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Objective Preterm prelabour rupture of membranes occurs in over one third of pregnant women with a cervical cerclage in situ. In the setting of preterm prelabour rupture of membranes, clinicians are faced with the difficult decision of the optimal timing for removing the cerclage. We compared the maternal and neonatal outcomes following immediate removal or retention of the cervical cerclage. Study design Women were retrospectively identified from St Thomas’s Hospital Preterm Surveillance clinic database. Asymptomatic women with preterm prelabour rupture of membranes were identified and separated into those that had the cerclage removed and those that had the cerclage retained within 24 h of presentation. Women who were symptomatic at presentation and who delivered within 24 h of presentation were excluded from the analysis. Maternal outcomes measured were latency between preterm prelabour rupture of membranes and delivery, gestation at delivery and maternal chorioamnionitis and infection markers. Neonatal outcomes including birthweight and Apgar scores were also measured. Results 43 women with cerclage retained for over 24 h following preterm prelabour rupture of membranes were compared to 25 women in whom the cerclage was removed. The latency between preterm prelabour rupture of membranes and delivery was on average 70.4 h longer in women who had their cerclage retained compared to the removed group (p = 0.009). Rates of chorioamnionitis, maternal blood results, neonatal birthweight and Apgar scores did not differ significantly between the two groups, however a trend towards higher rates of chorioamnionitis (60 % vs 45 %) were seen in the retained group. Conclusion Cervical cerclage retention in women following preterm prelabour rupture of membranes was associated with a longer latency period to delivery and was not significantly associated with any adverse obstetric, maternal or neonatal outcomes. Therefore, in women at risk of spontaneous preterm birth, cerclage retention may be beneficial, however these women and their babies should be monitored closely for any signs of infection. Further prospective randomised controlled studies assessing these outcomes as well as longer-term outcomes in these women and their children are needed.

Chorioamnionitis is present in up to 70% of spontaneous preterm births. It is defined as an acute inflammation of the chorion, with or without involvement of the amnion, and is evidence of a maternal immunological response to infection. A fetal inflammatory response can coexist and is diagnosed on placental histopathology postnatally. Fetal inflammatory response syndrome (FIRS) is associated with poorer fetal and neonatal outcomes. The only antenatal diagnostic test is amniocentesis which carries risks of miscarriage or preterm birth. Imaging of the fetal immune system, in particular the thymus and the spleen, and the placenta may give valuable information antenatally regarding the diagnosis of fetal inflammatory response. While ultrasound is largely limited to structural information, MRI can complement this with functional information that may provide insight into the metabolic activities of the fetal immune system and placenta. This review discusses fetal and placental imaging in pregnancies complicated by chorioamnionitis and their potential future use in achieving non-invasive antenatal diagnosis.

Background: Women with a prior pregnancy at term are generally considered to be at reduced risk for subsequent spontaneous preterm birth (sPTB), whereas a previous sPTB is a major predictor for a future sPTB. Aims: The objective of this study was to investigate the risk of recurrent sPTB in women with a prior term birth and a subsequent sPTB. Materials and Methods: This is a retrospective cohort study conducted at St Thomas’ Hospital in London, UK. There were 430 women included: 230 with a term birth (caesarean section or vaginal delivery) preceding a sPTB (term + sPTB group) and 200 with a prior sPTB only (sPTB only group). The primary outcome was sPTB

Objectives: The ability to predict spontaneous PTB (sPTB) has improved greatly, allowing women at risk to be managed with prophylactic interventions such as cervical cerclage and the Arabin pessary. Cervicovaginal fetal fibronectin (qfFN) concentration and ultrasound measurement of cervical length (CL) are the two most established tools to predict sPTB. There is however limited data regarding the predictive value of qfFN and CL tests following insertion of an Arabin pessary. Our aim was therefore to determine the clinical use of qfFN and CL measurements to predict sPTB in women fitted with an Arabin pessary. Study design: This study is a secondary analysis on the SUPPORT trial data. Data were prospectively collected from women attending high-risk preterm surveillance clinics in 3 London centres between July 2015 and April 2020. The matched control group was pregnant women attending the same high-risk preterm surveillance clinics who had not received an Arabin pessary. Receiver operating characteristic (ROC) curves for prediction of birth by 34 and by 37 weeks’ gestation were generated for qfFN and CL measurements combined for both study groups. A formal comparison of area under the curve before 34 weeks’ gestation (AUC < 34 weeks) was made between the two study groups. Results: At our primary endpoint of sPTB < 34 weeks' gestation, qfFN was a good predictor of sPTB in cases with an Arabin pessary in situ (AUC, 0.79, 95% CI: 0.62–0.90) and no worse than the control group who did not have an Arabin pessary, (AUC 0.74, 95% CI: 0.48–0.96). CL had good prediction for sPTB < 34 weeks’ gestation in the control group (AUC 0.76, 95% CI: 0.63–0.88) but was lower and non-significant in the Arabin pessary case group (AUC 0.60, 95% CI: 0.43–0.76). Conclusions: This study showed that cervicovaginal qfFN concentration is equally reliable in the prediction of sPTB in pregnant women at increased risk of sPTB with and without an Arabin pessary in situ, and significantly better than CL measurement alone for predicting delivery before 34 weeks. This commonly used test therefore has utility in predicting sPTB in pregnant women fitted with an Arabin pessary.

Emergency caesarean sections (EmCS), particularly those performed in the second stage of labour, have been associated with a risk of subsequent preterm birth. More worrying is that the risk of sPTB recurrence appears to be high in women who have had a second stage EmCS and a subsequent sPTB. However, there is a paucity of evidence regarding the risk of recurrence in women who have had a prior term EmCS at any stage of labour followed by a sPTB. This study aims to investigate the relationship between all term in labour EmCS and the risk of recurrent spontaneous preterm birth (sPTB).This is an observational, retrospective cohort study conducted at St Thomas' Hospital, a tertiary-level maternity hospital in London, United Kingdom. 259 women were included; 59 women with a term in labour EmCS preceding a sPTB (EmCS group) and 200 women with a prior sPTB only (control group). The initial EmCS was further categorised into first stage (FS)-EmCS or second stage (SS)-EmCS. Primary outcome was sPTB in Pregnancy C 37 weeks' gestation. Secondary outcomes included sPTB 34 weeks' and 24 weeks' gestation.54% (32/59) of the EmCS group had a recurrent sPTB 37 weeks compared to 20% (40/200) of the control women (p 0.0001) with a relative risk of 2.71 [95%CI 1.87-3.87]). Of women who had a SS-EmCS and a subsequent PTB, 61.9% (13/21) had a further sPTB (RR 3.0 [95%CI, 1.8-4.5] compared to control women). In addition, there is nearly a 6-fold increased risk of a recurrent sPTB or midtrimester loss 24 weeks' gestation in these women (RR 5.65 [95%CI2.6-12.0]).In women who have had a previous sPTB in which a term in labour EmCS is a risk factor, the risk of a further sPTB is much higher than in those women where a prior sPTB is the sole risk factor. Furthermore, EmCS at both the first and second stage of labour are associated with a increased risk of recurrent sPTB. Further work should ascertain which women who have had a prior term EmCS are at risk of sPTB and recurrence, and how best to identify and treat them.

Objective: Emergency cervical cerclage is often considered a controversial salvage measure for those pregnancies at high risk of mid-trimester loss or early preterm birth. To determine the efficacy and benefit of emergency cerclage insertion, we assessed the predictive value of quantitative fetal fibronectin (fFN) concentration in cervicovaginal fluid for spontaneous preterm birth in women with exposed fetal membranes prior to cerclage insertion. Study design: This was a retrospective observational study from St Thomas’ Hospital, London of a cohort of women with singleton pregnancy and exposed fetal membranes presenting between 18 and 23+6 weeks of gestation (n = 35), in the period 2015-2018. fFN concentrations in cervicovaginal fluid were measured quantitatively at presentation in all women within 24 h prior to cerclage insertion. Results: 35 eligible women with exposed fetal membranes who underwent an emergency cervical cerclage were identified. The median gestational age was 20 + 0 weeks (18 + 6−21 + 2) at presentation and 29 + 3 weeks (23 + 3−38 + 2) at delivery, with a median time from emergency cerclage to delivery of 65.5 days (17–126.5). In total, 12 women (34 %) delivered within 28 days of emergency cerclage insertion. 60 % of women with an fFN level above 500 ng/mL delivered within 28 days of cerclage insertion, and they all delivered before 37 weeks gestation. No women with fFN levels below 10 ng/mL delivered within 28 days and 75 % of these women delivered at term. Concentration of quantitative fFN at presentation correlated negatively with time to delivery (Spearman's rs = −0.52, p = 0.0016). Mann–Whitney U analysis demonstrated a significant difference in the distribution of qfFN concentrations in women who delivered preterm compared to those who did not, both within 28 days from testing (p = 0.0048) and

We have previously designed a library of lentiviral vectors to generate somatic-transgenic rodents to monitor signalling pathways in diseased organs using whole-body bioluminescence imaging, in conscious, freely moving rodents. We have now expanded this technology to adeno-associated viral vectors. We first explored bio-distribution by assessing GFP expression after neonatal intravenous delivery of AAV8. We observed widespread gene expression in, central and peripheral nervous system, liver, kidney and skeletal muscle. Next, we selected a constitutive SFFV promoter and NFκB binding sequence for bioluminescence and biosensor evaluation. An intravenous injection of AAV8 containing firefly luciferase and eGFP under transcriptional control of either element resulted in strong and persistent widespread luciferase expression. A single dose of LPS-induced a 10-fold increase in luciferase expression in AAV8-NFκB mice and immunohistochemistry revealed GFP expression in cells of astrocytic and neuronal morphology. Importantly, whole-body bioluminescence persisted up to 240 days. We have validated a novel biosensor technology in an AAV system by using an NFκB response element and revealed its potential to monitor signalling pathway in a non-invasive manner in a model of LPS-induced inflammation. This technology complements existing germline-transgenic models and may be applicable to other rodent disease models. ispartof: SCIENTIFIC REPORTS vol:10 issue:1 ispartof: location:England status: published

Pelvic radiotherapy can lead to scarring and atrophy of reproductive organs including the uterus. This may lead to complications, such as preterm birth, during pregnancy. The mechanism by which preterm birth is associated with pelvic radiation is believed to be due to inefficient uterine stretch or a deficient cervix. We report a case of cervical shortening during the second trimester in a pregnant woman with a history of pelvic radiotherapy in childhood. Ultrasound surveillance and cervical cerclage inserted in the shortening cervix successfully prevented preterm labour in this case. Cerclage insertion led to a longer cervix and lower fibronectin. Although cervical cerclage does not influence uterine stretch, it may be able to prevent cervical dilatation and therefore prevent ascending infections and subsequent inflammatory sequelae which results in preterm labour. We recommend cervical surveillance and targeted cerclage interventions to prevent preterm labour in women with prior childhood pelvic radiotherapy.

Funding Information: Andrew Shennan reports payment/honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Manipal India; support for attending meetings and/or travel from Hologic; leadership or fiduciary roles in the HTA Commissioning Board UK and Action on Pre‐eclampsia charity. Natalie Suff reports no conflicts of interest. Jo Leigh Simpson reports royalties from Springer and Elsevier; consulting fees from the Illumina Clinical Expert Panel 2020; payment or honoraria for lectures, presentations, speakers bureaus, or educational events from the 1 and 2 International Congresses on the Future of Women's Health, and a speaker's bureau at ASRM 2019; participation on a data safety monitoring board or advisory board for the FDA DSMB; and leadership or fiduciary roles in IFFS and PGDIS. Bo Jacobbson reports research grants from Swedish Research Council, Norwegian Research Council, March of Dimes, Burroughs Wellcome Fund and the US National Institute of Health; clinical diagnostic trials on NIPT with Ariosa (completed), Natera (ongoing), Vanadis (completed) and Hologic (ongoing) with expendidures reimbused per patient; clinical probiotic studies with product provided by FukoPharma (ongoing, no funding) and BioGaia (ongoing; also provided a research grant for the specific study); collaboration in IMPACT study where Roche, Perkin Elmer and Thermo Fisher provided reagents to PLGF analyses; coordination of scientific conferences and meetings with commercial partners as such as NNFM 2015, ESPBC 2016 and a Nordic educational meeting about NIPT and preeclampsia screening. Bo Jacobbson is also Chair of the FIGO Working Group for Preterm Birth and the European Association of Perinatal Medicine's special interest group of preterm delivery; steering group member of Genomic Medicine Sweden; chairs the Genomic Medicine Sweden complex diseases group; and is Swedish representative in the Nordic Society of Precision Medicine. Ben W. Mol reports an investigator grant from NHMRC; consultancy for ObsEva; and research funding from Guerbet, Ferring, and Merck KGaA. William A. Grobman reports no conflicts of interest. st nd

INTRODUCTION Emergency cesarean sections (EMCS) are associated with subsequent preterm birth, particularly at full dilation (FDCS), which is a cause of both second trimester miscarriages and early, recurrent spontaneous preterm birth (sPTB). The optimal management for these women in subsequent pregnancies is currently unknown. This study aims to assess efficacy of transvaginal cervical cerclage (TVC) in prevention of preterm birth among women who have had an EMCS followed by a subsequent late miscarriage or sPTB. MATERIAL AND METHODS A historical cohort study was performed assessing outcomes of women attending the Preterm Surveillance Clinic at St Thomas' Hospital, London, who received TVC, with a history of EMCS (pregnancy A) followed by a sPTB/late miscarriage (pregnancy B) and a subsequent pregnancy (pregnancy C). A historical reference group managed in the same clinic was identified comprising women with any risk factor for sPTB, who required TVC. Incidence of delivery >24 to

Preterm deliveries have multiple aetiologies and management is dependent on cause. Recent studies have shown that caesarean sections performed late in labour have been associated with recurrent, early premature births and late miscarriages (Figure 1). Both the prediction and management of these under‐recognised high‐risk cases needs to be elucidated.

Background A transabdominal cerclage has been shown in a recent randomized controlled trial to be superior to a low vaginal cerclage in reducing the risk of early preterm birth (8% [3/39] vs 33% [11/33]; relative risk, 0.23; 95% confidence interval, 0.07–0.76; P=.01570) and fetal loss (3% [1/39] vs 21% [7/33]; relative risk, 0.12; 95% confidence interval, 0.016–0.930) in women with a previous failed vaginal cerclage. 1 Objective We sought to create a video illustrating a transabdominal cerclage procedure for use as a teaching resource and describing this uncommon but important procedure for dissemination among clinicians. Study Design Transabdominal cerclage insertion in a non-gravid and gravid uterus (less than 14 weeks’ gestation) via laparotomy and laparoscopy was filmed with patients’ and clinicians’ consent in main theatres at St Thomas’ Hospital and University College London Hospital. The film footage was edited, and an audio narration by the surgeon was included to provide a description of the procedures. Results We developed an 8-minute video with an audio narration describing the insertion and management issues of an abdominal cerclage for free dissemination among clinicians who wish to learn how to perform this procedure. Conclusion An abdominal cerclage has been shown to significantly reduce early preterm birth and fetal loss more effectively than a low vaginal cerclage in women with a previous failed cerclage. More obstetricians and gynecologists need to be trained on how to perform the transabdominal cerclage procedure to increase its availability to suitable women. This procedure is technically straightforward and can be taught via video, which can easily be shared among clinicians at a low cost.

SUMMARY Preterm birth, defined as birth occurring prior to 37 weeks gestation, is a serious obstetric problem accounting for 11% of pregnancies worldwide. It is associated with significant neonatal morbidity and mortality. Predictive tests for preterm birth are incredibly important, given the huge personal, economic, and health impacts of preterm birth. They can provide reassurance for women who are unlikely to deliver early, but they are also important for highlighting those women at higher risk of premature delivery so that we can offer prophylactic interventions and help guide antenatal management decisions. Unfortunately, there is unlikely to be a single test for predicting preterm birth, but a combination of tests is likely to improve clinical prediction. This review explores the clinical utility of the currently marketed predictive tests for preterm birth in both singleton and multiple pregnancies, as well as discussing novel predictive tests that may be useful in the future.

We have previously designed a library of lentiviral vectors to generate somatic-transgenic rodents to monitor signalling pathways in diseased organs using whole-body bioluminescence imaging, in conscious, freely moving rodents. We have now expanded this technology to adeno-associated viral vectors. We first explored bio-distribution by assessing GFP expression after neonatal intravenous delivery of AAV8. We observed widespread gene expression in, central and peripheral nervous system, liver, kidney and skeletal muscle. Next, we selected a constitutive SFFV promoter and NFκB binding sequence for bioluminescence and biosensor evaluation.An intravenous injection of AAV8 containing firefly luciferase and eGFP under transcriptional control of either element resulted in strong and persistent widespread luciferase expression. A single dose of LPS-induced a 10-fold increase in luciferase expression in AAV8-NFκB mice and immunohistochemistry revealed GFP expression in cells of astrocytic and neuronal morphology. Importantly, whole-body bioluminescence persisted up to 240 days.To further restrict biosensor activity to the CNS, we performed intracerebroventricular injection of each vector. We observed greater restriction of bioluminescence to the head and spine with both vectors. Immunohistochemistry revealed strongest expression in cells of neuronal morphology. LPS administration stimulated a 4-fold increase over baseline bioluminescence.We have validated a novel biosensor technology in an AAV system by using an NFκB response element and revealed its potential to monitor signalling pathway in a non-invasive manner using a model of LPS-induced inflammation. This technology employs the 3R’s of biomedical animal research, complements existing germline-transgenic models and may be applicable to other rodent disease models with the use of different response elements.

Preterm birth is a serious global health problem and the leading cause of infant death before 5 years of age. At least 40% of cases are associated with infection. The most common way for pathogens to access the uterine cavity is by ascending from the vagina. Bioluminescent pathogens have revolutionized the understanding of infectious diseases. We hypothesized that bioluminescent Escherichia coli can be used to track and monitor ascending vaginal infections. Two bioluminescent strains were studied: E. coli K12 MG1655-lux, a nonpathogenic laboratory strain, and E. coli K1 A192PP-lux2, a pathogenic strain capable of causing neonatal meningitis and sepsis in neonatal rats. On embryonic day 16, mice received intravaginal E. coli K12, E. coli K1, or phosphate-buffered saline followed by whole-body bioluminescent imaging. In both cases, intravaginal delivery of E. coli K12 or E. coli K1 led to bacterial ascension into the uterine cavity, but only E. coli K1 induced preterm parturition. Intravaginal administration of E. coli K1 significantly reduced the proportion of pups born alive compared with E. coli K12 and phosphate-buffered saline controls. However, in both groups of viable pups born after bacterial inoculation, there was evidence of comparable brain inflammation by postnatal day 6. This study ascribes specific mechanisms by which exposure to intrauterine bacteria leads to premature delivery and neurologic inflammation in neonates.

Objectives Studies have demonstrated an association between congenital heart disease (CHD) and neurodevelopmental delay. Neuroimaging studies have also demonstrated a high incidence of preoperative brain abnormalities. The aim of this study was to perform a systematic review to quantify the non-surgical risk of brain abnormalities and of neurodevelopmental delay in infants with CHD. Methods MEDLINE, EMBASE and The Cochrane Library were searched electronically without language restrictions, utilizing combinations of the terms congenital heart, cardiac, neurologic, neurodevelopment, magnetic resonance imaging, ultrasound, neuroimaging, autopsy, preoperative and outcome. Reference lists of relevant articles and reviews were hand-searched for additional reports. Cohort and case–control studies were included. Studies reporting neurodevelopmental outcomes and/or brain lesions on neuroimaging in infants with CHD before heart surgery were included. Cases of chromosomal or genetic abnormalities, case reports and editorials were excluded. Between-study heterogeneity was assessed using the I2 test. Results The search yielded 9129 citations. Full text was retrieved for 119 and the following were included in the review: 13 studies (n = 425 cases) reporting on brain abnormalities either preoperatively or in those who did not undergo congenital cardiac surgery and nine (n = 512 cases) reporting preoperative data on neurodevelopmental assessment. The prevalence of brain lesions on neuroimaging was 34% (95% CI, 24–46; I2 = 0%) in transposition of the great arteries, 49% (95% CI, 25–72; I2 = 65%) in left-sided heart lesions and 46% (95% CI, 40–52; I2 = 18.1%) in mixed/unspecified cardiac lesions, while the prevalence of neurodevelopmental delay was 42% (95% CI, 34–51; I2 = 68.9). Conclusions In the absence of chromosomal or genetic abnormalities, infants with CHD are at increased risk of brain lesions as revealed by neuroimaging and of neurodevelopmental delay. These findings are independent of the surgical risk, but it is unclear whether the time of onset is fetal or postnatal. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Infectious diseases are one of the leading causes of death worldwide. Modelling and understanding human infection is imperative to developing treatments to reduce the global burden of infectious disease. Bioluminescence imaging is a highly sensitive, non-invasive technique based on the detection of light, produced by luciferase-catalysed reactions. In the study of infectious disease, bioluminescence imaging is a well-established technique; it can be used to detect, localize and quantify specific immune cells, pathogens or immunological processes. This enables longitudinal studies in which the spectrum of the disease process and its response to therapies can be monitored. Light producing transgenic rodents are emerging as key tools in the study of host response to infection. Here, we review the strategies for identifying biological processes in vivo, including the technology of bioluminescence imaging and illustrate how this technique is shedding light on the host-pathogen relationship.

Background:Preterm birth is increasing in incidence and current therapies are relatively ineffective. It is responsible for >1million neonatal deaths per annum worldwide and long term complications in survivors. Approximately 50% of PTBs are preceded by microbial invasion of the intrauterine space; current clinical management centres on diagnosis of intrauterine bacterial presence by identifying the resultant inflammatory response. To investigate the relationship between intrauterine bacterial presence and inflammation we developed two separate gene technology approaches:1. Intravaginal bioluminescent bacteria to measure bacterial ascent into the uterus which mimics the ascending vaginal infection seen in preterm birth.2. Lentiviral gene transfer of an NFKB activated luciferase reporter construct to allow bioluminescent imaging of the subsequent systemic NFKB response.Methods:An NFkB response element was cloned into a lentivirus vector upstream of the genes encoding a codon-optimised firefly luciferase. High titred virus was injected intravenously at birth to neonatal female C57BL/6 J-Tyrc-2J mice to achieve luciferase expression predominantly in the liver (to monitor systemic inflammatory response). These mice received Escherichia coli (non-pathogenic K-12, MG1655 with integrated luxABCDE operon) intra-vaginally once reaching adulthood and intraperitoneal lipopolysaccharide (LPS) three weeks later. Luciferase expression was monitored by whole body bioluminescence imaging. Local inflammation was determined using H&E, ICAM-1 (Intracellular adhesion molecule 1) and Ly6g immunohistochemistry and enzyme-linked immunosorbent assays for serum and uterine TNF-α and IL1-β cytokines.Results:Bioluminescent imaging revealed that C57BL/6 J-Tyrc-2J mice were the most susceptible mice breeds for modelling of ascending vaginal infection with E. coli luxABCDE operon. Intraperitoneal LPS induced an NF-KB response in the liver by biosensing (p

Introduction Antihypertensive drugs lower blood pressure by direct vascular effects or central vasodilatory mechanisms. Methyldopa is a commonly used in hypertensive disorders in pregnancy. Although methyldopa is effective in controlling maternal blood pressure, its effects on fetal growth and wellbeing is unknown. The aim of this study was to ascertain the effect of methyldopa on uterine artery and fetal dopplers in women with hypertensive disorders in pregnancy. Methods MEDLINE (1966 – March 2012), EMBASE (1974 - March 2012) and The Cochrane library (inception–March 2012), utilising combinations of the terms methyldopa, hypertens*, pre-eclamp*, preeclamp*, pre eclamp*, pregnan*, uterine, uteroplacental, umbilical, middle cerebral artery and doppler. Between-study heterogeneity was assessed using the I2 statistic. Results The search yielded 429 citations. Full manuscripts were retrieved for 32 and 6 were included in the review and meta-analysis. Six studies (n = 188) have reported the effect of methyldopa on uterine artery doppler pulsatility index (PI). The standardised mean difference (SMD) was –0.22 (95% CI: –0.43 to –0.02). Five studies (n = 110) were included that evaluated the effect of methyldopa on umbilical artery Doppler PI. The SMD was –0.05 (95% CI: –0.32 to 0.21). Four studies (n = 82) reported the effect of methyldopa on middle cerebral artery PI. The SMD was –0.34 (95% CI: –0.65 to 0.03). Conclusion In pregnancies complicated by hypertension, methyldopa seems to have a small favourable effect on uterine artery dopplers. These results provide reassurance that the maternal hypotensive effect of methyldopa is unlikely to have a clinically significant adverse effect on the pregnancy.

Objectives Studies have demonstrated an association between congenital heart disease (CHD) and neurodevelopmental delay, partly attributed to the risk of brain injury during cardiac surgery. However, neuroimaging studies have demonstrated a high incidence of preoperative brain abnormalities. The aim of this study was to perform a systematic review in order to quantify the non-surgical risk of brain abnormalities and neurodevelopmental delay in fetuses/newborns with CHD. Methods MEDLINE, EMBASE and The Cochrane Library, without language restrictions were searched electronically, utilising combinations of the terms congenital heart, cardiac, neurologic, neurodevelopment, MRI, ultrasound, neuroimaging, autopsy, preoperative and outcome. Reference lists of relevant articles and reviews were hand searched for additional reports. Cohort and case-control studies were included. Case reports and editorials were excluded. Between-study heterogeneity was assessed using the I2 statistic. Results The search yielded 9,129 citations. Full manuscripts were retrieved for 119, and 30 were included in the review and meta-analysis. 21 studies (n = 953) have reported brain abnormalities in fetuses, newborn or infants with CHD, either preoperatively or in those who did not undergo congenital cardiac surgery. The remaining 9 studies (n = 512) have reported preoperative data on neurodevelopmental assessment in newborn or infants with CHD. The prevalence of brain abnormalities was 36% (95% CI, 26%, 47%; I² = 90.5%) and of the neurodevelopmental delay 42% (95% CI, 34%, 51%; I² = 68.9%), though with heterogeneity between studies. Conclusions In the absence of chromosomal or genetic abnormalities, fetuses with CHD are at increased risk of brain abnormalities and neurodevelopmental delay, which are independent of the surgical risk.

Introduction Pre-eclampsia (PE), particularly early-onset PE (PE requiring delivery before 34 weeks), is commonly associated with fetal growth restriction (FGR). The evidence for an association between FGR and a more severe PE phenotype is controversial. Objectives The main aim of this study was to investigate whether the presence of FGR in women with early-onset PE is associated with more severe maternal disease compared to those with appropriately grown fetuses (AGA). Methods This was a retrospective cohort study of women with early-onset PE between 2001 and 2010 at University College London Hospital. The diagnosis of PE was made according to the criteria defined by the International Society of the Study of Hypertension in Pregnancy (ISSHP). PE was diagnosed when the systolic blood pressure was 140mmHg or more and/or the diastolic blood pressure 90mmHg or more on at least two occasions four hours apart developing after 20 weeks of gestation in previously normotensive women with proteinuria of 300 mg or more in 24h or two readings of at least ++ on dipstick analysis of midstream or catheter urine specimens if no 24-h collection is available. FGR was defined as birthweight less than the 5th centile, with abnormal umbilical artery Doppler (raised pulsatility index, absent or reversed end-diastolic flow). Maternal, fetal and neonatal data were collected and study groups compared using Chi-square test or Fisher's exact test (categorical variables), and Mann Whitney- U test (continuous variables). Data analysis was performed using SPSS 16.0. Results In women with early-onset PE ( n =134), FGR ( n =66, 49%) was associated with significantly higher perinatal mortality ( p =0.02). Gestational age at delivery was significantly lower in the FGR group (median, IQR: 29.0 weeks, 28.0–32.8 vs 32.0, 30.0–33.2, p =0.01). However, maternal indicators of PE severity, including blood pressure 3 160mmHg systolic or 3 110mmHg diastolic, ALT>100U/L, platelet count 9 /L, use of magnesium sulphate or use of antihypertensive therapy, were similar in the two groups. Conclusion In women with early onset PE, FGR was associated with worse perinatal outcome, but was not associated with a more severe maternal PE phenotype. This may be because the presence of FGR in these women leads to earlier iatrogenic delivery, before the maternal condition deteriorates, but further studies are needed to investigate this.