Maternal mental health: a key area for future research among women with congenital heart disease.

In this viewpoint, we respond to the recently published national priorities for research in congenital heart disease (CHD) among adults, established through the James Lind Alliance Priority Setting Partnership, with specific attention to priority 3 (mental health) and priority 5 (maternal health). Our recent policy impact project explored how maternal mental health is currently addressed in adult congenital heart disease (ACHD) services in the National Health Service, identified gaps and discussed possible ways forward. Our multidisciplinary discussion groups, which included women with lived experience of CHD and pregnancy, cardiology and obstetrics clinicians and medical anthropologists, found that while pregnancy and the postnatal period increase the mental health challenges faced by women with CHD, current services are not yet equipped to address them. Based on this work, we welcome the prioritisation of both mental health and maternal health in ACHD, and suggest that future research should focus on the overlaps between these two priority areas.

Carbohydrate and fatty acid perturbations in the amniotic fluid of the recipient twin of pregnancies complicated by twin-twin transfusion syndrome in relation to treatment and fetal cardiovascular risk.

INTRODUCTION: Twin-twin transfusion syndrome (TTTS) complicates 15% of monochorionic twin pregnancies, often being associated with recipient cardiac dysfunction. Untreated, it has a fetal mortality rate of at least 90%; although treatment by fetoscopic laser coagulation significantly improves prognosis. Measurement of recipient amniotic fluid metabolites, such as cardiac Troponin T and atrial natriuretic polypeptide, correlate with cardiac function in this fetus. The aim of this study is to describe the amniotic fluid metabolomic profile in TTTS, relate this to fetal recipient cardiac function and assess the metabolomic changes induced by fetoscopic laser coagulation. METHODS: Prospective single centre cohort study. The metabolomics profile of the amniotic fluid from the recipient sac of TTTS pregnancies was assessed using ultra high performance liquid chromatography-mass spectrometry. Profiles were compared pre- and post-laser coagulation and related to fetal recipient cardiac function, as assessed using Doppler ultrasound within 4 h of treatment. RESULTS: Eleven metabolites had significant associations with recipient fetal right and left ventricular myocardial performance index pre-laser. 200 metabolites in recipient amniotic fluid demonstrated a change in relative concentrations when comparing pre- and post-laser coagulation (p < 0.005). The most prominent change is in the balance of carbohydrate and fatty acid metabolic profile contributing to fetal or placental energy metabolism. These changes were also associated with the echocardiographic measures of recipient cardiac function. DISCUSSION: Changes in carbohydrate and fatty acid metabolic profiles are noted in recipients with cardiac dysfunction, and further changes are noted after treatment. Validation and investigation may identify targets for potential pharmacological treatment.

Maternal plasma and amniotic fluid cytokines in monochorionic, diamniotic twin pregnancies complicated by twin-to-twin transfusion syndrome.

INTRODUCTION: Cytokine imbalance has been implicated in placental-related pathologies, i.e. recurrent miscarriage and pre-eclampsia. Such conditions are more prevalent in multiple pregnancies. Twin-to-twin transfusion syndrome (TTTS) is associated with asymmetric placental blood flow and intra-cardiac pressures. We hypothesised that cytokine expression may be aberrant in this condition and that fetoscopic laser ablation (FLA) may cause local cytokine release. MATERIAL AND METHODS: A prospective cohort of monochorionic, diamniotic twins with TTTS (n = 23) was studied. Circulating T helper cell type 1 (TH1)/TH2 maternal cytokines and cytokine-related and angiogenic factors were measured in plasma and amniotic fluid before and after FLA by human FASTQuant or ELISA. Basal comparisons were made with uncomplicated monochorionic and dichorionic (DC) twins. RESULTS: Median maternal plasma platelet-derived growth factor-BB was highest in uncomplicated DC twins (p = 0.049), whereas tissue inhibitor of metalloproteinases (TIMP)-1 was highest in TTTS twins (p = 0.003). In TTTS amniotic fluid, interleukin (IL)-6, IL-1ß, tumour necrosis factor-α, IL-10, IL-4, IL-8, interferon-γ, TIMP-1 and intercellular adhesion molecule-1 were significantly higher than maternal plasma concentrations. There were no significant differences in plasma or amniotic fluid cytokines after FLA, with the exception of amniotic fluid keratinocyte growth factor, which was significantly reduced. DISCUSSION: TTTS is associated with minimal changes in cytokine levels when compared to uncomplicated twins, although the majority of cytokine levels were higher in amniotic fluid than maternal blood. It does not appear that FLA evokes a significant change in cytokines.

Maternal cell-free messenger RNA in twin pregnancies: the effects of chorionicity and severe twin to twin transfusion syndrome (TTTS).

OBJECTIVE: To investigate the effects of chorionicity and severe twin to twin transfusion (TTTS) on maternal circulating cell-free messenger RNA (cf-mRNA). DESIGN: Prospective cohort study. SETTING: A UK tertiary referral Fetal Medicine Center. POPULATION: All monochorionic (MC) twins complicated by severe TTTS (n= 23) and a cohort of uncomplicated dichorionic (DC) (n= 10) and MC (n= 7) pregnancies, between October 2006 and December 2007. METHODS: Maternal cf-mRNA encoding glyceraldehyde 3-phosphate dehydrogenase (GAPDH), vascular endothelial growth factor receptor 1(VEGFR-1(Flt-1)), vascular endothelial growth factor A (VEGF-A), Endoglin, placental growth factor (PlGF), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (Tie-1), angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2) were measured by a quantitative two-step real-time PCR assay after extraction from maternal plasma. RESULTS: The amounts of cf-mRNA detectable are reported for uncomplicated DC, MC and TTTS pregnancies, respectively: GAPDH - 80, 100 and 96%; VEGFR-1 - 10, 0 and 26%; VEGF-A- 80, 71 and 96%; Endoglin-70, 71 and 91%; PlGF-70, 57, 26%; Tie-1 0, 43, 0%; Ang-1 71, 50 and 60% and Ang-2 83, 50 and 89%. There was a significant difference in VEGF-A (medians DC -337.3, MC - 390.8, TTTS - 618.6 copies/mL plasma p= 0.024), Endoglin (medians DC-14.49, MC-1171, TTTS - 2896 copies/mL plasma p= 0.027) and Ang-2 (medians DC-13.66, MC-8.49, TTTS 44.80 copies/mL plasma p= 0.007). CONCLUSION: Maternal cf-mRNA could be reliably detected for GAPDH, PlGF, VEGF-A, Endoglin, Ang-1 and Ang-2 in twin pregnancies and a significant difference was demonstrated in VEGF-A, Endoglin and Ang-2 between uncomplicated twins and MC twin pregnancies complicated by TTTS. If such alterations in maternal cf-mRNA precede the onset of clinically apparent disease, this may be used as an adjuvant blood test to complement ultrasound screening.

Assimilating evidence quality at a glance using graphic display: research synthesis on labor induction.

Evidence profiled in the World Health Organization induction of labor guideline extended to 84 tables and 116 pages, which is hard to assimilate. Summarizing this evidence graphically can present information on key outcomes succinctly, illustrating where the gaps, strengths and weaknesses lie. For induction of labor, graphic representation clearly showed that evidence was lacking on maternal complications when comparing oxytocin with other agents, evidence was strong on birth within 24 h when comparing vaginal prostaglandins with placebo or no treatment, but again it was weak on uterine hyperstimulation when comparing oxytocin with vaginal prostaglandins. These graphs/plots allow readers to capture the essence of the information gathered at a glance. The use of graphical displays when interpreting and publishing data on several comparisons and outcomes is encouraged.

Systematic reviews to evaluate causation: an overview of methods and application.

Currently systematic reviews focus on diagnosis or effectiveness of treatment. It is the understanding of disease aetiology that underpins medical education, practice and research. Whether an association meets causal criteria is usually assessed qualitatively. However, this can also be examined through evidence synthesis and systematic reviews to evaluate disease causation and mechanisms are much needed. It is important in such a review to specify the questions to be addressed regarding causal criteria such as strength, consistency, temporality, specificity, biological gradient, plausibility and experimental evidence. The next step is to conduct a thorough literature search to identify the relevant studies and to assess them for their quality, particularly in relation to the risk of bias, ascertainment of exposures and ascertainment of outcomes. Data synthesis can then examine if the observed associations in collated studies are consistent, strong and temporal using techniques such as meta-analysis, testing for heterogeneity and meta-regression. Biological plausibility and coherence with existing theories can also be examined systematically through an assessment of the basic scientific literature. Experimental evidence might also be collated and synthesised to determine if removal of a causal agent alters the outcome. Through these steps a systematic review can help to establish whether an association is causal or not.

Reversed twin-to-twin transfusion syndrome following successful laser therapy.

We report a case of severe twin-to-twin transfusion syndrome (TTTS) in which fetoscopic laser ablation was successfully performed at 21 weeks' gestation. Despite successful resolution of signs on ultrasound examination after a period of 7 weeks, the donor developed polyhydramnios whereas the 'initial' recipient maintained normal liquor volume, features suggestive of 'reversed TTTS'. Two live babies were delivered at 31 weeks' gestation with good neonatal outcome. The karyotype of both babies was normal. No significant inter-twin difference in umbilical vein haemoglobin levels was present at delivery and placental injection studies did not identify persistent anastomoses. This case report supports the importance of close monitoring of the pregnancy following apparently successful laser therapy. Further research is needed to understand the pathophysiology of this condition.