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Glycogen storage disease type 1a (GSD 1a) is a metabolic disorder caused by deficiency of an enzyme required for glycogen breakdown, causing hypoglycaemia and lactic acidosis. Metabolic derangements cause disease manifestations affecting the kidneys, liver and platelet function. Physiological changes in pregnancy worsen fasting intolerance and increase reliance on exogenous glucose to avoid lactic acidosis. Fetal macrosomia and declining respiratory function result in high rates of caesarean sections. We report the multidisciplinary team (MDT) management of a 25-year-old woman with GSD 1a in an unplanned pregnancy. Existing percutaneous endoscopic gastrostomy tube feeding, alongside high-calorie drinks and intravenous dextrose during labour, managed the risks of hypoglycaemia and lactic acidosis. Metabolic parameters were regularly monitored and fortnightly growth scans were assessed for macrosomia. Allopurinol was continued throughout the pregnancy to reduce the risk of hyperuricaemia. MDT management optimised maternal and fetal care throughout pregnancy and labour, resulting in a successful vaginal delivery.

OBJECTIVE This study assessed prevalence of connective tissue disease (CTDs), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPL) in women with previous adverse pregnancy outcome compared with uncomplicated livebirths. DESIGN Retrospective case-control study. SETTING UK Primary Care. POPULATION OR SAMPLE Records of women, 18 years and older, within the Clinical Practice Research Datalink (CPRD) (1 January 2000-31 December 2013). METHODS Clinical Practice Research Datalink was searched for pregnancy terms to identify adverse pregnancy outcome. Each identified case was matched to five livebirths. MAIN OUTCOME MEASURES Diagnosis of SLE, CTD, APS or autoimmune antibodies. Poisson regression was performed to calculate relative risk ratios (RR), comparing adverse pregnancy outcome with livebirth cohorts. RESULTS Clinical Practice Research Datalink identified 20 123 adverse pregnancy outcomes matched to 97 323 livebirths, with a total of 875 590 person-years follow up. Median follow up from study entry was 7.29 years (SD 4.39). Compared with women with an uncomplicated livebirth, women with adverse pregnancy outcome had an increased risk of developing CTD or autoimmune antibodies (RR 3.20, 95% CI 2.90-3.51). Risk was greatest following a stillbirth (RR 5.82, 95% CI 4.97-6.81). For CTD and SLE, the risk was greatest within the first 5 years of adverse pregnancy outcome. Risk for aPL and APS diagnosis was highest ≥5 years from adverse pregnancy outcome. CONCLUSIONS Adverse pregnancy outcome is associated with increased risk of developing maternal CTD, including SLE. Either immunological factors predispose women to adverse pregnancy outcome and subsequent CTD diagnosis or, alternatively, adverse pregnancy outcome initiates autoimmune events which culminate in CTD in later life. TWEETABLE ABSTRACT Stillbirth is associated with increased maternal risk of developing systemic lupus erythematosus (SLE).

Objectives The purpose of this study was to describe the maternal and fetal outcomes in patients with inflammatory rheumatic diseases attending a joint rheumatology and obstetric clinic in the UK. Methods Electronic records of 98 patients attending the joint rheumatology and obstetric clinic between January 2018 and January 2020 were analysed. Data on patient demographics, characteristics (including age, ethnicity, diagnosis, and medications taken during pregnancy), pregnancy outcomes (miscarriage, stillbirth or live birth), maternal complications [infection, post-partum haemorrhage (PPH) or pre-eclampsia] and fetal complications (sepsis, congenital heart block, prematurity and low birth weight) were tabulated. Subgroups of patients based on maternal diagnosis, medications and Ro/La antibody status were described in a similar manner. Results The cohort was found to be predominantly Caucasian women >30 years of age, diagnosed with a CTD. Of 98 pregnancies, 97% (n = 95) resulted in a live birth, with only 2% resulting in miscarriage (n = 2) and 1% in stillbirth (n = 1). The median duration of gestation was 38 (interquartile range 37–39) weeks, and the majority of patients had a normal vaginal delivery (35%, n = 34), whereas 30% had emergency Caesarean sections (n = 29). The median birth weight was 3120 (interquartile range 2690–3410) g. The most common maternal complications were PPH (56%, n = 54) and infection (22%, n = 21). The most common fetal complications were prematurity (23%, n = 22) and low birth weight (17%, n = 16). Conclusion We report favourable outcomes from this service model, including a high live birth rate, a low miscarriage rate and a high median birth weight. With limited reported data of pregnancy outcomes from joint obstetric/rheumatology clinics, this service model might be beneficial in other centres.

Chronic histiocytic intervillositis (CHI) is a rare, but highly recurrent inflammatory placental lesion wherein maternal macrophages infiltrate the intervillous space. Pregnancies with CHI are at high risk of fetal growth restriction, miscarriage or stillbirth. Presently, the diagnosis can only be made after histopathological examination of the placenta. Given its proposed immunological etiology, current treatments include aspirin, heparin, and immunomodulatory agents. However, the rationale for these medications is largely based upon small case series and reports as there is a lack of larger studies investigating treatment efficacy. Therefore, this study sought to determine whether inclusion of immunomodulatory medications was effective at reducing the severity of lesions and improving pregnancy outcomes in subsequent pregnancies. Thirty-three women with a history of CHI in at least one pregnancy (index case) were identified retrospectively through medical records. Twenty-eight participants presented with a first subsequent pregnancy and a further 11 with a second subsequent pregnancy at a specialist clinic for pregnancy after loss. Data on maternal demographics, medical history, medication, pregnancy outcome, and placental pathology was collected and compared between pregnancies. Twenty-seven (69%) subsequent pregnancies were treated with at least one or both of prednisolone and hydroxychloroquine. Inclusion of at least one immunomodulatory agent in treatment regimen resulted in an almost 25% increase in overall livebirth rate (61.5 vs. 86.2%). In women treated with immunomodulatory medication a greater proportion of placentas had reduced severity of lesions compared to those treated without (86.7 vs. 33.3%, respectively). A reduction in CHI severity was associated with a 62.3% improvement in livebirth rate compared to those where severity remained unchanged in relation to the index case. These data provide preliminary evidence that the use of immunomodulatory medication in the management of CHI improves histopathological lesions and the chance of livebirth in subsequent pregnancies. Due to CHI's rarity and ethical and feasibility issues, randomized controlled trials in affected women are challenging to conduct. As a result, collaboration between centers is required in future to increase study sample sizes and elucidate the mechanisms of hydroxychloroquine and prednisolone in reducing pathology.

Background/Aims The Lupus in Pregnancy Scanning (LIPS) clinic, a joint obstetrics and rheumatology clinic was established in 2010 at Saint Mary’s Hospital, Manchester, UK for women with systemic lupus erythematosus (SLE) and other complex rheumatological conditions. We aimed to describe pregnancy outcomes of women attending this clinic to establish a baseline for future changes aimed at improving the service. Methods Data were collected retrospectively from electronic records of patients who attended the LIPS clinic at least once between 1st January 2018 and 31st December 2019. Results Pregnancy outcomes were available in 105/125 (84%) women (Table). The median age [inter-quartile range] was 30.6 years [IQR 27.7 - 33.6] and 40 (38%) were of non-Caucasian background. Sixty-one (58%) had a connective tissue disease (CTD) of whom 36 (59%) had SLE. Other rheumatological diagnoses included inflammatory arthritis, primary anti-phospholipid syndrome (APS) and systemic vasculitis. Anti-Ro was found in 32 (31%) and anti-phospholipid antibodies in 25 (24%). During pregnancy, 65 (62%) received aspirin and 40 (38%) had low molecular weight heparin (LMWH). In the antenatal period, 43 (41%) took steroids, 52 (50%) had conventional disease modifying anti-rheumatic drugs and 8 (8%) received biologics. Active disease in the antenatal period was noted in 14 (13%) women. Regarding pregnancy outcomes (Table), still-births were low (0.95%). The rate of C-sections (45%) and assisted deliveries (19.6%) was comparable to previously published data from similar clinics. P096 Table 1:Pregnancy outcomes over a 2-year period in women attending the LIPS clinic at St. Mary's HospitalPregnancy Outcomen (%)Miscarriage3 (2.9)Deliveries• Live101 (96.2)• Still-birth1 (0.95)Median Gestation (weeks) [inter-quartile range (IQR)]38 [37 - 39]Sex of Neonate• Female57 (56)• Male45 (44)Mode of Delivery• Normal vaginal36 (35.3)• Assisted20 (19.6)• Elective Caesarean Section15 (14.7)• Emergency Caesarean Section31 (30.4)Median Neonatal Birth Weight (grams) [IQR]3137 [2724 - 3428]• Low Birth Weight Conclusion In this cohort we report a high live birth rate and comparable rates of assisted delivery to similar cohorts. Infection and post-partum haemorrhage are maternal complications that are common, and reflect the complex clinical presentations and therapeutic regimes in these conditions. Overall this specialist clinic achieves favourable maternal and foetal outcomes in this high-risk population. Disclosure T. David: None. R. Hum: None. Y. Lau: None. S. Thornber: None. L. Simcox: None. I. Bruce: None. C. Tower: None. P. Ho: None.

Preterm deliveries remain the leading cause of neonatal morbidity and mortality. Current therapies target only myometrial contractions and are largely ineffective. As labor involves multiple coordinated events across maternal and fetal tissues, identifying fundamental regulatory pathways of normal term labor is vital to understanding successful parturition and consequently labor pathologies. We aimed to identify transcriptomic signatures of human normal term labor of two tissues: in the fetal-facing choriodecidua and the maternal myometrium. Microarray transcriptomic data from choriodecidua and myometrium following term labor were analyzed for functional hierarchical networks, using Cytoscape 2.8.3. Hierarchically high candidates were analyzed for their regulatory casual relationships using Ingenuity Pathway Analysis. Selected master regulators were then chemically inhibited and effects on downstream targets were assessed using real-time quantitative PCR (RT-qPCR). Unbiased network analysis identified upstream molecular components in choriodecidua including vimentin, TLR4, and TNFSF13B. In the myometrium, candidates included metallothionein 2 (MT2A), TLR2, and RELB. These master regulators had significant differential gene expression during labor, hierarchically high centrality in community cluster networks, interactions amongst the labor gene set, and strong causal relationships with multiple downstream effects. In vitro experiments highlighted MT2A as an effective regulator of labor-associated genes. We have identified unique potential regulators of the term labor transcriptome in uterine tissues using a robust sequence of unbiased mathematical and literature-based in silico analyses. These findings encourage further investigation into the efficacy of predicted master regulators in blocking multiple pathways of labor processes across maternal and fetal tissues, and their potential as therapeutic approaches.

Background\ud Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage.\ud \ud Methods\ud In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283.\ud \ud Findings\ud Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group.\ud \ud Interpretation\ud Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.\ud \ud Funding\ud London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.

For hypertensive women in CHIPS (Control of Hypertension in Pregnancy Study), we assessed whether the maternal benefits of tight control could be achieved, while minimizing any potentially negative effect on fetal growth, by delaying initiation of antihypertensive therapy until later in pregnancy. For the 981 women with nonsevere, chronic or gestational hypertension randomized to less-tight (target diastolic blood pressure, 100 mm Hg), or tight (target, 85 mm Hg) control, we used mixed-effects logistic regression to examine whether the effect of less-tight (versus tight) control on major outcomes was dependent on gestational age at randomization, adjusting for baseline factors as in the primary analysis and including an interaction term between gestational age at randomization and treatment allocation. Gestational age was considered categorically (quartiles) and continuously (linear or quadratic form), and the optimal functional form selected to provide the best fit to the data based on the Akaike information criterion. Randomization before (but not after) 24 weeks to less-tight (versus tight) control was associated with fewer babies with birth weight P interaction =0.005), but more preterm birth ( P interaction =0.043), and no effect on perinatal death or high-level neonatal care >48 hours ( P interaction =0.354). For the mother, less-tight (versus tight) control was associated with more severe hypertension at all gestational ages but particularly so before 28 weeks ( P interaction =0.076). In women with nonsevere, chronic, or gestational hypertension, there seems to be no gestational age at which less-tight (versus tight) control is the preferred management strategy to optimize maternal or perinatal outcomes. Clinical Trial Registration— URL: https://www.isrctn.com . Unique identifier: ISRCTN71416914.

Key points Venous thromboembolism (VTE) in pregnancy remains a leading cause of direct maternal mortality in the developed world and identifiable risk factors are increasing in incidence. VTE is approximately 10-times more common in the pregnant population (compared with non-pregnant women) with an incidence of 1 in 1000 and the highest risk in the postnatal period. If pulmonary imaging is required, ventilation perfusion scanning is usually the preferred initial test to detect pulmonary embolism within pregnancy. Treatment should be commenced on clinical suspicion and not be withheld until an objective diagnosis is obtained. The mainstay of treatment for pulmonary thromboembolism in pregnancy is anticoagulation with low molecular weight heparin for a minimum of 3 months in total duration and until at least 6 weeks postnatal. Low molecular weight heparin is safe, effective and has a low associated bleeding risk. Educational aims To inform readers about the current guidance for diagnosis and management of pulmonary thromboembolism in pregnancy. To highlight the risks of venous thromboembolism during pregnancy. To introduce the issues surrounding management of pulmonary thromboembolism around labour and delivery, Diagnosis and management of pulmonary thromboembolism in #pregnancy and labour http://ow.ly/UvyyW

There is a paucity of strong evidence associated with adverse pregnancy outcomes and thrombophilia in pregnancy. These problems include both early (recurrent miscarriage) and late placental vascular-mediated problems (fetal loss, pre-eclampsia, placental abruption and intra-uterine growth restriction). Due to poor quality case-control and cohort study designs, there is often an increase in the relative risk of these complications associated with thrombophilia, particularly recurrent early pregnancy loss, late fetal loss and pre-eclampsia, but the absolute risk remains very small. It appears that low-molecular weight heparin has other benefits on the placental vascular system besides its anticoagulant properties. Its use is in the context of antiphospholipid syndrome and recurrent pregnancy loss and also in women with implantation failure to improve live birth rates. There is currently no role for low-molecular weight heparin to prevent late placental-mediated complications in patients with inherited thrombophilia and this may be due to small patient numbers in the studies involved in summarising the evidence. There is potential for low-molecular weight heparin to improve pregnancy outcomes in women with prior severe vascular complications of pregnancy such as early-onset intra-uterine growth restriction and pre-eclampsia but further high quality randomised controlled trials are required to answer this question.

We read with interest the paper by Bhagra et al 1 and wish to add further information from two recent publications which emphasise their key points that ‘pregnancy in women with mechanical heart valves is high risk’ and that ‘a multidisciplinary team approach to the management of pregnant women with Prosthetic Heart Valves is necessary to ensure optimal outcomes.’ A recent prospective observational national study of women in the UK with pregnancies between February 2013 and January 2015, estimated the incidence of mechanical prosthetic heart valves (MPHVs) in …

This case report describes a baby who was diagnosed antenatally with a significant left-sided congenital cystic adenomatoid malformation. Following diagnosis of a fluid-filled, macrocystic structure on the left side of the chest, the mother was referred at 27 weeks’ gestation to her regional fetal medicine unit for assessment and ongoing management. Fetal MRI demonstrated a cyst measuring 6.7 mm × 4.3 mm, associated with mediastinal shift and affecting cardiac contractility. Scalp …

Preterm birth is defined as birth before 37 weeks of gestation and is the single biggest cause of neonatal morbidity and mortality. The UK preterm birth rate is 7.9%, therefore approximately 1 in 13 babies are born prematurely. This is despite advances in prediction of those at risk, prevention strategies and treatment. Transvaginal ultrasound and fetal fibronectin have been the major advances in the prediction of preterm labour, and with the use of both of these tests it may be possible to predict up to 75% of those who will deliver prematurely. At best, tocolytics are able to delay preterm labour long enough for the administration of corticosteroids. Labour involves complex and co-ordinated events, greater knowledge of which is necessary to understand processes involved in premature labour and advance healthcare in this field.

The prevalence of vitamin D deficiency in pregnant white-skinned women (WSW) and their infants has not been investigated at northern latitudes in a developed county. A 2-year observational cohort study was undertaken in the North West of England to determine 25-hydroxyvitamin D (25OHD) levels in WSW and their infants during pregnancy and 4 months postdelivery and to explore factors associated with these levels. Nutritional and lifestyle questionnaires were completed and 25OHD levels measured at 28 weeks and 4 months postdelivery. Twenty-seven percent and 7% of WSW had insufficient and deficient levels of 25OHD during pregnancy and 48% and 11% four months postdelivery. WSW with Fitzpatrick skin-type I (FST I) have significantly lower 25OHD than other skin types after controlling for time spent outside and vitamin D intake. Twenty-four percent and 13% of infants had insufficient and deficient 25OHD levels at 4 months. Unsupplemented breast-fed infants have the highest level of insufficiency (67%) compared with formula-fed infants (2%). Factors associated with infant serum 25OHD levels at 4 months included breast feeding, supplementation, and time outside. WSW have a high prevalence of insufficiency and deficiency during pregnancy which doubles 4 months after birth. Breast-fed infants of WSW are rarely considered at risk of vitamin D insufficiency but have high rates compared with formula-fed infants. This is the first study to show the finding that FST I WSW have significantly lower levels of 25OHD than those with FST II–IV (difference adjusted for diet and time outside 14 (95%CI 7–21) nmol/L).

Clinicians increasingly investigate women for thrombophilias due to their associations with venous thromboembolism and placenta-mediated pregnancy complication. These associations, however, are modest and based largely on retrospective data from studies with heterogeneous classifications and populations, leading to discordance between evidence and guidelines. Current evidence suggests a contributory rather than causative role for thrombophilia in placenta-mediated pregnancy complication and venous thromboembolism. With little evidence of benefit from antithrombotic therapy in placenta-mediated pregnancy complication, thrombophilia screening remains controversial. Given the low absolute risk of placenta-mediated pregnancy complication and gestational venous thromboembolism with heritable thrombophilia, universal screening is inappropriate. Selective screening for antiphospholipid syndrome is supported by robust evidence of benefit. Conversely, selective screening for heritable thrombophilia has not been shown to effectively manage placenta-mediated pregnancy complication. Therefore, at present heritable thrombophilia screening is not warranted for placenta-mediated pregnancy complication. Until we have better evidence from better stratified patient groups, caution should remain if we wish to practice evidence-based medicine.

It is estimated that 20% of women experience symptoms of depression during pregnancy and antidepressant medication is prescribed for between 2% and 8% of pregnant women depending on the country of report. In the UK antidepressant prescribing during pregnancy increased fourfold from 1992 to 2006, with Selective Serotonin Reuptake Inhibitors (SSRIs) most often chosen. SSRIs cross the human placenta, with fetal levels varying according to treatment type and are found in amniotic fluid. The significance of prenatal exposure to SSRIs and outcomes in terms of the physical health and the neurodevelopment of the infant and child remainunclear. Several prescribed medications are known to be human teratogens, causing increased prevalence of a range of physical and neurodevelopmental deficits in exposed infants. Research into infant outcomes following prenatal exposure is challenging. Ethical constraints do not permit the most rigorous design for investigation, i.e.randomized double-blind controlled studies. In addition, variations in drug type, timing of exposure, dose, duration of exposure, placental passage and genetic factors all require consideration alongside maternal and infant demographic influences (e.g. maternal illness, socioeconomic status). Furthermore, a specific outcome type may be associated with specific risk variables and require targeted investigation. Maternal depression itself, either directly or indirectly, has been reported to influence obstetric and neonatal outcomes. Although beyond the scope of this review, research often fails to consider fetal exposure to antidepressants. Maternal antenatal depression is an important predictor of postnatal depression which may also impact on infant neurodevelopment. Understanding the risks of maternal depression and its treatment with regard to the development of the child is of paramount importance for clinical decision making. Serotonin is known to play a role in the development and physiology of the central nervous system, the gastrointestinal and the cardiovascular systems. In the fetal brain serotonin modulates different developmental processes including neurogenesis, apoptosis and axon branching and therefore alterations in the serotonin system may directly impact on later neuronal development. The role of serotonin in fetal development raises the possibility that SSRI exposure in utero may predispose to structural birth defects and poorer longer term outcomes, however, to date such a relationship is unclear. This review aims to bring together clinical research that examines the immediate and longer term physical and developmental risks to the child that may be associated with prenatal exposure to SSRIs. The article also examines the methodological issues that may contribute to conflicting findings.

Envelope glycoproteins of human endogenous retrovirus (HERV), such as syncytin 1 (HERV-W), are highly expressed in the placenta and some family members have immunomodulatory properties. Placental microvesicles (MV), which are shed into the maternal circulation during pregnancy, have been demonstrated to induce immune cell activation. Therefore, the aim of this study was to investigate the immunological properties of the highly expressed placental HERV-W protein, syncytin 1, and its potential involvement in placental MV modulation of immune cell activity. The MV shed from first trimester, normal term and pre-eclamptic term placentas, and from the BeWo trophoblast cell line, all contain syncytin 1. Recombinant syncytin 1 and syncytin 1-positive BeWo trophoblast MV both induced peripheral blood mononuclear cell (PBMC) activation, indicated through production of cytokines and chemokines. Reducing syncytin 1 content in BeWo MV inhibited PBMC activation. Recombinant syncytin 1 and syncytin-1-positive BeWo MV dampened PBMC responses to lipopolysaccharide challenge. Our findings suggest that syncytin 1 is shed from the placenta into the maternal circulation in association with MV, and modulates immune cell activation and the responses of immune cells to subsequent lipopolysaccharide stimulation. These studies implicate placental MV-associated HERV in fetal regulation of the maternal immune system.

Objective To investigate the hypothesis that women achieving pregnancy after two or more failed embryo transfers (ETs) of good quality embryos have increased incidence of preeclamptic toxemia (PET) or fetal growth restriction (FGR) compared with those conceiving in the first ET after in vitro fertilization (IVF). Design Case-control study. Setting Tertiary infertility center. Patient(s) Women who underwent IVF at the St. Mary's Hospital, Manchester, between January 2000 and June 2008 and conceived in the first ET, versus those who conceived after two or more failed ETs. Intervention(s) Retrospective case-note review. Main Outcome Measure(s) Incidence of PET or FGR. Result(s) Case notes of 364 eligible patients were identified: 125 conceived after two or more failed ETs and 239 in the first ET. The incidence of the primary outcome (PET or FGR) for the total number of pregnancies showed no significant difference between cases and controls (age and multiplicity adjusted odds ratio 1.2, 95% confidence interval 0.5–3.0). There were no significant differences between case and control subjects for the secondary outcomes. Conclusion(s) This study failed to demonstrate that women conceiving after two or more unsuccessful ETs are at increased risk of PET or FGR. More studies are required to investigate the relationship further.

Preparing and applying for consultant posts requires careful thought and planning. Organised your curriculum vitae in advance, considering all aspects; clinical, academic, management and leadership, and your personal qualities with equal importance. Give careful consideration to advertised jobs, taking into account your personal requirements. Choose posts that are best suited to you. When completing an application, tailor your application form to the personal specification without overstating your capabilities. Once you are shortlisted, you will be told the format of the interview and who will be on the panel. It is important to use pre-interview visits to gain insights to the department and Trust which will further inform your approach to the interview. Read around current healthcare issues and policies. Try to predict what questions might be asked, develop answers for these and practice your answers.

Angiotensin II (Ang II) is locally generated in the placenta and regulates syncytial transport, vascular contractility and trophoblast invasion. It acts through two receptor subtypes, AGTR1 and AGTR2 (AT1 and AT2), which typically mediate antagonising actions. The objectives of this study are to characterise the cellular distribution of AGTR1 and AGTR2 at the maternal–fetal interface and explore the effects on cytotrophoblast turnover. Low levels ofAGTR2mRNA were detected in first trimester placental homogenates using real-time PCR. Immunohistochemistry using polyclonal antibodies against AGTR1 and AGTR2 detected the receptors in first trimester placenta, decidua basalis and villous tip outgrowths in culture. Serial staining with cytokeratin-7 was used to identify extravillous trophoblasts (EVTs). AGTR1 was found in the syncytiotrophoblast microvillous membrane, in a subpopulation of villous cytotrophoblasts, and in Hofbauer cells. AGTR1 was strongly upregulated in cytotrophoblasts in cell columns and villous tip outgrowths, but was absent in interstitial and endovascular EVTs within the decidua. AGTR2 immunostaining was present in Hofbauer cells and villous cytotrophoblasts, but was absent from syncytiotrophoblast. Faint staining was detected in cell column cytotrophoblasts and villous outgrowths, but not in EVTs within the decidua. Both receptors were detected in placental homogenates by western blotting. Ang II significantly increased proliferation of cytotrophoblasts in both villous explants and villous tip outgrowths, but did not affect apoptosis. Blockade of AGTR1 and AGTR2 together abrogated this effect. This study shows specific expression patterns for AGTR1 and AGTR2 in distinct trophoblast populations at the maternal–fetal interface and suggests that Ang II plays a role in placental development and generation of EVTs.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that disproportionally affects women, especially in their reproductive years. SLE is associated with considerable pregnancy-related morbidity--including fetal loss, preterm birth, fetal growth restriction and pre-eclampsia. CD4+CD25+ regulatory T (T(REG)) cells have a potent immunosuppressive function and contribute to immunological self-tolerance. These cells might be essential for successful placental development by ensuring fetal tolerance. The numbers of T(REG) cells are augmented during normal pregnancy and, conversely, diminished numbers are associated with pregnancy loss and pre-eclampsia. Several studies have shown that patients with SLE have decreased numbers of T(REG) cells that might be functionally defective. This defective T(REG) cell functioning could predispose women with SLE to pregnancy complications. This article provides an overview of current knowledge of the role and function of T(REG) cells in SLE and pregnancy and how these cells might contribute to improving pregnancy-related outcomes in patients with SLE in the future.

Pregnancy in peri- and postmenopausal women is associated with an increased risk of complications and represents several challenges in terms of clinical management. Women in these age groups typically fall into one of two distinct groups, those who have conceived following assisted reproductive techniques, using ovum donation and those who have conceived spontaneously. While both have age in common, they differ in terms of additional risk factors. Recipients of assisted reproductive technologies have pregnancy risks associated with that treatment, but are at lower risks of a fetus affected by aneuploidy. Furthermore, they have been rigorously screened for medical complications, but are more likely to be primiparous and have multiple pregnancies. In contrast, women conceiving spontaneously are more likely to be of high parity and have additional medical complications such as obesity, hypertension or diabetes. In addition to the increased risk of antenatal complications such as miscarriage, ectopic pregnancies, gestational diabetes and hypertension, these women have a high risk of unexplained stillbirth. They also have a very high rate of Caesarean section. All these risk factors interact to modify clinical management. However, there are no randomized trials available to guide clinical management, thus decisions must be made on a case-by-case basis.

Objectives: To investigate prognosis of the fetus with isolated gastroschisis and bowel dilatation from a systematic review of the literature. We aimed to compare the incidence of (a) intrauterine death, (b) death within 4 weeks of delivery, (c) bowel resection, (d) length of time to oral feeds and (e) time as inpatient in fetuses with gastroschisis with and without evidence of bowel dilatation. Methods: Literature was identified by searching two bibliographical databases between 1980 and 2007. Studies were assessed for quality and stratified according to the definition of bowel dilatation. The data extracted were inspected for clinical and methodological heterogeneity. Results: The search strategy yielded 1335 potentially relevant citations. Full manuscripts were retrieved for 92 citations. 10 studies (273 patients) were finally included in the systematic review. No difference was found between groups for death within 4 weeks of delivery (OR = 0.62 (95% CI 0.11 to 3.32); heterogeneity p = 0.39) or bowel resection (OR = 3.35 (95% CI 0.82 to 13.74); heterogeneity p = 0.39). There were insufficient data to compare the risk of intrauterine death and length of time to oral feeds. The mean inpatient stay was not significantly different between groups (OR = 16.63 (95% CI 0.98 to 32.28); heterogeneity p = 0.23). Conclusion: Current available evidence suggests that fetuses with isolated gastroschisis and bowel dilatation are not at increased risk of adverse perinatal outcome compared to those without bowel dilatation. However, there is a paucity of studies, and a randomised controlled trial is urgently needed.

Adverse pregnancy outcomes, such as pregnancy loss and pre-eclampsia, are associated with thrombotic mechanisms and thrombophilia. Antithrombotic interventions, particularly low-molecular-weight heparin, have been investigated in women identified by previous pregnancy outcome; however, the results have been inconsistent. This may reflect heterogeneity of both the study groups and the disease processes resulting in inadequate stratification to guide antithrombotic interventions. Furthermore, the variation in gestation at initiation of low-molecular-weight heparin treatment might be important. Despite limited evidence of efficacy, low-molecular-weight heparin is often used in an attempt to prevent these complications, owing to the lack of other effective treatments and its perceived safety in pregnancy. Research is required to better understand the disease processes, identify possible biomarkers and thereby more homogeneous groups for targeted treatment.

Fetal growth restriction (FGR) is a common clinical problem that has a significant effect on perinatal morbidity and mortality. In addition, it also adversely influences adult health, as it increases the risk of cardiovascular disease and impaired glucose tolerance. There is growing evidence that genes play a role in the pathogenesis. Karyotypic abnormalities, affecting both the fetus and the placenta, are known to be associated with fetal growth restriction. This not only impacts on clinical management but has also aided the understanding of the mechanisms controlling fetal growth. In particular, there is an increasing appreciation of the role of imprinted genes in growth and development. There is good genetic epidemiological evidence that genes also play a role in the more common, multifactorial fetal growth restriction, seen in the presence of a normal karyotype. The number of candidate genes studies is increasing and includes members of the renin angiotensin system and the insulin-like growth factor axis. The most extensively investigated to date are the inherited thrombophilias and meta-analyses seem to support an association with fetal growth restriction. However, larger studies are urgently required to confirm this association. There is currently no evidence to support screening low-risk pregnant women for inherited thrombophilias, and there are no randomised controlled trials to suggest that treatment with anticoagulants improve outcome. At present screening or treatment should occur only within such trials.

In 2003, the angiotensinogen (AGT) gene was found to be associated with infants small for gestational age (SGA). The present study of 107 pregnancies affected by SGA infants and 101 normal pregnancies was designed to further investigate this association. Maternal or fetal AGT genotype or haplotype frequencies did not differ between SGA and normal pregnancies (P > 0.35). Quantitative trait analysis of mothers with normal pregnancies demonstrated an association between AGT haplotype and blood pressure and body mass index at antenatal booking (P= 0.04), suggesting that AGT may play a role in the complex relationship between body mass and blood pressure in healthy pregnant women.

The angiotensin II type 1 (AT1) receptor, transforming growth factor beta1 (TGFbeta1) and Oncostatin M (OSM) control key pathways that may be important during placentation. Although interactions between them exist in other tissues, trophoblast cells have not been investigated. Extravillous trophoblast cells, SGHPL-4, were stimulated with 10 ng/ml TGFbeta1 +/- 100 ng/ml OSM for 24 h. Real-time PCR showed that AT1 expression increased 2.76-fold [95% confidence interval (CI) = 1-6.74, P = 0.05] in response to TGFbeta1 and 4.21-fold (95% CI = 1.33-11.76, P = 0.03) with TGFbeta1 + OSM. Luciferase reporter gene constructs containing three haplotypes of the 59 flanking region of the AT1 receptor gene were transfected into SGHPL-4 and HepG2 cells and stimulated with 0.1, 1 and 10 ng/ml TGFbeta1 and 50 ng/ml OSM. Responses were dose and cell dependent. Luciferase activity increased in HepG2 cells in response to TGFbeta1 alone or together with OSM (P < 0.001); transcriptional activation differed between AT1 receptor gene haplotypes. In SGHPL-4 cells, luciferase activity was reduced on exposure to low concentrations of TGFbeta1 or high concentrations of TGFbeta1 combined with OSM (P = 0.003); the response was unaffected by haplotype. Interaction between AT1 and TGFbeta1 is a novel observation in trophoblast and suggests new avenues for the study of placentation.

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that predominantly affects women of reproductive age. As clinical outcomes improve, pregnancy in these women is becoming more common. Although epidemiological data have documented an improvement in the prognosis of pregnancy in these women over recent years, they are still at significantly increased risk of pregnancy complications, such as miscarriage, stillbirth, pre-eclampsia and impaired foetal growth. The pathogenesis of SLE involves marked immune dysfunction, and in particular, the function of immunosuppressive elements of the immune system is impaired, including regulatory T-cell function. Because regulatory T cells are likely to be the key cell-modulating feto-maternal tolerance, this review overviews the possibility that regulatory T-cell impairments contribute to pregnancy pathology in women with SLE and contribute to the clinical challenge of managing these women during pregnancy. © 2013 John Wiley & Sons Ltd.

Current therapies for preterm labour (PTL) focus on arresting myometrial contractions but are largely ineffective, thus alternative therapeutic targets need to be identified. Leukocytes infiltrate the uterus around the time of labour, and are in particularly abundant in decidua (maternal-fetal interface). Moreover, decidual inflammation precedes labour in rat pregnancies and thus may contribute to initiation of labour. We hypothesized that chemokines mediate decidual leukocyte trafficking during preterm labour (PTL) and term labour (TL), thus representing potential targets for preventing PTL. Women were recruited into 4 groups: TL, term not in labour (TNL), idiopathic PTL and PTL with infection (PTLI). Choriodecidual RNA was subjected to a pathway-specific PCR array for chemokines. Differential expression of 12 candidate chemokines was validated by real time RT-PCR and Bioplex assay, with immunohistochemistry to confirm cellular origin. 25 chemokines were upregulated in choriodecidua from TL compared to TNL. A similar pattern was detected in PTL, however a distinct profile was observed in PTLI consistent with differences in leukocyte infiltration. Upregulation of CCL2, CCL4, CCL5, CXCL8 and CXCL10 mRNA and protein was confirmed in TL, with CCL8 upregulated in PTL. Significant correlations were detected between these chemokines and decidual leukocyte abundance previously assessed by immunohistochemical and image analysis. Chemokines were primarily expressed by decidual stromal cells. In addition, CXCL8 and CCL5 were significantly elevated in maternal plasma during labour, suggesting chemokines contribute to peripheral inflammatory events during labour. Differences in chemokine expression patterns between TL and idiopathic PTL may be attributable to suppression of chemokine expression by betamethasone administered to women in PTL; this was supported by in vitro evidence of chemokine downregulation by clinically relevant concentrations of the steroid. The current study provides compelling evidence that chemokines regulate decidual leukocyte recruitment during labour. The 6 chemokines identified represent potential novel therapeutic targets to block PTL.

Normal pregnancy is associated with the presence of circulating placental microvesicles (MVs). Increased MV shedding and altered immune activation are seen in patients with preeclampsia, suggesting that placental MVs may play a role in the pathophysiology of this disease. Therefore, the aim of this study was to investigate the activation of peripheral blood mononuclear cells (PBMCs) by MVs shed by first-trimester, normal term, and preeclamptic term placenta. First-trimester and preeclamptic term, but not normal term, placental-derived MVs activated PBMCs, as evidenced by elevated IL1B. Significant changes were also seen with several other cytokines and chemokines, and in general when compared to normal term MVs, preeclamptic MVs induced a greater pro-inflammatory response in PBMCs. Pretreatment of PBMCs with first-trimester or normal term placental MVs resulted in a dampened IL1B response to a subsequent lipopolysaccharide (LPS) challenge. In contrast, treatment of PBMCs with preeclamptic term placental MVs exacerbated the LPS response. This was also the case for several other cytokines and chemokines. These studies suggest that placental MVs can modulate basal peripheral immune cell activation and responsiveness to LPS during normal pregnancy, and that in preeclampsia this effect is exacerbated.

Preterm delivery is the leading cause of perinatal mortality and morbidity. Current tocolytics target myometrial contractions, a late step in the labor cascade. Identifying earlier events in parturition may lead to more effective therapeutic strategies. We hypothesized that inflammatory events in decidua (the maternal-fetal interface), characterized by leucocyte infiltration, are an early event during term and preterm labor (PTL). Leucocyte abundance in decidua of human pregnancies was quantified following term labor and PTL (idiopathic and infection associated), in conjunction with investigation of temporal inflammatory events in rat uterus during the perilabor period and in PTL induced by mifepristone. In human decidua, macrophage numbers were 4-fold higher in term labor (P < 0.01) and 2.5-fold higher in non-infection-associated PTL (P < 0.05) than in term nonlaboring samples. Neutrophil abundance was unchanged with labor but elevated in PTL with infection (5- to 53-fold increase; P < 0.01). T and NK cells were more abundant in idiopathic PTL than TL (P < 0.05). In rat, decidual macrophage infiltration increased 4.5-fold 12 h prior to labor and remained elevated during labor and early postpartum (P < 0.01). Decidual infiltration preceded that of the myometrium and was 4-fold higher (P < 0.01). In rat PTL, decidual macrophage numbers were also elevated (P < 0.01) and exceeded those of the myometrium (P < 0.05). These studies show for the first time that leucocytes infiltrate decidua during labor at term and preterm, supporting a role for leucocyte-derived inflammatory mediators in decidual activation. In the rat, this occurred prior to labor, suggesting it is an early event during parturition and thus a potential target for intervention.

This case describes a woman who presented with raised α-fetoprotein (AFP) on second trimester screening, and developed early onset fetal growth restriction (FGR) and severe pre-eclampsia (PET) before 24 weeks' gestation requiring magnesium sulphate and intravenous antihypertensives. Ultrasonography revealed a structurally normal fetus with estimated weight

Birthweight predicts health later in life and is influenced by inherited factors. We investigated the association of the c.61G > A, and c.2566G > A polymorphisms in the epidermal growth factor (EGF) gene [GenBank NM_001963] with birthweight in three groups of healthy pregnant women, and in women with pregnancies affected by fetal growth restriction (FGR). Subjects comprised 171 Sinhalese women with normal pregnancies (Group A), 64 white Western European women with normal pregnancies (Group B), 101 white Western European women with normal pregnancies and their babies (Group C) and 107 women with pregnancies affected by FGR, their partners and their babies (Group D). Maternal EGF genotypes were associated with birthweight of healthy babies of women in Groups A (P = 0.03), B (P = 0.001) and C (P = 0.01). The association persisted following adjustment for confounding by gestational age, sex, maternal weight, parity and smoking habit. The trend from heaviest to lightest birthweights in all these groups was c.61AA > c.61GA > c.61GG and c.2566GG > c.2566GA > c.2566AA. The EGF haplotype associated with lower birthweight (c.61G, c.2566A) was transmitted at increased frequency from heterozygous parents to babies affected by FGR in Group D (P = 0.02). These findings support the hypothesis that growth factors expressed by the feto-maternal unit affect birthweight, and implicates polymorphism in the EGF gene in the aetiology of birthweight variability.

Fetal growth restriction (FGR) predisposes to significant short- and long-term health problems. Epidemiological studies have suggested a role for inherited factors in its pathogenesis. The angiotensin II receptor genes, AGTR1 and AGTR2, are candidate genes because they mediate processes that are important for placentation. This study investigated AGTR1 and AGTR2 haplotypes and genotypes in FGR. A total of 107 families (father, mother, and baby) with FGR, and 101 families with normal pregnancies were genotyped at five sites in AGTR1 and six sites across AGTR2. All of the participants were white western Europeans. FGR was identified antenatally by ultrasound scans and confirmed postnatally by correcting the birth weight centile for gestation, infant sex, maternal height, weight, and parity. Fetal genes were investigated using transmission disequilibrium testing (TDT), and a case-control comparison of maternal haplotypes was conducted. FGR was associated with maternal (but not paternal) transmission of the AGTR1 haplotype (GenBank AF245699.1) g.4955T, g.5052T, g.5245C, g.5612A, and haplotype g.4955T, g.5052T, g.5245T, g.5612A. Haplotype g.4955A, g.5052G, g.5245T, g.5612G was undertransmitted (P = 0.002). TDT of the AGTR1 genotype showed undertransmission of maternal AGTR1 genotypes g.4955TA (odds ratio (OR), 0.34 (95% confidence interval (CI), 0.14-0.86); P = 0.02), g.5052TG (OR, 0.18 (0.06-0.48); P0.001), and g.5612AG (OR, 0.21 (0.08-0.55); P0.001) in FGR. There were no differences in maternal haplotype frequencies between normal pregnancy and FGR for AGTR1 or AGTR2 (P0.10). This is the first study to show distortion of transmission of maternal AGTR1 haplotypes in FGR, which suggests that this gene plays a role in FGR. In particular, maternal-fetal gene sharing may be an important factor.

Angiotensin II (AII) acts as a growth factor in local systems, mediating diverse effects such as cellular proliferation and apoptosis. These effects are controlled through two main receptor subtypes: AGTR1 and AGTR2. We studied the haplotype frequencies of both receptor genes in women with preeclamptic pregnancies and normotensive pregnant women. We also looked for any association between AGTR1 genotype at sites in the 5' flanking region and binding of AII to platelets, which express AGTR1, in 58 normotensive pregnant women. There were nine common haplotypes of AGTR1, with no significant difference in haplotype frequency between the two groups of women. Platelet AII binding in normotensive pregnant women was associated with the genotype at g.5245C>T in the 5' flanking region of AGTR1 (GenBank AF245699.1), with CC homozygotes at g.5245 having the lowest levels, and g.5245 TT homozygotes having the highest levels (P=0.05). Two novel polymorphisms were identified in AGTR2 (GenBank AY324607.1) at nucleotides g.1701T>C and g.2184A>T. Variation of AGTR2 could be explained by the existence of four common haplotypes. There was evidence for a significant increase in the frequency of the haplotype TAATGC at nucleotides g.1701, g.2041, g.2184, g.4673, g.4679, and g.4975, respectively (P=0.004), in women with preeclampsia.