It is widely debated whether fetal membranes possess a genuine microbiome, and if bacterial prese... more It is widely debated whether fetal membranes possess a genuine microbiome, and if bacterial presence and load is linked to inflammation. Chorioamnionitis is an inflammation of the fetal membranes. This research focussed on inflammatory diagnosed histological chorioamnionitis (HCA) and aims to determine whether the bacterial load in fetal membranes correlates to inflammatory response, including histological staging and inflammatory markers in HCA. Methods Fetal membrane samples were collected from patients with preterm spontaneous labour and histologically phenotyped chorioamnionitis (HCA; n=12), or preterm (n=6) and term labour without HCA (n=6). The bacterial profile of fetal membranes was analysed by sequencing the V4 region of the 16S rRNA gene. Bacterial load was determined using qPCR copy number/mg of tissue. The association between bacterial load and bacterial profile composition was assessed using correlation analysis. Results Bacterial load was significantly greater within HCA amnion (p=0.002) and chorion (p=0.042), compared to preterm birth without HCA. Increased bacterial load was positively correlated with increased histological staging (p=0.001) and the expression of five inflammatory markers; IL8, TLR1, TLR2, LY96 and IRAK2 (p=<0.050). Bacterial profiles were significantly different between membranes with and without HCA in amnion (p=0.012) and chorion (p=0.001), but no differences between specific genera were detected. Discussion 4 Inflammatory HCA is associated with infection and increased bacterial load in a dose response relationship. Bacterial load is positively correlated with HCA severity and the TLR signalling pathway. Further research should investigate the bacterial load threshold required to generate an inflammatory response in HCA. Short title: Fetal membrane bacterial load is increased in HCA Highlights:-Increased bacterial load was significantly associated with inflammation-Bacterial load is correlated with HCA severity in a dose dependent manner-Bacterial load is correlated to the TLR signalling pathway-Non-HCA samples and negative controls are not distinct in bacterial load.
Health technology assessment (Winchester, England), 2017
The National Institute for Health and Care Excellence (NICE) guidelines highlighted the need for ... more The National Institute for Health and Care Excellence (NICE) guidelines highlighted the need for 'large, high-quality prospective studies comparing the various methods of measuring proteinuria in women with new-onset hypertensive disorders during pregnancy'. The primary objective was to evaluate quantitative assessments of spot protein-creatinine ratio (SPCR) and spot albumin-creatinine ratio (SACR) in predicting severe pre-eclampsia (PE) compared with 24-hour urine protein measurement. The secondary objectives were to investigate interlaboratory assay variation, to evaluate SPCR and SACR thresholds in predicting adverse maternal and fetal outcomes and to assess the cost-effectiveness of these models. This was a prospective diagnostic accuracy cohort study, with decision-analytic modelling and a cost-effectiveness analysis. The setting was 36 obstetric units in England, UK. Pregnant women (aged ≥ 16 years), who were at > 20 weeks' gestation with confirmed gestational ...
BackgroundCurrent pathways for testing fetuses at increased risk of a chromosomal anomaly because... more BackgroundCurrent pathways for testing fetuses at increased risk of a chromosomal anomaly because of an ultrasound anomaly involve karyotyping after rapid aneuploidy exclusion. Chromosomal microarray (CMA) may detect more clinically significant chromosomal imbalances than karyotyping but evidence to guide UK health service providers on whether or not CMA should replace karyotyping is limited.Objectives(1) To compare detection rates of copy number variants (CNVs) and laboratory turnaround times (TATs) by karyotyping and CMA in fetuses with ultrasound anomalies, (2) to calculate test costs and the cost per additional pathogenic CNV detected by CMA relative to karyotyping and (3) to determine what factors influence parents’ and health professionals’ choice and decision-making about CMA.DesignA multicentre experimental research cohort study with an additional cost analysis.SettingA total of 20 fetal medicine units and nine cytogenetic laboratories across England and Wales.ParticipantsWo...
Where a licence is displayed above, please note the terms and conditions of the licence govern yo... more Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive.
Gestational diabetes affects 3 to 5% of pregnancies in the United Kingdom, contributing to signif... more Gestational diabetes affects 3 to 5% of pregnancies in the United Kingdom, contributing to significant maternal and fetal morbidity. Understanding the pathophysiology is important as it guides diagnostic screening and treatment. The insulin resistance of normal pregnancy facilitates provision of metabolic substrates to the fetus and is multifactorial in origin. Recent identification of hepatic and skeletal muscle lipid deposition in Type 2 diabetics, demonstrated by novel magnetic resonance spectroscopy techniques, is likely to be the underlying cause of pathological insulin resistance. Similar mechanisms almost certainly underlie gestational diabetes, although further studies are required to prove this. Women who develop gestational diabetes have demonstrable insulin resistance prior to pregnancy that is part of a chronic process of lipid accumulation ultimately leading to type 2 diabetes later in life. The importance of lifestyle advice and dietary modification and the rationale b...
In-utero MRI (iuMRI) has shown promise as an adjunct to ultrasound but the comparative diagnostic... more In-utero MRI (iuMRI) has shown promise as an adjunct to ultrasound but the comparative diagnostic performance has been poorly defined. We aimed to assess whether the diagnostic accuracy and confidence of the prenatal diagnosis of fetal brain abnormalities is improved with iuMRI and assess the clinical impact and patient acceptability of iuMRI. We did a multicentre, prospective, cohort study in the UK, at 16 fetal medicine centres, of pregnant women aged 16 years or older whose fetus had a brain abnormality detected by ultrasound at a gestational age of 18 weeks or more, had no contraindications to iuMRI, and consented to enter the study. Women carrying a fetus suspected of having a brain anomaly on ultrasound had iuMRI done within 14 days of ultrasound. The findings were reviewed by two independent panels and used to estimate diagnostic accuracy and confidence by comparison with outcome diagnoses. Changes in diagnosis, prognosis, and clinical management brought about by iuMRI and pa...
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2016
Condensation This pilot RCT suggests day-case management of severe nausea and vomiting in pregnan... more Condensation This pilot RCT suggests day-case management of severe nausea and vomiting in pregnancy is an effective alternative to in-patient management for some women.
Histological chorioamnionitis (HCA) is an established marker of ascending infection, a major caus... more Histological chorioamnionitis (HCA) is an established marker of ascending infection, a major cause of preterm birth. No studies have characterised the global change in expression of genes involved in the toll-like receptor (TLR) signalling pathways in the presence of HCA in the setting of preterm birth (pHCA). Fetal membranes were collected immediately after delivery and underwent histological staging for inflammation to derive 3 groups; term spontaneous labour without HCA (n = 9), preterm birth <34 weeks gestation without HCA (n = 8) and pHCA <34 weeks (n = 12). Profiling arrays ran in triplicate for each group were used to determine the expression of 84 genes associated with TLR signalling and screen for genes of interest (fold change >2; p<0.1). Expression of identified genes was validated individually for all samples, relative to GAPDH, using RT-PCR. Expression of TLR 1, TLR 2, lymphocyte antigen 96, interleukin 8 and Interleukin-1 receptor-associated kinase-like 2 w...
Background: Maternal obesity is associated with an increased risk of pregnancy complications, inc... more Background: Maternal obesity is associated with an increased risk of pregnancy complications, including gestational diabetes. Physical activity (PA) might improve glucose metabolism and reduce the incidence of gestational diabetes. The purpose of this study was to explore patterns of PA and factors associated with change in PA in obese pregnant women. Methods: PA was assessed objectively by accelerometer at 16-18 weeks' (T0), 27-28 weeks' (T1) and 35-36 weeks' gestation (T2) in 183 obese pregnant women recruited to a pilot randomised trial of a combined diet and PA intervention (the UPBEAT study). Results: Valid PA data were available for 140 (77%), 76 (42%) and 54 (30%) women at T0, T1 and T2 respectively. Moderate and vigorous physical activity as a proportion of accelerometer wear time declined with gestation from a median of 4.8% at T0 to 3% at T2 (p < 0.05). Total activity as a proportion of accelerometer wear time did not change. Being more active in early pregnancy was associated with a higher level of PA later in pregnancy. The intervention had no effect on PA. Conclusions: PA in early pregnancy was the factor most strongly associated with PA at later gestations. Women should be encouraged to participate in PA before becoming pregnant and to maintain their activity levels during pregnancy. There is a need for effective interventions, tailored to the needs of individuals and delivered early in pregnancy to support obese women to be sufficiently active during pregnancy. Trial registration: Current Controlled Trials ISRCTN89971375 (Registered 28/11/2008).
Human parturition is associated with a modification in the sensitivity of the myometrium to proge... more Human parturition is associated with a modification in the sensitivity of the myometrium to progesterone. The molecular basis for this change, however, remains unclear. It is well documented that progesterone can exert its effects through non-genomic mechanisms, including acting through membrane-bound progesterone receptors (mPRs). Recently, a novel membrane-bound PR, termed mPR␣, was cloned. mPR␣ was unlike any other PR in the databases, but it was seen to have significant homology to Gprotein-coupled receptors (GPCR). In this study, we examined the spatio-temporal expression of mPR␣ mRNA in human cervix and both lower and upper myometrial segments from non-pregnant (NP), pregnant (P) and spontaneously labouring (SL) women. We observed an incremental increase in mPR␣ mRNA expression in NP and P samples with the peak level being observed in SL tissues. No major differences were observed between upper or lower pregnant myometrial regions. Interestingly, levels of mPR␣ transcripts were substantially greater in labouring lower segment myometrium compared with labouring upper segment. Significantly, we failed to detect mPR␣ message in either unripe or ripe human cervices. These data suggest that mPR␣ protein function may play a role in regulating lower segment myometrial activity during labour. Whether it functions in the cervix, however, remains unclear.
In humans, the factors that govern the switch from myometrial quiescence to coordinated contracti... more In humans, the factors that govern the switch from myometrial quiescence to coordinated contractions at the initiation of labor are not well defined. The onset of parturition is itself associated with increases in a number of proinflammatory mediators, many of which are regulated by the nuclear factor B (NF-B) family of transcription factors. Recently, we have provided evidence that the RelA NF-B subunit associates with protein kinase A in pregnant myometrial tissue, suggesting links with the G␣s/cAMP/protein kinase A pathway. TNF␣ is a potent activator of NF-B, and levels of this cytokine are increased within the myometrium at term. In the current study, using primary cultures of myometrial cells, TNF␣ was observed to repress expression of G␣s while, at the same time, stimulating NF-B activity. Furthermore, this effect could be
New proteinuria Presence of proteinuria as shown by ≥ + (300 mg/l) on dipstick testing, a protein... more New proteinuria Presence of proteinuria as shown by ≥ + (300 mg/l) on dipstick testing, a protein to creatinine ratio of ≥ 30 mg/mmol on a random sample, or a urine protein excretion of ≥ 300 mg in 24 hours Quantified proteinuria Urine protein excretion ≥ 300 mg in 24 hours Pre-eclampsia New hypertension and quantified proteinuria at or after 20 weeks of pregnancy, confirmed if it resolves after delivery Superimposed pre-eclampsia Development of features of pre-eclampsia in context of pre-existing hypertension or pre-existing proteinuria, or both Further details concerning the guideline are on bmj.com
Background: Preterm birth is a global problem, with a prevalence of 8 to 12% depending on locatio... more Background: Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location.. Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth). Although an improvement in short term neonatal outcomes has been shown in some trials these have not consistently been confirmed in meta-analyses. Additionally data on longer term outcomes is limited to a single trial where no difference in outcomes was demonstrated at four years of age of the child, despite those in the "progesterone" group having a lower incidence of preterm birth. Methods/Design: The OPPTIMUM study is a double blind randomized placebo controlled trial to determine whether progesterone prophylaxis to prevent preterm birth has long term neonatal or infant benefit. Specifically it will study whether, in women with singleton pregnancy and at high risk of preterm labour, prophylactic vaginal natural progesterone, 200 mg daily from 22-34 weeks gestation, compared to placebo, improves obstetric outcome by lengthening pregnancy thus reducing the incidence of preterm delivery (before 34 weeks), improves neonatal outcome by reducing a composite of death and major morbidity, and leads to improved childhood cognitive and neurosensory outcomes at two years of age. Recruitment began in 2009 and is scheduled to close in Spring 2013. As of May 2012, over 800 women had been randomized in 60 sites.
Background Around one-third of pregnant women suffer from moderate to severe nausea and vomiting,... more Background Around one-third of pregnant women suffer from moderate to severe nausea and vomiting, causing physical and emotional distress and reducing their quality of life. There is no cure for nausea and vomiting in pregnancy. Management focuses on relieving symptoms and preventing morbidity, and often requires antiemetic therapy. National guidelines make recommendations about first-, second- and third-line antiemetic therapies, although care varies in different hospitals and women report feeling unsupported, dissatisfied and depressed. Objectives To determine whether or not, in addition to intravenous rehydration, ondansetron compared with no ondansetron and metoclopramide compared with no metoclopramide reduced the rate of treatment failure up to 10 days after drug initiation; improved symptom severity at 2, 5 and 10 days after drug initiation; improved quality of life at 10 days after drug initiation; and had an acceptable side effect and safety profile. To estimate the increme...
Background In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unc... more Background In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unclear because limitation of maternal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of neonatal or infant outcomes, compared with expectant management (usual care) in women with late preterm pre-eclampsia. Methods In this parallel-group, non-masked, multicentre, randomised controlled trial done in 46 maternity units across England and Wales, we compared planned delivery versus expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia from 34 to less than 37 weeks' gestation and a singleton or dichorionic diamniotic twin pregnancy. The co-primary maternal outcome was a composite of maternal morbidity or recorded systolic blood pressure of at least 160 mm Hg with a superiority hypothesis. The co-primary perinatal outcome was a composite of perinatal deaths or neonatal unit admission up to infant hospital discharge with a noninferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were by intention to treat, together with a per-protocol analysis for the perinatal outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN01879376. The trial is closed to recruitment but follow-up is ongoing.
Background: Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem ... more Background: Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem complications in the mother. The adverse outcomes of pre-eclampsia include severe hypertension, stroke, renal and hepatic injury, haemorrhage, fetal growth restriction and even death. The optimal time to instigate delivery to prevent morbidity when pre-eclampsia occurs between 34 and 37 weeks' gestation, without increasing problems related to infant immaturity or complications, remains unclear. Methods/design: The PHOENIX trial is a non-masked, randomised controlled trial, comparing planned early delivery (with initiation of delivery within 48 h of randomisation) with usual care (expectant management) in women with pre-eclampsia between 34 + 0 and 36 + 6 weeks' gestation. The primary objectives of the trial are to determine if planned delivery reduces adverse maternal outcomes, without increasing the short-term harm to infants (composite of perinatal deaths or neonatal unit admissions up to infant hospital discharge) or impacting long-term infant neurodevelopmental status at 2 years corrected age (Parent Report of Cognitive Abilities-Revised). Discussion: Current practice in the UK at the time of trial commencement for management of pre-eclampsia varies by gestation. Previous trials have shown that in women with pre-eclampsia after 37 weeks of gestion, delivery is initiated, as maternal complications are reduced without increasing fetal risks. Prior to 34 weeks of gestation, usual management aims to prolong pregnancy for fetal benefit, unless severe complications occur, necessitating preterm delivery. This trial aims to address the uncertainty for women where the balance of benefits and risks of delivery compared to expectant management are uncertain. Previous trials in this area have been undertaken, but have not provided a definitive answer, and the research question remains active. The results of this trial are expected to influence clinical practice internationally, through direct adoption and by incorporation into guidelines in countries with similar settings.
To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia... more To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35. Randomised, phase III, double blinded international, multicentre clinical trial. 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). 2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses. Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation. The primary outcome was...
It is widely debated whether fetal membranes possess a genuine microbiome, and if bacterial prese... more It is widely debated whether fetal membranes possess a genuine microbiome, and if bacterial presence and load is linked to inflammation. Chorioamnionitis is an inflammation of the fetal membranes. This research focussed on inflammatory diagnosed histological chorioamnionitis (HCA) and aims to determine whether the bacterial load in fetal membranes correlates to inflammatory response, including histological staging and inflammatory markers in HCA. Methods Fetal membrane samples were collected from patients with preterm spontaneous labour and histologically phenotyped chorioamnionitis (HCA; n=12), or preterm (n=6) and term labour without HCA (n=6). The bacterial profile of fetal membranes was analysed by sequencing the V4 region of the 16S rRNA gene. Bacterial load was determined using qPCR copy number/mg of tissue. The association between bacterial load and bacterial profile composition was assessed using correlation analysis. Results Bacterial load was significantly greater within HCA amnion (p=0.002) and chorion (p=0.042), compared to preterm birth without HCA. Increased bacterial load was positively correlated with increased histological staging (p=0.001) and the expression of five inflammatory markers; IL8, TLR1, TLR2, LY96 and IRAK2 (p=<0.050). Bacterial profiles were significantly different between membranes with and without HCA in amnion (p=0.012) and chorion (p=0.001), but no differences between specific genera were detected. Discussion 4 Inflammatory HCA is associated with infection and increased bacterial load in a dose response relationship. Bacterial load is positively correlated with HCA severity and the TLR signalling pathway. Further research should investigate the bacterial load threshold required to generate an inflammatory response in HCA. Short title: Fetal membrane bacterial load is increased in HCA Highlights:-Increased bacterial load was significantly associated with inflammation-Bacterial load is correlated with HCA severity in a dose dependent manner-Bacterial load is correlated to the TLR signalling pathway-Non-HCA samples and negative controls are not distinct in bacterial load.
Health technology assessment (Winchester, England), 2017
The National Institute for Health and Care Excellence (NICE) guidelines highlighted the need for ... more The National Institute for Health and Care Excellence (NICE) guidelines highlighted the need for 'large, high-quality prospective studies comparing the various methods of measuring proteinuria in women with new-onset hypertensive disorders during pregnancy'. The primary objective was to evaluate quantitative assessments of spot protein-creatinine ratio (SPCR) and spot albumin-creatinine ratio (SACR) in predicting severe pre-eclampsia (PE) compared with 24-hour urine protein measurement. The secondary objectives were to investigate interlaboratory assay variation, to evaluate SPCR and SACR thresholds in predicting adverse maternal and fetal outcomes and to assess the cost-effectiveness of these models. This was a prospective diagnostic accuracy cohort study, with decision-analytic modelling and a cost-effectiveness analysis. The setting was 36 obstetric units in England, UK. Pregnant women (aged ≥ 16 years), who were at > 20 weeks' gestation with confirmed gestational ...
BackgroundCurrent pathways for testing fetuses at increased risk of a chromosomal anomaly because... more BackgroundCurrent pathways for testing fetuses at increased risk of a chromosomal anomaly because of an ultrasound anomaly involve karyotyping after rapid aneuploidy exclusion. Chromosomal microarray (CMA) may detect more clinically significant chromosomal imbalances than karyotyping but evidence to guide UK health service providers on whether or not CMA should replace karyotyping is limited.Objectives(1) To compare detection rates of copy number variants (CNVs) and laboratory turnaround times (TATs) by karyotyping and CMA in fetuses with ultrasound anomalies, (2) to calculate test costs and the cost per additional pathogenic CNV detected by CMA relative to karyotyping and (3) to determine what factors influence parents’ and health professionals’ choice and decision-making about CMA.DesignA multicentre experimental research cohort study with an additional cost analysis.SettingA total of 20 fetal medicine units and nine cytogenetic laboratories across England and Wales.ParticipantsWo...
Where a licence is displayed above, please note the terms and conditions of the licence govern yo... more Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive.
Gestational diabetes affects 3 to 5% of pregnancies in the United Kingdom, contributing to signif... more Gestational diabetes affects 3 to 5% of pregnancies in the United Kingdom, contributing to significant maternal and fetal morbidity. Understanding the pathophysiology is important as it guides diagnostic screening and treatment. The insulin resistance of normal pregnancy facilitates provision of metabolic substrates to the fetus and is multifactorial in origin. Recent identification of hepatic and skeletal muscle lipid deposition in Type 2 diabetics, demonstrated by novel magnetic resonance spectroscopy techniques, is likely to be the underlying cause of pathological insulin resistance. Similar mechanisms almost certainly underlie gestational diabetes, although further studies are required to prove this. Women who develop gestational diabetes have demonstrable insulin resistance prior to pregnancy that is part of a chronic process of lipid accumulation ultimately leading to type 2 diabetes later in life. The importance of lifestyle advice and dietary modification and the rationale b...
In-utero MRI (iuMRI) has shown promise as an adjunct to ultrasound but the comparative diagnostic... more In-utero MRI (iuMRI) has shown promise as an adjunct to ultrasound but the comparative diagnostic performance has been poorly defined. We aimed to assess whether the diagnostic accuracy and confidence of the prenatal diagnosis of fetal brain abnormalities is improved with iuMRI and assess the clinical impact and patient acceptability of iuMRI. We did a multicentre, prospective, cohort study in the UK, at 16 fetal medicine centres, of pregnant women aged 16 years or older whose fetus had a brain abnormality detected by ultrasound at a gestational age of 18 weeks or more, had no contraindications to iuMRI, and consented to enter the study. Women carrying a fetus suspected of having a brain anomaly on ultrasound had iuMRI done within 14 days of ultrasound. The findings were reviewed by two independent panels and used to estimate diagnostic accuracy and confidence by comparison with outcome diagnoses. Changes in diagnosis, prognosis, and clinical management brought about by iuMRI and pa...
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2016
Condensation This pilot RCT suggests day-case management of severe nausea and vomiting in pregnan... more Condensation This pilot RCT suggests day-case management of severe nausea and vomiting in pregnancy is an effective alternative to in-patient management for some women.
Histological chorioamnionitis (HCA) is an established marker of ascending infection, a major caus... more Histological chorioamnionitis (HCA) is an established marker of ascending infection, a major cause of preterm birth. No studies have characterised the global change in expression of genes involved in the toll-like receptor (TLR) signalling pathways in the presence of HCA in the setting of preterm birth (pHCA). Fetal membranes were collected immediately after delivery and underwent histological staging for inflammation to derive 3 groups; term spontaneous labour without HCA (n = 9), preterm birth <34 weeks gestation without HCA (n = 8) and pHCA <34 weeks (n = 12). Profiling arrays ran in triplicate for each group were used to determine the expression of 84 genes associated with TLR signalling and screen for genes of interest (fold change >2; p<0.1). Expression of identified genes was validated individually for all samples, relative to GAPDH, using RT-PCR. Expression of TLR 1, TLR 2, lymphocyte antigen 96, interleukin 8 and Interleukin-1 receptor-associated kinase-like 2 w...
Background: Maternal obesity is associated with an increased risk of pregnancy complications, inc... more Background: Maternal obesity is associated with an increased risk of pregnancy complications, including gestational diabetes. Physical activity (PA) might improve glucose metabolism and reduce the incidence of gestational diabetes. The purpose of this study was to explore patterns of PA and factors associated with change in PA in obese pregnant women. Methods: PA was assessed objectively by accelerometer at 16-18 weeks' (T0), 27-28 weeks' (T1) and 35-36 weeks' gestation (T2) in 183 obese pregnant women recruited to a pilot randomised trial of a combined diet and PA intervention (the UPBEAT study). Results: Valid PA data were available for 140 (77%), 76 (42%) and 54 (30%) women at T0, T1 and T2 respectively. Moderate and vigorous physical activity as a proportion of accelerometer wear time declined with gestation from a median of 4.8% at T0 to 3% at T2 (p < 0.05). Total activity as a proportion of accelerometer wear time did not change. Being more active in early pregnancy was associated with a higher level of PA later in pregnancy. The intervention had no effect on PA. Conclusions: PA in early pregnancy was the factor most strongly associated with PA at later gestations. Women should be encouraged to participate in PA before becoming pregnant and to maintain their activity levels during pregnancy. There is a need for effective interventions, tailored to the needs of individuals and delivered early in pregnancy to support obese women to be sufficiently active during pregnancy. Trial registration: Current Controlled Trials ISRCTN89971375 (Registered 28/11/2008).
Human parturition is associated with a modification in the sensitivity of the myometrium to proge... more Human parturition is associated with a modification in the sensitivity of the myometrium to progesterone. The molecular basis for this change, however, remains unclear. It is well documented that progesterone can exert its effects through non-genomic mechanisms, including acting through membrane-bound progesterone receptors (mPRs). Recently, a novel membrane-bound PR, termed mPR␣, was cloned. mPR␣ was unlike any other PR in the databases, but it was seen to have significant homology to Gprotein-coupled receptors (GPCR). In this study, we examined the spatio-temporal expression of mPR␣ mRNA in human cervix and both lower and upper myometrial segments from non-pregnant (NP), pregnant (P) and spontaneously labouring (SL) women. We observed an incremental increase in mPR␣ mRNA expression in NP and P samples with the peak level being observed in SL tissues. No major differences were observed between upper or lower pregnant myometrial regions. Interestingly, levels of mPR␣ transcripts were substantially greater in labouring lower segment myometrium compared with labouring upper segment. Significantly, we failed to detect mPR␣ message in either unripe or ripe human cervices. These data suggest that mPR␣ protein function may play a role in regulating lower segment myometrial activity during labour. Whether it functions in the cervix, however, remains unclear.
In humans, the factors that govern the switch from myometrial quiescence to coordinated contracti... more In humans, the factors that govern the switch from myometrial quiescence to coordinated contractions at the initiation of labor are not well defined. The onset of parturition is itself associated with increases in a number of proinflammatory mediators, many of which are regulated by the nuclear factor B (NF-B) family of transcription factors. Recently, we have provided evidence that the RelA NF-B subunit associates with protein kinase A in pregnant myometrial tissue, suggesting links with the G␣s/cAMP/protein kinase A pathway. TNF␣ is a potent activator of NF-B, and levels of this cytokine are increased within the myometrium at term. In the current study, using primary cultures of myometrial cells, TNF␣ was observed to repress expression of G␣s while, at the same time, stimulating NF-B activity. Furthermore, this effect could be
New proteinuria Presence of proteinuria as shown by ≥ + (300 mg/l) on dipstick testing, a protein... more New proteinuria Presence of proteinuria as shown by ≥ + (300 mg/l) on dipstick testing, a protein to creatinine ratio of ≥ 30 mg/mmol on a random sample, or a urine protein excretion of ≥ 300 mg in 24 hours Quantified proteinuria Urine protein excretion ≥ 300 mg in 24 hours Pre-eclampsia New hypertension and quantified proteinuria at or after 20 weeks of pregnancy, confirmed if it resolves after delivery Superimposed pre-eclampsia Development of features of pre-eclampsia in context of pre-existing hypertension or pre-existing proteinuria, or both Further details concerning the guideline are on bmj.com
Background: Preterm birth is a global problem, with a prevalence of 8 to 12% depending on locatio... more Background: Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location.. Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth). Although an improvement in short term neonatal outcomes has been shown in some trials these have not consistently been confirmed in meta-analyses. Additionally data on longer term outcomes is limited to a single trial where no difference in outcomes was demonstrated at four years of age of the child, despite those in the "progesterone" group having a lower incidence of preterm birth. Methods/Design: The OPPTIMUM study is a double blind randomized placebo controlled trial to determine whether progesterone prophylaxis to prevent preterm birth has long term neonatal or infant benefit. Specifically it will study whether, in women with singleton pregnancy and at high risk of preterm labour, prophylactic vaginal natural progesterone, 200 mg daily from 22-34 weeks gestation, compared to placebo, improves obstetric outcome by lengthening pregnancy thus reducing the incidence of preterm delivery (before 34 weeks), improves neonatal outcome by reducing a composite of death and major morbidity, and leads to improved childhood cognitive and neurosensory outcomes at two years of age. Recruitment began in 2009 and is scheduled to close in Spring 2013. As of May 2012, over 800 women had been randomized in 60 sites.
Background Around one-third of pregnant women suffer from moderate to severe nausea and vomiting,... more Background Around one-third of pregnant women suffer from moderate to severe nausea and vomiting, causing physical and emotional distress and reducing their quality of life. There is no cure for nausea and vomiting in pregnancy. Management focuses on relieving symptoms and preventing morbidity, and often requires antiemetic therapy. National guidelines make recommendations about first-, second- and third-line antiemetic therapies, although care varies in different hospitals and women report feeling unsupported, dissatisfied and depressed. Objectives To determine whether or not, in addition to intravenous rehydration, ondansetron compared with no ondansetron and metoclopramide compared with no metoclopramide reduced the rate of treatment failure up to 10 days after drug initiation; improved symptom severity at 2, 5 and 10 days after drug initiation; improved quality of life at 10 days after drug initiation; and had an acceptable side effect and safety profile. To estimate the increme...
Background In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unc... more Background In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unclear because limitation of maternal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of neonatal or infant outcomes, compared with expectant management (usual care) in women with late preterm pre-eclampsia. Methods In this parallel-group, non-masked, multicentre, randomised controlled trial done in 46 maternity units across England and Wales, we compared planned delivery versus expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia from 34 to less than 37 weeks' gestation and a singleton or dichorionic diamniotic twin pregnancy. The co-primary maternal outcome was a composite of maternal morbidity or recorded systolic blood pressure of at least 160 mm Hg with a superiority hypothesis. The co-primary perinatal outcome was a composite of perinatal deaths or neonatal unit admission up to infant hospital discharge with a noninferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were by intention to treat, together with a per-protocol analysis for the perinatal outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN01879376. The trial is closed to recruitment but follow-up is ongoing.
Background: Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem ... more Background: Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem complications in the mother. The adverse outcomes of pre-eclampsia include severe hypertension, stroke, renal and hepatic injury, haemorrhage, fetal growth restriction and even death. The optimal time to instigate delivery to prevent morbidity when pre-eclampsia occurs between 34 and 37 weeks' gestation, without increasing problems related to infant immaturity or complications, remains unclear. Methods/design: The PHOENIX trial is a non-masked, randomised controlled trial, comparing planned early delivery (with initiation of delivery within 48 h of randomisation) with usual care (expectant management) in women with pre-eclampsia between 34 + 0 and 36 + 6 weeks' gestation. The primary objectives of the trial are to determine if planned delivery reduces adverse maternal outcomes, without increasing the short-term harm to infants (composite of perinatal deaths or neonatal unit admissions up to infant hospital discharge) or impacting long-term infant neurodevelopmental status at 2 years corrected age (Parent Report of Cognitive Abilities-Revised). Discussion: Current practice in the UK at the time of trial commencement for management of pre-eclampsia varies by gestation. Previous trials have shown that in women with pre-eclampsia after 37 weeks of gestion, delivery is initiated, as maternal complications are reduced without increasing fetal risks. Prior to 34 weeks of gestation, usual management aims to prolong pregnancy for fetal benefit, unless severe complications occur, necessitating preterm delivery. This trial aims to address the uncertainty for women where the balance of benefits and risks of delivery compared to expectant management are uncertain. Previous trials in this area have been undertaken, but have not provided a definitive answer, and the research question remains active. The results of this trial are expected to influence clinical practice internationally, through direct adoption and by incorporation into guidelines in countries with similar settings.
To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia... more To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35. Randomised, phase III, double blinded international, multicentre clinical trial. 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). 2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses. Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation. The primary outcome was...
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Papers by Stephen Robson