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Cauldwell M, Steer PJ, von Klemperer K, et al., 2020, Maternal and neonatal outcomes in women with history of coronary artery disease, Heart, Vol: 106, Pages: 380-386, ISSN: 1355-6037
Background Pregnancy outcomes in women with pre-existing coronary artery disease (CAD) are poorly described. There is a paucity of data therefore on which to base clinical management to counsel women, with regard to both maternal and neonatal outcomes.Method We conducted a retrospective multicentre study of women with established CAD delivering at 16 UK specialised cardiac obstetric clinics. We included pregnancies of 24 weeks’ gestation or more, delivered between January 1998 and October 2018. Data were collected on maternal cardiovascular, obstetric and neonatal events.Results 79 women who had 92 pregnancies (94 babies including two sets of twins) were identified. 35.9% had body mass index >30% and 24.3% were current smokers. 18/79 (22.8%) had prior diabetes, 27/79 (34.2%) had dyslipidaemia and 21/79 (26.2%) had hypertension. The underlying CAD was due to atherosclerosis in 52/79 (65.8%), spontaneous coronary artery dissection (SCAD) in 11/79 (13.9%), coronary artery spasm in 7/79 (8.9%) and thrombus in 9/79 (11.4%).There were six adverse cardiac events (6.6% event rate), one non-ST elevation myocardial infarction at 23 weeks’ gestation, two SCAD recurrences (one at 26 weeks’ gestation and one at 9 weeks’ postpartum), one symptomatic deterioration in left ventricular function and two women with worsening angina. 14% of women developed pre-eclampsia, 25% delivered preterm and 25% of infants were born small for gestational age.Conclusion Women with established CAD have relatively low rates of adverse cardiac events in pregnancy. Rates of adverse obstetric and neonatal events are greater, highlighting the importance of multidisciplinary care.
Cocker A, Shah N, Raj I, et al., 2020, Pregnancy gestation impacts on HIV-1-specific granzyme B response and central memory CD4 T cells, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224
Pregnancy induces alterations in peripheral T-cell populations with both changes in subset frequencies and anti-viral responses found to alter with gestation. In HIV-1 positive women anti-HIV-1 responses are associated with transmission risk, however detailed investigation into both HIV-1-specific memory responses associated with HIV-1 control and T-cell subset changes during pregnancy have not been undertaken. In this study we aimed to define pregnancy and gestation related changes to HIV-1-specific responses and T-cell phenotype in ART treated HIV-1 positive pregnant women. Eleven non-pregnant and 24 pregnant HIV-1 positive women were recruited, peripheral blood samples taken, fresh cells isolated, and compared using ELISpot assays and flow cytometry analysis. Clinical data were collected as part of standard care, and non-parametric statistics used. Alterations in induced IFNγ, IL-2, IL-10, and granzyme B secretion by peripheral blood mononuclear cells in response to HIV-1 Gag and Nef peptide pools and changes in T-cell subsets between pregnant and non-pregnant women were assessed, with data correlated with participant clinical parameters and longitudinal analysis performed. Cross-sectional comparison identified decreased IL-10 Nef response in HIV-1 positive pregnant women compared to non-pregnant, while correlations exhibited reversed Gag and Nef cytokine and protease response associations between groups. Longitudinal analysis of pregnant participants demonstrated transient increases in Gag granzyme B response and in the central memory CD4 T-cell subset frequency during their second trimester, with a decrease in CD4 effector memory T cells from their second to third trimester. Gag and Nef HIV-1-specific responses diverge with pregnancy time-point, coinciding with relevant T-cell phenotype, and gestation associated immunological adaptations. Decreased IL-10 Nef and both increased granzyme B Gag response and central memory CD4 T cells implies that amplified a
Ibeto L, Antonopoulos A, Grassi P, et al., 2020, Insights into the hyperglycosylation of human chorionic gonadotropin revealed by glycomics analysis, PLoS One, Vol: 15, ISSN: 1932-6203
Human chorionic gonadotropin (hCG) is a glycoprotein hormone that is essential for the maintenance of pregnancy. Glycosylation of hCG is known to be essential for its biological activity. "Hyperglycosylated" variants secreted during early pregnancy have been proposed to be involved in initial implantation of the embryo and as a potential diagnostic marker for gestational diseases. However, what constitutes "hyperglycosylation" is not yet fully understood. In this study, we perform comparative N-glycomic analysis of hCG expressed in the same individuals during early and late pregnancy to help provide new insights into hCG function, reveal new targets for diagnostics and clarify the identity of hyperglycosylated hCG. hCG was isolated in urine collected from women at 7 weeks and 20 weeks' gestation. hCG was also isolated in urine from women diagnosed with gestational trophoblastic disease (GTD). We used glycomics methodologies including matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass spectrometry (MS) and MS/MS methods to characterise the N-glycans associated with hCG purified from the individual samples. The structures identified on the early pregnancy (EP-hCG) and late pregnancy (LP-hCG) samples corresponded to mono-, bi-, tri-, and tetra-antennary N-glycans. A novel finding was the presence of substantial amounts of bisected type N-glycans in pregnancy hCG samples, which were present at much lower levels in GTD samples. A second novel observation was the presence of abundant LewisX antigens on the bisected N-glycans. GTD-hCG had fewer glycoforms which constituted a subset of those found in normal pregnancy. When compared to EP-hCG, GTD-hCG samples had decreased signals for tri- and tetra-antennary N-glycans. In terms of terminal epitopes, GTD-hCG had increased signals for sialylated structures, while LewisX antigens were of very minor abundance. hCG carries the same N-glycans throughout pregnancy but in different propo
Sliwa K, Baris L, Sinning C, et al., 2020, Pregnant women with uncorrected congenital heart disease heart failure and mortality, JACC: Heart Failure, Vol: 8, Pages: 100-110, ISSN: 2213-1779
ObjectivesThe purpose of this work was to study maternal and fetal outcomes of women with uncorrected congenital heart disease (CHD).BackgroundGlobally, CHD is an important cause of maternal morbidity and mortality in women reaching reproductive stage. Data are lacking from larger cohorts of women with uncorrected CHD.MethodsThe 10-year data from the European Society of Cardiology EORP ROPAC (EURObservational Research Programme Registry of Pregnancy and Cardiac disease) registry of women with uncorrected CHD were analyzed.ResultsOf 5,739 pregnancies in 53 countries, 3,295 women had CHD, 1,059 of which were uncorrected cases. Of these, 41.4% were from emerging countries. There were marked differences between the cardiac defects in uncorrected cases versus those in corrected CHD cases with primary shunt lesions (44.7% vs. 32.4%, respectively), valvular abnormalities (33.5% vs. 12.6%, respectively), and Tetralogy of Fallot and pulmonary atresia (0.8% vs. 20.3%, respectively; p < 0.001). In patients with uncorrected CHD, 6.8% were in modified World Health Organization risk class IV, approximately 10% had pulmonary hypertension (PH), and 3% were cyanotic prior to pregnancy. Maternal mortality and heart failure (HF) in the women with uncorrected CHD were 0.7% and 8.7%, respectively. Eisenmenger syndrome was associated with a very high risk of cardiac events (65.5%), maternal mortality (10.3%), and HF (48.3%). Coming from an emerging country was associated with higher pre-pregnancy signs of HF, PH, and cyanosis (p < 0.001) and worse maternal and fetal outcomes, with a 3-fold higher rate of hospital admissions for cardiac events and intrauterine growth retardation (p < 0.001).ConclusionsMarked differences between cardiac conditions in pregnant women with uncorrected CHD and those in corrected CHD were found, with a markedly worse outcome, particularly in women with Eisenmenger syndrome and from emerging countries.
Zöllner J, Howe LG, Edey LF, et al., 2020, LPS-induced hypotension in pregnancy: the effect of progesterone supplementation, Shock, Vol: 53, Pages: 199-207, ISSN: 1073-2322
Our previous work has shown that pregnancy exacerbates the hypotensive response to both infection and LPS. The high levels of progesterone (P4) associated with pregnancy have been suggested to be responsible for the pregnancy-induced changes in the cardiovascular response to infection. Here, we test the hypothesis that P4 supplementation exacerbates the hypotensive response of the maternal cardiovascular to LPS.Female CD1 mice had radiotelemetry probes implanted to measure haemodynamic function non-invasively and were time-mated. From day 14 of pregnancy, mice received either 10 mg of P4 or vehicle alone per day and on day 16, intraperitoneal LPS (10 μg of serotype 0111:B4) was injected. In two identically treated cohorts of mice, tissue and serum (for RNA, protein studies) were collected at 6 and 12 hours.Administration of LPS resulted in a fall in blood pressure in vehicle treated, but not P4 supplemented mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors and in both circulating and tissue inflammatory cell numbers, but with reduced left ventricular expression of cytokines in P4-supplemented mice. However, left ventricular expression of markers of cardiac dysfunction and apoptosis were similar.This study demonstrates that P4 supplementation prevented LPS-induced hypotension in pregnant mice in association with reduced myocardial inflammatory cytokine gene expression. These observations suggest that rather than being detrimental, P4 supplementation has a protective effect on the maternal cardiovascular response to sepsis.
Shah NM, Edey LF, Imami N, et al., 2020, Human labour is associated with altered regulatory T cell function and maternal immune activation, Clinical & Experimental Immunology, Vol: 199, Pages: 182-200, ISSN: 0009-9104
During human pregnancy, regulatory T cell (Treg) function is enhanced and immune activation is repressed allowing the growth and development of the feto–placental unit. Here, we have investigated whether human labour is associated with a reversal of the pregnancy‐induced changes in the maternal immune system. We tested the hypothesis that human labour is associated with a decline in Treg function, specifically their ability to modulate Toll‐like receptor (TLR)‐induced immune responses. We studied the changes in cell number, activation status and functional behaviour of peripheral blood, myometrial (myoMC) and cord blood mononuclear cells (CBMC) with the onset of labour. We found that Treg function declines and that Treg cellular targets change with labour onset. The changes in Treg function were associated with increased activation of myoMC, assessed by their expression of major histocompatibility complex (MHC) class II molecules and CBMC inflammatory cells. The innate immune system showed increased activation, as shown by altered monocyte and neutrophil cell phenotypes, possibly to be ready to respond to microbial invasion after birth or to contribute to tissue remodelling. Our results highlight changes in the function of the adaptive and innate immune systems that may have important roles in the onset of human labour.
Lai PF, Georgiou EX, Tribe RM, et al., 2020, The impact of progesterone and RU-486 on classic pro-labour proteins & contractility in human myometrial tissues during 24-hour exposure to tension & Interleukin-1β, Molecular and Cellular Endocrinology, Vol: 500, ISSN: 0303-7207
Increased expression of pro-labour genes that encode cyclooxygenase-2 (COX-2), oxytocin receptor (OTR) and connexin-43 (Cx43) at parturition is often attributed to P4 functional withdrawal, based on findings from animal models and human primary myometrial cells. However, the cause of reduced myometrial P4 responsiveness that promotes contractions at labour is not fully determined. Uterine stretch occurs with advancing gestation but most in vitro experimental models do not take this into consideration. We aimed to examine whether tissue-level myometrial stretch influences the ability of P4 to regulate pro-labour protein abundance by using myometrial biopsies from term gestation pregnant women to assess the impact of 24 h exposure to combinations of (i) stretch-mediated tension, (ii) P4 (100 nM) and (iii) an anti-progestin, RU-486 (1 μM). Firstly, we observed baseline COX-2 and Cx43 protein levels increased, whereas P4 content along with calponin-1 and progesterone receptor (PR) protein abundance decreased, in vehicle-treated tissues. P4 supplementation subtly reduced COX-2 levels in un-stretched tissues. Spontaneous and oxytocin-augmented contractility were unchanged by tissue culture exposure to P4 and/or RU-486. Interleukin-1β (IL-1β; 1 ng/ml) enhanced COX-2 protein and PGE2 content in un-stretched tissues. Overall, tissue stretch may, in part, regulate P4-sensitive pro-labour protein levels, but this is likely to be reliant on interaction with other in utero factors that were absent in our tissue cultures. More complex culture conditions should be evaluated in future to aid further development of a physiologically relevant model to improve our understanding of in utero myometrial P4 responsiveness.
Greer O, Shah NM, Johnson MR, 2020, Maternal sepsis update: current management and controversies, The Obstetrician & Gynaecologist, Vol: 22, Pages: 45-55, ISSN: 1467-2561
•Sepsis is a leading cause of maternal morbidity and mortality, globally and in the UK.•In pregnancy and the puerperium, women may be more susceptible to rapid deterioration of illness following an infection.•Sepsis has a complex pathophysiology and the immunological and cardiovascular adaptations of normal pregnancy may have an adverse impact on the maternal response to infection. Furthermore, physiological changes of pregnancy, which mimic those of sepsis, often delay optimal management.•‘Bedside’ identification of pathogens and their antibiotic resistance patterns may help to improve clinical outcomes.•Recent updates in sepsis management, areas of controversy and the importance of translational research and clinical trials for pregnancy and the puerperium are discussed.
Roos-Hesselink J, Baris L, Johnson M, et al., 2019, Pregnancy outcomes in women with cardiovascular disease: evolving trends over 10 years in the ESC Registry Of Pregnancy And Cardiac disease (ROPAC), European Heart Journal, Vol: 40, Pages: 3848-3855, ISSN: 1522-9645
AIMS: Reducing maternal mortality is a World Health Organization (WHO) global health goal. Although maternal deaths due to haemorrhage and infection are declining, those related to heart disease are increasing and are now the most important cause in western countries. The aim is to define contemporary diagnosis-specific outcomes in pregnant women with heart disease. METHODS AND RESULTS: From 2007 to 2018, pregnant women with heart disease were prospectively enrolled in the Registry Of Pregnancy And Cardiac disease (ROPAC). Primary outcome was maternal mortality or heart failure, secondary outcomes were other cardiac, obstetric, and foetal complications. We enrolled 5739 pregnancies; the mean age was 29.5. Prevalent diagnoses were congenital (57%) and valvular heart disease (29%). Mortality (overall 0.6%) was highest in the pulmonary arterial hypertension (PAH) group (9%). Heart failure occurred in 11%, arrhythmias in 2%. Delivery was by Caesarean section in 44%. Obstetric and foetal complications occurred in 17% and 21%, respectively. The number of high-risk pregnancies (mWHO Class IV) increased from 0.7% in 2007-2010 to 10.9% in 2015-2018. Determinants for maternal complications were pre-pregnancy heart failure or New York Heart Association >II, systemic ejection fraction <40%, mWHO Class 4, and anticoagulants use. After an increase from 2007 to 2009, complication rates fell from 13.2% in 2010 to 9.3% in 2017. CONCLUSION: Rates of maternal mortality or heart failure were high in women with heart disease. However, from 2010, these rates declined despite the inclusion of more high-risk pregnancies. Highest complication rates occurred in women with PAH.
Zöllner J, Lambden S, Nasri NM, et al., 2019, Inhibition of dimethylarginine dimethylaminohydrolase 1 improves the outcome of sepsis in pregnant mice., Shock, ISSN: 1073-2322
Sepsis is one of the most important causes of maternal mortality. In our previous work, we established a polymicrobial sepsis (caecal ligation and puncture, [CLP]) model in murine pregnancy and found that pregnant mice had a greater susceptibility to septic shock. In this model, mortality appeared to be associated with the development of early haemodynamic dysfunction and although circulating cytokine levels were similar, "off target" lung inflammatory cell numbers were greater in pregnant mice.Here, we have used the same CLP model to test the hypothesis that inhibiting the metabolism of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine would improve the outcome of sepsis in pregnancy. We used a dimethylarginine dimethylaminohydrolase 1-selective inhibitor (L-257), which reduces vascular nitric oxide synthesis without impairing immune cell function, in combination with a broad-spectrum antibiotic (Imipenem) and studied the outcome of septic shock in pregnant mice. Treatments were administered 3 hours after CLP and samples were taken 3 hours later. Both Imipenem and L-257 treatment alone slightly improved mortality rates from 13% (NaCl) to 20% (Imipenem) and 33% (L-257), while the combination of Imipenem and L-257, significantly improved survival to 50%. Imipenem and L-257 together prevented cardiovascular collapse and improved both organ function and bacterial killing but did not reduce lung inflammatory cell numbers and actually increased lung cytokine levels.These data suggest that conventional management in combination with selective inhibition of DDAH1 may have therapeutic potential in the management of sepsis in pregnancy.
Shah NM, Imami N, Kelleher P, et al., 2019, Pregnancy-related immune suppression leads to altered influenza vaccine recall responses, Clinical Immunology, Vol: 208, ISSN: 1521-6616
Pregnancy is a risk factor for severe influenza infection. Despite achieving seroprotective antibody titres post immunisation fewer pregnant women experience a reduction in influenza-like illness compared to non-pregnant cohorts. This may be due to the effects that immune-modulation in pregnancy has on vaccine efficacy leading to a less favourable immunologic response.To understand this, we investigated the antigen-specific cellular responses and leukocyte phenotype in pregnant and non-pregnant women who achieved seroprotection post immunisation. We show that pregnancy is associated with better antigen-specific inflammatory (IFN-γ) responses and an expansion of central memory T cells (Tcm) post immunisation, but low-level pregnancy-related immune regulation (HLA-G, PIBF) and associated reduced B-cell antibody maintenance (TGF-β) suggest poor immunologic responses compared to the non-pregnant.Thus far, studies of influenza vaccine immunogenicity have focused on the induction of antibodies but understanding additional vaccine-related cellular responses is needed to fully appreciate how pregnancy impacts on vaccine effectiveness.
Singh N, Herbert B, Sooranna G, et al., 2019, Distinct preterm labor phenotypes have unique inflammatory signatures and contraction associated protein profiles, Biology of Reproduction, Vol: 101, Pages: 1031-1045, ISSN: 0006-3363
Preterm labor (PTL) is the predominant cause of childhood morbidity and mortality. It has several phenotypes, each with a distinct etiology often involving inflammation. Here, in samples of reproductive tissues obtained in early PTL from women with phenotypically defined PTL, we examined the presence and distribution of inflammation and its relationship with prolabor gene expression. In chorioamnionitis (CA-PTL), cytokine protein concentrations were increased across all tissues; in idiopathic (I-PTL), the inflammatory changes were limited to the choriodecidua; inflammation was not a feature of placental abruption (PA-PTL). CA-PTL was associated with activation of p65 in the myometrium and AP-1 in the choriodecidua, and PA-PTL with CREB in the choriodecidua. In the myometrium, PGHS-2 mRNA level was increased in CA- and I-PTL; in the amnion, PGHS-2 mRNA level was higher in PA- and I-PTL, while in CA-PTL, OT, OTR mRNA, and CX-43 expression were increased. In the choriodecidua, PGHS-2 mRNA level was unchanged, but in CA and I-PTL, OT mRNA level were increased and OTR was reduced. These data show that CA-PTL is associated with widespread inflammation and prolabor gene expression. In contrast, in I-PTL, inflammation is limited to the choriodecidua, with discrete increases in PGHS-2 in the amnion and OT in the choriodecidua. Inflammation is not a feature of PA-PTL, which is associated with increased OT and OTR in the amnion.
Cauldwell M, Steer PJ, Curtis SL, et al., 2019, Maternal and fetal outcomes in pregnancies complicated by Marfan syndrome., Heart, Vol: 105, Pages: 1725-1731, ISSN: 1355-6037
OBJECTIVES: Information to guide counselling and management for pregnancy in women with Marfan syndrome (MFS) is limited. We therefore conducted a UK multicentre study. METHODS: Retrospective observational study of women with MFS delivering between January 1998 and March 2018 in 12 UK centres reporting data on maternal and neonatal outcomes. RESULTS: In total, there were 258 pregnancies in 151 women with MFS (19 women had prior aortic root replacements), including 226 pregnancies ≥24 weeks (two sets of twins), 20 miscarriages and 12 pregnancy terminations. Excluding miscarriages and terminations, there were 221 live births in 139 women. Only 50% of women received preconception counselling. There were no deaths, but five women experienced aortic dissection (1.9%; one type A and four type B-one had a type B dissection at 12 weeks and subsequent termination of pregnancy). Five women required cardiac surgery postpartum. No predictors for aortic dissection could be identified. The babies of the 131 (65.8%) women taking beta-blockers were on average 316 g lighter (p<0.001). Caesarean section rates were high (50%), particularly in women with dilated aortic roots. In 55 women, echocardiographic aortic imaging was available prepregnancy and postpregnancy; there was a small but significant average increase in AoR size of 0.84 mm (Median follow-up 2.3 months) CONCLUSION: There were no maternal deaths, and the aortic dissection rate was 1.9% (mainly type B). There with no identifiable factors associated with aortic dissection in our cohort. Preconception counselling rates were low and need improvement. Aortic size measurements increased marginally following pregnancy.
Greer O, Shah NM, Sriskandan S, et al., 2019, Sepsis: precision-based medicine for pregnancy and the puerperium, International Journal of Molecular Sciences, Vol: 20, Pages: 1-18, ISSN: 1422-0067
Sepsis contributes significantly to global morbidity and mortality, particularly in vulnerable populations. Pregnant and recently pregnant women are particularly prone to rapid progression to sepsis and septic shock, with 11% of maternal deaths worldwide being attributed to sepsis. The impact on the neonate is considerable, with 1 million neonatal deaths annually attributed to maternal infection or sepsis. Pregnancy specific physiological and immunological adaptations are likely to contribute to a greater impact of infection, but current approaches to the management of sepsis are based on those developed for the non-pregnant population. Pregnancy-specific strategies are required to optimise recognition and management of these patients. We review current knowledge of the physiology and immunology of pregnancy and propose areas of research, which may advance the development of pregnancy-specific diagnostic and therapeutic approaches to optimise the care of pregnant women and their babies.
Viljoen CA, Sliwa K, Azibani F, et al., 2019, Prospective randomized study on implanted cardiac rhythm recorders in pregnant women with symptomatic arrhythmia and/or structural heart disease, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: Oxford University Press (OUP), Pages: 1496-1496, ISSN: 0195-668X
BackgroundCardiac arrhythmia is an important cause of maternal morbidity and mortality in pregnancy, but is difficult to diagnose.PurposeThe aim of this single-centre, prospective, randomized pilot study was to compare the implantable loop recorder (ILR) with standard assessment of arrhythmia (12-lead ECG; 24-hour Holter ECG) in terms of acceptability, detection of arrhythmias and impact on outcome in pregnant women with symptomatic arrhythmias and/or structural heart disease (SHD).MethodsThe study recruited 40 consecutive patients from a weekly, dedicated cardiac obstetric clinic. Inclusion criteria: symptoms of arrhythmia and/or having SHD at risk of arrhythmia. Patients were randomized to either standard care (SC) or standard care plus ILR (SC-ILR). ILR recordings were read at the monthly visits and/or when presenting with symptoms.ResultsThere were no demographic differences between the study groups. Seventeen patients consented to ILR insertion, all of whom found the procedure acceptable. No arrhythmias were recorded by the 12-lead ECGs. Holter monitoring detected arrhythmias in 10 of 23 patients (43%) from the SC group. In the SC-ILR group, 8 of 17 patients (47%) had arrhythmias detected by Holter, whereas 13 of 17 patients (76%) patients had arrhythmias detected by ILR (p=0.157). One of 4 patients with supraventricular tachycardia, 2 of 3 patients with premature ventricular complexes and 2 patients with paroxysmal atrial fibrillation (AF) recorded by ILR did not have the arrhythmias detected by Holter monitoring (Figure 1A shows a scatter plot of the variable R-R intervals seen in AF and 1B a rhythm strip of AF with irregular RR intervals and the absence of P waves, both downloaded from the ILR). Four of these 5 patients (80%) had a change in management as a direct result of their ILR recordings. There were no maternal deaths up to 42 days postpartum in either of the study groups. Nine babies were born with a low birthweight (<2500g), 5 stillbirth/neonatal
Herbert BR, Markovic D, Georgiou E, et al., 2019, Aminophylline and progesterone prevent inflammation-induced preterm parturition in the mouse, Biology of Reproduction, Vol: 101, Pages: 813-822, ISSN: 1529-7268
Although progesterone (P4) supplementation is the most widely used therapy for the prevention of preterm labor (PTL), reports of its clinical efficacy have been conflicting. We have previously shown that the anti-inflammatory effects of P4 can be enhanced by increasing intracellular cAMP levels in primary human myometrial cells. Here we have examined whether adding aminophylline (Am), a non-specific phosphodiesterase (PDE) inhibitor that increases intracellular cyclic adenosine monophosphate (cAMP) levels, to P4 might improve its efficacy using in vivo and in vitro models of PTL. In a mouse model of lipopolysaccharide (LPS)-induced PTL, we found that the combination of P4 and Am delayed the onset of LPS-induced PTL, while the same dose of P4 and Am alone had no effect. Pup survival was not improved by either agent alone or in combination. Myometrial prolabor and inflammatory cytokine gene expression was reduced, but the reduction was similar in P4 and P4/Am treated mice. There was no effect of the combination of P4 and Am on an ex vivo assessment of myometrial contractility. In human myometrial cells and myometrial tissue explants, we found that the combination had marked anti-inflammatory effects, reducing cytokine and COX-2 mRNA and protein levels to a greater extent than either agent alone. These data suggest that the combination of P4 and Am has a more potent anti-inflammatory effect than either agent alone and may be an effective combination in women at high-risk of PTL.
Charani E, Cunnington AJ, Yousif AHA, et al., 2019, In transition: current health challenges and priorities in Sudan, BMJ Global Health, Vol: 4:e001723, ISSN: 2059-7908
A recent symposium and workshop in Khartoum, the capital of the Republic of Sudan, brought together broad expertise from three universities to address the current burden of communicable and non-communicable diseases facing the Sudanese healthcare system. These meetings identified common challenges that impact the burden of diseases in the country, most notably gaps in data and infrastructure which are essential to inform and deliver effective interventions. Non-communicable diseases, including obesity, type 2 diabetes, renal disease and cancer are increasing dramatically, contributing to multimorbidity. At the same time, progress against communicable diseases has been slow, and the burden of chronic and endemic infections remains considerable, with parasitic diseases (such as malaria, leishmaniasis and schistosomiasis) causing substantial morbidity and mortality. Antimicrobial resistance has become a major threat throughout the healthcare system, with an emerging impact on maternal, neonatal, and paediatric populations. Meanwhile, malnutrition, micronutrient deficiency, and poor perinatal outcomes remain common and contribute to a lifelong burden of disease. These challenges echo the UN sustainable development goals and concentrating on them in a unified strategy will be necessary to address the national burden of disease. At a time when the country is going through societal and political transition, we draw focus on the country and the need for resolution of its healthcare needs.
Maric T, Kanu C, Johnson MR, et al., 2019, Maternal, neonatal insulin resistance and neonatal anthropometrics in pregnancies following bariatric surgery, METABOLISM-CLINICAL AND EXPERIMENTAL, Vol: 97, Pages: 25-31, ISSN: 0026-0495
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Bauersachs J, König T, van der Meer P, et al., 2019, Pathophysiology, diagnosis and management of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on peripartum cardiomyopathy, European Journal of Heart Failure, Vol: 21, Pages: 827-843, ISSN: 1388-9842
Peripartum cardiomyopathy (PPCM) is a potentially life-threatening condition typically presenting as heart failure with reduced ejection fraction (HFrEF) in the last month of pregnancy or in the months following delivery in women without another known cause of heart failure. This updated position statement summarizes the knowledge about pathophysiological mechanisms, risk factors, clinical presentation, diagnosis and management of PPCM. As shortness of breath, fatigue and leg oedema are common in the peripartum period, a high index of suspicion is required to not miss the diagnosis. Measurement of natriuretic peptides, electrocardiography and echocardiography are recommended to promptly diagnose or exclude heart failure/PPCM. Important differential diagnoses include pulmonary embolism, myocardial infarction, hypertensive heart disease during pregnancy, and pre-existing heart disease. A genetic contribution is present in up to 20% of PPCM, in particular titin truncating variant. PPCM is associated with high morbidity and mortality, but also with a high probability of partial and often full recovery. Use of guideline-directed pharmacological therapy for HFrEF is recommended in all patients respecting contraindications during pregnancy/lactation. The oxidative stress-mediated cleavage of the hormone prolactin into a cardiotoxic fragment has been identified as a driver of PPCM pathophysiology. Pharmacological blockade of prolactin release using bromocriptine as a disease-specific therapy in addition to standard therapy for heart failure treatment has shown promising results in two clinical trials. Thresholds for devices (implantable cardioverter-defibrillators, cardiac resynchronization therapy and implanted long-term ventricular assist devices) are higher in PPCM than in other conditions because of the high rate of recovery. The important role of education and counselling around contraception and future pregnancies is emphasised.
Baris L, Cornette J, Johnson MR, et al., 2019, Postpartum cardiomyopathy and endocrinopathy, Heart, Vol: 105, Pages: 1047-1047, ISSN: 1355-6037
Baris L, Cornette J, Johnson MR, et al., 2019, PPCM and the endocrine system., Heart, Vol: 105, Pages: 1047-1048, ISSN: 1468-201X
We sincerely thank Dr Jolobe for the response to our paper1 and very much appreciate the interesting addition2 to the discussion on this difficult topic. It is true that autoimmunity has been proposed to play a role in the aetiology of Peripartum Cardiomyopathy (PPCM), as we mention in our introduction. Furthermore, it is indeed well known that congestive heart failure due to (dilated) cardiomyopathy can occur in patients with hypopituitarism or acute pituitary failure,3 4 as well as in adrenal insufficiency3 and thyroid dysfunction.5 However, there are numerous case reports supporting that this is certainly not exclusive to a peripartum onset.6–8 According to the latest definition from the Heart Failure Association of the European Society of Cardiology (ESC) Working Group on PPCM, PPCM is defined as an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found.9 We therefore believe that the women Dr Jolobe mentions in the response, while very interesting and certainly worth discussing in the context of our paper, did not suffer from PPCM. Of course, the endocrine system and specifically the pituitary will undergo major changes during pregnancy, and many cases of acute heart failure due to Sheenan syndrome and postpartum haemorrhage have been reported in the literature.3 10 11 However, cardiomyopathy secondary to Sheenan syndrome is just that. While the peripartum onset mimics PPCM and thus poses a diagnostic dilemma, it is important to make the distinction for, as Dr Jolobe rightly points out, patients may not benefit from conventional heart failure therapy.11 We therefore wholeheartedly agree with Dr Jolobe that in women with peripartum-onset heart failure of unknown cause, evaluation of the endocrine status is mandatory.
Cauldwell M, Steer P, Johnson MR, 2019, Response to 'Pregnancy in women with pre-existent ischaemic heart disease', Heart, Vol: 105, Pages: 893-894, ISSN: 1355-6037
Pollock T, Kanu C, Lai P, et al., 2019, Placental expression of corticotrophin-releasing hormone and tumour necrosis factor in pregnancies with previous bariatric surgery compared to those without, Publisher: WILEY, Pages: 60-61, ISSN: 1470-0328
Stanfield Z, Lai PF, Lei K, et al., 2019, Corrigendum: Myometrial transcriptional signatures of human parturition, Frontiers in Genetics, Vol: 10, ISSN: 1664-8021
A Corrigendum onMyometrial Transcriptional Signatures of Human Parturitionby Stanfield, Z., Lai, P. F., Lei, K., Johnson, M. R., Blanks, A. M., Romero, R., et al. (2019). Front. Genet. 10:185. doi: 10.3389/fgene.2019.00185“Pei F. Lai” and “Kaiyu Lei” were not included as authors in the published article. Due to the addition of authors, the list of affiliations had been updated accordingly. The corrected Author Contributions Statement appears below.
Stanfield Z, Johnson MR, Blanks AM, et al., 2019, Myometrial transcriptional signatures of human parturition, Frontiers in Genetics, Vol: 10, ISSN: 1664-8021
The process of parturition involves the transformation of the quiescent myometrium (uterine smooth muscle) to the highly contractile laboring state. This is thought to be driven by changes in gene expression in myometrial cells. Despite the existence of multiple myometrial gene expression studies, the transcriptional programs that initiate labor are not known. Here, we integrated three transcriptome datasets, one novel (NCBI Gene Expression Ominibus: GSE80172) and two existing, to characterize the gene expression changes in myometrium associated with the onset of labor at term. Computational analyses including classification, singular value decomposition, pathway enrichment, and network inference were applied to individual and combined datasets. Outcomes across studies were integrated with multiple protein and pathway databases to build a myometrial parturition signaling network. A high-confidence (significant across all studies) set of 126 labor genes were identified and machine learning models exhibited high reproducibility between studies. Labor signatures included both known (interleukins, cytokines) and unknown (apoptosis, MYC, cell proliferation/differentiation) pathways while cyclic AMP signaling and muscle relaxation were associated with non-labor. These signatures accurately classified and characterized the stages of labor. The data-derived parturition signaling networks provide new genes/signaling interactions to understand phenotype-specific processes and aid in future studies of parturition.
Bonney EA, Johnson MR, 2019, The role of maternal T cell and macrophage activation in preterm birth: Cause or consequence?, PLACENTA, Vol: 79, Pages: 53-61, ISSN: 0143-4004
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Shah NM, Lai PF, Imami N, et al., 2019, Progesterone-related immune modulation of pregnancy and labor, Frontiers in Endocrinology, Vol: 10, ISSN: 1664-2392
Pregnancy involves a complex interplay between maternal neuroendocrine and immunological systems in order to establish and sustain a growing fetus. It is thought that the uterus at pregnancy transitions from quiescent to laboring state in response to interactions between maternal and fetal systems at least partly via altered neuroendocrine signaling. Progesterone (P4) is a vital hormone in maternal reproductive tissues and immune cells during pregnancy. As such, P4 is widely used in clinical interventions to improve the chance of embryo implantation, as well as reduce the risk of miscarriage and premature labor. Here we review research to date that focus on the pathways through which P4 mediates its actions on both the maternal reproductive and immune system. We will dissect the role of P4 as a modulator of inflammation, both systemic and intrinsic to the uterus, during human pregnancy and labor.
Vieira MC, Relph S, Copas A, et al., 2019, The DESiGN trial (DEtection of small for gestational age neonate), evaluating the effect of the Growth Assessment Protocol (GAP): study protocol for a randomised controlled trial, Trials, Vol: 20, ISSN: 1745-6215
BackgroundStillbirth rates in the United Kingdom (UK) are amongst the highest of all developed nations. The association between small-for-gestational-age (SGA) foetuses and stillbirth is well established, and observational studies suggest that improved antenatal detection of SGA babies may halve the stillbirth rate. The Growth Assessment Protocol (GAP) describes a complex intervention that includes risk assessment for SGA and screening using customised fundal-height growth charts. Increased detection of SGA from the use of GAP has been implicated in the reduction of stillbirth rates by 22%, in observational studies of UK regions where GAP uptake was high. This study will be the first randomised controlled trial examining the clinical efficacy, health economics and implementation of the GAP programme in the antenatal detection of SGA.Methods/designIn this randomised controlled trial, clusters comprising a maternity unit (or National Health Service Trust) were randomised to either implementation of the GAP programme, or standard care. The primary outcome is the rate of antenatal ultrasound detection of SGA in infants found to be SGA at birth by both population and customised standards, as this is recognised as being the group with highest risk for perinatal morbidity and mortality. Secondary outcomes include antenatal detection of SGA by population centiles, antenatal detection of SGA by customised centiles, short-term maternal and neonatal outcomes, resource use and economic consequences, and a process evaluation of GAP implementation. Qualitative interviews will be performed to assess facilitators and barriers to implementation of GAP.DiscussionThis study will be the first to provide data and outcomes from a randomised controlled trial investigating the potential difference between the GAP programme compared to standard care for antenatal ultrasound detection of SGA infants. Accurate information on the performance and service provision requirements of the GAP protoc
Baris L, Cornette J, Johnson MR, et al., 2019, Peripartum cardiomyopathy: disease or syndrome?, Heart, Vol: 105, Pages: 357-362, ISSN: 1355-6037
Peripartum cardiomyopathy (PPCM) is a rare form of pregnancy-associated heart failure and is considered to be a diagnosis of exclusion. There are many hypotheses on the aetiology of PPCM; however, the exact pathophysiological mechanism remains unknown. It shows many resemblances to other conditions, such as familial dilated cardiomyopathy or myocarditis, and therefore it can be hard to make a definite diagnosis. We describe four cases of peripartum-onset heart failure in women who were suspected of having PPCM. We discuss the differential diagnosis, pathophysiological mechanisms and various diagnostic modalities.
Sooranna GR, Shah NM, Singh N, et al., 2019, The Immune Modulatory Effects of Both Progesterone and a Combination of Progesterone and Aminophylline on the Maternal Immune System., 66th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 293A-293A, ISSN: 1933-7191
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