Reference ranges for third-trimester maternal cardiovascular function parameters measured in normotensive pregnant women using a non-invasive cardiac output monitor: A study based on data from the prospective PEACH cohort study.

OBJECTIVE: We defined reference ranges for maternal cardiac output, systemic vascular resistance, and stroke volume measured in the third trimester of pregnancy using the Ultrasound Cardiac Output Monitor 1A. DESIGN: Based on data from the prospective PEACH (PreEclampsia, Angiogenesis, Cardiac dysfunction and Hypertension) cohort study. SETTING: Rigshospitalet and Hvidovre Hospital, Denmark. SAMPLE: Normotensive pregnant women aged 18-45 years with singleton pregnancies, enrolled in the PEACH study in 2016-2018. METHODS: We modelled cardiac output, systemic vascular resistance and stroke volume as a function of gestational age using multilevel linear models with fractional polynomials. MAIN OUTCOME MEASURES: Unconditional and conditional reference ranges for cardiovascular parameters measured in gestational weeks 28-40. RESULTS: Our study cohort included 405 healthy pregnant women who contributed 1210 cardiovascular function measurements for analysis. Maximum cardiac output and stroke volume values were measured in gestational weeks 30-32 and decreased over the third trimester, whereas systemic vascular resistance increased during the same period. We created reference ranges for eight combinations of maternal height, age and parity. We also created a simple calculator to allow for implementation of the reference ranges in clinical practice. CONCLUSIONS: Our reference ranges allow the use of a bedside ultrasound device to non-invasively assess cardiac function in pregnancy and identify women at risk of complications. The unconditional ranges allow clinicians to evaluate isolated measurements and identify women needing follow-up. The conditional ranges incorporate information from previous measurements and improve monitoring over time.

Cohort profile: The PreEclampsia, Angiogenesis, Cardiac dysfunction and Hypertension (PEACH) Study.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) remain a leading cause of maternal morbidity and mortality worldwide, with implications for maternal and neonatal well-being in the short term and for long-term maternal cardiovascular health. Although the mechanisms behind HDP remain incompletely understood, evidence suggests that preeclampsia in particular is a syndrome with more than one distinct subtype. OBJECTIVES: The PEACH (PreEclampsia, Angiogenesis, Cardiac dysfunction, Hypertension) Study was established to identify new HDP subtyping systems reflecting aetiology and prognosis and to find markers of later cardiovascular disease risk associated with preeclampsia. POPULATION: The PEACH Study recruited pregnant women referred to two Copenhagen-area hospitals with suspected preeclampsia (mean gestational age at enrolment: 36.7 weeks) and a group of frequency-matched pregnant women planning delivery at the same hospitals and healthy when enrolled mid-pregnancy. DESIGN: Prospective, longitudinal pregnancy cohort. METHODS: Participants underwent repeated third-trimester blood sample collection, longitudinal cardiac function assessments using the USCOM-1A during the third trimester and at 1 year postpartum and collection of placental samples immediately after delivery. Medical information was abstracted from medical records and hospital databases. PRELIMINARY RESULTS: During 2016-2018, we recruited 1149 pregnant women, of whom 1101 were followed to delivery. Among 691 women enrolled with suspected preeclampsia, 310 and 172 developed preeclampsia and gestational hypertension respectively. Among 410 women with healthy pregnancies when enrolled mid-pregnancy, 37 later developed hypertensive disorders of pregnancy. Of 1089 women still in the cohort 1 year postpartum, 578 (53.1%) participated in the follow-up assessment. CONCLUSIONS: The PEACH Study's rich data from women with and without HDP will enable us to identify new, clinically useful HDP subtypes to aid in decision-making regarding monitoring and treatment. Continued postpartum follow-up will help us develop algorithms to identify women at risk of persistent postpartum cardiac dysfunction and later cardiovascular disease after pregnancies complicated by HDP.

[Venous thromboembolism in patients with COVID-19].

The importance of venous thromboembolism (VTE) as a major complication in patients with severe corona virus disease 2019 (COVID-19) is becoming increasingly evident. In this review, we describe the proposed pathophysiology of the prothrombotic coagulation changes observed in patients with COVID-19. Further, based on a review of the currently available evidence on VTE prevalence in patients with COVID-19, we present and discuss the recommendations from the Danish Society of Thrombosis and Haemostasis on the use of thromboprophylaxis in patients with COVID-19.

[Anticoagulant therapy of patients undergoing cardioversion for atrial fibrillation].

Cardioversion of atrial fibrillation entails a risk of thromboembolic events, especially ischaemic stroke. Oral anticoagulation therapy before and after cardioversion is therefore crucial. Assessing ischaemic stroke risk and time of arrhythmia onset is important when deciding on the optimal anticoagulation strategy. For decades, vitamin K antagonists (VKA) have been the primary anticoagulant drugs used in relation to cardioversion, but non-VKA oral anticoagulants may be preferred because of their rapid onset of action and predictable anticoagulant effect without the need for monitoring.

Lectin pathway proteins of the complement system in normotensive pregnancy and pre-eclampsia.

PROBLEM: The lectin pathway of the complement system may be involved in the pathogenesis of pre-eclampsia. We aimed to investigate changes in serum concentrations of a broad range of lectin pathway proteins during normal pregnancy and their association with pre-eclampsia, placental infarctions and intrauterine growth restriction (IUGR). METHOD OF STUDY: We included 51 women with normotensive pregnancies and 54 women with pregnancies complicated by pre-eclampsia. Blood samples were obtained at gestational weeks 16, 33, 37, and after delivery for the normotensive pregnant women and before and after delivery for women with pre-eclampsia. Mannose-binding lectin (MBL), H- and M-ficolin, collectin liver-1 (CL-L1), MBL-associated serine protease (MASP)-1, MASP-2 and MASP-3 and MBL-associated proteins of 19 (MAp19) and 44 (MAp44) kDa were analysed. Clinical information was obtained from medical records. The placentae were examined by two experienced perinatal pathologists. RESULTS: Lectin pathway protein concentrations generally increased during normal pregnancy and decreased after delivery in both normotensive pregnant women and women with pre-eclampsia. Exceptions were MASP-3 which increased after delivery in both groups (P < 0.0001) and H-ficolin which increased after delivery in pre-eclampsia (P < 0.0001). H-ficolin (P < 0.0001), M-ficolin (P = 0.005) and MASP-3 (P = 0.03) concentrations were lower in women with pre-eclampsia than in normotensive pregnant women. Low MASP-3 concentrations were associated with placental infarction (P = 0.03) and IUGR (P = 0.04). Low H-ficolin concentrations were associated with IUGR (P < 0.01). CONCLUSION: In general, lectin pathway protein serum concentrations increased during normal pregnancy. H-ficolin and MASP-3 may be involved in the pathophysiology of pre-eclampsia and IUGR and could be potential future pre-eclampsia biomarkers.

[Masked hypertension during pregnancy].

Hypertension during pregnancy is one of the leading causes of maternal and foetal morbidity and mortality. Monitoring of blood pressure is therefore an essential part of prenatal care. Masked hypertension, where blood pressure levels are elevated at home despite normal blood pressure levels monitored in a clinical setting, may lead to cardiovascular and obstetric complications equal to those of sustained hypertension. This article discusses masked hypertension and the need for further investigation of blood pressure monitoring during pregnancy.

[Pregnancy predispose to higher incidence of venous thromboembolism]. / Graviditet medfører øget risiko forvenøs tromboemboli.

Venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality despite the possibility to prevent and treat the disorder. The hypercoagulability of normal pregnancy predispose to an approximately six-fold higher incidence of VTE in pregnancy. Identification of risk pregnancies and start of prophylaxis is essential, as is early diagnosis of VTE to prevent progression and pulmonary embolism. For anticoagulant treatment and prophylaxis in pregnancy, low molecular weight heparin is the drug of choice and prophylaxis, if indicated, should initiate as soon as pregnancy is confirmed.

Vabrasio is a reliable test to rule out endometrial cancer.

INTRODUCTION: Endometrial cancer is the most common gynaecological cancer in Denmark, and its incidence peaks in the postmenopausal years. The aim of the present study was to evaluate the effectiveness of vacuum aspirator (vabrasio) for the detection of endometrial cancer in terms of sensitivity, specificity and predictive value. METHODS: A cohort counting 503 women who had vabrasio was evaluated retrospectively. The women included were consecutive patients who had received vabrasio at the Department of Gynaecology and Obstetrics at Herning Hospital, Denmark, during a two-year period. They were identified by searching the hospital database for the International Classification of Diseases, tenth version (ICD-10) code for vabrasio. RESULTS: The indications for vabrasio were postmenopausal bleeding (45%), meno/metrorrhagia (43%) and thickened endometrium/polyp (6%). The first evaluation by vabrasio was normal in 381 women (76%), insufficient in 83 women (17%), 22 (4%) had endometrial cancer and 17 (3%) had another non-malignant diagnosis. The first evaluation for cancer with vabrasio had a sensitivity of 81%, a specificity of 100% and predictive values of 100% (positive) and 99% (negative). CONCLUSION: Vabrasio has a good diagnostic reliability with respect to endometrial cancer, but has some shortcomings due to insufficient sampling for diagnosis. FUNDING: none. TRIAL REGISTRATION: not relevant. Danish Data Protection Agency: case no.: 1-16-02-601-14.

Urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion increases in normal pregnancy but not in preeclampsia.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) serum values have been shown to increase in preeclampsia. The goal of the present study was to evaluate changes in urinary NGAL concentrations during uncomplicated pregnancy and in cases of preeclampsia and hypertension. METHODS: Fifty-one pregnant women who developed preeclampsia and 28 diagnosed with essential or gestational hypertension were investigated for urinary NGAL concentrations during pregnancy. As controls, 100 healthy pregnant women with uncomplicated singleton pregnancies were randomly selected. Urinary NGAL as well as urinary creatinine and albumin were measured by a standardized clinical chemistry platform (ARCHITECT®; Abbott Diagnostics, Abbott Park, IL, USA). RESULTS: Urinary NGAL concentrations increased during pregnancy in healthy pregnant women, whereas this increase was not detected in preeclampsia. In order to correct for diuresis, spot urine concentrations were also determined as NGAL/creatinine ratio. NGAL/creatinine ratio in pregnancy week 36-38 was significantly lower in preeclampsia than in healthy pregnant women or pregnant women with hypertension. NGAL urinary concentrations did not correlate with albumin concentration in urine. CONCLUSIONS: Urinary NGAL is not a valuable early biomarker for preeclampsia.

Inflammatory and procoagulant cytokine levels during pregnancy as predictors of adverse obstetrical complications.

INTRODUCTION: Disturbances in cytokine networks are believed to be associated with increased risk of adverse pregnancy complications. METHODS: Plasma samples collected from pregnant women with preterm deliveries, high-risk pregnancy complications including postpartum hemorrhage, hypertensive disorders, and multiple gestations, and normal pregnancies were analyzed at different periods throughout gestation and postpartum. Interleukin (IL) 1ß , IL-6, IL-8, IL-10, tumor necrosis factor α, and antiprotein Z antibody levels were measured by enzyme-linked immunosorbent assay. RESULTS: The IL-6 levels in preterm delivery patients were elevated during pregnancy with statistically significant differences observed at 21 to 32 weeks (P < .01) and 33+ weeks (P < .001). The IL-10 levels were increased in normal pregnancy at all time points compared to the other patient groups (P < .05). The TNF-α levels were elevated in the high-risk pregnancy group versus normal controls (P < .001 at <21 weeks and P < .05 at 21-32 weeks). CONCLUSION: Analysis of the maternal plasma for elevated IL-6 and reduced IL-10 levels may be of value in the early prediction of pregnancy complications.

Venous thromboembolism in pregnancy: prophylaxis and treatment with low molecular weight heparin.

OBJECTIVE: To evaluate the safety of individually dosed low molecular weight heparin (LMWH) for prophylaxis and treatment of thromboembolic complications in pregnancy. DESIGN: Cohort study with a chronologic register-based control group. SETTING: Department of Obstetrics and Gynecology, Hillerød Hospital, Denmark. POPULATION: All 166 women treated with LMWH in pregnancy between 1 January 2001 and 31 December 2005. METHODS: Women treated with LMWH in pregnancy were identified and individual case records reviewed retrospectively. General data on the LMWH-treated women were compared to the 18,020 untreated pregnancies within the same period and with 306 matched controls as regards to postpartum hemorrhage (PPH). MAIN OUTCOME MEASURES: Side effects of treatment, thromboembolic manifestations, postpartum bleeding and obstetric outcome. RESULTS: There were no thromboembolic events during therapy, few side effects of treatment and no osteoporotic fractures or episodes of heparin-induced thrombocytopenia. The 166 pregnancies resulted in 159 live infants. There was a significantly higher risk of preterm delivery (13% vs. 6%) and intrauterine growth restriction (4.4% vs. 3.5%). Delivery by cesarean section was more common in these high-risk LMWH-treated pregnancies (33.1%) than in untreated pregnancies (19.2%). In the LMWH-group, the occurrence of PPH was 7.2% compared with 8.8% in the matched untreated control group (p = 0.675). None of the events in the LMWH group were serious and all 166 women were in good health at discharge. CONCLUSIONS: Individually dosed LMWH is well tolerated and safe for prophylaxis and treatment of thromboembolic complications during pregnancy, delivery and the postpartum period.

Soluble human leukocyte antigen-G isoforms in maternal plasma in early and late pregnancy.

PROBLEM: Human Leukocyte Antigen (HLA)-G is a class Ib gene located in the human major histocompatibility complex (MHC). Several lines of investigation indicate that the HLA-G molecule is involved in the maternal acceptance of the semi-allogenic fetus during pregnancy and in the development of tolerance. Expression of soluble HLA-G (sHLA-G) is positively correlated with successful in vitro fertilization (IVF) treatments, and aberrant expression of HLA-G in certain complications of pregnancy, such as pre-eclampsia and spontaneous abortion, has been reported. The main purpose of this study was to investigate the levels of different soluble HLA-G isoforms in maternal plasma in early and late pregnancy. METHOD OF STUDY: Soluble HLA-G (sHLA-G) can be detected in maternal blood, and in this study, two different isoforms of sHLA-G, namely sHLA-G1 generated by shedding of membrane-bound HLA-G1 and HLA-G generated by specific HLA-G transcripts, have been investigated early [median of 16.4 weeks of gestation (GW)] and late (median: 38.9 GW) in pregnancy in an original cohort of 580 pregnant Caucasian women. RESULTS: Lower concentrations of sHLA-G1 were found late in pregnancy (>32 GW) in a group of women with severe pre-eclampsia compared with controls with uncomplicated pregnancies (P = 0.029, P(C) = 0.09; Mann-Whitney; Logistic regression analysis: P = 0.024, OR = 0.920, 95% CI: 0.855-0.989). However, this was not the case with HLA-G5, and significantly more of the cases with severe pre-eclampsia had detectable plasma HLA-G5 compared with that of the control group (P = 0.013, P(C) = 0.04; Mann-Whitney). Similar findings were not observed in women with gestational hypertension or existing hypertension continuing into pregnancy. Furthermore, there was a trend toward lower maternal plasma sHLA-G1 in a group of women with premature birth (<37 GW) compared with that of the control group (P = 0.028, P(C) = 0.17; Mann-Whitney). On the contrary, HLA-G5 was lower in the control group compared with that in the premature group (P = 0.004, P(C) = 0.02; Mann-Whitney). CONCLUSION: This study shows in line with other published studies that a high, detectable soluble HLA-G concentration in maternal plasma or serum is not mandatory for a successful pregnancy. However, complications during pregnancy, such as (severe) pre-eclampsia, spontaneous abortion, IUGR, and premature birth, are associated with a low or undetectable level of soluble HLA-G in the maternal blood circulation. Also, this study indicates that sHLA-G1 is the interesting soluble HLA-G isoform in pre-eclampsia, and that low or undetectable levels of HLA-G5 at the end of pregnancy seem to be associated with an uncomplicated normal pregnancy, whereas in severe pre-eclampsia and possibly other pregnancy complications, such as preterm birth and IUGR, the level of HLA-G5 is higher.

Prognostic value of screening for irregular antibodies late in pregnancy in rhesus positive women.

BACKGROUND: To evaluate the prognostic value of screening for irregular antibodies late in pregnancy (third trimester) in rhesus positive women. Only those cases where irregular antibodies have not previously been demonstrated during routine screening in the first trimester with regard to clinically relevant complications in the newborn, were studied. MATERIALS AND METHODS: All women living in Frederiksborg county and giving birth in 1996 (n = 4216) were assessed for inclusion in the study. This was done by gathering the files at the Hillerød and Hørsholm Hospitals' blood banks for antibody test results. Six hundred women were excluded because of the lack of either the rhesus type or the late antibody test. RESULTS: Of the 3616 women, 3046 were rhesus positive, and 3012 of these had a negative first trimester screen test. Fifteen of the 3012 women later developed irregular antibodies in the third trimester, and were included in the study. This corresponds to only 0.5%, and none of these cases entailed perinatal complications for the mother or the child. CONCLUSION: Routine screening of rhesus positive pregnant women in the third trimester is not rational from a cost-benefit perspective, if the only purpose is to prevent hemolytic disease of the newborn.