The KIR2DL4 gene is characterized by alleles with either 9 or 10 consecutive adenines in exon 7, which encodes the transmembrane domain. The 9A variant produces either a protein with a truncated cytoplasmic tail or one lacking the transmembrane region. This causes a lack of KIR2DL4 expression. In contrast, 10A alleles encode receptors that may be expressed at the cell surface. We tested 438 healthy individuals for polymorphism of the KIR2DL4 gene. KIR2DL4 9A/10A alleles were distinguished by the high resolution melting (HRM) method, and restriction fragment length polymorphism (RFLP) was used for genotyping of three other single nucleotide polymorphisms (SNPs) spanning the near vicinity of the poly-adenine fragment. We found a weak difference between males and females in 9769 C/A genotypes and alleles. In addition, we observed complete linkage disequilibrium (LD) between 9A insertion/deletion in the 9620 position and the 9571T/C position of the gene (r(2) = 1) both in females and males and almost complete LD with the 9797G/A position (r(2) = 0.963 for females and r(2) = 0.892 for males). Most importantly, we detected, in a group of fertile women, a high frequency (30.2%) of homozygosity for the defective 9A variant, which suggests that KIR2DL4 as a functional cell surface receptor is not absolutely necessary for reproduction. On the other hand, lower representation of 10A/10A homozygotes and high frequency of 10A/9A heterozygotes indicates a need for both cell membrane-anchored and soluble KIR2DL4 molecules. Finally, cost-reducing RFLP instead of HRM is proposed for typing 9A and 10A variants.

Identification and treatment of iron-deficiency anemia in pregnancy and postpartum: A systematic review and quality appraisal of guidelines using AGREE II.

BACKGROUND: Several international guidelines provide recommendations for the optimal management of iron-deficiency anemia (IDA) in the pregnant and postpartum populations. OBJECTIVES: To review the quality of guidelines containing recommendations for the identification and treatment of IDA in pregnancy and postpartum using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument and to summarize their recommendations. SEARCH STRATEGY: PubMed, Medline, and Embase databases were searched from inception to August 2, 2021. A web engine search was also performed. SELECTION CRITERIA: Clinical practice guidelines that focused on the management of IDA in pregnancy and/or postpartum populations were included. DATA COLLECTION AND ANALYSIS: Included guidelines were appraised using AGREE II independently by two reviewers. Domain scores greater than 70% were considered high-quality. Overall scores of six or seven (out of a possible seven) were considered high-quality guidelines. Recommendations on IDA management were extracted and summarized. MAIN RESULTS: Of 2887 citations, 16 guidelines were included. Only six (37.5%) guidelines were deemed high-quality and were recommended by the reviewers. All 16 (100%) guidelines discussed the management of IDA in pregnancy, and 10 (62.5%) also included information on the management of IDA in the postpartum period. CONCLUSIONS: The complex interplay of racial, ethnic, and socioeconomic disparities was rarely addressed, which limits the generalizability of the recommendations. In addition, many guidelines failed to identify barriers to implementation, strategies to improve uptake or iron treatment, and resource and cost implications of clinical recommendations. These findings highlight important areas to target future work.

Hematologic characteristics and coagulopathy in pregnancy with COVID-19 succeeding the first wave: a multicenter retrospective cross-sectional study.

Background: Early reports have demonstrated an association of COVID-19 infection during pregnancy and postpartum period with coagulopathy and bleeding complications and indicated that pregnant people with COVID-19 are more likely to experience coagulopathy and venous thromboembolism. A recent report concerning such complications during the first wave of the pandemic was reassuring; however, no publications have evaluated these issues in the context of increased illness severity with the emergence of SARS-CoV-2 variants of concern. Objectives: We performed a retrospective, multinational cohort study in Canada, Romania, and the United Kingdom, aiming to provide a comprehensive analysis of the hematologic test characteristics of pregnancies affected by COVID-19 after the first wave of the pandemic. Results: Three-hundred-seventy patients were evaluated. Markers of inflammation and endothelial dysfunction were significantly elevated, in keeping with observations in the nonpregnant population. Reassuringly, despite more severe disease noted in succeeding waves of the pandemic, there was no significant evidence of COVID-19-associated coagulopathy, and overall, no association was demonstrated between isolated coagulation abnormalities and bleeding risk. Notably, fibrinogen below 2g/L was again linked with the risk of postpartum hemorrhage. Finally, venous thromboembolism risk was low but noted more frequently in those with severe illness despite thromboprophylaxis. Conclusion: Our findings add valuable insights into the nature of hematologic test characteristics, bleeding, and thrombotic complications for those affected with COVID-19 in pregnancy, reassuring readers of the low incidence of bleeding and thrombotic complications but inviting further debate as to the degree of thromboprophylaxis that may benefit the subgroup with severe disease.

Report of the ISTH registry on pregnancy and COVID-19-associated coagulopathy (COV-PREG-COAG).

Background: Concerns about COVID-19-associated coagulopathy (CAC) in pregnant individuals were raised in early pandemic. Methods: An ISTH-sponsored COVID-19 coagulopathy in pregnancy (COV-PREG-COAG) international registry was developed to describe incidence of coagulopathy, VTE, and anticoagulation in this group. Results: All pregnant patients with COVID-19 from participating centers were entered, providing 430 pregnancies for the first pandemic wave. Isolated abnormal coagulation parameters were seen in 20%; more often with moderate/severe disease than asymptomatic/mild disease (49% vs 15%; p < 0.0001). No one met the ISTH criteria for disseminated intravascular coagulopathy (DIC), though 5/21 (24%) met the pregnancy DIC score. There was no difference in antepartum hemorrhage (APH) with asymptomatic/mild disease versus moderate/severe disease (3.4% vs 7.7%; p = 0.135). More individuals with moderate/severe disease experienced postpartum hemorrhage (PPH) (22.4% vs 9.3%; p = 0.006). There were no arterial thrombotic events. Only one COVID-associated venous thromboembolism (VTE) was reported. Conclusions: Low rates of coagulopathy, bleeding, and thrombosis were observed among pregnant people in the first pandemic wave.

High-peak-power, high-energy, high-average-power pulsed fiber laser system with versatile pulse duration and shape.

We present a pulsed fiber laser system with average power up to 265 W, pulse energy up to 10.6 mJ, pulse duration adjustable in the range 500 ps-500 ns, repetition rate fully controllable from single-shot operation up to 1 MHz, and the ability to control peak power independently of pulse energy. The system has a compact, all-spliced construction. Such a versatile laser will have wide applications in materials processing.

[Pancreatojejunostomy in pancreatic head resection using a resorbable monofilament for internal drainage of the anastomosis - clinical experience and perioperative results]. / Pankreatojejunostomie bei der Pankreaskopfresektion unter Verwendung eines resorbierbaren monofilen Fadens zur inneren Schienung der Anastomose - klinische Erfahrungen und perioperative Ergebnisse.

BACKGROUND: Pancreatic fistulas are relevant in perioperative outcome, morbidity and mortality after pancreatic head resection. We analysed the potential benefit of an internal pancreatic duct draining technique by a resorbable monofilament suture if performing a two-layer duct-to-mucosa pancreatojejunostomy. PATIENTS AND METHODS: From 2006 to 2010, 139 pancreatic head resections were performed in our department (124 pylorus-preserving, 15 Whipple). Indications for surgery were malignancies (n = 97), chronic pancreatitis (n = 24) or others (n = 18). In 64 cases, internal drainage of the pancreatic anastomosis was performed as described. Perioperative results were evaluated by the ISGPF classification (International Study Group for Pancreatic Fistula, type A-C) and Accordion classification (degree 1-6). RESULTS: Pancreatic anastomosis was performed in 99 cases as pancreatojejunostomy and in 41 cases as pancreatogastrostomy. Morbidity (Accordion 1-6) was 48 %, and mortality was 5.8 %. Pancreatic fistulas (A-C) occurred in 27 (19.4 %) cases. Only one patient died as a direct consequence of a pancreatic fistula (type C fistula after pylorus-preserving pancreatic head resection and pancreatogastrostomy). In the subgroup of patients with a two-layer duct-to-mucosa pancreatojejunostomy with internal pancreatic duct drainage by a resorbable monofilament suture (n = 64), a pancreatic fistula occurred in 20.3 % (n = 13). According to the ISGPF classification, they were type A (n = 10), type B (n = 2) and type C fistulas (n = 1). In this subgroup with pancreatic duct drainage, morbidity (Accordion 1-6) was 55 % (n = 35) and mortality (Accordion 6) was 6.2 % (n = 4). Complications due to the pancreatic duct drainage were not observed. CONCLUSION: Internal drainage of the duct-to-mucosa pancreatojejunostomy using monofilament suture material is a safe and feasible method. Pancreatic fistula occurred in 20 % both in the entire group as well as in subgroups with or without pancreatic duct drainage. A reduction of the rate of pancreatic fistula could not be achieved by internal drainage of the pancreatojejunostomy.

Outcomes of Pregnancy in Women With Bioprosthetic Heart Valves With or Without Valve Dysfunction.

BACKGROUND: Although pregnancy outcomes in women with normally functioning bioprosthetic valves (BPVs) are often good, structural valve dysfunction (SVD) may adversely affect pregnancy outcomes, but this has not been studied. OBJECTIVES: The aim of this study was to examine outcomes in pregnant women with BPVs and the association with SVD. METHODS: Pregnancy outcomes in women with BPVs were prospectively collected. Adverse maternal cardiac events (CEs) included cardiac death or arrest, sustained arrhythmia, heart failure, thromboembolism, and stroke. Adverse fetal events were also studied. Determinants of adverse events were examined using logistic regression. RESULTS: Overall, 125 pregnancies in women with BPVs were included, 27% with left-sided and 73% with right-sided BPV. SVD was present in 27% of the pregnancies (44% with left-sided BPVs vs 21% with right-sided BPVs; P = 0.009). CEs occurred in 13% of pregnancies and were more frequent in women with SVD compared with those with normally functioning BPVs (26% vs 8%; P = 0.005). CEs were more common in women with left-sided BPVs with SVD vs normally functioning BPVs (47% vs 5%; P = 0.01) but not in women with right-sided BPVs (11% in those with SVD vs 8% in those without SVD; P = 0.67). Left-sided SVD (P = 0.007), maternal age >35 years (P = 0.001), and a composite variable of "high-risk" features (P = 0.006) were predictors of CEs. Fetal events occurred in 28% of pregnancies. CONCLUSIONS: In this cohort of young women with BPVs, SVD was present in 27% at the first antenatal visit and negatively affected pregnancy outcomes. In particular, SVD of left-sided BPVs was associated with high rates of adverse outcomes.

Frequencies of killer immunoglobulin-like receptor genotypes influence susceptibility to spontaneous abortion.

Natural killer (NK) cells are the most abundant lymphocyte population in the decidua. These cells express killer immunoglobulin-like receptors (KIRs), which upon recognition of HLA class I molecules on trophoblasts may either stimulate NK cells (activating KIRs) or inhibit them (inhibitory KIRs) to produce soluble factors necessary for the maintenance of pregnancy. KIR genes exhibit extensive haplotype polymorphism; individuals differ in both the number and kind (activating vs. inhibitory) of KIR genes. This polymorphism affects NK cell reactivity and susceptibility to diseases, including gynecological disorders. Therefore we KIR-genotyped 149 spontaneously aborting women and 117 control multiparae (at least 2 healthy-born children). Several genotypes (i.e. combinations of various KIR genes) were differently distributed among the patients and control subjects. Differences were observed in the numbers and the ratios of activating to inhibitory KIRs between patients and healthy women: (i) genotypes containing 6 activating KIR genes were less frequent and those containing 6 inhibitory KIR genes were more frequent in patients than in control subjects, and (ii) an excess of inhibitory KIRs (activating-to-inhibitory KIR gene ratios of 0.33 to 0.83) was associated with miscarriage, whereas ratios close to equilibrium (0.86-1.25) seemed to be protective. In addition, the results suggest for the first time that sporadic and recurrent spontaneous abortions as well as miscarriage in the presence or absence of autoantibodies may have different KIR genotypic backgrounds.

Adaptive pulse shape control in a diode-seeded nanosecond fiber MOPA system.

We demonstrate active shaping of the driving electrical pulses to a laser diode in order to compensate for the pulse shaping effects of gain saturation in an Yb doped fiber amplifier cascade and to allow the generation of user defined customized output pulse shapes. In particular we demonstrate the generation of square output pulses, which have the potential to significantly increase the maximum pulse energy extractable from an amplifier before the peak power reaches the threshold for SRS, and for high efficiency frequency conversion.

Optimisation of cascaded Yb fiber amplifier chains using numerical-modelling.

We show that it is possible to adapt existing software packages developed originally for modeling telecommunication devices and systems to reliably predict and optimize the performance of high-power Ytterbium-doped fiber amplifier and laser systems. The ready availability of a flexible, user-friendly design tool should be of considerable practical interest to scientists and engineers working with this important new laser technology since Ytterbium amplifier and amplifier cascades are often difficult to optimize experimentally due to the three-level nature of the Ytterbium laser transition. As examples of the utility and accuracy of the software, as well as the complexity of the systems and amplifier properties that can be successfully modeled, we present a comparison of experimental and theoretical results for individual core and cladding pumped amplifiers, and also for an ultra-short pulse four-stage amplifier system optimized both to provide a broad gain bandwidth and to minimize nonlinear effects. We also show how high energy 100 ns pulses with complex user definable temporal profiles can be created in a gain-saturated amplifier by suitable pre-shaping of the low-energy input pulses. Furthermore, with appropriate modifications the same software package can be applied to fiber amplifiers based on other rare-earth elements and glass hosts.

Cladding pumped Ytterbium-doped fiber laser with holey inner and outer cladding.

We have fabricated an ytterbium doped all-glass double-clad large mode area holey fiber. A highly efficient cladding pumped single transverse mode holey fiber laser has been demonstrated, allowing continuous-wave output powers in excess of 1W with efficiencies of more than 80%. Furthermore both Q-switched and mode-locked operation of the laser have been demonstrated.

Soliton transmission and supercontinuum generation in holey fiber, using a diode pumped Ytterbium fiber source.

We report linear dispersion compensation, soliton pulse formation, soliton compression, and ultra-broad supercontinuum generation in a holey fiber with anomalous dispersion at wavelengths above 800nm. The holey fiber was seeded with ultrashort pulses from a diode pumped, Ytterbium (Yb)-doped fiber source operating at 1.06 microm. The results highlight the compatibility of the rapidly developing holey fiber technology with short pulse Yb-doped fiber lasers for wide application.