Do maternal haemodynamics have a causal influence on treatment for gestational diabetes?

BACKGROUND: Arterial stiffening is believed to contribute to the worsening of insulin resistance, and factors which are associated with needing pharmacological treatment of gestational diabetes (GDM), such as maternal obesity or advanced age, are associated with impaired cardiovascular adaptation to pregnancy. In this observational study, we aimed to investigate causal relationships between maternal haemodynamics and treatment requirement amongst women with GDM. METHODS: We assessed maternal haemodynamics in women with GDM, comparing those who remained on dietary treatment with those who required pharmacological management. Maternal haemodynamics were assessed using the Arteriograph® (TensioMed Ltd, Budapest, Hungary) and the NICOM® non-invasive bio-reactance method (Cheetah Medical, Portland, Oregon, USA). A graphical causal inference technique was used for statistical analysis. RESULTS: 120 women with GDM were included in the analysis. Maternal booking BMI was identified as having a causative influence on treatment requirement, with each unit increase in BMI increasing the odds of needing metformin and/or insulin therapy by 12% [OR 1.12 (1.02 - 1.22)]. The raw values of maternal heart rate (87.6 ± 11.7 vs. 92.9 ± 11.90 bpm, p = 0.014) and PWV (7.8 ± 1.04 vs. 8.4 ± 1.61 m/s, p = 0.029) were both significantly higher amongst the women requiring pharmacological management, though these relationships did not remain significant in causal logistic regression. CONCLUSIONS: Maternal BMI at booking has a causal, rather than simply associational, relationship on the need for pharmacological treatment of GDM. No significant causal relationships were found between maternal haemodynamics and the need for pharmacological treatment.

This observational study is the first to examine relationships between maternal haemodynamics and treatment requirement for gestational diabetes (GDM). This is also the first study to demonstrate a causative, rather than simply associational, relationship between maternal body mass index (BMI) and the need for pharmacological treatment of GDM, with each unit increase in BMI increasing the odds of needing metformin and/or insulin therapy by 12%. Maternal heart rate and pulse wave velocity were significantly higher among women with GDM requiring pharmacological management, but this finding did not remain significant in logistic regression analysis, and no causative relationships between maternal hemodynamics and treatment requirement were identified. Our findings highlight the importance of pre- and peri-conception weight control, but do not support a role for measurement of maternal hemodynamics in the prediction of women who are likely to require pharmacological management of GDM.

Chorionicity-associated variation in metabolic phenotype of cord blood in twin.

BACKGROUND: Monochorionic (MC) twins present a higher incidence of unfavorable clinical perinatal outcomes than dichorionic (DC) twins, often in association with placental vascular anastomosis. In this study, we profiled the umbilical cord plasma metabolomes of uncomplicated MC and DC twin pregnancies and related these to several offspring outcomes, previously associated with birthweight. METHODS: Umbilical vein blood samples were collected at birth from 25 pairs of uncomplicated MC twins and 24 pairs of uncomplicated DC twins. The samples were subjected to gas chromatography-mass spectrometry-based metabolomics. 152 metabolites were identified from the cord plasma samples of MC and DC twins. Partial least squares discriminant analysis and pathway analysis were performed to compare within DC/MC twin pairs and between DC and MC twins. A generalized estimating equation (GEE) model was utilized to explore the correlation between metabolic differences and birthweight discordance within and between twin pairs. RESULTS: Our study revealed clear differences between the metabolite profiles of umbilical cord plasma of MC and DC twins. Metabolite profiles in MC within twin pairs and DC within twin pairs were characterized by the differences in 2 - hydroxyglutaramic acid levels and nicotinamide levels, respectively. The metabolic pathways of GSH, tryptophan, and fatty acid metabolism, were significantly downregulated in MC twins compared to DC twins. In addition, the concentration of caffeine and decamethyl-cyclopentasiloxane (D5) was positively correlated with birthweight in MC and DC twins. CONCLUSION: This study demonstrated that the altered metabolites in umbilical plasma made contributions to the different chorionicities between uncomplicated MC twins and DC twins. The chorionicity of twins seems to affect the metabolic cross-talk between co-twin pairs and be related to birthweight discordance of twins.

Kasr Alainy simplified uterine preserving surgery for conservative management of placenta accreta spectrum (PAS): A modified surgical approach.

OBJECTIVE: The incidence of placenta accreta spectrum (PAS) is rising rapidly due to the global surge in Caesarean delivery. It is associated with significant maternal morbidity and mortality. It is usually managed with Caesarean hysterectomy. However, uterine preserving surgeries can have advantages over Caesarean hysterectomy and intentional placental retention techniques. STUDY DESIGN: We present a modified technique of uterine preserving surgery that uses a safe approach for placental bed surgical devascularization. This is followed by resection of the invaded uterine segment and uterine wall reconstruction. RESULTS: The technique was used in the management of 20 patients with antenatally suspected PAS that were confirmed at laparotomy. It was successful in preserving the uterus in 18/20 (90 %) women. The mean intraoperative blood loss in was 1305 CC (SD: +361.6) with a mean operative time of 123 min (SD: ±38.7). There was only one urinary bladder injury and no other maternal morbidity. CONCLUSION: Our surgical technique is safe and may be useful for conservative surgical management of PAS, particularly in low- and middle-income countries, where access to complex resources, such as interventional radiology, is limited.

Arterial stiffness throughout pregnancy: Arteriograph device-specific reference ranges based on a low-risk population.

OBJECTIVE: The maternal cardiovascular system undergoes significant adaptation during pregnancy. We aimed to examine the changes in arterial stiffness parameters during normal pregnancy and establish reference ranges for the general population. METHODS: We performed a prospective cross-sectional observational study at the University Hospitals of Leicester. We included low-risk healthy pregnant women with singleton and viable pregnancies with no evidence of foetal abnormality or aneuploidy. Smokers, women with pre-existing or gestational hypertensive disorders and diabetes, booking BMI at least 30, on medication that could affect cardiac function and/or those who delivered before 37 completed weeks of gestation, and/or a neonate with birthweight less than 10th centile were excluded. Brachial (BrAIx) and aortic augmentation indices (AoAIx), and pulse wave velocity (PWV) were assessed using the Arteriograph. Data were analysed using a linear mixed model. RESULTS: We analysed a total of 571 readings from 259 women across different gestational ages and present the 10th, 25th, 50th, 75th and 90th centiles for BrAIx, AoAIx and PWV from 12+0 to 42+0 weeks' gestation. All haemodynamic variables were significantly associated with maternal heart rate. BrAIx, AoAIx and PWV demonstrated significant change with gestation, with all reaching their lowest value in the second trimester. CONCLUSION: The current study presents reference ranges for BrAIx, AoAIx and PWV in low-risk singleton pregnancies. Further work is required to establish if women in whom measures of arterial stiffness lie above the 90th centile could be at increased risk of adverse pregnancy outcomes and to identify the optimum time for screening.

Effect of metformin on biomarkers of placental- mediated disease: A systematic review and meta-analysis.

Metformin reduces the incidence of placental-mediated disease (PMD) in pregnancies with and without diabetes, but the mechanism through which it exerts these effects is not yet fully understood. We performed a systematic review and meta-analysis to examine the effect of metformin on biomarkers implicated in the pathogenesis of PMD. We searched Medline, Embase and the Cochrane Library for studies of metformin and biomarkers of PMD in pregnancy. Meta-analysis was undertaken where comparable data were obtained from two or more studies. 12 studies were included in the final review. Meta-analysis of 2 studies including 323 pregnant women showed significantly reduced CRP levels following treatment with metformin compared to placebo [mean difference = -1.72, 95% CI (-2.97; -0.48); p = 0.007]. Metformin exposure was also associated with decreased levels of the inflammatory cytokines TNFα, IL-1a, IL-1b and IL-6 in serum, placenta and omental tissue taken from pregnant women. Metformin significantly decreased the release of anti-angiogenic factors sFlt-1 and sEng from ex-vivo placental and umbilical vein tissue, and increased maternal serum levels of non-phosphorylated IGFBP-1. Overall, our findings show that metformin mediates several molecular pathways implicated in the pathogenesis of pre-eclampsia and intrauterine growth retardation. Metformin therefore has exciting potential as a therapeutic, as well as preventative, agent in the treatment of PMD, which warrants further investigation.

Noninvasive prenatal screening in twin pregnancies with cell-free DNA using the IONA test: a prospective multicenter study.

BACKGROUND: In singleton pregnancies, studies investigating cell-free DNA in maternal blood have consistently reported high detection rate and low false-positive rate for the 3 common fetal trisomies (trisomies 21, 18, and 13). The potential advantages of noninvasive prenatal testing in twin pregnancies are even greater than in singletons, in particular lower need for invasive testing and consequent fetal loss rate. However, several organizations do not recommend cell-free DNA in twin pregnancies and call for larger prospective studies. OBJECTIVE: In response to this, we undertook a large prospective multicenter study to establish the screening performance of cell-free DNA for the 3 common trisomies in twin pregnancies. Moreover, we combined our data with that reported in published studies to obtain the best estimate of screening performance. STUDY DESIGN: This was a prospective multicenter blinded study evaluating the screening performance of cell-free DNA in maternal plasma for the detection of fetal trisomies in twin pregnancies. The study took place in 6 fetal medicine centers in England, United Kingdom. The primary outcome was the screening performance and test failure rate of cell-free DNA using next generation sequencing (the IONA test). Maternal blood was taken at the time of (or after) a conventional screening test. Data were collected at enrolment, at any relevant invasive testing throughout pregnancy, and after delivery until the time of hospital discharge. Prospective detailed outcome ascertainment was undertaken on all newborns. The study was undertaken and reported according to the Standards for Reporting of Diagnostic Accuracy Studies. A pooled analysis was also undertaken using our data and those in the studies identified by a literature search (MEDLINE, Embase, CENTRAL, Cochrane Library, and ClinicalTrials.gov) on June 6, 2020. RESULTS: A total of 1003 women with twin pregnancies were recruited, and complete data with follow-up and reference data were available for 961 (95.8%); 276 were monochorionic and 685 were dichorionic. The failure rate was 0.31%. The mean fetal fraction was 12.2% (range, 3%-36%); all 9 samples with a 3% fetal fraction provided a valid result. There were no false-positive or false-negative results for trisomy 21 or trisomy 13, whereas there was 1 false-negative and 1 false-positive result for trisomy 18. The IONA test had a detection rate of 100% for trisomy 21 (n=13; 95% confidence interval, 75-100), 0% for trisomy 18 (n=1; 95% confidence interval, 0-98), and 100% for trisomy 13 (n=1; 95% confidence interval, 3-100). The corresponding false-positive rates were 0% (95% confidence interval, 0-0.39), 0.10% (95% confidence interval, 0-0.58), and 0% (95% confidence interval, 0-0.39), respectively. By combining data from our study with the 11 studies identified by literature search, the detection rate for trisomy 21 was 95% (n=74; 95% confidence interval, 90-99) and the false-positive rate was 0.09% (n=5598; 95% confidence interval, 0.03-0.19). The corresponding values for trisomy 18 were 82% (n=22; 95% confidence interval, 66-93) and 0.08% (n=4869; 95% confidence interval, 0.02-0.18), respectively. There were 5 cases of trisomy 13 and 3881 non-trisomy 13 pregnancies, resulting in a computed average detection rate of 80% and a false-positive rate of 0.13%. CONCLUSION: This large multicenter study confirms that cell-free DNA testing is the most accurate screening test for trisomy 21 in twin pregnancies, with screening performance similar to that in singletons and very low failure rates (0.31%). The predictive accuracy for trisomies 18 and 13 may be less. However, given the low false-positive rate, offering first-line screening with cell-free DNA to women with twin pregnancy is appropriate in our view and should be considered a primary screening test for trisomy 21 in twins.

Mechanical and surgical interventions for treating primary postpartum haemorrhage.

BACKGROUND: Primary postpartum haemorrhage (PPH) is commonly defined as bleeding from the genital tract of 500 mL or more within 24 hours of birth. It is one of the most common causes of maternal mortality worldwide and causes significant physical and psychological morbidity. An earlier Cochrane Review considering any treatments for the management of primary PPH, has been split into separate reviews. This review considers treatment with mechanical and surgical interventions. OBJECTIVES: To determine the effectiveness and safety of mechanical and surgical interventions used for the treatment of primary PPH. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (26 July 2019) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of mechanical/surgical methods for the treatment of primary PPH compared with standard care or another mechanical/surgical method. Interventions could include uterine packing, intrauterine balloon insertion, artery ligation/embolism, or uterine compression (either with sutures or manually). We included studies reported in abstract form if there was sufficient information to permit risk of bias assessment. Trials using a cluster-RCT design were eligible for inclusion, but quasi-RCTs or cross-over studies were not. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and risk of bias, independently extracted data and checked data for accuracy. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included nine small trials (944 women) conducted in Pakistan, Turkey, Thailand, Egypt (four trials), Saudi Arabia, Benin and Mali. Overall, included trials were at an unclear risk of bias. Due to substantial differences between the studies, it was not possible to combine any trials in meta-analysis. Many of this review's important outcomes were not reported. GRADE assessments ranged from very low to low, with the majority of outcome results rated as very low certainty. Downgrading decisions were mainly based on study design limitations and imprecision; one study was also downgraded for indirectness. External uterine compression versus normal care (1 trial, 64 women) Very low-certainty evidence means that we are unclear about the effect on blood transfusion (risk ratio (RR) 2.33, 95% confidence interval (CI) 0.66 to 8.23). Uterine arterial embolisation versus surgical devascularisation plus B-Lynch (1 trial, 23 women) The available evidence for hysterectomy to control bleeding (RR 0.73, 95% CI 0.15 to 3.57) is unclear due to very low-certainty evidence. The available evidence for intervention side effects is also unclear because the evidence was very low certainty (RR 1.09; 95% CI 0.08 to 15.41). Intrauterine Tamponade Studies included various methods of intrauterine tamponade: the commercial Bakri balloon, a fluid-filled condom-loaded latex catheter ('condom catheter'), an air-filled latex balloon-loaded catheter ('latex balloon catheter'), or traditional packing with gauze. Balloon tamponade versus normal care (2 trials, 356 women) One study(116 women) used the condom catheter. This study found that it may increase blood loss of 1000 mL or more (RR 1.52, 95% CI 1.15 to 2.00; 113 women), very low-certainty evidence. For other outcomes the results are unclear and graded as very low-certainty evidence: mortality due to bleeding (RR 6.21, 95% CI 0.77 to 49.98); hysterectomy to control bleeding (RR 4.14, 95% CI 0.48 to 35.93); total blood transfusion (RR 1.49, 95% CI 0.88 to 2.51); and side effects. A second study of 240 women used the latex balloon catheter together with cervical cerclage. Very low-certainty evidence means we are unclear about the effect on hysterectomy (RR 0.14, 95% CI 0.01 to 2.74) and additional surgical interventions to control bleeding (RR 0.20, 95% CI 0.01 to 4.12). Bakri balloon tamponade versus haemostatic square suturing of the uterus (1 trial, 13 women) In this small trial there was no mortality due to bleeding, serious maternal morbidity or side effects of the intervention, and the results are unclear for blood transfusion (RR 0.57, 95% CI 0.14 to 2.36; very low certainty). Bakri balloon tamponade may reduce mean 'intraoperative' blood loss (mean difference (MD) -426 mL, 95% CI -631.28 to -220.72), very low-certainty evidence. Comparison of intrauterine tamponade methods (3 trials, 328 women) One study (66 women) compared the Bakri balloon and the condom catheter, but it was uncertain whether the Bakri balloon reduces the risk of hysterectomy to control bleeding due to very low-certainty evidence (RR 0.50, 95% CI 0.05 to 5.25). Very low-certainty evidence also means we are unclear about the results for the risk of blood transfusion (RR 0.97, 95% CI 0.88 to 1.06). A second study (50 women) compared Bakri balloon, with and without a traction stitch. Very low-certainty evidence means we are unclear about the results for hysterectomy to control bleeding (RR 0.20, 95% CI 0.01 to 3.97). A third study (212 women) compared the condom catheter to gauze packing and found that it may reduce fever (RR 0.47, 95% CI 0.38 to 0.59), but again the evidence was very low certainty. Modified B-Lynch compression suture versus standard B-Lynch compression suture (1 trial, 160 women) Low-certainty evidence suggests that a modified B-Lynch compression suture may reduce the risk of hysterectomy to control bleeding (RR 0.33, 95% CI 0.11 to 0.99) and postoperative blood loss (MD -244.00 mL, 95% CI -295.25 to -192.75). AUTHORS' CONCLUSIONS: There is currently insufficient evidence from RCTs to determine the relative effectiveness and safety of mechanical and surgical interventions for treating primary PPH. High-quality randomised trials are urgently needed, and new emergency consent pathways should facilitate recruitment. The finding that intrauterine tamponade may increase total blood loss > 1000 mL suggests that introducing condom-balloon tamponade into low-resource settings on its own without multi-system quality improvement does not reduce PPH deaths or morbidity. The suggestion that modified B-Lynch suture may be superior to the original requires further research before the revised technique is adopted. In high-resource settings, uterine artery embolisation has become popular as the equipment and skills become more widely available. However, there is little randomised trial evidence regarding efficacy and this requires further research. We urge new trial authors to adopt PPH core outcomes to facilitate consistency between primary studies and subsequent meta-analysis.

Fármacos antifibrinolíticos para tratar la hemorragia posparto primaria / Antifibrinolytic drugs for treating primary postpartum hemorrhage

No disponible

An integrated in utero MR method for assessing structural brain abnormalities and measuring intracranial volumes in fetuses with congenital heart disease: results of a prospective case-control feasibility study.

PURPOSE: To refine methods that assess structural brain abnormalities and calculate intracranial volumes in fetuses with congenital heart diseases (CHD) using in utero MR (iuMR) imaging. Our secondary objective was to assess the prevalence of brain abnormalities in this high-risk cohort and compare the brain volumes with normative values. METHODS: We performed iuMR on 16 pregnant women carrying a fetus with CHD and gestational age ≥ 28-week gestation and no brain abnormality on ultrasonography. All cases had fetal echocardiography by a pediatric cardiologist. Structural brain abnormalities on iuMR were recorded. Intracranial volumes were made from 3D FIESTA acquisitions following manual segmentation and the use of 3D Slicer software and were compared with normal fetuses. Z scores were calculated, and regression analyses were performed to look for differences between the normal and CHD fetuses. RESULTS: Successful 2D and 3D volume imaging was obtained in all 16 cases within a 30-min scan. Despite normal ultrasonography, 5/16 fetuses (31%) had structural brain abnormalities detected by iuMR (3 with ventriculomegaly, 2 with vermian hypoplasia). Brain volume, extra-axial volume, and total intracranial volume were statistically significantly reduced, while ventricular volumes were increased in the CHD cohort. CONCLUSION: We have shown that it is possible to perform detailed 2D and 3D studies using iuMR that allow thorough investigation of all intracranial compartments in fetuses with CHD in a clinically appropriate scan time. Those fetuses have a high risk of structural brain abnormalities and smaller brain volumes even when brain ultrasonography is normal.

Haemodynamic differences amongst women who were screened for gestational diabetes in comparison to healthy controls.

AIM: To assess the changes in haemodynamics amongst pregnant women who were screened for gestational diabetes mellitus (GDM) in comparison to low-risk healthy pregnant controls. METHODOLOGY: A total of 120 pregnant women of mean (standard deviation) age 31.03 (5.41) years who attended their oral glucose tolerance test as part of the national screening for GDM (study), and 60 low-risk healthy pregnant women (control) of mean age 29.71 (5.33) years, were invited to participate in this study. All women included in the study booked at the University Hospitals of Leicester NHS Trust and fulfilled the relevant inclusion criteria. Non-invasive assessment of arterial stiffness and cardiac output were undertaken on participants between 26 and 28 weeks of pregnancy. The mean difference between GDM and low-risk group for each of the arterial stiffness and cardiac output measurements was assessed by a two-sample unpaired t-test. RESULTS: Significant differences were found between the study and control groups for brachial (-64.5 vs. -69.5, p < 0.04) and aortic augmentation indices (5.2 vs. 2.7, p = 0.04), though there was no significant difference for PWV (8.3 vs. 8.1, p = 0.49). Cardiac output (7.6 vs. 7.0, p = 0.011), stroke volume (84.4 vs. 76.9, p = 0.013) and central mean arterial pressure (71 vs. 58, <0.001) were also significantly different between groups. However, no significant differences were reported for heart rate, systolic and diastolic blood pressure, or total peripheral resistance. CONCLUSION: Pregnant women at risk of GDM between gestational weeks 26 and 28 had significantly increased measures of arterial stiffness, as assessed by brachial and aortic augmentation indices, compared with low-risk healthy controls. Whether these women are at greater long-term cardiovascular disease risk warrants further investigation.

The effects of metformin on maternal haemodynamics in gestational diabetes mellitus: A pilot study.

BACKGROUND: Gestational diabetes mellitus (GDM) is a major clinical challenge and is likely to remain so as the incidence of GDM continues to increase. AIM: To assess longitudinal changes in maternal haemodynamics amongst women diagnosed with GDM requiring either metformin or dietary intervention in comparison to low-risk healthy controls. METHODOLOGY: Fifty-six pregnant women attending their first appointment at the GDM clinic and 60 low-risk healthy pregnant controls attending their routine antenatal clinics were recruited and assigned to three groups: GDM Metformin (GDM-M), GDM Diet (GDM-D) and Control. Non-invasive assessment of maternal haemodynamics, using recognised measures of arterial stiffness and central blood pressure (Arteriograph®), were undertaken under controlled conditions within four gestational windows: antenatal; AN1 (26-28 weeks), AN2 (32-34 weeks) and AN3 (37-40 weeks), and postnatal (PN) (6-8 weeks after delivery). Data were analysed using a linear mixed model incorporating gestational age and other relevant predictors, including age, blood pressure (BP), baseline bodyweight and pulse as fixed effects, and patient as a random effect. RESULTS: Fitted linear mixed models showed evidence of a two-way interaction effect between groups (GDM-D, GDM-M and Control) and stages of gestation (AN1, AN2, AN3 and PN) for maternal haemodynamic parameters: brachial artery augmentation index (AIx) (p = 0.004), aortic AIx (p = 0.008), and central systolic BP (p = 0.001). However, differences in respect of aortic pulse wave velocity (p = 0.001) and heart rate (p < 0.001) were only significant for gestational stage. At AN2, we did not observe any evidence that the mean brachial Aix in the GDM-M was different from the control group (p = 0.158). CONCLUSION: AIx and central systolic BP measures of arterial stiffness are adversely affected by GDM in comparison to controls during pregnancy. The possible beneficial effects of metformin therapy seen at 32 to 34 weeks of gestation require further exploration.

Antifibrinolytic drugs for treating primary postpartum haemorrhage.

BACKGROUND: Postpartum haemorrhage (PPH) - heaving bleeding within the first 24 hours after giving birth - is one of the main causes of death of women after childbirth. Antifibrinolytics, primarily tranexamic acid (TXA), have been shown to reduce bleeding in surgery and safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events.An earlier Cochrane review on treatments for primary PPH covered all the various available treatments - that review has now been split by types of treatment. This new review concentrates only on the use of antifibrinolytic drugs for treating primary PPH. OBJECTIVES: To determine the effectiveness and safety of antifibrinolytic drugs for treating primary PPH. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (28 May 2017) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), including cluster-randomised trials of antifibrinolytic drugs (aprotinin, TXA, epsilon-aminocaproic acid (EACA) and aminomethylbenzoic acid, administered by whatever route) for primary PPH in women.Participants in the trials were women after birth following a pregnancy of at least 24 weeks' gestation with a diagnosis of PPH, regardless of mode of birth (vaginal or caesarean section) or other aspects of third stage management.We have not included quasi-randomised trials, or cross-over studies. Studies reported as abstracts have not been included if there was insufficient information to allow assessment of risk of bias.In this review we only identified studies looking at TXA. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each study using an agreed form. We entered data into Review Manager software and checked for accuracy.For key review outcomes, we rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach. MAIN RESULTS: Three trials (20,412 women) met our inclusion criteria. Two trials (20,212 women) compared intravenous (IV) TXA with placebo or standard care and were conducted in acute hospital settings (labour ward, emergency department) (in high-, middle- and low-income countries).One other trial (involving 200 women) was conducted in Iran and compared IV TXA with rectal misoprostol, but did not report on any of this review's primary or GRADE outcomes. There were no trials that assessed EACA, aprotinin or aminomethylbenzoic acid.Standard care plus IV TXA for the treatment of primary PPH compared with placebo or standard care aloneTwo trials (20,212 women) assessed the effect of TXA for the treatment of primary PPH compared with placebo or standard care alone. The larger of these (The WOMAN trial) contributed over 99% of the data and was assessed as being at low risk of bias. The quality of the evidence varied for different outcomes, Overall, evidence was mainly graded as moderate to high quality.The data show that IV TXA reduces the risk of maternal death due to bleeding (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.65 to 1.00; two trials, 20,172 women; quality of evidence: moderate). The quality of evidence was rated as moderate due to imprecision of effect estimate. The effect was more evident in women given treatment between one and three hours after giving birth with no apparent reduction when given after three hours (< one hour = RR 0.80, 95% CI 0.55 to 1.16; one to three hours = RR 0.60, 95% CI 0.41 to 0.88; > three hours = RR 1.07, 95% 0.76 to 1.51; test for subgroup differences: Chi² = 4.90, df = 2 (P = 0.09), I² = 59.2%). There was no heterogeneity in the effect by mode of birth (test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.91), I² = 0%). There were fewer deaths from all causes in women receiving TXA, although the 95% CI for the effect estimate crosses the line of no effect (RR 0.88, 95% CI 0.74 to 1.05; two trials, 20,172 women, quality of evidence: moderate). Results from one trial with 151 women suggest that blood loss of ≥ 500 mL after randomisation may be reduced (RR 0.50, 95% CI 0.27 to 0.93; one trial, 151 women; quality of evidence: low). TXA did not reduce the risk of serious maternal morbidity (RR 0.99, 95% CI 0.83 to 1.19; one trial, 20,015 women; quality of evidence: high), hysterectomy to control bleeding (RR 0.95, 95% CI 0.81 to 1.12; one trial, 20,017 women; quality of evidence: high) receipt of blood transfusion (any) (RR 1.00, 95% CI 0.97 to 1.03; two trials, 20,167 women; quality of evidence: moderate) or maternal vascular occlusive events (any), although results were imprecise for this latter outcome (RR 0.88, 95% CI 0.54 to 1.43; one trial, 20,018 women; quality of evidence: moderate). There was an increase in the use of brace sutures in the TXA group (RR 1.19, 95% CI 1.01, 1.41) and a reduction in the need for laparotomy for bleeding (RR 0.64, 95% CI 0.49, 0.85). AUTHORS' CONCLUSIONS: TXA when administered intravenously reduces mortality due to bleeding in women with primary PPH, irrespective of mode of birth, and without increasing the risk of thromboembolic events. Taken together with the reliable evidence of the effect of TXA in trauma patients, the evidence suggests that TXA is effective if given as early as possible.Facilities for IV administration may not be available in non-hospital settings therefore, alternative routes to IV administration need to be investigated.

Association between arterial stiffness and wave reflection with subsequent development of placental-mediated diseases during pregnancy: findings of a systematic review and meta-analysis.

OBJECTIVE: We present a comprehensive systematic review of published literature to examine, whether arterial stiffness and wave reflection measurements during pregnancy differed between healthy patients and patients with placental-mediated diseases including preeclampsia (PET), small for gestational age (SGA), fetal death, and placental abruption, and a quantitative assessment of the findings using the meta-analysis approach. METHODS: We searched Medline, Embase, and The Cochrane Library for studies of arterial stiffness in pregnancy, analyzed pregnancy outcomes and conducted the meta-analysis of data evaluated by trimesters of pregnancy. Hemodynamic parameters evaluated included: pulse wave velocity (PWV), augmentation index (AIx), and augmentation index-75 (AIx-75). RESULTS: We screened 2806 citations, reviewed 36 studies and included nine (n = 15 923) studies for further quantitative assessment. Compared with healthy pregnancy, measures of arterial stiffness and wave reflection were consistently increased among pregnant women who subsequently developed PET during all trimesters. In the first trimester, mean AIx-75 (%) in the PET group was significantly higher with estimated standardized mean difference (SMD) of 0.90 [95% confidence intervals (95% CI) 0.07-1.73; P = 0.034]. In the second trimester, the PET group had significantly higher PWV (m/s) with estimated SMD of 1.26 (95% CI 0.22-2.30; P = 0.018). Concerning the SGA group, mean AIx (%) was greater during the second trimester only: 65.5 (SD 15.6) vs. 57.0 (11.2), P < 0.01. CONCLUSION: There is significant increase in arterial stiffness and wave reflection parameters among pregnant women who subsequently developed PET and SGA fetuses. Larger studies with consistent methodological designs are required to evaluate the role and usefulness of arterial stiffness and wave reflection measurements as a screening tool for placental-mediated diseases during pregnancy.

Longitudinal study to assess changes in arterial stiffness and cardiac output parameters among low-risk pregnant women.

AIM: A single-centre, prospective longitudinal study to assess changes in maternal arterial stiffness and cardiac output parameters among low-risk healthy pregnant women. METHODOLOGY: Thirty low-risk, healthy, pregnant women attending their routine antenatal dating ultrasound scan were recruited. Non-invasive assessment of arterial stiffness and cardiac output was undertaken at five gestational windows from 11 to 40 weeks of pregnancy. Data were analysed using a linear mixed model incorporating time and other relevant predictors as fixed effects, and patient as a random effect. RESULTS: Gestational age had a significant effect on all arterial stiffness parameters, including brachial augmentation index (AIx) (p = .001), aortic AIx (p = .002) and aortic pulse wave velocity (p = .002). The aortic AIx (%) reduced during pregnancy: the lowest mean (standard error, SE) was 4.07 (1.01) at 28 weeks before it increased to 7.04 (SE 1.64) at 40 weeks. Similarly, non-invasive assessments of cardiac output (p < .001), stroke volume (p = .014), heart rate (p < .001) and total peripheral resistance (p < .001) demonstrated significant changes with gestational age. Mean cardiac output (l/m) increased during pregnancy reaching a peak at 28 weeks gestation 6.66 (SE 0.28), but dropped thereafter to reach 5.71 (SE 0.25) around term. CONCLUSION: The current study provides pregnancy normograms for gestational changes in arterial stiffness and cardiac output parameters among low-risk, healthy pregnant women. Further work will be required to assess the risk of placental mediated diseases and pregnancy outcome among pregnant women with parameters outside the normal range.

Diurnal variation and repeatability of arterial stiffness and cardiac output measurements in the third trimester of uncomplicated pregnancy.

AIM: To investigate same day repeated measures and diurnal variation of arterial stiffness, cardiac output (CO), stroke volume (SV) and total peripheral resistance (TPR) during the third trimester of normal pregnancy. METHODOLOGY: Pulse wave velocity (PWV) and augmentation index (AIx) were recorded using the Arteriograph, while CO, SV and TPR were recorded using noninvasive cardiac output monitoring. The measurements were obtained in the third trimester of pregnancy from 21 healthy pregnant women at four time points (morning, afternoon, evening and midnight) over a 24-h period. Triplicate measurements of 67 women were obtained at 5-min intervals to assess repeatability between measurements within a patient. RESULTS: Diurnal measurements of arterial stiffness for brachial AIx, aortic AIx and PWV were not statistically significantly different at any of the four time points. Estimated means (SD) for PWV at the four stated time points were 7.81 (2.05), 8.45 (1.68), 7.87 (1.74) and 7.64 m/s (1.15), respectively (P = 0.267). Estimates for AIx at those time points were 10.22 (15.62), 4.44 (10.07), 6.49 (10.92) and 8.40% (8.16), respectively (P = 0.295). Similarly, mean arterial pressure, SV, SV index and TPR did not show any evidence of diurnal variation. However, we observed that the mean CO, cardiac index (CI) and heart rate (HR) varied from morning to midnight; the mean CO, HR and CI increased significantly in the afternoon compared with the corresponding mean morning measurements in a similar fashion to HR. Mean (SD) CO estimates at the four stated time points were 5.90 (1.33), 6.38 (1.49), 6.18 (1.43) and 5.80 ml/min (1.19), respectively, (P < 0.001), whereas mean CI estimates were 3.65 (0.58), 3.93 (0.68), 3.81 (0.65), and 3.57 (0.48), respectively, (P < 0.001), and mean HR estimates were 95 (12), 98 (13), 95 (12) and 88 (12.98), respectively (P < 0.001). Triplicate measurements of 61 women in our repeatability study showed moderate-to-high correlation between observations on the same woman for all Arteriograph and noninvasive cardiac output monitoring variables (estimates of intraclass correlation ranged from 0.49 to 0.91). CONCLUSION: With the exception of CO, CI and HR which showed a diurnal variation, measurements of most haemodynamic parameters did not change significantly from morning to midnight, suggesting there was no evidence of systematic differences in the mean values of these variables at these time points. Multiple consecutive noninvasive measurements of vascular stiffness, CO, SV and TPR were highly correlated confirming repeatability of measurements in the third trimester of uncomplicated pregnancy, so these haemodynamic measurements do not need to be undertaken at a specific time period of the day.

Renal anomalies and lymphedema distichiasis syndrome. A rare association?

Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, characterized by lower limb lymphedema and distichiasis. Other associated features that have been reported include varicose veins, cleft palate, congenital heart defects, and ptosis. We update a previously reported family with a pathogenic variant in FOXC2 (c.412-413insT) where five affected individuals from the youngest generation had congenital renal anomalies detected on prenatal ultrasound scan. These included four fetuses with hydronephrosis and one with bilateral renal agenesis. A further child with LDS had prominence of the left renal pelvis on postnatal renal ultrasound. We also describe a second family in whom the proband and his affected son had congenital renal anomalies; left ectopic kidney, right duplex kidney, and bilateral duplex collecting systems with partial duplex kidney with mild degree of malrotation, respectively. Foxc2 is expressed in the developing kidney and therefore congenital renal anomalies may well be associated, potentially as a low penetrance feature. We propose that all individuals diagnosed with LDS should have a baseline renal ultrasound scan at diagnosis. It would also be important to consider the possibility of renal anomalies during prenatal ultrasound of at risk pregnancies, and that the presence of hydronephrosis may be an indication that the baby is affected with LDS.