The presence of lupus nephritis additionally increases the risk of preeclampsia among pregnant women with systemic lupus erythematosus.

INTRODUCTION: Pregnant women with systematic lupus erythematosus (SLE) have an increased risk of obstetric complications, such as preeclampsia and premature births. Previous studies have suggested that renal involvement could further increase the risk for adverse obstetric outcomes. Aims: The aim of this study was to compare the obstetric outcomes in a Swedish cohort of patients with SLE with and without lupus nephritis (LN). PATIENTS AND METHODS: The study was conducted as a retrospective observational study on 103 women with SLE, who gave birth at the Karolinska University Hospital between the years 2000-2017. Thirty-five women had previous or active LN and 68 women had non-renal lupus. Data was collected from digital medical records. The outcomes that were analysed included infants born small for gestational age (SGA), premature birth, preeclampsia, SLE- or nephritis flare and caesarean section. RESULTS: Women with LN, both with previous and with renal flare during pregnancy suffered from pre-eclampsia more often compared to women with non-renal lupus (25.7% vs 2.9%, p = 0.001) and this complication was associated with premature birth (p = 0.021) and caesarean section (p = 0.035). CONCLUSIONS: Lupus nephritis is a significant risk factor for adverse obstetric outcomes in women with SLE, including preeclampsia. Those patients could benefit from more frequent antenatal controls and more vigorous follow-up.

The impact of cardiovascular diseases on maternal deaths in the Nordic countries.

INTRODUCTION: Cardiovascular diseases have become increasingly important as a cause of maternal death in the Nordic countries. This is likely to be associated with a rising incidence of pregnant women with congenital and acquired cardiac diseases. Through audits, we aim to prevent future maternal deaths by identifying causes of death and suboptimal factors in the clinical management. MATERIAL AND METHODS: Maternal deaths in the Nordic countries from 2005 to 2017 were identified through linked registers. The national audit groups performed case assessments based on hospital records, classified the cause of death, and evaluated the standards of clinical care provided. Key messages were prepared to improve treatment. RESULTS: We identified 227 maternal deaths, giving a maternal mortality rate of 5.98 deaths per 100 000 live births. The most common cause of death was cardiovascular disease (n = 36 deaths). Aortic dissection/rupture, myocardial disease, and ischemic heart disease were the most common diagnoses. In nearly 60% of the cases, the disease was not recognized before death. In more than half of the deaths, substandard care was identified (59%). In 11 deaths (31%), improvements to care that may have made a difference to the outcome were identified. CONCLUSIONS: Between 2005 and 2017, cardiovascular diseases were the most common causes of maternal deaths in the Nordic countries. There appears to be a clear potential for a further reduction in these maternal deaths. Increased awareness of cardiac symptoms in pregnant women seems warranted.

Obstetric and neonatal outcomes in pregnant women treated with high-dose thromboprophylaxis: a retrospective, single-center study.

INTRODUCTION: It is well established that women with very high risk of developing antenatal thrombosis benefit from high-dose thromboprophylaxis, however data on outcomes and the safety and efficacy of thromboprophylaxis are scarce. The aim of the study was to evaluate the safety and effectiveness of the Swedish guidelines for high-dose thromboprophylaxis and the obstetric outcomes in a single-center patient cohort. PATIENTS AND METHODS: Forty-seven women treated at the Department of Obstetrics and Gynecology, Karolinska University Hospital, Solna, Sweden, between 2004 and 2017 were included in this retrospective study. Data on treatment, obstetric, and neonatal outcomes and medical history were collected. Data derived from the Swedish Medical Birth Registry on women giving birth in Stockholm County 2004-2016 were used as controls. The protocol of the study was approved by the Regional Ethics Committee in Stockholm, Sweden. RESULTS: The initial thromboprophylaxis dose was 5000 IU dalteparin twice daily. No patient developed ablatio placentae or preeclampsia. One patient suffered antenatal muscle vein thrombosis. Six patients (12.7%) suffered postpartum hemorrhage (PPH); however only one patient had severe PPH. Forty-eight children were born. Three children (6%) were diagnosed with intrauterine growth retardation, five (10%) were born small for gestational age and seven (15%) were born premature, the majority of which (except for two premature) to women with thrombophilia. DISCUSSION: High-dose thromboprophylaxis was effective and safe. The incidence of preeclampsia and ablatio was lower than in controls; however, neonatal outcomes were worse, especially among mothers with thrombophilia. Due to the diversity of the thrombophilic traits, no thrombophilia-specific conclusion could be drawn. Stricter adherence to the guidelines could further decrease the risk for bleeding, whereas more frequent antenatal controls could possible improve neonatal outcomes.

Natural killer cells and type II interferon in Ro/SSA and La/SSB autoantibody-exposed newborns at risk of congenital heart block.

OBJECTIVE: Congenital heart block (CHB) with immune cell infiltration develops in the fetus after exposure to maternal Ro/La autoantibodies. CHB-related serology has been extensively studied, but reports on immune-cell profiles of anti-Ro/La-exposed neonates are lacking. In the current study, we characterised circulating immune-cell populations in anti-Ro/La+mothers and newborns, and explored potential downstream effects of skewed neonatal cell populations. METHODS: In total, blood from mothers (n=43) and neonates (n=66) was sampled at birth from anti-Ro/La+ (n=36) and control (n=30) pregnancies with or without rheumatic disease and CHB. Flow cytometry, microarrays and ELISA were used for characterising cells and plasma. RESULTS: Similar to non-pregnant systemic lupus erythematosus and Sjögren-patients, anti-Ro/La+mothers had altered B-cell subset frequencies, relative T-cell lymphopenia and lower natural killer (NK)-cell frequencies. Surprisingly, their anti-Ro/La exposed neonates presented higher frequencies of CD56dimCD16hi NK cells (p<0.01), but no other cell frequency differences compared with controls. Type I and II interferon (IFN) gene-signatures were revealed in neonates of anti-Ro/La+ pregnancy, and exposure of fetal cardiomyocytes to type I IFN induced upregulation of several NK-cell chemoattractants and activating ligands. Intracellular flow cytometry revealed IFNγ production by NK cells, CD8+ and CD4+ T cells in anti-Ro/La exposed neonates. IFNγ was also detectable in their plasma. CONCLUSION: Our study demonstrates an increased frequency of NK cells in anti-Ro/La exposed neonates, footprints of type I and II IFN and an upregulation of ligands activating NK cells in fetal cardiac cells after type I IFN exposure. These novel observations demonstrate innate immune activation in neonates of anti-Ro/La+pregnancy, which could contribute to the risk of CHB.

Changes in the plasma microvesicle proteome during the ovarian hyperstimulation phase of assisted reproductive technology.

The incidence of pulmonary and venous thromboembolism is increased during the first trimester of pregnancies after assisted reproductive technology (ART) compared to spontaneous conception. We previously found that haemostatic plasma variables changed but within normal limits during controlled ovarian hyperstimulation (COH) concomitant with a major increase in plasma microvesicles (MVs) and markers indicating cell activation. We now explored the proteome of these MVs. Thirty-one women undergoing ART were blood sampled at down-regulation (DR) of oestrogen and at high level stimulation (HLS) with its 10-100-fold increased oestrogen level. Samples were analysed by liquid chromatography and tandem mass spectrometry to identify and quantify the proteome. We identified 306 proteins in the MVs and 72 had changed significantly at HLS compared to DR and more than 20% of them were associated with haemostasis. Thus, proteins related to both haemostasis and complement activation altered in plasma MVs in parallel with MV activation during COH. This needs to be further explored in the clinical context.

Management and outcomes of newborns at risk for inherited antithrombin deficiency.

BACKGROUND: As levels of antithrombin (AT) are low at birth, diagnosing inherited AT deficiency in newborns is challenging. In Stockholm, Sweden, pregnant women with known AT deficiency are referred to the Karolinska University Hospital, where local guidelines for management of newborns at risk of inherited AT deficiency have been established. Data on pregnancy, obstetric, and neonatal outcomes are recorded in a registry. OBJECTIVES: We aimed to evaluate the current practice at the Karolinska University Hospital for managing delivery of newborns at risk for AT deficiency, the predictive value of AT levels at birth, and the neonatal outcomes of newborns with AT deficiency. PATIENTS/METHODS: This was an observational, retrospective study. All children born to mothers with AT deficiency at the Karolinska University Hospital 2003-2018 were identified from the registry and included in the study. Data were collected from the medical records and the registry. AT activity was measured postnatally and after 6 months of age. RESULTS: The total study cohort included 41 newborns. There was a significant association between low AT values postnatally and after 6 months of age (P = .001). Half (21/41) of the children were diagnosed with AT deficiency; two suffered from sinus thrombosis, which presented at 10 days of age. Both children with sinus thrombosis were delivered using vacuum extraction. CONCLUSIONS: The current practice of testing newborns can in most cases predict inherited AT deficiency. The risk for thrombosis during the neonatal period is enhanced by the use of instrumental delivery.

[Program for clinical care of immune thrombocytopenic purpura in pregnancy]. / Immunologisk trombocytopen purpura ­ vård under graviditet - Vårdprogram utvärderat i en svensk studie.

A program for care of women with immune thrombocytopenic purpura (ITP) with the recommendation to avoid treatment if platelets were >20 × 109/l during pregnancy, with the target level 100 × 109/l at delivery, was introduced. Treatment should be given with intravenous immunoglobulin (IVIG) or corticosteroids. Out of 75 pregnancies with ITP, 39 percent were treated and the treatment period was shorter with IVIG. Blood loss at delivery was similar as the reference population. Epidural analgesia was given in only 17 percent of the vaginal deliveries. Twenty-three percent of the infants had platelet counts less than 50 × 109/l during the first days after birth. If the women had prior neonatal trombocytopenia 63 percent got a child with thrombocytopenia and 40 percent of those with platelets <20 × 109/l during pregnancy had a child with thrombocytopenia. Multidisciplinary care of pregnant women with ITP including obstetricians, hematologists and neonatologists is recommended.

Blood inflammatory and endothelial markers in women with von Willebrand disease.

INTRODUCTION: VWD-affected females often experience menorrhagia. Periodical fluctuations of the sex steroids during the menstrual cycle cause changes both in the coagulation and immune system. The aim of the current study was to assess the changes in selected inflammatory and endothelial markers in women with VWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with corresponding data from healthy controls. MATERIALS AND METHODS: The study group included 12 VWD-affected females with regular menstrual cycle, with none of them being prescribed hormone treatment. They were not pregnant or breastfeeding. The control group consisted of 102 healthy females, matched for age and BMI. RESULTS: Within the VWD group, endostatin was higher during the follicular phase, compared to the luteal phase, although the difference was not significant (p = 0.062). sICAM-1 and IL-6 were higher in VWD-affected females, compared to the controls, sVCAM-1, cathepsin S and sP-selectin were lower (p<0.003 for all cases). The pattern was constant throughout the menstrual cycle. CONCLUSIONS: Higher levels of endostatin during early follicular phase could potentially predispose women with VWD to the development of heavy menstrual bleeding, due to antiangiogenic properties and ability to suppress several coagulation factors. Lower p-selectin levels in VWD group, compared to controls, may also contribute to the bleeding tendency. Changes in other proteins, involved in angiogenesis are hypothetically related to the formation of angiodysplasia-common complication of VWF deficiency. The latter statement requires confirmation in larger studies.

Thrombin generation during a regular menstrual cycle in women with von Willebrand disease.

Fluctuations of the sex steroids during the menstrual cycle might significantly influence hemostasis. This association, derived from a number of the observations on healthy women, is yet to be described in females affected by bleeding disorders. The aim of the current study was to assess the changes in hemostatic variables in women with vWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with healthy controls. The study group included 12 vWD-affected females with regular menstrual cycle, with none of them being prescribed any hormonal treatment. The control group consisted of 102 healthy females, matched for age and BMI. Within the vWD group FVIII and FX were both significantly higher during follicular phase than in luteal phase (p = 0.013 and p = 0.033 respectively). AT, FII, FVII and FX were higher in women with vWD, compared with controls during both phases of the menstrual cycle (p < 0.0005, p < 0.0005, p = 0.001 and p < 0.0005). In women with vWD, lag time and time to peak were prolonged during both phases of the menstrual cycle(p < 0.0005), while peak thrombin concentration was reduced (p = 0.003 and p = 0.002 during follicular and luteal phase respectively) compared to healthy peers. Lower levels of FVIII and FX during luteal phase may predispose women to the development of the menorrhagia - common complication of vWD. Women with vWD need more time to reach the peak thrombin concentration, while the latter still remains less than in healthy women. Higher levels of AT in vWD-affected females, compared to controls, may also contribute to the existing bleeding tendency in this cohort.

Obstetric antiphospholipid syndrome.

The present clinical and laboratory classification criteria for antiphospholipid syndrome (APS) were established in Sydney, Australia, in 2006. In this review, we focus on the obstetric subset of APS (OAPS), defined by persistent positivity for antiphospholipid antibodies together with either early recurrent pregnancy loss, early fetal death, stillbirth or premature birth <34 gestational weeks due to pre-eclampsia, eclampsia and placental insufficiency. It is important to diagnose these cases since most women suffering from OAPS can, when given appropriate treatment, have successful pregnancies. Furthermore, patients with OAPS may, depending on the antibody profile, be at enhanced risk of thrombotic events later in life. We present an update on the present knowledge of possible underlying pathogenesis, risk factors and risk estimations for adverse pregnancy outcomes before and during pregnancy, current treatment concepts, and long-term outcomes for women with OAPS and their children.

Enhanced Th1 and inflammatory mRNA responses upregulate NK cell cytotoxicity and NKG2D ligand expression in human pre-eclamptic placenta and target it for NK cell attack.

PROBLEM: Pre-eclampsia (PE), a severe human pregnancy disorder, is associated with exaggerated systemic inflammation, enhanced cytokine production, and increased shedding of microvesicles leading to endothelial dysfunction, coagulopathy, and extensive placenta destruction. The cause of PE is still unclear. Evidence suggests that its origin lies in the placenta and that the maternal immune system is involved. A shift in cytokine production in PE pregnancy promotes NK cell activation, suggested to be important in PE pathogenesis. In line with this suggestion, we studied NK cell cytotoxicity in peripheral blood of PE patients and controls and the mRNA expression of cytokines and of the NKG2D receptor and its ligands MICA/B and ULBP1-3 in PE- and normal placenta. METHOD OF STUDY: The cytotoxic capacity of peripheral blood NK cells was analyzed using K562 target cells. The cytokine mRNA profiles and the mRNA expression of the NKG2D receptor and its ligands MICA/B and ULBP 1-3 in PE placenta were assessed and compared to those in normal placenta using real-time quantitative RT-PCR. RESULTS: The cytotoxicity of peripheral blood NK cells was upregulated in PE cases. Further, we found an enhanced inflammatory cytokine mRNA response combined with a dysregulated regulatory response and a significant mRNA overexpression of NKG2D receptor and its ligands MICA/B and ULBP in PE placenta. CONCLUSION: The destruction of chorionic villi observed in PE placenta might be conveyed by an enhanced local cytotoxic response through the NKG2D receptor-ligand pathway, which in turn might be promoted by an intense inflammatory response not counteracted by regulatory cytokine responses.

Efficacy of treatment immune thrombocytopenic purpura in pregnancy with corticosteroids and intravenous immunoglobulin: a prospective follow-up of suggested practice.

: The current study is performed to assess a routine for treatment of immune thrombocytopenic purpura in pregnancy. A prospective programme for monitoring and treatment with intravenous immunoglobulin or cortisone in pregnancies with immune thrombocytopenic purpura was suggested to all delivery units in Sweden. Treatment should be avoided if platelet counts were more than 20 × 10/l during pregnancy with no bleeding complications and with a target of 100 × 10/l at delivery. Descriptive statistics and logistic regression analysis were used. Seventy-five pregnancies were followed; treatment was given in 29 (39%) of the pregnancies; in 13 intravenous immunoglobulin, in six cortisone, in nine a combination of both immunoglobulin and cortisone and in one platelets was given. The mean platelet increase before delivery after immunoglobulin was 46 × 10/l approximately 3 days later. At delivery, 34 (45%) of all pregnancies reached target platelet level more than 100 × 10/l, whereas five (7%) had platelets less than 50 × 10/l. Mode of delivery and blood loss were similar to a reference group. Of the neonates, 23% had platelets less than 50 × 10/l with a nadir reached on day 2-4; 9% required treatment. Women with platelets less than 20 × 10/l in pregnancy or with prior neonatal thrombocytopenia were at a, respectively, five-fold and eight-fold increased risk of neonatal thrombocytopenia. A routine to avoid treatment when platelets are at least 20 × 10/l during pregnancy and to aim for 100 × 10/l at delivery seem safe. Severe maternal thrombocytopenia and prior neonatal thrombocytopenia were predictors of neonatal thrombocytopenia.

Cardiac function, myocardial mechano-energetic efficiency, and ventricular-arterial coupling in normal pregnancy.

OBJECTIVE: To assess cardiac function, myocardial mechanoenergetic efficiency (MEE), and ventricular-arterial coupling (VAC) longitudinally during normal pregnancy, and to study if there was an association between cardiac structure and function, and fetal growth. METHODS: Cardiac structure and function, MEE, and ventricular-arterial coupling was assessed longitudinally in 52 healthy nulliparous women at 14, 24, and 34 weeks' gestation and 9-month postpartum. RESULTS: Left atrial diameter increased during pregnancy (30.41 ±â€Š3.59 mm in the nonpregnant state and 31.02 ±â€Š3.91, 34.06 ±â€Š3.58, and 33.9 ±â€Š2.97 mm in the first, second, and third trimesters, P < 0.001). Left ventricular mass increased 117.12 ±â€Š45.0 g in the nonpregnant state and 116.5 ±â€Š33.0, 126.9 ±â€Š34.5, 128.4 ±â€Š36 g in the first, second, and third trimesters (P < 0.001). Cardiac output increased from 3.4 ±â€Š1.2 l/min to 4.3 ±â€Š0.7 l/min in the second and third trimesters (P < 0.001). Diastolic function decreased as both E/A and e'/a' decreased during pregnancy (P < 0.05 and P < 0.001, respectively). MEE and VAC were retained during pregnancy. Heart rate was associated with birth weight centile in the first (r = 0.41, P = 0.002) and second (r = 0.46, P = 0.002) trimester. CONCLUSION: The increase in cardiac output during normal pregnancy is obtained by an increase in heart rate, followed by structural cardiac changes. The impaired systolic function is accomplished by a deteriorated diastolic function. Despite these rapid changes, the myocardium manages to work efficient with a preserved MEE. Cardiac and arterial adaption to pregnancy seems to appear parallel as evidenced by a preserved VAC.

Thrombin activatable fibrinolysis inhibitor (TAFI) - A possible link between coagulation and complement activation in the antiphospholipid syndrome (APS).

BACKGROUND: Thrombosis and complement activation are pathogenic features of antiphospholipid syndrome (APS). Their molecular link is Plasma carboxypeptidase-B, also known as thrombin activatable fibrinolysis inhibitor (TAFIa), which plays a dual role: anti-fibrinolytic, by cleaving carboxyl-terminal lysine residues from partially degraded fibrin, and anti-inflammatory, by downregulating complement anaphylatoxins C3a and C5a. AIM: To investigate the levels of TAFI (proenzyme) and TAFIa (active enzyme) in relation to complement activation, fibrin clot permeability and fibrinolytic function in clinical and immunological subsets of 52 APS patients and 15 controls. RESULTS: TAFI (p<0.001), TAFIa (p<0.05) and complement factor C5a (p<0.001) were increased, while fibrin permeability (p<0.01) was decreased and clot lysis time (CLT) was prolonged (p<0.05) in APS patients compared to controls. Furthermore, TAFIa was increased (p<0.01) in samples from APS patients affected by arterial thrombosis compared to other APS-phenotypes. Positive associations were found between TAFI and age, fibrinogen and C5a, and between TAFIa and age, fibrinogen and thrombomodulin. CONCLUSION: TAFI and TAFIa levels were increased in patients with APS as a potential response to complement activation. Interestingly, TAFI activation was associated with arterial thrombotic APS manifestations. Thus, TAFIa may be considered a novel biomarker for arterial thrombosis in APS.

Correction: Postpartum Hemorrhage in Women with Von Willebrand Disease - A Retrospective Observational Study.

[This corrects the article DOI: 10.1371/journal.pone.0164683.].

Postpartum Hemorrhage in Women with Von Willebrand Disease - A Retrospective Observational Study.

INTRODUCTION: von Willebrand disease (VWD) is a hereditary bleeding disorder, caused by a deficiency in the levels and/or function of von Willebrand factor (VWF). Women with VWD appear to be at increased risk of experiencing postpartum hemorrhage (PPH), though the levels of VWF increase during pregnancy. There is limited knowledge of how PPH is associated with the subtype of VWD, plasma levels of other coagulations factors than VWF and given hemostatic treatment. AIMS: The aims were to investigate the incidence of PPH in women with VWD and to analyse the correlation between PPH and: (1) type of VWD, (2) laboratory monitoring of VWF and FVIII and (3) hemostatic drug treatment. METHODS: This was a retrospective observational study. The study participants (n = 34) were recruited from the Coagulation Unit, Karolinska University hospital. Fifty-nine deliveries, which occurred in 14 different obstetrics units (years 1995-2012) were included in the study. RESULTS: The incidence of primary PPH was 44%, severe primary PPH 20% and secondary PPH 12%. VWD type 3 was associated with a higher risk of experiencing severe primary PPH compared to other subtypes. FVIII:C in pregnancy was inversely correlated to blood loss during delivery. There was a significantly higher incidence of secondary PPH when the VWD diagnosis was unknown at time of delivery. CONCLUSIONS: The women with VWD are at higher risk of PPH, especially those with type 3 VWD or when diagnosis is unknown prior to delivery. Identification of pregnant women with undiagnosed VWD may be of importance in order to prevent PPH.

Heavy menstrual bleeding and health-associated quality of life in women with von Willebrand's disease.

Women with the inherited bleeding disorder von Willebrand's disease (VWD) face gender-specific hemostatic challenges during menstruation. Heavy menstrual bleeding (HMB) can negatively affect their overall life activities and the health-associated quality of life. The purpose of the present study was to investigate whether women with VWD experienced HMB and an impaired health-associated quality of life. The study subjects were recruited from the Coagulation Unit of Karolinska University Hospital. Information was retrieved from various self-administered forms and medical records. Of the 30 women (18-52 years) that were included in the present study, 50% suffered from HMB, although the majority received treatment for HMB. In addition, almost all the included women perceived limitations in the overall life activities due to menstruation. The health-associated quality of life for women with HMB was significantly lower (P<0.10) with regards to 'bodily pain' compared with Swedish women of the general population. In conclusion, women with VWD experienced reduced health-associated quality of life as a result of HMB. Therefore, preventing limitations in overall life activities and improving their health-associated quality of life thorough counseling on menstrual bleeding is important for women with VWD.